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1. WO2015058160 - BROMODOMAIN INHIBITORS

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

BROMODOMAIN INHIBITORS

CROSS REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 61/893,133, filed October 18, 2013, and U.S. Provisional Application No. 61/931,467, filed January 24, 2014, the contents of which are hereby incorporated by reference in their entireties.

BACKGROUND

[0002] A need exists in the art for an effective treatment of cancer and neoplastic disease.

BRIEF SUMMARY OF THE INVENTION

[0003] Provided herein are substituted heterocyclic derivative compounds and

pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for epigenetic regulation by inhibition of bromodomain-mediated recognition of acetyl lysine regions of proteins, such as histones. Furthermore, the subject compounds and compositions are useful for the treatment of cancer, such as NUT midline carcinoma, Burkitts lymphoma, prostate cancer, breast cancer, bladder cancer, lung cancer and/or melanoma and the like. The substituted heterocyclic derivative compounds described herein are based upon isoquinolinones and related heterocyclic structures. Said

isoquinolinones and related heterocyclic structures are substituted at the 4-position with a group such as an aryl, a heteroaryl and the like, and on the nitrogen atom of the

isoquinolinone or related heterocyclic structure with a small alkyl group, such as a methyl group.

[0004] One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof,


Formula (I)

wherein,

Pv2 is selected from CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3; X5 is C-R5 or N;

X6 is C-R6 or N;

X7 is C-R7 or N;

X8 is C-R or N; wherein no more than two of X5, X6, X7, or X8 may be N;

R5 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R6 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R7 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

Q

R is h drogen, halogen, or alkyl;


X2 is N or C-R , wherein R is hydrogen, halogen, alkyl, or alkoxy;

R13 is -Y-Z;

Y is selected from a bond, -CH2-, -CH(Ci-C4 alkyl)-;

Z is selected from -S02R21, -N(R22)S02R21, -S02N(R22)2, -N(R22)S02N(R22)2, -CON(R22)2, N(R22)C02R21, -N(R22)CON(R22)2, -N(R22)COR21, -COR21, -OC(0)N(R22)2, -OS02N(R22)2, or -N(R22)S03R21;

X3 is N or C-R14, wherein R14 is hydrogen, halogen, -CN, alkyl, cycloalkyl, or alkoxy; X4 is N or C-R15, wherein R15 is hydrogen, halogen, alkyl, -CN, or alkoxy;

R16 is hydrogen, halogen, or -W-X, wherein W is a bond, -0-, -S-, or -NH-, and X is selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkynyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0005] One embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt thereof,

O Formula (II)

wherein,

2

R is alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl;

X6 is C-H or N;

X5 is C-R5 or N; provided that if X6 is N, then X5 is C-R5, and if X5 is N, then X6 is CH; R5 is hydrogen, halogen, -OH, -CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R6 is hydrogen, halogen, -OH, -CN, alkyl, cycloalkyl, cycloalkylalkyl, amino, alkylamino, dialkylamino, cycloalkylalkylamino, alkoxy, -S-alkyl, cycloalkylalkoxy, heterocyclyl, aralkox , heteroaryloxy, aryloxy, alkynyloxy, or -N(H)COalkyl;


X2 is N or C-R , wherein R is hydrogen, halogen, alkyl, or alkoxy;

R13 is -Y-Z;

Y is selected from a bond, -CH2-, or -CH(Ci-C4alkyl)-;

Z is selected from -S02R21, -N(R22)S02R21, -S02N(R22)2, -N(R22)S02N(R22)2, -CON(R22)2, -N(R22)C02R21, -N(R22)CON(R22)2, -N(R22)COR21, -COR21, -OC(0)N(R22)2, -OS02N(R22)2, or -N(R22)S03R21;

X3 is N or C-R14, wherein R14 is hydrogen, halogen, -CN, alkyl, cycloalkyl, or alkoxy;

X4 is N or C-R15, wherein R15 is hydrogen, halogen, -CN, alkyl, alkoxy, aryloxy, aralkyloxy, cycloalkylalkyloxy, heterocyclyloxy, heteroarylalkyloxy, or alkynyloxy;

R16 is hydrogen, halogen, -N(H)COX, or -W-X, wherein W is a bond, -0-, -S-, or -NH-, and X is selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkynyl,

cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

provided that when X6 is N, then R5 and R6 are not hydrogen.

[0006] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0007] One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula (I), or a pharmaceutically acceptable salt thereof. One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula (II), or a pharmaceutically acceptable salt thereof.

INCORPORATION BY REFERENCE

[0008] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

[0009] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all

combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, may "consist of or "consist essentially of the described features.

Definitions

[0010] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0011] "Amino" refers to the -NH2 radical.

[0012] "Cyano" refers to the -CN radical.

[0013] "Nitro" refers to the -N02 radical.

[0014] "Oxa" refers to the -O- radical.

[0015] "Oxo" refers to the =0 radical.

[0016] "Thioxo" refers to the =S radical.

[0017] "Imino" refers to the =N-H radical.

[0018] "Oximo" refers to the =N-OH radical.

[0019] "Hydrazino" refers to the =N-NH2 radical.

[0020] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., Ci-Cs alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C -C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., Ci-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl (n -propyl), 1 -methylethyl (z'so-propyl), 1 -butyl (n -butyl), 1 -methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1 , 1-dimethylethyl (tert-bvXyl), 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(0)-Ra, -N(Ra)2, -C(0)Ra, -C(0)ORa, -C(0)N(Ra)2, -N(Ra)C(0)ORa, -OC(O)- N(Ra)2, -N(Ra)C(0)Ra,

-N(Ra)S(0),Ra (where t is 1 or 2), -S(0),ORa (where t is 1 or 2), -S(0),Ra (where t is 1 or 2) and -S(0)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl

(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl,

carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),

heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0021] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0022] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta-l,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(0)-Ra, -N(Ra)2, -C(0)Ra, -C(0)ORa, -C(0)N(Ra)2, -N(Ra)C(0)ORa, -OC(O)- N(Ra)2, -N(Ra)C(0)Ra, -N(Ra)S(0)tRa (where t is 1 or 2), -S(0),ORa (where t is 1 or 2), -S(0),Ra (where t is 1 or 2) and -S(0),N(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0023] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond,

having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl has two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(0)-Ra, -N(Ra)2, -C(0)Ra, -C(0)ORa, -C(0)N(Ra)2, -N(Ra)C(0)ORa, -OC(O)- N(Ra)2, -N(Ra)C(0)Ra, -N(Ra)S(0),Ra (where t is 1 or 2), -S(0),ORa (where t is 1 or 2), -S(0),Ra (where t is 1 or 2) and -S(0)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0024] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., Ci-C8 alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., Ci-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C5-Cs alkylene). In other embodiments, an alkylene comprises two to five

carbon atoms (e.g., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(0)-Ra, -N(Ra)2, -C(0)Ra, -C(0)ORa, -C(0)N(Ra)2, -N(Ra)C(0)ORa, -OC(O)- N(Ra)2, -N(Ra)C(0)Ra, -N(Ra)S(0)tRa (where t is 1 or 2), -S(0),ORa (where t is 1 or 2), -S(0)tRa (where t is 1 or 2) and -S(0)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0025] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkynylene comprises two to eight carbon atoms (e.g., C2-Cs alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (e.g., C2-C5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (e.g., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C5-C8 alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (e.g., C2-Cs alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C3-C5 alkynylene). Unless stated otherwise specifically in the

specification, an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(0)-Ra, -N(Ra)2, -C(0)Ra, -C(0)ORa, -C(0)N(Ra)2, -N(Ra)C(0)ORa, -OC(O)- N(Ra)2,

-N(Ra)C(0)Ra, -N(Ra)S(0)tRa (where t is 1 or 2), -S(0),ORa (where t is 1 or 2), -S(0)tRa (where t is 1 or 2) and -S(0)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0026] "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hiickel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(0)-Ra, -Rb-OC(0)-ORa, -Rb-OC(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(0)Ra, -Rb-C(0)ORa, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)ORa, -Rb-N(Ra)C(0)Ra, -Rb-N(Ra)S(0),Ra (where t is 1 or 2), -Rb-S(0),Ra (where t is 1 or 2), -Rb-S(0),ORa (where t is 1 or 2) and -Rb-S(0),N(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0027] "Aralkyl" refers to a radical of the formula -Rc-aryl where Rc is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0028] "Aralkenyl" refers to a radical of the formula -Rd-aryl where Rd is an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0029] "Aralkynyl" refers to a radical of the formula -Re-aryl, where Re is an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0030] "Aralkoxy" refers to a radical bonded through an oxygen atom of the formula -0-Rc-aryl where Rc is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0031] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl may be saturated, (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds.) A fully saturated carbocyclyl radical is also referred to as "cycloalkyl." Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An

unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e.,

bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(0)-Ra, -Rb-OC(0)-ORa, -Rb-OC(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(0)Ra, -Rb-C(0)ORa, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)ORa,

-Rb-N(Ra)C(0)Ra, -Rb-N(Ra)S(0)tRa (where t is 1 or 2), -Rb-S(0)tRa (where t is 1 or 2), -Rb-S(0),ORa (where t is 1 or 2) and -Rb-S(0),N(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0032] "Carbocyclylalkyl" refers to a radical of the formula -Rc-carbocyclyl where Rc is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0033] "Carbocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula -0-Rc-carbocyclyl where Rc is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0034] "Carbocyclylalkynyl" refers to a radical of the formula -Rc-carbocyclyl, where Rc is an alkynylene chain as defined above. The carbocyclyl part of the carbocyclylalkynyl radical is optionally substituted as described above for an carbocyclyl group. In some embodiments the carbocyclyl group is a cycloalkyl group. The alkynylene chain part of the

carbocyclylalkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0035] As used herein, "carboxylic acid bioisostere" refers to a functional group or moiety that exhibits similar physical, biological and/or chemical properties as a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include, but are not limited to,


[0036] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.

[0037] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like. The alkyl part of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group.

[0038] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. The heteroatoms in the heterocyclyl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl may be attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,

thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl,

thiamorpholinyl, 1 -oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more

substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa,

-Rb-OC(0)-Ra, -Rb-OC(0)-ORa, -Rb-OC(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(0)Ra, -Rb-C(0)ORa, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)ORa, -Rb-N(Ra)C(0)Ra,

-Rb-N(Ra)S(0),Ra (where t is 1 or 2), -Rb-S(0),Ra (where t is 1 or 2), -Rb-S(0),ORa (where t is 1 or 2) and -Rb-S(0)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),

fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0039] "N-heterocyclyl" or "N-attached heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An N-heterocyclyl radical is optionally substituted as described above for

heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0040] "C-heterocyclyl" or "C-attached heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. A C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

[0041] "Heterocyclyl alkyl" refers to a radical of the formula -Rc-heterocyclyl where Rc is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally

substituted as defined above for a heterocyclyl group.

[0042] "Heterocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula -0-R°-heterocyclyl where Rc is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0043] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hiickel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[¾][l,4]dioxepinyl,

benzo[b][l,4]oxazinyl, 1 ,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl,

benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl,

benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl,

benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl,

cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,

5,6-dihydrobenzo[h]quinazolinyl, 5, 6-dihydrobenzo[h] cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9, 10-hexahydrocycloocta[d]pyrimidinyl,

5,6,7,8,9, 10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl,

naphthyridinyl, 1 ,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9, 10,1 Oa-octahydrobenzo[h]quinazolinyl, 1 -phenyl- lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl,

5.6.7.8- tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,

6.7.8.9- tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,

5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(0)-Ra, -Rb-OC(0)-ORa, -Rb-OC(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(0)Ra, -Rb-C(0)ORa, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)ORa, -Rb-N(Ra)C(0)Ra, -Rb-N(Ra)S(0),Ra (where t is 1 or 2), -Rb-S(0)tRa (where t is 1 or 2), -Rb-S(0),ORa (where t is 1 or 2) and -Rb-S(0)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0044] "N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0045] "C-heteroaryl" refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0046] "Heteroarylalkyl" refers to a radical of the formula -Rc-heteroaryl, where Rc is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0047] "Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula -0-Rc-heteroaryl, where Rc is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0048] The compounds disclosed herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers {e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term "geometric isomer" refers to E or Z geometric isomers {e.g., cis or trans) of an alkene double bond. The term "positional isomer" refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0049] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein may, in certain embodiments, exist as tautomers. In circumstances where tautomerization is

possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric e uilibrium include:


[0050] "Optional" or "optionally" means that a subsequently described event or

circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.

[0051] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the substituted heterocyclic derivative compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0052] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates,

metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates,

dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al,

"Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997)). Acid addition salts of basic compounds may be prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0053] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts may be formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al, supra.

[0054] As used herein, "treatment" or "treating," or "palliating" or "ameliorating" are used interchangeably herein. These terms refers to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By "therapeutic benefit" is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or

more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder. For prophylactic benefit, the compositions may be

administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.

[0055] "Prodrug" is meant to indicate a compound that may be converted under

physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism {see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).

[0056] A discussion of prodrugs is provided in Higuchi, T., et al, "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0057] The term "prodrug" is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amine functional groups in the active compounds and the like.

[0058] Unless otherwise stated, structures depicted herein are intended to include

compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched carbon are within the scope of the present disclosure.

[0059] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with 2H, nC, 13C, 14C, 15C, 12N, 13N, 15N, 16N, 160, 170, 14F, 15F, 16F, 17F, 18F, 33S, 34S, 35S, 36S, 35C1, 37C1, 79Br, 81Br, 125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0060] In certain embodiments, the compounds disclosed herein have some or all of the 1H atoms replaced with H atoms. The methods of synthesis for deuterium-containing substituted heterocyclic derivative compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0061] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing substituted heterocyclic derivative compounds. Large numbers of deuterium-containing reagents and building blocks are available commerically from chemical vendors, such as Aldrich Chemical Co.

[0062] Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-d3 (CD3I), are readily available and may be employed to transfer a deuterium-substituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD3I is illustrated, by way of example only, in the reaction schemes below.



[0063] Deuterium-transfer reagents, such as lithium aluminum deuteride (L1AID4), are employed to transfer deuterium under reducing conditions to the reaction substrate. The use of L1AID4 is illustrated, by way of example only, in the reaction schemes below.

L1AI D4 D D

" R OH

LiAID,

CN

D D

O

L1AI D4 D R'

R OH

[0064] Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon-carbon linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of exam le only, in the reaction schemes below.


EtOAc

[0065] In one embodiment, the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeable 1H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.

Substituted Heterocyclic Derivative Compounds

[0066] Substituted heterocyclic derivative compounds are described herein that are bromodomain inhibitors. These compounds, and compositions comprising these compounds, are useful for the treatment of cancer and neoplastic disease. The compounds described herein may, therefore, be useful for treating NUT midline carcinoma, Burkitts lymphoma, prostate cancer, breast cancer, bladder cancer, lung cancer and/or melanoma and the like.

[0067] One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof,


Formula (I)

wherein,

R2 is selected from CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3;

X5 is C-R5 or N;

X6 is C-R6 or N;

X7 is C-R7 or N;

X8 is C-R or N; wherein no more than two of X5, X6, X7, or X8 may be N;

R5 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R6 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R7 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R is h drogen, halogen, or alkyl;


X2 is N or C-R , wherein R is hydrogen, halogen, alkyl, or alkoxy;

R13 is -Y-Z;

Y is selected from a bond, -CH2-, -CH(Ci-C4 alkyl)-;

Z is selected from -S02R21, -N(R22)S02R21, -S02N(R22)2, -N(R22)S02N(R22)2, -CON(R22)2, -N(R22)C02R21, -N(R22)CON(R22)2, -N(R22)COR21, -COR21, -OC(0)N(R22)2, -OS02N(R22)2, or -N(R22)S03R21;

X3 is N or C-R14, wherein R14 is hydrogen, halogen, -CN, alkyl, cycloalkyl, or alkoxy;

X4 is N or C-R15, wherein R15 is hydrogen, halogen, alkyl, -CN, or alkoxy;

R16 is hydrogen, halogen, or -W-X, wherein W is a bond, -0-, -S-, or -NH-, and X is selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkynyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0068] Another embodiment provides a compound of Formula (I), wherein R is CH3.

Another embodiment provides a compound of Formula (I), wherein R is CD3. Another embodiment provides a compound of Formula (I), wherein X5 is N. Another embodiment provides a compound of Formula (I), wherein X6 is N. Another embodiment provides a compound of Formula (I), wherein X7 is N. Another embodiment provides a compound of Formula (I), wherein X8 is N. Another embodiment provides a compound of Formula (I), wherein none of X5, X6, X7, or X8 is N. Another embodiment provides a compound of

Formula (I), wherein R 5 and R 8 are hydrogen. Another embodiment provides a compound of Formula (I), wherein R5, R6, R7 andR8 are hydrogen. Another embodiment provides a compound of Formula (I), wherein R7 is a halogen. Another embodiment provides a compound of Formula (I), wherein R6 is a halogen. Another embodiment provides a compound of Formula (I), wherein R6 is a heteroaryl. Another embodiment provides a compound of Formula (I), wherein R6 is an aryl. Another embodiment provides a compound of Formula (I), wherein R6 is an alkyl. Another embodiment provides a compound of Formula (I), wherein R6 is an aryl.

[0069] Another embodiment provides a compound of Formula (I), wherein Y is a bond. Another embodiment provides a compound of Formula (I), wherein Y is a -CH2-. Another embodiment provides a compound of Formula I), wherein Z is -S02R 1. Another embodiment provides a compound of Formula I), wherein Z is -N(R22)S02R21. Another embodiment provides a compound of Formula I), wherein Z is -S02N(R22)2. Another embodiment provides a compound of Formula I), wherein Z is -N(R22)S02N(R22)2. Another embodiment provides a compound of Formula I), wherein Z is -CON(R )2. Another

22 21

embodiment provides a compound of Formula (I), wherein Z is -N(R )C02R . Another embodiment provides a compound of Formula (I), wherein Z is -N(R 22 )CON(R 22 )2. Another embodiment provides a compound of Formula (I), wherein R 21 is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment provides a compound of Formula (I), wherein R 21 is alkyl. Another embodiment provides a compound of Formula (I), wherein R14 is hydrogen, halogen, or alkyl. Another embodiment provides a compound of Formula (I), wherein X4 is C-R15. Another embodiment provides a compound of Formula (I), wherein W is -0-.

Another embodiment provides a compound of Formula (I), wherein W is -NH-. Another embodiment provides a compound of Formula (I), wherein X is alkyl. Another embodiment provides a compound of Formula (I), wherein X is aryl. Another embodiment provides a compound of Formula (I), wherein X is cycloalkylalkyl. Another embodiment provides a compound of Formula (I), wherein W is -O- and X is alkyl. Another embodiment provides a compound of Formula (I), wherein W is -O- and X is aryl. Another embodiment provides a compound of Formula (I), wherein W is -O- and X is cycloalkylalkyl. Another embodiment provides a compound of Formula (I), wherein R 5 and R 8 are hydrogen. Another embodiment provides a compound of Formula (I), wherein R5 and R8 are hydrogen, and R6 is heteroaryl.

[0070] One embodiment provides a compound of Formula (la), or a pharmaceutically acceptable salt thereof,


Formula (la)

wherein,

R2 is selected from CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3;

X5 is C-R5 or N;

X6 is C-R6 or N;

X7 is C-R7 or N;

Q

X8 is C-R or N; wherein no more than two of X5, X6, X7, or X8 may be N;

R5 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R6 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R7 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

Q

R is h drogen, halogen, or alkyl;


X2 is N or C-R , wherein R is hydrogen, halogen, alkyl, or alkoxy;

R13 is -Y-Z;

Y is selected from a bond, or -CH2-;

Z is selected from -S02R21, -N(R22)S02R21, -S02N(R22)2, -N(R22)S02N(R22)2, -CON(R22)2, -N(R22)C02R21, -N(R22)CON(R22)2, -N(R22)COR21, -OC(0)N(R22)2, -OS02N(R22)2, or -N(R22)S03R21;

X3 is N or C-R14, wherein R14 is hydrogen, halogen, -CN, alkyl, cycloalkyl, or alkoxy;

X4 is N or C-R15, wherein R15 is hydrogen, halogen, alkyl, -CN, or alkoxy;

R16 is hydrogen, halogen, or -W-X, wherein W is a bond, -0-, -S-, or -NH-, and X is selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,

heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0071] Another embodiment provides a compound of Formula (la), wherein R is CH3. Another embodiment provides a compound of Formula (la), wherein R is CD3. Another embodiment provides a compound of Formula (la), wherein X5 is N. Another embodiment provides a compound of Formula (la), wherein X6 is N. Another embodiment provides a compound of Formula (la), wherein X7 is N. Another embodiment provides a compound of Formula (la), wherein X8 is N. Another embodiment provides a compound of Formula (la), wherein none of X5, X6, X7, or X8 is N. Another embodiment provides a compound of

Formula (la), wherein R 5 and R 8 are hydrogen. Another embodiment provides a compound of Formula (la), wherein R5, R6, R7 and R8 are hydrogen. Another embodiment provides a compound of Formula (la), wherein R7 is a halogen. Another embodiment provides a

compound of Formula (la), wherein R6 is a halogen. Another embodiment provides a compound of Formula (la), wherein R6 is a heteroaryl. Another embodiment provides a compound of Formula (la), wherein R6 is an aryl. Another embodiment provides a compound of Formula (la), wherein R6 is an alkyl. Another embodiment provides a compound of Formula (la), wherein R6 is an aryl.

[0072] Another embodiment provides a compound of Formula (la), wherein Y is a bond. Another embodiment provides a compound of Formula (la), wherein Y is a -CH2-. Another

21

embodiment provides a compound of Formula (la), wherein Z is -S02R . Another embodiment provides a compound of Formula (la), wherein Z is -N(R 22 )S02R 21. Another embodiment provides a compound of Formula (la), wherein Z is -S02N(R 22 )2. Another

22 22 embodiment provides a compound of Formula (la), wherein Z is -N(R )S02N(R )2.

Another embodiment provides a compound of Formula (la), wherein Z is -CON(R 22 )2.

Another embodiment provides a compound of Formula (la), wherein Z is -N(R 22 )C02R 21.

Another embodiment provides a compound of Formula (la), wherein Z is -N(R 22 )CON(R 22 )2.

Another embodiment provides a compound of Formula (la), wherein R 21 is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment provides a compound of Formula (la), wherein R 21 is alkyl. Another embodiment provides a compound of Formula (la), wherein R14 is hydrogen, halogen, or alkyl. Another embodiment provides a compound of Formula (la), wherein X4 is C-R15. Another embodiment provides a compound of Formula (la), wherein W is -0-. Another embodiment provides a compound of Formula (la), wherein W is -NH-. Another embodiment provides a compound of Formula (la), wherein X is alkyl. Another embodiment provides a compound of Formula (la), wherein X is aryl. Another embodiment provides a compound of Formula (la), wherein X is cycloalkylalkyl. Another embodiment provides a compound of Formula (la), wherein W is -O- and X is alkyl. Another

embodiment provides a compound of Formula (la), wherein W is -O- and X is aryl. Another embodiment provides a compound of Formula (la), wherein W is -O- and X is

cycloalkylalkyl. Another embodiment provides a compound of Formula (la), wherein R5 and

R 8 are hydrogen. Another embodiment provides a compound of Formula (la), wherein R 5 and R8 are hydrogen, and R6 is heteroaryl.

[0073] One embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb),


Formula (lb)

wherein,

R is selected from CH3;

X5 is C-H;

X6 is C-R6;

X7 is C-R7;

X8 is C-H;

R6 is hydrogen, or halogen;

R7 is hydrogen, or halogen;


X2 is C-H;

R13 is -Y-Z;

Y is selected from a bond, or -CH2-;

Z is selected from -S02R21, -N(R22)S02R21, -S02N(R22)2, -N(R22)S02N(R22)2, -CON(R22)2, N(R22)C02R21, -N(R22)CON(R22)2, -N(R22)COR21, -OC(0)N(R22)2, -OS02N(R22)2, or -N(R22)S03R21;

X3 is C-R14, wherein R14 is hydrogen, halogen, Ci-C3 alkyl, or Ci-C3 alkoxy;

X4 is C-R15, wherein R15 is hydrogen, or halogen;

R16 is -W-X, wherein W is a bond, -0-, -S-, or -NH-, and X is selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0074] Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb), wherein R6 is halogen, and R7 is hydrogen. Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb), wherein R6 is hydrogen, and R7 is halogen.

Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb), wherein R6 is hydrogen, and R7 is hydrogen.

[0075] Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb), wherein Y is -CH2-. Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb), wherein Y is -CH2-, and Z is -S02R21, or -N(R22)S02R21. Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the

22

structure of Formula (lb), wherein R is hydrogen or methyl.

[0076] Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb), wherein Y is a bond. Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb), wherein Y is a bond, and Z is -N(R22)S02R21, or -N(R22)S02N(R22)2. Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the

21

structure of Formula (lb), wherein Y is a bond, and Z is -S02R . Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of

21 21

Formula (lb), wherein Y is a bond, Z is -S02R , and R is heterocyclyl, or

heterocyclylalkyl. Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb), wherein Y is a bond, Z is - S0 21 21

2R , and R is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula

21 21

(lb), wherein Y is a bond, Z is -S02R , R is alkyl, and the alkyl is a C1-C4 alkyl.

[0077] Another embodiment provides a compound, or a pharmaceutically acceptable salt

22 thereof, having the structure of Formula (lb), wherein Y is a bond, and Z is -S02N(R )2. Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof,

22

having the structure of Formula (lb), wherein R is hydrogen or methyl. Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the

22 22 structure of Formula (lb), wherein Y is a bond, Z is -S02N(R )2, and at least one R is alkyl, cycloalkyl, or aralkyl.

[0078] Another embodiment provides a compound, or a pharmaceutically acceptable salt

21

thereof, having the structure of Formula (lb), wherein R is heterocyclyl, or

heterocyclylalkyl.

[0079] Another embodiment provides a compound, or a pharmaceutically acceptable salt

22

thereof, having the structure of Formula (lb), wherein R is hydrogen or methyl. Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb), wherein at least one 22

R is alkyl, cycloalkyl, or aralkyl.

Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb), wherein 21

R is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb), wherein the alkyl is a C1-C4 alkyl. Another

embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb), wherein the C1-C4 alkyl is a Ci alkyl.

[0080] Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb), wherein R14 is hydrogen, and R15 is hydrogen.

[0081] Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb), wherein W is -NH-. Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb), wherein W is -S-. Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb), wherein W is a bond. Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb), wherein W is -0-.

[0082] Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb), wherein X is alkyl. Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb), wherein W is -NH-, and X is alkyl. Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb), wherein W is -O- and X is alkyl. Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb), wherein W is a bond, and X is alkyl.

[0083] Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb), wherein X is cycloalkylalkyl. Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb), wherein W is -NH-, and X is cycloalkylalkyl. Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb), wherein W is -O- and X is cycloalkylalkyl. Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb), wherein W is a bond, and X is cycloalkylalkyl.

[0084] Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb), wherein X is aryl. Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb), wherein W is -NH-, and X is aryl. Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb), wherein W is -0-, and X is aryl. Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb), wherein W is a bond, and X is aryl.

[0085] Another embodiment provides a compound, or a pharmaceutically acceptable salt

21

thereof, having the structure of Formula (lb), wherein Y is a bond, Z is -S02R , W is -0-, and X is aryl or cycloalkylalkyl. Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb), wherein Y is

21

a bond, Z is -S02R , W is -0-, and X is cycloalkylalkyl.

[0086] One embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt thereof,


Formula (II)

wherein,

2

R is alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl;

X6 is C-H or N;

X5 is C-R5 or N; provided that if X6 is N, then X5 is C-R5, and if X5 is N, then X6 is CH; R5 is hydrogen, halogen, -OH, -CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R6 is hydrogen, halogen, -OH, -CN, alkyl, cycloalkyl, cycloalkylalkyl, amino, alkylamino, dialkylamino, cycloalkylalkylamino, alkoxy, -S-alkyl, cycloalkylalkoxy, heterocyclyl, aralkox , heteroaryloxy, aryloxy, alkynyloxy, or -N(H)COalkyl;


X2 is N or C-R , wherein R is hydrogen, halogen, alkyl, or alkoxy;

R is -Y-Z;

Y is selected from a bond, -CH2-, or -CH(Ci-C4alkyl)-;

Z is selected from -S02R21, -N(R22)S02R21, -S02N(R22)2, -N(R22)S02N(R22)2, -CON(R22)2, -N(R22)C02R21, -N(R22)CON(R22)2, -N(R22)COR21, -COR21, -OC(0)N(R22)2, -OS02N(R22)2, or -N(R22)S03R21;

X3 is N or C-R14, wherein R14 is hydrogen, halogen, -CN, alkyl, cycloalkyl, or alkoxy;

X4 is N or C-R15, wherein R15 is hydrogen, halogen, -CN, alkyl, alkoxy, aryloxy, aralkyloxy, cycloalkylalkyloxy, heterocyclyloxy, heteroarylalkyloxy, or alkynyloxy;

R16 is hydrogen, halogen, -N(H)COX, or -W-X, wherein W is a bond, -0-, -S-, or -NH-, and X is selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkynyl,

cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

provided that when X6 is N, then R5 and R6 are not hydrogen.

[0087] One embodiment provides a compound of Formula (Ha), or a pharmaceutically acceptable salt thereof,


Formula (Ila)

wherein,

R2 is CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3;

X6 is C-H or N;

X5 is C-R5 or N; provided that if X6 is N, then X5 is C-R5, and if X5 is N, then X6 is CH; R5 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R6 is hydrogen, halogen, -OH,-CN, alkyl, cycloalkyl, cycloalkylalkyl, amino, alkylamino, dialkylamino, cycloalkylalkylamino, alkoxy, or cycloalkylalkoxy;


X2 is N or C-R 12 , wherein R 12 is hydrogen, halogen, alkyl, or alkoxy;

R13 is -Y-Z;

Y is selected from a bond, or -CH2-;

Z is selected from -S02R21, -N(R22)S02R21, -S02N(R22)2, -N(R22)S02N(R22)2, -CON(R22)2, - N(R22)C02R21, -N(R22)CON(R22)2, -N(R22)COR21, -OC(0)N(R22)2, -OS02N(R22)2, or - N(R22)S03R21;

X3 is N or C-R14, wherein R14 is hydrogen, halogen, -CN, alkyl, cycloalkyl, or alkoxy;

X4 is N or C-R15, wherein R15 is hydrogen, halogen, -CN, alkyl, or alkoxy;

R16 is hydrogen, halogen, or -W-X, wherein W is a bond, -0-, -S-, or -NH-, and X is selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,

heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

provided that when X6 is N, then R5 and R6 are not hydrogen.

[0088] Another embodiment provides a compound of Formula (Ila), wherein X2 is N.

Another embodiment provides a compound of Formula (Ila), wherein X3 is N. Another embodiment provides a compound of Formula (Ila), wherein X4 is N. Another embodiment provides a compound of Formula (Ila), wherein X2 and X3 are N. Another embodiment provides a compound of Formula (Ila), wherein X2 is C-R12, X3 is C-R14, and X4 is C-R15.

[0089] Another embodiment provides a compound of Formula (Ila), wherein R is CH3. Another embodiment provides a compound of Formula (Ila), wherein X6 is C-H. Another embodiment provides a compound of Formula (Ila), wherein X6 is N. Another embodiment provides a compound of Formula (Ila), wherein X5 is C-R5. Another embodiment provides a compound of Formula (Ila), wherein X5 is N. Another embodiment provides a compound of Formula (Ila), wherein R5 is hydrogen, halogen, or alkyl. Another embodiment provides a compound of Formula (Ila), wherein R6 is hydrogen, halogen, or alkyl.

[0090] Another embodiment provides a compound of Formula (Ila), wherein Y is a bond.

Another embodiment provides a compound of Formula (Ila), wherein Y is a -CH2-. Another embodiment provides a compound of Formula (Ila), wherein Z is -S02R 21. Another embodiment provides a compound of Formula (Ila), wherein Z is -N(R 22 )S02R 21. Another embodiment provides a compound of Formula (Ila), wherein Z is -S02N(R )2. Another embodiment provides a compound of Formula (Ila), wherein Z is -N(R 22 )S02N(R 22 )2.

Another embodiment provides a compound of Formula (Ila), wherein Z is -CON(R 22 )2.

Another embodiment provides a compound of Formula (Ila), wherein Z is -N(R 22 )C02R 21. Another embodiment provides a compound of Formula (Ila), wherein Z is - N(R 22 )CON(R 22 )2. Another embodiment provides a compound of Formula (Ila), wherein R 21 is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment provides a compound of

Formula (Ila), wherein R 21 is alkyl. Another embodiment provides a compound of Formula (Ila), wherein R14 is hydrogen, halogen, or alkyl. Another embodiment provides a compound of Formula (Ila), wherein X4 is C-R15. Another embodiment provides a compound of Formula (Ila), wherein W is -0-. Another embodiment provides a compound of Formula (Ila), wherein W is -NH-. Another embodiment provides a compound of Formula (Ila), wherein X is alkyl. Another embodiment provides a compound of Formula (Ila), wherein X is aryl. Another embodiment provides a compound of Formula (Ila), wherein X is cycloalkylalkyl. Another embodiment provides a compound of Formula (Ila), wherein W is -O- and X is alkyl. Another embodiment provides a compound of Formula (Ila), wherein W is -O- and X is aryl. Another embodiment provides a compound of Formula (Ila), wherein W is -O- and X is cycloalkylalkyl. Another embodiment provides a compound of Formula (Ila), wherein the R6 is CD3.

[0091] One embodiment provides a compound of Formula (lib), or a pharmaceutically acceptable salt thereof,


Formula (lib)

wherein,

R2 is CH3;

X6 is C-H;

X5 is C-R5;

R5 is hydrogen;

R6 is halo en or alkyl;

X2 is N;

R13 is -Y-Z;

Y is selected from a bond, or -CH2-;

Z is selected from -S02R21, -N(R22)S02R21, -S02N(R22)2, -N(R22)S02N(R22)2, -CON(R22)2, - N(R22)C02R21, -N(R22)CON(R22)2, -N(R22)COR21, -OC(0)N(R22)2, -OS02N(R22)2, or - N(R22)S03R21;

X3 is N;

X4 is C-R15, wherein R15 is hydrogen, halogen, -CN, alkyl, or alkoxy;

R16 is -W-X, wherein W is a bond, -0-, -S-, or -NH-, and X is selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0092] Another embodiment provides a compound of Formula (lib), wherein R6 is halogen. Another embodiment provides a compound of Formula (lib), wherein R6 is alkyl. Another embodiment provides a compound of Formula (lib), wherein R6 is Ci-C3 alkyl. Another embodiment provides a compound of Formula (lib), wherein R6 is Ci alkyl.

[0093] Another embodiment provides a compound of Formula (lib), wherein Y is a bond. Another embodiment provides a compound of Formula (lib), wherein Y is a -CH2-. Another embodiment provides a compound of Formula -S02R 21

(lib), wherein Z is . Another embodiment provides a compound of Formula 22 21

(lib), wherein Z is -N(R )S02R . Another embodiment provides a compound of Formula 22

(lib), wherein Z is -S02N(R )2. Another

22 22 embodiment provides a compound of Formula (lib), wherein Z is -N(R )S02N(R )2.

Another embodiment provides a compound of Formula n Z is -CON(R 22

(lib), wherei )2.

Another embodiment provides a compound of Formula wherein Z is -N(R 22 )C02R 21

(lib), .

22 22

Another embodiment provides a compound of Formula (lib), wherein Z is -N(R )CON(R )2.

Another embodiment provides a compound of Formula 21

(lib), wherein R is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment provides a compound of Formula 21

(lib), wherein R is alkyl. Another embodiment provides a compound of Formula 21

(lib), wherein R is Ci-C2 alkyl.

[0094] Another embodiment provides a compound of Formula (lib), wherein W is -0-. Another embodiment provides a compound of Formula (lib), wherein W is -NH-. Another

embodiment provides a compound of Formula (lib), wherein W is a bond. Another embodiment provides a compound of Formula (lib), wherein X is alkyl. Another embodiment provides a compound of Formula (lib), wherein X is aryl. Another embodiment provides a compound of Formula (lib), wherein X is cycloalkylalkyl. Another embodiment provides a compound of Formula (lib), wherein W is -O- and X is alkyl. Another embodiment provides a compound of Formula (lib), wherein W is -O- and X is aryl. Another embodiment provides a compound of Formula (lib), wherein W is -O- and X is cycloalkylalkyl. Another embodiment provides a compound of Formula (lib), wherein W is a bond and X is alkyl. Another embodiment provides a compound of Formula (lib), wherein W is a bond and X is aryl. Another embodiment provides a compound of Formula (lib), wherein W is a bond and X is cycloalkylalkyl. Another embodiment provides a compound of Formula (lib), wherein the R6 is CD3.

[0095] One embodiment provides a compound of Formula (III), or a pharmaceutically acceptable salt thereof,


O Formula (III)

wherein,

R2 is CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3;

XI is C-H or N;

ring B is an optionally substituted 5- or 6-membered heterocyclic ring containing at least one oxygen or nitrogen atom;


X2 is N or C-R , wherein R is hydrogen, halogen, alkyl, or alkoxy;

R13 is -Y-Z;

Y is selected from a bond, -CH2-, or -CH(Ci-C4 alkyl)-;

Z is selected from -S02R21, -N(R22)S02R21, -S02N(R22)2, -N(R22)S02N(R22)2, -CON(R22)2, - N(R22)C02R21, -N(R22)CON(R22)2, -N(R22)COR21, -OC(0)N(R22)2, -OS02N(R22)2, or - N(R22)S03R21;

X3 is N or C-R14, wherein R14 is hydrogen, halogen, -CN, alkyl, cycloalkyl, or alkoxy; or optionally when X4 is C-R15, R14 and R15 connect to form a ring;

X4 is N or C-R , wherein R is hydrogen, halogen, -CN, alkyl, or alkoxy;

R16 is hydrogen, halogen, or -W-X, wherein W is a bond, -0-, -S-, or -NH-, and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; or optionally when X4 is C-R15, R16 and R15 connect to form a ring;

each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0096] Another embodiment provides a compound of Formula (III), wherein X2 is N.

Another embodiment provides a compound of Formula (III), wherein X3 is N. Another embodiment provides a compound of Formula (III), wherein X4 is N. Another embodiment provides a compound of Formula (III), wherein X2 and X3 are N. Another embodiment provides a compound of Formula (III), wherein X2 is C-R12, X3 is C-R14, and X4 is C-R15.

[0097] Another embodiment provides a compound of Formula (III), having the structure of Formula (Ilia):


Formula (Ilia)

wherein,

ring B is a 6-membered ring having one nitrogen atom;

23 24 24

R is selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, -COR , -C02R , -CONH(R24), -CON(R24)2, or S02R24; and

each R 24 is independently selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0098] Another embodiment provides a compound of Formula (III), wherein R is CH3. Another embodiment provides a compound of Formula (III), wherein XI is C-H. Another embodiment provides a compound of Formula (III), wherein XI is N.

[0099] Another embodiment provides a compound of Formula (III), wherein Y is a bond. Another embodiment provides a compound of Formula (III), wherein Y is a -CH2-. Another embodiment provides a compound of Formula (III), wherein Z is -S02R 21. Another embodiment provides a compound of Formula (III), wherein Z is -N(R 22 )S02R 21. Another embodiment provides a compound of Formula (III), wherein Z is -S02N(R 22 )2. Another

embodiment provides a compound of Formula (III), wherein Z is -N(R )S02N(R )2.

Another embodiment provides a compound of Formula (III), wherein Z is -CON(R 22 )2.

22 21

Another embodiment provides a compound of Formula (III), wherein Z is -N(R )C02R . Another embodiment provides a compound of Formula (III), wherein Z is - 22 22 21

N(R )CON(R )2. Another embodiment provides a compound of Formula (III), wherein R is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment provides a compound of

21

Formula (III), wherein R is alkyl. Another embodiment provides a compound of Formula (III), wherein R14 is hydrogen, halogen, or alkyl. Another embodiment provides a compound of Formula (III), wherein X4 is C-R15. Another embodiment provides a compound of Formula (III), wherein W is -0-. Another embodiment provides a compound of Formula (III), wherein W is -NH-. Another embodiment provides a compound of Formula (III), wherein X is alkyl. Another embodiment provides a compound of Formula (III), wherein X is alkynyl. Another embodiment provides a compound of Formula (III), wherein X is aryl. Another embodiment provides a compound of Formula (III), wherein X is cycloalkylalkyl. Another embodiment provides a compound of Formula (III), wherein X is

cycloalkylalkynyl. Another embodiment provides a compound of Formula (III), wherein W is -O- and X is alkyl. Another embodiment provides a compound of Formula (III), wherein W is -O- and X is alkynyl. Another embodiment provides a compound of Formula (III), wherein W is -O- and X is aryl. Another embodiment provides a compound of Formula (III), wherein W is -O- and X is cycloalkylalkyl. Another embodiment provides a compound of Formula (III), wherein W is -O- and X is cycloalkylalkynyl.

[00100] One embodiment provides a compound of Formula (IV), or a

pharmaceutically acceptable salt thereof,


υ Formula (IV)

wherein,

Q is N and T is C, or Q is C and T is N;

Ring B is an optionally substituted 5-membered aromatic nitrogen-containing heteroaryl ring containing one or more nitrogen atoms;

R2 is selected from CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3;

XI is C-H or N;

X2 is N or C-R , wherein R is hydrogen, halogen, alkyl, or alkoxy;

R13 is -Y-Z;

Y is selected from a bond, or -CH2-;

Z is selected from -S02R21, -N(R22)S02R21, -S02N(R22)2, -N(R22)S02N(R22)2, -CON(R22)2, -N(R22)C02R21, -N(R22)CON(R22)2, -N(R22)COR21, -OC(0)N(R22)2, -OS02N(R22)2, or -N(R22)S03R21;

X3 is N or C-R14, wherein R14 is hydrogen, halogen, -CN, alkyl, cycloalkyl, or alkoxy;

X4 is N or C-R15, wherein R15 is hydrogen, halogen, -CN, alkyl, or alkoxy;

R16 is hydrogen, halogen, or -W-X, wherein W is a bond, -0-, -S-, or -NH-, and X is selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,

heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[00101] Another embodiment provides a compound of Formula (IV), wherein X2 is N. Another embodiment provides a compound of Formula (IV), wherein X3 is N. Another embodiment provides a compound of Formula (IV), wherein X4 is N. Another embodiment provides a compound of Formula (IV), wherein X2 and X3 are N. Another embodiment provides a compound of Formula (IV), wherein X2 is C-R12, X3 is C-R14, and X4 is C-R15.

[00102] Another embodiment provides a compound of Formula (IV), wherein the compound of Formula (IV) is selected from the group:


[00103] Another embodiment provides a compound of Formula (IV), wherein the compound of Formula (IV) has the structure:


[00104] Another embodiment provides a compound of Formula (IV), wherein Q is N and T is C. Another embodiment provides a compound of Formula (IV), wherein Q is C and T is N. Another embodiment provides a compound of Formula (IV), wherein R is CH3. Another embodiment provides a compound of Formula (IV), wherein XI is C-H. Another embodiment provides a compound of Formula (IV), wherein XI is N.

[00105] Another embodiment provides a compound of Formula (IV), wherein Y is a bond. Another embodiment provides a compound of Formula (IV), wherein Y is a -CH2-.

21

Another embodiment provides a compound of Formula (IV), wherein Z is -S02R . Another

22 21 embodiment provides a compound of Formula (IV), wherein Z is -N(R )S02R . Another embodiment provides a compound of Formula (IV), wherein Z is -S02N(R 22 )2. Another

22 22 embodiment provides a compound of Formula (IV), wherein Z is -N(R )S02N(R )2.

22

Another embodiment provides a compound of Formula (IV), wherein Z is -CON(R )2.

22 21

Another embodiment provides a compound of Formula (IV), wherein Z is -N(R )C02R . Another embodiment provides a compound of Formula (IV), wherein Z is - 22 22 21

N(R )CON(R )2. Another embodiment provides a compound of Formula (IV), wherein R is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment provides a compound of

Formula (IV), wherein R 21 is alkyl. Another embodiment provides a compound of Formula (IV), wherein R14 is hydrogen, halogen, or alkyl. Another embodiment provides a compound of Formula (IV), wherein X4 is C-R15. Another embodiment provides a compound of Formula (IV), wherein W is -0-. Another embodiment provides a compound of Formula (IV), wherein W is -NH-. Another embodiment provides a compound of Formula (IV), wherein X is alkyl. Another embodiment provides a compound of Formula (IV), wherein X is aryl. Another embodiment provides a compound of Formula (IV), wherein X is cycloalkylalkyl. Another embodiment provides a compound of Formula (IV), wherein W is -O- and X is alkyl. Another embodiment provides a compound of Formula (IV), wherein W is -O- and X is aryl. Another embodiment provides a compound of Formula (IV), wherein W is -O- and X is cycloalkylalkyl.

[00106] Another embodiment provides a compound of Formula (V), or a

pharmaceutically acceptable salt thereof,


Formula (V)

wherein,

R2 is selected from CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3;

X5 is C-R5 or N;

X6 is C-R6 or N;

X7 is C-R7 or N;

X8 is C-R or N; wherein no more than two of X5, X6, X7, or X8 may be N;

R5 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R6 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R7 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R is h drogen, halogen, or alkyl;


X2 is N or C-R , wherein R is hydrogen, halogen, alkyl, or alkoxy;

R13 is -Y-Z;

Y is selected from a bond, or -CH2-;

Z is selected from -S02R21, -N(R22)S02R21, -S02N(R22)2, -N(R22)S02N(R22)2, -CON(R22)2, -N(R22)C02R21, -N(R22)CON(R22)2, -N(R22)COR21, -OC(0)N(R22)2, -OS02N(R22)2, or -N(R22)S03R21;

X3 is N or C-R14, wherein R14 is hydrogen, halogen, alkyl, cycloalkyl, or alkoxy;

X4 is N or C-R15, wherein R15 is hydrogen, halogen, alkyl, or alkoxy;

R is hydrogen, halogen, or -W-X, wherein W is a bond, -0-, -S-, or -NH-, and X is selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,

heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[00107] Another embodiment provides a compound of Formula (V), wherein X2 is N. Another embodiment provides a compound of Formula (V), wherein X3 is N. Another embodiment provides a compound of Formula (V), wherein X4 is N. Another embodiment provides a compound of Formula (V), wherein X2 and X3 are N. Another embodiment provides a compound of Formula (V), wherein X2 is C-R12, X3 is C-R14, and X4 is C-R15.

[00108] Another embodiment provides a compound of Formula (V), wherein R is CH3. Another embodiment provides a compound of Formula (V), wherein R is CD3.

Another embodiment provides a compound of Formula (V), wherein X5 is N. Another embodiment provides a compound of Formula (V), wherein X6 is N. Another embodiment provides a compound of Formula (V), wherein X7 is N. Another embodiment provides a compound of Formula (V), wherein X8 is N. Another embodiment provides a compound of Formula (V), wherein none of X5, X6, X7, or X8 is N. Another embodiment provides a compound of Formula (V), wherein R 5 andR 8 are hydrogen. Another embodiment provides a compound of Formula (V), wherein R5, R6, R7 and R8 are hydrogen. Another embodiment provides a compound of Formula (V), wherein R7 is a halogen. Another embodiment provides a compound of Formula (V), wherein R6 is a halogen. Another embodiment provides a compound of Formula (V), wherein R6 is a heteroaryl. Another embodiment provides a compound of Formula (V), wherein R6 is an aryl. Another embodiment provides a compound of Formula (V), wherein R6 is an alkyl. Another embodiment provides a compound of Formula (V), wherein R6 is an aryl.

[00109] Another embodiment provides a compound of Formula (V), wherein Y is a bond. Another embodiment provides a compound of Formula (V), wherein Y is a -CH2-.

21

Another embodiment provides a compound of Formula (V), wherein Z is -S02R . Another embodiment provides a compound of Formula (V), wherein Z is -N(R 22 )S02R 21. Another embodiment provides a compound of Formula (V), wherein Z is -S02N(R 22 )2. Another

22 22 embodiment provides a compound of Formula (V), wherein Z is -N(R )S02N(R )2.

Another embodiment provides a compound of Formula (V), wherein Z is -CON(R 22 )2.

Another embodiment provides a compound of Formula (V), wherein Z is -N(R )C02R .

22 22

Another embodiment provides a compound of Formula (V), wherein Z is -N(R )CON(R )2.

Another embodiment provides a compound of Formula (V), wherein R 21 is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment provides a compound of Formula (V), wherein R 21 is alkyl. Another embodiment provides a compound of Formula (V), wherein R14 is hydrogen, halogen, or alkyl. Another embodiment provides a compound of Formula (V), wherein X4 is C-R15. Another embodiment provides a compound of Formula (V), wherein W is -0-. Another embodiment provides a compound of Formula (V), wherein W is -NH-. Another embodiment provides a compound of Formula (V), wherein X is alkyl. Another embodiment provides a compound of Formula (V), wherein X is aryl. Another embodiment provides a compound of Formula (V), wherein X is cycloalkylalkyl. Another embodiment provides a compound of Formula (V), wherein W is -O- and X is alkyl. Another

embodiment provides a compound of Formula (V), wherein W is -O- and X is aryl. Another embodiment provides a compound of Formula (V), wherein W is -O- and X is

cycloalkylalkyl. Another embodiment provides a compound of Formula (V), wherein R5 and

R 8 are hydrogen. Another embodiment provides a compound of Formula (V), wherein R 5 and R8 are hydrogen, and R6 is heteroaryl.

[00110] One embodiment provides a compound of Formula (Via), or a pharmaceutically acceptable salt thereof,


υ Formula (Via)

wherein,

R2 is CH3 or CD3;

R5 is hydrogen or CH ;

R6 is h drogen, CH3, CI, F, Br, NH2, N(CH3)2, NH(alkyl), or


R is -Y-Z;

Y is selected from a bond or -CH2-;

Z is -S02R21;

R14 is hydrogen, F, or CI;

Rlb is -W-X, wherein W is -O- or -NH-, and X is selected from CH3, CH2CH3, CH2CH2CH3, CH(CH )2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CH2-(cyclopropyl), C6H5, 4-fluoro(C6H4), 2,4-difluoro(C6H3), 2-fiuoro(C6H4), 4-tetrahydropyranyl, 3-tetrahydropyranyl, oxolan-3-yl, 4,4-difluorocyclohexyl, and 4-hydroxycyclohexyl; and

each R21 is CH3 or CH2CH3.

[00111] Another embodiment provides a compound of Formula (Via), wherein Y is a bond. Another embodiment provides a compound of Formula (Via), wherein Y is -CH2-. Another embodiment provides a compound of Formula (Via), wherein W is -0-. Another embodiment provides a compound of Formula (Via), wherein W is -NH-. Another embodiment provides a compound of Formula (Via), wherein R is CH3. Another embodiment provides a compound of Formula (Via), wherein R is CD3.

[00112] One embodiment provides a compound of Formula (VIb), or a pharmaceutically acce table salt thereof,


R2 is CH3 or CD3;

R5 is hydrogen or CH3;

R6 is h drogen, CH3, CI, F, Br, NH2, N(CH3)2, NH(alkyl), or CD3;


R is -NHS02Rzl;

R14 is hydrogen, F, or CI;

R16 is -W-X, wherein W is -O- or -NH-, and X is selected from CH3, CH2CH3, CH2CH2CH3, CH(CH )2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CH2-(cyclopropyl), C6H5, 4-fluoro(C6H4), 2,4-difluoro(C6H ), 2-fluoro(C6H4), 4-tetrahydropyranyl, 3-tetrahydropyranyl, oxolan-3-yl, 4,4-difluorocyclohexyl, and 4-hydroxycyclohexyl; and

each R21 is CH3 or CH2CH3.

Another embodiment provides a compound of Formula (VIb), wherein W is -0-. Another embodiment provides a compound of Formula (VIb), wherein W is -NH-. Another

2

embodiment provides a compound of Formula (VIb), wherein R is CH3. Another

embodiment provides a compound of Formula (VIb), wherein R is CD3.

[00113] One embodiment provides a compound of Formula (Vic), or a pharmaceutically acce table salt thereof,


R2 is CH3 or CD3;

R5 is hydrogen or CH ;

R6 is hydrogen, CH3, CI, F, Br, NH2, N(CH3)2, NH(alkyl), or CD3;


R is -Y-Z;

Y is selected from a bond or -CH2-;

Z is -S02R21;

R16 is -W-X, wherein W is -O- or -NH-, and X is selected from CH3, CH2CH3, CH2CH2CH3, CH(CH )2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CH2-(cyclopropyl), C6H5, 4-fluoro(C6H4), 2,4-difluoro(C6H3), 2-fluoro(C6H4), 4-tetrahydropyranyl, 3-tetrahydropyranyl, oxolan-3-yl, 4,4-difluorocyclohexyl, and 4-hydroxycyclohexyl; and

each R21 is CH3 or CH2CH3.

[00114] Another embodiment provides a compound of Formula (Vic), wherein Y is a bond. Another embodiment provides a compound of Formula (Vic), wherein Y is -CH2-. Another embodiment provides a compound of Formula (Vic), wherein W is -0-. Another embodiment provides a compound of Formula (Vic), wherein W is -NH-. Another embodiment provides a compound of Formula (Vic), wherein R is CH3. Another embodiment provides a compound of Formula (Vic), wherein R is CD .

[00115] One embodiment provides a compound of Formula (VId), or a pharmaceutically acceptable salt thereof,

O Formula (VId)

wherein,

R2 is CH3 or CD3;

R5 is hydrogen or CH ;

R6 is hydrogen, CH3, CI, F, Br, NH2, N(CH3)2, NH(alkyl), or CD3;


Rlb is -W-X, wherein W is -O- or -NH-, and X is selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CH2-(cyclopropyl), C6H5, 4-fluoro(C6H4), 2,4-difluoro(C6H ), 2-fluoro(C6H4), 4-tetrahydropyranyl, 3-tetrahydropyranyl, oxolan-3-yl, 4,4-difluorocyclohexyl, and 4-hydroxycyclohexyl; and

each R21 is CH3 or CH2CH3.

[00116] Another embodiment provides a compound of Formula (VId), wherein W is -0-. Another embodiment provides a compound of Formula (VId), wherein W is -NH-. Another embodiment provides a compound of Formula (VId), wherein R is CH3. Another

embodiment provides a compound of Formula (VId), wherein R is CD3.

[00117] One embodiment provides a compound of Formula (Vie), or a pharmaceutically acce table salt thereof,


2

R is hydrogen, CH3, or CHF2;

R6 is CH3 CD3, cyclopropyl, NH(CH3), NH(CH2CH3), F, or CI;

R is -Y-Z;

Y is selected from -NH- or -CH2-;

21

Z is selected from -S02R ;

R14 is hydrogen, CH3, or F;

X9 is N or CH;

R16 is -W-X, wherein W is -O- or -NH-, and X is selected from CH3, CH2CH3, CH2CH2CH3, CH2-(cyclopropyl), CH2CH2CFH2, 2,4-difiuoro(C6H3), 2,3-difiuoro(C6H3), 2-chloro-4-fluoro(C6H3), 2-fluoro(C6H4), and 2-chloro(C6H4); and

each R21 is independently selected from CH3, CH2CH3, CH2CH2CH3, CH2CH2CHF2, CH2-(cyclopropyl), and cyclopropyl.

[00118] Another embodiment provides a compound of Formula (Vie), wherein Y is -NH-. Another embodiment provides a compound of Formula (Vie), wherein Y is -CH2-. Another embodiment provides a compound of Formula (Vie), wherein W is -0-. Another embodiment provides a compound of Formula (Vie), wherein W is -NH-. Another embodiment provides a compound of Formula (Vie), wherein X9 is N. Another embodiment provides a compound of Formula (Vie), wherein X9 is CH. Another embodiment provides a compound of Formula (Vie), wherein R is hydrogen. Another embodiment provides a compound of Formula (Vie), wherein R 2 is CH3. Another embodiment provides a compound of Formula (Vie), wherein R 2

is CHF2.

[00119] One embodiment provides a compound of Formula (VII), or a

pharmaceutically acceptable salt thereof,


Formula (VII)

wherein,

R2 is CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3;

X6 is C-H or N;

X5 is C-R5 or N; provided that if X6 is N, then X5 is C-R5, and if X5 is N, then X6 is CH; R5 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R6 is hydrogen, halogen, -OH,-CN, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl,

cycloalkylalkynyl, amino, alkylamino, dialkylamino, heterocyclyl, cycloalkylalkylamino, alkox , cycloalkyloxy, cycloalkylalkoxy, alkyl-S-, cycloalkyl-S-, and cycloalkylalkyl-S-;


X2 is N or C-R , wherein R is hydrogen, halogen, alkyl, or alkoxy;

R13 is -Y-Z;

Y is selected from a bond, -CH2-, or -CH(Ci-C4 alkyl)-;

Z is selected from -S02R21, -N(R22)S02R21, -S02N(R22)2, -N(R22)S02N(R22)2, -CON(R22)2, - N(R22)C02R21, -N(R22)CON(R22)2, -N(R22)COR21, -OC(0)N(R22)2, -OS02N(R22)2, or - N(R22)S03R21;

X3 is N or C-R14, wherein R14 is hydrogen, halogen, -CN, alkyl, cycloalkyl, or alkoxy; or optionally when X4 is C-R15, R14 and R15 connect to form a ring;

X4 is N or C-R15, wherein R15 is hydrogen, halogen, -CN, alkyl, or alkoxy;

R16 is hydrogen, halogen, or -W-X, wherein W is a bond, -0-, -S-, or -NH-, and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; or optionally when X4 is C- R15, R16 and R15 connect to form a ring;

each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[00120] Another embodiment provides a compound of Formula (VII), wherein X2 is N.

Another embodiment provides a compound of Formula (VII), wherein X3 is N. Another embodiment provides a compound of Formula (VII), wherein X4 is N. Another embodiment provides a compound of Formula (VII), wherein X2 and X3 are N. Another embodiment provides a compound of Formula (VII), wherein X2 is C-R12, X3 is C-R14, and X4 is C-R15.

[00121] Another embodiment provides a compound of Formula (VII), wherein R is CH3. Another embodiment provides a compound of Formula (VII), wherein X6 is C-H. Another embodiment provides a compound of Formula (VII), wherein X6 is N. Another embodiment provides a compound of Formula (VII), wherein X5 is C-R5. Another embodiment provides a compound of Formula (VII), wherein X5 is N. Another embodiment provides a compound of Formula (VII), wherein R5 is hydrogen, halogen, or alkyl. Another embodiment provides a compound of Formula (VII), wherein R6 is hydrogen, halogen, or alkyl. Another embodiment provides a compound of Formula (VII), wherein R6 is heterocyclyl. Another embodiment provides a compound of Formula (VII), wherein R6 is cycloalkylalkynyl. Another

embodiment provides a compound of Formula (VII), wherein R6 is alkoxy, cycloalkyloxy, or cycloalkylalkoxy.

[00122] Another embodiment provides a compound of Formula (VII), wherein Y is a bond. Another embodiment provides a compound of Formula (VII), wherein Y is a -CH2-.

21

Another embodiment provides a compound of Formula (VII), wherein Z is -S02R . Another embodiment provides a compound of Formula (VII), wherein Z is -N(R 22 )S02R 21. Another embodiment provides a compound of Formula (VII), wherein Z is -S02N(R 22 )2. Another

22 22 embodiment provides a compound of Formula (VII), wherein Z is -N(R )S02N(R )2.

Another embodiment provides a compound of Formula (VII), wherein Z is -CON(R 22 )2.

Another embodiment provides a compound of Formula (VII), wherein Z is -N(R 22 )C02R 21. Another embodiment provides a compound of Formula (VII), wherein Z is - 22 22 21

N(R )CON(R )2. Another embodiment provides a compound of Formula (VII), wherein R is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment provides a compound of

Formula (VII), wherein R 21 is alkyl. Another embodiment provides a compound of Formula (VII), wherein R14 is hydrogen, halogen, or alkyl. Another embodiment provides a compound of Formula (VII), wherein X4 is C-R15. Another embodiment provides a compound of Formula (VII), wherein W is -0-. Another embodiment provides a compound of Formula (VII), wherein W is -NH-. Another embodiment provides a compound of Formula (VII), wherein X is alkyl. Another embodiment provides a compound of Formula (VII), wherein X is alkynyl. Another embodiment provides a compound of Formula (VII), wherein X is aryl. Another embodiment provides a compound of Formula (VII), wherein X is cycloalkylalkyl. Another embodiment provides a compound of Formula (VII), wherein X is cycloalkylalkynyl. Another embodiment provides a compound of Formula (VII), wherein W is -O- and X is alkyl. Another embodiment provides a compound of Formula (VII), wherein W is -O- and X is alkynyl. Another embodiment provides a compound of Formula (VII), wherein W is -O- and X is aryl. Another embodiment provides a compound of Formula (VII), wherein W is -O- and X is cycloalkylalkyl. Another embodiment provides a compound of Formula (VII), wherein W is -O- and X is cycloalkylalkynyl. Another embodiment provides a compound of Formula (VII), wherein the R6 is CD3.

[00123] One embodiment provides a compound of Formula (Vila), or a

pharmaceutically acceptable salt thereof,

Formula (Vila)

wherein,

R2 is CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3;

X6 is C-H or N;

X5 is C-R5 or N; provided that if X6 is N, then X5 is C-R5, and if X5 is N, then X6 is CH; R5 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R6 is hydrogen, halogen, -OH,-CN, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl,

cycloalkylalkynyl, amino, alkylamino, dialkylamino, heterocyclyl, cycloalkylalkylamino, alkoxy, cycloalkyloxy, cycloalkylalkoxy, alkyl-S-, cycloalkyl-S-, and cycloalkylalkyl-S-;


X2 is N or C-R 12 , wherein R 12 is hydrogen, halogen, alkyl, or alkoxy;

R13 is -Y-Z;

Y is selected from a bond, -CH2-, or -CH(Ci-C4 alkyl)-;

Z is selected from -N(R22)S02R21, -N(R22)C02R21, -N(R22)COR21, or -N(R22)S03R21;

X3 is N or C-R14, wherein R14 is hydrogen, halogen, -CN, alkyl, cycloalkyl, or alkoxy; or optionally when X4 is C-R15, R14 and R15 connect to form a ring;

X4 is N or C-R15, wherein R15 is hydrogen, halogen, -CN, alkyl, or alkoxy;

R16 is hydrogen, halogen, or -W-X, wherein W is a bond, -0-, -S-, or -NH-, and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; or optionally when X4 is C- R15, R16 and R15 connect to form a ring;

each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; or optionally when R 21 and

R 22 are alkyl, R 21 and R 22 connect to form a ring; and

each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[00124] Another embodiment provides a compound of Formula (Vila), wherein X2 is N. Another embodiment provides a compound of Formula (Vila), wherein X3 is N. Another embodiment provides a compound of Formula (Vila), wherein X4 is N. Another embodiment provides a compound of Formula (Vila), wherein X2 and X3 are N. Another embodiment provides a compound of Formula (Vila), wherein X2 is C-R12, X3 is C-R14, and X4 is C-R15.

[00125] Another embodiment provides a compound of Formula (Vila), wherein R is CH3. Another embodiment provides a compound of Formula (Vila), wherein X6 is C-H. Another embodiment provides a compound of Formula (Vila), wherein X6 is N. Another embodiment provides a compound of Formula (Vila), wherein X5 is C-R5. Another embodiment provides a compound of Formula (Vila), wherein X5 is N. Another embodiment provides a compound of Formula (Vila), wherein R5 is hydrogen, halogen, or alkyl. Another embodiment provides a compound of Formula (Vila, wherein R6 is hydrogen, halogen, or alkyl. Another embodiment provides a compound of Formula (Vila), wherein R6 is heterocyclyl. Another embodiment provides a compound of Formula (Vila), wherein R6 is cycloalkylalkynyl.

Another embodiment provides a compound of Formula (Vila), wherein R6 is alkoxy, cycloalkyloxy, or cycloalkylalkoxy.

[00126] Another embodiment provides a compound of Formula (Vila), wherein Y is a bond. Another embodiment provides a compound of Formula (Vila), wherein Y is a -CH2-.

Another embodiment provides a compound of Formula (Vila), wherein Z is -N(R 22 )S02R 21.

Another embodiment provides a compound of Formula (Vila), wherein Z is -N(R 22 )C02R 21.

Another embodiment provides a compound of Formula (Vila), wherein R 21 is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment provides a compound of Formula (Vila), wherein R 21 is alkyl. Another embodiment provides a compound of Formula (Vila), wherein

R 22 is alkyl. Another embodiment provides a compound of Formula (Vila), wherein both R 21 and R 22 are alkyl and connect to form a ring. Another embodiment provides a compound of Formula (Vila), wherein R14 is hydrogen, halogen, or alkyl. Another embodiment provides a compound of Formula (Vila), wherein X4 is C-R15. Another embodiment provides a compound of Formula (Vila), wherein W is -0-. Another embodiment provides a compound of Formula (Vila), wherein W is -NH-. Another embodiment provides a compound of Formula (Vila), wherein X is alkyl. Another embodiment provides a compound of Formula (Vila), wherein X is alkynyl. Another embodiment provides a compound of Formula (Vila), wherein X is aryl. Another embodiment provides a compound of Formula (Vila), wherein X is cycloalkylalkyl. Another embodiment provides a compound of Formula (Vila), wherein X is cycloalkylalkynyl. Another embodiment provides a compound of Formula (Vila), wherein W is -O- and X is alkyl. Another embodiment provides a compound of Formula (Vila), wherein W is -O- and X is alkynyl. Another embodiment provides a compound of Formula (Vila), wherein W is -O- and X is aryl. Another embodiment provides a compound of Formula (Vila), wherein W is -O- and X is cycloalkylalkyl. Another embodiment provides a compound of Formula (Vila), wherein W is -O- and X is cycloalkylalkynyl. Another embodiment provides a compound of Formula (Vila), wherein the R6 is CD3.

[00127] One embodiment provides a compound of Formula (VIII), or a

pharmaceutically acceptable salt thereof,


Formula (VIII)

wherein,

R2 is selected from CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3;

X5 is C-R5 or N;

X6 is C-R6 or N;

X7 is C-R7 or N;

X8 is C-R or N; wherein no more than two of X5, X6, X7, or X8 may be N;

R5 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R6 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R7 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R is h drogen, halogen, or alkyl;

X2 is N or C-R 12 , wherein R 12 is hydrogen, halogen, alkyl, or alkoxy;

R13 is -Y-Z;

Y is selected from a bond, -CH2-, or -CH(Ci-C4 alkyl)-;

Z is selected from -S02R21, -N(R22)S02R21, -S02N(R22)2, -N(R22)S02N(R22)2, -CON(R22)2, -N(R22)C02R21, -N(R22)CON(R22)2, -N(R22)COR21, -OC(0)N(R22)2, -OS02N(R22)2, or -N(R22)S03R21;

X3 is N or C-R14, wherein R14 is hydrogen, halogen, -CN, alkyl, cycloalkyl, or alkoxy; or optionally when X4 is C-R15, R14 and R15 connect to form a ring;

X4 is N or C-R15, wherein R15 is hydrogen, halogen, -CN, alkyl, or alkoxy;

R16 is hydrogen, halogen, or -W-X, wherein W is a bond, -0-, -S-, or -NH-, and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; or optionally when X4 is C- R15, R16 and R15 connect to form a ring;

each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[00128] Another embodiment provides a compound of Formula (VIII), wherein R is CH3. Another embodiment provides a compound of Formula (VIII), wherein R is CD3. Another embodiment provides a compound of Formula (VIII), wherein X5 is N. Another embodiment provides a compound of Formula (VIII), wherein X6 is N. Another

embodiment provides a compound of Formula (VIII), wherein X7 is N. Another

embodiment provides a compound of Formula (VIII), wherein X8 is N. Another

embodiment provides a compound of Formula (VIII), wherein none of X5, X6, X7, or X8 is

5 8

N. Another embodiment provides a compound of Formula (VIII), wherein R and R are hydrogen. Another embodiment provides a compound of Formula (VIII), wherein R5, R6, R7

Q

and R are hydrogen. Another embodiment provides a compound of Formula (VIII), wherein R7 is a halogen. Another embodiment provides a compound of Formula (VIII), wherein R6 is a halogen. Another embodiment provides a compound of Formula (VIII), wherein R6 is a heteroaryl. Another embodiment provides a compound of Formula (VIII), wherein R6 is an aryl. Another embodiment provides a compound of Formula (VIII), wherein R6 is an alkyl. Another embodiment provides a compound of Formula (VIII), wherein R6 is an aryl.

[00129] Another embodiment provides a compound of Formula (VIII), wherein Y is a bond. Another embodiment provides a compound of Formula (VIII), wherein Y is a -CH2-.

Another embodiment provides a compound of Formula (VIII), wherein Z is -S02R .

22 21

Another embodiment provides a compound of Formula (VIII), wherein Z is -N(R )S02R .

22

Another embodiment provides a compound of Formula (VIII), wherein Z is -S02N(R )2. Another embodiment provides a compound of Formula (VIII), wherein Z is - 22 22

N(R )S02N(R )2. Another embodiment provides a compound of Formula (VIII), wherein Z

22

is -CON(R )2. Another embodiment provides a compound of Formula (VIII), wherein Z is - 22 21

N(R )C02R . Another embodiment provides a compound of Formula (VIII), wherein Z is - 22 22

N(R )CON(R )2. Another embodiment provides a compound of Formula (VIII), wherein

R 21 is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment provides a compound of

Formula (VIII), wherein R 21 is alkyl. Another embodiment provides a compound of Formula (VIII), wherein R14 is hydrogen, halogen, or alkyl. Another embodiment provides a compound of Formula (VIII), wherein X4 is C-R15. Another embodiment provides a compound of Formula (VIII), wherein W is -0-. Another embodiment provides a compound of Formula (VIII), wherein W is -NH-. Another embodiment provides a compound of Formula (VIII), wherein X is alkyl. Another embodiment provides a compound of Formula (VIII), wherein X is aryl. Another embodiment provides a compound of Formula (VIII), wherein X is cycloalkylalkyl. Another embodiment provides a compound of Formula (VIII), wherein W is -O- and X is alkyl. Another embodiment provides a compound of Formula (VIII), wherein W is -O- and X is aryl. Another embodiment provides a compound of Formula (VIII), wherein W is -O- and X is cycloalkylalkyl. Another embodiment provides a compound of Formula (VIII), wherein R 5 andR 8 are hydrogen. Another embodiment provides a compound of Formula (VIII), wherein R5 and R8 are hydrogen, and R6 is heteroaryl.

[00130] One embodiment provides a compound of Formula (Villa), or a

pharmaceutically acceptable salt thereof,


Formula (Villa)

wherein,

R2 is selected from CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3;

X5 is C-R5 or N;

X6 is C-R6 or N;

X7 is C-R7 or N;

X8 is C-R or N; wherein no more than two of X5, X6, X7, or X8 may be N;

R5 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R6 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R7 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

Q

R is hydrogen, halogen, or alkyl;


X2 is N or C-R 12 , wherein R 12 is hydrogen, halogen, alkyl, or alkoxy;

R13 is -Y-Z;

Y is selected from a bond, -CH2-, or -CH(Ci-C4 alkyl)-;

Z is selected from -N(R22)S02R21, -N(R22)C02R21, -N(R22)COR21, or -N(R22)S03R21;

X3 is N or C-R14, wherein R14 is hydrogen, halogen, -CN, alkyl, cycloalkyl, or alkoxy; or optionally when X4 is C-R15, R14 and R15 connect to form a ring;

X4 is N or C-R15, wherein R15 is hydrogen, halogen, -CN, alkyl, or alkoxy;

R16 is hydrogen, halogen, or -W-X, wherein W is a bond, -0-, -S-, or -NH-, and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; or optionally when X4 is C- R15, R16 and R15 connect to form a ring;

each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; or optionally when R 21 and

R 22 are alkyl, R 21 and R 22 connect to form a ring; and

each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[00131] Another embodiment provides a compound of Formula (Villa), wherein R is

CH3. Another embodiment provides a compound of Formula (Villa), wherein R is CD3.

Another embodiment provides a compound of Formula (Villa), wherein X5 is N. Another embodiment provides a compound of Formula (Villa), wherein X6 is N. Another

embodiment provides a compound of Formula (Villa), wherein X7 is N. Another

embodiment provides a compound of Formula (Villa), wherein X8 is N. Another

embodiment provides a compound of Formula (Villa), wherein none of X5, X6, X7, or X8 is N. Another embodiment provides a compound of Formula (Villa), wherein R 5 and R 8 are hydrogen. Another embodiment provides a compound of Formula (Villa), wherein R5, R6,

R 7' and R 8° are hydrogen. Another embodiment provides a compound of Formula (Villa), wherein R7 is a halogen. Another embodiment provides a compound of Formula (Villa), wherein R6 is a halogen. Another embodiment provides a compound of Formula (Villa), wherein R6 is a heteroaryl. Another embodiment provides a compound of Formula (Villa), wherein R6 is an aryl. Another embodiment provides a compound of Formula (Villa), wherein R6 is an alkyl. Another embodiment provides a compound of Formula (Villa), wherein R6 is an aryl.

[00132] Another embodiment provides a compound of Formula (Villa), wherein Y is a bond. Another embodiment provides a compound of Formula (Villa), wherein Y is a -CH2-.

22 21

Another embodiment provides a compound of Formula (Villa), wherein Z is -N(R )S02R . Another embodiment provides a compound of Formula (Villa), wherein Z is - N(R 22 )C02R 21. Another embodiment provides a compound of Formula (Villa), wherein R 21 is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment provides a compound of

Formula (Villa), wherein R 21 is alkyl. Another embodiment provides a compound of

Formula (Villa), wherein R 22 is alkyl. Another embodiment provides a compound of

Formula (Villa), wherein both R 21 and R 22 are alkyl and connect to form a ring. Another embodiment provides a compound of Formula (Villa), wherein R14 is hydrogen, halogen, or alkyl. Another embodiment provides a compound of Formula (Villa), wherein X4 is C-R15. Another embodiment provides a compound of Formula (Villa), wherein W is -0-. Another embodiment provides a compound of Formula (Villa), wherein W is -NH-. Another embodiment provides a compound of Formula (Villa), wherein X is alkyl. Another embodiment provides a compound of Formula (Villa), wherein X is aryl. Another embodiment provides a compound of Formula (Villa), wherein X is cycloalkylalkyl.

Another embodiment provides a compound of Formula (Villa), wherein W is -O- and X is alkyl. Another embodiment provides a compound of Formula (Villa), wherein W is -O- and X is aryl. Another embodiment provides a compound of Formula (Villa), wherein W is -O-and X is cycloalkylalkyl. Another embodiment provides a compound of Formula (Villa), wherein R 5 and R 8 are hydrogen. Another embodiment provides a compound of Formula (Villa), wherein R5 andR8 are hydrogen, and R6 is heteroaryl.

[00133] One embodiment provides a compound of Formula (IX), or a

pharmaceutically acceptable salt thereof,


Formula (IX)

wherein,

Q is N and T is C, or Q is C and T is N;

Ring B is an optionally substituted 5-membered aromatic nitrogen-containing heteroaryl ring containing one or more nitrogen atoms;

R2 is selected from CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3;

XI is C-H or N;


X2 is N or C-R , wherein R is hydrogen, halogen, alkyl, or alkoxy;

R13 is -Y-Z;

Y is selected from a bond, -CH2-, or -CH(Ci-C4 alkyl)-;

Z is selected from -S02R21, -N(R22)S02R21, -S02N(R22)2, -N(R22)S02N(R22)2, -CON(R22)2, -N(R22)C02R21, -N(R22)CON(R22)2, -N(R22)COR21, -OC(0)N(R22)2, -OS02N(R22)2, or -N(R22)S03R21;

X3 is N or C-R14, wherein R14 is hydrogen, halogen, -CN, alkyl, cycloalkyl, or alkoxy; or optionally when X4 is C-R15, R14 and R15 connect to form a ring;

X4 is N or C-R15, wherein R15 is hydrogen, halogen, -CN, alkyl, or alkoxy;

R16 is hydrogen, halogen, or -W-X, wherein W is a bond, -0-, -S-, or -NH-, and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; or optionally when X4 is C- R15, R16 and R15 connect to form a ring;

each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[00134] Another embodiment provides a compound of Formula (IX), wherein X2 is N. Another embodiment provides a compound of Formula (IX), wherein X3 is N. Another embodiment provides a compound of Formula (IX), wherein X4 is N. Another embodiment provides a compound of Formula (IX), wherein X2 and X3 are N. Another embodiment provides a compound of Formula (IX), wherein X2 is C-R12, X3 is C-R14, and X4 is C-R15.

[00135] Another embodiment provides a compound of Formula (IX), wherein the compound of Formula (IX) is selected from the group:


[00136] Another embodiment provides a compound of Formula (IX), wherein Q is N and T is C. Another embodiment provides a compound of Formula (IX), wherein Q is C and T is N. Another embodiment provides a compound of Formula (IX), wherein R is CH3. Another embodiment provides a compound of Formula (IX), wherein XI is C-H. Another embodiment provides a compound of Formula (IX), wherein XI is N.

[00137] Another embodiment provides a compound of Formula (IX), wherein Y is a bond. Another embodiment provides a compound of Formula (IX), wherein Y is a -CH2-.

21

Another embodiment provides a compound of Formula (IX), wherein Z is -S02R . Another

22 21

embodiment provides a compound of Formula (IX), wherein Z is -N(R )S02R . Another embodiment provides a compound of Formula (IX), wherein Z is -S02N(R 22 )2. Another

22 22 embodiment provides a compound of Formula (IX), wherein Z is -N(R )S02N(R )2.

22

Another embodiment provides a compound of Formula (IX), wherein Z is -CON(R )2.

22 21

Another embodiment provides a compound of Formula (IX), wherein Z is -N(R )C02R . Another embodiment provides a compound of Formula (IX), wherein Z is - 22 22 21

N(R )CON(R )2. Another embodiment provides a compound of Formula (IX), wherein R is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment provides a compound of

21

Formula (IX), wherein R is alkyl.

[00138] Another embodiment provides a compound of Formula (IX), wherein R14 is hydrogen, halogen, or alkyl. Another embodiment provides a compound of Formula (IX), wherein X4 is C-R15. Another embodiment provides a compound of Formula (IX), wherein W is -0-. Another embodiment provides a compound of Formula (IX), wherein W is -NH-. Another embodiment provides a compound of Formula (IX), wherein X is alkyl. Another embodiment provides a compound of Formula (IX), wherein X is aryl. Another embodiment provides a compound of Formula (IX), wherein X is cycloalkylalkyl. Another embodiment provides a compound of Formula (IX), wherein W is -O- and X is alkyl. Another embodiment provides a compound of Formula (IX), wherein W is -O- and X is aryl.

Another embodiment provides a compound of Formula (IX), wherein W is -O- and X is cycloalkylalkyl.

[00139] One embodiment provides a compound of Formula (XII), or a

pharmaceutically acceptable salt thereof,


Formula (XII)

wherein,

R2 is selected from CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3;

X5 is C-R5 or N;

X6 is C-R6 or N;

X7 is C-R7 or N;

X8 is C-R or N; wherein no more than two of X5, X6, X7, or X8 may be N;

R5 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R6 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R7 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R is hydrogen, halogen, or alkyl;


X2 is N or C-R , wherein R is hydrogen, halogen, alkyl, or alkoxy;

R13 is -Y-Z;

Y is selected from a bond, -CH2-, or -CH(Ci-C4 alkyl)-;

Z is selected from -S02R21, -N(R22)S02R21, -S02N(R22)2, -N(R22)S02N(R22)2, -CON(R22)2, -N(R22)C02R21, -N(R22)CON(R22)2, -N(R22)COR21, -OC(0)N(R22)2, -OS02N(R22)2, or -N(R22)S03R21;

X3 is S;

X4 is N or C-R , wherein R is hydrogen, halogen, alkyl, or alkoxy;

R16 is hydrogen, halogen, or -W-X, wherein W is a bond, -0-, -S-, or -NH-, and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

2

[00140] Another embodiment provides a compound of Formula (XII), wherein R is

2

CH3. Another embodiment provides a compound of Formula (XII), wherein R is CD3. Another embodiment provides a compound of Formula (XII), wherein X5 is N. Another embodiment provides a compound of Formula (XII), wherein X6 is N. Another embodiment provides a compound of Formula (XII), wherein X7 is N. Another embodiment provides a compound of Formula (XII), wherein X8 is N. Another embodiment provides a compound of Formula (XII), wherein none of X5, X6, X7, or X8 is N. Another embodiment provides a

5 8

compound of Formula (XII), wherein R andR are hydrogen. Another embodiment provides a compound of Formula (XII), wherein R5, R6, R7 and R8 are hydrogen. Another embodiment provides a compound of Formula (XII), wherein R7 is a halogen. Another embodiment provides a compound of Formula (XII), wherein R6 is a halogen. Another embodiment provides a compound of Formula (XII), wherein R6 is a heteroaryl. Another embodiment provides a compound of Formula (XII), wherein R6 is an aryl. Another embodiment provides a compound of Formula (XII), wherein R6 is an alkyl. Another embodiment provides a compound of Formula (XII), wherein R6 is an aryl.

[00141] Another embodiment provides a compound of Formula (XII), wherein Y is a bond. Another embodiment provides a compound of Formula (XII), wherein Y is a -CH2-.

21

Another embodiment provides a compound of Formula (XII), wherein Z is -S02R . Another

22 21 embodiment provides a compound of Formula (XII), wherein Z is -N(R )S02R . Another

22

embodiment provides a compound of Formula (XII), wherein Z is -S02N(R )2. Another

22 22 embodiment provides a compound of Formula (XII), wherein Z is -N(R )S02N(R )2.

22

Another embodiment provides a compound of Formula (XII), wherein Z is -CON(R )2.

22 21

Another embodiment provides a compound of Formula (XII), wherein Z is -N(R )C02R . Another embodiment provides a compound of Formula (XII), wherein Z is - 22 22 21

N(R )CON(R )2. Another embodiment provides a compound of Formula (XII), wherein R is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment provides a compound of

21

Formula (XII), wherein R is alkyl. Another embodiment provides a compound of Formula (XII), wherein W is -0-. Another embodiment provides a compound of Formula (XII), wherein W is -NH-. Another embodiment provides a compound of Formula (XII), wherein X is alkyl. Another embodiment provides a compound of Formula (XII), wherein X is aryl. Another embodiment provides a compound of Formula (XII), wherein X is cycloalkylalkyl. Another embodiment provides a compound of Formula (XII), wherein W is -O- and X is alkyl. Another embodiment provides a compound of Formula (XII), wherein W is -O- and X is aryl. Another embodiment provides a compound of Formula (XII), wherein W is -O- and X is cycloalkylalkyl. Another embodiment provides a compound of Formula (XII), wherein

5 8

RJ and R° are hydrogen. Another embodiment provides a compound of Formula (XII), wherein R5 and R8 are hydrogen, and R6 is heteroaryl.

00142] Another embodiment provides a compound of Formula (XII), wherein RA is


00143] Another embodiment provides a compound of Formula (XII), wherein RA is


00144] Another embodiment provides a compound of Formula (XII), wherein RA is


[00145] Another embodiment provides a compound of Formula (XII), wherein R is


[00146] Another embodiment provides a compound of Formula (XII), wherein R is


[00147] Another embodiment provides a compound of Formula (XII), wherein RA is


[00148] One embodiment provides a compound of Formula (XIII), or a

pharmaceutically acceptable salt thereof,


Formula (XIII)

wherein,

R is selected from CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3;

X5 is C-R5 or N;

X6 is C-R6 or N;

X7 is C-R7 or N;

Q

X8 is C-R or N; wherein no more than two of X5, X6, X7, or X8 may be N;

R5 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R6 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R7 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

Q

R is hydrogen, halogen, or alkyl;


R is hydrogen or C1-C4 alkyl;

R13 is -Y-Z;

Y is selected from -CH2-, or -CH(Ci-C4 alkyl)-;

Z is selected from -S02R21, -S02N(R22)2, or -CON(R22)2;

R15 is hydrogen, halogen or C1-C4 alkyl;

R16 is hydrogen, halogen, or -W-X, wherein W is a bond, -0-, -S-, or -NH-, and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; or optionally, R16 and R15 connect to form a ring;

each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[00149] Another embodiment provides a compound of Formula (XIII), wherein R is CH3. Another embodiment provides a compound of Formula (XIII), wherein R is CD3. Another embodiment provides a compound of Formula (XIII), wherein X5 is N. Another embodiment provides a compound of Formula (XIII), wherein X6 is N. Another

embodiment provides a compound of Formula (XIII), wherein X7 is N. Another

embodiment provides a compound of Formula (XIII), wherein X8 is N. Another

embodiment provides a compound of Formula (XIII), wherein none of X5, X6, X7, or X8 is

5 8

N. Another embodiment provides a compound of Formula (XIII), wherein R and R are hydrogen. Another embodiment provides a compound of Formula (XIII), wherein R5, R6, R7

Q

and R are hydrogen. Another embodiment provides a compound of Formula (XIII), wherein R7 is a halogen. Another embodiment provides a compound of Formula (XIII), wherein R6 is a halogen. Another embodiment provides a compound of Formula (XIII), wherein R6 is a

heteroaryl. Another embodiment provides a compound of Formula (XIII), wherein R6 is an aryl. Another embodiment provides a compound of Formula (XIII), wherein R6 is an alkyl. Another embodiment provides a compound of Formula (XIII), wherein R6 is an aryl.

[00150] Another embodiment provides a compound of Formula (XIII), wherein Y is a

21

-CH2-. Another embodiment provides a compound of Formula (XIII), wherein Z is -S02R .

22

Another embodiment provides a compound of Formula (XIII), wherein Z is -S02N(R )2.

22

Another embodiment provides a compound of Formula (XIII), wherein Z is -CON(R )2.

Another embodiment provides a compound of Formula (XIII), wherein R 21 is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment provides a compound of Formula

21

(XIII), wherein R is alkyl. Another embodiment provides a compound of Formula (XIII), wherein W is -0-. Another embodiment provides a compound of Formula (XIII), wherein W is -NH-. Another embodiment provides a compound of Formula (XIII), wherein X is alkyl. Another embodiment provides a compound of Formula (XIII), wherein X is aryl. Another embodiment provides a compound of Formula (XIII), wherein X is cycloalkylalkyl. Another embodiment provides a compound of Formula (XIII), wherein W is -O- and X is alkyl. Another embodiment provides a compound of Formula (XIII), wherein W is -O- and X is aryl. Another embodiment provides a compound of Formula (XIII), wherein W is -O-and X is cycloalkylalkyl. Another embodiment provides a compound of Formula (XIII), wherein R 5 and R 8 are hydrogen. Another embodiment provides a compound of Formula (XIII), wherein R5 andR8 are hydrogen, and R6 is heteroaryl.

[00151] One embodiment provides a compound of Formula (XIV), or a

pharmaceutically acceptable salt thereof,


Formula (XIV)

wherein,

R2 is CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3;

X6 is C-H or N;

X5 is C-R5 or N; provided that if X6 is N, then X5 is C-R5, and if X5 is N, then X6 is CH; R5 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R6 is hydrogen, halogen, -OH,-CN, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl,

cycloalkylalkynyl, amino, alkylamino, dialkylamino, heterocyclyl, cycloalkylalkylamino, alkoxy, cycloalkyloxy, cycloalkylalkoxy, alkyl-S-, cycloalkyl-S-, and cycloalkylalkyl-S-;


R is hydrogen or C1-C4 alkyl;

R13 is -Y-Z;

Y is selected from -CH2-, or -CH(d-C4 alkyl)-;

Z is selected from -S02R21, -S02N(R22)2, or -CON(R22)2;

R15 is hydrogen, halogen or C1-C4 alkyl;

R16 is hydrogen, halogen, or -W-X, wherein W is a bond, -0-, -S-, or -NH-, and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; or optionally, R16 and R15 connect to form a ring;

each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[00152] Another embodiment provides a compound of Formula (XIV), wherein R is CH3. Another embodiment provides a compound of Formula (XIV), wherein X6 is C-H. Another embodiment provides a compound of Formula (XIV), wherein X6 is N. Another embodiment provides a compound of Formula (XIV), wherein X5 is C-R5. Another embodiment provides a compound of Formula (XIV), wherein X5 is N. Another embodiment provides a compound of Formula (XIV), wherein R5 is hydrogen, halogen, or alkyl. Another embodiment provides a compound of Formula (XIV), wherein R6 is hydrogen, halogen, or alkyl. Another embodiment provides a compound of Formula (XIV), wherein R6 is heterocyclyl. Another embodiment provides a compound of Formula (XIV), wherein R6 is cycloalkylalkynyl.

Another embodiment provides a compound of Formula (XIV), wherein R6 is alkoxy, cycloalkyloxy, or cycloalkylalkoxy.

[00153] Another embodiment provides a compound of Formula (XIV), wherein Y is a -CH2-.

Another embodiment provides a compound of Formula (XIV), wherein Z is -S02R 21. Another embodiment provides a compound of Formula (XIV), wherein Z is -S02N(R 22 )2. Another

embodiment provides a compound of Formula (XIV), wherein Z is -CON(R )2. Another embodiment provides a compound of Formula (XIV), wherein R 21 is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment provides a compound of Formula (XIV), wherein R 21 is alkyl. Another embodiment provides a compound of Formula (XIV), wherein W is -0-. Another embodiment provides a compound of Formula (XIV), wherein W is -NH-. Another embodiment provides a compound of Formula (XIV), wherein X is alkyl. Another embodiment provides a compound of Formula (XIV), wherein X is alkynyl. Another embodiment provides a compound of Formula (XIV), wherein X is aryl. Another embodiment provides a compound of Formula (XIV), wherein X is cycloalkylalkyl. Another embodiment provides a compound of Formula (XIV), wherein X is cycloalkylalkynyl.

Another embodiment provides a compound of Formula (XIV), wherein W is -O- and X is alkyl. Another embodiment provides a compound of Formula (XIV), wherein W is -O- and X is alkynyl. Another embodiment provides a compound of Formula (XIV), wherein W is -O-and X is aryl. Another embodiment provides a compound of Formula (XIV), wherein W is -O- and X is cycloalkylalkyl. Another embodiment provides a compound of Formula (XIV), wherein W is -O- and X is cycloalkylalkynyl. Another embodiment provides a compound of Formula (XIV), wherein the R6 is CD3.

[00154] One embodiment provides a compound of Formula (XV), or a pharmaceutically acceptable salt thereof,


υ Formula (XV)

wherein,

Ring B is an optionally substituted 5-membered heteroaryl ring containing at least one oxygen or sulfur atom;

R2 is selected from CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3; XI is C-H or N;


X2 is N or C-R 12 , wherein R 12 is hydrogen, halogen, alkyl, or alkoxy;

R13 is -Y-Z;

Y is selected from a bond, -CH2-, or -CH(Ci-C4 alkyl)-;

Z is selected from -S02R , -N(Rzz)S02R , -S02N(RZZ)2, -N(Rzz)S02N(Rzz)2, -CON(Rzz)2, -N(R22)C02R21, -N(R22)CON(R22)2, -N(R22)COR21, -OC(0)N(R22)2, -OS02N(R22)2, or -N(R22)S03R21;

X3 is N or C-R14, wherein R14 is hydrogen, halogen, -CN, alkyl, cycloalkyl, or alkoxy; or optionally when X4 is C-R15, R14 and R15 connect to form a ring;

X4 is N or C-R15, wherein R15 is hydrogen, halogen, -CN, alkyl, or alkoxy;

R16 is hydrogen, halogen, or -W-X, wherein W is a bond, -0-, -S-, or -NH-, and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; or optionally when X4 is C- R15, R16 and R15 connect to form a ring;

each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[00155] Another embodiment provides a compound of Formula (XV), wherein X2 is N. Another embodiment provides a compound of Formula (XV), wherein X3 is N. Another embodiment provides a compound of Formula (XV), wherein X4 is N. Another embodiment provides a compound of Formula (XV), wherein X2 and X3 are N. Another embodiment provides a compound of Formula (XV), wherein X2 is C-R12, X3 is C-R14, and X4 is C-R15.

[00156] Another embodiment provides a compound of Formula (XV), wherein the compound of Formula (XV) has a formula selected from:


wherein each R is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, -OH, -OR31, -NHR31, -N(R31)2, -CONHR31, -CON(R31)2; and R31 is C1-C4 alkyl.

[00157] Another embodiment provides a compound of Formula (XV), wherein the compound of Formula (XV) has a formula selected from:


wherein each R is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, -OH, -OR31, -NHR31, -N(R31)2, -CONHR31, -CON(R31)2; and R31 is C1-C4 alkyl.

[00158] Another embodiment provides a compound of Formula (XV), wherein the compound of Formula (XV) has a formula selected from:


wherein each RJU is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, -OH,

-OR31, -NHR31, -N(R31)2, -CONHR31, -CON(R31)2; and R31 is C1-C4 alkyl.

[00159] Another embodiment provides a compound of Formula (XV), wherein R is

CH3. Another embodiment provides a compound of Formula (XV), wherein XI is C-H.

Another embodiment provides a compound of Formula (XV), wherein XI is N.

[00160] Another embodiment provides a compound of Formula (XV), wherein Y is a bond. Another embodiment provides a compound of Formula (XV), wherein Y is a -CH2-.

Another embodiment provides a compound of Formula (XV), wherein Z is -S02R 21.

Another embodiment provides a compound of Formula (XV), wherein Z is -N(R 22 )S02R 21.

Another embodiment provides a compound of Formula (XV), wherein Z is -S02N(R 22 )2. Another embodiment provides a compound of Formula (XV), wherein Z is - 22 22

N(R )S02N(R )2. Another embodiment provides a compound of Formula (XV), wherein Z

22

is -CON(R )2. Another embodiment provides a compound of Formula (XV), wherein Z is - 22 21

N(R )C02R . Another embodiment provides a compound of Formula (XV), wherein Z is - 22 22

N(R )CON(R )2. Another embodiment provides a compound of Formula (XV), wherein

R 21 is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment provides a compound of

Formula (XV), wherein R 21 is alkyl.

[00161] Another embodiment provides a compound of Formula (XV), wherein X3 is C-R14. Another embodiment provides a compound of Formula (XV), wherein R14 is hydrogen, halogen, or alkyl. Another embodiment provides a compound of Formula (XV), wherein X4 is C-R15. Another embodiment provides a compound of Formula (XV), wherein W is -0-. Another embodiment provides a compound of Formula (XV), wherein W is -NH-. Another embodiment provides a compound of Formula (XV), wherein X is alkyl. Another embodiment provides a compound of Formula (XV), wherein X is alkynyl. Another embodiment provides a compound of Formula (XV), wherein X is aryl. Another

embodiment provides a compound of Formula (XV), wherein X is cycloalkylalkyl. Another embodiment provides a compound of Formula (XV), wherein X is cycloalkylalkynyl.

Another embodiment provides a compound of Formula (XV), wherein W is -O- and X is alkyl. Another embodiment provides a compound of Formula (XV), wherein W is -O- and X is aryl. Another embodiment provides a compound of Formula (XV), wherein W is -O-and X is alkynyl. Another embodiment provides a compound of Formula (XV), wherein W is -O- and X is cycloalkylalkyl. Another embodiment provides a compound of Formula (XV), wherein W is -O- and X is cycloalkylalkynyl.

[00162] Another embodiment provides a compound of Formula (XVI), or a pharmaceutically acceptable salt thereof,


Formula (XVI)

wherein,

R2 is selected from CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3;

X5 is C-R5 or N;

X6 is C-R6 or N;

X7 is C-R7 or N;

X8 is C-R or N; wherein no more than two of X5, X6, X7, or X8 may be N;

R5 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R6 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R7 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R is hydrogen, halogen, or alkyl;

X2 is N or C-R , wherein R is hydrogen, halogen, alkyl, or alkoxy;

R13 is -Y-Z;

Y is selected from a bond, -CH2-, or -CH(Ci-C4 alkyl)-;

Z is selected from -S02R21, -N(R22)S02R21, -S02N(R22)2, -N(R22)S02N(R22)2, -CON(R22)2, -N(R22)C02R21, -N(R22)CON(R22)2, -N(R22)COR21, -OC(0)N(R22)2, -OS02N(R22)2, or -N(R22)S03R21;

X3 is N or C-R14, wherein R14 is hydrogen, halogen, -CN, alkyl, cycloalkyl, or alkoxy; or optionally when X4 is C-R15, R14 and R15 connect to form a ring;

X4 is N or C-R15, wherein R15 is hydrogen, halogen, -CN, alkyl, or alkoxy;

R16 is hydrogen, halogen, or -W-X, wherein W is a bond, -0-, -S-, or -NH-, and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; or optionally when X4 is C- R15, R16 and R15 connect to form a ring;

each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[00163] Another embodiment provides a compound of Formula (XVI), wherein X2 is N. Another embodiment provides a compound of Formula (XVI), wherein X3 is N. Another embodiment provides a compound of Formula (XVI), wherein X4 is N. Another

embodiment provides a compound of Formula (XVI), wherein X2 and X3 are N. Another embodiment provides a compound of Formula (XVI), wherein X2 is C-R12, X3 is C-R14, and

15

X4 is C-R

2

[00164] Another embodiment provides a compound of Formula (XVI), wherein R is

2

CH3. Another embodiment provides a compound of Formula (XVI), wherein R is CD3. Another embodiment provides a compound of Formula (XVI), wherein X5 is N. Another embodiment provides a compound of Formula (XVI), wherein X6 is N. Another

embodiment provides a compound of Formula (XVI), wherein X7 is N. Another

embodiment provides a compound of Formula (XVI), wherein X8 is N. Another

embodiment provides a compound of Formula (XVI), wherein none of X5, X6, X7, or X8 is

N. Another embodiment provides a compound of Formula (XVI), wherein R 5 andR 8 are hydrogen. Another embodiment provides a compound of Formula (XVI), wherein R5, R6, R7

and R are hydrogen. Another embodiment provides a compound of Formula (XVI), wherein R7 is a halogen. Another embodiment provides a compound of Formula (XVI), wherein R6 is a halogen. Another embodiment provides a compound of Formula (XVI), wherein R6 is a heteroaryl. Another embodiment provides a compound of Formula (XVI), wherein R6 is an aryl. Another embodiment provides a compound of Formula (XVI), wherein R6 is an alkyl. Another embodiment provides a compound of Formula (XVI), wherein R6 is an aryl.

[00165] Another embodiment provides a compound of Formula (XVI), wherein Y is a bond. Another embodiment provides a compound of Formula (XVI), wherein Y is a -CH2-.

21

Another embodiment provides a compound of Formula (XVI), wherein Z is -S02R .

Another embodiment provides a compound of Formula (XVI), wherein Z is -N(R 22 )S02R 21.

Another embodiment provides a compound of Formula (XVI), wherein Z is -S02N(R 22 )2. Another embodiment provides a compound of Formula (XVI), wherein Z is - 22 22

N(R )S02N(R )2. Another embodiment provides a compound of Formula (XVI), wherein Z

22

is -CON(R )2. Another embodiment provides a compound of Formula (XVI), wherein Z is - 22 21

N(R )C02R . Another embodiment provides a compound of Formula (XVI), wherein Z is - 22 22

N(R )CON(R )2. Another embodiment provides a compound of Formula (XVI), wherein

R 21 is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment provides a compound of

Formula (XVI), wherein R 21 is alkyl. Another embodiment provides a compound of Formula (XVI), wherein R14 is hydrogen, halogen, or alkyl. Another embodiment provides a compound of Formula (XVI), wherein X4 is C-R15. Another embodiment provides a compound of Formula (XVI), wherein W is -0-. Another embodiment provides a compound of Formula (XVI), wherein W is -NH-. Another embodiment provides a compound of Formula (XVI), wherein X is alkyl. Another embodiment provides a compound of Formula (XVI), wherein X is aryl. Another embodiment provides a compound of Formula (XVI), wherein X is cycloalkylalkyl. Another embodiment provides a compound of Formula (XVI), wherein W is -O- and X is alkyl. Another embodiment provides a compound of Formula (XVI), wherein W is -O- and X is aryl. Another embodiment provides a compound of Formula (XVI), wherein W is -O- and X is cycloalkylalkyl. Another embodiment provides a compound of Formula (XVI), wherein R 5 and R 8 are hydrogen. Another embodiment provides a compound of Formula (XVI), wherein R5 andR8 are hydrogen, and R6 is heteroaryl.

[00166] One embodiment provides a compound of Formula (XVII), or a

pharmaceutically acceptable salt thereof,

Formula (XVII)

wherein,

R2 is CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3;

X6 is C-H or N;

X5 is C-R5 or N; provided that if X6 is N, then X5 is C-R5, and if X5 is N, then X6 is CH; R5 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R6 is hydrogen, halogen, -OH,-CN, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl,

cycloalkylalkynyl, amino, alkylamino, dialkylamino, heterocyclyl, cycloalkylalkylamino, alkoxy, cycloalkyloxy, cycloalkylalkoxy, alkyl-S-, cycloalkyl-S-, and cycloalkylalkyl-S-;


X2 is N or C-R 12 , wherein R 12 is hydrogen, halogen, alkyl, or alkoxy;

R13 is -Y-Z;

Y is selected from a bond, -CH2-, or -CH(Ci-C4 alkyl)-;

Z is selected from -S02R21, -N(R22)S02R21, -S02N(R22)2, -N(R22)S02N(R22)2, -CON(R22)2, N(R22)C02R21, -N(R22)CON(R22)2, -N(R22)COR21, -OC(0)N(R22)2, -OS02N(R22)2, or -N(R22)S03R21;

X3 is S;

X4 is N or C-R14, wherein R14 is hydrogen, halogen, alkyl, or alkoxy;

R16 is hydrogen, halogen, or -W-X, wherein W is a bond, -0-, -S-, or -NH-, and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[00167] Another embodiment provides a compound of Formula (XVII), wherein RA is

R1


[00168] Another embodiment provides a compound of Formula (XVII), wherein RA is

R1


[00169] Another embodiment provides a compound of Formula (XVII), wherein RA is

R1


[00170] Another embodiment provides a compound of Formula (XVII), wherein RA is

R1


[00171] Another embodiment provides a compound of Formula (XVII), wherein RA is

R1


[00172] Another embodiment provides a compound of Formula (XVII), wherein RA is

R1


[00173] Another embodiment provides a compound of Formula (XVII), wherein R is CH3. Another embodiment provides a compound of Formula (XVII), wherein X6 is C-H. Another embodiment provides a compound of Formula (XVII), wherein X6 is N. Another embodiment provides a compound of Formula (XVII), wherein X5 is C-R5. Another embodiment provides a compound of Formula (XVII), wherein X5 is N. Another embodiment provides a compound of Formula (XVII), wherein R5 is hydrogen, halogen, or alkyl. Another embodiment provides a compound of Formula (XVII), wherein R6 is hydrogen, halogen, or alkyl. Another embodiment provides a compound of Formula (XVII), wherein R6 is heterocyclyl. Another embodiment provides a compound of Formula (XVII), wherein R6 is cycloalkylalkynyl. Another embodiment provides a compound of Formula (XVII), wherein R6 is alkoxy, cycloalkyloxy, or cycloalkylalkoxy.

[00174] Another embodiment provides a compound of Formula (XVII), wherein Y is a bond. Another embodiment provides a compound of Formula (XVII), wherein Y is a -CH2-.

21

Another embodiment provides a compound of Formula (XVII), wherein Z is -S02R .

22 21

Another embodiment provides a compound of Formula (XVII), wherein Z is -N(R )S02R .

22

Another embodiment provides a compound of Formula (XVII), wherein Z is -S02N(R )2. Another embodiment provides a compound of Formula (XVII), wherein Z is - 22 22

N(R )S02N(R )2. Another embodiment provides a compound of Formula (XVII), wherein Z

22

is -CON(R )2. Another embodiment provides a compound of Formula (XVII), wherein Z is - 22 21

N(R )C02R . Another embodiment provides a compound of Formula (XVII), wherein Z is - 22 22

N(R )CON(R )2. Another embodiment provides a compound of Formula (XVII), wherein

R 21 is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment provides a compound of

Formula (XVII), wherein R 21 is alkyl. Another embodiment provides a compound of Formula (XVII), wherein W is -0-. Another embodiment provides a compound of Formula (XVII), wherein W is -NH-. Another embodiment provides a compound of Formula (XVII), wherein X is alkyl. Another embodiment provides a compound of Formula (XVII), wherein X is alkynyl. Another embodiment provides a compound of Formula (XVII), wherein X is aryl. Another embodiment provides a compound of Formula (XVII), wherein X is cycloalkylalkyl. Another embodiment provides a compound of Formula (XVII), wherein X is

cycloalkylalkynyl. Another embodiment provides a compound of Formula (XVII), wherein W is -O- and X is alkyl. Another embodiment provides a compound of Formula (XVII), wherein W is -O- and X is alkynyl. Another embodiment provides a compound of Formula (XVII), wherein W is -O- and X is aryl. Another embodiment provides a compound of Formula (XVII), wherein W is -O- and X is cycloalkylalkyl. Another embodiment provides a compound of Formula (XVII), wherein W is -O- and X is cycloalkylalkynyl. Another embodiment provides a compound of Formula (XVII), wherein the R6 is CD3.

[00175] One embodiment provides a compound of Formula (XVIII), or a pharmaceutically acceptable salt thereof,


Formula (XVIII)

wherein,

R2 is CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3;

XI is C-H or N;

ring B is an optionally substituted 5- or 6-membered heterocyclic ring containing at least one oxygen or nitrogen atom;


X2 is N or C-R 12 , wherein R 12 is hydrogen, halogen, alkyl, or alkoxy;

R13 is -Y-Z;

Y is selected from a bond, -CH2-, or -CH(Ci-C4 alkyl)-;

Z is selected from -S02R21, -N(R22)S02R21, -S02N(R22)2, -N(R22)S02N(R22)2, -CON(R22)2, - N(R22)C02R21, -N(R22)CON(R22)2, -N(R22)COR21, -OC(0)N(R22)2, -OS02N(R22)2, or - N(R22)S03R21;

X3 is S;

X4 is N or C-R14, wherein R14 is hydrogen, halogen, alkyl, or alkoxy;

R16 is hydrogen, halogen, or -W-X, wherein W is a bond, -0-, -S-, or -NH-, and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[00176] One embodiment provides a compound of Formula (XIX), or a pharmaceutically acceptable salt thereof,


Formula (XIX)

wherein,

Q is N and T is C, or Q is C and T is N;

Ring B is an optionally substituted 5-membered aromatic nitrogen-containing heteroaryl ring containing one or more nitrogen atoms;

R2 is selected from CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3; XI is C-H or N;


X2 is N or C-R , wherein R is hydrogen, halogen, alkyl, or alkoxy;

R13 is -Y-Z;

Y is selected from a bond, -CH2-, or -CH(Ci-C4 alkyl)-;

Z is selected from -S02R21, -N(R22)S02R21, -S02N(R22)2, -N(R22)S02N(R22)2, -CON(R22)2, N(R22)C02R21, -N(R22)CON(R22)2, -N(R22)COR21, -OC(0)N(R22)2, -OS02N(R22)2, or - N(R22)S03R21;

X3 is S;

X4 is N or C-R , wherein R is hydrogen, halogen, alkyl, or alkoxy;

R16 is hydrogen, halogen, or -W-X, wherein W is a bond, -0-, -S-, or -NH-, and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[00177] Another embodiment provides a compound of Formula (XIX), wherein X2 is N.

Another embodiment provides a compound of Formula (XIX), wherein X4 is N. Another

12

embodiment provides a compound of Formula (XIX), wherein X2 is C-R . Another embodiment provides a compound of Formula (XIX), wherein X4 is C-R14.

[00178] Another embodiment provides a compound of Formula (XIX), wherein the compound of Formula (XIX) is selected from the group:

[00179] Another embodiment provides a compound of Formula (XIX), wherein Q is N and T is C. Another embodiment provides a compound of Formula (XIX), wherein Q is C and T is N. Another embodiment provides a compound of Formula (XIX), wherein R is CH3.

Another embodiment provides a compound of Formula (XIX), wherein XI is C-H. Another embodiment provides a compound of Formula (XIX), wherein XI is N.

[00180] Another embodiment provides a compound of Formula (XIX), wherein Y is a bond. Another embodiment provides a compound of Formula (XIX), wherein Y is a -CH2-.

21

Another embodiment provides a compound of Formula (XIX), wherein Z is -S02R . Another

22 21 embodiment provides a compound of Formula (XIX), wherein Z is -N(R )S02R . Another

22

embodiment provides a compound of Formula (XIX), wherein Z is -S02N(R )2. Another

22 22 embodiment provides a compound of Formula (XIX), wherein Z is -N(R )S02N(R )2.

22

Another embodiment provides a compound of Formula (XIX), wherein Z is -CON(R )2.

22 21

Another embodiment provides a compound of Formula (XIX), wherein Z is -N(R )C02R . Another embodiment provides a compound of Formula (XIX), wherein Z is - 22 22 21

N(R )CON(R )2. Another embodiment provides a compound of Formula (XIX), wherein R is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment provides a compound of

Formula (XIX), wherein R 21 is alkyl.

[00181] Another embodiment provides a compound of Formula (XIX), wherein W is -0-. Another embodiment provides a compound of Formula (XIX), wherein W is -NH-. Another embodiment provides a compound of Formula (XIX), wherein X is alkyl. Another embodiment provides a compound of Formula (XIX), wherein X is aryl. Another

embodiment provides a compound of Formula (XIX), wherein X is cycloalkylalkyl. Another embodiment provides a compound of Formula (XIX), wherein W is -O- and X is alkyl.

Another embodiment provides a compound of Formula (XIX), wherein W is -O- and X is aryl. Another embodiment provides a compound of Formula (XIX), wherein W is -O- and X is cycloalkylalkyl.

[00182] One embodiment provides a compound of Formula (XX), or a pharmaceutically acceptable salt thereof,


υ Formula (XX)

wherein,

Ring B is an optionally substituted 5-membered heteroaryl ring containing at least one oxygen or sulfur atom;

R2 is selected from CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3;

XI is C-H or N;


X2 is N or C-R 12 , wherein R 12 is hydrogen, halogen, alkyl, or alkoxy;

R13 is -Y-Z;

Y is selected from a bond, -CH2-, or -CH(Ci-C4 alkyl)-;

Z is selected from -S02R21, -N(R22)S02R21, -S02N(R22)2, -N(R22)S02N(R22)2, -CON(R22)2, N(R22)C02R21, -N(R22)CON(R22)2, -N(R22)COR21, -OC(0)N(R22)2, -OS02N(R22)2, or -N(R22)S03R21;

X3 is S;

X4 is N or C-R14, wherein R14 is hydrogen, halogen, alkyl, or alkoxy;

R16 is hydrogen, halogen, or -W-X, wherein W is a bond, -0-, -S-, or -NH-, and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[00183] Another embodiment provides a compound of Formula (XX), wherein X2 is N. Another embodiment provides a compound of Formula (XX), wherein X4 is N. Another

12

embodiment provides a compound of Formula (XX), wherein X2 is C-R . Another embodiment provides a compound of Formula (XX), wherein X4 is C-R14.

[00184] Another embodiment provides a compound of Formula (XX), wherein the compound of Formula (XX) has a formula selected from:


wherein each R 30 is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, -OH, -OR31, -NHR31, -N(R31)2, -CONHR31, -CON(R31)2; and R31 is C1-C4 alkyl.

[00185] Another embodiment provides a compound of Formula (XX), wherein the compound of Formula (XX) has a formula selected from:


wherein each RJU is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, -OH, -OR31, -NHR31, -N(R31)2, -CONHR31, -CON(R31)2; and R31 is C1-C4 alkyl.

[00186] Another embodiment provides a compound of Formula (XX), wherein the compound of Formula (XX) has a formula selected from:


30

wherein each R is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, -OH,

-OR31, -NHR31, -N(R31)2, -CONHR31, -CON(R31)2; and R31 is C1-C4 alkyl.

[00187] Another embodiment provides a compound of Formula (XX), wherein R is

CH3. Another embodiment provides a compound of Formula (XX), wherein XI is C-H.

Another embodiment provides a compound of Formula (XX), wherein XI is N.

[00188] Another embodiment provides a compound of Formula (XX), wherein Y is a bond. Another embodiment provides a compound of Formula (XX), wherein Y is a -CH2-.

21

Another embodiment provides a compound of Formula (XX), wherein Z is -S02R .

22 21

Another embodiment provides a compound of Formula (XX), wherein Z is -N(R )S02R .

22

Another embodiment provides a compound of Formula (XX), wherein Z is -S02N(R )2. Another embodiment provides a compound of Formula (XX), wherein Z is - 22 22

N(R )S02N(R )2. Another embodiment provides a compound of Formula (XX), wherein Z

22

is -CON(R )2. Another embodiment provides a compound of Formula (XX), wherein Z is - 22 21

N(R )C02R . Another embodiment provides a compound of Formula (XX), wherein Z is - 22 22

N(R )CON(R )2. Another embodiment provides a compound of Formula (XX), wherein

21

R is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment provides a compound of

21

Formula (XV), wherein R is alkyl.

[00189] Another embodiment provides a compound of Formula (XX), wherein W is -0-. Another embodiment provides a compound of Formula (XX), wherein W is -NH-. Another embodiment provides a compound of Formula (XX), wherein X is alkyl. Another embodiment provides a compound of Formula (XX), wherein X is alkynyl. Another embodiment provides a compound of Formula (XX), wherein X is aryl. Another

embodiment provides a compound of Formula (XX), wherein X is cycloalkylalkyl. Another embodiment provides a compound of Formula (XX), wherein X is cycloalkylalkynyl.

Another embodiment provides a compound of Formula (XX), wherein W is -O- and X is alkyl. Another embodiment provides a compound of Formula (XX), wherein W is -O- and X is aryl. Another embodiment provides a compound of Formula (XX), wherein W is -O- and X is alkynyl. Another embodiment provides a compound of Formula (XX), wherein W is -O- and X is cycloalkylalkyl. Another embodiment provides a compound of Formula (XX), wherein W is -O- and X is cycloalkylalkynyl.

[00190] One embodiment provides a compound of Formula (XXI), or a pharmaceutically acceptable salt thereof,


Formula (XXI)

wherein,

R2 is CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3;

XI is C-H or N;

ring B is an optionally substituted 5- or 6-membered heterocyclic ring containing at least one ox en or nitrogen atom;


R is hydrogen or C1-C4 alkyl;

R13 is -Y-Z;

Y is selected from -CH2-, or -CH(d-C4 alkyl)-;

Z is selected from -S02R21, -S02N(R22)2, or -CON(R22)2;

R15 is hydrogen, halogen or C1-C4 alkyl;

R16 is hydrogen, halogen, or -W-X, wherein W is a bond, -0-, -S-, or -NH-, and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; or optionally, R and R connect to form a ring;

each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[00191] One embodiment provides a compound of Formula (XXII), or a pharmaceutically acceptable salt thereof,


υ Formula (XXII)

wherein,

Q is N and T is C, or Q is C and T is N;

Ring B is an optionally substituted 5-membered aromatic nitrogen-containing heteroaryl ring containing one or more nitrogen atoms;

R2 is selected from CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3;

XI is C-H or N;


R 12 is hydrogen or C1-C4 alkyl;

R13 is -Y-Z;

Y is selected from -CH2-, or -CH(d-C4 alkyl)-;

Z is selected from -S02R21, -S02N(R22)2, or -CON(R22)2;

R15 is hydrogen, halogen or C1-C4 alkyl;

R16 is hydrogen, halogen, or -W-X, wherein W is a bond, -0-, -S-, or -NH-, and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; or optionally, R16 and R15 connect to form a ring;

eeaacchh RR 2 211 iiss iinnddeeppeennddeenntly selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

each R is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[00192] Another embodiment provides a compound of Formula (XXII), wherein the compound of Formula (XXII) is selected from the group:


[00193] Another embodiment provides a compound of Formula (XXII), wherein Q is N and T is C. Another embodiment provides a compound of Formula (XXII), wherein Q is C and T is N. Another embodiment provides a compound of Formula (XXII), wherein R is CH3.

Another embodiment provides a compound of Formula (XXII), wherein XI is C-H. Another embodiment provides a compound of Formula (XXII), wherein XI is N.

[00194] Another embodiment provides a compound of Formula (XXII), wherein Y is a -CH2- 21

. Another embodiment provides a compound of Formula (XXII), wherein Z is -S02R .

Another embodiment provides a compound of Formula (XXII), wherein Z is -S02N(R 22 )2.

Another embodiment provides a compound of Formula (XXII), wherein Z is -CON(R 22 )2.

Another embodiment provides a compound of Formula (XXII), wherein R 21 is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment provides a compound of Formula (XXII), wherein R21 is alkyl.

[00195] Another embodiment provides a compound of Formula (XXII), wherein W is -0-. Another embodiment provides a compound of Formula (XXII), wherein W is -NH-. Another embodiment provides a compound of Formula (XXII), wherein X is alkyl. Another embodiment provides a compound of Formula (XXII), wherein X is aryl. Another

embodiment provides a compound of Formula (XXII), wherein X is cycloalkylalkyl. Another embodiment provides a compound of Formula (XXII), wherein W is -O- and X is alkyl. Another embodiment provides a compound of Formula (XXII), wherein W is -O- and X is aryl. Another embodiment provides a compound of Formula (XXII), wherein W is -O- and X is cycloalkylalkyl.

[00196] One embodiment provides a compound of Formula (XXIII), or a pharmaceutically acceptable salt thereof,


Formula (XXIII)

wherein,

Ring B is an optionally substituted 5-membered heteroaryl ring containing at least one oxygen or sulfur atom;

R2 is selected from CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3; XI is C-H or N;


R is hydrogen or C1-C4 alkyl;

R13 is -Y-Z;

Y is selected from -CH2-, or -CH(Ci-C4 alkyl)-;

Z is selected from -S02R21, -S02N(R22)2, or -CON(R22)2;

R15 is hydrogen, halogen or C1-C4 alkyl;

R16 is hydrogen, halogen, or -W-X, wherein W is a bond, -0-, -S-, or -NH-, and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; or optionally, R16 and R15 connect to form a ring;

each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[00197] Another embodiment provides a compound of Formula (XXIII), wherein the compound of Formula (XXIII) has a formula selected from:


30

wherein each R is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, -OH, -OR31, -NHR31, -N(R31)2, -CONHR31, -CON(R31)2; and R31 is C1-C4 alkyl.

[00198] Another embodiment provides a compound of Formula (XXIII), wherein the compound of Formula (XXIII) has a formula selected from:


wherein each RJU is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, -OH, -OR31, -NHR31, -N(R31)2, -CONHR31, -CON(R31)2; and R31 is C1-C4 alkyl.

[00199] Another embodiment provides a compound of Formula (XXIII), wherein the compound of Formula (XXIII) has a formula selected from:


30

wherein each R is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, -OH,

-OR31, -NHR31, -N(R31)2, -CONHR31, -CON(R31)2; and R31 is C1-C4 alkyl.

[00200] Another embodiment provides a compound of Formula (XXIII), wherein R is

CH3. Another embodiment provides a compound of Formula (XXIII), wherein XI is C-H.

Another embodiment provides a compound of Formula (XXIII), wherein XI is N.

[00201] Another embodiment provides a compound of Formula (XXIII), wherein Y is a -CH2-. Another embodiment provides a compound of Formula (XXIII), wherein Z is - S0 21

2R . Another embodiment provides a compound of Formula (XXIII), wherein Z is - S0 22

2N(R )2. Another embodiment provides a compound of Formula (XXIII), wherein Z is - 22 21

CON(R )2. Another embodiment provides a compound of Formula (XXIII), wherein R is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment provides a compound of Formula (XXIII), wherein R21 is alkyl.

[00202] Another embodiment provides a compound of Formula (XXIII), wherein W is -0-. Another embodiment provides a compound of Formula (XXIII), wherein W is -NH-.

Another embodiment provides a compound of Formula (XXIII), wherein X is alkyl. Another embodiment provides a compound of Formula (XXIII), wherein X is alkynyl. Another embodiment provides a compound of Formula (XXIII), wherein X is aryl. Another embodiment provides a compound of Formula (XXIII), wherein X is cycloalkylalkyl.

Another embodiment provides a compound of Formula (XXIII), wherein X is

cycloalkylalkynyl. Another embodiment provides a compound of Formula (XXIII), wherein W is -O- and X is alkyl. Another embodiment provides a compound of Formula (XXIII), wherein W is -O- and X is aryl. Another embodiment provides a compound of Formula (XXIII), wherein W is -O- and X is alkynyl. Another embodiment provides a compound of Formula (XXIII), wherein W is -O- and X is cycloalkylalkyl. Another embodiment provides a compound of Formula (XXIII), wherein W is -O- and X is cycloalkylalkynyl.

[00203] One embodiment provides a compound of Formula (XXIV), or a

pharmaceutically acceptable salt thereof,


Formula (XXIV)

wherein,

R is -Y-Z;

Y is selected from a bond, or -CH2-;

Z is selected from -S02R21, -N(R22)S02R21, -S02N(R22)2, -N(R22)S02N(R22)2, -CON(R22)2, -N(R22)C02R21, -N(R22)CON(R22)2, -N(R22)COR21, -COR21, -OC(0)N(R22)2, -OS02N(R22)2, -N(R22)S03R21, or -N(R22)2;

R14 is hydrogen, halogen, Ci-C3 alkyl, or Ci-C3 alkoxy;

R15 is halogen or U-V, wherein U is a bond, -0-, or -CH2-; and V is -CN, alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R16 is hydrogen;

each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

wherein

R2 is CH3;

X5 is C-H;

X6 is C-R6;

X7 is C-R7;

X8 is C-H;

R6 is hydrogen, or halogen;

7 is hydrogen, or halogen; or


wherein

R2 is CH3;

X6 is C-H;

X5 is C-R5;

R5 is hydrogen, or halogen;

6 is hydrogen, alkyl, alkoxy, or halogen; or


wherein

Ring B is an optionally substituted 5-membered heteroaryl ring containing at least one oxygen or sulfur atom;

R2 is CH3; and

XI is C-H.

[00204] Another embodiment provides a compound of Formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein Y is -C¾-. Another embodiment provides a compound of Formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein Y is a bond.

[00205] Another embodiment provides a compound of Formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein Z is -S02R21, -N(R22)S02R21, or -N(R22)2. Another embodiment provides a compound of Formula (XXIV), or a pharmaceutically

21 22 21

acceptable salt thereof, wherein Z is -S02R or -N(R )S02R . Another embodiment provides a compound of Formula (XXIV), or a pharmaceutically acceptable salt thereof,

22 )S0 21

wherein Z is -N(R 2R . Another embodiment provides a compound of Formula

21

(XXIV), or a pharmaceutically acceptable salt thereof, wherein Z is -S02R .

[00206] Another embodiment provides a compound of Formula (XXIV), or a

21

pharmaceutically acceptable salt thereof, wherein R is heterocyclyl or heterocyclylalkyl. Another embodiment provides a compound of Formula (XXIV), or a pharmaceutically

21

acceptable salt thereof, wherein R is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment provides a compound of Formula (XXIV), or a pharmaceutically acceptable

21

salt thereof, wherein R is alkyl, and the alkyl is a C1-C4 alkyl.

[00207] Another embodiment provides a compound of Formula (XXIV), or a

22

pharmaceutically acceptable salt thereof, wherein R is alkyl, cycloalkyl, or aralkyl.

Another embodiment provides a compound of Formula (XXIV), or a pharmaceutically

22

acceptable salt thereof, wherein R is hydrogen or methyl.

[00208] Another embodiment provides a compound of Formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein R14 is hydrogen.

[00209] Another embodiment provides a compound of Formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein U is a bond. Another embodiment provides a compound of Formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein U is -0-.

[00210] Another embodiment provides a compound of Formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein U is -CH2-.

[00211] Another embodiment provides a compound of Formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein V is alkyl. Another embodiment provides a compound of Formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein V is aryl. Another embodiment provides a compound of Formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein V is aralkyl. Another embodiment provides a compound of Formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein V is

cycloalkylalkyl. Another embodiment provides a compound of Formula (XXIV), or a

pharmaceutically acceptable salt thereof, wherein V is heterocyclylalkyl. Another embodiment provides a compound of Formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein V is heteroaryl. Another embodiment provides a compound of Formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein V is heteroarylalkyl. Another embodiment provides a compound of Formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein V is alkynyl.

[00212] Another embodiment provides a compound of Formula (XXIV), or a

22 21 pharmaceutically acceptable salt thereof, wherein Y is a bond, Z is -N(R )S02R , U is -0-, and V is aryl, aralkyl or cycloalkylalkyl. Another embodiment provides a compound of Formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein Y is a bond, Z is - 21

S02R , U is -0-, and V is aryl, aralkyl or cycloalkylalkyl.

[00213] Another embodiment provides a compound of Formula (XXIV), or a


pharmaceutically acceptable salt thereof, wherein R° is O

[00214] Another embodiment provides a compound of Formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein R6 is halogen, and R7 is hydrogen.

Another embodiment provides a compound of Formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein R6 is hydrogen, and R7 is halogen. Another embodiment provides a compound of Formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein R6 is hydrogen, and R7 is hydrogen.

[00215] Another embodiment provides a compound of Formula XXIV), or a


pharmaceutically acceptable salt thereof, wherein R° is O . Another embodiment provides a compound of Formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen, and R6 is alkyl. Another embodiment provides a compound of Formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein R6 is methyl.

[00216] Another embodiment provides a compoun or a


pharmaceutically acceptable salt thereof, wherein R is O . Another embodiment provides a compound of Formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein Ring B is an optionally substituted 5-membered heteroaryl ring containing one oxygen.

[00217] One embodiment provides a compound of Formula (XXV), or a

pharmaceutically acceptable salt thereof,


O Formula (XXV)

wherein,

Ring B is an optionally substituted 5-, 6-, or 7-membered, non-aromatic carbocyclyl ring; R2 is selected from CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3;

X3 is C-H or N;


X2 is N or C-R , wherein R is hydrogen, halogen, alkyl, or alkoxy;

R13 is -Y-Z;

Y is selected from a bond, or -CH2-;

Z is selected from -S02R21, -N(R22)S02R21, -S02N(R22)2, -N(R22)S02N(R22)2, -CON(R22)2, -N(R22)C02R21, -N(R22)CON(R22)2, -N(R22)COR21, -OC(0)N(R22)2, -OS02N(R22)2, or -N(R22)S03R21;

X3 is N or C-R14, wherein R14 is hydrogen, halogen, -CN, alkyl, cycloalkyl, or alkoxy;

X4 is N or C-R15, wherein R15 is hydrogen, halogen, -CN, alkyl, or alkoxy;

R16 is hydrogen, halogen, or -W-X, wherein W is a bond, -0-, -S-, or -NH-, and X is selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,

heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[00218] Another embodiment provides a compound of Formula (XXV), or a pharmaceutically acceptable salt thereof, wherein Ring B is an optionally substituted 5-membered, non-aromatic carbocyclyl ring. Another embodiment provides a compound of Formula (XXV), or a pharmaceutically acceptable salt thereof, wherein Ring B is an optionally substituted 6-membered, non-aromatic carbocyclyl ring. Another embodiment provides a compound of Formula (XXV), or a pharmaceutically acceptable salt thereof, wherein Ring B is an optionally substituted 7-membered, non-aromatic carbocyclyl ring.

[00219] Another embodiment provides a compound of Formula (XXV), or a pharmaceutically acceptable salt thereof, wherein R is CH3.

[00220] Another embodiment provides a compound of Formula (XXV), or a pharmaceutically acceptable salt thereof, wherein X3 is C-H. Another embodiment provides a compound of Formula (XXV), or a pharmaceutically acceptable salt thereof, wherein X3 is N.

[00221] Another embodiment provides a compound of Formula (XXV), or a pharmaceutically acceptable salt thereof, wherein Y is a bond. Another embodiment provides a compound of Formula (XXV), or a pharmaceutically acceptable salt thereof, wherein Y is a -CH2-.

[00222] Another embodiment provides a compound of Formula (XXV), or a

21

pharmaceutically acceptable salt thereof, wherein Z is -S02R . Another embodiment provides a compound of Formula (XXV), or a pharmaceutically acceptable salt thereof, wherein Z is -N(R22)S02R21.

[00223] Another embodiment provides a compound of Formula (XXV), or a pharmaceutically acceptable salt thereof, wherein Z is -S02N(R 22 )2. Another embodiment provides a compound of Formula (XXV), or a pharmaceutically acceptable salt thereof,

22 22

wherein Z is -N(R )S02N(R )2. Another embodiment provides a compound of Formula

(XXV), or a pharmaceutically acceptable salt thereof, wherein Z is -CON(R 22 )2. Another embodiment provides a compound of Formula (XXV), or a pharmaceutically acceptable salt

22 21

thereof, wherein Z is -N(R )C02R . Another embodiment provides a compound of Formula (XXV), or a pharmaceutically acceptable salt thereof, wherein Z is -N(R22)CON(R22)2.

[00224] Another embodiment provides a compound of Formula (XXV), or a pharmaceutically acceptable salt thereof, wherein R 21 is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment provides a compound of Formula (XXV), or a pharmaceutically

21

acceptable salt thereof, wherein R is alkyl.

[00225] Another embodiment provides a compound of Formula (XXV), or a pharmaceutically acceptable salt thereof, wherein R14 is hydrogen, halogen, or alkyl.

Another embodiment provides a compound of Formula (XXV), or a pharmaceutically acceptable salt thereof, wherein X4 is C-R15. Another embodiment provides a compound of Formula (XXV), or a pharmaceutically acceptable salt thereof, wherein W is -0-. Another embodiment provides a compound of Formula (XXV), or a pharmaceutically acceptable salt thereof, wherein W is -NH-.

[00226] Another embodiment provides a compound of Formula (XXV), or a pharmaceutically acceptable salt thereof, wherein X is alkyl. Another embodiment provides a compound of Formula (XXV), or a pharmaceutically acceptable salt thereof, wherein X is aryl. Another embodiment provides a compound of Formula (XXV), or a pharmaceutically acceptable salt thereof, wherein X is cycloalkylalkyl.

[00227] Another embodiment provides a compound of Formula (XXV), or a pharmaceutically acceptable salt thereof, wherein W is -O- and X is alkyl. Another embodiment provides a compound of Formula (XXV), or a pharmaceutically acceptable salt thereof, wherein W is -O- and X is aryl. Another embodiment provides a compound of Formula (XXV), or a pharmaceutically acceptable salt thereof, wherein W is -O- and X is cycloalkylalkyl.

[00228] In some embodiments, the substituted heterocyclic derivative compound disclosed herein has the structure provided in Table 1.

TABLE 1















































































[00229] In some embodiments, the substituted heterocyclic derivative compound disclosed herein has the structure provided in Table 2.

TABLE 2













180

181

ı82





0

0 0


190

191

ı93

ı94


ı97

Preparation of the Substituted Heterocyclic Derivative Compounds

[00230] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd.

(Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG

(Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[00231] Methods known to one of ordinary skill in the art are identified through various reference books and databases. Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al, "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry:

Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992.

Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis:

Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1 ; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[00232] Specific and analogous reactants may also be identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (the American Chemical Society, Washington, D.C., may be contacted for more details). Chemicals that are known but not commercially available in catalogs may be prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of

pharmaceutical salts of the substituted heterocyclic derivative compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[00233] General methods for the synthesis of substituted heterocyclic derivatives are provided in, but not limited to, the following references: WO 2009/158396; WO 2005/63768; WO 2006/1 12666; Briet et. al, Tetrahedron (2002), 58(29), 5761-5766; WO 2008/77550; WO 2008/77551; WO 2008/77556; WO 2007/12421; WO 2007/12422; US 2007/99911; WO 2008/77550; Havera et al, J. Med. Chem. (1999), 42, 3860-3873; WO 2004/29051; and US 2009/0054434. Additional examples of the synthesis of substituted heterocyclic derivatives are found in the following references: WO 2012/171337; WO 201 1/044157; WO 2009/097567;

WO 2005/030791; EP 203216; Becknell et al, Bioorganic & Medicinal Chemistry Letters (2011), 21(23), 7076-7080; Svechkarev et al, Visnik Kharkivs'kogo Natsional'nogo Universitetu im. V. N. Karazina (2007), 770, 201-207; Coskun et al, Synthetic Communications (2005), 35(18), 2435-2443; Alvarez et al, Science of Synthesis (2005), 15, 839-906; Kihara et al, Heterocycles (2000), 53(2), 359-372; Couture et al, Journal of the Chemical Society, Perkin Transactions 1 : Organic and Bio-Organic Chemistry (1999), (7), 789-794; Kihara et al., Heterocycles (1998), 48(12), 2473-2476; Couture et al, Tetrahedron (1996), 52(12), 4433-48; Couturre et al, Tetrahedron Letters (1996), 37(21), 3697-3700; Natsugari et al, Journal of Medicinal Chemistry (1995), 38(16), 3106-20; Moehrle et al, Archiv der Pharmazie

(Weinheim, Germany) (1988), 321(10), 759-64; Gore et al, Journal of the Chemical Society, Perkin Transactions 1 : Organic and Bio-Organic Chemistry (1972-1999) (1988), (3), 481-3; Narasimhan et al, Journal of the Chemical Society, Chemical Communications (1987), (3), 191-2; Henry et al., Journal of Organic Chemistry (1975), 40(12), 1760-6; Berti, Gazzetta Chimica Italiana (1960), 90, 559-72; Berti et al, Annali di Chimica (Rome, Italy) (1959), 49, 2110-23; Berti et al, Annali di Chimica (Rome, Italy) (1959), 49, 1253-68; WO 2012/000595; Couture et al, Tetrahedron (1996), 52(12), 4433-48; WO 2010/069504; WO 2010/069504; WO

2006/030032; WO 2005/095384; US 2005/0222159; WO 2013/064984; Mishra et al, European Journal of Organic Chemistry (2013), 2013(4), 693-700; Vachhani et al, Tetrahedron (2013), 69(1), 359-365; Xie et al, European Journal of Medicinal Chemistry (2010), 45(1), 210-218; Mukaiyama et al, Bioorganic & Medicinal Chemistry (2007), 15(2), 868-885; JP 2005/089352; Wang et al, Molecules (2004), 9(7), 574-582; WO 2000/023487; US 2006/0287341; CN 103183675 ; Hares et al, Egyptian Journal of Pharmaceutical Sciences (1991), 32(1-2), 303-14; DE 2356005 ; DE 2133898 ; DE 2133998; US 3816422; DE 2011970; and Staehle et al, Justus Liebigs Annalen der Chemie (1973), (8), 1275-81.

[00234] In some embodiments, the substituted heterocyclic derivative compounds disclosed herein are prepared by the general synthetic routes described below in Schemes 1-6. These schemes are intended to exemplary to one of skill in the art and are not limiting. Additional methods for the synthesis of the substituted heterocyclic derivative compounds disclosed herein are readily available to one of skill in the art.

Scheme 1


1 -6

[00235] A method for preparing compounds of Formula (I) is provided in Scheme 1. 6- Bromo-2-methylisoquinolin-l(2H)-one (1-1) is subjected to a palladium-catalyzed cross coupling reaction to provide isoquinolinone 1-2. Bromination under acidic conditions provides compound 1-3. Further palladium-catalyzed cross coupling reaction with a boronic acid, or ester, provides the isoquinolinone 1-4. Alternatively, palladium-catalyzed cross coupling of compound 1-3 with 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane under the conditions described by Miyaura (Ishiyama et al, J. Org. Chem. 1995, 60, 7508-7510) provides the boron ester 1-5. Further palladium-catalyzed cross coupling reaction of compound 1-5 with a suitable halide provides the isoquinolinone 1-6.

Scheme 2


2-4 2-5

[00236] A method for preparing compounds of Formula (I) is provided in Scheme 2. 6- Bromo-2-methylisoquinolin-l(2H)-one (2-1) is subjected to a palladium-catalyzed cross coupling reaction with 4,4,5, 5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2- dioxaborolane to provide boron ester 2-2. Further palladium-catalyzed cross coupling reaction of compound 2-2 with a suitable halide provides compound 2-3. Bromination under acidic conditions provides compound 2-4. Further palladium-catalyzed cross coupling reaction with a boronic acid, or ester, provides the isoquinolinone 2-5.

Scheme 3


3-1 3-2 3-3

[00237] A method for preparing compounds of Formula (II) is provided in Scheme 3. 5- Bromopyridin-2-ol derivative (3-1) is subjected to alkylation with methyl iodide under basic conditions to provide the related 5-bromo-l-methylpyridin-2(lH)-one derivative (3-2).

Further palladium-catalyzed cross coupling reaction of compound 3-2 with a suitable halide provides compound 3-3.

Scheme 4


4-5 4-6

[00238] A method for preparing compounds of Formula (II) is provided in Scheme 4. 3- Amino-5-bromo-l-methylpyridin-2(lH)-one derivative 4-1 is used as a starting material for several routes. In one route, compound 4-1 is directly subjected to a palladium-catalyzed cross coupling reaction to provide pyridone 4-3. The amino group of compound 4-3 is

subjected to a reductive animation with an aldehyde and a reducing agent, such as sodium cyanoborohydride, to provide the substituted amino derivative compound 4-7. A second route involving selective alkylation of the amino group of compound 4-1 begins with protection of the amino group as the BOC carbamate. Alkylation of the carbamate under basic conditions followed by removal of the BOC carbamate under acidic conditions provides the secondary amine compound 4-5. Treatment of 4-5 with a suitable halide under palladium-catalyzed cross coupling conditions affords compound 4-6.

Scheme 5


5-1 5-2 5-3

[00239] A method for preparing compounds of Formula (IV) is provided in Scheme 5. 5- Bromo-l-methylpyrazin-2(lH)-one (5-1) is subjected to an imidazole annulation reaction by treatment with tosylmethisocyanide (TosMIC) under basic conditions (Hoogenboom et al., Organic Syntheses, Coll. Vol. 6, p. 987 (1988)) to provide 5-bromo-7-methylimidazo[l,5- a]pyrazin-8(7H)-one (5-2). Palladium-catalyzed cross coupling reaction of compound 5-2 with a suitable halide provides the compound 5-3.

Scheme 6


6-4 6-5

[00240] A method for preparing compounds of Formula (III) is provided in Scheme 6. 2,6- Naphthyridin-l-ol (6-1) is subjected to alkylation with methyl iodide under basic conditions to provide 2-methyl-2,6-naphthyridin-l(2H)-one (6-2). Chlorination of 6-2 with N- chlorosuccinimide provides chloro compound 6-3. Treatment of 6-3 under palladium- catalyzed cross coupling conditions with a suitable halide provides compound 6-4. Selective reduction of the 2,6-naphthyridinone derivative provides the 5,6,7,8-tetrahydro-2,6-naphthyridin-l(2H)-one derivative 6-5.

[00241] In each of the above reaction procedures or schemes, the various substituents may be selected from among the various substituents otherwise taught herein.

Pharmaceutical Compositions

[00242] In certain embodiments, the substituted heterocyclic derivative compound as described herein is administered as a pure chemical. In other embodiments, the substituted heterocyclic derivative compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[00243] Accordingly, provided herein is a pharmaceutical composition comprising at least one substituted heterocyclic derivative compound, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof, together with one or more

pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject) of the composition.

[00244] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), (la), or (lb), or a pharmaceutically acceptable salt thereof, and a

pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (II), (Ila), or (lib), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (III), or (Ilia), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (V), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (Via), (VIb), (Vic), (VId), or (Vie), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (VII), or (Vila), or a

pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (VIII), or (Villa), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (IX), or a pharmaceutically acceptable salt thereof, and a

pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (XII), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (XIII), or a

pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (XIV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (XV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (XVI), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (XVII), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (XVIII), or a

pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (XIX), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (XX), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (XXI), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (XXII), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (XXIII), or a

pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (XXIV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (XXV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[00245] In certain embodiments, the substituted heterocyclic derivative compound as described herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as contaminating intermediates or by-products that are created, for example, in one or more of the steps of a synthesis method.

[00246] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. Suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g.,

Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[00247] The dose of the composition comprising at least one substituted heterocyclic derivative compound as described herein may differ, depending upon the patient's (e.g., human) condition, that is, stage of the disease, general health status, age, and other factors that a person skilled in the medical art will use to determine dose.

[00248] Pharmaceutical compositions may be administered in a manner appropriate to the disease to be treated (or prevented) as determined by persons skilled in the medical arts. An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses may generally be determined using experimental models and/or clinical trials. The optimal dose may depend upon the body mass, weight, or blood volume of the patient.

[00249] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.

Bromodomain Inhibition

[00250] Chromatin is the complex of DNA and protein that makes up chromosomes.

Histones are the major protein component of chromatin, acting as spools around which DNA winds. Changes in chromatin structure are affected by covalent modifications of histone proteins and by non-histone binding proteins. Several classes of enzymes are known which modify histones at various sites.

[00251] Epigenetics is the study of heritable changes in gene expression caused by

mechanisms other than the underlying DNA sequence. Molecular mechanisms that play a role in epigenetic regulation include DNA methylation and chromatin/histone modifications.

[00252] The genomes of eukaryotic organisms are highly organized within the nucleus of the cell. Tremendous compaction is required to package the 3 billion nucleotides of the human genome into the nucleus of a cell.

[00253] Histones are the chief protein components of chromatin. There are a total of six classes of histones (HI, H2A, H2B, H3, H4, and H5) organized into two classes: core histones (H2A, H2B, H3, and H4) and linker histones (HI and H5). The basic unit of chromatin is the nucleosome, which consists of about 147 base pairs of DNA wrapped around the core histone octamer, consisting of two copies each of the core histones H2A, H2B, H3, and H4.

[00254] Basic nucleosome units are then further organized and condensed by the aggregation and folding of nucleosomes to form a highly condensed chromatin structure. A range of different states of condensation are possible, and the tightness of chromatin structure varies during the cell cycle, being most compact during the process of cell division.

[00255] Chromatin structure plays a critical role in regulating gene transcription, which cannot occur efficiently from highly condensed chromatin. The chromatin structure is controlled by a series of post translational modifications to histone proteins, notably histones H3 and H4, and most commonly within the histone tails which extend beyond the core nucleosome structure. These modifications include acetylation, methylation, phosphorylation, ribosylation sumoylation, ubiquitination, citrullination, deimination, and biotinylation. The core of histones H2A and H3 can also be modified. Histone modifications are integral to diverse biological processes such as gene regulation, DNA repair, and chromosome condensation.

Histone Acetylation and Bromodomains

[00256] Histone acetylation is generally associated with the activation of gene transcription, as the modification is known to loosen the interaction of the DNA and the histone octamer by changing the electrostatics. In addition to this physical change, specific proteins are known to bind to acetylated lysine residues within histones in order to read the epigenetic code.

Bromodomains are small (~110 amino acid) distinct domains within proteins that are known to bind to acetylated lysine residues commonly, but not exclusively, in the context of histones. Around 50 proteins are known to contain bromodomains, and they have a range of functions within the cell.

[00257] The BET family of bromodomain containing proteins comprises 4 proteins (BRD2, BRD3, BRD4 and BRD-t) which contain tandem bromodomains capable of binding to two acetylated lysine resides in close proximity, increasing the specificity of the interaction.

[00258] Bromodomain-containing proteins that recognize acetylated lysines on histones (such as BET proteins and non-BET proteins) have been implicated in proliferative disease. BRD4 knockout mice die shortly after implantation and are compromised in their ability to maintain an inner cell mass, and heterozygotes display pre- and postnatal growth defects associated with reduced proliferation rates. BRD4 regulates genes expressed during M/Gl, including growth-associated genes, and remains bound to chromatin throughout the cell cycle (Dey, et al. (2009) Mol. Biol. Cell 20:4899-4909). BRD4 also physically associates with Mediator and P-TEFb (CDK9/cyclin Tl) to facilitate transcriptional elongation (Yang, et al. (2005) Oncogene 24: 1653-1662; Yang, et al. (2005) Mol. Cell 19:535-545). CDK9 is a validated target in chronic lymphocytic leukemia (CLL), and is linked to c-Myc-dependent

transcription (Phelps, et al. Blood 113:2637-2645; Rahl, et al. (2010) Cell 141 :432-445).

[00259] BRD4 is translocated to the NUT protein in patients with lethal midline carcinoma, an aggressive form of human squamous carcinoma (French, et al. (2001) Am. J. Pathol. 159: 1987-1992; French, et al. (2003) Cancer Res. 63:304-307). In vitro analysis with RNAi supports a causal role for BRD4 in this recurrent t(15;19) chromosomal translocation. Also, inhibition of the BRD4 bromodomains has been found to result in growth

arrest/differentiation of BRD4-NUT cell lines in vitro and in vivo (Filippakopoulos, et al. "Selective Inhibition of BET Bromodomains," Nature (published online September 24, 2010)).

[00260] Bromodomain-containing proteins (such as BET proteins) have also been implicated in inflammatory diseases. BET proteins (e.g., BRD2, BRD3, BRD4, and BRDT) regulate assembly of histone acetylation-dependent chromatin complexes that control inflammatory gene expression (Hargreaves, et al. (2009) Cell 138: 129-145; LeRoy, et al. (2008) Mol. Cell 30:51-60; Jang, et al. (2005) Mol. Cell 19:523-534; Yang, et al. (2005) Mol. Cell 19:535-545). Key inflammatory genes (secondary response genes) are down-regulated upon bromodomain inhibition of the BET subfamily, and non-responsive genes (primary response genes) are poised for transcription. BET bromodomain inhibition protects against LPS-induced endotoxic shock and bacteria-induced sepsis in vivo (Nicodeme, et al. "Suppression of Inflammation by a Synthetic Histone Mimic," Nature (published online November 10, 2010)).

[00261] Bromodomain-containing proteins (such as BET proteins) have also been found to play a role in viral infection. For example, BRD4 is implicated in the primary phase of human papilloma virus (HPV) infection, in which the viral genome is maintained in an extra-chromosomal episome in basal epithelia. In some strains of HPV, BRD4 binding to the HPV E2 protein functions to tether the viral genome to chromosomes. E2 is critical for both the repression of E6/E7 and the activation of HPV viral genes. Disruption of BRD4 or the BRD4-E2 interaction blocks E2-dependent gene activation. BRD4 also functions to tether other classes of viral genomes to host chromatin (e.g., Herpes virus, Epstein-Barr virus).

[00262] Bromodomain-containing proteins has also been found to bind to acetylated lysine residues on proteins other than histones. For example, the bromodomain of CREB binding protein transcriptional coactivator (CBP) allows for recognition of p53 with acetylated Lys382. The interaction between the bromodomain and acetyl-p53 follows DNA damage and promotes p53-induced transcriptional activation of the CDK inhibitor p21 and cell cycle arrest.

[00263] Another novel bromodomain-containing protein is BAZ2B, whose biological function, is believed to function similarly to ACF1, the Drosophila BAZ2B ortholog. ACF complexes play roles in establishing regular nucleosome spacing during chromatin assembly and influencing different remodeling outcomes at target loci.

[00264] One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (I), (la), or (lb). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (II), (Ila), or (lib). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (III), or (Ilia). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (IV). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (V). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (Via), (VIb), (Vic), (VId), or (Vie). One

embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (VII) or (Vila). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (VIII), or (Villa). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (IX). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (XII). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (XIII). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (XIV). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (XV). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (XVI). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (XVII). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (XVIII). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (XIX). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (XX). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (XXI). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (XXII). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (XXIII). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (XXIV). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (XXV).

[00265] One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (I), (la), or (lb). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (II), (Ila), or (lib). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (III), or (Ilia). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (IV). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (V). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (Via), (VIb), (Vic), (VId), or (Vie). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (VII), or (Vila). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (VIII), or (Villa). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (IX). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (XII). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (XIII). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (XIV). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (XV). One embodiment provides a method of inhibiting

bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (XVI). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (XVII). One

embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (XVIII). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (XIX). One embodiment provides a method of inhibiting

bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (XX). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (XXI). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (XXII). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (XXIII). One embodiment provides a method of inhibiting

bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (XXIV). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (XXV).

[00266] One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain-containing protein to a compound of Formula (X), or a pharmaceutically acceptable salt thereof,


Formula (X)

wherein,

R2 is selected from CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3;

X5 is C-R5 or N;

X6 is C-R6 or N;

X7 is C-R7 or N;

X8 is C-R or N; wherein no more than two of X5, X6, X7, or X8 may be N;

R5 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R6 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R7 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R is hydrogen, halogen, or alkyl; and

RA is an aryl group or a heteroaryl group.

[00267] Another embodiment provides the method of regulating gene transcription in a cell, wherein the compound of Formula (X) has the structure wherein RA is a substituted phenyl group.

[00268] Another embodiment provides a method of inhibiting of bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (X). Another embodiment provides the method of inhibiting of bromodomain-mediated recognition of an acetyl lysine region of a protein, wherein the compound of Formula (X) has the structure wherein RA is a substituted phenyl group.

[00269] One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain-containing protein to a compound of Formula (XI), or a pharmaceutically acceptable salt thereof,


Formula (XI)

wherein,

R2 is CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3;

X3 is C-H or N;

X5 is C-R5 or N; provided that if X3 is N, then X5 is C-R5, and if X5 is N, then X3 is CH; R5 is hydrogen, halogen, -OH,-CN, -OR61, -NHR61, -N(R61)2, alkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R6 is hydrogen, halogen, -OH,-CN, alkyl, cycloalkyl, cycloalkylalkyl, amino, alkylamino, dialkylamino, cycloalkylalkylamino, alkoxy, or cycloalkylalkoxy; and RA is an aryl group or a heteroaryl group.

[00270] Another embodiment provides the method of regulating gene transcription in a cell, wherein the compound of Formula (XI) has the structure wherein RA is a substituted phenyl group.

[00271] Another embodiment provides a method of inhibiting of bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (XI). Another embodiment provides the method of inhibiting of bromodomain-mediated recognition of an acetyl lysine region of a protein, wherein the compound of Formula (XI) has the structure wherein RA is a substituted phenyl group.

Methods of Treatment

[00272] Compounds and compositions described herein are generally useful for the inhibition of activity of one or more proteins involved in epigenetic regulation. Thus, one embodiment provides a method of modulating epigenetic regulation mediated by one or more proteins containing acetyl-lysine recognition motifs, also known as bromodomains (e.g., BET proteins, such as BRD2, BRD3, BRD4, and/or BRDT, and non-BET proteins, such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ, TAFl, and/or BRPFl), by administering a substituted heterocyclic derivative compound as described herein.

[00273] In some embodiments, the substituted heterocyclic derivative compounds as described herein are capable of inhibiting the activity of a bromodomain-containing protein, such as a BET protein (BRD2, BRD3, BRD4 and/or BRDT), non-BET proteins (such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ, TAFl, and/or BRPFl) or a mutant thereof, in a biological sample in manner useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays.

[00274] In some embodiments is provided a method of inhibiting the activity of a

bromodomain-containing protein, such as a BET protein (BRD2, BRD3, BRD4 and/or BRDT), non-BET proteins (such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ, TAFl, and/or BRPFl) or a mutant thereof, in a patient comprising the step of administering to said patient a substituted heterocyclic derivative compound as described herein, or a composition comprising said compound.

[00275] In some embodiments is provided a method of inhibiting the activity of a

bromodomain-containing protein, such as a BET protein (BRD2, BRD3, BRD4 and/or BRDT), non-BET proteins (such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ, TAFl, and/or BRPFl) or a mutant thereof, in a biological sample comprising the step of contacting said biological sample with a substituted heterocyclic derivative compound as described herein. In some embodiments, the bromodomain-containing protein is a BET protein. In some embodiments, the BET protein is BRD4.

[00276] In some embodiments is provided a method of inhibiting the activity of a

bromodomain-containing protein, such as a BET protein (BRD2, BRD3, BRD4 and/or BRDT), non-BET proteins (such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ, TAFl, and/or BRPFl) or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a substituted heterocyclic derivative compound as described herein. In some embodiments, the bromodomain-containing protein is a BET protein. In some embodiments, the BET protein is BRD4.

[00277] Diseases and conditions treatable according to the methods of this invention include cancer, neoplastic disease and other proliferative disorders. Thus, one aspect is a method of treating a subject having cancer, a neoplastic disease and other proliferative disorder, the method comprising administration of a substituted heterocyclic derivative compound as described herein to the subject. In one embodiment, a human patient is treated with a substituted heterocyclic derivative compound as described herein and a pharmaceutically acceptable excipent, wherein said compound is present in an amount to measurably inhibit bromodomain-containing protein activity (such as BRD2, BRD3, BRD4, and/or BRDT) in the patient.

[00278] The invention further provides a method of treating a subject, such as a human, suffering from cancer, a neoplastic disease and other proliferative disorder. The method comprises administering to a subject in need of such treatment a therapeutically effective amount of one or more substituted heterocyclic derivative compound as described herein, which function by inhibiting a bromodomain and, in general, by modulating gene expression, to induce various cellular effects, in particular induction or repression of gene expression, arresting cell proliferation, inducing cell differentiation and/or inducing apoptosis.

[00279] The invention further provides a therapeutic method of modulating protein methylation, gene expression, cell proliferation, cell differentiation and/or apoptosis in vivo in conditions, illnesses, disorders or diseases disclosed herein, in particular cancer, inflammatory disease, and/or viral disease comprising administering to a subject in need of such therapy a pharmacologically active and therapeutically effective amount of one or more substituted heterocyclic derivative compound as described herein.

[00280] The invention further provides a method of regulating endogenous or heterologous promoter activity by contacting a cell with a substituted heterocyclic derivative compound as described herein.

[00281] The invention further relates to a method for treating or ameliorating cancer, neoplastic disease, or another proliferative disorder by administration of an effective amount of a substituted heterocyclic derivative compound as described herein, to a mammal, in particular a human, in need of such treatment. In some aspects of the invention, the disease to be treated by the methods of the present invention is cancer.

[00282] In certain embodiments, the cancer is NUT midline carcinoma, prostate cancer, breast cancer, bladder cancer, lung cancer, or melanoma. In another embodiment the cancer is Burkitts lymphoma.

[00283] One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula (I), (la), or (lb), or a pharmaceutically acceptable salt thereof. One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula (II), (Ila), or (lib), or a pharmaceutically acceptable salt thereof. One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula (III), or (Ilia), or a pharmaceutically acceptable salt thereof. One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula (IV), or a pharmaceutically acceptable salt thereof. One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula (V), or a pharmaceutically acceptable salt thereof. One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula (Via), (VIb), (Vic), (VId), or (Vie), or a pharmaceutically acceptable salt thereof. One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula (VII), or (Vila), or a pharmaceutically acceptable salt thereof. One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula (VIII), or (Villa), or a pharmaceutically acceptable salt thereof. One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula (IX), or a pharmaceutically acceptable salt thereof. One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula (XII), or a pharmaceutically acceptable salt thereof. One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula (XIII), or a pharmaceutically acceptable salt thereof. One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula (XIV), or a pharmaceutically acceptable salt thereof. One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula (XV), or a pharmaceutically acceptable salt thereof. One

embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula (XVI), or a pharmaceutically acceptable salt thereof. One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula (XVII), or a pharmaceutically acceptable salt thereof. One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula (XVIII), or a pharmaceutically acceptable salt thereof. One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula (XIX), or a pharmaceutically acceptable salt thereof. One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula (XX), or a pharmaceutically acceptable salt thereof. One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula (XXI), or a pharmaceutically acceptable salt thereof. One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula (XXII), or a pharmaceutically acceptable salt thereof. One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula (XXIII), or a pharmaceutically acceptable salt thereof. One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula (XXIV), or a pharmaceutically acceptable salt thereof. One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula (XXV), or a pharmaceutically acceptable salt thereof.

[00284] Other embodiments and uses will be apparent to one skilled in the art in light of the present disclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way.

EXAMPLES

I. Chemical Synthesis

[00285] Unless otherwise noted, reagents and solvents were used as received from

commercial suppliers. Anhydrous solvents and oven-dried glassware were used for synthetic transformations sensitive to moisture and/or oxygen. Yields were not optimized. Reaction times are approximate and were not optimized. Column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise noted. Spectra are given in ppm (δ) and coupling constants (J) are reported in Hertz. For 1H NMR spectra, the solvent peak was used as the reference peak.

[00286] Chemistry Example 1 is 2-methyl-4-phenylisoquinolin-l-one which was purchased from a commercial vendor.

Example 2: 4-(3-methoxyphenyl)-2-meth lisoquinolin-l-one


[00287] A mixture of 4-bromo-2-methylisoquinolin-l(2H)-one (100 mg, 0.42 mmol), and (3-methoxyphenyl)boronic acid (70 mg, 0.46 mmol), PPh3 (66 mg, 0.25 mmol), Na2C03 (133 mg, 1.26 mmol), and Pd(dppf)Cl2 (62 mg,0.084 mmol) in dioxane (2.5 mL) and water (0.5 mL) was heated overnight at 90 °C. Extractive work up with ethyl acetate followed by preparative TLC (PE:EA=1 : 1) gave the title compound (18 mg, 0.07 mmol) as a white solid in 17% yield. 1H NMR (DMSO, 400 MHz): δ 8.30 (d, 1H, J=7.68), 7.68 (t, 1H, J=7.56), 7.50-7.55 (m, 3H), 7.40 (t, 1H, J= 7.44), 6.97-7.00 (m, 3H), 3.78 (s, 3H), 3.54 (s, 3H). MS (m/z, relative intensity): 266 (M+, 1).

Examples 3-14 in Table 3 were prepared from 4-bromo-2-methylisoquinolin-l(2H)-one and the appropriate boronic acid/ester in a manner similar to Example 2.

Table 3



2-methyl-4-(3- (DMSO- g) 1.67 (t, J=6.64 Hz, 4 369 pyrrolidin-1- H) 3.18 (t, J=6.44 Hz, 4 H) 3.57 ylsulfonylphenyl)i


soquinolin-l-one (s, 3 H) 7.42 (d, J=8.20 Hz, 1 H)

7.56 (t, J=7.61 Hz, 1 H) 7.61 (s,

1 H) 7.68 - 7.80 (m, 4 H) 7.85 (d, J=6.83 Hz, 1 H) 8.33 (d, J=8.20

Hz, 1 H).

N-[[3-(2-methyl- (DMSO-dg) 2.87 (s, 3 H) 3.56 (s, 343 1-oxoisoquinolin- 3 H) 4.22 (d, J=6.05 Hz, 2 H)

4- o o yl)phenyl]methyl] 7.31 - 7.44 (m, 3 H) 7.45 - 7.62

methanesulfonami

(m, 5 H) 7.64 - 7.72 (m, 1 H)

de

8.32 (d, J=7.61 Hz, 1 H)

N-[3-(2-methyl-l- (DMSO-dg) 3.03 (s, 3 H) 3.55 (s, 329 oxoisoquinolin-4- 3 H) 7.16 (d, J=7.61 Hz, 1 H) yl)phenyl]methane

H

sulfonamide 7.23 - 7.28 (m, 2 H) 7.45 (t,

J=8.30 Hz, 1 H) 7.48 - 7.57 (m, 3 H) 7.67 - 7.72 (m, 1 H) 8.31 (d,

J=7.03 Hz, 1 H) 9.88 (br. s., 1 H)

N-ethyl-3-(2- (DMSO-de) 0.92 - 1.02 (m, 3 H) 343 methyl-1- 2.76 - 2.86 (m, 2 H) 3.56 (s, 3 H) oxoisoquinolin-4- o o yl)benzenesulfona 7.43 (d, J=8.20 Hz, 1 H) 7.53 - mide

7.60 (m, 2 H) 7.64 (t, J=5.66 Hz, 1 H) 7.68 - 7.75 (m, 3 H) 7.80 - 7.88 (m, 2 H) 8.29 - 8.36 (m, 1

H)

4-(3- (CHLOROFORM-;/) 1.33 (t, 328 ethylsulfonylphen

J=7.42 Hz, 3 H) 3.18 (q, J=7.42 yl)-2- o o methylisoquinolin Hz, 2 H) 3.65 - 3.69 (m, 3 H)

-1-one

7.10 (s, 1 H) 7.43 (d, J=8.01 Hz, 1 H) 7.51 - 7.57 (m, 1 H) 7.60 - 7.76 (m, 3 H) 7.93 - 7.98 (m, 2

H) 8.53 (dd, J=8.01, 0.98 Hz, 1

H)

4-[3- (DMSO- g) 2.71 (s, 6 H) 3.55 (s, 358

(dimethylsulfamo

N N 3 H) 7.10 (d, J=7.03 Hz, 1 H)

ylamino)phenyl] - H J M.e 2-methyl-l - 7.22 - 7.25 (m, 2 H) 7.41 (t,

oxoisoquinoline

J=7.71 Hz, 1 H) 7.48 (s, 1 H)

7.50 - 7.56 (m, 2 H) 7.67 - 7.72

(m, 1 H) 8.31 (d, J=7.81 Hz, 1

H) 10.02 (br. s., 1 H)

N-[3-(2-methyl-l- (DMSO-dg) 1.20 (t, J=7.13 Hz, 3 343 oxoisoquinolin-4- H) 3.13 (q, J=7.29 Hz, 2 H) 3.55

yl)phenyl] ethanes


ulfonamide (s, 3 H) 7.14 (d, J=7.03 Hz, 1 H)

7.25 (br. s., 2 H) 7.38 - 7.59 (m,

4 H) 7.69 (t, J=7.61 Hz, 1 H)

8.31 (d, J=8.01 Hz, 1 H) 9.92 (s,

1 H)

2-methyl-4-(3- (DMSO-de) 3.02 - 3.09 (m, 4 H) 385 morpholin-4- 3.68 (s, 3 H) 3.73 - 3.80 (m, 4 H)

¾ N ylsulfonylphenyl)i

O O soquinolin-l-one 7.09 (s, 1 H) 7.43 (d, J=7.81 Hz,

1 H) 7.53 - 7.58 (m, 1 H) 7.61 - 7.73 (m, 3 H) 7.78 - 7.84 (m, 2

H) 8.55 (d, J=7.03 Hz, 1 H)

Example 15: N-benzyl-2-methoxy-5-(2 -methyl- 1 -oxoisoquinolin-4-yl)benzenesulfonamide


[00288] For about 3 min, N2 was bubbled through the mixture of 4-bromo-2-methylisoquinolin-l(2H)-one (56 mg, 0.24 mmol), [3-(benzylsulfamoyl)-4-methoxyphenyljboronic acid (83 mg, 0.26 mmol), aqueous 2M Na2C03 (0.375 mL) and Pd(dppf)Cl2 (9 mg,0.001 mmol) in dioxane (1.5 mL) which was then microwaved at 120 °C for 1 h and then filtered through a plug of anhydrous Na2S04 using ethyl acetate to transfer and rinse. Silica gel chromatography, eluting with 0-60% EA in hexane over 6 min and continuing 60% isocratic EA gave the title compound (60 mg, 0.14 mmol) as a white solid in

58% yield. 1H NMR (400 MHz, DMSO-d6) δ 3.57 (s, 3 H), 3.89 (s, 3 H), 4.1 1 (d, J=6.32 Hz, 2 H), 7.16 - 7.23 (m, 6 H), 7.34 (d, J=8.08 Hz, 1 H), 7.47 (s, 1 H), 7.53 - 7.59 (m, 2 H), 7.65 (d, J=2.27 Hz, 1 H), 7.72 - 7.77 (m, 1 H), 7.94 (t, J=6.32 Hz, 1 H), 8.34 (d, J=7.33 Hz, 1 H). LCMS (M+H)+ 435.

[00289] Examples 16-17 in Table 4 were prepared from 4-bromo-2-methylisoquinolin-l(2H)- one and the appropriate boronic acid/ester in a manner similar to Example 15.

Table 4



Step 1 : N-benzyl-5-bromo-2-methoxybenzamide


[00290] To an ice bath cooled mixture of 5-bromo-2-methoxybenzoic acid (439 mg, 1.9 mmol) in 1 : 1 CH2C12:DMF (4 mL) was added benzylamine (0.228 mL, 2.1 mmol), EDCI (438mg, 2.3 mmol), HOBt (311 mg, 2.3 mmol) and NEtiPr2 (0.496 mL, 2.85 mmol). The mixture was then stirred at room temperature until the reaction was complete. Extractive work up with ethyl acetate, washing with saturated aqueous NaHC03, H20, saturated aqueous KHSO4 and brine, gave the title compound (550 mg) after isolation which was carried forward without purification. LCMS (M+H)+ 320, 322.

[00291] Step 2: N-benzyl-2-methoxy-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide


[00292] For about 3 min, N2 was bubbled through a mixture of the title compound of N-benzyl-5-bromo-2-methoxybenzamide (174 mg, 0.54 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (166 mg, 0.65 mmol), potassium acetate (159 mg, 1.62 mmol) and Pd(dppf)Cl2 (20 mg,0.03 mmol) in anhydrous DMF (4.2 mL). After heating at 90 °C for about 2 h under N2, silica gel chromatography, eluting with 0-40% EA in hexane over 7 min and continuing 40% isocratic EA gave the title compound (138 mg, 0.38 mmol) as a white solid in 70% yield. LCMS (M+H)+ 368.

[00293] Step 3: N-benzyl-2-methoxy-5-(2-methyl-l-oxoisoquinolin-4-yl)benzamide


[00294] For about 3 min, N2 was bubbled through a mixture of N-benzyl-2-methoxy-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide (51 mg, 0.14 mmol), 4-bromo-2-methylisoquinolin-l(2H)-one (30 mg, 0.13 mmol), aqueous 1M K3P04 (0.3 mL) and

Pd(dppf)Cl2 (10 mg,0.013 mmol) in dioxane (1.15 mL) which was then micro waved at 100 °C for 1 h. Work up similar to Example 15 and purification by silica gel chromatography, eluting with 5-50% EA in hexane over 4 min and continuing 50% isocratic EA gave the title compound (37 mg, 0.14 mmol) as a tan solid in 71% yield. 1H NMR (400 MHz, DMSO-d6) δ

3.57 (s, 3 H), 3.97 (s, 3 H), 4.52 (d, J=6.06 Hz, 2 H), 7.21 - 7.37 (m, 6 H), 7.47 - 7.51 (m, 2 H), 7.56 (td, J=5.37, 2.15 Hz, 2 H), 7.68 - 7.73 (m, 1 H), 7.79 (d, J=2.27 Hz, 1 H), 8.33 (d, J=7.83 Hz, 1 H), 8.79 (t, J=6.06 Hz, 1 H). LCMS (M+H)+ 399.

Examples 19-31 in Table 5 were prepared from 4-bromo-2-methylisoquinolin-l(2H)-one and the appropriate boronic acid/ester in a manner similar to Example 18, step 3. For Examples 20-26 the microwave temperature was increased to 120 °C. Aniline hydrochlorides were prepared by treating the aniline with anhydrous HCl in methanol as the final step.

Table 5




7.47 (s, 1 H) 7.55 (dd, J=7.58,

5.05 Hz, 2 H) 7.65 - 7.73 (m, 1

H) 8.31 - 8.37 (m, 1 H) 9.04 (s,

1 H)

tert-butyl N- (DMSO-de) 1.41 (s, 9 H) 3.24 365 methyl-N-[3- N(Me)C02Bu (s, 3 H) 3.57 (s, 3 H) 7.25 (d,

(2 -methyl- 1- oxoisoquinolin J=7.33 Hz, 1 H) 7.32 - 7.38 (m,

-4- 2 H) 7.44 - 7.60 (m, 4 H) 7.67 - yl)phenyl]carb

amate 7.73 (m, 1 H) 8.34 (d, J=7.83

Hz, 1 H)

Example 32: 2-methyl-4-[3-(meth lamino)phenyl]isoquinolin-l-one hydrochloride


[00295] To the title compound of Example 31 (48 mg, 0.13 mmol) was added 4 M HC1 in dioxane (3 mL). After stirring about 1 h, the volatile components were removed under vacuum. Hexane was added and evaporated (x2). The resulting white solid was dried under vacuum to give the title compound (39 mg, 0.13 mmol) in quantitative yield. 1H NMR (400 MHz, DMSO-dg) δ ppm 2.85 (s, 3 H), 3.57 (s, 3 H), 7.10 (br. s., 3 H), 7.44 (br. s., 1 H), 7.51 -7.60 (m, 3 H), 7.68 - 7.74 (m, 1 H), 8.34 (d, J=7.58 Hz, 1 H). LCMS (M+H)+ 265.

Example 33: N-methyl-N-[3-(2-methyl-l-oxoisoquinolin-4-yl)phenyl]methanesulfonamide


[00296] To the title compound of Example 32 (35 mg, 0.12 mmol) in anhydrous CH2CI2 (0.3 mL), pyridine (0.1 mL) and NEtiPr2 (0.021 mL, 0.12 mmol) was added methanesulfonyl chloride (0.011 mL, 0.14 mmol). After 0.5-1 h, ice was added to the mixture followed by water and ethyl acetate. Extractive work up, washing with H20, a 1 : 1 aqueous saturated KHS04:H20, and brine, and purification on silica gel eluting with 35-80% EA in hexane over 6 min and continuing 80% isocratic EA gave the title compound (22 mg, 0.06 mmol) as a cream solid in 54% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.00 (s, 3 H), 3.30 (s, 3 H), 3.58 (s, 3 H), 7.40 (d, J=7.58 Hz, 1 H), 7.45 - 7.61 (m, 6 H), 7.71 (td, J=7.58, 1.26 Hz, 1 H), 8.34 (dd, J=8.21, 1.14 Hz, 1 H). LCMS (M+H)+ 343.

Examples 34-40 in Table 6 were prepared in one step by sulfonylation of the aniline Examples 23-26 from Table 5 using methanesulfonyl chloride in a manner similar to

Example 33 (1 step from the indicated Example No.) or in two steps from 4-bromo-2- methylisoquinolin-l(2H)-one and the appropriate aniline boronic acid/ester in a manner similar to Example 23 followed by sulfonylation of the aniline with methanesulfonyl chloride in a manner similar to Example 33 (2 steps).

Table 6



Example 41: N-[4-fluoro-3-[2-methyl-6-(l-methylpyrazol-4-yl)-l-oxoisoquinolin-4- yl]phenyl]methanesulfonamide

Step 1 : 2-methyl-6-(l-methylpyrazol-4-yl)isoquinolin-l-one


[00297] A mixture of 6-bromo-2-methylisoquinolin-l-one (3.8 g, 16 mmol), 1 -methyl -4- (tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (6.69 g, 32 mmol), CsF (7.29 g, 48 mmol), Pd(PPh3)2Cl2 (0.4 g, lmmol) in dioxane/H20 (60 /10 mL) was stirred at 90 °C for 12 h under N2. The mixture was concentrated and the residue was purified by silica gel chromatography (PE:EA = 2: 1) to give the title compound (3.1 g, 81%) as a yellow solid. 1H NMR (CDC13, 400 MHz) δ 8.40 (d, J = 12 Hz, 1 H), 7.87 (s, 1 H), 7.74 (s, 1 H), 7.59-7.56 (dt, Ji = 4 Hz, h = 8 Hz, 2 H), 7.07 (d, J = 4 Hz, 1 H), 6.48 (d, J = 8 Hz, 1 H) 3.98 (s, 3 H), 3.61 (s, 3 H). LCMS: 240.0 (M+H)+

Step 2 : 4-bromo-2-methyl-6-( 1 -methylpyrazol-4-yl)isoquinolin- 1 -one


[00298] Bromine (1.8 g, 11.25 mmol) in HO Ac (6 mL) was added to the title compound of 2-methyl-6-(l-methylpyrazol-4-yl)isoquinolin-l-one (3 g, 12.5 mmol) in HO Ac (24 mL) at 0 °C. The mixture was stirred at 30 °C for 15 min, quenched with H20 (100 mL), and the resulting yellow solid was collected by filtration to give the title compound (2.04 g, 56%). 1H NMR (CDC13, 400 MHz) δ 8.42 (d, J = 8.4 Hz, 1 H), 7.87 (d, J = 28.8 Hz, 2 H), 7.82(d, J = 15.6 Hz, 2 H), 7.65 (d, J = 8 Hz, 2 H), 7.38 (s, 1 H), 4.00 (s, 3 H), 3.61 (s, 3 H). LCMS: 318.0 (M+H) +

Step 3: 4-(5-amino-2-fluorophenyl)-2-methyl-6-(l-methylpyrazol-4-yl)isoquinolin-l-one


[00299] 4-Bromo-2-methyl-6-(l-methylpyrazol-4-yl)isoquinolin-l-one (35 mg, 0.11 mmol), 4-fluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (29 mg, 0.12 mmol), Pd(dppf)Cl2 (8 mg, 0.01 mmol) and aqueous 1 M K3PO4 (0.3 mL) in dioxane (1.2 mL) were microwaved at 120 °C for 1.25 h. Work up was similar to that described for Example 18, step 3. Silica gel chromatography, eluting with 100% EA followed by 10% methanol in EA, gave the title compound (25 mg, 0.07 mmol) as a cream solid in 64% yield. LCMS (M+H)+ 349.

Step 4: N-[4-fluoro-3-[2-methyl-6-(l-methylpyrazol-4-yl)-l-oxoisoquinolin-4-yl]phenyl]methanesulfonamide

[00300] 4-(5-Amino-2-fluorophenyl)-2-methyl-6-(l-methylpyrazol-4-yl)isoquinolin-l-one (25 mg, 0.07 mmol) in pyridine (0.1 mL) and anhydrous CH2CI2 (0.3 mL) was treated with methanesulfonyl chloride (0.007 mL, 0.09 mmol) in a manner similar to Example 33. After a similar work up, silica gel chromatography, eluting with 50-100% EA in heaxane over 4 min and continuing isocratic 100% EA, gave the title compound (24 mg, 0.06 mmol) as a white solid in 78% yield. 1H NMR (400 MHz, DMSO-d6) δ 3.06 (s, 3 H), 3.56 (s, 3 H), 3.85 (s, 3 H), 7.22 - 7.45 (m, 4 H), 7.59 (s, 1 H), 7.76 (dd, J=8.34, 1.52 Hz, 1 H), 7.85 (s, 1 H), 8.16 (s, 1 H), 8.29 (d, J=8.34 Hz, 1 H), 9.82 (s, 1 H). LCMS (M+H)+ 427.

Examples 42-45 in Table 7 were prepared from title compound of Example 41, step 2, in one step using the appropriate phenyl boronic acid/ester in a manner similar to Example 18, step 3, (1 step) or in two steps from the aniline boronic acid/ester followed sulfonylation of the aniline with the either methanesulfonyl chloride or ethanesulfonyl chloride in a manner similar to Example 41, steps 3 and 4, (2 steps).

Table 7



45 CI N-[4-chloro-3- 2 steps (DMSO-de) 1.14 - 1.28 457,

[2-methyl-6-(l- (m, 3 H) 3.11 - 3.28 (m, 459

NHS02E methylpyrazol- 4-yl)-l- 2 H) 3.55 (s, 3 H) 3.84 (s, oxoisoquinolin- 3 H) 7.13 (s, 1 H) 7.26

4- yl]phenyl]ethan (d, J=2.53 Hz, 1 H) 7.36 esulfonamide

(dd, J=8.72, 2.65 Hz, 1

H) 7.54 (s, 1 H) 7.61 (d,

J=8.84 Hz, 1 H) 7.72 - 7.77 (m, 1 H) 7.81 (s, 1

H) 8.12 (s, 1 H) 8.28 (d,

J=8.34 Hz, 1 H) 10.08 (s,

1 H)

Example 46: 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyl-6-(l -methylpyrazol-4-yl)isoquinolin- 1 -one

Step 1 : 2-bromo-l-(cyclopropylmethox -4-methanesulfonylbenzene


[00301] A mixture of 2-bromo-4-methanesulfonylphenol (7.2 g, 29 mmol),

(chloromethyl)cyclopropane (4.3 g, 32 mmol) and K2CO3 (8 g, 58 mmol) in acetone (80 mL) was stirred at 80 °C for 5 h. The mixture was quenched with water (40 mL). Extractive work up with ethyl acetate and purification by preparative HPLC gave the title compound (2.5 g, 28.6%). 1H NMR (CDCI3, 400 MHz) δ 8.12 (d, J=2.3 Hz, 1 H), 7.84 (dd, Jj = 2.3 Hz, j2 = 8.7 Hz, 1 H), 6.97 (d, J = 8.8 Hz, 1 H), 3.99 (d, J = 6.7 Hz, 2 H), 3.05 (s, 3 H), 1.23-1.43 (m, 1 H), 0.70 (d, J = 7.9 Hz, 2 H), 0.44 (d, J = 5.4 Hz, 2 H).

Step 2 : 2-methyl-6-( 1 -methylpyrazol-4-yl)-4-(4,4, 5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)isoquinolin- 1 -one


[00302] A mixture of the title compound of Example 41, step 2 (1.4 g, 4.41 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (2.24 g, 8.83

mmol), KOAc (1.08 g, 11.08mmol), Pd(dppf)Cl2 (100 mg, 0.137 mmol) in dioxane (50 mL) was stirred at 90 °C for 12 h under N2. Purification by column chromatography on silica gel (PE:EA = 3: 1) gave the title compound (200 mg, 12%) as a yellow solid. 1H NMR (CDC13, 400 MHz) δ 8.55 (d, J = 1.5 Hz,l H), 8.40 (d, J = 8.4 Hz, 1 H), 7.90 (s,l H), 7.71 (d, J = 16.8 Hz, 2 H), 4.00 (s, 3 H), 3.63 (s, 3 H), 1.40 (s, 12 H)

Step 3: 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyl-6-(l-methylpyrazol-4-yl)isoquinolin- 1 -one


[00303] A mixture of 2-bromo-l-(cyclopropylmethoxy)-4-methanesulfonylbenzene (20.8 mg, 0.068 mmol), 2-methyl-6-(l-methylpyrazol-4-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one (30 mg, 0.08 mmol), NaHC03 (14.28 mg, 0.17 mmol), and

Pd(dppf)Cl2 (10 mg, 0.014 mmol) in dioxane (2.0 mL) and H20 (0.5 mL) was microwaved under N2 at 100 °C for 30 min. Purification by preparative HPLC gave the title compound (11 mg, 28%) as a white solid. 1H NMR (CDC13, 400 MHz) δ 8.48 (d, J =8.4 Hz, 1 H), 7.98-8.04 (m, 1 H), 7.89 (d, J=2.4 Hz, 1 H), 7.68 (s, 1 H), 7.63 (s, 1 H), 7.58-7.62 (m, 1 H), 7.19-7.21 (m, 1 H), 7.11-7.15 (m, 1 H), 7.09 (s, 1 H), 3.93 (s, 3 H), 3.83-3.91 (m, 2 H), 3.66 (s, 3 H), 3.12 (s, 3 H), 0.94-1.04 (m, 1 H), 0.30-0.40 (m, 2 H), 0.00-0.12 (m, 2 H). LCMS: 464.1 (M+H) +

Example 47: N-[3-(6-fluoro-2-methyl- 1 -oxoisoquinolin-4-yl)phenyl]methanesulfonamide Step 1 : 6-fluoro-2-methylisoquinolin-l-one


[00304] Sodium hydride (60%> in mineral oil) (211 mg, 5.27 mmol) was added to 6-fluoro-1,2-dihydroisoquinolin-l-one (716 mg, 4.39 mmol) in anhydrous DMF (6 mL) cooled in an ice bath. The mixture was stirred for about 30 min at room temperature and methyl iodide (0.328 mL, 5.27 mmol) was added dropwise. After 1 h, the reaction was judged to be about 60% complete and additional methyl iodide (0.2 mL, 3.2 mmol) was added. After about 1 h, ice and water and ethyl acetate were added to the mixture. After extractive work up with

ethyl acetate, the title compound (836 mg) was obtained as a cream solid and carried on without purification.

Step 2: 4-bromo-6-fluoro-2-methylisoquinolin-l-one


[00305] Bromine (232 mg, 1.45 mmol, 0.097 mL) in acetic acid (1.0 mL) was added dropwise, quickly to 6-fluoro-2-methylisoquinolin-l-one (283 mg, 1.61 mmol) in acetic acid (7.0 mL) under N2 and cooled in an ice bath. The ice bath was removed and the thick suspension was stirred for 10 min at room temperature. Ice and water and ethyl acetate were added. Extractive work up with ethyl acetate, washing with aqueous 0.5 N NaOH, H20, saturated aqueous KHSO4 and brine, gave the title compound as a cream solid (313 mg) which was carried on without purification.

Step 3 : N-[3-(6-fluoro-2-methyl- 1 -oxoisoquinolin-4-yl)phenyl]methanesulfonamide


[00306] For about 3 min N2 was bubbled through a mixture of 4-bromo-6-fluoro-2-methylisoquinolin-l-one (41 mg, 0.16 mmol), (3-methanesulfonamidophenyl)boronic acid (38 mg, 0.18 mmol), aqueous 1 M K3PO4 (0.3 mL) and Pd(dppf)Cl2 (12 mg,0.016 mmol) in dioxane (1.2 mL) which was then microwaved for 1 h at 120 °C. Work up was similar to that described for Example 18, step 3. Purification using silica gel chromatography, eluting with 40-80% EA in hexane over 5 min and continuing 80% isocratic EA gave the title compound (28 mg, 0.08 mmol) as a cream solid in a combined yield of 38% over steps 1-3. 1H NMR (400 MHz, DMSO-dg) δ 3.06 (s, 3 H), 3.56 (s, 3 H), 7.15 - 7.22 (m, 2 H), 7.25 - 7.31 (m, 2 H), 7.41 (td, J=8.65, 2.65 Hz, 1 H), 7.45 - 7.52 (m, 1 H), 7.61 (s, 1 H), 8.40 (dd, J=9.09, 6.06 Hz, 1 H), 9.88 (s, 1 H). LCMS (M+H)+ 347.

Examples 48-50 in Table 8 were prepared from title compound of Example 47, step 2, in one step using the appropriate phenyl boronic acid/ester in a manner similar to Example 47, step 3 (1 step) or in two steps from the appropriate aniline boronic acid/ester in a manner similar to Example 47, step 3 followed by sulfonylation of the aniline with either methanesulfonyl chloride or ethanesulfonyl chloride in a manner similar to Example 41 , step 4 (2 steps).

Table 8



n-4- (d, J=2.53 Hz, 1 H) 7.34 yl)phenyl]etha (dd, J=8.59, 2.78 Hz, 1 H)

nesulfonamid 7.40 (td, J=8.72, 2.53 Hz, 1

e H) 7.60 (d, J=8.84 Hz, 1 H)

7.65 (s, 1 H) 8.38 (dd,

J=8.84, 5.81 Hz, 1 H) 9.86

- 10.28 (m, 1 H)

Example 51: N-[3-(2-met lyl- 1 -oxo-2,7-naphthyridin-4-yl)phenyl]methanesulfonamide

Step 1 : 2-methyl-2,7-naphthyridin-l


[00307] Sodium hydride (2.9 g, 72.5 mmol, 60% in oil) was added in portions to 2H-2,7-naphthyridin-l-one (3.5 g, 24.0 mmol) in dry DMF (50 mL) at 0 °C. After stirring at 0 °C for 30 min, Mel (17.0 g, 118.7 mmol) was added and the mixture was stirred for an additional 30 min. Saturated aqueous NH4C1 (250 mL) and ethyl acetate (100 mL) were added. Extractive work up with ethyl acetate and purification by silica gel chromatography (DCM:MeOH = 100: 1 to 10: 1) gave the title compound (0.5 g, 13.1 %) as a yellow solid. 1H NMR (CDC13, 400 MHz) δ 9.54 (1 H, s), 8.64-8.62 (1 H, d, J = 5.6 Hz), 7.27-7.26 (1 H, d, J = 5.2 Hz), 7.22-7.20 (1 H, d, J = 5.6 Hz), 6.37-6.35 (1 H, d, J = 7.2 Hz), 3.54 (3 H, s).

Step 2: 4-bromo-2-methyl-2,7-naphthyridin-l-one


[00308] Bromine (1.1 g, 6.87 mmol) in acetic acid (10 mL) was added dropwise to2-methyl-2,7-naphthyridin-l-one (1.1 g, 6.87 mmol) in acetic acid (60 mL) at 10-15 °C. After stirring at 15 °C for 1 h, the mixture was concentrated under vacuum. Purification by silica gel chromatography (DCM: MeOH = 50: 1 to 10: 1) gave the title compound (0.45 g, 27.4 %) as a yellow solid.

1H NMR (CDC13, 400 MHz) δ 9.61 (1 H, s), 8.86-8.85 (1 H, d, J = 5.6 Hz), 7.62-7.60 (1 H, d, J = 5.6 Hz), 7.56 (1 H, s), 3.63 (3 H, s).

Step 3 : N- [3 -(2 -methyl- 1 -oxo-2,7-naphthyridin-4-yl)phenyl]methanesulfonamide


[00309] A mixture of 4-bromo-2-methyl-2,7-naphthyridin-l-one (50 mg, 0.21 mmol), [3- (methanesulfonamido)phenyl]boronic acid (68 mg, 0.31 mmol), Pd(dppf)Ci2 (15.3 mg, 0.021 mmol) and aqueous K3PO4 (1 M, 0.3 mL, 0.3 mmol) in dioxane (3 mL) was microwaved at 90 °C for 40 min. Purification by silica gel chromatography (PE:EA = 100: 1 to 1 : 1) followed by preparative HPLC gave the title compound (48.1 mg, 69.8 %) as a white solid. 1H NMR (400 MHz, Methanol-d4) δ 9.56 (s, 1 H), 8.68 (d, J = 6.4 Hz, 1 H), 7.96 (s, 1 H), 7.81 (d, J = 6.4 Hz, 1 H), 7.51 (t, J = 7.6 Hz, 1 H), 7.37 (d, J = 2.0 Hz, 1 H), 7.34 (d, J = 1.6 Hz, 1 H), 7.26 (d, J = 7.6 Hz, 1 H), 3.71 (s, 3 H), 3.03 (s, 3 H). LCMS : 330.0 (M+H) +

Examples 52-56 in Table 9 were prepared from title compound of Example 51 , step 2, in one step using the appropriate phenyl boronic acid/ester in a manner similar to Example 51 , step 3.

Table 9


N-ethyl-3-(2- 1H NMR (400 MHz, CDC13) 344 methyl-l-oxo- δ 9.72 (s, 1 H), 8.73 (d, J =

o o 2,7- 5.6 Hz, 1 H), 7.95 (d, J =

naphthyridin- 7.2 Hz, 1 H), 7.92 (s, 1 H),

4- 7.67-7.62 (m, 2 H), 7.33 (s, yl)benzenesul 1 H), 7.30 (d, J = 5.6 Hz, 1

fonamide H), 4.48 (s, 1 H), 3.70 (s, 3

H), 3.13-3.12 (m, 2 H), 1.18 (t, J = 7.2 Hz, 3 H)

N-benzyl-2- 1H NMR (400 MHz, CDC13) 436 methoxy-5-(2- δ 9.72 (s, 1 H), 8.74 (d, J =

0 0 methyl-l-oxo- 5.6 Hz, 1 H), 7.93 (s, 1 H),

2,7- 7.54 (dd, Ji = 8.4 Hz, J2 = naphthyridin- 2.4 Hz, 1 H), 7.27-7.26 (s, 6

4- H), 7.19 (d, J = 3.2 Hz, 1 H) yl)benzenesul 7.06 (d, J = 8.4 Hz, 1 H),

fonamide 5.26 (s, 1 H), 4.20 (d, J =

5.2 Hz, 2 H), 3.96 (s, 3 H),

3.70 (s, 3 H)

3-(2-methyl- 1H NMR (400 MHz, 316

¾i^^S02NH2 l-oxo-2,7- DMSO-d6) δ 9.46 (d, J = 9.2

naphthyridin- Hz,l H), 8.73 (d, J = 5.6 Hz,

4- 1 H), 7.89-7.88 (m, 3 H), yl)benzenesul 7.73-7.69 (m, 2 H), 7.39- fonamide 7.38 (d, J = 5.2 Hz, 1 H),

3.60 (s, 3 H)

56 2-methoxy-5- H NMR (400 MHz, 346

(2 -methyl- 1- DMSO-d6) δ 9.44 (s, 1 H),


oxo-2,7- 8.72 (d, J = 5.6 Hz, 1 H),

naphthyridin- 7.80 (s, 1 H), 7.77 (d, J =

4- 2.4 Hz, 1 H), 7.65-7.63 (dd,

yl)benzenesul Ji = 8.4 Hz, h = 2.4 Hz, 1

fonamide H), 7.34 (d, J = 8.4 Hz, 1

H), 7.33 (d, J = 5.2 Hz, 1

H), 3.97 (s, 3 H), 3.59 (s, 3

H)

Example 57: N-[4-(2,4-difluorophenoxy)-3-(2-methyl-l -oxo-2,7-naphthyridin-4-yl)phenyl] ethanesulfonamide

Step 1 : 4-(2,4-difluorophenox -3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline


[00310] A mixture of 3-bromo-4-(2,4-difluorophenoxy)aniline (300 mg, 1 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (518 mg, 2 mmol), KOAc (300 mg, 3 mmol) and Pd(dppf)Cl2 (73.2 mg, 0.1 mmol) in dioxane (6 mL) was microwaved at 100 °C for 2 h. Purification by silica gel chromatography (PE:EA = 10: 1 to 5:1) gave the title compound (200 mg, 56 %). LCMS: 348.0 (M+H) +

Step 2: 4-[5-amino-2-(2,4-difl rophenoxy)phenyl]-2-methyl-2,7-naphthyridin-l-one


[00311] For 5 min, N2 was bubbled through a mixture of 4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (64.8 mg, 0.187 mmol), the title compound of Example 51, step 2 (30.0 mg, 0.124 mmol), K2C03 (51.6 mg, 0.374 mmol) and Pd(dppf)Cl2 (18.3 mg, 0.025 mmol) in dioxane (2.0 mL) and water (0.2 mL) which was then microwaved at 100 °C for 1 h. Purification by preparative TLC (DCM:MeOH = 20: 1, Rf title compound (25.0 mg, 53 %) as yellow gum. LCMS: 380.0 (M+H) +

Step 3 : N-[4-(2,4-difluorophenoxy)-3-(2 -methyl- 1 -oxo-2,7-naphthyridin-4-yl)phenyl] ethanesulfonamide


[00312] Ethanesulfonyl chloride (25.4 mg, 0.198 mmol) was added to 4-[5-amino-2-(2,4-difluorophenoxy)phenyl]-2-methyl-2,7-naphthyridin-l-one (25.0 mg, 0.066 mmol) and TEA (20.0 mg, 0.198 mmol) in DCM (5 mL) at 0 °C. The mixture was stirred at room temperature for 18 h and then purified by preparative HPLC to give the title compound (8.5 mg, 27.4 %) as yellow gum. 1H NMR (Methanol-d4, 400 MHz) δ 9.54 (s, 1 H), 8.68 (d, J = 4.4 Hz, 1 H), 8.00 (s, 1 H), 7.66 (d, J = 8.4 Hz, 1 H), 7.38 - 7.33 (m, 2 H), 7.09 - 6.99 (m, 2 H), 6.96 - 6.94 (d, J = 8.4 Hz, 1 H), 6.91 - 6.85 (m, 1 H), 3.70 (s, 3 H), 3.15 (q, J = 7.6 Hz, 2 H), 1.35 (t, J = 7.6 Hz, 3 H). LCMS: 472.1 (M+H) +

Example 58: N-[3-(7-fluoro-2-methyl- 1 -oxoisoquinolin-4-yl)phenyl]methanesulfonamide Step 1 : 7-fluoro-2-methylisoquinol -l-one


[00313] Under N2, sodium hydride (710 mg, 29.4 mmol) was added to 7-fluoro-2H-isoquinolin-l-one (4 g, 24.55 mmol) in dry DMF (40 mL) at 0 °C. After stirring at 0 °C for 20 min, CH3I (5.2 g, 36.7 mmol) was added. The mixture was stirred at 26 °C for 2 h. Saturated aqueous NH4CI (20 mL) was added and after extractive work up with ethyl acetate, purification by silica gel chromatography (PE:EA = 10: 1) gave the title compound (2.2 g, 50 %) as an off-white solid. 1H NMR (CDCI3, 400 MHz) δ 8.06 (dd, Ji = 9.6 Hz, J2 = 2.8 Hz, 1 H), 7.50 (dd, Ji = 8.8 Hz, J2 = 5.2 Hz, 1 H), 7.38-7.36 (m, 1 H), 7.03 (d, J = 7.6 Hz, 1 H), 6.48 (d, J = 7.2 Hz, 1 H), 3.61 (s, 3 H). LCMS: 178.1 [M+H]+

Step 2: 4-bromo-7-fluoro-2H-isoquinolin-l-one

[00314] Bromine (3.8 g, 24 mmol) in acetic acid (6 mL) was added slowly to a mixture of 7- fluoro-2-methylisoquinolin-l-one (4 g, 22.4 mmol) in acetic acid (8 mL) at 0 °C. After stirring at 26 °C for 2 h, the mixture was poured into water (100 mL) and the solid was collected by filtration. Purification by silica gel chromatography (PE:EA = 20: 1) gave the title compound (1.4 g, 44%) as an off-white solid. 1H NMR (CDC13, 400 MHz) δ 8.11 (d, J = 9.2 Hz, 1 H), 7.84 (dd, Ji = 9.6 Hz, J2 = 4.8 Hz, 1 H), 7.49-7.45 (m, 1 H), 7.34 (s, 1 H), 3.62 (3 H, s). LCMS: 255.9 [M+H]+

Step 3 : N-[3-(7-fluoro-2-methyl- 1 -oxoisoquinolin-4-yl)phenyl]methanesulfonamide


[00315] 4-Bromo-7-fluoro-2H-isoquinolin-l-one was treated with [3- (methanesulfonamido)phenyl]boronic acid in a manner similar to Example 51, step 3.

Isolation and purification also in a similar manner gave the title compound (18 mg, 26.5 %) a white solid. 1H NMR (400 MHz, CDC13) δ 8.17 (dd, Ji = 9.2 Hz, J2 = 2.8 Hz, 1 H), 7.52 (dd, Jl = 8.0 Hz, J2 = 4.0 Hz 1 H), 7.50-7.45 (m, 1 H), 7.38-7.32 (m, 1 H), 7.31-7.27 (m, 2 H), 7.26-7.21 (m, 1 H), 7.03 (s, 1 H), 6.72 (brs, 1 H), 3.67 (s, 3 H), 3.09 (s, 3 H). LCMS: 347.0 (M+H) +.

Examples 59-64 in Table 10 were prepared from title compound of Example 58, step 2 using the appropriate phenyl boronic acid/ester in a manner similar to Example 18, step 3.

Table 10


No. (ppm (δ). 400 M i l /.)

Example 65: 2-methyl-4-(l-methylpyrazol-4-yl)isoquinolin-l-one


[00316] For 3 min, N2 was bubbled through a mixture of 4-bromo-2-methylisoquinolin- l(2H)-one (54 mg, 0.23 mmol), (l-methylpyrazol-4-yl)boronic acid (31 mg, 0.25 mmol), aqueous 2M Na2C03 (0.375 mL) and Pd(dppf)Cl2 (8 mg, 0.01 mmol) in 1,4-dioxane (1.5 mL) which was then micro waved at 120 °C for 1 h. Work up in a manner similar to Example 18, step 3, and two successive silica gel chromatographies, eluting with 15-80% EA in hexane over 6 min and continuing 80% isocratic EA followed by a second chromatography 15-100% EA in hexane over 6 min and continuing 100% isocratic EA gave the title compound (28 mg, 0.12 mmol) as a cream solid in 51% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.54 (s, 3 H) 3.92 (s, 3 H) 7.50 (s, 1 H) 7.55 (ddd, J=8.02, 5.87, 2.27 Hz, 1 H) 7.60 - 7.64 (m, 1 H) 7.70 - 7.80 (m, 2 H) 7.95 (s, 1 H) 8.31 (d, J=7.83 Hz, 1 H). LCMS (M+H)+ 240.

Examples 66-71 in Table 1 1 were prepared from 4-bromo-2-methylisoquinolin-l(2H)-one in a similar manner to Example 65 using commercially available boronic acids/esters or from commercially available tin compounds using standard Stille-type coupling conditions.

Table 11


xampe : - - -met y- - -met ypyr n- -y - -oxosoquno n- - yl]phenyl] ethanesulfonamide

Step 1: 2-methyl-6-(6-methylpyridin-3-yl)isoquinolin-l-one

[00317] A mixture of 6-bromo-2-methylisoquinolin-l-one (160 mg, 0.67 mmol), (6-methylpyridin-3-yl)boronic acid (166 mg, 0.32 mmol), Pd(dppf)Cl2 (60 mg, 0.08 mmol) and saturated aqueous NaHC03 (0.6 mL) in dioxane (6.5 mL) was microwaved at 110 °C for 1.5 h. Purification using silica gel chromatography (PE:EA = 3: 1 to 2:3) gave the title compound (160 mg, 95.2 %) as a yellow solid. LCMS: 251.2 (M+H) +

Step 2: 4-bromo-2-methyl-6-(6-meth lpyridin-3-yl)isoquinolin-l-one


[00318] Bromine (97 mg, 0.61 mmol) in acetic acid (0.61 mL) was added dropwise to 2-methyl-6-(6-methylpyridin-3-yl)isoquinolin-l-one (160 mg, 0.64 mmol) in acetic acid (6 mL) at 0 °C. After stirring at room temperature for 17 min, water (22 mL) was added and the pH was adjusted to 7-8 with 1M NaOH. Extractive work up with ethyl acetate and purification by silica gel chromatography (PE:EA = 2: 1 to 3:2) gave the title compound (135 mg, 64.3 %) as a yellow solid. LCMS: 329.0 (M+H) +

Step 3 : N-[3-[2-methyl-6-(6-methylpyridin-3-yl)- 1 -oxoisoquinolin-4-yl]phenyl] ethanesulfonamide


[00319] A mixture of 4-bromo-2-methyl-6-(6-methylpyridin-3-yl)isoquinolin-l-one (135 mg, 0.41 mmol), [3-(ethylsulfonylamino)phenyl]boronic acid (141 mg, 0.62 mmol), Pd(dppf)Cl2 (35 mg, 0.05 mmol) and aqueous 1M K P04 (1.03 mL) in dioxane (6 mL) was microwaved at 100 °C for 1 h. Purification by silica gel chromatography (PE:EA = 3: 1 to 1 :2) followed by preparative HPLC gave the title compound (25 mg, 14.1 %) as a white solid. 1H NMR (CDC13, 400 MHz) δ 8.74 (d, J = 2.0 Hz, 1 H), 8.41 (d, J = 8.4 Hz, 1 H), 7.96 (d, J = 8.0 Hz, 1 H), 7.86 (d, J = 8.8 Hz, 1 H), 7.75 (s, 1 H), 7.58 (s, 1 H), 7.47 (t, J = 8.0 Hz, 1 H), 7.39 (s, 1 H), 7.35 (d, J = 8.4 Hz, 1 H), 7.30 (d, J = 8.4 Hz, 1 H), 7.24 (d, J = 8.4 Hz, 1 H), 3.59 (s, 3 H), 3.59 (s, 3 H), 3.15 (q, J = 7.2 Hz, 2 H), 1.19 (t, J = 7.2 Hz, 3 H). LCMS: 434.1 (M+H) +.

Examples 73-74 in Table 12 were prepared from 6-bromo-2-methylisoquinolin-l-one and phenylboronic acid in three steps in a manner similar to Example 72, steps 1-3. For Example 74, [3-(methanesulfonamido)phenyl]boronic acid was substituted for [3-(ethylsulfonylamino)phenyl]boronic acid in step 3.

Table 12


Example 75: N-[3-(2,6-dimethyl-l-oxoisoquinolin-4-yl)phenyl]ethanesulfonamide

Step 1 : 2,6-dimethylisoquinolin-l-one

[00320] A mixture of 6-bromo-2-methylisoquinolin-l-one (200.0 mg, 0.84 mmol), methylboronic acid (251.0 mg, 4.2 mmol), Pd(PPh3)4 (93.0 mg, 0.08 mmol), K2C03 (232.0 mg, 1.68 mmol) and H20 (2 drops) in dioxane (10.0 mL) was microwaved at 120 °C for 1 h. Purification by silica gel chromatography (PE:EA = 5: 1) gave the title compound (120.0 mg, 82.8 %) as a light yellow solid. LCMS: 174.3 (M+H) +.

Step 2: 4-bromo-2,6-dimethylisoquinolin-l-one


[00321] 2,6-Dimethylisoquinolin-l-one (120.0 mg, 0.60 mmol) in acetic acid (4 mL) was treated with Br2 (96 mg, 0.6 mmol) in acetic acid (0.6 mL) at 0 °C in a manner similar to Example 72, step 2. Isolation, also in a similar manner, gave the title compound (145.0 mg, 82.9 %) as a white yellow solid. 1H NMR (CDC13, 400 MHz) δ 8.33 (d, J = 8.0 Hz, 1 H), 7.60 (s, 1 H), 7.37 (d, J = 8.0 Hz, 1 H), 7.35 (s, 1 H), 3.60 (s, 3 H), 2.54 (s, 3 H). LCMS: 252.1 (M+H) +

Step 3 : N-[3-(2,6-dimethyl- 1 -oxoiso uinolin-4-yl)phenyl]ethanesulfonamide


[00322] 4-Bromo-2,6-dimethylisoquinolin-l-one (75.0 mg, 0.30 mmol), [3-(ethylsulfonylamino)phenyl]boronic acid (82.0 mg, 0.36 mmol), Pd(dppf)Cl2 (22 mg, 0.03 mmol) and aqueous 1M K3P04 (0.75 mL) in dioxane (4 mL) were reacted in a manner similar to Example 72, step 3. Isolation, also in a similar manner, gave the title compound (60.0 mg, 48.1 %) as a white solid. 1H NMR (CDC13, 400 MHz) δ 8.42 (d, J = 8.4 Hz, 1 H), 7.46 (t, J = 8.0 Hz, 1 H), 7.34 (d, J = 8.0 Hz, 1 H), 7.29-7.27 (m, 2 H), 7.24 (d, J = 8.0 Hz, 1 H), 7.03 (s, 1 H), 6.68 (s, 1 H), 3.65 (s, 3 H), 3.21 (q, J = 7.2 Hz, 2 H), 2.42 (s, 3 H), 1.43 (t, J = 7.2 Hz, 3 H). LCMS: 357.0 (M+H) +

Examples 76-78 in Table 13 were prepared in three steps in a similar manner to Example 75 steps 1-3. For Examples 76 and 77, ethylboronic acid was substituted for methylboronic acid

in step 1. For Examples 77 and 78, [3-(methanesulfonamido)phenyl]boronic acid was substituted for [3-(ethylsulfonylamino)phenyl]boronic acid in step 3.

Table 13


mide

78 Methyl Methy N-[3-(2,6- (DMSO-d^) 9.88 (brs, 1 H), 8.23 343 1

dimethyl-1- (d, J = 8.0 Hz, 1 H), 7.49-7.45 (m,

oxoisoquinoli 2 H), 7.39 (d, J = 8.4 Hz, 1 H),

n-4- 7.33 (s, 1 H), 7.28-7.24 (m, 2 H),

yl)phenyl]me 7.19 (d, J = 8.0 Hz, 1 H), 3.55 (s,

thanesulfona 3 H), 3.06 (s, 3 H), 2.39 (s, 3 H)

mide

Example 79: 4-(5-ethylsulfonyl-2-methoxyphenyl)-2-methyl-6-(l -methylpyrazol-4-yl)isoquinolin- 1 -one

Step 1 : 2-bromo-4-ethylsulfanyl-l-fluorobenzene


[00323] To a mixture of 3-bromo-4-fluorobenzenethiol (2.07 g, 10 mmol) and K2CO3 (4.14 g, 30 mmol) in acetone (20 mL) was added Etl (3.12 g, 20 mmol). The mixture was stirred at room temperature for 12 h, filtered, and the volatile components were removed under vacuum to give the title compound (2.34 g) as light yellow oil which was carried on without purification. 1H NMR (CDC13, 400 MHz): d 7.54 (dd, J 1 = 6.4 Hz, J 2 = 2.4 Hz, 1 H), 7.26-7.25 (m, 1 H), 7.05 (t, J = 8.4 Hz, 1 H), 2.91 (q, J = 7.6 Hz, 2 H), 1.30 (t, J = 7.6 Hz, 3 H). Step 2: 2-bromo-4-ethylsulfonyl-l-flu robenzene


[00324] To 2-bromo-4-ethylsulfanyl-l-fluorobenzene (2.2 g, 9.36 mmol) in DCM (20 mL) was added m-CPBA (6.47 g, 37.4 mmol). The mixture was stirred at room temperature for 12 h. Aqueous saturated Na2S203 (100 mL) was added, and extractive work up with CH2C12 gave the title compound (1.5 g, 50 %) as a yellow solid which was carried on without purification. 1H NMR (CDCI3, 400 MHz) δ 8.15 (dd, Ji = 6.4 Hz, J2 = 2.4 Hz, 1 H), 7.88-7.85 (m, 1 H), 7.32 (t, J = 8.4 Hz, 1 H), 3.14 (q, J = 7.2 Hz, 2 H), 1.31 (t, J = 7.6 Hz, 3 H).

Step 3: 2-bromo-4-ethylsulfonyl-l-methox benzene

[00325] A mixture of 2-bromo-4-ethylsulfonyl-l-fluorobenzene (0.6 g, 2.25 mmol) and sodium methoxide (1.2 g, 22.2 mmol) in THF (20 mL) was stirred at room temperature for 18 h. Water (30 mL) was added and extractive work up with ethyl acetate followed by silica gel chromatography (PE:EA = 10: 1 to 1 : 1) gave the title compound (0.5 g, 79.4 %) as a yellow solid. 1H NMR (CDC13, 400 MHz) δ 8.08 (d, J = 2.4 Hz, 1 H), 7.87-7.84 (dd, Ji = 8.6 Hz, J2 = 2.4 Hz, 1 H), 7.04 (d, J = 8.8 Hz, 1 H), 3.99 (s, 3 H), 3.11 (q, J = 7.4 Hz, 2 H), 1.30 (t, J = 7.4 Hz, 3 H).

Step 4: 4-(5-ethylsulfonyl-2-methoxyphenyl)-2-methyl-6-(l-methylpyrazol-4-yl)isoquinolin-1-one


[00326] For 5 min N2 was bubbled into a mixture of 2-bromo-4-ethylsulfonyl-l-methoxybenzene (300 mg, 1.07 mmol), the title compound of Example 46, step 2 (300 mg, 0.82 mmol), K3P04 (435.6 mg, 2.05 mmol) and Pd(dppf)Cl2 (120.2 mg, 0.16 mmol) in dioxane (8 mL) and water (0.8 mL) which was then micro waved at 110 °C for 30 min.

Purification by silica gel chromatography (DCM:MeOH = 100:0 to 20: 1) gave the title compound (200 mg, 55.7 %) as a yellow solid. 1H NMR (CDC13, 400 MHz) δ 8.51 (d, J = 8.4 Hz, 1 H), 8.03 (dd, Ji = 8.8 Hz, J2 = 2.8 Hz, 1 H), 7.86 (d, J = 2.4 Hz, 1 H), 7.72 (s, 1 H), 7.64 (s, 1 H), 7.63-7.61 (m, 1H), 7.19 (d, J = 8.8 Hz, 1 H), 7.15 (d, J = 1.2 Hz, 1 H), 7.09 (s, 1 H), 3.97 (s, 3 H), 3.85 (s, 3 H), 3.68 (s, 3 H), 3.18 (q, J = 7.6 Hz, 2 H), 1.35 (t, J = 7.6 Hz, 3 H). LCMS: 438.1 (M+H) +

Example 80: 4-(5-ethylsulfonyl-2-hydroxyphenyl)-2-methyl-6-(l -methylpyrazol-4-yl)isoquinolin- 1 -one


[00327] At -78 °C, a 4 M solution of BBr3 (2.3 mL, 9.2 mmol) in CH2C12 was added to the title compound of Example 79 (200.0 mg, 0.458 mmol) in dry CH2C12 (8 mL). The mixture

was refluxed for 18 h. Extractive work up with CH2CI2 and purification by silica gel chromatography (DCM:MeOH = 100: 1 to 20: 1) gave the title compound (70 mg, 36.1 %) as a brown solid. 1H NMR (CDCI3, 400 MHz) δ 8.39 (d, J = 8.4 Hz, 1 H), 7.99 (s, 1 H), 7.87 (dd, Ji = 8.8 Hz, h = 2.4 Hz, 1 H), 7.80 (s, 1 H), 7.79 (s, 1 H), 7.76 (d, J = 1.6 Hz, 1 H), 7.39 (s, 1 H), 7.35 (d, J = 1.2 Hz, 1 H), 7.18 (d, J = 8.8 Hz, 1 H), 3.91 (s, 3 H), 3.67 (s, 3 H), 3.25 (q, J = 7.6 Hz, 2 H), 1.27 (t, J = 7.6 Hz, 3 H). LCMS: 424.0 (M+H) +

Example 81: 4-(2-ethoxy-5-ethylsulfonylphenyl)-2-methyl-6-(l-methylpyrazol-4-yl)isoquinolin- 1 -one


[00328] A mixture of the title compound of Example 80 (25.0 mg, 0.059 mmol), ethyl iodide (27.7 mg, 0.177 mmol), and K2CO3 (24.5 mg, 0.177 mmol) in acetone (2 mL) was stirred at room temperature for 18 h. After CH2CI2 extractive work up, purification by preparative TLC (PE:EA = 2: 1) gave the title compound (15.8 mg, 60%) as a white solid. 1H NMR: (CDC13, 400 MHz) δ 8.48 (d, J = 8.4 Hz, 1 H), 7.97 (dd, Ji = 8.4 Hz, J2 = 2.4 Hz, 1 H), 7.86 (d, J = 2.4 Hz, 1 H), 7.68 (s, 1 H), 7.62 (s, 1 H), 7.61 (dd, Ji = 8.4 Hz, J2 = 1.6 Hz, 1 H), 7.17 (d, J = 1.2 Hz, 1 H), 7.15 (d, J = 8.4 Hz, 1 H), 7.08 (s, 1 H), 4.3 (q, J = 7.2 Hz, 2 H), 3.94 (s, 3 H), 3.66 (s, 3 H), 3.17 (q, J = 7.6 Hz, 2 H), 1.35 (t, J = 7.6 Hz, 3 H), 1.18 (t, J = 7.2 Hz, 3 H). LCMS: 452.1 (M+H) +

Examples 82-84 in Table 14, the title compound of Example 80 was O-alkylated with the appropriate alkyl halide in a similar manner to Example 81. Example 85 in Table 14 was prepared in two steps by O-alkylation with tert-butyl N-(2-bromoethyl)carbamate in a similar manner to Example 81 followed by deprotection of the the Boc group in a manner similar to Example 32.

Table 14




Example 86: N-[2-fluoro-4-methoxy-5- 2-methyl-6-( 1 -methylpyrazol-4-yl)- - oxoisoquinolin-4-yl]phenyl]ethanesulfonamide

Step 1 : l-bromo-4-fluoro-2-methoxy-5-nitrobenzene and l-bromo-2-fluoro-4-methoxy-5- nitrobenzene

[00329] At 0 °C, sodium methoxide (344 mg, 6.3 mmol) in dry MeOH (7 mL) was added dropwise to l-bromo-2,4-difluoro-5-nitrobenzene (1 g, 4.2 mmol) in dry MeOH (18 mL). The mixture was stirred at room temperature for 10 h and then refluxed for 8 h. After extractive work up, purification by silica gel chromatography (PE:EA = 1 :0 to 10: 1) gave a mixture of the two title compounds (765 mg, 72.9 %) in about a 2: 1 ratio as a yellow solid. LCMS: 249.9 (M+H) +

Step 2: 5-bromo-2-fluoro-4-methoxyaniline


[00330] Zinc dust (0.95 g, 14.5 mmol) was added to the mixture of two title compounds from step 1 (725 mg, 2.9 mmol) in 2: 1 MeOH saturated aqueous NH4C1 (10 mL) at 0 °C. After stirring at room temperature for 30 min, extractive work upwith ethyl acetate and purification by silica gel chromatography (PE:EA = 1 :0 to 10: 1) gave the title compound (260 mg, 41 %) as a yellow solid free of the corresponding regioisomer. 1H NMR (400 MHz, DMSO-d6) δ 7.00 (d, J = 9.6 Hz, 1 H), 6.94 (d, J = 13.2 Hz, 1 H), 4.88 (s, 2 H), 3.72 (s, 3 H). LCMS: 219.9 (M+H) +

Step 3: N-(5-bromo-2-fluoro-4-methoxyphenyl)ethanesulfonamide


[00331] At 0 °C, ethansulfonylchloride (1.4 g, 10.9 mmol) was added dropwise to a solution of 5-bromo-2-fluoro-4-methoxyaniline (3.5 g, 24.0 mmol) in pyridine (1.3 g, 16.4 mmol) and dry CH2CI2 (20 mL). After stirring at room temperature for 10 h, CH2CI2 extractive work up and purification by silica gel chromatography (PE:EA = 10:0 to 3: 1) gave the title compound (2.5 g, 73.5 %) as a yellow solid. 1H NMR (400 MHz, CDCI3) δ 7.77 (d, J = 8.4 Hz, 1 H), 6.73 (d, J = 11.6 Hz, 1 H), 6.27 (s, 1 H), 3.89 (s, 3 H), 3.10 (q, J = 7.6 Hz, 2 H), 1.40 (t, J = 7.6 Hz, 3 H). LCMS: 334.0 (M+Na) +

Step 4: N-[2-fluoro-4-methoxy-5-[2-methyl-6-(l-methylpyrazol-4-yl)-l-oxoisoquinolin-4^ yl]phenyl] ethanesulfonamide


[00332] A mixture of N-(5-bromo-2-fluoro-4-methoxyphenyl)ethanesulfonamide (63 mg, 0.20 mmol), the title compound of Example 46, step 2 (75 mg, 0.21 mmol), Pd(dppf)Cl2 (19 mg, 0.03 mmol) and aqueous K3PO4 (1 M, 0.5 mL, 0.5 mmol) in dioxane (3 mL) was microwaved at 100 °C for 1 h. Purification by silica gel chromatography (PE:EA = 1 : 1 to 1 :4) followed by preparative HPLC gave the title compound (25 mg, 26.3 %) as a white solid. 1H NMR (400 MHz, CDCI3) δ 8.48 (d, J = 8.4 Hz, 1 H), 7.72 (s, 1 H), 7.69 (s, 1 H), 7.58 (d, J = 7.2 Hz, 1 H), 7.49 (d, J = 9.2 Hz, 1 H), 7.25 (s, 1 H), 7.04 (s, 1 H), 6.85 (d, J = 12.0 Hz, 1 H), 6.37 (s, 1 H), 3.94 (s, 3 H), 3.75 (s, 3 H), 3.65 (s, 3 H), 3.17 (q, J = 7.2 Hz, 2 H), 1.46 (t, J = 7.2 Hz, 3 H). LCMS: 471.1 (M+H) +

Example 87: N-[3-(2-methyl-l-oxo-6-pyridin-2-ylisoquinolin-4-yl)phenyl] ethanesulfonamide

Step 1 : 2-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one


[00333] For 5 min N2 was bubbled through a mixture of 6-bromo-2-methylisoquinolin-l-one (0.5 g, 2.1 mmol), 4,4,5, 5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l, 3,2-dioxaborolane (0.8 g, 3.1 mmol), Pd(dppf)Cl2 (153.6 mg, 0.21 mmol) and KOAc (0.51 g, 5.2 mmol) in dioxane (5 mL) which was then microwaved at 110 °C for 40 min. Purification by silica gel chromatography (PE:EA = 20: 1 to 5: 1) gave the title compound (0.45 g, 75.0 %) as yellow gum.

Step 2: 2-methyl-6-pyridin-2-ylisoquinolin-l-one


[00334] A mixture of 2-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one (420 mg, 1.47 mmol), 2-bromopyridine (698 mg, 4.42 mmol), Pd(dppf)Cl2 (107 mg, 0.15 mmol) and saturated aqueous NaHC03 (3.5 mL) in DMSO (25 mL) was microwaved at 150 °C for 45 min. After extractive work up with ethyl acetate, purification by silica gel chromatography (PE:EA = 3: 1 to 3:2) gave the title compound (160 mg, 46.0 %) as a white solid. 1H NMR (CDC13, 400 MHz) δ 8.76 (d, J = 4.8 Hz, 1 H), 8.53 (d, J = 8.0 Hz, 1 H), 8.20 (d, J = 1.2 Hz, 1 H), 8.07 (dd, Ji = 8.4 Hz, J2 = 1.6 Hz, 1 H), 7.85- 7.82 (m, 2 H), 7.34- 7.30 (m, 1 H), 7.11 (d, J = 7.2 Hz, 1 H), 6.6 (d, J = 7.2 Hz, 1 H), 3.64 (s, 3 H). LCMS: 237.2 (M+H) +

Step 3: 4-bromo-2-methyl-6-pyridin-2-ylisoquinolin-l-one


[00335] At 0 °C, bromine (78 mg, 0.49 mmol) in acetic acid (0.3 mL) was added dropwise to 2-methyl-6-pyridin-2-ylisoquinolin-l-one (115 mg, 0.49 mmol) in acetic acid (20 mL). The mixture was stirred at room temperature for 20 min. Extractive work up with CH2CI2 and purification by silica gel chromatography (PE:EA = 5: 1 -— ' 1 : 1) gave the title compound (73.0 mg, 47.7 %) as a yellow solid. 1H NMR (CDC13, 400 MHz) δ 8.79 (d, J = 4.4 Hz, 1 H), 8.55 (d, J = 8.4 Hz, 1 H), 8.44 (s, 1 H), 8.19 (d, J = 8.8 Hz, 1 H), 7.90 (d, J = 8.0 Hz, 1 H), 7.85 (t, J = 7.2 Hz, 1 H), 7.42 (s, 1 H), 7.36-7.34 (m, 1 H), 3.64 (s, 3 H). LCMS: 314.9 (M+H) + Step 4: N-[3-(2-methyl-l-oxo-6-pyridin-2-ylisoquinolin-4-yl)phenyl]ethanesulfonamide


[00336] For 5 min, N2 was bubbled through a mixture of 4-bromo-2-methyl-6-pyridin-2-ylisoquinolin-l-one (48.1 mg, 0.153 mmol), [3-(ethylsulfonylamino)phenyl]boronic acid (35.0 mg, 0.153 mmol), Pd(dppf)Cl2 (22.3 mg, 0.03 mmol) and aqueous 1M K3P04 (0.38

mL, 0.38 mmol, 1 M) in dioxane (5 mL) which was then microwaved at 80 °C for 20 min. Purification by silica gel chromatography (PE:EA = 3 : 1 to 1 :2) followed by preparative HPLC gave the title compound (2.5 mg, 3.9 %) as a white solid. 1H NMR (Methanol-d4, 400 MHz) δ 8.69 (d, J = 8.4 Hz, 1 H), 8.59 (d, J = 8.4 Hz, 1 H), 8.23 (d, J = 1.2 Hz, 1 H), 8.15-8.22 (m, 1 H), 8.10 (dd, Ji = 8.4 Hz, J2 = 1.6 Hz, 2 H ), 7.65-7.62 (m, 1 H), 7.50-7.45 (m, 3 H), 7.38-7.30 (m, 2 H), 3.71 (s, 3 H), 3.16 (q, J = 7.2 Hz, 2 H), 1.32 (t, J = 7.2 Hz, 3 H). LCMS: 420.1 (M+H) +

Example 88: 4-[4-fluoro-2-methoxy-5-(methylsulfonylmethyl)phenyl]-2-methyl-6-(l-methylpyrazol-4-yl)isoquinolin- 1 -one

Step 1 : 4-[4-fluoro-2-methoxy-5-(methylsulfonylmethyl)phenyl]-2-methyl-6-(l-methylpyrazol-4-yl)isoquinolin- 1 -one


[00337] At 0-10 °C, Br2 (24 g, 150 mmol) in acetic acid (100 mL) was added drop-wise to a solution of methyl 2-fluoro-4-hydroxybenzoate (25.5 g, 150 mmol) in acetic acid (600 mL). The mixture was stirred at room temperature overnight. Extractive work up with ethyl acetate and purification by silica gel chromatography (100 % DCM) gave the title compound (32.0 g, 86.5 %) as a white solid. 1H NMR (Methanol-d4, 400 MHz) δ 8.03 (d, J = 7.2 Hz, 1 H), 6.68 (d, J = 12.0 Hz, 1 H), 3.86 (s, 3 H). LCMS: 249.1 (M+H)+

Step 2: 5- methyl 5-bromo-2-fluoro-4-methoxybenzoate


[00338] Methyl iodide (10.6 g, 74.9 mmol) was added drop-wise to 4-[4-fluoro-2-methoxy-5-(methylsulfonylmethyl)phenyl] -2-methyl-6-( 1 -methylpyrazol-4-yl)isoquinolin- 1 -one (6.0 g, 24.1 mmol) and K2C03 (9.98 g, 72.3 mmol) in MeCN (120 mL). The mixture was heated at 80 °C overnight. Extractive work up with ethyl acetate and purification by silica gel chromatography (PE:EA = 60: 1 to 40: 1) gave the title compound (5.1 g, 80.4 %) as a white solid which was carried on without purification. 1H NMR (CDC1 , 400 MHz) δ 8.15 (d, J = 7.6 Hz, 1 H), 6.66 (d, J = 12.0 Hz, 1 H), 3.94 (s, 3 H), 3.91 (s, 3 H). LCMS: 263.0 (M+H)+ Step 3: (5-bromo-2-fluoro-4-methoxyphenyl)methanol


[00339] DIBAL-H (45.6 mL, 1M in toluene) was added drop-wise to a solution of 5- methyl 5-bromo-2-fluoro-4-methoxybenzoate (5.0 g, 19.0 mmol) in anhydrous CH2CI2 (300 mL) at -78 °C. The mixture was stirred at -78 °C for 3 h and then quenched with MeOH and water. The mixture was filtered and the filter cake rinsed with CH2CI2. The filtrate was washed with brine, dried over Na2S04, filtered, and concentrated to give the title compound (4.18 g, 94.4 %) as a white solid which was carried on without purification. 1H NMR (DMSO-d6, 400 MHz) δ 7.59 (d, J = 7.6 Hz, 1 H), 7.02 (d, J = 12.4 Hz, 1 H), 5.25 (t, J = 5.6 Hz, 1 H), 4.45 (d, J = 5.6 Hz, 2 H), 3.84 (s, 3 H).

Step 4: l-bromo-5-(bromomethyl)-4-fluoro-2-methoxybenzene


[00340] PBr3 (4.7 g, 17.4 mmol) was added drop-wise to a solution of (5-bromo-2-fluoro-4-methoxyphenyl)methanol (4.1 g, 17.4 mmol) in anhydrous CH2CI2 (40 mL) at 0 °C. The mixture was stirred at room temperature for 3 h and poured into ice water. The pH was adjusted to 8 with saturated aqueous NaHC03. Extractive work up with CH2CI2 gave the title compound (4.9 g, 94.8 %) as a white solid which was carried on without purification. 1H NMR (DMSO-de, 400 MHz) δ 7.56 (d, J = 8.0 Hz, 1 H), 6.65 (d, J = 11.6 Hz, 1 H), 4.46 (s, 2 H), 3.89 (s, 3 H).

Step 5 : 1 -bromo-4-fluoro-2-methoxy-5-(methylsulfanylmethyl)benzene


[00341] Thiomethoxide (1.19 g, 17.0 mmol) was added to a solution of l-bromo-5-(bromomethyl)-4-fluoro-2-methoxybenzene (4.9 g, 16.4 mmol) in anhydrous DMF (25 mL) at 0 °C. The mixture was stirred at room temperature for 5 h, and then poured into water (40 mL). Extractive work up with ethyl acetate gave the title compound (4.3 g, 99.0 %) as colorless oil which was carried on without purification. 1H NMR (CDC13, 400 MHz) δ 7.50 (d, J = 8.0 Hz, 1 H), 6.64 (d, J = 11.2 Hz, 1 H), 3.88 (s, 3 H), 3.63 (s, 2 H), 2.04 (s, 3 H).

Step 6: l-bromo-4-fluoro-2-methoxy-5-(methylsulfonylmethyl)benzene


[00342] Oxone (20.9 g, 34.1 mmol) in H20 (100 mL) was added drop-wise to a solution of 1-bromo-4-fluoro-2-methoxy-5-(methylsulfanylmethyl)benzene (4.3 g, 16.2 mmol) in MeOH (100 mL) at 0 °C. The mixture was then stirred at room temperature for 3 h and then poured into water. Extractive work up with ethyl acetate, washing with saturated aqueous Na2S03 (40 mL) and brine, gave a solid that was triturated with 1 : 10/EA:MTBE to give the title compound (4.40 g, 93.0 %) as a white solid. 1H NMR (CDC13, 400 MHz) δ 7.66 (d, J = 8.0 Hz, 1 H), 6.72 (d, J = 11.2 Hz, 1 H), 4.22 (s, 2 H), 3.92 (s, 3 H), 2.83 (s, 3 H). LCMS: 318.9 (M+Na) +

Step 7: 4-[4-fluoro-2-methoxy-5-(methylsulfonylmethyl)phenyl]-2-methyl-6-(l-methylpyrazol-4-yl)isoquinolin- 1 -one


[00343] l-Bromo-4-fluoro-2-methoxy-5-(methylsulfonylmethyl)benzene (34.0 mg, 0.114 mmol), the title compound of Example 46, step 2 (50.0 mg, 0.137 mmol), Pd(dppf)Cl2 (20.0 mg, 0.027 mmol) and 1 M aqueous K3PO4 (0.47 mL, 0.47 mmol) in dioxane (3.0 mL) were micro waved at 100 °C for 40 min. Preparative HPLC gave the title compound (10.0 mg, 18 %) as a light yellow solid. 1H NMR: (CDCI3, 400 MHz) δ 8.47 (d, J = 8.0 Hz, 1 H), 7.74 (s, 1 H), 7.73 (s, 1 H), 7.60 (d, J = 8.4 Hz, 1 H), 7.42 (d, J = 8.4 Hz, 1 H), 7.27 (s, 1 H), 7.05 (s, 1 H), 6.85 (d, J = 12.0 Hz, 1 H), 4.32 (d, J = 6.4 Hz, 2 H), 3.93 (s, 3 H), 3.77 (s, 3 H), 3.64 (s, 3 H), 2.93 (s, 3 H). LCMS: 456.1 (M+H) +.

Example 89: 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one

Step 1 : 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one

[00344] A suspension of 4-bromo-2-methylisoquinolin-l-one (100 mg, 0.42 mmol), bis(pinacolato)diboron (214 mg, 0.84 mmol), Pd(dppf)Cl2 (31 mg, 0.04 mmol) and potassium acetate (104 mg, 1.05 mmol) in dioxane (2 mL) under nitrogen was warmed up to 90 °C for 135 minutes. It was then cooled down to room temperature and diluted with ethyl acetate (8 mL). The mixture was washed with aqueous saturated solution of NaHC03 (8 mL) and brine (8 mL). The organic phase was separated, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purifed by normal phase column chromatography (10-90% EtOAc/Hexanes) to give the title compound (44 mg, 37%). 1H NMR (CDC13, 400 MHz) δ 8.43 (d, J = 7.9 Hz, 1 H), 8.40 (dd, J = 8.2 Hz, 0.9 Hz, 1 H), 7.68 (s, 1 H), 7.65 (ddd, J = 8.2, 8.2, 1.1 Hz, 1 H), 7.46 (t, J = 7.5 Hz, 1 H), 3.63 (s, 3H), 1.38 (s, 12H). LCMS (M+H)+ 286. Step 2: 4-[2-(cyclopropylmethox -5-methylsulfonylphenyl]-2-methylisoquinolin-l-one


[00345] The title compound was prepared in a manner similar to Example 18, step 3, substituting 2-bromo-l-(cyclopropylmethoxy)-4-methylsulfonylbenzene for 4-bromo-2-methylisoquinolin-l(2H)-one and 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one for N-benzyl-2-methoxy-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide. 1H NMR (DMSO-d6, 400 MHz) δ 0.09 (m, 2 H), 0.29 (m, 1H), 0.35 (m, 1H),

0.94 (m, 1H), 3.22 (s, 3H), 3.57 (s, 3H), 3.95 (m, 2H), 7.16 (d, J = 7.9 Hz, 1H), 7.37 (d, J =

8.8 Hz, 1H), 7.53 (m, 2H), 7.65 (t, J = 7.6 Hz, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.97 (dd, J = 8.8,

2.4 Hz, 1H), 8.30 (d, J = 8.1 Hz, 1H). LCMS (M+H)+ 384.

[00346] Alternatively, 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one can be prepared as described below.

Step 1 : 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one


[00347] A mixture of 4-bromo-2-methylisoquinolin-l-one (8.0 g, 33.6 mmol),

bis(pinacolato)diboron (17.1 g, 67.2 mmol), KOAc (6.6 g, 67.2 mmol), Pd2(dba)3 (3.1 g, 3.36 mmol) and X-Phos (1.6 g, 3.36 mmol) in anhydrous dioxane (200 mL) was stirred at 60 °C for 12 h. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (PE : EA = 15 : 1) to give the title compound (6.0 g, 62 %) as a solid.

Step 2: 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one

[00348] The title compound from Step 1 (5.0 g, 17.5 mmol), 2-bromo-l-(cyclopropylmethoxy)-4-methylsulfonylbenzene (6.4 g, 21 mmol), K3PO4 (9.3 g, 43.9 mmol) and Pd(dppf)Cl2 (1.4 g, 1.75 mmol) in a dioxane/water (100 mL / 10 mL) mixture were stirred at 60 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (EA : DCM = 1 : 4).

Appropriate fractions were combined and concentrated under reduce pressure. The resultant solid was recrystallized from DCM / MTBE (1 : 1, 50 mL) to give the title compound (4.0 g, 60 %) as a white solid. 1H NMR: (CDC13, 400 MHz) δ 8.51 (dd, Ji = 8.0 Hz, J2 = 0.8 Hz, 1 H), 7.98 (dd, Ji = 8.4 Hz, J2 = 2.4 Hz, 1 H), 7.86 (d, J = 2.4 Hz, 1 H), 7.53 (m, 2 H), 7.16 (d, J = 7.6 Hz, 1 H), 7.10 (m, 2 H), 3.88 (m, 2 H), 3.66 (s, 3 H), 3.09 (s, 3 H), 1.02-0.98 (m, 1 H), 0.44-0.38 (m, 2 H), 0.11-0.09 (m, 2 H). LCMS: 384.1 (M+H)+

Example 90: 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-fluoro-2-methylisoquinolin- 1 -one

Step 1 : 2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane

[00349] The title compound was prepared in a manner similar to Example 89, step 1, substituting 2-bromo-l-(cyclopropylmethoxy)-4-methylsulfonylbenzene for 4-bromo-2-methylisoquinolin-l-one. 1H NMR (CDC13, 400 MHz) δ 0.46 (m, 2 H), 0.60 (m, 2H), 1.24 (m, 1H), 1.35 (s, 12H), 3.02 (s, 3H), 3.97 (d, J = 6.0, 2H), 6.91 (d, J = 8.7 Hz, 1H), 7.92 (dd, J = 8.7, 2.5 Hz, 1H), 8.15 (d, J = 2.4 Hz, 1H). LCMS (M+H)+ 353.

Step 2: 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-fluoro-2-methylisoquinolin-l-one


[00350] The title compound was prepared in a manner similar to Example 18, step 3, substituting the title compound of Example 47, step 2 for 4-bromo-2-methylisoquinolin-l(2H)-one and 2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane for N-benzyl-2-methoxy-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide. 1H NMR (DMSO-d6, 400 MHz) δ 0.12 (m, 2 H), 0.32 (m, 1H), 0.39 (m, 1H), 0.99 (m, 1H), 3.22 (s, 3H), 3.56 (s, 3H), 3.97 (m, 2H), 6.82 (dd, J = 10.5, 2.4 Hz, 1H), 7.39 (m, 2H), 7.61 (s, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.98 (dd, J = 8.74, 2.4 Hz, 1H), 8.36 (dd, J = 8.9, 6.1 Hz, 1H). LCMS (M+H)+ 402.

Example 91 : 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-7-fluoro-2-methylisoquinolin- 1 -one


[00351] The title compound was prepared in a manner similar to Example 18, step 3, substituting the title compound of Example 58, step 2 for 4-bromo-2-methylisoquinolin-l(2H)-one and 2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane for N-benzyl-2-methoxy-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide. 1H NMR (DMSO-d6, 400 MHz) δ 0.10 (m, 2 H), 0.30 (m, 1H), 0.39 (m, 1H),

0.94 (m, 1H), 3.22 (s, 3H), 3.58 (s, 3H), 3.95 (m, 2H), 7.24 (dd, J = 9, 5.3 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.54 (s, 1H), 7.56 (m, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.96 (m, 2H). LCMS (M+H)+ 402.

[00352] Example 92: 4-[2-(2,4-difluorophenoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin- 1 -one


[00353] The title compound was prepared in a manner similar to Example 18, step 3, substituting l-(2-bromo-4-methylsulfonylphenoxy)-2,4-difluorobenzene for 4-bromo-2-methylisoquinolin-l(2H)-one and 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one for N-benzyl-2-methoxy-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide. 1H NMR (DMSO-d6, 400 MHz) δ 3.27 (s, 3H), 3.58 (s, 3H), 7.03 (d, J = 9.2 Hz, 1H), 7.13 (m, 1H), 7.35 (m, 2H), 7.48 (m, 1H), 7.54 (t, J = 7.5, 1H), 7.67 (s, 1H), 7.69 (m, 1H), 7.97 (m, 1H), 7.98 (s, 1H), 8.30 (d, J = 8.1, 1H). LCMS (M+H)+ 442.

Example 93: N-[4-(2,4-difluorophenoxy)-3-(2-methyl-l -oxoisoquinolin-4-yl)phenyl] ethanesulfonamide


[00354] The title compound was prepared in a manner similar to Example 18, step 3, substituting N-[3-bromo-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide for 4-bromo-2-methylisoquinolin-l(2H)-one and 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one for N-benzyl-2-methoxy-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide. 1H NMR (DMSO-d6, 400 MHz) δ 1.23 (t, J = 7.3 Hz, 3H), 3.13 (q, J = 7.8 Hz, 2H), 3.53 (s, 3H), 6.95 (m, 2H), 7.09 (m, 1H), 7.28 (m, 3H), 7.51 (m, 2H), 7.65 (t, J = 6.9 Hz, 1H), 8.26 (d, J = 0.8 Hz, 1H), 9.83 (s, 1H). LCMS (M+H)+ 471.

Example 94: N-[3-(l -methyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide


[00355] A mixture of 5-bromo-l-methylpyridin-2-one (100 mg, 0.532 mmol), [3-(methanesulfonamido)phenyl]boronic acid (171.1 mg, 0.798 mmol), KOAc (130.0 mg, 1.326 mmol) and Pd(dppf)Cl2 (38.9 mg, 0.05 mmol) in dioxane/H20 (2 mL/0.5 mL) was stirred at 90 °C for 20 min. The mixture was concentrated and the residue was purified by column chromatography on silica gel (PE:EA = 1 : 1) to give the title compound (30.0 mg, 20 %) as a brown solid. 1H NMR (CDC13, 400 MHz) δ 7.65-7.60 (dd, Ji = 7.6 Hz, J2 = 2.4 Hz, 1 H), 7.54 (d, J = 2.4 Hz, 1 H), 7.41 (t, J = 8.0 Hz, 1 H), 7.33 (s, 1 H), 7.24 (d, J = 7.6 Hz, 1 H), 7.17 (d, J = 7.6 Hz, 1 H), 6.86 (brs, 1 H), 6.67 (d, J = 9.2 Hz, 1 H), 3.65 (s, 3 H), 3.05 (s, 3 H). LCMS (M+H)+ 279.

Example 95: N-[3-(l ,4-dimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide

Step 1 : 5-bromo-l,4-dimethylpyridin-2-one


[00356] To a solution of 5-bromo-4-methylpyridin-2-ol (1.12 g, 6.0 mmol) in anhydrous THF (20 mL) was added NaH (288.0 mg, 12.0 mmol) and the reaction mixture was stirred at 0 °C for 30 min. Then, methyl iodide (1.7 g, 12.0 mmol) was added and stirred at room

temperature for 3 h. Saturated NH4CI (100 mL) was added and the resulting mixture was extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2S04 and concentrated. The residue was purified by column chromatography on silica gel (PE:EA = 10: 1 to 2: 1) to give the title compound (1.0 g, 83.3 %) as a yellow solid. 1H NMR (CDC13, 400 MHz) δ 7.44 (s, 1 H), 6.94 (s, 1 H), 3.51 (s, 3 H), 2.24 (s, 3 H). LCMS (M+H)+ 202.

Step 2 : N- [3 -( 1 -methyl-6-oxopyridin-3 -yl)phenyl]methanesulfonamide


[00357] 5-Bromo-l,4-dimethylpyridin-2-one was treated with [3- (methanesulfonamido)phenyl]boronic acid in a manner similar to Example 94 to give the title compound as a white solid. 1H NMR (CDCI3, 400 MHz) δ 7.43 (t, J = 8.0 Hz, 1 H), 7.20 (d, J = 8.0 Hz, 1 H), 7.16 (s, 1 H), 7.07 (d, J = 7.6 Hz, 1 H), 6.71 (s, 1 H), 6.69 (s, 1 H), 3.67 (s, 3 H), 3.07 (s, 3 H), 2.16 (s, 3 H). LCMS (M+H)+ 293.

Example 96: N-[3-(l ,5-dimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide

Step 1 : 5-bromo-l,3-dimethylpyridin-2-one


[00358] The title compound of step 1 was prepared in a manner similar to Example 95, step 1 using 5-bromo-3-methylpyridin-2-ol instead of 5-bromo-4-methylpyridin-2-ol to give 5-bromo-l,3-dimethylpyridin-2-one. 1H NMR (CDC13, 400 MHz): 7.30 (d, J = 2.0 Hz, 1 H), 7.26 (d, J = 1.6 Hz, 1 H), 3.53 (s, 3 H), 2.16 (s, 3 H). LCMS (M+H)+ 202.

Step 2: N-[3-(l ,5-dimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide


[00359] 5-Bromo-l,3-dimethylpyridin-2-one was treated with [3- (methanesulfonamido)phenyl]boronic acid in a manner similar to Example 94 to give the title compound as a white solid. 1H NMR (DMSO-d6, 400 MHz): 9.74 (s, 1 H), 7.91 (d, J = 2.4 Hz, 1 H), 7.62 (s, 1 H), 7.37 (t, J = 7.6 Hz, 1 H), 7.32 (s, 1 H), 7.29 (d, J = 7.6 Hz, 1 H), 7.13 (d, J = 7.6 Hz, 1 H), 3.52 (s, 3 H), 3.02 (s, 3 H), 2.08 (s, 3 H). LCMS (M+H)+ 293.

Example 97: N-[3-(l ,4,5-trimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide

Step 1 : 5-bromo-3,4-dimethyl-lH-pyridin-2-one


[00360] To a mixture of 5-bromo-3,4-dimethylpyridin-2-amine (0.6 g, 3.0 mmol) and H2SO4 (98 %, 1.62 mL) and H20 (18 mL) is added a solution of NaN02 (243.6 mg, 4.2 mmol) in H20 (1.6 mL) drop-wise at 0 °C. Then, it was stirred at 31 °C for 30 minutes and filtered. The resulting solid is washed with water to provide the title compound (375.0 mg, 62 %) as a white solid. 1H NMR (CDC13, 400 MHz) δ 7.48 (s, 1 H), 2.32 (s, 3 H), 2.19 (s, 3 H). LCMS (M+H)+ 202.

Step 2: 5-bromo-l,3,4-trimethylpyridin-2-one


[00361] To a solution of 5-bromo-3,4-dimethyl-lH-pyridin-2-one (402.0 mg, 2.0 mmol) in anhydrous THF (20 mL) was added NaH (96.0 mg, 2.4 mmol). The resulting mixture was stirred at 0 °C for 30 min. Methyl iodide (568.0 mg, 4.0 mmol) was added and the reaction was stirred at 32 °C for 3 h. Then, saturated aqueous NH4CI (100 mL) was added and the mixture extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2S04j filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EA = 10: 1 to 2: 1) to give the title compound (350.0 mg, 80 %) as a white solid. 1H NMR (CDCI3, 400 MHz) δ 7.38 (s, 1 H), 3.52 (s, 3 H), 2.27 (s, 3 H), 2.20 (s, 3 H). LCMS (M+H)+ 216.

Step 3 : N-[3-(l ,4,5-trimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide


[00362] 5-Bromo-l,3,4-trimethylpyridin-2-one was treated with [3- (methanesulfonamido)phenyl]boronic acid in a manner similar to Example 94 to give the title compound as a white solid. 1H NMR (CDCI3, 400 MHz) δ 7.42 (s, 1 H), 7.39 (t, J = 7.6 Hz, 1 H), 7.24 (s, 1 H), 7.16 (s, 1 H), 7.08 (s, 1 H), 7.05 (d, J = 7.6 Hz, 1 H), 3.59 (s, 3 H), 3.06 (s, 3 H), 2.19 (s, 3 H), 2.06 (s, 3 H). LCMS (M+H)+ 307.

Example 98: 5- [2-(cyclopropylmethoxy)-5 -methylsulfonylphenyl] - 1 -methylpyridin-2-one Step 1 : l-methyl-5-(4,4,5,5-tetrameth -l,3,2-dioxaborolan-2-yl)pyridin-2-one


[00363] A solution of 5-bromo-l-methylpyridin-2-one (200.0 mg, 1.06 mmol),

bis(pinacolato)diboron (410.0 mg, 1.61 mmol), potassium acetate (270 mg, 2.67 mmol), Pd (dppf)Cl2 (80 mg, 0.11 mmol) in dioxane (5 mL) was heated at 100 °C for 2 h under microwave. The mixture was filtered, washed with water and extracted with ethyl acetate (20 mL x 3). The combined organics were dried over Na2S04, filtered and concentrated to give the crude title compound (59.0 mg, 23.6%). LCMS (M+H)+ 236.

Step 2 : 5 -[2-(cyclopropylmethoxy)-5 -methylsulfonylphenyl] - 1 -methylpyridin-2-one


[00364] l-Methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one was treated with 2-bromo-l-(cyclopropylmethoxy)-4-methylsulfonylbenzene in a manner similar to Example 94 to give the title compound. 1H NMR (CDC13, 400 MHz): δ 7.86 (dd, Ji = 8.8 Hz, h = 2.4 Hz, 1 H), 7.81 (d, J = 2.0 Hz, 1 H), 7.68-765 (m, 2 H), 7.03 (d, J = 8.4 Hz, 1 H), 6.66 (d, J = 8.8 Hz, 1 H), 3.95 (d, J = 6.8 Hz, 2 H), 3.64 (s, 3 H), 3.07 (s, 3 H), 1.28-1.25 (m, 1 H), 0.69-0.65 (m, 2 H), 0.34-0.38 (m, 2 H). LCMS (M+H)+ 334.

Example 99: N-[4-(2,4-difluorophenoxy)-3-(l-methyl-6-oxopyridin-3-yl)phenyl] ethanesulfonamide

Step 1 : 5-[5-amino-2-(2,4-difluorophenoxy)phenyl]-l-methylpyridin-2-one


[00365] A mixture of the title compound of step 1 in Example 57 (100 mg, 0.289 mmol), 5-bromo-l-methylpyridin-2-one (45.27 mg, 0.240 mmol), K3PO4 (127.6 mg, 0.60 mmol) and Pd(dppf)Cl2 (20 mg, 0.027 mmol) in dioxane/H20 (4/0.5 mL) was stirred at 100 °C for 40 min under microwave. The mixture was concentrated and the residue was purified by column chromatography on silica gel (PE:EA =1 :2) to give the title compound (60 mg, 76 %). LCMS (M+H)+ 328.

Step 2: N-[4-(2,4-difluorophenoxy)-3-(l-methyl-6-oxopyridin-3-yl)phenyl] ethanesulfonamide


[00366] To a solution of 5-[5-amino-2-(2,4-difluorophenoxy)phenyl]-l-methylpyridin-2-one (30 mg, 0.09 mmol) in DCM (4 mL) was added TEA (27.3 mg, 0.27 mmol) and EtS02Cl (35.39 mg, 0.27 mmol). The mixture was stirred at 30 °C for 12 h. Water (4 mL) was added and the mixture was extracted with DCM (4 mL x 3). The organic layer was concentrated and the residue was purified by prep-HPLC to give the title compound (10 mg, 26 %) as light yellow gum. 1H NMR (CDCI3, 400 MHz) 57.68-7.66 (m, 2 H), 7.28 (d, J = 2.4 Hz, 1 H), 7.13-7.10 (m, 1 H), 7.09 (s, 1 H), 7.00-6.92 (m, 2 H), 6.84-6.86 (m, 1 H), 6.78 (d, J = 8.4 Hz, 1 H), 6.73 (d, J = 9.2 Hz, 1 H), 3.65 (s, 3 H), 3.14 (q, J = 7.2 Hz, 2 H), 1.41 (t, J = 7.2 Hz, 3 H). LCMS (M+H)+ 421.

Example 100: N-[4-(2,4-difluorophenoxy)-3-(l-methyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide


[00367] Preparation was carried out in a manner similar to Example 99, substituting methanesulfonyl chloride for ethanesulfonyl chloride in step 2 to give the title compound as a light yellow gum. 1H NMR (CDC13, 400 MHz) δ 7.64-7.62 (m, 2 H), 7.29 (d, J = 4.8 Hz, 1

H), 7.13-7.12 (m, 1 H), 6.69-6.95 (m, 2 H), 6.79 (m, 1 H), 6.79 (d, J = 8.4 Hz, 1 H), 6.62 (d, J

= 9.4 Hz, 1 H), 3.61 (s, 3 H), 3.04 (s, 3 H). LCMS (M+H)+ 407.

Example 101: N-[4-(2,4-difluorophenoxy)-3-(l,4-dimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamid


[00368] Preparation was carried out in a manner similar to Example 100, substituting 5-bromo-l,4-dimethylpyridin-2-one for 5-bromo-l-methylpyridin-2-one in step 1 to give the title compound. 1H NMR (CDC13, 400 MHz) δ 7.21-7.16 (m, 4 H), 6.95-6.93 (m, 2 H), 6.86- 6.80 (m, 1 H), 6.77 (d, J = 8.8 Hz, 1 H), 6.53 (s, 1 H), 3.57 (s, 3 H), 3.04 (s, 3 H), 2.10 (s, 3 H). LCMS (M+H)+ 421.

Example 102: N-[4-(2,4-difluorophenoxy)-3-(l ,5-dimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide


[00369] Preparation was carried out in a manner similar to Example 100, substituting 5-bromo-l,3-dimethylpyridin-2-one for 5-bromo-l-methylpyridin-2-one to give the title compound. 1H NMR (CDC13, 400 MHz) δ 7.53 (s, 2 H), 7.40 (s., 1 H), 7.31 (d, J = 2.4 Hz, 1 H), 7.17 (dd, Ji = 8.8 Hz, J2 = 2.4 Hz, 1 H), 6.99-6.90 (m, 2 H), 6.87-6.80 (m, 1 H), 6.80 (d, J = 8.8 Hz, 1 H ), 3.63 (s, 3 H), 3.03 (s, 3 H), 2.19 (s, 3 H). LCMS (M+H)+ 421.

Example 103: N-[4-(2,4-difluorophenoxy)-3-(l ,4,5-trimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide


[00370] Preparation was carried out in a manner similar to Example 100, substituting 5-bromo-l,3,4-trimethylpyridin-2-one for 5-bromo-l-methylpyridin-2-one to give the title compound. 1H NMR (Methanol-d4, 400 MHz) δ 7.65 (dd, J i = 8.8 Hz, J 2 = 2.4 Hz, 1 H), 7.58 (d, J = 2.8 Hz, 1 H), 7.39 (s, 1 H), 7.05-7.01 (m, 2 H), 6.94-6.91 (m, 2 H), 3.55 (s, 3 H), 3.31 (s, 3 H), 2.13 (s, 3 H), 2.08 (s, 3 H). LCMS (M+18+H)+ 453.

Example 104 : 3 -amino- 1 -methyl-5 -(3 -methylsulfonylphenyl)pyrazin-2-one

Step 1 : 3-amino-5-bromo-l-methylpyrazin-2-one


[00371] A solution of 3,5-dibromo-l-methylpyrazin-2-one (500.0 mg, 2.46 mmol), NH3H20 (5.0 mL) in dioxane (30.0 mL) was heated at 105 °C for 20 h. The mixture was concentrated, diluted with EtOAc (50 mL) and filtrated to give the title compound (300.0 mg, 79.0 %) which was carried on without purification. LCMS (M+H)+ 204.

Step 2: 3 -amino- 1 -methyl-5 -(3 -methylsulfonylphenyl)pyrazin-2-one


[00372] A solution of 3-amino-5-bromo-l-methylpyrazin-2-one (81.0 mg, 0.4 mmol), (3-methylsulfonylphenyl)boronic acid (120.0 mg, 0.6 mmol), Cs2C03 (391.0 mg, 1.2 mmol), Pd(PPh3) 4 (20.0 mg, 0.017 mmol) in dioxane (20.0 mL) and water (2.0 mL) was stirred at 95 °C for 12 h under N2. The mixture was concentrated and purified by silica gel

chromatography (PE: EA = 3:2) to give the title compound (20.0 mg, 18 %). 1H NMR (DMSO-de 400 MHz): δ 8.35 (s, 1 H), 8.11 (d, J = 8.0 Hz, 1 H), 7.80 (d, J = 8.0 Hz, 1 H),

7.73 (s, 1 H), 7.66 (t, J = 8.0 Hz, 1 H), 6.93 (brs, 2 H), 3.50 (s, 3 H), 3.24 (s, 3 H).. LCMS (M+H)+ 280.

Example 105: 3-amino-5-(3-ethylsulfonylphenyl)- 1 -methylpyrazin-2-one


[00373] Preparation was carried out in a manner similar to Example 104, step 2, substituting (3-ethylsulfonylphenyl)boronic acid for (3-methylsulfonylphenyl)boronic acid to give the title compound. 1H NMR (DMSO-d6 400 MHz): δ 8.30 (t, J = 1.6 Hz, 1 H), 8.11 (d, J = 8.0 Hz, 1 H), 7.74 (d, J = 8.0 Hz, 1 H), 7.71 (s, 1 H), 7.65 (t, J = 8.0 Hz, 1 H), 6.90 (brs, 2 H), 3.48 (s, 3 H), 3.29 (q, J = 7.2 Hz, 2 H), 1.11 (t, J = 7.2 Hz, 3 H). LCMS (M+H)+ 294.

Example 106: N-[5-(6-amino-4-methyl-5-oxopyrazin-2-yl)-2-methoxyphenyljmethanesulfonamide


[00374] Preparation was carried out in a manner similar to Example 104, step 2, substituting [3-(methanesulfonamido)-4-methoxyphenyl]boronic acid for (3-methylsulfonylphenyl)boronic acid to give the title compound. 1H NMR (DMSO-d6 400 MHz): δ 8.91 (s, 1 H), 7.68 (d, J = 2.4 Hz, 1 H), 7.61 (dd, Ji = 8.8 Hz, J2 = 2.4 Hz, 1 H), 7.38 (s, 1 H), 7.08 (d, J = 8.8 Hz, 1 H), 6.88-6.64 (m, 2 H), 3.84 (s, 3 H), 3.46 (s, 3 H), 2.95 (s, 3 H). LCMS (M+H)+ 325.

Example 107: 3 -amino- 1 -methyl-5 -(3 -methylsulfonylphenyl)pyridin-2-one


[00375] Preparation was carried out in a manner similar to Example 104, step 2, substituting 3-amino-5-bromo-l-methylpyridin-2-one for 3-amino-5-bromo-l-methylpyrazin-2-one to give the title compound. 1H NMR (Methanol-d4, 400 MHz) δ 8.06 (t, J = 2.0 Hz, 1 H), 7.89-7.85 (m, 2 H), 7.67 (t, J = 8.0 Hz, 1 H), 7.39 (d, J = 2.0 Hz ,1 H), 7.03 (d, J = 2.4 Hz ,1 H), 3.67 (s, 3 H), 3.17 (s, 3 H). LCMS (M+H)+ 279.

Example 108: 3-amino-5-(3-ethylsulfon lphenyl)- 1 -methylpyridin-2-one


[00376] Preparation was carried out in a manner similar to Example 105, substituting 3-amino-5-bromo-l-methylpyridin-2-one for 3-amino-5-bromo-l-methylpyrazin-2-one to give the title compound. 1H NMR (Methanol-d4, 400MHz) δ 8.01 (t, J = 2.0 Hz, 1 H), 7.88-7.83 (m, 2 H), 7.68 (t, J = 8.0 Hz, 1 H), 7.39 (d, J = 2.0 Hz ,1 H), 7.03 (d, J = 2.4 Hz ,1 H), 3.67 (s, 3 H), 3.26 (q, J = 7.6 Hz, 2 H), 1.25 (t, J = 7.6 Hz, 3 H). LCMS (M+H)+ 293.

Example 109: N-[5-(5-amino-l-methyl-6-oxopyridin-3-yl)-2-methoxyphenyljmethanesulfonamide


[00377] Preparation was carried out in a manner similar to Example 106, substituting 3-amino-5-bromo-l-methylpyridin-2-one for 3-amino-5-bromo-l-methylpyrazin-2-one to give the title compound. 1H NMR (Methanol-d4, 400 MHz) δ 7.53 (d, J = 2.4 Hz, 1 H), 7.34 (dd,

Ji = 8.8 Hz, = 2.4 Hz, 1 H), 7.18 (d, J = 2.4 Hz, 1 H), 7.09 (d, J = 8.8 Hz, 1 H), 6.96 (d, J 2.4 Hz, 1 H), 3.92 (s, 3 H), 3.64 (s, 3 H), 2.94 (s, 3 H). LCMS (M+H)+ 324.

Example 110: N-[2-methoxy-5-[ 1 -methyl-5-(methylamino)-6-oxopyridin-3-yl]phenyl]methanesulfonamide

Step 1 : tert-butyl N-(5-bromo-l-methyl-2-oxopyridin-3-yl)carbamate


[00378] To a solution of 3-amino-5-bromo-l-methylpyridin-2-one (404.0 mg, 2.0 mmol) in DCM (30 mL) was added (Boc)20 (654.0 mg, 3.0 mmol), Et3N (606.0 mg, 6.0 mmol) dropwise and DMAP (123.0 mg, 1.0 mmol). The reaction mixture was stirred for 12 h at 30 °C, quenched with saturated aqueous NH4C1 (50 mL), extracted with EA (50 mL), dried over Na2S04, filtered and concentrated. Silica gel chromatography (PE:EA = 2: 1) gave the impure title compound (400.0 mg) as a green solid, which was carried on to the next step. LCMS (M-55)+ 247.

Step 2: tert-butyl N-(5-bromo-l-methyl-2-oxopyridin-3-yl)-N-methylcarbamate


[00379] To a solution of tert-butyl N-(5-bromo-l-methyl-2-oxopyridin-3-yl)carbamate (150.0 mg, impure) in DMF (10 mL) was added NaH (60.0 mg, 1.5 mol, 60 % in oil) in portions at 0

°C. It was stirred for 30 min. Then CH3I (231.0 mg, 1.5 mmol) was added dropwise at 0 °C.

The reaction mixture was stirred for 2 h at 30 °C. The reaction was quenched with saturated aqueous NH4C1 (15 mL), extracted with EA (20 mL), washed with brine (20 mL), dried over

Na2S04, filtered and concentrated to give the title compound (120.0 mg, crude) as a green solid, which was used directly in the next step without purification.

Step 3: 5 -bromo-l-methyl-3 -(methyl amino)pyridin-2-one


[00380] To a solution of tert-butyl N-(5-bromo-l-methyl-2-oxopyridin-3-yl)-N-methylcarbamate (94.8 mg, crude) in DCM (10 mL) was added HCl/dioxane (1 mL, 4 M)

dropwise with stirring at 30 °C. The reaction mixture was stirred at 30 °C for 30 min. The mixture was filtered and the filter cake collected. The filtrate was adjusted to pH = 9 with saturated aqueous NaHC03, extracted with ethyl acetate (20 mL), dried over Na2S04, filtered and concentrated to give a green solid which was combined with the filter cake to give the title compound (43.2 mg). 1H NMR (CDC13 400MHz): δ 6.74 (d, J = 2.4 Hz, 1 H), 6.18 (d, J =2.4 Hz, 1 H), 5.15 (s, 1 H), 3.53 (s, 3 H), 2.83 (s, 3 H). LCMS (M+H)+ 217.

Step 4: N-[2-methoxy-5-[l-methyl-5-(methylamino)-6-oxopyridin-3-yl]phenyl]methanesulfonamide


[00381] The title compound was prepared in a manner similar to Example 106, substituting the title compound of step 3 for 3-amino-5-bromo-l-methylpyrazin-2-one. 1H NMR

(Methanol-d4, 400 MHz): δ 7.55 (d, J = 2.0 Hz, 1 H), 7.38 (dd, Ji = 8.8, J2 = 2.4 Hz, 1 H), 7.13-7.08 (m, 2 H), 6.52 (d, J = 2.0 Hz, 1 H), 3.93 (s, 3 H), 3.63 (s, 3 H), 2.94 (s, 3 H), 2.88 (s, 3 H).. LCMS (M+H)+ 338.

Example 111: N-[5-[5-(ethylamino)-l-methyl-6-oxopyridin-3-yl]-2-methoxyphenyljmethanesulfonamide

Step 1 : tert-butyl N-(5-bromo-l-methy -2-oxopyridin-3-yl)-N-ethylcarbamate


[00382] To a solution of the title compound from Example 110, step 1 (150.0 mg, crude) in DMF (10 mL) was added NaH (60.0 mg, 1.5 mmol, 60 % in oil) in portions at 0 °C and stirred for 30 min. Then iodoethane (234.0 mg, 1.5 mmol) was added dropwise at 0 °C. The reaction mixture was stirred for 2 h at 30 °C. It was then quenched with saturated aqueous NH4CI (15 mL), extracted with ethyl acetate (20 mL), washed with brine (20 mL), dried over Na2SC"4, filtered and concentrated to give the title compound (120.0 mg, crude) as a light green solid which was carried forward without purification.

Step 2: 5-bromo-3-(ethylamino)-l-methylpyridin-2-one


[00383] To a solution of tert-butyl N-(5-bromo-l-methyl-2-oxopyridin-3-yl)-N-ethylcarbamate (99.0 mg, crude) in DCM (10 mL) was added HCl/dioxane (1 mL, 4 M) dropwise with stirring at 30 °C. The reaction mixture was stirred for 30 min at 30 °C. Then the mixture was filtered and the filter cake collected. The filtrate was adjusted to pH = 9 with saturated aqueous NaHC03, extracted with EA (20 mL), dried over Na2S04, filtered and concentrated to give a light green solid which is combined with the filter cake to give the title compound (46.0 mg) which was carried forward without purification. 1H NMR (CDC13 400MHz): δ 6.72 (d, J = 2.4 Hz, 1 H), 6.20 (d, J = 1.6 Hz, 1 H), 3.51 (s, 3 H), 3.09 (q, J = 7.2 Hz, 2 H), 1.27 (t, J = 7.2 Hz, 3 H). LCMS (M+H)+ 231.

thStep 3: N-[5-[5-(ethylamino)-l-methyl-6-oxopyridin-3-yl]-2-methoxyphenyljmethanesulfonamide


[00384] The title compound was prepared in a manner similar to Example 106, substituting the title compound of step 2 for 3-amino-5-bromo-l-methylpyrazin-2-one. H NMR (CDC13

400MHz): δ 7.63 (d, J = 2.0 Hz, 1 H), 6.16 (dd, Ji = 8.4 Hz, ]x = 2.4 Hz, 1 H), 6.95 (d, J = 8.4 Hz, 1 H), 6.82-6.80 (m, 1 H), 6.39 (d, J = 2.4 Hz, 1 H), 3.93 (s, 3 H), 3.64 (s, 3 H), 3.19 (q, J = 7.2 Hz, 2 H), 2.98 (s, 3 H), 1.32 (t, J = 7.2 Hz, 3 H). LCMS (M+H)+ 352.

Example 112: N-[5-[5-(cyclopropylmethylamino)- 1 -methyl-6-oxopyridin-3-yl]-2-methoxyphenyljmethanesulfonamide


[00385] To a solution of compound from Example 109 (64.6 mg, 0.2 mmol) in MeOH (3 mL) and AcOH (0.3 mL) was added cyclopropanecarbaldehyde (14.0 mg, 0.2 mmol) dropwise with stirring at 30 °C. NaBH3CN (24.5 mg, 0.4 mol) was added in portions at 30 °C. The reaction mixture was stirred for 2 h at 30 °C. It was then quenched with saturated aqueous NH4CI (5 mL), extracted with EtOAc (20 mL), dried over Na2S04, filtered and concentrated. The residue was purified by prep-HPLC to give the title compound (10.0 mg, 13.2%) as a light green solid. 1H NMR (Methanol-d4 400 MHz): δ 7.55 (d, J = 2.4 Hz, 1 H), 7.36 (dd, J = 8.4, 2.4 Hz, 1 H), 7.16-7.07 (m, 2 H), 6.61 (d, J = 2.4 Hz, 1 H), 3.94 (s, 3 H), 3.66 (s, 3 H), 3.05 (s, 2 H), 2.95 (s, 3 H), 1.21-1.14 (m, 1 H), 0.64-0.56 (m, 2 H), 0.35-0.28 (m, 2 H).

LCMS (M+H)+ 378.

[00386] Example 113: N-[5-[5-(dimethylamino)-l-methyl-6-oxopyridin-3-yl]-2-methoxyphenyljmethanesulfonamide


[00387] To a solution of compound from Example 109 (64.6 mg, 0.2 mmol) in MeOH (3 mL) and AcOH (0.3 mL) was added HCHO (30.0 mg, 1.0 mmol) dropwise with stirring at 30 °C. NaBH3CN (61 mg, 1.0 mol) was added in portions at 30 °C. The reaction mixture was stirred for 2 h at 30 °C. It was then quenched with saturated aqueous NH4CI (5 mL), extracted with EtOAc (20 mL), dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EA = 2:3) to give the title compound (30 mg , 43%) as a light green solid. 1H NMR (Methanol-d4 400 MHz): δ 7.54 (d, J = 2.4 Hz, 1 H), 7.47 (d, J = 2.4 Hz, 1 H), 7.37 (dd, Ji = 2.4, J2 = 8.4 Hz, 1 H), 7.11 (d, J = 8.4 Hz, 1 H), 7.04 (d, J = 2.4 Hz, 1 H), 3.93 (s, 3 H), 3.63 (s, 3 H), 2.94 (s, 3 H), 2.86 (s, 6 H). LCMS (M+H)+ 352.

Example 114: N-[5-[5-(diethylamino)-l-methyl-6-oxopyridin-3-yl]-2-methoxyphenyljmethanesulfonamide


[00388] The title compound was prepared in a manner similar to Example 113, substituting acetaldehyde for formaldehyde. 1H NMR (Methanol-d4 400 MHz): δ 7.55 (d, J = 2.4 Hz, 1 H), 7.49 (d, J = 2.4 Hz, 1 H), 7.37 (dd, Ji = 8.4 Hz, J2=2.4 Hz, 1 H), 7.17-7.11 (m, 1 H), 7.06 (d, J = 2.4 Hz, 1 H), 3.95 (s, 3 H), 3.65 (s, 3 H), 3.34 (m, 4H), 2.97 (s, 3 H), 1.11 (t, J = 7.2 Hz, 6 H). LCMS (M+H)+ 380.

Example 115: N-[3-(5-amino-l-methyl-6-oxopyridin-3-yl)-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide

Step 1 : 3-amino-5-[5-amino-2- 2,4-difluorophenoxy)phenyl]-l-methylpyridin-2-one


[00389] The title compound of step 1 was prepared in a manner similar to Example 107, substituting the title compound of Example 57, step 1 for (3-methylsulfonylphenyl)boronic acid. LCMS (M+H)+ 344.

Step 2: N-[3-(5-amino-l-methyl-6-oxopyridin-3-yl)-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide


[00390] The title compound was prepared in a manner similar to Example 99, step 2. H

NMR (DMSO- 6, 400 MHz) 59.78 (s, 1 H), 7.45-7.39 (m, 1 H), 7.23-7.22 (m, 2 H), 7.14

(dd, Ji = 7.2 Hz, J2 = 1.6 Hz, 1 H), 7.10-7.02 (m, 2 H), 6.85 (d, J = 8.8 Hz, 1 H), 6.79 (d, J = 2.0 Hz , 1 H), 3.49 (s, 3 H), 3.09 (q, J = 7.2 Hz, 2 H), 1.21 (t, J = 7.6 Hz, 3 H). LCMS (M+H)+ 436.

Example 116: 3-amino-5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]- 1 -methylpyridin-2-one


[00391] The title compound was prepared in a manner similar to Example 107, substituting the title compound of Example 90, step 1 for (3-methylsulfonylphenyl)boronic acid. H NMR

(CDCls, 400 MHz) δ 7.84-7.81 (m, 2 H), 7.11 (d, J = 2.0 Hz, 1 H), 7.02 (d, J = 2.4 Hz, 1 H), 6.84 (d, J = 2.4 Hz, 1 H), 3.95 (d, J = 6.8 Hz, 2 H), 3.65 (s, 3 H), 3.06 (s, 3 H), 1.31-1.27 (m, 1 H), 0.68 (q, J = 5.6 Hz, 2 H), 0.37 (q, J =5.2 Hz, 2 H). LCMS (M+H)+ 349.

Example 117: 4-ethoxy-3-(l-meth l-6-oxopyridin-3-yl)benzenesulfonamide


[00392] A mixture of the title compound of Example 98, step 1 (40 mg, 0.17 mmol),

Pd(dppf)Cl2 (10 mg, 8%) and 3 -bromo-4-ethoxybenzene-l -sulfonamide (48 mg, 0.17 mmol) was suspended in 1,4-dioxane (880 μ ) and saturated bicarbonate solution (aq) (220 μί). The mixture was heated to 95 °C using microwave irradiation (normal) for 60 min. The crude reaction mixture was filtered through a short plug of celite, the plug was washed with additional 1,4-dioxane (1 ml), and the combined filtrate was purified by prep-HP LC. The fractions were combined and lyophilized to give the title compound (14 mg, 27%) as a white solid. 1HNMR (DMSO, 400 MHz): δ 1.33 (t, J=6.9, 3 H), 3.49 (s, 3H), 4.15 (q, J=6.9, 2H), 6.45 (d, J=9.4 Hz, 1 H), 7.20-7.23 (m, 3H), 7.64 (dd, J=2.6, 9.4 Hz, 1 H), 7.72-7.74 (m, 2 H), 7.89 (d, J=2.6 Hz, 1 H). LCMS (M+H)+ = 309.

Example 118: 4-(2,4-difluorophenoxy)-3-(l-methyl-6-oxopyridin-3-yl)benzenesulfonamide

Step 1 : 3-bromo-4-fluorobenzenesulfonamide


[00393] A solution of 3-bromo-4-fluorobenzenesulfonyl chloride (lg, 3.3 mmol, 90% pure) stirred at 0 °C in THF (15 ml) and DCM (5 ml) was treated with aqueous ammonium hydroxide (28%) by dropwise addition over 15 min. After stirring at 0 °C for 210 min, the mixture was acidified (pH = 1) by addition of 1 N HC1 (aq). After the mixture was concentrated in vacuo to near dryness, it was treated with water (50 ml), sonicated for 3 min and filtered. After the filter cake was washed sequentially with water (50 ml) and hexanes (100 ml), it was dried in vacuo to afford the title compound (503 mg, 60%>) as a white solid which was carried forward without purification. LCMS (M-H)~ = 253.

Step 2: 3-bromo-4-(2,4-difluoro henoxy)benzenesulfonamide


[00394] A solution of 3-bromo-4-fluorobenzenesulfonamide (400 mg, 1.6 mmol) and 2,4-difluorophenol (228 mg, 1.76 mmol) in DMSO (16 ml) was treated with cesium carbonate (1 g, 3.2 mmol). The resulting mixture was heated to 120 °C for 20 min by microwave irridation (normal). The mixture was treated with water (100 ml) and extracted with EtOAc (3 X 50 ml). The combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo to afford a tan solid. The solid was purified by silica gel chromatography (12 g ISCO, 30%> EtOAc in hexanes 30 ml/min) to give the title compound (340 mg, 58%) as a tan solid LCMS (M-H)~ = 362.

Step 3 : 4-(2,4-difluorophenoxy)-3- l -methyl-6-oxopyridin-3-yl)benzenesulfonamide


[00395] 3-Bromo-4-(2,4-difluorophenoxy)benzenesulfonamide (1 eq., 62 mg), the title compound of Example 98, step 1 (40 mg, 0.17 mmol), Pd(dppf)Cl2 (10 mg, 8%) in 1,4-dioxane (880 μί) and saturated bicarbonate solution (aq) (220 μ ) were reacted at 105 °C for 30 min in a manner similar to Example 117. Work up and preparative HPLC, also in a similar manner, gave the title compound (12 mg, 18%) as a white solid. 1H NMR (DMSO, 400

MHz): 53.51 (s, 3 H), 6.49 (d, J=9.4, 1H), 4.15 (q, J=6.9, 2H), 6.45 (d, J=9.4 Hz, 1 H), 7.20-7.23 (m, 3H), 7.64 (dd, J=2.6, 9.4 Hz, 1 H), 7.72-7.74 (m, 2 H), 7.89 (d, J=2.6 Hz, 1 H). LCMS (M+H)+ = 393.

Example 119: 5 - [2-(cyclopropylmethoxy)-5 -methylsulfonylphenyl] -3 -fluoro- 1 -methylpyridin-2-one

Step 1 : 5-bromo-3-fluoro-l-methylpyridin-2-one


[00396] A mixture of 5-bromo-3-fluoropyridin-2-ol (1 g, 5.2 mmol), iodomethane (356 mg, 5.7 mmol) and K2C03 (1.4 g, 10.4 mmol) in DMF (10 mL) was stirred at rt for 12 h. The mixture was treated with water (70 ml) and extracted with EtOAc (3 X 50 ml). The combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (1 g, 93 %) as a white solid which was carried forward without purification. LCMS (M+H)+ = 207.

Step 2: 3-fiuoro-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one


[00397] A mixture of 5-bromo-3-fluoro-l-methylpyridin-2-one (1 g, 4.9 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (2.5 g, 9.8 mmol), KOAc (1.2 g, 12.3 mmol), and Pd(dppf)Cl2 (286 mg, 8%) was suspended in 1,4-dioxane (15 mL). After purging the reaction vial with nitrogen for 5 min, the capped vial was stirred at 80 °C for 1 h. The mixture was treated with water (70 ml) and extracted with EtOAc (3 X 40 ml). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a dark residue. The residue was purified by silica gel chromatography (12 g ISCO, gradient 05-75 % EtOAc in hexanes) to give the title compound (682 mg, 55%) as a reddish brown solid.

Step 3: 5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-3-fluoro-l-methylpyridin-2-one


[00398] 3-Fluoro-l -methyl-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyridin-2-one (40 mg, 0.16 mmol), 2-bromo-l-(cyclopropylmethoxy)-4-methanesulfonylbenzene (49 mg, 0.16mmol), and Pd(dppf)Ci2 (12 mg, 10%) in 1,4-dioxane (880 μ ) and saturated bicarbonate solution (aq) (220 μ ) were reacted, worked up, and purified in a manner similar to Example 117. The title compound (22 mg, 46%) was obtained as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 0.31 - 0.42 (m, 2 H) 0.53 - 0.63 (m, 2 H) 1.17 - 1.34 (m, 1 H) 3.20 (s, 3 H) 3.58 (s, 3 H) 3.95 - 4.06 (m, 2 H) 7.24 - 7.33 (m, 1 H) 7.72 - 7.79 (m, 1 H) 7.80 - 7.87 (m, 1 H) 7.84 (s, 1 H) 7.88 - 7.93 (m, 1 H) LCMS (M+H)+ = 351.

Example 120: 5-[2-(2,4-difluorophenoxy)-5-methylsulfonylphenyl]-3-fluoro- 1 -methylpyridin-2-one


[00399] The title compound of Example 119, step 2 (40 mg, 0.16 mmol), l-(2-bromo-4-methylsulfonylphenoxy)-2,4-difluorobenzene (58 mg, 0.16mmol) and Pd(dppf)Ci2 (12 mg, 10%)) in 1,4-dioxane (880 μ ) and saturated bicarbonate solution (aq) (220 μί) were reacted, worked up and purified in a manner similar to Example 117. The title compound (26 mg, 46%) was obtained as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 3.25 (s, 3 H) 3.60 (s, 3 H) 6.91 - 6.99 (m, 1 H) 7.16 - 7.30 (m, 1 H) 7.49 - 7.62 (m, 2 H) 7.76 - 7.86 (m, 2 H) 8.00 (m, 2 H) LCMS (M+H)+ = 410.

Example 121 : 5-[2-(2,4-difluorophenoxy)-5-ethylsulfonylphenyl]-3-fluoro- 1 -methylpyridin- 2-one


[00400] The title compound of Example 119, step 2 (40 mg, 0.16 mmol), l-(2-bromo-4-ethylsulfonylphenoxy)-2,4-difluorobenzene (60 mg, 0.16mmol), and Pd(dppf)Cl2 (12 mg, 10%) in 1,4-dioxane (880 μ ) and saturated bicarbonate solution (aq) (220 μί) were reacted, worked up and purified in a manner similar to Example 117. The title compound (18 mg, 27%) was obtained as a tan solid. 1H NMR (400 MHz, DMSO-d6) 5 1.13 (t, J=7.33 Hz, 3 H) 3.34 (q, J=7.33 Hz, 2 H) 3.59 (s, 3 H) 6.92 - 6.98 (m, 1 H) 7.19 - 7.27 (m, 1 H) 7.50 - 7.61 (m, 2 H) 7.76 - 7.84 (m, 2 H) 7.92 - 7.96 (m, 1 H) 7.97 - 8.01 (m, 1 H)LCMS (M+H)+ = 424. Example 122: N-[4-(2,4-difluorophenoxy)-3-(5-fluoro-l-methyl-6-oxopyridin-3-yl)phenyl] ethanesulfonamide

Step 1 : N-[3-bromo-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide


[00401] Ethylsulfonyl chloride (177 mg, 1.4 mmol) was added dropwise to a stirred solution of 3-bromo-4-(2,4-difluorophenoxy)aniline ( 328 mg, 1.1 mmol) and pyridine ( 178 μί, 2.2 mmol) in dichloromethane (2 ml) at 0 °C under nitrogen. After the mixture was allowed to warm to rt and stir overnight, it was treated with IN HC1 (10 ml) and extracted with dichloromethane (3 X 10 ml); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (430 mg, 99 %>) as a tan solid which was carried forward without purification. LCMS (M-H)~ = 391.

Step 2: N-[4-(2,4-difluorophenoxy)-3-(5-fluoro-l-methyl-6-oxopyridin-3-yl)phenyl] ethanesulfonamide


[00402] N-[3-Bromo-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide (77 mg, 0.2 mmol), the title compound of Example 119, step 2 (50 mg, 0.2 mmol), and Pd(dppf)Cl2 (14 mg, 10%) in 1,4-dioxane (1 mL) and saturated bicarbonate solution (aq) (333 μί) were reacted, worked up and purified in a manner similar to Example 117. The title compound (31 mg, 27%) was obtained as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 1.22 (t, J=7.3, 3 H) 3.11 (q, J=7.3 Hz, 2 H) 3.55 (s, 3 H) 6.86 (d, J=8.6 Hz, 1 H) 7.02 - 7.12 (m, 1 H) 7.13 - 7.23 (m, 2 H) 7.26 (d, J=2.8 Hz, 1 H) 7.35 - 7.52 (m, 1 H) 7.60 (m, 1 H) 7.79 (s, 1 H) 9.48 - 9.96 (m, 1 H).

LCMS (M+H)+ = 439.

Example 123: N-[3-(2-methyl-l-oxo-2,6-naphthyridin-4-yl)phenyl]ethanesulfonamide Step 1 : 4-chloro-2-methyl-2,6-naphthyridin-l-one


[00403] N-chlorosuccinimide (0.8 g, 6.2 mmol) was added in portions to a solution of 2-methyl-2,6-naphthyridin-l-one (1.0 g, 6.2 mmol) in acetonitrile (25 mL) which was then heated at 65 °C for 18 h. Extractive work up with ethyl acetate and purification by silica gel chromatography (PE: EA = 5: 1-1 : 1) gave the title compound of step 1 (0.6 g, 56 %>) as a yellow solid. 1H NMR: (CDC13, 400 MHz) δ 9.29 (s, 1 H), 8.81 (d, J = 3.6 Hz, 1 H), 8.21 (d, J = 5.2 Hz, 1 H), 7.31 (s, 1 H), 3.63 (s, 3 H). LCMS: 195.0 (M+H)+.

Step 2: N-[3-(2-methyl-l-oxo-2,6-naphthyridin-4-yl)phenyl]ethanesulfonamide


[00404] A mixture of 4-chloro-2-methyl-2,6-naphthyridin-l-one (50.0 mg, 0.26 mmol), [3-(ethylsulfonylamino)phenyl]boronic acid (88.0 mg, 0.38 mmol), Pd(dppf)Cl2 (15.3 mg, 0.026 mmol) and K3PO4 (190 mg, 0.9 mmol) in dioxane (3 mL) and water (0.5 mL) was

micro waved at 120 °C under microwave for 2 h. Purification by silica gel chromatography on (PE:EA = 10: 1 to 1 : 1) followed by preparative HPLC gave the title compound (5.9 mg, 6.8 %) as a yellow solid. 1H NMR (Methanol-d4, 400 MHz) δ 8.99 (brs, 1 H), 8.71 (d, J = 6.0 Hz, 1 H), 8.39 (d, J = 5.6 Hz, 1H), 7.62 (s, 1 H), 7.51 (t, J = 8.0 Hz„l H), 7.41-7.40 (m, 1 H), 7.36 (dd, Ji = 8.0 Hz, J2 = 1.2 Hz, 1 H), 7.29 (d, J = 5.6 Hz, 1 H), 3.72 (s, 3 H), 3.17 (q, J = 7.6 Hz, 2 H), 1.35 (t, J = 7.6 Hz, 3 H). LCMS: 344.1 (M+H) +.

Examples 124-126 in Table 15 were prepared from title compound of Example 123, step 1 , using the appropriate phenyl boronic acid/ester in a manner similar to Example 123, step 2. Example 127 in Table 15 was prepared in two steps from the title compound of Example 123, step 1 , and the the title compound of Example 57, step 1 , by coupling the aniline boronic ester in a manner similar to Example 123, step 1 , except that the temperature was raised from 120 °C to 150 °C and NMP was used instead of dioxane (step 1), followed by sulfonylation of the aniline in a manner similar to Example 57, step 3 (step 2).

Table 15


Example 128: 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methy l-6-(4- methylpyrazol- 1 -yl)isoquinolin- 1 -one

Step 1 : 2-methyl-6-(4-methylpyrazol-l-yl)isoquinolin-l-one


[00405] 6-Bromo-2-methylisoquinolin-l-one (300.0 mg, 1.27 mmol), 4-methyl-lH-pyrazole (210.0 mg, 2.54 mmol), Cul (30.0 mg, 0.127 mmol) and K2C03 (360.0 mg, 2.54 mmol) in NMP (3.0 mL) were microwaved at 195 °C for 5 h. Extractive work up with ethyl acetate followed by silica gel chromatography (PE:EA = 5 : 1) gave the title compound of step 1 (160.0 mg, 52 %) as a light yellow solid. 1H NMR (CDC13, 400 MHz) δ 8.49 (d, J = 8.8 Hz, 1 H), 7.84 (s, 1 H), 7.83 (d, J = 2.0 Hz, 1 H), 7.74 (dd, Jl = 8.8 Hz, J2 = 2.0 Hz, 1 H), 7.59 (s, 1 H), 7.10 (d, J = 7.6 Hz, 1 H), 6.52 (d, J = 7.6 Hz, 1 H), 3.62 (s, 3 H), 2.19 (s, 3 H). LCMS: 240.0 (M+H)+.

Step 2 : 4-bromo-2-methyl-6-(4-methylpyrazol- 1 -yl)isoquinolin- 1 -one


[00406] Bromine (94 mg, 0.59 mmol) in acetic acid (2 mL) was added drop-wise to a solution of 2-methyl-6-(4-methylpyrazol-l-yl)isoquinolin-l-one (140.0 mg, 0.583 mmol) in acetic acid (4 mL) at 0 °C. The mixture was then stirred at room temperature for 17 min and quenched with water (10 mL). The pH was adjusted to about 7-8 with aqueous 1M NaOH. Extractive work up with ethyl acetate followed by purification using silica gel

chromatography (PE:EA = 1 : 1) gave the title compound of step 2 (120.0 mg, 56 %) as a light yellow solid. 1H NMR (CDC13, 400 MHz) δ 8.51 (d, J = 8.8 Hz, 1 H), 8.06 (d, J = 2.0 Hz, 1 H), 7.89 (s, 1 H), 7.87 (dd, Jl = 8.8 Hz, J2 = 2.0 Hz, 1 H), 7.63 (s, 1 H), 7.42 (s, 1 H), 3.62 (s, 3 H), 2.20 (s, 3 H). LCMS: 319.8 (M+H)+.

Step 3 : 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyl-6-(4-methylpyrazol- 1 -yl)isoquinolin- 1 -one


[00407] 4-Bromo-2-methyl-6-(4-methylpyrazol-l-yl)isoquinolin-l-one (40.0 mg, 0.126 mmol), the title compound of Example 90, step 1 (53.2 mg, 0.152 mmol), Pd(dppf)Cl2 (200.0 mg, 0.05 mmol) and aqueous 1M K3PO4 (0.38 mL, 0.38 mmol) in dioxane (3 mL) were heat in a microwave at 100 °C for 1 h. Purification by preparative HPLC gave the title compound (15.0 mg, 25 %) as a white solid. 1H NMR (CDC13, 400 MHz) δ 8.57 (d, J = 8.4 Hz, 1 H), 8.00 (d, J = 8.4 Hz, 1 H), 7.90 (s, 1 H), 7.75 (d, J = 7.6 Hz, 1 H), 7.73 (s, 1 H), 7.54 (s, 1 H), 7.50 (s, 1 H), 7.14 (s, 1 H), 7.12 (s, J = 9.2 Hz, 1 H), 3.96-3.83 (m, 2 H), 3.68 (s, 3 H), 3.13 (s, 3 H), 2.15 (s, 3 H), 1.01-0.94 (m, 1 H), 0.38-0.28 (m, 2 H), 0.08-0.02 (m, 2 H). LCMS: 464.1 (M+H)+.

Example 129: N-[4-(2,4-difluorophenoxy)-3-(7-methyl-8-oxoimidazo[l,5-a]pyrazin-5-yl)phenyl] ethanesulfonamide

Step 1 : 5-bromo-7-methylimidazo[l,5-a]pyrazin-8-one


[00408] To a solution of 5-bromo-l-methylpyrazin-2-one (500.0 mg, 2.65 mmol) and (p-tolylsulfonyl)methyl isocyanide (573.0 mg, 2.94 mmol) in THF (4 mL) was added a suspension of NaH (235.0 mg, 5.9 mmol) in THF (2 mL) at 0 °C under N2. After stirring at 0 °C for 30 min, the mixture was stirred at 30 °C for another 1.5 h. The reaction mixture was quenched with H20 (20 mL) at 0 °C, and extracted with EtOAc (30 mL x 2). The organic phases were combined, washed with brine (30 mL), dried over Na2S04, filtered and evaporated. The crude product was purified by column chromatography (PE:EA = 1/1) to give the title compound (300.0 mg, 50 %) as a light yellow solid. 1H NMR (CDC13 400 MHz) δ 8.06 (d, J=4.4 Hz ,1 H), 6.61 (s, 1 H), 3.48 (s, 3 H). LCMS (M+H)+ 228.

Step 2: 5-[5-amino-2-(2,4-difluorophenoxy)phenyl]-7-methylimidazo[l,5-a]pyrazin-8-one


[00409] A solution of 5-bromo-7-methylimidazo[l,5-a]pyrazin-8-one (114.0 mg, 0.5 mmol), the title compound of Example 57, step 1 (208.0 mg, 0.6 mmol), Pd(dppf)2Cl2 (37.0 mg, 0.05 mmol), NaHCC"3 (126.0 mg, 1.5 mmol) in dioxane (10 mL) and H20 (1 mL) was stirred in microwave at 110 °C with N2 atmosphere for 3 hours. The solvent was evaporated to give the crude product, which was purified by column chromatography (PE:EA = 3/1) to give the title compound (110 mg, 60 %) as a yellow solid. 1H NMR (CDCI3 400 MHz) δ 7.94 (s, 1 H), 7.82 (s, 1 H), 6.93-6.82 (m, 2 H), 6.79-6.74 (m, 4 H), 6.41 (s, 1 H), 3.50 (s, 3 H). LCMS (M+H)+ 369.

Step 3: N-[4-(2,4-difluorophenoxy)-3-(7-methyl-8-oxoimidazo[l,5-a]pyrazin-5-yl)phenyl] ethanesulfonamide

[00410] The title compound was prepared in a manner similar to Example 99, step 2, substituting the title compound of step 2 for the title compound of Example 99, step 1. 1H NMR (CDC13 400 MHz) δ 8.57 (s, 1 H), 8.14 (s, 1 H), 7.50 (d, J = 2.4 Hz, 1 H), 7.30 (dd, Ji = 8.8 Hz, J2 = 2.4, 1 H), 7.20-7.16 (m, 1 H), 6.99-6.87 (m, 2 H), 6.83 (s, 1 H), 6.55 (d, J = 8.8 Hz, 1 H), 3.59 (s, 3 H), 3.13 (q, J = 7.2 Hz, 2 H), 1.39 (t, J = 7.2 Hz, 3 H). LCMS (M+H)+ 461.

Example 130: 5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-7-methylimidazo[ 1 ,5-a]pyrazin-8-one


[00411] The title compound was prepared in a manner similar to Example 129, step 2, substituting 2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane for 4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)aniline to give the title compound. 1H NMR (CDCI3 400 MHz) δ 8.08 (dd, Ji = 8.8 Hz, J2 = 2.4, 1 H), 8.03 (s, 1 H), 7.98 (d, J = 2.4 Hz, 1 H), 7.58 (s, 1 H), 7.16 (d, J = 8.8 Hz, 1 H), 6.50 (s, 1 H), 3.97 (d, J = 7.2 Hz, 2 H), 3.54 (s, 3 H), 3.11 (s, 3 H), 1.15-1.02 (m, 1 H), 0.59-0.49 (m, 2 H), 0.26 -0.17 (m, 2 H). LCMS (M+H)+ 374.

Example 131: 7-methyl-5-(3-methylsulfonylphenyl)imidazo[l,5-a]pyrazin-8-one


[00412] A solution of compound from Example 129, step 1 (80 mg, 0.35 mmol), (3-methylsulfonylphenyl)boronic acid (77 mg, 0.6 mmol), Na2C03 (106 mg, 1 mmol), Pd(PPh3)2Cl2 (30.0 mg) in dioxane (3 mL) and water (0.5 mL) was stirred at 120 °C for 18 h under N2. After cooling to room temperature, the mixture was filtered, concentrated and purified by prep-HPLC to give the title compound (20.0 mg, 20 %). 1H NMR (Methanol-d4 400 MHz): δ 8.70-8.65 (m, 1 H), 8.30-8.20 (m, 2 H), 8.16 (d, J = 8.0 Hz, 1 H), 8.05 (d, J = 8.0 Hz, 1 H), 7.88 (t, J = 8.0 Hz, 1 H), 7.22 (s, 1 H), 3.56 (s, 3 H), 3.24 (s, 3 H). LCMS (M+H)+ 304.

Example 132 : N- [2-methoxy-5 -(7 -methyl-8 -oxoimidazo [ 1 ,5 -a]pyrazin-5 -yl)phenyl]methanesulfonamide


[00413] The title compound was prepared in a manner similar to Example 131, substituting [3-(methanesulfonamido)-4-methoxyphenyl]boronic acid for (3-methylsulfonylphenyl)boronic acid to give the title compound. 1H NMR (Methanol-d4 400 MHz): δ 8.81 (s, 1 H), 8.29 (s, 1 H), 7.70 (s, 1 H), 7.50 (m, 2 H), 7.28 (d, J = 8.0 Hz, 1 H), 7.12 (s, 1 H), 4.01 (s, 3 H), 3.56 (s, 3 H), 3.08 (s, 3 H). LCMS (M+H)+ 349.

Example 133: 5-(3-ethylsulfonylphenyl)-7-methylimidazo[l,5-a]pyrazin-8-one


[00414] The title compound was prepared in a manner similar to Example 131, substituting (3-ethylsulfonylphenyl)boronic acid for (3-methylsulfonylphenyl)boronic acid to give the title compound. 1H NMR (Methanol-d4 400 MHz): δ 8.83 (s, 1 H), 8.27 (s, 1 H), 8.21 (s, 1 H), 8.10 (d, J = 7.6 Hz, 1 H), 8.05 (d, J = 8.0 Hz, 1 H), 7.89 (t, J = 8.0 Hz, 1 H), 7.24 (s, 1 H), 3.56 (s, 3 H), 3.31 (q, J = 7.6 Hz, 2 H), 1.28 (t, J = 7.6 Hz, 3 H). LCMS (M+H)+ 318.

Example 134: N-[3-(5-chloro-l-methyl-6-oxopyridin-3-yl)-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide


[00415] The title compound was prepared in a manner similar to Example 122, substituting 3-chloro-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one for 3-fluoro-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one. LCMS (M+H)+ 455. Example 135: 4-[2-(cyclopropylmethox -5-ethylsulfonylphenyl]-2-methylisoquinolin-l-one


[00416] The title compound was prepared in a manner similar to Example 89, substituting 2-bromo- 1 -(cyclopropylmethoxy)-4-ethylsulfonylbenzene for 2-bromo- 1 -(cyclopropylmethoxy)-4-methylsulfonylbenzene. LCMS (M+H)+ 398.

Example 136: 6-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2,4-dimethylpyridazin-3 -one


[00417] The title compound was prepared in a manner similar to Example 90, substituting 6-chloro-2,4-dimethylpyridazin-3-one for 4-bromo-6-fluoro-2-methylisoquinolin-l-one..

LCMS (M+H)+ 349.

Example 137: 6-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2,5-dimethylpyridazin-3 -one


[00418] The title compound was prepared in a manner similar to Example 90, substituting 6-chloro-2,5-dimethylpyridazin-3-one for 4-bromo-6-fluoro-2-methylisoquinolin-l-one. LCMS (M+H)+ 349.

Example 138: N-[4-(2,4-difluorophenoxy)-3-[l-methyl-6-oxo-5-(trifluoromethyl)pyridin-3-yl]phenyl] ethanesulfonamide


[00419] The title compound was prepared in a manner similar to Example 122, substituting 1-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-one for 3-fluoro- 1 -methyl-5 -(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)pyridin-2-one. LCMS (M+H)+ 489.

Example 139: N-[4-(2,4-difluorophenoxy)-3-(4-fluoro-l-methyl-6-oxopyridin-3-yl)phenyl] ethanesulfonamide


Step 1 : 2-chloro-5-[2-(2,4-difluorophenoxy)-5-nitrophenyl]-4-fluoropyridine


[00420] A mixture of 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (170 mg, 0.66 mmol), 2-bromo-l-(2,4-difluorophenoxy)-4-nitrobenzene (326 mg, 0.98 mmol), Pd2(dba)3 (30 mg, 5%), and tricyclohexylphosphine (280 mg, 10%) was suspended in 1,4-dioxane (4 mL) and aqueous 1M K3PO4 (2 mL). The mixture was heated to 70 °C using microwave irradiation (normal) for 45 min. The crude reaction mixture was filtered through a short plug of celite and the celite plug was washed with EtOAc (~ 50 mL). The filtrate was washed with water (2 x 30 mL), brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column

chromatography (12 g ISCO, gradient 05-75 % EtOAc in hexanes) to afford the free base of the desired product, 2-chloro-5-[2-(2,4-difluorophenoxy)-5-nitrophenyl]-4-fluoropyridine as a yellow solid (144 mg, 57%). LCMS (M+H)+ = 381.

Step 2: 5- [2-(2,4-difluorophenox -5 -nitrophenyl] -4-fluoro- 1 -methylpyridin-2-one


[00421] A mixture of 2-chloro-5-[2-(2,4-difluorophenoxy)-5-nitrophenyl]-4-fluoropyridine (140 mg, 0.37 mmol), KOH (62 mg, 1.11 mmol), Pd2(dba)3 (17 mg, 5%), and XPhos (18 mg, 10%)) was suspended in 1,4-dioxane (1.9 mL) and water (316 μί). After purging the reaction vial with nitrogen for 5 min, the capped vial was stirred at 100 °C for 1 h. After the mixture cooled to rt, it was treated with IN HC1 (aq) (1 mL) and EtOAc (5 mL). The biphasic mixture was filtered through a short plug of celite and the celite plug was washed with EtOAc (~ 50 mL). The filtrate was washed with water (2 x 30 mL), brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a orange solid, 5-[2-(2,4-difluorophenoxy)-5-nitrophenyl]-4-fluoropyridin-2-ol ( LCMS (M+H)+ = 363). After the solid was diluted with DMF (2.4 mL), it was treated with K2C03 (112 mg) and Mel (23 μΐ,). After stirring at rt for 5 h, the mixture was treated with water (10 mL) and extracted with EtOAc (3 x 10 mL); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered, concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (4 g ISCO, gradient 05-95 % EtOAc in hexanes) to afford the desired product, 5-[2-(2,4-difluorophenoxy)-5-nitrophenyl]-4-fluoro- 1 -methylpyridin-2-one as a tan solid (95 mg). LCMS (M+H)+ = 377.

Step 3 : 5-[5-amino-2-(2,4-difluoro henoxy)phenyl]-4-fluoro-l -methylpyridin-2-one


[00422] A mixture of 5-[2-(2,4-difluorophenoxy)-5-nitrophenyl]-4-fluoro-l-methylpyridin-2-one (90 mg, 0.24 mmol), ammonium chloride (26 mg, 0.48 mmol), iron powder (67 mg, 1.2 mmol) suspended in THF (500 μί), water (180 μ ) and ethanol (500 μ ) was heated to 100 °C using microwave irradiation (normal) for 3 h. The crude reaction mixture was filtered through a short plug of celite and the celite plug was washed with heated (50 °C) MeOH (~ 10 mL). The resulting filtrate was concentrated in vacuo. The resulting residue was diluted with EtOAc (20 ml) and washed with saturated bicarbonate solution (aq), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the desired product, 5-[5-amino-2-(2,4-difluorophenoxy)phenyl]-4-fiuoro-l-methylpyridin-2-one (75 mg, 90%). LCMS (M+H)+ = 347. The material was carried forward without any further purification.

Step 4: N-[4-(2,4-difluorophenoxy)-3-(4-fluoro-l-methyl-6-oxopyridin-3-yl)phenyl] ethanesulfonamide


O

[00423] Ethylsulfonyl chloride (177 mg, 1.4 mmol) was added dropwise to a stirred solution of 5-[5-amino-2-(2,4-difluorophenoxy)phenyl]-4-fluoro-l-methylpyridin-2-one (72 mg, 0.21 mmol) and pyridine (50 μί, 0.63 mmol) in dichloromethane (500 μί) at 0 °C under nitrogen. After the mixture was allowed to warm to rt and stir for 2 h, it was treated with IN HCl (3 mL) and extracted with dichloromethane (3 x 10 mL); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column

chromatography (4 g ISCO, gradient 0-10 % MeOH in dichloromethane) to afford the desired product, N-[4-(2,4-difluorophenoxy)-3-(4-fluoro- 1 -methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide (66 mg, 72 %) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.18 - 1.26 (m, 3 H), 3.07 - 3.16 (m, 2 H), 3.45 (s, 3 H), 6.22 - 6.33 (m, 1 H), 6.82 -6.93 (m, 1 H), 7.01 - 7.16 (m, 2 H), 7.18 - 7.28 (m, 2 H), 7.38 - 7.49 (m, 1 H), 7.95 - 8.05 (m, 1 H), 9.77 - 9.87 (s, 1 H). LCMS (M+H)+ = 439.

Example 140: N-[3-(5-cyclopropyl-l-methyl-6-oxopyridin-3-yl)-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide


[00424] The title compound was prepared in a manner similar to Example 122, substituting 3-cyclopropyl-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one for 3-fluoro-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one. LCMS (M+H)+ 461.

Example 141: N-{4-(2,4-difluorophenoxy)-3-[l-(2H3)methyl-6-oxopyridin-3-yl]phenyl} ethanesulfonamide


[00425] The title compound was prepared in a manner similar to Example 122, substituting 1- ( H3)methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one for 3-fluoro-l-methyl-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyridin-2-one. LCMS (M+H)+ 424.

Example 142: N-[4-(2,4-difluorophenoxy)-3-(2-methyl-l-oxo-5,6,7,8-tetrahydro-2,6-naphthyridin-4-yl)phenyl]ethanesulfonamide


[00426] The title compound of Example 127 (240 mg, 0.5 mmol) was hydrogenated (50 psi) at room temperature in anhydrous EtOH (30 mL) for 18 h using Pt02 (0.1 g). Purification by preparative HPLC gave the title compound (40 mg, 16.7 %) as a white solid. 1H NMR (Methanol-d4, 400 MHz) δ 7.36 (s., 1 H), 7.23 (dd, Ji = 8.8 Hz, J2 = 2.8 Hz 1 H), 7.14 (d, J = 2.8 Hz, 1 H), 7.06-6.96 (m, 2 H), 6.91-6.86 (m, 2 H), 3.83-3.49 (m, 2 H), 3.53 (s, 3 H), 3.16-2.89 (m, 2 H), 3.08 (q, J = 7.2 Hz, 2 H), 2.55 (t, J = 6.0 Hz, 2 H), 2.55 (t, J = 7.2 Hz, 3 H). LCMS (M+H)+ 476.

Example 143 : 4-[5-(cyclopropylmethoxy)-2-(methylsulfonylmethyl)pyrimidin-4-yl]-2-methylisoquinolin- 1 -one

Step 1 : 5-(cyclopropylmethoxy)-2-(methylsulfonylmethyl)pyrimidin-4-ol


[00427] To the title compound of Example 152, step 1 (5.00 g, 31.6 mmol) in THF (50 mL) at 0°C was added NaH (1.26 g, 31.6 mmol, 60% in mineral oil). Ethyl formate (2.57 g, 34.76 mmol) was added at 0°C and the mixture was heated at 70°C for 2 h. The mixture was then cooled to r.t and a pre-mixed solution of 2-(methylsulfonyl)-ethanimidamide (6.44 g 47.4 mmol) and EtONa (4.3 g, 63.2 mmol) in ethanol (50mL) was added dropwise. The mixture was heated at 90°C for 12 h, cooled to room temperature, and the solvent was removed under vacuum. Water (50 mL) was added to the residue and the pH was adjusted to 5 with 1M HC1. The resulting precipitate was collected and washed with water (100 ml), ethanol (50 ml) and methanol (30 mL) to give the title compound (1.9 g, yield: 23.4%) as a white solid. 1H NMR (DMSO- 6, 400 MHz) δ 11.49 (s, 1 H), 6.83 (s, 1 H), 6.49 (s, 2 H), 3.63 (d, J = 6.8 Hz, 2 H), 3.04 (s, 3 H), 1.14-1.10 (m, 1 H), 0.52-0.49 (m,2 H), 0.27-0.24 (m, 2 H). LCMS: 259.0 (M+l)+

Step 2 : 4-chloro-5 -(cyclopropylmethoxy)-2-(methylsulfonylmethyl)pyrimidine


[00428] To the title compound of step 1 (1.9 g, 7.36 mmol) in MeCN (30 mL) was added Me4NCl (1.6 g, 14.72 mmol) and POCl3 (6.8 g, 44.16 mmol). The mixture was heated at 80°C for 6 h. After concentration under vacuum, the residue was subjected to EA extractive work up. Trituration with methanol (20 mL) gave the title compound (1 g, yield: 49.3%) as a white solid. 1H NMR (CDC13, 400 MHz) δ 7.60 (s, 1 H), 5.50 (s, 2 H), 3.85 (d, J = 6.8 H z, 2 H), 3.09 (s, 3 H), 1.31-1.28 (m, 1 H), 0.70-0.65 (m, 2 H), 0.39-0.36 (m, 2 H). LCMS: 277.1 (M+l)+

Step 3 : 4-[5-(cyclopropylmethoxy)-2-(methylsulfonylmethyl)pyrimidin-4-yl]-2-methylisoquinolin- 1 -one


[00429] The title compound of step 2 (100 mg, 0.36 mmol), the title compound of Example 89, step 1 (124 mg, 0.43 mmol), Pd(dppf)Cl2 (27 mg, 0.03 mmol ) and K3P04 (154 mg, 0.72 mmol) in dioxane (5 mL) and water (5 drops) were N2 purged and heated to 70 °C for 18 h. After concentration under vacuum, the residue was purified using silica gel chromatography followed by prep-HP LC to give the title compound (61.7 mg, 42.7%) as a yellow solid. 1H NMR (DMSO- 6, 400 MHz) δ 8.29 (d, J = 7.2 Hz, 1 H), 7.69-7.65(m, 3 H), 7.53(t, J= 7.2 Hz, 1 H), 7.44 (d, J = 8.0 Hz, 1 H), 3.76 (d, J = 6.8 Hz, 2 H), 3.58 (s, 3 H), 3.26 (s, 3 H), 0.94-0.88 (m, 1 H), 0.35-0.31 (m, 2 H), 0.10-0.08 (m, 2 H). LCMS: 400.1 (M+l) +

Example 144: 5-[5-(cyclopropylmethoxy)-2-(methylsulfonylmethyl)pyrimidin-4-yl]-l ,3-dimethylpyridin-2-one


[00430] The title compound of Example 143, step 2 was reacted with l,3-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one in a manner similar to Example 143, step 3 to give the title compound. 1H NMR (CDC13, 400 MHz) δ 8.49 (d, J = 2.0 Hz, 1 H), 8.18 (s, 1 H), 7.60 (s, 1 H), 3.86 (d, J = 6.8 Hz, 2 H), 3.67 (s, 3 H), 3.11 (s, 3 H), 2.24 (s, 3 H), 1.29-1.27 (m, 1 H), 0.72-0.67 (m, 2 H), 0.39-0.35 (m, 2 H). LCMS: 364.1(M+1)+

Example 145: 4-[5-(cyclopropylmethoxy)-2-(methylsulfonylmethyl)pyrimidin-4-yl]-2-methyl-6-(l-methylpyrazol-4-yl)isoquinolin-l-one


[00431] The title compound of Example 143, step 2 was reacted with the title compound of Example 46, step 2 in a manner similar to Example 143, step 3 to give the title compound. 1H NMR (DMSO- 6, 400 MHz) δ 8.26 (d, J = 8.4 Hz, 1 H), 8.23 (s, 1 H), 7.91 (s, 1 H), 7.5 (d, J = 8.4 Hz, 1 H), 7.70 (s, 1 H), 7.66 (s, 1 H), 7.52 (s, 1 H), 3.87 (s, 3 H), 3.85-3.80 (m, 4 H), 3.57 (s, 3 H), 3.28 (s, 3 H), 0.88-0.87 (m, 1 H), 0.30-0.25 (m, 2 H), 0.07-0.04 (m, 2 H).

LCMS: 480.2 (M+l) +

Example 146: 5-[5-(2,4-difluorophenoxy)-2-(methylsulfonylmethyl)pyrimidin-4-yl]-3-methoxy-l-methylpyridin-2-one Step 1 : 5-(2,4-difluorophenoxy)-2-(methylsulfonylmethyl)pyrimidin-4-ol


[00432] To a stirred suspension of NaH (960 mg, 24 mmol, 60% in mineral oil) in anhydrous THF (33 mL) was added ethyl formate (1.8 g, 24.3 mmol) and 2-(2,4-difluorophenoxy)acetic acid ethyl ester (4.3 g, 19.9 mmol) in anhydrous THF (10 mL). The suspension was stirred at room temperature for 0.5 h and then refluxed for 3 h, cooled, and concentrated under vacuum. The residue was dissolved in EtOH (50 mL) and 2-(methylsulfonyl)-ethanimidamide (3.0 g, 22.1 mmol) was added and the mixture was refluxed for 18 h. After concentration under vacuum, water (50 mL) was added and the pH was adjusted to 5 with acetic acid. After EA extractive work up, the residue was dissolved in EA (20 mL) and PE (150 mL) was added. The resulting precipitate (3.0 g, crude) was collected as a grey solid to give the title compound. LCMS: 317.1 (M+l)+

Step 2: 4-chloro-5-(2,4-difluorophenoxy)-2-(methylsulfonylmethyl)pyrimidine


[00433] To the title compound of step 1 (3.0 g) and N(CH3)4C1 (1.6 g, 14.2 mmol) in anhydrous MeCN (30 mL), POCl3 (8.7 g, 56.9 mmol) was added dropwise. The mixture was stirred at r.t. for 0.5 h and then at 70°C for 6 h. After concentration under vacuum, water was added and EA extractive work up was carried out to give the title compound (3.0 g) as a light yellow solid. LCMS: 335.1 (M+l)+

Step 3 : 5-[5-(2,4-difluorophenoxy)-2-(methylsulfonylmethyl)pyrimidin-4-yl]-3-methoxy- 1 -methylpyridin-2-one


[00434] The title compound of Example 287, step 1 was treated with 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane in a maner similar to that outlined for Example 119, step 2 to give 3-methoxy-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one which was then reacted with the title compound of step 2 in a manner similar to Example 143, step 3 to give the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 8.37 (s, 1 H), 8.36 (d, J = 2.0 Hz, 1 H), 7.62 (d, J = 2.0 Hz, 1 H), 7.60-7.54 (m, 1 H), 7.51-7.45 (m, 1 H), 7.22-7.18 (m, 1 H), 4.78 (s, 2 H), 3.77 (s, 3 H), 3.56 (s, 3 H), 3.20 (s, 3 H). LCMS: 438.1 (M+l)+

Example 147: 5-[5-(2,4-difluorophenoxy)-2-(methylsulfonylmethyl)pyrimidin-4-yl]- 1 ,3-dimethylpyridin-2-one


[00435] The title compound of Example 146, step 2 was reacted with l,3-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one in a manner similar to Example 143, step 3 to give the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 8.58 (d, J = 2.0 Hz, 1 H),

8.35 (s, 1 H), 8.13 (s, 1 H), 7.60-7.54 (m, 1 H), 7.52-7.46 (m, 1 H), 7.22-7.17 (m, 1 H), 4.76 (s, 2 H), 3.56 (s, 3 H), 3.18 (s, 3 H), 2.08 (s, 3 H). LCMS: 422.1 (M+l)+

Example 148: 4-[5-(2,4-difluorophenoxy)-2-(methylsulfonylmethyl)pyrimidin-4-yl]-2-methylisoquinolin- 1 -one


[00436] The title compound of Example 146, step 2 was reacted with the title compound of Example 89, step 1 in a manner similar to Example 143, step 3 to give the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 8.62 (s, 1 H), 8.28 (d, J = 8.0 Hz, 1 H), 7.91 (s, 1 H), 7.69-7.68 (m, 2 H), 7.58-7.54 (m, 1 H), 7.45-7.34 (m, 2 H), 7.07-7.03 (m, 1 H), 4.83 (s, 2 H), 3.58 (s, 3 H), 3.17 (s, 3 H). LCMS: 458.1 (M+l)+

Example 149: 5-[5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidin-4-yl]-l,3-dimethylpyridin-2-one

Step 1 : 5-(2,4-difluorophenoxy)-2-meth lsulfanylpyrimidin-4-ol


[00437] To a solution of 2-(2,4-difluorophenoxy)acetic acid ethyl ester (8.0 g, 37.01 mmol) and ethyl formate (4.11 g, 55.51 mmol) in dry THF (200 mL) was added NaH (1.55 g, 38.75 mmol) slowly at 0°C. The mixture was then refluxed for 2 h. In a separate flask, sodium ethoxide (3.02 g, 44.41 mmol) and S-methylthiopseudourea hemisulfate (6.17 g, 44.41 mmol) in EtOH (100 mL) were stirred at 20°C for 2 h and then the resulting mixture was added to the above THF solution. The combined mixture was refluxed for 12 h. After concentration under vacuum, water (20 mL) and HC1 (10 mL, aq. IN) were added. The suspended solids were collected and washed with water (50 mL x 3) and EtOH (50 mL x 3) and dried to give the title compound (6.0 g, 60.0 % yield) as a light yellow solid. 1H NMR (DMSO-d6, 400

MHz) δ 7.84 (s, 1H), 7.42-7.34 (m, 1H), 7.04-7.01 (m, 1H), 6.95 (t, J = 9.6 Hz, 1H), 2.47 (s,

3H).

LCMS: 271.1 (M+l)+

Step 2: 4-chloro-5-(2,4-difluorophenoxy)-2-methylsulfanylpyrimidine


[00438] The title compound of step 1 (5.30 g, 19.63 mmol), P0C13 (18.06 g, 117.78 mmol), (Me)4NCl (3.23 g, 29.47 mmol) in dry CH3CN (60 mL) was refiuxed for 12 h. The mixture was poured into ice-water (50 mL) and subjected to EA extractive work up. Concentration under vacuum gave impure title compound (4.0 g), which was carried on to the next step. LCMS: 288.99 (M+l)+

Step 3 : 4-chloro-5-(2,4-difluorophenox -2-methylsulfonylpyrimidine


[00439] To a solution of the title compound of step 2 (4.60 g, 15.93 mmol) in CH2C12 (200 mL) was added mCPBA (13.75 g, 79.68 mmol) slowly at 0°C. The mixture was stirred at 20°C for 12 h and then sat. aq. Na2S03 (200 mL) was added. EA extractive work up and silica gel chromatography gave the title compound (2.0 g, 39.1% yield) as a yellow solid. 1H NMR (CDC13, 400 MHz) δ 8.18 (s, 1 H), 7.31-7.27 (m, 1 H), 7.10-7.01 (m, 2 H), 3.36 (s, 3 H). LCMS: 320.8 (M+l)+

Step 4: 5-[5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidin-4-yl]-l ,3-dimethylpyridin-2-one


[00440] A mixture of the title compound from step 3 (100 mg, 0.31 mmol), l,3-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one (93 mg, 0.37 mmol), Pd(dppf)Cl2 (23 mg, 0.31 mmol) and K3P04 (199 mg, 0.94 mmol) in dioxane/water (3 mL/0.5 mL) was N2 purged and heated at 70°C for 12 h. Concentration under vacuum and silica gel chromatography (PE: EA= 3: 1-0:1) followed by prep-HPLC gave the title compound (45 mg, 35.4%)^ NMR (CDC13, 400 MHz) δ 8.57 (s, 1 H), 8.25 (s, 1 H), 8.15 (s, 1 H), 7.25-7.24 (m, 1 H), 7.12-7.07 (m, 1 H), 7.03 (t, J = 8.0 Hz, 1 H), 3.68 (s, 3 H), 3.38 (s, 3 H), 2.25 (s, 3 H). LCMS: 407.9 (M+l)+

Example 150: 5-[5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidin-4-yl]-3-methoxy-l -methylpyridin-2-one


[00441] The title compound of Example 149, step 3 was reacted with 3-methoxy-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one (see Example 146, step 3) in a manner similar to Example 149, step 4 to give the title compound. 1H NMR (CDC13, 400 MHz) δ 8.35 (d, J = 2.0 Hz, 1 H), 8.18 (s, 1 H), 7.70 (d, J = 2.0 Hz, 1 H), 7.25-7.22 (m, 1 H), 7.12-7.08 (m, 1 H), 7.08-7.04 (m, 1 H), 3.93 (s, 3 H), 3.70 (s, 3 H), 3.38 (s, 3 H). LCMS: 423.9 (M+l) +

Example 151 : 4-[5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidin-4-yl]-2-methylisoquinolin- 1 -one


[00442] The title compound of Example 149, step 3 was reacted with the title compound of

Example 89, step 1 in a manner similar to Example 149, step 4 to give the title compound. H

NMR (CDCI3, 400 MHz) δ 8.52 (d, J = 8.0 Hz, 1 H), 8.32 (s, 1 H), 7.68 (s, 3 H), 7.59-7.56 (m, 1 H), 7.14-7.08 (m, 1 H), 7.05-7.00 (m, 1 H), 6.96-6.92 (m, 1 H), 3.72 (s, 3 H), 3.39 (s, 3 H). LCMS: 443.9 (M+l)+

Example 152: N-[5-(cyclopropylmethoxy)-4-(2 -methyl- l-oxoisoquinolin-4-yl)pyrimidin-2-yljmethanesulfonamide

Step 1 : ethyl 2-(cyclopropylmethoxy)acetate


[00443] Diazoacetic acid ethyl ester (80.00 g, 0.70 mol) was added dropwise to

cyclopropanemethanol (60.66 g, 0.84 mol) and [Rh(Ac20)2]2 (3.1 g, 7.02 mmol) in anhydrous CH2C12 (800 mL) at 0°C. The mixture was stirred at 0°C for 30 min and at room temperature for 4 h. CH2C12 extractive work up and silica gel chromatography (PE: EA = 100: 1-50:1)

gave the title compound (100 g, 90.4% yield) as a colorless oil. 1H NMR: (CDC13, 400 MHz) δ 4.23-4.19 (m, 2 H), 4.09 (s, 2 H), 3.38-3.36 (m, 2 H), 1.27 (t, J = 7.2 Hz, 3 H), 1.10-1.07 (m, 1 H), 0.57-0.52 (m, 2 H), 0.24-0.20 (m, 2 H).

Step 2: 5-(cyclopropylmethoxy)-2-methylsulfanylpyrimidin-4-ol


[00444] To a stirred suspension of NaH (35.20 g, 0.88 mol, 60%> in mineral oil) in anhydrous THF (1000 mL) was added ethyl formate (88.80 g, 0.90 mol) and the title compound of step 1 (126.0 g, 0.80 mol) in anhydrous THF (100 mL). The mixture was stirred at r.t. for 0.5 hour and refluxed for 3 h. In a separate flask, S-methylthiopseudourea hemisulfate (133.44 g, 0.96 mol) and sodium ethoxide (65.28 g, 0.96 mol) in EtOH (200 mL) were stirred at r.t. for 1 h, whereupon this mixture was added to the above mixture. There combined mixture was refluxed for 15 h, cooled, and the pHwas adjusted to 5 with acetic acid. After concentration under vacuum, silica gel chromatography (DCM: MeOH=50/l~10/l) gave the title compound (30.00 g, 17.7% yield) as a yellow solid. 1H NMR (CDC13, 400 MHz) δ 12.08 (s, 1 H), 7.49 (s, 1 H), 3.83-3.80 (m, 2 H), 2.55 (s, 3 H), 1.37-1.28 (m, 1 H), 0.65-0.62 (m, 2 H), 0.37-0.34 (m, 2 H).

Step 3 : 4-chloro-5-(cyclopropylmetho -2-methylsulfanylpyrimidine


[00445] To the title compound of step 2 (29.00 g, 136.79 mmol) and N(CH3)4C1 (22.47 g, 205.19 mmol) in anhydrous MeCN (300 mL), was added POCl3 (123.93 g, 820.74 mmol). The mixture was stirred at r.t. for 30 min and at 70°C for 1 h. After concentration under vacuum, EA extractive work up and silica gel chromatography (PE: EA = 50: 1-5: 1) gave the title compound (20 g, 63.6% yield) as a white solid. 1H NMR (CDC13, 400 MHz) δ 8.16 (s, 1 H), 3.95 (d, J = 6.8Hz, 2 H), 2.56 (s, 3 H), 1.33-1.28 (m, 1 H), 0.72-0.70 (m, 2 H), 0.41-0.37 (m, 2 H). LCMS: 230.9 (M+l)+

Step 4 : 4-chloro-5 -(cyclopropylmethoxy)-2-methylsulfonylpyrimidine


[00446] To the title compound of step 3 (19.0 g, 82.60 mmol) in dry CH2C12 (200 mL) at 0°C, m-CPBA (42.62 g, 247.80 mmol) was added over 15 min. The mixture was stirred at 0°C for 30 min and at r.t. overnight. Sat.aq. Na2S03 (100 mL) was added and CH2C12 extractive work up was carried out. Trituration with MTBE (300 mL) gave the title compound (17 g, 78.3% yield) as a white solid. 1H NMR (CDC13, 400 MHz) δ 8.37 (s, 1 H), 4.13 (d, J = 6.8 Hz, 2 H), 3.33 (s, 3 H), 1.39-1.35 (m, 1 H), 0.79-0.74 (m, 2 H), 0.49-0.45 (m, 2 H). LCMS: 263.0 (M+l)+

Step 5 : 4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyrimidin-4-yl]-2-methylisoquinolin- 1 -one


[00447] The title compound of step 4 (5.00 g, 19.08 mmol), the title compound of Example 89, step 1 (5.98 g, 20.99 mmol), K3P04 (12.13 g, 57.24mmol), and Pd(dppf)Cl2 (1.40 g, 1.91 mmol) in dioxane/H20 (50 mL / 5 mL) were N2 purged and heated at 80°C for 8 h. Silica gel chromatography (PE: EA=10/1~1/1) to gave the title compound (5.01 g, yield: 68%) as a yellow solid. 1H NMR (CDC13, 400 MHz) 58.53 (s, 2 H), 7.67-7.63 (m, 2 H), 7.57-7.52 (m, 2 H), 4.06 (d, J = 6.8 Hz, 2 H), 3.71 (s, 3 H), 3.37 (s, 3 H), 1.17 (m, 1 H), 0.61 (m, 2 H), 0.30 (m, 2 H). LCMS: 386.1 (M+l)+

Step 6: N-[5-(cyclopropylmethoxy)-4-(2 -methyl- l-oxoisoquinolin-4-yl)pyrimidin-2-yljmethanesulfonamide


[00448] Sodium hydride (0.93 g, 23.37 mmol, 60% in mineral oil) was added to MeS02NH2 (2.22 g, 23.37 mmol) in dry DMF (30 mL) at 0°C over 15 min. The mixture was stirred at 0°C for 1 h and the title compound of step 5 (3.00 g, 7.79 mmol) was added. The mixture was heated at 60°C for 6 h. After cooling, ice water was added and the pH was adjusted to 5 with acetic acid. The suspended solids were collected and washed with MTBE (50 mL) to afford

the title compound (3 g, yield: 96.7%) as an off-white solid. 1H NMR (CDC13, 400 MHz) δ 9.80 (s, 1 H), 8.53 (d, J = 8.0 Hz, 1 H), 8.42 (s, 1 H), 7.97 (d, J = 8.4 Hz, 1 H), 7.70 (m, 2 H), 7.56 (t, J = 7.6 Hz , 1 H), 3.87 (d, J = 7.2 Hz, 2 H), 3.70 (s, 3 H), 3.39 (s, 3 H), 1.12 (m, 1 H), 0.58 (m, 2 H), 0.24 (m, 2 H). LCMS: 401.1 (M+l) +

Example 153: N-[5-(cyclopropylmethoxy)-4-(l,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-2-yljmethanesulfonamide


[00449] The title compound of Example 152, step 4 was reacted with l,3-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one in a manner similar to Example 152, step 5 and the resulting product was treated with MeS02NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 10.97 (s, 1 H), 8.67 (s, 1 H), 8.42 (s, 1 H), 8.14 (s, 1 H), 4.03 (d, J = 6.4 Hz, 2 H), 3.54 (s, 3 H), 3.35 (s, 3 H), 2.08 (s, 3 H), 1.33-1.31 (m, 1 H), 0.63-0.61 (m, 2 H), 0.38-0.37 (m, 2 H). LCMS: 365.0 (M+l)+

Example 154: N-[5-(cyclopropylmethoxy)-4-[2-methyl-6-(l-methylpyrazol-4-yl)-l-oxoisoquinolin-4-yl]pyrimidin-2-yl methanesulfonamide


[00450] The title compound of Example 152, step 4 was reacted with the title compound of Example 46 step 2 in a manner similar to Example 152, step 5 and the resulting product was treated with MeS02NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (CDC13, 400 MHz) δ 11.15 (s, 1 H), 8.56 (s, 1 H), 8.27 (s, 1 H), 8.25 (d, J = 7.6 Hz, 1 H), 7.98 (s, 1 H), 7.79 (s, 1 H), 7.77 (d, J = 9.6 Hz, 1 H), 7.70 (s, 1 H), 3.95 (d, J = 7.2 Hz, 2 H), 3.85 (s, 3 H), 3.57 (s, 3 H), 3.32 (s, 3 H), 1.00-0.99 (m, 1 H), 0.37-0.32 (m, 2 H), 0.14-0.12 (m, 2 H). LCMS: 481.0 (M+l)+

Example 155: N-[5-(cyclopropylmethoxy)-4-(2 -methyl- l-oxoisoquinolin-4-yl)pyrimidin-2-yl] ethanesulfonamide

[00451] The title compound of Example 152, step 5 was treated with EtS02NH2 instead of MeS02NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (CDCls, 400 MHz) δ 9.00 (s, 1 H), 8.53 (d, J = 8.0 Hz, 1 H), 8.38 (s, 1 H), 7.97 (d, J = 8.0 Hz, 1 H), 7.69 (m, 2 H), 7.57 (t, J = 7.6 Hz , 1 H), 3.86 (d, J = 6.8 Hz, 2 H), 3.70 (s, 3 H), 3.63 (q, J = 7.2 Hz, 2 H), 1.43 (t, J = 7.2 Hz, 3 H), 1.13 (m, 1 H), 0.57 (m, 2 H), 0.25 (m, 2 H). LCMS: 415.0 (M+l) +

Example 156: 4-[5-(cyclopropylmethoxy)-2-(l , 1-dioxo-l ,2-thiazolidin-2-yl)pyrimidin-4-yl]-2-methylisoquinolin- 1 -one


[00452] The title compound of Example 152, step 5 was treated with 1,1-dioxidoisothiazolidine instead of MeS02NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 8.56 (s, 1H), 8.30 (d, J = 8.0 Hz, 1 H), 7.86 (s, 1 H), 7.77 (d, J = 8.0 Hz, 1 H), 7.67 (t, J = 7.6 Hz, 1 H), 7.55 (t, J = 7.6 Hz, 1 H), 3.93-3.91 (m, 4 H), 3.59 (s, 3 H), 2.38-2.31 (m, 2 H), 1.06-1.01 (m, 1 H), 0.44-0.39 (m, 2 H), 0.20-0.16 (m, 2 H). LCMS: 427.1 (M+H)+

Example 157: N-[5-(cyclopropylmethoxy)-4-(6-fluoro-2-methyl-l-oxoisoquinolin-4-yl)pyrimidin-2-yl]ethanesulfonamide


[00453] The title compound of Example 47, step 2 was treated with 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane in a manner similar to Example 89, step 1 and the resulting 6-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)isoquinolin-l-one was coupled to the title compound of Example 152, step 4 in a manner similar to Example 152, step 5 and the resulting 4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyrimidin-4-yl]-6-fluoro-2-methylisoquinolin-l-one was treated with

EtS02NH2 instead of MeS02NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 11.04 (brs, 1 H), 8.54 (s, 1 H), 8.36 (dd, Ji = 9.2 Hz, = 2.4 Hz, 1 H), 8.01 (s, 1 H), 7.65 (dd, ^ = 11.2 Hz, J2 = 2.4 Hz, 1 H), 7.45-7.38 (m, 1 H), 3.95 (d, J = 6.8 Hz, 2 H), 3.58 (s, 3 H), 3.48 (q, J = 7.2 Hz, 2 H), 1.22 (t, J = 7.2 Hz, 3 H), 1.16-1.04 (m, 1 H), 0.50-0.42 (m, 2 H), 0.27-0.20 (m, 2 H). LCMS: 433.0 (M+l)+

Example 158: N-[5-(cyclopropylmethoxy)-4-(7-fluoro-2-methyl-l-oxoisoquinolin-4-yl)pyrimidin-2-yl]methanesulfonamide


[00454] The title compound of Example 58, step 2 was treated with 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane in a manner similar to Example 89, step 1 and the resulting 7-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one was coupled to the title compound of Example 152, step 4 in a manner similar to Example 152, step 5 and the resulting 4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyrimidin-4-yl]-7-fluoro-2-methylisoquinolin-l-one was treated with

MeS02NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 11.15 (s, 1 H), 8.55 (s, 1 H), 8.36 (dd, Ji = 9.2 Hz, J2 = 6.0 Hz, 1 H), 8.00 (s, 1 H), 7.60 (dd, ^ = 11.2 Hz, J2 = 2.4 Hz, 1 H), 7.44-7.37 (m, 1 H), 3.95 (d, J = 7.2 Hz, 2 H), 3.58 (s, 3 H), 3.32 (s, 3 H), 1.15-1.03 (m, 1 H), 0.49-0.42 (m, 2 H), 0.26-0.20 (m, 2 H). LCMS: 419.0 (M+l)+

Example 159: N-[5-(cyclopropylmethoxy)-4-(6-fluoro-2-methyl-l-oxoisoquinolin-4-yl)pyrimidin-2-yl]methanesulfonami


[00455] The title compound of Example 47, step 2 was treated with 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane in a manner similar to Example 89, step 1 and the resulting 6-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one was coupled to the title compound of Example 152, step 4 in a manner similar to Example 152, step 5 and the resulting 4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyrimidin-4-yl]-6-fluoro-2-methylisoquinolin-l-one was treated with MeS02NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 11.14 (brs, 1 H), 8.56 (s, 1 H), 7.96 (dd, Ji = 9.2 Hz, J2 = 3.2 Hz, 1 H), 7.88 (s, 1 H), 7.85 (dd, Ji = 9.2 Hz, J2 = 3.6 Hz, 1 H), 7.62-7.55 (m, 1 H), 3.94 (d, J = 6.8 Hz, 2 H), 3.60 (s, 3 H), 3.32 (s, 3 H), 1.11-0.99 (m, 1 H), 0.47-0.40 (m, 2 H), 0.23-0.16 (m, 2 H). LCMS: 419.0 (M+l)+

Example 160: N-[5-(cyclopropylmethoxy)-4-(7-fluoro-2-methyl-l-oxoisoquinolin-4-yl)pyrimidin-2-yl]ethanesulfonamide


[00456] The title compound of Example 58, step 2 was treated with 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane in a manner similar to Example 89, step 1 and the resulting 7-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one was coupled to the title compound of Example 152, step 4 in a manner similar to Example 152, step 5 and the resulting 4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyrimidin-4-yl]-7-fluoro-2-methylisoquinolin-l-one was treated with with EtS02NH2 instead of MeS02NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (CDC13 400MHz) δ 8.53 (dd, Ji = 8.8 Hz, J2 = 6.0 Hz, 1 H), 8.40 (s, 1 H), 7.77 (s, 1 H), 7.69 (dd, J = 8.8 Hz, 1 H), 7.27-7.23 (m, 1 H), 3.88 (d, J = 6.8 Hz, 2 H), 3.69 (s, 3 H), 3.60 (q, J = 7.2 Hz, 2 H), 1.43 (t, J = 7.2 Hz, 3 H), 1.16-1.13 (m, 1 H), 0.62-0.56 (m, 2 H), 0.27-0.26 (m, 2 H). LCMS: 433.2 (M+l)+

Example 161 : N-[5-(cyclopropylmethoxy)-4-(2 -methyl- 1 -oxoisoquinolin-4-yl)pyrimidin-2-yl] -N-ethylmethanesulfonamide


[00457] Ethyl iodide (95 mg, 0.6 mmol) and K2CO3 (55 mg, 0.4 mmol) were added to a solution of the title compound of Example 152 (80 mg, 0.2 mmol) in MeCN (5 mL). After refluxing 1 h, the mixture was cooled, concentrated under vacuum and subjected to CH2CI2 extractive work up. HPLC purification gave the title compound (13.42 mg, yield: 15.2%) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.63 (s, 1H), 8.32 (d, J = 8.0 Hz, 1 H), 7.90 (s, 1 H), 7.77 (d, J = 8.0 Hz, 1 H), 7.69 (t, J = 7.6 Hz, 1 H), 7.56 (t, J = 7.6 Hz, 1 H), 4.02 (q, J = 6.8 Hz, 2 H), 3.97 (d, J = 7.2 Hz, 1 H), 3.60 (s, 3 H), 3.43 (s, 3 H), 1.25 (t, J = 6.8 Hz, 1 H), 1.10-1.07 (m, 1 H), 0.46-0.42 (m, 2 H), 0.24-0.20 (m, 2 H). LCMS: 429.1 (M+H) +

Example 162: N-[5-(cyclopropylmethoxy)-4-(l ,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-2-yl] -N-ethylmethanesulfonamide


[00458] The title compound of Example 153 was treated with ethyl iodide in a manner similar to Example 161 to give the title compound. 1H NMR (400 MHz, DMSO- 6) δ ppm 0.36-0.42 (m, 2 H) 0.60-0.66 (m, 2 H) 1.25 (t, J=6.82 Hz, 3 H) 1.29-1.40 (m, 1 H) 2.09 (s, 3 H) 3.48 (s, 3 H) 3.56 (s, 3 H) 3.88 - 4.20 (m, 4 H) 8.13 (s, 1 H) 8.49 (s, 1 H) 8.69 (s, 1 H). ). LCMS: 393 (M+H) +

Example 163: N-[5-(cyclopropylmethoxy)-4-(2-methyl-l-oxo-5,6,7,8-tetrahydroisoquinolin- 4-yl)pyrimidin-2-yl]methanesulfonamide

Step 1 : 2-methyl-5,6,7,8-tetrahydroisoquinolin-l-one


[00459] The title compound was prepared from the N-methylation of 5,6,7,8-tetrahydroisoquinolin-l(2H)-one in a manner similar to Example 47, step 1. 1H NMR (CDCI3,

400 MHz): δ 7.02 (d, J = 7.2 Hz, 1 H), 5.90 (d, J = 7.2 Hz, 1 H), 3.49 (s, 3 H), 2.54-2.45 (m, 4H), 1.74-1.69 (m, 4H).

Step 2: 4-bromo-2-methyl-5,6,7,8-tetrahydroisoquinolin-l-one


[00460] The title compound was prepared from the bromination of the title compound of step 1 in a manner similar to Example 47, step 2. LCMS: 241.9(M+H)+

Step 3 : 2-methyl-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-5, 6,7,8-tetrahydroisoquinolin- 1 -one


[00461] The title compound of step 2 (3.3 g, 13.7 mmol), 4,4,5, 5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (6.96 g, 27.4 mmol), Pd2(dba)3 (400 mg, 0.43 mmol), X-phos (400 mg, 0.84 mmol) and anhydrous KOAc (1.02 g, 41.1 mmol) in anhydrous dioxane (50 mL) were heated at 50°C under N2 for 12 h. Silica gel chromatography (PE: EA = 5:1) gave the title compound (1.5 g, yield: 38 %) as a yellow solid. 1H NMR (CDC13, 400 MHz): δ 7.62 (s, 1 H), 5.28 (s, 3 H), 2.82-2.76 (m, 2 H), 2.55-2.33 (m, 2 H), 1.72-1.70 (m, 4 H), 1.31 (s, 12 H). LCMS: 290.0(M+H)+

Step 4: 4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyrimidin-4-yl]-2-methyl-5, 6,7,8-tetrahydroisoquinolin- 1 -one


[00462] The title compound of step 3 (200 mg, 0.69 mmol), the title compound of Example 152, step 4 (218 mg, 0.83 mmol), K3P04 (440 mg, 2.07 mmol) and Pd(dppf)Cl2 (51 mg, 0.7 mmol) in 6: 1 dioxane/water (7 mL) were purged with nitrogen and heated at 70°C for 8 h.

After silica gel chromatography (PE: EA=1 : 1), the title compound (180 mg, yield: 67%) was obtained as a light yellow solid. 1H NMR (CDC13, 400 MHz): δ 8.42 (s, 1 H), 7.48 (s, 1 H), 4.04 (d, J = 7.2 Hz, 2 H), 3.60 (s, 3 H), 3.35 (s, 3 H), 2.65-2.62 (m, 2 H), 2.54-2.50 (m, 2 H), 1.80-1.78 (m, 2 H), 1.77-1.67 (m, 2H), 1.28-1.25 (m, 1 H), 0.73-0.71 (m, 2 H), 0.41-0.38 (m, 2 H).

Step 5: N-[5-(cyclopropylmethoxy)-4-(2-methyl-l-oxo-5,6,7,8-tetrahydroisoquinolin-4-yl)pyrimidin-2-yl]methanesulfonami


[00463] The title compound of step 4 was treated with MeS02NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (CDC13, 400 MHz): δ 8.18 (s, 1 H), 7.38 (s, 1 H), 3.74 (d, J = 6.4 Hz, 2 H), 3.51 (s, 3 H), 3.28 (s, 3 H), 2.60-2.53 (m, 2H), 2.50-2.46 (m, 2 H), 1.74-1.71 (m, 2 H), 1.64-1.59 (m, 2 H), 1.13-1.10 (m, 1 H), 0.60-0.58 (m, 2 H), 0.25-0.24 (m, 2 H). LCMS: 405.1(M+H)+

Example 164: N-[5-(cyclopropylmethoxy)-4-(2-methyl-l-oxo-5,6,7,8-tetrahydroisoquinolin-4-yl)pyrimidin-2-yl]ethanesulfonamide


[00464] The title compound of Example 163, step 4 was treated with treated with EtS02NH2 instead of MeS02NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (DMSO- 6, 400 MHz): δ 8.32 (s, 1 H), 7.64 (s, 1 H), 3.83 (d, J = 6.8 Hz, 2 H), 3.44 (s, 3 H), 3.30-3.20 (m, 2 H), 2.47-2.41 (m, 4 H), 1.67-1.57 (m, 4 H), 1.19-1.13 (m, 4 H), 0.51-0.49 (m, 2 H), 0.24-0.22 (m, 2 H). LCMS: 419.1(M+H)+

Example 165: N-[5-(2,4-difluorophenoxy)-4-(2-methyl-l-oxoisoquinolin-4-yl)pyrimidin-2-yljmethanesulfonamide


[00465] The title compound of Example 151 was treated with MeS02NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (DMSO-d6, 400 MHz) 5 11.50 (s, 1 H), 8.59 (s, 1 H), 8.25 (s, J = 8.0 Hz, 1 H), 7.87 (s, 1 H), 7.77 (d, J = 8.0 Hz, 1 H), 7.67 (t, J = 8.0 Hz, 1 H), 7.54 (t, J = 7.2 Hz, 1 H), 7.34-7.28 (m, 1 H), 7.20-7.13 (m, 1 H), 6.90 (t, J = 8.8 Hz, 1 H), 3.54 (s, 3 H), 3.35 (s, 3 H). LCMS: 459.0 (M+l)+

Example 166: N-[5-(2,4-difluorophenoxy)-4-(l ,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-2-yljmethanesulfonamide


[00466] The title compound of Example 149, step 4 was treated with MeS02NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (CDC13, 400 MHz) δ 8.42 (s, 1 H), 8.36 (s, 1 H), 8.10-8.12 (m, 2 H), 6.98-7.05 (m, 2 H), 6.87-6.92 (m, 1 H), 3.64 (s, 3 H), 3.45 (s, 3 H), 2.22 (s, 3 H). LCMS: 423.0 (M+l) +

Example 167: N-[5-(2,4-difluorophenoxy)-4-(5-methoxy-l -methyl-6-oxopyridin-3-yl)pyrimidin-2-yl]methanesulfonamide


[00467] The title compound of Example 150 was treated with MeS02NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (DMSO-d6, 400 MHz) 5 11.37 (s, 1 H), 8.34 (s, 1 H), 8.26 (s, 1 H), 7.58 (s, 1 H), 7.54-7.50 (m, 1 H), 7.28-7.23 (m, 1 H), 7.10-7.06 (m, 1 H), 3.74 (s, 3 H), 3.52 (s, 3 H), 3.39 (s, 3 H). LCMS: 439.0 (M+l)+

Example 168: N-[5-(2,4-difluorophenoxy)-4-(5-methoxy-l -methyl-6-oxopyridin-3-yl)pyrimidin-2-yl]ethanesulfonamide


[00468] The title compound of Example 150 was treated with EtS02NH2 instead of

MeS02NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (CDCls, 400 MHz) δ 8.35 (d, J = 2.0 Hz, 1 H), 8.18 (s, 1 H), 7.70 (d, J = 2.0 Hz, 1 H), 7.25-7.22 (m, 1 H), 7.12-7.07 (m, 1 H), 7.04-7.01 (m, 1 H), 3.93 (s, 3 H), 3.70 (s, 3 H), 3.38 (s, 3 H). LCMS: 423.9 (M+l) +

Example 169: N-[5-(2,4-difluorophenoxy)-4-(l ,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-2-yl] ethanesulfonamide


[00469] The title compound of Example 149, step 4 was treated with EtS02NH2 instead of MeS02NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 9.07 (s, 1 H), 8.42 (s, 1 H), 8.15 (s, 1 H), 8.11 (s, 1 H), 7.03-6.97 (m, 1 H), 6.91-6.87 (m, 1 H), 3.66-3.61 (m, 5 H), 2.22 (s, 3 H), 1.44 (t, J = 7.6 Hz, 3 H). LCMS: 437.0 (M+l)+

Example 170: N-[5-(2,4-difluorophenoxy)-4-(2-methyl-l-oxoisoquinolin-4-yl)pyrimidin-2-yl] ethanesulfonamide


[00470] The title compound of Example 151 was treated with with EtS02NH2 instead of MeS02NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR

(CDCI3, 400 MHz) δ 9.15 (s, 1 H), 8.49 (d, J = 7.6 Hz, 1 H), 8.34 (s, 1 H), 8.02 (d, J = 8.0 Hz, 1 H), 7.71-7.67 (m, 2 H), 7.54 (t, J = 7.6 Hz, 1 H), 6.92-6.86 (m, 2 H), 6.79-6.75 (m, 1 H), 3.67 (s, 3 H), 3.58 (q, J = 7.6 Hz, 2 H), 1.39 (t, J = 7.6 Hz, 3 H). LCMS: 473.0 (M+l)+ Example 171 : 4-[5-(2,4-difluorophenoxy)-2-(l , 1 -dioxo- 1 ,2-thiazolidin-2-yl)pyrimidin-4-yl]-2-methylisoquinolin- 1 -one


[00471] The title compound of Example 151 was treated with 1,1-dioxidoisothiazolidine instead of MeS02NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 8.63 (s, 1H), 8.24 (d, J = 8.0 Hz, 1 H), 7.86 (s, 1 H), 7.83 (d, J = 8.0 Hz, 1 H), 7.65 (t, J = 7.2 Hz, 1 H), 7.53 (t, J = 7.2 Hz, 1 H), 7.31-7.26 (m, 1 H), 7.13-7.07 (m, 1 H), 6.89-6.87 (m, 1 H), 3.97 (t, J = 6.4 Hz, 2 H), 3.57 (t, J = 7.2 Hz, 2 H), 3.54 (s, 3 H), 2.40-2.33 (m, 2 H). LCMS: 485.2 (M+H) +

Example 172: N-[5-(2,4-difluorophenoxy)-4-(2-methyl-l -oxo-5,6,7,8-tetrahydroisoquinolin-4-yl)pyrimidin-2-yl]methanesulfonamide


[00472] The title compound of Example 149, step 3 was reacted with the title compound of Example 163, step 3 in a manner similar to Example 163, step 4 and the resulting product was treated with MeS02NH2 in a manner similar to Example 163, step 5 to give the title compound. 1H NMR (DMSO- 6, 400 MHz): δ 8.16 (s, 1 H), 7.46 (s, 1 H), 7.25-7.20 (m, 1 H), 6.90-6.84 (m, 2 H), 3.34 (s, 3 H), 2.80 (s, 3 H), 2.41-2.29 (m, 4 H), 1.60-1.48 (m, 4 H). LCMS: 463.1(M+H)+

Example 173: N-[5-(2,4-difluorophenoxy)-4-(2-methyl-l-oxo-5,6,7,8-tetrahydroisoquinolin-4-yl)pyrimidin-2-yl]ethanesulfonamide


[00473] The title compound of Example 149, step 3 was reacted with the title compound of Example 163, step 3 in a manner similar to Example 163, step 4 and the resulting 4-[5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidin-4-yl]-2-methyl-5,6,7,8-tetrahydroisoquinolin-l-one was treated with EtS02NH2 instead of MeS02NH2 in a manner similar to Example 163, step 5 to give the title compound. 1H NMR (DMSO- 6, 400 MHz): δ 8.38 (s, 1 H), 7.61 (s, 1 H), 7.35-7.31 (m, 1 H), 7.04-6.95 (m, 2 H), 3.41 (s, 3 H), 3.30-3.20 (m, 2 H), 2.42-2.40 (m, 2 H), 2.32-2.30 (m, 2 H), 1.61-1.51 (m, 4 H), 1.18 (t, J = 7.2 Hz, 3 H). LCMS: 477.1(M+H)+ Example 174: 4-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-fluoro-2-methylisoquinolin- 1 -one


[00474] A mixture of 4-bromo-6-fluoro-2-methylisoquinolin-l-one (500.00 mg, 1.95 mmol), 2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.07 g, 2.92 mmol), K3P04 (1.24 g, 5.85 mmol) and Pd(dppf)Cl2 (0.1 g, cat.) in dioxane/H20 (30 mL / 4 mL) was stirred at 70 °C for 12 hrs under Ar. The mixture was concentrated and the residue purified by column chromatography (PE: EA = 1 : 1) to give a pink solid. The pink solid was further purified by column chromatography (DCM : EA = 4: 1) to afford the title compound (0.13 g, 16%) as a light yellow solid. 1H NMR (CDC13, 400 MHz) δ 8.54 (brs, 1 H), 7.96 (dd, J i = 8.8 Hz, J 2 = 2.4 Hz, 1 H), 7.81 (d, J = 2.0 Hz, 1 H), 7.22-7.20 (m,l H), 7.15-7.13 (m, 1 H), 7.1 (d, J = 8.8 Hz, 1 H), 6.78 (dd, J i = 10.4 Hz, J 2 = 2.4 Hz, 1 H), 3.90 (t, J = 7.6 Hz, 2 H), 3.68 (s, 3 H), 3.15 (q, J = 7.6 Hz, 2 H), 1.33 (t, J = 7.6 Hz, 3 H), 1.06 - 1.02 (m, 1 H), 0.50-0.43 (m, 2 H), 0.15-0.14 (m, 2 H). LCMS (M+H)+ = 416.0 (M+l) +

Example 175: 2-methyl-4-[5-methylsulfonyl-2-(oxolan-3-yloxy)phenyl]isoquinolin-l-one Step 1 : 4-(2-fluoro-5-methylsulfonyl henyl)-2-methylisoquinolin-l-one

[00475] A mixture of compound 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one (4.1 g, 14.5 mmol), 2-bromo-4-methylsulfonyl-l-fluorobenzene (3.5 g, 13.8 mmol) prepared in a similar manner to Example 79 steps 1-2, CsF (6.3 g, 41.3 mmol), and Pd(dppf)Cl2 (1.0 g, 1.38 mmol) in DME (70 mL) and MeOH (35 ml) was stirred at 70 °C for 12 h under N2. The mixture was concentrated and the residue was purified by column chromatography on silica gel (PE: EA = 2: 1-0: 1) to give the title compound (3.4 g, 74.4%) as a red solid. LCMS (M+H)+ = 331.9 (M+l)+

Step 2: 2-methyl-4-[5-methylsulfon l-2-(oxolan-3-yloxy)phenyl]isoquinolin-l-one


[00476] To a solution of oxolan-3-ol (175.0 mg, 1.99 mmol) in anhydrous DMF (3 mL) was added NaH (66.0 mg, 1.65 mmol, 60% in mineral oil) at 0 °C and then stirred at 0 °C for 0.5 hrs. 4-(2-fluoro-5-methylsulfonylphenyl)-2-methylisoquinolin-l-one (110.0 mg, 0.33 mmol) was added. The mixture was stirred at 0 °C for 0.5 h and then at r.t. for 3 hrs. It was then quenched with aqueous sat. NH4C1 (20 mL) and extracted with EA (20 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2S04, and concentrated under reduced pressure to afford a crude product which was purified by prep-HPLC to give the title compound (62.0 mg, 39.7 %) as a light yellow solid. 1H NMR (CDCI3,

400 MHz) δ 8.51 (d, J = 7.6 Hz, 1 H), 8.00 (dd, Ji = 8.8 Hz, J2 = 2.4 Hz, 1 H), 7.89 (d, J = 2.4 Hz, 1 H), 7.58-7.51 (m, 2 H), 7.11-7.03 (m, 3 H), 5.01-4.98 (m, 1 H), 3.97 (dd, Ji = 10.4 Hz, h = 4.8 Hz, 1 H), 3.76-3.70 (m, 2 H), 3.67 (s, 3 H), 3.61-3.42 (m, 1 H), 3.1 1 (s, 3 H), 2.18-1.88 (m, 2 H). LCMS (M+H)+ = 400.0 (M+l)+

Example 176: 2-methyl-4-[5-methylsulfon l-2-(oxan-4-yloxy)phenyl]isoquinolin-l-one


[00477] The title compound was prepared in a manner similar to Example 175, by

substituting oxan-4-ol for oxolan-3-ol in step 2. 1H NMR (CDC13, 400 MHz) δ 8.52 (d, J =

7.6 Hz, 1 H), 8.00 (dd, Ji = 8.8 Hz, J2 = 2.4 Hz, 1 H), 7.89 (d, J = 2.4 Hz, 1 H), 7.63-7.50 (m, 2 H), 7.19 (d, J = 7.6 Hz, 1 H), 7.11 (d, J = 8.8 Hz, 1 H), 7.09 (s, 1 H), 4.65-4.61 (m, 1 H), 3.71 (s, 3 H), 3.53-3.45 (m, 4 H), 3.11 (s, 3 H), 1.92-1.88 (m, 2 H), 1.62-1.54 (m, 2 H).

LCMS (M+H)+ = 414.1 (M+l)+

Example 177: 4-(2-ethoxy-5-methylsulfon lphenyl)-2-methylisoquinolin- 1 -one


[00478] The title compound was prepared in a manner similar to Example 175, by

substituting ethanol for oxolan-3-ol in step 2. 1H NMR (CDC13, 400 MHz) δ 8.52 (d, J = 8.0 Hz, 1 H), 8.01 (dd, Ji = 8.8 Hz, J2 = 2.4 Hz, 1 H), 7.86 (d, J = 2.4 Hz, 1 H), 7.57 (t, J = 7.2 Hz, 1 H), 7.52 (t, J = 7.2 Hz, 1 H), 7.13 (t, J = 7.2 Hz, 2 H), 7.08 (s, 1 H), 4.12-4.09 (m, 2 H), 3.68 (s, 3 H), 3.10 (s, 3 H), 1.18 (t, J = 7.2 Hz, 1 H). LCMS (M+H)+ = 358.0 (M+l) +

Example 178: 2-methyl-4-(5-methylsulfonyl-2-propoxyphenyl)isoquinolin-l-one


[00479] The title compound was prepared in a manner similar to Example 175, by

substituting propan-l-ol for oxolan-3-ol in step 2. 1H NMR (CDC13, 400 MHz) δ 8.51 (d, J = 8.0 Hz, 1 H), 8.00 (dd, Ji = 8.8 Hz, J2 = 2.4 Hz, 1 H), 7.86 (d, J = 2.4 Hz, 1 H), 7.56 (t, J = 7.2 Hz, 1 H), 7.50 (t, J = 7.2 Hz, 1 H), 7.14 (d, J = 7.2 Hz, 1 H), 7.12 (d, J = 8.8 Hz, 1 H), 7.07 (s, 1 H), 4.00-3.94 (m, 2 H), 3.67 (s, 3 H), 3.10 (s, 3 H), 1.60-1.52 (m, 2 H), 0.68 (t, J = 7.2 Hz, 1 H). LCMS (M+H)+ = 372.0 (M+l)+

Example 179: 2-methyl-4-[5-methylsulfonyl-2-(oxan-3-yloxy)phenyl]isoquinolin-l-one


[00480] The title compound was prepared in a manner similar to Example 175, by

substituting oxan-3-ol for oxolan-3-ol in step 2. 1H NMR (CDC13, 400 MHz) δ 8.51 (d, J = 8.0 Hz, 1 H), 7.98 (dd, Ji = 8.8 Hz, J2 = 2.4 Hz, 1 H), 7.88 (d, J = 2.4 Hz, 1 H), 7.56 (t, J = 7.2 Hz, 1 H), 7.52 (t, J = 7.2 Hz, 1 H), 7.18 (d, J = 8.0 Hz, 1 H), 7.12-7.06 (m, 2 H), 4.43-4.41 (m, 1 H), 3.79-3.78 (m, 1 H), 3.67 (s, 3 H), 3.66-3.63 (m, 1 H), 3.39-3.34 (m, 2 H), 3.10 (s, 3 H), 2.02-1.93 (m, 2 H), 1.59-1.48 (m, 2 H). LCMS (M+H)+ = 414.1 (M+l) +

Example 180: 4-[2-(trans-4-hydroxycyclohexyl)oxy-5-methylsulfonylphenyl]-2-methylisoquinolin- 1 -one

Step 1 : 4-[2-[4-[tert-butyl(dimethyl)silyl]oxycyclohexyl]oxy-5-methylsulfonylphenyl]-2-methylisoquinolin- 1 -one


[00481] The title compound was prepared in a manner similar to Example 175, by

substituting trans-4-[tert-butyl(dimethyl)silyl]oxycyclohexan-l-ol for oxolan-3-ol in step 2. LCMS (M+H)+ = 542.2 (M+l)+

Step 2: 4-[2-(trans-4-hydroxycyclohexyl)oxy-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one


[00482] To a solution of the title compound from step 1 (180.0 mg, 0.33 mmol) in dry MeOH (5 mL) and DCM (3 mL) was added dropwise HCl/MeOH (0.3 mL, 1.2 mmol, 4M) at 0 °C and then stirred at r.t. for 20 min. TLC showed the starting material was consumed completely. The mixture was concentrated and the residue was purified by prep-HPLC to afford the title compound (130.0 mg, 97.8 %) as a white solid. 1H NMR (CDC13, 400 MHz) δ 8.50 (d, J = 7.6 Hz, 1 H), 7.98 (dd, Ji = 8.8 Hz, J2 = 2.8 Hz, 1 H), 7.86 (d, J = 2.4 Hz, 1 H), 7.55 (t, J = 6.8 Hz, 1 H), 7.51 (t, J = 6.8 Hz, 1 H), 7.16 (d, J = 7.6 Hz, 1 H), 7.11 (d, J = 8.8 Hz, 1 H), 7.05 (s, 1 H), 4.42-4.35 (m, 1 H), 3.67 (s, 3 H), 3.65-3.62 (m, 1 H), 3.10 (s, 3 H), 2.01-1.89 (m, 2 H), 1.71-1.65 (m, 2 H), 1.36-1.34 (m, 4 H). LCMS (M+H)+ = 428.1 (M+l)+

Example 181 : 4-[5-ethylsulfonyl-2-(trans-4-hydroxycyclohexyl)oxyphenyl]-2-methylisoquinolin- 1 -one

Step 1 : 4-[2-[4-[tert-butyl(dimethyl)silyl]oxycyclohexyl]oxy-5-ethylsulfonylphenyl]-2-methylisoquinolin- 1 -one


[00483] The title compound was prepared in a manner similar to Example 175 by substituting 2-bromo-4-ethylsulfonyl-l -fluorobenzene for 2-bromo-4-methylsulfonyl-l -fluorobenzene in step 1. LCMS (M+H)+ = 345.9 (M+l)+

Step 2: 4-[5-ethylsulfonyl-2-(trans-4-hydroxycyclohexyl)oxyphenyl]-2-methylisoquinolin-l-one


[00484] To a solution of trans- 1,4-cyclohexanediol (504.0 mg, 4.34 mmol) in anhydrous DMF (4 mL) was added NaH (139.0 mg, 3.47 mmol, 60% in mineral oil) at 0 °C and then stirred at 0 °C for 1 h. The compound from step 1 (100.0 mg, 0.29 mmol) was added. The mixture was stirred at 0 °C for 0.5 h and then at r.t. 18 hrs. It was then quenched with MeOH (4 mL) and filtered. The filtrate was purified by prep-HP LC to give the title compound (37.0 mg, 30.0 %) as an off-white solid. 1H NMR (CDC13, 40 MHz) δ 8.51 (d, J = 7.6 Hz, 1 H), 7.94 (dd, Ji = 8.8 Hz, J2 = 2.4 Hz, 1 H), 7.83 (d, J = 2.0 Hz, 1 H), 7.56 (t, J = 6.8 Hz, 1 H), 7.51 (t, J = 6.8 Hz, 1 H), 7.16 (d, J = 7.6 Hz, 1 H), 7.11 (d, J = 8.8 Hz, 1 H), 7.05 (s, 1 H), 4.43-4.18 (m, 1 H), 3.67 (s, 3 H), 3.65-3.62 (m, 1 H), 3.16 (q, J = 7.6 Hz, 2 H), 2.00-1.90 (m, 2 H), 1.71-1.65 (m, 2 H), 1.42-1.30 (m, 7 H). LCMS (M+H)+ = 442.0 (M+l)+

Example 182: 4-[2-(trans-4-aminocyclohexyl)oxy-5-methylsulfonylphenyl]-2-methylisoquinolin- 1 -one


[00485] A mixture of 4-(2-fluoro-5-methylsulfonylphenyl)-2-methylisoquinolin-l-one (200 mg, 0.60 mmol), trans-4-aminocyclohexan-l-ol (278 mg, 2.42 mmol) and CS2CO3 (591 mg, 1.81 mmol) in DMSO (4 mL) was stirred at 120°C for 12 hrs. Water (20 mL) was added and the mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2S04 and concentrated. The residue was purified by prep-HPLC to give the title compound (103.15 mg, 36.9 %) as its hydrochloride salt. 1H NMR (DMSO-d6, 400 MHz) δ 8.28 (d, J = 8.0 Hz, 1 H), 8.10 (s, 3 H), 7.95 (dd, Ji = 8.8 Hz, h = 2.4 Hz, 1 H), 7.80 (d, J = 2.4 Hz, 1 H ), 7.63 (t, J = 7.2 Hz, 1 H ), 7.51-7.49 (m, 3 H), 7.14 (d, J = 8.0 Hz, 1 H), 4.50-4.44 (m, 1 H), 3.56 (s, 3 H), 3.22 (s, 3 H), 2.95-2.85 (m, 1 H), 2.00-1.94 (m, 2 H), 1.84 (d, J = 11.2 Hz, 2 H), 1.47-1.41 (m, 2 H), 1.20-1.12 (m, 2 H). LCMS (M+H)+ = 427.1 (M+H) +

Example 183 : 4- [2-(cis-4-aminocyclohexyl)oxy-5 -methylsulfonylphenyl] -2-methylisoquinolin- 1 -one


[00486] To compound cis-4-aminocyclohexan-l-ol (275 mg, 1.81 mmol) in DMF (3 mL), was added NaH (127 mg, 3.17 mmol, 60% in mineral oil) in one portion at 0°C. The mixture was stirred at 0 °C for 30 min, 4-(2-fluoro-5-methylsulfonylphenyl)-2-methylisoquinolin-l-one (150.00 mg, 0.45 mmol) was added in one portion and the mixture stirred at 0 °C for 2 hrs. The reaction was diluted with water (20 mL) and extracted with EA (3 x 20 mL). The combined organic layers were washed with saturated brine (2 x 20 mL), dried with anhydrous Na2S04, filtered and concentrated in vacuum. The residue was purified by prep-HPLC to give the title compound as its hydrochloride salt (91.01 mg, 47.1%). 1H NMR (DMSO-d6, 400

MHz) δ 8.29 (d, J = 8.0 Hz, 1 H), 8.00 (s, 3 H), 7.95 (dd, Ji = 8.8 Hz, J2 = 2.0 Hz, 1 H), 7.81 (d, J = 2.0 Hz, 1 H ), 7.64 (t, J = 7.2 Hz, 1 H ), 7.56 (s, 1 H), 7.51 (t, J = 7.2 Hz, 1 H ), 7.40 (d, J = 8.8 Hz, 1 H), 7.40 (d, J = 8.0 Hz, 1 H), 4.70 (s, 1 H), 3.59 (s, 3 H), 3.22 (s, 3 H), 2.96- 2.94 (m, 1 H), 1.85-1.82 (m, 1 H), 1.64-1.46 (m, 5 H), 1.32-1.26 (m, 1 H), 1.04-0.98 (m, 1 H). LCMS (M+H)+ = 427.0 (M+H)+

Example 184: 4-(2-but-2-ynoxy-5-methylsulfonylphenyl)-2-methylisoquinolin- 1 -one


[00487] The title compound was prepared in a manner similar to Example 175, by substituting but-2-yn-l-ol for oxolan-3-ol in step 2. 1H NMR: (CDC13, 400 MHz) δ: 8.52 (d, J=7.6 Hz, 1 H ), 8.03 (d, J=8.8 Hz, 1 H ), 7.87 (s, 1 H),7.59-7.50 (m, 2 H), 7.32 (d, J=8.8 Hz, 1 H ), 7.15 (d, J=8.4 Hz, 1 H ), 7.64 (t, J=8.0 Hz, 1 H), 7.08 (s, 1 H), 4.68 (s, 2 H), 3.67 (s, 3 H), 3.11 (s, 1 H), 1.85 (s, 1 H). LCMS (M+H)+ = 382.1 (M+H)+

Example 185: 4-(2-but-2-ynoxy-5-ethylsulfonylphenyl)-2-methylisoquinolin-l-one


[00488] The title compound was prepared in a manner similar to Example 181 , by substituting but-2-yn-l-ol for trans- 1,4-cyclohexanediol in step 2. 1H NMR: (CDCI3, 400 MHz) δ: 8.51 (d, J=7.6 Hz, 1 H), 8.00 (dd, Ji=8.8 Hz, J2=2.0 Hz, 1 H), 7.83 (s, 1 H), 7.61 (d, J=7.6 Hz, 1 H), 7.55 (d, J=7.6 Hz, 1 H), 7.33 (d, J=8.8 Hz, 1 H), 7.18 (d, J=8.0 Hz, 1 H), 7.12 (s, 1 H), 4.68 (s, 2 H), 3.72 (s, 3 H), 3.17 (q, J=7.2 Hz, 2 H), 1.85 (s, 3 H), 1.34(t, J=7.2 Hz, 3 H). LCMS (M+H)+ = 396.0 (M+H)+

Example 186: 6-fluoro-4-[2-(trans-4-hydroxycyclohexyl)oxy-5-methylsulfonylphenyl]-2-methylisoquinolin- 1 -one

Step 1 : 6-fluoro-4-(2-fluoro-5-methyl lfonylphenyl)-2-methylisoquinolin-l-one


[00489] The title compound was prepared in a manner similar to Example 174, by substituting 2-(2-fluoro-5-methylsulfonylphenyl)-4,4,5,5-tetramethyl-l ,3,2-dioxaborolane for 2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane. LCMS (M+H)+ = 349.9 (M+H) +

Step 2: 4-[2-[4-[tert-butyl(dimethyl)silyl]oxycyclohexyl]oxy-5-methylsulfonylphenyl]-6-fluoro-2-methylisoquinolin- 1 -one


[00490] The title compound was prepared in a manner similar to Example 180 step 1, by substituting 6-fluoro-4-(2-fluoro-5-methylsulfonylphenyl)-2-methylisoquinolin-l-one for 4-(2-fluoro-5-methylsulfonylphenyl)-2-methylisoquinolin-l-one. The crude product was used directly in the next step without further purification. LCMS (M+H)+ = 560.3 (M+H) + Step 3 : 6-fluoro-4-[2-(trans-4-hydroxycyclohexyl)oxy-5-methylsulfonylphenyl]-2-methylisoquinolin- 1 -one


The tert-butyl(dimethyl)silyl ether was deprotected in a manner similar to Example 180 step 2. 1H NMR (CDCI3, 400 MHz) δ 8.53-8.49 (m, 1 H), 7.99 (dd, Ji = 8.8 Hz, J2 = 2.4 Hz, 1 H), 7.85 (d, J = 2.0 Hz, 1 H), 7.21-7.18 (m, 1 H), 7.12 (d, J = 8.8 Hz, 1 H), 7.08 (s, 1 H), 6.78 (dd, Ji = 10.0 Hz, h = 2.4 Hz, 1 H), 4.46-4.44 (m, 1 H), 3.66-3.65 (m, 4 H), 3.10 (s, 3 H), 2.02-1.99 (m, 2 H), 1.73-1.71 (m, 2 H), 1.43-1.37 (m, 4 H). LCMS (M+H)+ = 446.0 (M+H) + Example 187: 7-fluoro-4-[2-(trans-4-hydroxycyclohexyl)oxy-5-methylsulfonylphenyl]-2-methylisoquinolin- 1 -one

[00491] The title compound was prepared in a manner similar to Example 186, by substituting 4-bromo-7-fluoro-2-methylisoquinolin-l-one for 4-bromo-6-fluoro-2-methylisoquinolin-l-one in step 1. 1H NMR (CDCI3, 400 MHz) δ 8.16-8.14 (m, 1 H), 7.99 (dd, Ji = 8.8 Hz, J2 = 2.4 Hz, 1 H), 7.86 (d, J = 2.4 Hz, 1 H), 7.28-7.27 (m, 1 H), 7.18-7.12 (m, 2 H), 7.01 (s, 1 H), 4.43-4.42 (m, 1 H), 3.67-3.66 (m, 4 H), 3.10 (s, 3 H), 1.98-1.97 (m, 2 H), 1.72-1.71 (m, 2 H), 1.39-1.32 (m, 4 H). LCMS (M+H)+ = 446.0 (M+H) +

Example 188: 4-[5-ethylsulfonyl-2-(trans-4-hydroxycyclohexyl)oxyphenyl]-6-fluoro-2-methylisoquinolin- 1 -one


[00492] The title compound was prepared in a manner similar to Example 186, by substituting 2-(5-ethylsulfonyl-2-fluorophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane for 2-(2-fluoro-5-methylsulfonylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane in step 1. 1H NMR (CDCI3, 400 MHz) δ 8.53-8.50 (m, 1 H), 7.97-7.94 (m, 1 H), 7.82 (d, J = 2.4 Hz, 1 H), 7.22-7.18 (m, 1 H), 7.13 (d, J = 8.8 Hz, 1 H), 7.08 (s, 1 H), 6.79-6.76 (m, 1 H), 4.46-4.44 (m, 1 H), 3.70-3.64 (m, 4 H), 3.16 (q, J = 7.6 Hz, 2 H), 2.00-1.88 (m, 3 H), 1.72-1.71 (m, 2 H), 1.40-1.30 (m, 7 H). LCMS (M+H)+ = 460.1 (M+H) +

Example 189: 4-[5-ethylsulfonyl-2-(trans-4-hydroxycyclohexyl)oxyphenyl]-7-fluoro-2-methylisoquinolin- 1 -one

Step 1 : 4-(5-ethylsulfonyl-2-fluoroph nyl)-7-fluoro-2-methylisoquinolin-l-one


[00493] A mixture of 4-bromo-7-fluoro-2-methylisoquinolin-l-one (100 mg, 0.39 mmol), 2-(5-ethylsulfonyl-2-fluorophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (148 mg, 0.47 mmol), Pd(dppf)Cl2 (29 mg, 0.04 mmol) and K3PO4 (207 mg, 0.98 mmol) in dioxane (6 mL) and H20 (1 mL) was heated to 70°C for 18 hrs under N2. The mixture was concentrated and the residue was purified by column chromatography on silica gel (PE: EA=1 : 1) to give compound 12 (70 mg, yield: 49%) as a yellow solid. LCMS (M+H)+ = 364.1 (M+H) +

Step 2: 4-[2-[4-[tert-butyl(dimethyl)silyl]oxycyclohexyl]oxy-5-ethylsulfonylphi

fluoro-2-methylisoquinolin- 1 -one


[00494] To a solution of trans-4-[tert-butyl(dimethyl)silyl]oxycyclohexan-l-ol (87 mg, 0.38 mmol) in dry DMF (2 mL) was added NaH (15 mg, 0.38 mmol, 60% in mineral oil) in portions under N2 at 0°C and the mixture was stirred at 20°C for 1 h. Then the title compound from step 1 (70 mg, 0.19 mmol) was added and the mixture was stirred at 20 °C for 4 hrs. The mixture was quenched with H20 (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over Na2S04 and concentrated to give the title compound as a yellow gum (65 mg) which was used directly in the next step without further purification. LCMS (M+H)+ = 574.3 (M+H) +

Step 3 : 4-[5-ethylsulfonyl-2-(trans-4-hydroxycyclohexyl)oxyphenyl]-7-fluoro-2-methylisoquinolin- 1 -one


[00495] The tert-butyl(dimethyl)silyl ether was deprotected in a manner similar to Example 180 step 2. 1H NMR (CDC13, 400 MHz) δ 8.16 (dd, Ji = 9.2 Hz, J2 = 2.4 Hz, 1 H), δ 7.96 (dd, Ji = 8.4 Hz, = 2.4 Hz, 1 H), 7.82 (d, J = 2.4 Hz, 1 H), 7.32-7.29 (m, 1 H), 7.18-7.11 (m, 2 H), 7.01 (s, 1 H), 4.42-4.42 (m, 1 H), 3.67 (s, 3 H), 3.18 (q, J = 7.6 Hz, 2 H), 1.97-1.88 (m, 3 H), 1.72-1.71 (m, 2 H), 1.40-1.32 (m, 7 H). LCMS (M+H)+ = 460.1 (M+H) +

Example 190: 2-methyl-4-[5-methylsulfonyl-2-(oxolan-3-ylamino)phenyl]isoquinolin-l-one Step 1 : N-(2-bromo-4-methylsulfonylphenyl)oxolan-3 -amine


[00496] A mixture of 2-bromo-l-fluoro-4-methylsulfonylbenzene (0.8 g, 3.16 mmol), oxolan-3-amine (1.38 g, 15.8 mmol) and K2C03 (0.87 g, 6.32 mmol) in DMSO (15 mL) was stirred

at 100°C for 5 hrs. It was cooled to r.t. and water (50 mL) was added. The mixture was extracted with EtOAc (50 mL x 3) and the combined organic layers were washed with brine (50 mL), dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography (PE: EA= 50: 1-3:1) to give the title compound (0.7 g, yield: 69.16 %).lH NMR (CDCI3, 400 MHz) δ 8.00 (d, J = 1.2 Hz, 1 H), 7.74 (d, J = 8.8 Hz, 1 H), 6.67 (d, J = 8.8 Hz, 1 H), 5.03 (d, J = 6.4 Hz, 1 H), 4.23-4.13 (m, 1 H), 4.07-3.98 (m, 2 H), 3.96-3.87 (m, 1 H), 3.83-3.76 (m, 1 H), 3.03 (s, 3 H), 2.43-2.32 (m, 1 H), 1.98-1.88 (m, 1 H). LCMS (M+H)+ = 320.0 (M+H) +, 322.0

Step 2 : 2-methyl-4- [5 -methylsulfonyl- -(oxolan-3 -ylamino)phenyl]isoquinolin- 1 -one


[00497] A mixture of 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one (100 mg, 0.35 mmol), the compound from Step 1 (102 mg, 0.32 mmol), Κ3Ρ04 (186 mg, 0.88 mmol) and Pd(dppf)Cl2 (29 mg, 0.04 mmol) in dioxane (5 mL) and H20 (1 mL) was purged 3 times with nitrogen and then stirred at 70°C for 18 hrs under N2. The mixture was filtered and concentrated. The residue was purified by prep-HPLC to give the title compound (56.02 mg, yield: 40.1 %) as a light yellow solid. 1H NMR (CDC13, 400 MHz) δ 8.54 (d, J = 8.0 Hz, 1 H), 7.89 (dd, Ji = 8.4 Hz, J2 = 2.4 Hz, 1 H), 7.69 (s, 1 H), 7.64-7.52 (m, 2 H), 7.13 (s, 1 H), 7.13-7.08 (m, 1 H), 6.78 (dd, Ji = 8.8 Hz, J2 = 5.6 Hz, 1 H), 4.17 (s, 2 H), 3.94-3.86 (m, 1 H), 3.79-3.72 (m, 1 H), 3.72-3.64 (m, 1 H), 3.67 (s, 3 H), 3.58-3.49 (m, 1 H), 3.07 (s, 3 H), 2.32-2.18 (m, 1 H), 1.76-1.63 (m, 1 H). LCMS (M+H)+ = 399.1 (M+H) +

Example 191: 2-methyl-4-[5-methylsulfonyl-2-(oxan-4-ylamino)phenyl]isoquinolin-l-one Step 1 : N-(2-bromo-4-methylsulfonylphenyl)oxan-4-amine


[00498] The title compound was prepared in a manner similar to Example 190 step 1, by substituting oxan-3-amine for oxolan-3-amine. 1H NMR (CDC13, 400 MHz) δ 7.98 (d, J = 1.8 Hz, 1 H), 7.70 (dd, Ji = 8.8 Hz, J2 = 1.8 Hz, 1 H), 6.70 (d, J = 8.8 Hz, 1 H), 4.85 (d, J = 7.2 Hz, 1 H), 4.08-3.99 (m, 2 H), 3.69-3.60 (m, 1 H), 3.60-3.52 (m, 2 H), 3.03 (s, 3 H), 2.10-2.02 (m, 2 H), 1.68-1.55 (m, 2 H). LCMS (M+H)+ = 334.0 (M+H) +, 336.0

Step 2: 2-methyl-4-[5-methylsulfony -2-(oxan-4-ylamino)phenyl]isoquinolin-l-one


[00499] The title compound was prepared in a manner similar to Example 190 step 2, by substituting N-(2-bromo-4-methylsulfonylphenyl)oxan-4-amine for N-(2-bromo-4-methylsulfonylphenyl)oxolan-3-amine. 1H NMR (CDC13, 400 MHz) δ 8.52 (d, J = 7.6 Hz, 1 H), 7.85 (dd, Ji = 8.8 Hz, J2 = 2.0 Hz, 1 H), 7.67 (d, J = 2.0 Hz, 1 H), 7.63-7.52 (m, 2 H), 7.16-7.11 (m, 2 H), 6.81 (d, J = 8.8 Hz, 1 H), 4.00 (d, J = 7.6 Hz, 1 H), 3.93-3.82 (m, 2 H), 3.64 (s, 3 H), 3.63-3.54 (m, 1 H), 3.51-3.42 (m, 2 H), 3.06 (s, 3 H), 1.95-1.87 (m, 2 H), 1.37-1.24 (m, 1 H). LCMS (M+H)+ = 413.0 (M+H) +

Example 192 : 4- [2-[(trans-4-hydroxycyclohexyl)amino] -5 -methylsulfonylphenyl] -2-methylisoquinolin- 1 -one


[00500] A mixture of 4-(2-fluoro-5-methylsulfonylphenyl)-2-methylisoquinolin-l-one (150 mg, 0.45 mmol) and trans-4-aminocyclohexan-l-ol (417 mg, 3.62 mmol) in NMP (0.2 mL) was heated for 20 min at 200-300°C. The cooled brownish residue was purified by prep-HPLC to give the title compound (55.64 mg, 28.8%) as a yellow solid. 1H NMR (CDC13, 400 MHz) δ 8.54 (d, J = 8.0 Hz, 1 H), 7.86 (dd, Ji = 8.8 Hz, J2 = 2.4 Hz, 1 H), 7.66 (d, J = 2.4 Hz, 1 H ), 7.60-7.55 (m, 2 H ), 7.15-7.13 (m, 2 H), 6.79 (d, J = 8.8 Hz, 1 H), 3.91-3.85 (m, 1 H), 3.67 (s, 3 H), 3.63-3.55 (m, 1 H), 3.37-3.34 (m, 1 H), 3.06 (s, 3 H), 2.04-1.92 (m, 5 H), 1.44-1.35 (m, 2 H), 1.11-1.02 (m, 2 H). LCMS (M+H)+ = 427.1 (M+H) +

Example 193 : 4- [2-(cyclopropylmethylamino)-5 -ethylsulfonylphenyl] -2-methylisoquinolin-1-one


[00501] The title compound was prepared in a manner similar to Example 190 step 2, by substituting 2-bromo-N-(cyclopropylmethyl)-4-ethylsulfonylaniline for N-(2-bromo-4-methylsulfonylphenyl)oxolan-3-amine. 1H NMR (CDC13, 400 MHz) δ 8.51 (d, J = 7.6 Hz, 1 H), 7.80 (dd, Ji = 8.8 Hz, J2 = 2.0 Hz, 1 H), 7.61-7.51 (m, 3 H), 7.15 (d, J = 8.0 Hz, 1 H), 7.13 (s, 1 H), 6.76 (d, J = 8.8 Hz, 1 H), 4.32 (t, J = 4.8 Hz, 1 H), 3.62 (s, 3 H), 3.09 (q, J = 7.2 Hz, 2 H), 3.01 (m, 2 H), 1.29 (t, J = 7.2 Hz, 3 H), 0.95-0.89 (m, 1 H), 0.46-0.38 (m, 2 H), 0.12-0.05 (m, 2 H). LCMS (M+H)+ = 397.1 (M+H) +

Example 194 : 4- [2-(cyclopropylmethylamino)-5 -methylsulfonylphenyl] -2-methylisoquinolin- 1 -one


[00502] The title compound was prepared in a manner similar to Example 190 step 2, by substituting 2-bromo-N-(cyclopropylmethyl)-4-methylsulfonylaniline for N-(2-bromo-4-methylsulfonylphenyl)oxolan-3-amine. 1H NMR (CDC13, 400 MHz) δ 8.54 (d, J = 7.6 Hz, 1 H), 7.80 (dd, Ji = 8.8 Hz, J2 = 2.4 Hz, 1 H), 7.67 (d, J = 2.4 Hz, 1 H), 7.60-7.55 (m, 2 H), 7.17 (d, J = 8.0 Hz, 1 H), 7.15 (s, 1 H), 6.77 (d, J = 8.8 Hz, 1 H), 4.24-4.23 (m, 1 H), 3.66 (s, 3 H), 3.06 (s, 3 H), 3.03-2.99 (m, 2 H), 0.93-0.91 (m, 1 H), 0.45-0.37 (m, 2 H), 0.12-0.054 (m, 2 H). LCMS (M+H)+ = 383.1 (M+H) +

Example 195: 4-[2-(cyclopropylmethylamino)-5-ethylsulfonylphenyl]-7-fluoro-2-methylisoquinolin- 1 -one

Step 1 : 7-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one


[00503] A mixture of compound 4-bromo-7-fluoro-2-methylisoquinolin-l-one (1.2 g, 4.69 mmol), bis(pinacolato)diboron (2.38 g, 9.37 mmol), AcOK (1.38 g, 14.07 mmol), Pd2(dba)3 (429 mg, 0.47 mmol) and X-phos (224 mg, 0.47 mmol) in dioxane (20 mL) was stirred at 70°C for 18 hrs under N2. The mixture was concentrated and the residue was purified by column chromatography to give the title compound (0.8 g, yield: 56.3%).1H NMR (CDC13, 400 MHz) δ 8.42 (dd, Ji = 9.2 Hz, J2 = 4.2 Hz, 1 H), 8.06 (dd, Ji = 9.2 Hz, J2 = 2.8 Hz, 1 H), 7.65 (s, 1 H), 7.42-7.35 (m, 1 H), 3.64 (s, 3 H), 1.38 (s, 12 H). LCMS (M+H)+ = 304.1 (M+H) +

Step 2: 4-[2-(cyclopropylmethylamino)-5-ethylsulfonylphenyl]-7-fluoro-2-methylisoquinolin- 1 -one


[00504] The title compound was prepared in a manner similar to Example 193, by

substituting 7-fluoro-2-methyl-4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)isoquinolin- 1 -one for 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one. 1H NMR (CDC13, 400 MHz) δ 8.17 (d, J = 8.4 Hz, 1 H), 7.82 (d, J = 8.4 Hz, 1 H), 7.61 (s, 1 H), 7.38-7.29 (m, 1 H), 7.21-7.13 (m, 1 H), 7.11 (s, 1 H), 6.77 (d, J = 8.4 Hz, 1 H), 3.67 (s, 3 H), 3.11 (q, J = 7.2 Hz, 2 H), 3.01 (d, J = 6.8 Hz, 2 H), 1.31 (t, J = 7.2 Hz, 3 H), 0.99-0.85 (m, 1 H), 0.51-0.36 (m, 2 H), 0.17-0.02 (m, 2 H). LCMS (M+H)+ = 415.1 (M+H) +

Example 196: 4-[2-(cyclopropylmethylamino)-5-methylsulfonylphenyl]-7-fluoro-2-methylisoquinolin- 1 -one


[00505] The title compound was prepared in a manner similar to Example 195, by

substituting 2-bromo-N-(cyclopropylmethyl)-4-methylsulfonylaniline for 2-bromo-N-(cyclopropylmethyl)-4-ethylsulfonylaniline in step 2. 1H NMR (CDC13, 400 MHz) δ 8.19 (dd, Ji = 9.2 Hz, = 2.8 Hz, 1 H), 7.86 (dd, Ji = 8.8 Hz, J2 = 2.0 Hz, 1 H), 7.66 (d, J = 2.4 Hz, 1 H), 7.37 - 7.30 (m, 1 H), 7.18 (dd, Ji = 8.8 Hz, J2 = 4.8 Hz, 1 H), 7.11 (s, 1 H), 6.77 (d, J = 8.8 Hz, 1 H), 4.14 (s, 1 H), 3.68 (s, 3 H), 3.06 (s, 3 H), 3.01 (d, J = 6.8 Hz, 2 H), 0.98 - 0.84 (m, 1 H), 0.51 - 0.37 (m, 2 H), 0.16 - 0.02 (m, 2 H). LCMS (M+H)+ = 401.1 (M+H) +

Example 197: 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyl-6-(trifluoromethoxy)isoquinolin- 1 -one


[00506] A mixture of 4-bromo-2-methyl-6-(trifluoromethyl)isoquinolin-l-one (40 mg, 0.13 mmol), 2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (46 mg, 0.13 mmol), K3P04 (68 mg, 0.33 mmol) and Pd(dppf)Cl2 (10 mg, 0.01 mmol) in dioxane (0.9 mL) and H20 (0.09 mL) was degassed with N2 for ten minutes and then stirred at 60 °C for 1.6 h. The reaction mixture was diluted with EtOAc (5 mL), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by normal phase silica gel column chromatography to give the title compound (27 mg, 46 %). 1H NMR (DMSO-d6, 400 MHz) δ 8.51 (d, Ji = 8.4 Hz, 1 H), 8.0 (dd, Ji = 8.7 Hz, J2 = 2.5 Hz, 1 H), 7.87 (s, 1 H), 7.85 (m, 1 H), 7.72 (s, 1H), 7.39 (m, 2 H), 4.02 (m, 1 H), 3.86 (m, 1H), 3.61 (s, 3 H), 3.23 (s, 3 H), 0.90 (m, 1 H), 0.31 (m, 2 H), 0.09 (m, 2 H). LCMS (M+H)+ = 452.2 Example 198: 4-(2-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl)-6-methoxy-2-methylisoquinolin- 1 (2H)-one


[00507] The title compound of Example 90, step 2 (30 mg, 0.075 mmol) in N,N-dimethylacetamide was treated with excess 25% sodium methoxide in methanol and heated at 85 °C until complete. Silica gel chromatography (40-80% EA in hexane over 8 min, then isocratic) gave the title compound 23 mg, 0.056 mmol, 74%>) as a white solid. 1H NMR (400 MHz, DMSO-de) δ ppm 0.06-0.20 (m., 2 H) 0.27-0.43 (m, 2 H) 0.83 - 1.05 (m, 1 H) 3.22 (s, 3 H) 3.53 (s, 3 H) 3.73 (s, 3 H) 3.83 - 4.16 (m, 2 H) 6.47 (s, 1 H) 7.04 - 7.20 (m, 1 H) 7.36 (d, J=8.59 Hz, 1 H) 7.50 (s, 1 H) 7.81 (s, 1 H) 7.96 (d, J=6.82 Hz, 1 H) 8.23 (d, J=8.59 Hz, 1 H). LCMS: 414(M+H)+

Example 199: 4-[3-(cyclopropylmethoxy)-6-methylsulfonylpyridin-2-yl]-2-methylisoquinolin- 1 -one

Step 1 : 6-methylsulfonylpyridin-3-ol


[00508] A mixture of 6-chloropyridin-3-ol (2.00 g, 15.44 mmol), MeS02Na (2.36 g, 23.16 mmol), Cul (882.16 mg, 4.63 mmol), L-proline (533.28 mg, 4.63 mmol), and K2C03 (640.19 mg, 4.63 mmol) in DMSO (20 mL) were charged into a microwave tube. The sealed tube was heated at 140 °C for 3 hrs under microwave. After cooling to room temperature, water (100 mL) was added. The mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2S04 ,filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (1.2 g, 44.8 %) as a yellow solid. 1H NMR (Methanol-d4, 400 MHz) δ 8.24 (d, J = 2.4 Hz, 1 H), 7.94 (d, J = 8.4 Hz, 1 H), 7.37 (dd, Ji = 8.8 Hz, j2 = 2.8 Hz, 1 H), 3.15 (s, 3 H). Step 2: 2-iodo-6-methylsulfonylpyridin-3-ol and 4-iodo-6-methylsulfonylpyridin-3-ol


[00509] A mixture of the title compound from Step 1 (3.0 g, 17.34 mmol), I2 (6.6 g, 26.01 mmol), NaHC03 (2.2 g, 26.20 mmol) and KI (0.72 g, 4.34 mmol) in THF (30 mL) and H20 (30 mL) was stirred at 60 °C for 18 hrs. Water (100 mL) was added and the mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 4-iodo-6-methylsulfonylpyridin-3-ol (700.0 mg) and 2-iodo-6-methylsulfonylpyridin-3-ol (700.0 mg). 2-iodo-6-methylsulfonylpyridin-3-ol: 1H NMR (CDC13, 400 MHz) δ 12.08 (brs, 1 H), 7.86 (d, J = 8.4 Hz, 1 H), 7.31 (d, J = 8.4 Hz, 1 H), 3.19 (s, 3 H). 4-iodo-6-methylsulfonylpyridin-3-ol: 1H NMR (CDC13, 400 MHz) δ 12.0 (brs, 1 H), 8.24 (s, 1 H), 8.17 (s, 1 H), 3.20 (s, 3 H).

Step 3: 3-(cyclopropylmethoxy)-2-iodo-6-methylsulfonylpyridine


[00510] A mixture of 2-iodo-6-methylsulfonylpyridin-3-ol (500.0 mg, 1.67 mmol), bromomethylcyclopropane (248.4 mg, 1.84 mmol) and K2CO3 (461.3 mg, 33.4 mmol) in ACN (15 mL) was stirred at 80 °C for 4 hrs. Water (30 mL) was added and the mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2S04 , filtered and concentrated to give the title compound (500.0 mg, 84.8

%). 1H NMR (CDCI3, 400 MHz) δ 7.96 (d, J = 8.8 Hz, 1 H), 7.52 (d, J = 8.4 Hz, 1 H), 4.09 (d, J = 6.8 Hz, 2 H), 3.22 (s, 3 H), 1.36-1.22 (m, 1 H), 0.69-0.57 (m, 2 H), 0.43-0.37 (m, 2 H). LCMS: 354.0 (M+l)+

Step 4:


[00511] A mixture of 3-(cyclopropylmethoxy)-2-iodo-6-methylsulfonylpyridine (140.0 mg, 0.40 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one (136.5 mg, 0.48 mmol), K3PO4 (252.7 mg, 1.19 mmol) and Pd(dppf)Cl2 (29.2 mg, 0.04 mmol) in dioxane (5 mL) and H20 (1 mL) was stirred at 70 °C for 18 hrs under N2. The mixture was filtered and concentrated. The residue was purified by prep-HPLC to give the title compound (81.0 mg, 53.1 %). 1H NMR (CDCI3, 400 MHz) δ 8.33 (dd, Ji = 8.4 Hz, J2 = 1.2 Hz, 1 H), 8.07 (d, J = 8.4 Hz, 1 H), 7.83 (d, J = 8.8 Hz, 1 H), 7.74 (s, 1 H), 7.67 (t, J = 8.4 Hz, 1 H), 7.55 (t, J = 8.4 Hz, 1 H), 7.39 (d, J = 8.0 Hz, 1 H), 4.01 (d, J = 6.8 Hz, 2 H), 3.60 (s, 3 H), 3.25 (s, 3 H), 1.10-0.98 (m, 1 H), 0.45-0.37 (m, 2 H), 0.23-0.17 (m, 2 H). LCMS: 385.1

(M+l)+

Example 200: 4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyridin-4-yl]-2-methylisoquinolin- 1 -one

Step 1 : 5-(cyclopropylmethoxy)-4-iodo-2-methylsulfonylpyridine


[00512] The title compound was prepared in a manner similar to Example 199 Step 3, by substituting 4-iodo-6-methylsulfonylpyridin-3-ol for 2-iodo-6-methylsulfonylpyridin-3-ol. 1H NMR (CDCI3, 400 MHz) δ 8.35 (s, 1 H), 8.32 (s, 1 H), 4.20 (d, J = 7.2 Hz, 2 H), 3.23 (s, 3 H), 1.36-1.25 (m, 1 H), 0.67-0.58 (m, 2 H), 0.44-0.37 (m, 2 H). LCMS: 354.0 (M+l)+ Step 2: 4-[5-(cyclopropylmethoxy)-2-meth lsulfonylpyridin-4-yl]-2-methylisoquinolin-l-one


[00513] The title compound was prepared in a manner similar to Example 199 Step 4, by substituting 5-(cyclopropylmethoxy)-4-iodo-2-methylsulfonylpyridine for 3-(cyclopropylmethoxy)-2-iodo-6-methylsulfonylpyridine. 1H NMR (CDCI3, 400 MHz) δ 8.66 (s, 1 H), 8.31 (d, J = 8.0 Hz, 1 H), 7.96 (s, 1 H), 7.70-7.66 (m, 2 H), 7.57-7.54 (t, J = 7.2 Hz, 1 H), 7.22 (d, J = 8.0 Hz, 1 H), 4.12 (d, J = 6.8 Hz, 2 H), 3.57 (s, 3 H), 3.28 (s, 3 H), 1.05-0.92 (m, 1 H), 0.43-0.27 (m, 2 H), 0.18-0.10 (m, 2 H). LCMS: 385.1 (M+l)+

Example 201 : 4-[3-(cyclopropylmethoxy)-6-methylsulfonylpyridin-2-yl]-7-fluoro-2-methylisoquinolin- 1 -one


[00514] The title compound was prepared in a manner similar to Example 199 Step 4, by substituting 7-fluoro-2-methyl-4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)isoquinolin- 1 -one for 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one. 1H NMR (DMSO-d6, 400 MHz) δ 8.07 (d, J = 8.4 Hz, 1 H), 7.97 (d, J = 7.6 Hz, 1 H), 7.83 (d, J = 8.4 Hz, 1 H), 7.75 (s, 1 H), 7.65-7.45 (m, 2 H), 4.01 (d, J = 6.4 Hz, 2 H), 3.61 (s, 3 H), 3.25 (s, 3 H), 1.11-0.98 (m, 1 H), 0.48-0.35 (m, 2 H), 0.27-0.15 (m, 2 H). LCMS: 403.1 (M+l)+

Example 202: 4-[3-(cyclopropylmethoxy)-6-methylsulfonylpyridin-2-yl]-6-fluoro-2-methylisoquinolin- 1 -one


[00515] The title compound was prepared in a manner similar to Example 199 Step 4, by substituting 6-fluoro-2-methyl-4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)isoquinolin- 1 -one for 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one. 1H NMR (DMSO-d6, 400 MHz) δ 8.37 (dd, Ji = 8.8 Hz, J2 = 6.4 Hz, 1 H), 8.07 (d, J = 8.4 Hz, 1 H), 7.84 (s, 1 H), 7.82 (d, J = 8.8 Hz, 1 H), 7.45-7.36 (td, Ji = 10.8 Hz, J2 = 2.4 Hz, 1 H), 7.18 (dd, Ji = 10.8 Hz, = 2.4 Hz, 1 H), 4.03 (d, J = 7.2 Hz, 2 H), 3.59 (s, 3 H), 3.25 (s, 3 H), 1.15-1.03 (m, 1 H), 0.48-0.39 (m, 2 H), 0.28-0.20 (m, 2 H). LCMS: 403.1 (M+l)+

Example 203: 4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyridin-4-yl]-7-fluoro-2-methylisoquinolin- 1 -one


[00516] The title compound was prepared in a manner similar to Example 200 Step 2, by substituting 7-fluoro-2-methyl-4-(4,4, 5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)isoquinolin- 1 -one for 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one. 1H NMR (DMSO-d6, 400 MHz) δ 8.08 (d, J = 8.4 Hz, 1 H), 7.97 (dd, Ji = 9.2 Hz, J2 = 2.8 Hz, 1 H), 7.83 (d, J = 8.4 Hz, 1 H), 7.75 (s, 1 H), 7.62-7.55 (td, Ji = 9.2 Hz, J2 = 2.4 Hz, 1 H), 7.50 (dd, Ji = 9.2 Hz, h = 5.2 Hz, 1 H), 4.01 (d, J = 6.8 Hz, 2 H), 3.61 (s, 3 H), 3.25 (s, 3 H), 1.11-0.99 (m, 1 H), 0.46-0.39 (m, 2 H), 0.24-0.18 (m, 2 H). LCMS: 403.2 (M+l)+

Example 204: 4-(2-ethoxy-5-ethylsulf nylthiophen-3-yl)-2-methylisoquinolin-l-one


[00517] A mixture of 3-bromo-2-ethoxy-5-ethylsulfonylthiophene (18.0 mg, 0.06 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one (24 mg, 0.08

mmol), K3PO4 (42 mg, 0.20 mmol) and Pd(dppf)Cl2 (6 mg, 0.008 mmol) in dioxane (0.5 mL) and H20 (0.05 mL) was stirred at 60 °C for 1.5 h. The reaction mixture was then poured over water (6 mL) and extracted with EtOAc (2 x 5 mL). The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by normal phase silica gel column chromatography to give the title compound (10.5 mg, 46 %). 1H NMR (DMSO-d6, 400 MHz) δ 8.29 (d, J = 7.9 Hz, 1 H), 7.71 (dd, J = 7.6, 7.6 Hz, 1 H), 7.57 (m, 3H), 7.35 (d, J = 7.9 Hz, 1 H), 4.25 (m, 2 H), 3.54 (s, 3H), 3.38 (m, 2H), 1.24 (m, 6 H). LCMS: 378.05 (M+l)+

Example 205: 4-[2-(cyclopropylmethylamino)-5-ethylsulfonylthiophen-3-yl]-2-methylisoquinolin- 1 -one


[00518] The title compound was prepared in a manner similar to Example 204, by

substituting 3-bromo-N-(cyclopropylmethyl)-5-ethylsulfonylthiophen-2-amine for 3-bromo-2-ethoxy-5-ethylsulfonylthiophene. 1H NMR (DMSO-d6, 400 MHz) δ 8.30 (d, J = 8.0 Hz, 1 H), 7.70 (m, 1 H), 7.53 (dd, J = 7.6, 7.6 Hz, 1 H), 7.5 (s, 1H), 7.32 (s, 1H), 7.26 (d, J = 8.0 Hz, 1 H), 6.91 (m, 1H), 3.53 (s, 3H), 3.25 (m, 2 H), 2.95 (m, 2H), 1.20 (dd, J = 7.3, 7.3 Hz, 3 H), 1.05 (m, 1H), 0.43 (m, 2H), 0.18 (m, 2 H). LCMS: 403.1 (M+l)+

Example 206: 4-[3-(cyclopropylmethoxy)-6-ethylsulfonylpyridin-2-yl]-2-methylisoquinolin-1-one

Step 1 : 5-bromo-2-ethylsulfanylpyridine


[00519] To a solution of 2,5-dibromopyridine (25 g, 105.5 mmol) in anhydrous DMSO (50 mL) at room temperature was added NaSEt (13.3 g, 158.3 mmol) in one portion. The mixture was stirred for 18 hrs. It was then diluted with water (500 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed by brine and dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA= 20: 1-10:1) to afford the title compound as light yellow oil (21 g yield: 91.3%).1H NMR (CDCI3, 400 MHz) δ 8.49 (dd, Ji = 2.0 Hz, J2 = 0.4 Hz, 1 H),

7.59 (dd, Ji = 8.8 Hz, J2 = 2.4 Hz, 1 H), 7.08 (dd, Ji = 8.4 Hz, J2 = 0.8 Hz, 1 H), 3.16 (q, J = 7.2 Hz, 2 H), 1.38 (t, 3 H). LCMS: 217.8 (M+l)+; 219.8

Step 2: 5-bromo-2-ethylsulfonylpyridine


[00520] To a solution of the title compound form Step 1 (21 g, 96.3 mmol) in DCM (200 mL) was added m-CPBA (58.2 g, 289 mmol, 85%purity) slowly at 0°C and then stirred at 20°C for 3 hrs. The reaction mixture was quenched with sat. aq. Na2S03 (200 mL) and then extracted with DCM (200 mL x 2). The combined organic layers were washed with sat. aq. NaHC03 (200 mL), water (200 mL), and brine (200 mL), dried over Na2S04, filtered and concentrated under reduced pressure to give 22 g of crude (-90% purity) title compound as a white solid that was used in the next step without further purification. 1H NMR (CDC13, 400 MHz) δ 8.82 (d, J = 2.0 Hz, 1 H), 8.13 (dd, Ji = 8.4 Hz, J2 = 2.0 Hz, 1 H), 8.01 (d, J = 8.0 Hz), 3.43 (q, J = 7.2 Hz, 2 H), 1.33 (t, J = 7.2 Hz, 3 H). LCMS: 249.8 (M+l)+; 251.8

Step 3: 2-ethylsulfonyl-5-methoxypyridine


[00521] To a solution of the title compound form Step 2 (21 g, 84 mmol) in MeOH (150 mL) was added MeONa (11.3 g, 210 mmol). The mixture was refluxed for 5 hour. It was then cooled to room temperature and concentrated under reduced pressure. The residue was triturated with isopropyl ether and filtered. The filtrate was concentrated under reduced pressure to give the title compound (4.5 g, yield, 23%> two steps.) as yellow oil. H NMR

(CDC13, 400 MHz) δ 8.42 (d, J = 2.8 Hz, 1 H), 8.07 (d, J = 8.4 Hz 1 H), 7.37 (dd, Ji h = 2.8 Hz, 1 H), 3.97 (s, 1 H), 3.38 (q, J = 7.2 Hz, 2 H),1.30 (t, J = 7.2 Hz,3 H).

Step 4: 6-ethylsulfonylpyridin-3-ol


[00522] The title compound form Step 3 (4.5 g, 22.4 mmol) and pyridinium hydrochloride (26 g, 224 mmol) was heated to 160 °C for 4 hours. It was cooled to room temperature, diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2S04 and concentrated. The residue was purified by column chromatography to afford the title compound (3 g, 72%) as a yellow

solid. 1H NMR (DMSO-d6, 400 MHz) δ: 8.87 (s, 1H), 8.86 (s, 1H), 8.45 (d, J = 8.4 Hz, 1 H), 7.93 (dd, Ji = 8.8 Hz, J2 = 2.4 Hz, 1 H), 3.82 (q, J = 7.2 Hz, 2 H),1.72 (t, J = 7.2 Hz,3 H). LCMS: 187.9 (M+l)+

Step 5: 6-ethylsulfonyl-2-iodopyridin-3-ol and 6-ethylsulfonyl-4-iodopyridin-3-ol


[00523] To a solution of the title compound from Step 4 (3 g, 16 mmol) in a mixture of THF (20 mL) and H20 (20 mL) was added KI (662 mg, 4 mmol) and iodine (6.1 g, 24 mmol). The reaction was stirred at rt for 1 hour and then heated to 60 °C for another 17 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure to remove the THF. The mixture was diluted with water (100 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SC"4, filtered and concentrated. The residue was purified by prep-HPLC to afford 6-ethylsulfonyl-2-iodopyridin-3-ol and 6-ethylsulfonyl-4-iodopyridin-3-ol as white solids. 6-ethylsulfonyl-2-iodopyridin-3-ol: 1H NMR (DMSO-d6, 400 MHz) δ 7.85 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1 H), 3.30 (q, J = 7.2 Hz, 2 H), 1.11 (t, J = 7.2 Hz 3 H). LCMS: 313.8 (M+l)+; 6-ethylsulfonyl-4-iodopyridin-3-ol: 1H NMR (DMSO-d6, 400 MHz) δ 8.23 (s, 1H), 8.18 (s, 1 H), 3.31 (q, J = 7.2 Hz, 2 H, overlapped with solvent peak), 1.10 (t, J = 7.2 Hz 3 H). LCMS: 313.8 (M+l)+

Step 6: 3-(cyclopropylmethoxy)-6-eth lsulfonyl-2-iodopyridine


[00524] The title compound was prepared in a manner similar to Example 199 Step 3, by substituting 6-ethylsulfonyl-2-iodopyridin-3-ol for 2-iodo-6-methylsulfonylpyridin-3-ol. 1H NMR (CDC13, 400 MHz) δ 7.98 (d, J = 8.4 Hz, 1 H), 7.06 (d, J = 8.4 Hz 1 H), 4.02 (d, J = 6.8 Hz 2 H), 3.40 (q, J = 7.2 Hz, 2 H), 1.38-1.26 (m, 4 H), 0.77-0.73 (m, 2 H), 0.49-0.46 (m, 2 H). LCMS: 367.8 (M+l)+

Step 7: 4-[3-(cyclopropylmethoxy)-6-ethylsulfonylpyridin-2-yl]-2-methylisoquinolin-l-one


[00525] To a solution of the title compound from Step 6 (45 mg, 0.12 mmol) and 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one (50 mg, 0.16 mmol) in dioxane (2.5 mL) and H20 (0.5 mL) was added Pd(dppf)Cl2 (9 mg, 0.013 mmol) and K3PO4 (86 mg, 0.4 mmol) in one portion at r.t. under N2. The mixture was stirred for 12 hours at 90°C under N2. Water (15 mL) was added and the mixture was extracted with DCM (30 mL x 3). The combined organic phases were dried over Na2S04, filtered, concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (16 mg, yield: 32%) as a white solid. 1H NMR (CDCI3, 400 MHz) δ 8.52 (d, J = 7.6 Hz, 1 H), 8.11 (d, J = 8.8 Hz 1 H), 7.61-7.56 (m, 1 H), 7.53-7.49 (m, 1 H), 7.42 (d, J = 8.8 Hz 1 H), 7.38 (s, 1 H), 7.34 (d, J = 7.6 Hz 1 H), 3.92 (d, J = 7.2 Hz 2 H), 3.68 (s, 3 H), 3.41 (q, J = 6.8 Hz, 2 H), 1.33 (t, 3 H), 1.08-1.02 (m, 1 H), 0.54-0.48 (m, 2 H), 0.22-0.21 (m, 2 H). LCMS: 399.1 (M+l)+

Example 207: 4-[5-(cyclopropylmethoxy)-2-ethylsulfonylpyridin-4-yl]-2-methylisoquinolin-1-one

Step 1 : 5-(cyclopropylmethoxy)-2- thylsulfonyl-4-iodopyridine


[00526] The title compound was prepared in a manner similar to Example 199 Step 3, by substituting 6-ethylsulfonyl-4-iodopyridin-3-ol for 2-iodo-6-methylsulfonylpyridin-3-ol. 1H NMR (CDCI3, 400 MHz) δ 8.48 (s, 1 H), 8.11 (s, 1 H), 4.12 (d, J = 6.8 Hz 2 H), 3.37 (q, J = 7.6 Hz, 2 H), 1.39-1.27 (m, 4 H), 0.76-0.73 (m, 2 H), 0.48-0.46 (m, 2 H). LCMS: 367.8

(M+l)+

Step 2: 4-[5-(cyclopropylmethoxy)-2- thylsulfonylpyridin-4-yl]-2-methylisoquinolin-l-one

[00527] The title compound was prepared in a manner similar to Example 206 Step 7, by substituting 6-ethylsulfonyl-4-iodopyridin-3-ol for 3-(cyclopropylmethoxy)-6-ethylsulfonyl-2-iodopyridine. 1H NMR (CDCI3, 400 MHz) 58.54-8.52 (m, 1 H), 8.45 (s, 1 H), 8.05 (s, 1 H), 7.63-7.58 (m, 1 H), 7.56-7.52 (m, 1 H), 7.16 (d, J = 8.8 Hz 1 H), 4.01 (d, J = 7.2 Hz 2 H), 3.68 (s, 3 H), 3.44 (q, J = 7.2 Hz, 2 H), 1.36 (t, 3 H), 1.09-1.05 (m, 1 H), 0.50-0.48 (m, 2 H), 0.19-0.18 (m, 2 H). LCMS: 399.1 (M+l)+

Example 208: 4-[5-(2-hydroxyethylsulfonyl)-2-methoxyphenyl]-2-methyl-6-(l-methylpyrazol-4-yl)isoquinolin- 1 -one

Step 1 : 2-(4-methoxyphenyl)sulfanyleth l a tate


[00528] 4-methoxybenzene-l -thiol (15.7 g, 0.11 mol), 2-bromoethyl acetate (18.8 g, 0.11 mol), and K2CO3 (46.6 g, 0.34mol) in acetone (200 mL) were stirred at room temperature for 12 h. Then the mixture was filtered. After CH2CI2 extractive work up and silica gel chromatography chromatography (PE: EA = 1 :0 ~ 10: 1) the title compound (21.1 g, 83.3%) was obtained as a colorless oil. 1H NMR: (CDCI3, 400 MHz) δ 7.40 (dd, Ji = 6.8 Hz, J2 = 2.0 Hz, 2 H), 6.86 (dd, Ji = 6.8 Hz, J2 = 2.0 Hz, 2 H), 4.18 (t, J = 7.2 Hz, 2 H), 3.80 (s, 3 H), 3.02 (t, J = 7.2 Hz, 2 H), 2.03 (s, 3 H). LCMS: 139.0 (M-87)+

Step 2: 2-(4-methoxyphenyl)sulfonylethyl acetate


[00529] m-CPBA (80.3 g, 467 mmol) was added to the title compound of step 1 (21.1 g, 93.4 mmol) in CH2C12 (500 mL). After stirring at r.t. for 12 h, the mixture was subjected to CH2C12 extractive work up & silica gel chromatography (PE: EA = 1 :0 ~ 1 : 1) to give the title compound (20.0 g, 83.3 %) as a colorless oil. 1H NMR: (CDC13, 400 MHz) δ 7.85 (dd, Ji = 6.8 Hz, h = 2.0 Hz, 2 H), 7.04 (dd, Ji = 6.8 Hz, J2 = 2.0 Hz, 2 H), 4.39 (t, J = 6.0 Hz, 2 H), 3.90 (s, 3 H), 3.43 (t, J = 6.0 Hz, 2 H), 1.89 (s, 3 H). LCMS: 280.9 (M+Na)+

Step 3: 2-(3-bromo-4-methoxyphenyl)sulfonylethanol


[00530] Br2 (25 g, 155.0 mmol) was added dropwise over 30 min to the title compound of step 2 (8.0 g, 31.0 mmol) in acetic acid (100 mL) at 0°C. The mixture was heated at 50°C for 12 h. Aqueous Na2S03 (200 mL) was added and the pH was adjusted to 8 with sat. aq.

NaHC03. The mixture was subjected to EA extractive work up and silica gel chromatography (PE: EA = 1 :0 ~ 1 : 1) to give the title compound (2.7 g, 27.3 %) as a white solid. 1H NMR (CDC13, 400 MHz) δ 8.11 (d, J = 2.4 Hz, 1 H), 7.87 (dd, Ji = 8.8 Hz, J2 = 2.4 Hz, 1 H), 7.04 (d, J = 2.4 Hz, 1 H), 4.05-4.00 (m, 5 H), 3.34-3.67 (m, 3 H). LCMS: 316.9, 318.9 (M+Na) + Step 4: 2-[2-(3-bromo-4-methoxyphenyl)sulfonylethoxy]oxane


[00531] To the title compound of step 3 (1.0 g, 3.4 mmol) in CH2C12 (10 mL) was added 3,4-dihydro-2H-pyran (1.4 g, 17.0 mmol) followed by pyridinium p-toluensulfonate (64.6 mg, 0.34 mmol). After stirring at r.t. 12 h, the mixture was subjected to CH2C12 extractive work up & silica gel chromatography (PE: EA = 1 :0 - 5: 1) to give the title compound (1.1 g, 85.6 %) as a yellow oil. 1H NMR (CDC13, 400 MHz) δ 8.11 (d, J = 2.4 Hz, 1 H), 7.86 (dd, Ji = 8.8 Hz, J2 = 2.4 Hz, 1 H), 7.00 (d, J = 8.8 Hz, 1 H), 4.51 (dd, Ji =4.0 Hz, J2 = 2.4 Hz, 1 H), 4.09-4.03(m, 1 H), 3.98 (s, 3 H), 3.84-3.79 (m, 1 H), 3.79-3.74 (m, 1 H), 3.50-3.46(m, 1 H), 3.45-3.42 (m, 2 H), 1.58-1.37 (m, 6 H). LCMS: 401.0, 403.0 (M+Na)+.

Step 5 : 2-[2-methoxy-5-[2-(oxan-2-yloxy)ethylsulfonyl]phenyl]-4,4,5,5-tetramethyl-l ,3,2-dioxaborolane


[00532] The title compound of step 4 (700 mg, 1.8 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (938 mg, 3.6mmol) Pd(dppf)Cl2 (263 mg, 0.36 mmol) and AcOK (1.05 g,10.8 mmol) in 1,4-dioxane (7 mL) was stirred at

70°C for 12h. After silica gel column chromatography (PE: EA = 1 :0 ~ 1 : 1) the title compound (300 mg, 39.2 %) was obtained as a yellow oil. 1H NMR (CDC13, 400 MHz) δ 8.20 (d, J = 2.4 Hz, 1 H), 7.94 (dd, Ji = 8.8 Hz, J2 = 2.8 Hz, 1 H), 6.95 (d, J = 8.8 Hz, 1 H), 4.52 (t, J = 4.0 Hz, 1 H), 4.08-4.01 (m, 2 H), 3.91 (s, 3 H), 3.82-3.74 (m, 2 H), 3.43(t, J = 2.4 Hz, 2 H), 1.58-1.42 (m, 6 H), 1.35 (s, 12 H). LCMS: 343.0 (M+H-THP)+.

Step 6: 4-[2-methoxy-5-[2-(oxan-2-yloxy)ethylsulfonyl]phenyl]-2-methyl-6-(l-methylpyrazol-4-yl)isoquinolin- 1 -one


[00533] The title compound of step 5 (325 mg, 0.76 mmol), the title compound of Example 41, step 2 (201 mg, 0.64 mmol), Pd(dppf)Cl2 (66 mg, 0.08 mmol) and AcOK (125 mg, 1.28 mmol) in 1,4-dioxane (6 mL) were heated at 70°C for 12 h. After silica gel column chromatography (PE: EA = 5: 1-0: 1) the title compound (80 mg, 23.6 %) was obtained as a gray solid. 1H NMR: (CDC13, 400 MHz) δ 8.48 (d, J = 8.4 Hz, 1 H), 8.03 (dd, Ji = 8.8 Hz, J2 = 2.4 Hz, 1 H) , 7.88 (d, J = 2.4 Hz, 1 H) ,7.58-7.69 (m, 2 H), 7.14-7.18 (m, 2 H), 7.06 (s, 1 H), 4.50 (t, J = 4.4 Hz, 2 H), 4.06-4.15 (m, 1 H), 3.93 (s, 3 H), 3.84-3.90 (m, 1 H), 3.84 (s, 3 H), 3.71-3.80 (m, 2 H), 3.65 (s, 3 H), 3.49 (t, J = 5.6 Hz, 2 H), 3.41-3.47(m, 1 H), 1.25-1.67 (m, 6 H). LCMS: 538.2 (M+H)+; 454.1 (M+H-THP) +.

Step 7: 4-[5-(2-hydroxyethylsulfonyl)-2-methoxyphenyl]-2-methyl-6-(l-methylpyrazol-4-yl)isoquinolin- 1 -one


[00534] The title compound of step 6 (80 mg, 0.15 mmol) and pyridinium p-toluensulfonate (59 mg , 0.31 mmol) in DCM (2 mL) were stirred at room temperature for 5 h. After purification by prep-TLC (DCM: MeOH = 10: 1), the title compound (16.47 mg, 24.4%) was obtained as an off-white solid. 1H NMR: (CDC13, 400 MHz) 58.49 (d, J = 8.4 Hz, 1 H), 8.05 (dd, Ji = 8.8 Hz, h = 2.4 Hz, 1 H), 7.88 (d, J = 2.4 Hz, 1 H), 7.68 (s, 1 H), 7.59-7.62 (m, 2 H), 7.20 (d, J = 8.8 Hz, 1 H), 7.12 (d, J = 1.2 Hz, 1 H), 7.07 (s, 1 H), 4.03-4.11 (m, 2 H), 3.94 (s, 3 H), 3.86 (s, 3 H), 3.66 (s, 3 H), 4.16(t, J = 5.2 Hz, 2 H), 2.72 (t, J = 6.4 Hz, 1 H). LCMS: 454.1 (M+H) +

Example 209: N-[4-(cyclopropylmethoxy)-2-fluoro-5-[2-methyl-6-(l-methylpyrazol-4-yl)-l-oxoisoquinolin-4-yl]phenyl]ethanesulfonamide


[00535] The title compound was prepared in 4 steps in a similar manner as Example 86 except that the alkoxide of cyclopropylmethanol was substituted for sodium methoxide in step 1. 1H NMR (DMSO-d6, 400 MHz) δ 9.46 (s,l H), 8.26 (d, J = 8.4 Hz, 1 H), 8.17 (s, 1 H), 7.84 (s,l H), 7.34 (d, J = 8.0 Hz, 1 H), 7.42 (s,l H), 7.27-7.25 (m, 1 H), 7.16 (d, J = 12.4 Hz, 1 H), 3.97-3.96 (m, 2 H, overlapped with solvent peak), 3.85 (s, 3 H), 3.54 (s, 3 H), 3.13-3.07 (m, 2 H), 1.30-1.26 (m, 2 H), 0.91-0.90 (m, 1 H), 0.27-0.22 (m, 2 H), 0.04-0.09 (m, 2 H). LCMS: 511.1 (M+l) +

Example 210: 4-(5-ethylsulfonyl-2-methoxyphenyl)-2-methyl-6-(l H-pyrazol-4-yl)isoquinolin- 1 -one


[00536] The title compound was prepared in a similar manner to Example 79 using 4-(tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole instead of l-methyl-4-(tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole. 1H NMR (DMSO- 6, 400 MHz) δ 8.26 (d, J=8.4 Hz, 1 H), 8.02 (s, 2 H), 7.97-8.00 (m, 1 H), 7.75-7.79 (m, 2 H), 7.50 (s, 1 H), 7.42 (d, J=8.8 Hz, 1 H), 7.16 (d, J=1.2 Hz, 1 H), 3.82 (s, 3 H), 3.54 (s, 3 H), 3.31 (q, J=7.2, 2 H), 1.13 (t, J=7.2 Hz, 3H). LCMS: 424.0 (M+l) +

Example 211: 4-(2-ethoxy-5-methylsulfonylphenyl)-2-methyl-6-(l -methylpyrazol-4-yl)isoquinolin- 1 -one


[00537] 2-(2-ethoxy-5-methanesulfonylphenyl)-4,4,5,5-tetramethyl-l ,3,2-dioxaborolane was prepared in a similar manner to Example 90, step 1 and coupled to the title compound of Example 41, step 2 in a manner similar to Example 90, step 2 to give the title compound. 1H NMR (CDCls, 400 MHz) δ 8.48 (d, J = 8.4 Hz, 1 H), 8.06-8.02(m, 1 H), 7.89 (d, J = 2.8 Hz, 1 H), 7.68 (s, 1 H), 7.62 (s, 1H), 7.61 (d, J = 1.6 Hz, 1 H), 7.18 (d, J = 1.2 Hz, 1 H), 7.14 (d, J = 8.8 Hz, 1 H), 7.08 (s, 1 H), 4.12 (q, J = 7.2 Hz, 2 H), 3.94 (s, 3 H), 3.66 (s, 3 H), 3.12 (s, 3 H), 1.17 (t, J = 7.2 Hz, 3 H). LCMS: 438.1 (M+l) +

Example 212: 2-methyl-6-(l-methylpyrazol-4-yl)-4-(5-methylsulfonyl-2-propoxyphenyl)isoquinolin- 1 -one


[00538] 2-(5-methanesulfonyl-2-propoxyphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane was prepared in a similar manner to Example 90, step 1 and coupled to the title compound of Example 41, step 2 in a manner similar to Example 90, step 2 to give the title compound. 1H NMR (CDCI3, 400 MHz) δ 8.49 (d, J = 8.4 Hz, 1 H), 8.02 (s, J = 6.8 Hz, 1 H), 7.90 (d, J = 2.4 Hz, 1 H), 7.68 (s,l H), 7.61 (s, 1 H), 7.60 (d, J = 6.8 Hz, 1 H), 7.18 (s,l H), 7.15 (d, J = 8.8 Hz, 1 H), 7.08 (s, 1 H), 4.00 (m, 2 H) 3.93 (s, 3 H), 3.66 (s, 3 H), 3.12 (s, 3 H), 1.56 (m, 2 H), 0.65 (t, J = 7.2 Hz, 3 H). LCMS: 452.0 (M+l) +

Example 213: N-[2-[2-methyl-6-(l-methylpyrazol-4-yl)-l-oxoisoquinolin-4-yl]pyridin-4-yl] ethanesulfonamide


[00539] The title compound was prepared after 2-chloropyridin-4-amine was sufonylated with ethanesulfonyl chloride and the resulting product was coupled to the title compound of Example 46, step 2. 1H NMR (CDC13, 400 MHz) δ 10.65 (brs,l H), 8.56 (s,l H),8.29 (d, J = 8.4 Hz, 1 H), 8.22 (s,l H), 8.01-7.73 (m, 4 H), 7.37 (s,l H), 7.18 (s,l H), 3.87 (s, 3 H), 3.59 (s, 3 H), 1.25 (t, J = 7.2 Hz, 3 H). LCMS: 424.0 (M+l) +

Example 214: [4-(cyclopropylmethoxy)-3-(2-methyl-l-oxoisoquinolin-4-yl)phenyl] sulfamate

Step 1 : [3-bromo-4-(cyclopropylmethoxy)phenyl] sulfamate


[00540] 3-bromo-4-(cyclopropylmethoxy)phenol (970 mg, 4.0 mmol) and sulfamoyl chloride (1.95 g, 16.0 mmol) in DMA (15 mL) were stirred at room temperature for 5 h. Extractive work up from EA and water gave the title compound (1.0 g, yield: 78.0 %) which was carried on without purification. 1H NMR (CDCI3, 400 MHz) δ 7.28 (d, J = 2.8 Hz, 1 H), 7.24 (dd, Ji = 8.8 Hz, = 2.8 Hz, 1 H), 6.88 (d, J = 8.8 Hz, 1 H), 5.07 (s, 2 H), 3.89 (d, J = 6.8 Hz, 2 H), 1.35-1.25 (m, 1 H), 0.70-0.63 (m, 2 H), 0.43-0.36 (m, 2 H). LCMS: 322.0 (M+l) +.

Step 2: [4-(cyclopropylmethoxy)-3- -methyl-l-oxoisoquinolin-4-yl)phenyl] sulfamate


[00541] The title compound of step 1 (300 mg, 0.935 mmol), the title compound of Example 89, step 1 (293 mg, 1.028 mmol), K3P04 (595 mg, 2.805 mmol) and Pd(dppf)Cl2 (15 mg) in dioxane (5 mL) and H20 (1 mL) were heated at 70°C for 18 h under N2 whereupon it was discovered that the sulfamoyl group had been cleaved to the phenol. HPLC purification gave the phenol (59 mg, 0.184 mmol) which was again treated with sulfamoyl chloride (100 mg, 0.87 mmol) in DMA (3 mL) in a manner similar to step 1. Preparative HPLC gave the title compound (64.21 mg, yield: 87.02 %) as grey solid. 1H NMR (CDC13, 400 MHz) δ 8.48 (d, J = 8.0 Hz, 1 H), 7.56 (t, J = 7.6 Hz, 1 H), 7.49 (d, J = 7.6 Hz, 1 H), 7.35 (dd, Ji = 9.2 Hz, J2 = 2.4 Hz, 1 H), 7.30-7.27 (m, 1 H), 7.26-7.22 (m, 1 H), 7.04 (s, 1 H), 6.98 (d, J = 9.2 Hz, 1 H), 5.14 (s, 2 H), 3.82-3.73 (m, 2 H), 3.62 (s, 3 H), 1.03-1.90 (m, 1 H), 0.45-0.32 (m, 2 H), 0.13-0.03 (m, 2 H). LCMS: 401.0 (M+l) +

Example 215: [4-(cyclopropylmethoxy)-3-(l ,5-dimethyl-6-oxopyridin-3-yl)phenyl] sulfamate


[00542] The title compound was prepared in a similar manner to Example 214, step 2 except that 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-2(lH)-pyridinone was substituted for the title compound of Example 89, step 1. 1H NMR (CDC13, 400 MHz) δ 7.54 (d, J = 2.0 Hz, 1 H), 7.50 (s, 1 H), 7.23-7.18 (m, 2 H), 6.92-6.87 (m, 1 H), 5.20 (s, 2 H), 3.84 (d, J = 6.8 Hz, 2 H), 3.61 (s, 3 H), 2.20 (s, 3 H), 1.25-1.17 (m, 1 H), 0.66-0.59 (m, 1 H), 0.36-0.29 (m, 1 H). LCMS: 365.1 (M+l) +

Example 216: 4-(2-ethoxy-5-methylsulfonylphenyl)-2-methyl-5,6,7,8-tetrahydroisoquinolin-1-one


[00543] 2-bromo-l-ethoxy-4-methanesulfonylbenzene was prepared in a similar manner as Example 46, step 1 except that iodoethane was substituted for (chloromethyl)cyclopropane. The title compound of Example 163, step 3 and 2-bromo-l-ethoxy-4-methanesulfonylbenzene were reacted in a simmilar manner as in Example 89, step 2 to give the title compound. 1H NMR (CDC13, 400 MHz): δ 7.92 (dd, Ji = 8.8 Hz, J2 = 2.0 Hz, 1 H), 7.68 (d, J = 2.0 Hz, 1 H), 7.03 (d, J = 8.8 Hz, 1 H), 6.69 (d, J = 8.8 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2 H), 3.59 (s, 3 H), 3.08 (s, 3 H), 2.70-2.60 (m, 2 H), 2.33-2.18 (m, 2 H), 1.65-1.61 (m, 4 H), 1.45-1.02 (t, J = 7.2 Hz, 3 H). LCMS: 362.0(M+H)+

Example 217: 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyl-5,6,7,8-tetrahydroisoquinolin- 1 -one


[00544] The title compound of Example 163, step 3 and 2-bromo-l-(cyclopropylmethoxy)-4-methylsulfonylbenzene were reacted in a simmilar manner as in Example 89, step 2 to give the title compound. 1H NMR (CDC13, 400 MHz): δ 7.92 (dd, Ji = 8.4 Hz, J2 = 2.0 Hz, 1 H), 7.70 (d, J = 2.0 Hz, 1 H), 7.06 (s, 1 H), 7.02 (d, J = 8.4 Hz, 1H), 3.92-3.87 (m, 2 H), 3.62 (s, 3 H), 3.08 (s, 3 H), 2.70-2.60 (m, 2 H), 2.40-2.30 (m, 2 H), 1.77-1.64 (m, 4 H), 1.21-1.17 (m, 1 H), 0.63-0.61 (m, 2 H), 0.29-0.27 (m, 2 H). LCMS: 388.1(M+H)+

Example 218: N-[4-(cyclopropylmethoxy)-2-fluoro-5-(2-methyl-l-oxo-5,6,7,8-tetrahydroisoquinolin-4-yl)phenyl]methanesulfonamide


[00545] N-[5-bromo-4-(cyclopropylmethoxy)-2-fluorophenyl]methanesulfonamide was prepared in 3 steps in a similar manner as Example 86 except that the alkoxide of

cyclopropylmethanol was substituted for sodium methoxide in step 1 and

methanesulfonylchloride was substituted for ethansulfonylchloride in step 3. The title compound of Example 163, step 3 and N-[5-bromo-4-(cyclopropylmethoxy)-2-fluorophenyljmethanesulfonamide were reacted in a simmilar manner as in Example 89, step 2 to give the title compound. 1H NMR (CDC13, 400 MHz): δ 7.29 (d, J = 9.2 Hz, 1 H), 6.96 (s, 1 H), 6.70 (d, J = 12.0 Hz, 1H), 6.21 (s, 1 H), 3.76-3.75 (m, 2 H), 3.56 (s, 3 H), 3.02 (s, 3 H), 2.70-2.60 (m, 2 H), 2.36-2.17 (m, 2 H), 1.80-1.70 (m, 2 H), 1.69-1.64 (m, 2 H), 1.20-1.10 (m, 1 H), 0.60-0.50 (m, 2 H), 0.27-0.25 (m, 2 H). LCMS: 421.1(M+H)+

Example 219: 4-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-2-methyl-5, 6,7,8-tetrahydroisoquinolin- 1 -one

[00546] 2-bromo-l-(cyclopropylmethoxy)-4-(ethanesulfonyl)benzene was prepared in a similar manner as Example 79, step 3 except that the alkoxide of cyclopropylmethanol was substituted for sodium methoxide. The title compound of Example 163, step 3 and 2-bromo-l-(cyclopropylmethoxy)-4-(ethanesulfonyl)benzene were reacted in a simmilar manner as in Example 89, step 2 to give the title compound. 1H NMR (DMSO- 6, 400 MHz): δ 7.83 (dd, Ji = 8.8 Hz, = 2.4 Hz, 1 H), 7.56 (d, J = 2.4 Hz, 1 H), 7.43 (s, 1 H), 7.65 (d, J = 8.8 Hz, 1H), 4.02-3.90 (m, 2 H), 3.43 (s, 3 H), 3.29-3.23 (m, 2 H), 2.49-2.44 (m, 4 H), 1.61-1.50 (m, 4 H), 1.15-1.08 (m, 5 H), 0.53-0.51 (m, 2 H), 0.29-0.27 (m, 2 H). LCMS: 402.0(M+H)+

Example 220: N- [2-(2 -methyl- 1-oxoisoquino lin-4-yl)-4-methylsulfonylphenyljcyclopropanecarboxamide


[00547] 2-bromo -4-methanesulfonylaniline was coupled to the title compound of Example 89, step 1 in a manner similar to Example 89, step 2. The resulting product was reacted with cyclopropanecarbonyl chloride using diisopropylethylamine in THF to prepare the title compound. 1H NMR (CDC13, 400 MHz) δ 9.38 (s, 1 H), 8.34 (d, J = 8.0 Hz, 1 H), 8.23 (d, J = 8.8 Hz, 1 H), 7.96 (d, J= 8.8 Hz, 1 H), 7.83 (s, 1 H), 7.53 - 7.64 (m, 3 H), 6.94 (d, J = 8.0 Hz, 1 H), 3.59 (s, 3 H), 3.25 (m, 3 H), 1.64 (brs, 1 H), 0.52 - 0.75 (m, 4 H). LCMS: 397.0 (M+l) + Example 221 : N-[2-(2 -methyl- 1 -oxoiso uinolin-4-yl)-4-methylsulfonylphenyl]propanamide


[00548] The title compound was prepared in the same manner as Example 220 except that propanoyl chloride was substituted for cyclopropanecarbonyl chloride. 1H NMR (CDC13, 400 MHz) δ 8.70 (d, J=8.8 Hz, 1 H), 8.57 (d, J=6.4 Hz, 1 H), 8.04 (dd, J=2.0, 8.8 Hz, 1 H), 7.88 (d, J=2.0 Hz, 1 H), 7.55-7.65 (m, 2 H), 7.19 (s, 1 H), 7.01-7.20 (m, 2 H), 3.67 (s, 3 H), 3.11 (s, 3 H), 2.00-2.21 (m, 2 H), 0.93 (t, J=7.2 Hz, 3 H). LCMS: 385.0 (M+l) +

Example 222: N-[2-(2 -methyl- 1 -oxoiso uinolin-4-yl)-4-methylsulfonylphenyl]acetamide


[00549] The title compound was prepared in the same manner as Example 220 except that acetyl chloride was substituted for cyclopropanecarbonyl chloride. 1H NMR (CDCI3, 400 MHz) δ 8.67 (d, J=8.8 Hz, 1 H), 8.51 (d, J=7.6 Hz, 1 H), 8.03 (dd, J=2.0, 6.8 Hz, 1 H), 7.86 (d, J=2.0 Hz, 1 H), 7.62-7.67 (m, 1 H), 7.57-7.62 (m, 1 H), 7.36 (s, 1 H), 7.16 (s, 1 H),7.07-7.10 (m, 1 H), 3.54 (s, 3 H), 3.10 (s, 3 H), 1.96 (s, 3 H). LCMS: 371.0 (M+l) +

Example 223: 4-[2-(cyclopropylmethylamino)-5-methylsulfonylphenyl]-2-methyl-5, 6,7,8-tetrahydroisoquinolin- 1 -one


[00550] The sulfonyl compound of Example 194 was coupled as described in Example 163 to give the title compound. 1H NMR (CDC13, 400 MHz): δ 7.89 (dd, Ji = 8.8 Hz, j2 = 2.4 Hz, 1 H), 7.51 (d, J = 2.4 Hz, 1 H), 7.10 (s, 1 H), 6.69 (d, J = 8.8 Hz, 1H), 3.62 (s, 3 H), 3.04-3.02 (m, 5 H), 2.67-2.62 (m, 2 H), 2.26-2.24 (m, 2 H), 1.78-1.76 (m, 2 H), 1.75-1.74 (m, 2 H), 1.05-1.02 (m, 1 H), 0.58-0.54 (m, 2 H), 0.23-0.21 (m, 2 H). LCMS: 387.0(M+H)+

Example 224: 8-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-methyl-2-(l -methylpyrazol-4-yl)pyrido [4,3 -d]pyrimidin-5 -one

Step 1 : ethyl 4-methyl-2-(l-methylpyrazol-4-yl)pyrimidine-5-carboxylate


[00551] Ethyl 2-chloro-4-methylpyrimidine-5-carboxylate (1.0 g, 5.0 mmol), l-methyl-4-(tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (1.24 g, 6.0 mmol), Κ3Ρ04 (3.18 mg, 15.0 mmol) and Pd(dppf)Cl2 (100 mg) in dioxane (15 mL) and H20 (3 mL) were heated at 120°C for 18 h under N2. Silica gel chromatography (PE: EA=3: 1 to 1 : 1) gave the title compound (72 mg, yield: 32.0 %).1H NMR (CDC13, 400 MHz) δ 9.08 (s, 1 H), 8.22 (s, 1 H), 8.15 (s, 1 H), 4.40 (q, J = 7.2 Hz, 2 H), 3.98 (s, 3 H), 2.82 (s, 3 H),1.42 (t, J = 7.2 Hz, 3 H). LCMS: 247.1 (M+l) +.

Step 2: ethyl 4-[(E)-2-(dimethylamino)ethenyl]-2-(l-methylpyrazol-4-yl)pyrimidine-5-carboxylate and ethyl 2-(l-methylpyrazol-4-yl)-4-[(E)-2-pyrrolidin-l-ylethenyl]pyrimidine-5 -carboxylate


[00552] The title compound from step 1 (800 mg, 3.22 mmol), DMF-DMA (15.0 mL) and pyrrolidine (3.0 mL) were heated at 120°C for 5 h. Extractive work up with EA gave a mixture of title compounds (500 mg, -70:30 by LCMS) which were carried on without purification. LCMS: 328.1 (M+l) +.

Step 3: 6-methyl-2-(l-methylpyrazol-4-yl)pyrido[4,3-d]pyrimidin-5-one


[00553] The mixture of title compounds from step 2 (500 mg) was treated with ethanolic methylamine (15 mL, 30% CH3NH2 in EtOH) and heated at 80°C for 5 h. After

concentration, the resulting solids were triturated with hexane (10 mL) and collected to give the title compound (220 mg, 55.0 %).1H NMR (CDC13, 400 MHz) δ 9.57 (s, 1 H), 8.27 (s, 1 H), 8.21 (s, 1 H), 7.46 (d, J = 7.6 Hz, 1 H), 6.59 (d, J = 7.6 Hz, 1 H), 4.00 (s, 3 H), 3.61 (s, 3 H). LCMS: 242.0 (M+l) +.

Step 4: 8-bromo-6-methyl-2-(l-methylpyrazol-4-yl)pyrido[4,3-d]pyrimidin-5-one


[00554] The title compound from step 3 (220 mg, 0.912 mmol) and Br2 (146 mg, 0.912 mmol) in HO Ac (15 mL) were stirred at room temperature for 2 h. Water (150 mL) was added, and the resulting solid was collected and triturated with DCM: PE=10: 1 (10 mL) to give the title compound (200 mg, yield: 69.0 %).1H NMR (CDC13, 400 MHz) δ 9.54 (s, 1 H), 8.33 (s, 1 H), 8.27 (s, 1 H), 7.77 (s, 1 H), 4.01 (s, 3 H), 3.62 (s, 3 H).

Step 5: 8-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-methyl-2-(l-methylpyrazol-4-yl)pyrido [4,3 -d]pyrimidin-5 -one


[00555] The title compound of step 4 (200 mg, 0.627 mmol), the title compound of Example 90, step 1 (266 mg, 0.752 mmol), K3PO4 (400 mg, 1.881 mmol) and Pd(dppf)Cl2 (10 mg) in dioxane (4 mL) and H20 (1 mL) were heated at 70°C for 18 h under N2. After preparative HPLC, the title compound (104.5 mg, 35.8 %) was obtained as an off white solid. 1H NMR (CDC13, 400 MHz) δ 9.64 (s, 1 H), 8.24-8.18 (m, 2 H), 8.07 (s, 1 H), 7.96 (dd, Ji = 8.8 Hz, J2 = 2.4 Hz, 1 H), 7.77 (s, 1 H), 7.10 (d, J = 8.8 Hz, 1 H), 3.95 (s, 3 H), 3.91(d, J = 7.2 Hz, 2 H), 3.68 (s, 3 H), 3.12 (s, 3 H), 1.13-1.01 (m, 1 H), 0.54-0.44 (m, 2 H), 0.21-0.14 (m, 1 H).

LCMS: 466.1 (M+l) +

Example 225: 8-(5-ethylsulfonyl-2-propoxyphenyl)-6-methyl-2-(l-methylpyrazol-4-yl)pyrido [4,3 -d]pyrimidin-5 -one

Step 1 : 2-bromo-4-ethylsulfonyl-l-propoxybenzene


[00556] To a solution of n-propanol (224 mg, 3.74 mmol) in THF (10 mL) was added NaH (112 mg, 2.80 mmol, 60% in mineral oil) at 0°C . After stirring at 0°C for 30 min, 2-bromo-4-(ethanesulfonyl)-l-fluorobenzene (500 mg, 1.87 mmol) was added and the mixture was

stirred at room temperature for 4 h. Addition of saturated NH4C1 (10 mL) followed by EA extractive work up gave the title compound (300 mg, yield: 52.3%) which was carried on directly.

Step 2: 2-(5-ethylsulfonyl-2-propoxy henyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane


[00557] The title compound of step 1 (300 mg, 0.98 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (622 mg, 2.45 mmol), KOAc (288 mg, 2.94 mmol), Pd2(dba)3 (92 mg, 0.10 mmol), and X-Phos(62 mg, 0.13 mmol) in dioxane (5 mL) were purged with Ar and heated at 70°C for 12 h. CH2C12 extractive work up and silica gel chromatography (PE:EA=20: 1-5: 1) gave the title compound (200 mg, yield: 57.7%) as a grey solid. 1H NMR (CDC13, 400 MHz) δ 8.13 (s, 1 H), 7.91 (d, J = 8.8 Hz, 1 H), 6.95 (d, J = 8.8 Hz,l H), 4.02 (t, J = 5.6 Hz, 2 H), 3.13 (q, J = 7.2 Hz, 2 H), 1.89 (q, J = 6.8 Hz, 2 H), 1.36-1.25 (m, 15 H), 1.12 (t, J = 6.8 Hz, 3 H). LCMS: 272.9 (M+l)+.

Step 3: 8-(5-ethylsulfonyl-2-propoxyphenyl)-6-methyl-2-(l-methylpyrazol-4-yl)pyrido[4,3-d]pyrimidin-5 -one


[00558] The title compound of step 2 (60 mg, 0.17 mmol), the title compound of Example 224, step 4 (64 mg, 0.20 mmol), K3PO4 (108 mg, 0.51 mmol), and Pd(dppf)Cl2 (15 mg, 0.02 mmol) in dioxane (8 mL) were purged with N2 and heated at 70°C for 18 h. CH2C12 extractive work up and preparative HPLC gave the title compound (66.11 mg, yield: 83.3%) as a grey solid. 1H NMR (CDC13, 400 MHz) δ 9.64 (s, 1 H), 8.19 (s, 1 H), 8.12 (d, J = 2.4 Hz, 1 H), 8.06 (s, 1 H), 7.96 (dd, Ji = 8.8 Hz, J2 = 2.4 Hz, 1 H), 7.70 (s, 1 H), 7.15 (d, J = 8.4 Hz, 1 H), 4.03-3.95 (m, 5 H), 3.67 (s, 3 H), 3.20 (q, J = 7.2 Hz, 2 H), 1.67-1.60 (m, 2 H), 1.36 (t, J = 7.2 Hz, 3 H), 0.81 (t, J = 7.2 Hz, 3 H). LCMS: 468.2 (M+l)+

Example 226: 8-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-methyl-2-(l -methylpyrazol-4-yl)pyrido [4,3 -d]pyrimidin-5 -one

[00559] The title compound was prepared in three steps in a similar manner as Example 225 except that cyclopropylmethanol was substituted for n-propanol in step 1. 1H NMR (CDC13, 400 MHz) δ 9.64 (s, 1 H), 8.22 (s, 1 H), 8.17 (d, J = 2.0 Hz, 1 H), 8.07 (s, 1 H), 7.92 (dd, Ji = 8.4 Hz, h = 2.0 Hz, 1 H ), 7.77 (s, 1 H), 7.10 (d, J = 8.4 Hz,l H), 3.96 (s, 3 H), 3.90 (d, J = 6.8 Hz, 2 H), 3.68 (s, 3 H), 3.17 (q, J = 7.2 Hz, 2 H), 1.33 (t, J = 7.2 Hz, 3 H), 1.08-1.06 (m, 1 H), 0.52-0.47 (m, 2 H), 0.21-0.17 (m, 2 H). LCMS: 480.2 (M+H)+

Example 227: 8-(2-ethoxy-5-ethylsulfonylphenyl)-6-methyl-2-(l-methylpyrazol-4-yl)pyrido [4,3 -d]pyrimidin-5 -one


[00560] The title compound was prepared in three steps in a similar manner as Example 225 except that ethanol was substituted for n-propanol in step 1. 1H NMR (CDCI3, 400 MHz) δ 9.64 (s, 1 H), 8.19 (s, 1 H), 8.10 (s, 1 H), 8.06 (s, 1 H), 7.94 (d, J = 8.8 Hz, 1 H), 7.69 (s, 1 H), 7.13 (d, J = 8.8 Hz, 1 H), 4.13 (q, J = 6.8 Hz, 2 H), 3.95 (s, 3 H), 3.67 (s, 3 H), 3.17 (q, J = 7.2 Hz, 2 H), 1.34 (t, J = 7.2 Hz, 3 H), 0.81 (t, J = 6.8 Hz, 3 H). LCMS: 454.1 (M+H)+ Example 228: 8-(2-ethoxy-5-ethylsulfonylphenyl)-6-methyl-2-(l-methylpyrazol-4-yl)pyrido [4,3 -d]pyrimidin-5 -one


[00561] 2-bromo-4-methylsulfonyl-l-propoxybenzene was prepared in a similar manner as

Example 46, step 1 except that 1-chloropropane was substituted for

(chloromethyl)cyclopropane and the resulting product was used to prepare 4,4,5,5-

tetramethyl-2-(5-methylsulfonyl-2-propoxyphenyl)-l,3,2-dioxaborolane in a manner similar to Example 225, step 2 which was then used to prepare the title compound in a manner similar as Example 225, step 3. 1H NMR (CDC13, 400 MHz) δ 9.64 (s, 1 H), 8.19 (s, 1 H), 8.16 (d, J = 2.4 Hz, 1 H), 8.07 (s, 1 H), 7.99 (dd, Ji = 8.8 Hz, J2 = 2.4 Hz, 1 H), 7.70 (s, 1 H), 7.14 (d, J = 8.8 Hz, 1 H), 4.01 (t, J = 6.4 Hz, 2 H), 3.96 (s, 3 H), 3.68 (s, 3 H), 3.12 (s, 3 H), 1.67-1.61 (m, 2 H), 0.78 (t, J = 7.2 Hz, 3 H). LCMS: 454.1 (M+H)+

Example 229: N-[4-(2,4-difluorophenoxy)-3-(l ,5-dimethyl-6-oxopyridin-3-yl)phenyl]-N-methylmethanesulfonamide


[00562] The title compound of Example 102 (56 mg, 0.13 mmol) in DMF (0.2 mL) was treated with NaH (60% dispersion in oil, 6 mg, 0.16 mmol). After about 15 min, methyl iodide (0.012 mL, 0.2 mmol) was added. After complete reaction, silica gel chromatography gave the title compound (55mg, 0.13 mmol) as a cream colored solid. 1H NMR (400 MHz, DMSO-de) δ ppm 1.96 - 2.17 (s, 3 H) 2.98 (s, 3 H) 3.25 (s, 3 H) 3.49 (s, 3 H) 6.82 (d, J=8.84 Hz, 1 H) 7.21 - 7.40 (m, 3 H) 7.40 - 7.54 (m, 2 H) 7.59 (s, 1 H) 7.82 (d, J=2.53 Hz, 1 H) LCMS (M+H)+ 435

Example 230: N-[4-(2,4-difluorophenoxy)-3-(l ,5-dimethyl-6-oxopyridin-3-yl)phenyl]-N-(oxetan-3 -yl)methanesulfonamide


[00563] The title compound of Example 102 (46 mg, 0.11 mmol), Cs2C03 (150 mg, 0.46 mmol), KI (10 mg, 0.06 mmol) and oxetan-3-yl 4-methylbenzenesulfonate (30 mg, 0.13 mmol) in DMF (0.9 mL) were microwaved at 130 °C for 2h. Additional oxetan-3-yl 4-methylbenzenesulfonate (65 mg, 0.29 mmol) and Cs2C03 (126 mg, 0.39 mmol) were added and microwave resumed at 130 °C for 2h more. The mixture was purified by silica gel

chromatography (EA) to give the title compound (20 mg, 0.04 mmol) as cream solids in 38% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.03 (s, 3 H) 2.98 (s, 3 H) 3.50 (s, 3 H) 4.41 (t, J=6.82 Hz, 2 H) 4.58 (t, J=6.95 Hz, 2 H) 5.30 (quin, J=7.01 Hz, 1 H) 6.83 (d, J=8.84 Hz, 1 H) 7.06 - 7.20 (m, 1 H) 7.22 - 7.35 (m, 2 H) 7.39 (d, J=2.53 Hz, 1 H) 7.43 - 7.57 (m, 1 H) 7.60 (s, 1 H) 7.83 (d, J=2.27 Hz, 1 H). LCMS (M+H)+ 477

Example 231 : 8- [2-(cyclopropylmethoxy)-5 -methylsulfonylphenyl] -6-methylpyrido [4,3 -d]pyrimidin-5-one Step 1 : 6H-pyrido[4 3-d]pyrimidin-5-one


[00564] Under N2, ethyl 3-oxobutanoate (40.12 g, 0.31mol) and 1,3,5-triazine (25.00 g, 0.31 mol) in dry EtOH (90 mL) were heated at 80°C for 2 h and EtONa (8.39 g, 0.12 mol) was added and heating continued at 80°C for 18 h. The mixture was concentrated and water (300 mL) was added. Acidification with concentrated HC1 (50 mL) resulted in a precipitate which was collected and washed with cold acetone (20 mL) and dried under vacuum to give the title compound (1.20 g, yield: 2.6%) as a brown solid. 1H NMR: (DMSO-d6, 400 MHz) δ: 11.92 (brs, 1 H), 9.41 (s, 1 H), 9.32 (s, 1 H), 7.72 (dd, Ji=7.6 Hz, j2=6.4 Hz, 1 H), 6.57 (d, J=7.6 Hz, 1 H).

Step 2: 8-bromo-6H-pyrido[4,3-d]pyrimidin-5-one


[00565] To the title compound of step 1 (200 mg, 1.36 mmol) in DMF (20 mL) was added NBS (242 mg, 1.36 mmol) at 0°C. The resulting mixture was stirred at 15°C for 2 h and then concentrated and treated with acetone (20 mL). The resulting solid was collected to give the title compound (220 mg, yield: 71.6%) as a yellow solid. 1H NMR: (DMSO-d6, 400 MHz) δ: 12.25 (brs, 1 H), 9.46 (s, 1 H), 9.42 (s, H), 8.12 (d, J=6.0 Hz, 1 H).

Step 3: 8-bromo-6-methylpyrido[4,3-d]pyrimidin-5-one


[00566] Sodium hydride (21 mg, 0.53 mmol, 60%> in mineral oil) was added to the title compound of step 2 (100 mg, 0.44 mmol) in DMF (10 mL) at 0°C. After stirring 0.5h, Mel

(126 mg, 0.88 mmol) was added and stirring continued at 0°C for 2h. Following extractive work up with EA, the title compound (80 mg, yield: 75.3%) was obtained as a yellow solid. 1H NMR: (DMSO-d6, 400 MHz) δ: 9.47 (s, 1 H), 9.46 (s, 1 H), 8.53 (s, 1 H), 3.54 (s, 3 H). LCMS: 240.0, 242.0 (M+H) +.

Step 4: 8-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-methylpyrido[4,3-d]pyrimidin-5 -one


[00567] The title compound of step 3 (100 mg, 0.42 mmol), the title compound of Example 90, step 1 (147 mg, 0.42 mmol), Pd(dppf)Cl2 (62 mg, 0.08 mmol), K3P04 (221 mg, 1.04 mmol) in dioxane (4 mL) and H20 (0.5 mL) was purged with N2 and heated at 100 °C for 18 h. Following CH2C12 extractive work up, silica gel chromatography (PE:EA=2: 1-0: 1) and preparative HPLC, the title compound (54.57 mg, yield: 34.2%) was obtained as a yellow solid. 1H NMR: (DMSO-d6, 400 MHz) δ: 9.54 (s, 1 H), 9.30 (s, 1 H), 8.18 (s, 1 H), 7.93 (dd, Ji=8.8 Hz, J2=2.4 Hz, 1 H), 7.85 (d, J=2.4 Hz, 1 H), 7.31 (d, J=8.8 Hz, 1 H), 3.91 (d, J=6.8 Hz, 2 H), 3.61 (s, 3 H), 3.20 (s, 3 H), 0.94-0.92 (m, 1 H), 0.35-0.30 (m, 2 H), 0.10-0.06 (m, 2 H). LCMS: 386.0 (M+H) +

Example 232: 8-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-methylpyrido[4,3-d]pyrimidin-5 -one


[00568] 2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane as prepared in Example 226 was reacted with the title compound of 231 , step 3 in a manner similar to 231, step 4 to give the title compound. 1H NMR: (DMSO-d6, 400 MHz) δ: 9.54 (s, 1 H), 9.30 (s, 1 H), 8.17 (s, 1 H), 7.88 (dd, Ji=8.8 Hz, J2=2.4 Hz, 1 H), 7.80 (d, J=2.4 Hz, 1 H), 7.31 (d, J=8.8 Hz, 1 H), 3.92 (d, J=6.8 Hz, 2 H), 3.61 (s, 3 H), 3.27 (q, J=7.2 Hz, 2 H), 1.14 (t, J=7.2 Hz, 3 H), 0.94-0.93 (m, 1 H), 0.34-0.32 (m, 2 H), 0.10-0.08 (m, 2 H). LCMS: 400.0 (M+H) +

Example 233: 8-[2-(2,4-difluorophenoxy)-5-methylsulfonylphenyl]-6-methylpyrido[4,3-d]pyrimidin-5 -one

Step 1 : 8-(2-fluoro-5-methylsulfonylphen l)-6-methylpyrido[4,3-d]pyrimidin-5-one


[00569] 2-bromo-l-fluoro-4-methylsulfonylbenzene was substituted for the title compound of Example 225, step 1 and was converted to 2-(2-fluoro-5-methylsulfonylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane in a manner similar to Example 225, step 2 and then reacted with the title compound of Example 231, step 3 in a manner similar to Example 231, step 4. LCMS: 333.9 (M+H) +.

Step 2: 8-[2-(2,4-difluorophenoxy)-5-methylsulfonylphenyl]-6-methylpyrido[4,3-d]pyrimidin-5 -one


[00570] The title compound of step 2 (60 mg, crude), 2,4-difluorophenol (35 mg, 0.27 mmol) and Cs2C03 (176 mg, 0.54 mmol) in DMSO (2 mL) was heated at 100°C for 12 h. EA extractive work up and preparative HPLC gave the title compound (10.04 mg, yield: 13.6% for two steps) as a yellow solid. 1H NMR (CDC13, 400 MHz) δ 9.73 (s, 1 H), 9.34 (s, 1 H), 8.02 (d, J = 2.4 Hz, 1 H), 7.92 (dd, Ji = 8.8 Hz, J2 = 2.4 Hz, 1 H), 7.72 (s, 1 H), 7.19-7.17 (m, 1 H), 6.97-6.89 (m, 3 H), 3.72 (s, 3 H), 3.12 (s, 3 H). LCMS: 444.1 (M+H) +

Example 234: 8-[2-(2,4-difluorophenoxy)-5-ethylsulfonylphenyl]-6-methylpyrido[4,3-d]pyrimidin-5 -one

Step 1 : l-(2-bromo-4-ethylsulfonylphenoxy)-2,4-difluorobenzene


[00571] 2-bromo-l-fluoro-4-ethylsulfonylbenzene (130 mg, 0.49 mmol), 2,4-difluorophenol (78 mg, 0.60 mmol) and Cs2C03 (478 mg, 1.47 mmol) in DMSO (5 mL) were heated at 100°C for 12 h. EA extractive work up gave the title compound (150 mg, yield: 80.5%) as a grey solid. 1H NMR (CDC13, 400 MHz) δ 8.18 (d, J = 2.0 Hz, 1 H), δ 7.75 (dd, Ji = 8.4 Hz, J2 = 1.6 Hz, 1 H), 7.22-7.16 (m, 1 H), 7.06-6.95 (m, 2 H), 6.80 (d, J = 8.8 Hz, 1 H), 3.16 (q, J = 7.2 Hz, 2 H), 1.33 (t, J = 7.6 Hz, 3 H). LCMS: 395.8 (M+NH4) +.

Step 2: 2-[2-(2,4-difluorophenoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane


[00572] The title compound of step 1 was substituted for the title compound of Example 225, step 1 and reacted in a similar manner as Example 225, step 2. 1H NMR (CDC13, 400 MHz) δ 8.11 (d, J = 2.8 Hz, 1 H), δ 7.95 (dd, Ji = 8.8 Hz, J2 = 2.4 Hz, 1 H), 7.55-7.50 (m, 1 H), 7.29-7.23 (m, 1 H), 7.16-7.12 (m, 1 H), 6.99 (d, J = 8.8 Hz, 1 H), 3.32 (q, J = 7.2 Hz, 2 H), 1.26 (s, 12 H), 1.12 (t, J = 7.2 Hz, 3 H). LCMS: 342.8 (M+H) (free boronic acid) +

Step 3 : 8-[2-(2,4-difluorophenoxy)-5-ethylsulfonylphenyl]-6-methylpyrido[4,3-d]pyrimidin-5 -one


[00573] The title compound of step 2 was substituted for the title compound of Example 225, step 2 and the title compound of Example 231, step 3 was substituted for the title compound of Example 224, step 4 and reacted in a similar manner as Example 225, step 3. 1H NMR (CDC13, 400 MHz) δ 9.60 (s, 1 H), 9.27 (s, 1 H), 8.12 (s, 1 H), 8.02 (d, J = 2.0 Hz, 1 H), 7.94 (dd, Ji = 8.8 Hz, J2 = 2.0 Hz, 1 H), 7.32-7.25 (m, 1 H), 7.15-7.09 (m, 1 H), 7.03-6.97 (m, 2

H), 3.70 (s, 3 H), 3.27 (q, J = 7.6 Hz, 2 H), 1.30 (t, J = 7.2 Hz, 3 H). LCMS: 458.0 (M+H)

Example 235: 5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-7-methyl- [l,2,4]triazolo[4,3-a]pyrazin-8-one

Step 1 : 5-bromo-7H-[l,2,4]triazolo[4,3-a]pyrazin-8-one


[00574] To a solution of 5-bromo-8-methoxy-[l,2,4]triazolo[4,3-a]pyrazine (Borchardt WO2011/112766) (500 mg, 2.18 mmol) in HOAc (3 mL) was added HC1 (1 N, 5.00 mL). The mixture was heated at 110°C for 4 h and concentrated to give the title compound (400 mg, yield: 85 %) as a yellow solid which was carried on without purification. 1H NMR (DMSO- 6, 400 MHz): δ 11.78 (s, 1 H), 9.25 (s, 1 H), 7.25 (d, J = 6.0 Hz, 1 H). LCMS: 214.9(M+H)+

Step 2: 5-bromo-7-methyl-[l,2,4]triazolo[4,3-a]pyrazin-8-one


[00575] To a solution of of the title compound of step 1 (400 mg, 1.86 mmol) in DMF (4 mL) was added NaH (149 mg, 3.72 mmol, 60 % in mineral oil) in portions at 0°C under N2. The mixture was stirred at 20°C for 1 h, and methyl iodide (792 mg, 5.58 mmol) was added. After stirring at 20°C for 5 h, water was added. Methylene chloride:2-propanol (10: 1) extractive work up gave the title compound (200 mg, yield: 47 %) as a light yellow solid which was carried on without purification. 1H NMR (DMSO- 6, 400 MHz): δ 9.26 (s, 1 H), 7.60 (s, 1 H), 3.42 (s, 3 H). LCMS: 228.9(M+H)+

Step 3 : 5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-7-methyl-[ 1 ,2,4]triazolo[4,3-a]pyrazin-8-one

[00576] The title compound of step 2 (40 mg, 0.175 mmol), the title compound of Example 90, step 1(62 mg, 0.175 mmol), K3P04 (93 mg, 0.438 mmol) and Pd(dppf)Cl2 (13 mg, 0.018 mmol) in dioxane (2 mL) and H20 (1 mL) was N2 purged and microwaved at 70°C for 2 h. Silica gel chromatography (PE : EA = 1 : 4) followed by preparative HPLC gave the title compound (31.89 mg, yield: 48.6 %) as an off-white solid. 1H NMR (DMSO- 6, 400 MHz): δ 8.91 (s, 1 H), 8.06 (dd, Ji = 8.8 Hz, J2 = 2.4 Hz, 1 H), 7.96 (d, J = 2.4 Hz, 1 H), 7.43-7.04 (m, 2 H), 4.04 (d, J = 6.8 Hz, 2 H), 3.52 (s, 3 H), 3.23 (s, 3 H), 0.99-0.96 (m, 1 H), 0.41-0.36 (m, 2 H), 0.23-0.20 (m, 2 H). LCMS: 375.0(M+H)+

Example 236: N-[4-(2,4-difluorophenoxy)-3-(7-methyl-8-oxo-[l,2,4]triazolo[4,3-a]pyrazin-5 -yl)phenyl] ethanesulfonamide


[00577] The title compound of Example 235, step2 (40 mg, 0.175 mmol), N-[4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]ethanesulfonamide

(77 mg, 0.175 mmol), K3P04 (93 mg, 0.438 mmol) and Pd(dppf)Cl2 (13 mg, 0.018 mmol) in dioxane (2 mL) and H20 (1 mL) was N2 purged and microwaved at 70°C for 2 h.

Preparative HPLCgave the title compound (38.75 mg, yield: 49.3 %) as an off-white solid. 1H

NMR (CDC13, 400 MHz): δ 8.60 (s, 1 H), 7.64 (d, J = 2.8 Hz, 1 H), 7.45 (dd, Ji = 8.8 Hz, J2 =

2.8 Hz, 1 H), 7.10-7.05 (m, 1 H), 6.99-6.88 (m, 3 H), 6.74 (d, J = 8.8 Hz, 1 H), 3.67 (s, 3 H),

3.18 (q, J = 7.2 Hz, 2 H), 1.40 (t, J = 7.2 Hz, 3 H). LCMS: 462.0(M+H)+

Example 237: 7- [2-(cyclopropylmethoxy)-5 -methylsulfonylphenyl] -5 -methyl- [l,3]oxazolo[4,5-c]pyridin-4-one

Step 1 : 3-nitro-4-hydroxy-l-methylpyridin-2-one


[00578] To 4-hydroxy-3-nitro-lH-pyridin-2-one (300 mg, 1.9 mmol) in DMF (5 mL) was added NaH (176 mg, 4.4 mmol, 60% in mineral oil) at 0 °C under N2. After stirring at 0 °C for 30 min, CH3I (272 mg, 1.9 mmol) in DMF (5 mL) was added dropwise, and the mixture was stirred for 2 h at 25 °C. Saturated aqueous NH4C1 was added, the pH was adjusted to ~3 with IN HCl and EA extractive work up gave a residue that was triturated with MeOH (0.5 ml) : EA (10 mL) : PE (5 mL). After filtration, the trituratate was evaporated to give the title compound (300 mg, 91%) as a yellow solid. 1H NMR: (CDC13, 400 MHz) δ: 7.75 (d, J=7.2Hz, 1 H), 6.17 (d, J=7.2Hz, 1 H) 3.54 (s, 3 H). LCMS: 171.0 (M+l)+

Step 2: l-methyl-3-nitro-4-phenylmethoxypyridin-2-one


[00579] To the title compound of step 1 (300 mg, 1.7 mmol) in CH3CN (15mL) was added K2C03 (726 mg, 5.2 mmol) at 25°C under N2. After stirring for 30min, benzyl bromide (450 mg, 2.6 mmol) was added, and the mixture was heated at 50°C for 20h. Following CH2C12 extractive work up, the residue was triturated with PE:EA (3: 1) to give the title compound (250 mg, 54%) as a yellow solid. 1H NMR: (CDC13, 400 MHz) δ: 7.43-7.29(m, 6 H), 6.12 (d, J=7.2 Hz, 1 H), 5.27(s, 2H), 3.57(s, 3 H). LCMS: 261.0 (M+l)+

Step 3: 3-amino-4-hydroxy-l-methylpyridin-2-one h drochloride


[00580] To the title compound of step 2 (2.00 g, 7.69 mmol, 1.00 Eq) in MeOH (50 mL) / EtOH (50 mL) / DMF (10 mL) was added Pd-C (10%, 0.2 g) under N2. The suspension was purged with H2 three times and hydrogenated under a balloon for 5h. The catalyst was removed by titration, and anhydrous HC1 in methanol (10 mL, 1.25 M) was added.

Concentration left a residue which was treated a second time with HC1 in methanol.

Evaporation of the volatile components and triturtion with DCM (30 mL) / hexane (30 mL) gave the title compound (1.29 g, 7.30 mmol, yield: 95%>) as a pink HC1 salt after drying. 1H

NMR: (DMSO-d6, 400 MHz) δ: 9.45-8.02(br, 3H), 7.64 (d, J=7.6 Hz, 1 H), 3.27 (d, J=7.6 Hz, 1 H), 3.43(s, 3H). LCMS: 163.0 (M +Na)+

Step 4: 5-methyl-[l,3]oxazolo[4,5-c]pyridin-4-one


[00581] The title compound of step 3 (500 mg, 2.8 mmol) in triethyl ortho formate (10 mL) was heated to reflux for 5h. The mixture was concentrated in vacuo at 55°C and purifified by silica gel chromatography (PE: EA=1 : 1) to give the title compound (130 mg, yield: 30%) as a yellow solid.

1H NMR (CDCI3, 400 MHz) δ 7.99 (s, 1 H), 7.36 (d, J = 8.0 Hz, 1 H), 6.60 (d, J = 8.0 Hz, 1 H), 3.69 (s, 3 H).

Step 5: 7-bromo-5-methyl-[l,3]oxazolo[4,5-c]pyridin-4-one


[00582] To the title compound of step 4 (100 mg, 0.7 mmol) in CH3CN (5 mL) was added NBS (154 mg, 0.8 mmol) at 20°C. After 2h, the mixture was concentrated in vacuum at 45°C. Purification by silica gel chromatography (PE: EA=5: 1-2:1) to gave the title compound (70 mg, yield: 45%) as a yellow solid. 1H NMR (CDC13, 400 MHz) δ 8.04 (s, 1 H ), 7.52 (s, 1 H), 3.69 (s, 3 H).

Step 6: 7-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-5-methyl-[l,3]oxazolo[4,5-c]pyridin-4-one


[00583] The title compound of step 5 (60 mg, 0.3 mmol) in dioxane (2 mL) and H20 (0.4 mL) was stirred at 15°C under N2 for 30 min. Pd(dppf)Cl2 (19 mg, 0.026 mmol), the title compound of Example 90, stepl (120 mg, 0.3 mmol) and K3P04 (166 mg, 0.8 mmol,) were added at 15°C under N2. The reaction mixture was heated at 60 °C for 12h. Purification by silica gel chromatography (EA) and preparative HPLC gave the title compound (20.63 mg, 20%) as a yellow solid. 1H NMR (CDC13, 400 MHz) δ 8.03 (d, J=2.0 Hz, 1 H), 8.02 (s, 1 H), 7.96 (dd, Ji = 8.4 Hz, J2 = 2.0 Hz, 1 H), 7.09 (d, J=8.4 Hz, 1 H), 3.96 (d, J = 6.8 Hz, 2 H), 3.76 (s, 3 H), 3.1(s, 3 H), 1.18(m, 1 H), 0.60(m, 2 H), 0.30(m, 2 H). LCMS: 375.1 (M+H)+ Example 238 : 7- [2-(cyclopropylmethoxy)-5 -methylsulfonylphenyl] -2,5 -dimethyl-[l,3]oxazolo[4,5-c]pyridin-4-one


[00584] The title compound was prepared from the title compound of Example 237, step 3 in a similar manner as Example 237, steps 4-6 except that triethyl orthoacetate was substituted for triethyl orthoformate. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.25 (q, J=4.72 Hz, 2 H) 0.48 (q, J=5.89 Hz, 2 H) 1.11 (m, 1 H) 2.54 (s, 3 H) 3.21 (s, 3 H) 3.60 (s, 3 H) 4.00 (d, J=6.82 Hz, 2 H) 7.34 (d, J=8.59 Hz, 1 H) 7.88 - 7.98 (m, 3 H). LCMS: 389 (M+H)+

Example 239: 5-methyl-7-[5-(methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]-[l,3]oxazolo[4,5-c]pyridin-4-one


[00585] The title compound of Example 237, step 5 and the title compound of Example 370, step 1 were reacted in a manner similar to Example 237, step 6 to give the title compound. 1H NMR (CDCls, 400 MHz) δ 8.00 (s, 1H), 7.62 (s, 1 H), 7.60 (s, 1 H), 7.47 (d, J = 8.4 Hz, 1 H), 7.02 (d, J = 8.4 Hz, 1 H), 4.42(q, j = 8.0 Hz, 2 H), 4.28 (s, 2 H), 3.74 (s, 3 H), 2.87 (s, 3 H). LCMS: 417.0(M+H)+

Example 240: N-[4-(2,4-difluorophenoxy)-3-(5-methyl-4-oxo-[l,3]oxazolo[4,5-c]pyridin-7-yl)phenyl] ethanesulfonamide


[00586] N-[4-(2,4-difiuorophenoxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl] ethanesulfonamide was prepared from the title compound of Example 122, step 1 and 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane in a manner similar to Example 208, step 5 and reacted with the title compound of Example 237, step 5 in a manner similar to Example 237, step 6. 1H NMR (CDC13, 400 MHz) δ 8.01 (s, 1H), 7.31 (d, J = 8.4 Hz, 1 H), 7.67 (s, 1 H), 7.48 (d, J=2.4 Hz, 1 H), 7.22 (dd, Ji=8.8 Hz, j2=2.4 Hz, 1 H), 7.18 (m, 1 H), 7.03 (m, 1 H), 6.84 (m, 2 H), 3.74 (s, 3 H), 3.17 (q, J=7.2 Hz, 2 H), 1.43 (t, j=7.2 Hz, 3 H). LCMS: 462.1 (M+H)+

Example 241: N-[4-(2,4-difluorophenoxy)-3-(2,5-dimethyl-4-oxo-[l,3]oxazolo[4,5-c]pyridin-7-yl)phenyl]ethanesulfonamide


[00587] 7-bromo-2,5-dimethyl-[l,3]oxazolo[4,5-c]pyridin-4-one prepared in Example 238 and N-[4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]ethanesulfonamide prepared in Example 240 were reacted in a manner similar to Example 237, step 6 to give the title compound. 1H NMR (400 MHz, DMSO- 6) δ ppm 1.23 (t, J=6.95 Hz, 3 H) 2.45 (s, 3 H) 3.13 (d, J=7.83 Hz, 2 H) 3.58 (s, 3 H) 6.95 (d, J=8.59 Hz, 1 H) 7.03 - 7.30 (m, 3 H) 7.30 - 7.48 (m, 2 H) 7.91 (s, 1 H) 9.86 (s, 1 H). LCMS: 476 (M+H)+ Example 242 : 5 - [2-(cyclopropylmethoxy)-5 -methylsulfonylphenyl] - 1 -(cyclopropylmethyl)-3 -methylpyridin-2-one

Step 1 : 5-[2-(cyclopropylmethoxy)-5-meth lsulfonylphenyl]-3-methyl-lH-pyridin-2-one


[00588] 5 -bromo-3 -methyl- lH-pyridin-2-one (950 mg, 5.05 mmol), the title compound of Example 90, step 1 (2.93 g, 5.95 mmol), Pd(dppf)Cl2 (365 mg, 0.5 mmol) and K3P04 (2.14 g, 10.1 mmol) in dioxane (30 mL) and water (5 mL) was purged with N2 and heated at 70°C for 12 h. Silica gel chromatography (PE:DCM:EA= 3 :0: 1 to 0: 1 :3) gave impure title compound

(990 mg) as a yellow solid which was used directly in the next step. H NMR (CDC13, 400

MHz) δ 12.57 (brs, 1 H), 7.84 (d, J = 8.8 Hz, 1 H), 7.82 (s, 1 H), 7.65 (s, 1 H), 7.03 (d, J = 8.8 Hz,l H), 3.96 (d, J = 7.2 Hz, 1 H), 3.07 (s, 3 H), 2.24 (s, 3 H), 1.40-1.25 (m, 1 H), 0.67-0.65 (m, 2 H), 0.37-0.36 (m, 2 H). LCMS: 334.1 (M+l) +

Step 2 : 5 -[2-(cyclopropylmethoxy)-5 -methylsulfonylphenyl] - 1 -(cyclopropylmethyl)-3 -methylpyridin-2-one


[00589] The title compound of step 1 (80 mg), K2C03 (77 mg, 0.56 mmol) bromomethylcyclopropane (62 mg, 0.46 mmol) in DMF (2 mL) were heated at 70°C for 4 h. EA extractive work up and preparative HPLC gave the title compound (17 mg) as a yellow solid. 1H NMR (CDC13, 400 MHz) δ 7.85-7.83 (m, 2 H), 7.67 (d, J = 2.0 Hz, 1 H), 7.53 (s, 1 H), 7.03 (d, J = 9.2 Hz, 1 H), 3.95 (d, J = 6.8 Hz, 1 H), 3.89 (d, J = 7.2 Hz, 1 H), 3.07 (s, 3 H), 2.23 (s, 3 H), 1.34-1.26 (m, 2 H), 0.68-0.65 (m, 2 H), 0.65-0.61 (m, 2 H), 0.44-0.43 (m, 2 H), 0.38-0.37 (m, 2 H). LCMS: 388.2 (M+l) +

Example 243 : 5 - [2-(cyclopropylmethoxy)-5 -methylsulfonylphenyl] -3 -methyl- 1 -(2-methylpropyl)pyridin-2-one


[00590] The title compound from Example 242, step 1 was reacted in a manner similar to Example 242, step 2 except that l-bromo-2-methylpropane was substituted for

bromomethylcyclopropane to give the title compound. 1H NMR (CDC13, 400 MHz) δ 7.85- 7.82 (m, 2 H), 7.56 (s, 1 H), 7.53 (s, 1 H), 7.03 (d, J = 8.4 Hz, 1 H), 3.94 (d, J = 7.2 Hz, 1 H),

3.83 (d, J = 7.2 Hz, 1 H), 3.07 (s, 3 H), 2.30-2.26 (m, 1 H), 2.23 (s, 3 H), 1.28-1.27 (m, 1 H), 1.00 (s, 3 H), 0.98 (s, 3 H), 0.69-0.65 (m, 2 H), 0.38-0.35 (m, 2 H). LCMS: 390.2 (M+l) + Example 244 : 5 - [2-(cyclopropylmethoxy)-5 -methylsulfonylphenyl] - 1 -(2-methoxyethyl)-3 -methylpyridin-2-one


[00591] The title compound from Example 242, step 1 was reacted in a manner similar to Example 242, step 2 except that l-bromo-2-methoxyethane was substituted for

bromomethylcyclopropane to give the title compound. 1H NMR (CDC13, 400 MHz) δ 7.86-7.83 (m, 2 H), 7.65 (d, J = 1.6 Hz, 1 H), 7.59 (s, 1 H), 7.03 (d, J = 8.4 Hz, 1 H), 4.22 (t, J = 4.8 Hz, 1 H), 3.96 (d, J = 6.8 Hz, 1 H), 3.74 (t, J = 4.8 Hz, 1 H), 3.34 (s, 3 H), 3.07 (s, 3 H), 2.23 (s, 3 H), 1.30-1.27 (m, 1 H), 0.70-0.66 (m, 2 H), 0.40-0.36 (m, 2 H). LCMS: 392.2 (M+l) +

Example 245: 5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-3-methyl- 1 -(oxetan-3-ylmethyl)pyridin-2-one


[00592] Sodium hydride (42 mg, 1.04 mmol, 60% in mineral oil) was added to the title compound from Example 242, step 1 (80 mg) in anhydrous DMF (4 mL) After stirring lh, oxetan-3-ylmethyl methanesulfonate (173 mg, 1.04 mmol) was added and stirring continued for 18h. EA extractive work up from 1 M HCl and preparative HPLC purification gave the title compound (24.0 mg) as an off-white solid. 1H NMR (CDC13, 400 MHz) δ 7.85 (d, J = 8.8 Hz, 1 H), 7.82 (s, 1 H), 7.62 (s, 1 H), 7.51 (s, 1 H), 7.03 (d, J = 8.8 Hz, 1 H), 4.83 (t, J = 7.2 Hz, 1 H), 4.57 (t, J = 6.4 Hz, 1 H), 4.30 (d, J = 7.2 Hz, 1 H), 3.95 (d, J = 6.8 Hz, 1 H), 3.62-3.56 (m, 1 H), 3.07 (s, 3 H), 2.21 (s, 3 H), 1.32-1.27 (m, 1 H), 0.72-0.68 (m, 2 H), 0.40-0.36 (m, 2 H). LCMS: 404.1 (M+l) +

Example 246 : 5 -[2-(cyclopropylmethoxy)-5 -methylsulfonylphenyl] -3 -methyl- 1 -( 1 ,3 -oxazol-4-ylmethyl)pyridin-2-one


[00593] The title compound from Example 242, step 1 was reacted in a manner similar to Example 245 except that l,3-oxazol-4-ylmethyl methanesulfonate was substituted for oxetan-3-ylmethyl methanesulfonate to give the title compound. 1H NMR (CDC13, 400 MHz) δ 7.82 (s, 5 H), 7.52 (s, 1 H), 7.01 (d, J = 9.2 Hz, 1 H), 5.11 (s, 2 H), 3.94 (d, J = 6.8 Hz, 1 H), 3.06 (s, 3 H), 2.21 (s, 3 H), 1.27-1.24 (m, 1 H), 0.68-0.65 (m, 2 H), 0.37-0.36 (m, 2 H). LCMS: 415.1 (M+l) +

Example 247: N-[3-[l-(cyclopropylmethyl)-5-methyl-6-oxopyridin-3-yl]-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide


[00594] 5 -bromo-3 -methyl- lH-pyridin-2-one was N-alkylated with

bromomethylcyclopropane to give 5-bromo-l-(cyclopropylmethyl)-3-methylpyridin-2-one. 5-bromo-l-(cyclopropylmethyl)-3-methylpyridin-2-one (100 mg, 0.41 mmol), [2-(2,4-difluorophenoxy)-5-(ethylsulfonylamino)phenyl]boronic acid (217 mg, 0.5 mol), K3PO4 (263 mg, 1.24 mmol) and Pd(dppf)Cl2 (30 mg, 41.3 umol) in dioxane (8 mL)/water (1 mL) were purged with N2 and heated at 70-80°C for 12 h. Preparative HPLC gave the title compound (56.0 mg, 28.6% yield) as dull-red semisolid. 1H NMR (CDC13, 400 MHz): δ 7.74 (s, 1 H), 7.61 (s, 1 H), 7.28 (d, J = 2.0 Hz, 1 H), 7.10-7.15(m, 1 H), 6.92-7.00 (m, 2 H), 6.82-6.89 (m, 1 H), 6.80 (d, J = 8.8 Hz, 1 H), 6.71 (br. s., 1 H), 3.93 (d, J=7.2 Hz, 3 H), 3.12-3.21 (m, 2 H), 2.24 (s, 3 H), 1.42 (t, J = 7.2 Hz, 3 H), 1.22-1.33 (m, 1 H), 0.57-0.67 (m, 2 H), 0.36-0.43 (m, 2 H). LCMS: 475.1 (M+l) +

Example 248: N-[4-[l-(cyclopropylmethyl)-5-methyl-6-oxopyridin-3-yl]-5-(2,4-difluorophenoxy)pyrimidin-2-yl]methanesulfonamide

Step 1 : 5-bromo-l-(cyclopropylmethyl)-3-methylpyridin-2-one


[00595] Potassium carbonate (1.32 g, 9.57 mmol) was added to 5 -bromo-3 -methyl-2-hydroxypyridine (600 mg, 3.19 mmol) and bromomethylcyclopropane (861 mg, 6.38 mmol) in DMF (6 mL). After heating at 70°C for 3 h, EA extractive work up and silca gel chromatography (PE: EA=30: 1-10: 1), the title compound (510 mg, yield: 66.0%) was obtained as a white solid. 1H NMR: (CDC13, 400 MHz) δ: 7.39 (d, J = 2.0 Hz, 1 H), 7.26 (d, J = 2.0 Hz, 1 H), 3.77 (d, J = 6.8 Hz, 2 H), 2.15 (s, 3 H), 0.65-0.60 (m, 2 H), 0.40-0.37 (m, 2 H). LCMS: 242.1; 244.1 (M+H)+

Step 2: l-(cyclopropylmethyl)-3-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one


[00596] The title compound of step 1 (480 mg, 1.98 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (1.01 g, 3.96 mmol), KOAc (582 mg, 5.94 mmol) and Pd(dppf)Cl2 (146 mg, 0.20 mmol) in dioxane (9 mL) was purged with N2 and heated to 70°C for 8 h. After silca gel chromatography (PE: EA=30: 1~10:1) the title compound (415 mg, -70% purity on 1H NMR, yield: 55.1%) was obtained as light yellow oil 1H NMR: (CDC13, 400 MHz) δ: 7.69 (s, 1 H), 7.49 (s, 1 H), 3.82 (d, J= 6.8 Hz, 2 H), 2.14 (s, 3 H), 1.32 (s, 12 H), 1.27-1.1.16 (m, 1 H), 0.61 -0.56 (m, 2 H), 0.42 -0.39 (m, 2 H). LCMS: 290.3 (M+H)+

Step 3 : 1 -(cyclopropylmethyl)-5-[5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidin-4-yl]-3 -methylpyridin-2-one


[00597] The title compound of Example 149, step 3 (200 mg, 0.62 mmol), the title compound of step 2 (250 mg, 0.69 mmol, 70% purity), Pd(dppf)Cl2 (88 mg, 0.12 mmol) and K3PO4 (3 M, 0.6 mL) in dioxane (6 mL) were purged with N2 and heated to 70°C for 4h. After silica gel chromatography (PE: EA=3: 1-1 : 1) the title compound (220 mg, yield: 78.8%) was obtained as a yellow solid. 1H NMR (CDC13, 400 MHz) δ 7.45 (d, J = 2.0 Hz, 1 H), 8.25 (s, 1 H), 8.16 (s, 1 H), 7.24-7.22 (m, 1 H), 7.12-7.10 (m, 1 H), 7.10-7.03 (m, 1 H), 3.92 (d, J= 7.2 Hz, 2 H), 3.38 (s, 3 H), 2.26 (s, 3 H), 1.27-1.21 (m, 1 H), 0.65-0.60 (m, 2 H), 0.42-0.38 (m, 2 H).

LCMS: 448.1 (M+H)+

Step 4 : N- [4- [ 1 -(cyclopropylmethyl)-5 -methyl-6-oxopyridin-3 -yl] -5 -(2,4-difluorophenoxy)pyrimidin-2-yl]methanesulfonamide


[00598] Methanesulfonamide (68 mg, 0.71 mmol), NaH (28 mg, 0.7 mmol, 60% in mineral oil) and the title compound from step 3 (80 mg, 0.18 mmol) in DMF (2 mL) were reacted in a similar manner as Example 152, step 6 to give the title compound (45.00 mg, yield: 54.4%) as an off-white solid. 1H NMR (CDC13, 400 MHz) δ 8.81 (s, 1 H), 8.60 (d, J = 2.0 Hz, 1 H), 8.14 (s, 1 H), 8.12 (s, 1 H), 7.05-6.98 (m, 2 H), 6.91-6.89 (m, 1 H), 3.87 (d, J= 7.2 Hz, 2 H), 3.45 (s, 3 H), 2.23 (s, 3 H), 1.25-1.22 (m, 1 H), 0.64-0.59 (m, 2 H), 0.40-0.37 (m, 2 H).

LCMS: 463.1 (M+H)+

Example 249: N-[4-[l-(cyclopropylmethyl)-5-methyl-6-oxopyridin-3-yl]-5-(2,4-difluorophenoxy)pyrimidin-2-yl]ethanesulfonamide


[00599] The title compound of Example 248, step 3 was treated with EtS02NH2 instead of MeS02NH2 in a manner similar to Example 248, step 4 to give the title compound. 1H NMR (CDC13, 400 MHz) δ 9.09 (s, 1 H), 8.60 (s, 1 H), 8.16 (s, 1 H), 8.11 (s, 1 H), 7.04-6.96 (m, 2 H), 6.91-6.89 (m, 1 H), 3.87 (d, J= 7.2 Hz, 2 H), 3.64 (q, J= 7.2 Hz, 2 H), 2.22 (s, 3 H), 1.44 (t, J= 7.2 Hz, 3 H), 1.25-1.23 (m, 1 H), 0.62-0.60 (m, 2 H), 0.38-0.37 (m, 2 H). LCMS: 477.2 (M+H)+

Example 250: 1 -(cyclopropylmethyl)-5-[6-(2,4-difluorophenoxy)-3-(methylsulfonylmethyl)-4-oxocyclohexa-l,5-dien-l-yl]-3-methylpyridin-2-one


[00600] The title compound from Example 248, step 2 was reacted with the title compound of Example 381, step 4 in a manner similar to Example 248, step 3 to give the title compound. 1H NMR (CDCI3, 400 MHz) δ 7.47 (s, 1 H), 7.41 (s, 1 H), 7.37 (s, 1 H), 7.18-7.16 (m, 1 H), 7.04-7.02 (m, 1 H), 7.01-6.98 (m, 1 H), 5.69 (s, 1 H), 5.17 (s, 2 H), 3.86 (d, J= 7.2 Hz, 2 H), 2.99 (s, 3 H), 2.20 (s, 3 H), 1.28-1.27 (m, 1 H), 0.65-0.60 (m, 2 H), 0.42-0.39 (m, 2 H).

LCMS: 477.1 (M+H) +

Example 251 : 1 -cyclopropyl-5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-3-methylpyridin-2-one

Step 1 : 5-bromo-l-cyclopropyl-3-methylpyridin-2-one


[00601] At room temperature, NBS (63 mg, 0.35 mmol) was added to l-cyclopropyl-3-methylpyridin-2-one (Racine, et. al. Chemical Communications 2013, 49, 67, 7412-7414) (53 mg, 0.36 mmol) in CH3CN (0.7 mL). After lh, EA extractive work up from saturated, aqueous NaHC03 gave the title compound as yellow solids in quantitative yield.

Step 2: l-cyclopropyl-5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-3-methylpyridin-2-one


[00602] The title compound of step 1 was reacted with2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane in a manner similar to Example 224, step 5. Silica gel chromatography (40-75% EA in hexane) gave the title compound (31 mg, 0.08 mmol, 42%) as a tan foam that turned to a glass upon standing. 1H NMR (400 MHz, CDC13) δ ppm 0.36-0.42 (m, 2 H) 0.60 - 0.75 (m, 2 H) 0.81 - 1.02 (m, 1 H, partially obscured) 1.05 - 1.37 (m, 7 H, partially obscured) 2.22 (s, 3 H) 3.12 (q, J=7.41 Hz, 2 H) 3.43 (br. s., 1 H) 3.94 (d, J=6.82 Hz, 2 H) 7.01 (d, J=9.35 Hz, 1 H) 7.45 - 7.53 (m, 1 H) 7.62 (br. s., 1 H) 7.72 - 7.83 (m, 2 H). ). LCMS: 388 (M+l) +

Example 252: 4-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-methylfuro[2,3-c]pyridin-7-one

Step 1 : 4-bromo-6H-furo[2,3-c]pyridin-7-one


[00603] A mixture of 6H-furo[2,3-c]pyridin-7-one (1.0 g, 7.4 mmol) in DMF (30 mL) was treated with NBS (1.32 g, 7.4 mmol) in three equal portions at 0°C. After the resulting mixture was stirred at 15 °C for 2 h, it was treated with water (100 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by

chromatography on silica gel (PE/EtOAc = 3: 1) to give the title compound (600 mg, 38%) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 11.92 (s, 1H), 8.23 (s, J = 2.0 Hz, 1 H), 7.47 (s, 1 H), 6.88 (m, 1 H), 6.88 (s, 1 H).

Step 2: 4-bromo-6-methylfuro[2,3-c]pyridin-7-one


[00604] To a solution of the title compound of step 1 (500 mg, 2.3 mmol) stirred at 0 °C in DMF (5 mL) was added NaH (68 mg, 2.81 mmol, 60% in mineral oil). After stirring at 0 °C for 30 min, methyl iodide (400 mg, 2.8 mmol) was added dropwise. The ice bath was removed, and mixture was stirred at rt for 4 h. The reaction mixture was treated with saturated NH4C1 (aq. 30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (PE/EtOAc = 10: 1) to give the title compound (500 mg, 94%). 1H NMR (CDC13, 400 MHz) δ 7.78 (d, J = 2.0 Hz, 1 H), 7.30 (s, 1 H), 6.70 (d, J = 2.0 Hz, 1 H), 3.66 (s, 3 H). LCMS (M+H)+ = 229.

Step 3 : 4-[2-(cyclopropylmethoxy)-5-eth lsulfonylphenyl]-6-methylfuro[2,3-c]pyridin-7-one


[00605] A mixture of the title compound of step 2 (150 mg, 0.66 mmol), 2-[2-(cyclopropylmethoxy)-5 -ethylsulfonylphenyl] -4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolane (336 mg, 1.0 mmol), NaHC03 (167 mg, 1.99 mmol), Pd(dppf)Cl2 (35 mg, 0.048 mmol) in dioxane/H20 (10 mL/2.5 mL) was bubbled with argon for 5 min. The sealed vial was stirred at 80 °C for 18 h. The reaction mixture was concentrated, treated with DCM (30 mL), washed with water (30 mL) and brine (30 mL), dried over Na2S04, filtered and concentrated in vacuo. The resulting residue was purified by prep-HPLC to give the title compound (63 mg, 25%) as a yellow solid. 1H NMR (CDC13, 400 MHz) δ 7.90-7.86 (m, 2 H), 7.75 (d, J = 1.6 Hz, 1 H), 7.31 (s, 1 H), 7.09 (d, J = 8.4 Hz, 1 H), 6.57 (d, J = 1.6 Hz, 1 H), 3.95 (d, J = 6.8 Hz, 2 H), 3.74 (s, 3 H), 3.18-3.12 (q, J = 7.6 Hz, 2 H), 1.34 (t, J = 7.6 Hz, 3 H), 1.16-1.15 (m, 1 H), 0.61-0.55 (m, 2 H), 0.31-0.27 (m, 2 H). LCMS (M+H)+ = 388.

Example 253: N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)phenyl] ethanesulfonamide


[00606] The title compound was prepared in a manner similar to step 3 of Example 252, by substituting N-[4-(2,4-difluorophenoxy)-3-(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)phenyl] ethanesulfonamide for 2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane. 1H NMR (CDC13, 400 MHz) δ 7.74 (s, 1 H) 7.38 (m, 2 H) 7.15 (m, 1 H) 6.93-9.92 (m, 2 H) 6.82-6.76 (m, 3 H) 6.44 (s, 1 H) 3.72 (s, 3 H) 3.19-3.16 (q, J = 7.2 Hz, 2 H) 1.45 (t, J = 7.2 Hz, 3 H). LCMS (M+H)+ = 461.

Example 254 : 4- [2-(cyclopropylmethoxy)-5 -methylsulfonylphenyl] -6-methylfuro [2,3 -c]pyridin-7-one


[00607] A mixture of 2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (115 mg, 0.33 mmol), 4-bromo-6-methyl-6H,7H-furo[2,3-c]pyridin-7-one (75 mg, 0.33 mmol), K3P04 (175 mg, 0.83 mmol), Pd(dppf)Cl2 (24 mg, 10 %) in dioxane/H20 (2.2 mL/200 uL) was bubbled with nitrogen for 5 min. The sealed vial

was stirred at 70 °C for 90 min. The reaction mixture was filtered through a short plug of celite; the celite plug was washed with EtOAc (15 mL). The filtrate was washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown residue. The resulting residue was purified by prep-HP LC to afford the title compound (60 mg, 49%) as a white solid. LCMS (M+H)+ = 374.

Example 255: N-[4-(cyclopropylmethoxy)-3-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)phenyl] ethanesulfonamide

Step 1 : 2-bromo-l-(cyclopropylmethox -4-nitrobenzene


[00608] A 0.2 M solution of cyclopropyl methanol (441 uL, 5.5 mmol) in THF stirred at 0 °C under an atmosphere of nitrogen was treated with 2 equal portions of KOtBu (579 mg, 5.2 mmol). After 5 min the ice bath was removed; the mixture was stirred for 30 min at rt before resubmerging in the ice bath and cooling to 0 °C. A solution of 2-bromo-l-fluoro-4-nitrobenzene (1 g, 4.5 mmol) in THF (3 mL) was added dropwise. After 20 min, the ice bath was removed and the mixture was stirred overnight. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 X 50 ml). The combined organic layers were washed brine (30 mL), dried over Na2S04, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using a gradient of EtOAc (5 to 50%) in hexanes to afford the title compound (1.07 g, 88%) as a yellow solid.

Step 2: 3-bromo-4-(cyclopropylmethoxy)aniline


[00609] A mixture of 2-bromo-l-(cyclopropylmethoxy)-4-nitrobenzene (1.07 g, 3.9 mmol), ammonium chloride (421 mg, 7.8 mmol), and iron powder (1.1 g, 20 mmol) suspended in THF (6.5 mL), water (2.5 mL) and ethanol (6.5 mL) was heated to 95 °C using microwave irradiation (normal) for 3 h. The crude reaction mixture was filtered through a short plug of celite; the celite plug was washed with MeOH (~ 10 mL). The resulting filtrate was concentrated in vacuo. The resulting residue was diluted with EtOAc (50 ml) and washed with saturated bicarbonate solution (aq), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound, (939 mg, 90%). The material was carried forward without any further purification. LCMS (M+H)+ = 242.

Step 3 : N- [3 -bromo-4-(cyclopropylmethoxy)phenyl] ethane- 1 -sulfonamide


[00610] Ethylsulfonyl chloride (233 uL, 2.4 mmol) was added to a stirred solution of 3-bromo-4-(cyclopropylmethoxy)aniline (520 mg, 2.2 mmol) and pyridine (520 uL, 6.5 mmol) in DCM (4 mL) at 0 °C under nitrogen. After the mixture was allowed to warm to rt and stir for 12 h, it was treated with IN HC1 (15 mL) and extracted with DCM (3 X 15 mL); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using a gradient of EtOAc (10 to 100%) in hexanes to afford the title compound (711 mg, 98%) as a yellow solid. LCMS (M+H)+ = 335.

Step 4 : N- [4-(cyclopropylmethoxy)-3 -(tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)phenyl] ethane- 1 -sulfonamide


[00611] A mixture of N-[3-bromo-4-(cyclopropylmethoxy)phenyl]ethane-l-sulfonamide (711 mg, 2.1 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (1.1 g, 4.3 mmol), KOAc (470 mg, 4.8 mmol), Pd2(dba)3 (59 mg. 3%), and l,3,5,7-Tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (62 mg, 10%) was suspended in anhydrous dioxane (14 mL). The stirred mixture was capped and purged with nitrogen for 6 min using an oil bubbler as an outlet. After the nitrogen inlet and outlet were removed, the capped flask was stirred at 70 °C for 3 h. After cooling to about 35 °C, the reaction mixture was filtered through a short plug of celite; the celite plug was washed with EtOAc (75 mL). The filtrate was treated with water and extracted with EtOAc; the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a tan residue. The residue was purified by silica gel column chromatography using a gradient of EtOAc (5 to 100 % ) in hexanes to afford the title compound (527 mg, 65%). LCMS (M+H)+ = 382.

Step 5 : N-[4-(cyclopropylmethoxy)-3-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)phenyl] ethanesulfonamide


[00612] A mixture of N-[4-(cyclopropylmethoxy)-3-(tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl] ethane- 1 -sulfonamide (138 mg, 0.38 mmol), 4-bromo-6-methyl-6H,7H-furo[2,3-c]pyridin-7-one (75 mg, 0.33 mmol), K3P04 (175 mg, 0.83 mmol), Pd(dppf)Cl2 (24 mg, 10 %) in dioxane (2.2 mL) and H20 (200 uL) was bubbled with nitrogen for 5 min. The sealed vial was stirred at 70 °C for 4 h. After the reaction mixture was filtered through a short plug of celite, the celite plug was washed with EtOAc (15 mL). The filtrate was washed with water and brine; the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford a tan residue. The resulting residue was purified by prep-HP LC to afford the title compound (21 mg, 16%) as a tan solid. 1H NMR (400 MHz, DMSO- 6) δ ppm 0.15 - 0.28 (m, 2 H) 0.35 - 0.52 (m, 2 H) 0.95 - 1.13 (m, 1 H) 1.14 - 1.26 (m, 3 H) 2.98 - 3.09 (m, 2 H) 3.57 - 3.65 (m, 3 H) 3.77 - 3.87 (m, 2 H) 7.04 - 7.22 (m, 3 H) 7.55 - 7.64 (m, 1 H) 8.05 - 8.17 (m, 1 H) 9.49 - 9.57 (m, 1 H). LCMS (M+H)+ = 403.

Example 256: N-[6-(2,4-difluorophenoxy)-5-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)pyridin-3 -yl] ethanesulfonamide

Step 1 : 3-bromo-2-(2,4-difluorophen xy)-5-nitropyridine


[00613] A solution of 3-bromo-2-chloro-5-nitropyridine (2.4 g, 10 mmol) and 2,4-difluorophenol (1 mL, 11 mmol) in NMP (20 ml) was treated with cesium carbonate (3.9 g, 12 mmol). The resulting mixture was heated to 60 °C for 12 h. The mixture was treated with water (100 ml) and extracted with EtOAc (3 X 50 ml); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow solid. The solid was purified by silica gel column chromatography (gradient of 5 to 30% EtOAc in hexanes) to afford the free base of the title compound (2 g, 59 %) as a yellow solid. LCMS (M+H)+ = 332.

Step 2: 5-bromo-6-(2,4-difluorophen xy)pyridin-3-amine


[00614] A mixture of 3-bromo-2-(2,4-difluorophenoxy)-5-nitropyridine (1.9 g, 5.9 mmol), ammonium chloride (637 mg, 11.8 mmol), and iron powder (1.65 g, 30 mmol) suspended in THF (10 mL), water (3 mL) and ethanol (10 mL) was heated to 90 °C using microwave irradiation (normal) for 5 h. The crude reaction mixture was filtered through a short plug of celite; the celite plug was washed with warm (50 °C) MeOH (- 50 mL). The resulting filtrate was concentrated in vacuo. The resulting residue was diluted with EtOAc (100 ml) and washed with saturated bicarbonate solution (aq), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound, (824 mg, 46%). LCMS (M+H)+ = 302.

Step 3 : 6-(2,4-difluorophenoxy)-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyridin-3-amine


[00615] A mixture of 5-bromo-6-(2,4-difluorophenoxy)pyridin-3-amine (400 mg, 1.33 mmol), 4,4,5 ,5-tetramethyl-2-(tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 ,3 ,2-dioxaborolane (675 mg, 2.7 mmol), KOAc (325 mg, 3.3 mmol), Pd2(dba)3 (36 mg, 3%), and 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (38 mg, 10%) was suspended in dioxane (9 mL). The stirred reaction mixture was capped and purged with nitrogen for 5 to 7 min using an oil bubbler as an outlet. After the nitrogen inlet and outlet were removed, the capped vial was stirred at 80 °C for 3 h. After cooling to rt, the reaction mixture was filtered through a short plug of celite; the celite plug was washed with EtOAc (50 mL). The filtrate was treated with water and extracted with EtOAc; the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a tan residue. The residue was purified by silica gel column chromatography using a gradient (20-70 %) of EtOAc in hexanes to afford the title compound (163 mg, 35%). LCMS (M+H)+ = 349.

Step 4: N-[6-(2,4-difluorophenoxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-3-yl] ethanesulfonamide


[00616] Ethylsulfonyl chloride (50 uL, 52 mmol) was added to a stirred solution of 6-(2,4-difluorophenoxy)-5 -(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)pyridin-3-amine (163 mg, 0.5 mmol) and pyridine (113 uL) in DCM (2.4 mL) at 0 °C under nitrogen. After the mixture was allowed to warm to rt and stir for 12 h, it was treated with water (15 mL) and extracted with DCM (3 X 15 mL); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using a gradient of EtOAc (0 to 100 %) in DCM to afford the title compound (181 mg, 88 %) as a tan solid. LCMS (M+H)+ = 441.

Step 5 : N-[6-(2,4-difluorophenoxy)-5-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)pyridin-3-yl] ethanesulfonamide


[00617] A mixture of N-[6-(2,4-difluorophenoxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-3-yl] ethanesulfonamide (145 mg, 0.38 mmol), 4-bromo-6-methyl-6H,7H-furo[2,3-c]pyridin-7-one (75 mg, 0.33 mmol), K3P04 (175 mg, 0.83 mmol), Pd(dppf)Cl2 (24 mg, 10 %) in dioxane/H20 (2.2 mL/200 uL) was bubbled with nitrogen for 5 min. The sealed vial was stirred at 70 °C for 4 h. After the reaction mixture was filtered through a short plug of celite, the plug was washed with EtOAc (15 mL). The filtrate was washed with water and brine, the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford a tan residue. The resulting residue was purified by prep-HPLC to afford the title compound (50 mg, 33%) as a white solid. 1H NMR (400 MHz, DMSO- 6) δ ppm 1.18 - 1.28 (m, 3 H) 3.10 - 3.21 (m, 2 H) 3.59 - 3.65 (m, 3 H) 6.85 - 6.95 (m, 1 H) 7.07 - 7.19 (m, 1 H) 7.35 - 7.51 (m, 2 H) 7.73 - 7.79 (m, 1 H) 7.80 - 7.85 (m, 1 H) 7.90 - 7.97 (m, 1 H) 8.14 - 8.20 (m, 1 H) 9.78 - 10.09 (m, 1 H). LCMS (M+H)+ = 461.

Example 257: N-[6-(cyclopropylmethoxy)-5-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)pyridin-3 -yl] ethanesulfonamide

Step 1 : 3-bromo-2-(cyclopropylmethox -5-nitropyridine

[00618] A solution of 3-bromo-2-chloro-5-nitropyridine (2.4 g, 10 mmol) and

cyclopropylmethanol (970 uL, 12 mmol) in THF (50 ml) was treated with KOtBu (3.3 g, 15 mmol). After stirring at rt for 12 h, the mixture was treated with water (150 ml) and extracted with EtOAc (3 X 50 ml); the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow solid. The solid was purified by silica gel column chromatography using a gradient of EtOAc (5 to 30 %) in hexanes to afford the title compound (1.3 g, 48%) as a yellow solid. LCMS (M+H)+ = 274. Step 2: 5-bromo-6-(cyclopropylmethox ridin-3-amine


[00619] A mixture of 3-bromo-2-(cyclopropylmethoxy)-5-nitropyridine (1 g, 3.7 mmol), ammonium chloride (600 mg, 11.1 mmol), and iron powder (1.05 g, 19 mmol) suspended in THF (6.2 mL), water (2.3 mL) and ethanol (6.2 mL) was heated to 100 °C using microwave irradiation (normal) for 5 h. The crude reaction mixture was filtered through a short plug of celite; the celite plug was washed with warm (50 °C) MeOH (50 mL). The resulting filtrate was concentrated in vacuo. The resulting residue was diluted with EtOAc (100 ml) and washed with saturated bicarbonate solution (aq), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound, (539 mg, 60%). LCMS (M+H)+ = 244.

Step 3 : N-[5-bromo-6-(cyclopropylmethoxy)pyridin-3-yl]ethanesulfonamide


[00620] Ethylsulfonyl chloride (170 uL, 1.8 mmol) was added to a stirred solution of 5-bromo-6-(cyclopropylmethoxy)pyridin-3 -amine (440 mg, 1.8 mmol) and pyridine (725 uL) in DCM (4.5 mL) at 0 °C under nitrogen. After the mixture was allowed to warm to rt and stir for 12 h, it was treated with IN HC1 (15 mL) and extracted with DCM (3 X 15 mL); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using a gradient of EtOAc (0 to 100 %) in DCM to afford the title compound (181 mg, 88 %) as a tan solid. LCMS (M+H)+ = 336.

Step 4: N-[6-(cyclopropylmethoxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-3 -yl] ethanesulfonamide

[00621] A mixture of N-[5-bromo-6-(cyclopropylmethoxy)pyridin-3-yl]ethanesulfonamide (150 mg, 0.45 mmol), 4,4,5, 5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (285 mg, 1.13 mmol), KOAc (132 mg, 1.35 mmol), and Pd(dppf)2(Cl)2 (33 mg, 10%) was suspended in anhydrous dioxane (5 mL). The stirred reaction mixture was capped and purged with nitrogen for 5 min using an oil bubbler as an outlet. After the nitrogen inlet and outlet were removed, the capped vial was stirred at 70 °C for 3 h. After cooling to rt, the reaction mixture was filtered through a short plug of celite; the celite plug was washed with EtOAc. The filtrate was treated with water and separated; after the aqueous layer was washed with EtOAC (3 X 25 mL), the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a dark tan residue. The residue was purified by silica gel column chromatography using a gradient of 5 to 70 % EtOAc in hexanes to afford the title compound (112 mg, 65%). LCMS (M+H)+ = 383.

Step 5 : N-[6-(cyclopropylmethoxy)-5-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)pyridin-3-yl] ethanesulfonamide


[00622] A mixture of N-[6-(cyclopropylmethoxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-3-yl] ethanesulfonamide (145 mg, 0.38 mmol), 4-bromo-6-methyl-6H,7H-furo[2,3-c]pyridin-7-one (25 mg, 0.11 mmol), K3P04 (58 mg, 0.28 mmol), Pd(dppf)Cl2 (8 mg, 10 %) in dioxane/H20 (1 mL/100 uL) was bubbled with nitrogen for 5 min. The sealed vial was stirred at 65 °C for 12 h. The reaction mixture was filtered through a short plug of celite; the celite plug was washed with EtOAc (15 mL). The filtrate was washed with water and brine; the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford a tan residue. The resulting residue was purified by prep-HPLC to afford the title compound (21 mg, 48%) as a white solid. 1H NMR (400 MHz, DMSO- 6) δ ppm 0.23 - 0.32 (m, 2 H) 0.41 - 0.52 (m, 2 H) 1.08 - 1.19 (m, 1 H) 1.20 - 1.29 (m, 3 H) 3.05 - 3.16 (m, 2 H) 3.58 - 3.63 (m, 3 H) 3.64 - 3.66 (m, 1 H) 4.08 - 4.17 (m, 2 H) 6.72 - 6.82 (m, 1 H) 7.58 - 7.65 (m, 1 H) 7.67 - 7.73 (m, 1 H) 7.95 - 8.06 (m, 1 H) 8.10 - 8.18 (m, 1 H) 9.41 - 9.86 (m, 1 H). LCMS (M+H)+ = 404.

Example 258: 6-methyl-4-[5-(methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl] furo [2,3 -c]pyridin-7-one

Step 1 : 6-methyl-4-(4,4,5,5-tetramethyl-l -dioxaborolan-2-yl)mro[2,3-c]pyridin-7-one


[00623] A solution of 4-bromo-6-methylfuro[2,3-c]pyridin-7-one (200 mg, 0.88 mmol), 4,4,5 ,5-tetramethyl-2-(tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 ,3 ,2-dioxaborolane (447 mg, 1.76 mmol), KOAc (259 mg, 2.64 mmol), Pd2(dba)3 (82 mg, 0.09 mmol), X-Phos(52 mg, 0.11 mmol) in dioxane (5 mL) was bubbled with nitrogen for 5 minutes and then stirred at 70 °C for 12 h. The reaction mixture was concentrated, treated with DCM (30 mL), washed with water (30 mL) and brine (30 mL), dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography (PE:EA=20: 1-5:1) to give the title compound (130 mg, 54%) as a gray solid. 1H NMR (CDC13, 400 MHz) δ 7.73 (s, 1 H) 7.62 (s, 1 H) 7.01 (s, 1 H) 3.68 (s, 3 H) 1.35 (s, 12 H). LCMS (M+H)+ = 276.

Step 2: 6-methyl-4-[5-(methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]furo[2,3-c]pyridin-7-one


[00624] A mixture of 2-bromo-4-(methylsulfonylmethyl)-l-(2,2,2-trifluoroethoxy)benzene (100 mg, 0.29 mmol), 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)furo[2,3-c]pyridin-7-one (96 mg, 0.35 mmol), K3P04 (184 mg, 0.87 mmol), Pd(dppf)Cl2 (22 mg, 10 %) in dioxane/H20 (2 mL/1 mL) was bubbled with nitrogen for 5 min. The sealed vial was heated to 70 °C for 2 h. The reaction mixture was filtered through a short plug of celite; the celite plug was washed with EtOAc (15 mL). The filtrate was washed with water and brine; the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by prep-HP LC to afford the title compound (40 mg, 33%) as an off-white solid. 1H NMR (CDC13, 400 MHz) δ 7.76 (d, J = 2.0 Hz, 1 H) 7.53 (d, J = 2.0 Hz, 1 H) 7.41-7.38 (m, 1 H) 7.37 (s, 1 H) 7.02 (d, J = 8.4, 1 H) 6.72 (d, J = 2.0 Hz, 2 H) 4.37 (q, J =

8.0 Hz, 2 H) 4.27 (s, 2 H) 3.73 (s, 3 H) 2.89 (s, 3 H). LCMS (M+H)+ = 416.

Example 259: 4-[3-(cyclopropylmethoxy)-6-methylsulfonylpyridin-2-yl]-6-methylfuro[2,3-c]pyridin-7-one


[00625] A mixture of 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)furo[2,3-c]pyridin-7-one (50 mg, 0.18 mmol), 3-(cyclopropylmethoxy)-2-iodo-6-methylsulfonylpyridine (53 mg, 0.15 mmol), K3PO4 (114 mg, 0.54 mmol), Pd(dppf)Cl2 (13 mg, 0.018 mmol) in dioxane (5 mL) was bubbled with nitrogen for 5 min and then stirred at 70 °C for 12 h. The reaction mixture was concentrated, treated with DCM (30 mL), washed with water (30 mL) and brine (30 mL), dried over Na2S04, filtered and concentrated. The residue was purified by prep-HPLC to give the title compound (35 mg, yield: 52%) as an off-white solid.

1H NMR (CDCI3, 400 MHz) δ 8.42 (s, 1 H) 8.10 (s, 1 H) 7.81 (d, J = 1.6 Hz, 1 H) 7.51 (s, 1

H) 6.66 (d, J = 1.6 Hz, 1 H) 4.08 (d, J = 7.6 Hz, 2 H) 3.77 (s, 3 H) 3.26 (s, 3 H) 1.26-1.19 (m,

1 H) 0.68-0.63 (m, 2 H) 0.37-0.33 (m, 2 H). LCMS (M+H)+ = 375.

Example 260: 2-chloro-4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-methylfuro[2,3-c]pyridin-7-one

Step 1 : 2-chloro-7-methoxyfuro[2,3-c]pyridine


[00626] A 0.13 M solution of 7-methoxyfuro[2,3-c]pyridine (250 mg, 1.7 mmol) in THF stirred at -78 °C under an atmosphere of nitrogen was treated with n-BuLi (1.6M in hexanes, 450 uL, 5.2 mmol) dropwise over 30 sec. The mixture was warmed gradually to -15 °C over a period of 7 to 10 min. After 1 h at -15 °C, the mixture was cooled to -65 °C and was treated with a 0.26 M solution of hexachloroethane (473 mg, 2 mmol) in THF by dropwise addition over 3 min. After stirring at -65 °C for 15 min, the mixture was allowed to gradually warm to rt. After the mixture was allowed to stir overnight, it was quenched with water (5 mL) and extracted with EtOAc (3 X 15 ml). The combined organic layers were washed brine (10 mL), dried over Na2S04, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using a gradient of EtOAc (5 to 30%) in hexanes to afford the title compound (266 mg, 87%) as an amber oil. 1H NMR (400 MHz, DMSO- 6) δ ppm 3.99 - 4.08 (m, 3 H) 7.13 (s, 1 H) 7.25 (d, J=5.31 Hz, 1 H) 7.95 (d, J=5.31 Hz, 1 H). LCMS (M+H)+ = 184.

Step 2: 2-chlorofuro[2,3-c]pyridin-7-ol


[00627] A 0.25M solution of 2-chloro-7-methoxyfuro[2,3-c]pyridine (263 mg, 1.4 mmol) in DCM stirred at -0 °C under an atmosphere of nitrogen was treated with BBr3 (1 M in DCM, 4.3 mL, 4.3 mmol) dropwise over 5 min. The mixture was allowed to warm gradually to rt. After the mixture was allowed to stir overnight, it was poured into ice water and extracted with DCM (3 X 15 mL). The combined organic layers were washed with water and brine (10 mL), dried over Na2S04, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using a gradient of EtOAc (15 to 75%) in hexanes to afford the title compound (115 mg, 47%) as light yellow solid. LCMS (M+H)+ = 170.

Step 3: 4-bromo-2-chlorofuro[2,3-c]pyridin-7-ol


[00628] A 0.15 M solution of 2-chlorofuro[2,3-c]pyridin-7-ol (113 mg, 0.7 mmol) in DMF stirred in the dark at 0 °C under an atmosphere of nitrogen was treated with NBS (120 mg, 0.7 mmol) in three equal portions. The ice bath was removed; the mixture was stirred at rt for 3 h. The reaction mixture was treated with a 10% aqueous solution of sodium thiosulfate (5 ml) and was extracted with EtOAc (3 X 30 mL). The combined organic layers were washed with water (15 mL), brine (20 mL), dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (hexanes/EtOAc = 4: 1) to afford the title compound (145 mg, 87%) as a white solid. LCMS (M+H)+ = 249.

Step 4: 4-bromo-2-chloro-6-methylfuro[2,3-c]pyridin-7-one


[00629] A 0.2 M solution of 4-bromo-2-chlorofuro[2,3-c]pyridin-7-ol (143 mg, 0.6 mmol) and K2CO3 (200 mg, 1.45 mmol) in DMF stirred at 0 °C under an atmosphere of nitrogen was treated with Mel (99 mg, 0.7 mmol). The ice bath was removed; the mixture was stirred at rt overnight. The reaction mixture was treated water (15 mL) and was extracted with EtOAc (3 X 10 mL). The combined organic layers were washed with water (15 mL), brine (20 mL), dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel using a gradient of EtOAc (10 to 100%) in hexanes to afford the title compound (113 mg, 85%) as a white solid. LCMS (M+H)+ = 263.

Step 5 : 2-chloro-4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-methylfuro[2,3-c]pyridin-7-one


[00630] A mixture of 2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (33 mg, 0.09 mmol), 4-bromo-2-chloro-6-methylfuro[2,3-c]pyridin-7-one (25 mg, 0.09 mmol), K3PO4 (50 mg, 0.24 mmol), Pd(dppf)Cl2 (7 mg, 10 %) in dioxane/H20 (700 uL/70 uL) was bubbled with nitrogen for 5 min. The sealed vial was stirred at 70 °C for 90 min. The reaction mixture was filtered through a short plug of celite; the celite plug was washed with EtOAc (10 mL). The filtrate was washed with water and brine; the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford a tan residue. The resulting residue was purified by prep-HPLC to afford the title compound (27 mg, 69%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.23 -0.34 (m, 2 H) 0.44 - 0.55 (m, 2 H) 1.00 - 1.13 (m, 1 H) 3.19 - 3.24 (m, 3 H) 3.61 (s, 3 H) 3.94 - 4.05 (m, 2 H) 6.82 - 6.89 (m, 1 H) 7.10 - 7.16 (m, 1 H) 7.26 - 7.35 (m, 1 H) 7.70 - 7.78 (m, 1 H) 7.87 - 7.94 (m, 1 H). LCMS (M+H)+ = 409.

Example 2611 2-fluoro-4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-methylfuro[2,3-c]pyridin-7-one

Step 1 : 2-fluoro-7-methoxyfuro[2,3-c]pyridine


[00631] The title compound was prepared in a manner similar to step 1 of Example 260, by substituting N-Fluorobenzenesulfonamide for hexachloroethane. 1H NMR (400 MHz,

DMSO-de) δ ppm 4.01 (s, 3 H) 6.46 (m, 1 H) 7.25 (d, J=5.4 Hz, 1 H) 7.96 (d, J=5.4 Hz, 1 H).

LCMS (M+H)+ = 168.

Step 2: 2-fluorofuro[2,3-c]pyridin-7-ol


[00632] The title compound was prepared in a manner similar to step 2 of Example 260, by substituting 2-fluoro-7-methoxyfuro[2,3-c]pyridine for 2-chloro-7-methoxyfuro[2,3-c]pyridine. LCMS (M+H)+ = 154.

Step 3: 4-bromo-2-fluorofuro[2,3-c]pyridin-7-ol


[00633] The title compound was prepared in a manner similar to step 3 of Example 260, by substituting 2-fluorofuro[2,3-c]pyridin-7-ol for 2-chlorofuro[2,3-c]pyridin-7-ol. LCMS (M+H)+ = 233.

Step 4: 4-bromo-2-fluoro-6-methylfuro[2,3-c]pyridin-7-one


[00634] The title compound was prepared in a manner similar to step 4 of Example 260, by substituting 4-bromo-2-fluorofuro[2,3-c]pyridin-7-ol for 4-bromo-2-chlorofuro[2,3-c]pyridin-7-ol. LCMS (M+H)+ = 247.

Step 5 : 2-fluoro-4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-methylfuro[2,3-c]pyridin-7-one


[00635] A mixture of N-[6-(cyclopropylmethoxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-3-yl]ethanesulfonamide (31 mg, 0.08 mmol), 4-bromo-2-fluoro-6-methylfuro[2,3-c]pyridin-7-one (20 mg, 0.08 mmol), K3PO4 (36 mg, 0.17 mmol), Pd(dppf)Cl2 (6 mg, 8%) in dioxane/H20 (830 uL/100 uL) was bubbled with nitrogen for 10 min. The

sealed vial was stirred at 67 °C for 90 min. The reaction mixture was filtered through a short plug of celite; the celite plug was washed with EtOAc (15 mL). The filtrate was washed with water and brine; the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford a tan residue. The resulting residue was purified by silica gel column chromatography using a gradient of MeOH (0 to 2%) in DCM. The fractions were combined and concentrated in vacuo to afford a white solid (10 mg). The solid had a minor impurity [LCMS (M+H)+= 578]; therefore, it was diluted in MeOH (lmL) and IN NaOH(aq) (500 uL) and purified by prep-HPLC to afford the title compound (6 mg, 17%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.28 (m, 2 H) 0.43 - 0.58 (m, 2 H) 0.56 - 0.58 (m, 1 H) 1.24 (m, 3 H) 3.09 (m, 2 H) 3.60 (s, 3 H) 4.12 (m, 2 H) 6.16 - 6.34 (m, 1 H) 7.52 - 7.72 (m, 1 H) 7.77 (s, 1 H) 7.90 - 8.14 (m, 1 H) 9.37 - 10.62 (bs, 1 H). LCMS (M+H)+ = 422.

Example 262: N-[5-(2,4-difluorophenoxy)-4-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)pyrimidin-2-yl]methanesulfonamide

Step 1 : 4-[5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidin-4-yl]-6-methylfuro[2,3-c]pyridin-7-one


[00636] A mixture of 4-chloro-5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidine (155 mg, 0.48 mmol), 4-bromo-2-fluoro-6-methylfuro[2,3-c]pyridin-7-one (120 mg, 0.44 mmol), NaHC03 (92 mg, 1.1 mmol), Pd(dppf)Cl2 (32 mg, 10%) in dioxane/H20 (4 mL/200 uL) was bubbled with nitrogen for 7 min. The sealed vial was stirred at 70 °C for 8 h. LCMS analysis showed complete consumption of the limiting reagent. The reaction mixture was filtered through a short plug of celite; the celite plug was washed with DCM. The filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column

chromatography using a gradient of EtOAc (10 to 100%) in DCM to afford the title compound (151 mg, 79%) as a yellow solid. LCMS (M+H)+ = 434.

Step 2: N-[5-(2,4-difluorophenoxy)-4-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)pyrimidin-2-yl]methanesulfonamide


[00637] A solution of methanesulfonamide (61 mg, 0.65 mmol) in DMF (2 mL) stirred at 0 °C under an atmosphere of nitrogen was treated with NaH (99 mg, 0.7 mmol). After the ice bath was removed, the mixture was stirred at rt for 15 min. The resulting suspension was treated with a solution of 4-[5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidin-4-yl]-6-methylfuro[2,3-c]pyridin-7-one (70 mg, 0.16 mmol) in DMF (1 mL). After the nitrogen inlet was removed, the capped mixture was heated to 70 °C for 3h. After cooling to 0 °C, the reaction mixture was stirred vigorously and treated water (500 uL). After 5 min, the cooled mixture was treated with IN HCl(aq) (1 mL). The resulting suspension was filtered; the filter cake was washed with additional IN HCl(aq) (1 mL) and isopropyl ether (5 mL) to afford the title compound (50 mg, 70%) as an off-white solid. 1H NMR (400 MHz, DMSO- 6) δ ppm 3.34 (s, 3 H) 3.60 (s, 3 H) 7.06 (m, 1 H) 7.28 (m, 1 H) 7.49 (m, 1 H) 7.80 (s, 1 H) 8.23 (s, 1 H) 8.43 (m, 2 H) 11.50 (bs, 1 H). LCMS (M+H)+ = 449.

Example 263: N-[5-(2,4-difluorophenoxy)-4-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)pyrimidin-2-yl]ethanesulfonami


[00638] The title compound (46 mg, 62%) was prepared in a manner similar to step 2 of

Example 262, by substituting ethanesulfonamide for methanesulfonamide. 1H NMR (400

MHz, DMSO-dg) δ ppm 1.20 - 1.27 (m, 3 H) 3.43 - 3.57 (m, 2 H) 3.57 - 3.67 (s, 3 H) 7.00 - 7.13 (m, 1 H) 7.20 - 7.37 (m, 1 H) 7.41 - 7.54 (m, 1 H) 7.72 - 7.87 (m, 1 H) 8.15 - 8.28 (m, 1

H) 8.30 - 8.49 (m, 2 H) 11.25 - 11.48 (bs, 1 H). LCMS (M+H)+ = 463.

Example 264: N-[5-(cyclopropylmethoxy)-4-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)pyrimidin-2-yl]ethanesulfonamide

Step 1 : 4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyrimidin-4-yl]-6-methylfuro[2,3-c]pyridin-7-one


[00639] The title compound was prepared in a manner similar to step 1 of Example 262, by substituting 4-chloro-5-(cyclopropylmethoxy)-2-methylsulfonylpyrimidine for 4-chloro-5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidine. LCMS (M+H)+ = 376.

Step 2: N-[5-(cyclopropylmethoxy)-4-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)pyrimidin-2-yl] ethanesulfonamide


[00640] The title compound was prepared in a manner similar to step 2 of Example 262, by substituting substituting ethanesulfonamide for methanesulfonamide and by substituting 4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyrimidin-4-yl]-6-methylmro[2,3-c]pyridin-7-one for 4-[5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidin-4-yl]-6-methylmro[2,3-c]pyridin-7-one. LCMS (M+H)+ = 405.

Example 265: 4-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-methyl-7-oxothieno[2,3-c]pyridine-2-carboxamide

Step 1 : methyl 4-bromo-6-methyl-7-oxothieno[2,3-c]pyridine-2-carboxylate


[00641] To a solution of methyl 4-bromo-7-hydroxythieno[2,3-c]pyridine-2-carboxylate (300 mg, 1.04 mmol) stirred at 0 °C in DMF (6.6 mL) under an atmosphere of nitrogen was added K2CO3 (358 mg, 2.6 mmol). After stirring at 0 °C for 15 min, methyl iodide (177 mg, 1.3 mmol) was added dropwise. The ice bath was removed, and mixture was stirred at rt for 20 min, 50 °C for 2h, and rt for lOh. The reaction mixture was treated with water (8 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of EtOAc (10 to 100%) in DCM to afford the title compound (284 mg, 90%) as a white solid. LCMS (M+H)+ = 303.

Step 2: 4-bromo-6-methyl-7-oxothieno[2,3-c]pyridine-2-carboxamide


[00642] Using a sealed tube, a solution of methyl 4-bromo-6-methyl-7-oxothieno[2,3-c]pyridine-2-carboxylate (250 mg, 65 mmol) in MeOH (6 mL) stirred at rt was treated with 2N NH3 in methanol (8 ml). The sealed tube was heated to 45 °C for 60 h. After cooling to 0 °C, the resulting suspension was filtered; the filter cake was washed with cooled (0 °C) MeOH (3 mL) and isopropyl ether (3 mL) to afford the title compound (215 mg, 95%) as a white solid. LCMS (M+H)+ = 288.

Step 3 : 4-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-methyl-7-oxothieno[2,3-c]pyridine-2-carboxamide


[00643] A mixture of 2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (77 mg, 0.22 mmol), 4-bromo-6-methyl-7-oxothieno[2,3-c]pyridine-2-carboxamide (50 mg, 0.18 mmol), K3P04 (93 mg, 0.44 mmol), Pd(dppf)Cl2 (13 mg, 10 %) in dioxane/H20 (1.6 mL/160 uL) was bubbled with nitrogen for 5 min. The sealed vial was stirred at 65 °C for 3 h. The reaction mixture was filtered through a short plug of celite; the celite plug was washed with EtOAc (15 mL). The filtrate was washed with water and brine; the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford a tan residue. The resulting residue was purified by prep-HPLC to afford the title compound (20 mg, 26%) as a white solid. 1H NMR (400 MHz, DMSO- 6) δ ppm 0.20 (m, 2 H) 0.36 (m, 2 H) 0.98 (m, 1 H) 1.14 (m, 3 H) 3.21 - 3.31 (m, 2 H) 3.61 (s, 3 H) 3.98 (m, 2 H) 7.38 (d, J=8.6 Hz, 1 H) 7.65 - 7.75 (m, 3 H) 7.78 (d, J=2.0 Hz, 1 H) 7.91 (dd, J=8.6, 2.0 Hz, 1 H) 8.24 (s, 1 H). LCMS (M+H)+ = 447.

Example 266: 4-[2-(cyclopropylmethoxy)-5-(ethylsulfonylamino)phenyl]-6-methyl-7-oxothieno[2,3-c]pyridine-2-carboxamide

[00644] The title compound was prepared in a manner similar to step 3 of Example 265, by substituting N-[4-(cyclopropylmethoxy)-3-(tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl] ethane- 1 -sulfonamide for 2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.09 - 0.19 (m, 2 H) 0.27 - 0.39 (m, 2 H) 0.86 - 1.02 (m, 1 H) 1.18 - 1.27 (m, 3 H) 2.97 - 3.09 (m, 2 H) 3.59 (s, 3 H) 3.77 - 3.86 (m, 2 H) 7.07 - 7.16 (m, 2 H) 7.21 - 7.27 (m, 1 H) 7.53 - 7.58 (m, 1 H) 7.61 - 7.67 (m, 1 H) 7.67 - 7.72 (m, 1 H) 8.19 - 8.30 (m, 1 H) 9.46 - 9.60 (m, 1 H). LCMS (M+H)+ = 462.

Example 267: 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-methyl-7-oxothieno[2,3-c]pyridine-2-carboxamide


[00645] The title compound was prepared in a manner similar to step 3 of Example 265, by substituting 2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane for 2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.11 - 0.26 (m, 2 H) 0.27 - 0.41 (m, 2 H) 0.89 - 1.05 (m, 1 H) 3.21 (s, 3 H) 3.61 (s, 3 H) 3.91 - 4.04 (m, 2 H) 7.34 - 7.41 (m, 1 H) 7.63 - 7.76 (m, 3 H) 7.81 - 7.88 (m, 1 H) 7.92 - 7.99 (m, 1 H) 8.21 - 8.29 (m, 1 H). LCMS (M+H)+ = 433.

Example 268: 4-[2-(cyclopropylmethoxy)-5-(ethylsulfonylamino)pyridin-3-yl]-6-methyl-7-oxothieno[2,3-c]pyridine-2-carboxami

[00646] The title compound was prepared in a manner similar to step 3 of Example 265, by substituting N-[6-(cyclopropylmethoxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-3 -yl] ethanesulfonamide for 2- [2-(cyclopropylmethoxy)-5 -ethylsulfonylphenyl] -4,4,5,5-tetramethyl-l,3,2-dioxaborolane. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.17 - 0.35 (m, 2 H) 0.39 - 0.57 (m, 2 H) 1.23 (m, 4 H) 3.00 - 3.17 (m, 2 H) 3.60 (s, 3 H) 4.01 - 4.26 (m, 2 H) 6.11 - 6.40 (m, 1 H) 7.52 - 7.69 (m, 1 H) 7.74 - 7.84 (m, 1 H) 7.94 - 8.09 (m, 1 H) 9.14 -10.31 (m, 1 H). LCMS (M+H)+ = 463.

Example 269: N-[4-(2,4-difluorophenoxy)-3-(2,6-dimethyl-7-oxoi iro[2,3-c]pyridin-4-yl)phenyl] ethanesulfonamide

Step 1 : 7-methoxy-2-methylfuro[2,3-c]pyridine


[00647] To a solution of 7-methoxyfuro[2,3-c]pyridine (2.9 g, 19.6 mmol) in THF (20 mL) stirred under an atmosphere of argon was added n-BuLi (7.8 mL, 19.6 mmol) at -78 °C; the mixture was transferred to a -30 °C ice bath and was stirred for 2 h. The mixture was cooled to -78 °C and Mel (4.2 g, 29.4 mmol) was added. After the mixture was stirred at rt for 18 h, the reaction mixture was quenched with water (30 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over Na2S04 and concentrated in vacuo to afford the title compound (3.2 g, 100%) as a yellow solid. The material was carried forward without any further purification. LCMS (M+H)+ = 164.

Step 2: 4-bromo-7-methoxy-2-methylfuro[2,3-c]pyridine


[00648] A solution of 7-methoxy-2-methylfuro[2,3-c]pyridine (3.2 g, 19.6 mmol) in ACN (30 mL) was treated with NBS (3.5 g, 19.7 mmol). After the mixture was stirred at rt for 18 h, it was concentrated in vacuo and purified by silica gel chromatography (PE/EA = 30: 1 ~ 5: 1) to afford the title compound (3.0 g, 64%) as a yellow solid. LCMS (M+H)+ = 243.

Step 3: 4-bromo-2-methyl-6H-furo[2,3-c]pyridin-7-one


[00649] To a mixture of 4-bromo-7-methoxy-2-methylfuro[2,3-c]pyridine (3.0 g, 12.4 mmol) in DCM (30 mL) was stirred at 0 °C under an atmosphere of nitrogen was added BBr3 (15.5 g, 62.0 mmol) dropwise. The mixture was stirred at 0 °C for 3 h. The mixture was concentrated in vacuo to afford the title compound (2.50 g, 88%). The material was immediately used in the next step without any further purification. LCMS (M+H)+ = 229. Step 4: 4-bromo-2,6-dimethylfuro[2,3-c]pyridin-7-one


[00650] The title compound was prepared in a manner similar to step 2 of Example 252, by substituting 4-bromo-2-methyl-6H-furo[2,3-c]pyridin-7-one for 4-bromo-6H,7H-furo[2,3-c]pyridin-7-one. 1H NMR (CDC13, 400 MHz) δ 7.26 (s, 1 H), 6.32 (s, 1 H), 3.64 (s, 3 H), 2.49 (s, 3 H). LCMS (M+H)+ = 243.

Step 5 : N-[4-(2,4-difluorophenoxy)-3-(2,6-dimethyl-7-oxofuro[2,3-c]pyridin-4-yl)phenyl] ethanesulfonamide


[00651] A mixture of 4-bromo-2,6-dimethylfuro[2,3-c]pyridin-7-one (200 mg, 0.83 mol), N-[4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl] ethanesulfonamide (364 mg, 0.99 mmol), Pd(dppf)Cl2 (66 mg, 0.09 mmol), K3P04 (527 mg, 2.49 mmol) in dioxane/water (4 mL/1 mL) was bubbled with argon for 5 min. The mixture was heated to 70 °C for 18 h. After cooling to rt, the reaction mixture was poured into water (10 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC to afford the title compound (49 mg, 12%) as a yellow solid. 1H NMR (CDC13, 400 MHz) δ 7.35-7.33 (m, 2 H) 7.12 (m, 1 H) 6.95-6.89 (m, 2 H) 6.81 (m, 2 H) 6.43 (s, 1 H) 6.38 (s, 1 H) 3.71 (s, 3 H) 3.16 (q, J = 7.2 Hz, 2 H) 2.47 (s, 3 H) 1.43 (t, J = 7.2 Hz, 3 H). LCMS (M+H)+ = 475.

Example 270: 4-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-2,6-dimethylfuro[2,3-c]pyridin-7-one


[00652] The title compound was prepared in a manner similar to step 5 of Example 269, by substituting 2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane for N-[4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenyl]ethanesulfonamide. 1H NMR (CDC13, 400 MHz) δ 7.89 (dd, Ji = 8.8 Hz, J2 = 2.4 Hz, 1 H) 7.85 (d, J = 2.4 Hz, 1 H) 7.34 (s, 1 H) 7.09 (d, J = 8.8 Hz, 1 H) 6.24 (s, 1 H) 3.94 (m, 2 H) 3.78 (s, 3 H) 3.14 (q, J = 7.2 Hz, 2 H) 2.48 (s, 3 H) 1.32 (t, J = 7.2 Hz, 3 H) 1.18-1.16 (m, 1 H) 0.64-0.59 (m, 2 H) 0.32-0.28 (m, 2 H). LCMS (M+H)+ = 402.

Example 271: N-[4-(2,4-difluorophenoxy)-3-(5-fluoro-l-methyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide


[00653] The title compound was prepared in a manner similar to Example 122, substituting N-[3-bromo-4-(2,4-difluorophenoxy)phenyl]methanesulfonamide for N-[3-Bromo-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide. 1H NMR (400 MHz, DMSO- 6) δ ppm 2.98 -3.07 (m, 3 H) 3.52 - 3.60 (m, 3 H) 6.80 - 6.94 (m, 1 H) 7.10 (s, 1 H) 7.14 - 7.24 (m, 2 H) 7.24 - 7.28 (m, 1 H) 7.38 - 7.51 (m, 1 H) 7.57 - 7.66 (m, 1 H) 7.76 - 7.86 (m, 1 H) 9.67 - 9.76 (m, 1 H). LCMS (M+H)+ = 425.

Example 272 : 3 -chloro-5 - [2-(cyclopropylmethoxy)-5 -ethylsulfonylphenyl] - 1 -methylpyridin-2-one


[00654] The title compound was prepared in a manner similar to Example 119, substituting 3-chloro-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one for 3-Fluoro- 1 -methyl-5 -(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)pyridin-2-one and 2-bromo- 1 - (cyclopropylmethoxy)-4-ethylsulfonylbenzene for 2-bromo- 1 -(cyclopropylmethoxy)-4-methanesulfonylbenzene. LCMS (M+H)+ = 382.

Example 273: 5-[5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidin-4-yl]-l-methyl-3-propan-2-ylpyridin-2-one


[00655] The title compound was prepared in three steps. Using conditions similar to those described by Malhotra, et. al. in Organic Letters 2013, Vol. 15, No. 14, pp. 3698-3701 (supporting information, compounds 4c and 3a), 3,5-dibromo-l-methylpyridin-2-one was alkylated at the 3 -position using isopropylmagnesium bromide to give 5-bromo-l-methyl-3-propan-2-ylpyridin-2-one which was then reacted with 4,4,5, 5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane using conditions similar to those described in Example 248, step 2 to give the pinacol ester, l-methyl-3-propan-2-yl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one. This pinacol ester was then substituted for the pinacol ester of Example 149, step 4 and reacted in the same manner to obtain the title compound. LCMS (M+H)+ = 436.

Example 274: 5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-3-fluoro- 1 -methylpyridin-2-one


[00656] The title compound was prepared in a manner similar to Example 119, substituting 2-bromo- 1 -(cyclopropylmethoxy)-4-ethylsulfonylbenzene for 2-bromo- 1 - (cyclopropylmethoxy)-4-methanesulfonylbenzene. LCMS (M+H)+ = 366.

Example 275 : 3 -chloro-5 - [2-(cyclopropylmethoxy)-5 -ethylsulfonylphenyl] - 1 -methylpyridin- 2-one


[00657] The title compound was prepared in a manner similar to Example 119, substituting 3-chloro-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one for 3-Fluoro-1 -methyl-5 -(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)pyridin-2-one and N-(cyclopropylmethyl)-4-ethylsulfonyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline for 2-bromo-l-(cyclopropylmethoxy)-4-methanesulfonylbenzene. LCMS (M+H)+ = 381. Example 276: 5-[2-(2,4-difluorophenoxy)-5-(methanesulfonylmethyl)phenyl]-3-(2H3)methyl- 1 -methyl- 1 ,2-dihydro ridin-2-one


[00658] The title compound was prepared in a manner similar to Example 119, substituting 3-(2H3)methyl- 1 -methyl-5 -(tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 ,2-dihydropyridin-2-one for 3-Fluoro-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one and 2-bromo- 1 -(2,4-difluorophenoxy)-4-(methylsulfonylmethyl)benzene for 2-bromo- 1 -(cyclopropylmethoxy)-4-methanesulfonylbenzene. 1H NMR (400 MHz, DMSO-^) δ ppm 2.93 (s, 3 H) 3.49 (s, 3 H) 4.42 - 4.52 (m, 2 H) 6.81 - 6.89 (m, 1 H) 7.04 - 7.16 (m, 1 H) 7.20 - 7.29 (m, 1 H) 7.30 - 7.35 (m, 1 H) 7.43 - 7.51 (m, 2 H) 7.53 - 7.57 (m, 1 H) 7.75 - 7.82 (m, 1 H) LCMS (M+H)+ = 423.

Example 277: N-[4-(2,4-difluorophenoxy)-3-[5-(2H3)methyl-l-methyl-6-oxo-l,6-dihydropyridin-3-yl]phenyl]methanesulfonamide


[00659] The title compound was prepared in a manner similar to Example 122, substituting N-[3-bromo-4-(2,4-difluorophenoxy)phenyl]methanesulfonamide for N-[3-Bromo-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide and 3-(2H3)methyl- 1 -methyl-5 -(tetramethyl-

l,3,2-dioxaborolan-2-yl)-l,2-dihydropyridin-2-one for 3-fluoro-l-methyl-5-(4 ,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one. 1H NMR (400 MHz, DMSO- 6) δ ppm 2.98 - 3.05 (m, 3 H) 3.44 - 3.50 (m, 3 H) 6.84 - 6.92 (m, 1 H) 7.01 - 7.18 (m, 3 H) 7.21 - 7.26 (m, 1 H) 7.38 - 7.47 (m, 1 H) 7.47 - 7.51 (m, 1 H) 7.73 - 7.79 (m, 1 H) 9.61 - 9.78 (bs, 1 H). LCMS (M+H)+ = 424.

Example 278: N-[4-(2,4-difluorophenoxy)-3-[5-(2H3)methyl-l-methyl-6-oxo-l,6-dihydropyridin-3 -yl]phenyl] ethan - 1 -sulfonamide


[00660] The title compound was prepared in a manner similar to Example 122, substituting 3-(2H3)methyl- 1 -methyl-5 -(tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 ,2-dihydropyridin-2-one for 3-fluoro- 1 -methyl-5 -(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)pyridin-2-one. 1H NMR

(400 MHz, DMSO-de) δ ppm 1.19 - 1.25 (m, 3 H) 3.05 - 3.16 (m, 2 H) 3.45 - 3.49 (m, 3 H) 6.85 - 6.92 (m, 1 H) 6.99 - 7.20 (m, 4 H) 7.23 (m, 1 H) 7.38 - 7.46 (m, 1 H) 7.46 - 7.50 (m, 1 H) 7.71 - 7.79 (m, 1 H) 9.60 - 9.85 (m, 1 H). LCMS (M+H)+ = 438.

Example 279: N-[3-(5-cyclopropyl-l-methyl-6-oxopyridin-3-yl)-4-(2,4-difluorophenoxy)phenyl]methanesulfonamide


[00661] The title compound was prepared in a manner similar to Example 122, substituting 3-cyclopropyl-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one for 3-Fluoro- 1 -methyl-5-(4,4,5 ,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridin-2-one and N-[3-bromo-4-(2,4-difluorophenoxy)phenyl]methanesulfonamide for N-[3-Bromo-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide. 1H NMR (400 MHz, DMSO- 6) δ ppm 0.46 -0.54 (m, 2 H) 0.77 - 0.88 (m, 2 H) 1.93 - 2.07 (m, 1 H) 2.98 - 3.05 (m, 3 H) 3.44 - 3.51 (m, 3 H) 6.89 - 6.95 (m, 1 H) 7.00 - 7.12 (m, 3 H) 7.13 - 7.19 (m, 1 H) 7.21 - 7.25 (m, 1 H) 7.39 -7.48 (m, 1 H) 7.71 (s, 1 H) 9.56 - 9.82 (bs, 1 H). LCMS (M+H)+ = 447.

Example 280: 3-cyclopropyl-5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]- 1 -methylpyridin-2-one


[00662] The title compound was prepared in a manner similar to Example 119, substituting 3-cyclopropyl-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one for 3-Fluoro- 1 -methyl-5-(4,4,5 ,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridin-2-one and 2-bromo- 1 -(cyclopropylmethoxy)-4-ethylsulfonylbenzene for 2-bromo- 1 -(cyclopropylmethoxy)-4-methanesulfonylbenzene. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.33 - 0.41 (m, 2 H) 0.55 -0.61 (m, 2 H) 0.63 - 0.69 (m, 2 H) 0.83 - 0.91 (m, 2 H) 1.07 - 1.14 (m, 3 H) 1.19 - 1.25 (m, 1 H) 2.01 - 2.12 (m, 1 H) 3.23 - 3.30 (m, 2 H) 3.52 (s, 3 H) 3.92 - 4.00 (m, 2 H) 7.22 - 7.29 (m,

2 H) 7.70 - 7.80 (m, 3 H). LCMS (M+H)+ = 388.

Example 281: N-[4-(2,4-difluorophenoxy)-3-(l-methyl-6-oxo-5-pyrrolidin-l-ylpyridin-3-yl)phenyl]methanesulfonamide


[00663] The title compound was prepared in a manner similar to Example 122, substituting 1-methyl-3-pyrrolidin-l-yl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one for 3-Fluoro- 1 -methyl-5-(4,4,5 ,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridin-2-one and N-[3-bromo-4-(2,4-difluorophenoxy)phenyl]methanesulfonamide for N-[3-Bromo-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide. LCMS (M+H)+ = 476.

Example 282 : 5 - [2-(cyclopropylmethoxy)-5 -ethylsulfonylphenyl] - 1 -methyl-3 -pyrrolidin- 1 -ylpyridin-2-one


[00664] The title compound was prepared in a manner similar to Example 119, substituting 1-methyl-3-pyrrolidin-l-yl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one for 3- Fluoro- 1 -methyl-5-(4,4,5 ,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridin-2-one and 2-bromo-1 -(cyclopropylmethoxy)-4-ethylsulfonylbenzene for 2-bromo- 1 -(cyclopropylmethoxy)-4-methanesulfonylbenzene. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.33 - 0.40 (m, 2 H) 0.53 -0.61 (m, 2 H) 1.08 - 1.14 (m, 3 H) 1.20 - 1.29 (m, 1 H) 1.81 - 1.90 (m, 4 H) 3.23 - 3.30 (m, 2 H) 3.35 - 3.35 (m, 1 H) 3.35 - 3.40 (m, 3 H) 3.48 (s, 3 H) 3.94 - 4.03 (m, 2 H) 6.60 - 6.66 (m, 1 H) 7.21 - 7.28 (m, 1 H) 7.31 - 7.38 (m, 1 H) 7.68 - 7.79 (m, 2 H). LCMS (M+H)+ = 417. Example 283: N-[4-(2,4-difluorophenoxy)-3-(5-ethynyl-l-methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide Step 1 : 5-bromo-3-iodo-l-methylpyridin-2-one


[00665] To a solution of 5-bromo-3-iodo-lH-pyridin-2-one (12.0 g, 40.01 mmol) stirred in dry DMF (120 mL) at 0°C under an atmosphere of nitrogen was added NaH (2.4 g, 60.02 mmol, 60% in mineral oil). After the mixture was stirred at 0°C for lh, iodomethane (11.4 g, 80.03 mmol) was added dropwise. The icebath was removed, and the reaction was stirred at rt for 1 h. The mixture was poured into ice water (200 mL); the resulting precipitate was filtered, collected and dried to give the title compound (12 g, 95%>) as a light yellow solid. The material was used without any further purification. 1H NMR (CDC13, 400 MHz): δ 8.01 (d, J = 3.2 Hz, 1 H), 7.46 (d, J = 3.2 Hz, 1 H), 3.60 (s, 3 H). LCMS (M+H)+ = 315.

Step 2: 5-bromo-l-methyl-3-(2-trimethylsilylethynyl)pyridin-2-one


[00666] A mixture of 5-bromo-3-iodo-l-methylpyridin-2-one (8.0 g, 25.48 mmol), ethynyltrimethylsilane (2.7 g, 27.52 mmol), Cul (485 mg, 2.55 mmol), Pd(PPh3)2Cl2 (1.79 g, 2.55 mmol) and triethylamine (12.9 g, 127.4 mmol) in dry THF (100 mL) was heated to 60°C under an atmosphere of nitrogen for 2 h. The mixture was concentrated and the residue was purified by column chromatography on silica gel (PE: EA=5: 1) to give the title compound (6 g, 82 %) as a yellow solid. 1H NMR (CDC13, 400 MHz): δ 7.61 (d, J = 2.4 Hz, 1 H), 7.42 (d, J = 2.4 Hz, 1 H), 3.54 (s, 3 H), 0.25 (s, 9H). LCMS (M+H)+ = 285.

Step 3: l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3-(2-trimethylsilylethynyl)pyridin-2-one

[00667] A mixture of 5-bromo-l-methyl-3-(2-trimethylsilylethynyl)pyridin-2-one (9.0 g, 31.67 mmol), 4,4,5, 5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l, 3,2-dioxaborolane (20.1 g, 79.16 mmol), Pd2(dba)3 (1.8 g, 3.17 mmol), X-Phos (1.5 g, 3.17 mmol) and KOAc (18.65 g, 189.99 mmol) in anhydrous dioxane (200 mL) was stirred at 70 °C under an atmosphere of argon for 12 h. After the mixture was concentrated in vacuo, the residue was purified by column chromatography on silica gel (PE: EA = 4: 1) to give the title compound (3.5 g, 33 %) as an off-white solid. 1H NMR (CDC13, 400 MHz): δ 7.88 (d, J = 2.0 Hz, 1 H), 7.75 (d, J = 2.0 Hz, 1 H), 3.56 (s, 3 H), 1.31 (s, 12 H), 0.25 (s, 9 H). LCMS (M+H)+ = 332 and 250.

Step 4: N-[4-(2,4-difluorophenoxy)-3-[l-methyl-6-oxo-5-(2-trimethylsilylethynyl)pyridin-3-yl]phenyl] ethanesulfonamide


[00668] A mixture of l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3-(2-trimethylsilylethynyl)pyridin-2-one (200 mg, 0.6 mmol), N-[3-Bromo-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide (197 mg, 0.5 mmol), Pd(dppf)Cl2 (37 mg, 0.05 mmol) and K3P04 (267 mg, 1.26 mmol) in dioxane (6 mL) and H20 (0.6 mL) was stirred at 70 °C under an atmosphere of argon for 12 h. After the mixture was concentrated, the residue was purified by column chromatography on silica gel (PE: EA=2: 1) to give the title compound (100 mg, 38%) as a yellow solid. 1H NMR (CDC13, 400 MHz): δ 7.82 (d, J = 2.4 Hz, 1 H), 7.67 (d, J = 2.4 Hz, 1 H), 7.23 (d, J = 2.4 Hz, 1 H), 7.16-7.12 (m, 1H), 6.99-6.91 (m, 2 H), 6.87-6.83 (m, 1 H), 6.78 (m, 1 H), 6.65 (s, 1 H), 3.61 (s, 3 H), 3.14 (q, J = 7.2 Hz, 2 H), 1.42 (t, J = 7.2 Hz, 3 H), 024 (s, 9 H). LCMS (M+H)+ = 517.

Step 5 : N-[4-(2,4-difluorophenoxy)-3-(5-ethynyl- 1 -methyl-6-oxopyridin-3-yl)phenyl] ethanesulfonamide


[00669] To a mixture of N-[4-(2,4-difluorophenoxy)-3-[l-methyl-6-oxo-5-(2-trimethylsilylethynyl)pyridin-3-yl]phenyl]ethanesulfonamide (100 mg, 0.19 mmol) in EtOH (10 mL) was added K2CO3 (157 mg, 1.14 mmol). The reaction was stirred at 20 °C for 12 h and poured into H20 (30 mL) and extracted with DCM (20 mL x 3). The organic phase was washed with brine (20 mL), dried over anhydrous MgS04 and concentrated in vacuo. The residue was purified by prep-HPLC to afford the title compound (48 mg, 56%) as an off-white solid. 1H NMR (CDC13, 400 MHz): δ 7.90 (d, J = 2.4 Hz, 1 H), 7.69 (d, J = 2.4 Hz, 1 H), 7.26 (d, J = 2.8 Hz, 1 H), 7.14-7.11 (m, 1 H), 7.01-6.94 (m, 2 H), 6.89-6.86 (m, 1 H), 6.77 (d, J = 8.8 Hz, 1 H), 6.55 (s, 1 H), 3.67 (s, 3 H), 3.34 (s, 1 H), 3.14 (q, J = 7.2 Hz, 2 H), 1.42 (t, J = 7.2 Hz, 3 H). LCMS (M+H)+ = 445.

Example 284: 5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-3-ethynyl-l-methylpyridin-2-one


[00670] The title compound was prepared in a manner similar to Example 283, substituting 2-bromo- 1 -(cyclopropylmethoxy)-4-ethylsulfonylbenzene for N-[3-Bromo-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide in Step 4. 1H NMR (CDCI3, 400 MHz): δ 7.93 (d, J = 2.4 Hz, 1 H), 7.84-7.81 (m, 1 H), 7.76 (d, J = 2.4 Hz, 1H), 7.68 (d, J = 2.8 Hz, 1 H), 7.03 (d, J = 8.4 Hz, 1 H), 3.96 (d, J = 7.2 Hz, 2 H), 3.66 (s, 3 H), 3.35 (s, 1 H), 3.13 (q, J = 7.2 Hz, 2 H), 1.32-1.27 (m, 4 H), 0.71-0.67 (m, 2 H), 0.40-0.37 (m, 2 H). LCMS (M+H)+ = 372. Example 285 : 5 - [2-(cyclopropylmethoxy)-5 -methylsulfonylphenyl] -3 -ethynyl- 1 -methylpyridin-2-one


[00671] The title compound was prepared in a manner similar to Example 283, substituting 2-bromo- 1 -(cyclopropylmethoxy)-4-methylsulfonylbenzene for N-[3-Bromo-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide in Step 4. 1H NMR: (CDCI3, 400 MHz) δ: 7.92 (d, J=2.0 Hz, 1 H), 7.86 (d, J=8.8 Hz, 1 H), 7.81 (s, 1 H), 7.69 (d, J=1.6 Hz, 1 H), 7.04 (d, J=8.4 Hz, 1 H), 3.96 (d, J=6.8 Hz, 3 H), 3.65 (s, 3 H), 3.34 (s, 1 H), 3.07 (s, 3 H), 1.28-1.27 (m, 1 H), 0.70 -0.68 (m, 2 H), 0.38 -0.37 (m, 2 H). LCMS (M+H)+ = 358.

Example 286: N-[4-(2,4-difluorophenoxy)-3-(5-ethynyl- 1 -methyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide


[00672] The title compound was prepared in a manner similar to Example 283, substituting N-[3-bromo-4-(2,4-difluorophenoxy)phenyl]methanesulfonamide for N-[3-Bromo-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide in Step 4. 1H NMR (CDC13, 400 MHz): δ 7.89 (d, J = 3.2 Hz, 1 H), 7.69 (d, J = 3.2 Hz, 1 H), 7.26-7.25 (m, 1 H), 7.15-7.10 (m, 1 H), 7.03-6.94 (m, 2 H), 6.91-6.84 (m, 1 H), 6.78 (d, J = 11.6 Hz, 1H), 6.45 (s, 1 H), 3.66 (s, 3 H), 3.35 (s, 1 H), 3.04 (s, 3 H). LCMS (M+H)+ = 431.

Example 287: 5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-3-(difluoromethoxy)-l-methylpyridin-2-one Step 1 : 5-bromo-3-methoxy-l-methylpyridin-2-one


[00673] To a solution of 5 -bromo-3 -hydroxy- lH-pyridin-2-one (5.00 g, 26.31 mmol) in DMF (100 mL) stirred at 0 °C was added NaH (2.16 g, 53.95 mmol, 60% in mineral oil). After 30 min, iodomethane (9.33 g, 65.78 mmol) was added over a period of 5 min. After the mixture was stirred at rt for 12 h, it was quenched with water (20 mL) and extracted with EtOAc (100 mL X 3). The combined organic layers were washed with brine (100 mL X 3), dried over Na2S04, and concentrated in vacuo to give the title compound (5.5 g, 96%>). The material was carried forward without further purification. LCMS (M+H)+ = 219.

Step 2: 5 -bromo-3 -hydroxy- 1 -methylpyridin-2-one


[00674] To a solution of 5-bromo-3-methoxy-l-methylpyridin-2-one (5.60 g, 25.7

mmol) stirred at 0 °C in DCM (100 mL) was added BBr3 (12.87 g, 51.4 mmol). The icebath was removed and the mixture was stirred at rt for 5 h. After the mixture was cooled to 0°C, it was quenched with MeOH (5 mL), concentrated to near dryness and purified by column chromatography on silica gel to give title compound (3 g, 57%) as a white solid. 1H NMR

(CDC13, 400 MHz) δ 7.49 (s, 1 H), 6.80 (s, 1 H), 3.44 (s, 3 H). LCMS (M+H)+ = 205.

Step 3 : 5-[2-(cyclopropylmethoxy)-5-eth lsulfonylphenyl]-3-hydroxy- 1 -methylpyridin-2-one


[00675] To a mixture of 5 -bromo-3 -hydroxy- 1 -methylpyridin-2-one (1.00 g, 4.9 mmol), 2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.80 g, 4.9 mmol) in dioxane (30 mL) and H20 (5 mL) was added K P04 (3.12 g, 14.7 mmol), Pd(dppf)Cl2 (358 mg, 0.49 mmol). After purging the mixture with nitrogen, the mixture was stirred at 90 °C under microwave irridation for 1 h. After the mixture was filtered, the filtrate was concentrated to dryness. The resulting residue was purified by prep-HP LC to give the title compound (0.9 g, 51%) as a purple solid. 1H NMR (CDC13, 400 MHz) δ 7.81 (dd, Ji = 8.8 Hz, = 2.4 Hz, 1 H), 7.77 (d, J = 2.4 Hz, 1 H), 7.16-7.15 (m, 2 H), 3.95 (d, J = 6.8 Hz, 2 H), 3.70 (s, 3 H), 3.12 (q, J = 7.6 Hz, 2 H), 1.32-1.27 (m, 4 H), 0.70-0.67 (m, 2 H), 0.39-0.36 (m, 2 H). LCMS (M+H)+ = 364.

Step 4 : 5 -[2-(cyclopropylmethoxy)-5 -ethylsulfonylphenyl] -3 -(difluoromethoxy)- 1 -methylpyridin-2-one


[00676] A mixture of 5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-3-hydroxy-l-methylpyridin-2-one (50 mg, 0.14 mmol), sodium chlorodifluoroacetate (252 mg, 1.65

mmol), K2CO3 (70 mg, 0.51 mmol) in dioxane (4 mL) was stirred at 100 °C for 18 h. After the mixture was filtered, the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC to give the title compound (16 mg, 28%) as a light pink solid. 1H NMR (CDCI3, 400 MHz) δ 7.84 (m, 1 H) 7.77 (d, J = 2.4 Hz, 1 H) 7.63 (d, J = 2.4 Hz, 1 H) 7.49 (d, J = 2.4 Hz, 1 H) 7.04 (m, 1 H) 3.95 (m, 2 H) 3.69 (s, 3 H) 3.13 (m, 3 H) 1.33-1.26 (m, 4H) 0.72-0.67 (m, 2H) 0.39-0.36 (m, 2H). LCMS (M+H)+ = 414.

Example 288: 5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]- 1 -methyl-3-(2,2,2-trifluoroethoxy)pyridin-2-one


[00677] A mixture of 5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-3-hydroxy-l-methylpyridin-2-one (50 mg, 0.14 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (33 mg, 0.14 mmol), Cs2C03 (134.48 mg, 0.42 mmol) in DMF (2 mL) was stirred at 20 °C for 2 h After the mixture was filtered, the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC to give the title compound (29 mg, 47%) as an off-white solid. 1H NMR (CDC13, 400 MHz) δ 7.84 (m, 1 H), 7.77 (m, 1 H), 7.41 (m, 2 H), 7.04 (m, 1 H), 4.58 (m, 2 H), 3.95 (m, 2 H), 3.70 (s, 3 H), 3.14 (m, 2 H), 1.33-1.27 (m, 4H), 0.72-0.69 (m, 2H), 0.39-0.35 (m, 2H). LCMS (M+H)+ = 446.

Example 289: N-[3-[5-(difluoromethoxy)-l-methyl-6-oxopyridin-3-yl]-4-(2,4-difluorophenoxy)phenyl] ethanesulfonamide Step 1 : 5 -bromo-3 -(difluoromethoxy)- 1 -methylpyridin-2-one


[00678] The title compound was prepared in a manner similar to step 4 in Example 287, substituting 5-bromo-3-hydroxy-l-methylpyridin-2-one for 5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl] -3 -hydroxy- 1 -methylpyridin-2-one. LCMS (M+H) = 255.

Step 2: N-[3-[5-(difluoromethoxy)-l-methyl-6-oxopyridin-3-yl]-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide


[00679] A mixture of 5-bromo-3-(difluoromethoxy)-l-methylpyridin-2-one (50 mg, 0.20 mmol), N-[4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]ethanesulfonamide (88 mg, 0.18 mmol), Pd(dppf)Cl2 (11 mg) and K3PO4 (85 mg, 0.40 mmol) in dioxane (5 mL) and water (5 drops) was purged with nitrogen, capped, and heated to 70 °C for 8 h. After the mixture was filtered, the filtrate was concentrated in vacuo and purified by prep-HPLC to afford the title compound (13 mg, 13%) as a white solid. 1H NMR (CDCI3, 400 MHz) δ 7.53 (m, 2 H) 7.25 (m, 1 H) 7.05 (m, 1 H) 7.12 (m, 1 H) 7.02-6.97 (m, 2H) 6.97-6.95 (m, 1 H) 6.77 (m, 1 H) 6.48 (bs, 1 H) 3.67 (s, 3 H) 3.15 (q, J = 7.4 Hz, 2 H) 1.42 (t, J = 7.4 Hz, 3 H). LCMS (M+H)+ = 487.

Example 290: N-[4-(2,4-difiuorophenoxy)-3-[l-methyl-6-oxo-5-(2,2,2-trifluoroethoxy)pyridin-3-yl]phenyl]ethanesulfonamide Step 1 : 5-bromo-l-methyl-3-(2,2,2-trifluoroethoxy)pyridin-2-one


[00680] The title compound was prepared in a manner similar to Example 288, substituting 5-bromo-3 -hydroxy- 1 -methylpyridin-2-one for 5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl] -3 -hydroxy- 1 -methylpyridin-2-one. LCMS (M+H)+ = 287.

Step 2: N-[4-(2,4-difluorophenoxy)-3-[l-methyl-6-oxo-5-(2,2,2-trifluoroethoxy)pyridin-3-yl]phenyl] ethanesulfonamide


[00681] A mixture of 5-bromo-l-methyl-3-(2,2,2-trifluoroethoxy)pyridin-2-one (50 mg, 0.18 mmol), N-[4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl] ethanesulfonamide (79 mg, 0.18 mmol), Pd(dppf)Cl2 (11 mg) and K3PO4 (76 mg, 0.36 mmol) in dioxane (5 mL) and water (5 drops) was purged with nitrogen, capped, and

heated to 70 °C for 8 h. After the mixture was filtered, the filtrate was concentrated in vacuo and purified by prep-HPLC to afford the title compound (11 mg, 11%) as a white solid. 1H NMR (CDCls, 400 MHz) δ 7.39 (m, 1 H) 7.32 (m, 1 H) 7.25 (d, J = 2.8 Hz, 1 H) 7.12 (dd, Ji = 2.8 Hz, h = 8.8 Hz, 1 H) 6.99-6.93 (m, 2 H) 6.88-6.83 (m, 1 H) 6.79 (d, J = 8.8 Hz, 1 H) 6.47 (b.s., 1 H), 4.56 (m, 2 H), 3.65 (s, 3 H) 3.15 (q, J = 7.2 Hz, 2 H) 1.42 (t, J = 7.2 Hz, 3H). LCMS (M+H)+ = 519.

Example 291: 3-(difluoromethoxy)-5-[2-(2,4-difluorophenoxy)-5-(ethylsulfonylmethyl)phenyl] - 1 -m thylpyridin-2-one


[00682] A mixture of 5-bromo-3-(difluoromethoxy)-l-methylpyridin-2-one (50 mg, 0.20 mmol), 2-[2-(2,4-difluorophenoxy)-5-(ethylsulfonylmethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (79 mg, 0.18 mmol), Pd(dppf)Cl2 (11 mg) and K3PO4 (76 mg, 0.36 mmol) in dioxane (5 mL) and water (5 drops) was purged with nitrogen, capped, and heated to 70 °C for 8 h. After the mixture was filtered, the filtrate was concentrated in vacuo and purified by prep-HPLC to afford the title compound (21 mg, 22%) as a white solid. 1H NMR (CDCI3, 400 MHz) δ 7.62 (d, J = 2.0 Hz, 1 H) 7.54 (d, J = 2.0 Hz, 1 H) 7.40 (d, J = 2.0 Hz, 1 H) 7.29 (d, J = 2.0 Hz, 1 H) 7.09-6.96 (m , 3 H) 6.93-6.88 (m , 1H) 6.78 (m, 1 H) 4.21 (s, 2 H) 3.70 (s, 3 H) 2.97 (q, J = 7.6 Hz, 2 H) 1.43 (t, J = 7.6 Hz, 3 H). LCMS (M+H)+ = 486. Example 292 : 5 - [2-(2,4-difluorophenoxy)-5 -(ethylsulfonylmethyl)phenyl] - 1 -methyl-3 -(2,2,2-trifluoroethoxy)pyridin-2-on


[00683] A mixture of 5-bromo-l-methyl-3-(2,2,2-trifluoroethoxy)pyridin-2-one (50 mg, 0.18 mmol), 2-[2-(2,4-difluorophenoxy)-5-(ethylsulfonylmethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (88 mg, 0.20 mmol), Pd(dppf)Cl2 (11 mg) and K3PO4 (85 mg, 0.40 mmol) in dioxane (5 mL) and water (5 drops) was purged with nitrogen, capped, and heated to 70°C for 8 h. After the mixture was filtered, the filtrate was concentrated in vacuo and purified by prep-HPLC to afford the title compound (21 mg, 22%) as a white solid. 1H NMR

(CDCI3, 400 MHz) δ 7.41 (m, 2 H) 7.35 (m, 1 H) 7.30 (m, 1 H) 7.07-6.96 (m, 2H) 6.92-6.87 (m, 1 H) 6.80 (m, 1 H), 4.51 (m, 2 H) 4.21 (s, 2 H) 3.69 (s, 3 H) 2.97 (m, 2 H) 1.44 (m, 3 H). LCMS (M+H)+ = 518.

Example 293 : 5 - [2-(cyclopropylmethoxy)-5 -methylsulfonylphenyl] - 1 -methyl-3 -( 1 -methylpyrazol-4-yl)oxypyridin-2-one Step 1 : 5 -bromo-1 -methyl-3 -(1 -methylpyrazol-4-yl)oxypyridin-2 -one


[00684] A 0.3M solution of 5-bromo-3-chloro-l-methylpyridin-2-one (124 mg, 0.56 mmol) in DMF was treated with CS2CO3 (546 mg, 1.7 mmol). The mixture was sonicated for 30 sec before heating to 140 °C by microwave irridation (normal) for 150 min. The resulting suspension was diluted with water and extracted with EtOAc (15 mL X 3). The combined organic layers were washed with brine, dried over Na2S04, and concentrated in vacuo. The resulting solid was purified by silica gel column chromatography using a gradient of EtOAc (5 to 60%) in hexanes to afford the title compound (33 mg, 19%) as a tan solid. LCMS (M+H)+ = 285.

Step 2 : 5 -[2-(cyclopropylmethoxy)-5 -methylsulfonylphenyl] - 1 -methyl-3 -( 1 -methylpyrazol-4-yl)oxypyridin-2 -one


[00685] A mixture of 5 -bromo-1 -methyl-3 -(l-methylpyrazol-4-yl)oxypyridin-2-one (30 mg, 0.11 mmol), 2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (44 mg, 0.16 mmol), Pd(dppf)Cl2 (8 mg) and K3PO4 (57 mg, 0.26 mmol) in dioxane (1.5 mL) and water (200 uL) was purged with nitrogen, capped, and heated to 75 °C for 12 h. After the mixture was filtered through a short bed of celite, the filtrate was concentrated in vacuo and purified by prep-HPLC to afford the title compound (35 mg, 78%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.12 - 0.36 (m, 2 H) 0.46 - 0.61 (m, 2 H) 0.99 - 1.17 (m, 1 H) 3.14 - 3.23 (m, 3 H) 3.55 - 3.60 (m, 3 H) 3.75 - 3.83 (m, 3 H) 3.88 - 3.96 (m, 2 H) 7.18 - 7.32 (m, 2 H) 7.32 - 7.40 (m, 1 H) 7.68 - 7.91 (m, 4 H). LCMS (M+H)+ = 430.

Example 294: 5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]- 1 -methyl-3-(l -propan-2-ylpyrazol-4-yl)oxypyridin-2-one Ste 1 : l-propan-2-ylpyrazol-4-ol


[00686] A 0.4 M solution of l-propan-2-yl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (472 mg, 2 mmol) in THF stirred at 0 °C was treated with a 2.5 M aqueous solution of NaOH (1.6 mL, 4 mmol) and 30% Η202 (aq) (453 μΐ, 4 mmol). The icebath was removed and the mixture was allowed to stir at rt for lh. After the pH was adjusted to 3 by the addition of aqueous 2N H2S04, the mixture was extracted with DCM. The combined organic layers were washed with brine, dried over MgS04, filtered, and concentrated in vacuo. The resulting solid was purified by silica gel column chromatography using a gradient of EtOAc (5 to 90%)) in hexanes to afford the title compound (240 mg, 95%>) as a white solid. LCMS (M+H)+ = 127.

Step 2 : 5 -[2-(cyclopropylmethoxy)-5 -methylsulfonylphenyl] -3 -iodo- 1 -methylpyridin-2-one


[00687] A 0.2 M solution of the title compound (264 mg, 0.8 mmol) from Example 98 in DMF stirred at 0 °C was treated with three equal portions of N-iodosuccinimide (187 mg, 84 mmol). After 15 min, the icebath was removed and the mixture was stirred at rt for 2 h. The reaction mixture was treated with 10% sodium thiosulfate (aq) (5 mL) and extracted with EtOAc (20 mL X 3). The combined organic layers were washed with water and brine, dried over MgS04, filtered, and concentrated in vacuo to afford a crude solid. The resulting solid was purified by silica gel column chromatography using a gradient of EtOAc (0 to 100%) in DCM to afford the title compound (333 mg, 91%) as a white solid. LCMS (M+H)+ = 460. Step 3 : 5 -[2-(cyclopropylmethoxy)-5 -methylsulfonylphenyl] - 1 -methyl-3 -( 1 -propan-2-ylpyrazol-4-yl)oxypyridin-2-one

[00688] A mixture of 5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-3-iodo-l-methylpyridin-2-one (91 mg, 0.2 mmol), l-propan-2-ylpyrazol-4-ol (45 mg, 0.36 mmol), Cul (4 mg, 10%), 2,2,6,6-tetramethyl-3,5-heptanedione (8 uL, 0.04 mmol) and K3P04 (85 mg, 0.4 mmol) in DMSO (1 mL) was purged with nitrogen for 10 min, capped, and heated to 110 °C for 13 h. After the mixture was filtered through a short bed of celite, the filtrate was concentrated in vacuo and purified by prep-HPLC to afford the title compound (36 mg, 40%>) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.18 - 0.26 (m, 2 H) 0.44 - 0.53 (m, 2 H) 1.03 - 1.10 (m, 1 H) 1.37 - 1.43 (m, 6 H) 3.17 - 3.21 (m, 3 H) 3.54 - 3.61 (m, 3 H) 3.87 -3.93 (m, 2 H) 4.33 - 4.46 (m, 1 H) 7.20 - 7.25 (m, 1 H) 7.25 - 7.28 (m, 1 H) 7.33 - 7.36 (m, 1 H) 7.70 - 7.74 (m, 1 H) 7.76 - 7.85 (m, 4 H). LCMS (M+H)+ = 458.

Example 295: 5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]- 1 -methyl-3-phenoxypyridin-2-one


[00689] The title compound was prepared in a manner similar to Step 3 of Example 294, substituting phenol for l-propan-2-ylpyrazol-4-ol. 1H NMR (400 MHz, DMSO- 6) δ ppm 0.23 - 0.30 (m, 2 H) 0.41 - 0.50 (m, 2 H) 1.05 - 1.16 (m, 1 H) 3.17 - 3.22 (m, 3 H) 3.54 - 3.61 (m, 3 H) 3.88 - 3.97 (m, 2 H) 6.95 - 7.01 (m, 2 H) 7.04 - 7.11 (m, 1 H) 7.21 - 7.27 (m, 1 H) 7.30 - 7.37 (m, 2 H) 7.49 - 7.54 (m, 1 H) 7.77 - 7.83 (m, 1 H) 7.83 - 7.92 (m, 2 H). LCMS (M+H)+ = 426

Example 296: N-[4-(l-butyl-5-methyl-6-oxopyridin-3-yl)-5-(2,4-difluorophenoxy)pyrimidin-2-yl]methanesulfonamide


[00690] The title compound was prepared in four steps in a similar manner to Example 248 except that 1-iodobutane was substituted for bromomethylcyclopropane in step 1. 1H NMR (CDC13, 400 MHz) δ 8.95 (s, 1 H), 8.40 (s, 1 H), 8.17 (s, 1 H), 8.09 (s, 1 H), 7.04-6.95 (m, 2 H), 6.90-6.88 (m, 1 H), 4.01 (t, J= 6.8 Hz, 2 H), 3.45 (s, 3 H), 2.22 (s, 3 H), 1.75-1.72 (m, 2 H), 1.39-1.33 (m, 2 H), 0.93 (t, J= 7.2 Hz, 3 H). LCMS: 465.1 (M+H)+

Example 297: N-[4-(l-butyl-5-methyl-6-oxopyridin-3-yl)-5-(2,4-difluorophenoxy)pyrimidin-2-yl]ethanesulfonamide


[00691] The title compound was prepared in four steps in a similar manner to Example 248 except that 1-iodobutane was substituted for bromomethylcyclopropane in step 1 and

EtS02NH2 was substituted for MeS02NH2 in step 4. 1H NMR (CDC13, 400 MHz) δ 8.83 (s, 1 H), 8.38 (s, 1 H), 8.16 (s, 1 H), 8.08 (s, 1 H), 7.04-6.95 (m, 2 H), 6.94-6.88 (m, 1 H), 4.00 (t, J= 7.2 Hz, 2 H), 3.64 (q, J= 7.2 Hz, 2 H), 2.21 (s, 3 H), 1.75-1.72 (m, 2 H), 1.45 (t, J= 7.2 Hz, 3 H), 1.37-1.33 (m, 2 H), 0.93 (t, J= 7.2 Hz, 3 H). LCMS: 479.1 (M+H)+

Example 298: N-[4-[l-(cyclobutylmethyl)-5-methyl-6-oxopyridin-3-yl]-5-(2,4-difluorophenoxy)pyrimidin-2-yl]methanesulfonamide


[00692] The title compound was prepared in four steps in a similar manner to Example 248 except that l-(bromomethyl)cyclobutane was substituted for bromomethylcyclopropane in step 1. 1H NMR (CDC13, 400 MHz) δ 8.96 (s, 1 H), 8.39 (s, 1 H), 8.14 (s, 1 H), 8.09 (s, 1 H), 7.02-6.96 (m, 2 H), 6.91-6.89 (m, 1 H), 4.03 (d, J= 7.2 Hz, 2 H), 3.44 (s, 3 H), 2.82-2.74 (m, 1 H), 2.21 (s, 3 H), 2.04-2.03 (m, 2 H), 1.89-1.85 (m, 2 H), 1.79-1.74 (m, 2 H). LCMS: 477.1 (M+H)+

Example 299: N-[4-[l-(cyclobutylmethyl)-5-methyl-6-oxopyridin-3-yl]-5-(2,4-difluorophenoxy)pyrimidin-2-yl]ethanesulfonamide


[00693] The title compound was prepared in four steps in a similar manner to Example 248 except that -(bromomethyl)cyclobutane was substituted for bromomethylcyclopropane in step

1 and EtS02NH2 was substituted for MeS02NH2 in step 4. 1H NMR (CDC13, 400 MHz) δ 8.38 (d, J= 2.4 Hz, 1 H), 8.13 (s, 1 H), 8.08 (s, 1 H), 7.04-6.98 (m, 2 H), 6.97-6.88 (m, 1 H),

4.02 (d, J= 7.2 Hz, 2 H), 3.63 (q, J= 7.2 Hz, 2 H), 2.80-2.76 (m, 1 H), 2.20 (s, 3 H), 2.04- 2.03 (m, 2 H), 1.89-1.76 (m, 4 H), 1.44 (t, J= 7.2 Hz, 3 H). LCMS: 491.1 (M+H)+

Example 300: N- [5 -ethyl-4-(2 -methyl- 1-oxoisoquino lin-4-yl)pyrimidin-2-yl] ethanesulfonamide

Step 1 :


[00694] 4-chloro-5-ethyl-2-methylsulfonylpyrimidine was prepared in a manner similar to Example 152, steps 2-4 except that ethyl butanoate was substituted for ethyl 2-(cyclopropylmethoxy)acetate in step 2. Thus prepared, 4-chloro-5-ethyl-2-methylsulfonylpyrimidine and the title compound of Example 89, step 1 were reacted in a similar manner as Example 152, step 5. Silica gel chromatography (PE: EA=1 : 1-0: 1) gave the title compound (120 mg, yield: 77%) as a yellow solid. 1H NMR (CDC13, 400 MHz) δ 8.90 (s, 1 H), 8.55 (d, J = 8 Hz, 1 H), 7.64-7.55 (m, 2 H), 7.28 (s, 1 H), 7.07 (d, J = 8 Hz, 1 H), 3.69 (s, 3H), 3.39 (s, 3 H), 2.67 (q, J = 8 Hz, 2 H), 1.17(t, J = 8 Hz, 3 H). LCMS: 344.0 (M+l) +

Step 2 : N- [5 -ethyl-4-(2 -methyl- 1 -oxoisoquinolin-4-yl)pyrimidin-2-yl] ethanesulfonamide


[00695] The title compound of step 1 was treated with EtS02NH2 in a manner similar to Example 155 to give the title compound. 1H NMR (CDC13, 400 MHz) δ 8.59 (s, 1 H ), 8.53 (d, J = 8 Hz, 1 H), 7.63 (t, J = 8 Hz, 1 H), 7.55 (t, J = 8 Hz, 1 H), 7.23 (d, J = 12 Hz, 1 H), 7.17 (s, 1 H), 3.68 (s, 3 H), 3.64 (t, J = 8 Hz, 2 H), 2.52 (q, J = 8 Hz, 2 H), 1.44 (t, J = 8 Hz, 3 H), 1.09 (t, J= 8 Hz, 3 H).

LCMS: 373.0 (M+l)+

Examples 301, 303-305 in Table 16 were prepared in a similar multi-step manner as

Example 300, step 1 wherein ethyl pentanoate was converted to 4-chloro-2-methylsulfonyl-5-

propylpyrimidine and ethyl hexanoate was converted to 5-butyl-4-chloro-2- methylsulfonylpyrimidine. Thus prepared, both the 4-chloro-2-methylsulfonyl-5- propylpyrimidine and the 5-butyl-4-chloro-2-methylsulfonylpyrimidine were each coupled to the title compound of Example 89, step 1 or l ,3-dimethyl-5-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)-2(lH)-pyridinone in a manner similar to Example 152, step 5 to give the title compounds. Example 302 was prepared from 4-chloro-5-ethyl-2- methylsulfonylpyrimidine (described in Example 300, step 1) and l ,3-dimethyl-5-(4,4,5,5- tetramethyl-l ,3,2-dioxaborolan-2-yl)-2(lH)-pyridinone which were also reacted in a manner similar to Example 152, step 5.

Example 302 in Table 16 was prepared from 4-chloro-5-ethyl-2-methylsulfonylpyrimidine (described in Example 300, step 1) and l ,3-dimethyl-5-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)-2(lH)-pyridinone which were also reacted in a manner similar to Example 152, step 5.

Table 16


304 ,N. .S02Me 4-(5-butyl-2- 372 methylsulfonyl

pyrimidin-4- yl)-2- 0 methylisoquin

olin-l-one

305 ,Ν. .S02Me 5-(5-butyl-2- ί Υ (CDCI3, 400 MHz) δ 8.70 (s, 1 336 methylsulfonyl

H), 7.84 (s, 1 H), 7.55 (s, 1 H), pyrimidin-4- yi)-i ,3- 3.67 (s, 3 H), 3.37 (s, 3 H),

Ο dimethylpyridi

2.84 (t, J = 8.0 Hz, 2 H), 2.24

n-2-one

(s, 3 H), 1.68 (m, 2 H,

overlapped with water peak),

1.41(m, 2 H), 0.96(t, J = 7.2

Hz, 3 H).

Examples 306-310 in Table 17 were prepared in a similar manner as Example 300, step 2 wherein Examples 301-305 were each treated with EtS02NH2 to give the title compound.

Table 17

-N. .NHS02Et N-[4-(l,5-dimethyl- (CDC13, 400 MHz) δ 337 302 ί Y 6-oxopyridin-3-yl)- 8.47 (s, 1H), 7.69 (s, 1

5 -ethylpyrimidin-2- yl] ethanesulfonamid H), 7.55 (s, 1 H), 3.67

0 e

(m, 5 H), 2.75 (q, J = 8

Hz, 2 H), 2.24 (s, 3 H),

1.45 (t, J = 8 Hz, 3 H),

1.26 (t, J = 8 Hz, 3 H)

-N. .NHS02Et N-[4-(l,5-dimethyl- (CDCI3, 400 MHz) δ 351 303

6-oxopyridin-3-yl)- 8.42 (s, 1 H), 7.67 (d, J

5 -propylpyrimidin-2- yl] ethanesulfonamid = 2 Hz, 1 H), 7.53 (s, 1 0 e

H), 3.69 (t, J = 8 Hz, 2

H), 3.65 (d, J = 8 Hz, 3

H), 2.66 (q, J = 8 Hz, 2

H), 2.23 (s, 3 H), 1.62- 1.60 (m, 2 H), 1.45 (t,

J=8 Hz, 3 H), 0.98 (t, J

= 8 Hz, 3 H)

-N. .NHS02Et (CDCI3, 400 MHz) δ 401 304

N-[5-butyl-4-(2- 8.57 (s, 1 H), 8.53 (d, J

methyl-1- = 8 Hz, 1 H), 7.65-7.61

O oxoisoquinolin-4- (m, 1 H), 7.58-7.53 (m,

yl)pyrimidin-2- 1 H), 7.24 (d, J = 8 Hz,

yl] ethanesulfonamid

1 H), 7.17 (s, 1 H), 3.68

e

(s, 3 H), 3.67-3.61 (m,

2 H), 2.48 (t , J = 8 Hz,

2 H), 1.46-1.39 (m, 5

H), 1.23-1.16 (m, 2 H),

0.76 (t, J =7.2 Hz, 3 H)

methylisoquinolin- 1 -one


[00696] The title compound of Example 152, step 5 was purified by preparative HPLC to give a cream colored powder. 1H NMR (CDCI3, 400 MHz) 58.53 (s, 2 H), 7.67-7.63 (m, 2 H), 7.57-7.52 (m, 2 H), 4.06 (d, J = 6.8 Hz, 1 H), 3.71 (s, 3 H), 3.37 (s, 3 H), 1.17 (m, 1 H), 0.61 (m, 2 H), 0.30 (m, 2 H). LCMS: 386.1 (M+l)+

Example 312: 5-(2-ethyl-5-methylsulfonylphenyl)-l-methylpyridin-2-one

Step 1 : l-ethyl-4-methylsulfonyl-2 -nitrobenzene


bromo-4-methylsulfonyl-2-nitrobenzene (2 g, 7.0 mmol), ethylboronic acid (0.57 g, 7.7 mmol), K2CO3 (3.0 g, 21mmol), Pd(dppf)Cl2 (0.29 g, 0.35mmol) in 1 ,4-dioxane/water (4: 1) (24 mL) were heated at 85 °C under N2 overnight. Silica gel chromatography (PE:EA =6: 1) gave the title compound (0.66 g, 40%) as a brown solid.

Step 2: 2-ethyl-5-methylsulfonylaniline


[00697] The title compound of step 1 (0.6 g, 2.6 mmol) and palladium on carbon (0.18 g) in CH3OH (20 mL) was hydrogenated at 1 atm. for 6 h. Silica gel chromatography (PE:EA =6: 1) gave the title compound (0.49 g, 94%) as a brown liquid.

Step 3: l-ethyl-2-iodo-4-methylsulfonylbenzene


[00698] To the title compound of step 2 (155 mg, 0.8 mmol) in 5M HC1 (3mL) and H20 (4 mL), cooled to 0 °C, was added NaN02 (66 mg, 0.96 mmol). After stirring 0 °C for 30 min, KI (1.33 g, 8 mmol) in water (2 mL) was added and the mixture was warmed to rt & stirred lh. Silica gel chromatography (PE:EA =3: 1) gave the title compound (213 mg, 86%) as a brown solid.

Step 4: 5-(2-ethyl-5-methylsulfonylphen -l-methylpyridin-2-one


[00699] The title compound of step 3 (62 mg, 0.2 mmol), l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one (57 mg, 0.24 mmol), K2C03 (82 mg, 0.6 mmol), Pd(dppf)Cl2 (6.2 mg) in 1 ,4-dioxane/water (4: 1) (5 mL) were heated at 85 °C under N2 overnight. Silica gel chromatography (PE:EA =1 : 1) gave the title compound (56.6 mg, 97%) as a brown oil. 1H NMR (300 MHz, CDC13): δ 1.66 (3H, t, J= 6.0 Hz ), 2.63-2.71 (2H, m), 3.05 (3H, s), 3.60 (3H, s), 6.64 (1H, d, J= 9.0 Hz), 7.28-7.33 (2H, m), 7.48 (1H, d, J= 9.0 Hz), 7.70 (1H, s), 7.82-7.85 (lH,m). LCMS: 292 (M+l)+

Example 313: 1 -methyl-5 -(5 -methyl lfonyl-2-propylphenyl)pyridin-2-one


[00700] The title compound was prepared in four steps in a similar manner to Example 312, steps 1-4 except that propylboronic acid was substituted for ethylboronic acid in step 1. 1H

NMR (CDC13, 400 MHz): δ 7.91 (d, J= 6.8 Hz, 1H), 7.77 (d, J= 15.2 Hz, 2H), 7.62-7.58

(m, 2H), 6.66 (d, J= 8.4 Hz, 1H), 3.67 (s, 3H), 3.16 (s, 3H), 2.74-2.78 (m, 2H), 1.63-1.58 (m, 2H), 0.93-0.90 (m, 3H). ). LCMS: 306 (M+l)+

Example 314: 2-methyl-4-(5 -methylsulfonyl-2-propylphenyl)isoquinolin- 1 -one


[00701] The title compound was prepared in four steps in a similar manner to Example 312, steps 1-4 except that propylboronic acid was substituted for ethylboronic acid in step 1 and the title compound of Example 89, step 1 was substituted for l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one in step 4. 1H NMR (CD30D, 400 MHz): δ 8.67 (d, J= 8.0 Hz, 1H), 8.20 (dd, Ji = 1.6 Hz, J2 = 2.4 Hz, 1H), 7.84 (s, 1H), 7.71-7.67 (m, 2H) , 7.63-7.59 (m, 1H), 7.42 (s, 1H), 7.08 (d, J= 8.8 Hz, 1H), 3.71 (s, 3H), 3.18 (m, 3H), 2.64-2.57 (m, 1H), 2.51-2.44 (m, 1H), 1.59-1.50 (m, 2H), 0.82-0.78 (m, 3H). ). LCMS: 356 (M+l)+

Example 315: 5 - [2-(2-cyclopropylethyl)-5 -methylsulfonylphenyl] - 1 -methylpyridin-2-one Step 1 : 2-(2-cyclopropylethynyl)-5-methylsulfonyl aniline


[00702] bromo-4-methylsulfonyl-2-nitrobenzene (1.5 g, 5.36 mmol), ethynylcyclopropane (0.7 g, 10.72 mmol), K2C03 (1.5 g, 10.72 mmol) in CH3CN (30 ml), Pd(ACN)2Cl2 (55.5 mg, 0.21 mmol) and X-phos (128 mg, 0.27 mmol) under N2 were heated at 45°C for 3h. EA extractive work up and preparative TLC (PE: EtOAc = 5: 1) gave the title compound (1.2 g). Step 2: 2-(2-cyclopropylethyl)-5-meth lsulfonyl aniline


[00703] The title compound of step 1 (1.2 g) was hydrogenated in MeOH (45 mL) in a manner similar to Example 312, step 2. Preparative HPLC gave the title compound (422 mg, 41%). 1H NMR (CDC13, 400 MHz): δ 7.19-7.13 (m, 3H), 2.95 (s, 3H), 2.60-2.56 (m, 2H), 1.50-1.44 (m, 2H) 0.68-0.65 (m, 1H), 0.43-0.38 (m, 2H), 0.03-0.01 (m, 2H).

Step 3: l-(2-cyclopropylethyl)-2-iodo-4-methylsulfonylbenzene

[00704] The title compound of step 2 (442 mg, 1.85 mmol) in 5M HC1 (10 mL) was treated with NaN02 (167 mg, 2.41 mmol) followed by KI (3.07 g, 18.50 mmol) in H20 ( 8 ml) in a manner similar to Example 312, step 3. EA extractive work up & silica gel chromatography (PE: EA=10: 1) gave the title compound (600 mg, 93%).1H NMR (CDC13, 400 MHz): δ 8.27 (d, J= 1.6 Hz, 1H), 7.74 (dd, Ji = 1.6 Hz, J2 = 6.4 Hz, 1H), 7.32 (d, J= 7.6 Hz, 1H), 2.98 (s, 3H), 2.86-2.82 (m, 2H), 1.47-1.41 (m, 2H), 0.69-0.64 (m, 1H), 1.42-0.37 (m, 2H), 0.04-0.01 (m, 2H).

Step 4 : 5 -[2-(2-cyclopropylethyl)-5 -m thylsulfonylphenyl] - 1 -methylpyridin-2-one


[00705] The title compound of step 3 (120 mg, 0.34 mmol), l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one (89 mg, 0.37 mmol), Na2C03 (72 mg,0.68 mmol) and Pd(dppf)Cl2 (15 mg) in DMF/H20 (6 ml/1.5 ml) under N2 were heated atl00°C for lh. EA extractive work up and preparative TLC (PE: EtOAc = 0: 1) gave the title compound (62 mg, 55%). 1H NMR (CD30D, 400 MHz): δ 7.92 (dd, Ji = 2.4 Hz, J2 = 5.6 Hz, 1H), 7.81 (d, J= 2 Hz, 1H), 7.78 (d, J= 2.4 Hz, 1H), 7.65-7.61 (m, 2H), 6.69 (m, J= 9.2 Hz, 1H), 3.69 (s, 3H), 3.17 (s, 3H), 2.89-2.86 (m, 2H), 1.51-1.45 (m, 2H), 0.68-0.65 (m, 1H), 0.45-0.40 (m, 2H), 0.04-0.00 (m, 2H). LCMS: 332 (M+l)+

Example 316: 4-(2-ethyl-5-methylsulf nylphenyl)-2-methylisoquinolin-l-one


[00706] The the title compound of Example 312, step 3 was reacted with the title compound of Example 89, step 1 in a manner similar to Example 312, step 4 to give the title compound. 1H NMR (400 MHz, CDC13): 5 1.10 (3H, t, J = 8.0 Hz ), 2.51-2.56 (2H, m), 3.10 (3H, s), 3.67 (3H, s), 6.97-7.02 (2H, m), 7 '.52-7 '.59 (3H, m), 7.80 (1H, s), 7.97 (1H, d, J= 8.0 Hz ), 8.54 (1H, d, J= 8.0 Hz). LCMS: 342 (M+l)+

Example 317: 5 -(2-butyl-5 -methylsulfonylphenyl)- 1 -methylpyridin-2-one


[00707] The title compound was prepared in four steps in a similar manner to Example 312, steps 1-4 except that butylboronic acid was substituted for ethylboronic acid in step 1. 1H NMR (400 MHz, MeOH-d4): δ 0.89 (3H, t, J= 8.0 Hz ), 1.28-1.35 (2H, m), 1.54-1.58 (2H, m), 2.73-2.77 (2H, m), 3.16 (3H, s), 3.67 (3H, s), 6.67 (1H, d, J= 4.0 Hz), 7.58-7.62 (2H, m), 7.78 (2H, d, J= 12.0 Hz), 7.89-7.92 (1H, m). LCMS: 320 (M+l)+

Example 318: 4-(2-butyl-5 -methyls lfonylphenyl)-2-methylisoquinolin- 1 -one


[00708] The title compound was prepared in four steps in a similar manner to Example 312, steps 1-4 except that butylboronic acid was substituted for ethylboronic acid in step 1 and the title compound of Example 89, step 1 was substituted for l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one in step 4. 1H NMR (300 MHz, MeOH-d4): δ 0.73 (3H, t, J= 7.5 Hz ), 1.14-1.21 (2H, m), 1.43-1.51 (2H, m), 2.45-2.64 (2H, m), 3.17 (3H, s), 3.70 (3H, s), 7.07 (1H, d, J= 9.0 Hz), 7.41 (1H, s ), 7.57-7.70 (3H, m), 7.82 (1H, d, J= 3.0 Hz), 7.98-8.01 (1H, m), 8.44-8.47 (1H, m ). LCMS: 370 (M+l)+

Example 319: 4-[2-(2-cyclopropylethyl)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one

[00709] The title compound of Example 315, step 3 was reacted with the title compound of Example 89, step 1 in a manner similar to Example 315, step 4 to give the title compound. 1H NMR (CD30D, 400 MHz): δ 8.67 (d, J= 8.0 Hz, 1H), 8.21 (dd, Jl = 2.0 Hz, J2 = 6.0 Hz, 1H), 8.03 (d, J= 2.0 Hz, 1H), 7.92-7.86 (m, 2H), 7.82-7.79 (m, 1H), 7.61 (s, 1H), 7.28 (d, J = 8.0 Hz, 1H), 3.91 (s, 3H), 3.38 (s, 3H), 2.94-2.89 (m, 1H), 2.83-2.77 (m, 1H), 1.64-1.55 (m, 2H), 0.75-0.71 (m, 1H), 0.51-0.47 (m, 2H), 0.01-0.00 (m, 2H). LCMS: 382 (M+l)+

Example 320: N-[6-(cyclopropylmethoxy)-5 -(2 -methyl- 1 -oxoisoquinolin-4-yl)pyridin-3-yl] ethanesulfonamide


[00710] A mixture of N-[5-bromo-6-(cyclopropylmethoxy)pyridin-3-yl]ethanesulfonamide (60 mg, 0.21 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one (77 mg, 0.23 mmol), Pd2(dba)3 (7 mg), XPhos (7 mg), and K3P04 (111 mg, 0.51 mmol) in dioxane (1.2 mL) and water (140 uL) was purged with nitrogen, capped, and heated to 70 °C for 2 h. After the mixture was filtered through a short bed of celite, the filtrate was concentrated in vacuo and purified by prep-HPLC to afford the title compound (45 mg, 52%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.09 - 0.15 (m, 2 H) 0.29 - 0.40 (m, 2 H) 0.97 - 1.08 (m, 1 H) 1.20 - 1.28 (m, 3 H) 3.07 - 3.16 (m, 2 H) 3.56 (s, 3 H) 4.02 - 4.18 (m, 2 H) 7.17 - 7.22 (m, 1 H) 7.52 (s, 3 H) 7.62 - 7.69 (m, 1 H) 8.06 - 8.11 (m, 1 H) 8.27 - 8.33 (m, 1 H) 9.47 - 10.31 (m, 1 H). LCMS (M+H)+ = 414.

Example 321 : 4-[2-(cyclopropylmethoxy)-5-methylsulfonylpyridin-3-yl]-2-methylisoquinolin-l-one Step 1 : 3-bromo-2-chloro-5-methylsulfonylpyridine


[00711] A 0.5 M solution of 5-bromo-6-chloropyridine-3-sulfonyl chloride (1.5 g, 5.2 mmol) in THF was added dropwise to a mixture of NaHC03 (521 mg) and sodium sulfite (847 mg) stirred at rt in water (15 mL). The reaction mixture was heated to 70 °C for 2h. After cooling to rt, the reaction mixture was treated with iodomethane (1.5 mL, 23 mmol) and then heated to 50 °C for for 12 h. The reaction mixture was extracted with EtOAc (20 ml X 3); the combined organic layers were washed with water, brine, dried over MgS04, filtered, and

concentrated in vacuo. The resulting solid was purified by silica gel column chromatography (20% EtOAc in hexanes) to afford the title compound (952 mg, 68%). LCMS (M+H)+ = 271. Step 2: 3-bromo-2-(cyclopropylmeth xy)-5-methylsulfonylpyridine


[00712] A solution of cyclopropylmethanol (146 uL, 1.8 mmol) stirred in DMF (3 mL) at 0°C was treated with NaH (75 mg, 1.9 mmol, 60% in mineral oil). After stirring at 0 °C for 30 min, the reaction mixture was treated with a solution of 3-bromo-2-chloro-5-methylsulfonylpyridine (400 mg, 1.5 mmol) in DMF (3 mL) by drop wise addition. After the ice bath was removed, the mixture was stirred at rt for 14 h. The reaction mixture was treated with water and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using a gradient of EtOAc (5 to 85%) in hexanes to give the title compound (298 mg, 65%). LCMS (M+H)+ = 307.

Step 3: 4-[2-(cyclopropylmethoxy)- -methylsulfonylpyridin-3-yl]-2-methylisoquinolin-l-one


[00713] A mixture of 3-bromo-2-(cyclopropylmethoxy)-5-methylsulfonylpyridine (67 mg, 0.22 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one (60 mg, 0.21 mmol), Pd2(dba)3 (6 mg), XPhos (7 mg), and K3P04 (111 mg, 0.51 mmol) in dioxane (1.2 mL) and water (140 uL) was purged with nitrogen, capped, and heated to 70 °C for 2 h. After the mixture was filtered through a short bed of celite, the filtrate was concentrated in vacuo and purified by prep-HPLC to afford the title compound (58 mg, 73%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.12 - 0.26 (m, 2 H) 0.28 - 0.47 (m, 2 H) 1.02 - 1.15 (m, 1 H) 3.30 - 3.32 (m, 3 H) 3.54 - 3.62 (m, 3 H) 4.02 - 4.41 (m, 2 H) 7.17 -7.27 (m, 1 H) 7.52 - 7.59 (m, 1 H) 7.60 - 7.64 (m, 1 H) 7.64 - 7.71 (m, 1 H) 8.16 - 8.22 (m, 1 H) 8.26 - 8.35 (m, 1 H) 8.70 - 8.79 (m, 1 H). LCMS (M+H)+ = 385.

Example 322: 4-[2-(cyclopropylmethoxy)-5-ethylsulfonylpyridin-3-yl]-2-methylisoquinolin- 1-one


[00714] The title compound was prepared in a manner similar to Example 321, substituting iodoethane for iodomethane in Step 1. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.09 - 0.15 (m, 2 H) 0.31 - 0.40 (m, 2 H) 0.98 - 1.07 (m, 1 H) 1.20 - 1.28 (m, 3 H) 3.07 - 3.17 (m, 2 H) 3.54 -3.58 (m, 3 H) 3.99 - 4.16 (m, 2 H) 7.16 - 7.23 (m, 1 H) 7.50 - 7.59 (m, 3 H) 7.63 - 7.70 (m, 1 H) 8.06 - 8.11 (m, 1 H) 8.27 - 8.32 (m, 1 H) 9.40 - 10.08 (m, 1 H). LCMS (M+H)+ = 399. Example 323: 5-[3-[(4-methoxyphenyl)methoxy]-5-methylsulfonylphenyl]-l ,3-dimethylpyridin-2-one


[00715] A mixture of l-bromo-3-[(4-methoxyphenyl)methoxy]-5-methylsulfonylbenzene (450 mg, 1.2 mmol), l,3-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one (300 mg, 1.2 mmol), Pd(dppf)Ci2 (88 mg) and K3PO4 (654 mg, 3 mmol) in dioxane (8 mL) and water (800 uL) was purged with nitrogen for 7 min, capped, and heated to 75 °C for 1 h. After the mixture was filtered through a short bed of celite, the filtrate was concentrated in vacuo and purified by silica gel column chromatography using a gradient of EtOAc (5 to 100%) in DCM to afford the title compound (416 mg, 83%) as a tan solid. 1H NMR (400 MHz, DMSO-de) δ ppm 2.05 - 2.14 (s, 3 H) 3.25 - 3.28 (s, 3 H) 3.49 - 3.57 (s, 3 H) 3.74 -3.81 (s, 3 H) 5.12 - 5.22 (s, 2 H) 6.93 - 7.03 (m, 2 H) 7.34 - 7.47 (m, 3 H) 7.52 - 7.59 (m, 1 H) 7.64 - 7.72 (m, 1 H) 7.82 - 7.90 (m, 1 H) 8.14 - 8.22 (m, 1 H). LCMS (M+H)+ = 414. Example 324: 1 ,3-dimethyl-5-(3-methylsulfonyl-5-phenylmethoxyphenyl)pyridin-2-one Step 1 : 5-(3-hydroxy-5-methylsulfon lphenyl)-l,3-dimethylpyridin-2-one


[00716] A solution of 5-[3-[(4-methoxyphenyl)methoxy]-5-methylsulfonylphenyl]-l,3-dimethylpyridin-2-one (410 mg, 1 mmol) in AcOH (10 mL) was heated to 100 °C for 8 h. After cooling to rt, the reaction mixture was evaporated to dryness in vacuo. The resulting residue was diluted with water and extracted with EtOAc (50 ml X 3); the combined organic layers were washed with brine, dried over MgS04, filtered, and concentrated in vacuo. The resulting solid was suspensed in ethyl ether, sonicated for 3 min, and filtered. The filter cake was collected to afford the title compound (290 mg, 68%) as a gray solid. LCMS (M+H)+ = 294.

Step 2 : 1 ,3 -dimethyl-5 -(3 -methylsulfonyl-5 -phenylmethoxyphenyl)pyridin-2-one


[00717] A capped mixture of 5-(3-hydroxy-5-methylsulfonylphenyl)-l,3-dimethylpyridin-2-one (25 mg, 0.085 mmol), benzyl bromide (20 mg, 0.12 mmol), and Na2C03 (18 mg, 0.17 mmol) in DMF (600 uL) was heated to 80 °C for 90 min. The mixture was filtered and the filter cake was washed with ACN (500 uL), the filtrate was purified by prep-HPLC to afford the title compound (8 mg, 25%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.08 -2.13 (m, 3 H) 3.26 - 3.28 (m, 3 H) 3.51 - 3.57 (m, 3 H) 5.22 - 5.34 (m, 2 H) 7.33 - 7.47 (m, 4 H) 7.48 - 7.53 (m, 2 H) 7.54 - 7.60 (m, 1 H) 7.67 - 7.71 (m, 1 H) 7.83 - 7.88 (m, 1 H) 8.17 -8.22 (m, 1 H). LCMS (M+H)+ = 384.

For Examples 325-340 in Table 18, the title compound of Step 1 in Example 324 was O-alkylated with the appropriate alkyl halide in a similar manner to Step 2 of Example 324. For Examples 332-340, Cs2C03 is substituted for Na2C03.

Table 18



one

yridin-2-one

Example 341: l,3-dimethyl-5- -methylsulfonyl-5-[(lR)-l-phenylethoxy]phenyl]pyridin-2-


[00718] A solution of (lS)-l-phenylethan-l-ol (14 mg, 0.11 mmol) in THF (1 mL) stirred at rt under an atmosphere of nitrogen was treated with triphenylphosphine (38 mg, 0.15 mmol) and 5-(3-hydroxy-5-methylsulfonylphenyl)-l,3-dimethylpyridin-2-one (33 mg, 0.11 mmol). After 30 min, the reaction mixture was treated with DIAD (29 mg, 0.15 mmol). The nitrogen inlet was removed and the mixture was stirred (closed system) for 18 h. After the reaction mixture was diluted with EtOAc (10 ml), it was washed with water, saturated sodium bicarbonate solution (aq), dried over Na2S04, filtered, and concentrated in vacuo. The crude residue was diluted with ACN (1 mL) and was purified by prep-HP LC to afford the title compound (21 mg, 48%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.61 (d. J=6.4, 3 H) 2.08 (s, 3 H) 3.20 (s, 3 H) 3.52 (s, 3 H) 5.70 - 5.80 (q. J=6.4, 1 H) 7.23 - 7.31 (m, 2 H) 7.35 - 7.41 (m, 2 H) 7.44 - 7.51 (m, 3 H) 7.56 - 7.63 (m, 1 H) 7.73 - 7.80 (m, 1 H) 8.08 - 8.15 (m, 1 H). LCMS (M+H)+ = 398.

Example 342: N-[3-(2,4-difluorophenoxy)-5-(l ,5-dimethyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide Step 1 : l-(3-bromo-5-nitrophenoxy)-2,4-difluorobenzene


[00719] A mixture of 2,4-difluorophenol (286 mg, 2.2 mmol) and l-bromo-3-fluoro-5-nitrobenzene (440 mg, 2 mmol) in DMF (4.5 mL) was treated with K2CO3 (304 mg, 2.2 mmol). The mixture was heated to 100 °C by microwave irridation (normal) for 5h. The resulting suspension was diluted with water and extracted with EtOAc (15 mL X 3). The combined organic layers were washed with IN NaOH (aq) (15 mL), water (15 mL), brine, dried over MgS04, and concentrated in vacuo. The crude solid was purified by silica gel column chromatography using a gradient of EtOAc (5 to 25%) in hexanes to afford the title compound (200 mg, 30%) as a yellow solid. LCMS (M+H)+ = 339.

Step 2: 3-bromo-5-(2,4-difluorophenoxy)aniline


[00720] A mixture of l-(3-bromo-5-nitrophenoxy)-2,4-difluorobenzene (54 mg, 0.16 mmol), ammonium chloride (18 mg, 0.32 mmol), and iron powder (45 mg, 0.80 mmol) suspended in THF (300 uL), water (100 uL) and ethanol (300 uL) was heated to 100 °C using microwave irradiation (normal) for 3 h. The crude reaction mixture was filtered through a short plug of celite; the celite plug was washed with MeOH (~ 5 mL). The resulting filtrate was concentrated in vacuo. The resulting residue was diluted with EtOAc (50 ml) and washed with saturated bicarbonate solution (aq), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude solid was purified by silica gel column chromatography using a gradient of EtOAc (5 to 20%>) in hexanes to afford the title compound (48 mg, 100%) as a yellow solid. LCMS (M+H)+ = 301.

Step 3 : N-[3-bromo-5-(2,4-difluorophenoxy)phenyl]ethanesulfonamide


[00721] Ethylsulfonyl chloride (15 uL, 0.16 mmol) was added dropwise to a stirred solution of 3-bromo-5-(2,4-difluorophenoxy)aniline (48 mg, 0.16 mmol) and pyridine (40 uL, 0.48 mmol) in DCM (320 uL) at 0 °C under nitrogen. After the mixture was allowed to warm to rt and stir for 12 h, it was treated with IN HC1 (1 mL) and extracted with DCM (3 X 5 mL); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo. The crude solid was purified by silica gel column chromatography using a gradient of EtOAc (5 to 60%) in hexanes to afford the title compound (60 mg, 95%) as a tan solid. LCMS (M+H)+ = 393.

Step 4: N-[3-(2,4-difluorophenoxy)-5-(l ,5-dimethyl-6-oxopyridin-3-yl)phenyl] ethanesulfonamide


[00722] A mixture of N-[3-bromo-5-(2,4-difluorophenoxy)phenyl]ethanesulfonamide (70 mg, 0.17 mmol), l,3-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one (44 mg, 0.18 mmol), Pd(dppf)Cl2 (12 mg) and K3P04 (92 mg, 0.42 mmol) in dioxane (1 mL) and water (133 uL) was purged with nitrogen, capped, and heated to 75 °C for 1 h. After the mixture was filtered through a short bed of celite, the filtrate was concentrated in vacuo and purified by silica gel column chromatography using a gradient of MeOH (0 to 10%) in DCM to afford the title compound (69 mg, 94%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.13 - 1.22 (m, 3 H) 2.07 (s, 3 H) 3.08 - 3.20 (m, 2 H) 3.50 (s, 3 H) 6.65 -6.70 (m, 1 H) 6.92 - 6.96 (m, 1 H) 7.05 - 7.10 (m, 1 H) 7.12 - 7.19 (m, 1 H) 7.28 - 7.37 (m, 1 H) 7.47 - 7.55 (m, 1 H) 7.56 - 7.59 (m, 1 H) 7.87 - 7.95 (m, 1 H) 9.76 - 9.94 (m, 1 H). LCMS (M+H)+ = 435.

Example 343 : 4- [3 -[(4-methoxyphenyl)methoxy] -5 -methylsulfonylphenyl] -2-methylisoquinolin- 1 -one


[00723] A mixture of l-bromo-3-[(4-methoxyphenyl)methoxy]-5-methylsulfonylbenzene (103 mg, 0.28 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-1-one (79 mg, 0.28 mmol), Pd(dppf)Cl2 (20 mg) and K3P04 (153 mg, 0.7 mmol) in dioxane (1.9 mL) and water (100 uL) was purged with nitrogen for 10 min, capped, and heated to 75 °C for 15 h. After the mixture was filtered through a short bed of celite, the filtrate was concentrated in vacuo and purified by silica gel column chromatography using a gradient of EtOAc (5 to 100%) in DCM to afford the title compound (100 mg, 80%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.30 (s, 3 H) 3.58 (s, 3 H) 3.77 (s, 3 H) 5.14 - 5.28 (m, 2 H) 6.88 - 7.04 (m, 2 H) 7.32 - 7.80 (m, 9 H) 8.29 -8.43 (m, 1 H). LCMS (M+H)+ = 450.

Example 344: 2-methyl-4-(3-methylsulfonyl-5-phenylmethoxyphenyl)isoquinolin- 1 -one Step 1 : 4-(3-hydroxy-5-methylsulfonylphenyl)-2-methylisoquinolin-l-one


[00724] The title compound was prepared in a manner similar to Example 324, substituting 4-[3 - [(4-methoxyphenyl)methoxy] -5 -methylsulfonylphenyl] -2-methylisoquinolin- 1 -one for 5 -[3-[(4-methoxyphenyl)methoxy]-5-methylsulfonylphenyl]- 1 ,3-dimethylpyridin-2-one in Step l . LCMS (M+H)+ = 330.

Step 2 : 2-methyl-4-(3 -methylsulfonyl-5 -phenylmethoxyphenyl)isoquinolin- 1 -one


[00725] A capped mixture of 4-(3-hydroxy-5-methylsulfonylphenyl)-2-methylisoquinolin-l-one (25 mg, 0.076 mmol), benzyl bromide (20 mg, 0.12 mmol), and CS2CO3 (50 mg, 0.15 mmol) in DMF (600 uL) was heated to 80 °C for 3 h. The mixture was filtered and the filter cake was washed with ACN (500 uL), the filtrate was purified by prep-HPLC to afford the title compound (12 mg, 38%) as a tan solid. LCMS (M+H)+ = 420.

Example 345: 4- [3 -(cyclopropylmethoxy)-5 -methylsulfonylphenyl] -2-methylisoquinolin- 1-one


[00726] The title compound was prepared in a manner similar to Example 344, substituting cyclopropylmethyl bromide for benzyl bromide in Step 2. LCMS (M+H)+ = 384.

Example 346: N-[4-(2,4-difluorophenoxy)-6-(l ,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-2-yl] ethanesulfonamide

Step 1 : 5-(2,6-dichloropyrimidin-4-yl)-l 3-dimethylpyridin-2-one


[00727] A mixture of 2,4,6-trichloropyrimidine (275 mg, 1.5 mmol), l,3-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one (246 mg, 1 mmol), Pd(OAc)2 (20 mg), triphenylphosphine (16 mg), and 2M Na2C03 (1 mL, 2 mmol) in THF (6.7 mL) was purged with nitrogen for 5 min, capped, and heated to 80 °C for 3 h. After the mixture was filtered through a short bed of celite, the filtrate was concentrated in vacuo and purified by silica gel column chromatography using a gradient (0 to 100%) EtOAc in DCM to afford the title compound (150 mg, 55%) as a white solid. LCMS (M+H)+ = 271.

Step 2: 5-[2-chloro-6-(2,4-difluorophenoxy)pyrimidin-4-yl]-l,3-dimethylpyridin-2-one and 5-[6-chloro-2-(2,4-difluoro henoxy)pyrimidin-4-yl]- -dimethylpyridin-2-one


[00728] A mixture of 2,4-difluorophenol (25 mg, 0.19 mmol) and 5-(2,6-dichloropyrimidin-4-yl)-l,3-dimethylpyridin-2-one (50 mg, 0.19 mmol) in DMF (0.5 mL) and THF (0.5 mL) was treated with K2C03 (304 mg, 0.23 mmol). The mixture was stirred at rt for 3 h. The resulting suspension was diluted with water and extracted with EtOAc (10 mL X 3). The combined organic layers were washed with IN NaOH (aq) (5 mL), water (15 mL), brine, dried over MgS04, and concentrated in vacuo. The crude solid was purified by silica gel column chromatography using a gradient of EtOAc (0 to 50%) in DCM to afford an unseparated mixture of regioisomeric title compounds (66 mg, 96%> combined) as a white solid. LCMS (M+H)+ = 364 for both regioisomers.

Step 3 : N-[4-(2,4-difluorophenoxy)-6-(l ,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-2-yl] ethanesulfonamide


[00729] A solution of ethanesulfonamide (80 mg, 0.73 mmol) in DMF (2 mL) was treated with NaH (27 mg, 0.68 mmol, 60 % by weight). After 15 min, the mixture was treated with a DMF (1 mL) solution of title compounds obtained from Step 2. The reaction mixture was stirred at 50 °C for 14 h. The resulting suspension was diluted with water and extracted with EtOAc (10 mL X 3). The combined organic layers were washed with brine, dried over Na2S04, and concentrated in vacuo. Preparative HPLC isolated both regioisomers as

Examples 346 and 347. The title compound (6 mg, 8%) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08 (t, J=7.1 Hz, 3 H) 2.07 (s, 3 H) 3.11 (q, J=7.1 Hz, 2 H) 3.54 (s, 3 H) 6.81 (s, 1 H) 7.17 (m, 1 H) 7.47 (s, 2 H) 7.79 (s, 1 H) 8.37 (s, 1 H) 11.37 (bs, 1 H). LCMS (M+H)+ = 437.

Example 347: N-[2-(2,4-difluorophenoxy)-6-(l ,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-4-yl] ethanesulfonamide


[00730] The preparative HPLC of Example 346, step 3 also isolated this regioisomer. The title compound (2 mg, 3%) was obtained as a white solid. 1H NMR (400 MHz, DMSO- 6) δ ppm 1.06 - 1.13 (m, 3 H) 2.08 - 2.12 (m, 3 H) 3.1 1 - 3.23 (m, 2 H) 3.54 - 3.57 (m, 3 H) 7.14 -7.28 (m, 2 H) 7.45 -7.54 (m, 2 H) 8.04 - 8.09 (m, 1 H) 8.52 - 8.57 (m, 1 H) 10.92 - 11.26 (m, 1 H), both as a white solids. LCMS (M+H)+ = 437.

Example 348 : 4- [3 -[ [2-(difluoromethoxy)phenyl]methoxy] -5 -methylsulfonylphenyl] -6-methylfuro[2,3-c]pyridin-7-one Step 1 : 4-[3-[(4-methoxyphenyl)methoxy]-5-methylsulfonylphenyl]-6-methylfuro[2,3-c]pyridin-7-one


[00731] A mixture of l-bromo-3-[(4-methoxyphenyl)methoxy]-5-methylsulfonylbenzene (470 mg, 1.27 mmol), 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)furo[2,3-c]pyridin-7-one (316 mg, 1.15 mmol), Pd(dppf)Cl2 (84 mg) and K3PO4 (610 mg, 2.9 mmol) in dioxane (7 mL) and water (700 uL) was purged with nitrogen for 7 min, capped, and heated to 70 °C for 2 h and rt for 48 h. After the mixture was diluted with EtOAc (5 mL) and water (5 mL), it was filtered through a short bed of celite. After the filtrate was separated, the aqueous layer was washed with EtOAc (25 mL X 3). The combined organic layers were washed with water and brine, dried over MgS04, and concentrated in vacuo. The crude solid was purified by silica gel column chromatography using a gradient of EtOAc (0 to 100%) in DCM to afford the title compound (375 mg, 74%) as a white solid. LCMS (M+H)+ = 440. Step 2 : 4-(3 -hydroxy-5 -methylsulfonylphenyl)-6-methylfuro [2,3 -c]pyridin-7-one


[00732] A solution of 4-[3-[(4-methoxyphenyl)methoxy]-5-methylsulfonylphenyl]-6-methylfuro[2,3-c]pyridin-7-one (370 mg, 0.84 mmol) in AcOH (6 mL) was heated to 100 °C for 12 h. After cooling to rt, the reaction mixture was evaporated to dryness in vacuo. The resulting residue was diluted with water and extracted with EtOAc (20 ml X 3); the combined organic layers were washed with brine, dried over MgS04, filtered, and concentrated in vacuo. The resulting solid was suspensed in a 1 : 1 mixture of EtOAc and hexanes, sonicated for 1 min, and filtered. The filter cake was collected to afford the title compound (210 mg, 78%) as a gray solid. LCMS (M+H)+ = 320.

Step 3 : 4-[3-[[2-(difluoromethoxy)phenyl]methoxy]-5-methylsulfonylphenyl]-6-methylfuro[2,3-c]pyridin-7-one


[00733] A capped mixture of 4-(3-hydroxy-5-methylsulfonylphenyl)-6-methylfuro[2,3-c]pyridin-7-one

(25 mg, 0.08 mmol), l-(bromomethyl)-2-(difluoromethoxy)benzene (28 mg, 0.12 mmol), and Cs2C03 (50 mg, 0.15 mmol) in DMF (900 uL) was heated to 80°C for 3 h. The mixture was filtered and the filter cake was washed with ACN (500 uL), the filtrate was purified by prep-HPLC to afford the title compound (22 mg, 58%) as a white solid. LCMS (M+H)+ = 476.

Example 349: 6-methyl-4-(3-methylsulfonyl-5-phenylmethoxyphenyl)furo[2,3-c]pyridin-7-one


[00734] The title compound was prepared in a manner similar to Example 348, substituting benzyl bromide for l-(bromomethyl)-2-(difluoromethoxy)benzene in Step 2. LCMS (M+H)

410.

Example 350 : 4- [3 -(cyclopropylmethoxy)-5 -methylsulfonylphenyl] -6-methylfuro [2,3 -c]pyridin-7-one


[00735] The title compound was prepared in a manner similar to Example 348, substituting bromomethylcyclopropane for l-(bromomethyl)-2-(difluoromethoxy)benzene in Step 3. LCMS (M+H)+ = 374.

Examples 351-356 in Table 19 were prepared in a similar multi-step manner as Example 300, step 1 wherein either ethyl pentanoate was converted to 4-chloro-2-methylsulfonyl-5- propylpyrimidine or ethyl hexanoate was converted to 5-butyl-4-chloro-2- methylsulfonylpyrimidine which were then each reacted with a) 3-methoxy-l-methyl-5- (4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyridin-2-one (described in Example 146, step 3), b) the title compound of Example 98, step 1 , or c) 3-chloro-l-methyl-5-(4,4,5,5- tetramethyl-l ,3,2-dioxaborolan-2-yl)pyridin-2-one (described in Example 134) in a manner similar to Example 152, step 5 to give the title compound.

Table 19


wherein Examples 351-356 were each treated with EtS02NH2 to give the title compound. Example 363 in Table 20 was prepared in a similar manner as Example 152, step 6 wherein Example 305 was treated with MeS02NH2 to give the title compound.

Table 20


Example 364: 4-[2-(cyclopropylmethoxy)-5-propan-2-ylsulfonylphi

methylisoquinolin- 1 -one

Step 1 : 5-bromo-7H-[l,2,4]triazolo[4 3-a]pyrazin-8-one


[00736] The title compound was prepared in three steps from 3-bromo-4-fluorobenzenethiol in a manner similar to Example 79, steps 1-3 except that 2-iodopropane was substituted for ethyl iodide in step 1 and the alkoxide of cyclopropylmethanol was substituted for sodium methoxide in step 3. 1H NMR (CDC13, 400 MHz) δ 8.05 (d, J = 2.4 Hz, 1 H), 7.76 (dd, Ji = 2.4 Hz, = 8.4, 1 H), 6.97 (d, J = 8.4 Hz, 1 H), 3.18 (m, 1 H), 1.29 (d, J = 6.8 Hz, 6 H), 0.86 (m, 1 H), 0.71 (d, J = 6.8 Hz, 2 H), 0.45 (d, J = 5.6 Hz, 2 H). LCMS: (M+H+): 333.0; 335.0 Step 2: 4-[2-(cyclopropylmethoxy)-5- ropan-2-ylsulfonylphenyl]-2-methylisoquinolin-l-one


[00737] The title compound of step 1 was coupled to the title compound of Example 89, step

1 in a manner similar Example 89, step 2 to give the title compound as a white solid. 1H NMR (CDC13, 400 MHz) δ 8.52 (d, J = 7.2 Hz, 1 H), 7.91 (dd, Ji = 6.4 Hz, J2 = 8.4, 1 H), 7.80 (d, J = 2.4 Hz, 1 H), 7.51-7.57 (m, 2 H), 7.15 (d, J = 8.0 Hz, 1 H), 7.09 (t, J = 8.4 Hz, 1 H), 3.89 (s,

2 H), 3.67 (s, 3 H), 3.18-3.25(m, 1 H), 1.33 (d, J = 6.8 Hz, 6 H), 0.99-1.02 (m, 1 H), 0.414 (m, 2 H), 0.11 (s, 2 H). LCMS: (M+H+): 412

Example 365: 8-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-methyl-4H-pyrido[4,3-b] [ 1 ,4]oxazine-3 ,5-dione

Step 1 : 6-methyl-4H-pyrido[4,3-b][l,4 oxazine-3,5-dione


[00738] To a solution of the title compound of Example 237, step 3 (1.6 g, 9.01 mmol, 1.00 Eq) in CH2C12 (150 mL) at 0°C under N2 is added chloroacetyl chloride (0.75 mL, 9 mmol) dropwise. Pyridine (2.2 mL, 37 mmol) is then added, and the mixture was stirred for 5 h at

room temperature. Saturated aqueous KHSO4 (100 mL) is added and the aqueous layer was extracted a total of three times with CH2CI2. The combined organic layers were dried over Na2SC"4, filtered, and then acetone (200 mL) followed by cesium carbonate (14.6 g, 45 mmol) were added directly to the filtrate (250 mL). The mixture was then heated at 50°C for 2 h. The volume was reduced and water was added. Extractive work up with 3 : 1 CH2CI2 : isopropanol followed by trituration with 1 :2 EA/PE gave the title compound (400 mg, yield: 24.67%) as a yellow solid. 1H NMR: (CDC13, 400 MHz) δ: 8.17-8.14 (br, 1H), 7.01 (d, J=7.2 Hz, 1 H), 6.07 (d, J=7.2 Hz, 1 H), 4.69 (s, 1 H), 3.59(s, 3H). LCMS: 181.0 (M +H)+

Step 2: 8-bromo-6-methyl-4H-pyrido[4,3-b][l,4]oxazine-3,5-dione


[00739] At room temperature, to the title compound of step 1 (90 mg, 0.5 mmol) in anhydrous CH3CN (1 mL) was added NBS (89 mg, 0.5 mmol). After stiring about 2h, additional NBS (75 mg, 0.4 mmol) was added and the reaction was complete within 20 min. EA extractive work up and silica gel chromatography gave the title compound (51 mg, 0.39 mmol) in 39% yield.

Step 3 : 8-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-methyl-4H-pyrido[4,3-b] [ 1 ,4]oxazine-3 ,5-dione


[00740] The title compound of step 2 was reacted with 2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane in a manner similar to Example 224, step 5. Silica gel chromatography (40-100% EA in hexane over 8 min) gave the title compound. 1H NMR: (DMSO-d6, 400 MHz) δ ppm 0.27-0.33 (m, 2 H) 0.51-0.57 (m, 2 H) 1.11 (t, J=7.33 Hz, 3 H) 1.14 - 1.22 (m, 1H, partially obscured) 3.22 - 3.28 (m, 2 H) 3.51 (s, 3 H) 3.96 (d, J=7.07 Hz, 2 H) 4.54 (s, 2 H) 7.27 (d, J=8.84 Hz, 1 H) 7.52 (s, 1 H) 7.67 (d, J=2.02 Hz, 1 H) 7.79 - 7.92 (m, 1 H) 10.10 (s, 1 H)LCMS: 419 (M +H)+

Example 366: 8-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-methyl-3,4,4a,8a-tetrahydro-2H-pyrido[4,3-b] [ 1 ,4]oxazin-5-one


[00741] The title compound of Example 365, step 3 in anhydrous THF was treated with excess 1M LAH in THF at room temperature. After about 30 min, ice, water, methanol and 1M HC1 were added followed by saturated aqueous NaHC03 and EA extractive work up. Silica gel chromatography (EA, followed by 5% methanol in EA) gave the title compound as a clear glass. 1H NMR: (DMSO-d6, 400 MHz) δ ppm 0.32 (br. s., 2 H) 0.54 (br. s., 2 H) 1.03 - 1.30 (m, 4 H) 3.45 (br. s., 3 H) 3.94 (br. s., 2 H) 4.09 (br. s., 2 H) 5.03 (br. s., 1 H) 7.05 (br. s., 1 H) 7.22 (br. s., 1 H) 7.62 (br. s., 1 H) 7.78 (br. s., 1 H). 1H NMR: (DMSO-d6/DCl, 400 MHz) δ ppm 0.29 (br. s., 2 H) 0.55 (br. s., 2 H) 1.10 (br. s., 4 H) 3.25 (br. s., 2 H) 3.45 (br. s., 2 H) 3.51 (br. s., 3 H) 3.93 (br. s., 2 H) 4.43 (br. s., 2 H) 7.27 (br. s., 1 H) 7.69 (br. s., 1 H) 7.84 (br. s., 2 H). LCMS: 405 (M +H)+

Example 367: N-[4-(2,4-difluorophenoxy)-3-(7-methyl-8-oxoimidazo[l,5-a]pyrazin-5-yl)phenyl]methanesulfonamide


[00742] To a solution of the title compound from Example 129, Step 2 (140 mg, 0.38 mmol) in THF (20 ml) was added pyridine (152 mg, 1.90 mmol). Then methanesulfonyl chloride (48 mg, 0.46 mmol) was added to the solution at 0 °C. The solution was allowed to warm up to room temperature and heated to reflux for overnight. The reaction mixture was concentrated under reduced pressure to yield the crude product that was purified by prep-HPLC to give the title compound (75.26 mg, 44%) as a yellow solid. 1H NMR (CDC13, 400 MHz) δ 8.60 (s, 1 H), 8.15 (s, 1 H), 7.50 (d, J = 2.8 Hz, 1 H), 7.30 (dd, J = 8.8, 2.4 Hz, 1 H), 7.18 (td, J = 8.8, 5.3 Hz, 1 H), 7.00-6.88 (m, 2 H), 6.83 (s, 1 H), 6.78 (d, J = 8.8 Hz, 1 ), 3.60 (s, 3 H), 3.03 (s, 3 H). LCMS: 447.0 (M+l) +.

Example 368: 5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-7-methylimidazo[ 1 ,5-a]pyrazin-8-one


[00743] To a microwave vial containing 5-bromo-7-methylimidazo[l,5-a]pyrazin-8-one (150 mg, 0.66 mmol), 2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (290 mg, 0.80 mmol) and NaHC03 (1 mL, 2M) in dioxane (3 mL) was added Pd(dppf)Cl2 (80 mg, 0.10 mmol). The mixture was purge with N2 for 2 min and sealed. The reaction was irradiated in microwave at 100 °C for 2 h. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried with Na2S04, filtered and concentrated in vacuum. The residue was purified by column chromatography (PE: EA = 5 : 1 to 1 : 1) to afford the title compound (55.3 mg, 22%) as a light yellow solid. 1H NMR (CDC13, 400 MHz) δ 8.03 (dd, Ji = 8.4 Hz, = 2.0 Hz, 2 H), 7.94 (d, J = 2.0 Hz, 1 H), 7.56 (s, 1 H), 7.15 (d, J = 8.8 Hz, 1 H), 6.49 (s, 1 H), 3.96 (d, J = 6.4 Hz, 2 H), 3.54 (s, 3 H), 3.16 (q, J = 7.6 Hz, 1 H), 1.33 (t, J = 7.6 Hz, 1 H), 1.08 (s, 1 H), 0.54 (d, J = 7.2 Hz, 2 H), 0.54 (d, J = 4.4 Hz, 2 H). LCMS: 388.1

+

(M+l)

Example 369 : 5 - [2-(2,4-difluorophenoxy)-5 -(ethylsulfonylmethyl)phenyl] -7-methylimidazo[ 1 ,5-a]pyrazin-8-one

Step 1 : 2-[2-(2,4-difluorophenoxy)-5-(ethylsulfonylmethyl)phenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane


[00744] A mixture of 2-bromo-l-(2,4-difluorophenoxy)-4-(ethylsulfonylmethyl)benzene (250 mg, 0.64 mmol), bis(pinacolato)diboron (255 mg, 0.96 mmol), KOAc (189 mg, 1.92 mmol) and Pd(dppf)Cl2 (44 mg, 0.06 mmol) in dioxane (5 mL) was stirred at 70 °C for 18 hrs under

N2. The mixture was concentrated and the residue was purified by column chromatography to give the title compound (150 mg, 53.4 %) as yellow solid. LCMS: 439.2 (M+l) +

Step 2: 5-[2-(2,4-difluorophenoxy)-5-(ethylsulfonylmethyl)phenyl]-7-methylimidazo[l,5-a]pyrazin-8-one


[00745] A mixture of the title compound from Step 1 (150 mg, 0.34 mmol), the title compound from Example 129 Step 1 (87 mg, 0.38 mmol), K3PO4 (217 mg, 1.02 mmol) and Pd(dppf)Cl2 (22 mg, 0.03 mmol) in dioxane (5 mL) and H20 (1 mL) was stirred at 70°C for 18 hrs under N2. The resulting mixture was filtered and concentrated. The residue was purified by prep-HPLC to give the title compound (70.0 mg, 45 %) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.83 (s, 1 H), 8.33 (s, 1 H), 7.64 (d, J = 2.0 Hz, 1H), 7.57 (dd, Ji = 8.8 Hz, h = 2.0 Hz, 1 H), 7.53-7.41 (m, 2 H), 7.37 (s, 1 H), 7.20 -7.12 (m, 1 H), 6.93 (d, J = 8.8 Hz, 1 H), 4.54 (s, 2 H), 3.45 (s, 3 H), 3.09 (q, J = 7.6 Hz, 2 H), 1.23 (t, J = 7.6 Hz, 3 H). LCMS: 460.1 (M+l) +

Example 370: 7-methyl-5-[5-(methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]imidazo[ 1 ,5-a]pyrazin-8-one

Step 1 : 4,4,5,5-tetramethyl-2-[5-(methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]-1 ,3,2-dioxaborolane


[00746] The title compound was prepared in a manner similar to Example 369 Step 1, by substituting 2-bromo-4-(methylsulfonylmethyl)-l-(2,2,2-trifluoroethoxy)benzene for 2-bromo-l-(2,4-difluorophenoxy)-4-(ethylsulfonylmethyl)benzene. LCMS: 395.2 (M+l) + Step 2 : 7-methyl-5 - [5 -(methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]imidazo [1,5-a]pyrazin-8-one


[00747] The title compound was prepared in a manner similar to Example 369 Step 2, by substituting 4,4,5,5-tetramethyl-2-[5-(methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]-l,3,2 dioxaborolane for 2-[2-(2,4-difluorophenoxy)-5-(ethylsulfonylmethyl)phenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane. 1H NMR (DMSO-d6,

400 MHz) δ 8.64 (s, 1 H), 8.32 (s, 1 H), 7.64 (dd, Ji = 8.8 Hz, J2 = 2.0 Hz, 1H), 7.56 (s, 1 H), 7.39 (d, J = 8.8 Hz, 1 H), 7.25 (s, 1 H), 4.86 (q, J = 8.8 Hz, 2 H), 4.53 (s, 2 H), 3.44 (s, 3 H), 2.94 (s, 3 H). LCMS: 416.1 (M+l) +

Example 371 : 5-[5-(ethylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]-7-methylimidazo[ 1 ,5-a]pyrazin-8-one

Step 1 : 2-[5-(ethylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane


[00748] The title compound was prepared in a manner similar to Example 369 Step 1, by substituting 2-bromo-4-(ethylsulfonylmethyl)-l-(2,2,2-trifluoroethoxy)benzene for 2-bromo-l-(2,4-difluorophenoxy)-4-(ethylsulfonylmethyl)benzene. LCMS: 409.2 (M+l) +

Step 2: 5-[5-(ethylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]-7-methylimidazo[l,5-a]pyrazin-8-one


[00749] The title compound was prepared in a manner similar to Example 369 Step 2, by substituting 2-[5-(ethylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane for 2-[2-(2,4-difluorophenoxy)-5-(ethylsulfonylmethyl)phenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane. 1H NMR (DMSO-d6, 400 MHz) δ 8.99 (s, 1 H), 8.47 (s, 1 H), 7.61 (d, J = 8.8 Hz, 1H), 7.52 (s, 1 H), 7.35 (d, J = 8.8 Hz, 1 H), 7.31 (s, 1 H), 4.82 (q, J = 8.4 Hz, 2 H), 4.48 (s, 2 H), 3.42 (s, 3 H), 3.04 (q, J = 7.2 Hz, 2 H), 2.94 (t, J = 7.2 Hz, 3 H). LCMS: 430.1 (M+l) +

Example 372 : 5 - [2-(2,4-difluorophenoxy)-5 -(methylsulfonylmethyl)phenyl] -7-methylimidazo[ 1 ,5-a]pyrazin-8-one

Step 1 : 2-[2-(2,4-difluorophenoxy)-5-(methylsulfonylmethyl)phenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane

[00750] The title compound was prepared in a manner similar to Example 369 Step 1, by substituting 2-bromo-l-(2,4-difluorophenoxy)-4-(methylsulfonylmethyl)benzene for 2-bromo-l-(2,4-difluorophenoxy)-4-(ethylsulfonylmethyl)benzene. LCMS: 442.2 (M+18) + Step 2 : 5 -[2-(2,4-difluorophenoxy)-5 -(methylsulfonylmethyl)phenyl] -7-methylimidazo [1,5-a]pyrazin-8-one


[00751] The title compound was prepared in a manner similar to Example 369 Step 2, by substituting 2-[2-(2,4-difluorophenoxy)-5-(methylsulfonylmethyl)phenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane for 2-[2-(2,4-difluorophenoxy)-5- (ethylsulfonylmethyl)phenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane. 1H NMR (DMSO-d6, 400 MHz) δ 8.59 (s, 1 H), 8.19 (s, 1 H), 7.65 (d, J = 2.0 Hz, 1H), 7.57 (dd, Ji = 8.8 Hz, J2 = 2.0 Hz, 1 H), 7.52-7.39 (m, 2 H), 7.30 (s, 1 H), 7.18-7.11 (m, 1 H), 6.94 (d, J = 8.8 Hz, 1 H), 4.55 (s, 2 H), 3.44 (s, 3 H), 2.96 (s, 3 H). LCMS: 446.1 (M+l) +

Example 373 : 5 - [2-(4 ,4 -difluorocyclohexyl)oxy- 5 -ethylsulfonylphenyl] -7 -methylimidazo[ 1 ,5-a]pyrazin-8-one

Step 1 : 2-(5-ethylsulfonyl-2-fluorophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane


[00752] bromo-4-ethylsulfonyl-l-fluorobenzene (5.00 g, 18.72 mmol), AcOK (3.88 g, 56.16 mmol, 3 eq), pinacol ester (9.51 g, 37.44 mmol, 2 eq), Pd2(dba)3 (17.14 g, 18.72 mmol, 1 eq) and XPhos (9.24 g, 18.72 mmol, 1 eq) in dioxane (300 mL) was degassed and then heated to 60 °C overnight under N2. The reaction mixture was poured into H20 (300 mL). The mixture was extracted with EA (3 x 250 mL). The combined organic phasse were washed with saturated brine (300 mL), dried over anhydrous MgS04, filtered and concentrated under reduced pressure to give a residue that was purified by silica gel column chromatography to afford the title compound (1.87 g, 32%) as a gray solid. 1H NMR: (CDC13, 400 MHz) δ: 8.34-8.31 (m, 1 H), 8.01-7.98 (m, 1 H), 7.22 (d, J = 8.8 Hz, 1H), 3.14 (q, J = 7.6 Hz, 2H),1.37 (s, 12 H), 1.27 (t, J = 7.6 Hz, 3H).

Step 2: 5-(5-ethylsulfonyl-2-fluorophenyl)-7-methylimidazo[l,5-a]pyrazin-8-one


[00753] 5-bromo-7-methylimidazo[l,5-a]pyrazin-8-one (600 mg, 2.63 mmol, 0.83 Eq), the title compound from Step 2 (1.00 g, 3.18 mmol, 1.00 Eq), K3P04 (2.03 g, 9.55 mmol, 3.00 Eq) and Pd(dppf)Cl2 (118 mg, 0.16 mmol, 0.05 Eq) in dioxane (20 mL) was degassed and then heated to 60 °C overnight under N2. The reaction mixture was poured into water. The mixture was extracted with EA (3 x 25 mL). The organic phase was washed with brine (30 mL), dried over anhydrous MgS04, filtered and concentrated under vacuum to give a residue which was purified by silica gel chromatography to afford the title compound (600 mg, yield: 56.24%) . 1H NMR: (CDC13, 400 MHz) δ: 8.50 (s, 1 H), 8.17 (s, 1 H), 8.12-8.08 (m, 2 H), 7.50 (t, J = 8.8 Hz, 1 H), 6.90 (s, 1 H), 3.59 (s, 3H), 3.17 (q, J = 7.2 Hz, 2 H), 0.89-0.83 (m, 3H).

Step 3 : 5-[2-(4,4-difluorocyclohexyl)oxy-5-ethylsulfonylphenyl]-7-methylimidazo[ 1 ,5-a]pyrazin-8-one


[00754] To a solution of 4,4-difluorocyclohexan-l-ol (162 mg, 1.19 mmol) in THF (10 mL) was added NaH (48 mg, 1.19 mmol, 60% in mineral oil) in one portion at 25°C under N2. The mixture was stirred at 25 °C for 30 minutes. Then the title compound from Step 2 (200 mg, 0.6 mmol) was added and the mixture was stirred at 25 °C for 18 hours. The reaction contents were poured into ice-water (v/v = 1/1) (150 mL) and stirred for 20 minutes. The aqueous phase was extracted with EA (40 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title compound

(57.35 mg, 22%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.63 (s, 1H), 8.26 (s, 1H), 8.04 (dd, Jl = 8.8 Hz, J 2= 2.4 Hz 1 H), 7.95 (d, J = 2.4 Hz, 1 H), 7.56 (d, J = 8.8 Hz, 1 H), 7.31 (s, 1 H), 4.90-4.84 (brs, 1 H), 3.44 (s, 3 H), 3.32 (q, J= 7.2 Hz, 2 H), 1.85-1.83 (m, 4 H), 1.69-1.61 (m, 4 H), 1.15 (t, J= 7.2 Hz, 3 H). LCMS: 452.2 (M+H)+

Example 374: 5-(2-cyclopentyloxy-5-ethylsulfonylphenyl)-7-methylimidazo[ 1 ,5-a]pyrazin-8 -one


[00755] The title compound was prepared in a manner similar to Example 373, by

substituting cyclopentanol for 4,4-difluorocyclohexan-l-ol in Step 3. 1H NMR (DMSO-d6,

400 MHz) δ 8.34 (s, 1H), 8.16 (s, 1H), 8.02 (d, J = 8.8 Hz, 1 H), 7.91 (s, 1 H), 7.42 (d, J = 8.8

Hz, 1 H), 7.24 (s, 1 H), 5.04-5.01 (brs, 1 H), 3.43 (s, 3 H), 3.31 (q, J= 6.8 Hz, 2 H), 1.91-1.80

(m, 2 H), 1.62-1.30 (m, 6 H), 1.14 (t, J= 6.8 Hz, 3 H). LCMS: 402.2 (M+H)+

Example 375 : 5 - [2-(cyclopropylmethylamino)-5 -ethylsulfonylphenyl] -7-methylimidazo [1,5-a]pyrazin-8-one


[00756] The title compound was prepared in a manner similar to Example 373, by

substituting cyclopropylmethanamme for 4,4-difluorocyclohexan-l-ol in Step 3. 1H NMR (DMSO-d6, 400 MHz) δ 8.28-8.24 (m, 2H), 7.76 (d, J = 8.8 Hz, 1 H), 7.64(s, 1 H), 6.98 (d, J = 8.8 Hz, 1 H), 6.47-6.41 (brs, 1 H), 3.44 (s, 3 H), 3.18 (q, J= 7.2 Hz, 2 H), 3.06-3.01 (m, 2 H), 1.12 (t, J= 6.8 Hz, 3 H), 1.06-0.98 (m, 1 H), 0.42-0.37 (m, 2 H), 0.16-0.11 (m, 2 H). LCMS: 387.2 (M+H) +

Example 376: 5-[2-(2,4-difluorophenoxy)-5-ethylsulfonylphenyl]-7-methylimidazo[ 1,5-a]pyrazin-8-one


[00757] The title compound was prepared in a manner similar to Example 373, by

substituting 2,4-difluorophenol for 4,4-difluorocyclohexan-l-ol in Step 3. 1H NMR (CDCI3,

400 MHz) δ 8.05 (d, J = 2.4 Hz, 1H), 8.03 (s, 1H), 7.97 (dd, Jl = 8.8 Hz, J 2= 2.4 Hz 1 H), 7.16-7.10 (m, 1 H), 7.05-7.00 (m, 1 H), 6.98-6.93 (m, 1 H), 7.97 (dd, Jl = 8.8 Hz, J 2= 1.2 Hz 1 H), 3.55 (s, 3 H), 3.18 (q, J= 7.2 Hz, 2 H), 1.36 (t, J= 7.2 Hz, 3 H). LCMS: 446.1 (M+H)+ Example 377: 7-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-5-methylfuro[3,2-c]pyridin-4-one

Step 1 : 7-bromo-5-methylfuro[3,2-c]pyridin-4-one


[00758] To a suspension of 7-bromo-5H-furo[3,2-c]pyridin-4-one (250 mg, 1.17 mmol) in DMF (5 mL) cooled to 0 °C was added HNa (56 mg, 1.4 mmol, 60% dispersion in mineral oil) in three portions. After stirring at room temperature for 45 min, Mel (87 μί, 1.4 mmol) was added drop wise over five minutes. The reaction was allowed to warm up to rt stirred for 2 h. It was then cooled to 0 °C followed by addition of sat. aq. NH4C1 (5 mL) drop wise. The resulting mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound. LCMS: 227.9 (M+H)+

Step 2: 5-methyl-7-(4,4,5,5-tetramethyl-l -dioxaborolan-2-yl)furo[3,2-c]pyridin-4-one


[00759] The title compound was prepared in a manner similar to Example 255, step 4, by substituting 7-bromo-5-methylfuro[3,2-c]pyridin-4-one for N-[4-(cyclopropylmethoxy)-3-(tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]ethane-l-sulfonamide. LCMS: 276.1 (M+H)+ Step 3 : 7-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-5-methylfuro[3,2-c]pyridin-4-one


[00760] The title compound was prepared in a manner similar to Example 197, by

substituting 5-methyl-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)mro[3,2-c]pyridin-4- one for 2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-l ,3,2-dioxaborolane and 2-bromo-l-(cyclopropylmethoxy)-4-methylsulfonylbenzene for 4-bromo-2-methyl-6-(trifiuoromethyl)isoquinolin-l-one. 1H NMR (CDC13, 400 MHz) δ 8.05 (s, 1 H), 7.92 (dd, Ji = 8.6 Hz, J2 = 1.8 Hz, 1 H), 7.50 (m, 2 H), 7.07 (m, 2 H), 3.95 (d, J = 6.7 Hz, 2 H), 3.70 (s, 3 H), 3.1 (s, 3 H), 1.15 (m, 1 H), 0.57 (m, 2 H), 0.28 (m, 2 H). LCMS: 374.1 (M+H)+

Example 378: 7-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-5-methylfuro[3,2-c]pyridin-4-one


[00761] The title compound was prepared in a manner similar to Example 197, by

substituting 2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane for 2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 7-bromo-5-methylfuro[3,2-c]pyridin-4-one for 4-bromo-2-methyl-6-(trifluoromethyl)isoquinolin-l-one. 1H NMR (DMSO-d6, 400 MHz) δ 7.88 (m, 4 H), 7.33 (d, J = 9.4 Hz, 1 H), 7.01 (d, J = 2.0 Hz, 1 H), 4.02 (d, J = 6.8 Hz, 2 H), 3.58 (s, 3H), 3.28 (m, 2H), 1.12 (t, J = 7.4 Hz, 3 H), 1.08 (m, 1H), 0.45 (m, 2H), 0.24 (m, 2H). LCMS: 388.1 (M+H)+

Example 379: N-[4-(2,4-difluorophenoxy)-3-(5-methyl-4-oxofuro[3,2-c]pyridin-7-yl)phenyl] ethanesulfonamide


[00762] The title compound was prepared in a manner similar to Example 197, by

substituting N-[4-(2,4-difluorophenoxy)-3-(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)phenyl] ethanesulfonamide for 2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5, 5 -tetramethyl- 1,3,2-dioxaborolane and 7-bromo-5-methylfuro[3,2-c]pyridin-4-one for 4-bromo-2-methyl-6-(trifluoromethyl)isoquinolin-l-one. 1H NMR (DMSO-d6, 400 MHz) δ 9.83 (s, 1H), 7.85 (d, J = 2.0 Hz, 1 H), 7.78 (s, 1H), 7.37 (m, 2H), 7.24 (dd, Ji = 8.8 Hz, J2 = 2.7 Hz, 1 H), 7.14 (m, 1H), 7.03 (m, 1H), 6.97 (d, J = 2.1 Hz, 1 H), 6.93 (d, J = 8.8 Hz, 1 H), 3.54 (s, 3 H), 3.12 (q, J = 7.3 Hz, 2 H), 1.12 (t, J = 7.3 Hz, 3 H). LCMS: 461.2 (M+H)+

Example 380: N-[4-(2,4-difluorophenoxy)-3-(5-methyl-4-oxofuro[3,2-c]pyridin-7-yl)phenyl]methanesulfonamide


[00763] The title compound was prepared in a manner similar to Example 197, by substituting N-[4-(2,4-difluorophenoxy)-3-(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)phenyl]methanesulfonamide for 2- [2-(cyclopropylmethoxy)-5 -methylsulfonylphenyl] -4,4,5, 5 -tetramethyl- 1, 3, 2-dioxaborolane and 7-bromo-5-methylfuro[3,2-c]pyridin-4-one for 4-bromo-2-methyl-6-(trifluoromethyl)isoquinolin-l-one. 1H NMR (DMSO-d6, 400 MHz) δ 9.77 (s, 1H), 7.85 (d, J = 2.1 Hz, 1 H), 7.79 (s, 1H), 7.38 (m, 2H), 7.25 (dd, Ji = 8.8 Hz, J2 = 2.8 Hz, 1 H), 7.12 (m, 1H), 7.04 (m, 1H), 6.97 (d, J = 2.1 Hz, 1 H), 6.94 (d, J = 8.8 Hz, 1 H), 3.54 (s, 3 H), 3.02 (s, 3 H). LCMS: 447.1 (M+H) +

Example 381 : 4-(cyclopropylmethoxy)-5-(l -methyl-6-oxopyridin-3-yl)- 1 -(methylsulfonylmethyl)pyridin-2-one

Step 1 : 5-bromo-4-(cyclopropylmethoxy)-2-methoxypyridine


[00764] To a solution of cyclopropylmethanol (446 mg, 6.18 mmol) in THF (10 mL) was added NaH (247 mg, 6.18 mmol, 60% in mineral oil) in one portion at 0 °C. The reaction mixture was warmed up to 20 °C over a period of 30 mins and stirred at 20 °C for 10 mins. Then 5-bromo-4-chloro-2-methoxypyridine (550 mg, 2.47 mmol) was added in one portion and the mixture was stirred at 70°C for 4 hours. The mixture was diluted with saturated ammonium aqueous solution (50 mL) and extracted by EtOAc (2 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product which was purified by silica gel column chromatography (PE : EA = 20 : 1 to 10 : 1) to afford the title compound (450 mg, 70.6%) as colorless oil. 1H NMR: (CDC13, 400 MHz) δ: 8.11 (s, 1 H), 6.18 (s, 1 H), 3.90 (s, 3 H), 3.89-3.88 (m, 2 H), 1.39-1.27 (m, 1 H), 0.70 -0.67 (m, 2 H), 0.46 -0.43 (m, 2 H). LCMS (M+H)+ = 258.0 (M+l)+; 260.0

Step 2: 5-bromo-4-(cyclopropylmethoxy)pyridin-2-ol


[00765] To a solution of the title compound from step 1 (450 mg, 1.74 mmol) in DMF (5 mL) was added LiCl (370 mg, 8.72 mmol) and TsOH H20 (1.52 g, 8.72 mmol) at room

temperature. The mixture was heated to 120°C and stirred for 1 hour. The mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic phase was washed with saturated brine (2 x 200 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to afford the title compound (380 mg, yield: 88.9%) as yellow solid which used directly for the next step without further purification. 1H NMR (CDC13, 400 MHz) δ 7.49 (s, 1 H), 5.91 (s, 1 H), 3.87 (d, J=6.8 Hz, 2 H), 1.36-1.22 (m, 1 H), 0.71 -0.67 (m, 2 H), 0.46 -0.42 (m, 2 H). LCMS: 244.0 (M+l)+; 246.0

Step 3 : 5 -bromo-4-(cyclopropylmethoxy)- 1 -(methylsulfanylmethyl)pyridin-2-one


[00766] To a solution of the title compound from Step 2 (330 mg, 1.35 mmol) in DMF (5 mL) was added NaH (40 mg, 2 mmol, 60% in mineral oil) at 0°C. The mixture was stirred at 0°C for 30 minutes. Then, chloromethyl methyl sulfide (131 mg, 1.35 mmol) was added. The mixture was warmed to room temperature and stirred for 5 hours. The mixture was quenched with saturated aqueous NH4C1 (30 mL) and extracted with EA (10 mL x 3). The combined organic layers were washed with saturated brine (20 mL x 2), dried over anhydrous Na2S04, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel (PE : EA = 3 : 1) to afford the title compound (205 mg, 50%) as yellow oil. 1H NMR (CDCI3, 400 MHz) δ 7.60 (s, 1 H), 5.86 (s, 1 H), 4.96 (s, 1 H), 3.84 (d, J=6.8 Hz, 2 H), 2.17 (s, 3 H),1.32-1.25 (m, 1 H), 0.70 -0.67 (m, 2 H), 0.41 -0.39 (m, 2 H).

Step 4 : 5 -bromo-4-(cyclopropylmethoxy)- 1 -(methylsulfonylmethyl)pyridin-2-one


[00767] To a solution of the title compound from Step 3 (150 mg, 0.5 mmoL) in DCM (5 mL), was added mCPBA (340 mg, 1.9 mmol). The mixture was stirred at 15°C for 2.5 hours. Water (30 mL) was added and the resulting mixture was extracted with EtOAc (120 mL x 3). The combined organic phases were washed with saturated brine (40 mL x 2), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE : EA = 5: 1 to 2: 1) to afford the title compound (120 mg, 72%) as a yellow solid. 1H NMR (CDC13, 400 MHz) δ 7.60 (s, 1 H), 5.91 (s, 1 H), 5.10 (s, 2 H), 3.89 (d, J=6.8 Hz, 2 H), 2.98 (s, 3 H),0.90-0.86 (m, 1 H), 0.75 -0.70 (m, 2 H), 0.45 -0.42 (m, 2 H). LCMS: 335.9 (M+l)+; 337

Step 5: 4-(cyclopropylmethoxy)-5-(l-methyl-6-oxopyridin-3-yl)-l-(methylsulfonylmethyl)pyridin-2-one


[00768] The title compound from step 4 (50 mg, 0.15 mmol), l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one (42 mg, 0.18 mmol), Pd(dppf)Cl2 (11 mg, 14.9 umol) and K3PO4 (63 mg, 0.3 mmol) in dioxane (5 mL) and water (5 drops) were degassed and then heated to 70°C under N2 overnight. The reaction mixture was then concentrated under reduced pressure. The residue was purified by column chromatography (PE : DCM : EA = 3 :0: 1 to 0: 1 :4) followed by preparative HPLC to afford the title compound (17.09 mg, 31.5%) as an off-white solid. 1H NMR (CDCI3, 400 MHz) δ 7.50 (dd, Ji = 9.2 Hz, h = 2.4 Hz, 1 H), 7.43 (d, J = 2.4 Hz, 1 H), 6.71 (d, J = 9.2 Hz, 1 H), 5.96 (s, 1 H), 5.16 (s, 2 H), 3.86 (d, J = 6.8 Hz, 1 H), 3.63 (s, 3 H), 2.99 (s, 3 H), 1.26-1.21 (m, 1 H), 0.70-0.66 (m, 2 H), 0.36-0.32 (m, 2 H). LCMS: 365.0 (M+l) +

Example 382 : 5 - [4-(cyclopropylmethoxy)- 1 -(methylsulfonylmethyl)-6-oxopyridin-3 -yl] -1,3-dimethylpyridin-2-one


[00769] The title compound was prepared in a manner similar to Example 381, by

substituting l,3-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one for 1-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one in step 5. 1H NMR (CDCls, 400 MHz) δ 7.35 (s, 1 H), 7.32 (s, 2 H), 5.97 (s, 1 H), 5.16 (s, 2 H), 3.87 (s, J = 7.2 Hz, 2 H), 3.62 (s, 3 H), 2.99 (s, 3 H), 2.20 (s, 3 H), 1.25-0.24 (m, 1 H), 0.70-0.65 (m, 2 H), 0.36-0.35 (m, 2 H). LCMS: 379.0 (M+l) +

Example 383: 4-[4-(cyclopropylmethoxy)-l-(methylsulfonylmethyl)-6-oxopyridin-3-yl]-7-fluoro-2-methylisoquinolin- 1 -one


[00770] The title compound was prepared in a manner similar to Example 381, by

substituting 7-fluoro-2-methyl-4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)isoquinolin- 1 -one for l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one in step 5. 1H NMR (CDCI3, 400 MHz) δ 8.13 (dd, Ji = 9.2 Hz, J2 = 2.4 Hz, 1 H), 7.37 (s, 1 H), 7.35-7.32 (m, 1 H), 7.30-7.28 (m, 1 H), 7.03 (s, 1 H), 5.99 (s, 3 H), 5.13 (d, J = 13.6 Hz, 1 H), 4.91 (d, J = 13.6 Hz, 1 H), 3.78 (t, J = 6.4 Hz, 2 H), 3.65 (s, 3 H), 3.04 (s, 3 H), 1.03-0.97 (m, 1 H), 0.48-0.42 (m, 2 H), 0.11 (s, 2 H). LCMS: 433.1 (M+l) +

Example 384: 4-[4-(cyclopropylmethoxy)-l-(methylsulfonylmethyl)-6-oxopyridin-3-yl]-2-methylisoquinolin- 1 -one


[00771] The title compound was prepared in a manner similar to Example 381, by

substituting 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one for 1-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one in step 5. 1H NMR (CDCI3, 400 MHz) δ 8.49 (d, J = 8.0 Hz, 1 H), 7.61 (t, J = 7.2 Hz, 1 H), 7.52 (t, J = 7.2 Hz, 1 H), 7.38 (s, 1 H), 7.27 (d, J = 8.0 Hz, 1 H), 7.07 (s, 1 H), 5.99 (s, 1 H), 5.45 (d, J = 14.4 Hz, 1 H), 4.89 (d, J = 14.4 Hz, 1 H), 3.79 (t, J = 8.0 Hz, 2 H), 3.65 (s, 3 H), 3.04 (s, 3 H), 1.02-0.96 (m, 1 H), 0.46-0.39 (m, 2 H), 0.10 (s, 2 H). LCMS: 415.1 (M+l) +

Example 385: 5-[4-(2,4-difluorophenoxy)- 1 -(methylsulfonylmethyl)-6-oxopyridin-3-yl]- 1 ,3-dimethylpyridin-2-one

Step 1 : 5-brorno-4-(2,4-difluorophenoxy)-l-(methylsulfonylmethyl)pyridin-2-one


[00772] The title compound was prepared in a manner similar to Example 381 Steps 1 through 4, by substituting 2,4-difluorophenol for cyclopropylmethanol in step 1. 1H NMR (CDCls, 400 MHz) δ 7.71 (s, 1 H), 7.21 (m, 1 H), 7.01 (m, 2 H), 5.66 (s, 1 H), 5.1 (s, 2 H), 2.96 (s, 3 H).

Step 2: 5-[4-(2,4-difluorophenoxy)-l-(methylsulfonylmethyl)-6-oxopyridin-3-yl]-l,3-dimethylpyridin-2-one


[00773] The title compound was prepared in a manner similar to Example 382, by

substituting the title compound from Step 1 for 5-bromo-4-(cyclopropylmethoxy)-l- (methylsulfonylmethyl)pyridin-2-one. 1H NMR (CDC13, 400 MHz) δ 7.40 (s, 1 H), 7.37 (s, 1

H), 7.33 (s, 1 H), 7.21-7.11 (m, 1 H), 7.07-6.93 (m, 2 H), 5.68 (s, 1 H), 5.16 (s, 2 H), 3.61 (s,

3 H), 2.99 (s, 3 H) , 2.20 (s, 3 H). LCMS: 437.0 (M+l)+

Example 386: 4-(2,4-difluorophenoxy)-5-(l-methyl-6-oxopyridin-3-yl)-l- (methylsulfonylmethyl)pyridin-2-o


[00774] The title compound was prepared in a manner similar to Example 381, by

substituting 5-bromo-4-(2,4-difluorophenoxy)-l-(methylsulfonylmethyl)pyridin-2-one for 5-bromo-4-(cyclopropylmethoxy)-l-(methylsulfonylmethyl)pyridin-2-one in step 5. 1H NMR (CDCI3, 400 MHz) δ 7.53 (dd, Ji = 2.4 Hz, J2 = 9.6 Hz, 1 H), 7.46 (d, J = 2.4 Hz, 1 H), 7.44 (s, 1 H), 7.19-7.13 (m, 1 H), 7.07-7.00 (m, 1 H), 7.00-6.93 (m, 1 H), 6.64 (d, J = 9.2 Hz, 1 H), 5.68 (s, 1 H), 5.17 (s, 2 H), 3.61 (s, 3 H), 2.98 (s, 3 H). LCMS: 423.0 (M+l)+

Example 387: 4-[4-(2,4-difluorophenoxy)- 1 -(methylsulfonylmethyl)-6-oxopyridin-3-yl]-2-methylisoquinolin- 1 -one


[00775] The title compound was prepared in a manner similar to Example 384, by

substituting 5-bromo-4-(2,4-difluorophenoxy)-l-(methylsulfonylmethyl)pyridin-2-one for 5-bromo-4-(cyclopropylmethoxy)-l-(methylsulfonylmethyl)pyridin-2-one. 1H NMR (CDCI3, 400 MHz) δ 8.50 (d, J = 8.0 Hz, 1 H), 7.72-7.67 (m, 1 H), 7.57-7.52 (m, 1 H), 7.49 (d, J = 9.2 Hz, 2 H), 7.20 (s, 1 H), 7.08-7.02 (m, 1 H), 7.01-6.94 (m, 1 H), 6.93-6.86 (m, 1 H), 5.74 (s, 1 H), 5.46 (d, J = 14.4 Hz, 1 H), 4.92 (d, J = 14.4 Hz, 1 H), 3.68 (s, 3 H), 3.05 (s, 3 H). LCMS: 473.0 (M+l)+

Example 388: 5-(2-but-2-ynoxy-5-methylsulfonylphenyl)-l ,3-dimethylpyridin-2-one Step 1 : 5-(2-fluoro-5-methylsulfonylphenyl)-l,3-dimethylpyridin-2-one


[00776] A mixture of l,3-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one (2.50 g, 10.0 mmol), 2-bromo-l-fluoro-4-methylsulfonylbenzene (2.54 g, 10.0 mmol), CsF (3.8 g, 25.0 mmol), Pd(dppf)Cl2 (0.73 g, 1.0 mmol) in DME (50 mL) and MeOH (25 ml) was stirred at 80 °C for 18 hrs under N2. The mixture was concentrated and the residue was purified by column chromatography on silica gel (PE: EA = 2: 1~0: 1) to give the title compound (1.8 g, 61%) as a red solid. LCMS: 295.9 (M+H) +

Step 2 : 5 -(2-but-2-ynoxy-5 -methylsulfonylphenyl)- 1 ,3 -dimethylpyridin-2-one


[00777] To a solution of but-2-yn-l-ol (191 mg, 2.72 mmol) in anhydrous DMF (3 mL) was added NaH (109 mg, 2.72 mmol, 60% in mineral oil) at 0°C. The mixture was stirred at this temperature for lhr. The title compound from Step 1 (200 mg, 0.68 mmol) was added and the reaction mixture was stirred at 0°C for 2 hrs. After this time, it was quenched with sat. NH4C1 solution (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2S04, filtered and concentrated to give a crude product that was purified by prep-HPLC to give the title compound (56.01 mg, 23.9 %) as a light yellow solid. 1H NMR (CDCI3, 400 MHz) δ 7.88 (dd, Ji = 8.8 Hz, J2 = 2.0 Hz, 1 H), 7.81 (d, J = 2.0 Hz, 1 H), 7.46 (s, 2 H), 7.24 (d, J = 8.8 Hz, 1 H), 4.79 (d, J = 2.0 Hz, 2 H), 3.62 (s, 3 H), 3.08 (s, 3 H), 2.22 (s, 3 H), 1.87 (s, 3 H). LCMS: 346.0 (M+H) +

Example 389: 5-(2-but-2-ynoxy-5-ethylsulfonylphenyl)-3-methoxy- 1 -methylpyridin-2-one Step 1 : 5-(5-ethylsulfonyl-2-fluorophenyl)-3-methoxy-l-methylpyridin-2-one


[00778] To a solution of 5-bromo-3-methoxy-l-methylpyridin-2-one (694 mg, 3.18 mmol), 2-(5-ethylsulfonyl-2-fluorophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1 g, 3.18 mmol), Pd(dppf)Cl2 (233 mg, 318.00 umol) in dioxane (26 mL) and H20 (2.6 mL) was added K3PO4 (2.02 g, 9.54 mmol, 3.00 Eq). The reaction was stirred at 70°C under N2 for 6 hrs. The mixture was concentrated and the residue was purified by silica gel column chromatography (PE/EA=3/1 to 1/2) to afford the title compound (0.9 g, 87%) as a brown solid. 1H NMR (CDCI3, 400 MHz) δ 7.93 (dd, Ji=7.2 Hz, J2=2.0 Hz, 1 H ), 7.88-7.84 (m, 1 H), 7.35 (dd, Ji=10.0 Hz, J2=8.8 Hz, 1 H), 7.23 (d, J=1.6 Hz, 1 H), 6.83 (s, 1 H), 3.89 (s, 3 H), 3.67 (s, 3 H), 3.16 (q, J=7.6 Hz, 2 H), 1.33 (t, J=7.6 Hz, 3 H). LCMS: 325.9 (M+H)+

Step 2 : 5 -(2-but-2-ynoxy-5 -ethylsulfonylphenyl)-3 -methoxy- 1 -methylpyridin-2-one


[00779] The title compound was prepared in a manner similar to Example 388 Step 2, by substituting 5-(5-ethylsulfonyl-2-fluorophenyl)-3-methoxy-l-methylpyridin-2-one for 5-(2-fluoro-5-methylsulfonylphenyl)-l,3-dimethylpyridin-2-one. 1H NMR (CDC13, 400 MHz) δ

7.88 (d, J=8.8 Hz, 1 H ), 7.80 (s, 1 H), 7.23 (d, J=8.4 Hz, 1 H), 7.19 (s, 1 H), 6.97 (s, 1 H), 4.78 (s, 2 H), 3.83 (s, 3 H), 3.70 (s, 3 H), 3.15 (q, J=7.2 Hz, 2 H), 1.87 (s, 3 H), 1.32 (t, J=7.2 Hz, 3 H). LCMS: 376.0 (M+H)+

Example 390: 5-(5-ethylsulfonyl- -pent-2-ynoxyphenyl)-3-methoxy- 1 -methylpyridin-2-one


[00780] The title compound was prepared in a manner similar to Example 389, by

substituting pent-2-yn-l-ol for but-2-yn-l-ol in Step 2. 1H NMR (CDC13, 400 MHz) δ 7.86 (dd, Ji = 8.8 Hz, = 2.0 Hz, 1 H), 7.79 (d, J = 2.4 Hz, 1 H), 7.23 (d, J = 8.8 Hz, 1 H), 7.18 (d, J = 2.0 Hz, 1 H), 6.94 (d, J = 1.6 Hz, 1 H), 4.80 (s, 2 H), 3.87 (s, 3 H), 3.67 (s, 3 H), 3.15 (q, J=7.6 Hz, 2 H), 2.24 (q, J=7.6 Hz, 2 H), 1.32 (t, J=7.6 Hz, 3 H), 1.14 (t, J=7.6 Hz, 3 H). LCMS: 390.2 (M+H) +

Example 391: 5-[2-(3-cyclopropylprop-2-ynoxy)-5-ethylsulfonylphenyl]-3-methoxy-l-methylpyridin-2-one


[00781] The title compound was prepared in a manner similar to Example 389, by

substituting 3-cyclopropylprop-2-yn-l-ol for but-2-yn-l-ol in Step 2. 1H NMR (CDC13, 400 MHz) δ 7.87 (d, J = 8.8 Hz, 1 H), 7.79 (s, 1 H), 7.22-7.20 (m, 2 H), 7.00 (s, 1 H), 4.77 (s, 2 H), 3.88 (s, 3 H), 3.70 (s, 3 H), 3.15 (q, J=7.2 Hz, 2 H), 1.32 (t, J=7.2 Hz, 3 H), 1.31-1.29 (m, 1 H), 0.84-0.81 (m, 2 H), 0.69-0.67 (m, 2 H). LCMS: 402.0 (M+H)+

Example 392: N-[4-(2,4-difluorophenoxy)-3-[l-methyl-6-oxo-5-(trifluoromethyl)pyridin-3-yl]phenyl] ethanesulfonamide

Step 1 : 5-bromo-l-methyl-3-(trifluorometh l)pyridin-2-one

[00782] To a solution of 5-bromo-3-(trifluoromethyl)pyridin-2-ol (6 g, 25 mmol) stirred at rt in THF (5 mL) was added NaH (1.5 g, 37 mmol, 60% in mineral oil). After stirring for 30 min, methyl iodide (7.1 g, 50 mmol) was added. After stirring at rt for 3 h, the reaction mixture was treated with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2S04, filtered, and concentrated in vacuo to afford the title compound (6 g, 97%) as a tan solid. The solid was carried forward without any further purification. 1H NMR (CDC13, 400 MHz) δ 7.79 (d, J = 2.0 Hz, 1 H), 7.65 (d, J = 2.0 Hz, 1 H), 3.60 (s, 3 H). LCMS (M+H)+ = 256.

Step 2 : 1 -methyl-5 -(3 ,3 ,4,4-tetramethylb 3 -(trifluoromethyl)pyridin-2-one


[00783] A suspension of compound 5-bromo-l-methyl-3-(trifluoromethyl)pyridin-2-one (3 g, 11.8 mmol), 4,4,5, 5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (3.6 g, 14.1 mmol), KOAc (3 g, 30.6 mmol), and Pd(dppf)2Cl2 (200 mg) in dioxane (50 mL) was stirred at 90°C for 4 h. After the reaction mixture was concentrated in vacuo, the resulting residue was purified by silica gel column chromatography (PE:EA=3 : 1-1 : 1) to give the title compound (1.2 g, 34%) as a red solid. 1H NMR (CDC13, 400 MHz) δ 8.02 (d, J = 2.0 Hz, 1 H), 7.94 (d, J = 2.0 Hz, 1 H), 3.60 (s, 3 H), 1.32 (s, 12 H). LCMS (M+H)+ = 304.

Step 3 : 5-[2-(2,4-difluorophenoxy)-5-ethylsulfonylphenyl]- 1 -methyl-3-(trifluoromethyl)pyridin-2-one


[00784] A mixture of l-methyl-5-(3,3,4,4-tetramethylborolan-l-yl)-3-(trifluoromethyl)pyridin-2-one

(100 mg, 0.33 mmol), l-(2-bromo-4-ethylsulfonylphenoxy)-2,4-difluorobenzene (100 mg, 0.27 mmol), Pd(dppf)Cl2 (24 mg) and K3P04 (107 mg, 0.80 mmol) in dioxane (4 mL) and water (1 mL) was purged with nitrogen, capped, and heated to 90 °C for 4 h. After the mixture was filtered through a short bed of celite, the filtrate was concentrated in vacuo and purified by prep-HPLC afford the title compound (43 mg, 34%) as a white solid. 1H NMR

(CDC13, 400 MHz)□ ppm 8.11 (s, 1 H) 7.88 (s, 2 H) 7.80 (m, 1 H), 7.23 - 7.10 (m, 1 H) 7.09 - 6.91 (m, 2 H) 6.91 - 6.78 (m, 1 H) 6.25 (s, 1 H) 3.70 (s, 3 H) 3.15 (q, J = 7.2 Hz, 2 H) 1.31 (t, J = 7.2 Hz, 3 H). LCMS (M+H)+ = 474.

Example 393 : 4-[2-(cyclopropylmethoxy)-5-propan-2-ylsulfonylphenyl]-6-methoxy-2-methylisoquinolin- 1 -one


[00785] Bromo-6-methoxy-2-methylisoquinolin-l-one (previously prepared in WO

2013/142390) was reacted with 4,4,5, 5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane in a manner similar to Example 248, step 2 to give 6-methoxy-2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one which was then reacted with the title compound of Example 364, step 1 in a manner similar to Example 364, step 2 to give the title compound. 1H NMR (CDC13, 400 MHz) δ 8.45 (d, J = 8.4 Hz, 1 H), 7.91 (dd, Jl = 2.0 Hz, J2 = 8.8, 1 H), 7.06-7.27 (m, 3 H), 6.53 (d, J = 2.8 Hz, 1 H), 3.89 (m, 2 H), 3.78 (s, 3 H), 3.65 (s, 3 H), 3.22 (m, 1 H), 1.33 (d, J = 6.4 Hz, 6 H), 1.03 (q, J = 6.8 Hz, 1 H), 0.45 (m, 2 H), 0.14 (s, 2 H). LCMS: 442.0(M+H+)

Example 394: 5-[2-(cyclopropylmethoxy)-5-propan-2-ylsulfonylphenyl]-l,3-dimethylpyridin-2-one


[00786] The title compound of Example 364, step 1 was reacted with l,3-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one in a manner similar to Example 364, step 2 to give the title compound. 1H NMR (CDC13, 400 MHz) δ 7.75-7.79 (m, 2 H), 7.59 (s, 1 H), 7.03 (d, J = 8.4 Hz, 1 H), 3.96 (d, J = 6.8 Hz, 2 H), 3.67 (s, 3 H), 3.15-3.25 (m, 1 H), 2.24 (s, 3 H), 1.31 (d, J = 7.2 Hz, 6 H), 1.27 (d, J = 7.2 Hz, 1 H), 0.66-0.70 (m, 2 H), 0.38 (q, J = 5.2 Hz, 2 H). LCMS: 376.0(M+H+)

Example 395: N-[3-(l,5-dimethyl-6-oxopyridin-3-yl)-5-phenylmethoxyphenyljethanesulfonamide

Step 1 : N-(3-bromo-5-phenylmethoxyphenyl)ethanesulfonamide


[00787] Ethylsulfonyl chloride (113 uL, 1.2 mmol) was added dropwise to a stirred solution of 3-bromo-5-phenylmethoxyaniline (284 mg, 1.0 mmol) and pyridine (247 uL, 3.1 mmol) in DCM (5 mL) at 0 °C under nitrogen. After the mixture was allowed to warm to rt and stir for 14 h, it was treated with IN HC1 (1 mL) and extracted with DCM (3 X 5 mL); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo. The crude solid was purified by silica gel column chromatography using a gradient of EtOAc (5 to 95%) in hexanes to afford the title compound (345 mg, 94%>) as an amber oil that solidified upon standing. LCMS (M+H)+ =

371.

Step 2: N-[3-(l ,5-dimethyl-6-oxopyridin-3-yl)-5-phenylmethoxyphenyl]ethanesulfonamide


[00788] A mixture of N-(3-bromo-5-phenylmethoxyphenyl)ethanesulfonamide (60 mg, 0.16 mmol), l,3-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one (40 mg, 0.16 mmol), Pd(dppf)Cl2 (12 mg) and K3P04 (88 mg, 0.40 mmol) in dioxane (1.5 mL) and water (150 uL) was purged with nitrogen, capped, and heated to 75 °C for 2 h. After the mixture was filtered through a short bed of celite, the filtrate was concentrated in vacuo and purified by silica gel column chromatography using a gradient of MeOH (0 to 10%) in DCM to afford the title compound (69 mg, 94%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 - 1.24 (m, 3 H) 2.04 - 2.13 (m, 3 H) 3.04 - 3.17 (m, 2 H) 3.48 - 3.54 (m, 3 H) 5.08 - 5.17 (m, 2 H) 6.74 - 6.80 (m, 1 H) 6.90 - 6.98 (m, 2 H) 7.33 - 7.49 (m, 5 H) 7.59 - 7.63 (m, 1 H) 7.90 - 7.95 (m, 1 H) 9.57 - 10.01 (b.s., 1 H). LCMS (M+H)+ = 413.

Examples 396-482 in Table 21 were prepared using Suzuki conditions to append an appropriately substituted aryl group to an appropriately substituted pyridinone. Chemical manipulation subsequent to the Suzuki reaction was also carried out as needed to give title compound.

Table 21










Example 483: l-cyclobutyl-5-[2-(cyclopropylmethoxy)-5-methylsulfonylphi

methylpyridin-2-one

Step 1 : l-cyclobutyl-3-methylpyridin-l-ium chloride


[00789] Cyclobutylamine (2.3 g, 32 mmol) was added to l-(2,4-dinitrophenyl)-3- methylpyridinium chloride (J. Org. Chem. 1997, 62, 729-33) (8.0 g, 31 mmol) in n-butanol (120 mL) at 20 °C and the deep red solution was refiuxed overnight. Concentration under vacuum left a residue that was treated with water (20 mL) and the precipitate was removed by filtration, and the operation was repeated twice. The combined aqueous phase was basified with concentrated ammonia (2 mL) and washed twice with EtOAc. Evaporation of the water to gave the title compound (3.2 g, 70%) as a brown oil. LCMS: 148 M+

Step 2: l-cyclobutyl-3-methylpyridin-2-one

[00790] A stirred solution of the title compound from step 2 (2.8 g, 18.9 mmol) in water (30 mL) was cooled to 5 °C and K3Fe(CN)6 in water (30 mL) was added dropwise over 1 h. Then KOH (16.7 g, 298.6 mmol) in water (5 mL) and toluene (30 mL) were added, and the mixture was heated at 40 °C for 30 min. The organic layer was separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with water, brine and dried over Na2S04, filtered and concentrated. Silica gel chromatography (DCM) gave the title compound (1.9 g, 62%) as a yellow oil. LCMS: 164 (M+H)+

Step 3: 5-bromo-l-cyclobutyl-3-methylpyridin-2-one


[00791] The title compound of step 3(1.5 g, 9.2 mmol) in acetic acid (30 mL) was stirred at rt for 10 min. Bromine (1.51 g, 9.5 mmol) was then added slowly, and after about 2 h, the mixture was diluted with water and extracted with DCM. The organic solution was washed with water, brine and dried over Na2S04, filtered, concentrated and purified by silica gel chromatography (DCM) to give the title compound (2.0 g, 82%) as a yellow oil. LCMS: 242, 244 (M+H)+

Step 4 : 1 -cyclobutyl-5 -[2-(cyclopropylmethoxy)-5 -methylsulfonylphenyl] -3 -methylpyridin-2-one


[00792] The title compound of step 4 (27 mg, 0.11 mmol), the title compound of Example 90, step 1 (46 mg, 0.13 mmol), K2C03 (46 mg, 0.33 mmol) and Pd(dppf)2Cl2 (8 mg, 0.011 mmol) in DMF (2 mL) was N2 purged and micro waved at 100 °C. After 2 h, the mixture was concentrated under vacuum and DCM was added which was washed with water, brine and dried over Na2S04. Purification by preparative TLC gave the title compound (25 mg, 58%) as a white solid.

1H NMR (CDCI3, 400 MHz): δ 7.85-7.81 (m, 2H), 7.79 (d, J= 1.6 Hz, 1H), 7.47 (s, 1H), 7.02 (d, J= 8.4 Hz, 1H), 5.27-5.23 (m, 1H), 3.94 (d, J= 8.0 Hz, 2H), 3.07 (s, 3H), 2.57-2.50 (m, 2H), 2.32-2.24 (m, 2H), 2.21 (s, 3H), 1.93-1.84 (m, 2H), 1.31-1.25 (m, 1H), 0.70-0.65 (m, 2H), 0.40-0.36 (m, 2H). LCMS: 388 (M+H)+

Example 484 : N- [3 -( 1 -cyclobutyl-5 -methyl-6-oxopyridin-3 -yl)-4-(2,4-difluorophenoxy)phenyl]methanesulfonamide


[00793] The title compound of Example 483, step 3 (27 mg, 0.11 mmol) , N-[4-(2,4-difluorophenoxy)-3 -(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)phenyl]methanesulfonamide (55 mg, 0.13 mmol), K2CO3 (46 mg, 0.33 mmol) and Pd(dppf)2Cl2 (8 mg, 0.011 mmol) in DMF (2 mL) were reacted and purified in a manner similar to Example 483, step 4 to give the title compound (16 mg, 32%) as a white solid. 1H NMR (CDCI3, 400 MHz): δ 7.65 (s, 1H), 7.42 (s, 1H), 7.26-7.27 (m, 1H), 7.13 (dd, J= 8.8, 2.8 Hz, 1H), 6.97-6.89 (m, 2H), 6.83 (d, J= 9.2 Hz, 2H), 6.54 (s, 1H), 5.09-5.18(m, 1H), 3.04 (s, 3H), 2.53-2.46 (m, 2H), 2.23-2.18 (m, 2H), 2.16 (s, 3H), 1.87-1.81 (m, 2H). LCMS: 461 (M+H)+

Example 485: l-benzyl-5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-3-methylpyridin-2-one


[00794] The title compound was prepared in a manner similar to Example 483, steps 1-4 except that benzylamine was substituted for cyclobutylamine in step 1. 1H NMR (CDCI3, 400 MHz): δ 7.79 (s, 1H), 7.62 (d, J= 2.8 Hz, 1H), 7.49-7.51 (m, 1H), 7.34-7.38 (m, 4H), 7.29-7.32 (m, 2H), 6.98 (d, J= 8.8 Hz, 1H), 5.20 (s, 2H), 3.89-3.94 (m, 2H), 3.04 (s, 3H), 2.22 (s, 3H), 1.13-1.18 (m, 1H), 0.58-0.62 (m, 2H), 0.28-0.34 (m, 2H). LCMS: 424 (M+H)+

Example 486: l,3-dimethyl-5-(2-methyl-5-methylsulfonyl-2,3-dihydro-l-benzofuran-7-yl)pyridin-2-one

Step 1 : 2-methyl-5-methylsulfonyl-2,3-dihydro-l-benzofuran

[00795] A mixture of 5-bromo-2-methyl-2,3-dihydro-l-benzofuran (1.0 g, 4.72

mmol), CH3S02Na (730 mg, 7.08 mmol), L-proline (110 mg, 0.94 mmol), K2C03 (120 mg, 0.94 mmol) and Cul (89 mg, 0.47 mmol) in DMSO (10 mL) was irradiated at 140°C for 2 h under microwave. The mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2S04, filtered and concentrated to give the crude product that was purified by column chromatography on silica gel (PE/EA = 2/1) to give the title compound (500 mg, 50 %). 1H NMR (CDC13, 400 MHz) δ 7.71-7.70 (m, 2 H), 6.86-6.82 (m, 1 H), 5.08-5.03 (m, 1 H), 3.41-3.35 (m, 1 H), 3.02 (s, 3 H), 2.89-2.83 (m, 1 H), 1.56 (d, J = 6.4 Hz, 3 H).

Step 2: 7-bromo-2-methyl-5-methylsulfonyl-2,3-dihydro-l-benzofuran


[00796] To a mixture of the title compound from Step 1 (300 mg, 1.42 mmol) in DCM (10 mL) was added Fe (159 mg, 2.84 mmol) and Br2 (454 mg, 2.84 mmol) in one portion under N2. The mixture was stirred at room temperature for 6 h. The reaction mixture was washed with saturated aqueous Na2S03 (200 mL) and extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EA = 3/1) to give the title compound (300 mg, 73 %) as a yellow solid. 1H NMR (CDC13, 400 MHz) δ 7.90 (d, J = 1.6 Hz, 1 H), 7.64 (d, J = 1.6 Hz, 1 H), 5.20-5.14 (m, 1 H), 3.53-3.47 (m, 1 H), 3.01-2.95 (m, 1 H), 3.04 (s, 3 H), 1.56 (d, J = 6.4 Hz, 3 H). LCMS: 291.0 (M+l) +; 293.0.

Step 3: l,3-dimethyl-5-(2-methyl-5-methylsulfonyl-2,3-dihydro-l-benzomran-7-yl)pyridin-2-one


[00797] A solution of the title compound in Step 2 (300 mg, 1.03 mmol), l,3-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one (309 mg, 1.24 mmol),

Pd(dppf)Cl2 (76 mg, 0.103 mmol), Na2C03 (328 mg, 3.09 mmol) in dioxane (8 mL) and H20 (1 mL) was stirred at 80°C under N2 for 16 h. The solvent was removed under reduced pressure to give a residue that was purified by column chromatography on silica gel (PE/EA = 1/2) to give the title compound (60.0 mg, 18 %) as a yellow solid. 1H NMR (DMSO-d6, 400MHz) δ 8.02 (s, 1 H), 7.76 (s, 1 H), 7.74 (s, 1 H),7.66 (s, 1 H), 5.15-5.13 (m, 1 H), 3.51 (s, 3 H), 3.49-3.42 (m, 1 H), 3.19 (s, 3 H), 2.94-2.88 (m, 1 H), 2.07 (s, 3 H), 1.44 (d, J = 5.2 Hz, 3 H). LCMS: 334.1 (M+l) +.

Example 487: 4-[5-(ethylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]-2-methylisoquinolin- 1 -one

Step 1 : methyl 3-bromo-4-(2,2,2-trifluoroethoxy)benzoate


[00798] To a solution of methyl 3-bromo-4-fluorobenzoate (100 mg, 0.43 mmol) in DMF was added 2,2,2-trifluoroethanol (52 mg, 0.52 mmol), K2C03 (119 mg, 0.86 mmol), and the mixture was stirred at 60°C for 2 h. The mixture was cooled and water (50 mL) was added. The aqueous layer was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (30 mL x 3), brine (30 mL), dried over anhydrous Na2S04, filtered, concentrated and purified by silica gel chromatography (PE : EA = 20 : 1) to afford compound 3 (95 mg, 88 %) as a white solid. 1H NMR (CDC13, 400 MHz) δ 8.29 (d, J = 2.0 Hz, 1 H), 8.00 (dd, Ji = 8.4 Hz, J2 = 2.0 Hz, 1 H), 6.93 (d, J = 8.4 Hz, 1 H), 4.48 (q, J = 8.0 Hz, 2 H), 3.92 (s, 3 H). LCMS: 313.0 (M+l)+

Step 2: [3-bromo-4-(2,2,2-trifluoroethoxy)phenyl]methanol


[00799] To solution of the title compound from Step 1 (2.00 g, 5.85 mmol) in THF (20.0 mL) was added LiAlH4 (0.18 g, 4.68 mmol) in several portions at -40 °C. The mixture was kept at -40°C and stirred for 45 mins. The reaction was quenched with water (0.2 mL), 15% NaOH aqueous (0.2 mL) and additional water (0.6 mL). The mixture was stirred at room

temperature for 15 min. It was then dried over Na2S04 and filtered. The filtrate was concentrated and the residue purified by silica gel chromatography (PE:EA=5: 1-3:1) to give the title compound (1.62 g, 89%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 7.55 (d,

J = 2.0 Hz, 1 H), 7.31-7.28 (m, 1 H), 7.19 (d, J = 8.4 Hz, 1 H), 4.83 (q, J

(s, 2 H).

Step 3 : 2-bromo-4-(chloromethyl)- 1 -(2,2,2-trifluoroethoxy)benzene


[00800] A solution of the title compound from Step 2 (300 mg, 1.05 mmol) in DCM (10 mL) was cooled to 0 °C and treated with triethylamine (91 mg, 1.15 mmol) and methanesulfonyl chloride (142 mg, 1.25 mmol). The reaction mixture was warmed to room temperature and stirred overnight. It was then diluted with DCM (10 mL) and washed with 1 M hydrochloric acid (10 mL) and sat. NaHC03 (10 mL). The organic phase was dried over Na2S04, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to afford the title compound (260 mg, 82%) as a white solid. 1H NMR (CDC13, 400 MHz) δ 7.63 (d, J = 2.0 Hz, 1 H), 7.32 (dd, Ji = 8.4 Hz, J2 = 2.0 Hz, 1 H), 6.92 (d, J = 8.4 Hz, 1 H), 4.53 (s, 2 H), 4.42 (q, J = 8.0 Hz, 2 H)

Step 4 : 2-bromo-4-(ethylsulfanylmethyl)- 1 -(2,2,2-trifluoroethoxy)benzene


[00801] To a solution of the title compound from Step 3 (2.00 g, 6.59 mmol) in DCM (200 mL) was added TEA (1 g, 9.89 mmol), Nal (898 mg, 5.99 mmol) and EtSH (613 mg, 9.89 mmol). The mixture was stirred at 30 °C for 4 hrs. The reaction was poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2S04 and filtered. Solvents were removed under reduced pressure and the residue was purified by silica gel chromatography (PE:EA=1 :0~3 : 1) to give the title compound (2.1 g, 96.8%) as a white solid. 1H NMR (CDC13, 400 MHz) δ 7.55 (d, J = 2.0 Hz, 1 H), 7.24 (dd, Ji = 8.4 Hz, J2 = 2.0 Hz, 1 H), 6.89 (d, J = 8.4 Hz, 1 H), 4.42 (q, J = 8.0 Hz, 2 H), 3.66 (s, 2 H), 2.47-2.41 (m, 2H), 1.26-1.22 (m, 3H).

Step 5 : 2-bromo-4-(ethylsulfonylmethyl)- 1 -(2,2,2-trifluoroethoxy)benzene


[00802] To a solution of the title compound from Step 4 (2.10 g, 6.38 mmol) in DCM (210 mL) was added MCPBA (4.41 g, 25.53 mmol) in several portions. The mixture was stirred at 25°C for 12 hrs. The reaction was poured into sat. aq. Na2S03 (100 mL) and extracted with DCM (80 mL x 3). The combined organic layers were washed with sat. NaHC03 (100 mL x 2) and brine (100 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:EA=1 :0~2:1) to give the title compound (2.10 g, 91%) as a white solid. 1H NMR (CDC13, 400 MHz) δ 7.64 (d, J = 2.0 Hz, 1 H), 7.37 (dd, Ji = 8.4 Hz, J2 = 2.4 Hz, 1 H), 6.95 (d, J = 8.4 Hz, 1 H), 4.43 (q, J = 8.0 Hz, 2 H), 4.15 (s, 2 H), 2.91 (q, J = 7.6 Hz, 2 H), 1.39 (t, J = 7.6 Hz, 3 H).

Step 6: 4-[5-(ethylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]-2-methylisoquinolin-l-one


[00803] The title compound from Step 5 (200 mg, 0.58 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one (197 mg, 0.69 mmol), Pd(PPh )4 (67 mg, 58.0 umol) and Na2C03 (184 mg, 1.74 mmol) in dioxane (6 mL) and water (6 drops) was degassed and then heated to 70 °C for 18 hours under N2. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (PE:EA= 5: 1-1 : 1) followed by prep-HP LC purification to afford the title compound (164.44 mg, 67%) as an off-white solid. 1H NMR (CDC13, 400 MHz) δ 8.52 (d, J = 8.0 Hz, 1 H), 7.58-7.48 (m, 3 H), 7.40 (d, J = 2.4 Hz, 1 H), 7.22 (d, J = 8.0, 1 H), 7.07 (t, J = 8.0, 2 H), 4.30 (q, J = 8.0 Hz, 2 H), 4.23 (s, 2 H), 3.67 (s, 3 H), 2.98 (q, J = 7.6 Hz, 2 H), 1.43 (t, J = 7.6 Hz, 3 H). LCMS: 440.0 (M+l)+

Example 488: 2-methyl-4-[5-(methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]isoquinolin- 1 -one

Step 1 : 2-bromo-4-(methylsulfanylmethyl)-l-(2,2,2-trifluoroethoxy)benzene


[00804] The title compound was prepared in a manner similar to Example 487 Step 4, by substituting methanethiol for ethanethiol. 1H NMR (CDC13, 400 MHz) δ 7.56 (d, J = 2.0 Hz,

1 H), 7.25 (dd, Ji = 8.4 Hz, J2 = 2.0 Hz, 1 H), 6.93-6.90 (m, 1 H), 4.44-4.35 (m, 2 H), 3.63 (s,

2 H), 2.02 (s, 3 H).

Step 2 : 2-bromo-4-(methylsulfonylmethyl)- 1 -(2,2,2-trifluoroethoxy)benzene


[00805] The title compound was prepared in a manner similar to Example 487 Step 5, by substituting 2-bromo-4-(methylsulfanylmethyl)-l-(2,2,2-trifluoroethoxy)benzene for 2-bromo-4-(ethylsulfanylmethyl)-l-(2,2,2-trifluoroethoxy)benzene. 1H NMR (CDC13, 400 MHz) δ 7.65 (d, J = 2.0 Hz, 1 H), 7.38 (dd, Ji = 8.4 Hz, J2 = 2.4 Hz, 1 H), 7.12-7.06 (m, 1 H), 4.43 (q, J = 8.0 Hz, 2 H), 4.19 (s, 2 H), 2.82 (s, 3 H).

Step 3: 2-methyl-4-[5-(methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]isoquinolin-l-one


[00806] The title compound was prepared in a manner similar to Example 487 Step 6, by substituting 2-bromo-4-(methylsulfonylmethyl)-l-(2,2,2-trifluoroethoxy)benzene for 2-bromo-4-(ethylsulfonylmethyl)-l-(2,2,2-trifluoroethoxy)benzene. 1H NMR (CDC13, 400 MHz) δ 8.52 (d, J = 8.0 Hz, 1 H), 7.60-7.49 (m, 3 H), 7.41 (d, J = 2.0 Hz, 1 H), 7.22 (d, J = 8.0, 1 H), 7.08-7.06 (m, 2 H), 4.33-4.27 (m, 4 H), 3.67 (s, 3 H), 2.87 (s, 3 H). LCMS: 426.0 (M+l)+

Example 489: l,3-dimethyl-5-(7-methylsulfonyl-2,3-dihydro-l,4-benzodioxin-5-yl)pyridin-2-one


[00807] The title compound was prepared in a manner similar to Example 486, by

substituting 6-bromo-2,3-dihydro-l,4-benzodioxine for 5-bromo-2-methyl-2,3-dihydro-l-benzofuran in step 1. 1H NMR (CDC13, 400 MHz) δ 7.51 (m, 2 H), 7.44 (d, J = 2.4 Hz, 1 H), 7.42 (d, J = 2.4 Hz, 1 H), 4.38 (m, 4 H), 3.68 (s, 3 H), 3.08 (s, 3 H), 2.24 (s, 3H). LCMS: 336.0 (M+l)+

Example 490: N-[2-ethyl-8-(2 -methyl- 1-oxoisoquino lin-4-yl)-3,4-dihydro-2H-chromen-6-yljmethanesulfonamide

Step 1 : 3,4-dihydro-2H-chromen-2-ylmethanol


[00808] A mixture of 4-oxochromene-2-carboxylic acid (20.0 g, 105 mmol) and Pd/C (3.0 g, w/w = 10%) in AcOH (200 mL) was placed in Parr hydrogenation apparatus under H2 (50 psi) and stirred for 25 h at rt. It was then filtered and concentrated. The residue was suspended in water (300 mL), stirred for 10 min, filtered and dried to give 3,4-dihydro-2H-chromene-2-carboxylic acid (13.5 g, 72%) as a white solid. BH3 (57 mL, 114 mmol, 2.0 M in THF) was added slowly to a solution of this carboxylic acid in THF (120 mL) at 0 °C. The reaction mixture was then warmed to rt and stirred for 5 h at this temperature. THF/H20 (30 mL, 1 : 1) was added drop wise while keeping the temperature between 0-5 °C and stirred for 20 min. K2C03 (26.0 g, 189 mmol) was added and the reaction was vigorously stirred for 30 min. The THF layer was separated and concentrated to give the title compound (11.0 g, 89%) as a brown oil. 1H NMR (400 MHz, CDC13): δ 7.10-7.03 (m, 2H), 6.86-6.81 (m, 2H), 4.14-4.08 (m, 1H), 3.85-3.68 (m, 2H), 2.92-2.84 (m, 1H), 2.80-2.73 (m, 1H), 1.98-1.92 (m, 1H), 1.90-1.79 (m, 1H). LCMS: 165 (M+l)+

Step 2: 3,4-dihydro-2H-chromen-2-ylmethyl trifluoromethanesulfonate


[00809] Trifluoromethanesulfonic anhydride (19.6 g, 69.5 mmol) in DCM (15 mL) was added to a solution of the title compound from Step 1 (9.50 g, 57.9 mmol) in DCM (100 and pyridine (11.0 g, 139 mmol) cooled to -5 C. The reaction was then stirred at 0°C for 1 h.

Water (150 mL) was added and the reaction was extracted with DCM (150 mL). The organic layer was washed with 1 M HC1 (180 mL), water (100 mL), and NaHC03 aqueous solution (100 mL). The organic phase was dried over Na2S04 ,filtered and concentrated to give the title compound (13.5 g, 79%) as a pale-brown oil. 1H NMR (400 MHz, CDC13): δ 7.12-7.04 (m, 2H), 6.90-6.83 (m, 2H), 4.66-4.61 (m, 2H), 4.36-4.31 (m, 1H), 2.96-2.79 (m, 2H), 2.09-2.03 (m, 1H), 1.95-1.84 (m, 1H). LCMS: 314 (M+ NH4)+

Step 3: 2-ethyl-3,4-dihydro-2H-chrom


[00810] MeMgBr (45.6 mL, 137 mmol, 3M in ether) was added to a mixture of the title compound from Step 2 (13.5 g, 45.6 mmol) and CuBr-Me2S (1.61 g, 7.74 mmol) in THF (150 mL) at -5 C. The reactions was stirred at rt for 2 h. It was then poured onto a solution of NH4C1 (55 g, 1.04 mol) in water (200 mL) and extracted with DCM (3 x 150 mL). The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure to give the title compound (6.66 g, 90%) as a brown oil. 1H NMR (400 MHz, CDC13): δ 7.09-7.02 (m, 2H), 6.82-6.78 (m, 2H), 3.93-3.87 (m, 1H), 2.84-2.72 (m, 2H), 2.02-1.96 (m, 1H), 1.81-1.61 (m, 3H), 1.04 (t, J = 7.2 Hz, 3H).

Step 4: 2-ethyl-6-nitro-3,4-dihydro-2H-chromene and 2-ethyl-8-nitro-3,4-dihydro-2H-chromene


[00811] The title compound from Step 3 (1.0 g, 6.17 mmol) was added to HNO3 (5 mL, 65- 68%) at 0 C, warmed to rt and stirred for 1 h. It was then poured onto an ice-water mixture, extracted with EtOAc (50 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA 100: 1 to 50: 1) to give a mixture of the title compounds (600 mg) which was used in the next step.

Step 5 : N-(2-ethyl-3,4-dihydro-2H-chromen-6-yl)methanesulfonamide


[00812] The mixture of the title compounds from Step 4 (600 mg) was suspended in MeOH (6 mL) and sat. NH4C1 solution (2 mL). Fe (810 mg, 14.5 mmol) was added and the mixture was heated to 85 C for 2.5 h. It was then filtered and extracted with EtOAc. The organic layer was dried and concentrated under reduced pressure to give a crude mixture of 2-ethyl-3,4-dihydro-2H-chromen-6-amine and 2-ethyl-3,4-dihydro-2H-chromen-8-amine. This mixture was dissolved in DCM (10 mL) and TEA (0.8 mL) and methanesulfonyl chloride (400 mg, 3.50 mmol) were added. The mixture was stirred at rt for 1 h. It was then extracted with DCM (45 mL x 2), dried over Na2S04, filtered, concentrated under reduced pressure and purified by column chromatography (PE/EA 50: 1 to 20: 1 to 10: 1) to give the title compound (190 mg, 12% for three steps) as a yellow solid. 1H NMR (300 MHz, CDCI3): δ 6.99-6.80 (m, 2H), 6.78 (d, J= 8.7 Hz, 1H), 6.16 (s, 1H), 3.95-3.90 (m, 1H), 2.96 (s, 3H), 2.83-2.76 (m, 2H), 2.04-1.97 (m, 1H), 1.81-1.64 (m, 3H), 1.05 (t, J = 7.2 Hz, 3H). LCMS: 273 (M+ NH4)+ Step 6 : N-(8-bromo-2-ethyl-3 ,4-dihydro-2H-chromen-6-yl)methanesulfonamide


[00813] To a solution of the title compound from Step 5 (170 mg, 0.667 mmol) in ACN (6 mL) was added NBS (156 mg, 0.867 mmol). The mixture was stirred for 7 h at rt. It was then extracted with DCM, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified with prep-TLC (PE/EA 3 : 1) to give the title compound (105 mg, 47%) as a gray solid. 1H NMR (400 MHz, CDC13): δ 7.23 (d, J= 2.4 Hz, 1H), 6.96 (d, J= 2.4 Hz, 1H), 6.24 (s, 1H), 4.01-3.99 (m, 1H), 2.97 (s, 3H), 2.84-2.77 (m, 2H), 2.04-1.99 (m, 1H), 1.85-1.66 (m, 3H), 1.09 (t, J = 7.2 Hz, 3H).

Step 7 : N-[2-ethyl-8-(2 -methyl- 1 -oxoisoquinolin-4-yl)-3 ,4-dihydro-2H-chromen-6-yljmethanesulfonamide


[00814] A mixture of the title compound from Step 6 (105 mg, 0.315 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one (108 mg, 0.379 mmol), K2CO3 (131 mg, 0.949 mmol) and Pd(dppf)Cl2 (23.1 mg, 0.032 mmol) in dioxane/H20 (10 mL/ 3 mL) was heated to 85 °C for 2 h. It was then filtered and extracted with EtOAc. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA 50: 1 to 20: 1 to 10: 1) to give the title compound (25 mg, 19%). 1H NMR (400 MHz, CD3OD) δ 8.31 (d, J= 8.4 Hz, 1H), 7.59-7.55 (m, 1H), 7.47-7.43 (m, 1H), 7.31-7.23 (m, 2H), 7.05 (s, 1H), 6.95 (d, J= 2.8 Hz, 1H), 3.77-3.71 (m, 1H), 3.60 (s, 3H), 2.95-2.75 (m, 5H), 1.95-1.92 (m, 1H), 1.66-1.54 (m, 1H), 1.38-1.22 (m, 2H), 0.59-0.55 (m, 1.25H), 0.42-0.38 (m, 1.75H). LCMS: 413.0 (M+l)+.

Example 491: N-[2-ethyl-8-(2 -methyl- 1-oxoisoquino lin-4-yl)-3,4-dihydro-2H-chromen-6-yl] ethanesulfonamide


[00815] The title compound was prepared in a manner similar to Example 490 by substituting ethanesulfonyl chloride for methanesulfonyl chloride in Step 5. 1H NMR (400 MHz,

CD3OD): δ 8.39 (d, J= 7.6 Hz, 1H), 7.67-7.63 (m, 1H), 7.56-7.52 (m, 1H), 7.37-7.30 (m, 2H), 7.12 (s, 1H), 7.03 (d, J= 2.8 Hz, 1H), 3.86-3.81 (m, 1H), 3.69 (s, 3H), 3.10 (q, J = 7.2 Hz, 2H), 3.02-2.81 (m, 2H), 2.03-1.99 (m, 1H), 1.75-1.41 (m, 3H), 1.36 (t, J = 7.6 Hz, 3H), 0.67-0.62 (m, 1.25H), 0.51-0.48 (m, 1.75H). LCMS: 427.0 (M+l)+.

Example 492: N-[8-(l ,5-dimethyl-6-oxopyridin-3-yl)-2-ethyl-3,4-dihydro-2H-chromen-6-yl] ethanesulfonamide


[00816] The title compound was prepared in a manner similar to Example 491 by substituting l,3-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one for 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one. 1H NMR (400 MHz, CD3OD): δ 7.69 (s, 1H), 7.66 (s, 1H), 7.02 (m, 1H), 7.0 (s, 1H), 3.96-3.93 (m, 1H), 3.65 (s, 3H), 3.07 (q, J = 7.5 Hz, 2H), 2.93-2.82 (m, 2H), 2.18 (s, 3H), 2.08-2.04 (m, 1H), 1.72-1.66 (m, 3H), 1.34 (t, J = 7.6 Hz, 3H), 1.04 (t, J = 7.2 Hz, 3H). LCMS: 391.0 (M+l)+.

Example 493 : 4-(2-cyclopropyl-5-methylsulfonyl-2,3-dihydro- 1 -benzofuran-7-yl)-2-methylisoquinolin- 1 -one

Step 1 : 7-bromo-2-cyclopropyl-5-meth lsulfonyl-l-benzofuran


[00817] To a solution of 2,6-dibromo-4-methylsulfonylphenol (1 g, 3.30 mmol) in pyridine (40 mL) was added ethynylcyclopropane (240 mg, 3.64 mmol) and Cu20 (260 mg, 1.82 mmol). The reaction mixture was degassed with N2. The mixture was heated to 130 °C for 3 hours. It was then concentrated and purified by column chromatography (PE to PE/EA=3/1) to give the title product (510 mg, 53%) as a gray solid. 1H NMR (CDCI3, 400 MHz) δ 7.99 (s, 1 H), 7.93 (s, 1 H), 6.52 (s, 1 H), 3.07 (s, 3 H), 2.13-2.11 (m, 1 H), 1.13-1.05 (m, 4 H).

Step 2 : 7-bromo-2-cyclopropyl-5 -meth lsulfonyl-2,3 -dihydro- 1 -benzofuran


[00818] To a solution of the title compound from Step 1 (250 mg, 0.7 9mmol) in Et3SiH (516 mg, 4.44 mmol) at 0 °C was added TFA (5.43 g, 47.59 mmol) in one portion. The reaction mixture was warmed up to rt and stirred for 48 hours. Aqueous NaOH solution (10 mL, 1 N) was added slowly to the above solution. The mixture was extracted with EtOAc (10 mL). The organic layer was dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography (PE to PE/EA=2/1) to give the title compound (83 mg, 33%) as a white solid. 1H NMR (CDC13, 400 MHz) δ 7.90 (s, 1 H), 7.64 (s, 1 H), 4.47-4.43 (m, 1 H), 3.51-3.47 (m, 1 H), 3.23-3.17 (m, 1 H), 3.04 (s, 3 H) , 1.24-1.22 (m, 1 H), 0.74-0.55 (m, 3 H), 0.44-0.41 (m, 1 H).

Step 3 : 4-(2-cyclopropyl-5-methylsulfonyl-2,3-dihydro- 1 -benzofuran-7-yl)-2-methylisoquinolin- 1 -one


[00819] To a solution of the title compound from Step 2 (80 mg, 252 umol) in dioxane (10.00 mL) and H20 (1.00 mL) was added Pd(dppf)Cl2 (9 mg, 12.61 umol), K3P04 (134 mg, 631 umol) and 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one (79 mg, 278 umol) in one portion. The reaction mixture was degassed with N2 and heated to 90 °C for 3 hours. It was then concentrated and purified by prep-HPLC to give the title compound (18.36 mg, 19% yield). 1H NMR (CDC13, 400 MHz) δ 8.53-8.51 (d, J=8.0 Hz, 1 H), 7.79 (s, 1 H), 7.75 (s, 1 H), 7.63-7.56 (m, 2 H), 7.33-7.31 (d, J = 8.0 Hz, 1 H), 7.15 (s, 1 H), 4.43-4.37 (m, 1 H), 3.68 (s, 3 H), 3.50-3.46 (m, 1 H), 3.32-3.16 (m, 1 H), 3.09 (s, 3 H), 1.21-1.06 (m, 1 H), 0.60-0.59 (m, 2 H), 0.39-0.32 (m, 2 H). LCMS: 396.0 (M+l) +

Example 494 : 4-(2-ethyl-5 -methylsulfonyl-2,3 -dihydro- 1 -benzofuran-7-yl)-2-methylisoquinolin- 1 -one

Step 1 : 2-ethyl-7-iodo-5-methylsulfon l-l-benzofuran


[00820] To a solution of 2,6-diiodo-4-methylsulfonylphenol (1.00 g, 2.36 mmol) in pyridine (10 mL) at 25°C was added but-l-yne (128 mg, 2.36 mmol) and Cu20 (135 mg, 0.944 mmol). The mixture was stirred at 130 °C for 3 h under a nitrogen atmosphere. The residue

was cooled to 25°C, diluted with IN HC1 (200 ml) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed by brine (100 mL), dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography (PE:EA=10: 1 to 5: 1) to afford the title compound (400 mg, 48%) as a solid. 1H NMR (CDC13, 400 MHz) δ 8.14 (d, J=1.6 Hz, 1 H), 8.06 (d, J=1.6 Hz, 1 H), 6.62 (s, 1 H), 3.09 (s, 3 H), 2.90 (q, J = 7.6 Hz, 2 H), 1.38 (t, J=7.6 Hz, 3 H). LCMS: 350.9 (M+H+)

Step 2 : 4-(2-ethyl-5 -methylsulfonyl- -benzofuran-7-yl)-2-methylisoquinolin- 1 -one


[00821] To a solution of 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one (82 mg, 286 umol) and the title compound from Step 1 (100 mg, 286 umol) in H20 (2 mL) and dioxane (20 mL) was added Pd(dppf)Cl2 (21 mg, 28.6 umol, 0.10 Eq) and Na2C03 (61 mg, 572 umol). The mixture was degassed with nitrogen and heated to 90 °C for 4 h. It was then cooled to rt and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EA=3 : 1 to 1 : 1) followed by prep-HPLC to afford the title compound (35.57 mg, 33%) as a white solid. 1H NMR (CDCI3, 400 MHz) δ 8.56 (d, J=7.2 Hz, 1 H), 8.19 (d, J=1.6 Hz, 1 H), 7.83 (d, J=1.6 Hz, 1 H), 7.60 -7.57 (m, 2 H), 7.29-7.27 (m, 2 H), 6.60 (s, 1 H), 3.73 (s, 3 H), 3.15 (s, 3 H) 2.75 (q, J=7.2 Hz, 2 H), 1.28 (t, J=7.2 Hz, 3 H). LCMS: 382.0 (M+H+)

Step 3 : 4-(2-ethyl-5 -methylsulfonyl-2,3 -dihydro- 1 -benzofuran-7-yl)-2-methylisoquinolin- 1 -one


[00822] To a solution of the title compound from Step 2 (130 mg, 340 umol) in MeOH (3 mL) was added Pd/C (70 mg, 10%> w/w) in one portion. The reaction mixture was stirred at 25 °C under H2 atmosphere (15 psi) for 8 h. After this time, the mixture was filtered through celite. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC to give the title compound (12.4 mg) as a gray solid. 1H NMR (CDC13, 300 MHz) δ 8.54-8.51 (d, J=7.5 Hz,l H), 7.79-7.75 (m, 2 H), 7.75-7.54 (m, 2 H), 7.32-7.29 (d, J=8.1 Hz, 1 H), 7.16 (s, 1 H), 4.90-4.85 (m, 1 H), 3.69 (s, 3 H), 3.49-3.41 (m, 1 H), 3.06-3.00 (m, 1 H), 1.85-1.70 (m, 2 H), 0.96-0.91 (t, J=7.5 Hz, 3 H). LCMS: 384.0 (M+l)

Example 495: N-[7-(l,5-dimethyl-6-oxopyridin-3-yl)-2-propyl-2,3-dihydro-l-benzofuran-5-yl] ethanesulfonamide

Step 1 : 2-cyclopropyl-7-iodo-5-nitro-l-benzofuran


[00823] A solution of 2,6-diiodo-4-nitrophenol (10 g, 25.6 mmol), ethynylcyclopropane (1.9 g, 28.8 mmol) and Cu20 (1.9 mg, 13.2 mmol) in 100 mL of dry pyridine was refluxed for 2 h, The reaction mixture was poured into 1 L of water and stirred for 10 min. The resulting mixture was filtered. The cake was purified by column chromatography on silica gel eluting with EtOAc/PE (0-20%) to give the title compound (6.6 g, 78% yield) as a yellow solid. 1H NMR (CDC13, 400 MHz): δ 8.47 (d, J = 2.4 Hz, 1H), 8.32 (d, J= 2.4 Hz, 1H), 6.58 (s, 1H), 2.13-2.07 (m, 1H), 1.14-1.04 (m, 4H).

Step 2: 2-cyclopropyl-7-iodo-l-benzofuran-5 -amine


[00824] To a solution of the title compound from Step 1 (2.0 g, 6.0 mmol) and Fe (1.0 g, 18 mmol) in MeOH (80 mL) was added sat. NH4CI solution (10 mL). The reaction mixture was refluxed for 1 h. The mixture was cooled to room temperature and poured into 400 mL of DCM. The resulting mixture was filtered and the filtrate was washed with water (100 mL) and brine. The organic layer was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give the crude title compound (1.5 g, 83% yield) as red oil that was used for the next step directly. 1H NMR (CDC13, 400 MHz): δ 6.87 (d, J= 2.4 Hz, 1H), 6.61 (d, J= 2.0 Hz, 1H), 6.19 (s, 1H), 3.45 (br, 2H), 1.97-1.90 (m, 1H), 0.95-0.85 (m, 4H). LCMS: 300 (M+l)+.

Step 3: N-(2-cyclopropyl-7-iodo-l-benzofuran-5-yl)ethanesulfonamide


[00825] To a solution of the title compound from Step 2 (1.0 g, 3.3 mmol) in 20 mL of dry DCM was added a solution of pyridine (793 mg, 10 mmol) in DCM (10 mL), followed by

addition of EtS02Cl (473 mg, 3.7 mmol). The reaction mixture was stirred at room temperature for 1 h. It was diluted with DCM (20 mL) and washed with water (20 mL x 2) and brine. The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure to give the crude title compound (1.3 g, 100% yield) that was used directly in the next step. 1H NMR (CDC13, 400 MHz): δ 7.42 (d, J= 2.0 Hz, 1H), 7.38 (d, J= 2.0 Hz, 1H), 6.88 (br, 1H), 6.40 (s, 1H), 3.09 (q, J= 7.2 Hz, 2H), 1.37 (t, J= 7.2 Hz, 3H), 2.04-2.08 (m, 1H), 1.06-0.97 (m, 4H). LCMS: 409 (M+18)+.

Step 4: N-[2-cyclopropyl-7-(l,5-dimethyl-6-oxopyridin-3-yl)-l-benzofuran-5-yl] ethanesulfonamide


[00826] To a solution of the title compound from Step 3 (500 mg, 1.3 mmol) and 1,3-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one (380 mg, 1.5 mmol) in 10 mL of DMF was added K2C03 (50 mg, 3.8 mmol), water (2 mL ) and Pd(dppf)Cl2 (30 mg) under N2. The reaction mixture was heated to 100 °C for 1 h. The resulting mixture was poured into 100 mL of water and extracted with DCM (100 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with EtOAc to give the title compound (230 mg, 47% yield) as a white solid. 1H NMR (CDC13, 400 MHz): δ 7.81 (d, J= 3.6 Hz, 1H), 7.67-7.66 (m, 1H), 7.26 (t, J= 1.2 Hz, 1H), 7.12 (d, J = 3.2 Hz, 1H), 6.54 (br, 1H), 6.36 (d, J= 0.8 Hz, 1H), 3.67 (s, 3H), 3.14-3.06 (m, 2H), 2.25 (s, 3H), 2.11-2.00 (m, 1H), 1.38-1.43 (m, 3H), 1.09-0.92 (m, 4H). LCMS: 387 (M+l)+. Step 5 : N-[7-(l ,5-dimethyl-6-oxopyridin-3-yl)-2-propyl-2,3-dihydro- 1 -benzofuran-5-yl] ethanesulfonamide


[00827] A mixture of the title compound from Step 4 (70 mg, 0.18 mmol) and 10 mg of Pd/C in 40 mL of MeOH was stirred under a H2 atmosphere at room temperature for 1 h. The

resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (10 mg, 14 % yield) as a white solid. 1H NMR (CDCI3, 300 MHz): δ 7.77 (d, J= 2.1 Hz, 1H), 7.56 (s, 1H), 7.04 (s, 1H), 7.01 (s, 1H), 6.26 (d, J= 2.7 Hz, 1H), 4.88-4.84 (m, 1H), 3.61 (s, 3H), 3.34-3.26 (m, 1H), 3.09 (q, J= 7.5 Hz, 2H), 2.90-2.84 (m, 1H), 2.21 (s, 3H), 1.87-1.82 (m, 1H), 1.72-1.63 (m, 1H), 1.56-1.43 (m, 2H), 1.38 (t, J= 7.2 Hz, 3H), 0.98 (t, J= 7.5 Hz, 3H). LCMS: 391 (M+l)+.

Example 496: N-[2-cyclopropyl-7-(l,5-dimethyl-6-oxopyridin-3-yl)-2,3-dihydro-l-benzofuran-5 -yl] ethanesulfonamide


[00828] To a mixture of the title compound from Example 495, Step 4, (30 mg, 0.08 mmol) in Et3SiH (1 mL) in a sealed tube was added TFA (0.2 mL) at 0 °C. It was allowed to warm up to room temperature and stirred overnight. The resulting mixture was diluted with DCM (30 mL) and washed with 1 N NaOH, water and brine. The organic phase was dried over Na2S04, filtered and concentrated under reduced pressure. The residue was recrystallized from EtOAc to give the title compound (3 mg, 10% yield) as a white solid. 1H NMR (CDC13, 300 MHz): δ 7.77 (s, 1H), 7.57 (s, 1H), 7.04 (d, J= 3.0 Hz, 2H), 6.44 (s, 1H), 4.37-4.29 (m, 1H), 3.63 (s, 3H), 3.37-3.29 (m, 1H), 3.13-3.03 (m, 3H), 2.22 (s, 3H), 1.40 (t, J= 7.5 Hz, 3H), 1.26-1.14 (m, 1H), 0.71-0.33 (m, 4H). LCMS: 389 (M+l)+.

Example 497: 4-[3-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-l,4-benzodioxin-5-yl]-2-methylisoquinolin- 1 -one

Step 1 : (6-bromo-2,3-dihydro-l,4-benzodioxin-2-yl)methanol and (6-bromo-2,3-dihydro-l,4-benzodioxin-3 -yl)methan


[00829] To a mixture of NaOH (1.6 g, 39.7 mmol) in THF (120 mL) and H20 (40 mL) was added 4-bromobenzene-l,2-diol (5 g, 26.5 mmol). Oxiran-2-ylmethanol (7.35 g, 79.5 mmol) was added in portion wise at room temperature under N2. The reaction was stirred at 100°C for 4 hrs. It was then cooled down to rt and extracted with EtOAc (50 mL x 2). The organic layers were washed with brine (40 mL x 2), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EA = 5/1) to give a mixture of the title compounds (4.7 g, 73 %). LCMS: 166 (M-80)+.

Step 2: (6-methylsulfonyl-2,3-dihydro-l,4-benzodioxin-2-yl)methanol and (6-methylsulfonyl-2,3-dihydro-l,4-benzodioxin-3-yl)methanol


[00830] The mixture from Step 1 (1 g, 4.08 mmol) was submitted to the experimental conditions described in Example 486, Step 1, to give a mixture of the title compounds (650 mg, 65%). LCMS: 245.1 (M+l)+.

Step 3: 2-(methoxymethyl)-6-methylsulfonyl-2,3-dihydro-l,4-benzodioxine and 3-(methoxymethyl)-6-methylsulfonyl-2,3-dihydro- 1 ,4-benzodioxine


[00831] To a solution of the mixture from Step 2 (2.5 g, 10.23 mmol) in THF (30 mL) was added NaH (614 mg, 15.35 mmol) at 0°C. The reaction was stirred at 0 °C for 1 hr. CH3I (1.45 g, 10.23 mmol) was added to the reaction mixture while keeping the internal temperature around 0°C. The reaction mixture was stirred at room temperature for another 3 hrs. It was then quenched with ice and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EA = 3/1) to give a mixture of the title compounds (1.5 g, 57%) as an oil. The mixture was further separated into its four individual components by chiral phase SFC to give the two enantiomers of 2-(methoxymethyl)-6-methylsulfonyl-2,3-dihydro-l,4-benzodioxine (200 mgs each) and the two enantiomers of 3-(methoxymethyl)-6-methylsulfonyl-2,3-dihydro-l,4-benzodioxine (200 and 120 mgs, respectively). Their absolute stereochemistry was not assigned. 2-(methoxymethyl)-6-methylsulfonyl-2,3-dihydro-l,4-benzodioxine 1H NMR (CDC13, 400 MHz) δ 7.44 (d, J = 1.6 Hz, 1 H), 7.41 (dd, Ji = 8.8 Hz, = 2.0 Hz, 1 H), 7.03 (d, J = 8.0 Hz, 1 H), 4.42-4.31 (m, 2 H), 4.10 (dd, Ji = 11.6 Hz, = 7.6 Hz, 1 H), 3.71-3.58 (m, 2 H), 3.42 (s, 3 H), 3.01 (s, 3 H). LCMS: 259 (M+l)+. 3-(methoxymethyl)-6-methylsulfonyl-2,3-dihydro-l,4-benzodioxine 1H NMR (CDC13, 400 MHz) δ 7.47 (d, J = 2.0 Hz, 1 H), 7.41 (dd, Ji = 8.8 Hz, J2 = 2.0 Hz, 1 H), 7.00 (d, J = 8.4 Hz, 1 H), 4.40-4.30 (m, 2 H), 4.18-4.10 (dd, Ji = 11.2 Hz, J2 = 7.2 Hz, 1 H), 3.70-3.58 (m, 2 H), 3.42 (s, 3 H), 3.00 (s, 3 H). LCMS: 259 (M+l)+.

Step 4: 5-bromo-3-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-l,4-benzodioxine


[00832] The title compound (single enantiomer, absolute stereochemistry not assigned) was prepared in a manner similar to Example 486, Step 2, by substituting 2-(methoxymethyl)-6-methylsulfonyl-2,3-dihydro-l,4-benzodioxine for 2-methyl-5-methylsulfonyl-2,3-dihydro-l-benzofuran. 1H NMR (CDC13, 400 MHz) δ 7.70 (d, J = 2.0 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1 H), 4.53 (dd, Ji = 2.2 Hz, J2 = 11.4 Hz, 1 H), 4.39-4.34 (m, 1 H), 4.26-4.21 (m, 1 H), 3.73-3.63 (m, 2 H), 3.45 (s, 3 H), 3.03 (s, 3 H).

Step 5 : 4-[3-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-l ,4-benzodioxin-5-yl]-2-methylisoquinolin- 1 -one


[00833] A mixture of the title compound from Step 4 (20 mg, 0.06 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one (20 mg, 0.07 mmol), Na2C03 (19 mg, 0.18 mmol), Pd(dppf)Cl2 (7 mg, 0.01 mmol) in dioxane (2 mL) and H20 (0.2 mL) was stirred at 80°C for 12 hrs under N2. The reaction mixture was poured over H20 (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give a residue that was purified by column chromatography followed by prep-HP LC to afford the title compound (12 mg, 24%). Absolute stereochemistry not assigned. 1H NMR (DMSO-d6, 400 MHz) δ 8.30 (d, J = 8.0 Hz, 1 H), 7.68-7.63 (m, 1 H), 7.55-7.52 (m, 3 H), 7.42 (s, 1 H), 7.28 (d, J = 8.4 Hz, 1 H), 4.43-4.35 (m, 2 H), 4.21-4.12 (m, 1 H), 3.56 (s, 3 H), 3.44-3.41 (m, 2H), 3.23 (s, 3 H), 3.09 (s, 3 H). LCMS: 416.0 (M+H)+

Example 498: 5-[3-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-l,4-benzodioxin-5-yl]-1 ,3-dimethylpyridin-2-one


[00834] The title compound (single enantiomer, absolute stereochemistry not assigned) was prepared in a manner similar to Example 497, by substituting l,3-dimethyl-5-(4,4,5,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)pyridin-2-one for 2-methyl-4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)isoquinolin-l-one in Step 5. 1H NMR (CDC13, 400 MHz) δ 7.53 (s, 1 H), 7.49 (s, 1 H), 7.43 (m, 2 H), 4.45-4.37 (m, 2 H), 4.18-4.17 (m, 1 H), 3.68-3.62 (m, 5 H), 3.44 (s, 3 H), 3.07(s, 3 H), 2.21 (s, 3H). LCMS: 380 (M+H) +

Example 499: 4-[3-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-l,4-benzodioxin-5-yl]-2-methylisoquinolin- 1 -one


[00835] The title compound (single enantiomer, absolute stereochemistry not assigned) was prepared in a manner similar to Example 497, by substituting the compound used in Step 4 for its enantiomer. 1H NMR (DMSO-d6, 400 MHz) δ 8.30 (d, J = 8.0 Hz, 1 H), 7.68 (t, J = 8.0 Hz, 1 H), 7.55-7.51 (m, 3 H), 7.42 (s, 1 H), 7.28 (d, J = 8.0 Hz, 1 H), 4.42-4.35 (m, 2 H), 4.21-4.14 (m, 1 H), 3.56 (s, 3 H), 3.44-3.39 (m, 2H), 3.24 (s, 3 H), 3.09 (s, 3 H). LCMS: 416.0 (M+H) +

Example 500: 5-[3-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-l,4-benzodioxin-5-yl]-1 ,3-dimethylpyridin-2-one


[00836] The title compound (single enantiomer, absolute stereochemistry not assigned) was prepared in a manner similar to Example 498 but using the other enantiomer of 5-bromo-3-

(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-l,4-benzodioxine. 1H NMR (CDCI3, 400 MHz) δ 7.59 (s, 1 H), 7.58 (s, 1 H), 7.44 (m, 2 H), 4.41-4.37 (m, 2 H), 4.20-4.18 (m, 1 H), 3.71-3.63 (m, 5 H), 3.44 (s, 3 H), 3.07 (s, 3 H), 2.24 (s, 3H). LCMS: 380.0 (M+H) +

Example 501: 4-[2-(methoxymethyl)-7-methylsulfonyl-2,3-dm^

methylisoquinolin- 1 -one

Step 1 : 5-bromo-2-(methoxymethyl)- -methylsulfonyl-2,3-dihydro-l,4-benzodioxine


[00837] The title compound (single enantiomer, absolute stereochemistry not assigned) was prepared in a manner similar to Example 497, Step 4, by substituting 2-(methoxymethyl)-6-methylsulfonyl-2,3-dihydro-l ,4-benzodioxine for 3-(methoxymethyl)-6-methylsulfonyl-2,3-dihydro-l,4-benzodioxine. LCMS: 359 (M+23) +

Step 2: 4-[2-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-l ,4-benzodioxin-5-yl]-2-methylisoquinolin- 1 -one


[00838] The title compound (single enantiomer, absolute stereochemistry not assigned) was prepared in a manner similar to Example 497, Step 5, by substituting 5-bromo-2-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro- 1 ,4-benzodioxine for 5-bromo-3-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-l,4-benzodioxine. 1H NMR (DMSO-d6, 400 MHz) δ 8.31 (d, J = 8.0 Hz, 1 H), 7.66-7.63 (m, 1 H), 7.56-7.51 (m, 3 H), 7.40 (s, 1 H), 7.30-7.16 (m, 1 H), 4.53-4.44 (m, 1 H), 4.36-4.28 (m, 1 H), 4.12-4.01 (m, 1 H), 3.61-3.56 (m, 5 H), 3.34 (s, 3 H), 3.24 (s, 3 H). LCMS: 416.0 (M+H) +

Example 502: 5-[2-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-l,4-benzodioxin-5-yl]-1 ,3-dimethylpyridin-2-one


[00839] The title compound (single enantiomer, absolute stereochemistry not assigned) was prepared in a manner similar to Example 501, by substituting l,3-dimethyl-5-(4,4,5,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)pyridin-2-one for 2-methyl-4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)isoquinolin-l-one. 1H NMR (CDC13, 400 MHz) δ 7.48 (m, 3 H), 7.41 (d, J = 2.4 Hz, 1 H), 4.47-4.34 (m, 2 H), 4.19-4.16 (m, 1 H), 3.71-3.65 (m, 5 H), 3.45 (s, 3 H), 3.05 (s, 3 H), 2.22 (s, 3H). LCMS: 380.0 (M+H) +

Example 503: 4-[2-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-l,4-benzodioxin-5-yl]-2-methylisoquinolin- 1 -one


[00840] The title compound (single enantiomer, absolute stereochemistry not assigned) was prepared in a manner similar to Example 501, by substituting the compound used in Step 1 for its enantiomer. 1H NMR (CD3OD, 400 MHz) 58.41 (d, J = 8.0 Hz, 1 H), 7.70 (t, J = 7.6 Hz, 1 H), 7.58-7.54 (m, 2 H), 7.48 (s, 1 H), 7.42 (s, 1 H), 7.33-7.30 (m, 1 H), 4.52-4.41 (m, 2

H), 4.20-4.12 (m, 1 H), 3.67 (s, 3 H), 3.47 (m, 2 H), 3.19-3.15 (m, 6 H). LCMS: 416.0 (M+H)

+

Example 504: 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin- 1 -one

Step 1 : ethyl 6,7-dihydro-5H-cyclopenta c]pyridine-l-carboxylate


[00841] Ethyl l,2,4-triazine-3-carboxylate (7 g, 45.8 mmol), cyclopentanone (4.9 mL, 55.0 mmol), and pyrrolidine (4.6 mL, 55.0 mmol) in toluene (100 mL) were heated to reflux for 12 h. The mixture was purified by column on silica gel chromatography (PE/EtOAc =5: 1) to give the title compound (2.02 g, 25%) as a brown oil. LCMS: 192 (M+l)+

Step 2: 6,7-dihydro-5H-cyclopenta[c ridine-l-carboxylic acid


[00842] A 2N solution of LiOH (50 mL) in water was slowly added to the title compound of step 1 (10 g, 52.4 mmol) in MeOH (250 mL) at 0 °C. The mixture was allowed to warm to rt and stirred for 30 min. The MeOH was reduced under vacuum and the residual aqueous solution was washed with EtOAc. The organic phase was re-extracted with water. The combined aqueous extracts were acidified to pH = 2 with IN HC1. The water was removed and preparative HPLC gave the title compound (5.4 g, 63%) as a white solid. 1H NMR (CD3OD, 400 MHz): δ 8.45 (d, J= 5.6 Hz, 1H), 7.88 (d, J= 5.6 Hz, 1H), 3.39 (t, J= 8.0, 7.6 Hz, 2H), 3.16 (d, t, J= 8.0, 7.6 Hz, 2H), 2.16-2.20 (m, 2H).

Step 3: tert-butyl N-(6,7-dihydro-5H-cyclopenta[c]pyridin-l-yl)carbamate

oc


[00843] The title compound of step 2 (1.0 g, 6.1 mmol), diphenylphosphoryl azide (2.64 mL 12.2 mmol), and triethylamine (1.64 mL, 12.2 mmol) in tBuOH (50 mL) under N2 were heated at 80 °C for 2 h. Silica gel chromatography (PE/EtOAc = 5: 1) gave the title compound (570 mg, 40%) as a white solid. 1H NMR (CDCI3, 300 MHz): δ 8.18 (d, J= 4.8 Hz, 1H), 7.04 (d, J= 4.8 Hz, 1H), 2.90-2.97 (m, 4H), 2.06-2.12 (m, 2H), 1.49 (s, 9H). LCMS: 235 (M+l)+ Step 4: 6,7-dihydro-5H-cyclopenta c]pyridin-l -amine hydrochloride


[00844] Anhydrous 1M HC1 in DCM (20 mL) was added slowly to the title compound of step 3 (570 mg, 2.43 mmol) in DCM (10 mL) at 0 °C. After stirring at rt for 1.5 h, evaporation of the volatile components gave the title compound (400 mg, 96%) as a white solid. 1H NMR (CD3OD, 300 MHz): δ 7.66 (d, J= 6.6 Hz, 1H), 6.88 (d, J= 6.6 Hz, 1H), 3.04 (t, J= 7.8, 7.2 Hz, 2H), 2.86 (t, J= 7.8, 7.2 Hz, 2H), 2.17-2.27 (m, 2H). LCMS: 135 (M+l)+

Step 5: 2,5,6,7-tetrahydrocyclopenta[c]pyridin-l-one


[00845] The title compound of step 4 (400 mg, 2.33 mmol) was dissolved in water (6.5 mL) and H3PO2 (2 mL, 50% w/w in water, 18.64 mmol) was added. The mixture was cooled to 0 °C and a solution of NaN02 (180 mg 2.68 mmol) in water (6.5 mL) was added dropwise. The mixture was stirred at 0 °C for 1 h and then at room temperature overnight. The pH was adjusted to about 7 by careful addition of NaHC03. Extractive work up using ethyl acetate gave the title compound (300 mg, 95%) as a yellow solid. 1H NMR (CDC13, 300 MHz): δ 12.55 (s, 1H), 7.24 (d, J= 6.3 Hz, 1H), 6.26 (d, J= 6.3 Hz, 1H), 2.84-2.89 (m, 4H), 2.04-2.11 (m, 2H). LCMS: 136 (M+l)+

Step 6: 2-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-l-one


[00846] The title compound of step 5 (260 mg, 1.93 mmol) was dissolved in DMF (5 mL) and cooled to 0 °C. NaH (94 mg, 2.31 mmol) was added and the mixture was stirred for 30 min. Methyl iodide (146 μί, 2.31 mmol) was added and the mixture stirred at rt for 2 h. The volatile components were removed under vacuum and silica gel chromatography (PE/EtOAc = 1 :1) gave the title compound (192.6 mg, 67%) as a brown oil. 1H NMR (CD3C1, 300 MHz): δ 7.13 (d, J= 6.6 Hz, 1H), 6.13 (d, J= 6.6 Hz, 1H), 3.53 (s, 3H), 2.79-2.85 (m, 4H), 2.01-2.11 (m, 2H). LCMS: 150 (M+l)+

Step 7: 4-bromo-2-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-l-one


[00847] The title compound of step 6 (140 mg, 1.04 mmol) was dissolved in ACN (5 mL) and NBS (188 mg, 1.06 mmol) was added. After stirring at rt for 1.5 h, purification by silica gel chromatography (PE/EtOAc =1 : 1) gave the title compound (196 mg, 89.5%>) as a white solid. 1H NMR (CD3C1, 300 MHz): δ 7.33 (s, 1H), 3.53 (s, 3H), 2.85-2.97 (m, 4H), 2.05-2.13 (m, 2H).

LCMS: 228, 230 (M+l)+

Step 8 : 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin- 1 -one

[00848] To a solution of the title compound of step 7 (60 mg, 0.26 mmol), the title compound of Example 90, step 1 (111.2 mg, 0.32 mmol) and K2CO3 (107 mg, 0.78 mmol) in dioxane (4 mL) and water (1 mL) was added Pd(dppf)Cl2 (6 mg) under N2. The mixture was heated at 85 °C overnight. EA extractive work up followed by prep-TLC (DCM / MeOH =25: 1) gave the title compound (47 mg, 48%) as a yellow solid. 1H NMR (DMSO-d6, 300 MHz): δ 7.83 (dd, J = 8.7, 2.7 Hz, 1H), 7.66 (d, J= 2.9 Hz, 1H), 7.58 (s, 1H), 7.25 (d, J= 8.7 Hz, 1H), 3.95 (d, J = 6.9 Hz, 2H), 3.46 (s, 3H), 3.17 (s, 3H), 2.65-2.70 (m, 4H), 1.91-1.97 (m, 2H), 1.13-1.18 (m, 1H), 0.50-0.54 (m, 2H), 0.26-0.30 (m, 2H). LCMS: 374 (M+l)+

Example 505: 4-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-2-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin- 1 -one


[00849] The title compound was prepared in a similar manner to Example 504, step 8 except that 2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane was substituted for the title compound of Example 90, step 1. 1H NMR (CD30D, 400 MHz): δ 7.91 (dd, J= 8.4, 2.0 Hz, 1H), 7.73 (d, J= 2.0 Hz, 1H), 7.56 (s, 1H), 7.27 (d, J= 8.4 Hz, 1H), 4.01 (d, J= 6.8 Hz, 2H), 3.66 (s, 3H), 3.23 (q, J= 7.6 Hz, 2H), 2.88 (t, J= 7.6 Hz, 2H), 2.82 (t, J= 7.6 Hz, 2H), 2.08-2.14 (m, 2H), 1.26 (t, J= 7.6 Hz, 3H), 1.08-1.27 (m, 1H), 0.60-0.65 (m, 2H), 0.33-0.37 (m, 2H). LCMS: 388 (M+l)+

Example 506: N-[4-(2,4-difluorophenoxy)-3-(2-methyl-l -oxo-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)phenyl]methanesulfonamide


[00850] The title compound was prepared in a similar manner to Example 504, step 8 except that N-[4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]methanesulfonamide was substituted for the title compound of Example 90, step 1. 1H NMR (DMSO-dtf, 400 MHz): δ 9.72 (s, 1H), 7.58 (s, 1H), 7.34-7.42 (m, 1H), 7.24-7.10 (m, 2H), 7.00-7.08(m, 2H), 6.91 (d, J= 8.4 Hz, 1H), 3.43 (s, 3H), 3.01 (s, 3H), 2.71 (t, J = 7.2 Hz, 2H), 2.65 (t, J= 7.2 Hz, 2H), 1.88-1.96 (m, 2H). LCMS: 447 (M+l)+

Example 507: N-[4-(2,4-difluorophenoxy)-3-(2-methyl-l -oxo-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)phenyl]ethanesulfonamide


[00851] The title compound was prepared in a similar manner to Example 504, step 8 except that N-[4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl] ethanesulfonamide

was substituted for the title compound of Example 90, step 1. 1H NMR (CD3C1, 400 MHz): δ 7.30 (s, 1H), 7.19 (d, J= 3.2 Hz, 1H), 7.14 (dd, J= 8.8, 3.2 Hz, 1H), 6.89-6.96 (m, 2H), 6.79-6.85 (m, 1H); 6.77 (d, J= 8.8Hz, 1H), 6.60 (s, 1H), 3.65 (s, 3H), 3.15 (q, J= 7.6 Hz, 2H), 2.96 (t, J= 7.6 Hz, 2H), 2.82 (t, J= 7.6 Hz, 2H), 2.02-2.06 (m, 2H), 1.41 (t, J= 7.6 Hz, 3H). LCMS: 461 (M+l)+

Examples 508-511

[00852] Examples 508-511 as described in Table 22 were prepared in three steps. Using conditions similar to those described in WO2005/40151 (Preparation 6), 5-bromo-3-methylpyridin-2-ol was N-alkylated with isopropyl bromide to give 5 -bromo-3 -methyl- 1-propan-2-ylpyridin-2-one which was then reacted with 4,4,5, 5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane using conditions similar to those described in Example 248, step 2 to give the pinacol ester, 3-methyl-l-propan-2-yl-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyridin-2-one. This pinacol ester was then substituted for the pinacol ester of the example shown under Synthetic Method in Table 22 and reacted in the same way as the example to obtain the title compounds.

Table 22



yl] ethanesulfonamide

Examples 512-514

[00853] Examples 512-514 as described in Table 23 were prepared in three steps. Using conditions similar to those described by Malhotra, et. al. in Organic Letters 2013, Vol. 15, No. 14, pp. 3698-3701 (supporting information, compounds 4c and 3a), 3,5-dibromo-l- methylpyridin-2-one was alkylated at the 3 -position using isopropylmagnesium bromide to give 5-bromo-l-methyl-3-propan-2-ylpyridin-2-one which was then reacted with 4,4,5,5- tetramethyl-2-(tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 ,3 ,2-dioxaborolane using conditions similar to those described in Example 248, step 2 to give the pinacol ester, l-methyl-3- propan-2-yl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one. This pinacol ester was then substituted for the pinacol ester of the example shown under Synthetic Method in Table 23 and reacted in the same way as the example to obtain the title compounds.

Table 23



II. Biological Evaluation

Example 1 : In Vitro Enzyme Inhibition Assay

[00854] Determination of the IC50 for the heterocyclic derivative BRD4 inhibitors disclosed herein was performed as follows. His-tagged BRD4 was cloned, expressed and purified to homogeneity (P. Filipakopoulos et al. Nature 468, 1067-1073, 2010). BRD4 binding and inhibition was assessed by monitoring the interaction of biotinylated H4-tetraacetyl peptide (AnaSpec, H4K5/8/12/16(Ac), biotin - labeled) with the target using the AlphaScreen technology (Life Technologies). In a 384-well ProxiPlate BRD4(BD1) (2 nM final) was combined with peptide (15 nM final) in 50 mM HEPES (pH 7.3), 10 mM NaCl, 0.25 mM TCEP, 0.1% (w/v) BSA, and 0.005% (w/v) Brij-35 either in the presence of DMSO (final 0.4% DMSO) or compound dilution series in DMSO. After 20 minute incubation at room temperature, Alpha streptavidin donor beads and Nickel Chelate acceptor beads were added to a final concentration of 5 μg/mL. After two hours of equilibration, plates were read on an Envision instrument and the IC50 was calculated using a four parameter non-linear curve fit.

Chemistry Example 1 (2-methyl-4-phenylisoquinolin-l-one) had an IC50 of 2.782 μΜ in this assay format.

[00855] The ability of the compounds disclosed herein to inhibit BRD4 activity was quantified and the respective IC50 value was determined. The IC50 values of various compounds disclosed herein is provided in Table 24.

Example 2: In Vitro Cell-based Assay

[00856] A colorimetric cellular proliferation assay (Cell-MTS assay) was performed to assess the ability of the heterocyclic derivative BRD4 inhibitors disclosed herein to effect the proliferation of established cancer cell lines.

Assay Principle

[00857] The Cell-MTS assay is a 7-day plate-based colorimetric assay which quantifies the amount of newly generated NADH in the presence or absence of test compound. The NADH level is used for the quantification of cancer cell proliferation.

Assay Method

[00858] Established cancer cell lines with a variety of driving mutations were obtained from American Type Culture Collection (ATCC) and routinely passaged according to ATCC protocols. For routine assay, these cells were seeded at densities which enabled -90% confluence after 7 days of culture. Raji, human Burkitts lymphoma cells, (cMYC) were seeded at 15,000 cells per 96-well. HL-60, human proleukemia cells, (NRAS, pl6, p53, c- Myc amplified) were seeded at 5,000 cells per 96-well. NCI-H460, human non-small cell lung cancer cells, (KRAS, PIK3CA, STLK1 1 , pl6) were seeded at 3,000 cells per 96-well. 24 hours after plating, cells received an 1 1 point dilution of test compound with final concentration ranges from 100 μΜ to 2.0 nM. Cells were incubated in the presence of compound for 168 hours at 37 °C, and 5% C02. At the end of this incubation period, 80 of media is removed and 20 μΐ^ of CellTiter 96® AQueous Non-Radioactive Cell

Proliferation Assay solution (Promega) was added. The cells were incubated until the OD490 was >0.6. IC50 values were calculated using the IDBS XLfit software package and include background subtracted OD490 values and normalization to DMSO controls. Cellular proliferation IC50 values were uploaded and archived using the Chem Biography Platform.

[00859] Table 24 provides the results of the in vitro enzyme inhibition assay experiments and the in vitro cell-based assay experiments performed with the compounds disclosed herein.

Table 24

yl)phenyl]metha Lnesulfonamide

yl)phenyl]ethar lesulfonamide

onan lide

5,6,7,8 -tetrahy droi soquinolin-l-one