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1. WO2018166528 - PYRIMIDINYL-PYRIDYLOXY-NAPHTHYL COMPOUNDS AND METHODS OF TREATING IRE1-RELATED DISEASES AND DISORDERS

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Claims

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Description

Title of Invention : PYRIMIDINYL-PYRIDYLOXY-NAPHTHYL COMPOUNDS AND METHODS OF TREATING IRE1-RELATED DISEASES AND DISORDERS

[0001]
CROSS-REFERENCE TO RELATED APPLICATIONS
[0002]
This application claims the benefit of priority to International Patent Application No. PCT/CN2017/077059 filed 17 March 2017, the contents of which application are hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

[0003]
Described herein are compounds that target inositol requiring enzyme 1 (IRE1 alpha, α) , including pharmaceutically acceptable salts, solvates, metabolites, prodrugs thereof, pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat, prevent or diagnose diseases.

BACKGROUND OF THE INVENTION

[0004]
The kinase/endoribonuclease inositol requiring enzyme 1 (IRE1 a, alpha, α) , one of the key sensors of misfolded protein accumulation in the endoplasmic reticulum that triggers the unfolded protein response (UPR) , is a potential therapeutic target for diverse diseases including cancer for inhibitors that bind to the ATP-binding site on the kinase moiety of IRE1α and block its endoribonuclease activity. IRE1α is a transmembrane, bifunctional protein with a luminal domain that binds to misfolded proteins, a transmembrane segment, and a cytoplasmic portion consisting of a kinase moiety and a tandem endoribonuclease domain. Structure-activity relationship (SAR) studies led to compounds selective in recombinant IRE1α kinase screens and potent against endoribonuclease activity of recombinant IRE1α as well as cellular IRE1α. IRE1α activity mediates certain cytoprotective and pro-survival functions of the UPR, increases viability and growth in certain tumor cell lines, and may be an effective therapeutic target for specific small molecule inhibitors that block malignant tumor growth, contrary to an earlier report (Harrington, P.E. et al (2015) ACS Med. Chem. Lett. 6: 68-72) . In addition, inhibitors of IRE1α may be therapeutically useful for other types of diseases besides cancer including certain autoimmune, neurodegenerative, fibrotic and metabolic disorders (Wang M. and Kaufman, R.J. (2016) Nature 529: 326-335) .
[0005]
Homeostatic regulation of protein folding in the endoplasmic reticulum (ER) is under the control of three key intracellular signaling pathways: IRE1α, PERK, and ATF6, which together orchestrate the unfolded protein response (UPR) (Schroder, et al (2005) Mutat Res- Fund Mol Mech Metagenesis 569: 29 -63) . An increase in demand for protein folding in the ER or certain types of cellular injury or stress lead to the accumulation of unfolded proteins in the ER -a condition called ER stress. Cells respond to ER stress by activating the UPR to help adjust or maintain their high-fidelity protein synthetic capacity (Walter, P. and Ron, D. (2011) Science, 334: 1081-1086) . IRE1α is the most evolutionarily conserved of the three branches of the UPR. Importantly, the UPR makes life/death decisions for the cell, depending on the severity and duration of ER stress, and the final outcome is either cell survival and recovery or programmed cell death (apoptosis) (Sovolyova et al, (2014) Biol Chem 395: 1-13) . All three pathways of the UPR form a coordinated reaction to the accumulation of unfolded proteins; and several studies have demonstrated that there is cross talk between the different pathways (Yamamoto et al, J. Biochem. (2004) 136: 343-350) ; Arai et al, FEBS Letts. (2006) 580: 184-190; Adachi et al, Cell Struct. Func. (2008) 33: 75-89) . ER stress and activation of the UPR can be caused by mechanical injury, inflammation, genetic mutations, infections, oxidative stress, metabolic stress, and other types of cellular stress associated with malignancy. ER stress has also been implicated in diseases that result in fibrotic remodeling of internal organs, such as chronic liver diseases (Galligan et al, J. Toxicol. (2012) Vol. 2012, Article ID 207594, 12 pgs.; Shin et al, Cell Reports (2013) 5: 654-665; Ji, Int. J. Hepatol. (2014) Vol. 2014, Article ID 513787, 11 pages) , pulmonary fibrosis (Baek et al, Am. J. Resp. Cell Mol. Bio. (2012) 46: 731-739) ; Tanjore et al, Biochim Biophys Acta (2012, online) , (2013) 1832: 940-947) , kidney fibrosis (Chiang et al, Mol. Med. (2011) 17: 1295-1305) , cardiovascular disease (Spitler &Webb, Hypertension (2014) 63: e40-e45) , and inflammatory bowel disease (Bogaert et al, PLoS One (2011) 6 (10) e25589; Cao et al, Gastroent (2013) 144: 989-1000) .
[0006]
IRE1α (alpha) is a transmembrane, bifunctional protein with cytoplasmic kinase and endoribonuclease activity. The N-terminal domain of IRE1α is proposed to sense the presence of unfolded proteins in the ER lumen, triggering activation of the cytoplasmic kinase domain, which, in turn, activates the C-terminal endoribonuclease. IRE1α transmits information across the ER lipid bilayer (Tirasophon et al, Genes &Develop. (2000) 14: 2725-2736) . Increased ER protein load and presence of unfolded proteins leads to the dissociation of the ER chaperone GRP78/BiP from IRE1α molecules, which bind to misfolded proteins and then undergo dimerization and trans-autophosphorylation in the cytoplasmic kinase domain. This leads to activation of the IRE1α endoribonuclease moiety in the cytosol. The IRE1α endoribonuclease has the ability to cleave the mRNA that encodes unspliced X box protein 1 (XBP1u) ; this excises a 26-nucleotide intron and leads to formation of spliced XBP1 (XBP1s) mRNA, which encodes a potent transcription factor. After transport into the nucleus, the XBP1s protein binds to UPR promoter elements to initiate transcription of genes that enhance the ability of the ER to cope with unfolded proteins, for example, through enhanced ER-associated degradation of misfolded proteins, and through elevated levels of chaperones and disulfide isomerases that support protein folding in the ER. IRE1α activation is also associated with enlargement of the ER volume, which has been interpreted as an adaptive mechanism to increase protein folding capacity (Sriburi et al, J. Cell. Bio. (2004) 167: 35-41) ; (Chen, Y. (2013) Trends Cell Biol., 23, 547-555) . In addition, the IRE1α endoribonuclease cleaves various mRNAs in a process called regulated IRE1α -dependent decay of mRNA (RIDD) , which reduces both protein translation and import of proteins into the ER to help reestablish homeostasis (Hollien &Weissman, Science (2006) 313: 104-107) . In cancer cells, IRE1α suppresses ER-stress-induced apoptosis by reducing the mRNA levels of death receptor 5 (DR5) through RIDD (Lu et al., Science (2014) 345: 98-101) .
[0007]
Besides degrading mRNA (Binet et al, Cell Metabol. (2013) 17: 353-371) , it was recently shown that IRE1α also has the ability to degrade microRNAs (miRs) (Upton et al, Science (2012) 338: 818-822) . miRs are short noncoding RNA oligonucleotides consisting of 17-25 nucleotides that generally act to inhibit gene expression by binding to complementary sequences in the 30-untranslated region of target mRNAs, either to repress mRNA translation or to induce mRNA cleavage. A number of cellular functions such as proliferation, differentiation, and apoptosis are regulated by miRs, and aberrant miR expression is observed in a variety of human diseases including fibrosis (Bowen et al, J. Pathol (2013) 229: 274-285) . Inhibitors that specifically target individual components of the UPR have recently been described. The inhibitor 4μ8C that stably binds to lysine 907 in the IRE1a endoribonuclease domain has been shown to inhibit both RIDD activity and XBP-1 splicing (Cross et al, Proc Natl. Acad. Sci. (2012) 109: E869-E878) . High levels of 4μ8C cause no measurable toxicity in cells and concentrations ranging from 80 to 128 lM of 4μ8C completely block XBP1 splicing without affecting IRE1α (alpha) kinase activity (Cross et al, 2012) . The inhibitor 4μ8C thus represents an important tool to delineate the functions of IRE1α in vivo as IRE1α-knockout mice die during embryonic development. Inhibition of IRE1α prevents activation of myofibroblasts and reduces fibrosis in animal models of liver and skin fibrosis. Pharmacological inhibition of IRE1α could revert the profibrotic phenotype of activated myofibroblasts isolated from patients with scleroderma and indicates that ER stress inhibitors should be taken into consideration when developing new strategies for the treatment of fibrotic diseases (Heindryckx, F. et al (2016) EMBO Molecular Medicine Vol 8 (7) : 729-744) .
[0008]
Activation of the UPR has been shown to be an important survival pathway for tumors of secretory cell origin like multiple myeloma that have a very high protein synthesis burden. Therefore, efforts to disrupt the UPR by blocking the IRE1α endoribonuclease cleavage and activation of XBP1 have been an active area of cancer research. As a specific IRE1α RNase product, XBP1s is a direct indicator of functional IRE1 inhibition. A potent and selective IRE1α inhibitor would serve as an important tool to test the hypothesis that, without full UPR activation, tumor cells would be driven to apoptosis. IRE1α inhibitors and activating compounds have been reported (Harrington, P.E. et al (2015) ACS Med. Chem. Lett. 6: 68-72; Volkmann, K., et al (2011) J. Biol. Chem., 286: 12743-12755; Cross, B.C.S., et al (2012) Proc. Natl. Acad. Sci. U.S.A., 109: E869-E878; Wang, L., et al (2012) Nat. Chem. Biol., 8: 982-989; Ghosh, R., et al (2014) Cell, 158: 534-548; Ranatunga, S., et al (2014) J. Med. Chem., 57, 4289-4301; US 9382230; US 8815885) .
[0009]
SUMMARY OF THE INVENTION
[0010]
The invention relates generally to heteroaryl compounds with IRE1 modulation activity or function having the Formula I structure:
[0011]
[0012]
or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and with the substituents and structural features described herein.
[0013]
An aspect of the invention is a pharmaceutical composition of a Formula I compound and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.
[0014]
An aspect of the invention is a process for making a Formula I compound or a pharmaceutical composition comprising a Formula I compound.
[0015]
An aspect of the invention is a method of treating an IRE1-related disease or disorder in a patient comprising administering a therapeutically effective amount of the pharmaceutical composition to a patient with an IRE1-related disease or disorder.
[0016]
An aspect of the invention is a kit for treating a condition mediated by an IRE1 receptor, comprising:
[0017]
a) a pharmaceutical composition comprising a Formula I compound; and
[0018]
b) instructions for use.
[0019]
DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS
[0020]
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents which may be included within the scope of the present invention as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The nomenclature used in this Application is based on IUPAC systematic nomenclature, unless indicated otherwise.
[0021]
Definitions
[0022]
The term “substituent” denotes an atom or a group of atoms replacing a hydrogen atom on the parent molecule. The term “substituted” denotes that a specified group bears one or more substituents. Where any group may carry multiple substituents and a variety of possible substituents is provided, the substituents are independently selected and need not to be the same. The term “unsubstituted” means that the specified group bears no substituents. The term “optionally substituted” means that the specified group is unsubstituted or substituted by one or more substituents, independently chosen from the group of possible substituents. When indicating the number of substituents, the term “one or more” means from one substituent to the highest possible number of substitution, i.e. replacement of one hydrogen up to replacement of all hydrogens by substituents.
[0023]
The term “alkyl” as used herein refers to a saturated linear or branched-chain monovalent hydrocarbon radical of one to twelve carbon atoms (C 1-C 12) , wherein the alkyl radical may be optionally substituted independently with one or more substituents described below. In another embodiment, an alkyl radical is one to eight carbon atoms (C 1-C 8) , or one to six carbon atoms (C 1-C 6) . Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3) , ethyl (Et, -CH 2CH 3) , 1-propyl (n-Pr, n-propyl, -CH 2CH 2CH 3) , 2-propyl (i-Pr, i-propyl, -CH (CH 3) 2) , 1-butyl (n-Bu, n-butyl, -CH 2CH 2CH 2CH 3) , 2-methyl-1-propyl (i-Bu, i-butyl, -CH 2CH (CH 3) 2) , 2-butyl (s-Bu, s-butyl, -CH (CH 3) CH 2CH 3) , 2-methyl-2-propyl (t-Bu, t-butyl, -C (CH 3) 3) , 1-pentyl (n-pentyl, -CH 2CH 2CH 2CH 2CH 3) , 2-pentyl (-CH (CH 3) CH 2CH 2CH 3) , 3-pentyl (-CH (CH 2CH 3) 2) , 2-methyl-2-butyl (-C (CH 3) 2CH 2CH 3) , 3-methyl-2-butyl (-CH (CH 3) CH (CH 3) 2) , 3-methyl-1-butyl (-CH 2CH 2CH (CH 3) 2) , 2-methyl-1-butyl (-CH 2CH (CH 3) CH 2CH 3) , 1-hexyl (-CH 2CH 2CH 2CH 2CH 2CH 3) , 2-hexyl (-CH (CH 3) CH 2CH 2CH 2CH 3) , 3-hexyl (-CH (CH 2CH 3) (CH 2CH 2CH 3) ) , 2-methyl-2-pentyl (-C (CH 3) 2CH 2CH 2CH 3) , 3-methyl-2-pentyl (-CH (CH 3) CH (CH 3) CH 2CH 3) , 4-methyl-2-pentyl (-CH (CH 3) CH 2CH (CH 3) 2) , 3-methyl-3-pentyl (-C (CH 3) (CH 2CH 3) 2) , 2-methyl-3-pentyl (-CH (CH 2CH 3) CH (CH 3) 2) , 2, 3-dimethyl-2-butyl (-C (CH 3) 2CH (CH 3) 2) , 3, 3-dimethyl-2-butyl (-CH (CH 3) C (CH 3) 3, 1-heptyl, 1-octyl, and the like.
[0024]
The term “alkyldiyl” as used herein refers to a saturated linear or branched-chain divalent hydrocarbon radical of about one to twelve carbon atoms (C 1-C 12) , wherein the alkyldiyl radical may be optionally substituted independently with one or more substituents described below. In another embodiment, an alkyldiyl radical is one to eight carbon atoms (C 1-C 8) , or one to six carbon atoms (C 1-C 6) . Examples of alkyldiyl groups include, but are not limited to, methylene (-CH 2-) , ethylene (-CH 2CH 2-) , propylene (-CH 2CH 2CH 2-) , and the like. An alkyldiyl group may also be referred to as an “alkylene” group.
[0025]
The term “alkenyl” refers to linear or branched-chain monovalent hydrocarbon radical of two to eight carbon atoms (C 2-C 8) with at least one site of unsaturation, i.e., a carbon-carbon, sp 2 double bond, wherein the alkenyl radical may be optionally substituted independently with one or more substituents described herein, and includes radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations. Examples include, but are not limited to, ethenyl or vinyl (-CH=CH 2) , allyl (-CH 2CH=CH 2) , and the like.
[0026]
The terms “alkenylene” or “alkenyldiyl” refer to a linear or branched-chain divalent hydrocarbon radical of two to eight carbon atoms (C 2-C 8) with at least one site of unsaturation, i.e., a carbon-carbon, sp 2 double bond, wherein the alkenylene radical may be optionally substituted independently with one or more substituents described herein, and includes radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations. Examples include, but are not limited to, ethenylene or vinylene (-CH=CH-) , allyl (-CH 2CH=CH-) , and the like.
[0027]
The term “alkynyl” refers to a linear or branched monovalent hydrocarbon radical of two to eight carbon atoms (C 2-C 8) with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond, wherein the alkynyl radical may be optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, ethynyl (-C≡CH) , 1-propynyl (-C≡CCH 3) , propargyl (-CH 2C≡CH) , and the like.
[0028]
The term “alkynylene” or “alkynyldiyl” refer to a linear or branched divalent hydrocarbon radical of two to eight carbon atoms (C 2-C 8) with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond, wherein the alkynylene radical may be optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, ethynylene (-C≡C-) , propynylene (propargylene, -CH 2C≡C-) , and the like.
[0029]
The terms “carbocycle” , “carbocyclyl” , “carbocyclic ring” and “cycloalkyl” refer to a monovalent non-aromatic, saturated or partially unsaturated ring having 3 to 12 carbon atoms (C 3-C 12) as a monocyclic ring or 7 to 12 carbon atoms as a bicyclic ring. Bicyclic carbocycles having 7 to 12 atoms can be arranged, for example, as a bicyclo [4, 5] , [5, 5] , [5, 6] or [6, 6] system, and bicyclic carbocycles having 9 or 10 ring atoms can be arranged as a bicyclo [5, 6] or [6, 6] system, or as bridged systems such as bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane and bicyclo [3.2.2] nonane. Spiro carbocyclyl moieties are also included within the scope of this definition. Examples of spiro carbocyclyl moieties include [2.2] pentanyl, [2.3] hexanyl, and [2.4] heptanyl. Examples of monocyclic carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. Carbocyclyl groups are optionally substituted independently with one or more substituents described herein.
[0030]
The term “carbocyclyldiyl” refers to a divalent non-aromatic, saturated or partially unsaturated ring having 3 to 12 carbon atoms (C 3-C 12) as a monocyclic ring or 7 to 12 carbon atoms as a bicyclic ring.
[0031]
“Aryl” means a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms (C 6-C 20) derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Some aryl groups are represented in the exemplary structures as “Ar” . Aryl includes bicyclic radicals comprising an aromatic ring fused to a saturated, partially unsaturated ring, or aromatic carbocyclic ring. Typical aryl groups include, but are not limited to, radicals derived from benzene (phenyl) , substituted benzenes, naphthalene, anthracene, biphenyl, indenyl, indanyl, 1, 2-dihydronaphthalene, 1, 2, 3, 4-tetrahydronaphthyl, and the like. Aryl groups are optionally substituted independently with one or more substituents described herein.
[0032]
The terms “arylene” or “aryldiyl” mean a divalent aromatic hydrocarbon radical of 6-20 carbon atoms (C 6-C 20) derived by the removal of two hydrogen atom from a two carbon atoms of a parent aromatic ring system. Some aryldiyl groups are represented in the exemplary structures as “Ar” . Aryldiyl includes bicyclic radicals comprising an aromatic ring fused to a saturated, partially unsaturated ring, or aromatic carbocyclic ring. Typical aryldiyl groups include, but are not limited to, radicals derived from benzene (phenyldiyl) , substituted benzenes, naphthalene, anthracene, biphenylene, indenylene, indanylene, 1, 2-dihydronaphthalene, 1, 2, 3, 4-tetrahydronaphthyl, and the like. Aryldiyl groups are also referred to as “arylene” , and are optionally substituted with one or more substituents described herein.
[0033]
The terms “heterocycle, ” “heterocyclyl” and “heterocyclic ring” are used interchangeably herein and refer to a saturated or a partially unsaturated (i.e., having one or more double and/or triple bonds within the ring) carbocyclic radical of 3 to about 20 ring atoms in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus and sulfur, the remaining ring atoms being C, where one or more ring atoms is optionally substituted independently with one or more substituents described below. A heterocycle may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P, and S) , for example: a bicyclo [4, 5] , [5, 5] , [5, 6] , or [6, 6] system. Heterocycles are described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968) , particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley &Sons, New York, 1950 to present) , in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82: 5566. “Heterocyclyl” also includes radicals where heterocycle radicals are fused with a saturated, partially unsaturated ring, or aromatic carbocyclic or heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, morpholin-4-yl, piperidin-1-yl, piperazinyl, piperazin-4-yl-2-one, piperazin-4-yl-3-one, pyrrolidin-1-yl, thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl, azocan-1-yl, azetidin-1-yl, octahydropyrido [1, 2-a] pyrazin-2-yl, [1, 4] diazepan-1-yl, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1, 3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinylimidazolinyl, imidazolidinyl, 3-azabicyco [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanyl, azabicyclo [2.2.2] hexanyl, 3H-indolyl quinolizinyl and N-pyridyl ureas. Spiro heterocyclyl moieties are also included within the scope of this definition. Examples of spiro heterocyclyl moieties include azaspiro [2.5] octanyl and azaspiro [2.4] heptanyl. Examples of a heterocyclic group wherein 2 ring atoms are substituted with oxo (=O) moieties are pyrimidinonyl and 1, 1-dioxo-thiomorpholinyl. The heterocycle groups herein are optionally substituted independently with one or more substituents described herein.
[0034]
The term “heterocyclyldiyl” refers to a divalent, saturated or a partially unsaturated (i.e., having one or more double and/or triple bonds within the ring) carbocyclic radical of 3 to about 20 ring atoms in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus and sulfur, the remaining ring atoms being C, where one or more ring atoms is optionally substituted independently with one or more substituents as described.
[0035]
The term “heteroaryl” refers to a monovalent aromatic radical of 5-, 6-, or 7-membered rings, and includes fused ring systems (at least one of which is aromatic) of 5-20 atoms, containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups are pyridinyl (including, for example, 2-hydroxypyridinyl) , imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl) , pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Heteroaryl groups are optionally substituted independently with one or more substituents described herein.
[0036]
The term “heteroaryldiyl” refers to a divalent aromatic radical of 5-, 6-, or 7-membered rings, and includes fused ring systems (at least one of which is aromatic) of 5-20 atoms, containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[0037]
The heterocycle or heteroaryl groups may be carbon (carbon-linked) , or nitrogen (nitrogen-linked) bonded where such is possible. By way of example and not limitation, carbon bonded heterocycles or heteroaryls are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.
[0038]
By way of example and not limitation, nitrogen bonded heterocycles or heteroaryls are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or β-carboline.
[0039]
The terms “treat” and “treatment” refer to therapeutic treatment, wherein the object is to slow down (lessen) an undesired physiological change or disorder, such as the development or spread of arthritis or cancer. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total) , whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those with the condition or disorder.
[0040]
The phrase “therapeutically effective amount” means an amount of a compound of the present invention that (i) treats the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. In the case of cancer, the therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the cancer. To the extent the drug may prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic. For cancer therapy, efficacy can be measured, for example, by assessing the time to disease progression (TTP) and/or determining the response rate (RR) .
[0041]
The terms “cancer” refers to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. A “tumor” comprises one or more cancerous cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer) , lung cancer including small-cell lung cancer, non-small cell lung cancer ( “NSCLC” ) , adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer.
[0042]
"Hematological malignancies" (British spelling "Haematological" malignancies) are the types of cancer that affect blood, bone marrow, and lymph nodes. As the three are intimately connected through the immune system, a disease affecting one of the three will often affect the others as well: although lymphoma is a disease of the lymph nodes, it often spreads to the bone marrow, affecting the blood. Hematological malignancies are malignant neoplasms ( "cancer" ) , and they are generally treated by specialists in hematology and/or oncology. In some centers "Hematology/oncology" is a single subspecialty of internal medicine while in others they are considered separate divisions (there are also surgical and radiation oncologists) . Not all hematological disorders are malignant ( "cancerous" ) ; these other blood conditions may also be managed by a hematologist. Hematological malignancies may derive from either of the two major blood cell lineages: myeloid and lymphoid cell lines. The myeloid cell line normally produces granulocytes, erythrocytes, thrombocytes, macrophages and mast cells; the lymphoid cell line produces B, T, NK and plasma cells. Lymphomas, lymphocytic leukemias, and myeloma are from the lymphoid line, while acute and chronic myelogenous leukemia, myelodysplastic syndromes and myeloproliferative diseases are myeloid in origin. Leukemias include Acute lymphoblastic leukemia (ALL) , Acute myelogenous leukemia (AML) , Chronic lymphocytic leukemia (CLL) , Chronic myelogenous leukemia (CML) , Acute monocytic leukemia (AMOL) and small lymphocytic lymphoma (SLL) . Lymphomas include Hodgkin′s lymphomas (all four subtypes) and Non-Hodgkin′s lymphomas (NHL, all subtypes) .
[0043]
A “chemotherapeutic agent” is a chemical compound useful in the treatment of cancer, regardless of mechanism of action. Classes of chemotherapeutic agents include, but are not limited to: alkylating agents, antimetabolites, spindle poison plant alkaloids, cytotoxic/antitumor antibiotics, topoisomerase inhibitors, antibodies, photosensitizers, and kinase inhibitors. Chemotherapeutic agents include compounds used in “targeted therapy” and conventional chemotherapy. Examples of chemotherapeutic agents include proteasome inhibitors such as bortezomib ( Millennium Pharm., CAS Reg. No. 179324-69-7) , carfilzomib ( Amgen, CAS Reg. No. 868540-17-4) and ixazomib ( Takeda, CAS Reg. No. 1072833-77-2) ; lenalidomide ( Celgene, CAS Reg. No. 191732-72-6) ; pomalidomide ( Celgene, CAS Reg. No. 19171-19-8) ; venetoclax ( GDC-0199, ABT-199, AbbVie/Genentech, CAS Reg. No. 1257044-40-8) ; ibrutinib (IMBRUVICA TM, APCI-32765, Pharmacyclics Inc. /Janssen Biotech Inc.; CAS Reg. No. 936563-96-1, US 7514444) , idelalisib ( CAL-101, GS 1101, GS-1101, Gilead Sciences Inc.; CAS Reg. No. 1146702-54-6) , erlotinib ( Genentech/OSI Pharm. ) , docetaxel ( Sanofi-Aventis) , 5-FU (fluorouracil, 5-fluorouracil, CAS Reg. No. 51-21-8) , gemcitabine ( Lilly) , PD-0325901 (CAS No. 391210-10-9, Pfizer) , cisplatin ( (SP-4-2) -diamminedichloroplatinum (II) , cis-diamine, dichloroplatinum (II) , CAS No. 15663-27-1) , carboplatin (CAS No. 41575-94-4) , paclitaxel ( Bristol-Myers Squibb Oncology, Princeton, N.J. ) , trastuzumab ( Genentech) , temozolomide (4-methyl-5-oxo-2, 3, 4, 6, 8-pentazabicyclo [4.3.0] nona-2, 7, 9-triene-9-carboxamide, CAS No. 85622-93-1, Schering Plough) , tamoxifen ( (Z) -2- [4- (1, 2-diphenylbut-1-enyl) phenoxy] -N, N-dimethylethanamine, ) , and doxorubicin ( CAS No. 23214-92-8) , Akti-1/2, HPPD, and rapamycin.
[0044]
Chemotherapeutic agents include inhibitors of B-cell receptor targets such as BTK, Bcl-2 and JAK inhibitors.
[0045]
More examples of chemotherapeutic agents include: oxaliplatin ( Sanofi) , sutent ( SU11248, Pfizer) , letrozole ( Novartis) , palbociclib, ( Pfizer) , imatinib mesylate ( Novartis) , cobimetinib (COTELLIC TM, GDC-0973, XL-518, Exelixis, WO 2007/044515, CAS Reg. No. 934660-93-2) , ARRY-886 (Mek inhibitor, AZD6244, Array BioPharma, Astra Zeneca) , SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals) , BEZ-235 (PI3K inhibitor, Novartis) , XL-147 (PI3K inhibitor, Exelixis) , PTK787/ZK 222584 (Novartis) , fulvestrant ( AstraZeneca) , leucovorin (folinic acid) , rapamycin (sirolimus, Wyeth) , lapatinib ( GSK572016, Glaxo Smith Kline) , lonafarnib (SARASAR TM, SCH 66336, Schering Plough) , sorafenib ( BAY43-9006, Bayer Labs) , gefitinib ( AstraZeneca) , irinotecan ( CPT-11, Pfizer) , tipifarnib (ZARNESTRA TM, Johnson &Johnson) , ABRAXANE TM (Cremophor-free) , albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, Il) , vandetanib (rINN, ZD6474, AstraZeneca) , chlorambucil, AG1478, AG1571 (SU 5271; Sugen) , temsirolimus ( Wyeth) , pazopanib (GlaxoSmithKline) , canfosfamide ( Telik) , thiotepa and cyclosphosphamide alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone) ; a camptothecin (including the synthetic analog topotecan) ; bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs) ; cryptophycins (particularly cryptophycin 1 and cryptophycin 8) ; dolastatin; duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1) ; eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, calicheamicin gamma1I, calicheamicin omegaI1 (Angew Chem. Intl. Ed. Engl. (1994) 33: 183-186) ; dynemicin, dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores) , aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin) , epirubicin, esorubicin, idarubicin, nemorubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU) ; folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; polysaccharide complex (JHS Natural Products, Eugene, OR) ; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2, 2’, 2”-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine) ; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ( “Ara-C” ) ; cyclophosphamide; thiotepa; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16) ; ifosfamide; mitoxantrone; vincristine; vinorelbine novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine ( Roche) ; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO) ; retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.
[0046]
Also included in the definition of “chemotherapeutic agent” are: (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs) , including, for example, tamoxifen (including tamoxifen citrate) , raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, ketoxifene, LY117018, onapristone, and (toremifine citrate) and selective estrogen receptor modulators (SERDs) such as brilanestrant (GDC-0810, AR810, Genentech, Seragon) , GDC-0927 (Genentech, Seragon) , fulvestrant ( Astra Zeneca) ; (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4 (5) -imidazoles, aminoglutethimide, (megestrol acetate) , (exemestane; Pfizer) , formestanie, fadrozole, (vorozole) , (letrozole; Novartis) , and (anastrozole; AstraZeneca) ; (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; as well as troxacitabine (a 1, 3-dioxolane nucleoside cytosine analog) ; (iv) protein kinase inhibitors such as MEK inhibitors, such as cobimetinib (WO 2007/044515) ; (v) lipid kinase inhibitors, such as taselisib (GDC-0032, Genentech Inc. ) ; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, for example, PKC-alpha, Raf and H-Ras, such as oblimersen ( Genta Inc. ) ; (vii) ribozymes such as VEGF expression inhibitors (e.g., ) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, and rIL-2; topoisomerase 1 inhibitors such as rmRH; (ix) anti-angiogenic agents such as bevacizumab ( Genentech) ; and pharmaceutically acceptable salts, acids and derivatives of any of the above.
[0047]
Also included in the definition of “chemotherapeutic agent” are therapeutic antibodies such as atezolizumab ( anti-PDL-1, Genentech, CAS Reg. No. 1380723-44-3) , nivolumab ( Bristol-Myers Squib, CAS Reg. No. 946414-94-4) , daratumumab ( anti-CD38, Janssen Biotech, CAS Reg. No. 945721-28-8) , pembrolizumab ( MK-3475, lambrolizumab, Merck, anti-PD1, CAS Reg. No. 1374853-91-4) , alemtuzumab (Campath) , bevacizumab ( Genentech) ; cetuximab ( Imclone) ; panitumumab ( Amgen) , rituximab ( Genentech/Biogen Idec) , pertuzumab (PERJETA TM, 2C4, Genentech) , trastuzumab ( Genentech) , trastuzumab emtansine ( Genentech Inc. ) , and tositumomab (BEXXAR, Corixia) .
[0048]
A “metabolite” is a product produced through metabolism in the body of a specified compound or salt thereof. Metabolites of a compound may be identified using routine techniques known in the art and their activities determined using tests such as those described herein. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound. Accordingly, the invention includes metabolites of compounds of the invention, including compounds produced by a process comprising contacting a Formula I compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.
[0049]
The term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products.
[0050]
The term “chiral” refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
[0051]
The term “stereoisomers” refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
[0052]
“Diastereomer” refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.
[0053]
“Enantiomers” refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.
[0054]
Stereochemical definitions and conventions used herein generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds” , John Wiley &Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center (s) . The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50: 50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity. Enantiomers may be separated from a racemic mixture by a chiral separation method, such as supercritical fluid chromatography (SFC) . Assignment of configuration at chiral centers in separated stereoisomers may be tentative, and depicted in Table 1 structures for illustrative purposes, before stereochemistry is definitively established, such as from x-ray crystallographic data.
[0055]
The term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.
[0056]
The term “pharmaceutically acceptable salts” denotes salts which are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts. The phrase “pharmaceutically acceptable” indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
[0057]
The term “pharmaceutically acceptable acid addition salt” denotes those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids selected from aliphatic, cycloaliphatic, aromatic, aryl-aliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid “mesylate” , ethanesulfonic acid, p-toluenesulfonic acid, and salicyclic acid.
[0058]
The term “pharmaceutically acceptable base addition salt” denotes those pharmaceutically acceptable salts formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, and polyamine resins.
[0059]
A “solvate” refers to an association or complex of one or more solvent molecules and a compound of the invention. Examples of solvents that form solvates include, but are not limited to, water (i.e., “hydrate” ) , isopropanol, ethanol, methanol, DMSO, ethylacetate (EtOAc) , acetic acid (AcOH) , and ethanolamine.
[0060]
The term “EC 50” is the half maximal effective concentration” and denotes the plasma concentration of a particular compound required for obtaining 50%of the maximum of a particular effect in vivo.
[0061]
The term “Ki” is the inhibition constant and denotes the absolute binding affinity of a particular inhibitor to a receptor. It is measured using competition binding assays and is equal to the concentration where the particular inhibitor would occupy 50%of the receptors if no competing ligand (e.g. a radioligand) was present. Ki values can be converted logarithmically to pKi values (-log Ki) , in which higher values indicate exponentially greater potency.
[0062]
The term “IC 50” is the half maximal inhibitory concentration and denotes the concentration of a particular compound required for obtaining 50%inhibition of a biological process in vitro. IC 50 values can be converted logarithmically to pIC 50 values (-log IC 50) , in which higher values indicate exponentially greater potency. The IC 50 value is not an absolute value but depends on experimental conditions e.g. concentrations employed, and can be converted to an absolute inhibition constant (Ki) using the Cheng-Prusoff equation (Biochem. Pharmacol. (1973) 22: 3099) . Other percent inhibition parameters, such as IC 70, IC 90, etc., may be calculated.
[0063]
The terms “compound of this invention, ” and “compounds of the present invention” and “compounds of Formula I” include compounds of Formula I, and stereoisomers, geometric isomers, tautomers, solvates, metabolites, and pharmaceutically acceptable salts and prodrugs thereof.
[0064]
Any formula or structure given herein, including Formula I compounds, is also intended to represent hydrates, solvates, and polymorphs of such compounds, and mixtures thereof.
[0065]
Any formula or structure given herein, including Formula I compounds, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as, but not limited to 2H (deuterium, D) , 3H (tritium) , 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl, and 125I. Various isotopically labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated. Such isotopically labeled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. Deuterium labeled or substituted therapeutic compounds of the invention may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism, and excretion (ADME) . Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. An 18F labeled compound may be useful for PET or SPECT studies. Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. Further, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent in the compound of the formula (I) . The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this invention any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as "H" or "hydrogen" , the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this invention any atom specifically designated as a deuterium (D) is meant to represent deuterium.
[0066]
IRE1 Assays
[0067]
Inhibition of IRE1α RNase activity was determined in an enzyme assay that measured cleavage of the XBP1 stem loop by autophosphorylated IRE1α. This assay format was chosen to ensure that inhibitors of either the IRE1α kinase or the RNase domains would be identified. Binding to the ATP pocket and inhibition of IRE1α kinase activity are not necessarily required to inhibit the RNase activity. Compounds were also profiled in cellular assays by direct measurement of XBP1s (B-DNA assay) or by quantification of the luciferase signal in HT1080 XBP1-Luc, which carries a luciferase fusion that is only in frame and expressed from the spliced XBP1 transcript. In the IRE1α enzyme and XPB1-Luc assays, pyrimidinyl-pyridyloxy-naphthyl compounds described herein (e.g., compounds in Tables 1 and 2) demonstrated activity.
[0068]
Pyrimidinyl-pyridyloxy-naphthyl Compounds
[0069]
The present invention provides pyrimidinyl-pyridyloxy-naphthyl compounds of Formula I including subgeneric formulas and pharmaceutical formulations thereof, which are potentially useful in the treatment of diseases, conditions and/or disorders modulated by inositol requiring enzyme 1 (IRE1) .
[0070]
Compounds of the invention include salt forms of Formula I compounds.
[0071]
In an effort to probe this pathway and identify suitable therapeutic compounds, IRE1α inhibitors were designed and prepared.
[0072]
Formula I compounds have the structure:
[0073]
[0074]
or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein:
[0075]
R 1 is selected from C 3-C 12 cycloalkyl, C 3-C 12 heterocyclyl, C 1-C 12 heteroaryl, C 6-C 20 aryl, - (C 1-C 6 alkyldiyl) - (C 3-C 12 cycloalkyl) , and - (C 1-C 6 alkyldiyl) - (C 3-C 12 heterocyclyl) ;
[0076]
R 2 is selected from H, F, Cl, -CN, -OCH 3, -OCH 2CH 3, and C 1-C 6 alkyl;
[0077]
R 3 and R 4 are independently selected from H, -CN, C 3-C 12 cycloalkyl, C 3-C 12 heterocyclyl, C 1-C 12 heteroaryl, C 6-C 20 aryl, -O- (C 1-C 12 heteroaryl) , -O- (C 1-C 6 alkyldiyl) - (C 6-C 20 aryl) , -NR 8R 9, -NR 8C (O) R 9, -NR 8C (O) OR 9, -NR 8C (O) NHR 9, -NR 8SO 2- (C 1-C 6 alkyl) , -NR 8SO 2- (C 1-C 6 alkenyl) , -NR 8SO 2- (C 1-C 12 heteroaryl) , -NR 8SO 2- (C 1-C 6 alkyldiyl) - (C 3-C 12 cycloalkyl) , -NR 8SO 2- (C 1-C 6 alkyldiyl) - (C 3-C 12 heterocyclyl) , -NR 8SO 2- (C 1-C 6 alkyldiyl) - (C 1-C 12 heteroaryl) , -NR 8SO 2- (C 1-C 6 alkyldiyl) - (C 6-C 20 aryl) , -NR 8SO 2NR 8R 9, and -SO 2NR 8R 9;
[0078]
R 5 and R 7 are independently selected from H, F, Cl, -CN, -CH 2OH, -C (O) NH 2, -OH, -OCH 3, -OCH 2CH 3, and C 1-C 6 alkyl;
[0079]
R 6 are independently selected from H, F, Cl, Br, I, -CN, -NO 2, and C 1-C 6 alkyl;
[0080]
R 8 is independently selected from H, and C 1-C 6 alkyl;
[0081]
R 9 is independently selected from C 1-C 6 alkyl, C 2-C 6 alkenyl, C 3-C 12 cycloalkyl, C 3-C 12 heterocyclyl, C 1-C 12 heteroaryl, C 6-C 20 aryl; - (C 1-C 6 alkyldiyl) - (C 3-C 12 cycloalkyl) , - (C 1-C 6 alkyldiyl) - (C 3-C 12 heterocyclyl) , - (C 1-C 6 alkyldiyl) - (C 1-C 6 heteroaryl) , - (C 1-C 6 alkyldiyl) - (C 6-C 20 aryl) , and - (C 1-C 6 alkyldiyl) -O- (C 6-C 20 aryl) ; and
[0082]
n is 0, 1, 2, or 3;
[0083]
wherein cycloalkyl, heterocyclyl, heteroaryl, aryl, alkyl, alkyldiyl, and alkenyl are optionally and independently substituted with one or more groups selected from F, Cl, Br, I, -CN, -CH 3, -CH 2CH 3, -CH 2CH 2CH 3, -CH (CH 3) 2, -CH 2CH (CH 3) 2, -CH (CH 3) CH 2CH 3, -CH 2C (CH 3) 3, -CH 2OH, -CH 2OCH 3, -CH 2CH 2OH, -C (CH 3) 2OH, -CH (OH) CH (CH 3) 2, -C (CH 3) 2CH 2OH, -CH 2CH 2CH 2OH, -CH 2CH 2C (CH 3) 2OH, -CH 2CH 2OCH 3, -CH 2CH (CH 3) OCH 3, -CH 2CH 2CH 2OCH 3, -CH 2CH 2C (CH 3) 2OCH 3, -CH 2CH 2SO 2CH 3, -CH 2OP (O) (OH) 2, -CH 2F, -CHF 2, -CH 2NH 2, -CH 2NHSO 2CH 3, -CH 2NHCH 3, -CH 2N (CH 3) 2, -CF 3, -CH 2CF 3, -CH 2CHF 2, -CH 2CH 2CHF 2, -CH 2CH 2CF 3, -CH (CH 3) CN, -C (CH 3) 2CN, -CH 2CN, -CO 2H, -COCH 3, -CO 2CH 3, -CO 2C (CH 3) 3, -COCH (OH) CH 3, -CONH 2, -CONHCH 3, -CONHCH 2CH 3, -CONHCH (CH 3) 2, -CON (CH 3) 2, -C (CH 3) 2CONH 2, -NH 2, -NHCH 3, -N (CH 3) 2, -N (CH 3) CH 2CH 3, -NHCOCH 3, -N (CH 3) COCH 3, -NHS (O) 2CH 3, -N (CH 3) C (CH 3) 2CONH 2, -N (CH 3) CH 2CH 2S (O) 2CH 3, -NO 2, =O, -OH, -OCH 3, -OCH 2CH 3, -OCH 2CH 2OCH 3, -OCH 2CH 2OH, -OCH 2CH 2N (CH 3) 2, -OP (O) (OH) 2, -S (O) 2N (CH 3) 2, -SCH 3, -S (O) 2CH 3, -S (O) 3H, cyclopropyl, cyclopropylamide, cyclobutyl, oxetanyl, azetidinyl, 1-methylazetidin-3-yl) oxy, N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, phenyl, piperazin-1-yl, piperidin-1-yl, morpholinomethyl, morpholino-methanone, and morpholino.
[0084]
In some embodiments of the compound of the Formula I, or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, the compound is other than Compound Nos. 1x-17x of Table 1X. In some embodiments of the Formula I, or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein R 3 is other than -NH- (heteroaryl) .
[0085]
Table 1X
[0086]
[0087]
[0088]
In some embodiments, provided is a compound of the Formula I′:
[0089]
[0090]
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
[0091]
R 1 is C 3-C 12 cycloalkyl, C 3-C 12 heterocyclyl, C 1-C 12 heteroaryl, C 6-C 20 aryl, - (C 1-C 6 alkyldiyl) - (C 3-C 12 cycloalkyl) , or - (C 1-C 6 alkyldiyl) - (C 3-C 12 heterocyclyl) ;
[0092]
R 2 is H, F, Cl, -CN, -OCH 3, -OCH 2CH 3, or C 1-C 6 alkyl;
[0093]
R 3 is H, -CN, C 3-C 12 cycloalkyl, C 3-C 12 heterocyclyl, C 1-C 12 heteroaryl, C 6-C 20 aryl, -O- (C 1-C 12 heteroaryl) , -O- (C 1-C 6 alkyldiyl) - (C 6-C 20 aryl) , -N (R 8) (C 1-C 6 alkyl) , -NR 8C (O) R 9, -NR 8C (O) OR 9, -NR 8C (O) NHR 9, -NR 8SO 2- (C 1-C 6 alkyl) , -NR 8SO 2- (C 1-C 6 alkenyl) , -NR 8SO 2- (C 3-C 12 cycloalkyl) , -NR 8SO 2- (C 1-C 12 heteroaryl) , -NR 8SO 2- (C 1-C 6 alkyldiyl) - (C 3-C 12 cycloalkyl) , -NR 8SO 2- (C 1-C 6 alkyldiyl) - (C 3-C 12 heterocyclyl) , -NR 8SO 2- (C 1-C 6 alkyldiyl) - (C 1-C 12 heteroaryl) , -NR 8SO 2- (C 1-C 6 alkyldiyl) - (C 6-C 20 aryl) , -NR 8SO 2NR 8R 9, or -SO 2NR 8R 9;
[0094]
R 4 is H, -CN, C 3-C 12 cycloalkyl, C 3-C 12 heterocyclyl, C 1-C 12 heteroaryl, C 6-C 20 aryl, -O- (C 1-C 12 heteroaryl) , -O- (C 1-C 6 alkyldiyl) - (C 6-C 20 aryl) , -NR 8R 9, -NR 8C (O) R 9, -NR 8C (O) OR 9, -NR 8C (O) NHR 9, -NR 8SO 2- (C 1-C 6 alkyl) , -NR 8SO 2- (C 1-C 6 alkenyl) , -NR 8SO 2- (C 1-C 12 heteroaryl) , -NR 8SO 2- (C 3-C 12 cycloalkyl) , -NR 8SO 2- (C 3-C 12 heterocyclyl) , -NR 8SO 2- (C 1-C 6 alkyldiyl) - (C 3-C 12 cycloalkyl) , -NR 8SO 2- (C 1-C 6 alkyldiyl) - (C 3-C 12 heterocyclyl) , -NR 8SO 2- (C 1-C 6 alkyldiyl) - (C 1-C 12 heteroaryl) , -NR 8SO 2- (C 1-C 6 alkyldiyl) - (C 6-C 20 aryl) , -NR 8SO 2NR 8R 9, or -SO 2NR 8R 9;
[0095]
each R 5 and R 7 are independently H, F, Cl, -CN, -CH 2OH, -C (O) NH 2, -OH, -OCH 3, -OCH 2CH 3, or C 1-C 6 alkyl;
[0096]
n is 0, 1, 2, or 3;
[0097]
each R 6 is independently H, F, Cl, Br, I, -CN, -NO 2, -O- (C 1-C 6 alkyl) or C 1-C 6 alkyl;
[0098]
each R 8 is independently H, or C 1-C 6 alkyl;
[0099]
each R 9 is independently C 1-C 6 alkyl, C 2-C 6 alkenyl, C 3-C 12 cycloalkyl, C 3-C 12 heterocyclyl, C 1-C 12 heteroaryl, C 6-C 20 aryl; - (C 1-C 6 alkyldiyl) - (C 3-C 12 cycloalkyl) , - (C 1-C 6 alkyldiyl) - (C 3-C 12 heterocyclyl) , - (C 1-C 6 alkyldiyl) - (C 1-C 6 heteroaryl) , - (C 1-C 6 alkyldiyl) - (C 6-C 20 aryl) , or - (C 1-C 6 alkyldiyl) -O- (C 6-C 20 aryl) ; and
[0100]
wherein cycloalkyl, heterocyclyl, heteroaryl, aryl, alkyl, alkyldiyl, and alkenyl are optionally and independently substituted with one or more (e.g., 1 to 2, 1 to 3, 1 to 4, or 1 to 5) substituents selected from the group consisting of F, Cl, Br, I, -CN, -CH 3, -CH 2CH 3, -CH 2CH 2CH 3, -CH (CH 3) 2, -CH 2CH (CH 3) 2, -CH (CH 3) CH 2CH 3, -CH 2C (CH 3) 3, -CH 2OH, -CH 2OCH 3, -CH 2CH 2OH, -C (CH 3) 2OH, -CH (OH) CH (CH 3) 2, -C (CH 3) 2CH 2OH, -CH 2CH 2CH 2OH, -CH 2CH 2C (CH 3) 2OH, -CH 2CH 2OCH 3, -CH 2CH (CH 3) OCH 3, -CH 2CH 2CH 2OCH 3, -CH 2CH 2C (CH 3) 2OCH 3, -CH 2CH 2SO 2CH 3, -CH 2OP (O) (OH) 2, -CH 2F, -CHF 2, -CH 2NH 2, -CH 2NHSO 2CH 3, -CH 2NHCH 3, -CH 2N (CH 3) 2, -CF 3, -CH 2CF 3, -CH 2CHF 2, -CH 2CH 2CHF 2, -CH 2CH 2CF 3, -CH (CH 3) CN, -C (CH 3) 2CN, -CH 2CN, -CO 2H, -COCH 3, -CO 2CH 3, -CO 2C (CH 3) 3, -COCH (OH) CH 3, -CONH 2, -CONHCH 3, -CONHCH 2CH 3, -CONHCH (CH 3) 2, -CON (CH 3) 2, -C (CH 3) 2CONH 2, -NH 2, -NHCH 3, -N (CH 3) 2, -N (CH 3) CH 2CH 3, -NHCOCH 3, -N (CH 3) COCH 3, -NHS (O) 2CH 3, -N (CH 3) C (CH 3) 2CONH 2, -N (CH 3) CH 2CH 2S (O) 2CH 3, -NO 2, =O, -OH, -OCH 3, -OCH 2CH 3, -OCH 2CH 2OCH 3, -OCH 2CH 2OH, -OCH 2CH 2N (CH 3) 2, -OP (O) (OH) 2, -S (O) 2N (CH 3) 2, -SCH 3, -S (O) 2CH 3, -S (O) 3H, cyclopropyl, cyclopropylamide, cyclobutyl, oxetanyl, azetidinyl, 1-methylazetidin-3-yl) oxy, N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, phenyl, piperazin-1-yl, piperidin-1-yl, morpholinomethyl, morpholino-methanone, and morpholino.
[0101]
In some embodiments of the compound of Formula I′, or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein R 1 is optionally substituted C 3-C 12 cycloalkyl or optionally substituted C 3-C 12 heterocyclyl. In some embodiments, R 1 is cyclohexyl or piperidinyl, optionally substituted with one or more (e.g., 1 to 2, 1 to3, 1 to 4, or 1 to 5) substituents selected from the group consisting of F, -CH 3, and -NH 2. In some embodiments, R 1 is piperidinyl (e, g, 3-piperidinyl) optionally substituted with one or more substituents selected from the group consisting of F, -CH 3 and -OCH 3. In some embodiments, R 1 is piperidinyl (e, g, 3-piperidinyl) optionally substituted with one to four substituents selected from the group consisting of F, -CH 3 and -OCH 3. In some embodiments, R 1 is selected from the group consisting of piperidin-3-yl, 5-fluoropiperidin-3-yl, 5-methylpiperidin-3-yl and 5-fluro-5-methylpiperidin-3-yl. In some embodiments, R 2 is H, F, Cl or C 1-C 6 alkyl. In some embodiments, R 2 is C 1-C 6 alkyl (e.g., methyl) . In some embodiments, R 3 is H, C 3-C 12 heterocyclyl, -N (R 8) (C 1-C 6 alkyl) , -NR 8C (O) R 9, -NR 8SO 2- (C 1-C 6 alkyl) , -NR 8SO 2- (C 1-C 6 alkenyl) , -NR 8SO 2- (C 3-C 12 cycloalkyl) , -NR 8SO 2- (C 1-C 12 heteroaryl) , -NR 8SO 2- (C 1-C 6 alkyldiyl) - (C 3-C 12 cycloalkyl) , -NR 8SO 2- (C 1-C 6 alkyldiyl) - (C 3-C 12 heterocyclyl) , -NR 8SO 2- (C 1-C 6 alkyldiyl) - (C 1-C 12 heteroaryl) , -NR 8SO 2- (C 1-C 6 alkyldiyl) - (C 6-C 20 aryl) , -NR 8SO 2NR 8R 9, or -SO 2NR 8R 9. In some embodiments, R 3 is H, and R 4 is C 3-C 12 cycloalkyl, C 3-C 12 heterocyclyl, C 1-C 12 heteroaryl, C 6-C 20 aryl, -O- (C 1-C 12 heteroaryl) , -O- (C 1-C 6 alkyldiyl) - (C 6-C 20 aryl) , -NR 8R 9, -NR 8C (O) R 9, -NR 8C (O) OR 9, -NR 8C (O) NHR 9, -NR 8SO 2- (C 1-C 6 alkyl) , -NR 8SO 2- (C 1-C 6 alkenyl) , -NR 8SO 2- (C 1-C 12 heteroaryl) , -NR 8SO 2- (C 3-C 12 cycloalkyl) , -NR 8SO 2- (C 3-C 12 heterocyclyl) , -NR 8SO 2- (C 1-C 6 alkyldiyl) - (C 3-C 12 cycloalkyl) , -NR 8SO 2- (C 1-C 6 alkyldiyl) - (C 3-C 12 heterocyclyl) , -NR 8SO 2- (C 1-C 6 alkyldiyl) - (C 1-C 12 heteroaryl) , -NR 8SO 2- (C 1-C 6 alkyldiyl) - (C 6-C 20 aryl) , -NR 8SO 2NR 8R 9, or -SO 2NR 8R 9. In some embodiments, R 5 is H, F, Cl or CH 3. In some embodiments, R 5 is H. In some embodiments, R 7 is hydrogen or fluoro. In some embodiments, R 5 and R 7 are hydrogen. In any of these embodiments, cycloalkyl, heterocyclyl, heteroaryl, aryl, alkyl, alkyldiyl, and alkenyl are optionally and independently substituted as defined for Formula I′.
[0102]
Exemplary embodiments of Formula I or I′compounds include Formula Ia:
[0103]
[0104]
wherein R 10 is selected from H, F, -CH 3, and -NH 2.
[0105]
Exemplary embodiments of Formula Ia compounds include Formula Ib:
[0106]
[0107]
Exemplary embodiments of Formula I or I′compounds include Formula Ic:
[0108]
[0109]
wherein R 11 is selected from C 1-C 6 alkyl, C 1-C 6 alkenyl, C 1-C 12 heteroaryl, (C 1-C 6 alkyldiyl) - (C 3-C 12 heterocyclyl) , (C 1-C 6 alkyldiyl) - (C 1-C 12 heteroaryl) , (C 1-C 6 alkyldiyl) - (C 6-C 20 aryl) , (C 1-C 6 alkyldiyl) - (C 6-C 20 aryl) , NR 7- (C 1-C 12 heteroaryl) , NR 7- (C 1-C 6 alkyl) , and NR 7- (C 1-C 6 alkyldiyl) - (C 6-C 20 aryl) .
[0110]
Formula Ic compounds include wherein R 11 is selected from benzyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentanyl, cyclopentanylmethyl, cyclohexyl, cyclohexylmethyl, pyrrolidin-1-yl, piperidin-1-yl, pyridyl, pyridylmethyl, tetrahydrofuranyl, tetrahydrofuranylmethyl, and tetrahydropyranyl, tetrahydropyranylmethyl, thiazolyl, and thiazolylmethyl, optionally and independently substituted with one groups selected from fluoro, chloro, bromo, -CH 3, -CH 2CH 3, -CH 2OH, and -CN.
[0111]
Formula Ic compounds include wherein R 11 is selected from -CH 3, -CH 2CH 3, -CH=CH 2, -CH 2CH 2CH 3, -CH (CH 3) 2, -CH 2CH (CH 3) 2, -CH (CH 3) CH 2CH 3, -CH 2C (CH 3) 3, -CH 2CHF 2, -CH 2CH 2CHF 2, -CH 2CF 3, -CH 2CH 2CF 3, -CH 2CH 2OCH 3, -CH 2CH 2CH 2OCH 3, -CH 2CH (CH 3) OCH 3, -CH 2F, -CH 2Cl, -CH 2Br, -CH 2CN, -NH 2, -NHCH 3, -N (CH 3) 2, and -N (CH 3) CH 2CH 3.
[0112]
Exemplary embodiments of Formula Ic compounds have Formula Id:
[0113]
[0114]
Exemplary embodiments of Formula Id compounds have Formula Ie:
[0115]
[0116]
Exemplary embodiments of Formula Ie compounds have Formula If:
[0117]
[0118]
Formula If compounds include wherein R 5 is F, having Formula Ig:
[0119]
[0120]
In some embodiments of the compound of Formula I or I′, or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein R 1 is optionally substituted piperidin-3-yl. In some embodiments, the compound is of Formula Ih:
[0121]
[0122]
wherein R 10a and R 10b are independently H, F, -CH 3 or -NH 2; and R 2, R 3, R 4, R 5, R 6 and R 7 are as described for Formula I or I′. In some embodiments, R 2 is H, F, Cl or C 1-C 6 alkyl. In some embodiments, R 2 is C 1-C 6 alkyl (e.g., methyl) . In some embodiments, R 5 is H, F, Cl or CH 3. In some embodiments, R 7 is hydrogen or fluoro. In some embodiments, R 5 and R 7 are hydrogen. In some embodiments, R 6 is H, F, Cl, Br, -OCH 3, or C 1-C 6 alkyl (e.g., methyl and ethyl) . In some embodiments, R 6 is H. In some embodiments, R 10a and R 10b are independently H, F or -CH 3.
[0123]
In some embodiments of the compound of Formula Ih, or a variation thereof, the compound is of the Formula Ii:
[0124]
[0125]
In some embodiments of the compound of Formula I′, or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, n is 0 and the compound is of Formula Ij:
[0126]
[0127]
wherein R 11 is C 1-C 6 alkyl, C 1-C 6 alkenyl, C 1-C 12 heteroaryl, C 3-C 12 cycloalkyl, C 3-C 12 heterocyclyl, - (C 1-C 6 alkyldiyl) - (C 3-C 12 cycloalkyl) , - (C 1-C 6 alkyldiyl) - (C 3-C 12 heterocyclyl) , - (C 1-C 6 alkyldiyl) - (C 1-C 12 heteroaryl) , - (C 1-C 6 alkyldiyl) - (C 6-C 20 aryl) , -NR 8- (C 1-C 12 heteroaryl) , -NR 8- (C 1-C 6 alkyl) , or -NR 8- (C 1-C 6 alkyldiyl) - (C 6-C 20 aryl) ; and R 1, R 2, R 3, R 4, R 5, R 6, R 7 and R 8 are as described for Formula I′. In some embodiments, R 11 is C 1-C 6 alkyl, C 1-C 6 alkenyl, C 1-C 12 heteroaryl, C 3-C 12 cycloalkyl, C 3-C 12 heterocyclyl, - (C 1-C 6 alkyldiyl) - (C 3-C 12 cycloalkyl) , - (C 1-C 6 alkyldiyl) - (C 3-C 12 heterocyclyl) , - (C 1-C 6 alkyldiyl) - (C 1-C 12 heteroaryl) , or - (C 1-C 6 alkyldiyl) - (C 6-C 20 aryl) . In some embodiments, R 11 is -NR 8- (C 1-C 12 heteroaryl) , -NR 8- (C 1-C 6 alkyl) , or -NR 8- (C 1-C 6 alkyldiyl) - (C 6-C 20 aryl) ; and R 8 is H or -CH 3. In some embodiments, R 11 is selected from the group consisting of benzyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentanyl, cyclopentanylmethyl, cyclohexyl, cyclohexylmethyl, pyrrolidin-1-yl, piperidin-1-yl, pyridyl, pyridylmethyl, tetrahydrofuranyl, tetrahydrofuranylmethyl, and tetrahydropyranyl, tetrahydropyranylmethyl, thiazolyl, and thiazolylmethyl; each of which is optionally and independently substituted with one or more (e.g., 1 to 2, 1 to 3, 1 to 4, or 1 to 5) substituents selected from fluoro, chloro, bromo, -CH 3, -CH 2CH 3, -CH 2OH, and -CN. In some embodiments, R 11 is selected from the group consisting of -CH 3, -CH 2CH 3, -CH=CH 2, -CH 2CH 2CH 3, -CH (CH 3) 2, -CH 2CH (CH 3) 2, -CH (CH 3) CH 2CH 3, -CH 2C (CH 3) 3, -CH 2CHF 2, -CH 2CH 2CHF 2, -CH 2CF 3, -CH 2CH 2CF 3, -CH 2CH 2OCH 3, -CH 2CH 2CH 2OCH 3, -CH 2CH (CH 3) OCH 3, -CH 2F, -CH 2Cl, -CH 2Br, -CH 2CN, -NH 2, -NHCH 3, -N (CH 3) 2, and -N (CH 3) CH 2CH 3. In some embodiments, R 2 is H, F, Cl or C 1-C 6 alkyl. In some embodiments, R 2 is C 1-C 6 alkyl (e.g., methyl) . In some embodiments, R 3 is H. In some embodiments, R 5 is H, F, Cl or CH 3. In some embodiments, R 7 is hydrogen or fluoro. In some embodiments, R 5 and R 7 are hydrogen. In some embodiments, R 6 is H, F, Cl, Br, -OCH 3, or C 1-C 6 alkyl (e.g., methyl and ethyl) . In some embodiments, R 6 is H.
[0128]
In some embodiments of the compound of Formula Ij, or a variation thereof, the compound is of the Formula Ik:
[0129]
[0130]
wherein R 10a and R 10b are independently H, F or -CH 3. In some embodiments, R 10a and R 10b are H. In some embodiments, one of R 10a and R 10b is F and the other one of R 10a and R 10b is H. In some embodiments, one of R 10a and R 10b is H and the other one of R 10a and R 10b is -CH 3. In some embodiments, one of R 10a and R 10b is F and the other one of R 10a and R 10b is -CH 3.
[0131]
In some embodiments of the compound of Formula Ik, or a variation thereof, R 2 is -CH 3, R 3, R 6 and R 7 are H, R 5 is F; and the compound is of the Formula Il:
[0132]
[0133]
In some embodiments of the compound of Formula Il, or a variation thereof, R 10a and R 10b are H; and the compound is of the Formula Im:
[0134]
[0135]
In some embodiments of the compound of Formula Il, or a variation thereof, R 10a is F and R 10b is H; and the compound is of the Formula In:
[0136]
[0137]
In some embodiments of the compound of Formula Il, or a variation thereof, R 10a is H and R 10b is -CH 3; and the compound is of the Formula Io:
[0138]
[0139]
In some embodiments of the compound of Formula Il, or a variation thereof, R 10a is F and R 10b is -CH 3; and the compound is of the Formula Ip:
[0140]
[0141]
In some embodiments of the compound of Formula I or I′, or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein n is 0, R 2 is -CH 3, R 3 and R 7 are H, R 1 is optionally substituted piperidin-3-yl, and the compound is of Formula Iq:
[0142]
[0143]
wherein R 10a and R 10b are independently H, F or CH 3; and R 4 and R 5 are as described for Formula I or I′. In some embodiments, R 4 is -CN, C 3-C 12 cycloalkyl, C 3-C 12 heterocyclyl, C 1-C 12 heteroaryl, C 6-C 20 aryl, -O- (C 1-C 12 heteroaryl) , -O- (C 1-C 6 alkyldiyl) - (C 6-C 20 aryl) , -NR 8R 9, -NR 8C (O) R 9, -NR 8C (O) OR 9, -NR 8C (O) NHR 9, or -SO 2NR 8R 9. In some embodiments, R 4 is C 3-C 12 heterocyclyl, C 1-C 12 heteroaryl, -NR 8R 9, -NR 8C (O) R 9, -NR 8C (O) OR 9, -NR 8C (O) NHR 9 or -SO 2NR 8R 9. In some embodiments, R 4 is C 3-C 12 heterocyclyl, C 1-C 12 heteroaryl, -NR 8R 9 or -NR 8C (O) R 9. In some embodiments, R 5 is H, F, Cl or CH 3. In some embodiments, R 5 is H or F. In one variation, R 5 is H. In another variation, R 5 is F. In some of these embodiments, R 10a and R 10b are H. In some of these embodiments, one of R 10a and R 10b is F and the other one of R 10a and R 10b are H. In some of these embodiments, one of R 10a and R 10b is H and the other one of R 10a and R 10b is -CH 3. In some of these embodiments, one of R 10a and R 10b is F and the other one of R 10a and R 10b is -CH 3.
[0144]
In some embodiments of the compound of Formula Iq, or a variation thereof, the compound is of the Formula Ir:
[0145]
[0146]
In some embodiments of the compound of Formula Iq, or a variation thereof, the compound is of the Formula Is:
[0147]
[0148]
In some embodiments of the compound of Formula Iq, or a variation thereof, the compound is of the Formula It:
[0149]
[0150]
In some embodiments of the compound of Formula Iq, or a variation thereof, the compound is of the Formula Iu:
[0151]
[0152]
In some embodiments of the compound of Formula Iq, or a variation thereof, the compound is of the Formula Iv:
[0153]
[0154]
In some embodiments of the compound of Formula Iq, or a variation thereof, the compound is of the Formula Iw:
[0155]
[0156]
In some embodiments of the compound of Formula I or I′, or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein R 4 and R 5 are H, R 1 is optionally substituted piperidin-3-yl, and the compound is of Formula Ix:
[0157]
[0158]
wherein R 10a and R 10b are independently H, F or CH 3; and R 2, R 3, R 6 and R 7 are as described for Formula I or I′. In some embodiments, R 2 is H, F, Cl or C 1-C 6 alkyl. In some embodiments, R 2 is C 1-C 6 alkyl (e.g., methyl) . In some embodiments, R 6 is H, F, Cl, Br, -OCH 3, or C 1-C 6 alkyl (e.g., methyl and ethyl) . In some embodiments, R 6 is H. In some embodiments, R 7 is hydrogen or fluoro. In some embodiments, R 7 is hydrogen. In some embodiments, R 3 is -CN, C 3-C 12 cycloalkyl, C 3-C 12 heterocyclyl, C 1-C 12 heteroaryl, C 6-C 20 aryl, -O- (C 1-C 12 heteroaryl) , -O- (C 1-C 6 alkyldiyl) - (C 6-C 20 aryl) , -N (R 8) (C 1-C 6 alkyl) , -NR 8C (O) R 9, -NR 8C (O) OR 9, -NR 8C (O) NHR 9, -NR 8SO 2- (C 1-C 6 alkyl) , -NR 8SO 2- (C 1-C 6 alkenyl) , -NR 8SO 2- (C 3-C 12 cycloalkyl) , -NR 8SO 2- (C 1-C 12 heteroaryl) , -NR 8SO 2- (C 1-C 6 alkyldiyl) - (C 3-C 12 cycloalkyl) , -NR 8SO 2- (C 1-C 6 alkyldiyl) - (C 3-C 12 heterocyclyl) , -NR 8SO 2- (C 1-C 6 alkyldiyl) - (C 1-C 12 heteroaryl) , -NR 8SO 2- (C 1-C 6 alkyldiyl) - (C 6-C 20 aryl) , -NR 8SO 2NR 8R 9, or -SO 2NR 8R 9. In some embodiments, R 3 is C 3-C 12 heterocyclyl, -N (R 8) (C 1-C 6 alkyl) or -NR 8C (O) R 9. In some embodiments, R 3 is -NR 8SO 2- (C 1-C 6 alkyl) , -NR 8SO 2- (C 1-C 6 alkenyl) , -NR 8SO 2- (C 3-C 12 cycloalkyl) , -NR 8SO 2- (C 1-C 12 heteroaryl) , -NR 8SO 2- (C 1-C 6 alkyldiyl) - (C 3-C 12 cycloalkyl) , -NR 8SO 2- (C 1-C 6 alkyldiyl) - (C 3-C 12 heterocyclyl) , -NR 8SO 2- (C 1-C 6 alkyldiyl) - (C 1-C 12 heteroaryl) , -NR 8SO 2- (C 1-C 6 alkyldiyl) - (C 6-C 20 aryl) or -NR 8SO 2NR 8R 9. In some embodiments, R 3 is -NR 8SO 2- (C 1-C 6 alkyl) . In some of these embodiments, R 10a and R 10b are H. In some of these embodiments, one of R 10a and R 10b is F and the other one of R 10a and R 10b are H. In some of these embodiments, one of R 10a and R 10b is H and the other one of R 10a and R 10b is -CH 3. In some of these embodiments, one of R 10a and R 10b is F and the other one of R 10a and R 10b is -CH 3.
[0159]
In some embodiments of the compound of Formula Ix, R 2 is C 1-C 6 alkyl (e.g., methyl) , R 3 is C 3-C 12 heterocyclyl, -N (R 8) (C 1-C 6 alkyl) or -NR 8C (O) R 9 and R 7 is hydrogen. In some embodiments of the compound of Formula Ix, R 2 is C 1-C 6 alkyl (e.g., methyl) , R 3 is -NR 8SO 2- (C 1-C 6 alkyl) and R 7 is fluoro.
[0160]
In some embodiments of the compound of Formula Ix, or a variation thereof, where R 2 and R 6 are hydrogen, and the compound is of the Formula Iy:
[0161]
[0162]
In some embodiments, R 7 is hydrogen or fluoro. In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is fluoro.
[0163]
In some embodiments of the compound of Formula Ix, or a variation thereof, where R 2 and R 6 are hydrogen, and the compound is of the Formula Iz:
[0164]
[0165]
In some embodiments, R 7 is hydrogen or fluoro. In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is fluoro.
[0166]
In some embodiments of the compound of Formula Ix, or a variation thereof, where R 2 and R 6 are hydrogen, and the compound is of the Formula Iaa:
[0167]
[0168]
In some embodiments, R 7 is hydrogen or fluoro. In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is fluoro.
[0169]
In some embodiments of the compound of Formula Ix, or a variation thereof, where R 2 is hydrogen and R 7 is fluoro, and the compound is of the Formula Iab:
[0170]
[0171]
wherein R 11 is as described for the Formula Ij or a variation thereof.
[0172]
In some embodiments of the compound of Formula Iab, or a variation thereof, wherein R 6 is hydrogen, and the compound is of the Formula Iac:
[0173]
[0174]
In some embodiments of the compound of Formula Iab, or a variation thereof, wherein R 6 is hydrogen, and the compound is of the Formula Iad:
[0175]
[0176]
In some embodiments of the compound of Formula Iab, or a variation thereof, wherein R 6 is hydrogen, and the compound is of the Formula Iae:
[0177]
[0178]
Formula I or I′compounds include wherein R 1 is C 3-C 12 cycloalkyl or C 3-C 12 heterocyclyl.
[0179]
Formula I or I′compounds include wherein R 1 is cyclohexyl or piperidinyl, optionally substituted with one or more groups selected from F, -CH 3, and -NH 2.
[0180]
Formula I or I′compounds include wherein R 2 is -CH 3.
[0181]
Formula I compounds include wherein R 3 is selected from -NR 6R 7, -NR 6C (O) R 7, -NR 6C (O) R 7, -NR 6C (O) OR 7, -NR 6C (O) NR 6, -NR 6SO 2- (C 1-C 6 alkyl) , -NR 6SO 2- (C 1-C 6 alkenyl) , -NR 6SO 2- (C 1-C 12 heteroaryl) , -NR 6SO 2- (C 1-C 6 alkyldiyl) - (C 3-C 12 heterocyclyl) , -NR 6SO 2- (C 1-C 6 alkyldiyl) - (C 1-C 12 heteroaryl) , -NR 6SO 2- (C 1-C 6 alkyldiyl) - (C 6-C 20 aryl) , -NR 6SO 2NR 6- (C 1-C 12 heteroaryl) , -NR 6SO 2NR 6- (C 1-C 6 alkyl) , and -NR 6SO 2NR 6- (C 1-C 6 alkyldiyl) - (C 6-C 20 aryl) .
[0182]
Formula I compounds include wherein each of the three R 6 is H.
[0183]
Formula I compounds include wherein R 4 is selected from -NR 6R 7, -NR 6C (O) R 7, -NR 6C (O) R 7, -NR 6C (O) OR 7, -NR 6C (O) NR 6, -NR 6SO 2- (C 1-C 6 alkyl) , -NR 6SO 2- (C 1-C 6 alkenyl) , -NR 6SO 2- (C 1-C 12 heteroaryl) , -NR 6SO 2- (C 1-C 6 alkyldiyl) - (C 3-C 12 heterocyclyl) , -NR 6SO 2- (C 1-C 6 alkyldiyl) - (C 1-C 12 heteroaryl) , -NR 6SO 2- (C 1-C 6 alkyldiyl) - (C 6-C 20 aryl) , -NR 6SO 2NR 6- (C 1-C 12 heteroaryl) , -NR 6SO 2NR 6- (C 1-C 6 alkyl) , and -NR 6SO 2NR 6- (C 1-C 6 alkyldiyl) - (C 6-C 20 aryl) .
[0184]
In any of the embodiments described for the Formulae Ia -Iad, or variations thereof, where applicable, cycloalkyl, heterocyclyl, heteroaryl, aryl, alkyl, alkyldiyl, and alkenyl are optionally and independently substituted as defined for Formula I or I′.
[0185]
Exemplary embodiments of Formula I or I′compounds include the compounds of Tables 1, 2 and 3.
[0186]
In some embodiments, provided is a compound of Formula I or I′, or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of one or more of Compound Nos. 101-392 of Table 1, Compound Nos. 393-500 of Table 2, and Compound Nos. 501-545 of Table 3. In some embodiments, the compound is selected from the group consisting of Compound Nos. 101-392 in Table 1. In some embodiments, the compound is selected from the group consisting of Compound Nos. 393-500 of Table 2. In some embodiments, the compound is selected from the group consisting of Compound Nos. 501-545 of Table 3.
[0187]
Biological Evaluation
[0188]
The relative efficacies of Formula I or I′compounds as inhibitors of an enzyme activity (or other biological activity) can be established by determining the concentrations at which each compound inhibits the activity to a predefined extent and then comparing the results. Typically, the preferred determination is the concentration that inhibits 50%of the activity in a biochemical assay, i.e., the 50%inhibitory concentration or “IC 50” . Determination of IC 50 values can be accomplished using conventional techniques known in the art. In general, an IC 50 can be determined by measuring the activity of a given enzyme in the presence of a range of concentrations of the inhibitor under study. The experimentally obtained values of enzyme activity then are plotted against the inhibitor concentrations used. The concentration of the inhibitor that shows 50%enzyme activity (as compared to the activity in the absence of any inhibitor) is taken as the IC 50 value. Analogously, other inhibitory concentrations can be defined through appropriate determinations of activity. For example, in some settings it can be desirable to establish a 90%inhibitory concentration, i.e., IC 90, etc.
[0189]
Cell proliferation, cytotoxicity, and cell viability of the Formula I or I′compounds can be measured by the Luminescent Cell Viability Assay (Promega Corp. ) . The Luminescent Cell Viability Assay is a homogeneous method of determining the number of viable cells in culture based on quantitation of the ATP present, an indicator of metabolically active cells. The Assay is designed for use with multiwell formats, making it ideal for automated high-throughput screening (HTS) , cell proliferation and cytotoxicity assays. The homogeneous assay procedure involves adding the single reagent ( Reagent) directly to cells cultured in serum-supplemented medium. Cell washing, removal of medium and multiple pipetting steps are not required. The system detects as few as 15 cells/well in a 384-well format in 10 minutes after adding reagent and mixing.
[0190]
Biological activity of Formula I or I′compounds was measured by an IRE1 biochemical binding assay (Example 901) , a biochemical RNase assay (Example 902) , a cellular PD assay, XBP1s-LUC reporter (Example 903) , and an IRE1α-based inhibition of multiple myeloma (MM) cell proliferation assay.
[0191]
All of the exemplary Formula I or I′compounds in Tables 1 and 2 were made and characterized by LCMS [M+H] + (liquid chromatography mass spectroscopy) with detection of parent ion. All of the exemplary Formula I compounds in Tables 1 and 2 were prepared according to the procedures of the Schemes, General Procedures, and Examples. All of the exemplary Formula I or I′compounds in Tables 1 and 2 were tested for binding to IRE1 (inositol requiring enzyme 1 alpha) and biological activity according to the assays and protocols of Example 901-903. Exemplary Formula I or I′compounds in Tables 1 and 2 have the following structures, corresponding IUPAC names (ChemBioDraw, Version 12.0.2, CambridgeSoft Corp., Cambridge MA) , and biological activity. Where more than one name is associated with a Formula I or I′compound or intermediate in Tables 1 and 2 and the Experimental Procedures, the chemical structure shall define the compound. Assignment of configuration at chiral centers in separated stereoisomers may be tentative, and depicted in Tables 1 and 2 structures for illustrative purposes, before stereochemistry is definitively established, such as from x-ray crystallographic data. In some cases, stereoisomers are separated and tested for biological activity before the stereochemistry of the separated stereoisomers is determined; and stereochemistry in some instances was inferred based on structure-activity relationship (SAR) knowledge from previous compounds. In some cases, the compounds are tested as racemic or diastereomeric mixtures. Where more than one potency value is entered on a row, separated stereoisomers represented by the structure and name on that row were tested. Exemplary compounds of Formula I or I′in Table 3 can be prepared using methods known in the art or according to procedures similar to those described in the Schemes, General Procedures, and Examples 101-500. Biological activities of compounds in Table 3 can be tested in biological assays, for example, those in Examples 901, 902 and 903 described herein.
[0192]
Table 1
[0193]
[0194]
[0195]
[0196]
[0197]
[0198]
[0199]
[0200]
[0201]
[0202]
[0203]
[0204]
[0205]
[0206]
[0207]
[0208]
[0209]
[0210]
[0211]
[0212]
[0213]
[0214]
[0215]
[0216]
[0217]
[0218]
[0219]
[0220]
[0221]
[0222]
[0223]
[0224]
[0225]
[0226]
[0227]
[0228]
[0229]
[0230]
[0231]
[0232]
[0233]
[0234]
[0235]
[0236]
[0237]
[0238]
Table 2
[0239]
[0240]
[0241]
[0242]
[0243]
[0244]
[0245]
[0246]
[0247]
[0248]
[0249]
[0250]
[0251]
[0252]
[0253]
[0254]
[0255]
[0256]
Table 3
[0257]
[0258]
[0259]
[0260]
[0261]
[0262]
[0263]
Administration of Compounds
[0264]
The compounds of the invention may be administered by any route appropriate to the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural) , transdermal, rectal, nasal, topical (including buccal and sublingual) , vaginal, intraperitoneal, intrapulmonary and intranasal. For local immunosuppressive treatment, the compounds may be administered by intralesional administration, including perfusing or otherwise contacting the graft with the inhibitor before transplantation. It will be appreciated that the preferred route may vary with for example the condition of the recipient. Where the compound is administered orally, it may be formulated as a pill, capsule, tablet, etc. with a pharmaceutically acceptable carrier or excipient. Where the compound is administered parenterally, it may be formulated with a pharmaceutically acceptable parenteral vehicle and in a unit dosage injectable form, as detailed below.
[0265]
A dose to treat human patients may range from about 10 mg to about 1000 mg of Formula I or I′compound. A typical dose may be about 100 mg to about 300 mg of the compound. A dose may be administered once a day (QID) , twice per day (BID) , or more frequently, depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism, and excretion of the particular compound. In addition, toxicity factors may influence the dosage and administration regimen. When administered orally, the pill, capsule, or tablet may be ingested daily or less frequently for a specified period of time. The regimen may be repeated for a number of cycles of therapy.
[0266]
Methods of Treatment
[0267]
Formula I or I′compounds of the present invention are useful for treating a human or animal patient suffering from a disease or disorder arising from abnormal cell growth, function or behavior associated with the UPR pathway such as cancer, an immune disorder, cardiovascular disease, viral infection, inflammation, a metabolism/endocrine disorder or a neurological disorder, may thus be treated by a method comprising the administration thereto of a compound of the present invention as defined above. A human or animal patient suffering from cancer may also be treated by a method comprising the administration thereto of a compound of the present invention as defined above. The condition of the patient may thereby be improved or ameliorated.
[0268]
Methods of the invention also include treating cancer selected from breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma (NSCLC) , small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, pancreatic, myeloid disorders, lymphoma, hairy cells, buccal cavity, naso-pharyngeal, pharynx, lip, tongue, mouth, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, Hodgkin’s, leukemia, bronchus, thyroid, liver and intrahepatic bile duct, hepatocellular, gastric, glioma/glioblastoma, endometrial, melanoma, kidney and renal pelvis, urinary bladder, uterine corpus, uterine cervix, multiple myeloma, acute myelogenous leukemia, chronic myelogenous leukemia, lymphocytic leukemia, chronic lymphoid leukemia (CLL) , myeloid leukemia, oral cavity and pharynx, non-Hodgkin lymphoma, melanoma, and villous colon adenoma.
[0269]
In one aspect, provided is a method of treating an IRE1-related disease or disorder in a patient comprising administering a therapeutically effective amount of a compound of Formula I or I′, or any variations detailed herein, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, to a patient with an IRE1-related disease or condition. In another aspect, the method comprises administering to a patient with an IRE1-related disease or condition an effective amount of a pharmaceutical composition comprising a compound of Formula I or I′, or any variations detailed herein, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, glidant, diluent, or excipient. In some embodiments, the compound is of the Formula I excluding compounds of Table 1X. In other embodiments, the compound is of the Formula I including compounds of Table 1X. In some embodiments, the compound is of the Formula I′or variations thereof. In some embodiments, the compound is selected from Tables 1, 2 and 3, or a pharmaceutically acceptable salt thereof. In some embodiments, the patient is a human patient.
[0270]
In one aspect, provided is a compound of Formula I or I′, or any variations detailed herein, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in a method for treating an IRE1-related disease or disorder. In one aspect, provided is a use of a compound of Formula I or I′, or any variations detailed herein, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an IRE1-related disease or disorder.
[0271]
In some embodiments, the IRE1-related disease or disorder is cancer selected from the group consisting of squamous cell cancer, small-cell lung cancer, non-small cell lung cancer ( “NSCLC” ) , adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, stomach cancer, gastrointestinal cancer, esophageal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, and head and neck cancer.
[0272]
In some embodiments, the IRE1-related disease or disorder is a hematological malignancy selected from the group consisting of lymphomas, lymphocytic leukemia, myeloma, acute and chronic myelogenous leukemia, myelodysplastic syndrome and myeloproliferative disease.
[0273]
In some embodiments, the IRE1-related disease or disorder is multiple myeloma. In some embodiments, wherein the IRE1-related disease or disorder is a breast cancer (e.g., a triple-negative breast cancer ( “TNBC” ) ) .
[0274]
In some embodiments of the method of treating an IRE1-related disease or disorder in a patient comprising administering a therapeutically effective amount of a compound of Formula I or I′, or any variations detailed herein, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, to a patient with an IRE1-related disease or condition, the method further comprising administering one or more additional therapeutic agent (s) selected from the group consisting of an anti-inflammatory agent, a corticosteroid, an immunomodulatory agent, chemotherapeutic agent, an apoptosis-enhancer, a neurotropic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, an agent for treating metabolic disorders, an agent for treating autoimmune disorders, an agent for treating immunodeficiency disorders, and combinations thereof. In some embodiments, the additional therapeutic agent is a corticosteroid, a proteasome inhibitor, an IMiD, an antibody, or a combination thereof. In some embodiments, the additional therapeutic agent is a proteasome inhibitor (e.g. carfilzomib, bortezomib, or ixazomib) . In some embodiments, the additional therapeutic agent is an IMiD (e.g. lenalidomide or pomalidomide) . In some embodiments, the additional therapeutic agent is an antibody (e.g., an anti-CD38 antibody, an anti-VEGF-A antibody, an anti-PD-1 antibody, an anti-PD-L1 antibody or an anti-interleukin-6 antibody) . In some embodiments, the additional therapeutic agent is a corticosteroid (e.g., dexamethasone) . In some embodiments, the method further comprises radiotherapy.
[0275]
Also provided herein is a method of treating a disease caused by abnormal levels of Ire1 activity in a human or animal patient in need of such treatment with a Formula I or I′compound. The disease may be caused by an amount of Ire1 activity that is too low or too high. For example, the disease may be caused by a deficiency in Ire1 activity or by abnormally high Ire1 activity (e.g., hyperactivity of Ire1) . The method includes administering to the patient a therapeutically effective amount of an Ire1 modulator Formula I or I′compound.
[0276]
Ire1 deficiency is a decreased amount of Ire1 activity compared to normal levels of Ire1 activity in a particular subject or a population of healthy subjects. The decreased amount of Ire1 activity results in excessive amounts of misfolded protein accumulation thereby causing the disease state.
[0277]
Ire1 hyperactivity is an increased amount of Ire1 activity compared to normal levels of Ire1 activity in a particular subject or a population of healthy subjects. The increased amount of Ire1 activity may result in, for example, excessive amounts of cell proliferation thereby causing the disease state.
[0278]
In some embodiments, the disease is associated with Ire1 deficiency. Such diseases include, but are not limited to, cystic fibrosis, retinitis pigmentosa, diabetes, or a neurodegenerative disease. The neurodegenerative disease may include Alexander′s disease, Alper′s disease, Alzheimer′s disease, Amyotrophic lateral sclerosis, Ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease) . Bovine spongiform encephalopathy (BSF) , Canavan disease, Cockayne syndrome, Corticobasal degeneration, Creutzfeldt-Jakob disease, Huntington′s disease, HIV-associated dementia, Kennedy′s disease, Krabbe′s disease, Lewy body dementia, Machado-Joseph disease (Spinocerebellar ataxia type 3) , Multiple sclerosis, Multiple System Atrophy, Narcolepsy, Neuroborreliosis, Parkinson′s disease, Pelizaeus-Merzbacher Disease, Pick′s disease, Primary lateral sclerosis, Prion diseases, Refsum′s disease, Sandhoff′s disease, Schilder′s disease, Subacute combined degeneration of spinal cord secondary to Pernicious Anaemia, Schizophrenia, Spinocerebellar ataxia (multiple types with varying characteristics) , Spinal muscular atrophy, Steele-Richardson-Olszewski disease, or Tabes dorsalis.
[0279]
In other embodiments, the disease is associated with abnormally high Ire1. Such diseases include, but are not limited, to cancers, inflammatory diseases, and autoimmune diseases. Exemplary cancers include, but am not limited to, breast cancer and multiple myeloma. In one embodiment, the disease is multiple myeloma. In one embodiment, the disease is a triple-negative breast cancer. Exemplary inflammatory diseases include, but are not limited to, asthma, chronic inflammation, chronic prostatitis, glomerulonephritis, hypersensitivities, inflammatory bowel diseases, pelvic inflammatory disease; reperfusion injury, rheumatoid arthritis, transplant rejection, and vasculitis. Exemplary autoimmune diseases include, but are not limited to, XBP1-linked Crohn′s disease, Coeliac disease, diabetes mellitus type 1 (IDDM) , systemic lupus erythematosus (SLE) , Sjogren′s syndrome, Churg-Strauss Syndrome, Hashimoto′s thyroiditis, Graves′disease, idiopathic thrombocytopenic purpura, and rheumatoid arthritis. In one embodiment, the disease is XBP1-linked. Crohn′s disease.
[0280]
Pharmaceutical Formulations
[0281]
In order to use a Formula I or I′compound for the therapeutic treatment of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. According to this aspect of the invention there is provided a pharmaceutical composition comprising a compound of this invention in association with a pharmaceutically acceptable diluent or carrier.
[0282]
A typical formulation is prepared by mixing a compound of the present invention and a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like. The particular carrier, diluent or excipient used will depend upon the means and purpose for which the compound of the present invention is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300) , etc. and mixtures thereof. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament) .
[0283]
The formulations may be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., compound of the present invention or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexation agent) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. The compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with the prescribed regimen.
[0284]
The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass) , sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
[0285]
Pharmaceutical formulations of the compounds of the present invention may be prepared for various routes and types of administration. For example, a compound of Formula I or I′having the desired degree of purity may optionally be mixed with pharmaceutically acceptable diluents, carriers, excipients or stabilizers (Remington′s Pharmaceutical Sciences (1980) 16th edition, Osol, A. Ed. ) , in the form of a lyophilized formulation, milled powder, or an aqueous solution. Formulation may be conducted by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed. The pH of the formulation depends mainly on the particular use and the concentration of compound, but may range from about 3 to about 8. Formulation in an acetate buffer at pH 5 is a suitable embodiment.
[0286]
The compound ordinarily can be stored as a solid composition, a lyophilized formulation or as an aqueous solution.
[0287]
The pharmaceutical compositions of the invention will be formulated, dosed and administered in a fashion, i.e., amounts, concentrations, schedules, course, vehicles and route of administration, consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The "therapeutically effective amount" of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to ameliorate, or treat the hyperproliferative disorder.
[0288]
As a general proposition, the initial pharmaceutically effective amount of the inhibitor administered parenterally per dose will be in the range of about 0.01-100 mg/kg, namely about 0.1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day.
[0289]
Acceptable diluents, carriers, excipients and stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol) ; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes) ; and/or non-ionic surfactants such as TWEEN TM, PLURONICS TM or polyethylene glycol (PEG) . The active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly- (methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington′s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980) .
[0290]
Sustained-release preparations of compounds of Formula I or I′may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a compound of Formula I or I′, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly (2-hydroxyethyl-methacrylate) , or poly (vinyl alcohol) ) , polylactides (US 3773919) , copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT TM (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D- (-) -3-hydroxybutyric acid.
[0291]
The formulations include those suitable for the administration routes detailed herein. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington′s Pharmaceutical Sciences (Mack Publishing Co., Easton, PA) . Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
[0292]
Formulations of a compound of Formula I or I′suitable for oral administration may be prepared as discrete units such as pills, capsules, cachets or tablets each containing a predetermined amount of a compound of Formula I or I′. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom. Tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, e.g., gelatin capsules, syrups or elixirs may be prepared for oral use. Formulations of compounds of Formula I or I′intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
[0293]
For treatment of the eye or other external tissues, e.g., mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the active ingredient (s) in an amount of, for example, 0.075 to 20%w/w. When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1, 3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs. The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier, it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier (s) with or without stabilizer (s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the invention include 60, 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
[0294]
Aqueous suspensions of Formula I or I′compounds contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin) , a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate) , a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol) , a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate) . The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
[0295]
The pharmaceutical compositions of compounds of Formula I or I′may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1, 3-butanediol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer′s solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.
[0296]
The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95%of the total compositions (weight: weight) . The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 μg of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.
[0297]
Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
[0298]
Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of about 0.5 to 20%w/w, for example about 0.5 to 10%w/w, for example about 1.5%w/w.
[0299]
Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
[0300]
Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
[0301]
Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns (including particle sizes in a range between 0.1 and 500 microns in increments microns such as 0.5, 1, 30 microns, 35 microns, etc. ) , which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis disorders as described below.
[0302]
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
[0303]
The formulations may be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.
[0304]
The invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefore. Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.
[0305]
Combination Therapy
[0306]
The compounds of Formula I or I′may be employed alone or in combination with additional therapeutic agents for the treatment of a disease or disorder described herein, such as inflammation or a hyperproliferative disorder (e.g., cancer) . In certain embodiments, a compound of Formula I or I′is combined in a pharmaceutical combination formulation, or dosing regimen as combination therapy, with an additional, second therapeutic compound that has anti-inflammatory or anti-hyperproliferative properties or that is useful for treating an inflammation, immune-response disorder, or hyperproliferative disorder (e.g., cancer) . The additional therapeutic may be a Bcl-2 inhibitor, a JAK inhibitor, a PI3K inhibitor, an mTOR inhibitor, an anti-inflammatory agent, an immunomodulatory agent, chemotherapeutic agent, an apoptosis-enhancer, a neurotropic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, and an agent for treating immunodeficiency disorders. The second therapeutic agent may be an NSAID anti-inflammatory agent. The second therapeutic agent may be a chemotherapeutic agent. The second compound of the pharmaceutical combination formulation or dosing regimen preferably has complementary activities to the compound of Formula I or I′such that they do not adversely affect each other. Such compounds are suitably present in combination in amounts that are effective for the purpose intended. In one embodiment, a composition of this invention comprises a compound of Formula I or I′, or a stereoisomer, tautomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof, in combination with a therapeutic agent such as an NSAID.
[0307]
The combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations. The combined administration includes coadministration, using separate formulations or a single pharmaceutical formulation, and consecutive administration in either order, wherein preferably there is a time period while both (or all) active agents simultaneously exert their biological activities.
[0308]
Suitable dosages for any of the above coadministered agents are those presently used and may be lowered due to the combined action (synergy) of the newly identified agent and other therapeutic agents or treatments.
[0309]
The combination therapy may provide "synergy" and prove "synergistic" , i.e., the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately. A synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined, unit dosage formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen. When delivered in alternation therapy, a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g., by different injections in separate syringes, separate pills or capsules, or separate infusions. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together.
[0310]
In a particular embodiment of therapy, a compound of Formula I or I′, or a stereoisomer, tautomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof, may be combined with other therapeutic, hormonal or antibody agents such as those described herein, as well as combined with surgical therapy and radiotherapy. Combination therapies according to the present invention thus comprise the administration of at least one compound of Formula I or I′, or a stereoisomer, tautomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof, and the use of at least one other cancer treatment method. The amounts of the compound (s) of Formula I or I′, and the other pharmaceutically active therapeutic agent (s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
[0311]
In some embodiments, a compound of Formula I or I′, or a pharmaceutically acceptable salt thereof, is used in combination with an aromatase inhibitor, a phosphoinositide 3-kinase (PI3K) /mTOR pathway inhibitor, a CDK 4/6 inhibitor, a HER-2 inhibitor, an EGFR inhibitor, a PD-1 inhibitor, poly ADP-ribose polymerase (PARP) inhibitor, a histone deacetylase (HDAC) inhibitor, an HSP90 inhibitor, a VEGFR inhibitor, an AKT inhibitor, chemotherapy, or any combination thereof.
[0312]
In some embodiments, a pharmaceutical composition comprising a compound of Formula I or I′, or a pharmaceutically acceptable salt thereof, is administered in combination with a therapeutic agent selected from paclitaxel, anastrozole, exemestane, cyclophosphamide, epirubicin, fulvestrant, letrozole, palbociclib, gemcitabine, trastuzumab ( Genentech) , trastuzumab emtansine ( Genentech) , pegfilgrastim, filgrastim, tamoxifen, docetaxel, toremifene, vinorelbine, capecitabine, and ixabepilone.
[0313]
In some embodiments, a compound of Formula I or I′, or a pharmaceutically acceptable salt thereof, is used in combination with hormone blocking therapy, chemotherapy, radiation therapy, monoclonal antibodies, or combinations thereof.
[0314]
Metabolites of Compounds of Formula I or I′
[0315]
Also falling within the scope of this invention are the in vivo metabolic products of Formula I or I′described herein. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound. Accordingly, the invention includes metabolites of compounds of Formula I or I′, including compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.
[0316]
Metabolite products typically are identified by preparing a radiolabelled (e.g., 14C or 3H) isotope of a compound of the invention, administering it parenterally in a detectable dose (e.g., greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples. These products are easily isolated since they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite) . The metabolite structures are determined in conventional fashion, e.g., by MS, LC/MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well known to those skilled in the art. The metabolite products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention.
[0317]
Articles of Manufacture
[0318]
In another embodiment of the invention, an article of manufacture, or "kit" , containing materials useful for the treatment of the diseases and disorders described above is provided. In one embodiment, the kit comprises a container comprising a compound of Formula I or I′, or a stereoisomer, tautomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof. The kit may further comprise a label or package insert on or associated with the container. The term "package insert" is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products. Suitable containers include, for example, bottles, vials, syringes, blister pack, etc. The container may be formed from a variety of materials such as glass or plastic. The container may hold a compound of Formula I or I′or a formulation thereof which is effective for treating the condition and may have a sterile access port (for example, the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle) . At least one active agent in the composition is a compound of Formula I or I′. The label or package insert indicates that the composition is used for treating the condition of choice, such as cancer. In addition, the label or package insert may indicate that the patient to be treated is one having a disorder such as a hyperproliferative disorder, neurodegeneration, cardiac hypertrophy, pain, migraine or a neurotraumatic disease or event. In one embodiment, the label or package inserts indicates that the composition comprising a compound of Formula I or I′can be used to treat a disorder resulting from abnormal cell growth. The label or package insert may also indicate that the composition can be used to treat other disorders. Alternatively, or additionally, the article of manufacture may further comprise a second container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI) , phosphate-buffered saline, Ringer′s solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.
[0319]
The kit may further comprise directions for the administration of the compound of Formula I or I′and, if present, the second pharmaceutical formulation. For example, if the kit comprises a first composition comprising a compound of Formula I or I′and a second pharmaceutical formulation, the kit may further comprise directions for the simultaneous, sequential or separate administration of the first and second pharmaceutical compositions to a patient in need thereof.
[0320]
In another embodiment, the kits are suitable for the delivery of solid oral forms of a compound of Formula I or I′, such as tablets or capsules. Such a kit preferably includes a number of unit dosages. Such kits can include a card having the dosages oriented in the order of their intended use. An example of such a kit is a "blister pack" . Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms. If desired, a memory aid can be provided, for example in the form of numbers, letters, or other markings or with a calendar insert, designating the days in the treatment schedule in which the dosages can be administered.
[0321]
According to one embodiment, a kit may comprise (a) a first container with a compound of Formula I or I′contained therein; and optionally (b) a second container with a second pharmaceutical formulation contained therein, wherein the second pharmaceutical formulation comprises a second compound with anti-hyperproliferative activity. Alternatively, or additionally, the kit may further comprise a third container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI) , phosphate-buffered saline, Ringer′s solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.
[0322]
In certain other embodiments wherein the kit comprises a composition of Formula I or I′and a second therapeutic agent, the kit may comprise a container for containing the separate compositions such as a divided bottle or a divided foil packet, however, the separate compositions may also be contained within a single, undivided container. Typically, the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral) , are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
[0323]
Preparation of Formula I or I′Compounds
[0324]
Formula I or I′compounds may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein, and those for other heterocycles described in: Comprehensive Heterocyclic Chemistry II, Editors Katritzky and Rees, Elsevier, 1997, e.g. Volume 3; Liebigs Annalen der Chemie, (9) : 1910-16, (1985) ; Helvetica Chimica Acta, 41: 1052-60, (1958) ; Arzneimittel-Forschung, 40 (12) : 1328-31, (1990) , each of which are expressly incorporated by reference. Starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, WI) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-23, Wiley, N.Y. (1967-2006 ed. ) , or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database) . Formula I or I′compounds may also be made following the procedures found in US 8476434, US 7880000, WO 2005/113494, US 7868177, and WO 2007/100646.
[0325]
Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing Formula I or I′compounds and necessary reagents and intermediates are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989) ; T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley and Sons (1999) ; and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.
[0326]
Compounds of Formula I or I′may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000 compounds, or 10 to 100 compounds. Libraries of compounds of Formula I or I′may be prepared by a combinatorial ‘split and mix’ approach or by multiple parallel syntheses using either solution phase or solid phase chemistry, by procedures known to those skilled in the art. Thus according to a further aspect of the invention there is provided a compound library comprising at least 2 compounds, or pharmaceutically acceptable salts thereof.
[0327]
The Examples provide exemplary methods for preparing Formula I or I′compounds. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the Formula I or I′compounds. Although specific starting materials and reagents are depicted and discussed in the Examples, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the exemplary compounds prepared by the described methods can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.
[0328]
In preparing compounds of Formula I or I′, protection of remote functionality (e.g., primary or secondary amine) of intermediates may be necessary. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC) , benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc) . The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley &Sons, New York, 1991.
[0329]
In the methods of preparing Formula I or I′compounds, it may be advantageous to separate reaction products from one another and/or from starting materials. The desired products of each step or series of steps is separated and/or purified to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
[0330]
Another class of separation methods involves treatment of a mixture with a reagent selected to bind to or render otherwise separable a desired product, unreacted starting material, reaction by product, or the like. Such reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, or the like. Alternatively, the reagents can be acids in the case of a basic material, bases in the case of an acidic material, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid/liquid ion extraction reagents (LIX) , or the like. Selection of appropriate methods of separation depends on the nature of the materials involved, such as, boiling point and molecular weight in distillation and sublimation, presence or absence of polar functional groups in chromatography, stability of materials in acidic and basic media in multiphase extraction, and the like.
[0331]
Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride) , separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Also, some of the compounds of the present invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of a chiral HPLC column.
[0332]
A single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Eliel, E. and Wilen, S. “Stereochemistry of Organic Compounds, ” John Wiley &Sons, Inc., New York, 1994; Lochmuller, C.H., (1975) J. Chromatogr., 113 (3) : 283-302) . Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: “Drug Stereochemistry, Analytical Methods and Pharmacology, ” Irving W. Wainer, Ed., Marcel Dekker, Inc., New York (1993) .
[0333]
Under method (1) , diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, α-methyl-β-phenylethylamine (amphetamine) , and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid. The diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography. For separation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.
[0334]
Alternatively, by method (2) , the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (E. and Wilen, S. “Stereochemistry of Organic Compounds” , John Wiley &Sons, Inc., 1994, p. 322) . Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the pure or enriched enantiomer. A method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g., (-) menthyl chloroformate in the presence of base, or Mosher ester, α-methoxy-α- (trifluoromethyl) phenyl acetate (Jacob III. J. Org. Chem. (1982) 47: 4165) , of the racemic mixture, and analyzing the 1H NMR spectrum for the presence of the two atropisomeric enantiomers or diastereomers. Stable diastereomers of atropisomeric compounds can be separated and isolated by normal-and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (WO 96/15111) . By method (3) , a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase ( “Chiral Liquid Chromatography” (1989) W. J. Lough, Ed., Chapman and Hall, New York; Okamoto, J. Chromatogr., (1990) 513: 375-378) . Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.
[0335]
Formula I or I′compounds can be prepared by procedures in the Examples, the General Procedures, and generally by Schemes 1-4, where R groups are as described in Formula I or I′compounds, or precursors thereof.
[0336]
Scheme 1
[0337]
[0338]
Scheme 1 shows coupling of a (2-halopyridin-3-yl) boronic acid or ester compound A (R = H, C 1-C 6 alkyl, pinacol; X 1 = halogen) with a 4-chloro-2- (methylthio) pyrimidine compound B (R = C 1-C 6 alkyl, X 2 = halogen) under palladium catalysis to form 4- (2-halopyridin-3-yl) -2- (alkylthio) pyrimidine compound C.
[0339]
Scheme 2
[0340]
[0341]
Scheme 2 shows coupling of a naphthalen-1-ol compound D with a 4- (2-halopyridin-3-yl) -2- (alkylthio) pyrimidine compound C to form a 4- (2- (naphthalen-1-yloxy) pyridin-3-yl) pyrimidine-2-alkylthiol E compound. Oxidation of the sulfur atom forms 2- (alkylsulfinyl) -4- (2- (naphthalen-1-yloxy) pyridin-3-yl) pyrimidine compound F. The sulfoxide is displaced with a primary amine (R 1-NH 2) to form a Formula I or I′compound, or an intermediate to be converted to a Formula I or I′compound.
[0342]
Scheme 3
[0343]
[0344]
Scheme 3 shows an alternative route to Formula I or I′compounds where a 4- (2-halopyridin-3-yl) -2- (alkylthio) pyrimidine compound C is oxidized to a 4- (2-halopyridin-3-yl) -2- (alkylsulfinyl) pyrimidine compound G. The sulfoxide is displaced with a primary amine (R 1-NH 2) to form a 4- (2-halopyridin-3-yl) -N-alkylpyrimidin-2-amine compound H. Coupling of compound H with a naphthalen-1-ol compound D forms a Formula I or I′compound, or an intermediate to be converted to a Formula I or I′compound.
[0345]
Scheme 4
[0346]
[0347]
Scheme 4 shows the general preparation of exemplary compounds from aniline intermediate, tert-butyl (S) -3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (see, Example 101) . The aniline intermediate is treated with a carboxlic acid (R aCOOH) and a coupling reagent, such as 1- [Bis (dimethylamino) methylene] -1H-1, 2, 3-triazolo [4, 5-b] pyridinium 3-oxid hexafluorophosphate (HATU) as in General Procedure C, or alternatively with an acid chloride (R aCOCl) and an amine base such as diisopropylethylamine (DIPEA) or pyridine, to form Boc-protected, amide intermediates (top) . The aniline intermediate is treated with a sulfonyl chloride (R bSO 2Cl) and an amine base to form Boc-protected, sulfonamide intermediates (middle) as in General Procedure A. The aniline intermediate is treated with an alkylating agent as in General Procedure G, or by reductive amination (R cCHO) to form Boc-protected, amine intermediates (bottom) as in General Procedure E. The Boc-protected intermediates are deprotected with acid, such as hydrochloric acid as in General Procedure B, to form exemplary compounds, such as those in Tables 1 and 2 and the following Examples.
[0348]
The following General Procedures illustrate synthetic reactions and operations useful to prepare certain Example compounds (Tables 1 and 2) . The reagents, solvents, amounts, equivalents, and conditions are illustrative and exemplary, and not meant to be limiting.
[0349]
General Procedure A -sulfonamide synthesis:
[0350]
To a solution of the aniline (1.0 equiv) in pyridine (5 mL/mmol) and a solvent such as dichloromethane (DCM) at 0 ℃ or room temperature (rt) was added the corresponding sulfonyl chloride (1.2 equiv typically otherwise noted) . After the addition was completed, the reaction solution was stirred at rt for about 16 h. Water (10 mL) was added. The mixture was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.
[0351]
General Procedure B -Boc deprotection
[0352]
To a mixture of the t-butyl-carbamate (Boc) intermediate (100 mg, 0.16 mmol) in DCM (25 mL/mmol) or EtOAc was added hydrochloric acid (4 M in dioxane, 10 mL/mmol) . The mixture was then stirred at rt for 1 h and concentrated in vacuo or the resulting HCl salt was isolated by filtration.
[0353]
General Procedure C -amide coupling using carboxylic acids:
[0354]
To a solution of the aniline intermediate (1.05 equiv otherwise indicated) and DIPEA (3.0 equiv otherwise indicated) in DCM (16 mL/mmol otherwise indicated) was added HATU (2.0 equiv otherwise indicated) . The mixture was stirred at rt for 0.5 h. The acid (1.0 equiv otherwise indicated) was added and the resulting mixture was refluxed overnight. The mixture was diluted in DCM, washed with water and brine, dried on anhydrous sodium sulfate, and concentrated in vacuo. Alternatively, to a solution of the aniline in CH 2Cl 2 was added the acid chloride followed by addition of (iPr) 2NEt or Et 3N or pyridine and stirring at rt. Alternatively, to a solution of the aniline in DMF was added the carboxylic acid and HATU followed by addition of (iPr) 2NEt or Et 3N and stirring at rt. Other coupling reagents may be used in General Procedure C. The crude product was isolated and purified using methods known in the art or as described in the Examples.
[0355]
General Procedure E -reductive amination:
[0356]
To a mixture of aniline and aldehyde in CH 2Cl 2 was added sodium triacetoxyborohydride and HOAc (caution bubbling -vent vessel) and the mixture stirred at rt. The crude product was isolated and purified using methods known in the art or as described in the Examples.
[0357]
General Procedure F -epoxide ring opening:
[0358]
A mixture of aniline and epoxide in HOAc was stirred at rt unless otherwise noted. When complete, the mixture was concentrated in vacuo. The crude product was isolated and purified using methods known in the art or as described in the Examples.
[0359]
General Procedure G -aniline alkylation with alkyl halides:
[0360]
A mixture of aniline, alkyl-halide, cesium carbonate, Cs 2CO 3 and tetrabutylammonium iodide in DMF was heated at 50 ℃. The crude product was isolated and purified using methods known in the art or as described in the Examples.
[0361]
General Procedure H -Cbz deprotection:
[0362]
A mixture of benzyl-carbamate, palladium on carbon (Pd/C) and ammonium formate in iPrOH was heated at 60 ℃. When complete, the mixture was filtered through celite using MeOH/CH 2Cl 2 and concentrated in vacuo.
[0363]
Analytical Methods:
[0364]
LCMS (Liquid Chromatography Mass Spectrometry) methods to separate and characterize the exemplary compounds were performed on the following:
[0365]
SHIMADZU LC-MS 2010EV coupled with SHIMADZU LC20AB using ESI as ionization source. The LC separation was using Column: MERCK, RP-18e 25-2 mm; Detector: PDA, ELSD; Wavelength: UV 220 nm; Column temperature: 50 ℃; mobile Phase: 1.5 mL/4 LTFA in water (solvent A) and 0.75 mL/4 L TFA in acetonitrile (solvent B) , using the elution gradient 5%-95% (solvent B) over 0.7 minutes and holding at 95%for 0.4 minutes at a flow rate of 1.5 mL/min;
[0366]
SHIMADZU LC-MS 2010EV coupled with SHIMADZU LC20AB using ESI as ionization source. The LC separation was using Column: MERCK, RP-18e 25-2 mm; Detector: PDA, ELSD; Wavelength: UV 220 nm; Column temperature: 50℃; mobile Phase: 1.5 mL/4 L TFA in water (solvent A) and 0.75 mL/4 L TFA in acetonitrile (solvent B) , using the elution gradient 5%-95% (solvent B) over 0.7 minutes and holding at 95%for 0.4 minutes at a flow rate of 1.5 mL/min;
[0367]
Agilent 1200 Series coupled with 6110 Quadrupole mass spectrometer, using ESI as ionization source. The LC separation was using Column: Xtimate C18 2.1 x 30mm, 3 μm; Wavelength: UV 220 nm; Column temperature: 50 ℃; Detector: PDA&ELSD. mobile Phase: 1.5 mL/4 L TFA in water (solvent A) and 0.75 mL/4 LTFA in acetonitrile (solvent B) , using the elution gradient 10%-80% (solvent B) over 0.9 minutes and holding at 80%for 0.6 minutes at a flow rate of 1.2 mL/min.
[0368]
SHIMADZU 2020 HPLC coupled with SHIMADZU MSD mass spectrometer using ESI as ionization source. The LC separation was using an Shim-Pack XR-ODS-C18, 50 x 3.0 mm column with a 1 ml /minute flow rate. Solvent A is water with 0.05%TFA and solvent B is acetonitrile with 0.05%TFA. The gradient consisted with 5 -100%solvent B over 2.2 minutes and hold 100%B for 1 minute. LC column temperature is 40 ℃. UV absorbance was collected from 190 nm to 400 nm and mass spec full scan was applied to all experiments.
[0369]
SHIMADZU 2020 HPLC coupled with SHIMADZU MSD mass spectrometer using ESI as ionization source. The LC separation was using an Gemini-NX 3μ C18 110A, 50 x 3.0 mm column with a 1.2 ml /minute flow rate. Solvent A is water with 0.4%NH 4HCO3 and solvent B is acetonitrile. The gradient consisted with 10 -50%solvent B over 4 minutes and hold 50%B for 1.2 minutes. LC column temperature is 40 ℃. UV absorbance was collected from 190 nm to 400 nm and mass spec full scan was applied to all experiments.
[0370]
SHIMADZU UFLC-MS 2010EV coupled with SHIMADZU MSD mass spectrometer using ESI as ionization source. The LC separation was using a Shim-pack XR-ODS-C18, 50 x 3.0 mm column with a 1 ml /minute flow rate. Solvent A is water with 0.05%TFA and solvent B is acetonitrile with 0.05%TFA. The gradient consisted with 5 -100%solvent B over 2.2 minutes and hold 100%B for 1 minute. LC column temperature is 40 ℃. UV absorbance was collected from 190 nm to 400 nm and mass spec full scan was applied to all experiments.
[0371]
Waters Alliance 2695 HPLC with column heater coupled with Waters ZQ 2000 mass spectrometer using ESI as ionization source (ES+, 100-1200 amu) . The LC separation was using an XBridge C18, 3.5μm, 4.6 x 30mm column at 25℃ with a 3.0 mL /minute flow rate. Solvent A is Milli-Q H2O + 10mM Ammonium Formate pH: 3.8, and solvent B is acetonitrile. The gradient consisted of isocratic 5% solvent B for 0.2 min, 5%to 100%B in 1.8 minutes; hold 100%B for 1 minute. LC column temperature is 25 ℃. UV absorbance was collected from 195 -320 nm using a Waters PDA 996 UV detector and mass spec full scan was applied to all experiments.
[0372]
Waters Alliance 2695 HPLC with column heater coupled with Waters ZQ 2000 mass spectrometer using ESI as ionization source (ES+, 100-1200 amu) . The LC separation was using an XBridge C18, 3.5μm, 4.6 x 30mm column at 25℃ with a 3.0 mL /minute flow rate. Solvent A is Milli-Q H2O + 10mM Ammonium Bicarbonate pH: 10, and solvent B is acetonitrile. The gradient consisted of isocratic 5%solvent B for 0.2 min, 5%to 100%B in 1.8 minutes; hold 100%B for 1 minute. LC column temperature is 25 ℃. UV absorbance was collected from 195 -320 nm using a Waters PDA 996 UV detector and mass spec full scan was applied to all experiments.
[0373]
EXAMPLES
[0374]
Synthetic Examples
[0375]
Example 101 (S) -3- (2-Cyanopropan-2-yl) -N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) benzamide 101
[0376]
Step 1: tert-Butyl 5-hydroxynaphthalen-1-ylcarbamate
[0377]
[0378]
To a 5 L 4-necked round-bottom flask was placed 5-aminonaphthalen-1-ol (400 g, 2.51 mol, 1.00 equiv. ) , di-tert-butyl dicarbonate, Boc 2O (660 g, 3.01 mol, 1.20 equiv. ) and 1, 4-dioxane (2.5 L) . The resulting solution was stirred at rt for 30 min and then heated under reflux for 3 h. The reaction mixture was then cooled to rt and concentrated in vacuo. The product was re-crystallized from ethyl acetate: petroleum ether (1∶5) to yield 500 g (77%) of the title compound as a gray solid. LCMS (ESI) [M+H-56] + = 204.
[0379]
Step 2: tert-Butyl 6- ( (diethylamino) methyl) -5-hydroxynaphthalen-1-ylcarbamate
[0380]
[0381]
To a 2000-mL 4-necked round-bottom flask was placed tert-butyl N- (5-hydroxynaphthalen-1-yl) carbamate (100 g, 386 mmol) , methanol (800 mL) , diethylamine (31.4 g, 424 mmol, 1.10 equiv. ) and formaldehyde (35 g, 424 mmol, 37%solution in water) . The resulting solution was stirred at rt for 1 h and concentrated in vacuo. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1∶5-1∶3) to yield 100 g (75%) of the title compound as a reddish oil. LCMS (ESI) [M+H] + = 345.
[0382]
Step 3: tert-Butyl 5-hydroxy-6-methylnaphthalen-1-ylcarbamate
[0383]
[0384]
To a 3 L 4-necked round-bottom flask was placed tert-butyl N- [6- [ (diethylamino) methyl] -5-hydroxynaphthalen-1-yl] carbamate (200 g, 581 mmol) , ethanol (1.5 L) and palladium on carbon (30 g) . Hydrogen, H 2 (gas) was introduced via a hydrogen balloon) to the above system. The resulting suspension was stirred at rt (room temperature) overnight and filtered. The filtrate was concentrated in vacuo to yield 200 g of the crude title compound as a brown oil. LCMS (ESI) [M+H-56] + = 218.
[0385]
Step 4: 5-Amino-2-methylnaphthalen-1-ol hydrochloride
[0386]
[0387]
To a 5 L 4-necked round-bottom flask was placed a solution of tert-butyl N- (5-hydroxy-6-methylnaphthalen-1-yl) carbamate (100 g, 366 mmol) in dichloromethane, DCM (3 L) followed by bubbling hydrogen chloride, HCl (gas) . The resulting solution was stirred at rt for 2 h and concentrated in vacuo. The crude product was purified by re-crystallization from DCM. The solids were collected by filtration and dried in vacuo to yield 73 g (95%) of the title compound as a white solid. LCMS (ESI) [M+H] + = 174.
[0388]
Step 5: 4- (2-Fluoropyridin-3-yl) -2- (methylthio) pyrimidine
[0389]
[0390]
To a 3 L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 4-chloro-2- (methylsulfanyl) pyrimidine (80 g, 498 mmol) , (2-fluoropyridin-3-yl) boronic acid (98.7 g, 697 mmol) , sodium carbonate (117 g, 1.10 mol) , tetrakis (triphenylphosphine) palladium (0) (29 g, 24.9 mmol) , water (160 mL) and 1, 4-dioxane (1.6 L) . The resulting solution was stirred at 100 ℃ in an oil bath overnight, cooled to rt, and filtered. The filtrate was diluted with brine and was then extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified via flash silica chromatography (solvent gradient: 10-50%ethyl acetate in petroleum ether) to yield 80 g (73%) of the title compound as a yellow solid. LCMS (ESI) [M+H] + = 222.
[0391]
Step 6: 6-Methyl-5- (3- (2- (methylthio) pyrimidin-4-yl) pyridin-2-yloxy) naphthalen-1-amine
[0392]
[0393]
To a 2 L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 5-amino-2-methylnaphthalen-1-ol hydrochloride (100 g, 477 mmol) , N-methyl-2-pyrrolidone, NMP (1 L) , 4- (2-fluoropyridin-3-yl) -2- (methylsulfanyl) pyrimidine (105 g, 477 mmol) , and caesium carbonate (328 g, 1.00 mol) . The resulting solution was stirred at 120 ℃ in an oil bath overnight, cooled to room temperature, and diluted with 1 L of brine. The resulting solution was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified via flash silica chromatography (solvent gradient: 20-50%ethyl acetate in petroleum ether) to yield 80 g (45%) of the title compound as a brown solid. LCMS (ESI) [M+H] + = 375.
[0394]
Alternatively, the title compound can be prepared by the following scheme where 4-chloro-2- (methylthio) pyrimidine and (2-chloropyridin-3-yl) boronic acid are coupled as in Step 5 to form 4- (2-chloropyridin-3-yl) -2- (methylthio) pyrimidine which is reacted with 5-amino-2-methylnaphthalen-1-ol hydrochloride:
[0395]
[0396]
Step 7: 6-Methyl-5- ( (3- (2- (methylsulfinyl) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-amine
[0397]
[0398]
To a 3 L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 6-methyl-5- ( [3- [2- (methylsulfanyl) pyrimidin-4-yl] pyridin-2-yl] oxy) naphthalen-1-amine (100 g, 267 mmol) , DCM (2 L) and 3-chlorobenzene-1- carboperoxoic acid (56 g, 321 mmol) . The resulting solution was stirred at rt for 4 h and quenched with the addition of 1 L of a saturated solution of sodium hydrogenocarbonate. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified via flash silica chromatography (solvent gradient: 20%ethyl acetate in petroleum ether and then 2%methanol in DCM) to yield 65 g (62%) of the title compound as a yellow solid.
[0399]
Step 8: tert-Butyl (S) -3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0400]
[0401]
To a 2 L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 5- [ [3- (2-methanesulfinylpyrimidin-4-yl) pyridin-2-yl] oxy] -6-methylnaphthalen-1-amine (75 g, 192 mmol) , tert-butyl (3S) -3-aminopiperidine-1-carboxylate (152 g, 768 mmol) , 1, 4-dioxane (1 L) and DIPEA (98 g, 768 mmol) . The resulting solution was stirred at 110 ℃ in an oil bath overnight, cooled to rt and concentrated in vacuo. The residue was purified via flash silica chromatography (solvent gradient: 20%ethyl acetate in petroleum ether and then 2%methanol in DCM) to yield 50.5 g (50%) of the title compound as a yellow solid. LCMS: (ES, m/z) : [M+H] + = 527.
[0402]
Step 9: (S) -tert-Butyl 3- (4- (2- (4- (3- (2-cyanopropan-2-yl) benzamido) -2-methylnaphthalen-1-yloxy) pyridin-3-yl) pyrimidin-2-ylamino) piperidine-1-carboxylate
[0403]
[0404]
A solution of tert-butyl (S) -3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (275 mg, 0.52 mmol) , 1- [Bis (dimethylamino) methylene] -1H-1, 2, 3-triazolo [4, 5-b] pyridinium 3-oxid hexafluorophosphate, HATU, CAS Reg. No. 148893-10-1, (218 mg, 0.57 mmol) , DIPEA (134 mg, 1.04 mmol) , and 3- (2-cyanopropan-2-yl) benzoic acid (108 mg, 0.57 mmol) in dry N, N- dimethylformamide (10 mL) was stirred at room temperature for 12 h. The reaction mixture was poured into water and then extracted with ethyl acetate. The organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude was purified by silica gel column chromatography (petroleum /EtOAc = 2∶1 to 1∶1) to yield 200 mg (55%yield) of the title compound as a white solid. LCMS (ESI) [M+H] + = 698.8.
[0405]
Step 10: (S) -3- (2-Cyanopropan-2-yl) -N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) benzamide
[0406]
[0407]
The General Procedure B was followed, using (S) -tert-butyl 3- (4- (2- (4- (3- (2-cyanopropan-2-yl) benzamido) -2-methylnaphthalen-1-yloxy) pyridin-3-yl) pyrimidin-2-ylamino) piperidine-1-carboxylate (200 mg, 0.31 mmol) , ethylacetate (3 mL) and hydrochloric acid (4 M in dioxane, 3 mL, 12 mmol) . The residue was purified by Prep-HPLC to yield 100 mg (65%) of 101 as a white solid. LCMS (ESI) : [M+H] + = 598.3; NMR (400 MHz, DMSO-d 6) δ 10.57 (s, 1H) , 8.51 (d, J = 7.7 Hz, 1H) , 8.42 (d, J = 5.1 Hz, 1H) , 8.20 (t, J = 1.9 Hz, 1H) , 8.13 -8.08 (m, 1H) , 8.06 (dd, J = 5.0, 1.9 Hz, 1H) , 7.85 (d, J = 8.7 Hz, 1H) , 7.83 -7.78 (m, 1H) , 7.65 (t, J = 7.8 Hz, 2H) , 7.55 (dd, J = 7.4, 1.3 Hz, 1H) , 7.50 (dd, J = 8.4, 5.7 Hz, 2H) , 7.46 (d, J = 5.2 Hz, 1H) , 7.27 (dd, J = 7.6, 4.8 Hz, 1H) , 7.11 (d, J = 8.0 Hz, 1H) , 4.09 (q, J = 5.2 Hz, 1H) , 3.89 (s, 1H) , 3.10 (d, J = 11.7 Hz, 1H) , 2.78 (m, 1H) , 2.47 -2.37 (m, 2H) , 2.23 (s, 3H) , 1.93 (d, J = 11.6 Hz, 1H) , 1.78 (s, 6H) , 1.64 (m, 1H) , 1.56 -1.36 (m, 2H) .
[0408]
Example 102 (S) -1- (2-Chlorophenyl) -N- (2-fluoro-6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) methanesulfonamide 102
[0409]
Step 1: (S) -tert-Butyl 3- ( (4- (2- ( (5- ( (2-chlorophenyl) methylsulfonamido) -6-fluoro-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0410]
[0411]
Prepared using (S) -tert-butyl 3- ( (4- (2- ( (5-amino-6-fluoro-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate from Example 275 (65 mg, 0.12 mmol) , pyridine (0.14 mL, 1.79 mmol) , DMAP (1.5 mg, 0.01 mmol) , DCM (0.9 mL) , and (2-chlorophenyl) methanesulfonyl chloride (54 mg, 0.24 mmol) . After stirring 1 h at rt, the reaction was diluted with DCM and washed with 1N KHSO 4 (aq) (10 mL) , dried (Na 2SO 4) , filtered and evaporated. The crude product was purified by flash chromatography through silica gel (0 -50%EtOAc/DCM) to provide 58 mg (88%yield) of the title compound as a solid. LCMS (ESI) [M+H] + = 733.5, rt = 2.04 min.
[0412]
Step 2: (S) -1- (2-Chlorophenyl) -N- (2-fluoro-6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) methanesulfonamide
[0413]
[0414]
Prepared using (S) -tert-butyl 3- ( (4- (2- ( (5- ( (2-chlorophenyl) methylsulfonamido) -6-fluoro-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (58 mg, 0.08 mmol) , 1, 4-dioxane (0.5 mL) and hydrochloric acid (4 M in dioxane, 0.73 mL, 2.92 mmol) . After 60 min, the suspension was diluted with Et 2O (15 mL) and the precipitate was filtered and washed with Et 2O. The precipitate was dissolved in MeCN and water and lyophilized to provide 46 mg (88%yield) of 102 as a fluffy light yellow solid. LCMS (ESI) [M+H] + = 633.5, rt = 1.53 min; 1H NMR (400 MHz, d6-dmso) δ 10.04 (s, 1H) , 8.84 (bs, 2H) , 8.66 (s, 1H) , 8.48 (d, J = 5.2 Hz, 1H) , 8.09 (dd, J = 4.8, 2.0 Hz, 1H) , 8.02 (d, J = 8.8 Hz, 1H) , 7.74 (dd, J = 9.2, 5.1 Hz, 1H) , 7.66 -7.46 (m, 6H) , 7.46 -7.36 (m, 2H) , 7.29 (dd, J = 7.6, 4.8 Hz, 1H) , 4.77 (s, 2H) , 4.27 (s, 1H) , 3.50 -3.37 (m, 1H) , 3.21 (d, J = 12.0 Hz, 1H) , 2.96 -2.74 (m, 2H) , 2.19 (s, 3H) , 2.07 -1.97 (m, 1H) , 1.97 -1.87 (m, 1H) , 1.82 -1.55 (m, 2H) .
[0415]
Example 103 (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) ethanesulfonamide 103
[0416]
Step 1: tert-Butyl (S) -3- (4- (2- (5- (ethylsulfonamido) -2-methylnaphthalen-1-yloxy) pyridin-3-yl) pyrimidin-2-ylamino) piperidine-1-carboxylate
[0417]
[0418]
The General Procedure A was followed, using tert-butyl (S) -3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate from Example 101 (100 mg, 0.19 mmol) , pyridine (2 mL) and ethanesulfonyl chloride (29 mg, 0.23 mmol) . The residue was purified by Prep-TLC (normal phase, petroleum ether/ethyl acetate = 2 /1) to yield 110 mg (93%) of the title compound as a white solid. LCMS (ESI) [M+H] + = 619.
[0419]
Step 2: (S) -N- (6-Methyl-5- (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yloxy) naphthalen-1-yl) ethanesulfonamide hydrochloride
[0420]
[0421]
The General Procedure B was followed, using tert-butyl (S) -3- (4- (2- (5- (ethylsulfonamido) -2-methylnaphthalen-1-yloxy) pyridin-3-yl) pyrimidin-2-ylamino) piperidine-1-carboxylate (110 mg, 0.18 mmol) , DCM (5 mL) and hydrochloric acid (4 M in dioxane, 2 mL, 8 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%TFA) B: ACN) to yield 40 mg (40%) of hydrochloride 103 as a white solid. LCMS (ESI) : [M+H] + = 519.7; 1H NMR (400 MHz, CD 3OD) δ 8.67 (m, 1H) , 8.46 (d, J = 5.6 Hz, 1H) , 8.16 (d, J = 8.8 Hz, 1H) , 8.01 (m, 1H) , 7.71 (d, J = 5.6 Hz, 1H) , 7.64 (d, J = 8.8 Hz, 1H) , 7.57 (s, 1H) , 7.54 (s, 1H) , 7.39 (t, J = 8 Hz, 15.6 Hz, 1H) , 7.26-7.22 (m, 1H) , 4.37-4.36 (m, 1H) , 3.66-3.61 (m, 1H) , 3.37-3.32 (m, 1H) , 3.21-3.15 (m, 2H) , 3.11-3.04 (m, 2H) , 2.29 (s, 3H) , 2.23-2.11 (m, 2H) , 1.93-1.83 (m, 2H) , 1.41-1.31 (m, 3H) .
[0422]
Example 104 (S) -N- (6-Methyl-5- (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yloxy) naphthalen-1-yl) propane-1-sulfonamide hydrochloride 104
[0423]
Step 1: tert-Butyl (S) -3- (4- (2- (2-methyl-5- (propylsulfonamido) naphthalen-1-yloxy) pyridin-3-yl) pyrimidin-2-ylamino) piperidine-1-carboxylate
[0424]
[0425]
The General Procedure A was followed, using tert-butyl (3S) -3- [ [4- [2- [ (5-amino-2-methyl-1-naphthyl) oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (100 mg, 0.19 mmol) , pyridine (2 mL) and 1-propanesulfonyl chloride (200 mg, 1.4 mmol) . The crude was then purified by Prep-TLC (petroleum ether/ethyl acetate = 1 /1) to yield 100 mg (82%yield) of the title compound as a brown solid. LCMS (ESI) [M+H] + = 633.
[0426]
Step 2: (S) -N- (6-Methyl-5- (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yloxy) naphthalen-1-yl) propane-1-sulfonamide hydrochloride
[0427]
[0428]
The General Procedure B was followed, using tert-butyl (3S) -3- [ [4- [2- [ [2-methyl-5- (propylsulfonylamino) -1-naphthyl] oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (100 mg, 0.16 mmol) , DCM (5 mL) and hydrochloric acid (4 M in dioxane, 2 mL, 8 mmol) . The residue was purified by Prep-HPLC to yield 52 mg (62%) of 104 as a white solid. LCMS (ESI) : [M+H] + = 533; 1H NMR (400 MHz, DMSO-d 6) δ 8.54 (s, 1H) , 8.43 (d, J = 5.1 Hz, 1H) , 8.33 (s, 1H) , 8.13 (d, J = 8.7 Hz, 1H) , 8.04 (dd, J = 4.8, 1.9 Hz, 1H) , 7.56 -7.51 (m, 2H) , 7.49 (d, J = 5.1 Hz, 1H) , 7.46 -7.37 (m, 2H) , 7.32 -7.24 (m, 2H) , 4.06 (s, 1H) , 3.24 (d, J = 10.5 Hz, 1H) , 3.16 -3.08 (m, 2H) , 2.97 (d, J = 12.3 Hz, 1H) , 2.71 -2.54 (m, 2H) , 2.21 (s, 3H) , 1.96 (s, 1H) , 1.83 -1.69 (m, 3H) , 1.56 (s, 2H) , 0.96 (t, J = 7.4 Hz) .
[0429]
Example 105 (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) cyclopropanesulfonamide hydrochloride 105
[0430]
Step 1: tert-Butyl (S) -3- (4- (2- (2-methyl-5- (cyclopropanesulfonamido) naphthalen-1-yloxy) pyridin-3-yl) pyrimidin-2-ylamino) piperidine-1-carboxylate
[0431]
[0432]
The General Procedure A was followed, using tert-butyl (S) -3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate from Example 101 (100 mg, 0.19 mmol) , pyridine (2 mL) and cyclopropanesulfonyl chloride (200 mg, 1.4 mmol) . The crude was then purified by Prep-TLC (petroleum ether/ethyl acetate = 1 /1) to yield 37 mg (29%yield) of the title compound as a white solid. LCMS (ESI) [M+H] + = 631.
[0433]
Step 2: (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) cyclopropanesulfonamide hydrochloride
[0434]
[0435]
The General Procedure B was followed, using tert-butyl (S) -3- (4- (2- (2-methyl-5- (cyclopropanesulfonamido) naphthalen-1-yloxy) pyridin-3-yl) pyrimidin-2-ylamino) piperidine-1-carboxylate (37 mg, 0.16 mmol) , DCM (5 mL) and hydrochloric acid (4 M in dioxane, 1 mL, 4 mmol) . The residue was purified by Prep-HPLC to yield 16 mg (52%) of hydrochloride 105 as a white solid. LCMS (ESI) : [M+H] + = 531; 1H NMR (400 MHz, CD3OD) δ 8.67 (d, J = 6.8 Hz, 1H) , 8.58 (s, 1H) , 8.44 (d, J = 5.2 Hz, 1H) , 8.21 (d, J = 8.7 Hz, 1H) , 8.07 -7.95 (m, 1H) , 7.76 -7.65 (m, 2H) , 7.56 (dd, J = 12.2, 8.1 Hz, 2H) , 7.39 (t, J = 7.9 Hz, 15.8 Hz, 1H) , 7.23 (dd, J = 7.5, 4.9 Hz, 1H) , 4.33 (s, 1H) , 3.58 (d, J = 9.8 Hz, 1H) , 3.27 (s, 1H) , 2.98 (t, J = 10.8 Hz, 21.6 Hz, 2H) , 2.73 -2.56 (m, 1H) , 2.28 (s, 3H) , 2.19 (d, J = 11.1 Hz, 1H) , 2.07 (d, J = 14.1 Hz, 1H) , 1.96 -1.68 (m, 2H) , 1.03 (d, J = 3.2 Hz, 2H) , 0.95 (d, J = 7.5 Hz, 2H) .
[0436]
Example 106 (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) methylethylsulfonamide hydrochloride 106
[0437]
Step 1: tert-Butyl (S) -3- (4- (2- (2-methyl-5- (methylethylpropanesulfonamido) naphthalen-1-yloxy) pyridin-3-yl) pyrimidin-2-ylamino) piperidine-1-carboxylate
[0438]
[0439]
The General Procedure A was followed, using tert-butyl (S) -3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate from Example 101 (100 mg, 0.19 mmol) , pyridine (2 mL) and isopropylsulfonyl chloride (32 mg, 0.23 mmol) . The crude was then purified by Prep-TLC (petroleum ether/ethyl acetate = 2 /1) to yield (50 mg, 0.08 mmol, 40%yield) as a white solid.
[0440]
Step 2: (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) methylethylsulfonamide hydrochloride
[0441]
[0442]
The General Procedure B was followed, using tert-butyl (3S) -3- [ [4- [2- [ [2-methyl-5- (propylsulfonylamino) -1-naphthyl] oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (50 mg, 0.08 mmol) , DCM (5 mL) and hydrochloric acid (4 M in dioxane, 1 mL, 4 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%TFA) B: ACN) to yield 30 mg (60%) of hydrochloride 106 as a white solid. LCMS (ESI) : [M+H] + = 533.7; 1H NMR (400 MHz, CD 3OD) δ 8.66 (d, J = 6.8Hz, 1H) , 8.46 (d, J = 5.2Hz, 1H) , 8.17 (d, J = 8.8Hz, 1H) , 8.01 (m, 1H) , 7.71 (d, J = 5.2Hz, 1H) , 7.63-7.54 (m, 3H) , 7.38 (t, J = 8 Hz, 16.4 Hz, 1H) , 7.26-7.22 (m, 1H) , 4.37 (s, 1H) , 3.66-3.62 (m, 1H) , 3.41-3.28 (m, 2H) , 3.11-3.04 (m, 2H) , 2.28 (s, 3H) , 2.23-2.11 (m, 2H) , 1.92-1.80 (m, 2H) , 1.42 (s, 3H) , 1.40 (s, 3H) .
[0443]
Example 107 (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) cyclobutanesulfonamide hydrochloride 107
[0444]
Step 1: tert-Butyl (S) -3- ( (4- (2- ( (5- (Cyclobutanesulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0445]
[0446]
The General Procedure A was followed, using tert-butyl (S) -3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate from Example 101 (100 mg, 0.19 mmol) , pyridine (2 mL) and cyclobutanesulfonyl chloride (35 mg, 0.23 mmol) . The crude was then purified by Prep-TLC (petroleum ether/ethyl acetate = 1 /1) to yield 120 mg (95%yield) of the title compound as a brown solid. LCMS (ESI) [M+H] + = 645.
[0447]
Step 2: (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) cyclobutanesulfonamide hydrochloride
[0448]
[0449]
The General Procedure B was followed, using tert-butyl (3S) -3- [ [4- [2- [ [2-methyl-5- (propylsulfonylamino) -1-naphthyl] oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (120 mg, 0.19 mmol) , DCM (5 mL) and hydrochloric acid (4 M in dioxane, 2 mL, 8 mmol) . The residue was purified by Prep-HPLC to yield 90 mg (88%yield) of 107 as a white solid. LCMS (ESI) : [M+H] + = 560; 1H NMR (400 MHz, CD 3OD) δ 8.68 (d, J = 7.2 Hz, 1H) , 8.45 (d, J = 5.6 Hz, 1H) , 8.10 (d, J = 8.4 Hz, 1H) , 8.01 (m, 1H) , 7.74 (s, 1H) , 7.64 (d, J = 8.4 Hz, 1H) , 7.53 (t, J = 8.8 Hz, 16.4 Hz, 2H) , 7.38 (t, J = 8.4 Hz, 16.8 Hz, 1H) , 7.26-7.23 (m, 1H) , 4.39 (s, 1H) , 3.97-3.88 (m, 1H) , 3.66-3.62 (m, 1H) , 3.37-3.32 (m, 1H) , 3.11-3.03 (m, 2H) , 2.56-2.46 (m, 2H) , 2.28-2.21 (m, 7H) , 2.12-1.88 (m, 4H) .
[0450]
Example 108 (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) pyrrolidine-1-sulfonamide hydrochloride 108
[0451]
Step 1: tert-Butyl (S) -3- ( (4- (2- ( (2-methyl-5- (pyrrolidine-1-sulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0452]
[0453]
The General Procedure A was followed, using tert-butyl (S) -3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate from Example 101 (100 mg, 0.19 mmol) , pyridine (2 mL) and pyrrolidine-1-sulfonyl chloride (200 mg, 1.18 mmol) . The crude was then purified by Prep-TLC (petroleum ether/ethyl acetate = 1 /1) to yield 100 mg (73%yield) of the title compound as a white solid. LCMS (ESI) [M+H] + = 660.
[0454]
Step 2: (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) pyrrolidine-1-sulfonamide hydrochloride
[0455]
[0456]
The General Procedure B was followed, using tert-butyl (S) -3- ( (4- (2- ( (2-methyl-5- (pyrrolidine-1-sulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (100 mg, 0.15 mmol) , DCM (5 mL) and hydrochloric acid (4 M in dioxane, 2 mL, 8 mmol) . The residue was purified by Prep-HPLC to yield 36 mg (42%yield) of hydrochloride 108 as a white solid. LCMS (ESI) : [M+H] + = 560; 1H NMR (400 MHz, DMSO-d 6) δ 8.54 (s, 1H) , 8.43 (d, J = 5.1 Hz, 1H) , 8.35 (s, 1H) , 8.15 (d, J = 8.7 Hz, 1H) , 8.04 (dd, J = 4.7, 1.8 Hz, 1H) , 7.51 (dd, J = 13.4, 7.2 Hz, 4H) , 7.39 (t, J = 7.9 Hz, 15.8 Hz, 1H) , 7.34 -7.21 (m, 2H) , 4.05 (s, 1H) , 3.19 (s, 5H) , 2.96 (d, J = 11.2 Hz, 1H) , 2.73 -2.53 (m, 2H) , 2.21 (s, 3H) , 1.96 (s, 1H) , 1.78 -1.73 (m, 5H) , 1.56 (d, J = 8.6 Hz, 2H) .
[0457]
Example 109 4- [2- [ [5- (Dimethylsulfamoylamino) -2-methyl-1-naphthyl] oxy] -3-pyridyl] -2- [ [ (3S) -3-piperidyl] amino] pyrimidine hydrochloride 109
[0458]
Step 1: tert-Butyl 3- (4- (2- (5- (N, N-dimethylsulfamoylamino) -2-methylnaphthalen-1-yloxy) pyridin-3-yl) pyrimidin-2-ylamino) piperidine-1-carboxylate
[0459]
[0460]
The General Procedure A was followed, using tert-butyl (S) -3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate from Example 101 (100 mg, 0.19 mmol) , pyridine (2 mL) and dimethylsulfamoyl chloride (200 mg, 1.39 mmol) . The crude was then purified by Prep-TLC (petroleum ether/ethyl acetate = 1 /1) to yield 90 mg (70%yield) of the title compound as a white solid. LCMS (ESI) [M+H] + = 634.
[0461]
Step 2: 4- [2- [ [5- (Dimethylsulfamoylamino) -2-methyl-1-naphthyl] oxy] -3-pyridyl] -2- [ [ (3S) -3-piperidyl] amino] pyrimidine hydrochloride
[0462]
[0463]
The General Procedure B was followed, using tert-butyl (3S) -3- [ [4- [2- [ [5- (dimethylsulfamoylamino) -2-methyl-1-naphthyl] oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (90 mg, 0.14 mmol) , DCM (5 mL) and hydrochloric acid (4 M in dioxane, 3 mL, 12 mmol) . The residue was purified by Prep-HPLC to yield 42 mg (55%yield) of hydrochloride 109 as a white solid. LCMS (ESI) : [M+H] + = 534; 1H NMR (400 MHz, DMSO-d 6) δ 8.55 (s, 1H) , 8.43 (d, J = 5.1 Hz, 1H) , 8.34 (s, 1H) , 8.17 (d, J = 8.7 Hz, 1H) , 8.04 (dd, J = 4.8, 1.8 Hz, 1H) , 7.49 (dd, J = 16.7, 8.1 Hz, 4H) , 7.40 -7.33 (m, 1H) , 7.33 -7.22 (m, 2H) , 4.06 (s, 1H) , 3.23 (s, 1H) , 2.95 (s, 1H) , 2.72 (s, 6H) , 2.62 (s, 2H) , 2.21 (s, 3H) , 1.97 (s, 1H) , 1.76 (s, 1H) , 1.56 (s, 2H) .
[0464]
Example 110 N- (4- ( (3- (2- ( ( (1r, 4r) -4-aminocyclohexyl) amino) pyrimidin-4-yl) pyridin-2-yl) oxy) -3-methylnaphthalen-1-yl) -1-phenylmethanesulfonamide hydrochloride 110
[0465]
Step 1: tert-Butyl ( (trans) -4- ( (4- (2- ( (2-methyl-4- ( (phenylmethyl) sulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) cyclohexyl) carbamate
[0466]
[0467]
The General Procedure A was followed, using tert-butyl N- [4- [ [4- [2- [ (4-amino-2-methyl-1-naphthyl) oxy] -3-pyridyl] pyrimidin-2-yl] amino] cyclohexyl] carbamate (90 mg, 0.17 mmol) , pyridine (2 mL) and alpha-toluenesulfonylchloride (222 mg, 1.17 mmol) . The crude was then purified by Prep-TLC (petroleum ether/ethyl acetate = 1 /1) to yield 100 mg (86%yield) of the title compound as a yellow solid. LCMS (ESI) [M+H] + = 695.
[0468]
Step 2: N- (4- ( (3- (2- ( ( (trans) -4-aminocyclohexyl) amino) pyrimidin-4-yl) pyridin-2-yl) oxy) -3-methylnaphthalen-1-yl) -1-phenylmethanesulfonamide
[0469]
[0470]
The General Procedure B was followed, using tert-butyl ( (1r, 4r) -4- ( (4- (2- ( (2-methyl-4- ( (phenylmethyl) sulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) cyclohexyl) carbamate (100 mg, 0.14 mmol) , DCM (5 mL) and hydrochloric acid (4 M in dioxane, 3 mL, 12 mmol) . The residue was purified by Prep-HPLC to yield 39 mg (42%yield) of the title compound as a yellow solid.
[0471]
Example 111 N- (4- ( (3- (2- ( ( (trans) -4-Aminocyclohexyl) amino) pyrimidin-4-yl) pyridin-2-yl) oxy) -3-methylnaphthalen-1-yl) cyclobutanesulfonamide hydrochloride 111
[0472]
Step 1: tert-Butyl ( (trans) -4- ( (4- (2- ( (4- (Cyclobutanesulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) cyclohexyl) carbamate
[0473]
[0474]
The General Procedure A was followed, using tert-butyl N- [4- [ [4- [2- [ (4-amino-2-methyl-1-naphthyl) oxy] -3-pyridyl] pyrimidin-2-yl] amino] cyclohexyl] carbamate (100 mg, 0.19 mmol) , pyridine (2 mL) and cyclobutanesulfonyl chloride (43 mg, 0.28 mmol) . The crude was then purified by Prep-TLC (petroleum ether/ethyl acetate = 1 /1) to yield 60 mg (50%yield) of the title compound as a white solid. LCMS (ESI) [M+H] + = 660.
[0475]
Step 2: N- (4- ( (3- (2- ( ( (trans) -4-Aminocyclohexyl) amino) pyrimidin-4-yl) pyridin-2-yl) oxy) -3-methylnaphthalen-1-yl) cyclobutanesulfonamide hydrochloride
[0476]
[0477]
The General Procedure B was followed, using tert-butyl ( (1r, 4r) -4- ( (4- (2- ( (4- (cyclobutanesulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) cyclohexyl) carbamate (60 mg, 0.09 mmol) , DCM (5 mL) and hydrochloric acid (4 M in dioxane, 1 mL, 4.1 mmol) . The residue was purified by Prep-HPLC to yield 42 mg (55%yield) of 111 as a yellow solid. LCMS (ESI) : [M+H] + = 560; 1H NMR (400 MHz, CD 3OD) δ 8.61 (d, J = 7.6 Hz, 1H) , 8.40 (d, J = 5.6 Hz, 1H) , 8.23 (d, J = 8.4 Hz, 1H) , 8.04 (d, J = 4.4 Hz, 1H) , 7.75 (d, J = 8.8 Hz, 1H) , 7.76-7.68 (m, 1H) , 7.56 (d, J = 7.2 Hz, 1H) , 7.53 (s, 1H) , 7.46 (t, J = 15.2, 8 Hz, Hz, 1H) , 7.27-7.25 (m, 1H) , 3.94-4.02 (m, 2H) , 3.20-3.14 (m, 1H) , 2.56-2.48 (m, 2H) , 2.33-2.28 (m, 7H) , 2.14-2.11 (m, 2H) , 2.05-1.96 (m, 2H) , 1.51-1.72 (m, 4H) .
[0478]
Example 112 (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) -1-phenylmethanesulfonamide hydrochloride 112
[0479]
Step 1: tert-Butyl (S) -3- ( (4- (2- ( (2-methyl-5- ( (phenylmethyl) sulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0480]
[0481]
The General Procedure A was followed, using tert-butyl (S) -3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate from Example 101 (90 mg, 0.17 mmol) , pyridine (2 mL) and alpha-toluenesulfonylchloride (162 mg, 0.85 mmol) . The crude was then purified by Prep-TLC (petroleum ether/ethyl acetate = 1 /1) to yield 130 mg (72%yield) of the title compound as a white solid. LCMS (ESI) [M+H] + = 681.
[0482]
Step 2: (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) -1-phenylmethanesulfonamide hydrochloride
[0483]
[0484]
The General Procedure B was followed, using tert-butyl (S) -3- ( (4- (2- ( (2-methyl-5- ( (phenylmethyl) sulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (130 mg, 0.19 mmol) , DCM (5 mL) and hydrochloric acid (4 M in dioxane, 4 mL, 16 mmol) . The residue was purified by Prep-HPLC to yield 60 mg (50%yield) of 112 as a white solid. LCMS (ESI) : [M+H] + = 581; 1H NMR (400 MHz, CD 3OD) δ 8.68 (d, J = 6.4 Hz, 1H) , 8.46 (d, J = 5.2 Hz, 1H) , 8.02-8.00 (m, 2H) , 7.74 (d, J = 5.2 Hz, 1H) , 7.62 (d, J = 8.0 Hz, 1H) , 7.51-7.48 (m, 2H) , 7.38-7.33 (m, 6H) , 7.26-7.23 (m, 1H) , 4.48 (s, 2H) , 4.41-4.36 (m, 1H) , 3.64 (dd, J = 12.4, 3.2 Hz, 1H) , 3.32-3.42 (m, 1H) , 3.11-3.03 (m, 2H) , 2.33 (s, 3H) , 2.28-2.11 (m, 2H) , 1.93-1.80 (m, 2H) .
[0485]
Example 113 4- [2- [ [5- [ [Ethyl (methyl) sulfamoyl] amino] -2-methyl-1-naphthyl] oxy] -3-pyridyl] -2- [ [ (3S) -3-piperidyl] amino] pyrimidine hydrochloride 113
[0486]
Step 1: tert-Butyl (S) -3- ( (4- (2- ( (5- ( (N-ethyl-N-methylsulfamoyl) amino) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0487]
[0488]
The General Procedure A was followed, using tert-butyl (S) -3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate from Example 101 (90 mg, 0.17 mmol) , pyridine (2 mL) and N-ethyl-N-methyl-sulfamoyl chloride (269 mg, 1.71 mmol) . The crude was then purified by Prep-TLC (petroleum ether/ethyl acetate = 1 /1) to yield 80 mg (72%yield) of the title compound as a yellow solid. LCMS (ESI) [M+H] + = 648.
[0489]
Step 2: 4- [2- [ [5- [ [Ethyl (methyl) sulfamoyl] amino] -2-methyl-1-naphthyl] oxy] -3-pyridyl] -2- [ [ (3S) -3-piperidyl] amino] pyrimidine hydrochloride
[0490]
[0491]
The General Procedure B was followed, using tert-butyl (S) -3- ( (4- (2- ( (5- ( (N-ethyl-N-methylsulfamoyl) amino) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (80 mg, 0.12 mmol) , DCM (8 mL) and hydrochloric acid (4 M in dioxane, 4 mL, 16 mmol) . The residue was purified by Prep-HPLC to yield 18 mg (25%yield) of 113 as a white solid. LCMS (ESI) : [M+H] + = 548; 1H NMR (400 MHz, CD 3OD) δ 8.66 (d, J = 6.8 Hz, 1H) , 8.46 (d, J = 5.2 Hz, 1H) , 8.16 (d, J = 8.8 Hz, 1H) , 8.01 (dd, J = 1.6, 4.8 Hz, 1H) , 7.71 (d, J = 5.2 Hz, 1H) , 7.60-7.52 (m, 3H) , 7.39-7.35 (m, 1H) , 7.25-7.22 (m, 1H) , 4.40-4.33 (m, 1H) , 3.63 (dd, J = 3.2, 12.4 Hz, 1H) , 3.38-3.32 (m, 1H) , 3.25-3.18 (m, 2H) , 3.08-3.02 (m, 2H) , 2.83 (s, 3H) , 2.28 (s, 3H) , 2.24-2.09 (m, 2H) , 1.95-1.77 (m, 2H) , 1.09-1.05 (m, 3H) .
[0492]
Example 114 _ (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) piperidine-1-sulfonamide hydrochloride 114
[0493]
Step1: tert-Butyl (S) -3- ( (4- (2- ( (2-methyl-5- (piperidine-1-sulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0494]
[0495]
The General Procedure A was followed, using tert-butyl (S) -3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate from Example 101 (100 mg, 0.19 mmol) , pyridine (2 mL) and piperidine-1-sulfonylchloride (200 mg, 1.09 mmol) . The crude was then purified by Prep-TLC (petroleum ether/ethyl acetate = 1 /1) to yield 100 mg (78%yield) of the title compound as a white solid. LCMS (ESI) [M+H] + = 674.
[0496]
Step 2: (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) piperidine-1-sulfonamide hydrochloride
[0497]
[0498]
The General Procedure B was followed, using tert-butyl (S) -3- ( (4- (2- ( (2-methyl-5- (piperidine-1-sulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (100 mg, 0.15 mmol) , DCM (5 mL) and hydrochloric acid (4 M in dioxane, 3 mL, 12 mmol) . The residue was purified by Prep-HPLC to yield 42 mg (55%yield) of 114 as a white solid. LCMS (ESI) : [M+H] + = 574; 1H NMR (400 MHz, DMSO-d 6) δ 9.77 (s, 1H) , 8.71 (s, 2H) , 8.58 (s, 1H) , 8.48 (d, J = 5.2 Hz, 1H) , 8.15 (d, J = 8.7 Hz, 1H) , 8.06 (dd, J = 4.7, 1.8 Hz, 1H) , 7.65 -7.48 (m, 5H) , 7.41 (t, J = 7.9 Hz, 15.8 Hz, 1H) , 7.27 (dd, J = 7.5, 4.9 Hz, 1H) , 4.25 (s, 1H) , 3.45 (s, 1H) , 3.23 (d, J = 12.8 Hz, 1H) , 3.13 (s, 4H) , 2.86 (s, 2H) , 2.21 (s, 3H) , 2.02 (d, J = 10.0 Hz, 1H) , 1.93 (d, J = 13.9 Hz, 1H) , 1.81 -1.57 (m, 2H) , 1.52 -1.40 (m, 6H) .
[0499]
Example 115 (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) benzamide hydrochloride 115
[0500]
Step1: tert-Butyl (S) -3- ( (4- (2- ( (5-benzamido-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0501]
[0502]
To an ice-cooled solution of tert-butyl (3S) -3- [ [4- [2- [ (5-amino-2-methyl-1-naphthyl) oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (100 mg, 0.19 mmol) and pyridine (1 mL) in dichloromethane (5 mL) was added benzoyl chloride (29 mg, 0.21 mmol) . After being stirred at room temperature for 1 h, the mixture was concentrated to give crude tert-butyl (3S) -3- [ [4- [2- [ (5-benzamido-2-methyl-1-naphthyl) oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (120 mg, 94%yield) as a yellow solid, which was used in the next step without further purification. LCMS (ESI) [M+H] + = 631.3.
[0503]
Step 2: (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) benzamide hydrochloride
[0504]
[0505]
The General Procedure B was followed, using tert-butyl (S) -3- ( (4- (2- ( (2-methyl-5- (piperidine-1-sulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (120 mg, 0.19 mmol) , DCM (5 mL) and hydrochloric acid (4 M in dioxane, 2 mL, 8 mmol) . The residue was purified by Prep-HPLC to yield 99 mg (91%yield) of 115 as a white solid. LCMS (ESI) : R T (min) = 1.562, [M+H] + = 531.3, method = A; 1H NMR (400 MHz, CD 3OD) δ 8.68 (d, J = 6.8 Hz, 1H) , 8.48 (d, J = 5.2 Hz, 1H) , 8.11-8.09 (m, 2H) , 8.03-8.02 (m, 1H) , 7.92-7.91 (m, 1H) , 7.77-7.76 (m, 1H) , 7.72-7.64 (m, 2H) , 7.61-7.57 (m, 3H) , 7.53-7.45 (m, 2H) , 7.25 (dd, J = 4.8, 7.6 Hz, 1H) , 4.42-4.40 (m, 1H) , 3.65-3.62 (m, 1H) , 3.36-3.33 (m, 1H) , 3.12-3.03 (m, 2H) , 2.29 (s, 3H) , 2.23-2.11 (m, 2H) , 1.95-1.81 (m, 2H) .
[0506]
Example 116 (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) piperidine-1-carboxamide hydrochloride 116
[0507]
Step 1: tert-Butyl (S) -3- ( (4- (2- ( (2-methyl-5- (piperidine-1-carboxamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0508]
[0509]
To a solution of tert-butyl (3S) -3- [ [4- [2- [ (5-amino-2-methyl-1-naphthyl) oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (100 mg, 0.19 mmol) and triethylamine (38 mg, 0.38 mmol) in dry tetrahydrofuran (5 mL) was added triphosgene (33 mg, 0.11 mmol) at 0 ℃. After addition, the reaction mixture was stirred at rt for 1 h. Then piperidine (16 mg, 0.19 mmol) was added to the reaction and continued to stir at rt for 2 h. The reaction was concentrated to dryness and the residue was taken up in ethyl acetate (20 mL) . The organics were washed with water and brine. The organics were then separated and dried (magnesium sulphate) before concentration to dryness. The crude was then purified by Prep-TLC (petroleum ether/ethyl acetate = 1 /1) to yield 100 mg (56%yield) of the title compound as a white solid. LCMS (ESI) [M+H] + = 638.
[0510]
Step 2: (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) piperidine-1-carboxamide hydrochloride
[0511]
[0512]
To a mixture of tert-butyl (S) -3- ( (4- (2- ( (2-methyl-5- (piperidine-1-carboxamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (100 mg, 0.16 mmol) in DCM (5 mL) was added hydrochloric acid (4 M in dioxane, 3 mL, 12.48 mmol) . Then the mixture was stirred at rt for 1 h. The mixture was concentrated to dryness. The residue was purified by Prep-HPLC to yield 34 mg (40%yield) of 116 as a white solid. LCMS (ESI) : M+H] + = 538; 1H NMR (400 MHz, DMSO-d 6) δ 8.56 (s, 1H) , 8.44 (d, J = 5.2 Hz, 1H) , 8.35 (s, 1H) , 8.10 -8.03 (m, 1H) , 7.76 (d, J = 8.7 Hz, 1H) , 7.52 (d, J = 5.1 Hz, 1H) , 7.45 (d, J = 8.7 Hz, 2H) , 7.41 -7.30 (m, 3H) , 7.26 (dd, J = 7.6, 4.7 Hz, 1H) , 4.08 (s, 2H) , 3.51 (d, J = 5.6 Hz, 4H) , 3.25 (s, 1H) , 2.99 (d, J = 11.0 Hz, 1H) , 2.70 -2.57 (m, 2H) , 2.21 (s, 3H) , 1.98 (s, 1H) , 1.77 (s, 1H) , 1.62 (s, 2H) , 1.56 (s, 6H) .
[0513]
Example 117 (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) butyramide hydrochloride 117
[0514]
Step 1: tert-Butyl (S) -3- ( (4- (2- ( (5-butyramido-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0515]
[0516]
To a solution of tert-butyl (3S) -3- [ [4- [2- [ (5-amino-2-methyl-1-naphthyl) oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (100 mg, 0.19 mmol) and pyridine (0.05 mL, 0.57 mmol) in dry dichloromethane (10 mL) was added butyryl chloride (24 mg, 0.23 mmol) at 0 ℃. After addition completed, the mixture was stirred at 25 ℃ for 2 h. Methanol was added and the mixture was concentrated to yield 113 mg (99%yield) of the title compound as a yellow solid. LC-MS (ESI) : [M+H] + = 597.4.
[0517]
Step 2: (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) butyramide hydrochloride
[0518]
[0519]
The General Procedure B was followed, using tert-butyl (S) -3- ( (4- (2- ( (2-methyl-5- (piperidine-1-sulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (113 mg, 0.19 mmol) , DCM (3 mL) and hydrochloric acid (4 M in dioxane, 3 mL, 12 mmol) . The residue was purified by Prep-HPLC to yield 50 mg (50%yield) of 117 as a white solid. LCMS (ESI) : [M+H] + = 497.3; 1H NMR (400 MHz, CD 3OD) δ 8.69 (d, J = 7.6 Hz, 1H) , 8.47 (d, J = 5.2 Hz, 1H) , 8.02 (d, J = 2.4 Hz, 1H) , 7.90 (d, J = 8.8 Hz, 1H) , 7.77 (d, J = 5.6 Hz, 1H) , 7.63-7.51 (m, 3H) , 7.40 (t, J = 8.0 Hz, 1H) , 7.27-7.23 (m, 1H) , 4.41 (m, 1H) , 3.63 (dd, J = 12.4, 3.2 Hz, 1H) , 3.12-3.03 (m, 2H) , 2.56 (t, J = 7.2 Hz, 2H) , 2.29 (s, 3H) , 2.16-2.11 (m, 2H) , 1.93-1.81 (m, 4H) , 1.12 (t, J = 6.8 Hz, 3H) .
[0520]
Example 118 (S) -3-Fluoro-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) propane-1-sulfonamide hydrochloride 118
[0521]
Step 1: tert-Butyl (S) -3- ( (4- (2- ( (5- ( (3-fluoropropyl) sulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0522]
[0523]
The General Procedure A was followed, using tert-butyl (S) -3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate from Example 101 (100 mg, 0.19 mmol) , pyridine (2 mL) and 3-fluoropropane-1-sulfonyl chloride (30 mg, 0.19 mmol) . The crude was then purified by Prep-TLC (petroleum ether/ethyl acetate = 1 /1) to yield 100 mg (81%yield) of the title compound as a white solid. LCMS (ESI) [M+H] + = 651.
[0524]
Step 2: (S) -3-Fluoro-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) propane-1-sulfonamide hydrochloride
[0525]
[0526]
The General Procedure B was followed, using tert-butyl (S) -3- ( (4- (2- ( (5- ( (3-fluoropropyl) sulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (100 mg, 0.15 mmol) , DCM (5 mL) and hydrochloric acid (4 M in dioxane, 2 mL, 8 mmol) . The residue was purified by Prep-HPLC to yield 65 mg (75%yield) of 118 as a red solid. LCMS (ESI) : [M+H] + = 551; 1H NMR (400 MHz, DMSO-d 6) δ 8.56 (s, 1H) , 8.44 (d, J = 5.1 Hz, 1H) , 8.32 (s, 1H) , 8.14 (d, J = 8.6 Hz, 1H) , 8.05 (d, J = 4.6 Hz, 1H) , 7.49 (t, J = 10.1 Hz, 3H) , 7.40 (t, J = 8.5 Hz, 2H) , 7.34 (d, J = 7.3 Hz, 1H) , 7.30 -7.22 (m, 1H) , 4.60 (t, J = 5.9 Hz, 1H) , 4.48 (t, J = 5.8 Hz, 1H) , 4.07 (s, 1H) , 3.25 (s, 1H) , 3.23 -3.18 (m, 2H) , 3.00 (d, J = 12.0 Hz, 1H) , 2.71 -2.56 (m, 2H) , 2.21 (s, 3H) , 2.12 (d, J = 24.7 Hz, 2H) , 1.97 (s, 1H) , 1.77 (s, 1H) , 1.56 (s, 2H) .
[0527]
Example 119 N- (4- ( (3- (2- ( ( (trans) -4-aminocyclohexyl) amino) pyrimidin-4-yl) pyridin-2-yl) oxy) -3-methylnaphthalen-1-yl) cyclopentanesulfonamide hydrochloride 119
[0528]
Step1 : tert-Butyl ( (trans) -4- ( (4- (2- ( (4- (cyclopentanesulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) cyclohexyl) carbamate
[0529]
[0530]
The General Procedure A was followed, using tert-butyl N- [4- [ [4- [2- [ (4-amino-2-methyl-1-naphthyl) oxy] -3-pyridyl] pyrimidin-2-yl] amino] cyclohexyl] carbamate (100 mg, 0.18 mmol) , pyridine (2 mL) and cyclopentanesulfonylchloride (31 mg, 0.18 mmol) . The crude was then purified by Prep-TLC (petroleum ether/ethyl acetate = 1 /1) to yield 30 mg (24%yield) of the title compound as a yellowsolid. LCMS (ESI) [M+H] + = 573.
[0531]
Step 2: N- (4- ( (3- (2- ( ( (trans) -4-aminocyclohexyl) amino) pyrimidin-4-yl) pyridin-2-yl) oxy) -3-methylnaphthalen-1-yl) cyclopentanesulfonamide hydrochloride
[0532]
[0533]
The General Procedure B was followed, using tert-Butyl ( (trans) -4- ( (4- (2- ( (4- (cyclopentanesulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) cyclohexyl) carbamate (30 mg, 0.04 mmol) , DCM (2 mL) and hydrochloric acid (4 M in dioxane, 1 mL, 4 mmol) . The residue was purified by Prep-HPLC to yield 17 mg (62%yield) of 119 as a white solid. LCMS (ESI) : [M+H] + = 573; 1H NMR (400 MHz, CD 3OD) δ 8.60 (d, J = 6.4 Hz, 1H) , 8.40 (d, J = 5.6 Hz, 1H) , 8.29 (d, J = 8.4 Hz, 1H) , 8.04-8.03 (m, 1H) , 7.75 (d, J = 8.4 Hz, 1H) , 7.65 (d, J = 6.4 Hz, 1H) , 7.60-7.45 (m, 3H) , 7.25 (dd, J = 4.8, 7.6 Hz, 1H) , 4.06-3.92 (m, 1H) , 3.71-3.63 (m, 1H) , 3.18-3.14 (m, 1H) , 2.31-2.23 (m, 5H) , 2.17-2.11 (m, 4H) , 2.02-1.96 (m, 2H) , 1.68-1.60 (m, 2H) , 1.56-1.48 (m, 6H) .
[0534]
Example 120 (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) cyclopentanesulfonamide hydrochloride 120
[0535]
[0536]
Step 1: tert-Butyl (S) -3- ( (4- (2- ( (5- (cyclopentanesulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0537]
The General Procedure A was followed, using tert-butyl (S) -3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate from Example 101 (100 mg, 0.19 mmol) , pyridine (2 mL) and cyclopentanesulfonylchloride (32 mg, 0.19 mmol) . The crude was then purified by Prep-TLC (petroleum ether/ethyl acetate = 1 /1) to yield 90 mg (72%yield) of the title compound as a white solid. LCMS (ESI) [M+H] + = 659.
[0538]
Step 2: (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) cyclopentanesulfonamide hydrochloride
[0539]
[0540]
The General Procedure B was followed, using tert-butyl (S) -3- ( (4- (2- ( (5- (cyclopentanesulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (140 mg, 0.22 mmol) , DCM (4 mL) and hydrochloric acid (4 M in dioxane, 3 mL, 12 mmol) . The residue was purified by Prep-HPLC to yield 15 mg (18%yield) of 120 as a yellowsolid. LCMS (ESI) : [M+H] + = 559; 1H-NMR (400 MHz, CD 3OD) δ 8.68 (d, J = 7.6 Hz, 1H) , 8.46 (d, J = 5.6 Hz, 1H) , 8.16 (d, J = 8.8 Hz, 1H) , 8.01 (d, J = 4.8 Hz, 1H) , 7.73 (d, J = 5.6 Hz, 1H) , 7.64-7.54 (m, 3H) , 7.40-7.36 (m, 1H) , 7.26-7.23 (m, 1H) , 4.43-4.34 (m, 1H) , 3.65-3.60 (m, 2H) , 3.39-3.32 (m, 1H) , 3.10-3.03 (m, 2H) , 2.28 (s, 3H) , 2.22-1.76 (m, 10H) , 1.67-1.57 (m, 2H) .
[0541]
Example 121 (S) -2-Methyl-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) propane-1-sulfonamide hydrochloride 121
[0542]
Step 1: tert-Butyl (S) -3- ( (4- (2- ( (2-methyl-5- ( (2-methylpropyl) sulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0543]
[0544]
The General Procedure A was followed, using tert-butyl (S) -3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate from Example 101 (100 mg, 0.19 mmol) , pyridine (3 mL) and isobutanesulfonylchloride (0.15 mL, 1.15 mmol) . The crude was then purified by Prep-TLC (petroleum ether/ethyl acetate = 1 /1) to yield 120 mg (95%yield) of the title compound as a white solid. LCMS (ESI) [M+H] + = 647.
[0545]
Step 2: (S) -2-Methyl-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) propane-1-sulfonamide hydrochloride
[0546]
[0547]
The General Procedure B was followed, using tert-butyl (S) -3- ( (4- (2- ( (2-methyl-5- ( (2-methylpropyl) sulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (140 mg, 0.22 mmol) , DCM (3 mL) and hydrochloric acid (4 M in dioxane, 3 mL, 12 mmol) . The residue was purified by Prep-HPLC to yield 37 mg (29%yield) of 121 as a white solid. LCMS (ESI) : [M+H] + = 547; 1H-NMR (400 MHz, CD 3OD) δ : 8.69 (d, J = 7.3 Hz, 1H) , 8.57-8.56 (m, 1H) , 8.45-8.44 (m, 1H) , 8.14 (d, J = 4.6 Hz, 1H) , 7.69-7.63 (m, 2H) , 7.56 (s, 1H) , 7.55 (s, 1H) , 7.40 (t, J = 8.1 Hz, 1H) , 7.24 (q, J = 5.0 Hz, 1H) , 4.31-4.29 (m, 1H) , 3.55 (d, J = 7.2 Hz, 1H) , 3.30-3.26 (m, 1H) , 3.06 (s, 1H) , 3.04 (s, 1H) , 3.00-2.94 (m, 2H) , 2.32-2.25 (m, 4H) , 2.20-2.17 (m, 1H) , 2.09-2.05 (m, 1H) , 1.90-1.72 (m, 2H) , 1.08 (d, J = 7.8 Hz, 6H) .
[0548]
Example 122 (S) -2, 2, 2-Trifluoro-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) ethane-1-sulfonamide hydrochloride 122
[0549]
Step 1: tert-Butyl (S) -3- ( (4- (2- ( (2-methyl-5- ( (2, 2, 2-trifluoroethyl) sulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0550]
[0551]
The General Procedure A was followed, using tert-butyl (S) -3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate from Example 101 (150 mg, 0.28 mmol) , pyridine (2 mL) and 2, 2, 2-trifluoroethanesulfonyl chloride (52 mg, 0.28 mmol) . The crude was then purified by Prep-TLC (petroleum ether/ethyl acetate = 1 /1) to yield 170 mg (89%yield) of the title compound as a colorless oil. LCMS (ESI) [M+H] + = 673.
[0552]
Step 2: (S) -2, 2, 2-Trifluoro-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) ethane-1-sulfonamide hydrochloride
[0553]
[0554]
The General Procedure B was followed, using tert-butyl (S) -3- ( (4- (2- ( (2-methyl-5- ( (2, 2, 2-trifluoroethyl) sulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (170 mg, 0.25 mmol) , DCM (4 mL) and hydrochloric acid (4 M in dioxane, 2 mL, 8 mmol) . The residue was purified by Prep-HPLC to yield 100 mg (65%yield) of 122 as a white solid. LCMS (ESI) : [M+H] + = 592; 1H-NMR (400 MHz, CD 3OD) δ 8.68 (d, J = 6.8 Hz, 1H) , 8.46 (d, J = 5.2 Hz, 1H) , 8.13 (d, J = 8.8 Hz, 1H) , 8.01 (d, J = 2.8 Hz, 1H) , 7.74-7.70 (m, 2H) , 7.60-7.57 (m, 2H) , 7.43 (t, J = 8.0 Hz, 16 Hz, 1H) , 7.25 (dd, J = 4.8, 7.6 Hz, 1H) , 4.40-4.38 (m, 1H) , 4.24-4.18 (m, 2H) , 3.65-3.62 (m, 1H) , 3.10-3.03 (m, 2H) , 2.29 (s, 3H) , 2.23-2.11 (m, 2H) , 1.92-1.81 (m, 2H) .
[0555]
Example 123 (S) -3, 3, 3-Trifluoro-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) propane-1-sulfonamide hydrochloride 123
[0556]
Step 1: tert-Butyl (S) -3- ( (4- (2- ( (2-methyl-5- ( (3, 3, 3-trifluoropropyl) sulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0557]
[0558]
The General Procedure A was followed, using tert-butyl (S) -3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate from Example 101 (100 mg, 0.19 mmol) , pyridine (3 mL) and 3, 3, 3-trifluoropropane-1-sulfonylchloride (300 mg, 1.53 mmol) . The crude was then purified by Prep-TLC (petroleum ether/ethyl acetate = 1 /2) to yield 70 mg (54%yield) of the title compound as a white solid. LCMS (ESI) [M+H] + = 587.
[0559]
Step 2: (S) -3, 3, 3-Trifluoro-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) propane-1-sulfonamide hydrochloride
[0560]
[0561]
The General Procedure B was followed, using tert-butyl (S) -3- ( (4- (2- ( (2-methyl-5- ( (3, 3, 3-trifluoropropyl) sulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (70 mg, 0.10 mmol) , DCM (3 mL) and hydrochloric acid (4 M in dioxane, 3 mL, 12 mmol) . The residue was purified by Prep-HPLC to yield 51 mg (80%yield) of 123 as a yellow solid. LCMS (ESI) : [M+H] + = 587.2; 1H-NMR (400 Hz, CD 3OD) δ 8.70 (d, J = 7.2 Hz, 1H) , 8.47 (d, J = 5.5 Hz, 1H) , 8.14 (d, J = 8.7 Hz, 1H) , 8.02 (dd, J = 4.9, 1.6 Hz, 1H) , 7.76 (d, J =4.9 Hz, 1H) , 7.69 (d, J = 8.5 Hz, 1H) , 7.60-7.55 (m, 2H) , 7.42 (t, J = 2.0 Hz, 1H) , 7.27-7.24 (m, 1H) , 4.40 (s, 1H) , 3.64 (dd, J = 12.2, 8.6 Hz, 1H) , 3.43-3.39 (m, 3H) , 3.11-3.03 (m, 2H) , 2.83-2.71 (m, 2H) , 2.30 (s, 3H) , 2.29-2.11 (m, 2H) , 1.93-1.79 (m, 2H) .
[0562]
Example 124 (S) -1-Cyclopropyl-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) methanesulfonamide hydrochloride 124
[0563]
Step 1: tert-Butyl (S) -3- ( (4- (2- ( (5- ( (cyclopropylmethyl) sulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0564]
[0565]
The General Procedure A was followed, using tert-butyl (S) -3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate from Example 101 (100 mg, 0.19 mmol) , pyridine (2 mL) and cyclopropylmethanesulfonyl chloride (100 mg, 0.65 mmol) . The crude was then purified by Prep-TLC (petroleum ether/ethyl acetate = 1 /1) to yield 120 mg (98%yield) of the title compound as a white solid. LCMS (ESI) [M+H] + = 645.
[0566]
Step 2: (S) -1-Cyclopropyl-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) methanesulfonamide hydrochloride
[0567]
[0568]
The General Procedure B was followed, using tert-butyl (S) -3- ( (4- (2- ( (5- ( (cyclopropylmethyl) sulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (120 mg, 0.19 mmol) , DCM (4 mL) and hydrochloric acid (4 M in dioxane, 3 mL, 12 mmol) . The residue was purified by Prep-HPLC to yield 97 mg (89%yield) of 124 as a yellow solid. LCMS (ESI) : [M+H] + = 545; 1H-NMR : (400 MHz, CD 3OD) δ 8.68 (d, J = 6.8 Hz, 1H) , 8.46 (d, J = 5.2 Hz, 1H) , 8.16 (d, J = 8.4 Hz, 1H) , 8.01 (d, J = 3.6 Hz, 1H) , 7.74 (d, J = 5.6 Hz, 1H) , 7.63-7.54 (m, 3H) , 7.41-7.37 (m, 1H) , 7.24 (dd, J = 4.8, 7.2 Hz, 1H) , 4.43-4.32 (m, 1H) , 3.66-3.62 (m, 1H) , 3.39-3.36 (m, 1H) , 3.13-3.03 (m, 4H) , 2.29-2.11 (m, 5H) , 1.92-1.80 (m, 2H) , 1.21-1.12 (m, 1H) , 0.66-0.61 (m, 2H) , 0.37-0.33 (m, 2H) .
[0569]
Example 125 (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) -1- (pyridin-3-yl) methanesulfonamide hydrochloride 125
[0570]
Step 1: tert-Butyl (S) -3- ( (4- (2- ( (2-methyl-5- ( (pyridin-3-ylmethyl) sulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0571]
[0572]
The General Procedure A was followed, using tert-butyl (S) -3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate from Example 101 (100 mg, 0.19 mmol) , pyridine (2 mL) and 3-pyridylmethanesulfonyl chloride (200 mg, 1.04 mmol) . The crude was then purified by Prep-TLC (petroleum ether/ethyl acetate = 1 /1) to yield 25 mg (19%yield) of the title compound as a white solid. LCMS (ESI) [M+H] + = 682.
[0573]
Step 2: (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) -1- (pyridin-3-yl) methanesulfonamide hydrochloride
[0574]
[0575]
The General Procedure B was followed, using tert-butyl (S) -3- ( (4- (2- ( (2-methyl-5- ( (pyridin-3-ylmethyl) sulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (25 mg, 0.04 mmol) , DCM (4 mL) and hydrochloric acid (4 M in dioxane, 1 mL, 4 mmol) . The residue was purified by Prep-HPLC to yield 97 mg (89%yield) of 125 as a yellow solid. LCMS (ESI) : [M+H] + = 582; 1H-NMR : (400 MHz, CD 3OD) δ 8.86-8.79 (m, 3H) , 8.59 (d, J = 8.0 Hz, 1H) , 8.49 (d, J = 5.2 Hz, 1H) , 8.11 (d, J = 4.0 Hz, 1H) , 8.04-7.98 (m, 2H) , 7.91-7.87 (m, 1H) , 7.69-7.58 (m, 3H) , 7.45-7.41 (m, 1H) , 7.34-7.31 (m, 1H) , 4.92-4.83 (m, 2H) , 4.62-4.47 (m, 1H) , 3.69-3.62 (m, 1H) , 3.43-3.36 (m, 1H) , 3.13-3.09 (m, 2H) , 2.31-2.13 (m, 5H) , 1.98-1.81 (m, 2H) .
[0576]
Example 126 (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) -1- (pyridin-2-yl) methanesulfonamide hydrochloride 126
[0577]
Step 1: tert-Butyl (S) -3- ( (4- (2- ( (2-methyl-5- ( (pyridin-2-ylmethyl) sulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0578]
[0579]
The General Procedure A was followed, using tert-butyl (S) -3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate from Example 101 (100 mg, 0.19 mmol) , pyridine (2 mL) and 2-pyridylmethanesulfonyl chloride (200 mg, 1.04 mmol) . After addition completed, the reaction mixture was stirred at 40 ℃ overnight. The crude was then purified by Prep-TLC (petroleum ether/ethyl acetate = 1 /1) to yield 85 mg (65%yield) of the title compound as a white solid. LCMS (ESI) [M+H] + = 682.
[0580]
Step 2: (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) -1- (pyridin-2-yl) methanesulfonamide hydrochloride
[0581]
[0582]
The General Procedure B was followed, using tert-butyl (S) -3- ( (4- (2- ( (2-methyl-5- ( (pyridin-2-ylmethyl) sulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (25 mg, 0.04 mmol) , DCM (4 mL) and hydrochloric acid (4 M in dioxane, 1 mL, 4 mmol) . The residue was purified by Prep-HPLC to yield 25 mg (32%yield) of 126 as a yellow solid. LCMS (ESI) : [M+H] + = 582; 1H-NMR : (400 MHz, CD 3OD) δ 8.86-8.79 (m, 3H) , 8.59 (d, J = 8.0 Hz, 1H) , 8.49 (d, J = 5.2 Hz, 1H) , 8.11 (d, J = 4.0 Hz, 1H) , 8.04-7.98 (m, 2H) , 7.91-7.87 (m, 1H) , 7.69-7.58 (m, 3H) , 7.45-7.41 (m, 1H) , 7.34-7.31 (m, 1H) , 4.92-4.83 (m, 2H) , 4.62-4.47 (m, 1H) , 3.69 -3.62 (m, 1H) , 3.43-3.36 (m, 1H) , 3.13-3.09 (m, 2H) , 2.31-2.13 (m, 5H) , 1.98-1.81 (m, 2H) .
[0583]
Example 127 (S) -1-Cyclobutyl-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) methanesulfonamide 127
[0584]
Step 1: (S) -tert-Butyl 3- ( (4- (2- ( (5- (cyclobutylmethylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0585]
[0586]
The General Procedure A was followed, using (S) -tert-butyl 3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (100 mg, 0.19 mmol) , pyridine (2 mL) and cyclobutylmethanesulfonyl chloride (38 mg, 0.23 mmol) . The mixture was concentrated, dissolved in dichloromethane (20 mL) and washed with H 2O (15 mL x 2) . The organic phase was dried over anhydrous sodium sulfate, concentrated to yield 100 mg (crude) of the title compound as a brown oil. LCMS (ESI) [M+H] + = 659.2.
[0587]
Step 2: (S) -1-Cyclobutyl-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) methanesulfonamide
[0588]
[0589]
The General Procedure B was followed, using (S) -tert-butyl 3- ( (4- (2- ( (5- (cyclobutylmethylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (100 mg, 0.15 mmol) , dichloromethane (1 mL) and hydrochloric acid (4 M in ethyl acetate, 0.4 mL, 1.6 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%HCl) ; B: ACN) to yield 28 mg (30%, HCl salt) of 127 as a brown solid. LCMS (ESI) [M+H] + = 559.1; 1H NMR (400 MHz, DMSO-d 6) δ 9.79 (s, 1H) , 9.31-9.01 (m., 2H) , 8.85 -8.59 (m, 1H) , 8.48 (d, J = 5.2 Hz, 1H) , 8.12 (d, J = 8.4 Hz, 1H) , 8.09 -8.04 (m, 1H) , 7.76 -7.58 (m, 2H) , 7.56 -7.49 (m, 2H) , 7.48 -7.38 (m, 2H) , 7.31 -7.24 (m, 1H) , 4.50 -4.05 (m, 1H) , 3.47 -3.38 (m, 1H) , 3.30 -3.26 (m, 2H) , 3.24 -3.15 (m, 1H) , 2.91 -2.73 (m, 3H) , 2.21 (s, 3H) , 2.11 -2.00 (m, 3H) , 1.94 -1.74 (m, 6H) , 1.69 -1.58 (m, 1H) .
[0590]
Example 128 (S) -1-Cyclopentyl-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) methanesulfonamide 128
[0591]
Step 1: (S) -tert-Butyl 3- ( (4- (2- ( (5- (cyclopentylmethylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0592]
[0593]
The General Procedure A was followed, using tert-butyl (3S) -3- [ [4- [2- [ (5-amino-2-methyl-1-naphthyl) oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (100 mg, 0.19 mmol) , pyridine (2 mL) and cyclopentylmethanesulfonyl chloride (38 mg, 0.21 mmol) . The resulting solution was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, and concentrated in vacuo to yield 110 mg of the crude title compound as a yellow solid. LCMS (ESI) [M+Na] + = 695.1.
[0594]
Step 2: (S) -tert-Butyl 3- ( (4- (2- ( (5- (cyclopentylmethylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0595]
[0596]
The General Procedure B was followed, using tert-butyl (3S) -3- [ [4- [2- [ [2-methyl-5- (sec-butylsulfonylamino) -1-naphthyl] oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (110 mg, 0.16 mmol) , dichloromethane (2 mL) and hydrochloric acid (4 M in dioxane, 2 mL, 8 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%HCl) ; B: ACN) to yield 22.8 mg (22%, yield HCl salt) of 128 as a yellow solid. LCMS (ESI) [M+H] + = 573.1. 1H NMR (400 MHz, DMSO-d 6) δ 9.82 (s, 1H) , 9.22 (s, 2H) , 8.49 (d, J = 4.8 Hz, 1H) , 8.14 (d, J = 8.8 Hz, 1H) , 8.07 (s., 1H) , 7.65 (s., 1H) , 7.57-7.54 (m, 2H) , 7.48 -7.38 (m, 2H) , 7.30 -7.27 (m, 1H) , 4.38 (s, 1H) , 3.80 (s, 1H) , 3.45 -3.40 (m, 1H) , 3.19 (d, J = 6.4 Hz, 2H) , 2.89 -2.78 (m, 2H) , 2.33 -2.27 (m, 1H) , 2.21 (s, 3H) , 2.06 -1.77 (m, 5H) , 1.68 -1.43 (m, 5H) , 1.32 -1.19 (m, 2H) .
[0597]
Example 129 (S) -2-Cyclopropyl-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) ethanesulfonamide 129
[0598]
Step 1: (S) -tert-Butyl 3- ( (4- (2- ( (5- (2-cyclopropylethylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0599]
[0600]
The General Procedure A was followed, using (S) -tert-butyl 3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (100 mg, 0.19 mmol) , pyridine (2 mL) and 2-cyclopropylethanesulfonyl chloride (38 mg, 0.23 mmol) . The mixture was concentrated, dissolved in dichloromethane (20 mL) , and washed with H 2O (15 mL x 2) . The organic phase was dried over anhydrous sodium sulfate, concentrated to give 100 mg (crude) of the title compound as a brown oil. LCMS (ESI) [M+H] + = 659.1.
[0601]
Step 2: (S) -2-Cyclopropyl-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) ethanesulfonamide
[0602]
[0603]
The General Procedure B was followed, using (S) -tert-butyl 3- ( (4- (2- ( (5- (2-cyclopropylethylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (100 mg, 0.15 mmol) , dichloromethane (1 mL) and hydrochloric acid (4 M in ethyl acetate, 0.4 mL, 1.6 mmol) . The residue was purified via Prep-HPLC (mobile phase: A: water (0.05%HCl) ; B: ACN) to yield 26 mg (28%, yield HCl salt) of 129 as a brown solid. LCMS (ESI) [M+H] + = 559.1; 1H NMR (400 MHz, DMSO-d 6) δ 9.85 (s, 1H) , 9.51 -9.14 (m, 2H) , 8.90 -8.67 (m, 1H) , 8.50 (d, J = 5.2 Hz, 1H) , 8.13 (d, J = 8.4 Hz, 1H) , 8.09 -8.06 (m, 1H) , 7.94 -7.62 (m, 2H) , 7.59 -7.53 (m, 2H) , 7.48 -7.40 (m, 2H) , 7.31 -7.25 (m, 1H) , 4.51 -4.27 (m, 1H) , 3.47 -3.37 (m, 1H) , 3.26 -3.15 (m, 3H) , 2.89 -2.79 (m, 2H) , 2.22 (s, 3H) , 2.07 -1.98 (m, 1H) , 1.96 -1.87 (m, 1H) , 1.85 -1.72 (m, 1H) , 1.70 -1.60 (m, 3H) , 0.86 -0.72 (m, 1H) , 0.42 -0.35 (m, 2H) , 0.09 -0.01 (m, 2H) .
[0604]
Example 130 (S) -2-Cyclohexyl-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) acetamide 130
[0605]
Step 1: (S) -tert-Butyl 3- ( (4- (2- ( (5- (2-cyclohexylacetamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0606]
[0607]
The General Procedure A was followed, using (S) -tert-butyl 3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (100 mg, 0.19 mmol) , pyridine (2 mL) and 2-cyclohexylacetyl chloride (46 mg, 0.28 mmol) . The mixture was concentrated, dissolved in dichloromethane (20 mL) and washed with H 2O (15 mL x 2) . The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to give 100 mg (crude) of the title compound as a brown oil. LCMS (ESI) [M+H] + = 651.3
[0608]
Step 2: (S) -2-Cyclohexyl-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) acetamide
[0609]
[0610]
The General Procedure B was followed, using (S) -tert-butyl 3- ( (4- (2- ( (5- (2-cyclohexylacetamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (100 mg, 0.15 mmol) , dichloromethane (1 mL) and hydrochloric acid (4 M in ethyl acetate, 0.4 mL, 1.6 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%HCl) ; B: ACN) to yield 54 mg (59%, yield HCl salt) of 130 as a brown solid. LCMS (ESI) [M+H] + = 551.3; 1H NMR (400 MHz, DMSO-d 6) δ 9.95 (s, 1H) , 9.45 -9.11 (m, 2H) , 8.90 -8.67 (m, 1H) , 8.50 (d, J = 5.2 Hz, 1H) , 8.07 (d, J = 4.8 Hz, 1H) , 7.95 -7.89 (m, 1H) , 7.87 -7.73 (m, 1H) , 7.67 -7.57 (m, 2H) , 7.54 -7.45 (m, 2H) , 7.42 -7.37 (m, 1H) , 7.30 -7.25 (m, 1H) , 4.46 -4.33 (m, 1H) , 3.49 -3.36 (m, 1H) , 3.25 -3.14 (m, 1H) , 2.91 -2.76 (m, 2H) , 2.40 -2.36 (m, 2H) , 2.22 (s, 3H) , 2.07 -1.98 (m, 1H) , 1.96 -1.88 (m, 1H) , 1.83 -1.61 (m, 8H) , 1.32 -1.15 (m, 3H) , 1.12 -1.00 (m, 2H) .
[0611]
Example 131 (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) cyclobutanecarboxamide 131
[0612]
Step 1: (S) -tert-Butyl 3- ( (4- (2- ( (5- (cyclobutanecarboxamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0613]
[0614]
The General Procedure A was followed, using (S) -tert-butyl 3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (100 mg, 0.19 mmol) , pyridine (2 mL) and cyclobutanecarbonyl chloride (34 mg, 0.28 mmol) . The mixture was concentrated, dissolved in dichloromethane (20 mL) and washed with H 2O (15 mL x 2) . The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to yield 100 mg (crude) of the title compound as a yellow oil.
[0615]
Step 2: (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) cyclobutanecarboxamide
[0616]
[0617]
The General Procedure B was followed, using (S) -tert-butyl 3- ( (4- (2- ( (5- (cyclobutanecarboxamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (100 mg, 0.16 mmol) , dichloromethane (1 mL) and hydrochloric acid (4 M in ethyl acetate, 0.4 mL, 1.6 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%HCl) ; B: ACN) to yield 66 mg (72%, yield HCl salt) of 131 as a yellow solid. LCMS (ESI) [M+H] + = 509.2; 1H NMR (400 MHz, DMSO-d 6) δ 9.86 (s, 1H) , 9.77 -9.53 (m, 1H) , 9.45 -9.27 (m, 1H) , 9.00 -8.81 (m, 1H) , 8.53 (d, J = 4.8 Hz, 1H) , 8.42 -8.22 (m, 1H) , 8.16 -8.06 (m, 1H) , 7.89 (d, J = 8.4 Hz, 1H) , 7.83 -7.71 (m, 1H) , 7.61 (d, J = 6.8 Hz, 1H) , 7.53 -7.46 (m, 2H) , 7.43 -7.37 (m, 1H) , 7.31 -7.26 (m, 1H) , 4.61 -4.35 (m, 1H) , 3.54 -3.38 (m, 2H) , 3.24 -3.14 (m, 1H) , 2.92 -2.79 (m, 2H) , 2.35 -2.26 (m, 2H) , 2.24 -2.15 (m, 5H) , 2.08 -1.78 (m, 5H) , 1.74 -1.59 (m, 1H) .
[0618]
Example 132 (S) -3-Methoxy-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) propane-1-sulfonamide hydrochloride 132
[0619]
Step 1: tert-Butyl (S) -3- ( (4- (2- ( (5- ( (3-methoxypropyl) sulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0620]
[0621]
The General Procedure A was followed, using tert-butyl (S) -3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate from Example 101 (100 mg, 0.19 mmol) , pyridine (3 mL) and 3-methoxypropane-1-sulfonyl chloride (32 mg, 0.19 mmol) . LCMS (ESI) [M+H] + = 689.
[0622]
Step 2: (S) -3-Methoxy-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) propane-1-sulfonamide hydrochloride
[0623]
[0624]
The General Procedure B was followed, using crude tert-butyl (S) -3- ( (4- (2- ( (5- ( (3-methoxypropyl) sulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate, DCM (4 mL) and hydrochloric acid (4 M in dioxane, 3 mL, 12 mmol) . The residue was purified by Prep-HPLC to yield 59 mg (52%yield over 2 steps) of 132 as a white solid. LCMS (ESI) : [M+H] + = 589; 1H-NMR : (400 MHz, CD 3OD) 1HNMR (400 MHz, CD3OD) δ 8.68 (d, J = 6.9 Hz, 1 H) , 8.47 (d, J = 5.5 Hz, 1 H) , 8.15 (d, J = 9.7 Hz, 1 H) , 8.01 (d, J = 4.7 Hz, 1 H) , 7.73 (s, 1 H) , 7.65 (d, J = 8.5 Hz, 1 H) , 7.56 (d, J = 8.1 Hz, 2 H) , 7.40 (t, J = 7.9 Hz, 1 H) , 7.27-7.23 (m, 1 H) , 4.38 (s, 1 H) , 3.64 (dd, J = 12.2, 2.8 Hz, 1 H) , 3.47 (t, J = 6.0 Hz, 2 H) , 3.37 (s, 1 H) , 3.29 (s, 1 H) , 3.25 -3.22 (m, 2 H) , 3.10 -3.03 (m, 2 H) , 2.29 (s, 3 H) , 2.23 -2.07 (m, 4 H) , 1.93 -1.80 (m, 2 H) .
[0625]
Example 133 _ (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) -1- (tetrahydro-2H-pyran-4-yl) methanesulfonamide hydrochloride 133
[0626]
Step 1: tert-Butyl (S) -3- ( (4- (2- ( (2-methyl-5- ( ( (tetrahydro-2H-pyran-4-yl) methyl) sulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0627]
[0628]
The General Procedure A was followed, using tert-butyl (S) -3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate from Example 101 (100 mg, 0.19 mmol) , pyridine (2 mL) and tetrahydropyran-4-ylmethanesulfonyl chloride (45 mg, 0.19 mmol) . LCMS (ESI) [M+H] + = 689.
[0629]
Step 2: (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) -1- (tetrahydro-2H-pyran-4-yl) methanesulfonamide hydrochloride
[0630]
[0631]
The General Procedure B was followed, using crude tert-butyl (S) -3- ( (4- (2- ( (2-methyl-5- ( ( (tetrahydro-2H-pyran-4-yl) methyl) sulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate, DCM (4 mL) and hydrochloric acid (4 M in dioxane, 3 mL, 12 mmol) . The residue was purified by Prep-HPLC to yield 59 mg (52%yield over 2 steps) of 133 as a white solid. LCMS (ESI) : [M+H] + = 589; 1HNMR (400 MHz, CD 3OD) δ 8.70 (s, 1H) , 8.46 (d, J = 5.4 Hz, 1H) , 8.14 (d, J = 8.8 Hz, H) , 8.02 (d, J = 4.5 Hz, 1H) , 7.77 (s, 1 H) , 7.65 (d, J = 8.4 Hz, 1H) , 7.56 (d, J = 8.0 Hz, 2H) , 740 (t, J =7.5 Hz, 1H) , 7.25 (q, J = 4.8 Hz, 1H) , 4.41 (s, 1H) , 3.91 -3.88 (m, 2H) , 3.65 (d, J = 11.5 Hz, 1H) , 3.40 (t, J = 11.8 Hz, 3H) , 3.12 -3.04 (m, 4H) , 2.29 (s, 3H) , 2.26 -2.11 (m, 3H) , 1.96 -1.80 (m, 4H) , 1.45 -1.35 (m, 2H) .
[0632]
Example 134 N- (6-Methyl-5- ( (3- (2- ( (S) -piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) butane-2-sulfonamide 134
[0633]
Step 1: (3S) -tert-Butyl 3- ( (4- (2- ( (2-methyl-5- (1-methylpropylsulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0634]
[0635]
The General Procedure A was followed, using tert-butyl (3S) -3- [ [4- [2- [ (5-amino-2-methyl-1-naphthyl) oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (100 mg, 0.19 mmol) , pyridine (2 mL) and butane-2-sulfonyl chloride (45 mg, 0.28 mmol) . The resulting solution was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, and concentrated in vacuo to yield 110 mg of the crude title compound as a yellow solid. LCMS (ESI) [M+H] + = 647.1.
[0636]
Step 2: N- (6-Methyl-5- ( (3- (2- ( (S) -piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalene-1-yl) butane-2-sulfonamide
[0637]
[0638]
The General Procedure B was followed, using tert-butyl (3S) -3- [ [4- [2- [ [2-methyl-5- (sec-butylsulfonylamino) -1-naphthyl] oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (100 mg, 0.15 mmol) , dichloromethane (2 mL) and hydrochloric acid (4 M in dioxane, 2 mL, 8 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%HCl) ; B: ACN) to yield 38.4 mg (42%, yield HCl salt) of 134 as a yellow solid and as a racemic mixture of enantiomers. LCMS (ESI) [M+H] + = 547.1. 1H NMR (400 MHz, DMSO-d 6) δ 9.81 (s, 1H) , 9.49 (s, 1H) , 9.22 (s, 1H) , 8.84 (s, 1H) , 8.50 (d, J = 5.2 Hz, 1H) , 8.15 (d, J = 8.4 Hz, 1H) , 8.08 (s, 1H) , 7.70 (s, 1H) , 7.58 -7.52 (m, 2H) , 7.50 -7.45 (m, 1H) , 7.44 -7.37 (m, 1H) , 7.32 -7.26 (m, 1H) , 4.50 -4.30 (m, 1H) , 3.45 -3.40 (m, 1H) , 3.25 -3.16 (m, 1H) , 3.15 -3.05 (m, 1H) , 2.95 -2.80 (m, 2H) , 2.23 (s, 3H) , 2.02 -1.82 (m, 3H) , 1.81 -1.70 (m, 1H) , 1.69 -1.55 (m, 1H) , 1.51 -1.47 (m, 1H) , 1.31 (d, J = 6.4 Hz, 3H) , 0.94 (d, J = 6.8 Hz, 3H) .
[0639]
Example 135 (S) -1- (2-Chlorophenyl) -N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) methanesulfonamide 135
[0640]
Step 1: (S) -tert-Butyl 3- ( (4- (2- ( (5- ( (2-chlorophenyl) methylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0641]
[0642]
The General Procedure A was followed, using tert-butyl (3S) -3- [ [4- [2- [ (5-amino-2-methyl-1-naphthyl) oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (100 mg, 0.19 mmol) , pyridine (2 mL) and (2-chlorophenyl) methanesulfonyl chloride (47 mg, 0.21 mmol) . The reaction mixture was concentrated and the residue taken up in ethyl acetate (20 mL) and then washed with water (10 mL) . The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to yield (140 mg crude) of the title compound as a pale brown oil. LCMS (ESI) [M+H] + = 715.2.
[0643]
Step 2: (S) -1- (2-Chlorophenyl) -N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) methanesulfonamide
[0644]
[0645]
The General Procedure B was followed, using (S) -tert-butyl 3- ( (4- (2- ( (5- ( (2-chlorophenyl) methylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate ( (140 mg, 0.20 mmol) ) , ethyl acetate (2 mL) and hydrochloric acid (4 M in ethyl acetate, 2 mL, 8 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%HCl) ; B: ACN) to yield 59 mg (46%, yield HCl salt) of 135 as a white solid. LCMS (ESI) : [M+H] + = 615.1; 1H NMR (400 MHz, DMSO-d 6) δ 10.12 (s, 1H) , 9.35 -8.78 (m, 2H) , 8.49 (d, J = 5.6 Hz, 1H) , 8.10 -8.06 (m, 2H) , 7.80 -7.60 (m, 1H) , 7.58 -7.32 (m, 8H) , 7.30 -7.25 (m, 1H) , 4.72 (s, 2H) , 4.40 -4.35 (m, 1H) , 3.45 -3.40 (m, 1H) , 3.22 -3.17 (m, 1H) , 2.80 -2.70 (m, 2H) , 2.22 (s, 3H) , 2.05 -1.90 (m, 2H) , 1.88 -1.63 (m, 2H) .
[0646]
Example 136 (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) butane-1-sulfonamide 136
[0647]
Step 1: (S) -tert-Butyl 3- ( (4- (2- ( (5- (butylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0648]
[0649]
The General Procedure A was followed, using tert-butyl (3S) -3- [ [4- [2- [ (5-amino-2-methyl-1-naphthyl) oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (100 mg, 0.19 mmol) , pyridine (3 mL) and 1-butanesulfonyl chloride (36 mg, 0.23 mmol) . The solution was concentrated to afford 120 mg of the crude title compound as a brown solid. LCMS (ESI) [M+H] + = 647.1.
[0650]
Step 2: (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalene-1-yl) butane-1-sulfonamide
[0651]
[0652]
The General Procedure B was followed, using (S) -tert-butyl 3- ( (4- (2- ( (5- (butylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (100 mg, 0.15 mmol) , dichloromethane (5 mL) and hydrochloric acid (4 M in ethyl acetate, 2 mL, 8 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%HCl) ; B: ACN) to yield 67 mg (80%, yield HCl salt) of 136 as a white solid. LCMS (ESI) : [M+H] + = 547.1; 1H NMR (400 MHz, DMSO-d 6) δ 9.85 (s, 1H) , 9.72 (s, 1H) , 9.36 (s, 1H) , 8.92 (s, 1H) , 8.53 (d, J = 5.2 Hz, 1H) , 8.18 -8.06 (m, 2H) , 7.79 (s, 1H) , 7.60 -7.51 (m, 2H) , 7.48 -7.39 (m, 2H) , 7.31 -7.26 (m, 1H) , 4.66 -4.41 (m, 1H) , 3.48 -3.36 (m, 2H) , 3.17 -3.10 (m, 2H) , 2.86 (d, J = 10.0 Hz, 2H) , 2.22 (s, 3H) , 2.08 -1.88 (m, 2H) , 1.87 -1.59 (m, 4H) , 1.42 -1.38 (m, 2H) , 0.85 (t, J = 7.2 Hz, 3H) .
[0653]
Example 137 (S) -2-Methoxy-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) ethanesulfonamide 137
[0654]
Step 1: (S) -tert-Butyl 3- ( (4- (2- ( (5- (2-methoxyethylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0655]
[0656]
The General Procedure A was followed, using tert-butyl (3S) -3- [ [4- [2- [ (5-amino-2-methyl-1-naphthyl) oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (100 mg, 0.19 mmol) , pyridine (3 mL) and 2-methoxy-1-ethanesulfonyl chloride (36 mg, 0.23 mmol) . The solution was concentrated to yield 100 mg of the crude title compound as a yellow solid. LCMS (ESI) [M+H] + = 649.1.
[0657]
Step 2: (S) -2-Methoxy-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) ethanesulfonamide
[0658]
[0659]
The General Procedure B was followed, using (S) -tert-butyl 3- ( (4- (2- ( (5- (2-methoxyethylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (100 mg, 0.15 mmol) , dichloromethane (5 mL) and hydrochloric acid (4 M in ethyl acetate, 2 mL, 8 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%HCl) ; B: ACN) to yield 76 mg (84%, yield HCl salt) of 137 as a white solid. LCMS (ESI) : [M+H] + = 549.1; 1H NMR (400 MHz, DMSO-d 6) δ 9.88 (s, 1H) , 9.57 (s, 1H) , 9.28 (s, 1H) , 8.86 (s, 1H) , 8.51 (d, J = 5.4 Hz, 1H) , 8.15 (d, J = 8.5 Hz, 1H) , 8.10 (d, J = 3.5 Hz, 1H) , 7.80 -7.52 (m, 2H) , 7.52 -7.46 (m, 1H) , 7.46 -7.38 (m, 1H) , 7.32 -7.27 (m, 1H) , 4.60 -4.20 (m, 1H) , 3.73 (t, J = 6.0 Hz, 2H) , 3.43 (t, J = 6.4 Hz, 3H) , 3.23 (s, 3H) , 3.20 -3.16 (m, 1H) , 2.90 -2.80 (m, 2H) , 2.22 (s, 3H) , 2.08 -1.57 (m, 4H) .
[0660]
Example 138 2-Methoxy-N- (6-methyl-5- ( (3- (2- ( (S) -piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) propane-1-sulfonamide 138
[0661]
Step 1: (3S) -tert-Butyl 3- ( (4- (2- ( (5- (2-methoxypropylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0662]
[0663]
The General Procedure A was followed, using tert-butyl (3S) -3- [ [4- [2- [ (5-amino-2-methyl-1-naphthyl) oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (100 mg, 0.19 mmol) , pyridine (3 mL) and 2-methoxypropane-1-sulfonyl chloride (33 mg, 0.19 mmol) . The solution was concentrated to afford 130 mg of the crude title compound as a yellow solid. LCMS (ESI) [M+H] + = 663.1.
[0664]
Step 2: 2-Methoxy-N- (6-methyl-5- ( (3- (2- ( (S) -piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) propane-1-sulfonamide
[0665]
[0666]
The General Procedure B was followed, using (3S) -tert-butyl 3- ( (4- (2- ( (5- (2-methoxypropylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (100 mg, 0.15 mmol) , dichloromethane (5 mL) and hydrochloric acid (4 M in ethyl acetate, 2 mL, 8 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%HCl) ; B: ACN) to yield 73 mg (81%, yield HCl salt) of 138 as a yellow solid. LCMS (ESI) : [M+H] + = 563.1; 1H NMR (400 MHz, DMSO-d 6) δ 9.91 -9.80 (m, 1H) , 9.68 (s, 1H) , 9.34 (s, 1H) , 8.89 (s, 1H) , 8.52 (d, J = 4.8 Hz, 1H) , 8.16 (d, J = 8.8 Hz, 1H) , 8.10 (s, 1H) , 7.76 (s, 1H) , 7.56 (t, J = 9.2 Hz, 2H) , 7.52 -7.47 (m, 1H) , 7.47 -7.36 (m, 1H) , 7.33 -7.26 (m, 1H) , 4.47 -4.53 (m, 1H) , 3.85 -3.76 (m, 1H) , 3.46 -3.35 (m, 2H) , 3.27 -3.20 (m, 2H) , 3.19 (s, 3H) , 2.85 (d, J = 9.6 Hz, 2H) , 2.22 (s, 3H) , 2.07 -1.61 (m, 4H) , 1.20 (d, J = 6.4 Hz, 3H) .
[0667]
Example 139 ( (S) -2, 2-Dimethyl-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) propane-1-sulfonamide 139
[0668]
Step 1: (S) -tert-Butyl 3- ( (4- (2- ( (5- (2, 2-dimethylpropylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0669]
[0670]
The General Procedure A was followed, using tert-butyl (3S) -3- [ [4- [2- [ (5-amino-2-methyl-1-naphthyl) oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (100 mg, 0.19 mmol) , pyridine (2 mL) and 2, 2-dimethylpropane-1-sulfonyl chloride (39 mg, 0.230 mmol) . The resulting solution was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, and concentrated in vacuo to yield 120 mg of the crude title compound as a yellow solid. LCMS (ESI) [M+H] + = 661.2.
[0671]
Step 2: (S) -2, 2-Dimethyl-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) propane-1-sulfonamide
[0672]
[0673]
The General Procedure B was followed, using (S) -tert-butyl-3- ( (4- (2- ( (5- (2, 2-dimethylpropylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (110 mg, 0.16 mmol) , dichloromethane (2 mL) and hydrochloric acid (4 M in dioxane, 2 mL, 8 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%HCl) ; B: ACN) to yield 31 mg (30%, yield HCl salt) of 139 as a yellow solid. LCMS (ESI) [M+H] + = 561.3. 1H NMR (400 MHz, DMSO-d 6) δ 9.82 (s, 1H) , 9.05 (s, 1H) , 8.48 (d, J = 4.8 Hz, 1H) , 8.13 (d, J = 8.8 Hz, 1H) , 8.07 (s, 1H) , 7.70 -7.61 (m, 2H) , 7.54 (d, J = 5.2 Hz, 2H) , 7.50 -7.40 (m, 2H) , 7.31 -7.25 (m, 1H) , 3.45 -3.40 (m, 1H) , 3.22 -3.18 (m, 1H) , 3.13 (s, 2H) , 2.90 -2.80 (m, 3H) , 2.21 (s, 3H) , 2.04 -1.97 (m, 1H) , 1.95 -1.85 (m, 1H) , 1.83 -1.76 (m, 1H) , 1.72 -1.65 (m, 1H) , 1.09 (s, 9H) .
[0674]
Example 140 (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) cyclohexanesulfonamide 140
[0675]
Step 1: (S) -tert-Butyl 3- ( (4- (2- ( (5- (cyclohexanesulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0676]
[0677]
The General Procedure A was followed, using (S) -tert-butyl 3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (100 mg, 0.19 mmol) , pyridine (2 mL) and cyclohexanesulfonylchloride (42 mg, 0.23 mmol) . The mixture was concentrated in vacuo and dissolved in dichloromethane (15 mL) and washed with H 2O (15 mL x 2) . The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to yield 100 mg (crude) of the title compound as a yellow oil.
[0678]
Step 2: (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) cyclohexanesulfonamide
[0679]
[0680]
The General Procedure B was followed, using (S) -tert-butyl 3- ( (4- (2- ( (5- (cyclohexanesulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (100 mg, 0.15 mmol) , dichloromethane (1 mL) and hydrochloric acid (4 M in ethyl acetate, 0.4 mL, 1.6 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%HCl) ; B: ACN) to yield 78 mg (85%, yield HCl salt) of 140 as a yellow solid. LCMS (ESI) [M+H] + = 573.1; 1H NMR (400 MHz, DMSO-d 6) δ 9.80 (s, 1H) , 9.50 -9.31 (m, 1H) , 9.02 -8.81 (m, 1H) , 8.59 -8.27 (m, 2H) , 8.19 -8.08 (m, 2H) , 7.87 -7.67 (m, 1H) , 7.59 -7.53 (m, 2H) , 7.50 -7.45 (m, 1H) , 7.44 -7.38 (m, 1H) , 7.32 -7.26 (m, 1H) , 4.69 -4.40 (m, 1H) , 3.48 -3.37 (m, 1H) , 3.24 -3.13 (m, 1H) , 3.12 -3.02 (m, 1H) , 2.94 -2.78 (m, 2H) , 2.22 (s, 3H) , 2.16 -1.99 (m, 3H) , 1.94 -1.59 (m, 6H) , 1.52 -1.38 (m, 2H) , 1.32 -1.04 (m, 3H) .
[0681]
Example 141 N- (6-Methyl-5- ( (3- (2- ( (S) -piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) -1- (tetrahydrofuran-2-yl) methanesulfonamide 141
[0682]
[0683]
Step 1: (3S) -tert-Butyl 3- ( (4- (2- ( (2-methyl-5- ( (tetrahydrofuran-2-yl) methylsulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0684]
[0685]
The General Procedure A was followed, using (S) -tert-butyl 3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (100 mg, 0.19 mmol) , pyridine (2 mL) and tetrahydrofuran-2-ylmethanesulfonyl chloride (70 mg, 0.38 mmol) . The mixture was concentrated and dissolved in dichloromethane (20 mL) , washed with H 2O (15 mL x 2) . The organic phase was dried over anhydrous sodium sulfate and concentrated to yield 100 mg (crude) of the title compound as a brown oil.
[0686]
Step 2: N- (6-Methyl-5- ( (3- (2- ( (S) -piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) -1- (tetrahydrofuran-2-yl) methanesulfonamide
[0687]
[0688]
The General Procedure B was followed, using (S) -tert-butyl 3- ( (4- (2- ( (5- (cyclobutanecarboxamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (100 mg, 0.15 mmol) , dichloromethane (2 mL) and hydrochloric acid (4 M in ethyl acetate, 0.37 mL, 1.48 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%HCl) ; B: ACN) to yield 55 mg (65%, yield HCl salt) of 141 as a yellow solid. LCMS (ESI) [M+H] + = 575.1; 1H NMR (400 MHz, DMSO-d 6) δ 9.86 (s, 1H) , 9.73 -9.23 (m, 1H) , 8.99 -8.76 (m, 1H) , 8.56 -8.47 (m, 1H) , 8.25 -8.15 (m, 3H) , 7.75 -7.25 (m, 7H) , 4.45 -4.22 (m, 2H) , 3.78 -3.58 (m, 2H) , 3.35 -3.33 (m, 3H) , 3.25 -3.13 (m, 1H) , 2.93 -2.80 (m, 2H) , 2.29 -2.18 (m, 3H) , 2.10 -1.99 (m, 2H) , 1.97 -1.76 (m, 4H) , 1.72 -1.60 (m, 2H) .
[0689]
Example 142 (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) -1- (2- (trifluoromethyl) phenyl) methanesulfonamide 142
[0690]
Step 1: (S) -tert-Butyl 3- ( (4- (2- ( (2-methyl-5- ( (2- (trifluoromethyl) phenyl) methylsulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0691]
[0692]
Prepared using (S) -tert-butyl 3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (400 mg, 0.760 mmol) , pyridine (1 mL) , DCM (3 mL) , and (2- (trifluoromethyl) phenyl) methanesulfonyl chloride (295 mg, 1.14 mmol) . After 20 h, the mixture was diluted with DCM (75 mL) and washed with saturated NaHCO 3 (aq) (25 mL) , dried (Na 2SO 4) , filtered and concentrated in vacuo. The crude was purified by flash chromatography through silica gel (0 -100%EtOAc/hexanes) to provide 392 mg (69 %yield) of the title compound as a light yellow gum. LCMS (ESI) [M+H] + = 749.1, rt = 2.02 min.
[0693]
Step 2: (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) -1- (2- (trifluoromethyl) phenyl) methanesulfonamide
[0694]
[0695]
Prepared using (S) -tert-butyl 3- ( (4- (2- ( (2-methyl-5- ( (2- (trifluoromethyl) phenyl) methylsulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (392 mg, 0.524 mmol) , EtOAc (3 mL) , and hydrochloric acid (4 M in dioxane, 3 mL, 12 mmol) . After 3 h, the mixture was concentrated in vacuo and the crude solid was washed with EtOAc (3 x 3 mL) and then MeCN (3 x 3 mL) . The solid product was then sonicated, concentrated in vacuo with MeCN (3 x 3 mL) and then dissolved in H 2O and MeCN. Lyophilization provided 292 mg (81%yield) of 142 as a fluffy white solid. LCMS (ESI) [M+H] + = 649.3, rt = 1.48 min; 1H NMR (400 MHz, DMSO-d 6) δ 10.19 (s, 1H) , 8.96 -8.73 (m, 2H) , 8.69 -8.54 (m, 1H) , 8.48 (d, J = 5.2 Hz, 1H) , 8.13 -8.04 (m, 2H) , 7.78 (d, J = 7.9 Hz, 1H) , 7.74 -7.66 (m, 2H) , 7.64 -7.51 (m, 5H) , 7.49 -7.40 (m, 2H) , 7.28 (dd, J = 7.5, 4.8 Hz, 1H) , 4.72 (s, 2H) , 4.38 -4.16 (m, 1H) , 3.21 (d, J = 11.3 Hz, 2H) , 2.95 -2.76 (m, 2H) , 2.22 (s, 3H) , 2.09 -1.84 (m, 2H) , 1.83 -1.55 (m, 2H) .
[0696]
Example 143 (S) -1- (4-Chlorophenyl) -N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) methanesulfonamide 143
[0697]
Step 1: (S) -tert-Butyl 3- ( (4- (2- ( (5- ( (4-chlorophenyl) methylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0698]
[0699]
The General Procedure A was followed, using (S) -tert-butyl 3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (100 mg, 0.19 mmol) , pyridine (2 mL) and (4-chlorophenyl) methanesulfonylchloride (64 mg, 0.28 mmol) . The mixture was concentrated, dissolved in ethyl acetate (20 mL) , and washed with H 2O (15 mL x 2) . The organic phase was dried over anhydrous sodium sulfate, concentrated to yield 100 mg (crude) of the title compound as a brown oil.
[0700]
Step 2: (S) -1- (4-Chlorophenyl) -N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) methanesulfonamide
[0701]
[0702]
The General Procedure B was followed, using (p) -1- (4-chlorophenyl) -N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) methanesulfonamide (100 mg, 0.14 mmol) , dichloromethane (1 mL) and hydrochloric acid (4 M in ethyl acetate, 0.4 mL, 1.6 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%HCl) ; B: ACN) to yield 42 mg (46%, yield HCl salt) of 143 as a brown solid. LCMS (ESI) [M+H] + = 615.1; 1H NMR (400 MHz, DMSO-d 6) δ 9.91 (s, 1H) , 9.23 -8.83 (m, 2H) , 8.78 -8.61 (m, 1H) , 8.53 -8.42 (m, 1H) , 8.13 -7.96 (m, 2H) , 7.66 -7.49 (m, 3H) , 7.48 -7.36 (m, 4H) , 7.30 -7.25 (m, 1H) , 4.66 -4.48 (m, 2H) , 4.40 -4.21 (m, 1H) , 3.46 -3.18 (m, 2H) , 2.93 -2.77 (m, 2H) , 2.24 -2.07 (m, 3H) , 2.06 -1.86 (m, 2H) , 1.84 -1.58 (m, 2H) .
[0703]
Example 144 (S) -1- (3-Chlorophenyl) -N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) methanesulfonamide 144
[0704]
Step 1: (S) -tert-Butyl 3- ( (4- (2- ( (5- ( (3-Chlorophenyl) methylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0705]
[0706]
The General Procedure A was followed, using tert-butyl (3S) -3- [ [4- [2- [ (5-amino-2-methyl-1-naphthyl) oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (100 mg, 0.19 mmol) , pyridine (2 mL) and (3-chlorophenyl) methanesulfonyl chloride (51 mg, 0.22 mmol) . The resulting solution was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, and concentrated in vacuo to yield 115 mg of the crude title compound as a yellow solid. LCMS (ESI) [M+H] + = 715.0.
[0707]
Step 2: (S) -1- (3-Chlorophenyl) -N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) methanesulfonamide
[0708]
[0709]
The General Procedure B was followed, using (S) -tert-butyl 3- ( (4- (2- ( (5- ( (3-chlorophenyl) methylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (110 mg, 0.15 mmol) , dichloromethane (2 mL) and hydrochloric acid (4 M in dioxane, 2 mL, 8 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%HCl) ; B: ACN) to yield 99 mg (95%, yield HCl salt) of 144 as a yellow solid. LCMS (ESI) [M+H] + = 615.3. 1H NMR (400 MHz, DMSO-d 6) δ 9.95 (s, 1H) , 8.91 (s, 1H) , 8.48 (d, J = 5.2 Hz, 1H) , 8.09 -8.05 (m, 1H) , 8.02 (d, J = 8.8 Hz, 1H) , 7.50 -7.60 (m, 4H) , 7.48 -7.34 (m, 6H) , 7.29 -7.26 (m, 1H) , 4.60 (s, 2H) , 4.28 (s, 1H) , 3.21 (d, J = 12.0 Hz, 2H) , 2.85 -2.81 (m, 2H) , 2.21 (s, 3H) , 2.04 -1.96 (m, 1H) , 1.92 -1.85 (m, 1H) , 1.75 -1.66 (m, 1H) , 1.65 -1.55 (m, 1H) .
[0710]
Example 145 (S) -1- (2-Fluorophenyl) -N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) methanesulfonamide 145
[0711]
Step 1: (S) -tert-Butyl 3- ( (4- (2- ( (5- ( (2-fluorophenyl) methylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0712]
[0713]
The General Procedure A was followed, using (S) -tert-butyl 3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (100 mg, 0.19 mmol) , pyridine (4 mL) and (2-fluorophenyl) methanesulfonyl chloride (47.5 mg, 0.23 mmol) . The mixture was concentrated, dissolved in dichloromethane (30 mL) and washed with H 2O (40 mL x 2) . The organic phase was dried over anhydrous sodium sulfate and concentrated to give 110 mg (83%yield) of the title compound as a brown oil.
[0714]
Step 2: (S) -1- (2-Fluorophenyl) -N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) methanesulfonamide
[0715]
[0716]
The General Procedure B was followed, using (S) -tert-butyl 3- ( (4- (2- ( (5- ( (2-fluorophenyl) methylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (110 mg, 0.16 mmol) , ethyl acetate (1 mL) and hydrochloric acid (4 M in ethyl acetate, 3 mL, 12 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%HCl) ; B: ACN) to yield 45.7 mg (46%, yield HCl salt) of 145 as a white solid. LCMS (ESI) [M+H] + = 599.2.; 1H NMR (400 MHz, DMSO-d 6) δ 10.07 (s, 1H) , 9.69 -9.00 (m, 2H) , 8.85 (s, 1H) , 8.51 (d, J = 5.2 Hz, 1H) , 8.14 -8.04 (m, 2H) , 7.72 (m, 1H) , 7.58 (d, J = 8.4 Hz, 1H) , 7.54 (d, J = 8.8 Hz, 1H) , 7.50 -7.37 (m, 4H) , 7.31 -7.27 (m, 1H) , 7.24 -7.19 (m, 2H) , 4.60 (s, 2H) , 4.54 -4.44 (m, 1H) , 3.53 -3.37 (m, 1H) , 3.28 -3.13 (m, 1H) , 2.93 -2.79 (m, 2H) , 2.22 (s, 3H) , 2.09 -1.98 (m, 1H) , 1.97 -1.86 (m, 1H) , 1.85 -1.73 (m, 1H) , 1.72 -1.56 (m, 1H) .
[0717]
Example 146 (S) -1- (2-Cyanophenyl) -N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) methanesulfonamide 146
[0718]
Step 1: (S) -tert-Butyl 3- ( (4- (2- ( (5- ( (2-chlorophenyl) methylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0719]
[0720]
The General Procedure A was followed, using tert-butyl (3S) -3- [ [4- [2- [ (5-amino-2-methyl-1-naphthyl) oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (100 mg, 0.19 mmol) , pyridine (2 mL) and (2-cyanophenyl) methanesulfonyl chloride (49 mg, 0.23 mmol) (47 mg, 0.21mmol) . The reaction mixture was concentrated and the residue was taken up in ethyl acetate (20 mL) and washed with water (10 mL) . The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to yield (130 mg crude) of the title compound as a pale brown oil. LCMS (ESI) [M+H] + = 705.1.
[0721]
Step 2: (S) -1- (2-Cyanophenyl) -N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) methanesulfonamide
[0722]
[0723]
The General Procedure B was followed, using (S) -tert-butyl 3- ( (4- (2- ( (5- ( (2-chlorophenyl) methylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (130 mg, 0.18 mmol) , ethyl acetate (2 mL) and hydrochloric acid (4 M in ethyl acetate, 2 mL, 8 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%NH 4OH) ; B: ACN) to yield 32 mg (30%, yield HCl salt) of 146 as a white solid. LCMS (ESI) : [M+H] + = 606.1; 1H NMR (400 MHz, DMSO-d 6) δ 8.55 (s, 1H) , 8.46 (d, J = 5.2 Hz, 1H) , 8.19 (d, J = 8.8 Hz, 1H) , 8.06 -8.04 (m, 1H) , 7.82 (d, J = 7.6 Hz, 1H) , 7.55 (t, J = 4.8 Hz, 1H) , 7.56 -7.49 (m, 3H) , 7.40 -7.30 (m, 3H) , 7.15 -7.11 (m, 2H) , 4.44 (s, 2H) , 4.14 -4.09 (m, 1H) , 3.08 -3.04 (m, 2H) , 2.71 -2.65 (m, 2H) , 2.20 (s, 3H) , 2.02 -1.98 (m, 1H) , 1.85 -1.80 (m, 1H) , 1.65 -1.55 (m, 2H) .
[0724]
Example 147 (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) ethenesulfonamide 147
[0725]
Step 1: (S) -tert-Butyl 3- ( (4- (2- ( (2-methyl-5- (vinylsulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0726]
[0727]
The General Procedure A was followed, using tert-butyl (3S) -3- [ [4- [2- [ (5-amino-2-methyl-1-naphthyl) oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (100 mg, 0.19 mmol) , pyridine (3 mL) and 2-methoxypropane-1-sulfonyl chloride (33 mg, 0.19 mmol) . The solution was concentrated to yield 140 mg of the crude title compound as a yellow solid. LCMS (ESI) [M+H] + = 617.1.
[0728]
Step 2: (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) ethenesulfonamide
[0729]
[0730]
The General Procedure B was followed, using (S) -tert-butyl 3- ( (4- (2- ( (2-methyl-5- (vinylsulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (100 mg, 0.16 mmol) , dichloromethane (5 mL) and hydrochloric acid (4 M in ethyl acetate, 2 mL, 8 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%HCl) ; B: ACN) to yield 3 mg (4%, yield HCl salt) of 147 as a yellow solid. LCMS (ESI) : [M+H] + = 517.1; 1H NMR (400 MHz, DMSO-d 6) δ 8.87 (s, 1H) , 8.49 (d, J = 6.0 Hz, 1H) , 8.12 (d, J = 8.8 Hz, 3H) , 7.62 (d, J = 8.4 Hz, 1H) , 7.54 (d, J = 8.8 Hz, 1H) , 7.47 (d, J = 7.5 Hz, 1H) , 7.41 -7.29 (m, 2H) , 6.79 (dd, J = 16.4, 10.0, 1H) , 6.08 (d, J = 16.8 Hz, 1H) , 5.91 (d, J = 9.6 Hz, 1H) , 4.63 (s, 1H) , 3.68 (d, J = 11.6 Hz, 1H) , 3.40 (d, J = 12.8 Hz, 1H) , 3.18 -3.03 (m, 2H) , 2.34 -2.09 (m, 5H) , 2.05 -1.81 (m, 2H) .
[0731]
Example 148 N- (5- ( (3- (2- ( ( (3S, 5R) -5-Fluoropiperidin-3-yl) amino) pyrimidin-4-yl) pyridin-2-yl) oxy) -6-methylnaphthalen-1-yl) -1-phenylmethanesulfonamide 148
[0732]
Step 1: (3S, 5R) -Benzyl 3- ( (tert-butoxycarbonyl) amino) -5-fluoropiperidine-1-carboxylate
[0733]
[0734]
To a solution of tert-butyl ( (3S, 5R) -5-fluoropiperidin-3-yl) carbamate (500 mg, 0.23 mmol) in THF (2 mL) and H 2O (1 mL) was added sodium carbonate (48.6 mg, 0.46 mmol) . Benzyl chloroformate (0.03 ml, 0.23 mmol) was added dropwise at 0 ℃ and stirred at 0 ℃ to rt for 1 h. The mixture was concentrated to dryness and the residue was dissolved in dichloromethane (20 mL) and washed with H 2O (10 mL x 2) . The organic phase was dried over anhydrous sodium sulfate, concentrated and purified by silica gel chromatography (eluting with 0-1%methanol in dichloromethane ) to yield 200 mg (82%yield) of the title compound as a colorless oil; LCMS (ESI) [M+H] + = 398.1; 1H NMR (400 MHz, CDCl 3) δ 7.41 -7.29 (m, 5H) , 5.28 -5.03 (m, 3H) , 4.95 -4.63 (m, 1H) , 4.45 -4.25 (m, 1H) , 4.19 -3.97 (m, 1H) , 3.95 -3.81 (m, 1H) , 3.35 -3.02 (m, 2H) , 2.17 -1.82 (m, 2H) , 1.40 (s, 9H) .
[0735]
Step 2: (3S, 5R) -Benzyl 3-amino-5-fluoropiperidine-1-carboxylate
[0736]
[0737]
To a solution of benzyl (3S, 5R) -3- (tert-butoxycarbonylamino) -5-fluoro-piperidine-1-carboxylate (200 mg, 0.57 mmol) in ethyl acetate (1 mL) was added (4 M in ethyl acetate, 3 mL, 12 mmol) and stirred at 25 ℃ for 1 h. The mixture was concentrated to yield 138 mg (84%yield) of the title compound as a white solid. 1H NMR (400 MHz, CD 3OD) δ 7.44 -7.29 (m, 5H) , 5.28 -5.07 (m, 2H) , 4.96 (s, 1H) , 4.31 -4.08 (m, 2H) , 3.60 -3.35 (m, 3H) , 2.30 -2.10 (m, 2H) .
[0738]
Step 3: (3R, 5S) -Benzyl 3-fluoro-5- ( (4- (2- ( (2-methyl-5- (phenylmethylsulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0739]
[0740]
To a stirred solution of N- [6-methyl-5- [ [3- (2-methylsulfinylpyrimidin-4-yl) -2-pyridyl] oxy] -1-naphthyl] -1-phenyl-methanesulfonamide, made following the procedures of Example 101 (100 mg, 0.18 mmol) :
[0741]
[0742]
in 1, 4-dioxane (3 mL) was added N, N-diethylpropan-2-amine (0.16 mL, 0.92 mmol) and (3S, 5R) -benzyl 3-amino-5-fluoropiperidine-1-carboxylate (64 mg, 0.22 mmol) , the mixture was stirred at 140 ℃ for 88 h. After cooling down, the mixture was concentrated and the residue was dissolved in ethyl acetate (20 mL) and washed with H 2O (20 mL) . The organic phase was dried over anhydrous sodium sulfate, concentrated and purified by Prep-TLC (5%methanol in dichloromethane, R f = 0.5) to give 65 mg (48%yield) of the title compound as a white solid. LCMS (ESI) [M+H] += 733.1.
[0743]
Step 4: N- (5- ( (3- (2- ( ( (3S, 5R) -5-Fluoropiperidin-3-yl) amino) pyrimidin-4-yl) pyridin-2-yl) oxy) -6-methylnaphthalen-1-yl) -1-phenylmethanesulfonamide
[0744]
[0745]
To a solution of (3R, 5S) -benzyl 3-fluoro-5- ( (4- (2- ( (2-methyl-5- (phenylmethylsulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (80 mg, 0.11 mmol) in methanol (10 mL) was added 10%wet palladium (30 mg) on carbon followed by stirring at 40 ℃ under hydrogen gas (35 Psi) for 12 h. The mixture was filtered and purified by Prep-HPLC (mobile phase: A: water (0.05%HCl) ; B: ACN) to yield 2.6 mg (3.9%yield) of 148 as a white solid; LCMS (ESI) [M+H] + = 599.1; 1H NMR (400MHz, DMSO-d 6) δ 9.87 (s, 1H) , 9.37 -9.19 (m, 1H) , 8.51 (d, J = 5.2 Hz, 1H) , 8.12 -8.02 (m, 2H) , 7.65 -7.55 (m, 2H) , 7.52 (d, J = 8.8 Hz, 1H) , 7.45 -7.40 (m, 2H) , 7.38 -7.33 (m, 5H) , 7.29 -7.26 (m, 1H) , 5.16 -4.98 (m, 1H) , 4.54 (s, 2H) , 4.50 -4.41 (m, 1H) , 3.53 -3.42 (m, 2H) , 3.26 -3.18 (m, 1H) , 3.08 -3.02 (m, 1H) , 2.21 (s, 3H) , 2.13 -2.00 (m, 2H) .
[0746]
Example 149 (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) pyridine-3-sulfonamide 149
[0747]
Step 1: (S) -tert-Butyl 3- ( (4- (2- ( (2-methyl-5- (pyridine-3-sulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0748]
[0749]
The General Procedure A was followed, using (S) -tert-butyl 3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (100 mg, 0.19 mmol) , pyridine (3 mL) and pyridine-3-sulfonylchloride (37.1 mg, 0.21mmol) . The mixture was concentrated, dissolved in ethyl acetate (20 mL) and washed with H 2O (15 mL x 2) . The organic phase was dried over anhydrous sodium sulfate and concentrated to give 100 mg (crude) of the title compound as a brown solid.
[0750]
Step 2: (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) pyridine-3-sulfonamide
[0751]
[0752]
The General Procedure B was followed, using (S) -tert-butyl 3- ( (4- (2- ( (5- (cyclobutanecarboxamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (100 mg, 0.15 mmol) , dichloromethane (2 mL) and hydrochloric acid (4 M in ethyl acetate, 0.4 mL, 1.6 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%HCl) ; B: ACN) to yield 29.4 mg (32%, yield as HCl salt) of 149 as a yellow solid. LCMS (ESI) [M+H] + = 568.1; 1H NMR (400 MHz, DMSO-d 6) δ 10.69 -10.60 (m, 1H) , 9.18 -9.05 (m, 1H) , 8.85 -8.73 (m, 2H) , 8.51 -8.43 (m, 1H) , 8.14 -8.01 (m, 2H) , 7.88 -7.79 (m, 1H) , 7.70 -7.53 (m, 3H) , 7.45 -7.40 (m, 1H) , 7.38 -7.31 (m, 1H) , 7.30 -7.23 (m, 1H) , 7.15 -7.09 (m, 1H) , 3.48 -3.14 (m, 2H) , 2.92 -2.75 (m, 2H) , 2.16 (s, 3H) , 2.06 -1.86 (m, 2H) , 1.84 -1.57 (m, 2H) .
[0753]
Example 150 (S) -1- (4-Fluorophenyl) -N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) methanesulfonamide 150
[0754]
Step 1: (S) -tert-Butyl 3- ( (4- (2- ( (5- ( (4-fluorophenyl) methylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0755]
[0756]
The General Procedure A was followed, using tert-butyl (3S) -3- [ [4- [2- [ (5-amino-2-methyl-1-naphthyl) oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (100 mg, 0.19 mmol) , pyridine (2 mL) and 4-fluorophenyl) methanesulfonylchloride (48 mg, 0.23 mmol) . The reaction mixture was concentrated in vacuo and the residue taken up in ethyl acetate (20 mL) and washed with water (10 mL) . The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to yield (130 mg crude) of the title compound as a pale brown oil. LCMS (ESI) [M+H] + = 699.3.
[0757]
Step 2: (S) -1- (4-Fluorophenyl) -N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) methanesulfonamide
[0758]
[0759]
The General Procedure B was followed, using (S) -tert-butyl 3- ( (4- (2- ( (5- ( (4-fluorophenyl) methylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (130 mg, 0.19 mmol) , ethyl acetate (2 mL) and hydrochloric acid (4 M in ethyl acetate, 2 mL, 8 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%HCl) ; B: ACN) to yield 47 mg (40%yield) of 150 as a white solid. LCMS (ESI) : [M+H] + = 599.3; 1H NMR (400 MHz, DMSO-d 6) δ 9.90 (s, 1H) , 9.17 (s, 1H) , 8.50 (d, J = 5.2 Hz, 1H) , 8.13 -8.00 (m, 2H) , 7.65 (s, 1H) , 7.58 -7.50 (m, 2H) , 7.47 -7.34 (m, 3H) , 7.30 -7.27 (m, 1H) , 7.20 (t, J = 8.8 Hz, 2H) , 4.56 (s, 2H) , 4.40 -4.35 (m, 1H) , 3.45 -3.38 (m, 1H) , 3.22 -3.15 (m, 1H) , 2.90 -2.80 (m, 2H) , 2.22 (s, 3H) , 2.07 -2.00 (m, 1H) , 1.96 -1.88 (m, 1H) , 1.85 -1.71 (m, 1H) , 1.69 -1.62 (m, 1H) .
[0760]
Example 151 _ (S) -1-Chloro-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) methanesulfonamide 151
[0761]
Step 1: (S) -tert-Butyl 3- ( (4- (2- ( (5- (chloromethylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0762]
[0763]
The General Procedure A was followed, using (S) -tert-butyl 3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (300 mg, 0.57 mmol) , pyridine (2 mL) and chloromethanesulfonylchloride (0.06 mL, 0.68 mmol) . The mixture was concentrated and dissolved in dichloromethane (100 mL) and washed with H 2O (80 mL x 2) . The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to yield 110 mg (83%yield) of the title compound as a brown oil. LCMS (ESI) [M+H] + = 639.1.
[0764]
Step 2: (S) -1-Chloro-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) methanesulfonamide
[0765]
[0766]
The General Procedure B was followed, using (S) -tert-butyl 3- ( (4- (2- ( (5- (chloromethylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (110 mg, 0.17 mmol) , ethyl acetate (1 mL) and hydrochloric (4 M in ethyl acetate, 0.6 mL, 2.4 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%HCl) ; B: ACN) to yield 34 mg (34%yield) of 151 as a yellow solid. LCMS (ESI) [M+H] + = 539.1; 1H NMR (400 MHz, DMSO-d 6) δ 10.44 (s, 1H) , 9.10 -8.60 (m, 2H) , 8.48 (d, J = 5.6 Hz, 1H) , 8.14 (d, J = 8.8 Hz, 1H) , 8.06 (d, J = 3.2 Hz, 1H) , 7.65 -7.54 (m, 4H) , 7.52 -7.47 (m, 1H) , 7.46 -7.40 (m, 1H) , 7.29 -7.26 (m, 1H) , 5.05 (s, 2H) , 4.36 -4.25 (m, 1H) , 3.48 -3.38 (m, 1H) , 3.26 -3.14 (m, 1H) , 2.90 -2.80 (m, 2H) , 2.22 (s, 3H) , 2.07 -1.97 (m, 1H) , 1.95 -1.85 (m, 1H) , 1.81 -1.70 (m, 1H) , 1.67 -1.55 (m, 1H) .
[0767]
Example 152 N- (5- ( (3- (2- ( ( (trans) -4-Aminocyclohexyl) amino) pyrimidin-4-yl) pyridin-2-yl) oxy) -6-methylnaphthalen-1-yl) -1-phenylmethanesulfonamide 152
[0768]
Step 1: tert-Butyl ( (trans) -4- ( (4- (2- ( (2-methyl-5- (phenylmethylsulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) cyclohexyl) carbamate
[0769]
[0770]
To a stirred solution of N- [6-methyl-5- [ [3- (2-methylsulfinylpyrimidin-4-yl) -2-pyridyl] oxy] -1-naphthyl] -1-phenyl-methanesulfonamide from Example 148 (100 mg, 0.18 mmol) in 1, 4-dioxane (3 mL) was added N, N-diisopropylethylamine (0.1 mL, 0.55 mmol) and tert-butyl N- (4-aminocyclohexyl) carbamate (39 mg, 0.18 mmol) . The mixture was stirred at 130 ℃ for 3 days and then concentrated in vacuo and purified by flash column chromatography eluting with 0-2%methanol in dichloromethane (Rf = 0.5) to yield 100 mg (78%yield) of the title compound as a brown solid. LCMS (ESI) [M+H] + = 695.4.
[0771]
Step 2: N- (5- ( (3- (2- ( ( (trans) -4-Aminocyclohexyl) amino) pyrimidin-4-yl) pyridin-2-yl) oxy) -6-methylnaphthalen-1-yl) -1-phenylmethanesulfonamide
[0772]
[0773]
The General Procedure B was followed, using tert-butyl ( (1r, 4r) -4- ( (4- (2- ( (2-methyl-5- (phenylmethylsulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) cyclohexyl) carbamate (100 mg, 0.14 mmol) , dichloromethane (5 mL) and hydrochloric acid (4 M in ethyl acetate, 2 mL, 8 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%HCl) ; B: ACN) to yield 73 mg (80%yield) of 152 as a yellow solid. LCMS (ESI) : [M+H] + = 595.4; 1H NMR (400 MHz, DMSO-d 6) δ 9.92 (s, 1H) , 8.59 -8.43 (m, 2H) , 8.25 -8.04 (m, 5H) , 7.74 -7.27 (m, 12H) , 4.58 -4.51 (m, 2H) , 3.99 -3.84 (m, 1H) , 3.09 -2.97 (m, 1H) , 2.22 (s, 3H) , 2.15 -1.98 (m, 4H) , 1.60 -1.39 (m, 4H) .
[0774]
Example 153 (S) -Ethyl (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) carbamate 153
[0775]
Step 1: (S) -tert-Butyl 3- ( (4- (2- ( (5- ( (ethoxycarbonyl) amino) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0776]
[0777]
The General Procedure A was followed, using tert-butyl (3S) -3- [ [4- [2- [ (5-amino-2-methyl-1-naphthyl) oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (150 mg, 0.28 mmol) , triethylamine (0.16 mL, 1.14 mmol) and ethyl chloroformate (0.26 mL, 2.76 mmol) . The solution was concentrated to afford 200 mg of the crude title compound as a yellow solid. LCMS (ESI) [M+Na] + = 621.1.
[0778]
Step 2: (S) -Ethyl (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) carbamate
[0779]
[0780]
The General Procedure B was followed, using (S) -tert-butyl 3- ( (4- (2- ( (5- ( (ethoxycarbonyl) amino) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (100 mg, 0.17 mmol) , dichloromethane (5 mL) and hydrochloric acid (4 M in ethyl acetate, 2 mL, 8 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%HCl) ; B: ACN) to yield 29 mg (34%yield) of 153 as a yellow solid. LCMS (ESI) : [M+H] + = 517.2; 1H NMR (400 MHz, DMSO-d 6) δ 9.59 (s, 1H) , 9.22 (s, 1H) , 8.50 (d, J = 5.2 Hz, 1H) , 8.07 (d, J = 3.2 Hz, 1H) , 7.94 (d, J = 8.4 Hz, 1H) , 7.67 (s, 1H) , 7.56 (d, J = 7.1 Hz, 1H) , 7.48 (t, J = 8.8 Hz, 2H) , 7.43 -7.36 (m, 1H) , 7.27 (d, J = 7.7 Hz, 1H) , 4.42 (s, 1H) , 4.14 (s, 2H) , 3.43 (d, J = 8.4 Hz, 1H) , 3.19 (d, J = 12.0 Hz, 1H) , 2.85 (t, J = 9.6 Hz, 2H) , 2.27 -2.13 (m, 3H) , 2.03 (d, J = 9.2 Hz, 1H) , 1.96 -1.87 (m, 1H) , 1.86 -1.72 (m, 1H) , 1.65 (d, J = 9.6 Hz, 1H) , 1.28 (t, J = 7.2 Hz, 3H) .
[0781]
Example 154 (S) -1-Methyl-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) cyclopropane-1-carboxamide 154
[0782]
Step 1: tert-Butyl (S) -3- ( (4- (2- ( (2-methyl-5- (1-methylcyclopropane-1-carboxamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0783]
[0784]
The General Procedure C was followed, using tert-butyl (S) -3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate from Example 101 (138 mg, 0.25 mmol) , 1-methycyclopropane carboxylic acid (25 mg, 0.25 mmol) , DIPEA (0.131 mL, 0.75 mmol) , HATU (194 mg, 0.50 mmol) and DCM (4 mL) . The crude was used in the next steps without further purification.
[0785]
Step 2: (S) -1-Methyl-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) cyclopropane-1-carboxamide
[0786]
[0787]
The General Procedure B was followed, using crude tert-butyl (S) -3- ( (4- (2- ( (2-methyl-5- (1-methylcyclopropane-1-carboxamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate, DCM (4 mL) and hydrochloric acid (4 M in dioxane, 3 mL, 12 mmol) . The residue was purified via reverse-phase HPLC and lyophilized to yield 50 mg (39%yield over 2 steps) of 154. LCMS (ESI) : [M+H] + = 509.2; 1H NMR (400 MHz, DMSO-d 6) δ 9.47 (s, 1H) , 8.54 -8.47 (m, 1H) , 8.42 (d, J = 5.1 Hz, 1H) , 8.03 (dd, J = 4.8, 2.0 Hz, 1H) , 7.71 (d, J = 8.7 Hz, 1H) , 7.56 (d, J = 8.0 Hz, 1H) , 7.51 -7.45 (m, 2H) , 7.42 -7.34 (m, 2H) , 7.25 (dd, J = 7.6, 4.8 Hz, 1H) , 7.19 (d, J = 7.9 Hz, 1H) , 3.96 (s, 1H) , 3.20 -3.12 (m, 1H) , 2.87 (d, J = 12.8 Hz, 1H) , 2.22 (s, 3H) , 1.99 -1.90 (m, 1H) , 1.73 -1.65 (m, 1H) , 1.52 (s, 3H) , 1.54 -1.46 (m, 1H) , 1.18-1.13 (m, 2H) , 0.72 -0.68 (m, 2H) .
[0788]
Example 155 _ (S) -1-Fluoro-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) cyclopropane-1-carboxamide 155
[0789]
Step 1: tert-Butyl (S) -3- ( (4- (2- ( (5- (1-fluorocyclopropane-1-carboxamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0790]
[0791]
The General Procedure C was followed, using tert-butyl (S) -3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate from Example 101 (133 mg, 0.25 mmol) , 1-fluorocyclopropanecarboxylic acid (25 mg, 0.24 mmol) , DIPEA (0.126 mL, 0.72 mmol) , HATU (186 mg, 0.48 mmol) and DCM (4 mL) . The crude was directly used in the next step.
[0792]
Step 2: (S) -1-Fluoro-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) cyclopropane-1-carboxamide
[0793]
[0794]
The General Procedure B was followed, using crude tert-butyl (S) -3- ( (4- (2- ( (5- (1-fluorocyclopropane-1-carboxamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate, DCM (4 mL) and hydrochloric acid (4 M in dioxane, 3 mL, 12 mmol) . The residue was purified via reverse-phase HPLC and lyophilized to yield 68 mg (55%yield over 2 steps) of 155. LCMS (ESI) : [M+H] + = 513.2; 1H NMR (400 MHz, DMSO-d 6) δ 10.45 (d, J = 2.0 Hz, 1H) , 8.50 (d, J = 7.6 Hz, 1H) , 8.41 (d, J = 5.1 Hz, 1H) , 8.04 (dd, J = 4.8, 2.0 Hz, 1H) , 7.75 (d, J = 8.7 Hz, 1H) , 7.65 -7.58 (m, 1H) , 7.52 (d, J = 8.7 Hz, 1H) , 7.48 -7.40 (m, 3H) , 7.26 (dd, J = 7.5, 4.8 Hz, 1H) , 7.13 (d, J = 8.0 Hz, 1H) , 3.90 (s, 1H) , 3.14 -3.05 (m, 1H) , 2.85 -2.75 (m, 1H) , 2.48 -2.41 (m, 2H) , 2.22 (s, 3H) , 1.97 -1.88 (m, 1H) , 1.68 -1.59 (m, 1H) , 1.58 -1.27 (m, 6H) .
[0795]
Example 156 (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) -1- (thiazol-4-yl) methanesulfonamide 156
[0796]
Step 1: Thiazol-4-ylmethanesulfonyl chloride
[0797]
[0798]
A mixture of 4- (chloromethyl) thiazole (1.0 g, 7.5 mmol) , sodium sulfite (1.10 g, 9.0 mmol) , and tetrabutylammonium bromide (120 mg, 0.37 mmol) in water (10 mL) was heated at 80 ℃ overnight, concentrated in vacuo, azeotroped with toluene (2x) , and dried under high vacuum to afford thiazol-4-ylmethylsulfonyloxysodium. The crude product was used in the next step without further purification.
[0799]
Thiazol-4-ylmethylsulfonyloxysodium (1.3 g, 6.5 mmol) was suspended in DMF (10 mL) cooled in ice bath. Thionyl chloride (0.71 mL, 9.7 mmol) was added dropwise. The resulting yellow mixture was allowed to warm to room temperature, stirred for 30 min. It was poured into crushed ice (~75 mL) , extracted with iPrOAc (2 x 40 mL) , washed with brine, dried over MgSO 4, filtered and concentrated in vacuo to afford 523 mg (41%yield) of the title compound as off-white solid. LCMS (ESI) [M+H] + = 198. The material obtained after work-up was used immediately in the next step.
[0800]
Step 2: tert-Butyl (S) -3- ( (4- (2- ( (2-methyl-5- ( (thiazol-4-ylmethyl) sulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0801]
[0802]
The General Procedure A was followed, using tert-butyl (3S) -3- [ [4- [2- [ (5-amino-2-methyl-1-naphthyl) oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (100 mg, 0.19 mmol) , pyridine (2 mL) , DCM (2 mL) , and thiazol-4-ylmethanesulfonyl chloride (523 mg, 2.64 mmol) . After work up, the title compound was obtained as a brown solid (145 mg, 100%yield) . The product was used in the next step without further purification. LCMS (ESI) [M+H] + = 688.
[0803]
Step 4: (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) -1- (thiazol-4-yl) methanesulfonamide
[0804]
[0805]
The General Procedure B was followed, using tert-butyl (S) -3- ( (4- (2- ( (2-methyl-5- ( (thiazol-4-ylmethyl) sulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (145 mg, 211 mmol) . The crude product was purified via reverse-phase HPLC and lyophilized to yield 20.3 mg (16.5%yield) of 156 as an off-white solid. LCMS (ESI) [M+H] + = 588; 1H NMR (400 MHz, DMSO-d 6) δ 9.06 (d, J = 2.0 Hz, 1H) , 8.51 (d, J = 7.7 Hz, 1H) , 8.42 (d, J = 5.1 Hz, 1H) , 8.13 (d, J = 8.7 Hz, 1H) , 8.05 (dd, J = 4.8, 2.0 Hz, 1H) , 7.68 (d, J = 2.0 Hz, 1H) , 7.50 -7.39 (m, 3H) , 7.36 -7.29 (m, 1H) , 7.25 (dd, J = 7.6, 4.8 Hz, 1H) , 7.21 (d, J = 7.9 Hz, 1H) , 4.59 (s, 2H) , 3.98 (s, 1H) , 3.20 (d, J = 16.6 Hz, 2H) , 2.90 (d, J = 12.2 Hz, 1H) , 2.61 -2.53 (m, 1H) , 2.20 (s, 3H) , 1.99 -1.92 (m, 1H) , 1.75 -1.68 (m, 1H) , 1.57 -1.46 (m, 2H) .
[0806]
Example 157 (S) -1- (2, 4-Difluorophenyl) -N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) methanesulfonamide 157
[0807]
Step 1: (S) -tert-Butyl 3- ( (4- (2- ( (5- ( (2, 4-difluorophenyl) methylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0808]
[0809]
The General Procedure A was followed, using tert-butyl (3S) -3- [ [4- [2- [ (5-amino-2-methyl-1-naphthyl) oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (150 mg, 0.28 mmol) , pyridine (3 mL) and 2, 4-difluorophenyl) methanesulfonyl chloride (65 mg, 0.28 mmol) . The solution was concentrated to afford 150 mg (74%yield) of the crude title compound as a yellow solid. LCMS (ESI) [M+H] + = 717.1.
[0810]
Step 2: (S) -1- (2, 4-Difluorophenyl) -N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) methanesulfonamide
[0811]
[0812]
The General Procedure B was followed, using (S) -tert-butyl 3- ( (4- (2- ( (5- ( (2, 4-difluorophenyl) methylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (150 mg, 0.21 mmol) , dichloromethane (5 mL) and hydrochloric acid (4 M in ethyl acetate, 2 mL, 8 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%HCl) ; B: ACN) to yield 38 mg (29%yield) of 157 as a yellow solid. LCMS (ESI) : [M+H] + = 517.2; 1H NMR (400 MHz, DMSO-d 6) δ 10.12 -10.02 (m, 1H) , 9.67 (s, 1H) , 9.35 (s, 1H) , 8.89 (s, 1H) , 8.52 (d, J = 5.6 Hz, 1H) , 8.15 -8.02 (m, 2H) , 7.74 (s, 1H) , 7.60 -7.38 (m, 5H) , 7.34 -7.23 (m, 2H) , 7.12 (t, J = 8.4 Hz, 1H) , 4.59 (s, 2H) , 4.49 (s, 1H) , 3.51 -3.13 (m, 2H) , 2.94 -2.78 (m, 2H) , 2.21 (s, 3H) , 2.09 -1.56 (m, 4H) .
[0813]
Example 158 N- (5- ( (3- (2- ( ( (trans) -4-Aminocyclohexyl) amino) pyrimidin-4-yl) pyridin-2-yl) oxy) -6-methylnaphthalen-1-yl) propane-1-sulfonamide 158
[0814]
Step 1: tert-Butyl ( (trans) -4- ( (4- (2- ( (2-methyl-5- (propylsulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) cyclohexyl) carbamate
[0815]
[0816]
To a stirred solution of N- (6-methyl-5- ( (3- (2- (methylsulfinyl) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) propane-1-sulfonamide (100 mg, 0.20 mmol) in 1, 4-dioxane (3 mL) was added N, N-diisopropylethylamine (0.1 mL, 0.55 mmol) and tert-butyl N- (4-aminocyclohexyl) carbamate (65 mg, 0.30 mmol) . The mixture was stirred at 130 ℃ for 16 h. The reaction was concentrated to dryness and purified by flash column chromatography eluting with 0-10%methanol in dichloromethane (Rf = 0.5) to yield 100 mg (77%yield) of the title compound as a yellow solid. LCMS (ESI) [M+H] + = 647.1.
[0817]
Step 2: N- (5- ( (3- (2- ( ( (trans) -4-Aminocyclohexyl) amino) pyrimidin-4-yl) pyridin-2-yl) oxy) -6-methylnaphthalen-1-yl) propane-1-sulfonamide
[0818]
[0819]
The General Procedure B was followed, using tert-butyl ( (1r, 4r) -4- ( (4- (2- ( (2-methyl-5- (propylsulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) cyclohexyl) carbamate (100 mg, 0.15 mmol) , dichloromethane (5 mL) and hydrochloric acid (4 M in ethyl acetate, 2 mL, 8 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%HCl) ; B: ACN) to yield 45 mg (49%yield) of 158 as a yellow solid. LCMS (ESI) : [M+H] + = 547.1; 1H NMR (400 MHz, DMSO-d 6) δ 9.84 (s, 1H) , 8.63 -8.43 (m, 3H) , 8.24 -8.13 (m, 5H) , 7.70 -7.66 (m, 1H) , 7.63 -7.54 (m, 2H) , 7.49 -7.41 (m, 2H) , 7.36 -7.31 (m, 1H) , 3.96 -3.85 (m, 1H) , 3.17 -3.10 (m, 2H) , 3.08 -2.97 (m, 1H) , 2.23 (s, 3H) , 2.14 -1.99 (m, 4H) , 1.83 -1.71 (m, 2H) , 1.62 -1.38 (m, 4H) , 0.97 (t, J = 7.2 Hz, 3H) .
[0820]
Example 159 (S) -1-Fluoro-N- (6-methyl-5- (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yloxy) naphthalen-1-yl) methanesulfonamide 159
[0821]
Step 1: (S) -tert-Butyl 3- (4- (2- (5- (fluoromethylsulfonamido) -2-methylnaphthalen-1-yloxy) pyridin-3-yl) pyrimidin-2-ylamino) piperidine-1-carboxylate
[0822]
[0823]
The General Procedure A was followed, using tert-butyl (3S) -3- [ [4- [2- [ (5-amino-2-methyl-1-naphthyl) oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (50 mg, 0.095 mmol) , pyridine (1 mL) and fluoromethanesulfonyl chloride (81 mg, 0.61 mmol) . The crude was then purified by flash chromatography (gradient 0 to 80%of 1: 4 MeOH/DCM in DCM) to yield 38 mg (64%yield) of the title compound as a brown solid. LCMS (ESI) [M+H] + = 623.3.
[0824]
Step 2: (S) -1-Fluoro-N- (6-methyl-5- (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yloxy) naphthalen-1-yl) methanesulfonamide
[0825]
[0826]
To (S) -tert-butyl 3- (4- (2- (5- (fluoromethylsulfonamido) -2-methylnaphthalen-1-yloxy) pyridin-3-yl) pyrimidin-2-ylamino) piperidine-1-carboxylate (38 mg, 0.061 mmol) in DCM (6 mL) was added trifluoroacetic acid (1 mL) . The mixture was concentrated and the residue purified by Prep-HPLC to yield 19.8 mg (40%yield) of 159 as a white solid. LCMS (ESI) : [M+H] + = 523.1; 1H NMR (400 MHz, DMSO-d 6) δ 8.45 (d, J = 5.2 Hz, 2H) , 8.23 (m, 1H) , 8.04 (dd, J = 4.8, 2.0 Hz, 1H) , 7.54 (d, J = 5.2 Hz, 1H) , 7.37 (d, J = 7.5 Hz, 1H) , 7.29 (d, J = 8.7 Hz, 1H) , 7.23 (dd, J = 7.6, 4.8 Hz, 1H) , 7.21 -7.10 (m, 2H) , 7.01 (d, J = 8.1 Hz, 1H) , 5.03 (d, J = 47.8 Hz, 2H) , 4.14 (s, 1H) , 3.09 (dd, J = 10.4, 6.4 Hz, 1H) , 2.82-2.68 (m, 2H) , 2.18 (s, 3H) , 2.00 (s, 1H) , 1.84 (s, 1H) , 1.62 (q, J = 10.7 Hz, 2H) .
[0827]
Example 160 (S) -1- (4- (Difluoromethyl) phenyl) -N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) methanesulfonamide 160
[0828]
Step 1: (S) -tert-Butyl 3- ( (4- (2- ( (5- ( (4- (difluoromethyl) phenyl) methylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0829]
[0830]
The General Procedure A was followed, using tert-butyl (3S) -3- [ [4- [2- [ (5-amino-2-methyl-1-naphthyl) oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (100 mg, 0.19 mmol) , pyridine (2 mL) and [4- (difluoromethyl) phenyl] methanesulfonyl chloride (91 mg, 0.38 mmol) . The resulting solution was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, and concentrated in vacuo to yield 80 mg of the crude title compound as a yellow solid. LCMS (ESI) [M+Na] + = 753.1.
[0831]
Step 2: (S) -1- (4- (Difluoromethyl) phenyl) -N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) methanesulfonamide
[0832]
[0833]
The General Procedure B was followed, using (S) -tert-butyl 3- ( (4- (2- ( (5- ( (4- (difluoromethyl) phenyl) methylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (80 mg, 0.11 mmol) , dichloromethane (2 mL) and hydrochloric acid (4 M in dioxane, 2 mL, 8 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%HCl) ; B: ACN) to yield 33 mg (45%yield) of 160 as a yellow solid. LCMS (ESI) [M+H] + = 631.1. 1H NMR (400 MHz, DMSO-d 6) δ 9.96 (s, 1H) , 9.44 (s, 1H) , 9.22 (s, 1H) , 8.82 (s, 1H) , 8.50 (d, J = 5.4 Hz, 1H) , 8.09 (d, J = 3.2 Hz, 1H) , 8.04 (d, J = 8.8 Hz, 1H) , 7.90 (s, 1H) , 7.68 (s, 1H) , 7.60 -7.50 (m, 5H) , 7.49 -7.38 (m, 2H) , 7.31 -7.26 (m, 1H) , 7.05 (t, J = 56.0 Hz 1H) , 4.64 (s, 2H) , 4.45 -4.35 (m, 1H) , 3.46 -3.42 (m, 1H) , 3.22 -3.18 (m, 1H) , 2.90 -2.80 (m, 2H) , 2.22 (s, 3H) , 2.04 -1.97 (m, 1H) , 1.95 -1.88 (m, 1H) , 1.85 -1.75 (m, 1H) , 1.65 (m, 1H) .
[0834]
Example 161 N- (5- ( (3- (2- ( ( (3S, 5R) -5-Methoxypiperidin-3-yl) amino) pyrimidin-4-yl) pyridin-2-yl) oxy) -6-methylnaphthalen-1-yl) -1-phenylmethanesulfonamide 161
[0835]
Step 1: Benzyl 3- ( (tert-butoxycarbonyl) amino) -5-hydroxypiperidine-1-carboxylate
[0836]
[0837]
To a solution of benzyl chloroformate, Cbz-Cl (1.03 mL, 7.21 mmol) , and sodium bicarbonate (505 mg, 6.01 mmol) in tetrahydrofuran (5 mL) was added tert-butyl-N- (5-hydroxy-3-piperidyl) carbamate (1.3 g, 6.01 mmol) . The mixture was stirred at 21 ℃ for 4 h. The solution was concentrated and purified by chromatography on silica (solvent gradient: methanol in dichloromethane) to yield 2 g (95%yield) of the title compound as a white solid. LCMS (ESI) [M+Na] + = 372.9.
[0838]
Step 2: Benzyl 3- ( (tert-butoxycarbonyl) amino) -5-methoxypiperidine-1-carboxylate
[0839]
[0840]
To a solution of benzyl 3- ( (tert-butoxycarbonyl) amino) -5-hydroxypiperidine-1-carboxylate (3.0 g, 8.6 mmol) , silver oxide, Ag 2O (2 g, 8.6 mmol) in acetonitrile (60 mL) and N, N-dimethylformamide (15 mL) was added iodomethane, MeI (7.0 mL, 111.46 mmol) . The mixture was stirred at 25 ℃ for 24 h. The solution was filtered and concentrated. The residue was purified by chromatography on silica (solvent gradient: 0-40%ethyl acetate in petroleum ether) to yield 2.3 g (74%yield) of the title compound as a colorless oil. LCMS (ESI) [M+Na] + = 387.1.
[0841]
Step 3: Benzyl 3-amino-5-methoxypiperidine-1-carboxylate
[0842]
[0843]
To a solution of benzyl 3- ( (tert-butoxycarbonyl) amino) -5-methoxypiperidine-1-carboxylate (2.2 g, 6.04 mmol) in dichloromethane (20 mL) was added 4M hydrochloric acid (10 mL, 44 mmol) in ethyl acetate and the mixture was stirred at 25 ℃ for 1 h. The reaction solution was concentrated in vacuo to yield 2 g of the crude title compound as a white solid. LCMS (ESI) [M+H] + = 264.9.
[0844]
Step 4: Benzyl 3-methoxy-5- ( (4- (2- ( (2-methyl-5- (phenylmethylsulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0845]
To a solution of N- [6-methyl-5- [ [3- (2-methylsulfinylpyrimidin-4-yl) -2-pyridyl] oxy] -1-naphthyl] -1-phenyl-methanesulfonamide from Example 148 (600 mg, 1.1 mmol) in 1, 4-dioxane (5 mL) was added N, N-diisopropylethylamine (0.59 mL, 3.3 mmol) and benzyl 3-amino-5-methoxypiperidine-1-carboxylate (420.0 mg, 1.59 mmol) . The mixture was stirred at 130 ℃ for 16 h. The solution was concentrated and purified by prep-TLC (5%methanol in dichloromethane, Rf = 0.5) and then purified by using chiral SFC (SFC80; Chiralpak AD 250 × 30 mm I.D., 10 μm; supercritical CO 2 /MeOH+NH 3·H 2O = 55/55; 80 mL/min) to afford (3S, 5R) -benzyl 3-methoxy-5- ( (4- (2- ( (2-methyl-5- (phenylmethylsulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (300 mg, 40%yield, Rt = 1.80 min) and (3R, 5S) -benzyl-3-methoxy-5- ( (4- (2- ( (2-methyl-5- (phenylmethylsulfonamido) naphthalen-1-yl) oxy) pyridine-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (250 mg, 33.3%yield, Rt = 3.06 min) as a yellow solid. LCMS (ESI) [M+H] + = 745.2.
[0846]
Step 5: N- (5- ( (3- (2- ( ( (3S, 5R) -5-Methoxypiperidin-3-yl) amino) pyrimidin-4-yl) pyridin-2-yl) oxy) -6-methylnaphthalen-1-yl) -1-phenylmethanesulfonamide
[0847]
[0848]
To a solution of thiourea (77 mg, 1.01 mmol) , 1-methylimidazole (66 mg, 0.81 mmol) and (3R, 5S) -benzyl3-methoxy-5- ( (4- (2- ( (2-methyl-5- (phenylmethylsulfonamido) naphthalen-1-yl) oxy) pyridin -3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (150 mg, 0.20 mmol, the second peak in step 2) in redistilled acetonitrile (2 mL) was added iodotrimethylsilane (0.23 mL, 1.65 mmol) dropwise. Then the mixture was stirred for 16 h. Then the mixture was quenched with water (15 mL) and extracted with ethyl acetate (20 mL x 3) . The combined organic extracts were concentrated in vacuo and the residue was purified by Prep-HPLC (mobile phase: A: water (0.05%NH 4OH) ; B: ACN) to afford 161 (37 mg, 29.5%yield) as a white solid (ee = 95%) . LCMS (ESI) [M+H] + = 611.1; 1H NMR (400 MHz, CDCl 3) δ 8.63 -8.54 (m, 1H) , 8.37 (d, J = 5.4 Hz, 1H) , 8.01 (d, J = 4.8 Hz, 1H) , 7.69 (d, J = 8.4 Hz, 1H) , 7.65 -7.56 (m, 3H) , 7.44 -7.28 (m, 6H) , 7.26 (d, J = 2.0 Hz, 1H) , 7.11 (d, J = 7.6 Hz, 1H) , 6.21 (s, 1H) , 4.39 (s, 2H) , 4.20 -4.15 (m, 1H) , 3.44 (s, 3H) , 3.41 -3.35 (m, 1H) , 3.09 -2.91 (m, 4H) , 2.30 (s, 3H) , 2.20 -2.16 (m, 1H) , 1.93 -1.88 (m, 1H) .
[0849]
Example 162 N- (5- ( (3- (2- ( (4-Fluoropiperidin-3-yl) amino) pyrimidin-4-yl) pyridin-2-yl) oxy) -6-methylnaphthalen-1-yl) -1-phenylmethanesulfonamide 162
[0850]
Step 1: tert-Butyl 4-fluoro-3- ( (4- (2- ( (2-methyl-5- (phenylmethylsulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0851]
[0852]
To a stirred solution of N- (6-methyl-5- ( (3- (2- (methylsulfinyl) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) propane-1-sulfonamide (100 mg, 0.18 mmol) in 1, 4-dioxane (3 mL) was added N, N-diisopropylethylamine (0.1 mL, 0.55 mmol) and trans-tert-butyl N- (4-aminocyclohexyl) carbamate (40 mg, 0.18 mmol) , the mixture was stirred at 135 ℃ for 4 days. The reaction was concentrated in vacuo and purified by flash column chromatography eluting with 0-10%methanol in dichloromethane (Rf = 0.5) to yield 100 mg (78%yield) of the title compound as a yellow solid. LCMS (ESI) [M+H] + = 699.1.
[0853]
Step 2: N- (5- ( (3- (2- ( (4-Fluoropiperidin-3-yl) amino) pyrimidin-4-yl) pyridin-2-yl) oxy) -6-methylnaphthalen-1-yl) -1-phenylmethanesulfonamide
[0854]
[0855]
The General Procedure B was followed, using tert-butyl ( (1r, 4r) -4- ( (4- (2- ( (2-methyl-5- (propylsulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) cyclohexyl) carbamate (100 mg, 0.14 mmol) , dichloromethane (5 mL) and hydrochloric acid (4 M in ethyl acetate, 2 mL, 8 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%HCl) ; B: ACN) to yield 17 mg (18%yield) of 162 as a yellow solid (as mixture of enantiomers) . LCMS (ESI) : [M+H] + = 599.1; 1H NMR (400 MHz, DMSO-d 6) δ 9.90 (s, 1H) , 9.44 (s, 1H) , 8.98 -8.42 (m, 2H) , 8.13 -7.92 (m, 3H) , 7.80 -7.62 (m, 1H) , 7.59 -7.49 (m, 2H) , 7.44 -7.33 (m, 7H) , 7.31 -7.25 (m, 1H) , 5.03 -4.74 (m, 2H) , 4.59 -4.48 (m, 2H) , 3.53 -3.26 (m, 2H) , 3.11 -2.89 (m, 2H) , 2.39 -2.29 (m, 1H) , 2.21 (s, 3H) , 2.13 -1.98 (m, 1H) .
[0856]
Example 163 (S) -N- (3-Methyl-4- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) -1-phenylmethanesulfonamide 163
[0857]
Step 1: (S) -tert-Butyl 3- ( (4- (2- ( (2-methyl-4- (phenylmethylsulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0858]
[0859]
The General Procedure A was followed, using tert-butyl (3S) -3- [ [4- [2- [ (4-amino-2-methyl-1-naphthyl) oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (200 mg, 0.38 mmol) , pyridine (2 mL) and phenylmethanesulfonyl chloride (108 mg, 0.57 mmol) . The reaction was then concentrated in vacuo to yield 200 mg of the crude title compound as a brown solid. LCMS (ESI) [M+Na] + = 703.1.
[0860]
Step 2: (S) -N- (3-Methyl-4- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) -1-phenylmethanesulfonamide
[0861]
[0862]
The General Procedure B was followed, using (S) -tert-butyl 3- ( (4- (2- ( (2-methyl-4- (phenylmethylsulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (200 mg, 0.29 mmol) , dichloromethane (5 mL) and hydrochloric acid (4 M in dioxane, 2 mL, 8 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%HCl) ; B: ACN) to yield 56 mg (30%yield) of 163 as a yellow solid. LCMS (ESI) : [M+H] + = 581.1; 1H NMR (400 MHz, DMSO-d 6) δ 9.89 -9.78 (m, 1H) , 9.60 -9.18 (m, 2H) , 8.94 -8.70 (m, 1H) , 8.55 -8.46 (m, 1H) , 8.40 -8.07 (m, 2H) , 8.05 -7.62 (m, 3H) , 7.54 -7.37 (m, 6H) , 7.33 -7.26 (m, 2H) , 4.58 (s, 2H) , 4.46 -4.38 (m, 1H) , 3.49 -3.38 (m, 1H) , 3.26 -3.14 (m, 1H) , 2.93 -2.77 (m, 2H) , 2.18 (s, 3H) , 2.07 -1.87 (m, 2H) , 1.86 -1.59 (m, 2H) .
[0863]
Example 164 (S) -N- (3-Methyl-4- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) propane-1-sulfonamide 164
[0864]
Step 1: (S) -tert-Butyl 3- ( (4- (2- ( (2-methyl-4- (propylsulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0865]
[0866]
The General Procedure A was followed, using tert-butyl (3S) -3- [ [4- [2- [ (4-amino-2-methyl-1-naphthyl) oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (200 mg, 0.38 mmol) , pyridine (2 mL) and 1-propanesulfonyl chloride (82 mg, 0.57 mmol) . The reaction mixture was then concentrated to yield 200 mg of the crude title compound as a brown oil. LCMS (ESI) [M+Na] + = 655.1.
[0867]
Step 2: (S) -N- (3-Methyl-4- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) propane-1-sulfonamide
[0868]
[0869]
The General Procedure B was followed, using (S) -tert-butyl 3- ( (4- (2- ( (2-methyl-4- (propylsulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (200 mg, 0.31 mmol) , dichloromethane (5 mL) and hydrochloric acid (4 M in dioxane, 2 mL, 8 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%HCl) ; B: ACN) to yield 56 mg (30%yield) of 164 as a yellow solid. LCMS (ESI) : [M+H] + = 533.1; 1H NMR (400 MHz, DMSO-d 6) δ 9.83 -9.47 (m, 2H) , 9.41 -9.19 (m, 1H) , 9.02 -8.74 (m, 1H) , 8.56 -8.46 (m, 1H) , 8.30 -8.05 (m, 3H) , 7.83 -7.62 (m, 2H) , 7.59 -7.52 (m, 1H) , 7.48 -7.42 (m, 2H) , 7.32 -7.27 (m, 1H) , 4.67 -4.33 (m, 1H) , 3.48 -3.38 (m, 1H) , 3.24 -3.11 (m, 3H) , 2.92 -2.79 (m, 2H) , 2.22 (s, 3H) , 2.09 -1.99 (m, 1H) , 1.96 -1.87 (m, 1H) , 1.86 -1.74 (m, 3H) , 1.73 -1.60 (m, 1H) , 0.99 (t, J = 7.2 Hz, 3H) .
[0870]
Example 165 N- (5- ( (3- (2- ( ( (3S, 5S) -5-Fluoropiperidin-3-yl) amino) pyrimidin-4-yl) pyridin-2-yl) oxy) -6-methylnaphthalen-1-yl) propane-1-sulfonamide 165
[0871]
Step 1: N- (5- ( (3- (2- ( ( (3S, 5S) -5-Fluoro-1- (4-methoxybenzyl) piperidin-3-yl) amino) pyrimidin-4-yl) pyridin-2-yl) oxy) -6-methylnaphthalen-1-yl) propane-1-sulfonamide
[0872]
[0873]
To a solution of N- [6-methyl-5- [ [3- (2-methylsulfinylpyrimidin-4-yl) -2-pyridyl] oxy] -1-naphthyl] propane-1-sulfonamide (100 mg, 0.2 mmol) in 1, 4-dioxane (3 mL) was added N, N-diisopropylethylamine (0.11 mL, 0.6 mmol) and (3S, 5S) -5-fluoro-1- [ (4-methoxyphenyl) methyl] piperidin-3-amine (52.8 mg, 0.22 mmol) . The mixture was stirred at 120 ℃ for 64 h. After cooling down, the mixture was concentrated in vacuo, dissolved in dichloromethane (30 mL) and washed with H 2O (30 mL x 2) . The organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo and the residue was purified by Prep-TLC (5%methanol in dichloromethane, Rf = 0.6) to yield 34 mg (25%yield) of the title compound as a yellow solid; LCMS (ESI) [M+H] + = 671.0
[0874]
Step 2: N- (5- ( (3- (2- ( ( (3S, 5S) -5-Fluoropiperidin-3-yl) amino) pyrimidin-4-yl) pyridin-2-yl) oxy) -6-methylnaphthalen-1-yl) propane-1-sulfonamide
[0875]
[0876]
To a solution of N- [5- [ [3- [2- [ [ (3S, 5S) -5-fluoro-1- [ (4-methoxyphenyl) methyl] -3-piperidyl] amino] pyrimidin-4-yl] -2-pyridyl] oxy] -6-methyl-1-naphthyl] propane-1-sulfonamide (24 mg, 0.04 mmol) in 1, 2-dichloroethane (1 mL) was added triethylamine (6.8 mL, 0.36 mmol) and 1-chloroethyl chloroformate (51.2 mg, 0.36 mmol) . The mixture was stirred at 20 ℃ for 4 h and then concentrated and dissolved in methanol (20 mL) . Heating at 70 ℃ for 16 h, followed by concentration in vacuum and purification by Prep-HPLC (mobile phase: A: water (0.05%NH 4OH) ; B: ACN) yielded 5.1 mg (18%yield) of 165 as a white solid; LCMS (ESI) [M+H] + = 551.3; 1H NMR (400 MHz, DMSO-d 6) δ 8.58 -8.47 (m, 1H) , 8.42 (d, J = 4.8 Hz, 1H) , 8.12 (d, J = 8.4 Hz, 1H) , 8.04 -8.03 (m, 1H) , 7.60 -7.51 (m, 2H) , 7.49 -7.38 (m, 3H) , 7.30 -7.19 (m, 2H) , 4.92 -4.71 (m, 1H) , 4.28 -4.09 (m, 1H) , 3.15 -3.00 (m, 3H) , 2.95 -2.82 (m, 1H) , 2.77 -2.70 (m, 1H) , 2.42 -2.39 (m, 1H) , 2.26 -2.08 (m, 4H) , 1.95 -1.67 (m, 3H) , 0.96 (t, J = 7.6 Hz, 3H) .
[0877]
Example 166 (S) -1- (2- (Hydroxymethyl) phenyl) -N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) methanesulfonamide 166
[0878]
Step 1: (S) -tert-Butyl 3- ( (4- (2- ( (5- ( (2- (methoxycarbonyl) phenyl) methylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0879]
[0880]
The General Procedure A was followed, using tert-butyl (3S) -3- [ [4- [2- [ (5-amino-2-methyl-1-naphthyl) oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (400 mg, 0.76 mmol) , pyridine (10 mL) and 2, 4-difluorophenyl methanesulfonyl chloride (189 mg, 0.76 mmol) . The organic layer was concentrated and purified by column chromatography on silica (solvent gradient: methanol in dichloromethane) to yield 500 mg (89%yield) of the title compound as a yellow solid. LCMS (ESI) [M+H] + = 739.1.
[0881]
Step 2: (S) -tert-Butyl 3- ( (4- (2- ( (5- ( (2- (hydroxymethyl) phenyl) methylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0882]
[0883]
To a solution of (S) -tert-butyl 3- ( (4- (2- ( (5- ( (2- (methoxycarbonyl) phenyl) methylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (400 mg, 0.54 mmol) in tetrahydrofuran (20 mL) was added lithium aluminum hydride (21 mg, 0.54 mmol) at -40 ℃. The mixture was stirred at -40 ℃ for 5 h. The solution was added water (10 mL) and anhydrous sodium sulfate (10 g) . The solution was filtered and concentrated in vacuo to yield 300 mg (78%yield) as a yellow solid. LCMS (ESI) [M+H] + = 711.3.
[0884]
Step 3: (S) -1- (2- (Hydroxymethyl) phenyl) -N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) methanesulfonamide
[0885]
[0886]
The General Procedure B was followed, using (S) -tert-butyl 3- ( (4- (2- ( (5- ( (2- (hydroxymethyl) phenyl) methylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (50 mg, 0.07 mmol) , dichloromethane (5 mL) and hydrochloric acid (4 M in ethyl acetate, 2 mL, 8 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%NH 4OH) ; B: ACN) to yield 13 mg (28%yield) of 166 as a yellow solid. LCMS (ESI) : [M+H] + = 611.1; 1H NMR (400 MHz, DMSO-d 6) δ 9.97 (s, 1H) , 9.08 (s, 1H) , 8.49 (d, J = 5.6 Hz, 1H) , 8.13 -8.04 (m, 2H) , 7.63 (s, 1H) , 7.59 -7.50 (m, 2H) , 7.47 -7.38 (m, 3H) , 7.34 (t, J = 7.2 Hz, 1H) , 7.31 -7.21 (m, 3H) , 4.65 (s, 2H) , 4.62 (s, 2H) , 4.36 -4.30 (m, 1H) , 3.45 -3.40 (m, 1H) , 3.22 -3.18 (m, 1H) , 2.90 -2.80 (m, 2H) , 2.25 (s, 3H) , 2.09 -1.58 (m, 4H) .
[0887]
Example 167 (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) -1- (pyridin-4-yl) methanesulfonamide 167
[0888]
Step 1: tert-Butyl (S) -3- ( (4- (2- ( (2-methyl-5- ( (pyridin-4-ylmethyl) sulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0889]
[0890]
The General Procedure A was followed. To a solution of tert-butyl (3S) -3- [ [4- [2- [ (5-amino-2-methyl-1-naphthyl) oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (100 mg, 0.19 mmol) in pyridine (1.25 mL) was added (4-pyridylmethyl) sulfonyl chloride triflate (97.3 mg, 0.29 mmol) followed by stirring at room temperature for 72 h with an extra (1.45 mmol) of (4-pyridylmethyl) sulfonyl chloride triflate added in between. The mixture was diluted with 10%citric acid, extracted with iPrOAc (2 x 10 mL) , dried over MgSO 4 and concentrated. The residue was purified by silica gel chromatography (24 g column) eluting with 0-5%MeOH/DCM to give 32 mg (25%yield) of a brown solid. This product was used in the next step without further purification. LCMS (ESI) [M+H] + = 682.
[0891]
Step 2: (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) -1- (pyridin-4-yl) methanesulfonamide
[0892]
[0893]
The General Procedure B was followed, using tert-butyl (S) -3- ( (4- (2- ( (2-methyl-5- ( (pyridin-4-ylmethyl) sulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (32 mg, 0.047 mmol) . The crude product was purified via reverse-phase HPLC and lyophilized to yield 11.8 mg (43%yield) of 167 as an off-white solid. LCMS (ESI) [M+H] + = 582; 1H NMR (400 MHz, DMSO-d 6) δ 8.53 -8.50 (m, 2H) , 8.45 (d, J = 5.2 Hz, 1H) , 8.09 (d, J = 8.7 Hz, 1H) , 8.05 (dd, J = 4.8, 2.0 Hz, 1H) , 7.53 (d, J = 5.2 Hz, 1H) , 7.43 -7.39 (m, 1H) , 7.39 -7.30 (m, 5H) , 7.26 (dd, J = 7.6, 4.8 Hz, 1H) , 4.44 (s, 2H) , 4.12 (s, 1H) , 3.06 (d, J = 12.4 Hz, 1H) , 2.77 -2.65 (m, 2H) , 2.20 (s, 3H) , 2.02 -1.94 (m, 1H) , 1.86 -1.78 (m, 1H) , 1.69 -1.54 (m, 2H) .
[0894]
Example 168 (S) -3-Methyl-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) isothiazole-5-sulfonamide 168
[0895]
Step 1: tert-Butyl (S) -3- ( (4- (2- ( (2-methyl-5- ( (3-methylisothiazole) -5-sulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0896]
[0897]
The General Procedure A was followed, using tert-butyl (3S) -3- [ [4- [2- [ (5-amino-2-methyl-1-naphthyl) oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (50 mg, 0.09 mmol) and 3-methylisothiazole-5-sulfonyl chloride (28.16 mg, 0.14 mmol) in pyridine (1 mL) to afford 55 mg (65.3%yield) of the title compound as a brown solid. It was carried on as is. LCMS (ESI) [M+H] + = 688.
[0898]
Step 2: (S) -3-Methyl-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) isothiazole-5-sulfonamide
[0899]
[0900]
The General Procedure B was followed, using tert-butyl (S) -3- ( (4- (2- ( (2-methyl-5- ( (3-methylisothiazole) -5-sulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (55 mg, 0.08 mmol) . The crude product was purified via reverse-phase HPLC and lyophilized to yield 11.5 mg (24.5%yield) of 168 as an off-white solid. LCMS (ESI) [M+H] + = 588; 1H NMR (400 MHz, DMSO-d 6) δ 8.50 (s, 2H) , 8.45 (d, J = 5.2 Hz, 1H) , 8.25 (d, J = 8.6 Hz, 1H) , 8.04 (dd, J = 4.8, 2.0 Hz, 1H) , 7.55 (d, J = 5.2 Hz, 1H) , 7.43 (d, J = 7.4 Hz, 1H) , 7.25 -7.18 (m, 3H) , 7.10 (dd, J = 7.7, 1.2 Hz, 1H) , 7.04 (t, J = 7.9 Hz, 1H) , 6.83 (d, J = 8.2 Hz, 1H) , 4.21 (s, 1H) , 3.43 (d, J = 12.6 Hz, 2H) , 3.18 (d, J = 12.8 Hz, 1H) , 2.89-2.78 (m, 2H) , 2.31 (s, 3H) , 2.16 (s, 3H) , 2.04 -1.97 (m, 1H) , 1.94 -1.86 (m, 1H) , 1.74 -1.58 (m, 2H) .
[0901]
Example 169 N- (6-Methyl-5- ( (3- (2- ( (4-methylpiperidin-3-yl) amino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) propane-1-sulfonamide 169
[0902]
Step 1: tert-Butyl 4-methyl-3- ( (4- (2- ( (2-methyl-5- (propylsulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0903]
[0904]
To a 100 mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed N- [6-methyl-5- [ [3- (2-methylsulfinylpyrimidin-4-yl) -2-pyridyl] oxy] -1-naphthyl] propane-1-sulfonamide (2.0 g, 4.03 mmol) , tert-butyl 3-amino-4-methyl-piperidine-1-carboxylate (1.0 g, 4.83 mmol) , 1, 4-dioxane (20 mL) and N, N-diisopropylethylamine (2.11 mL, 12.08 mmol) . The resulting solution was stirred at 130 ℃ in an oil bath for 36 h, cooled to room temperature and concentrated in vacuo. The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%NH 4OH) ; B: ACN) to give two major products. First HPLC peak: 950 mg (16%yield) ; second HPLC peak: 170 mg (3%yield) . The second peak corresponds to the title product which was obtained as a white solid. LCMS (ESI) [M+H] + = 647.1. The trans relative stereochemistry of the title compound was based on 2D-NMR analysis.
[0905]
Step 2: tert-Butyl 4-methyl-3- ( (4- (2- ( (2-methyl-5- (propylsulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0906]
[0907]
tert-Butyl4-methyl-3- [ [4- [2- [ [2-methyl-5- (propylsulfonylamino) -1-naphthyl] oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (170 mg, 0.26 mmol) (second peak on HPLC in step 1) was purified by SFC (AS (250 mm x 30 mm, 10 μm) ; 0.1%NH 3H 2O EtOH: 40%; flow rate (80 mL /min) to give trans-tert-butyl 4-methyl-3- [ [4- [2- [ [2-methyl-5- (propylsulfonylamino) -1-naphthyl] oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (70 mg, 41%yield) (first peak on SFC, Rt = 4.49 min) and trans-tert-butyl 4- methyl-3- [ [4- [2- [ [2-methyl-5- (propylsulfonylamino) -1-naphthyl] oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (70 mg, 41%yield) (second peak on SFC, Rt = 4.82 min) as a white solid.
[0908]
Step 3: N- (6-Methyl-5- ( (3- (2- ( ( (3S, 4R) -4-methylpiperidin-3-yl) amino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) propane-1-sulfonamide
[0909]
[0910]
The General Procedure B was followed, using 4-methyl-3- [ [4- [2- [ [2-methyl-5- (propylsulfonylamino) -1-naphthyl] oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (70 mg, 0.11 mmol) (second peak on SFC in step 2) , dichloromethane (2 mL) and hydrochloric acid (4 M in dioxane, 2 mL, 8 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%ammonia hydroxide) B: ACN) to yield 45 mg (74%yield) of 169 as a white solid. LCMS (ESI) : [M+H] + = 547.1; 1H NMR (400 MHz, DMSO-d 6) δ 8.52 (s, 1H) , 8.39 (d, J = 5.2 Hz, 1H) , 8.14 (d, J = 8.8 Hz, 1H) , 8.05 -8.01 (m, 1H) , 7.49 (d, J = 8.8 Hz, 1H) , 7.43 (d, J = 5.2 Hz, 1H) , 7.42 -7.33 (m, 2H) , 7.29 -7.22 (m, 1H) , 7.17 (d, J = 8.8 Hz, 1H) , 3.68 (s, 1H) , 3.16 (s, 1H) , 3.10 -3.04 (m, 2H) , 2.93 -2.90 (m, 1H) , 2.52 -2.52 (m, 1H) , 2.31 (d, J = 10.4 Hz, 1H) , 2.20 (s, 3H) , 1.80 -1.66 (m, 3H) , 1.65 -1.54 (m, 1H) , 1.27 -1.12 (m, 1H) , 0.99 -0.91 (m, 1H) , 0.99 -0.91 (m, 5H) . The absolute stereochemistry was tentatively assigned based on the XBP1 reporter potency.
[0911]
Example 170 (S) -1- (2- (Fluoromethyl) phenyl) -N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) methanesulfonamide 170
[0912]
Step 1: (S) -tert-Butyl 3- ( (4- (2- ( (5- ( (2- (fluoromethyl) phenyl) methylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0913]
[0914]
To a solution of tert-butyl (3S) -3- [ [4- [2- [ [5- [ [2- (hydroxymethyl) phenyl] methylsulfonylamino] -2-methyl-1-naphthyl] oxy] -3-pyridyl] pyrimidin- 2-yl] amino] piperidine-1-carboxylate (200 mg, 0.28 mmol) in dichloromethane (2 mL) was added diethylaminosulfur trifluoride (59 mg, 0.37 mmol) in dichloromethane (2 mL) dropwised at -78 ℃. The mixture was stirred at -78 ℃ for 0.5 h. The solution was washed with water (10 mL) and extracted with dichloromethane (20 mL x 3) . The organic layer was concentrated to yield 200 mg (99%yield) of the title compound as a yellow solid. LCMS (ESI) : [M+H] + = 713.0.
[0915]
Step 2: (S) -1- (2- (Fluoromethyl) phenyl) -N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) methanesulfonamide
[0916]
[0917]
The General Procedure B was followed, using (S) -tert-butyl 3- ( (4- (2- ( (5- ( (2- (fluoromethyl) phenyl) methylsulfonamido) -2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (200 mg, 0.28 mmol) , dichloromethane (5 mL) and hydrochloric acid (4 M in ethyl acetate, 2 mL, 8 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%HCl) B: ACN) to yield 13 mg (7 %) yield of 170 as a yellow solid. LCMS (ESI) : [M+H] + = 613.1; 1H NMR (400 MHz, DMSO-d 6) δ 10.08 -10.01 (m, 1H) , 9.11 (s, 1H) , 8.50 (d, J = 5.6 Hz, 1H) , 8.08 (d, J = 7.2 Hz, 2H) , 7.70 -7.51 (m, 3H) , 7.51 -7.36 (m, 6H) , 7.29 (d, J = 7.2 Hz, 1H) , 5.67 -5.48 (m, 2H) , 4.73 -4.62 (m, 2H) , 4.41 -4.34 (m, 1H) , 3.49 -3.13 (m, 2H) , 2.93 -2.76 (m, 2H) , 2.22 (s, 3H) , 2.09 -1.58 (m, 4H) .
[0918]
Example 171 (S) -6-Methyl-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) pyridine-2-sulfonamide 171
[0919]
Step 1: (S) -tert-Butyl 3- ( (4- (2- ( (2-methyl-5- (6-methylpyridine-2-sulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0920]
[0921]
The General Procedure A was followed, using tert-butyl (3S) -3- [ [4- [2- [ (5-amino-2-methyl-1-naphthyl) oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (100 mg, 0.19 mmol) , pyridine (2 mL) and 6-methylpyridine-2-sulfonyl chloride (44 mg, 0.23 mmol) . The reaction mixture was concentrated in vacuo and the residue was taken up in ethyl acetate (20 mL) , and washed with water (10 mL) . The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to yield (130 mg crude) of the title compound as a pale brown oil. LCMS (ESI) [M+H] + = 682.1.
[0922]
Step 2: (S) -6-Methyl-N- (6-methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) pyridine-2-sulfonamide
[0923]
[0924]
The General Procedure B was followed, using (S) -tert-butyl 3- ( (4- (2- ( (2-methyl-5- (6-methylpyridine-2-sulfonamido) naphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (130 mg, 0.19 mmol) , ethyl acetate (2 mL) and hydrochloric acid (4 M in ethyl acetate, 2 mL, 8 mmol) . The residue was purified by Prep-HPLC (mobile phase: A: water (0.05%HCl) B: ACN) to yield 73 mg (62%yield) of 171 as a white solid. LCMS (ESI) : [M+H] + = 582.1; 1H NMR (400 MHz, DMSO-d 6) δ 10.58 (s, 1H) , 9.37 (s, 1H) , 8.51 (d, J = 4.8 Hz, 1H) , 8.12 -7.99 (m, 2H) , 7.91 -7.81 (m, 1H) , 7.61 (d, J = 8.0 Hz, 1H) , 7.55 -7.39 (m, 3H) , 7.36 -7.24 (m, 2H) , 7.21 (d, J = 7.6 Hz, 1H) , 4.40 -4.35 (m, 1H) , 3.45 -3.40 (m, 1H) , 3.20 -3.15 (m, 1H) , 2.90 -2.80 (m, 2H) , 2.57 (s, 3H) , 2.17 (s, 3H) , 2.04 -1.99 (m, 1H) , 1.97 -1.58 (m, 3H) .
[0925]
Example 172 (S) -1-Bromo-N- (6-methyl-5- (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yloxy) naphthalen-1-yl) methanesulfonamide 172
[0926]
Step 1: (S) -tert-Butyl 3- (4- (2- (5- (bromomethylsulfonamido) -2-methylnaphthalen-1-yloxy) pyridin-3-yl) pyrimidin-2-ylamino) piperidine-1-carboxylate
[0927]
[0928]
The General Procedure A was followed, using tert-butyl (3S) -3- [ [4- [2- [ (5-amino-2-methyl-1-naphthyl) oxy] -3-pyridyl] pyrimidin-2-yl] amino] piperidine-1-carboxylate (50 mg, 0.095 mmol) , pyridine (1 mL) and bromomethanesulfonyl chloride (250 mg, 1.3 mmol) . The mixture was concentrated and the crude product was directly used in step 2. LCMS (ESI) [M+H] + = 683.2.
[0929]
Step 2: (S) -1-Bromo-N- (6-methyl-5- (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yloxy) naphthalen-1-yl) methanesulfonamide
[0930]
[0931]
To the crude (S) -tert-butyl 3- (4- (2- (5- (bromomethylsulfonamido) -2-methylnaphthalen-1-yloxy) pyridin-3-yl) pyrimidin-2-ylamino) piperidine-1-carboxylate from step 1 in DCM (6 mL) was added trifluoroacetic acid (1 mL) . The mixture was concentrated and the residue purified by Prep-HPLC to yield 4.7 mg (9%yield) of 172 as a white solid. LCMS (ESI) : [M+H] + = 583.1; 1H NMR (400 MHz, DMSO-d 6) δ 8.55 (s, 1H) , 8.47 (dd, J = 5.2, 3.4 Hz, 1H) , 8.21-8.10 (m, 1H) , 8.07-8.00 (m, 1H) , 7.63 -7.27 (m, 6H) , 7.11-6.97 (m, 1H) , 4.87 (d, J = 27.4 Hz, 2H) , 4.23 (s, 1H) , 3.21 (d, J = 12.8 Hz, 1H) , 2.85 (q, J = 11.7 Hz, 2H) , 2.21 (s, 3H) , 2.01 (s, 1H) , 1.90 (s, 1H) , 1.75-1.62 (m, 2H) .
[0932]
Example 173 (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) propionamide 173
[0933]
Step 1: tert-Butyl (S) -3- ( (4- (2- ( (2-methyl-5-propionamidonaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate
[0934]
[0935]
The General Procedure C was followed, using tert-butyl (S) -3- ( (4- (2- ( (5-amino-2-methylnaphthalen-1-yl) oxy) pyridin-3-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate from Example 101 (90 mg, 0.17 mmol) , propionic acid (19 mg, 0.26 mmol) , DIPEA (0.089 mL, 0.51 mmol) , HATU (97 mg, 0.26 mmol) and DCM (1.7 mL) . The crude was directly used in the next step.
[0936]
Step 2: (S) -N- (6-Methyl-5- ( (3- (2- (piperidin-3-ylamino) pyrimidin-4-yl) pyridin-2-yl) oxy) naphthalen-1-yl) propionamide