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1. (WO2009106980) INDAZOLE DERIVATIVES
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INDAZOLE DERIVATIVES

Field of the Invention
The present invention provides pharmaceutically active indazole compounds and analogues. Such compounds have cannabinoid (CB)1 receptor binding activity. The present invention also relates to pharmaceutical compositions, methods of treatment and use, comprising the above derivatives for the treatment of disease conditions mediated by CB1 receptor binding activity.
Background of the Invention
Cannabinoid receptors, endogenous cannabinoids and the enzymes that synthesize and degrade endocannabinoids make up the endocannabinoid system. CB1 and CB2 are two subtypes of cannabinoid receptors. CB1 and CB2 are both G protein coupled receptors. CB1 receptors primarily exist in the central nervous system, but are also found in some peripheral tissues including pituitary gland, immune cells, reproductive tissues, gastrointestinal tissues, sympathetic ganglia, heart, lung, urinary bladder and adrenal gland. CB2 receptors primarily exist in immune cells.
Cannabinoid agonists are believed to be useful in the treatment of pain and several other indications.
There is a need to provide new CB1 ligands that are good drug candidates. They should be well absorbed from the gastrointestinal tract, be metabolically stable and possess favorable pharmacokinetic properties. Furthermore, the ideal drug candidate will exist in a physical form that is stable, non-hygroscopic and easily formulated.

Summary of the Invention
The present invention is directed to pharmaceutically active indazole
compounds.
Such compounds are useful for as CB1 agonists.
This invention is directed, in part, to compounds that generally fall within the structure of Formula I:

or a pharmaceutically acceptable salt thereof, wherein
X is CH or N;
R1 is H, CrC6 alkyl-, CrC6 cyanoalkyl, C1-C6 alkyl-C(O)-(CH2)n-, CrC6 alkoxy-C(O)-(CH2)n-, CrC6 haloalkyl, d-C6 haloalkoxy-(CH2)n-, R6i-5-heterocyclyl-(CH2)n-, R6t 5-heterocyclyl-C(O)-(CH2)n-, R7I-5-C3-C7 cycloalkyl-(CH2)n-, R^-5-C3-C7 cycloalkyl-NR8-C(O)-, R7L5-C3-C7 cycloalkyl-NR8-C(O)-(CH2)n-, R7I-5-C3-C7 cycloalkyl-C(O)-(CH2)n-, R81-5-aryl-C(O)-(CH2)n-, NR9R10-C(O)-(CH2)n-, or R41i-5-aryl-(CH2)n-; wherein
each R6 is independently H or oxo;
each R7 is independently H, halo or CrC6 alkyl;
each R8 is independently H, CrCβ alkyl, cyano, halo, CrCβ haloalkyl or CrC6 haloalkoxy;
R9 and R10 are independently H or CrC6 alkyl;
R2 is
NR11R12-C(O)-R13CH-,
R14-C(O)-NR15-(CH2)n-R13CH-,
R16-C(O)-R13CH-,
Ci-C6 alkoxy-C(O)-(CH2)n-NR15-C(O)-R13CH-,
NR17R18-C(O)-(CH2)n-NR19-C(O)-R13CH-,
R20-SO2-NR21-(CH2)n-R13CH-,
R22R23CH-,
R24i-5-heteroaryl,
R24i-5-heteroaryl-R13CH-,
R241-5-heteroaryl-NR15-C(O)-R13CH-,
R25i-5-heterocyclyl,
R251.5-heterocyclyl-(CH2)n-,
R26I 5-C3-C7 cycloalkyl,
NR27R28-(CH2)n-NR29-C(O)-R13CH-, R30-Sθ2-NR31-(CH2)n-NR15-C(O)-R13CH-,
R30-SO2-(CH2)n-NR31-C(O)-R13CH-,
R32-C(O)-R33CH-NR34-C(O)-R13CH-1
R32-C(O)-(CH2)n-NR34-C(O)-R13CH-,
R35i.5-heteroaryl-(CH2)n-NR36-C(O)-R13CH-,
R37i.5-heterocyclyl-(CH2)n-NR36-C(O)-R13CH-,
R37i-5-heterocyclyl-C(O)-R13CH-,
R38i-5-aryl-R39C-NR40-C(O)-R13CH-,
R381-5-aryl-(CH2)n-NR40-C(O)-R13CH-,
R411-5-aryl-(CH2)n-,
NR17R18-C(O)-CH(R42)-NR19-C(O)-R13CH-, or
R43-CH(OH)-CH2-NR19-C(O)-R13CH-;
wherein
R11 and R12 are independently H, OH, C1-C6 alkyl, d-C6 haloalkyl, OH-CrC6 alkyl, (OH)2-Ci-C6 alkyl, (OH)3-C4-C6 alkyl, C1-C6 alkoxy-(CH2)n-, C3-C7 cycloalkyl, benzo-fused C3-C7
cycloalkyl, cyano-CrC6 alkyl, NH2-C(NH)-CrC6 alkyl,
(OH-CrC6 alkyl)2-CrC6 alkylene, OH-C3-C7
cycloalkyl-(CH2)n-, OH-(CH2)n-C3-C7 cycloalkyl-, OH-C3-C7 cycloalkyl-, CrC6 alkoxy-C(O)-C3-C7 cycloalkyl-, (CrC6
alkoxy-aryl)-C3-C7 cycloalkyl-, NH2-C(O)-C3-C7 cycloalkyl-, OH-aryl, or R24i-5-heteroaryl-O-(CH2)n-;
R13 is H, CrC6 alkyl, OH-CrC6 alkyl, aryl, aryl-(CH2)n-, or C3-C7
cycloalkyl;
R14 is (CrC6 alkyl)2N-, aryl, CrC6 alkyl, or C3-C7 cycoalkyl;
R15, R21, R29, R31, R34, and R40 are independently H or C1-C6 alkyl; R16 is OH or C1-C6 alkoxy;
R17 and R18 are independently H, C1-C6 alkyl, C3-C7 cycoalkyl,
OH-C1-C6 alkyl, (OH)2-C1-C6 alkyl, or R241-5-heteroaryl-;
each R19 is independently H or C1-C6 alkyl;
R20 is C1-C6 alkyl, C1-C6 haloalkyl, or (C1-C6 alkyl)2N-;

-A- R22 and R23 are independently Ci-C6 alkyl, C3-C7
cycloalkyl-(CH2)n-, OH-CrC6 alkyl, aryl, or aryl-OH-CrC6 alkylene;
each R24 is independently H, CrC6 alkyl, C3-C7 cycloalkyl, CrC6 haloalkyl, oxo, OH1 NH2, C1-C6 alkoxy-C(O)-,
NH2-C(O)-(CH2)O-, NH2-C(O)-, NH2-C(O)-NH-, OH-C(O)-,
NH2-C(O)-(CH2)n-NH-C(O)-, (OH)2-CrC6 alkyl-NH-C(O)-,
OH-CrC6 alkyl-NH-C(O)-, or C3-C7 cycloalkyl-C(O)-NH-; each R25 is independently H or oxo;
each R26 is independently H, OH, OH-CrC6 alkyl, aryl-(CH2)n-O-, NH2-C(O)- or CrC6 alkoxy-C(O)-;
R27 and R28 independently are H, NH2-C(O)-, C3-C7
cycloalkyl-C(O)-, or R24i-5-heteroaryl-;
R30 is C1-C6 alkyl, C3-C7 cycloalkyl, NH2, C1-C6 alkyl-NH-, C3-C7 cycloalkyl-(CH2)n-NH-, morpholin-4-yl, or R38i.5-phenyl;

R32 is OH or C1-C6 alkoxy-;
each R33 is independently H, C1-C6 alkyl, or OH-C1-C6 alkyl;
each R35 is independently H, C1-C6 alkyl, NH2-C(O)-, C1-C6
alkoxy-C(O)-, C3-C7 cycloalkyl, OH, phenyl, or heteroaryl, or two adjacent R35 groups may together form -(CH2)3-6-;
each R36 is independently H, Ci-C6 alkyl, C1-C6 alkoxy-, or
NH2-C(O)-;
each R37 is independently H, NH2C(O)-, OH, halo, cyano, oxo,
OH-C1-C6 alkyl, (OH)2-CrC6 alkyl, NH2C(O)-(CH2)n-,
NH2C(O)-(CH2)π-C(O)-, NH2C(O)-NH-(CH2)H-, C1-C6
alkyl-NH-C(O)-O-, (OH)-C1-C6 alkyl-NH-C(O)-, (OH)2-C1-C6 alkyl-NH-C(O)-, C1-C6 alkyl-C(O)-, d-C6 alkoxy-C(O)-,
C3-C7 cycloalkyl-C(O)-NH-(CH2)n-, C1-C6 alkyl-SO2-, C3-C7 cycloalkyl-SO2-, or C3-C7 cycloalkyl-SO2-NH-(CH2)n-;
each R38 is independently H, NH2SO2-, cyano, heteroaryl, OH, halo, C1-C6 alkoxy, OH-C(O)-, or C1-C6 alkoxy-C(O)-;
each R39 is independently H, C1-C6 alkyl, or OH-C1-C6 alkyl;
each R41 is independently H, C1-C6 alkoxy or halo;

R42 is H1 CrC6 alkyl, OH-C1-C6 alkyl, aryl, aryl-(CH2)n- or
NH2-C(O)-CH2;
R43 is OH-C(O)-, CrC6 alkoxy-C(O)-, NH2-C(O)- or R44R45NCH2-;
and
R44 and R45 are independently CrC6 alkyl or OH-CrC6 alkyl, or
R44 and R45 together with the nitrogen atom to which they are
attached form a pyrrolidine, piperidine or morpholine ring;
n is an integer from 1 to 6; and
each R3 is independently H, halo, CrC6 alkyl, aryl, NH2-C(O)-, d-C6 alkoxy or heteroaryl.
This invention also includes pharmaceutically acceptable salts, solvates and hydrates. This invention also includes all tautomers and stereochemical isomers of these compounds.
This invention also is directed, in part, to a method for treating a CB1 mediated disorder in a mammal. Such CB1 mediated disorders include pain, rheumatoid arthritis and osteoarthritis. The method comprises administering an above-described compound or pharmaceutically acceptable salt thereof, to the mammal in an amount that is therapeutically-effective to treat the condition.
Further benefits of Applicants' invention will be apparent to one skilled in the art from reading this specification.

Detailed Description of the Invention
The invention will be more carefully understood from the following description given by way of example only. The present invention is directed to a class of indazole compounds. In particular, the present invention is directed to indazole compounds useful as CB1 agonists. While the present invention is not so limited, an appreciation of various aspects of the invention will be gained through the following discussion and the examples provided below.

Definitions
The following is a list of definitions of various terms used herein:
The symbol ^ΛΛ^ represents the point of attachment.

The term "alkane" refers to a saturated acyclic hydrocarbon which can be either a straight chain or branched chain.
The term "alkyl" refers to a straight or branched chain univalent radical derived from an alkane by removal of one hydrogen. Examples of such alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, hexyl, isohexyl, and the like.
The term "alkylene" refers to a straight chain or branched bivalent radical derived from alkane by the removal of H from each of the two terminal carbons.
|_ _ | I H2_H2 S
Examples include methylene: * CH2 t , ethylene: 1 c c I 1 propylene:

1 and the |jke


The term "alkoxy" means alkyl-O-, wherein alkyl is as defined above. Examples of such a substituent include methoxy (CH3-O-), ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.
The term "cycloalkyl" means a saturated carbocyclyl substituent containing from 3 to about 20 carbon atoms. A cycloalkyl may be a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
The term "aryl" means an aromatic carbocyclyl containing from 6 to 14 carbon ring atoms. The term aryl embraces both single and multiple rings. Examples of aryls include phenyl, naphthalenyl, and indenyl.
The term "arylalkyl" means alkyl substituted with aryl, wherein alkyl and aryl are as defined above.
The term "carboxy" or "carboxyl" means OH-C(O)-, which also may be depicted as:



The term "formyl" means HC(O)-, which may also be depicted as:

The symbol "C(O)" means C=O which also may be depicted as:



The term "oxo" means a keto radical, and may be depicted as =0.
The term "hydroxy" or "hydroxyl" means OH-.
The term "hydroxyalkyl" means alkyl substituted with one more hydroxyl, wherein hydroxyl and alkyl are as defined above.
The term "halo" or "halogen" refers to bromo, chloro, fluoro or iodo.
The term "oxy" means an ether substituent, and may be depicted as -O-.
The term "sulfonyl" means SO2-.
The term "thio" means SH-.
The term "alkylthio" is an alkyl substituted thio, which is also depicted as:

* , wherein thio and alkyl are as defined above.
The term "heterocyclyl" means a saturated or partially saturated ring structure containing a total of 3 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.
A heterocyclyl may be a single ring, which typically contains from 3 to 7 ring atoms, more typically from 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms. Examples of heterocyclyls include piperidinyl, morpholinyl, thiomorpholinyl,
tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperazinyl and diazepanyl.
The term "heteroaryl" means an aromatic heterocyclyl containing from 5 to 14 ring atoms. A heteroaryl may be a single ring or 2 or 3 fused rings. Examples of heteroaryl substituents include isoxazolyl, pyridinyl, furyl, oxadiazolyl, tetrazolyl, dihydroimidazolyl, thiadiazolyl, oxazolyl, triazolyl and dihydroisoxazolyl.
The terms "substituent" and "radical" are interchangeable.

If substituents are described as being "independently selected" from a group, each substituent is selected independent of the other. Each substituent therefore may be identical to or different from the other substituent(s).
The term "pharmaceutically-acceptable" is used adjectivally in this specification to mean that the modified noun is appropriate for use as a pharmaceutical product or as a part of a pharmaceutical product.

Compounds of the Invention
In a first embodiment, this invention is directed to compounds of Formula I:



or a pharmaceutically acceptable salt thereof, wherein
X is CH or N;
R1 is H, CrC6 alkyl-, CrC6 cyanoalkyl, CrC6 alkyl-C(O)-(CH2)n-, CrC6 alkoxy-C(O)-(CH2)n-, CrC6 haloalkyl, CrC6 haloalkoxy-(CH2)n-, R6i.5-heterocyclyl-(CH2)n-, R61-5-heterocyclyl-C(O)-(CH2)n-, R7I-5-C3-C7 cycloalkyl-(CH2)n-, R7I-5-C3-C7 cycloalkyl-NR8-C(O)-, R71-5-C3-C7 cycloalkyl-NR8-C(O)-(CH2)π-, R7I-5-C3-C7 cycloalkyl-C(O)-(CH2)n-, R81.5-aryl-C(OHCH2)n-, NR9R10-C(O)-(CH2)n-, or R41i.5-aryl-(CH2)n-; wherein
each R6 is independently H or oxo;
each R7 is independently H, halo or CrC6 alkyl;
each R8 is independently H, CrC6 alkyl, cyano, halo, CrC6 haloalkyl or
CrC6 haloalkoxy;
R9 and R10 are independently H or CrC6 alkyl;
R2 is
NR11R12-C(O)-R13CH-,
R14-C(O)-NR15-(CH2)n-R13CH-,
R16-C(O)-R13CH-,
Ci-C6 alkoxy-C(OHCH2)n-NR15-C(O)-R13CH-,
NR17R18-C(O)-(CH2)n-NR19-C(O)-R13CH-, R20-Sθ2-NR21-(CH2)n-R13CH-,
R22R23CH-,
R241-5-heteroaryl,
R24i-5-heteroaryl-R13CH-,
R241-5-heteroaryl-NR15-C(O)-R13CH-,
R25i-5-heterocyclyl,
R25i.5-heterocyclyl-(CH2)n-,
R26I S-C3-C7 cycloalkyl,
NR27R28-(CH2)π-NR29-C(O)-R13CH-,
R30-SO2-NR31-(CH2)n-NR15-C(O)-R13CH-,
R30-SO2-(CH2)n-NR31-C(O)-R13CH-,
R^-CCOJ-R^CH-NR^-CCOJ-R^CH-,
R32-C(OHCH2)n-NR34-C(O)-R13CH-l
R351.5-heteroaryl-(CH2)n-NR36-C(O)-R13CH-,
R37i.5-heterocyclyl-(CH2)n-NR36-C(O)-R13CH-,
R371.5-heterocyclyl-C(O)-R13CH-,
R^.s-aryl-R^C-NR^-CfOJ-R^CH-,
R38i.5-aryl-(CH2)n-NR40-C(O)-R13CH-,
R411-5-aryl-(CH2)n-,
NR17R18-C(O)-CH(R42)-NR19-C(O)-R13CH-, or
R43-CH(OH)-CH2-NR19-C(O)-R13CH-;
wherein
R11 and R12 are independently H, OH, C1-C6 alkyl, Ci-C6 haloalkyl, OH-CrC6 alkyl, (OH)2-CrC6 alkyl, (OH)3-C4-C6 alkyl, CrC6 alkoxy-(CH2)n-, C3-C7 cycloalkyl, benzo-fused C3-C7
cycloalkyl, cyano-CrC6 alkyl, NH2-C(NH)-CrC6 alkyl,
(OH-CrC6 alkyl)2-CrC6 alkylene, OH-C3-C7
cycloalkyl-(CH2)n-, OH-(CH2)n-C3-C7 cycloalkyl-, OH-C3-C7 cycloalkyl-, CrC6 alkoxy-C(O)-C3-C7 cycloalkyl-, (CrC6
alkoxy-aryl)-C3-C7 cycloalkyl-, NH2-C(O)-C3-C7 cycloalkyl-, OH-aryl, or R241.5-heteroaryl-O-(CH2)n-;
R13 is H, C1-C6 alkyl, OH-CrC6 alkyl, aryl, aryl-(CH2)n-, or C3-C7
cycloalkyl;

R14 is (CrC6 alkyl)2N-, aryl, CrC6 alkyl, or C3-C7 cycoalkyl;
R15 R21 R29 R31 R34 and R4o gre jndependently H or d-C6 alkyl;

R16 is OH or CrC6 alkoxy;
R17 and R18 are independently H, CrC6 alkyl, C3-C7 cycoalkyl,
OH-CrC6 alkyl, (OH)2-CrC6 alkyl, or R2V5-heteroaryl-; each R19 is independently H or CrC6 alkyl;
R20 is CrC6 alkyl, CrC6 haloalkyl, or (CrC6 alkyl)2N-;
R22 and R23 are independently C1-C6 alkyl, C3-C7
cycloalkyl-(CH2)n-, OH-CrC6 alkyl, aryl, or aryl-OH-CrC6 alkylene;
each R24 is independently H, CrC6 alkyl, C3-C7 cycloalkyl, CrC6 haloalkyl, oxo, OH, NH2, C1-C6 alkoxy-C(O)-,
NH2-C(O)-(CH2)n-, NH2-C(O)-, NH2-C(O)-NH-, OH-C(O)-,
NH2-C(O)-(CH2)n-NH-C(O)-, (OH)2-C1-C6 alkyl-NH-C(O)-,
OH-C1-C6 alkyl-N H-C(O)-, or C3-C7 cycloalkyl-C(O)-NH-; each R25 is independently H or oxo;
each R26 is independently H, OH, OH-C1-C6 alkyl, aryl-(CH2)n-O-, NH2-C(O)- or C1-C6 alkoxy-C(O)-;
R27 and R28 independently are H, NH2-C(O)-, C3-C7
cycloalkyl-C(O)-, or R241.5-heteroaryl-;
R30 is C1-C6 alkyl, C3-C7 cycloalkyl, NH2, C1-C6 alkyl-NH-, C3-C7 cycloalkyl-(CH2)n-NH-, morpholin-4-yl, or R381-5-phenyl;

R32 is OH or CrC6 alkoxy-;
each R33 is independently H, C1-C6 alkyl, or OH-C1-C6 alkyl;
each R35 is independently H, C1-C6 alkyl, NH2-C(O)-, C1-C6
alkoxy-C(O)-, C3-C7 cycloalkyl, OH, phenyl, or heteroaryl, or two adjacent R35 groups may together form -(CH2)3-6-;
each R36 is independently H, C1-C6 alkyl, C1-C6 alkoxy-, or
NH2-C(O)-;
each R37 is independently H, NH2C(O)-, OH, halo, cyano, oxo,
OH-C1-C6 alkyl, (OH)2-C1-C6 alkyl, NH2C(O)-(CH2)n-,
NH2C(O)-(CH2)n-C(O)-, NH2C(O)-NH-(CH2)n-, C1-C6
alkyl-NH-C(O)-O-, (OH)-C1-C6 alkyl-NH-C(O)-, (OH)2-CrC6 alkyl-NH-C(O)-, C1-C6 alkyl-C(O)-, Ci-C6 alkoxy-C(O)-,
C3-C7 cycloalkyl-C(O)-NH-(CH2)n-, CrC6 alkyl-SO2-, C3-C7
cycloalkyl-SO2-, or C3-C7 cycloalkyl-SO2-NH-(CH2)n-;
each R38 is independently H, NH2SO2-, cyano, heteroaryl, OH,
halo, CrC6 alkoxy, OH-C(O)-, or Ci-C6 alkoxy-C(O)-;
each R39 is independently H, d-C6 alkyl, or OH-CrC6 alkyl;
each R41 is independently H, CrC6 alkoxy or halo;
R42 is H, CrC6 alkyl, OH-C1-C6 alkyl, aryl, aryl-(CH2)n- or
NH2-C(O)-CH2;
R43 is OH-C(O)-, CrC6 alkoxy-C(O)-, NH2-C(O)- or R44R45NCH2-;
and
R44 and R45 are independently CrC6 alkyl or OH-C1-C6 alkyl, or
R44 and R45 together with the nitrogen atom to which they are
attached form a pyrrolidine, piperidine or morpholine ring;
n is an integer from 1 to 6; and
each R3 is independently H, halo, C1-C6 alkyl, aryl, NH2-C(O)-, C1-C6 alkoxy or heteroaryl.

Among its many further embodiments, the present invention includes compounds or pharmaceutically acceptable salts thereof, having a structure according to Formula I:



wherein
X is CH or N;
R1 is H, C1-C6 cyanoalkyl, C1-C6 alkyl-C(O)-(CH2)n-, C1-C6 alkoxy-C(O)-(CH2)n-, C1-C6 haloalkyl, R61.5-heterocyclyl-(CH2)n-, R61.5-heterocyclyl-C(O)-(CH2)n-, RV5-C3-C7 cycloalkyl-(CH2)n-, RV5-C3-C7 cycloalkyl-NR8-C(O)-, RV5-C3-C7 cycloalkyl-NR8-C(O)-(CH2)n-, RV5-C3-C7 cycloalkyl-C(O)-(CH2)n-, R81.5-aryl-C(O)-(CH2)n-, NR9R10-C(O)-(CH2)n-, or R411.5-aryl-(CH2)n-; wherein each R6 is independently H or oxo;
each R7 is independently H, halo or CrC6 alkyl;
each R8 is independently H, C1-C6 alkyl, cyano, halo, CrC6 haloalkyl or CrC6 haloalkoxy;
R9 and R10 are independently H or d-C6 alkyl;
R2 is NR11R12-C(O)-R13CH-, R14-C(O)-NR15-(CH2)n-R13CH-, R16-C(O)-R13CH-, Ci-C6 alkoxy-C(O)-(CH2)n-NR15-C(O)-R13CH-, NR17R18-C(O)-(CH2)n-NR19-C(O)-R13CH-, R20-SO2-NR21-(CH2)n-R13CH-, R22R23CH-, R2V5-heteroaryl,
R24i-5-heteroaryl-R13CH-, R24i-5-heteroaryl-NR15-C(O)-R13CH-, R251-5-heterocyclyl, R2V 5-heterocyclyl-(CH2)n-, R26I-5-C3-C7 cycloalkyl, NR27R28-(CH2)n-NR29-C(O)-R13CH-, R30-SO2-NR31-(CH2)n-NR15-C(O)-R13CH-, R30-SO2-(CH2)n-NR31-C(O)-R13CH-, R32-C(O)-R33CH-NR34-C(O)-R13CH-, R^-CCOHCHzVNR^-CCOJ-R^CH-, R35i.5-heteroaryl-(CH2)n-NR36-C(O)-R13CH-, R371-5-heterocyclyl-(CH2)n-NR36-C(O)-R13CH-, R37I-5-heterocyclyl-C(O)-R13CH-, R38i-5-aryl-R39C-NR40-C(O)-R13CH-, R38i.5-aryl-(CH2)n-NR40-C(O)-R13CH- or R41i-5-aryl-(CH2)n-; wherein
R11 and R12 are independently H, CrC6 alkyl, OH-CrC6 alkyl, (OH)2-C1- C6 alkyl, CrC6 alkoxy-(CH2)n-, C3-C7 cycloalkyl, cyano-d-C6 alkyl, (OH-CrC6 alkyl)2-Ci-C6 alkylene, OH-C3-C7 cycloalkyl-(CH2)n-, OH-(CH2)n-C3-C7 cycloalkyl- , or OH-aryl;
R13 is H, CrC6 alkyl, OH-CrC6 alkyl, aryl, aryl-(CH2)n-, or C3-C7
cycloalkyl;
R14 is (CrC6 alkyl)2N-, aryl, CrC6 alkyl, or C3-C7 cycoalkyl;
R15, R21, R29, R31, R33, R34, R36, R39 and R40 are independently H or C1-C6 alkyl;
R16 is OH or C1-C6 alkoxy;
R17, R18 and R19 are independently H or C1-C6 alkyl;
R20 is C1-C6 alkyl, C1-C6 haloalkyl, or (C1-C6 alkyl)2N-;
R22 and R23 are independently C1-C6 alkyl, C3-C7 cycloalkyl-(CH2)n-, OH- C1-C6 alkyl, aryl, or aryl-OH-CrC6 alkylene;
each R24 is independently H, CrC6 alkyl, C3-C7 cycloalkyl, C1-C6
haloalkyl, oxo, NH2, C1-C6 alkoxy-C(O)-, NH2-C(O)-(CH2)n-, NH2-C(O)-, NH2- C(O)-NH-, OH-C(O)-, NH2-C(O)-(CH2)n-NH-C(O)-, (OH)2-C1-C6 alkyl-NH-C(O)-, or OH-C1-C6 alkyl-NH-C(O)-;

each R25 is independently H or oxo;
each R26 is independently H, OH, OH-C1-C6 alkyl, aryl-(CH2)n-O-, NH2- C(O)- or CrC6 alkoxy-C(O)-;
R27 and R28 independently are H, NH2-C(O)-, or C3-C7 cycloalkyl-C(O)-;
R30 is CrC6 alkyl, C3-C7 cycloalkyl or NH2;
R32 is OH;
R35 is independently H, d-C6 alkyl, NH2-C(O)-, CrC6 alkoxy-C(O)- or C3- C7 cycloalkyl;
each R37 is independently H, NH2C(O)- or OH;
each R38 is independently H, NH2SO2-, cyano, heteroaryl, OH, halo, d- C6 alkoxy, OH-C(O)-, or CrC6 alkoxy-C(O)-;
each R41 independently from H, CrC6 alkoxy or halo;
n is an integer from 1 to 6; and
each R3 is independently H, halo, CrC6 alkyl, aryl, NH2-C(O)-, CrC6 alkoxy or heteroaryl.

In another embodiment X is CH or N;
R1 is H1 cyano-(CH2)3-, cyano-(CH2)2-, (CHs)3C-C(O)- CH2-, (CH3J3C-O-C(O)-CH2-, CF3(CH2)4-, R6i-5-tetrehydropyranyl-CH2-, R6i.5-tetrahydrofuranyl-CH2-, RV5-tetrahydrothiopyranyl-CH2-, R6i-5-piperidinyl-C(O)- CH2-, R6i-5-thiomorpholinyl-C(O)-CH2-,
R7i-5-cyclohexyl-CH2-, R7i-5-cycloheptly-CH2-, R7i-5-cyclobutyl-CH2-, R7i-5-cyclopentyl-NR8-C(O)-,
R7I-5-C3-C7 cyclohexyl-NR8-C(O)-CH2-, R7I-5-C3-C7 cyclohexyl-C(O)-CH2-, R81-5-phenyl-C(O)-CH2-, NR9R10-C(O)-CH2-, or NR9R10-C(O)-(CH2)4-; wherein
each R6 is independently H or oxo;
each R7 is independently H, F or CH3;
each R8 is independently H, CH3, cyano, F, CF3 or CF3-O-;
R9 and R10 are independently H or (CH3)3C-;
R2 is NR11R12-C(O)-R13CH-, R14-C(O)-NR15- CH2-R13CH-, R16-C(O)-R13CH-, (CH3)3C-O-C(O)-CH2-NR15-C(O)-R13CH-, NR17R18-C(O)-CH2-NR19-C(O)-R13CH-, NR17R18-C(O)- (CH2)2-NR19-C(O)-R13CH-, R20-SO2-NR21-CH2-R13CH-, R22R23CH-, R241-5-dihydroimidazolyl, R24i-5-isoxazolyl, R24i.5-thiadiazolyl, R2V5-isoxazolyl-R13CH-, R24i-5-oxazolyl-R13CH-, R24i-5-furyl-R13CH-, R2V5-oxadiaxolyl-R13CH-, R24i-5-triazolyl-R13CH-, R241-5-dihydroisoxazolyl-R13CH-, R2V5-tetrazolyl-R13CH-, R241.5-isoxazolyl-NR15-C(O)-R13CH-, R241.5-thiadiazolyl-NR15-C(O)-R13CH-, R251-5-tetrahydrofuranyl, R25i-5-tetrahydrofuranyl-CH2-, R26i.5-cyclohexyl, R2V5-tetrahydronapthyl, R26i-5-dihydroindenyl, NR27R28-(CH2)2-NR29-C(O)-R13CH-, R30-SO2-NR31-(CH2)2-NR15-C(O)-R13CH-, R30-SO2-(CH2)2-NR31-C(O)-R13CH-, R32-C(O)-R33CH-NR^-C(O)-R13CH-, R32-C(O)-(CH2)2-NR34-C(O)-R13CH-, R35i-5-oxadiazole-(CH2)2-NR36-C(O)-R13CH-, R35i-5-oxadiazole-CH2-NR36-C(O)- R13CH-, R35i-5-pyridinyl-CH2-NR36-C(O)- R13CH-, R351-5-tetrazolyl-CH2-NR36-C(O)- R13CH-, R3V5-tetrahydropyranyl-CH2-NR36-C(O)-R13CH-,
R37i-5-piperidinyl-C(O)-R13CH-, R371-5-pyrrolidinyl-C(O)-R13CH-, R37i-5-moφholinyl-(CH2)2-NR36-C(O)-R13CH-, R371-5-piperidinyl-(CH2)2-NR36-C(O)-R13CH-, R37I-5-piperazinyl-(CH2)2-NR36-C(O)-R13CH-, R37i-5-tertrahydropyranyl-(CH2)2-NR36-C(O)-R13CH-, R381-5-phenyl-R39C-NR40-C(O)-R13CH-, R381.5-phenyl-(CH2)2-NR40-C(O)-R13CH-, R381.5-phenyl-(CH2)3-NR40-C(O)-R13CH- or
R41i-5-benzyl; wherein
R11 and R12 independently are H, CH3, (CH3)2CH-, cyclobutyl,
cyclopropyl, CH3O(CH2)2-, OH-ethyl, OH-propyl, (OH)2-propyl, cyano-CH2-,
(OH-CH2)2-CH-, OH-CyClOPrOPyI-CH2-, OH-cyclopentyl-CH^, OH-methyl- cyclopropyl or OH-phenyl;
R13 is H, (CHa)3C-, (CH3)2CHCH2-, (CH3)2CH-, OH-ethyl, benzyl, phenyl, or cyclohexyl;
R14 is (CH3CH2)2N-, phenyl, (CH3)3C-, or cyclopropyl;
R15, R21, R29, R31, R33, R34, R36, R39 and R40 are independently H or CH3;
R16 is OH or CH3O;
R17, R18 and R19 are independently H or CH3;
R20 is (CHs)2CH-, CH3, CF3, or (CH3)2N-;
R22 and R23 are independently (CH3)3C-, (CH3)2CH-, cyclohexyl- CH2-,
OHCH2, phenyl, OH-isopropyl, OH-ethyl, or phenyl-OHCH-;
each R24 is independently H, CH3, CH3CH2-, (CH3)3C-, cyclopropyl, CF3, oxo, NH2, CH3CH2-O-C(O)-, NH2-C(O)-CH2 -, NH2-C(O)-, NH2-C(O)-NH-, OH- C(O)-, NH2-C(O)-CH2-NH-C(O)-, (OH)2-propyl-NH-C(O)- or OH-ethyl-NH-C(O)-;

each R25 is independently H or oxo;
each R26 is independently H, OH, OHCH2, benzyl-O-, NH2-C(O)- or
CH3CH2-O-C(O)-;
R27 and R28 are independently H, NH2-C(O)-, or cyclopropyl-C(O)-;
R30 is CH3, cyclopropyl or NH2;
R32 is OH;
each R35 is independently H, CH3, NH2-C(O)-, CH3CH2-O-C(O)-, or cyclopropyl;
each R37 is independently H, NH2C(O)- or OH;
each R38 is independently H, NH2SO2-, cyano, tetrazolyl, OH, chloro, CH3-O-, OH-C(O)-, or CH3-O-C(O)-;
each R41 is independently H, CH3O or fluoro; and
each R3 is independently H, CH3, chloro, bromo, fluoro, phenyl, NH2-C(O)-, CH3O, pyridinyl or oxazolyl.
In another embodiment X is CH or N;
R1 is H


R2 is




each R3 is independently H, CH3, chloro, bromo, fluoro, phenyl, NH2-C(O)-, CH3O-, 3-pyridinyl, 4-pyridinyl, or 2-oxazolyl.

In one embodiment a compound of formula I or a pharmaceutically acceptable salt thereof, wherein
X is CH or N;
R1 is H1 CrC6 cyanoalkyl, d-C6 alkyl-C(O)-(CH2)n-, CrC6 alkoxy-C(O)-(CH2)n-, CrC6 haloalkyl, R6L5-heterocyclyl-(CH2)n-, R6i.5-heterocyclyl-C(OMCH2)n-, R7I-5-C3-C7 cycloalkyl-(CH2)n-, R7L5-C3-C7 cycloalkyl-NR8-C(O)-, R7L5-C3-C7 cycloalkyl-NR8-C(O)-(CHa)n-, R7L5-C3-C7 cycloalkyl-C(O)-(CH2)n-, R8L5-aryl-C(O)-(CH2)n- or NR9R10-C(O)-(CH2)n-; wherein
each R6 is independently H or oxo;
each R7 is independently H1 halo or CrC6 alkyl;
each R8 is independently H, CrC6 alkyl, cyano, halo, Ci-C6 haloalkyl or Ci-C6 haloalkoxy;
R9 and R10 are independently H or Ci-C6 alkyl;
R2 is NR11R12-C(O)-R13CH-, R14-C(O)-NR15-(CH2)n-R13CH-, R16-C(O)-R13CH-, Ci-C6 alkoxy-C(O)-(CH2)n-NR15-C(O)-R13CH-, NR17R18-C(O)-(CH2)n-NR19-C(O)-R13CH-, R20-SO2-NR21-(CH2)n-R13CH-, R22R23CH-, R24L5-heteroaryl, R241-5-heteroaryl-R13CH-, R241-5-heteroaryl-NR15-C(O)-R13CH-, R25i-5-heterocyclyl, R25i-5-heterocyclyl-(CH2)n-, R26L5-C3-C7 cycloalkyl, NR27R28-(CH2)n-NR29-C(O)-R13CH-, R30-SO2-NR31-(CH2)n-NR15-C(O)-R13CH-, R30-SO2-(CH2)n-NR31-C(O)-R13CH-, R32-C(O)-R33CH-NR34-C(O)-R13CH-, R32-C(O)-(CH2)n-NR34-C(O)-R13CH-, R35L5-heteroaryl-(CH2)n-NR36-C(O)-R13CH-, R37L5-heterocyclyl-(CH2)n-NR36-C(O)-R13CH-, R37Ls-heterocyclyl-C(O)-R13CH-, R38i-5-aryl-R39C-NR40-C(O)-R13CH- or R38i.5-aryl-(CH2)n-NR40-C(O)-R13CH-; wherein

R11 and R12 are independently H, CrC6 alkyl, OH-CrC6 alkyl, CrC6 alkoxy-(CH2)n-, C3-C7 cycloalkyl, cyano-CrC6 alkyl, (OH-C1-C6 alkyl)2-CrC6 alkylene, OH-C3-C7 cycloalkyl-(CH2)n-, OH-(CH2)n-C3-C7 cycloalkyl or OH-aryl;
R13 is H, CrC6 alkyl, OH-CrC6 alkyl, aryl, aryl-(CH2)n-, or C3-C7
cycloalkyl;
R14 is (CrC6 alkyl)2N-, aryl, CrC6 alkyl, or C3-C7 cycoalkyl;
R15, R17, R18, R19, R21, R29, R31, R33, R34, R36, R39 and R40 are
independently H or CrC6 alkyl;
R16 is OH or CrC6 alkoxy;
R20 is CrC6 alkyl, d-C6 haloalkyl, or (CrC6 alkyl)2N-;

R22 and R23 are independently H, C1-C6 alkyl, C3-C7 cycloalkyl-(CH2)n-> OH-Ci-C6 alkyl, aryl, or aryl-OH-Ci-C6 alkylene;
each R24 is independently H, CrC6 alkyl, C3-C7 cycloalkyl, Ci-C6
haloalkyl, oxo ,NH2, Ci-C6 alkoxy-C(O)-, NH2-C(O)-(CH2),,-, or NH2-C(O)-;
each R25 is independently H or oxo;
each R26 is independently H, OH, OH-Ci-C6 alkyl, aryl-(CH2)n-O-, NH2- C(O)- or CrC6 alkoxy-C(O)-;
R27 and R28 are independently are H, NH2-C(O)-, or C3-C7 cycloalkyl- C(O)-;
R30 is CrC6 alkyl, C3-C7 cycloalkyl or NH2;
R32 is OH;
R35 is independently H, C1-C6 alkyl, NH2-C(O)-, or CrC6 alkoxy-C(O)-;
each R37 is independently H, NH2C(O)- or OH;
each R38 is independently H, NH2SO2-, cyano, heteroaryl, OH, halo, C1- C6 alkoxy, OH-C(O)-, or C1-C6 alkoxy-C(O)-;
n is an integer from 1 to 6; and
each R3 is independently H, halo, C1-C6 alkyl, aryl, NH2-C(O)-, C1-C6 alkoxy or heteroaryl.
In another embodiment X is CH or N;
R1 is H, cyano-(CH2)3-, cyano-(CH2)2-, (CH3)3C-C(O)- CH2-, (CH3)3C--O-C(O)-CH2-, CF3(CH2).,-, R61.5-tetrehydropyranyl- CH2-, R61.5-tetrahydrofuranyl- CH2-, RVs-tetrahydrothiopyranyl- CH2-, R6i-5-piperidinyl-C(O)-CH2-, R61.5-thiomorpholinyl-C(O)-CH2 -,
R7i-5-cyclohexyl-CH2-,
R71-5-cyclobutyl-CH2-, R71.5-cyclopentyl-NR8-C(0)-,
RV5-C3-C7 cyclohexyl-NR8-C(O)-CH2-, R7Y5-C3-C7 cyclohexyl-C(O)-CH2-, R81-5-phenyl-C(O)-CH2-, NR9R10-C(O)-CH2- or NR9R10-C(O)-(CH2)4-; wherein
each R6 is independently H or oxo;
each R7 is independently H, F or CH3;
each R8 is independently H, CH3, cyano, F, CF3 or CF3-O-;
R9 and R10 are independently H or (CH3)3C-;
R2 is NR11R12-C(O)-R13CH-, R14-C(O)-NR15- CH2-R13CH-, R16-C(O)-R13CH-, (CH3)3C-O-C(O)-CH2-NR15-C(O)-R13CH-, NR17R18-C(O)-CH2-NR19-C(O)-R13CH-, NR17R18-C(O)-(CH2)2-NR19-C(O)-R13CH-, R20-SO2-NR21-CH2-R13CH-, R22R23CH-, R2V 5-dihydroimidazolyl, R24i.5-isoxazolyl,
R24i.5-thiadiazolyl, R2V5-isoxazolyl- R13CH-, R24i-5-oxazolyl-R13CH-, R241-5-furyl-R13CH-, R24i-5-oxadiaxolyl-R13CH-, R24i-5-triazolyl-R13CH-, R2V5-dihydroisoxazolyl-R13CH-, R24i.5-tetrazolyl-R13CH-, R24i-5-isoxazolyl-NR15-C(O)-R13CH-, R24i-5-thiadiazolyl-NR15-C(O)-R13CH-, R25i-5-tetrahydrofuranyl, R251-5-tetrahydrofuranyl-CH2-, R26i-5-cyclohexyl, R26i-5-tetrahydronapthyl, R26i.5-dihydroindenyl, NR27R28-(CH2)2-NR29-C(O)-R13CH-, R30-SO2-NR31-(CH2)2-NR15-C(O)-R13CH-,
R30-SO2-(CH2)2-NR31-C(O)-R13CH-, R32-C(O)-R33CH-NR34-C(O)-R13CH-, R32-C(O)-(CH2)2-NR34-C(O)-R13CH-, R35i-5-oxadiazole-(CH2)2-NR36-C(O)-R13CH-, R35I-5-oxadiazole-CH2-NR36-C(O)- R13CH-, R351-5-pyridinyl-CH2-NR36-C(O)- R13CH-, R3V5-tetrazolyl-CH2-NR36-C(O)- R13CH-, R371-5-tetrahydropyranyl-CH2-NR36-C(O)-R13CH-, R37i-5-piperidinyl-C(O)-R13CH-, R37i-5-pyrrolidinyl-C(O)-R13CH-, R38i.5-phenyl-R39C-NR40-C(O)-R13CH-, R38i-5-phenyl-(CH2)2-NR40-C(O)-R13CH- or
R38i.5-phenyl-(CH2)3-NR40-C(O)-R13CH-; wherein
R11 and R12 are independently H, CH3, (CH3)2CH-, cyclobutyl,
cyclopropyl, CH3O(CH2)2-, OH-ethylene, OH-propyl, (OH)2-propyl, cyano-CH2-, (OH-CrC6 alkyl)2-CH-, OH-cyclopropyl-CHr, OH-cyclopently-CH^, OH-methyl- cyclopropyl-, or OH-phenyl;
R13 is H, (CHa)3C-, (CH3)2CHCH2-, (CH3)2CH-, OH-ethyl, benzyl, phenyl, or cyclohexyl;
R14 is (CH3CH2J2N-, phenyl, (CH3)3C-, or cyclopropyl;
R15, R17, R18, R19, R21, R29, R31, R33, R34, R36, R39 and R40 are
independently H or CH3;
R16 is OH or CH3O;
R20 is (CHa)2CH-, CH3, CF3, or (CH3)2N-;
R22 and R23 are independently H, (CH3)3C-, (CH3)2CH-, cyclohexyl- CH2-, OHCH2-, phenyl, OH-isopropyl, OH-ethyl, or phenyl-OHCH-;
each R24 is independently H, CH3, CH3CH2-, (CH3)3C-, cyclopropyl, CF3, oxo, NH2, CH3CH2-O-C(O)-, NH2-C(O)-CH2- or NH2-C(O)-;
each R25 is independently H or oxo;
each R26 is independently H, OH, OHCH2, benzyl-O-, NH2-C(O)- or
CH3CH2-O-C(O)-;

R27 and R28 are independently H, NH2-C(O)-, or cyclopropyl-C(O)-;
R30 is CH3, cyclopropyl or NH2;
R32 is OH;
each R35 is independently H, CH3, NH2-C(O)-, or CH3CH2-O-C(O)-;
each R37 is independently H, NH2C(O)- or OH;
each R38 is independently H, NH2SO2-, cyano, tetrazolyl, OH, chloro, CH3-O-, OH-C(O)-, or CH3-O-C(O)-;and
each R3 is independently H, CH3, chloro, bromo, fluoro, phenyl, NH2-C(O)-, CH3O, pyridinyl or oxazolyl.
In another embodiment X is CH or N;
R1 is H,



R2 is




each R3 is independently H, CH3, chloro, bromo, fluoro, phenyl, NH2-C(O)-, CH3O, 3-pyridinyl, 4-pyridinyl, or 2-oxazolyl.

In one embodiment a compound or pharmaceutically acceptable salt thereof, selected from
N-[(1 S)-1 -(aminocarbonyl)-2-methylpropyl]-1 -(3-cyanopropyl)-1 H-indazole-3-carboxamide;
N-[(1 S)-2-amino-2-oxo-1 -phenylethyl]-1 -(3-cyanopropyl)-1 H-indazole-3-carboxamide;
N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-1-(4-cyanobutyl)-1H-indazole-3-carboxamide;
N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-1-(4-cyanobutyl)-1H-indazole-3-carboxamide;
N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-1-(3-cyanopropyl)-1 H-indazole-3-carboxamide;
N-[(1S)-2-amino-2-oxo-1-phenylethyl]-1-(4-cyanobutyl)-1 H-indazole-3-carboxamide;

Nalpha-fli-^-cyanopropyO-IH-indazol-S-ylJcarbonylJ-L-phenylalaninamide;
Nalpha-tfi-^-cyanobutyO-I H-indazol-S-yllcarbonylJ-L-phenylalaninamide;
i^cyclohexylmethylJ-N-^ISJ-i-^S-hydroxypropylJaminolcarbonyl}^-methylpropyl]-1H-indazole-3-carboxamide;
N-[(1 S)-2-amino-2-oxo-1 -phenylethyl]-1 -(tetrahydro-2H-pyran-2-ylmethyl)-1 H-indazole-3-carboxamide;
Nalpha-{[1-(tetrahydro-2H-pyran-2-ylmethyl)-1H-indazol-3-yl]carbonyl}-L-phenylalaninamide;
1-(cyclohexylmethyl)-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-methylpropyl]-1H-indazole-3-carboxamide;
1-(cyclohexylmethyl)-N-[(1S)-1-(hydroxymethyl)-2-methylpropyl]-1H-indazole-3-carboxamide;
1-(cyclohexylmethyl)-N-[(1S)-2-hydroxy-1-phenylethyl]-1H-indazole-3-carboxamide;
N-[(1 S,2S)-2-(benzyloxy)cyclohexyl]-1 -(cyclohexylmethyl)-i H-indazole-3-carboxamide;
i^cyclohexylmethyO-N-^IS^S^-hydroxy-i^hydroxymethyl^-phenylethyl]-1 H-indazole-3-carboxamide;
N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-1-(tetrahydro-2H-pyran-2-ylmethyl)-1 H-indazole-3-carboxamide;
N-{[1 -(cyclohexylmethyl)-i H-indazol-3-yl]carbonyl}-L-valine;
tert-butyl N-{[1 -(cyclohexylmethyl)-i H-indazol-3-yl]carbonyl}-L-valylglycinate
N-{(1S)-1-[(benzoylamino)methyl]-2,2-dimethylpropyl}-1-(cyclohexylmethyl)-1 H-indazole-3-carboxamide;
i^cyclohexylmethyO-N-^IS^I-^diethylaminoJcarbonyllaminoJmethyl)^^-dimethylpropyl]-1 H-indazole-3-carboxamide;
1-(cyclohexylmethyl)-N-[(1S)-2,2-dimethyl-1-{[(methylsulfonyl)amino]methyl}propyl]-1 H-indazole-3-carboxamide;
1-(cyclohexylmethyl)-N-[(1S)-1-{[(isopropylsulfonyl)amino]methyl}-2,2-dimethylpropyl]-1 H-indazole-3-carboxamide;
1-(cyclohexylmethyl)-N-[(1S)-1-{[(cyclopropylcarbonyl)amino]methyl}-2,2-dimethylpropyl]-1 H-indazole-3-carboxamide;

1-(cyclohexylmethyl)-N-[(1S)-1-{[(2,2-dimethylpropanoyl)amino]methyl}-2,2-dimethylpropyl]-1H-indazole-3-carboxamide;
i^cyclohexylmethylJ-N-^ISJ-i-d^dimethylaminoJsulfonyllaminoJmethyl)^^-dimethylpropyl]-1H-indazole-3-carboxamide;
1 -(cyclohexylmethyl)-N-[(1 S)-2,2-dimethyl-1 -({[(trifluoromethyl)sulfonyl]amino}methyl)propyl]-1H-indazole-3-carboxamide;
1-(cyclohexylmethyl)-N-{(1S)-1-[(cyclopropylamino)carbonyl]-2-methylpropyl}-1 H-indazole-3-carboxamide;
1-(cyclohexylmethyl)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)propyl]-1H-indazole-3-carboxamide;
1-(cyclohexylmethyl)-N-{(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl}-1H-indazole-3-carboxamide;
N-{(1 S)-1 -[(cyclobutylamino)carbonyl]-2,2-dimethylpropyl}-1 -(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
1-(3-cyanopropyl)-N-{(1S)-1-[(cyclobutylamino)carbonyl]-2,2-dimethylpropyl}-1 H-indazole-3-carboxamide;
1-(4-cyanobutyl)-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1 H-indazole-3-carboxamide;
1-(cyclohexylmethyl)-N-[(1S)-1-{[(3-hydroxypropyl)amino]carbonyl}-2,2-dimethylpropyl]-1 H-indazole-3-carboxamide;
1-(4-cyanobutyl)-N-{(1S)-1-[(cyclopropylamino)carbonyl]-2,2-dimethylpropyl}-1 H-indazole-3-carboxamide;
1-(4-cyanobutyl)-N-[(1S)-1-{[(3-hydroxypropyl)amino]carbonyl}-2,2-dimethylpropyl]-1 H-indazole-3-carboxamide;
1-(3-cyanopropyl)-N-[(1S)-1-{[(3-hydroxypropyl)amino]carbonyl}-2,2-dimethylpropyl]-1 H-indazole-3-carboxamide;
N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-1-{[(2R)-5-oxotetrahydrofuran-2-yl]methyl}-1 H-indazole-3-carboxamide;
N-[(1S)-1-{[(3-hydroxypropyl)amino]carbonyl}-2,2-dimethylpropyl]-1-{[(2R)-5-oxotetrahydrofuran-2-yl]methyl}-1 H-indazole-3-carboxamide;
N-[(1S)-2,2-dimethyl-1-(2H-tetrazol-5-yl)propyl]-1-{[(2R)-5-oxotetrahydrofuran-2-yl]methyl}-1 H-indazole-3-carboxamide;

N-[(1S)-1-({[(2S)-2,3-dihydroxypropyl]amino}carbonyl)-2,2-dimethylpropyl]-1-{[(2R)-5-oxotetrahydrofuran-2-yl]methyl}-1 H-indazole-3-carboxamide;
N-[(1 S)-1 -{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1 -{[(2R)-5-oxotetrahydrofuran-2-yl]methyl}-1 H-indazole-3-carboxamide;
1-(3-cyanopropyl)-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1H-indazole-3-carboxamide;
N-{[1-(3-cyanopropyl)-1 H-indazol-3-yl]carbonyl}-3-methyl-L-valylglycinamide;

N-{[1-(4-cyanobutyl)-1H-indazol-3-yl]carbonyl}-3-methyl-L-valyl-beta-alaninamide;
N-{[1-(cyclohexylmethyl)-1H-indazol-3-yl]carbonyl}-3-methyl-L-valyl-beta-alanine;
3-methyl-N-{[1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazol-3-yl]carbonyl}-L-valyl-beta-alaninamide;
N-{[1-(3-cyanopropyl)-1H-indazol-3-yl]carbonyl}-3-methyl-L-valyl-beta-alaninamide;
N-{[1-(cyclohexylmethyl)-1H-indazol-3-yl]carbonyl}-3-methyl-L-valyl-beta-alaninamide;
N-[(1S)-1-{[(3-hydroxypropyl)amino]carbonyl}-2,2-dimethylpropyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
1-(4-cyanobutyl)-N-{(1S)-1-[(cyclobutylamino)carbonyl]-2,2-dimethylpropyl}-1H-indazole-3-carboxamide;
N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
N-III^-cyanobutyO-IH-indazol-S-yllcarbonylJ-S-methyl-L-valylglycinamide;
3-methyl-N-{[1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazol-3-yl]carbonyl}-L-valylglycinamide;
1-(3-cyanopropyl)-N-{(1S)-1-[(cyclopropylamino)carbonyl]-2,2-dimethylpropyl}-1 H-indazole-3-carboxamide;
1-(cyclohexylmethyl)-N-[(1S)-1-{[(2-methoxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1 H-indazole-3-carboxamide;
N-^IS^I-^cyclopropylaminoJcarbonyll^^-dimethylpropylJ-i-^etrahydro^H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;

1-(cyclohexylmethyl)-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1 H-indazole-3-carboxamide;
N-{[1-(cyclohexylmethyl)-1 H-indazol-3-yl]carbonyl}-3-methyl-L-valylglycinamide; i^cyclohexylmethyO-N-^ISJ-i-^isopropylaminoJcarbonyll^^-dimethylpropyl}-1 H-indazole-3-carboxamide;
N-{(1S)-1-[(cyclobutylamino)carbonyl]-2,2-dimethylpropyl}-1-(cyclohexylmethyl)-1 H-indazole-3-carboxamide;
1-(cyclohexylmethyl)-N-{(1S)-1-[(cyclopropylamino)carbonyl]-2,2-dimethylpropyl}-1 H-indazole-3-carboxamide;
i^cyclohexylmethyO-N-KISJ-I^.S^-tetrahydronaphthalen-i-yll-IH-indazole-S-carboxamide;
N-[(1S)-2-cyclohexyl-1-(hydroxymethyl)ethyl]-1-(cyclohexylmethyl)-1 H-indazole-3-carboxamide;
N-{[1-(cyclohexylmethyl)-1H-indazol-3-yl]carbonyl}-L-valylglycinamide;
1-(cyclohexylmethyl)-N-[(3S)-2-oxotetrahydrofuran-3-yl]-1H-indazole-3-carboxamide;
1-(cyclohexylmethyl)-N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]-1H-indazole-3-carboxamide;
N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-1-(tetrahydro-2H-pyran-2-ylmethyl)-1 H-indazole-3-carboxamide;
N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-5-fluoro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-1-(cyclohexylmethyl)-5-fluoro-1 H-indazole-3-carboxamide;
5-fluoro-N-[(1S)-1-{[(3-hydroxypropyl)amino]carbonyl}-2,2-dimethylpropyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
N-^ISJ-i-^cyclopropylaminoJcarbonyll^^-dimethylpropylJ-δ-fluoro-i-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
1-(cyclohexylmethyl)-N-{(1S)-1-[(cyclopropylamino)carbonyl]-2,2-dimethylpropyl}-5-fluoro-1 H-indazole-3-carboxamide;
1-(4-cyanobutyl)-N-{(1S)-1-[(cyclopropylamino)carbonyl]-2,2-dimethylpropyl}-5-fluoro-1 H-indazole-3-carboxamide;

N-{[1-(4-cyanobutyl)-5-fluoro-1H-indazol-3-yl]carbonyl}-3-methyl-L-valylglycinamide;
1-(4-cyanobutyl)-5-fIuoro-N-[(1S)-1-{[(3-hydroxypropyl)amino]carbonyl}-2,2-dimethylpropyl]-1H-indazole-3-carboxamide;
1-(4-cyanobutyl)-5-fluoro-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1H-indazole-3-carboxamide;
N-^IS^I^aminocarbonyO^^-dimethylpropyll-i^-cyanobutyO-S-fluoro-IH-indazole-3-carboxamide;
1-(cyclohexylmethyl)-5-fluoro-N-[(1S)-1-{[(3-hydroxypropyl)amino]carbonyl}-2,2-dimethylpropyl]-1H-indazole-3-carboxamide;
N-{[1-(cyclohexylmethyl)-5-fluoro-1 H-indazol-3-yl]carbonyl}-3-methyl-L-valylglycinamide;
5-fluoro-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
N-{[5-fluoro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazol-3-yl]carbonyl}-3-methyl-L-valylglycinamide;
i^cyclohexylmethyO-δ-fluoro-N-^ISJ-i-l^-hydroxyethylJaminolcarbonyl}^^-dimethylpropyl]-1H-indazole-3-carboxamide;
N-^ISJ-i^aminocarbonyl^^-dimethylpropyll-i^cyclohexylmethyO-Z-fluoro-1 H-indazole-3-carboxamide;
1-(cyclohexylmethyl)-N-{(1S)-1-[(cyclopropylamino)carbonyl]-2,2-dimethylpropyl}-7-fluoro-1 H-indazole-3-carboxamide;
^(cyclohexylmethyO-Z-fluoro-N-^ISJ-i-I^S-hydroxypropylJaminolcarbonyl}^^-dimethylpropyl]-1 H-indazole-3-carboxamide;
N-{[1-(cyclohexylmethyl)-7-fluoro-1 H-indazol-3-yl]carbonyl}-3-methyl-L-valylglycinamide;
^(cyclohexylmethyO-Z-fluoro-N-^ISJ-i-t^-hydroxyethyOaminolcarbonyl}^^-dimethylpropyl]-1 H-indazole-3-carboxamide;
N-(1-methyl-2-oxo-2,5-dihydro-1 H-imidazol-4-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
N-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;

N-[(2,5-dimethyl-3-furyl)methyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
N-(5-methyl-1 ,3,4-thiadiazol-2-yl)-1 -(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
N-[(5-methylisoxazol-3-yl)methyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
N-CS-ethyl-I.S^-thiadiazol^-yO-i-Ctetrahydro^H-pyran^-ylmethyO-IH-indazole-3-carboxamide;
N-(5-tert-butyl-1 ,3,4-thiadiazol-2-yl)-1 -(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
N-(3-methylisoxazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
N-[(2,5-dimethyl-1 ,3-oxazol-4-yl)methyl]-1 -(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
N~1 —cyclopentyl-N-S—^.S-dimethyl-S-furyOmethyll-i H-indazole-1 ,3-dicarboxamide;
N-(tetrahydrofuran-2-ylmethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
N-[(1 S)-1 -(aminocarbonyl)-2,2-dimethylpropyl]-1 -(3,3-dimethyl-2-oxobutyl)-1 H-indazole-3-carboxamide;
N-{[5-methyl-2-(trifluoromethyl)-3-furyl]methyl}-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
N-[(3-oxo-2,3-dihydroisoxazol-5-yl)methyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
N-KS-cyclopropyMH-i ^^-triazol-S-yOmethyll-i-^etrahydro^H-pyran^-ylmethyl)-1 H-indazole-3-carboxamide;
N-(3,4-dimethylisoxazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
N-^ISJ-i^aminocarbonyl^^-dimethylpropylJ-i^cyclohexylmethylJ-I H-indazole-3-carboxamide;
ethyl (1 R,2S)-2-({[1-(cyclohexylmethyl)-1 H-indazol-3-yl]carbonyl}amino)cyclohexanecarboxylate;

N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-1-(4-cyanobutyl)-5-methyl-1H-indazole-3-carboxamide;
N-[(1S,2R)-1-(aminocarbonyl)-2-hydroxypropyl]-1-(4-cyanobutyl)-5-methyl-1H-indazole-3-carboxamide;
N-^ISJ-i-iaminocarbonyO^-methylpropyll-i^-cyanobutylJ-δ-methyl-IH-indazole-3-carboxamide;
N-[(1 S)-1 -(aminocarbonyl)-3-methylbutyl]-1 -(4-cyanobutyl)-5-methyl-1 H-indazole-3-carboxamide;
1-(4-cyanobutyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-5-methyl-1H-indazole-3-carboxamide;
N-^ISJ-i^aminocarbonyl^^-dimethylpropyll-δ-chloro-i^-cyanobutyO-IH-indazole-3-carboxamide;
N-[(1S,2R)-1-(aminocarbonyl)-2-hydroxypropyl]-5-chloro-1-(4-cyanobutyl)-1 H-indazole-3-carboxamide;
N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-5-chloro-1-(4-cyanobutyl)-1H-indazole-3-carboxamide;
N-[(1S)-1-(aminocarbonyl)-3-methylbutyl]-5-chloro-1-(4-cyanobutyl)-1H-indazole-3-carboxamide;
5-chloro-1 -(4-cyanobutyl)-N-[(1 S,2S)-2-hydroxycyclohexyl]-1 H-indazole-3-carboxamide;
5-chloro-1-(4-cyanobutyl)-N-[(1S)-1 ,2,3,4-tetrahydronaphthalen-1-yl]-1 H-indazole-3-carboxamide;
Nalpha-^δ-chloro-i^-cyanobutyO-IH-indazol-S-yllcarbonylJ-L-phenylalaninamide;
5-chloro-1-(4-cyanobutyl)-N-{(1S)-1-[(cyclopropylamino)carbonyl]-2,2-dimethylpropyl}-1 H-indazole-3-carboxamide;
5-chloro-1-(4-cyanobutyl)-N-{(1S)-1-[(cyclobutylamino)carbonyl]-2,2-dimethylpropyl}-1 H-indazole-3-carboxamide;
5-chloro-1-(4-cyanobutyl)-N-[(1R,2S)-2-(hydroxymethyl)cyclohexyl]-1H-indazole-3-carboxamide;

5-chloro-1-(4-cyanobutyl)-N-[(5-methylisoxazol-3-yl)methyl]-1 H-indazole-3-carboxamide;
ethyl (1 R,2S)-2-({[5-chloro-1-(4-cyanobutyl)-1 H-indazol-3-yl]carbonyl}amino)cyclohexanecarboxylate;
5-chloro-1-(4-cyanobutyl)-N-[(1S)-1-{[(3-hydroxypropyl)amino]carbonyl}-2,2-dimethylpropyl]-1H-indazole-3-carboxamide;
N-{[1-(4-cyanobutyl)-1H-indazol-3-yl]carbonyl}-3-methyl-L-valine;
N-{[5-chloro-1-(4-cyanobutyl)-1 H-indazol-3-yl]carbonyl}-3-methyl-L-valine;
N-[(1 S)-1 -(aminocarbonyl)-2-methylpropyl]-5-chloro-1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
S-chloro-N^ISJ-i-^-hydroxyethyOaminolcarbonyl^^-dimethylpropyll-i-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
N-{[5-chloro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazol-3-yl]carbonyl}-3-methyl-L-valylglycinamide;
5-chloro-N-{(1 S)-1 -[(cyclopropylamino)carbonyl]-2,2-dimethylpropyl}-1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
S-chloro-N-^ISJ-i-^cyclobutylamino^arbonylJ^^-dimethylpropylJ-i-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
5-chloro-N-[(1S)-2,2-dimethyl-1-(2H-tetrazol-5-yl)propyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
5-chloro-N-[(1S)-1-({[(2S)-2,3-dihydroxypropyl]amino}carbonyl)-2,2-dimethylpropyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
N-[(1S)-1-(5-amino-1 ,3,4-oxadiazol-2-yl)-2,2-dimethylpropyl]-5-chloro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
5-chloro-N-[(1 S)-1 -{[(3-hydroxypropyl)amino]carbonyl}-2,2-dimethylpropyl]-1 -(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
S-chloro-N-^.S-dimethyl-S-furyOmethyll-i-Oetrahydro^H-pyran^-ylmethyO-IH-indazole-3-carboxamide;
N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-5-chloro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
5-chloro-1-(4-cyanobutyl)-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1H-indazole-3-carboxamide;

methyl N-{[5-chloro-1 -(4-cyanobutyl)-1 H-indazol-3-yl]carbonyl}-3-methyl-L-valinate;
methyl N-{[1 -(4-cyanobutyl)-1 H-indazol-3-yl]carbonyl}-3-methyl-L-valinate;
methyl 3-methyl-N-{[1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazol-3-yl]carbonyl}-L-valinate;
methyl N-{[1 -(cyclohexylmethyl)-i H-indazol-3-yl]carbonyl}-3-methyl-L-valinate; methyl N-{[1 -(2-tert-butoxy-2-oxoethyl)-1 H-indazol-3-yl]carbonyl}-3-methyl-L-valinate;
5-chloro-1-(4-cyanobutyl)-N-[(2,5-dimethyl-3-furyl)methyl]-1 H-indazole-3-carboxamide;
N-{[5-chloro-1-(4-cyanobutyl)-1H-indazol-3-yl]carbonyl}-3-methyl-L-valylglycinamide;
S-chloro-i^-cyanobutyO-N-KIS^R^-hydroxy^.S-dihydro-IH-inden-i-ylJ-I H-indazole-3-carboxamide;
δ-chloro-i^-cyanobutyO-N-^ISJ-i^hydroxymethyO^^-dimethylpropyll-IH-indazole-3-carboxamide;
1 -(4-cyanobutyl)-5-methyl-N-[(1 S)-1 ,2,3,4-tetrahydronaphthalen-1 -yl]-1 H-indazole-3-carboxamide;
Nalpha-{[1 -(4-cyanobutyl )-5-methyl-1 H-indazol-3-yl]carbonyl}-L-phenylalaninamide;
1 -(4-cyanobutyl )-N-{(1 S)-1 -[(cyclopropylaminojcarbonyl^^-dimethylpropylj-δ-methyl-1 H-indazole-3-carboxamide;
1-(4-cyanobutyl)-N-[(1S,2R)-2-(hydroxymethyl)cyclohexyl]-5-methyl-1H-indazole-3-carboxamide;
N-{[1-(4-cyanobutyl)-5-methyl-1H-indazol-3-yl]carbonyl}-3-methyl-L-valylglycinamide;
ethyl (1 R,2S)-2-({[1-(4-cyanobutyl)-5-methyl-1 H-indazol-3-yl]carbonyl}amino)cyclohexanecarboxylate;
i^-cyanobutyO-N-^ISJ-i-^cyclobutylamino^arbonyll^^-dimethylpropylJ-δ-methyl-1 H-indazole-3-carboxamide;
1-(4-cyanobutyl)-N-[(1S,2R)-2-hydroxy-2,3-dihydro-1 H-inden-1-yl]-5-methyl-1 H-indazole-3-carboxamide;

^(^cyanobutyO-N-^ISJ-i^hydroxymethyl^^-dimethylpropyll-S-methyl-I H-indazole-3-carboxamide;
N-[(1R)-1-(aminocarbonyl)-3-methylbutyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
N-[(1 S)-1 -(aminocarbonyl)-2,2-dimethylpropyl]-1 -(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
N-Ii^aminocarbonyOcyclohexyll-i-Oetrahydro^H-pyran^-ylmethyO-IH-indazole-3-carboxamide;
N-^IS^RJ-i^aminocarbonyl^-hydroxypropyll-i^cyclohexylmethyO-IH-indazole-3-carboxamide;
N-[(1S,2R)-1-(aminocarbonyl)-2-hydroxypropyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
N-[1 -(aminocarbonyl)cyclohexyl]-1 -(cyclohexylmethyl)-i H-indazole-3-carboxamide;
ethyl (1 R,2S)-2-({[1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazol-3-yl]carbonyl}amino)cyclohexanecarboxylate;
N-[(1S)-1-(aminocarbonyl)-3-methylbutyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
Nalpha-{[1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazol-3-yl]carbonyl}-L-phenylalaninamide;
N-^ISJ-i^aminocarbonyl^-methylpropylJ-i^cyclohexylmethylJ-IH-indazole-S-carboxamide;
N-(2-amino-1 ,1-dimethyl-2-oxoethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
N-[(1 R)-1-(aminocarbonyl)-3-methylbutyl]-1-(cyclohexylmethyl)-1 H-indazole-3-carboxamide;
N-^ISJ-i-CaminocarbonyO-S-methylbutylJ-i-^yclohexylmethyO-IH-indazole-S-carboxamide;
Nalpha-ni^cyclohexylmethyO-IH-indazol-S-ylJcarbonylJ-L-phenylalaninamide;

5-chloro-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
N-{[1-(cyclohexylmethyl)-1H-indazol-3-yl]carbonyl}-3-methyl-L-valine;
3-methyl-N-{[1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazol-3-yl]carbonyl}-L-valine;

N-ltδ-chloro-i-Oetrahydro-ZH-pyran^-ylmethyO-I H-indazol-S-ylJcarbonylJ-S-methyl-L-valine;
N-{[1-(4-cyanobutyl)-5-methyl-1 H-indazol-3-yl]carbonyl}-3-methyl-L-valine;
^(cyclohexylmethyO-N-^IS^I-^pS^.S-dihydroxypropyllaminoJcarbonyl)^^-dimethylpropyl]-1H-indazole-3-carboxamide;
N-[(1 S)-1 -({[(2S)-2,3-dihydroxypropyl]amino}carbonyl)-2,2-dimethylpropyl]-1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
1-(4-cyanobutyl)-N-[(1S)-1-({[(2S)-2,3-dihydroxypropyl]amino}carbonyl)-2,2-dimethylpropyl]-1H-indazole-3-carboxamide;
N-{(1S)-1-[({2-[(aminocarbonyl)amino]ethyl}amino)carbonyl]-2,2-dimethylpropyll-i^cyclohexylmethyO-IH-indazole-S-carboxamide;
N-{(1S)-1-[({2-[(aminocarbonyl)amino]ethyl}amino)carbonyl]-2,2-dimethylpropyl}-1 -(4-cyanobutyl)-1 H-indazole-3-carboxamide;
1-[(4,4-difluorocyclohexyl)methyl]-N-[(1S)-1-({[(2R)-2,3-dihydroxypropyl]amino}carbonyl)-2,2-dimethylpropyl]-1 H-indazole-3-carboxamide;
i-^^-difluorocyclohexylJmethyll-N-^ISJ-i-f^-hydroxyethyOaminolcarbonyl}-2,2-dimethylpropyl]-1 H-indazole-3-carboxamide;
N-{(1S)-1-[({2-[(aminocarbonyl)amino]ethyl}amino)carbonyl]-2,2-dimethylpropyl}-1-[(4,4-difluorocyclohexyl)methyl]-1 H-indazole-3-carboxamide;
1-[(4,4-difluorocyclohexyl)methyl]-N-[(1S)-1-({[(2S)-2,3-dihydroxypropyl]amino}carbonyl)-2,2-dimethylpropyl]-1 H-indazole-3-carboxamide;
N-^i-^^-difluorocyclohexyOmethylJ-IH-indazol-S-ylJcarbonylJ-S-methyl-L-valylglycinamide;
1 -[(4,4-difluorocyclohexyl)methyl]-N-[(1 S)-1 -{[(3-hydroxypropyl)amino]carbonyl}-2,2-dimethylpropyl]-1 H-indazole-3-carboxamide;
N-^i-^^-difluorocyclohexylJmethylJ-IH-indazol-S-ylJcarbonylJ-S-methyl-L-valylglycine;
1 -(4-cyanobutyl )-N-{( 1 S)-1 -[({2- [(cyclopropylsulfonylJaminolethylJamino^arbonyll^^-dimethylpropylJ-I H-indazole-S-carboxamide;
N-{(1S)-1-[({2-[(cyclopropylsulfonyl)amino]ethyl}amino)carbonyl]-2,2-dimethylpropyl}-1-[(4,4-difluorocyclohexyl)methyl]-1 H-indazole-3-carboxamide;

1 -(4-cyanobutyl)-N-{(1 S)-1 -[({2- [(cyclopropylcarbonyl)amino]ethyl}amino)carbonyl]-2,2-dimethylpropyl}-1H-indazole-3-carboxamide;
N-{(1S)-1-[({2-[(cyclopropylcarbonyl)amino]ethyl}amino)carbonyl]-2,2-dimethylpropylJ-i-^^-difluorocyclohexylJmethylJ-IH-indazole-S-carboxamide;
N^fi-^^-difluorocyclohexyOmethyll-IH-indazol-S-ylJcarbonyO-S-methyl-L-valyl-D-alanine;
1 -[(4,4-difluorocyclohexyl)methyl]-N-[(1 S)-2,2-dimethyl-1 -({[2-(methylsulfonyl)ethyl]amino}carbonyl)propyl]-1H-indazole-3-carboxamide;
N-[(1 S)-1 -({[2-(aminosulfonyl)ethyl]amino}carbonyl)-2,2-dimethylpropyl]-1 -[(4,4-difluorocyclohexyOmethyll-IH-indazole-S-carboxamide;
1-[(4,4-difluorocyclohexyl)methyl]-N-[(1S)-1-({[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]amino}carbonyl)-2,2-dimethylpropyl]-1H-indazole-3-carboxamide;
1-(4-cyanobutyl)-N-{(1S)-1-[(cyclopropylamino)carbonyl]-2,2-dimethylpropyl}-7-fluoro-1H-indazole-3-carboxamide;
1-(4-cyanobutyl)-7-fluoro-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1H-indazole-3-carboxamide;
1-(4-cyanobutyl)-7-fluoro-N-[(1S)-1-{[(3-hydroxypropyl)amino]carbonyl}-2,2-dimethylpropyl]-1H-indazole-3-carboxamide;
N-{[1-(4-cyanobutyl)-7-fluoro-1 H-indazol-3-yl]carbonyl}-3-methyl-L-valylglycinamide;
N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-1-(4-cyanobutyl)-7-fluoro-1 H-indazole-3-carboxamide;
1-(4-cyanobutyl)-7-fluoro-N-[(1S)-1-{[(3-hydroxypropyl)amino]carbonyl}-2,2-dimethylpropyl]-1 H-indazole-3-carboxamide;
N-{(1 S)-1 -[(cyclopropylamino)carbonyl]-2,2-dimethylpropyl}-7-fluoro-1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
7-fluoro-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
7-fluoro-N-[(1 S)-1 -{[(3-hydroxypropyl)amino]carbonyl}-2,2-dimethylpropyl]-1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
N-{[7-fluoro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazol-3-yl]carbonyl}-3-methyl-L-valylglycinamide;

N-^ISJ-i^aminocarbonyl^^-dimethylpropyll-Z-fluoro-i-^etrahydro^H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
N-{(1 S)-1 -[(benzylamino)carbonyl]-2,2-dimethylpropyl}-1 -(cyclohexylmethyl)-7-fluoro-1H-indazole-3-carboxamide;
1-(cyclohexylmethyl)-N-[(1S)-2,2-dimethyl-1-{[(2-phenylethyOaminolcarbonylJpropyll-Z-fluoro-IH-indazole-S-carboxamide;
i-CcyclohexylmethyO-N-KIS^^-dimethyl-i-t^S-phenylpropyOaminolcarbonylJpropyll-Z-fluoro-IH-indazole-S-carboxamide;
1-(cyclohexylmethyl)-N-[(1S)-2,2-dimethyl-1-{[(pyridin-3-ylmethyl)amino]carbonyl}propyl]-7-fluoro-1H-indazole-3-carboxamide;
1-(cyclohexylmethyl)-N-[(1S)-2,2-dimethyl-1-{[(pyridin-4-ylmethyl)amino]carbonyl}propyl]-7-fluoro-1 H-indazole-3-carboxamide;
N-[(1 S)-1 -{[(4-cyanobenzyl)amino]carbonyl}-2,2-dimethylpropyl]-1 -(cyclohexylmethylJ-Z-fluoro-IH-indazole-S-carboxamide;
1-(cyclohexylmethyl)-7-fluoro-N-[(1S)-1-{[(2-methoxybenzyl)amino]carbonyl}-2,2-dimethylpropyl]-1H-indazole-3-carboxamide;
methyl 4-{[(N-{[1 -(cyclohexylmethyl)-7-fluoro-1 H-indazol-3-yl]carbonyl}-3-methyl-L-valyl)amino]methyl}benzoate;
^(cyclohexylmethyO-T-fluoro-N-^ISJ-i-f^S-methoxybenzyOaminolcarbonyl}-2,2-dimethylpropyl]-1 H-indazole-3-carboxamide;
i^cyclohexylmethyO-Z-fluoro-N-^ISJ-i-t^-methoxybenzyOaminolcarbonyl}-2,2-dimethylpropyl]-1 H-indazole-3-carboxamide;
N-{(1S)-1-[(benzylamino)carbonyl]-2,2-dimethylpropyl}-1-(4-cyanobutyl)-7-fluoro-1H-indazole-3-carboxamide;
N-{(1S)-1-[(benzylamino)carbonyl]-2,2-dimethylpropyl}-7-fluoro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
1-(cyclohexylmethyl)-N-{(1S)-1-[(cyclopropylamino)carbonyl]-2,2-dimethylpropyl}-6-fluoro-1 H-indazole-3-carboxamide;
1-(cyclohexylmethyl)-6-fluoro-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1H-indazole-3-carboxamide;
i^cyclohexylmethyO-θ-fluoro-N-^ISJ-i-I^S-hydroxypropyOaminolcarbonyl}^^-dimethylpropyl]-1 H-indazole-3-carboxamide;

N-{[1-(cyclohexylmethyl)-6-fluoro-1 H-indazol-3-yl]carbonyl}-3-methyl-L-valylglycinamide;
N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-1-(cyclohexylmethyl)-6-fluoro-1 H-indazole-3-carboxamide;
N-^IS^I-^cyclopropylaminoJcarbonyll^^-dimethylpropylJ-β-fluoro-i-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
6-fluoro-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
β-fluoro-N-^ISJ-i-^S-hydroxypropyOaminolcarbonylJ^^-dimethylpropyll-i-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
N-{[6-fluoro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazol-3-yl]carbonyl}-3-methyl-L-valylglycinamide;
i-C^cyanobutyO-e-fluoro-N-^ISJ-i-^S-hydroxypropyOaminoJcarbonyl}^^-dimethylpropyl]-1 H-indazole-3-carboxamide;
N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-6-fluoro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
1-(4-cyanobutyl)-N-{(1S)-1-[(cyclopropylamino)carbonyl]-2,2-dimethylpropyl}-6-fluoro-1 H-indazole-3-carboxamide;
1 -(4-cyanobutyl)-6-fluoro-N-[(1 S)-1 -{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1 H-indazole-3-carboxamide;
N-{[1-(4-cyanobutyl)-6-fluoro-1 H-indazol-3-yl]carbonyl}-3-methyl-L-valylglycinamide;
N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-1-(4-cyanobutyl)-6-fluoro-1H-indazole-3-carboxamide;
N-{[1-(cyclohexylmethyl)-7-fluoro-1 H-indazol-3-yl]carbonyl}-3-methyl-L-valylglycine;
N-{[7-fluoro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazol-3-yl]carbonyl}-3-methyl-L-valylglycine;
N-{[1-(4-cyanobutyl)-7-fluoro-1 H-indazol-3-yl]carbonyl}-3-methyl-L-valylglycine;

4-{[(N-{[1-(cyclohexylmethyl)-7-fluoro-1H-indazol-3-yl]carbonyl}-3-methyl-L-valyl)amino]methyl}benzoic acid;
N-[(1S)-1-{[(2-chlorobenzyl)amino]carbonyl}-2,2-dimethylpropyl]-1-(cyclohexylmethyl)-7-fluoro-1 H-indazole-3-carboxamide;

N-[(1 S)-1 -{[(3-chlorobenzyl)amino]carbonyl}-2,2-dimethylpropyl]-1 -(cyclohexylmethyl^-fluoro-IH-indazole-S-carboxamide;
i^cyclohexylmethylJ-T-fluoro-N-^IS^I-t^-hydroxybenzyOaminolcarbonyl}^^-dimethylpropyl]-1H-indazole-3-carboxamide;
^(cyclohexylmethyO-Z-fluoro-N-^ISJ-i-l^-hydroxybenzyOaminolcarbonyl}^^-dimethylpropyl]-1H-indazole-3-carboxamide;
1 -(cyclohexylmethyl)-7-fluoro-N-[(1 S)-1 -{[(4-hydroxy-3-methoxybenzylJaminolcarbonylJ^^-dimethylpropyll-I H-indazole-S-carboxamide;
N-[(1S)-1-({[3-(aminosulfonyl)benzyl]amino}carbonyl)-2,2-dimethylpropyl]-1-(cyclohexylmethyl^-fluoro-I H-indazole-S-carboxamide;
N-[(1S)-1-({[4-(aminosulfonyl)benzyl]amino}carbonyl)-2,2-dimethylpropyl]-1-(cyclohexylmethylJ-Z-fluoro-IH-indazole-S-carboxamide;
1-(cyclohexylmethyl)-N-[(1S)-2,2-dimethyl-1-({[(1 R)-1-phenylethyl]amino}carbonyl)propyl]-7-fluoro-1H-indazole-3-carboxamide;
1 -(cyclohexylmethyl)-N-[(1 S)-2,2-dimethyl-1 -({[(1 S)-1 -phenylethyllaminoJcarbonyOpropyll-y-fluoro-IH-indazole-S-carboxamide;
N-[(1S)-1-{[(cyanomethyl)amino]carbonyl}-2,2-dimethylpropyl]-1-(cyclohexylmethyO-Z-fluoro-I H-indazole-S-carboxamide;
1 -(cyclohexylmethyl)-7-fluoro-N-[(1 S)-1 -({[2-hydroxy-1 -(hydroxymethyOethyllaminoJcarbonyO^^-dimethylpropyll-I H-indazole-S-carboxamide;

N-[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]-7-fluoro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
N-[(1S)-2,2-dimethyl-1-({[(1S)-1-phenylethyl]amino}carbonyl)propyl]-7-fluoro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
N-[(1S)-1-{[(cyanomethyl)amino]carbonyl}-2,2-dimethylpropyl]-7-fluoro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
7-fluoro-N-[(1S)-1-({[2-hydroxy-1-(hydroxymethyl)ethyl]amino}carbonyl)-2,2-dimethylpropyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
1-(4-cyanobutyl)-N-[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyllaminoJcarbonylJpropyll^-fluoro-IH-indazole-S-carboxamide;
1-(4-cyanobutyl)-N-[(1S)-2,2-dimethyl-1-({[(1S)-1-phenylethyl]amino}carbonyl)propyl]-7-fluoro-1 H-indazole-3-carboxamide;

1-(4-cyanobutyl)-7-fluoro-N-[(1S)-1-({[2-hydroxy-1-(hydroxymethyOethylJaminoJcarbonyl^^-dimethylpropyll-I H-indazole-S-carboxamide; i-^yclohexylmethyO-N-tCIS^^-dimethyl-i-^t^i H-tetrazol-S-yl)benzyl]amino}carbonyl)propyl]-7-fluoro-1H-indazole-3-carboxamide;
N-^ISJ-i-fliS-cyanobenzyOaminolcarbonylJ^^-dimethylpropyll-i-(cyclohexylmethyl^-fluoro-IH-indazole-S-carboxamide;
N-[(1S)-1-(5-amino-1 ,3,4-oxadiazol-2-yl)-2,2-dimethylpropyl]-7-fluoro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
N-[(1S)-1-({[(2S)-2,3-dihydroxypropyl]amino}carbonyl)-2,2-dimethylpropyl]-7-fluoro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
N-^ISJ-i-U^R^.S-dihydroxypropyllaminoJcarbonyO^^-dimethylpropyl]-?-fluoro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
N-[(1S)-1-(5-amino-1 ,3,4-oxadiazol-2-yl)-2,2-dimethylpropyl]-1-(4-cyanobutyl)-7-fluoro-1H-indazole-3-carboxamide;
1-(4-cyanobutyl)-N-[(1S)-1-({[(2S)-2,3-dihydroxypropyl]amino}carbonyl)-2,2-dimethylpropyl]-7-fluoro-1H-indazole-3-carboxamide;
1-(4-cyanobutyl)-N-[(1S)-1-({[(2R)-2,3-dihydroxypropyl]amino}carbonyl)-2,2-dimethylpropyl]-7-fluoro-1 H-indazole-3-carboxamide;
N-[(1S)-1-(5-amino-1 ,3,4-oxadiazol-2-yl)-2,2-dimethylpropyl]-1-(4-cyanobutyl)-6-fluoro-1 H-indazole-3-carboxamide;
1-(4-cyanobutyl)-N-[(1S)-1-({[(2S)-2,3-dihydroxypropyl]amino}carbonyl)-2,2-dimethylpropyl]-6-fluoro-1H-indazole-3-carboxamide;
1-(4-cyanobutyl)-N-[(1S)-1-({[(2R)-2,3-dihydroxypropyl]amino}carbonyl)-2,2-dimethylpropyl]-6-fluoro-1H-indazole-3-carboxamide;
N-[(1S)-1-(5-amino-1 ,3,4-oxadiazol-2-yl)-2,2-dimethylpropyl]-6-fluoro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
(ISJ-i-^pS^.S-dihydroxypropyllaminoJcarbonyl^^-dimethylpropyl θ-fluoro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxylate;
N-[(1S)-1-({[(2R)-2,3-dihydroxypropyl]amino}carbonyl)-2,2-dimethylpropyl]-6-fluoro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
N-{(1S)-1-[({2-[(cyclopropylsulfonyl)amino]ethyl}amino)carbonyl]-2,2-dimethylpropyl}-7-fluoro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;

1-(4-cyanobutyl)-N-{(1S)-1-[({2- [(cyclopropylsulfonyOaminolethy^aminoJcarbonylJ^^-dimethylpropylJ-Z-fluoro-I H-indazole-3-carboxamide;
N-^ISJ-i-t^-^cyclopropylsulfonyOaminolethylJaminoJcarbonyl]^^-dimethylpropyl}-6-fluoro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
1 -(4-cyanobutyl)-N-{(1 S)-1 -[({2- [(cyclopropylsulfonylJaminoJethylJaminoJcarbonyll^^-dimethylpropylJ-β-fluoro-I H-indazole-3-carboxamide;
N-{(1S)-1-[({[5-(aminocarbonyl)-1 ,3,4-oxadiazol-2-yl]methyl}amino)carbonyl]-2,2-dimethylpropyl}-7-fluoro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
N-^ISJ-i-^dS^aminocarbonyO-I .SΛ-oxadiazol^-yllmethylJaminoJcarbonyl]-2,2-dimethylpropyl}-1-(4-cyanobutyl)-7-fluoro-1 H-indazole-3-carboxamide;
N-^ISJ-i-K^δ^aminocarbonyO-I.S^-oxadiazol^-yllmethylJaminoJcarbonyl]-2,2-dimethylpropyl}-6-fluoro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
N-{(1S)-1-[({[5-(aminocarbonyl)-1,3,4-oxadiazol-2-yl]methyl}amino)carbonyl]-2,2-dimethylpropyl}-1-(4-cyanobutyl)-6-fluoro-1 H-indazole-3-carboxamide;
1-[(3,3-difluorocyclobutyl)methyl]-N-[(1S)-1-({[(2S)-2,3-dihydroxypropyl]amino}carbonyl)-2,2-dimethylpropyl]-7-fluoro-1H-indazole-3-carboxamide;
N-({1-[(3,3-difluorocyclobutyl)methyl]-7-fluoro-1 H-indazol-3-yl}carbonyl)-3-methyl-L-valylglycinamide;
N-^IS^I-^cyclopropylaminoJcarbonyll^^-dimethylpropylJ-i-^S.S-difluorocyclobutyOmethyl^-fluoro-IH-indazole-S-carboxamide;
1-(4-cyanobutyl)-6-fluoro-N-[(1S)-1-({[2-hydroxy-1-(hydroxymethyl)ethyl]amino}carbonyl)-2,2-dimethylpropyl]-1 H-indazole-3-carboxamide;

6-fluoro-N-[(1S)-1-({[2-hydroxy-1-(hydroxymethyl)ethyl]amino}carbonyl)-2,2-dimethylpropyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
N-{[1-(cyclohexylmethyl)-1 H-indazol-3-yl]carbonyl}-3-methyl-L-valylglycine;
N-{[1-(4-cyanobutyl)-1H-indazol-3-yl]carbonyl}-3-methyl-L-valyl-beta-alanine;
N-{[1-(3-cyanopropyl)-1H-indazol-3-yl]carbonyl}-3-methyl-L-valylglycine;

3-methyl-N-{[1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazol-3-yl]carbonyl}-L-valylglycine;
N-[(1 S)-1 -(5-amino-1 ,3,4-oxadiazol-2-yl)-2,2-dimethylpropyl]-1 -(cyclohexylmethyl)-i H-indazole-3-carboxamide;
N-{[1-(3-cyanopropyl)-1H-indazol-3-yl]carbonyl}-3-methyl-L-valyl-beta-alanine;

N-{[1-(4-cyanobutyl)-1H-indazol-3-yl]carbonyl}-3-methyl-L-valylglycine;
N-[(1 S)-1 -(5-amino-1 ,3,4-oxadiazol-2-yl)-2,2-dimethylpropyl]-1 -(4-cyanobutyl)-1 H-indazole-3-carboxamide;
N-[(1 S)-1 -(5-amino-1 ,3,4-oxadiazol-2-yl)-2,2-dimethylpropyl]-1 -(3-cyanopropyl)-1 H-indazole-3-carboxamide;
ethyl 5-[(1S)-1-({[1-(cyclohexylmethyl)-1H-indazol-3-yl]carbonyl}amino)-2,2-d imethyl propyl]- 1 ,2 ,4-oxad iazole-3-carboxylate;
N-^ISJ-i-Cδ-amino-I .SΛ-oxadiazol^-yl^^-dimethylpropyll-i-Ctetrahydro^H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
ethyl 5-[(1S)-1-({[1 -(4-cyanobutyl)-1 H-indazol-3-yl]carbonyl}amino)-2,2-dimethylpropyl]-1 ,2,4-oxadiazole-3-carboxylate;
ethyl 5-[(1S)-1-({[1 -(3-cyanopropyl)-1H-indazol-3-yl]carbonyl}amino)-2,2-dimethylpropyl]-1 ,2,4-oxadiazole-3-carboxylate;
ethyl 5-[(1S)-2,2-dimethyl-1-({[1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazol-3-yl]carbonyl}amino)propyl]-1 ,2,4-oxadiazole-3-carboxylate;
N-{1 -[3-(2-amino-2-oxoethyl)-1 ,2,4-oxadiazol-5-yl]-2,2-dimethylpropyl}-1 -(cyclohexylmethyl)-i H-indazole-3-carboxamide;
N-{1 -[3-(2-amino-2-oxoethyl)-1 ,2,4-oxadiazol-5-yl]-2,2-dimethylpropyl}-1 -(3-cyanopropyl)-1 H-indazole-3-carboxamide;
N-{1 -[3-(2-amino-2-oxoethyl)-1 ,2,4-oxadiazol-5-yl]-2,2-dimethylpropyl}-1 -(4-cyanobutyl)-1 H-indazole-3-carboxamide;
1-(cyclohexylmethyl)-N-[(1S)-2,2-dimethyl-1-{[(2H-tetrazol-5-ylmethyl)amino]carbonyl}propyl]-1 H-indazole-3-carboxamide;
N-{1 -[3-(aminocarbonyl)-1 ,2,4-oxadiazol-5-yl]-2,2-dimethylpropyl}-1 -(4-cyanobutyl)-1 H-indazole-3-carboxamide;
N-{1 -[3-(aminocarbonyl)-1 ,2,4-oxadiazol-5-yl]-2,2-dimethylpropyl}-1 -(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;

N-{1 -[3-(aminocarbonyl)-1 ,2,4-oxadiazol-5-yl]-2,2-dimethylpropyl}-1 -(3-cyanopropyl)-1 H-indazole-3-carboxamide;
N-{1-[3-(2-amino-2-oxoethyl)-1 ,2,4-oxadiazol-5-yl]-2,2-dimethylpropyl}-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
N-{1-[3-(aminocarbonyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylpropyl}-1-(cyclohexylmethyl)-1 H-indazole-3-carboxamide;
1-(4-cyanobutyl)-N-[(1S)-2,2-dimethyl-1-({[(5-methyl-1)3,4-oxadiazol-2-yl)methyl]amino}carbonyl)propyl]-1H-indazole-3-carboxamide;
1-(cyclohexylmethyl)-N-[(1S)-2,2-dimethyl-1-({[(5-methyl-1 ,3,4-oxadiazol-2-yl)methyl]amino}carbonyl)propyl]-1H-indazole-3-carboxamide;
N-[(1 S)-2,2-dimethyl-1 -({[(5-methyl-1 ,3,4-oxadiazol-2-yl)methyl]amino}carbonyl)propyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
ethyl 5-{[(N-{[1 -(4-cyanobutyl)-1 H-indazol-3-yl]carbonyl}-3-methyl-L-valyl)amino]methyl}-1 ,3,4-oxadiazole-2-carboxylate;
ethyl 5-{[(N-{[1 -(cyclohexylmethyl)-i H-indazol-3-yl]carbonyl}-3-methyl-L-valyl)amino]methyl}-1,3,4-oxadiazole-2-carboxylate;
ethyl 5-{[(3-methyl-N-{[1 -(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazol-3-yl]carbonyl}-L-valyl)amino]methyl}-1 ,3,4-oxadiazole-2-carboxylate;
N-{(1S)-1-[({[5-(aminocarbonyl)-1 ,3,4-oxadiazol-2-yl]methyl}amino)carbonyl]-2,2-dimethylpropyl}-1-(4-cyanobutyl)-1H-indazole-3-carboxamide;
N-{(1S)-1-[({[5-(aminocarbonyl)-1 ,3,4-oxadiazol-2-yl]methyl}amino)carbonyl]-2,2-dimethylpropyl}-1-(cyclohexylmethyl)-1 H-indazole-3-carboxamide;
N-{(1S)-1-[({[5-(aminocarbonyl)-1 ,3,4-oxadiazol-2-yl]methyl}amino)carbonyl]-2,2-dimethylpropyl}-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;

1-(4-cyanobutyl)-N-[(1S)-2,2-dimethyl-1-({[(5-methyl-1 ,2,4-oxadiazol-3-yl)methyl]amino}carbonyl)propyl]-1H-indazole-3-carboxamide;
1-(cyclohexylmethyl)-N-[(1S)-2,2-dimethyl-1-({[(5-methyl-1 ,2,4-oxadiazol-3-yl)methyl]amino}carbonyl)propyl]-1 H-indazole-3-carboxamide;
N-[(1 S)-2,2-dimethyl-1 -({[(5-methyl-1 ,2,4-oxadiazol-3-yl)methyl]amino}carbonyl)propyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;

1 -(cyclohexylmethyl)-N-{(1 S)-1 -[(4-hydroxypiperidin-1 -yl)carbonyl]-2,2-dimethylpropyl}-1 H-indazole-3-carboxamide;
1 -(4-cyanobutyl )-N-{( 1 S )- 1 -[(4-hyd roxypiperidi n- 1 -yl )carbonyl]-2 , 2-dimethylpropyl}-1H-indazole-3-carboxamide;
N-{(1S)-1-[(4-hydroxypiperidin-1-yl)carbonyl]-2,2-dimethylpropyl}-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
ethyl 3-{[(N-{[1 -(4-cyanobutyl )-1 H-indazol-3-yl]carbonyl}-3-methyl-L-valyl)amino]methyl}-1 ,2,4-oxadiazole-5-carboxylate;
ethyl 3-{[(N-{[1 -(cyclohexylmethyl)-i H-indazol-3-yl]carbonyl}-3-methyl-L-valyl)amino]methyl}-1,2,4-oxadiazole-5-carboxylate;
ethyl 3-{[(3-methyl-N-{[1 -(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazol-3-yl]carbonyl}-L-valyl)amino]methyl}-1 ,2,4-oxadiazole-5-carboxylate;
N-{(1S)-1-[({[5-(aminocarbonyl)-1,2,4-oxadiazol-3-yl]methyl}amino)carbonyl]-2,2-dimethylpropyl}-1-(cyclohexylmethyl)-1H-indazole-3-carboxamide;
N-{(1S)-1-[({[5-(aminocarbonyl)-1,2,4-oxadiazol-3-yl]methyl}amino)carbonyl]-2,2-dimethylpropyl}-1-(4-cyanobutyl)-1H-indazole-3-carboxamide;
N-^ISJ-i-røδ^aminocarbonyO-i^^-oxadiazol-S-yllmethylJaminoJcarbonyl]-2,2-dimethylpropyl}-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;

1-(4-cyanobutyl)-N-[(1S)-2,2-dimethyl-1-({[(3-methyl-1 ,2,4-oxadiazol-5-yl)methyl]amino}carbonyl)propyl]-1H-indazole-3-carboxamide;
N-[(1 S)-2,2-dimethyl-1 -({[(3-methyl-1 ,2,4-oxadiazol-5-ylJmethyllaminoJcarbonyOpropyll-i-Ctetrahydro^H-pyran^-ylmethylJ-IH-indazole-S-carboxamide;
N-^IS^I-^-IS-CaminocarbonyO-i ^^-oxadiazol-S-yllethylJaminoJcarbonyl]-2,2-dimethylpropyl}-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;

N-^ISJ-i-^-tδ-CaminocarbonyO-i ^^-oxadiazol-S-yllethyQaminoJcarbonyl]-2,2-dimethylpropyl}-1-(4-cyanobutyl)-1H-indazole-3-carboxamide;
N-{(1S)-1-[({[5-(aminocarbonyl)-1,3,4-oxadiazol-2-yl]methyl}amino)carbonyl]-2,2-dimethylpropyl}-1-[(4,4-difluorocyclohexyl)methyl]-1H-indazole-3-carboxamide;
1-(4-cyanobutyl)-N-[(1S)-1-({[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]amino}carbonyl)-2,2-dimethylpropyl]-1 H-indazole-3-carboxamide;
N-[(1S)-1-({[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]amino}carbonyl)-2,2-dimethylpropyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;

N-{(1S)-1-[({[5-(aminocarbonyl)-1 )2,4-oxadiazol-3-yl]methyl}amino)carbonyl]-2,2-dimethylpropyl}-1-[(4,4-difluorocyclohexyl)methyl]-1H-indazole-3-carboxamide;
1-(4-cyanobutyl)-N-[(1S)-1-{[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}-2,2-dimethylpropyl]-1 H-indazole-3-carboxamide;
N-[(1S)-1-{[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}-2,2-dimethylpropyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
N-{(1 SJ-i-^cyclopropylaminoJcarbonylJ^^-dimethylpropylJ-i -(2-0X0-2-phenylethyl)-1 H-indazole-3-carboxamide;
N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1 -(2-0X0-2-phenylethyl)-1H-indazole-3-carboxamide;
3-methyl-N-{[1-(2-oxo-2-phenylethyl)-1H-indazol-3-yl]carbonyl}-L-valylglycinamide;
N-[(1-benzyl-1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)carbonyl]-3-methyl-L-valylglycine;
1-(2-cyclohexyl-2-oxoethyl)-N-{(1S)-1-[(cyclopropylamino)carbonyl]-2,2-dimethylpropyl}-1 H-indazole-3-carboxamide;
1-(2-cyclohexyl-2-oxoethyl)-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1 H-indazole-3-carboxamide;
N-{[1-(2-cyclohexyl-2-oxoethyl)-1H-indazol-3-yl]carbonyl}-3-methyl-L-valylglycinamide;
N-{[1-(2-fluorobenzyl)-1 H-indazol-3-yl]carbonyl}-3-methyl-L-valylglycine
1-[2-(4-cyanophenyl)-2-oxoethyl]-N-{(1S)-1-[(cyclopropylamino)carbonyl]-2,2-dimethylpropyl}-1 H-indazole-3-carboxamide;
1-[2-(4-cyanophenyl)-2-oxoethyl]-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1 H-indazole-3-carboxamide;
N-({1-[2-(4-cyanophenyl)-2-oxoethyl]-1 H-indazol-3-yl}carbonyl)-3-methyl-L-valylglycinamide;
N-[(1S)-1-(aminocarbonyl)-2)2-dimethylpropyl]-5-fluoro-1-(4-fluorobenzyl)-1 H-indazole-3-carboxamide;
1-[2-(cyclohexylamino)-2-oxoethyl]-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1H-indazole-3-carboxamide;
1-[2-(cyclohexylamino)-2-oxoethyl]-N-{(1S)-1-[(cyclopropylamino)carbonyl]-2,2-dimethylpropyl}-1 H-indazole-3-carboxamide;

N-({1-[2-(cyclohexylamino)-2-oxoethyl]-1H-indazol-3-yl}carbonyl)-3-methyl-L-valylglycinamide;
N-^i-^^-difluorocyclohexyOmethyll-IH-indazol-S-ylJcarbonyO-S-methyl-L-valylglycine;
3-methyl-N-{[1-(2-oxo-2-piperidin-1-ylethyl)-1H-indazol-3-yl]carbonyl}-L-valylglycinamide;
N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1-(2-oxo-2-piperidin-1 -ylethyl)-1 H-indazole-3-carboxamide;
N-^ISJ-i-^cyclopropylaminoJcarbonyll^^-dimethylpropylJ-i^-oxo^-piperidin-1 -ylethyl)-1 H-indazole-3-carboxamide;
N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-1-{2-oxo-2-[4-(trifluoromethoxy)phenyl]ethyl}-1 H-indazole-3-carboxamide;
N-^ISJ-i-^cyclopropylaminoJcarbonyll^^-dimethylpropylJ-i^-oxo^-^-(trifluoromethoxy)phenyl]ethyl}-1 H-indazole-3-carboxamide;
N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1-{2-oxo-2-[4-(trifluoromethoxy)phenyl]ethyl}-1 H-indazole-3-carboxamide;
3-methyl-N-[(1-{2-oxo-2-[4-(trifluoromethoxy)phenyl]ethyl}-1H-indazol-3-yl)carbonyl]-L-valylglycinamide;
1 -(cyclohexylmethyl)-N-{(1 S)-2,2-dimethyl-1 -[(2H-tetrazol-5-ylamino)carbonyl]propyl}-1 H-indazole-3-carboxamide;
N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-1-[(4,4-difluorocyclohexyl)methyl]-5-fluoro-1 H-indazole-3-carboxamide;
1-{2-[cyclohexyl(methyl)amino]-2-oxoethyl}-N-{(1S)-1-[(cyclopropylamino)carbonyl]-2,2-dimethylpropyl}-1 H-indazole-3-carboxamide;
1-{2-[cyclohexyl(methyl)amino]-2-oxoethyl}-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1 H-indazole-3-carboxamide;
N-^i^-lcyclohexyKmethyOaminol^-oxoethylJ-I H-indazol-S-yOcarbonylJ-S-methyl-L-valylglycinamide;
N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-1-(cyclohexylmethyl)-5,7-dimethyl-1 H-indazole-3-carboxamide;
i^δ-amino-S-oxopentyO-N-^IS^I-^cyclopropylaminoJcarbonyl]^^-dimethylpropyl}-1 H-indazole-3-carboxamide;

i^δ-amino-S-oxopentyO-N-^IS^I-^-hydroxyethyOaminoJcarbonylJ^.Z-dimethylpropyl]-1H-indazole-3-carboxamide;
N-{[1-(5-amino-5-oxopentyl)-1 H-indazol-3-yl]carbonyl}-3-methyl-L-valylglycinamide;
N-[(1S)-1-{[(2-chlorobenzyl)amino]carbonyl}-2,2-dimethylpropyl]-1-(cyclohexylmethyl)-7-fluoro-1 H-indazole-3-carboxamide;
N-{(1S)-1-[(cyclopropylamino)carbonyl]-2,2-dimethylpropyl}-1-(2-oxo-2-thiomorpholin-4-ylethyl)-1H-indazole-3-carboxamide;
N-[(1 S)-1 -{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1 -(2-0X0-2-thiomorpholin-4-ylethyl)-1H-indazole-3-carboxamide;
3-methyl-N-{[1-(2-oxo-2-thiomorpholin-4-ylethyl)-1H-indazol-3-yl]carbonyl}-L-valylglycinamide;
N-^ISJ-i-Caminocarbonyl^^-dimethylpropyll-i-^-C^fluorophenyO^-oxoethyl]-1 H-indazole-3-carboxamide;
N-{(1S)-1-[(cyclopropylamino)carbonyl]-2,2-dimethylpropyl}-1-[2-(4-fluorophenyl)-2-oxoethyl]-1 H-indazole-3-carboxamide;
1-[2-(4-fluorophenyl)-2-oxoethyl]-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1 H-indazole-3-carboxamide;
N-({1-[2-(4-fluorophenyl)-2-oxoethyl]-1H-indazol-3-yl}carbonyl)-3-methyl-L-valylglycinamide;
N-{(1S)-1-[5-(2-amino-2-oxoethyl)-1 ,3,4-oxadiazol-2-yl]-2,2-dimethylpropyl}-1-(4-fluorobenzyl)-1 H-indazole-3-carboxamide;
N-^ISJ-i-^cyclopropylaminoJcarbonyll^^-dimethylpropylJ-i^-oxo^-^-(trifluoromethyl)phenyl]ethyl}-1 H-indazole-3-carboxamide;
N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1-{2-oxo-2-[4-(trifluoromethyl)phenyl]ethyl}-1 H-indazole-3-carboxamide;
3-methyl-N-[(1-{2-oxo-2-[4-(trifluoromethyl)phenyl]ethyl}-1 H-indazol-3-yl)carbonyl]-L-valylglycinamide;
2-[(1S)-1-({[1-(4-fluorobenzyl)-1 H-indazol-3-yl]carbonyl}amino)-2,2-dimethylpropyl]-5-methyl-1 ,3-oxazole-4-carboxylic acid;
1-(4-fluorobenzyl)-N-[(1S)-1-({[(1-hydroxycyclopropyl)methyl]amino}carbonyl)-2,2-dimethylpropyl]-1 H-indazole-3-carboxamide;

N-{(1S)-1-[4-(aminocarbonyl)-5-methyl-1 ,3-oxazol-2-yl]-2,2-dimethylpropyl}-3-(4-fIuorobenzyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;
1-(4-fluorobenzyl)-N-[(1S)-1-{[(3-hydroxyphenyl)amino]carbonyl}-2,2-dimethylpropyl]-1H-indazole-3-carboxamide;
N-({1-[(4,4-difluorocyclohexyl)methyl]-7-fluoro-1H-indazol-3-yl}carbonyl)-3-methyl-L-valylglycine;
1-(4-fluorobenzyl)-N-[(1S)-1-({[(1-hydroxycyclopentyl)methyl]amino}carbonyl)-2,2-dimethylpropyl]-1H-indazole-3-carboxamide;
i-CcyclohexylmethyO-N-^IS^^-dimethyl-i-dμ^i H-tetrazol-δ-yl)benzyl]amino}carbonyl)propyl]-7-fluoro-1H-indazole-3-carboxamide;
1-(cycloheptylmethyl)-N-{(1S)-1-[(cyclopropylamino)carbonyl]-2,2-dimethylpropyl}-1 H-indazole-3-carboxamide;
^(cycloheptylmethylJ-N-^ISJ-i-fP-hydroxyethyOaminolcarbonyl}^^-dimethylpropyl]-1 H-indazole-3-carboxamide;
N-fli^cycloheptylmethyO-IH-indazol-S-yllcarbonylJ-S-methyl-L-valylglycinamide;
N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-7-chloro-1-[(4,4-difluorocyclohexyOmethyll-IH-indazole-S-carboxamide;
1-(4-cyanobutyl)-N-[(1S)-1-({[1-(hydroxymethyl)cyclopropyl]amino}carbonyl)-2,2-dimethylpropyl]-1H-indazole-3-carboxamide;
i^-fluorobenzyO-N-^ISJ-i-dti^hydroxymethyOcyclopropyllaminoJcarbonyl)-2,2-dimethylpropyl]-1 H-indazole-3-carboxamide;
N-{(1S)-1-[(cyclopropylamino)carbonyl]-2,2-dimethylpropyl}-1-(5,5,5-trifluoropentyl)-1 H-indazole-3-carboxamide;
N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1 -(5,5,5-trifluoropentyl)-1 H-indazole-3-carboxamide;
3-methyl-N-{[1-(5,5,5-trifluoropentyl)-1H-indazol-3-yl]carbonyl}-L-valylglycinamide;
N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-1-[2-(tert-butylamino)-2-oxoethyl]-1 H-indazole-3-carboxamide;
1-[2-(tert-butylamino)-2-oxoethyl]-N-{(1S)-1-[(cyclopropylamino)carbonyl]-2,2-dimethylpropyl}-1 H-indazole-3-carboxamide;

1-[2-(tert-butylamino)-2-oxoethyl]-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1 H-indazole-3-carboxamide;
N-({1-[2-(tert-butylamino)-2-oxoethyl]-1 H-indazol-3-yl}carbonyl)-3-methyl-L-valylglycinamide;
N-{(1S)-1-[({[5-(aminocarbonyl)-1 ,2,4-oxadiazol-3-yl]methyl}amino)carbonyl]-2,2-dimethylpropyl}-1-[(4,4-difluorocyclohexyl)methyl]-1H-indazole-3-carboxamide;
N-^IS^I-IIS^aminocarbonyOpiperidin-i-yllcarbonylJ^^-dimethylpropyl]-!^-fluorobenzyl)-1 H-indazole-3-carboxamide;
N-{(1S)-1-[({[5-(aminocarbonyl)-1,3,4-oxadiazol-2-yl]methyl}amino)carbonyl]-2,2-dimethylpropyl}-7-fluoro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
N-^ISJ-i-^cyclopropylaminoJcarbonyll^^-dimethylpropylJ-i-^etrahydro^H-thiopyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1-(tetrahydro-2H-thiopyran-4-ylmethyl)-1H-indazole-3-carboxamide;
3-methyl-N-{[1-(tetrahydro-2H-thiopyran-4-ylmethyl)-1H-indazol-3-yl]carbonyl}-L-valylglycinamide;
i-benzyl-N-^ISJ-i-^-^cyclopropylcarbonyOaminolethylJamino^arbonyl]^^-dimethylpropyl}-1 H-indazole-3-carboxamide;
N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-1-(cyclohexylmethyl)-5-(trifluoromethoxy)-1H-indazole-3-carboxamide;
i-icyclohexylmethyO-N-^IS^I-fP-hydroxyethyOaminoJcarbonyl}^^-dimethylpropyl]-5-(trifluoromethoxy)-1H-indazole-3-carboxannide;
i^cyclohexylmethyO-N-^ISJ-i-^S-hydroxypropyOaminolcarbonyl}^^-dimethylpropyl]-5-(trifluoromethoxy)-1H-indazole-3-carboxamide;
N-lti^cyclohexylmethyO-S-^rifluoromethoxyJ-I H-indazol-S-yllcarbonylJ-S-methyl-L-valylglycinamide;
^(cyclohexylmethyO-N-^ISJ-i-t^yclopropylamino^arbonyl]^^-dimethylpropyl}-5-(trifluoromethoxy)-1H-indazole-3-carboxamide;
1-(cyclohexylmethyl)-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-5-methoxy-1H-indazole-3-carboxamide;
N-^IS^I^aminocarbonyO^^-dimethylpropylJ-i^cyclohexylmethyO-δ-methoxy-1 H-indazole-3-carboxamide;

1-(cyclohexylmethyl)-N-{(1S)-1-[(cyclopropylamino)carbonyl]-2,2-dimethylpropyl}-5-methoxy-1 H-indazole-3-carboxamide;
^(cyclohexylmethyO-N-^ISJ-i-^S-hydroxypropyOaminoJcarbonyl}^^-dimethylpropyl]-5-methoxy-1H-indazole-3-carboxamide;
N-{[1-(cyclohexylmethyl)-5-methoxy-1H-indazol-3-yl]carbonyl}-3-methyl-L-valylglycinamide;
N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-5-(trifluoromethoxy)-1H-indazole-3-carboxamide;
N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-5-(trifluoromethoxy)-1H-indazole-3-carboxamide;
N-KISJ-i-^cyclopropylamino^arbonyll^^-dimethylpropylJ-i-^etrahydro^H-pyran-4-ylmethyl)-5-(trifluoromethoxy)-1H-indazole-3-carboxamide;
3-methyl-N-{[1-(tetrahydro-2H-pyran-4-ylmethyl)-5-(trifluoromethoxy)-1H-indazol-3-yl]carbonyl}-L-valylglycinamide;
N-{[5-fluoro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazol-3-yl]carbonyl}-3-methyl-L-valylglycine;
N-{[1-(cyclohexylmethyl)-5-fluoro-1 H-indazol-3-yl]carbonyl}-3-methyl-L-valylglycine;
N-di^-cyanobutyO-δ-fluoro-IH-indazol-S-yllcarbonyll-S-methyl-L-valylglycine;

N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-1-(cyclohexylmethyl)-5-hydroxy-1 H-indazole-3-carboxamide;
N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-1-[(4,4-difluorocyclohexyl)methyl]-7-fluoro-1 H-indazole-3-carboxamide;
N-^ISJ-i-^cyclopropylamino^arbonyll^^-dimethylpropylJ-i-^^-difluorocyclohexyl)methyl]-7-fluoro-1 H-indazole-3-carboxamide;
1-[(4,4-difluorocyclohexyl)methyl]-7-fluoro-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1 H-indazole-3-carboxamide;
1-[(4,4-difluorocyclohexyl)methyl]-7-fluoro-N-[(1S)-1-{[(3-hydroxypropyl)amino]carbonyl}-2,2-dimethylpropyl]-1 H-indazole-3-carboxamide;
N-({1-[(4,4-difluorocyclohexyl)methyl]-7-fluoro-1H-indazol-3-yl}carbonyl)-3-methyl-L-valylglycinamide;
N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-1-[(4,4-difluorocyclohexyl)methyl]-5-fluoro-1 H-indazole-3-carboxamide;

N-^ISJ-i-^cyclopropylaminoJcarbonyll^^-dimethylpropylJ-i-^^-difluorocyclohexyl)methyl]-5-fluoro-1 H-indazole-3-carboxamide;
1-[(4,4-clifluorocyclohexyl)methyl]-5-fluoro-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1H-indazole-3-carboxamide;
1-[(4,4-difluorocyclohexyl)methyl]-5-fluoro-N-[(1S)-1-{[(3-hydroxypropyl)amino]carbonyl}-2,2-dimethylpropyl]-1 H-indazole-3-carboxamide;

N-({1-[(4,4-difluorocyclohexyl)methyl]-5-fluoro-1H-indazol-3-yl}carbonyl)-3-methyl-L-valylglycinamide;
N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-1-(cyclohexylmethyl)-5,7-dimethyl-1H-indazole-3-carboxamide;
N-({1-[(4,4-difluorocyclohexyl)methyl]-7-fluoro-1 H-indazol-3-yl}carbonyl)-3-methyl-L-valylglycine;
N-[(1 S)-1 -(aminocarbonyl)-2,2-dimethylpropyl]-7-chloro-1 -[(4,4-difluorocyclohexyOmethylJ-I H-indazole-S-carboxamide;
7-chloro-N-{(1 S)-1 -[(cyclopropylamino)carbonyl]-2,2-dimethylpropyl}-1 -[(4,4-difluorocyclohexyOmethyll-IH-indazole-S-carboxamide;
7-chloro-1-[(4,4-difluorocyclohexyl)methyl]-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1 H-indazole-3-carboxamide;
7-chloro-1-[(4,4-difluorocyclohexyl)methyl]-N-[(1S)-1-{[(3-hydroxypropyl)amino]carbonyl}-2,2-dimethylpropyl]-1H-indazole-3-carboxamide;
N-({7-chloro-1-[(4,4-difluorocyclohexyl)methyl]-1 H-indazol-3-yl}carbonyl)-3-methyl-L-valylglycinamide;
1-(cyclohexylmethyl)-N-{(1S)-2,2-dimethyl-1-[(1 ,3,4-thiadiazol-2-ylamino)carbonyl]propyl}-1 H-indazole-3-carboxamide;
N-{(1S)-2,2-dimethyl-1-[(1 ,3,4-thiadiazol-2-ylamino)carbonyl]propyl}-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-3-carboxamide;
1-(4-cyanobutyl)-N-{(1S)-2,2-dimethyl-1-[(1 ,3,4-thiadiazol-2-ylamino)carbonyl]propyl}-1 H-indazole-3-carboxamide;
1-(3-cyanopropyl)-N-{(1S)-2,2-dimethyl-1-[(1 ,3,4-thiadiazol-2-ylamino)carbonyl]propyl}-1 H-indazole-3-carboxamide;
1-(cyclohexylmethyl)-N-{(1S)-1-[(isoxazol-4-ylamino)carbonyl]-2,2-dimethylpropyl}-1 H-indazole-3-carboxamide;

N-{(1S)-1-[(isoxazol-4-ylamino)carbonyl]-2,2-dimethylpropyl}-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
1-(4-cyanobutyl)-N-{(1S)-1-[(isoxazol-4-ylamino)carbonyl]-2,2-dimethylpropyl}-1 H-indazole-3-carboxamide;
1-(3-cyanopropyl)-N-{(1S)-1-[(isoxazol-4-ylamino)carbonyl]-2,2-dimethylpropyl}-1 H-indazole-3-carboxamide;
N-[(1 S)-1 -({[2-hydroxy-1 -(hydroxymethyl)ethyl]amino}carbonyl)-2,2-dimethylpropyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-indazole-3-carboxamide;
1-(4-cyanobutyl)-N-[(1S)-1-({[2-hydroxy-1- (hydroxymethyl)ethyl]amino}carbonyl)-2,2-dimethylpropyl]-1 H-indazole-3-carboxamide; or
1 -(3-cyanopropyl)-N-[(1 S)-1 -({[2-hydroxy-1 -(hydroxymethyl)ethyl]amino}carbonyl)-2,2-dimethylpropyl]-1 H-indazole-3-carboxamide.

In one embodiment X is N;
R1 is CrC6 cyanoalkyl, R6i.5-heterocyclyl-(CH2)n- or R7I-5-C3-C7 cycloalkyl-(CH2)n-; wherein
each R6 is independently H or oxo;
each R7 is independently H, halo or CrC6 alkyl;
R2 is NR11R12-C(O)-R13CH-, R16O(O)-R13CH-, R22R23CH- Or R26I-5-C3-C7 cycloalkyl; wherein
R11 and R12 are independently H, CrC6 alkyl, CrC6 alkoxy-(CH2)n-, C3- C7 cycloalkyl, cyano-Ci-C6 alkyl, (OH-CrC6 alkyl)2-CrC6 alkylene, OH-C3-C7 cycloalkyl-(CH2)n-, OH-(CH2)n-C3-C7 cycloalkyl- or OH-aryl;
R13 is H, CrC6 alkyl, OH-CrC6 alkyl, aryl, aryl-(CH2)n- or cycloalkyl;
R16 is OH or CrC6 alkoxy;
R22 and R23 are independently H, CrC6 alkyl, cycloalkyl-(CH2)n-, OH-d- C6 alkyl, aryl, or aryl-OH-CrC6 alkylene;
each R26 is independently H, OH, OH-CrC6 alkyl, aryl-(CH2)n-O-, NH2- C(O)- or CrC6 alkoxy-C(O)-;
n is an integer from 1 to 6; and
each R3 is independently H, halo, C1-C6 alkyl, aryl, NH2-C(O)-, CrC6 alkoxy or heteroaryl.

In another embodiment X in N;
R1 is cyano-(CH2)3-, R6i-5-tetrehydropyranyl- CH2- or R7i-5-cyclohexyl- CH2-; wherein
each R6 is independently H;
each R7 is independently H;
R2 is NR11R12-C(O)-R13CH-, R16O(O)-R13CH-, R22R23CH-, R261-5-cyclohexyl, R26i-5-tetrahydronapthyl or R2V5-dihydroindenyl; wherein
R11 and R12 are independently H;
R13 is H, (CHa)3C, (CH3)2CHCH2) (CH3)2CH, OH-ethyl, benzyl or
cyclohexyl;
R16 is OH or CH3O;
R22 and R23 are independently H, (CH3)3C, OHCH2 or OH-isopropyl; each R26 is independently H or OH; and
each R3 is independently H.

In another embodiemtn X is N;
R1 is



R2 IS


each R3 is independently H.

In one embodiment a compound or pharmaceutically acceptable salt thereof, selected from
N-[(1S,2R)-1-(aminocarbonyl)-2-hydroxypropyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide;
N-[(1 S)-1 -(aminocarbonyl)-2-methylpropyl]-1 -(tetrahydro-2H-pyran-4-ylmethyl)-1 H-pyrazolo[3,4-b]pyridine-3-carboxamide;
N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide;
N-[(1S,2S)-2-hydroxycyclohexyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-pyrazolo[3,4-b]pyridine-3-carboxamide;
N-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide;
N-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-pyrazolo[3,4-b]pyridine-3-carboxamide;
N-[(1S)-2-amino-1-cyclohexyl-2-oxoethyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-pyrazolo[3,4-b]pyridine-3-carboxamide;
N-[(1 S)-1 -(aminocarbonyl)-2,2-dimethylpropyl]-1 -(4-cyanobutyl)-1 H-pyrazolo[3,4-b]pyridine-3-carboxamide;
methyl 3-methyl-N-{[1 -(tetrahydro-2H-pyran-4-ylmethyl)-1 H-pyrazolo[3,4-b]pyridin-3-yl]carbonyl}-L-valinate;
N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-1-(4-cyanobutyl)-1 H-pyrazolo[3,4-b]pyridine-3-carboxamide;
1-(4-cyanobutyl)-N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]-1 H-pyrazolo[3,4-b]pyridine-3-carboxamide;
N-[(1S)-1-(aminocarbonyl)-3-methylbutyl]-1-(4-cyanobutyl)-1 H-pyrazolo[3,4-b]pyridine-3-carboxamide;
N-[(1 S,2R)-1 -(aminocarbonyl)-2-hydroxypropyl]-1 -(4-cyanobutyl)-1 H-pyrazolo[3,4-b]pyridine-3-carboxamide;
N-[(1S)-2-hydroxy-1-(hydroxymethyl)-2-methylpropyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide;

Nalpha-{[1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]carbonyl}-L-phenylalaninamide;
N-[(1S)-1-(aminocarbonyl)-3-methylbutyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide;
N-[(1 S)-1 -(aminocarbonyl)-2,2-dimethylpropyl]-1 -(cyclohexylmethyl)-i H-pyrazolo[3,4-b]pyridine-3-carboxamide;
N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-pyrazolo[3,4-b]pyridine-3-carboxamide; or
3-methyl-N-{[1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-pyrazolo[3,4-b]pyridin-3-yl]carbonyl}-L-valine.
In one embodiment the present invention is a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt, enantiomer, or racemate thereof.
In one embodiment the present invention is a method for the treatment of a CB1 mediated disorder in a subject in need of such treatment or prevention, wherein the method comprises administering to the subject an amount of a compound of Formula I or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein the amount of the compound is effective for the treatment or prevention of the CB1 mediated disorder.
In one embodiment the CB1 mediated disorder is pain.

Salts of the Compounds of this Invention
The compounds of this invention may be used in the form of salts derived from inorganic or organic acids. Depending on the particular compound, a salt of the compound may be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidities, or a desirable solubility in water or oil. In some instances, a salt of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound.

Where a salt is intended to be administered to a patient (as opposed to, for example, being used in an in vitro context), the salt preferably is pharmaceutically acceptable. Pharmaceutically acceptable salts include salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. In general, these salts typically may be prepared by conventional means with a compound of this invention by reacting, for example, the appropriate acid or base with the compound.
Pharmaceutically-acceptable acid addition salts of the compounds of this invention may be prepared from an inorganic or organic acid. Examples of suitable inorganic acids include hydrochloric, hydrobromic acid, hydroionic, nitric, carbonic, sulfuric, and phosphoric acid. Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclyl, carboxyic, and sulfonic classes of organic acids. Specific examples of suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate,
toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylaminosulfonate, algenic acid, b-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, bisulfate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate, glycoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, nicotinate, 2-naphthalesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, thiocyanate, tosylate, undecanoate and naphthalene-1 ,5-disulfonate.
Pharmaceutically-acceptable base addition salts of the compounds of this invention include, for example, metallic salts and organic salts. Preferred metallic salts include alkali metal (group Ia) salts, alkaline earth metal (group Ma) salts, and other physiological acceptable metal salts. Such salts may be made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc. Preferred organic salts may be made from tertiary amines and quaternary amine salts, such as tromethamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Basic
nitrogen-containing groups may be quaternized with agents such as lower alkyl (CrCβ) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibuytl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), arylalkyl halides (e.g., benzyl and phenethyl bromides), and others.

Also within the scope of the invention are so-called 'prodrugs' of the compounds of formula (I). Thus certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. E B Roche, American
Pharmaceutical Association).
Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985). Some examples of prodrugs in accordance with the invention include:
(i) where the compound of formula (I) contains an alcohol functionality (-OH), an ether thereof, for example, replacement of the hydrogen with (Cr
C6)alkanoyloxymethyl ;
(ii) where the compound of formula (I) contains carboxy group, an ester thereof, for example, replacement of the OH of the carboxy with CrCe alkyl; and
(ii) where the compound of formula (I) contains a primary or secondary amino functionality (-NH2 or -NHR where R ≠ H), an amide thereof, for example,
replacement of one or both hydrogens with (Ci-Cio)alkanoyl.
Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.
Finally, certain compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I).
Compounds of formula (I) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism ('tautomerism') can occur. It follows that a single compound may exhibit more than one type of isomerism.

Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (I), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine.
Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture.
Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art - see, for example, "Stereochemistry of Organic Compounds" by E L EHeI (Wiley, New York, 1994).
The present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 123I and 125I, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P, and sulphur, such as 35S.

Certain isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
Substitution with positron emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.

All of the compounds of the formula (I) can be prepared by the procedures described in the general methods presented below or by the specific methods described in the Examples section and the Preparations section, or by routine modifications thereof. The present invention also encompasses any one or more of these processes for preparing the compounds of formula (I), in addition to any novel intermediates used therein.

Treating Conditions Using the Compounds of this Invention
The method of the present invention is useful for, but not limited to, the treatment of disorders that are mediated by CB1 in a subject. For example, the compounds described herein would be useful for the treatment of any symptoms associated with a CB1 meditated disorder described below.
As used herein, the terms "treating", "treatment", "treated", or "to treat," can be used interchangeably. Treatment includes palliative treatment, preventive treatment and restorative treatment. Palliative treatment includes alleviation, elimination of causation of pain and/or inflammation associated with a CB1 mediated disorder.
Preventaive treatment means to prevent or to slow the appearance of symptoms associated with a CB 1 mediated disorder. For methods of prevention, the subject is any subject, and preferably is a subject that is in need of prevention of a CB1 mediated disorder.
The term "subject" for purposes of treatment includes any human or animal subject who is in need of the prevention of, or who has a TNFα-mediated inflammatory disease or disorder. The subject is typically a mammal.
In some embodiments, the methods and compositions of the present invention encompass the treatment of conditions including pain and neurodegenerative disorders. (See Annυ. Rev. Pharmacol. Toxicol. (2006) 46:101-22; Clinical
Neuroscience Research (2005)5 185-199; Prostaglandins, Leukotrienes and Essential Fatty Acids (2002) 66(2&3), 101-121.)
In some embodiments, the methods and compositions of the present invention encompass the treatment of pain, including but not limited to chronic pain, acute pain, joint pain, nociceptive pain, neuropathic pain, allodynia, hyperalgesia, burn pain, menstrual cramps, kidney stones, headache, migraine headache, sinus headaches, tension headaches, dental pain, myasthenia gravis, rheumatoid arthritic pain, osteoarthritic pain, back pain, cancer pain, multiple sclerosis, sarcoidosis, Behcet's syndrome, myositis, polymyositis, gingivitis, hypersensitivity, swelling occurring after injury, closed head injury, endometriosis, stroke, and the like.
In other embodiments, the methods and compositions of the present invention encompass the treatment of the connective tissue and joint disorders selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, fibromyalgia, spondyloarthopathies, gouty arthritis, lumbar spondylarthrosis, carpal tunnel syndrome, psoriatic arthritis, sclerodoma , canine hip dysplasia, systemic lupus erythematosus, juvenile arthritis, osteoarthritis, tendonitis and bursitis.
In other embodiments, the methods and compositions of the present invention encompass the treatment of neurological dosirders including neuroinflammation and neurodegenerative disorders selected from the group consisting of neuritis,
Alzheimer's disease, multiple sclerosis (MS), Parkinson's disease, Tourette's syndrome, spasticity and epilepsy.
In other embodiments, the methods and compositions of the present invention encompass the treatment of neuropathies including HIV related neuropathy, nerve injury, spinal cord injury, sciatica, neuralgia, diabetic neuropathy, nerve pain, and some peripheral neuropathies and neurodegenerative disorders.
In other embodiments, the methods and compositions of the present invention encompass the treatment of the respiratory disorders selected from the group consisting of cough, asthma, bronchitis, chronic obstructive pulmonary disease
(COPD), broncho constriction, cystic fibrosis, pulmonary edema, pulmonary embolism, pneumonia, pulmonary sarcoisosis, silicosis, pulmonary fibrosis, respiratory failure, acute respiratory distress syndrome, seasonal allergic rhinitis, reversible airway obstruction, adult respiratory disease syndrome, cryptogenic fibrosing alveolitis and emphysema.
In other embodiments, the methods and compositions of the present invention encompass the treatment of the dermatological disorders selected from the group consisting of acne, psoriasis, eczema, burns, poison ivy, poison oak and dermatitis.
In other embodiments, the methods and compositions of the present invention encompass the treatment of the surgical disorders selected from the group consisting of pain and swelling following surgery, infection following surgery and inflammation following surgery.
In other embodiments, the methods and compositions of the present invention encompass the treatment of the gastrointestinal disorders selected from the group consisting of colitis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, gastritis, irritable bowel syndrome, diarrhea, constipation, dysentery, ulcerative colitis, gastric esophageal reflux, gastric ulcers, gastric varices, ulcers, functional gastrointestinal disorder, and heartburn.
In other embodiments, the methods and compositions of the present invention encompass the treatment of the ophthalmic disorders selected from the group consisting of retinopathies, uveitis, ocular photophobia, acute injury to the eye tissue, conjunctivitis, age-related macular degeneration diabetic retinopathy, detached retina, glaucoma, vitelliform macular dystrophy type 2, gyrate atrophy of the choroid and retina, conjunctivitis, corneal infection, fuchs' dystrophy, iridocorneal endothelial syndrome, keratoconus, lattice dystrophy, map-dot-fingerprint dystrophy, ocular herpes, pterygium, myopia, hyperopia, and cataracts.
Cannabinoid agonists are believed to be useful in the treatment of other disorders including acute cerebral ischemia, neuroprotection, anxiety, cerebrovascular ischemia, cachexia, nausea, emesis, chemotherapy-induced emesis, cutaneous T cell lymphoma, diabetes, osteoporosis, glomerulonephritis, renal ischemia, nephritis, hepatitis, cerebral stroke, vasodialation, hypertension, vasculitis, myocardial infarction and cerebral ischemia.

Pharmaceutical Compositions Containing the Compounds of this Invention
This invention also is directed to pharmaceutical compositions (or
"medicaments") comprising the compounds described above (including tautomers of the compounds, and pharmaceutically-acceptable salts of the compounds and tautomers), and to methods for making pharmaceutical compositions comprising those compounds in combination with one or more conventional non-toxic, pharmaceutically-acceptable carriers, diluents, wetting or suspending agents, vehicles, and/or adjuvants (the carriers, diluents, wetting or suspending agents, vehicles, and adjuvants sometimes being collectively referred to in this specification as "carrier materials"); and/or other active ingredients. The preferred composition depends on the method of administration. Formulation of drugs is generally discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA: 1975) (incorporated by reference into this specification). See also, Liberman, H.A., Lachman, L., eds., Pharmaceutical Dosage Forms (Marcel Decker, New York, N. Y., 1980) (incorporated by reference into this specification).
In many embodiments, the pharmaceutical composition is made in the form of a dosage unit containing a particular amount of the active ingredient. Typically, the pharmaceutical composition contains from about 0.1 to 1000 mg (and more typically, 7.0 to 350 mg) of the compound.
The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or
1 ,1 ,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

The pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
A suitable solution formulation for use in an atomiser using
electrohydrodynamics to produce a fine mist may contain from 1μg to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1μl to 100μl. A typical formulation may comprise a compound of the invention, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and
programmed release.
In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or "puff' containing from 0.001 mg to 10mg of the compound of the invention. The overall daily dose will typically be in the range 0.001 mg to 40mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
Solid dosage forms for oral administration include, for example, hard or soft capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds are ordinarily combined with one or more adjuvants. If administered per os, the compounds may be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation, as may be provided in a dispersion of the compound of this invention in hydroxypropylmethyl cellulose. In the case of capsules, tablets, and pills, the dosage forms also may comprise buffering agents, such as sodium citrate, or magnesium or calcium carbonate or bicarbonate. Tablets and pills additionally may be prepared with enteric coatings.
Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions also may comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents.
"Parenteral administration" includes subcutaneous injections, intravenous injections, intramuscular injections, intrasternal injections, and infusion. Injectable preparations (e.g., sterile injectable aqueous or oleaginous suspensions) may be formulated according to the known art using suitable dispersing, wetting agents, and/or suspending agents. Acceptable carrier materials include, for example, water,
1 ,3-butanediol, Ringer's solution, isotonic sodium chloride solution, bland fixed oils (e.g., synthetic mono- or diglycerides), dextrose, mannitol, fatty acids (e.g., oleic acid), dimethyl acetamide, surfactants (e.g., ionic and non-ionic detergents), and/or polyethylene glycols (e.g., PEG 400).
Formulations for parenteral administration may, for example, be prepared from sterile powders or granules having one or more of the carriers materials mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, com oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. The pH may be adjusted, if necessary, with a suitable acid, base, or buffer.

General Synthesis
Compounds of formula (I) illustrated in the Examples hereinafter, and the requisite intermediates for preparing the compounds of formula (I), may be prepared using the methods described in the following Schemes A and B. The skilled man will appreciate that the compounds of the invention could be made by methods other than those specifically described herein, for example by adaptation of the herein described methods according to the known art. In the methods below, unless otherwise specified, the groups X, R1, R2, and R3M are as described above for a compound of formula (I).

Scheme A



Starting compound 1 , wherein X is either carbon or nitrogen and R* is a carboxyl protecting group such as alkyl or aralkyl, can be treated with a base and an alkylating agent. Exemplary bases include sodium hydride, potassium terf-butoxide, sodium hexamethyldisilazide, and potassium carbonate, and exemplary alkylating agents include R1-L where L is a leaving group, such as a halogen, or a mesylate, or a tosylate, and R1 is as described in the description of general formula (I). The reaction generally produces a mixture of regioisomers wherein the alkylation occurs either on N1 or N2 position of the indazole ring, depending upon the base and the alkylating agent. The desired N 1 -alkylated regioisomer is isolated in pure form by either chromatographic separation, or recrystallization of the crude product mixture. Saponification of the alkylated product with an aqueous base such as sodium hydroxide, potassium hydroxide, or lithium hydroxide gives compound 2.
Compound 2 may be coupled with an amine 3 by using reaction conditions well known in the art for peptide bond synthesis [see, for example, Bodanszky and Bodanszky, The Practice of Peptide Chemistry. Springer- Verlag (1984); Bodanszky, Principles of Peptide Synthesis. Springer-Verlag (1984); Han, S-Y and Kim, Y-A, Tetrahedron, vol. 60, pp 2447-2467 (2004)] to give a compound of formula (I). Exemplary reagents for activating the carboxyl group of compound 2 for reacting with the amine 3 include carbodiimide reagents such as A/,/V-dicyclohexylcarbodiimide (DCC) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodimide (EDC), either alone or in combination with 1-hydroxybenzotriazole (HOBt), and uronium reagents such as O-(7-azabenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-1,1 ,3,3-tetrarnethyluronium hexafluorophosphate (HBTU), and O-(benzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TBTU).
Scheme B


Starting compound 1, wherein X is a carbon and R* is a carboxyl protecting group such as alkyl or aralkyl, can be prepared from compound 4 according to the procedure of Johnson, B. L.; Rodgers, J. D. Syn. Comm. 2005, 35, 2681-2684 as shown in Scheme B. Thus, compound 4 is converted to compound 5 via base-catalyzed ring opening followed by diazotization. Reduction of compound 5 to produce compound 6, and subsequent ring closure gives compound 7. Esterification of compound 7 with a suitable alcohol of the formula R*-OH and an acid catalyst gives compound 1.

Starting compound 1 , wherein X is a nitrogen and R* is a carboxyl protecting group such as alkyl or aralkyl, can be prepared according to known methods in the literature [see, for example, Lynch, B. M. et al, Canadian Journal of Chemistry, vol. 66, pp 420-428 (1988); Huang, S. et al, Bioorαanic & Medicinal Chemistry Letters, vol. 17, pp1243-1245 (2007); Lin, R. et al, Bioorαanic & Medicinal Chemistry Letters, vol. 17, pp 4297-4302 (2007)].
Amine compounds 3 (R2-NH2) are either commercially available, or readily prepared according to methods known in the art as depicted in the protocols for representative Preparations herein.
Compounds of the invention are available by either the methods described herein in the Methods, Examples and Preparations, or suitable adaptations thereof using methods known in the art. It is to be understood that the synthetic transformations mentioned herein may be carried out in various different sequences in order that the desired compounds may be efficiently assembled. The skilled chemist will exercise his judgment and skill as to the most efficient sequence of reactions for synthesis of a given target compound.
The compounds, salts and solvates (including hydrates) of the invention may be separated and purified by conventional methods.
Separation of diastereomers may be achieved by conventional techniques, e.g. by chromatography or HPLC of a stereoisomeric mixture of a compound of formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound of formula (I) may also be prepared from a corresponding optically pure intermediate or by resolution, such as by chromatography of the corresponding racemate using a suitable chiral support or by fractional crystallization of the diastereomeric salts formed by a reaction of the corresponding racemate with a suitable optically active acid or base.

BIOLOGICAL EVALUATION
Method for assessing biological activities:
The Human CB1 receptor binding affinity and other biological activities of the compounds of this invention are determined by the following procedures.
Membrane preparation: Human Embryonic Kidney (HEK) Cells expressing the human CB 1 receptor under transcriptional regulation of a tetracycline inducible promoter were grown in Dulbecco's Modified Essential Medium with sodium pyruvate (Invitrogen, Carlsbad, CA) containing 10% tetracycline free fetal bovine serum (Clonetech, Mountain View, CA) 100 μg/ml hygromycin (Calbiochem, San Diego, CA), 5 ug/ml blasticidin (Invitrogen). CB1 receptor expression was induced by addition of 1 μg/ml doxycycline (Calbiochem) and incubation for an additional 24 hours. Cells were released from flasks using Cell Dissociation Buffer (Invitrogen). Cells were pelleted by centrifugation at 500 X G for 5 minutes. Membranes were prepared by resuspending cells in ice cold TEE Buffer (25mM Tris pH 7.4, 5mM EDTA, 5mM EGTA, Complete Protease Inhibitor (Roche, Basel, Switzerland)). Cells were lysed with 12 strokes of a dounce homogenizer. Unlysed cells were pelleted by centrifugation at 500 X G for 5 minutes. Membranes were pelleted by centrifugation at 25,000 X G for 30 minutes. Membranes were resuspended in TEE, dounced 12 strokes, and pelleted a second time at 25,000 X G for 30 minutes. Membrane pellet was resuspended in 5OmM Tris pH 7.4, 10OmM NaCI, 3mM MgCI2, 0.2mM EGTA, Complete Protease Inhibitor (Roche). Protein concentration was determined using the Micro-BCA Protein Assay Kit (Pierce, Rockford, IL) using BSA as a standard. Membranes were quick frozen and stored at -80 degrees Celsius until use.

Binding experiments: 50 μl of test compound was incubated with 50 μl of [3H] CP-55,940 (Perkin Elmer, Boston, MA) (final concentration = 500 pM) and 150 μl of membrane homogenate (1 μg/well) in polypropylene 96-well plates (Corning, Acton, MA). Final reaction conditions were 5OmM Tris pH 7.4, 10OmM NaCI, 3mM MgCI2, 0.2mM EGTA, 0.04% BSA. Nonspecific binding was determined by incubation with 50 μM WIN-55,212-2 (Tocris, Ellisville, MO). After incubation at room temperature for 60 minutes reactions were harvested by vacuum filtration through Unifilter GF/B-96 filters (Perkin Elmer) that had been presoaked in assay buffer containing 0.5% BSA (Sigma, St. Louis, MO) using a FilterMate Plate Harvester (Perkin Elmer). Filters were rinsed 4 times with 5OmM Tris pH 7.4, 0.025% Tween-20 and dried at 50 degrees Celsius for at least 30 minutes. 40 μl of Microscint-20 (Perkin Elmer) was added per well, and plates were counted using a Top-Count Microplate Scintillation Counter (Perkin Elmer).
Binding data were analyzed and EC5O and Ki values calculated using Graph Pad Prism 4.0 Software.

GTPvS Binding:
Membrane preparation: CHO cells expressing the human CB1 receptor were grown to 80% confluence in Ham's F-12 Nutrient Medium (Invitrogen) containing 10% fetal bovine serum (Invitrogen), 1% pen/strep (Invitogen), 1% Nonessential amino acids (Invitrogen) and 500 μg/ml G418 (Invitrogen). Cells were released from flasks using Cell Dissociation Buffer (Invitrogen). Cells were pelleted by centrifugation at 500 X G for 5 minutes. Membranes were prepared by resuspending cells in ice cold Assay Buffer (25mM Tris pH 7.4, 5mM EDTA, 5mM EGTA, Complete Protease Inhibitor (Roche)). Cells were lysed with 12 strokes of a dounce homogenizer. Unlysed cells were pelleted by centrifugation at 500 X G for 5 minutes. Membranes were pelleted by centrifugation at 25,000 X G for 30 minutes. Membranes were resuspended in TEE1 dounced 12 strokes, and pelleted a second time at 25,000 X G for 30 minutes.
Membrane pellet was resuspended in 5OmM Tris pH 7.4, 10OmM NaCI, 3mM MgCb, 0.2mM EGTA, Complete Protease Inhibitor (Roche). Protein concentration was determined using the Micro-BCA Protein Assay Kit (Pierce) using BSA as a standard. Membranes were frozen and stored at -80 degrees Celsius until use.

GTPvS Binding: 40 μl of test compound was incubated with 20 μl of [35 S] GTPyS (Perkin Elmer) (1250 Ci/millimole) and 140 μl of membrane homogenate (5 ug/well) in polypropylene 96-well plates (Corning). Final reaction conditions were 5OmM Tris pH 7.4, 10OmM NaCI, 3mM MgCI2, 0.2mM EGTA, 0.04% BSA. After incubation at 37 degrees Celsius for 45 minutes reactions were harvested by vacuum filtration through Unifilter GF/B-96 filters (Perkin Elmer) using a FilterMate Plate Harvester (Perkin Elmer). Filters were rinsed 4 times with ice cold 5OmM Tris pH 7.4, 3mM MgCb, 0.2mM EGTA and dried at 50 degrees Celsius for at least 30 minutes. 40 μl of Microscint-20 (Perkin Elmer) was added per well, and plates were counted using a Top-Count Microplate Scintillation Counter (Perkin Elmer). Binding data were analyzed and EC5O values were calculated using Graph Pad Prism 4.0 Software.
The above protocol assays were used to determine biological activity. The Ki towards human CB1 receptors for certain compounds of the invention are measured to be 0.01-1000 nM. The EC50 towards human CB1 receptors in the GTPyS assay for certain compounds of the invention are measured to be 0.1-5000 nM. Table 1 shows certain biological activities for some of the exemplified compounds.

*ND = Not determined

Examples and Preparations
The invention is illustrated in the following non-limiting examples and preparations in which, unless stated otherwise: all operations were carried out at room or ambient temperature, that is, in the range of 18-25 degrees Celsius; evaporation of solvent was carried out using a rotary evaporator under reduced pressure with a bath temperature of up to 60 degrees Celsius; reactions were monitored by thin layer chromatography (TLC) and reaction times are given for illustration only; melting points (mp) given are uncorrected (polymorphism may result in different melting points); the structure and purity of all isolated compounds were assured by at least one of the following techniques: TLC (Merck silica gel 60 F2S4 precoated TLC plates or Merck NH2 gel (an amine coated silica gel) F2S4S precoated TLC plates), mass spectrometry, nuclear magnetic resonance spectra (NMR), infrared absorption spectra (IR) or microanalysis. Yields are given for illustrative purposes only. Workup with a cation-exchange column was carried out using SCX cartridge (Varian BondElute), which was preconditioned with methanol. Flash column chromatography was carried out using Merck silica gel 60 (63-200 Dm), Wako silica gel 300HG (40-60 Dm), Fuji Silysia NH gel (an amine coated silica gel) (30-50 Dm), Biotage KP-SIL (32-63 Dm) or Biotage AMINOSILICA (an amine coated silica gel) (40-75 Dm). Preparative TLC was carried out using Merck silica gel 60 F254 precoated TLC plates (0.5 or 1.0 mm thickness). Low-resolution mass spectral data (El) were obtained on an Integrity (Waters) mass spectrometer. Low-resolution mass spectral data (ESI) were obtained on ZMD™ or ZQ™ (Waters) and mass spectrometer. NMR data were determined at 270 MHz (JEOL JNM-LA 270 spectrometer), 300 MHz (JEOL JNM-LA300 spectrometer) or 600 MHz (Bruker AVANCE 600 spectrometer) using deuterated chloroform (99.8% D) or dimethylsulfoxide (99.9% D) as solvent unless indicated otherwise, relative to tetramethylsilane (TMS) as internal standard in parts per million (ppm); conventional abbreviations used are: s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m = multiplet, bs = broad singlet, etc. IR spectra were measured by a Fourier transform infrared spectrophotometer (Shimazu FTIR-8300). Chemical symbols have their usual meanings; bp (boiling point), mp (melting point), rt (room temperature), L (liter(s)), mL (milliliter(s)), g (gram(s)), mg (milligram(s)), mol (moles), mmol (millimoles), eq.
(equivalent(s)), quant, (quantitative yield). Following abbreviations may be used in examples: CDI (N, N'- carbonyldiimidazole), DMF (Λ/,Λ/-dimethylformamide), DMSO (dimethylsulfoxide), EDCHCI (1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride), HATU [2-(7-aza-1 H-benzotriazol-1 -yl)-1 , 1 ,3,3-tetramethyluronium hexafluorophosphate], TBTU [2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate], EtOH (ethanol), HOBt (1 -Hydroxy- 7H-benzotriazole), MeOH
(methanol), THF (tetrahydrofuran), and TFA (trifluoroacetic acid). Rf means retention time measured by LC/MS (Waters 2790) under the following condition;
Column: Xterra, C18, 5μm, 4.6 x 50 mm (40 degrees Celsius)
flow :2.0ml_/min
Gradient: Water / MeOH /1%HCO2H aq.= 90/5/5 to 0/95/5
Total run time: 2.5 minutes.

Example IM-tfiSf-i-faminocarbonyl^^-dimethylpropylJ-i-fi-cyanopropyty-IH-indazole-3-carboxamide

Step 1: Methyl 1-(3-cyanopropyl)-1H-indazole-3-carboxylate



To a solution of methyl indazole-3-carboxylate (1.0 g, 5.67 mmol) in dry THF (36 mL), cooled in an ice bath was added potassium tert-butoxide (694 mg, 6.18 mmol), and the mixture was stirred at room temperature for 1 h. 4-bromo-butyronitrile (1.32 g, 8.96 mmol) was added to the reaction mixture while cooling at 00C, and the mixture was stirred for 18 hr. The reaction was then quenched by the addition of water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to get the crude product, which on column chromatography over silica gel (100-200 mesh) using 15% ethyl acetate-hexane as eluant to afford pure product methyl 1-(3-cyanopropyl)-1 H-indazole-3-carboxylate (yield 87%).
1H NMR (400 MHz, CDCI3) δ: 2.32-2.40 (m, 4H), 4.04 (s, 3H), 4.60-4.63 (m, 2H), 7.33-7.37 (m, 1H), 7.47-7.54 (m, 2H), 8.22-8.24 (m, 1H). FIA- MS: 244.1 [M+H]+, 266.0 [M+H+Na]+.
Step 2: 1-(3-Cyanopropyl)-1H-indazole-3-carboxylic acid



To a solution of methyl i-^-cyanopropyO-IH-indazole-S-carboxylate (1.6 g, 6.58 mmol) in methanol (10 mL) was added 1M NaOH (10 mL). The mixture was stirred for 12 h at ambient temperature. After completion of the reaction, the mixture was evaporated upto dryness. The residue was dissolved in water, acidified to pH 6 with 1N HCI, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to afford desired product i-β-cyanopropyO-IH-indazole-S-carboxylic acid as white solid (1.2 g, yield 80%).
1H NMR (400 MHz, DMSOd6) δ: 2.49-2.55 (m, 4H), 4.50-4.59 (m, 2H)1 7.29-7.34 (m,

1H), 7.47-7.51 (m, 1 H), 7.80 (d, J=8.4 Hz, 1H), 8.09 (d, J=8.4 Hz, 1 H). FIA- MS: 230.3

[M+H]+.

Step 3: N-[(1S)-1 -(aminocarbonyl)-2,2-dimethylpropyl]-1-(3-cyanopropy I)-IH-indazole-3-carboxamide



A mixture of i-^-cyanopropyO-IH-indazole-S-carboxylic acid (100 mg, 0.43 mmol), (S)-2-Amino-3,3-dimethylbutyramide (86.6 mg, 0.66 mmol), EDCHCI (128 mg, 0.66 mmol), HOBt (90 mg, 0.66 mmol) and Λ/,Λ/-diisopropylethylamine (0.38 ml_, 2.22 mmol) in dry DMF (5 ml_) was stirred at room temperature for 18 h. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give crude material, which on column chromatography over silica gel (100-200 mesh) using 50% ethyl acetate-hexane as eluant to afford Λ/-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-1-(3-cyanopropyl)-1H-indazole-3-carboxamide as white solid (80 mg, yield 54%).
1H NMR (400 MHz, CD3OD) δ: 1.09 (s, 9H), 2.30-2.33 (m, 2H), 2.47-2.52 (m, 2H), 4.52 (s, 1 H), 4.62 (t, J=6.8 Hz, 2H), 7.30 (t, J=8.0 Hz, 1H), 7.47-7.51 (m, 1H), 7.68 (d, J=8.4 Hz, 1H), 8.22 (d, J=8.4 Hz, 1H). FIA- MS: 342.3 [M+H]+, 364.4 [M+H+Na]+.

Example 2: N-[(1 S)-1 -(aminocarbonyl)-2-methylpropyl]-1 -(3-cyanopropyl)-1 H-indazole-3-carboxamide


A mixture of 1-(3-cyanopropyl)-1H-indazole-3-carboxylic acid (Example 1 , Step 2, 100 mg, 0.43 mmol), L-valinamide (77.2 mg, 0.66 mmol), EDCHCI (128 mg, 0.66 mmol), HOBt (90 mg, 0.66 mmol) and Λ/,Λ/-diisopropylethylamine (0.38 ml_, 2.22 mmol) in dry DMF (5 ml.) was stirred at room temperature for 18 h. Then after completion of the reaction, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give crude material, which on column chromatography over silica gel (100- 200 mesh) using 60% ethyl acetate-hexane eluant to afford Λ/-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-1 -(3-cyanopropyl)-1 H-indazole-3-carboxamide as white sticky solid (70 mg, yield 50%).
1H NMR (400 MHz, CD3OD) δ: 1.02-1.07 (m, 6H), 2.18-2.23 (m, 1H), 2.30-2.35 (m, 2H), 2.47-2.51 (m, 2H), 4.50 (d, J=6.4 Hz, 1H), 4.62 (t, J=6.4 Hz, 2H), 7.30 (t, J=7.6 Hz, 1H), 7.46-7.50 (m, 1 H), 7.67 (d, J=8.4 Hz, 1 H), 8.21 (d, J=8.4 Hz, 1 H). FIA- MS: 328.3 [M+H]+, 350.2 [M+H+Na]+.

Example 3: W-[(1 S)-2-amino-2-oxo-1 -phenylethyl]-1 -(3-cyanopropyl)-1 H-indazole-3-carboxamide



A mixture of i-β-cyanopropyO-I H-indazole-S-carboxylic acid (Example 1 , Step 2, 100 mg, 0.43 mmol), (S)-2-amino-2-phenylacetamide (100.0 mg, 0.66 mmol), EDCHCI (128 mg, 0.66 mmol), HOBt (90 mg, 0.66 mmol) and Λ/,Λ/-diisopropylethylamine (0.38 ml_, 2.22 mmol) in dry DMF (6 ml_) was stirred at room temperature for 18 h. Then after completion of the reaction, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give crude material, which on column chromatography over silica gel (100- 200 mesh) using 50% ethyl acetate-hexane as eluant to afford Λ/-[(1S)-2-amino-2-oxo-1-phenylethyl]-1-(3-cyanopropyl)-1H-indazole-3-carboxamide as white solid (90 mg, yield 57%).
1H NMR (400 MHz, CD3OD) δ: 2.30-2.35 (m, 2H), 2.48 (t, J=7.2 Hz, 2H), 4.61 (t, J=6.4 Hz, 2H), 5.68 (s, 1H), 7.26-7.40 (m, 4H), 7.45-7.49 (m, 1H), 7.53-7.55 (m, 2H), 7.67 (d, J=8.8 Hz, 1 H), 8.18 (d, J=8.4 Hz, 1H). FIA- MS: 362.2 [M+H]+, 384.2 [M+H+Na]+.

Example 4: A/-α-{[1-(3-cyanopropyl)-1H-indazol-3-yl]carbonyl}-L-phenylalanin-

amide

A mixture of i-β-cyanopropyO-I H-indazole-S-carboxylic acid (Example 1 , Step 2, 100 mg, 0.43 mmol), L-phenylalaninamide (108.5 mg, 0.66 mmol), EDCHCI (128 mg, 0.66 mmol), HOBt (90 mg, 0.66 mmol) and Λ/,Λ/-diisopropylethylamine (0.38 ml_, 2.22 mmol) in dry DMF (5 ml_) was stirred at room temperature for 18 h. Then after completion of the reaction, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give crude material, which on column chromatography over silica gel (100- 200 mesh) using 70% ethyl acetate-hexane as eluant to afford Λ/-α-{[1-(3-cyanopropyl)-1H-indazol-3-yl]carbonyl}-L-phenylalaninamide as white sticky solid (80 mg, yield 49%).
1H NMR (400 MHz, CD3OD) δ: 2.27-2.32 (m, 2H), 2.44-2.48 (m, 2H), 3.09-3.15 (m, 2H), 3.26-3.29 (m, 1 H), 4.56-4.60 (m, 2H), 7.16-7.20 (m, 1 H), 7.23-7.31 (m, 5H), 7.44-7.48 (m, 1 H), 7.64 (d, J=8.8 Hz, 1 H), 8.15 (d, J=8.4 Hz, 1 H). FIA- MS: 376.3 [M+H]+, 398.3 [M+H+Na]+.

Example 5: 1-(cyclohexylmethyl)-7-fluoro-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1H-indazole-3-carboxamide



Step 1: 7-Fluoro-1H-indazole-3-carboxylic acid



This compound was prepared following the procedure of Johnson, B. L.; Rodgers, J. D. Syn. Comm. 2005, 35, 2681-2684. A suspension of 5.28 g 7-fluoroisatin in 30 ml_ of water was added 1.30 g NaOH, in 10 mL water with stirring. The resulting dark red solution was stirred until all of the solids dissolved and was then cooled in an ice water bath. The solution was then slowly added a cooled (ice bath) solution of 2.21 g NaNO2 in 10 mL water. These combined solutions were then added slowly to cooled (ice bath) to solution of aqueous sulfuric acid (3.4 mL H2SO4 in 60 mL water). Ice was added to maintain a temperature of approximately O0C. After stirring for approximately 10 minutes, this dark red diazonium solution was added slowly to a chilled (O0C, ice bath) solution of 18 g SnCI22H2O in 30 mL concentrated HCI. Ice was again added to maintain a temperature of approximately O0C. After stirring for approximately 1 hour, the reaction was filtered and the resulting residue was dissolved in 1 N NaOH (60 mL), washed with ether (2 x 50 mL). The resulting yellow-brown solution was cooled in an ice bath and acidified to a pH~3 (litmus paper) with concentrated HCI, which resulted in the formation of a dark yellow precipitate. The precipitate was collected by filtration, washed with water, and dried over night in an oven to give 3.69 g (47%) of 7-fluoro-1/-/-indazole-3-carboxylic acid as an orange solid . 1H NMR (400 MHz, DMSO-d6) δ 14.35 (br s, 1H), 13.22 (br s, 1H), 7.89-7.87 (m, 1 H), 7.26-7.21 (m, 2H). MS (ESI) m/z 181 (M + H)+.
Step 2: Methyl 7-Fluoro-1H-indazole-3-carboxylate

A solution of 30 g 7-fluoro-1/-/-indazole-3-carboxylic acid in 1200 ml_ dry methanol was added 8 ml_ concentrated sulfuric acid. The resulting mixture was heated to reflux and was continued over night. Reaction was allowed to cool to room temperature and was diluted with ethyl acetate (1000 ml_). Organic solution was washed with saturated NaHCO3 (2 x 250 ml_), brine (2 x 250 ml_), dried (MgSO4), filtered and concentrated to a brown solid. Crude reaction was purified via MPLC (5%-30% ethyl ether/heptane) to afford 20.74 g (64%) of methyl 7-fluoro-1H-indazole-3-carboxylate as a bright yellow solid. 1H NMR (400 MHz, DMSO-Qf6) δ 14.49 (br s, 1 H), 7.85-7.83 (m, 1 H), 7.28-7.21 (m, 2 H), 3.92 (s, 3 H). MS (ESI) m/z 195 (M + H)+.
Step 3: methyl i-fcyclohexylmethyl^-fluoro-IH-indazole-S-carboxylate



A solution of (2.2 g, 11.7 mmol) ester in 60.0 ml_ dry THF was added (1.46 g,
13.01mmol) solid KOtBu in one portion at room temperature. The mixture was allowed to stir at room temperature. After 5 minutes, a precipitate formed through out the solution, To this mixture 5 mL DMF was added and mixture immediately became homogeneous. After stirring for 15 minutes 1.8 mL (2.3 g, 13mmol)
bromomethylcyclohexane was added drop wise and the reaction was stirred for at room temperature. After 2 hours reaction was checked by LCMS, mostly product. The reaction was allowed to cool to room temperature and was diluted with 250 mL water. The aqueous solution was extracted with ethyl acetate (3 x 75 mL). Combined organic solutions were washed with brine (2 x 50 mL), dried (MgSO4), filtered and concentrated. Crude reaction was purified via MPLC (0% ethyl ether to 30 % ether/heptane) to afford 987 mg (30%Y) of the product as a yellow solid.
Step 4: 1-(cyclohexylmethyl)-7-f1uoro-1H-indazole-3-carboxylic acid
A solution of (2.2g, 7.5mmol) ester in 30 mL THF was added 6.00 ml_ of 2.5 N
NaOH in one portion with stirring. After 1 hour reaction was checked by LCMS and approximately 50% complete. The reaction was heated to 5O0C for 1 hour. The reaction was checked and was complete by LCMS. The mixture was diluted with 50 mL water and washed with ethyl ether (2 x 25 mL). The aqueous solution was cooled in an ice bath and acidified with concentrated HCI to a pH~ 5 (litmus paper) which resulted with the formation of a white precipitate. The precipitate was collected, washed with water and dried under reduced pressure to afford 2.1 g (98%Y)as a white solid.
Step 5: 1-(cyclohexylmethyl)-7-fluoro-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1H-indazole-3-carboxamide



A solution of (40.0 mg, 0.14mmol) acid and 0.100 mL Hunig's base in 2.0 mL DMF was added (84.2 mg, 0.217mmol) HATU with stirring. The resulting mixture was allowed to stir for 10 minutes and was then added 59.9 mg of the amine in preparation 4. The resulting tan solution was allowed to stir at room temperature. After approximately 2 hours reaction was checked by LCMS and was complete. The mixture was heated to 5O0C and the solvent was removed under a stream nitrogen gas. The resulting residue was diluted with 2 mL brine and extracted with ethyl acetate (2 x 2mL). The combined organic solutions were were blown down under a stream of nitrogen gas. The residue was purified on reverse phase HPLC to leave 36.4 mg as a solid. 1 H NMR (400 MHz, DMSO-d6) D ppm 0.98 (s, 9 H) 1.01 - 1.10 (m, 2 H) 1.10 - 1.25 (m, 3 H) 1.44 - 1.71 (m, 5 H) 1.84 - 1.98 (m, 1 H) 3.07 - 3.24 (m, 2 H) 3.38 - 3.49 (m, 2 H) 4.42 (d, J=6.95 Hz, 2 H) 4.50 (d, J=9.52 Hz, 1 H) 4.62 (t, J=5.31 Hz, 1 H) 7.16 - 7.36 (m, 2 H) 7.59 (d, J=9.88 Hz, 1 H) 7.99 (d, J=8.05 Hz, 1 H) 8.20 - 8.32 (m, 1 H).

Example 6: N-[(1S)-1 '-(hydroxy methyl)-2,2-dimethylpropyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide


Step 1: Ethyl 1H-pyrazolo[3,4-b]pyridine-3-carboxylate



1H-Pyrazolo[3,4-b]pyridine-3-carboxylic acid (prepared according to the procedure in the literature; Lynch, B. M. et al, Can. J. Chem. 1988, 66, 420-428; 2 g, 9 mmol) was suspended in ethanol (60 ml_) and purged with HCI gas for 5 min. The resultant mixture was stirred at room temperature overnight. The reaction mixture was concentrated, diluted with water, neutralized with 2M Na2CC"3 solution, and extracted with ethyl acetate(3x20 ml_). The combined organic layers were concentrated and the residue was purified by chromatography using 40-60% ethyl acetate/hexane as eluent to give ethyl 1H-pyrazolo[3,4-b]pyridine-3-carboxylate as light brown solid (904 mg, 40%). LC-MS; 228, [M+H] +.

Step 2: ethyl 1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate



A solution of ethyl 1 H-pyrazolo[3,4-b]pyridine-3-carboxylate (1.19g, 5.23 mmol) in THF(IO mL) and the reaction mixture was cooled to O0C, and potassium tertButoxide in THF 1.1 equ. was added at OoC. To this solution was added the alkyl iodide (1.79 g, 10.5 mmol) in 10 mL of THF was added drop wise. The reaction mixture was aloud to warm on its own and stirred at ambient temperature overnight. The reaction was quenched by addition of water while cooling in an ice-bath, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by chromatography over silica gel using 40-60% ethyl acetate-hexane as eluent to afford the title compound as white solid (303 mg, 52%).
Step 3: 1-((tetrahydro-2H-pyran-4-yl)methyl)-1 H-pyrazolo[3,4-b]pyridine-3-carboxylic acid



A mixture of ethyl 1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (260 mg, 2.2 mmol), 1N NaOH (5 ml_), THF (5 ml_), and ethanol (5 mL) was stirred for 4 h at room temperature. The reaction was concentrated, diluted with water, and neutralized with 1N HCI solution. The resultant precipitate was collected by filtration, and air dried to give the pyridine-3-carboxylic acid as white solid (235 mg, 43%).
LC-MS; 262.28 [M+H]+, 284.3 [M+Na]+.
Step 4: N-[(1 S)-1 -(hydroxymethyl)-2,2-dimethylpropyl]-1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide



A mixture of 1-((tetrahydro-2H-pyran-4-yl)methyl)-1 H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (50 mg, 0.20 mmol), L-tert-leucinol, EDCHCI (57 mg, 0.30 mmol), HOBt (40 mg, 0.30 mmol) and Λ/,Λ/-diisopropylethylamine (0.17 mL, 0.98 mmol) in dry DMF (2 mL) was stirred at 5O0C overnight. The crude reaction mixture was subjected to purification by reverse-phase HPLC to afford N-[(1S)-1-(hydroxymethyl)-2,2- dimethylpropyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-pyrazolo[3,4-b]pyridine-3-carboxamide as gummy solid (17 mg, 38%).
1H NMR (400 MHz, DMSO-d6) d ppm 0.93 (s, 1 H) 0.95 (s, 9 H) 1.35 (br. s., 2 H) 2.13

(S1 1 H) 2.27 (br. s., 1 H) 3.25 (br. s., 2 H) 3.64 (br. s., 2 H) 3.81 (br. s., 2 H) 3.91 (br. s., 1 H) 4.46 (d, J=6.95 Hz, 2 H) 4.59 (br. s., 1 H) 7.35 (br. s., 1 H) 7.62 (s, 1 H) 8.52

(br. s., 1 H) 8.63 (br. s., 1 H)
MS (ESI) m/z 361 (M + H)+.

Example 7: N-{[1-(4-cyanobutyl)-1H-indazol-3-yl]carbonyl}-3-methyl-L-valylglycinamide



Step 1: ethyl 1-(4-cyanobutyl)-1H-indazole-3-carboxylate



A solution of ethyl 1 H-pyrazolo-3-carboxylate (5g, 26 mmol) and the potassium carbonate were suspended into 100 ml_ ACN and the alkyl bromide was added. A catalytic amount of Kl was added and the reaction mixture was heated to 50oC until

RPHPLC indicated complete.
The solution was returned to r.t. The solution was diluted with ethyl ether and filtered through Celite to collect salts. Filtrate is concentrated to a yellow oil. Purify using

Biotage. Elutant 100 hep to 75EA/25Hep over - 30 min. to result in 4.1 g (58%Y) of an oil. MS (ESI) m/z 372 (M + H)+.
Step 2: i-^-cyanobutyO-IH-indazole-S-carboxylic acid

A mixture of ethyl 1-(4-cyanobutyl)-1 H-indazole-3-carboxylate (3.7g, 14 mmol), 1 N NaOH (3 ml_), THF (5 ml_), and water (10 ml_) was stirred for 4 h at room temperature. The reaction was concentrated, diluted with water, and neutralized with 1N HCI solution. The resultant precipitate was collected by filtration, and air dried to give the indazole-3-carboxylic acid as white solid (3.3g, 97%). LC-MS; 235 [M+H]+.
Step 3: N-(1 -(2-amino-2-oxoethylamino)-3,3-dimethyl-1 -oxobutan-2-yl)-1 -(4-cyanobutyl)-1H-indazole-3-carboxamide



A solution of (50 mg, 0.19mmol) acid and (0.340 ml_, 1.1 mmol) Hunig's base in 2.0 mL DMF was added (223 mg, 0.3mmol) HATU with stirring. The resulting mixture was allowed to stir for 10 minutes and was then added (171.0 mg, 0.29mmol) of amine in a preparation 2.
Crude residue was purified via rp-HPLC (5% acetonitril to 70%
acetonitrile/water/0.02% trifluoroacetic acid). The collected fractions were combined and diluted with 25 mL saturated NaHCO3 and 25 mL brine. The aqueous solution was extracted with ethyl acetate (3 x 25 mL). Combined organic solutions were dried (MgSO4), filtered, and concentrated to afford 49.1 mg of a white solid. 1H NMR (400 MHz, DMSO-d6) D ppm 8.43 (1 H, t, J=5.7 Hz)1 8.17 (1 H, d, J=8.1 Hz), 7.81 (1 H, d, J=8.4 Hz), 7.60 (1 H, d, J=9.5 Hz), 7.48 (1 H, t, J=7.5 Hz), 7.28 (1 H, d, J=7.7 Hz)1 6.95 (1 H1 br. s.), 4.55 (2 H1 d, J=6.6 Hz), 4.51 - 4.58 (1 H1 m), 3.70 (2 H, d, J=5.9 Hz), 2.57 (1 H, s), 1.92 - 2.00 (2 H, m, J=7.5, 7.5, 7.3, 7.0 Hz)1 1.60 (1 H, d, J=7.7 Hz), 1.55 -1.63 (1 H, m), 1.01 (10 H, s). MS; 431 [M+H]+.

Example 8: N-[(1 S)-1 -(aminocarbonyl)-2,2-dimethylpropyl]-1 -[2-(tert-butylamino)-2-oxoethyl]-1H-indazole-3-carboxamide

Step 1: methyl 1-(5,5,5-trifluoropentyl)-1H-indazole-3-carboxylate



The methyl indazole carboxylate (2.5g, 13mmol) and the potassium carbonate (2g, 14.5mmol) were suspended into 20 ml_ ACN and the 5,5,5-trifluoropentyl 4-methylbenzenesulfonate (4g, 13.1mmol) was added, followed by a catalytic amount of Kl (100mg) was and the solution was heated to 7OC overnight.
The solution was returned to r.t. The solution was partitioned between EA and water. The were separated and the organic layer was washed with water and brine and dried over MgSO4. Filter and concentrate to yellow oil. The product was purified on SiO2 to separate the Nitrogen alkylated isomers to result in 1.1 g (30%) of the product. MS; 301 [M+H]+.
Step 2: 1-(5,5,5-trifluoropentyl)-1H-indazole-3-carboxylic acid



A suspension of methyl ester (1.1 g, 3.7mmol) in 10.0 mL water was added 2 ml_ of aq.

NaOH (50%,w) followed by MeOH (2 mL) at room temperature. The resulting mixture was then stirred at room temperature for 16hr.
The reaction was quenched with Cone, aq HCI (add dropwise until acidic). The product separated from solution and was filtered resulting in a white a solid, 950mg

(90%Y). MS; 287 [M+H]+.
Step 3: N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-1-[2-(tert-butylamino)-2-oxoethyl]-1H-indazole-3-carboxamide


A solution of indazole acid (50mg, 14.3mmol) was placed in vial and Hunig's base (0.35ml_, 50mmol) in 1.0 mL THF was added HBTU(150mg,46mmol) with stirring. The resulting mixture was allowed to stir for 10 minutes and was then added the
appropriate amine to the vial. The resulting tan solution was allowed to agitate on an orbital shaker at room temperature overnight. The reaction was monitored by LCMS and was complete.
The contents in the vial were concentrated. The resulting residue was purified on reverse phase HPLC to result in a white solid (26mg). 1H NMR (400 MHz, DMSO-d6) D ppm 0.98 (s, 9 H) 1.43 - 1.54 (m, 2 H) 1.92 (t, J=7.32 Hz, 2 H) 2.25 - 2.37 (m, 2 H) 3.68 (d, J=5.49 Hz1 2 H) 4.49 - 4.60 (m, 3 H) 7.00 (br. s., 1 H) 7.25 - 7.35 (m, 2 H) 7.47 (t, J=7.69 Hz, 1 H) 7.58 (d, J=9.52 Hz1 1 H) 7.81 (d, J=8.79 Hz, 1 H) 8.15 (d, J=8.42 Hz, 1 H) 8.48 (t, J=5.49 Hz, 1 H). MS; 456 [M+H]+.

Example 9: 1-[2-(tert-butylamino)-2-oxoethyl]-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2<limethylpropyl]-1H-indazole-3-carboxamide



Step 1: methyl 1-(2-(tert-butylamino)-2-oxoethyl)-1H-indazole-3-carboxylate



The indazole methyl ester (2g, 11mmol) and the potassium carbonate (3.1g, 22mmol) were suspended into 20 mL acetone and the N-tertButyl chloroacetamide (1.7g, 11.4mmol) (Aploo-lnter.) was added, followed by a catalytic amount of Kl was and the solution was heated to 7OC for 3 hrs. After the reaction was complete
the solution was returned to r.t. The reaction mixture was partitioned between EA and water. The organic layer was washed with water and brine and dried over MgSO4.

The organic solution was filtered and concentrated to a yellow oil. The product solidified on standing 2.1g (64%) MS; 390 [M+H]+.
Step 2: 1-(2-(tert-butylamino)-2-oxoethyl)-1 H-indazole-3-carboxylate



A suspension of methyl ester indazole (1.6g, 5.5mmol) in 10.0 mL of water was added

2 mL of aq. NaOH (50%) followed by MeOH (2 mL) at room temperature. The resulting mixture was then stirred at room temperature for 16hr.
The reaction was quenched with Cone, aq HCI (add dropwise until acidic). The product was filtered resulting in 1.5g 72%Y of the product as a white a solid. MS; 276

[M+H]+.
Step 3: 1-[2-(tert-butylamino)-2-oxoethyl]-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1H-indazole-3-carboxamide



A solution of indazole acid ( 50 mg, 1.8 mmol) was placed in vial and Hunig's base in 1.0 mL THF was added HBTU (120 mg, 3.6 mmol) with stirring. The resulting mixture was allowed to stir for 10 minutes and was then added the appropriate tert-leucinamide to the vial. The resulting tan solution was allowed to agitate on an orbital shaker at room temperature overnight. The reaction was monitored by LCMS and was complete. The contents in the vial were concentrated. The resulting residue was purified on reverse phase HPLC to give the product as a solid 24 mg 45%. 1H NMR (400 MHz, DMSO-d6) D ppm 0.38 (br. s., 1 H) 0.40 (d, J=6.95 Hz, 1 H) 0.61 (d, J=7.32 Hz, 2 H) 0.63 (br. s., 1 H) 0.91 - 0.99 (m, 9 H) 1.23 - 1.31 (m, 9 H) 2.64 (d, J=3.66 Hz, 1 H) 4.39 (d, J=9.52 Hz, 1 H) 5.14 (s, 2 H) 7.27 (t, J=7.50 Hz, 1 H) 7.45 (t, J=7.32 Hz, 1 H) 7.53 (d, J=9.52 Hz1 1 H) 7.63 (d, J=8.42 Hz, 1 H) 8.08 (s, 1 H) 8.14 (d, J=8.05 Hz, 1 H) 8.36 (d, J=4.03 Hz, 1 H), MS (ESI) m/z 428.5 (M + H)+.

Example 10: 1-(cycloheptylmethyl)-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1H-indazole-3-carboxamide



Step 1: methyl 1-(cycloheptylmethyl)-1H-indazole-3-carboxylate



The indazole methyl ester (2g, 11mmol) and the potassium carbonate (2eq) were suspended into 20 mL acetnitrile and Bromomethyl cycloheptane (2.1 g, 11.4 mmoml) was added, followed by a catalytic amount of Kl was and the solution was heated to 7OC for 18 hrs. After the reaction was complete the solution was returned to r.t. The reaction mixture was partitioned between EA and water. The organic layer was washed with water and brine and dried over MgSO4. The organic solution was filtered and concentrated to an oil. The product solidified on standing 2.1g (65%) MS; 387 [M+H]+.
Preperation of Bromomethyl cycloheptane



A solution of cycloheptane carboxylic acid (4.Og, 28 mmol) in dry THF (50 mL) was added dropwise to a suspension of LiAIH4 (40 mL, 40 mmol) in dry THF at oC. The resulting mixture was then warmed to room temperature and stirred overnight.
The mixture was cooled to oC and iced water (50 mL) and aqueous sulfuric acid (10%, 100 mL) were carefully added. The organic phase was separated. The aqueous phase -I l l-was extracted with ethyl acetate two times. The combined organic phase was washed with sat. NaHCO3 solution and then with brine, dried over sodium sulfate and concentrated under reduced pressure to give 3.5g of the product as a clear oil.
The clear hydroxymethyl cycloheptane (2 g, 15.6 mmol) was dissolved in dry ACN and treated with dibromotriphenylphosphorane (7.9g, 18.7 mmol). After 15 min, the mixture was concentrated.
The residue was triturated with 30 ml_ of 1 :3 etheπheptane. The solid was removed by filtration (medium frit) and washed with several 15 ml_ portions of the heptane mixture. The organic extracts were combined and evaporated to give the crude product. The product was used as is for the alkylation. This compound was used as is for the alkylation step.
Step 2: 1-(cycloheptylmethyl)-1H-indazole-3-carboxylic acid



A suspension of methyl ester in (2.0 g, 7 mmol) 10.0 ml. water was added 2 ml_ of aq.

NaOH (50%) followed by MeOH (2 mL) at room temperature. The resulting mixture was then stirred at room temperature for 16hr.
The reaction was quenched with Cone, aq HCI (add dropwise until acidic). The product was filtered resulting in a white a solid (1.4g, 74%). MS; 273 [M+H]+.
Step 3: 1-(cycloheptylmethyl)-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1H-indazole-3-carboxamide



A solution of indazole acid (50 mg, 1.8 mmol) was placed in vial and Hunig's base in 1.0 mL THF was added HBTU (1120 mg, 3.6 mmol) with stirring. The resulting mixture was allowed to stir for 10 minutes and was then added the appropriate tert-leucinamide to the vial. The resulting tan solution was allowed to agitate on an orbital shaker at room temperature overnight. The reaction was monitored by LCMS and was complete. The contents in the vial were concentrated. The resulting residue was purified on reverse phase HPLC to result in the product as a solid 16 mg. 1H NMR (400 MHz, DMSO-d6) D ppm 0.90 (s, 1 H) 0.92 - 1.02 (m, 3 H) 0.98 (s, 9H) 1.16 (t, J=7.32 Hz, 5 H) 2.85 (s, 3 H) 3.08 (q, J=7.20 Hz, 9 H) 7.40 (t, J=7.87 Hz, 2 H) 7.53 (t, J=7.69 Hz, 2 H) 7.71 (d, J=8.42 Hz, 1 H) 7.97 (d, J=8.05 Hz, 1 H)
MS (ESI) m/z 425.6 (M + H)+.

Example 11 : N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-1-{[(2R)-5-oxotetrahydrofuran-2-yl]methyl}-1H-indazole-3-carboxamide



Step 1: ethyl 1-((5-oxo-tetrahydrofuran-2-yl) methyl)-1H-indazole-3-carboxylate



To a slurry of sodium hydride (140 mg, 3.5 mmol) in 5 ml DMF was added ethyl indazole 3 carboxylate (555mg, 2.9 mmol) in a solution in 10 ml DMF. The resultant mixture was heated to 450C for 1 hour. To this mixture was added tosylate of the hydroxyl methyl pentalactone dropwise as a 1.0 M solution in DMF. The resultant mixture was heated to 850C overnight.
The reaction mixture was cooled to ambient temperature and quenched by addition of water (~ 100 ml). The aqueous mixture was extracted 3 X 30 ml EtOAc. The organics were combined, dried over Na2SO4 and concentrated in vacuo. The resultant reside was purified on SiO2 using ethyl acetate in heptane to separate the N alkylated regioisomers. Product was isolated after concentration of the appropriate fractions (472 mg. 56%). MS (ESI) m/z 289.3 (M + H)+.
Step 2: 1 -((5-oxo-tetrahydrof uran-2-yl)methyl)-1 H-indazole-3-carboxylate
To a solution of ethyl ester (472 mg, 1.6 mmol) in THF and ethanol was added 1.0 M NaOH. The reaction mixtures were allowed to stir at ambient temperature overnight. The reaction mixture was concentrated under a nitrogen stream. The resultant residue was diluted with water and pH adjusted to 6 with 1 N HCI. Ethyl acetate was added and the layers were separated. The aqueous layer was extracted 3 X 7 ml EtOAc. The organics were combined and concentrated to an oily residue that later solidified to give the product (350 mg 75%Y). MS (ESI) m/z 260.3 (M + H)+.
Step 3: N-[(1S)-1-([(2-hydroxyethyl)amino]carbonyl}-2>2-dimethylpropyl]-1-{[(2R)-5-oxotetrahydrofuran-2-yl]methyl}-1H-indazole-3-carboxamide



A mixture of indazole acid (35 mg, 0.13 mmol), HOBt (27 mg, 0.2 mmol), EDC HCI (39 mg, 0.2 mmol) diisopropylethyl amine (87 mg, 0.7 mmol) and respective amine from preparation 4 in 1 ml DMF were heated to 500C overnight. The reaction was cooled to ambient temperature and concentrated to a resiude. The residues were suspended in water (3 ml) and extracted 2 X 3 ml ethyl acetate. The organics were combined concentrated and dissolved in ml DMSO. The sample was purified via reverse phase liquid chromatography to result in ( 27.7 mg 49%) a solid. MS (ESI) m/z 417.4 (M + H)+.

Example 12: 3-methyl-N-{[1-(2-oxo-2-phenylethyl)-1H-indazol-3-yl]carbonyl}-L-valylglycinamide


Step 1: methyl 1-(2-oxoethyl -2-phenyl)-1H-indazole-3-carboxylate



A suspension of K2CO3 (5g, 30 mmol) in 50.0 mL dry acetone was added the methyl ester indazole (4.Og, 22.7 mmol) and one eq.bromo methylene ketone (4.5 g, 22 mmol) (Aldrich) at room temperature. The resulting mixture was then heated to 6O0C and reaction complete in 2 hr.
Reaction was allowed to cool to room temperature and was quenched with water (100 mL). The aqueous solution was extracted with ethyl acetate (100 mL). The organic solution is washed with brine (1 x 100 mL), dried (Na2SO4), filtered and concentrated to the product as a solid (5 g, 75%Y). MS (ESI) m/z 295.3 (M + H)+.
Step 2: 1-(2-oxoethyl -2-phenyl)-1H-indazole-3-carboxylate



A suspension of methyl ester indazole (3.Og, 10 mmol) in 50.0 mL water was added 2 g of NaOH pellets at room temperature. The resulting mixture was then stirred at room temperature for 4hr.
Reaction was quenched with aq HCI (100 mL). The product was filtered to a solid (2.8 g, 90%).
MS (ESI) m/z 281.3 (M + H)+.
Step 3: 3-methyl-N-{[1 -(2-oxo-2-phenylethyl)-1 H-indazol-3-yl]carbonyl}-L-valylglycinamide


A solution of indazole acid (50 mg, 0.18mmol) in avial and Hunig's base in 1.0 mL THF was added HBTU (120 mg, 0.36 mmol).) with stirring. The resulting mixture was allowed to stir for 10 minutes and was then added the appropriate amide from preparation 4. The resulting tan solution was allowed to stir at room temperature over night. The reaction was monitord by LCMS and was complete after 16 hours at room temperature.
The contents in the vial was concentrated. The resulting residue was purified by RPHPLC to result in the product as a solid (20 mg, 45%Y). 1H NMR (400 MHz, DMSO-d6) D ppm 0.96 (s, 9 H) 3.41 (q, J=5.86 Hz, 3 H) 3.38 - 3.45 (m, 2 H) 4.52 (d, J=9.52 Hz, 1 H) 4.68 (t, J=5.13 Hz, 1 H) 6.38 (s, 2 H) 7.31 (t, J=7.69 Hz, 1 H) 7.45 (t, J=7.32 Hz, 1 H) 7.68 - 7.81 (m, 2 H) 7.72 - 7.84 (m, 2 H) 8.12 (d, J=8.05 Hz, 2 H) 8.21 (d, J=8.05 Hz, 1 H) 8.33 (t, J=5.13 Hz, 1 H). MS (ESI) m/z 437.5 (M + H)+.

Preparations:
Preparation 1: L-tert-leucinamide



Step 1: Benzyl [(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]carbamate
o
VNH,
Ph-^O^NH
T O
To a solution of Λ/-[(benzyloxy)carbonyl]-tert-leucine (prepared according to the procedure in the literature; Emily, M. S. et al. Tetrahedron 2001 , 57, 5303-5320.; 3.7 g, 14 mmol) in DMF (80 mL) were added ammonium chloride (900 mg, 17 mmol), triethylamine (5.9 mL, 42 mmol), HOBt (2.8 g, 18 mmol), and EDC (3.1 g, 18 mmol) at rt. After 17 h, the reaction mixture was quenched by addition of sat. aq. sodium bicarbonate (100 ml_) and extracted with ethyl acetate (100 ml_ x 3). The combined organic layers were washed with water (100 mL x 3), brine (50 ml_), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (2/1-1/1) to afford 3.0 g (82%) of the title compound. MS (ESI) m/z 265 (M + H)+.

Step 2: L-terf-Leucinamide



To a solution of benzyl [(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]carbamate (3.7 g, 14 mmol) in THF (4OmL) was added 10 % Pd/C (710 mg). The flask was evacuated and flushed with H2 gas and this process was repeated three times. The flask was filled with H2 gas (4 atm) and stirred for 3 h at rt. Then the reaction mixture was filtered through a pad of Celite and concentrated in vacuo to give the title compound as white solid (crude; 1.8 g). 1H-NMR (300 MHz, DMSO-d6) δ 6.59 (bs, 1 H), 5.92 (bs, 1H), 3.12 (s, 1 H), 1.02 (s, 1 H). MS (ESI) m/z 131 (M + H)+.

Preparation 2: (S)-2-Amino-N-carbamoylmethyl-3,3-dimethylbutyramide hydrochloride

.

Step 1: [(S)-I -(Carbamoylmethylcarbamoyl)-2,2-dimethylpropyl]carbamic acid tert-butyl ester



To a solution of N-Boc-L-tert-leucine (1.0 g, 4.327 mmol) in dry DMF (10 ml), N1N-diisopropylethyl amine (5.1 ml, 30.3 mmol), EDCHCI (1.23 g, 6.5 mmol), HOBT (880 mg, 6.5 mmol) was added and stirred at rt under nitrogen atmosphere for 30 min. Glycinamide hydrochloride (720 mg, 6.5 mmol) was then added to it and stirring was continued for 18 h at rt. On completion of reaction (monitored by TLC, Rf = 0.3; solvent system 40% ethyl acetate in hexane, spots visualized with either KMnO4 or Iodine), the solution was diluted with distilled water (100 ml), extracted with ethyl acetate (100 ml), washed with brine (50 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude product (1.6 g). The crude mixture was subjected to column chromatography using 100-200 mesh silica gel, eluting with 30-50% ethyl acetate-hexane to afford desired product [(S)-I -(Carbamoylmethylcarbamoyl)-2,2-dimethylpropyl]- carbamic acid tert-butyl ester as gummy sticky mass (1.09 g, yield 87.9%).
Step 2: (S)-2-Amino-N-carbamoylmethyl-3,3-dimethylbutyramide hydrochloride:



.HCI
[(S)-I -(Carbamoylmethylcarbamoyl)-2,2-dimethyl-propyl]carbamic acid tert butyl ester (1.09 g, 3.79 mmol) was dissolved in 40 ml of 4N 1,4-dioxane-HCI solution and stirred at rt under nitrogen atmosphere for 4 hr. On completion of reaction (monitored by TLC, Rf = 0.1 ; solvent system 50% ethyl acetate in hexane, spots visualized with UV), dioxane was removed under reduced pressure to afford desired product (S)-2-Amino-N-carbamoylmethyl-3,3-dimethylbutyramide hydrochloride as gummy semi solid (750 mg, yield 88%). 1H NMR (400 MHz, DMSO-d6) δ : 0.99 (s, 9H), 3.56-3.59 (m, 1 H), 3.69-3.72 (m, 2H), 7.10 (br s, 1H), 7.47 (br s, 1 H), 8.25 (br s, 3H), 8.73 (br s, 1H). FIA-MS: 188.2 [M+H]+.
Preparation 3: ((S-2-Amino-3,3-dimethyl-butyrylamino)acetic acid benzyl ester hydrochloride



Step 1: ((S)-2-fe/t-Butoxycarbonylamino-3,3-dimethylbutyrylamino)acetic acid benzyl ester:

To a solution of Λ/-Boc-L-tert-leucine (1.5 g, 6.48 mmol) in dry DMF (40 ml_) N1N-diisopropylethylamine (8.0 ml_, 45.34 mmol), EDCHCI (1.89 g, 9.89 mmol) and HOBt (1.34 g, 9.89 mmol) were added under nitrogen atmosphere, and stirred at room temperature for 1 h. Then glycine benzyl ester (as p-toluenesulfonic acid salt) (3.33 g, 9.89 mmol) was added to the reaction mixture and stirred at room temperature for additional 18 h. After completion of the reaction (monitored by TLC, 30% ethyl acetate in hexane, Rf for product 0.5, spots visualized with UV and iodine), water (400 ml) was added to the reaction mixture and extracted with ethyl acetate (400 ml). The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give crude material (2.7 g), which on column chromatography over silica gel (100- 200 mesh) using 20% ethyl acetate-hexane as eluant afforded ((S)-2-tert-butoxycarbonylamino-3,3- dimethylbutyrylamino)acetic acid benzyl ester as white solid (2.0 g, yield 82%).
1H NMR (400 MHz, CDCI3) δ : 0.99 (s, 9H), 1.41 (s, 9H), 3.87 (d, J=8.8 Hz, 1H), 3.93-3.97 (m, 1H), 4.17-4.21 (m, 1 H), 5.14-5.23 (m, 3H), 6.19 (s, 1H), 7.31-7.38 (m, 5H). FIA- MS: 379.0 [M+H]\ 396.1 [M+H+NH3]+, 401.2 [M+H+NH3]+.
Step 2: ((S)-2-Amino-3,3-dimethylbutyrylamino)acetic acid benzyl ester hydrochloride



.HCI
((S^-te/t-Butoxycarbonylamino-S.S-dimethylbutyrylaminoJacetic acid benzyl ester (2.0 g, 5.29 mmol) was dissolved in 16 ml_ of 4N HCI-1,4-dioxane solution and stirred at room temperature under nitrogen atmosphere for 4 h. Upon completion of reaction (monitored by TLC, Rf = 0.1 ; solvent system 30% ethyl acetate in hexane, spots visualized with UV), dioxane was removed under reduced pressure to afford ((S)-2-amino-3,3-dimethylbutyrylamino)acetic acid benzyl ester hydrochloride as off-white solid (1.6 g, yield 96%).
1H NMR (400 MHz, CDCI3) δ : 1.09 (s, 9H)1 3.69 (m, 3H), 5.10 (s, 2H), 7.30-7.36 (m, 5H), 8.01 (brs, 3H), 8.60 (br s, 1 H).
The following intermediates were prepared in a similar manner:


Preparation 21 : (S)-5-((2-Amino-3,3-dimethylbutanamido)methyl)-1 ,3,4- oxadiazole-2-carboxylic acid ethyl ester, trifluoroacetate



.CF3CO2H
Step 1 : (S)-5-((2-(fert-butoxycarbonylamino)-3,3-dimethylbutanamido)methyl)-1,3,4-oxadiazole-2-carboxylic acid ethyl ester



To a solution of Λ/-Boc-L-te/?-leucine (4.91 g, 21.2 mmol) in dichloromethane (50 ml_) was added TBTU (10.2 g, 31.9 mmol) and triethylamine (8.88 ml_, 63.7 mmol). After fifteen minutes of stirring at ambient temperature, ethyl 5-(aminomethyl)-1 ,3,4-oxadiazole-2-carboxylate (prepared according to the procedure in the literature; KoIb, H. C. et al. US Patent 6951946.; 4.Og, 23.0 mmol) was added and stirring continued for 18 hours. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water (100 mL) and saturated sodium chloride (100 ml_) and dried over magnesium sulfate. Filtration and concentration provided the crude product as a brown oil. The material was purified using normal phase chromatography
(heptane/ethyl acetate) to provide the title compound as a colorless oil (5.72g, 64% yield).
1H NMR (400 MHz1 DMSO-cfe) δ ppm 0.91 (s, 9 H) 1.32 (t, 3 H) 1.38 (s, 9 H) 3.89 (d, J=9.38 Hz, 2 H) 4.41 (q, J=7.04 Hz1 2 H) 4.50 - 4.70 (m, 1 H) 6.54 (d, J=8.99 Hz, 1 H) 8.77 (t, J=5.08 Hz, 1 H)
Step 2: Ethyl (S)-5-((2-amino-3,3-dimethylbutanamido)methyl)-1,3,4-oxadiazole-2-carboxylate, trifluoroacetate salt



.CF3CO2H
To a solution of ethyl (S)-3-((2-(tert-butoxycarbonylamino)-3,3-dimethylbutanamido)methyl)-1 ,2,4-oxadiazole-5-carboxylate (900 mg, 2.34 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3 mL). The solution was stirred for one and concentrated in vacuo to provide the title compound as a brown oil (900 mg, quantitative yield). 1 H NMR (400 MHz, DMSOd6) δ ppm 1.00 (s, 9 H) 1.34 (t, J=7.23 Hz, 3 H) 3.53 (d, J=5.47 Hz, 2 H) 4.43 (q, J=7.03 Hz, 2 H) 4.48 - 4.77 (m, 1 H) 8.09 (br. s., 2 H) 9.07 - 9.22 (m, 1 H). MS: 285 (M+H)

The following intermediates were prepared in a similar manner:


Preparation 27: (S)-5-((2-amino-3,3-dimethylbutanamido)methyl)-1 ,3,4-oxadiazole-2-carboxamide, trifluoroacetate salt



.CF3CO2H
Step 2: (S)-7erf-butyl 1-((5-carbamoyl-1,3,4-oxadiazol-2-yl)methylamino)-3,3-dimethyl-1-oxobutan-2-ylcarbamate



(S)-ethyl 5-((2-(tert-butoxycarbonyl)-3,3-dimethylbutanamido)methyl)-1,3,4-oxadiazole-2-carboxylate (5.72 g, 14.9 mmol) was dissolved into methanol (20 mL) and 2N ammonia in methanol (15 mL) was added. The solution was stirred at ambient temperature for one hour. The solution was concentrated in vacuo to provide the desired material as a white foam (quantitative yield); 1H NMR (400 MHz, DMSO-Cf6) δ ppm 0.90 (s, 9 H) 1.38 (s, 9 H) 3.89 (d, J=9.77 Hz, 2 H) 4.46 - 4.66 (m, 1 H) 6.52 (d, J=8.99 Hz, 1 H) 8.18 (s, 1 H) 8.56 (s, 1 H) 8.73 (t, J=4.89 Hz1 1 H)
Step 3: (S)-5-((2-Amino-3,3-dimethylbutanamido)methyl)-1 ,3,4-oxadiazole-2-carboxamide, trifluoroacetate salt



The (S)-tert-butyl 1-((5-carbamoyl-1 ,3,4-oxadiazol-2-yl)methylamino)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (5.7 g, 14.9 mmol) was dissolved into dichloromethane (20 mL) and trifluoroacetic acid (10 mL) was added. The solution was stirred at ambient temperature for one hour. Concentration in vacuo followed by tritration with diethyl ether provided the desired compound as a white solid (5.21 g, 95% yield).
1H NMR (400 MHz, DMSO-d6) δ ppm 1.00 (s, 9 H) 3.54 (d, J=5.47 Hz, 2 H) 4.62 - 4.78 (m, 1 H) 8.11 (br. s., 2 H) 8.23 (s, 1 H) 8.61 (s, 1 H) 9.21 (t, 1 H)

Preparation 28: 5-((S)-1 -Amino-2,2-dimethylpropyl)-[1 ,3,4]oxadiazol-2-ylamine dihydrochloride



.2HCI
Step 1: ((S)-I -Hydrazinocarbonyl-2,2-dimethylpropyl)carbamic acid ferf-butyl ester
I Oo
SNHNH2
>f 1 °Y O m
To a solution of Λ/-Boc-L-tert-leucine (2.0 g, 8.647 mmol) in dry THF (20 ml_), N1N-carbonyl diimidazole (CDI) (1.54 g, 9.511 mmol) was added and stirred at room temperature under nitrogen atmosphere for 1.5 h. Hydrazine hydrate (1.3 ml, 26.6 mmol) was then added to it and stirring was continued for 18 h at room temperature. On completion of reaction (monitored by TLC, Rf = 0.3; solvent system 40% ethyl acetate in hexane), THF was evaporated up to dryness and the residual mass dissolved in 1 ,4-dioxane (50 ml_) and filtered. The filtrate was concentrated under reduced pressure and the residual mass (as white sticky material) was again dissolved in DCM. The solution was washed with distilled water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford desired product ((S)-I-hydrazinocarbonyl-2,2-dimethylpropyl)carbamic acid tert-butyl ester (2.3 g) as gummy sticky mass contaminated with imidazole.
1H NMR (400 MHz, DMSO-d6) δ : 0.87 (s, 9H), 1.37 (s, 9H), 3.80 (d, J=9.6 Hz, 1 H), 6.35 (d, J-9.6 Hz, 1 H), 9.10 (s, 1 H) + Imidazole : 7.01 (s, 2H), 7.63 (s, 1H). 1H NMR (400 MHz, DMSO-de- D2O exchange) δ : 0.88 (s, 9H), 1.35 (s, 9H), 3.77 (s, (1 H), + Imidazole : 7.01 (2H, 7.65 (s, 1 H). FIA- MS: 246.3 [M+H]+, 268.3 [M+H+Na]+.
Step 2: [1-(5 Amino-[1,3,4]oxadiazol-2-yl)-(S)-2,2-dimethylpropyl]carbamic acid ferf-butyl ester



To a clear solution of ((S)-I -hydrazinocarbonyl-2,2-dimethylpropyl)carbamic acid tert- butyl ester (1.5 g, 6.117 mmol) in 1,4-dioxane (5O mL), a solution of NaHCO3 (0.515 g, 6.117 mmol) in distilled water (15 ml_) was added to form a white suspension.
Cyanogen bromide (0.65 g, 6.117 mmol) was added portion wise to the reaction mixture and stirred for 18 h at room temperature. On completion of reaction (monitored by TLC, Rf= 0.5; solvent system 50% ethyl acetate in hexane), the dioxane was evaporated under reduced pressure and ethyl acetate (100 mL) was added. This solution was then washed twice with distilled water (2 x 100 mL), brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residual mass obtained was washed with hexane to afford desired product [1-(5-amino-[1 ,3,4]oxadiazol-2-yl)-(S)-2,2-dimethylpropyl]carbamic acid tert-butyl ester (0.7 g, yield 42%) as off white solid.
1H NMR (400 MHz, CDCI3) δ: 1.01 (s, 9H)1 1.27 (s, 9H), 4.65 (d, J=9.6 Hz, 1 H), 5.44 (d, J=8.4 Hz, 1H), 8.92 (br s, 2H). MS, 271.4 [M+H]+.
Step 3: 5-((S)-1 -Amino-2,2-dimethylpropyl)-[1 ,3,4]oxadiazol-2-ylamine
dihydrochloride



.2HCI
[1-(5-Amino-[1 ,3,4]oxadiazol-2-yl)-(S)-2,2-dimethylpropyl]carbamic acid tert-butyl ester (4.0 g, 14.81 mmol) was added to 75 mL of 4N HCI in dioxane solution and the solution was stirred at room temperature for 4 h. Evaporation of the reaction mixture under reduced pressure gave 5-((S)-1-amino-2,2-dimethylpropyl)-[1 ,3,4]oxadiazol-2-ylamine dihydrochloride as white solid (3.5 g, yield 98.59%).
1H NMR (400 MHz, DMSO-d6) δ: 0.95 (s, 9H), 4.31 (d, J= 5.6 Hz, 1H), 6.34 (br s, 3H), 7.60 (br s, 1H), 8.86 (d, J= 4.0 Hz, 3H). LC-MS, 171.1 [M+H]+.

Preparation 29: N-{5-[(1 S)-1 -amino-2,2-dimethylpropyl]-1 ,3,4-oxadiazol-2-yl}cyclopropane-carboxamide hydrochloride



.HCI Step 1: tert-butyl [(1S)-1-{5-[(cyclopropylcarbonyl)amino]-1,3,4-oxadiazol-2-yl}-2,2-dimethylpropyl]carbamate



To a mixture of tert-butyl [(1S)-1-(5-amino-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropyl]carbamate (Preparation 28, Step 2, 500 mg, 1.85 mmol) in pyridine (20 ml) was added cyclopropanecarbonyl chloride (202 Dl, 2.22 mmol) dropwise. The resultant solution was allowed to stir at ambient temperature. The mixture was poured onto water and extracted with ethyl acetate. The organic layer was concentrated to a residue. Purification was accomplished by SiU2 chromatography eluting with 0-50 % ethyl acetate/heptane, yielding 503 mg (80%) of desired product. 1H NMR (400 MHz1 DMSO-Cf6) δ ppm 0.80 - 0.88 (m, 4 H) 0.92 (s, 9 H) 1.19 - 1.29 (m, 1 H) 1.35 (s, 9 H) 1.79 - 1.89 (m, 1 H) 4.55 (d, J=8.86 Hz, 1 H) 7.50 (d, J=8.59 Hz, 1 H) 11.77 (s, 1 H). FIA-MS: 339.2 [M+H]+.
Step 2: N-{5-[(1 S)-1 -amino-2,2-dimethylpropyl]-1 ,3,4-oxadiazol-2-yl}cyclopropane-carboxamide hydrochloride



.HCl
To a solution of tert-butyl [(ISJ-i-lδ-^cyclopropylcarbonylJaminol-I .S^-oxadiazol^-yl}-2,2-dimethylpropyl]carbamate (502 mg, 1.48 mmol) in dioxane (5 ml) was added HCI (4.0 M in dioxane, 3 ml) at ambient temperature. The resultant mixture was allowed to stir at ambient temperature. The reaction mixture was concentrated to a solid. The solids were suspended in ethyl ether and collected by filtration. The hygroscopic solids were placed in a vacuum oven overnight to dry. 408 mg (94% yield). 1H NMR (400 MHz, DMSO-de) δ ppm 0.81 - 0.93 (m, 4 H) 0.96 - 1.02 (m, 9 H) 1.92 (t, J=4.57 Hz, 1 H) 3.36 (t, J=6.98 Hz, 1 H) 4.51 (s, 1 H) 5.73 (s, 1 H) 8.83 (br. s., 2 H) 12.14 (s, 1 H). FIA-MS: 237.3 [M+H]+.

Preparation 30: 1-{5-[(1S)-1-Amino-2,2-dimethylpropyl]-1 ,3,4-oxadiazol-2-yl}urea hydrochloride



HCl
Step 1: tert-Butyl [(1S)-1-{5-[(aminocarbonyl)amino]-1,3,4-oxadiazol-2-yl}-2,2-dimethylpropyl]carbamate



To a stirred solution of tert-butyl [(1S)-1-(5-amino-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropyl]carbamate (Preparation 28, Step 2, 250 mg, 0.9 mmol) in dry THF (5 ml) at O0C was added trichloroacetyl isocyanate (240 ul, 2 mmol) slowly, dropwise. The cooling bath was removed after complete addition and reaction mixture allowed to stir at ambient temperature for 1 hour. The mixture was concentrated in vacuo. The residue was dissolved in methanol (3 ml) and purged with ammonia gas for 3 minutes. The resultant mixture was allowed to stir at ambient temperature overnight. The reaction mixture was concentrated by rotary evaporator. The solids were triturated with diethyl ether and collected by filtration yielding 115.5 mg (40 %). 1H NMR (400 MHz, DMSO-de) δ ppm 0.96 (s, 9 H) 1.38 (s, 9 H) 4.54 (d, J=8.99 Hz, 1 H) 7.10 (br. s., 2 H) 7.51 (d, J=8.79 Hz, 1 H) 10.59 (s, 1 H). FIA-MS: 314.1 [M+H]+.
Step 2: 1-{5-[(1S)-1-Amino-2,2-dimethylpropyl]-1,3,4-oxadiazol-2-yl}urea hydrochloride



HCI
To a solution of tert-butyl [(1S)-1-{5-[(aminocarbonyl)amino]-1 ,3,4-oxadiazol-2-yl}-2,2-dimethylpropyl]carbamate (115 mg, 0.37 mmol) in dioxane (2 ml) was added HCI (4N in dioxane, 1.5 ml). The resultant mixture was allowed to stir at ambient temperature overnight. The mixture was concentrated under a nitrogen stream and placed on high vacuum yielding 125.4 mg of desired material. 1H NMR (400 MHz, DMSO-afe) δ ppm 1.03 (s, 9 H) 4.48 (d, J=5.47 Hz, 1 H) 7.08 (br. s., 2 H) 8.90 (d, J=4.30 Hz, 3 H). FIA-MS: 214.2 [M+H]+.

Preparation 31 : 5-[(1 S)-1 -amino-2,2-dimethylpropyl]-1 ,3,4-oxadiazole-2-carboxamide
hydrochloride



.HCI
Step 1 : [N'-((S)-2-tert-Butoxycarbonylamino-3,3-dimethyl-butyryl)-hydrazino]-oxo-acetic acid ethyl ester

O^NH O

To a solution of ((S)-Hydrazinocarbonyl-2,2-dimethyl-propyl)-carbamic acid tert-butyl ester (Preparation 28, Step 1, 500 mg, 2.0 mmol) and sodium bicarbonate (197 mg, 2.3 mmol) in THF (10 ml) at O0C was added ethyloxalyl chloride (239 Dl, 2.1 mmol) dropwise over 10 minutes. The reaction mixture was allowed to warm to ambient temperature overnight. The reaction mixture was filtered through a cake of Celite eluting with THF. The cloudy filtrate was concentrated to an oily residue. Toluene (~ 2ml) was added and triturated with ethyl ether. The ethereal solution was concentrated to a residue and purified by Siθ2 chromatograhpy eluting with 30-100 % ethyl acetate/heptane yielding 653.7 mg (93%). 1H NMR (400 MHz, DMSO-Cf6) δ ppm 0.90 (s, 9 H) 1.25 (t, J=7.12 Hz, 3 H) 1.35 (s, 9 H) 3.91 (d, J=9.67 Hz, 1 H) 4.22 (q, 2 H) 6.56 (d, J=9.67 Hz, 1 H) 10.08 (s, 1 H) 10.74 (s, 1 H). FIA-MS: 368.2 [M+Na]+.
Step 2: Ethyl 5-{(1S)-1-[(tert-butoxycarbonyl)amino]-2,2-dimethylpropyl}-1,3,4-oxadiazole-2-carboxylate



Triethylamine (600 μl, 4.2 mmol) and a solution of [N'-((S)-2-tert-Butoxycarbonylamino- 3,3-dimethyl-butyryl)-hydrazino]-oxo-acetic acid ethyl ester (350 mg, 1.0 mmol) in dry dichloromethane (5 ml) was added sequentially to a stirred solution of
triphenylphosphine (548 mg, 2.0 mmol) and iodine (851 mg, 2.0 mmol) in
dichloromethane (10 ml) at ambient temperature. The reaction was completed in 2 hours. The reaction mixture was extracted (2 X 30 ml) saturated sodium thiosulfate. The organic layer was concentrated and resultant residue purified by Siθ2
chromatography eluting with 0-75% ethyl acetate/heptane. The oily residue was placed under high vacuum yielding 151.3 mg (46%). 1H NMR (400 MHz, DMSO-cfe) δ ppm 0.97 (s, 9 H) 1.36 (q, 3 H) 1.34 (s, 9 H) 4.42 (q, J=7.04 Hz, 2 H) 4.73 (d, J=8.60 Hz, 1 H) 7.73 (d, J=8.60 Hz, 1 H). FIA-MS: 350.1 [M+Na]+.
Step 3: tert-butyl {(1S)-1-[5-(aminocarbonyl)-1,3,4-oxadiazol-2-yl]-2,2-dimethylpropyl} carbamate



To a solution of ethyl 5-{(1S)-1-[(tert-butoxycarbonyl)amino]-2,2-dimethylpropyl}-1 ,3,4-oxadiazole-2-carboxylate (150 mg, 0.46 mmol) in ethanol (3 ml) was bubbled ammonia gas for 2 minutes. The vial was sealed and heated at 500C overnight. The mixture was concentrated to a residue and dissolved in dichloromethane. The material was purified by Siθ2 chromatography eluting with 0-15% methanol/dichloromethane. The fractions were isolated and concentrated to a residue yielding 123.9 mg (91%). 1H NMR (400 MHz, DMSO-Of6) δ ppm 0.97 (s, 9 H) 1.38 (s, 9 H) 4.71 (d, J=8.60 Hz, 1 H) 7.67 (d, J=8.60 Hz, 1 H) 8.21 (s, 1 H) 8.57 (br. s., 1 H). FIA-MS: 321.1 [M+Na]+. Step 4: 5-[(1S)-1-amino-2,2-dimethylpropyl]-1,3,4-oxadiazole-2-carboxamide hydrochloride



.HCI
To a solution of tert-butyl {(1S)-1-[5-(aminocarbonyl)-1 ,3,4-oxadiazol-2-yl]-2,2-dimethylpropyl}carbamate (120 mg, 0.40 mmol) in dioxane (2 ml) was added 4N HCI in dioxane (1 ml). The resultant mixture was stirred at ambient temperature overnight.

The reaction mixture was concentrated to a residue. The residue was triturated with ethyl ether and collected by filtration yielding 72.0 mg (76%). 1H NMR (400 MHz, DMSO-cfe) δ ppm 1.04 (s, 9 H) 3.42 (br. s., 1 H) 8.33 (s, 1 H) 8.71 (s, 1 H) 8.92 (br. s., 3 H). FIA-MS: 199.1 [M+H]+.

Preparation 32: (1 S)-2,2-dimethyl-1 -(2H-tetrazol-5-yl)propan-1 -amine
hydrochloride



.HCI
Step 1 : Benzyl [(1S)-1-cyano-2,2-dimethylpropyl]carbamate



To a solution of benzyl [(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]carbamate
(Preparation 1 , Step 1 , 2.8 g, 10.9 mmol) in pyridine (25 ml) was added phosphorus oxychloride (1.2 ml, 2.0 g, 13.1 mmol) as a solution in dichloromethane (15 ml), dropwise at -100C. The resultant mixture stirred for 3 hours. The reaction mixture was poured over ice water (-100 ml). The layers were separated and organic extracted 1 X 30 ml 1.0 M CuSO4 solution, 2 x 50 ml water and 1 X 50 ml brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The oily residue was purified by SiO2 chromatography (70 g) eluting 0-10 % methanol/dichloromethane. The oil was taken on in subsequent reactions without additional purification and/or
characterization. 2.18 g. LC/MS 247.1 (M+H).
Step 2: Benzyl [(1S)-2,2-dimethyl-1-(2H-tetrazol-5-yl)propyl]carbamate



Sodium azide (633 mg, 9.7 mmol) and ammonium chloride (544 mg, 10.2 mmol) were added simultaneously to a solution of benzyl [(1S)-1-cyano-2,2-dimethylpropyl]carbamate (2.2 g, 8.8 mmol) in DMF (35 ml). The resultant reaction mixture was heated to 950C for 3 hours. Additional NaN3 (633 mg, 9.7 mmol) and NH4CI (544 mg, 10.2 mmol) was added and reaction heated to 950C. The incomplete reaction mixture was cooled to ambient temperature and quenched by pouring over ice water (~ 100 ml). The solution's pH was adjusted to 2 with 4 N HCI. The acidic solution was extracted 3 X 30 ml CH2CI2. The organic washes were washed with brine (1 X 30 ml) and dried over MgSO4. Purification was accomplished by Siθ2
chromatography (Flashmaster 70 g) eluting 10-60 % ethyl acetate/hexanes. 646.7 mg, 25 % yield. 1 H NMR (400 MHz, DMSOd6) δ ppm 0.89 (s, 10 H) 4.77 (d, J=8.59 Hz, 1 H) 4.99 (d, J=7.25 Hz, 2 H) 7.22 - 7.35 (m, 5 H) 7.90 (d, J=8.59 Hz, 1 H). LC/MS 290.1 (M+H).
Step 3: (1S)-2,2-dimethyl-1-(2H-tetrazol-5-yl)propan-1 -amine hydrochloride



.HCI
The 5% palladium/charcoal catalyst (20 mg) was added to the dry benzyl [(1S)-2,2-dimethyl-1-(2H-tetrazol-5-yl)propyl]carbamate (600 mg, 2.1 mmol) in a round bottomed flask. To the flask was added methanol (10 ml) under a nitrogen atmosphere. The atmosphere was escaped and purged with hydrogen twice before affixing a hydrogen balloon to the flask. The reaction was maintained at atmospheric pressure overnight at ambient temperature. The reaction mixture was purged with nitrogen gas and filtered through a cake of Celite. The Celite was washed with methanol and filtrate
concentrated to a pale tan solid. 320.1 mg , 99 % yield. 1H NMR (400 MHz, DMSO-dβ) □ ppm 0.90 (s, 10 H) 4.13 (s, 1 H) 7.99 (br. s., 2 H). LC/MS 156.1 (M+H).

Preparation 33: (S)-2-amino-N-benzyl-3,3-dimethylbutanamide



Step 1: (S)-tert-butyl 1-(benzylamino)-3,3-dimethyl-1-oxobutan-2-ylcarbamate
A solution of 3.2434 g BOC-L-T-Leucine in 47.0 ml_ DMF was added 8.1668 g HATU followed by 12.20 ml_ Hunig's base. The resulting yellow solution was allowed to stir for 5 minutes and was then added 2.35 mL benzyl amine. The resulting solution was allowed to stir at room temperature. The reaction was checked via LCMS after approximately 2 hours and was complete. The reaction was diluted with 250 mL of 1 M citric acid. The aqueous solution was extracted with ethyl acetate (3 x 100 mL). The combined organic solutions were washed with brine (2 x 100 mL), dried (MgSO4 1H NMR (400 MHz, DMSO-d6) d ppm 9.22 (1 H, t, J=5.9 Hz), 8.34 (2 H, br. s.), 7.15 -7.36 (4 H, m), 4.20 - 4.36 (2 H, m), 3.63 (1 H, s), 0.95 (9 H, s).
Step 2: (S)-2-amino-N-benzyl-3,3-dimethylbutanamide



The resulting oil was diluted in 30 mL dry dioxane and added 20.0 mL of 4 M HCI in dioxane. The mixture was stirred at room temperature for 1 hour, and checked LCMS and reaction complete. The solvent was removed under reduced pressure leaving a foam. 1 H NMR (400 MHz, DMSO-d6) d ppm 9.22 (1 H, t, J=5.9 Hz), 8.34 (2 H, br. s.), 7.15 - 7.36 (4 H, m), 4.20 - 4.36 (2 H, m), 3.63 (1 H, s).
The following compounds were prepared by the same method as preparation 33.






The following Examples were synthesized according to the general procedures used in the representative Examples and representative Preparations described above.


1-(aminocarbon








Structure MS

Example 1H NMR
IUPAC Name (M+H) dimethylpropyl]-5-methyl-1 H- indazole-3-carboxamide
1H NMR (400 MHz, DMSO-d6)
D ppm 0.89 (dd, J=18.48, 6.77
Hz, 6 H) 1.49 - 1.58 (m, 1 H)
1.54 (d, J=7.32 Hz1 1 H) 1.86 - 1.96 (m, J=7.23, 7.23, 7.23,
7.23 Hz, 2 H) 2.06 (d, J=6.59
83 Hz, 1 H) 2.40 (s, 3 H) 2.46 (br. 356
s., 1 H) 4.39 (dd, J=8.78, 6.22

Hz, 1 H) 4.48 (t, J=6.95 Hz1 2
N-[(1S)-1-(aminocarbonyl)-2- H) 7.12 (br. s., 1 H) 7.27 (d,
methylpropyl]-1 -(4-cyano- J=8.78 Hz, 1 H) 7.65 (d, J=8.42
butyl)-5-methyl-1 H-indazole- Hz, 2 H) 7.55 - 7.67 (m, 2 H)
3-carboxamide 7.91 (s, 1 H)
1H NMR (400 MHz, DMSO-d6)
D ppm 0.89 (d, J=2.93 Hz, 7 H)
1.51 - 1.57 (m, 2 H) 1.54 (d,
J=7.32 Hz, 2 H) 1.61 (d, J=9.88
Hz, 1 H) 1.87 - 1.97 (m, J=7.32,
7.32, 7.32, 7.32 Hz, 2 H) 2.40
84 (s, 3 H) 2.47 (br. s., 1 H) 4.47 370
(t, J=6.95 Hz, 2 H) 4.52 (dd,

J=8.78, 4.03 Hz, 1 H) 7.02 (br.
N-[(1 S)-1 -(aminocarbonyl)-3- s., 1 H) 7.27 (d, J=8.42 Hz, 1
methylbutyl]-1 -(4-cyanobutyl)- H) 7.48 (br. s., 1 H) 7.64 (d,
5-methyl-1 H-indazole-3- J=8.42 Hz, 1 H) 7.78 (d, J=8.78
carboxamide Hz, 1 H) 7.92 (s, 1 H)
1H NMR (400 MHz, DMSO-d6)
D ppm 1.22 (d, J=6.22 Hz, 3 H)
1.29 (br. s., 1 H) 1.50 - 1.56 (m,
1 H) 1.53 (d, J=7.69 Hz1 1 H)
1.92 (d, J=7.69 Hz, 3 H) 1.85 - 1.96 (m, 2 H) 2.40 (s, 3 H) 2.46
85 (br. s., 1 H) 3.27 (br. s., 1 H) 355
3.42 (d, J=4.76 Hz, 1 H) 3.58

(d, J=2.20 Hz, 1 H) 4.45 (t,
1 -(4-cyanobutyl)-N-[(1 S,2S)- J=6.95 Hz, 2 H) 4.58 (d, J=5.12
2-hydroxycyclohexyl]-5- Hz, 1 H) 7.25 (d, J=8.78 Hz, 1
methyl-1 H-indazole-3- H) 7.65 (br. s., 1 H) 7.62 (d,
carboxamide J=8.42 Hz, 2 H) 7.93 (s, 1 H)






Structure MS

Example 1H NMR
IUPAC Name (M+H)
1H NMR (400 MHz, DMSO-d6)
pppm 0.88 (d, J=5.49 Hz1 6 H)
ϊ .54 (d, J=6.95 Hz, 2 H) 1.49 - 1.58 (m, 2 H) 1.62 (d, J=10.98
Hz, 2 H) 1.87 - 1.97 (m, 1 H)
111 1.91 (d, J=7.32 Hz, 1 H) 2.46 390
(br. s., 2 H) 4.51 (t, J=6.77 Hz,

3 H) 7.02 (br. s., 1 H) 7.46 (d,
N-[(1 S)-1-(aminocarbonyl)-3- J=6.59 Hz, 2 H) 7.90 (d, J=8.42
methylbutyl]-5-chloro-1 -(4- Hz, 1 H) 7.84 (d, J=9.15 Hz, 1
cyanobutyl)-1 H-indazole-3- H) 8.10 (s, 1 H)
carboxamide
1H NMR (400 MHz, DMSO-d6)
D ppm 1.20 (br. s., 4 H) 1.50 - 1.62 (m, 2 H) 1.54 (d, J=7.69
Hz, 2 H) 1.84 - 1.95 (m, 2 H)
1.91 (d, J=7.32 Hz, 3 H) 2.46
112 (br. s., 2 H) 3.43 (d, J=4.39 Hz, 375
1 H) 3.59 (br. s., 1 H) 4.49 (t,

J=6.77 Hz, 2 H) 4.56 (d, J=5.49
5-chloro-1 -(4-cyanobutyl)-N- Hz, 1 H) 7.44 (d, J=8.78 Hz, 1
[(1S,2S)-2-hydroxy- H) 7.80 (t, J=9.70 Hz, 2 H) 8.12
cyclohexyl]-1 H-indazole-3- (s, 1 H)
carboxamide
1 H NMR (400 MHz, DMSO-d6)
D ppm 1.51 - 1.61 (m, J=7.23,
7.23, 7.23, 7.23 Hz, 2 H) 1.77
(d, J=9.15 Hz, 1 H) 1.96 (dd,
J=15.37, 7.32 Hz, 6 H) 2.80 (d,
J=8.78 Hz, 2 H) 2.77 (d, J=5.86
113 Hz1 1 H) 4.51 (t, J=6.77 Hz, 2 407
H) 5.29 (br. s., 1 H) 7.13 (d,

J=6.59 Hz, 3 H) 7.23 (d, J=6.59
5-chloro-1 -(4-cyanobutyl)-N- Hz, 1 H) 7.50 (d, J=8.78 Hz1 1
[(1S)-1 ,2,3,4-tetrahydro- H) 7.87 (d, J=9.15 Hz, 1 H)
naphthalen-1 -yl]-1 H-indazole- 8.20 (s, 1 H) 8.42 (d, J=9.15
3-carboxamide Hz1 1 H)
1 H NMR (400 MHz1 DMSO-d6)
pppm 1.51 - 1.61 (m, J=7.32,
7.32, 7.32, 7.32 Hz, 3 H) 1.89 - 1.99 (m, J=7.23, 7.23, 7.23,
114 7.23 Hz, 3 H) 2.89 (d, J=16.11 409
Hz, 1 H) 3.16 (dd, J=16.29,
4.58 Hz1 1 H) 4.54 (t, J=6.77
Hz1 4 H) 5.43 (d, J=4.76 Hz, 2

H) 7.17 - 7.28 (m, 4 H) 7.53 (d,
















ohexylmethyl)-5-f

















-1-(aminocarbon





luoro-1









































































)-1-[(3-carbamoyl



















* * * * * * * * *
The above detailed description of embodiments is intended only to acquaint others skilled in the art with the invention, its principles, and its practical application so that others skilled in the art may adapt and apply the invention in its numerous forms, as they may be best suited to the requirements of a particular use. This invention, therefore, is not limited to the above embodiments, and may be variously modified.