This application is a continuation of U.S. application Ser. No. 15/326,740, filed Jan. 17, 2017, which claims benefit of International Application No. PCT/US2015/040967, filed Jul. 17, 2015, which claims the benefit of U.S. Provisional Patent Application No. 62/026,214, filed Jul. 18, 2014, the. The entire contents of each of these applications are hereby incorporated by reference.

Provided are certain agents that inhibit IRAK4, and methods of making and using such agents.

Cellular immune responses depend on the ability of immune cells (e.g., macrophages, natural killer cells, T-cells) to detect and respond to cues in the extracellular environment by transmitting (transducing) signals across the cell membrane and into the intracellular (cytoplasmic) environment. Signals transmitted across the cell membrane may then effect a variety of “downstream” cytoplasmic and nuclear signal transduction pathways that subsequently produce a variety of immune cell responses (for example up- or down-regulation of gene transcription and translation or by releasing cytoplasmically stored components into the extracellular environment).

One cytoplasmic molecule responsible for the transmission of such downstream signals is known as “IRAK4”. IRAK4 functions in cytoplasmic signal transduction pathways by interacting with components (“adaptor proteins”) associated with the cytoplasmic portion of the Interleukin-1 receptor (IL-1R), Interleukin-18 receptor (IL-18R), and Toll-Like receptors (TLRs). These receptors (ILRs and the vertebrate TLRs) play important roles in innate immunity (i.e., general, non-specific immune system mechanisms of defense). In particular, TLRs play important roles in responding to microbial pathogens. TLRs are capable of eliciting a generalized immune response to pathogens via recognition of pathogen-associated molecular patterns (PAMPs). In response to such PAMPs, IL-1R/TLR signal transduction is initiated, across the cell membrane, by recruiting cytoplasmic adaptor proteins. Such adaptor proteins interact with homologous Toll/IL-1R (TIR) domains located in the cytoplasmic portion of IL-1R/TLR receptors.

The importance of adaptor proteins to immune system function is well established, as elimination of such adaptor proteins has been shown to induce significant disruptions of innate immune responses. Some examples of known IL-1R/TLR adaptor proteins are: MyD88; TIRAP/Mal; Trif/Ticam; and TRAM. MyD88, in particular, has a modular “death domain” (DD) that functions to recruit IRAK family proteins such as IRAK4. IRAK4 is thought to associate with MyD88 via IRAK4's own death domain. Moreover, loss of IRAK4/MyD88 association disrupts IL-1R/TLR signal transduction by preventing IRAK4 from phosphorylating (i.e., activating) IRAK1. Biologically, IRAK4 has been demonstrated to play a critical role in innate immunity.

›SUMMARY · 1 of 2

A first embodiment of the invention is a compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is selected from phenyl and 5- or 6-membered heteroaryl;

Ring B is selected from phenyl and 5- or 6-membered heteroaryl;

n is 0, 1, or 2;

p is 0, 1, or 2;

one of W and X is N, and the other of W and X is C;

Y is N or C—R 2 ;

R 1 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered saturated heterocyclyl, halo, —CN, —C(R 1a )═NR(OR 1a ), —C(R 1a )═N(R 1a ), —C(O)R 1a , —C(O) 2 R 1a , —C(O)N(R 1a ) 2 , —NO 2 , —N(R 1a ) 2 , —N(R 1a )C(O)R 1a , —N(R 1a )C(O) 2 R 1a , —N(R 1a )C(O)N(R 1a ) 2 , —N(R 1a )S(O) 2 R 1a , —OR 1a , —OC(O)R 1a , —OC(O)N(R 1a ) 2 , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)N(R 1a ) 2 , and —S(O) 2 N(R 1a ) 2 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, and 3- to 6-membered saturated heterocyclyl are optionally substituted with one or more R 10 ; or two R 1 substituents, together with their intervening atoms, form a C 5-7 cycloalkyl or a saturated 5- to 7-membered heterocyclic ring, wherein said C 5-7 cycloalkyl or a saturated 5- to 7-membered heterocyclic ring are optionally substituted with one or more R 15 ;

R 1a in each occurrence is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 6-membered monocyclic carbocyclyl, and 3- to 6-membered monocyclic heterocyclyl wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 6-membered monocyclic carbocyclyl, and 3- to 6-membered monocyclic heterocyclyl in each occurrence are optionally and independently substituted with one or more R 10 ;

R 10 in each occurrence is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 6-membered carbocyclyl, 3- to 6-membered heterocyclyl, halo, —CN, —C(R 10a )═NR(OR 10a ), —C(R 10a )═N(R 10a ), —C(O)R 10a , —C(O) 2 R 10a , —C(O)N(R 10a ) 2 , —NO 2 , —N(R 10a ) 2 , —N(R 10a )C(O)R 10a , —N(R 10a )C(O) 2 R 10a , —N(R 10a )C(O)N(R 10a ) 2 , —N(R 10a )S(O) 2 R 10a , —OR 10a , —OC(O)R 10a , —OC(O)N(R 10a ) 2 , —SR 10a , —S(O)R 10a , —S(O) 2 R 10a , —S(O)N(R 10a ) 2 , and —S(O) 2 N(R 10a ) 2 ;

R 10a in each occurrence is independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more halo;

R 15 in each occurrence is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 6-membered carbocyclyl, 3- to 6-membered heterocyclyl, halo, —CN, —C(R 15a )═NR(OR 15a ), —C(R 15a )═N(R 15a ), —C(O)R 15a , —C(O) 2 R 15a , —C(O)N(R 15a ) 2 , —NO 2 , —N(R 15a ) 2 , —N(R 15a )C(O)R 15a , —N(R 15a )C(O) 2 R 15a , —N(R 15a )C(O)N(R 15a ) 2 , —N(R 15a )S(O) 2 R 15a , —OR 15a , —OC(O)R 15a , —OC(O)N(R 15a ) 2 , —SR 15a , —S(O)R 15a , —S(O) 2 R 15a , —S(O)N(R 15a ) 2 , and —S(O) 2 N(R 15a ) 2 ;

R 15a in each occurrence is independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more halo;

R 2 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, halo, —CN, —C(R 2a )═NR(OR 2a ), —C(R 2a )═N(R 2a ), —C(O)R 2a , —C(O) 2 R 2a , —C(O)N(R 2a ) 2 , —NO 2 , —N(R 2a ) 2 , —N(R 2a )C(O)R 2a , —N(R 2a )C(O) 2 R 2a , —N(R 2a )C(O)N(R 2a ) 2 , —N(R 2a )S(O) 2 R 2a , —OR 2a , —OC(O)R 2a , —OC(O)N(R 2a ) 2 , —SR 2a , —S(O)R 2a , —S(O) 2 R 2a , —S(O)N(R 2a ) 2 , and —S(O) 2 N(R 2a ) 2 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 7-membered carbocyclyl, and 3-7 membered heterocyclyl are optionally substituted with one or more R 20 ;

R 2a in each occurrence is independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl in each occurrence is optionally and independently substituted with one or more R 20 ;

R 20 in each occurrence is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3- to 7-membered saturated heterocyclyl, halo, —CN, —C(R 20a )═NR(OR 20a ), —C(R 20a )═N(R 20a ), —C(O)R 20a , —C(O) 2 R 20a , —C(O)N(R 20a ) 2 , —NO 2 , —N(R 20a ) 2 , —N(R 20a )C(O)R 20a , —N(R 20a )C(O) 2 R 20a , —N(R 20a )C(O)N(R 20a ) 2 , —N(R 20a )S(O) 2 R 2a , —OR 20a , —OC(O)R 20a , —OC(O)N(R 20a ) 2 , —SR 20a , —S(O)R 20a , —S(O) 2 R 20a , —S(O)N(R 20a ) 2 , and —S(O) 2 N(R 20a ) 2 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, and 3-7 membered saturated heterocyclyl in each occurrence are optionally and independently substituted with one or more R 25 ;

R 20a in each occurrence is independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with R 25 ;

R 25 is selected from halo and —OR 25a ;

R 25a is selected from H and C 1-6 alkyl;

R 3 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered saturated heterocyclyl, halo, —CN, —C(R 3a )═NR(OR 3a ), —C(R 3a )═N(R 3a ), —C(O)R 3a , —C(O) 2 R 3a , —C(O)N(R 3a ) 2 , —NO 2 , —N(R 3a ) 2 , —N(R 3a )C(O)R 3a , —N(R 3a )C(O) 2 R 3a , —N(R 3a )C(O)N(R 3a ) 2 , —N(R 3a )S(O) 2 R 3a , —OR 3a , —OC(O)R 3a , —OC(O)N(R 3a ) 2 , —SR 3a , —S(O)R 3a , —S(O) 2 R 3a , —S(O)N(R 3a ) 2 , and —S(O) 2 N(R 3a ) 2 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, and 3- to 6-membered saturated heterocyclyl are optionally substituted with one or more R 30 ;

R 3a in each occurrence is independently selected from H, C 1-6 alkyl, 3- to 6-membered carbocyclyl, and 3- to 6-membered heterocyclyl, wherein said C 1-6 alkyl, 3- to 6-membered carbocyclyl, and 3- to 6-membered heterocyclyl in each occurrence are optionally and independently substituted with one or more R 30 ;

R 30 in each occurrence is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 6-membered carbocyclyl, 3- to 6-membered heterocyclyl, halo, —CN, —C(R 30a )═NR(OR 30a ), —C(R 30a )═N(R 30a ), —C(O)R 30a , —C(O) 2 R 30a , —C(O)N(R 30a ) 2 , —NO 2 , —N(R 30a ) 2 , —N(R 30a )C(O)R 30a , —N(R 30a )C(O) 2 R 30a , —N(R 30a )C(O)N(R 30a ) 2 , —N(R 30a )S(O) 2 R 30a , —OR 30a , —OC(O)R 30a , —OC(O)N(R 30a ) 2 , —SR 30a , —S(O)R 30a , —S(O) 2 R 30a , —S(O)N(R 30a ) 2 , and —S(O) 2 N(R 30a ) 2 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-6 membered carboyclyl, 3- to 6-membered heterocyclyl in each occurrence are optionally and independently substituted with one or more R 35 ;

›SUMMARY · 2 of 2

R 30a in each occurrence is independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more R 35 ;

R 35 in each occurrence is independently selected from halo and —OR 35a ;

R 35a in each occurrence is independently selected from H and C 1-6 alkyl;

R 4 is selected from H, halo, C 1-6 alkyl, N(R 4a ) 2 , and —OR 4a ; and

R 4a in each occurrence is independently selected from H and C 1-6 alkyl,

wherein the compound is not:

3-(1-(2,4-dichlorophenyl)-1H-indazol-6-yl)-N-(2-hydroxyethyl)benzamide, ethyl 3-(1-(2,4-dichlorophenyl)-1H-indazol-6-yl)benzoate, 3-(1-(2,4-dichlorophenyl)-1H-indazol-6-yl)benzoic acid, or N-(3-(1-(4-methoxyphenyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)phenyl)acetamide.

In a particular aspect, R 1 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered saturated heterocyclyl, halo, —CN, —C(R 1a )═NR(OR 1a ), —C(R 1a )═N(R 1a ), —C(O)R 1a , —C(O) 2 R 1a , —C(O)N(R 1a ) 2 , —N(R 1a ) 2 , —N(R 1a )C(O)R 1a , —N(R 1a )C(O) 2 R 1a , —N(R 1a )C(O)N(R 1a ) 2 , —N(R 1a )S(O) 2 R 1a , —OR 1a , —OC(O)R 1a , —OC(O)N(R 1a ) 2 , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)N(R 1a ) 2 , and —S(O) 2 N(R 1a ) 2 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, and 3- to 6-membered saturated heterocyclyl are optionally substituted with one or more R 10 ; or two R 1 substituents, together with their intervening atoms, form a C 5-7 cycloalkyl or a saturated 5- to 7-membered heterocyclic ring, wherein said C 5-7 cycloalkyl or a saturated 5- to 7-membered heterocyclic ring are optionally substituted with one or more R 15 .

In another particular aspect, the compound is not 6-(5-bromo-2-nitrophenyl)-1-phenyl-1H-indazole or 6-(2-nitrophenyl)-1-phenyl-1H-indazole.

Also provided is a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

Also provided is a method of decreasing the expression or activity of IRAK-4, or to otherwise affect the properties and/or behavior of IRAK-4 polypeptides or polynucleotides comprising administering to said mammal an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof.

Also provided is a method for treating an inflammatory disease in a subject, the method comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, thereby treating the inflammatory disease in the subject.

Also provided is a method for treating an autoimmune disease, cancer, cardiovascular disease, a disease of the central nervous system, a disease of the skin, an ophthalmic disease and condition, and bone disease in a subject, the method comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, thereby treating the autoimmune disease, cancer, cardiovascular disease, disease of the central nervous system, disease of the skin, ophthalmic disease and condition, and bone disease in the subject.

Other features or advantages will be apparent from the following detailed description of several embodiments, and also from the appended claims.

›BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graph showing the effect of administration of an IRAK4 inhibitor on the inflammatory responses of primary mouse kidney fibroblasts that were treated for 24 hours with 10 ng/ml recombinant IL-1β (a) or 100 ng/ml ultrapure LPS (b).

FIG. 2 is a graph showing that inhibition of IRAK4 reduces inflammation (a) and (b), tubular damage (c), and extracellular matrix deposition (d) in mouse models of ischemic kidney injury.

›DETAILED DESCRIPTION · 1 of 13

The compounds or pharmaceutically acceptable salts thereof as described herein, can have activity as IRAK4 modulators. In particular, compounds or pharmaceutically acceptable salts thereof as described herein, can be IRAK4 inhibitors.

A second embodiment of the invention is a compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein the values of the variables are as defined for the first embodiment.

A third embodiment of the invention is a compound of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein the values of the variables are as defined for the first embodiment.

A fourth embodiment of the invention is a compound of Formula (IV):

or a pharmaceutically acceptable salt thereof, wherein the values of the variables are as defined for the first embodiment.

In a fifth embodiment of the invention, the compound is represented by the formula (I), (II), (III), or (IV), wherein Ring A is 5- or 6-membered heteroaryl and Ring B is 5- or 6-membered heteroaryl, wherein the values of the other variables are as defined for the first embodiment.

In a sixth embodiment of the invention, the compound is represented by the formula (I), (II), (III), or (IV), wherein Ring A is a 5- or 6-membered heteroaryl and Ring B is phenyl, wherein the values of the other variables are as defined for the first embodiment.

In a seventh embodiment of the invention, the compound is represented by the formula (I), (II), (III), or (IV), wherein Ring A is a phenyl and Ring B is a 5- or 6-membered heteroaryl, wherein the values of the other variables are as defined for the first embodiment.

In an eighth embodiment of the invention, the compound is represented by the formula (I), (II), (III), or (IV), wherein the 5- or 6-membered heteroaryl in each occurrence is independently selected from pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, oxathianyl, triazinyl, or tetrazinyl, wherein the values of the other variables are as defined for the first, fifth, sixth, and seventh embodiments.

In a ninth embodiment of the invention, the compound is represented by the formula (I), (II), (III), or (IV), wherein the 5- or 6-membered heteroaryl in each occurrence is independently selected from pyridinyl, pyrimidinyl, pyrazinyl, thiazolyl, imidazolyl, oxazolyl pyrazolyl, and thiophenyl, wherein the values of the other variables are as defined for the first, fifth, sixth, seventh and eighth embodiments.

In a tenth embodiment of the invention, the compound is represented by the formula (I), (II), (III), or (IV), wherein Ring A is a phenyl and Ring B is phenyl, wherein the values of the other variables are as defined for the first embodiment.

In an eleventh embodiment of the invention, the compound is represented by the formula (I), (II), (III), or (IV), wherein n is 1 or 2, and each R 1 is in each occurrence independently selected from C 1-6 alkyl, C 3-6 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; 3- to 6-membered saturated heterocyclyl selected from aziridinyl, oxiranyl, thiiranyl, oxaziridinyl, dioxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, and trithianyl; halo, —CN, —C(R 1a )═NR(OR 1a ), —C(R 1a )═N(R 1a ), —C(O)R 1a , —C(O) 2 R 1a , —C(O)N(R 1a ) 2 , —N(R 1a ) 2 , —N(R 1a )C(O)R 1a , —N(R 1a )C(O) 2 R 1a , —OR 1a , —OC(O)R 1a , and —OC(O)N(R 1a ) 2 , wherein said C 1-6 alkyl, C 3-6 cycloalkyl, and 3- to 6-membered saturated heterocyclyl are optionally substituted with one to four R 10 ;

R 1a in each occurrence is independently selected from H, C 1-6 alkyl, 3- to 6-membered monocyclic carbocyclyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopenentyl, cyclohexenyl, cyclobutadienyl, cyclopentadienyl, cyclohexadienyl, and phenyl; and 3- to 6-membered monocyclic heterocyclyl selected from aziridinyl, oxiranyl, thiiranyl, oxaziridinyl, dioxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, trithianyl, dihydrofuranyl, imidazolinyl, dihydropyranyl, azirinyl, oxirenyl, thiirenyl, diazirinyl, azetyl, oxetyl, thietyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, oxathianyl, triazinyl, and tetrazinyl, wherein said C 1-6 alkyl, 3- to 6-membered monocyclic carbocyclyl, and 3- to 6-membered monocyclic heterocyclyl in each occurrence are optionally and independently substituted with one to three R 10 ;

R 10 in each occurrence is independently selected from C 1-6 alkyl, 3- to 6-membered carbocyclyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopenentyl, cyclohexenyl, cyclobutadienyl, cyclopentadienyl, cyclohexadienyl, and phenyl; 3- to 6-membered heterocyclyl selected from aziridinyl, oxiranyl, thiiranyl, oxaziridinyl, dioxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, trithianyl, dihydrofuranyl, imidazolinyl, dihydropyranyl, azirinyl, oxirenyl, thiirenyl, diazirinyl, azetyl, oxetyl, thietyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, oxathianyl, triazinyl, and tetrazinyl, halo, —CN, —C(R 10a )═NR(OR 10a ), —C(R 10a )═N(R 10a ), —C(O)R 10a , —C(O) 2 R 10a , —C(O)N(R 10a ) 2 , —NO 2 , —N(R 10a ) 2 , —N(R 10a )C(O)R 10a , —N(R 10a )C(O) 2 R 10a , —N(R 10a )C(O)N(R 10a ) 2 , —OR 10a , —OC(O)R 10a , and —OC(O)N(R 10a ) 2 ; and

›DETAILED DESCRIPTION · 2 of 13

R 10a in each occurrence is independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one to three halo, wherein the values of the other variables are as defined for the first and fifth, sixth, seventh, eighth, ninth and tenth embodiments.

In a twelfth embodiment of the invention, the compound is represented by the formula (I), (II), (III), or (IV), wherein n is 1 or 2, and each R 1 is in each occurrence independently selected from C 1-6 alkyl, C 3-6 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, 3- to 6-membered saturated heterocyclyl selected from aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, and morpholinyl; halo, —CN, —C(O) 2 R 1a , —C(O)N(R 1a ) 2 , —N(R 1a ) 2 , and —OR 1a , wherein said C 1-6 alkyl, C 3-6 cycloalkyl, and 3- to 6-membered saturated heterocyclyl are optionally substituted with one to four R 10 ;

R 1a in each occurrence is independently selected from H and C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted with one to three R 10 ;

R 10 in each occurrence is independently selected from C 1-4 alkyl, 3- to 6-membered carbocyclyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl; halo, —CN, —C(O) 2 R 10a , —C(O)N(R 10a ) 2 , —N(R 10a )C(O)R 10a , —N(R 10a ) 2 , and —OR 10a ; and

In a thirteenth embodiment of the invention, the compound is represented by the formula (I), (II), (III), or (IV), wherein n is 1 and R 1 is C 1-6 alkyl optionally substituted with —N(R 10a ) 2 ; and R 10a in each occurrence is independently selected from H and C 1-4 alkyl, wherein the values of the other variables are as defined for the first and fifth, sixth, seventh, eighth, ninth, tenth, eleventh and twelfth embodiments.

In a fourteenth embodiment of the invention, the compound is represented by the formula (I), (II), (III), or (IV), wherein R 1 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl 3- to 6-membered saturated heterocyclyl, halo, —CN, —C(R 1a )═NR(OR 1a ), —C(R 1a )═N(R 1a ), —C(O)R 1a , NO 2 , —N(R 1a ) 2 , N(R 1a )C(O)R 1a , N(R 1a )C(O) 2 R 1a , —N(R 1a )C(O)N(R 1a ) 2 , —N(R 1a )S(O) 2 R 1a , —OR 1a , —OC(O)R 1a , —OC(O)N(R 1a ) 2 , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)N(R 1a ) 2 , and —S(O) 2 N(R 1a ) 2 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and 3- to 6-membered saturated heterocyclyl are optionally substituted with one or more R 10 ; or two R 1 substituents, together with their intervening atoms, form a C 5-7 cycloalkyl or a saturated 5- to 7-membered heterocyclic ring, wherein said C 5-7 cycloalkyl or a saturated 5- to 7-membered heterocyclic ring are optionally substituted with one or more R 15 , wherein the values of the other variables are as defined for the first and fifth, sixth, seventh, eighth, ninth, and tenth, embodiments. Alternatively, the compound is represented by the formula (I), (II), (III), or (VI) wherein R 1 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl 3- to 6-membered saturated heterocyclyl, halo, —CN, —C(R 1a )═NR(OR 1a ), —C(R 1a )═N(R 1a ), —C(O)R 1a , —NO 2 , —N(R 1a ) 2 , —N(R 1a )C(O) 2 R 1a , —N(R 1a )C(O)N(R 1a ) 2 , —N(R 1a )S(O) 2 R 1a , —OR 1a , —OC(O)R 1a , —OC(O)N(R 1a ) 2 , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)N(R 1a ) 2 , and —S(O) 2 N(R 1a ) 2 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and 3- to 6-membered saturated heterocyclyl are optionally substituted with one or more R 10 ; or two R 1 substituents, together with their intervening atoms, form a C 5-7 cycloalkyl or a saturated 5- to 7-membered heterocyclic ring, wherein said C 5-7 cycloalkyl or a saturated 5- to 7-membered heterocyclic ring are optionally substituted with one or more R 15 , wherein the values of the other variables are as defined for the first and fifth, sixth, seventh, eighth, ninth, and tenth, embodiments.

In a fifteenth embodiment of the invention, the compound is represented by the formula (I), (II), (III), or (IV), wherein if X is N, Ring A and Ring B are phenyl, then R 1 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered saturated heterocyclyl, halo, —CN, —C(R 1a )═NR(OR 1a ), —C(R 1a )═N(R 1a ), —C(O)R 1a , NO 2 , —N(R 1a ) 2 , N(R 1a )C(O)R 1a , N(R 1a )C(O) 2 R 1a , —N(R 1a )C(O)N(R 1a ) 2 , —N(R 1a )S(O) 2 R 1a , —OR 1a , —OC(O)R 1a , —OC(O)N(R 1a ) 2 , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)N(R 1a ) 2 , and —S(O) 2 N(R 1a ) 2 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, and 3- to 6-membered saturated heterocyclyl are optionally substituted with one to four R 10 ; or two R 1 substituents, together with their intervening atoms, form a C 5-7 cycloalkyl or a saturated 5- to 7-membered heterocyclic ring, wherein said C 5-7 cycloalkyl or a saturated 5- to 7-membered heterocyclic ring are optionally substituted with one to four R 15 , wherein the values of the other variables are as defined for the first and fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth and fourteenth embodiments. Alternatively, the compound is represented by the formula (I), (II), or (III), or (IV), wherein X is N, Ring A and Ring B are phenyl, and R 1 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered saturated heterocyclyl, halo, —CN, —C(R 1a )═NR(OR 1a ), —C(R 1a )═N(R 1a ), —C(O)R 1a , NO 2 , —N(R 1a ) 2 , N(R 1a )C(O) 2 R 1a , —N(R 1a )C(O)N(R 1a ) 2 , —N(R 1a )S(O) 2 R 1a , —OR 1a , —OC(O)R 1a , —OC(O)N(R 1a ) 2 , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)N(R 1a ) 2 , and —S(O) 2 N(R 1a ) 2 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, and 3- to 6-membered saturated heterocyclyl are optionally substituted with one to four R 10 ; or two R 1 substituents, together with their intervening atoms, form a C 5-7 cycloalkyl or a saturated 5- to 7-membered heterocyclic ring, wherein said C 5-7 cycloalkyl or a saturated 5- to 7-membered heterocyclic ring are optionally substituted with one to four R 15 wherein the values of the other variables are as defined for the first and fifth, sixth, seventh, eighth, ninth, tenth, and fourteenth embodiments.

›DETAILED DESCRIPTION · 3 of 13

In a sixteenth embodiment of the invention, the compound is represented by the formula (I), (II), (III), or (IV), wherein n is 1 or 2, and each R 1 is in each occurrence independently selected from C 1-6 alkyl, C 3-6 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, 3- to 6-membered saturated heterocyclyl selected from aziridinyl, oxiranyl, thiiranyl, oxaziridinyl, dioxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, and trithianyl; halo, —CN, —C(R 1a )═NR(OR 1a ), —C(R 1a )═N(R 1a ), —C(O)R 1a , —N(R 1a ) 2 , —OR 1a , —OC(O)R 1a , and —OC(O)N(R 1a ) 2 , wherein said C 1-6 alkyl, C 3-6 cycloalkyl, and 3- to 6-membered saturated heterocyclyl are optionally substituted with one to four R 10 ;

R 10a in each occurrence is independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one to three halo; wherein the values of the other variables are as defined for the first and fifth, sixth, seventh, eighth, ninth, tenth, fourteenth and fifteenth embodiments.

In a seventeenth embodiment of the invention, the compound is represented by the formula (I), (II), (III), or (IV), n is 1 or 2, and each R 1 is in each occurrence independently selected from C 1-6 alkyl, C 3-6 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; 3- to 6-membered saturated heterocyclyl selected from aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, and morpholinyl; halo, —CN, —N(R 1a ) 2 , and —OR 1a , wherein said C 1-6 alkyl, C 3-6 cycloalkyl, and 3- to 6-membered saturated heterocyclyl are optionally substituted with one to four R 10 . In an alternative aspect, R 1 may also include C 2-6 alkenyl, C 2-6 alkynyl, and tetrahydrofuranyl.

R 1a in each occurrence is independently selected from H and C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted with one to three R 10 ;

R 10a in each occurrence is independently selected from H and C 1-4 alkyl, wherein the values of the other variables are as defined for the first and fifth, sixth, seventh, eighth, ninth, tenth, fourteenth, fifteenth and sixteenth embodiments. In an alternative aspect of this embodiment, R 10 may also include —SR 10a , C 2-6 alkenyl, C 2-6 alkynyl, —C(O)R 10a , —S(O) 2 R 10a , and —S(O)R 10a .

In an alternative seventeenth embodiment, the compound is represented by the formula (I), (II), (III), or (IV), n is 1, and R 1 is C 1-6 alkyl substituted with one, two, three or four groups selected from halo, —OR 1a , —N(R 1a ) 2 , cyclobutyl, and oxetanyl, wherein R 1a in each occurrence is independently selected from H and C 1-4 alkyl, wherein the values of the other variables are as defined for the first and fifth, sixth, seventh, eighth, ninth, tenth, fourteenth, fifteenth and sixteenth embodiments.

›DETAILED DESCRIPTION · 4 of 13

In an eighteenth embodiment of the invention, the compound is represented by the formula (I), (II), (III), or (IV), wherein n is 2 and two R 1 substituents, together with their intervening atoms, form a C 5-7 cycloalkyl ring or a saturated 5- to 7-membered heterocyclic ring, wherein said C 5-7 cycloalkyl ring or a saturated 5- to 7-membered heterocyclic ring are optionally substituted with one to three R 15 ;

R 15 in each occurrence is independently selected from C 1-4 alkyl, halo, —CN, —C(O)R 15a , —C(O) 2 R 15a , —C(O)N(R 15a ) 2 , —N(R 15a ) 2 , —N(R 15a )C(O)R 15a , —N(R 15a )C(O) 2 R 15a , —N(R 15a )C(O)N(R 15a ) 2 , —OR 15a , —OC(O)R 15a , and —OC(O)N(R 15a ) 2 ; and

R 15a in each occurrence is independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one to three halo, wherein the values of the other variables are as defined for the first and fifth, sixth, seventh, eighth, ninth, and tenth embodiments.

In a nineteenth embodiment of the invention, the compound is represented by the formula (I), (II), (III), or (IV), wherein the C 5-7 cycloalkyl ring selected from cyclopentyl, cyclohexyl, and cycloheptyl and the saturated 5- to 7-membered heterocyclic ring selected from pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, trithianyl, azepanyl, oxepanyl, and thiepanyl, said C 5-7 cycloalkyl ring or a saturated 5- to 7-membered heterocyclic ring are optionally substituted with C 1-4 alkyl or —N(R 15a ) 2 ; and R 15a in each occurrence is independently selected from H and C 1-4 alkyl; wherein the values of the other variables are as defined for the first and fifth, sixth, seventh, eighth, ninth, tenth and eighteenth embodiments.

In a twentieth embodiment of the invention, the compound is represented by the formula (I), (II), (III), or (IV), wherein the C 5-7 cycloalkyl ring is selected from cyclopentyl, cyclohexyl, and cycloheptyl and the saturated 5- to 7-membered heterocyclic ring selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, and azepanyl, said C 5-7 cycloalkyl ring or a saturated 5- to 7-membered heterocyclic ring are optionally substituted with C 1-4 alkyl or —N(R 15a ) 2 ; and R 15a in each occurrence is independently selected from H and C 1-4 alkyl, wherein the values of the other variables are as defined for the first and fifth, sixth, seventh, eighth, ninth, tenth, eighteenth and nineteenth embodiments.

In a twenty-first embodiment of the invention, the compound is represented by the formula (I), (II), (III), or (IV), wherein R 2 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 7-membered carbocyclyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopenentyl, cyclohexenyl, cycloheptenyl, cyclobutadienyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl, cycloheptatrienyl, and phenyl; 3- to 7-membered heterocyclyl selected from aziridinyl, oxiranyl, thiiranyl, oxaziridinyl, dioxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, trithianyl, azepanyl, oxepanyl, thiepanyl, azirinyl, oxirenyl, thiirenyl, diazirinyl, azetyl, oxetyl, thietyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, oxathianyl, triazinyl, tetrazinyl, azepinyl, oxepinyl, thiepinyl, diazepinyl, thiazepinyl, dihydrofuranyl, imidazolinyl, and dihydropyranyl; halo, —CN, —C(O)R 2a , —C(O) 2 R 2a , —C(O)N(R 2a ) 2 , —NO 2 , —N(R 2a ) 2 , —N(R 2a )C(O)R 2a , —N(R 2a )C(O) 2 R 2a , —N(R 2a )C(O)N(R 2a ) 2 , —OR 2a , —OC(O)R 2a , and —OC(O)N(R 2a ) 2 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 7-membered carbocyclyl, and 3-7 membered heterocyclyl are optionally substituted with one to three R 20 ;

R 2a in each occurrence is independently selected from H and C 1-6 alkyl, wherein said C 1-4 alkyl in each occurrence is optionally and independently substituted with one to three R 20 ;

R 20 in each occurrence is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, 3- to 7-membered saturated heterocyclyl selected from aziridinyl, oxiranyl, thiiranyl, oxaziridinyl, dioxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, trithianyl, azepanyl, oxepanyl, and thiepanyl; halo, —CN, —C(O)R 20a , —C(O) 2 R 20a , —C(O)N(R 20a ) 2 , —N(R 20a ) 2 , —N(R 20a )C(O)R 20a , —N(R 20a )C(O) 2 R 20a , —N(R 20a )C(O)N(R 20a ) 2 , —OR 20a , —OC(O)R 20a , and —OC(O)N(R 20a ) 2 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, and 3-7 membered saturated heterocyclyl in each occurrence are optionally and independently substituted with one to three R 25 ;

R 20a in each occurrence is independently selected from H and C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted with R 25 ;

R 25 is selected from halo and —OR 25a ; and

R 25a is selected from H and C 1-4 alkyl, wherein the values of the other variables are as defined for the first and fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth and twentieth embodiments.

›DETAILED DESCRIPTION · 5 of 13

In a twenty-second embodiment of the invention, the compound is represented by the formula (I), (II), (III), or (IV), wherein R 2 is H, C 1-4 alkyl, C 2-4 alkenyl, halo, —C(O) 2 R 2a , —C(O)N(R 2a ) 2 , —N(R 2a ) 2 , N(R 2a )C(O)R 2a , —CN, —OR 2a , cyclopropyl, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, azepanyl, oxepanyl, azirinyl, azetyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, azepinyl, diazepinyl, thiazepinyl, and imidazolinyl, wherein said C 1-4 alkyl is optionally substituted with one to three groups selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, —OR 20a , —N(R 20a ) 2 , N(R 20a )C(O)R 20a , and halo. In an alternative aspect, R 2 also includes C 2-4 alkynyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, dihydro-2H-pyranyl, tetrahydropyridinyl, morpholinyl, thiomorpholinyl, thiomorpholine 1,1-dioxidyl, morpholin-3-onyl, and dihydrooxazolyl; wherein the C 1-4 alkyl, C 2-4 alkynyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, dihydro-2H-pyranyl, tetrahydropyridinyl, morpholinyl, thiomorpholine 1,1-dioxidyl, morpholin-3-onyl, dihydrooxazolyl, thiomorpholinyl, cyclopropyl, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, azepanyl, oxepanyl, azirinyl, azetyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, azepinyl, diazepinyl, thiazepinyl, and imidazolinyl are optionally substituted with one to three groups selected from C 1-4 alkyl, halo, —OR 20a , CN, —C(O)R 20a , —C(O) 2 R 20a and morpholinyl; wherein the C 1-4 alkyl is optionally substituted with one to three groups selected from halo and —OR 25a ; wherein R 25a is H or C 1-4 alkyl.

R 2a in each occurrence is independently selected from H and C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted with cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In an alternative aspect, the wherein the C 1-4 alkyl is also optionally substituted with one to three groups selected from halo, —OR 20a , —N(R 20a ) 2 , —C(O)R 20a , piperdinyl and cyclobutyl; wherein the piperidinyl and cyclobutyl are optionally substituted with one to three halo; wherein R 20a is H and C 1-4 alkyl.

R 20a in each occurrence is independently selected from H and C 1-4 alkyl. In an alternative aspect, C 1-4 alkyl is also optionally substituted with halo and S(O) 2 R 20a . The values of the other variables are as defined for the first and fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth and twenty-first embodiments.

In a twenty-third embodiment of the invention, the compound is represented by the formula (I), (II), (III), or (IV), wherein R 2 is H or —OR 2a ; R 2a in each occurrence is independently selected from H and C 1-4 alkyl, wherein the values of the other variables are as defined for the first and fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first and twenty-second embodiments.

In an alternative twenty-third embodiment of the invention, the compound is represented by the formula (I), (II), (III), or (IV), wherein R 2 is H, —OR 2a , tetrahydrofuranyl, or pyrazolyl; wherein the tetrahydrofuranyl and pyrazolyl are optionally substituted with C 1-4 alkyl; R 2a in each occurrence is independently selected from H and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted with —OR 20a , wherein R 20a is H and C 1-4 alkyl, wherein the values of the other variables are as defined for the first and fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first and twenty-second embodiments.

In a twenty-fourth embodiment of the invention, the compound is represented by the formula (I), (II), (III), or (IV), wherein p is 1 or 2; each R 3 is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, 3- to 6-membered saturated heterocyclyl selected from aziridinyl, oxiranyl, thiiranyl, oxaziridinyl, dioxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, and trithianyl; halo, —CN, —C(O)R 3a , —C(O) 2 R 3a , —C(O)N(R 3a ) 2 , —N(R 3a ) 2 , —N(R 3a )C(O)R 3a , —N(R 3a )C(O) 2 R 3a , —N(R 3a )C(O)N(R 3a ) 2 , —OR 3a , —OC(O)R 3a , —OC(O)N(R 3a ) 2 , —SR 3a , —S(O)R 3a , —S(O) 2 R 3a , —S(O)N(R 3a ) 2 , and —S(O) 2 N(R 3a ) 2 , wherein said C 1-6 alkyl, C 3-6 cycloalkyl, and 3- to 6-membered saturated heterocyclyl are optionally substituted with one to three R 30 ;

R 3a in each occurrence is independently selected from H, C 1-6 alkyl, 3- to 6-membered carbocyclyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopenentyl, cyclohexenyl, cyclobutadienyl, cyclopentadienyl, cyclohexadienyl, and phenyl, and 3- to 6-membered heterocyclyl selected from aziridinyl, oxiranyl, thiiranyl, oxaziridinyl, dioxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, trithianyl, azirinyl, oxirenyl, thiirenyl, diazirinyl, azetyl, oxetyl, thietyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, oxathianyl, triazinyl, tetrazinyl, dihydrofuranyl, imidazolinyl, and dihydropyranyl; wherein said C 1-6 alkyl, 3- to 6-membered carbocyclyl, and 3- to 6-membered saturated heterocyclyl in each occurrence are optionally and independently substituted with one to three R 30 ;

›DETAILED DESCRIPTION · 6 of 13

R 30 in each occurrence is independently selected from C 1-6 alkyl, 3- to 6-membered carbocyclyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopenentyl, cyclohexenyl, cyclobutadienyl, cyclopentadienyl, cyclohexadienyl, and phenyl; 3- to 6-membered heterocyclyl selected from aziridinyl, oxiranyl, thiiranyl, oxaziridinyl, dioxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, trithianyl, azirinyl, oxirenyl, thiirenyl, diazirinyl, azetyl, oxetyl, thietyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, oxathianyl, triazinyl, tetrazinyl, dihydrofuranyl, imidazolinyl, and dihydropyranyl; halo, —CN, —C(O)R 30a , —C(O) 2 R 30a , —C(O)N(R 30a ) 2 , —N(R 30a ) 2 , —N(R 30a )C(O)R 30a , —N(R 30a )C(O) 2 R 30a , —N(R 30a )C(O)N(R 30a ) 2 , —OR 30a , —OC(O)R 30a , and —OC(O)N(R 30a ) 2 , SR 30a , —S(O)R 30a , —S(O) 2 R 30a , —S(O)N(R 30a ) 2 , and —S(O) 2 N(R 30a ) 2 , wherein said C 1-6 alkyl, 3-6 membered carboyclyl, and 3- to 6-membered heterocyclyl in each occurrence are optionally and independently substituted with one to three R 35 ;

R 30a in each occurrence is independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one to three R 35 ;

R 35 in each occurrence is independently selected from halo and —OR 35a ; and

R 35a in each occurrence is independently selected from H and C 1-6 alkyl, wherein the values of the other variables are as defined for the first and fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second and twenty-third embodiments.

In a twenty-fifth embodiment of the invention, the compound is represented by the formula (I), (II), (III), or (IV), wherein R 3 in each occurrence is independently selected from C 1-4 alkyl, —CN, halo, C(O) 2 R 3a , C(O)N(R 3a ) 2 , —NR 3a 2 , cyclopropyl, cyclobutyl, and —C(O)R 3a , wherein said C 1-4 alkyl, cyclopropyl and cyclobutyl are optionally substituted with one to three groups selected from halo, N(R 30a ) 2 , —CN, —S(O) 2 R 30a , —C(O)N(R 3a ) 2 , and —OR 3a ;

R 3a in each occurrence is independently selected from H, C 1-4 alkyl, and azetidinyl, wherein said C 1-4 alkyl and azetidinyl are optionally substituted with —OR 30a , N(R 30a ) 2 , —CN, —S(O) 2 R 30a , —C(O) 2 R 30a , and —C(O)N(R 30a ) 2 ; and

R 30a in each occurrence is independently selected from H and C 1-4 alkyl, wherein the values of the other variables are as defined for the first and fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third and twenty-fourth embodiments.

In a twenty-sixth embodiment of the invention, the compound is represented by the formula (I), (II), (III), or (IV), wherein R 3 is selected from C 1-4 alkyl and C(O)N(R 3a ) 2 , wherein said C 1-4 alkyl is optionally substituted with 1 to 3 groups selected from halo and —OR 3a ; and R 3a in each occurrence is independently selected from H and C 1-4 alkyl, wherein the values of the other variables are as defined for the first and fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, and twenty-fifth embodiments. In an alternative aspect, R 3 is C 1-4 alkyl, C(O)N(R 3a ) 2 , C(O) 2 R 3a 2 , halo, —CN, —C(O)R 3a , —C(O) 2 R 3a , and cyclobutyl, wherein the C 1-4 alkyl and cyclobutyl are optionally substituted with 1 to 4 groups selected from halo and —OR 30a and N(R 30a ) 2 ; and each R 3aa and R 30a in each occurrence is independently selected from H and C 1-4 alkyl. In a specific aspect, R 3 is C 1-4 alkyl substituted with —OR 3a ; and R 3a in each occurrence is independently selected from H and C 1-4 alkyl.

In a twenty-seventh embodiment of the invention, the compound is represented by the formula (I), (II), (III), or (IV), wherein R 4 is selected from H, halo, and C 1-4 alkyl, wherein the values of the other variables are as defined for the first and fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth and twenty-sixth embodiments.

In a twenty-eighth embodiment of the invention, the compound is represented by the formula (I), (II), (III), or (IV), wherein the compound is represented by the formula structural formula

or a pharmaceutically acceptable salt thereof, wherein

R 1 is C 1-6 alkyl optionally substituted with N(R 10 ) 2 ; R 10 is H or C 1-4 alkyl; R 2 is H, F or —OR 2a ; R 2a is H or C 1-4 alkyl; R 3 is C(O)N(R 3a ) 2 or C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted with one to three halo or —OR 3a ; and R 3a in each occurrence is independently selected from H and C 1-4 alkyl, wherein the values of the other variables are as defined for the first embodiment. In an alternative aspect of this embodiment, R 1 is C 1-6 alkyl optionally substituted one to three groups selected from N(R 10 ) 2 , OR 10 , halo, cyclobutyl, oxetanyl; R 10 is H or C 1-4 alkyl; R 2 is H, F, —OR 2a , tetrahydrofuranyl, or pyrazolyl, wherein the tetrahydrofuranyl, or pyrazolyl is optionally substituted with C 1-4 alkyl; R 2a is H or C 1-4 alkyl optionally substituted with —OR 20a ; R 20a is H or C 1-4 alkyl; R 3 is C(O)N(R 3a ) 2 or C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted with one to three halo or —OR 3a ; and R 3a in each occurrence is independently selected from H and C 1-4 alkyl, wherein the values of the other variables are as defined for the first embodiment.

›DETAILED DESCRIPTION · 7 of 13

In a twenty-ninth embodiment, the invention is any one the compounds disclosed in the Exemplification section as a neutral compound or a pharmaceutically acceptable salt thereof.

In a thirtieth embodiment of the invention, there is provided a compound selected from:

6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine; 2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-amine; 2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-4-amine; (6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methanamine; (2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-4-yl)methanamine; 4-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine; 5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine; 3-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)aniline; (2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-yl)methanamine; 4-methyl-5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine; 3-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-5-nitropyridin-2-ol; 3-amino-5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-4-ol; N-methyl-5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine; N,N-dimethyl-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methanamine; 5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-1,2,3,4-tetrahydroisoquinoline; 2-methyl-5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-1,2,3,4-tetrahydroisoquinoline; 6-(2-methylisoindolin-4-yl)-1-(6-methylpyridin-2-yl)-1H-indazole; N-methyl-1-(3-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)phenyl)methanamine; 3-(6-(3-aminophenyl)-1H-indazol-1-yl)benzonitrile; 3-(1-(pyridin-2-yl)-1H-indazol-6-yl)aniline; 6-(6-(3-aminophenyl)-1H-indazol-1-yl)picolinonitrile; 3-(1-(4,6-dimethylpyridin-2-yl)-1H-indazol-6-yl)aniline; 3-(1-(5,6-dimethylpyridin-2-yl)-1H-indazol-6-yl)aniline; 3-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)aniline; 5-(1-(6-cyclopropylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine; 5-(1-(6-cyclobutylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine; 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)picolinonitrile; 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)picolinic acid; 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)picolinamide; 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-methylpicolinamide; 3-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)benzonitrile; 2-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-6-methylisonicotinonitrile; 2-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)isonicotinonitrile; 5-(1-(4-methylpyrimidin-2-yl)-1H-indazol-6-yl)pyridin-3-amine; 2-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)pyrimidine-4-carbonitrile; 5-(1-(3-chloro-6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine; 5-(1-(4-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine; 5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine; 5-(3-(6-methylpyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-3-amine; 3-(3-(6-methylpyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)aniline; 5-(5-fluoro-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine; 5-(5-methyl-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine; 6-(6-(6-(aminomethyl)pyridin-2-yl)-1H-indazol-1-yl)picolinonitrile; 6-(6-(6-(aminomethyl)pyridin-2-yl)-1H-indazol-1-yl)picolinamide; (6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methanamine; methyl 6-(5-aminopyridin-3-yl)-1-(6-cyanopyridin-2-yl)-1H-indazole-4-carboxylate; methyl 6-(5-aminopyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylate; 6-(5-aminopyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylic acid; 6-(5-aminopyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxamide; 5-(4-(aminomethyl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine; (6-(5-aminopyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-4-yl)methanol; 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; methyl 6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylate; (6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-4-yl)methanol; 6-(6-(1-aminoethyl)pyridin-2-yl)-N,N-dimethyl-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxamide; 6-(6-(1-aminoethyl)pyridin-2-yl)-N-methyl-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxamide; 6-(5-aminopyridin-3-yl)-N,N-dimethyl-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxamide; 6-(5-aminopyridin-3-yl)-N-methyl-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxamide; 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine; 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5,6,7,8-tetrahydroquinolin-8-amine; 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N,N-dimethylpicolinamide; 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(2-hydroxyethyl)picolinamide; 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(3-hydroxypropyl)picolinamide; 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(2-hydroxypropyl)picolinamide; (6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)pyridin-2-yl)(3-hydroxyazetidin-1-yl)methanone; 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(2-(dimethylamino)ethyl)picolinamide; 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(2-cyanoethyl)picolinamide; 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(3-cyanopropyl)picolinamide; N-(2-aminoethyl)-6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)picolinamide; 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(cyanomethyl)picolinamide; 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(2-(methylsulfonyl)ethyl)picolinamide; 3-(6-(5-aminopyridin-3-yl)imidazo[1,5-a]pyridin-3-yl)benzonitrile; 6-(6-(5-aminopyridin-3-yl)imidazo[1,5-a]pyridin-3-yl)picolinonitrile; 6-(6-(5-aminopyridin-3-yl)imidazo[1,5-a]pyridin-3-yl)picolinamide; 5-(3-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-3-amine; 1-(6-(3-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)ethanamine; 2-(aminomethyl)-6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-4-amine; 2-(6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)pyridin-2-yl)acetonitrile; 2-(6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)pyridin-2-yl)acetic acid; 1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 3-amino-5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)benzoic acid; 3-amino-N-(cyanomethyl)-5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)benzamide; 6-amino-N-(cyanomethyl)-4-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)picolinamide; 3-amino-N-(2-aminoethyl)-5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)benzamide; 1-(3-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)phenyl)ethanamine; 1-(5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-3-yl)ethanamine; 1-(4-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrazine-2-carbonitrile; (6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrazin-2-yl)methanamine; 4-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidine-2-carbonitrile; (4-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-2-yl)methanamine; 6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrazin-2-amine; 6-(6-(pyrrolidin-2-yl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole; 6-(6-(1-methylpyrrolidin-2-yl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole; 1-(6-(3-(6-methylpyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)ethanamine; 6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-amine; 6-(6-(1-aminoethyl)pyridin-2-yl)-N-methyl-1-(6-methylpyridin-2-yl)-1H-indazol-4-amine; 6-(6-(1-aminoethyl)pyridin-2-yl)-N,N-dimethyl-1-(6-methylpyridin-2-yl)-1H-indazol-4-amine; N-(6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)acetamide; 1-(6-(4-(aminomethyl)-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; N-((6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)methyl)acetamide; 1-(6-(4-chloro-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 1-(6-(4-cyclopropyl-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 1-(6-(1-(6-methylpyridin-2-yl)-4-(prop-1-en-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 1-(6-(4-ethyl-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 1-(6-(4-isopropyl-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 1-(6-(1-(6-methylpyridin-2-yl)-4-(trifluoromethyl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; methyl 6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole-4-carboxylate; 6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole-4-carboxylic acid; 6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)methanol; 6-(6-(1-aminoethyl)pyridin-2-yl)-N-methyl-1-(6-methylpyridin-2-yl)-1H-indazole-4-carboxamide; N-methyl-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; N-methyl-1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 1-(6-(1-(6-cyclopropylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 1-(6-(1-(6-ethylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 1-(6-(1-(6-isopropylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 1-(6-(1-(pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; (6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; 1-(4-methyl-6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-4-(trifluoromethyl)pyridin-2-yl)ethanamine; 6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)picolinamide; 1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propan-1-amine; cyclopropyl(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methanamine; 2-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propan-2-amine; 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanol; cyclopropyl(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methanamine; 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-amine; 1-(6-(1-(4-methylthiazol-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 1-(6-(1-(5-methylthiazol-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 1-(6-(1-(2-methylthiazol-4-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 1-(6-(1-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 1-(6-(1-(1-methyl-1H-imidazol-4-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; (2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)thiazol-4-yl)methanamine; (2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)thiazol-5-yl)methanamine; (R)-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; (S)-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (R)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (R)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; 1-(6-methylpyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-7-amine; 2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)isonicotinamide; N,N-dimethyl-5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine; 1-(6-methylpyridin-2-yl)-6-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-indazole; 6-methyl-5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine; 5-(1-(6-cyclopentylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine; 5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-3,4-dihydroisoquinolin-1(2H)-one; 1-(6-(4-fluoro-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone; N-(5-(4-cyano-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-3-yl)-2,2,2-trifluoroacetamide; 1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one; 6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)picolinonitrile; 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydroquinolin-8(5H)-one; 6-amino-4-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)picolinic acid; 6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole-4-carbonitrile; 1-(6-(4-(aminomethyl)-2-(6-methylpyridin-2-yl)-2H-indazol-6-yl)pyridin-2-yl)ethanamine; N,N-dimethyl-1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; N-((6-(6-(1-aminoethyl)pyridin-2-yl)-2-(6-methylpyridin-2-yl)-2H-indazol-4-yl)methyl)acetamide; 1-(6-(4-chloro-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone; (Z)-1-(6-(4-chloro-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime; N,N-dimethyl-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; N,N-dimethyl-1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 1-(6-(3-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)ethanamine; 1-(6-(3-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)ethanamine; (Z)-1-(6-(3-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)ethanone oxime; tert-butyl (6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)(methyl)carbamate; (Z)-tert-butyl (6-(6-(1-(hydroxyimino)ethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)(methyl)carbamate; (Z)-1-(6-(4-(methylamino)-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime; 1-(6-(1-(6-ethylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone; 1-(6-(1-(pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone; (E)-1-(6-(1-(pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime; 2-(aminomethyl)-6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-4-amine; N,N-dimethyl-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 1-(6-(4-(dimethylamino)-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone; (E)-1-(6-(4-(dimethylamino)-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime; (E)-1-(6-(1-(6-ethylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime; 6-(6-(6-acetylpyridin-2-yl)-1H-indazol-1-yl)picolinonitrile; (E)-methyl 6-(6-(6-(1-(hydroxyimino)ethyl)pyridin-2-yl)-1H-indazol-1-yl)picolinate; 1-(6-(1-(4-methylthiazol-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone; 1-(6-(4-fluoro-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; (S)-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 1-(3-fluoro-6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; methyl 3-amino-6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)picolinate; 2,2,2-trifluoro-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanol; 1-(6-(4-ethoxy-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 1-(6-(4-methoxy-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 3-amino-3-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propan-1-ol; 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)picolinamide; 2-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)acetonitrile; 6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-ol; 1-(6-(4-(cyclopropylmethoxy)-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; (4-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)thiazol-2-yl)methanamine; N-((6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methyl)acetamide; 2-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-3-(trifluoromethyl)pyridin-2-yl)ethanamine; 2-(1-aminoethyl)-6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-4-amine; (1-methyl-4-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-1H-imidazol-2-yl)methanol; 2-amino-2-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)acetonitrile; 2,2,2-trifluoro-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 3-amino-3-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propanoic acid; methyl 3-amino-3-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propanoate; 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)cyclopropanamine; 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propan-1-amine; (R)-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-amine; (S)-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-amine; 1-(3-chloro-6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 2-amino-2-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)acetamide; 1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-amine; 6-(6-(6-(1-aminopropyl)pyridin-2-yl)-1H-indazol-1-yl)picolinamide; 2-(1-aminoethyl)-6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-4-amine; 2-amino-2-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanol; methyl 2-amino-2-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)acetate; 2-amino-2-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)acetic acid; 6-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)picolinamide; 1-(6-(3-(6-methylpyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)propan-1-amine; 1-(6-(3-(6-methylpyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)butan-1-amine; 2-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)propan-2-ol; 1-(6-(1-(6-(methoxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; (6-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; 1-(3-methyl-6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 1-(6-(1-(4-methylthiophen-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 1-(6-(1-(6-propylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 1-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanol; (4-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)oxazol-2-yl)methanamine; 1-(6-(1-(6-(tert-butyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 1-(6-(1-(6-(aminomethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 2-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)-2-methylpropanenitrile; 1-(6-(1-(6-(2-(methylsulfonyl)propan-2-yl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 1-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)cyclopropanecarbonitrile; (6-(6-(6-(aminomethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; 2-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)propan-2-amine; 1-(6-(3-(6-ethylpyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)ethanamine; (6-(6-(6-(1-aminopropyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; 1-(6-(4-(1H-imidazol-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 1-(6-(1-(4-methylpyrimidin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 1-(6-(1-(4-(trifluoromethyl)pyrimidin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 2-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propan-2-amine; 1-(1-methyl-4-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-1H-imidazol-2-yl)ethanol; (1-methyl-4-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-1H-imidazol-2-yl)methanamine; 2-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)-2-methylpropanamide; (6-(6-(6-(1-aminoethyl)pyridin-2-yl)imidazo[1,5-a]pyridin-3-yl)pyridin-2-yl)methanol; 1-(6-(1-(6-methylpyridin-2-yl)-4-(thiazol-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)cyclobutanecarbonitrile; 1-(1-methyl-4-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-1H-imidazol-2-yl)ethanamine; 1-(6-methylpyridin-2-yl)-6-(pyridin-2-yl)-1H-indazole; (6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-methoxy-1H-indazol-1-yl)pyridin-2-yl)methanol; 2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-amine; (6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)methanol; 1-(4-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)thiazol-2-yl)ethanamine; 1-(6-(8-chloro-3-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)ethanamine; 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)cyclobutanecarboxamide; 1-(6-methylpyridin-2-yl)-6-(6-(3,3,3-trifluoropropyl)pyridin-2-yl)-1H-indazole; 2-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanol; 1-(6-(1-(4,6-dimethylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-N-methyl-1H-indazole-4-carboxamide; 1-(6-(8-fluoro-3-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)ethanamine; (S)-(6-(6-(6-(1-aminopropyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; 1-(6-(1-(6-methylpyridin-2-yl)-4-(1H-pyrazol-3-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; (4-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)thiazol-2-yl)methanol; (6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-fluoro-1H-indazol-1-yl)pyridin-2-yl)methanol; (R)-(6-(6-(6-(1-aminopropyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; and 6-(1-methyl-1H-imidazol-4-yl)-1-(6-methylpyridin-2-yl)-1H-indazole,

›DETAILED DESCRIPTION · 8 of 13

or a pharmaceutically acceptable salt thereof.

In an alternative thirtieth embodiment, the compound is further selected from:

(6-(6-(6-ethylpyridin-2-yl)-4-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; 1-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)pyrrolidin-3-ol; (S)-(6-(6-(6-(1-aminopropyl)pyridin-2-yl)-1H-indazol-1-yl)pyrazin-2-yl)methanol; (1-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)pyrrolidin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(methylamino)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(oxazol-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyrazin-2-yl)methanol; (S)-(6-(6-(6-(1-aminopropyl)pyridin-2-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol; (6-(6-(6-((1R,2R)-1-amino-2-fluorobutyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(ethylamino)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-1-(6-(6-(1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)piperidin-4-ol; 1-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)piperidin-3-ol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyrazin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(3,3-difluoroazetidin-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminopropyl)pyridin-2-yl)-4-(methylamino)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-1-(6-(1-(4-(difluoromethyl)pyrimidin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-amine; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(fluoromethyl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-1-(4-(6-(6-(1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-methoxy-1H-indazol-1-yl)pyrazin-2-yl)methanol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-chloro-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(1-(6-(6-(1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)-3-(chloromethyl)azetidin-3-yl)methanol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(1-methyl-1H-imidazol-4-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(3,3-difluoropyrrolidin-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-4-(2-methylmorpholino)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (6-(6-(6-((1R,2S)-1-amino-2-fluorobutyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(pyrimidin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(difluoromethyl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(3-methoxypropoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminopentyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(1H-imidazol-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(3,6-dihydro-2H-pyran-4-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminopropyl)pyridin-2-yl)-4-(3-methoxypropoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(1,5-dimethyl-1H-pyrazol-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(5-methyl-1H-pyrazol-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(methoxymethyl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(amino(cyclopropyl)methyl)pyridin-2-yl)-4-methoxy-1H-indazol-1-yl)pyrazin-2-yl)methanol; (6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-4-(2,6-dimethylmorpholino)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(4-(1-aminobutyl)pyrimidin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; 3-((6-(6-((S)-1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)amino)-2-(chloromethyl)propanoic acid; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-((difluoromethoxy)methyl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(morpholinomethyl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-4-(6-(6-(1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)thiomorpholine 1,1-dioxide; (S)-(6-(6-(6-(1-amino-4,4,4-trifluorobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-thiomorpholino-1H-indazol-1-yl)pyridin-2-yl)methanol; 1-(6-(6-(6-((S)-1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyrazin-2-yl)methanol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(2-methylthiazol-4-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminopropyl)pyridin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyrazin-2-yl)methanol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(3-methoxypropoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(amino(cyclopropyl)methyl)pyridin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyrazin-2-yl)methanol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(1H-1,2,4-triazol-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-2-(6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)thiazole-4-carbonitrile; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(isothiazol-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(amino(cyclobutyl)methyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(tetrahydro-2H-pyran-4-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (6-(6-(6-((1R,2S)-1-amino-2-fluorobutyl)pyridin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-morpholino-1H-indazol-1-yl)pyridin-2-yl)methanol; (6-(6-(6-((1R,2R)-1-amino-2-fluorobutyl)pyridin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol; 1-(6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(3,3-dimethylazetidin-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-amino-4,4,4-trifluorobutyl)pyridin-2-yl)-4-methoxy-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminopropyl)pyridin-2-yl)-4-methoxy-1H-indazol-1-yl)pyrazin-2-yl)methanol; (S)-(6-(6-(6-(1-amino-3,3-difluorobutyl)pyridin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-1-(6-(4-methoxy-1-(4-(trifluoromethyl)pyrimidin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-amine; (6-(6-(6-(amino(oxetan-3-yl)methyl)pyridin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-1-(6-(4-ethoxy-1-(4-(trifluoromethyl)pyrimidin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-amine; (6-{6-[6-((S)-1-Amino-ethyl)-pyridin-2-yl]-4-fluoro-indazol-1-yl}-pyridin-2-yl)-methanol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-phenyl-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-amino-3,3-difluorobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(5-methylthiazol-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-4-(piperidin-3-ylmethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol; (6-{6-[6-((S)-1-Amino-butyl)-pyridin-2-yl]-4-isopropoxy-indazol-1-yl}-pyridin-2-yl)-methanol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; 1-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)pyrrolidine-3-carboxylic acid; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(pyrrolidin-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (6-(6-(6-(amino(oxetan-3-yl)methyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (R)-(6-(6-(4-(1-aminobutyl)pyrimidin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; 1-amino-1-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-2-ol; (6-{6-[6-((S)-1-Amino-butyl)-pyridin-2-yl]-4-fluoro-indazol-1-yl}-pyridin-2-yl)-methanol; 4-amino-4-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-2-ol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(4-methylpiperazin-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-amino-4-methoxybutyl)pyridin-2-yl)-4-methoxy-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-amino-4,4,4-trifluorobutyl)pyridin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-6-(6-(1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazole-4-carbonitrile; (S)-1-(6-(1-(4-(difluoromethyl)pyrimidin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propan-1-amine; (S)-(6-(6-(6-(1-amino-4-methoxybutyl)pyridin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(2,2,2-trifluoroethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-1-(4-(6-(6-(1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)piperidin-1-yl)ethanone; 1-amino-1-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-2-ol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(4-(trifluoromethyl)oxazol-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-((dimethylamino)methyl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-((3-chloro-2,2-dimethylpropyl)amino)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-1-(6-(1-(6-(fluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-amine; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(azetidin-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(4,4-difluoropiperidin-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-1-(6-(1-(6-(difluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-amine; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(3,3-difluoropiperidin-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-1-(6-(6-(1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)azetidine-3-carboxylic acid; (6-(6-(6-(1-amino-2-(methylthio)ethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (R)-1-(6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)-2,2,2-trifluoroethanol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(4-methylthiazol-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-amino-3-methylbutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (R)-(6-(6-(6-(amino(phenyl)methyl)pyridin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol; (6-(6-(6-((1R,2R)-1-amino-2-methoxybutyl)pyridin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(2-cyclopropylethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-methoxy-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(trifluoromethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(4,5-dihydrooxazol-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; 4-amino-4-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-2-ol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(difluoromethoxy)-1H-indazol-1-yl)pyrazin-2-yl)methanol; (S)-(6-(6-(6-(1-(methylamino)butyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (6-(6-(6-((S)-1-aminoethyl)pyridin-2-yl)-4-(4-methyl-4,5-dihydrooxazol-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-1-(6-(1-(6-(difluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 2-amino-2-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanol; (S)-(6-(6-(6-(1-amino-3-methylbut-3-en-1-yl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-1-(6-(1-(4-(trifluoromethyl)pyrimidin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-amine; (6-(6-(6-(1-amino-2-(methylsulfonyl)ethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; 1-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)piperidine-3-carboxylic acid; (S)-6-(6-(1-aminopropyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazole-4-carbonitrile; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(4,5-dimethylthiazol-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(piperidin-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (6-(6-(6-(1-amino-2-cyclopropylethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; 1-(6-(6-(6-((S)-1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanol; (6-{6-[6-((S)-1-Amino-butyl)-pyridin-2-yl]-4-fluoro-indazol-1-yl}-pyridin-2-yl)-methanol; 1-(6-(1-(6-methylpyridin-2-yl)-4-(oxazol-5-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; (S)-(6-(6-(4-(1-aminoethyl)pyrimidin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazole-4-carbonitrile; (6-(6-(6-(amino(cyclopropyl)methyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-1-(6-(1-(6-(difluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propan-1-amine; (S)-6-(6-(1-aminoethyl)pyridin-2-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazole-4-carboxamide; (S)-1-(6-(1-(4-(difluoromethyl)pyrimidin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 1-(6-(1-(6-methylpyridin-2-yl)-4-(oxazol-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (6-(6-(6-(1-amino-2-methoxyethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; 2-amino-2-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)-N,N-dimethylacetamide; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(thiazol-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-1-(6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)-2,2,2-trifluoroethanol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(5-(trifluoromethyl)thiazol-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-1-(6-(6-(1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)piperidine-4-carboxylic acid; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)-3-fluoropyridin-2-yl)methanol; (6-(6-(6-((1R,2S)-1-amino-2-methoxybutyl)pyridin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-1-(6-(1-(6-(trifluoromethyl)pyrazin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-amine; (S)-6-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)picolinaldehyde; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; 6-(6-((S)-1-aminoethyl)pyridin-2-yl)-N-(2-aminopropyl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazole-4-carboxamide; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(1H-pyrazol-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; 1-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol; 1-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol; (6-(6-(6-(1-amino-2-(3-methyloxetan-3-yl)ethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; 3,3,3-trifluoro-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propan-1-amine; 1-(6-(4-(5-methyl-1,3,4-oxadiazol-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 1-(6-(1-(6-methylpyrazin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine; 6-{6-[6-((S)-1-Amino-ethyl)-pyridin-2-yl]-indazol-1-yl}-pyridine-2-carboxylic acid; 2-amino-2-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)acetonitrile; 2-amino-2-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)acetamide; 4-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyrimidine-2-carbonitrile; (6-(6-(3-(1-aminoethyl)phenyl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (6-(6-(6-(1-aminoethyl)-3-fluoropyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (R)-(6-(6-(4-(1-aminoethyl)pyrimidin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)-5-fluoropyridin-2-yl)methanol; (S)-(6-(6-(6-(1-(dimethylamino)butyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; 1-(6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanol; 2-amino-2-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)-N-methylacetamide; (6-(6-(6-(1-amino-2-(methylsulfinyl)ethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-4-(1-methoxyethyl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-4-amino-4-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol; (S)-(6-(6-(6-(1-aminobut-3-en-1-yl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-4-amino-4-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-2-one; (S)-1-(6-(4-chloro-1-(4-(difluoromethyl)pyrimidin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-amine; (6-(6-(6-(pyrrolidin-2-yl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-4-(6-(6-(1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)-2-methylbut-3-yn-2-ol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(2-(trifluoromethyl)thiazol-4-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-1-(6-(1-(4-(difluoromethyl)pyrimidin-2-yl)-4-methoxy-1H-indazol-6-yl)pyridin-2-yl)butan-1-amine; (S)-(6-(6-(6-(1-aminopent-3-yn-1-yl)pyridin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(amino(phenyl)methyl)pyridin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol; (6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-4-((S)-pyrrolidin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-4-(tetrahydrofuran-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-4-(6-(6-(1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)morpholin-3-one; (S)-(6-(6-(4-(1-aminobutyl)pyrimidin-2-yl)-4-methoxy-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-amino-4-methoxybutyl)pyridin-2-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (R)-(6-(6-(4-(1-aminobutyl)pyrimidin-2-yl)-4-methoxy-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(pyrimidin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; deutero (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(5-fluoropyrimidin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(4-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(3-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)phenyl)methanol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(5-methyloxazol-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(1H-1,2,3-triazol-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-((trifluoromethoxy)methyl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(1-(difluoromethyl)-1H-pyrazol-5-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(pyrazin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(4-(1-aminopentyl)pyrimidin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (R)-3-amino-3-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propanenitrile; (S)-4-amino-4-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-4-methoxy-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol; (S)-4-amino-4-(6-(4-ethoxy-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyrazin-2-yl)methanol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyrazin-2-yl)methanol; (S)-(6-(6-(4-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(5-methyloxazol-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(4-(1-aminobutyl)pyrimidin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol; (R)-(6-(6-(4-(1-aminobutyl)pyrimidin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-2-((6-(6-(1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)oxy)ethanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(1,5-dimethyl-1H-pyrazol-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(2-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyrimidin-4-yl)methanol; (S)-(6-(6-(6-(1-aminopropyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyrazin-2-yl)methanol; 2-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)-3-chloropropan-1-ol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminopropyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(amino(cyclopropyl)methyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-amino-3,3-difluorobutyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-4-amino-4-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol; (R)-(6-(6-(6-(1-aminopropyl)pyridin-2-yl)-4-(1,5-dimethyl-1H-pyrazol-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (R)-(6-(6-(6-(1-amino-2-fluoroethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-1-(6-(1-(6-methylpyrazin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-amine; (S)-3-amino-3-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propanenitrile; (S)-4-amino-4-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butanenitrile; (S)-(6-(6-(2-(1-aminobutyl)pyrimidin-4-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (4R)-4-amino-3-fluoro-4-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol; (R)-(6-(6-(6-(1-amino-2-fluoroethyl)pyridin-2-yl)-4-(1,5-dimethyl-1H-pyrazol-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-4-amino-4-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol; (4R)-4-amino-3-fluoro-4-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol; (4S)-4-amino-3-fluoro-4-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol; (R)-(6-(6-(2-(1-aminobutyl)pyrimidin-4-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-4-amino-4-(6-(4-(1,5-dimethyl-1H-pyrazol-3-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(pyrimidin-4-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(pyridazin-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (R)-(6-(6-(6-(1-amino-2-fluoroethyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-4-amino-4-(6-(1-(6-(hydroxymethyl)pyrazin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol; (S)-(6-(6-(4-(1-aminobutyl)pyrimidin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol; (6-(6-(6-(1-aminocyclobutyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol; (R)-(6-(6-(4-(1-aminobutyl)pyrimidin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol; (4S)-4-amino-3-fluoro-4-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol; (S)-3-((6-(6-(1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)oxy)propan-1-ol; (S)-3-((6-(6-(1-aminopropyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)oxy)propan-1-ol; (S)-3-((6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)oxy)propan-1-ol; (6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-4-((2S,5R)-5-methyltetrahydrofuran-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-4-((2R,5R)-5-methyltetrahydrofuran-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-4-(tetrahydrofuran-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (R)-(6-(6-(6-(1-aminobutyl)pyrazin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (6-(6-(6-((1R)-1-amino-2-fluoropropyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol; (6-(6-(6-(1-aminocyclobutyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyrazin-2-yl)methanol; (6-(6-(6-(1-aminocyclopentyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol; (6-(6-(6-(3-aminotetrahydrofuran-3-yl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-1-((6-(6-(1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)oxy)-2-methylpropan-2-ol; (S)-(6-(6-(6-(1-aminobutyl)pyrazin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (6-(6-(6-((1S)-1-amino-2-fluoropropyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(1H-pyrazol-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(4-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyrimidin-2-yl)methanol; (6-(6-(8-amino-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (6-(6-(8-amino-8-propyl-5,6,7,8-tetrahydroquinolin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol; (6-(6-(6-(3-aminooxetan-3-yl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(2-(methylsulfonyl)ethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-((3,3-difluorocyclobutyl)methoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol; (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(1-methylpiperidin-4-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;

›DETAILED DESCRIPTION · 9 of 13

or a pharmaceutically acceptable salt thereof.

As used herein, the term “alkyl” refers to a fully saturated branched or unbranched hydrocarbon moiety. Preferably the alkyl comprises 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In some embodiments, an alkyl comprises from 6 to 20 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl.

“Alkenyl” refers to an unsaturated hydrocarbon group which may be linear or branched and has at least one carbon-carbon double bond. Alkenyl groups with 2-6 carbon atoms can be preferred. The alkenyl group may contain 1, 2 or 3 carbon-carbon double bonds, or more. Examples of alkenyl groups include ethenyl, n-propenyl, isopropenyl, n-but-2-enyl, n-hex-3-enyl and the like.

“Alkynyl” refers to an unsaturated hydrocarbon group which may be linear or branched and has at least one carbon-carbon triple bond. Alkynyl groups with 2-6 carbon atoms can be preferred. The alkynyl group may contain 1, 2 or 3 carbon-carbon triple bonds, or more. Examples of alkynyl groups include ethynyl, n-propynyl, n-but-2-ynyl, n-hex-3-ynyl and the like.

The number of carbon atoms in a group is specified herein by the prefix “C x-xx ”, wherein x and xx are integers. For example, “C 1-4 alkyl” is an alkyl group which has from 1 to 4 carbon atoms.

“Halogen” or “halo” may be fluoro, chloro, bromo or iodo.

As used herein, the term “heterocyclyl” refers to a saturated or unsaturated, monocyclic or bicyclic (e.g., bridged or spiro ring systems) ring system which has from 3- to 7-ring members, or in particular 3- to 6-ring members or 5- to 7-ring members, at least one of which is a heteroatom, and up to 4 (e.g., 1, 2, 3, or 4) of which may be heteroatoms, wherein the heteroatoms are independently selected from O, S and N, and wherein C can be oxidized (e.g., C(O)), N can be oxidized (e.g., N(O)) or quaternized, and S can be optionally oxidized to sulfoxide and sulfone. Unsaturated heterocyclic rings include heteroaryl rings.

As used herein, the term “heteroaryl” refers to an aromatic 5 or 6 membered monocyclic ring system, having 1 to 4 heteroatoms independently selected from O, S and N, and wherein N can be oxidized (e.g., N(O)) or quaternized, and S can be optionally oxidized to sulfoxide and sulfone. In one embodiment, a heterocyclyl is a 3- to 7-membered saturated monocyclic or a 3- to 6-membered saturated monocyclic or a 5- to 7-membered saturated monocyclic ring. In one embodiment, a heterocyclyl is a 3- to 7-membered monocyclic or a 3- to 6-membered monocyclic or a 5- to 7-membered monocyclic ring. In another embodiment, a heterocyclyl is a 6 or -7-membered bicyclic ring. The heterocyclyl group can be attached at a heteroatom or a carbon atom. Examples of heterocyclyls include aziridinyl, oxiranyl, thiiranyl, oxaziridinyl, dioxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, trithianyl, azepanyl, oxepanyl, thiepanyl, dihydrofuranyl, imidazolinyl, dihydropyranyl, and heteroaryl rings including azirinyl, oxirenyl, thiirenyl, diazirinyl, azetyl, oxetyl, thietyl, pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, oxathianyl, triazinyl, tetrazinyl, azepinyl, oxepinyl, thiepinyl, diazepinyl, and thiazepinyl and the like. Examples of bicyclic heterocyclic ring systems include 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.1]heptanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, and 5-azaspiro[2.3]hexanyl.

As used herein, the term “carbocyclyl” refers to saturated or unsaturated monocyclic or bicyclic hydrocarbon groups of 3-7 carbon atoms, 3-6, or 5-7 carbon atoms. The term “carbocyclyl” encompasses cycloalkyl groups and aromatic groups. The term “cycloalkyl” refers to completely saturated monocyclic or bicyclic hydrocarbon groups of 3-7 carbon atoms, 3-6 carbon atoms, or 5-7 carbon atoms. Exemplary monocyclic carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopenentyl, cyclohexenyl, cycloheptenyl, cyclobutadienyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl, phenyl and cycloheptatrienyl. Exemplary bicyclic carbocyclyl groups include bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, tricyclo[2.2.1.0 2,6 ]heptanyl, 6,6-dimethylbicyclo[3.1.1]heptyl, or 2,6,6-trimethylbicyclo[3.1.1]heptyl, spiro[2.2]pentanyl, and spiro[3.3]heptanyl.

The term “bridged ring system,” as used herein, is a ring system that has a carbocyclyl or heterocyclyl ring wherein two non-adjacent atoms of the ring are connected (bridged) by one or more (preferably from one to three) atoms selected from C, N, O, or S. A bridged ring system may have from 6-7 ring members.

The term “spiro ring system,” as used herein, is a ring system that has two rings each of which are independently selected from a carbocyclyl or a heterocyclyl, wherein the two ring structures having one ring atom in common. Spiro ring systems have from 5 to 7 ring members.

In cases where a compound provided herein is sufficiently basic or acidic to form stable nontoxic acid or base salts, preparation and administration of the compounds as pharmaceutically acceptable salts may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, α-ketoglutarate, or α-glycerophosphate. Inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.

›DETAILED DESCRIPTION · 10 of 13

Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.

Pharmaceutically-acceptable base addition salts can be prepared from inorganic and organic bases. Salts from inorganic bases, can include but are not limited to, sodium, potassium, lithium, ammonium, calcium or magnesium salts. Salts derived from organic bases can include, but are not limited to, salts of primary, secondary or tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines, disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines, triaryl amines, heteroaryl amines, diheteroaryl amines, triheteroaryl amines, heterocycloalkyl amines, diheterocycloalkyl amines, triheterocycloalkyl amines, or mixed di- and tri-amines where at least two of the substituents on the amine can be different and can be alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, or heterocycloalkyl and the like. Also included are amines where the two or three substituents, together with the amino nitrogen, form a heterocycloalkyl or heteroaryl group. Non-limiting examples of amines can include, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, or N-ethylpiperidine, and the like. Other carboxylic acid derivatives can be useful, for example, carboxylic acid amides, including carboxamides, lower alkyl carboxamides, or dialkyl carboxamides, and the like.

The disclosed compounds, or pharmaceutically acceptable salts thereof, can contain one or more asymmetric centers in the molecule. In accordance with the present disclosure any structure that does not designate the stereochemistry is to be understood as embracing all the various stereoisomers (e.g., diastereomers and enantiomers) in pure or substantially pure form, as well as mixtures thereof (such as a racemic mixture, or an enantiomerically enriched mixture). It is well known in the art how to prepare such optically active forms (for example, resolution of the racemic form by recrystallization techniques, synthesis from optically-active starting materials, by chiral synthesis, or chromatographic separation using a chiral stationary phase). The disclosed compounds may exist in tautomeric forms and mixtures and separate individual tautomers are contemplated. In addition, some compounds may exhibit polymorphism.

The compounds or pharmaceutically acceptable salts thereof as described herein, can contain one or more asymmetric centers in the molecule. In accordance with the present disclosure any structure that does not designate the stereochemistry is to be understood as embracing all the various stereoisomers (e.g., diastereomers and enantiomers) in pure or substantially pure form, as well as mixtures thereof (such as a racemic mixture, or an enantiomerically enriched mixture). It is well known in the art how to prepare such optically active forms (for example, resolution of the racemic form by recrystallization techniques, synthesis from optically-active starting materials, by chiral synthesis, or chromatographic separation using a chiral stationary phase). When a particular enantiomer of a compound used in the disclosed methods is depicted by name or structure, the stereochemical purity of the compounds is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5% or 99.9%. “Stererochemical purity” means the weight percent of the desired stereoisomer relative to the combined weight of all stereoisomers.

Unless otherwise indicated, any position occupied by hydrogen is meant to include enrichment by deuterium or tritium above the natural abundance of deuterium or tritium as well. For example, one or more hydrogen atoms are replaced with deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% incorporation of deuterium), at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). In one embodiment, hydrogen is present at all positions at its natural abundance. The compounds or pharmaceutically acceptable salts thereof as described herein, may exist in tautomeric forms and mixtures and separate individual tautomers are contemplated.

Another embodiment is a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

The compounds, or pharmaceutically acceptable salts thereof described herein may be used to decrease the expression or activity of IRAK-4, or to otherwise affect the properties and/or behavior of IRAK-4 polypeptides or polynucleotides, e.g., stability, phosphorylation, kinase activity, interactions with other proteins, etc.

›DETAILED DESCRIPTION · 11 of 13

One embodiment of the invention includes a method of decreasing the expression or activity of IRAK-4, or to otherwise affect the properties and/or behavior of IRAK-4 polypeptides or polynucleotides comprising administering to said mammal an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof.

One embodiment of the invention includes a method for treating an inflammatory disease in a subject, the method comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, thereby treating the inflammatory disease in the subject.

In one embodiment, the inflammatory disease is a pulmonary disease or a disease of the airway.

In one embodiment, the pulmonary disease and disease of the airway is selected from Adult Respiratory Disease Syndrome (ARDS), Chronic Obstructive Pulmonary Disease (OPD), pulmonary fibrosis, interstitial lung disease, asthma, chronic cough, and allergic rhinitis.

In one embodiment, the inflammatory disease is selected from transplant rejection, CD14 mediated sepsis, non-CD14 mediated sepsis, inflammatory bowel disease, Behcet's syndrome, ankylosing spondylitis, sarcoidosis, and gout.

One embodiment of the invention includes a method for treating an autoimmune disease, cancer, cardiovascular disease, a disease of the central nervous system, a disease of the skin, an ophthalmic disease and condition, and bone disease in a subject, the method comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, thereby treating the autoimmune disease, cancer, cardiovascular disease, disease of the central nervous system, disease of the skin, ophthalmic disease and condition, and bone disease in the subject.

In one embodiment, the autoimmune disease is selected from rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, diabetes, systemic sclerosis, and Sjogren's syndrome.

In one embodiment, the autoimmune disease is type 1 diabetes.

In one embodiment, the cancer is selected from Waldenstörm's macroglobulinemia, solid tumors, skin cancer, and lymphoma.

In one embodiment, the cardiovascular disease is selected from stroke and atherosclerosis.

In one embodiment, the disease of the central nervous system is a neurodegenerative disease.

In one embodiment, the disease of the skin is selected from rash, contact dermatitis, psoriasis, and atopic dermatitis.

In one embodiment, the bone disease is selected from osteoporosis and osteoarthritis.

In one embodiment, the inflammatory bowel disease is selected from Crohn's disease and ulcerative colitis.

One embodiment of the invention includes a method for treating an ischemic fibrotic disease, the method comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, thereby treating the ischemic fibrotic disease in the subject. In one embodiment, the ischemic fibrotic disease is selected from stroke, acute lung injury, acute kidney injury, ischemic cardiac injury, acute liver injury, and ischemic skeletal muscle injury.

One embodiment of the invention includes a method for treating post-organ transplantation fibrosis, the method comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, thereby treating post-organ transplantation fibrosis in the subject.

One embodiment of the invention includes a method for treating hypertensive or diabetic end organ disease, the method comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, thereby treating hypertensive or diabetic end organ disease in the subject.

One embodiment of the invention includes a method for treating hypertensive kidney disease, the method comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, thereby treating hypertensive kidney disease in the subject.

One embodiment of the invention includes a method for treating idiopathic pulmonary fibrosis (IPF), the method comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, thereby treating IPF in the subject.

One embodiment of the invention includes a method for treating scleroderma or systemic sclerosis, the method comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, thereby treating scleroderma or systemic sclerosis in the subject.

One embodiment of the invention includes a method for treating liver cirrhosis, the method comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, thereby treating liver cirrhosis in the subject.

One embodiment of the invention includes a method for treating fibrotic diseases wherein tissue injury and/or inflammation are present, the method comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, thereby treating fibrotic diseases where tissue injury and/or inflammation are present in the subject. The fibrotic diseases include, for example, pancreatitis, peritonitis, burns, glomerulonephritis, complications of drug toxicity, and scarring following infections.

Scarring of the internal organs is a major global health problem, which is the consequence of subclinical injury to the organ over a period of time or as the sequela of acute severe injury or inflammation. All organs may be affected by scarring and currently there are few therapies the specifically target the evolution of scarring. Increasing evidence indicates that scarring per se provokes further decline in organ function, inflammation and tissue ischemia. This may be directly due the deposition of the fibrotic matrix which impairs function such as in contractility and relaxation of the heart and vasculature or impaired inflation and deflation of lungs, or by increasing the space between microvasculature and vital cells of the organ that are deprived of nutrients and distorting normal tissue architecture. However recent studies have shown that myofibroblasts themselves are inflammatory cells, generating cytokines, chemokines and radicals that promote injury; and myofibroblasts appear as a result of a transition from cells that normally nurse and maintain the microvasculature, known as pericytes. The consequence of this transition of phenotype is an unstable microvasculature that leads to aberrant angiogenesis, or rarefaction.

›DETAILED DESCRIPTION · 12 of 13

The present disclosure relates to methods and compositions for treating, preventing, and/or reducing scarring in organs. More particularly, the present disclosure relates to methods and composition for treating, preventing, and/or reducing scarring in kidneys.

It is contemplated that the present disclosure, methods and compositions described herein can be used as an antifibrotic, or used to treat, prevent, and/or reduce the severity and damage from fibrosis.

It is additionally contemplated that the present disclosure, methods and compositions described herein can be used to treat, prevent, and/or reduce the severity and damage from fibrosis.

It is further contemplated that the present disclosure, methods and compositions described herein can used as an anti-inflammatory, used to treat inflammation.

Some non-limiting examples of organs include: kidney, hearts, lungs, stomach, liver, pancreas, hypothalamus, stomach, uterus, bladder, diaphragm, pancreas, intestines, colon, and so forth.

As used herein, the term “subject” and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment.

As used herein, the term “treating” or ‘treatment” refers to obtaining desired pharmacological and/or physiological effect. The effect can be therapeutic, which includes achieving, partially or substantially, one or more of the following results: partially or totally reducing the extent of the disease, disorder or syndrome; ameliorating or improving a clinical symptom or indicator associated with the disorder; or delaying, inhibiting or decreasing the likelihood of the progression of the disease, disorder or syndrome.

The dose of a compound provided herein, or a pharmaceutically acceptable salt thereof, administered to a subject can be 10 μg-500 mg; 10 μg to 1 mg; or 1 to 500 mg.

Administering a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal comprises any suitable delivery method. Administering a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal includes administering a compound described herein, or a pharmaceutically acceptable salt thereof, topically, enterally, parenterally, transdermally, transmucosally, via inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally or intravitreally to the mammal. Administering a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal also includes administering topically, enterally, parenterally, transdermally, transmucosally, via inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally or intravitreally to a mammal a compound that metabolizes within or on a surface of the body of the mammal to a compound described herein, or a pharmaceutically acceptable salt thereof.

Thus, a compound or pharmaceutically acceptable salt thereof as described herein, may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the compound or pharmaceutically acceptable salt thereof as described herein may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, or wafers, and the like. Such compositions and preparations should contain at least about 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions can be such that an effective dosage level will be obtained.

The tablets, troches, pills, capsules, and the like can include the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; or a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent.

The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.

Exemplary pharmaceutical dosage forms for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.

Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation can be vacuum drying and the freeze drying techniques, which can yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.

Exemplary solid carriers can include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the compounds or pharmaceutically acceptable salts thereof as described herein can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.

›DETAILED DESCRIPTION · 13 of 13

Useful dosages of a compound or pharmaceutically acceptable salt thereof as described herein can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949, which is incorporated by reference in its entirety.

The amount of a compound or pharmaceutically acceptable salt thereof as described herein, required for use in treatment can vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and can be ultimately at the discretion of the attendant physician or clinician. In general, however, a dose can be in the range of from about 0.1 to about 10 mg/kg of body weight per day.

The a compound or pharmaceutically acceptable salt thereof as described herein can be conveniently administered in unit dosage form; for example, containing 0.01 to 10 mg, or 0.05 to 1 mg, of active ingredient per unit dosage form. In some embodiments, a dose of 5 mg/kg or less can be suitable.

The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals.

The disclosed method can include a kit comprising a compound or pharmaceutically acceptable salt thereof as described herein and instructional material which can describe administering a compound or pharmaceutically acceptable salt thereof as described herein or a composition comprising a compound or pharmaceutically acceptable salt thereof as described herein to a cell or a subject. This should be construed to include other embodiments of kits that are known to those skilled in the art, such as a kit comprising a (such as sterile) solvent for dissolving or suspending a compound or pharmaceutically acceptable salt thereof as described herein or composition prior to administering a compound or pharmaceutically acceptable salt thereof as described herein or composition to a cell or a subject. In some embodiments, the subject can be a human.

›Examples53

›Example 1. 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine

Synthesis of 6-bromo-1-(6-methylpyridin-2-yl)-1H-indazole and 6-bromo-2-(6-methylpyridin-2-yl)-2H-indazole

To a solution of 6-bromo-1H-indazole (CAS #79762-54-2) (3.0 g, 15.3 mmol) in DMF (10 mL) was added NaH (440 mg, 18.36 mmol, 1.2 eq) at 0° C. After stirring at room temperature for 1 h, 2-fluoro-6-methylpyridine (CAS #407-22-7) (2.04 g, 18.36 mmol, 1.2 eq) was added to the mixture. The mixture was stirred at 105° C. for 16 h. After cooling down to room temperature, the mixture was diluted with water (50 mL) and stirred for 1 h. The residue was filtrated to give a yellow solid which was purified by Pre-TLC (PE/EA (10/1)).

6-bromo-1-(6-methylpyridin-2-yl)-1H-indazole, 1.0 g, as a yellow solid, Y: 23%. ESI-MS (M+H) + : 288.0. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.09 (s, 1H), 8.13 (s, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.71 (t, J=8.0 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.37 (dd, J=8.0, 1.2 Hz, 1H), 7.02 (d, J=7.6 Hz, 1H), 2.66 (s, 3H).

6-bromo-2-(6-methylpyridin-2-yl)-2H-indazole, 1.05 g, as a yellow solid, Y: 24%. ESI-MS (M+H) + : 288.0. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.04 (s, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.86 (s, 1H), 7.70 (t, J=8.0 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.11-7.08 (m, 2H), 2.54 (s, 3H).

Synthesis of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

A mixture of 6-bromo-1-(6-methylpyridin-2-yl)-1H-indazole (1.0 g, 3.5 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (CAS #73183-34-3) (930 mg, 3.66 mmol, 1.05 eq) and CH 3 COOK (686 mg, 7.0 mmol, 2.0 eq) in 1, 4-dioxane (25 mL) was stirred while purging N 2 at rt for 10 min. To this system was added Pd(dppf)Cl 2 (256 mg, 0.35 mmol, 0.1 eq) and heated to 90° C. for 2 h. The mixture was diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO 3 solution (50 mL) and brine (50 mL). The organics were dried (MgSO 4 ) and concentrated in vacuo. The crude mixture was purified by silica gel chromatography with PE/EA (10/1) as eluent to give 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 960 mg, as a yellow solid, Y: 82%. ESI-MS (M+H) + : 336.2.

Synthesis of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine

A mixture of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (100 mg, 0.3 mmol), 6-bromopyridin-2-amine (CAS #19798-81-3) (51 mg, 0.3 mmol, 1.0 eq) and K 2 CO 3 (83 mg, 0.6 mmol, 2.0 eq) in 1, 4-dioxane/H 2 O (5 mL/0.5 mL) was stirred while purging N 2 at room temperature for 10 min. To this system was added Pd(dppf)Cl 2 (22 mg, 0.03 mmol, 0.1 eq) and heated to 90° C. for 2 h. The mixture was diluted with EtOAc (10 mL) and washed with saturated aqueous NaHCO 3 solution (10 mL) and brine (10 mL). The organics were dried (MgSO 4 ) and concentrated in vacuo. The crude mixture was purified by pre-HPLC to give 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine. 54 mg, as a yellow solid, Y: 55%. ESI-MS (M+H) + : 302.1. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.28 (s, 1H), 8.25 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.80-7.77 (m, 3H), 7.57 (t, J=7.2 Hz, 1H), 7.12-7.10 (m, 2H), 6.58 (d, J=8.4 Hz, 1H), 2.64 (s, 3H).

›Example 2. 2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-amine

A mixture of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (134 mg, 0.4 mmol), 2-chloropyrimidin-4-amine (CAS #7461-50-9) (52 mg, 0.4 mmol, 1.0 eq) and K 2 CO 3 (110 mg, 0.8 mmol, 2.0 eq) in 1, 4-dioxane/H 2 O (5 mL/0.5 mL) was stirred while purging N 2 at rt for 10 min. To this system was added Pd(PPh 3 ) 2 Cl 2 (28 mg, 0.04 mmol, 0.1 eq) and heated to 130° C. for 16 h. The mixture was diluted with EA (50 mL) and washed with brine (20 mL). The organic phase was dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by pre-HPLC (MeOH/H 2 O with 0.05% NH 4 OH as mobile phase from 5% to 95%) to give 2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-amine. 40 mg, as a yellow solid, Y: 33%. ESI-MS (M+H) + : 303.1. HPLC: 100.00%. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.80 (s, 1H), 8.41 (d, J=6.0 Hz, 1H), 8.28 (dd, J=8.4, 1.2 Hz, 1H), 8.21 (s, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.73 (t, J=7.6 Hz, 1H), 7.04 (d, J=7.2 Hz, 1H), 6.40 (d, J=5.6 Hz, 1H), 4.94 (s, 2H), 2.72 (s, 3H).

›Example 3. 2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-4-amine

Synthesis of 2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-4-amine

The preparation of 2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-4-amine was the same as that of 2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-amine except the temperature was decreased to 90. 50 mg, as a yellow solid, Y: 55%. ESI-MS (M+H) + : 302.1. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.18 (s, 1H), 8.22 (s, 1H), 8.07 (d, J=5.6 Hz, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.79-7.73 (m, 2H), 7.67 (dd, J=8.8, 1.6 Hz, 1H), 7.08 (dd, J=6.0, 2.0 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.57 (dd, J=5.6, 2.0 Hz, 1H), 2.62 (s, 3H).

›Example 4. (6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methanamine

Synthesis of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)picolinonitrile

The preparation of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)picolinonitrile was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine. 90 mg, as a yellow solid, Y: 55%. ESI-MS (M+H) + : 312.1.

Synthesis of (6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methanamine

To a solution of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)picolinonitrile (90 mg, 0.29 mmol) in MeOH/HCl (5 mL/0.5 mL) was added Pd/C (9 mg, 10% w/w). Then the mixture was stirred at rt for 2 h under H 2 atmosphere. After filtration, the filtrate was concentrated and purified by pre-HPLC to give (6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methanamine. 12 mg, as a white solid, Y: 12%. ESI-MS (M+H) + : 316.1. HPLC: 93.18%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.51 (s, 1H), 8.24 (s, 1H), 8.02 (dd, J=8.8, 1.6 Hz, 1H), 7.89-7.86 (m, 3H), 7.79-7.78 (m, 2H), 7.35 (dd, J=6.4, 2.4 Hz, 1H), 7.10 (dd, J=6.0, 1.6 Hz, 1H), 4.14 (s, 2H), 2.63 (s, 3H).

›Example 5. (2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-4-yl)methanamine

Synthesis of 2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)isonicotinonitrile

The preparation of 2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)isonicotinonitrile was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine. 102 mg, as a yellow solid, Y: 63%. ESI-MS (M+H) + : 312.1.

Synthesis of (2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-4-yl)methanamine

The preparation of (2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-4-yl)methanamine was the same as that of (6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methanamine. 60 mg, as a yellow solid, Y: 59%. ESI-MS (M+H) + : 316.1. HPLC: 94.08%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.48 (s, 1H), 8.76 (d, J=5.2 Hz, 1H), 8.32 (s, 1H), 8.04 (s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.90 (dd, J=8.4, 2.0 Hz, 1H), 7.85-7.84 (m, 2H), 7.48 (d, J=3.6 Hz, 1H), 7.16 (dd, J=6.0, 2.0 Hz, 1H), 4.31 (s, 2H), 2.68 (s, 3H).

›Example 6. 4-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine

The preparation of 4-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine. 20 mg, as a yellow solid, Y: 19%. ESI-MS (M+H) + : 302.1. HPLC: 99.29%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.11 (s, 1H), 8.25 (s, 1H), 7.97 (d, J=4.0 Hz, 1H), 7.87 (dd, J=6.8, 1.2 Hz, 1H), 7.81-7.77 (m, 2H), 7.54 (d, J=6.8 Hz, 1H), 7.11 (d, J=4.8 Hz, 1H), 6.98 (d, J=4.8 Hz, 1H), 6.96 (s, 1H), 2.63 (s, 3H).

›Example 7. 5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine

Synthesis of 5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine

The preparation of 5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine. 58 mg, as a yellow solid, Y: 50%. ESI-MS (M+H) + : 302.1. HPLC: 92.66%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.06 (s, 1H), 8.26 (s, 1H), 8.13 (d, J=1.6 Hz, 1H), 7.98 (d, J=2.4 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.83-7.77 (m, 2H), 7.51 (d, J=8.4 Hz, 1H), 7.41 (t, J=2.0 Hz, 1H), 7.11 (d, J=6.0 Hz, 1H), 2.63 (s, 3H).

›Example 8. 3-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)aniline

Synthesis of 3-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)aniline

The preparation of 3-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)aniline was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine. 54 mg, as a yellow solid, Y: 51%. ESI-MS (M+H) + : 301.1. HPLC: 95.87%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.02 (s, 1H), 8.23 (s, 1H), 7.84-7.78 (m, 3H), 7.52 (dd, J=6.8, 1.2 Hz, 1H), 7.22 (t, J=6.8 Hz, 1H), 7.12-7.10 (m, 2H), 7.05 (d, J=6.0 Hz, 1H), 6.77 (dd, J=6.4, 1.2 Hz, 1H), 2.63 (s, 3H).

›Example 9. (2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-yl)methanamine

Synthesis of 2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyrimidine-4-carbonitrile

The preparation of 2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyrimidine-4-carbonitrile was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine except the reaction temperature was 130. 60 mg, as a yellow solid, Y: 35%. ESI-MS (M+H) + : 313.1.

Synthesis of (2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-yl)methanamine

To a solution of 2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyrimidine-4-carbonitrile (60 mg, 0.19 mmol) in MeOH (5 mL) was added Raney Ni (6 mg, 10% w/w). Then the mixture was stirred at room temperature for 2 h under H 2 atmosphere. After filtration, the filtrate was concentrated and purified by pre-HPLC (MeOH/H 2 O with 0.05% NH 4 OH as mobile phase from 5% to 95%) to give (2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-yl)methanamine. 32 mg, as a yellow solid, Y: 53%. ESI-MS (M+H) + : 317.0. HPLC: 95.54%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.99 (s, 1H), 8.82 (d, J=4.8 Hz, 1H), 8.42 (dd, J=4.8, 1.2 Hz, 1H), 8.30 (d, J=0.8 Hz, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.85-7.83 (m, 2H), 7.39 (d, J=4.8 Hz, 1H), 7.17 (dd, J=5.6, 2.0 Hz, 1H), 4.05 (s, 2H), 2.71 (s, 3H).

›Example 10. 4-methyl-5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine

Synthesis of 4-methyl-5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine

The preparation of 4-methyl-5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine. 54 mg, as a yellow solid, Y: 56%. ESI-MS (M+H) + : 316.1. HPLC: 100.00%. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.83 (s, 1H), 8.23 (s, 1H), 8.17 (s, 1H), 8.05 (s, 1H), 7.86-7.81 (m, 2H), 7.73 (t, J=8.0 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.01 (d, J=7.6 Hz, 1H), 3.96 (br, 2H), 2.58 (s, 3H), 2.19 (s, 3H).

›Example 11. 3-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-5-nitropyridin-2-ol

Synthesis of 3-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-5-nitropyridin-2-ol

The preparation of 3-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-5-nitropyridin-2-ol was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine except the reaction temperature was at 120. 50 mg, as a yellow solid, Y: 32%. ESI-MS (M+H) + : 348.1.

Synthesis of 5-amino-3-(1-(6-methylpyridin-2-ol

To a solution of 3-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-5-nitropyridin-2-ol (50 mg, 0.14 mmol) in MeOH (5 mL) was added Raney Ni (5 mg, 10% w/w). Then the mixture was stirred at 45° C. for 1 h under H 2 atmosphere. After filtration, the filtrate was concentrated and purified by pre-HPLC (MeOH/H 2 O with 0.05% NH 4 OH as mobile phase from 5% to 95%) to give 5-amino-3-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-ol. 16 mg, as a yellow solid, Y: 35%. ESI-MS (M+H) + : 318.0. HPLC: 95.53%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.12 (s, 1H), 8.26 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.82 (d, J=4.4 Hz, 2H), 7.61 (d, J=2.8 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.14-7.12 (m, 1H), 7.00 (d, J=2.8 Hz, 1H), 2.64 (s, 3H).

›Example 12. Synthesis of 3-amino-5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-4-ol

Synthesis of 3-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-5-nitropyridin-4-ol

The preparation of 3-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-5-nitropyridin-4-ol was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine. 91 mg, as a yellow solid, Y: 52%. ESI-MS (M+H) + : 348.1.

Synthesis of 3-amino-5-(1-(6-methylpyridin-2-yl)-indazol-6-yl)pyridin-4-ol

The preparation of 3-amino-5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-4-ol was the same as that of 5-amino-3-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-ol. 25 mg, as a yellow solid, Y: 30%. ESI-MS (M+H) + : 318.0. HPLC: 93.43%. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 11.42 (br, 1H), 9.14 (s, 1H), 8.38 (s, 1H), 7.90-7.78 (m, 3H), 7.71 (d, J=1.6 Hz, 1H), 7.65 (dd, J=8.4, 1.6 Hz, 1H), 7.18 (d, J=1.2 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 4.76 (br, 2H), 2.58 (s, 3H).

›Example 13. N-methyl-5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine

Synthesis of N-(5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-yl)acetamide

To a mixture of 5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine (65 mg, 0.22 mmol) and TEA (67 mg, 0.66 mmol, 3.0 eq) in THF (5 mL) was added AcCl (34 mg, 0.44 mmol, 2.0 eq) at room temperature. The mixture was stirred at rt for 3 h. After concentration, the residue was purified by pre-HPLC to give N-(5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-yl)acetamide as a white solid. (52 mg, Y: 70%). ESI-MS (M+H) + : 344.1.

Synthesis of N-methyl-N-(5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-yl)acetamide

To a solution of N-(5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-yl)acetamide (52 mg, 0.15 mmol) in THF (3 mL) was added NaH (7 mg, 0.18 mmol, 1.2 eq). The resulting solution was stirred at rt for 10 min and then MeI (0.01 mL, 0.15 mmol, 1.0 eq) was added. The reaction mixture was stirred at rt for 4 h and concentrated in vacuo. The residue was partitioned between DCM/H 2 O (10 mL/5 mL), then the aqueous phase was washed with DCM (3×10 mL). The combined organic phase was washed with brine (10 mL) and dried over Na 2 SO 4 . After filtration and concentration, the residue was purified by column chromatography (silica gel, PE/EA=1/1) to afford N-methyl-N-(5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-yl)acetamide as yellow oil (32 mg, Y: 60%). 1 H NMR (400 MHz, CDCl 3 ) δ: 9.18 (s, 1H), 8.97 (s, 1H), 8.55 (s, 1H), 8.23 (s, 1H), 7.95-7.83 (m, 3H), 7.74 (t, J=7.6 Hz, 1H), 7.49 (dd, J=8.8 Hz, 1.6 Hz, 1H), 7.04 (d, J=7.6 Hz, 1H), 3.39 (s, 3H), 2.63 (s, 3H), 2.02 (s, 3H).

Synthesis of N-methyl-5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine

To a solution of N-methyl-N-(5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-yl)acetamide (65 mg, 0.18 mmol, 1.0 eq) in EtOH/H 2 O (1 mL/2 mL) was added KOH (100 mg, 1.8 mmol, 10.0 eq). The reaction mixture was heated to 100° C. for 16 h. The reaction mixture was allowed to cool to rt and extracted with DCM (3×10 mL), then washed with brine (10 mL), dried over Na 2 SO 4 . After removing solvent in vacuo, the residue was suspended in MeOH and acidified with TFA, then purified by prep-HPLC to afford N-methyl-5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine as a white solid (30 mg, Y: 62%) 1H NMR (400 MHz, CD 3 OD) δ: 9.14-9.00 (m, 1H), 8.27-8.13 (m, 2H), 7.96-7.67 (m, 5H), 7.56-7.42 (m, 1H), 7.01-6.98 (m, 1H), 2.91-2.84 (m, 3H), 2.57-2.50 (m, 3H).

›Example 14. N,N-dimethyl-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methanamine

Synthesis of N,N-dimethyl-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methanamine

To a mixture of (6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methanamine (115 mg, 0.36 mmol) and HCHO (aq., excess) in MeOH (10 mL) was added NaBH(OAc) 3 (382 mg, 1.80 mmol, 5.0 eq) at rt. The mixture was stirred at rt for 2 h. After concentration, the residue was purified by pre-HPLC to give N,N-dimethyl-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methanamine as a white solid (60 mg, Y: 48%). ESI-MS (M+H) + : 344.1. HPLC: 94.59%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.44 (s, 1H), 8.22 (s, 1H), 7.93-7.74 (m, 6H), 7.39 (dd, J=7.2, 1.2 Hz, 1H), 7.08 (dd, J=7.2, 2.0 Hz, 1H), 3.70 (s, 2H), 2.60 (s, 3H), 2.33 (s, 6H).

›Example 15. 5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-1,2,3,4-tetrahydroisoquinoline

Synthesis of tert-butyl 5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

The preparation of tert-butyl 5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine. 100 mg, as a yellow solid, Y: 30%. ESI-MS (M+H) + : 441.2.

Synthesis of 5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-1,2,3,4-tetrahydroisoquinoline

A solution of tert-butyl 5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg, 0.23 mmol) in TFA/DCM (1 mL/3 mL) was stirred at rt for 2 h. After concentration, the residue was purified by pre-HPLC to give 5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-1,2,3,4-tetrahydroisoquinoline as a white solid (50 mg, Y: 65%). ESI-MS (M+H) + : 341.2. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 8.70 (s, 1H), 8.20-8.18 (m, 1H), 7.75-7.70 (m, 3H), 7.16-7.00 (m, 5H), 3.99 (s, 2H), 2.92-2.89 (m, 2H), 2.67-2.65 (m, 2H), 2.47 (s, 3H).

›Example 16. 2-methyl-5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-1,2,3,4-tetrahydroisoquinoline

Synthesis of 2-methyl-5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-1,2,3,4-tetrahydroisoquinoline

The preparation of 2-methyl-5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-1,2,3,4-tetrahydroisoquinoline was the same as that of N,N-dimethyl-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methanamine. 19 mg, as a white solid, Y: 31%. ESI-MS (M+H) + : 355.2. HPLC: 97.75%. 1 H NMR (400 MHz, CD 3 OD) δ: 8.68 (s, 1H), 8.18 (d, J=0.8 Hz, 1H), 7.74-7.70 (m, 3H), 7.16-6.98 (m, 5H), 3.62 (s, 2H), 2.76-2.74 (m, 2H), 2.57-2.55 (m, 2H), 2.45 (s, 3H), 2.36 (s, 3H).

›Example 17. 6-(2-methylisoindolin-4-yl)-1-(6-methylpyridin-2-yl)-1H-indazole

Synthesis of 6-(2-methylisoindolin-4-yl)-1-(6-methylpyridin-2-yl)-1H-indazole

The preparation of 6-(2-methylisoindolin-4-yl)-1-(6-methylpyridin-2-yl)-1H-indazole was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine except the reaction was performed at a temperature of 100. 47 mg, as a white solid, Y: 43%. ESI-MS (M+H) + : 341.2. HPLC: 95.23%. 1 H NMR (400 MHz, CD 3 OD) δ: 8.74 (s, 1H), 8.13 (s, 1H), 7.72-7.66 (m, 3H), 7.31-7.21 (m, 4H), 6.97-6.95 (m, 1H), 4.04 (s, 2H), 3.92 (s, 2H), 2.52 (s, 3H), 2.49 (s, 3H).

›Example 18. N-methyl-1-(3-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)phenyl)methanamine

Synthesis of tert-butyl methyl((6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methyl)carbamate

The preparation of tert-butyl methyl((6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methyl)carbamate was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine except the reaction temperature was 100. 110 mg, as a yellow solid, Y: 38%. ESI-MS (M+H) + : 430.2.

Synthesis of N-methyl-1-(3-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)phenyl)methanamine

The preparation of N-methyl-1-(3-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)phenyl)methanamine was the same as that of 5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-1,2,3,4-tetrahydroisoquinoline. 53 mg, as a yellow solid, Y: 52%. ESI-MS (M+H) + : 330.2. HPLC: 91.60%. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.56 (s, 1H), 8.20 (s, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.86-7.71 (m, 5H), 7.29-7.26 (m, 1H), 7.04 (d, J=7.2 Hz, 1H), 4.02 (s, 2H), 3.69 (s, 3H), 2.59 (s, 3H).

›Example 20. 3-(6-(3-aminophenyl)-1H-indazol-1-yl)benzonitrile

Synthesis of 3-(6-bromo-1H-indazol-1-yl)benzonitrile

A mixture of 4-bromo-2-fluorobenzaldehyde (CAS #57848-46-01) (350 mg, 1.73 mmol), 3-hydrazinylbenzonitrile hydrochloride (CAS #2881-99-4) (293 mg, 1.73 mmol, 1.0 eq) and K 2 CO 3 (358 mg, 2.60 mmol, 1.5 eq) in NMP (5 mL) was stirred at 130° C. for 4 h. After cooling down to rt, the mixture was diluted with H 2 O (20 mL) and stirred at rt for 30 min. After filtration, the solid was purified by silica gel chromatography with PE/EA (10/1) as eluent to give 3-(6-bromo-1H-indazol-1-yl)benzonitrile. 102 mg, as a yellow solid, Y: 20%. ESI-MS (M+H) + : 298.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.20 (s, 1H), 8.02 (s, 1H), 7.97 (dd, J=7.2, 2.0 Hz, 1H), 7.90 (s, 1H), 7.69-7.64 (m, 3H), 7.39 (dd, J=8.4, 1.2 Hz, 1H).

Synthesis of 3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)benzonitrile

The preparation of 3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)benzonitrile was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 100 mg, as a yellow solid, Y: 84%. ESI-MS (M+H) + : 346.2.

Synthesis of 3-(6-(3-aminophenyl)-1H-indazol-1-yl)benzonitrile

The preparation of 3-(6-(3-aminophenyl)-1H-indazol-1-yl)benzonitrile was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine. 25 mg, as a yellow solid, Y: 24%. ESI-MS (M+H) + : 311.1. HPLC: 95.39%. 1 H NMR (400 MHz, CD 3 OD) δ: 8.20 (s, 1H), 8.03-8.00 (m, 2H), 7.79-7.77 (m, 2H), 7.69-7.63 (m, 2H), 7.43 (dd, J=8.4, 1.2 Hz, 1H), 7.13 (t, J=7.6 Hz, 1H), 6.97 (s, 1H), 6.92 (d, J=7.6 Hz, 1H), 6.70 (dd, J=8.0, 1.2 Hz, 1H).

›Example 21. 3-(1-(pyridin-2-yl)-1H-indazol-6-yl)aniline

Synthesis of 6-bromo-1-(pyridin-2-yl)-1H-indazole

The preparation of 6-bromo-1-(pyridin-2-yl)-1H-indazole was the same as that of 6-bromo-1-(6-methylpyridin-2-yl)-1H-indazole. 100 mg, as a yellow solid, Y: 30%. ESI-MS (M+H) + : 274.0. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.10 (s, 1H), 8.54 (d, J=3.6 Hz, 1H), 8.16 (s, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.86-7.82 (m, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.39 (dd, J=8.4, 1.6 Hz, 1H), 7.18 (dd, J=6.8, 1.2 Hz, 1H).

Synthesis of 1-(pyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

The preparation of 1-(pyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 95 mg, as a yellow solid, Y: 83%. ESI-MS (M+H) + : 322.2.

Synthesis of 3-(1-(pyridin-2-yl)-1H-indazol-6-yl)aniline

The preparation of 3-(1-(pyridin-2-yl)-1H-indazol-6-yl)aniline was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine. 54 mg, as a yellow solid, Y: 54%. ESI-MS (M+H) + : 287.1. 1 H NMR (400 MHz, CD 3 OD) δ: 8.97 (s, 1H), 8.55 (dd, J=5.2, 1.2 Hz, 1H), 8.25 (s, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.93 (dd, J=7.6, 2.0 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.53 (dd, J=8.4, 1.6 Hz, 1H), 7.26-7.19 (m, 2H), 7.11 (d, J=2.0 Hz, 1H), 7.04 (d, J=7.6 Hz, 1H), 6.76 (dd, J=8.0, 1.6 Hz, 1H).

›Example 22. 6-(6-(3-aminophenyl)-1H-indazol-1-yl)picolinonitrile

Synthesis of 6-(6-bromo-1H-indazol-1-yl)picolinonitrile

The preparation of 6-(6-bromo-1H-indazol-1-yl)picolinonitrile was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole. 170 mg, as a yellow solid, Y: 56%. ESI-MS (M+H) + : 299.0. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.01 (s, 1H), 8.31 (d, J=7.6 Hz, 1H), 8.19 (s, 1H), 7.96 (t, J=8.4 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.58 (d, J=7.6 Hz, 1H), 7.47 (dd, J=8.4, 1.2 Hz, 1H).

Synthesis of 6-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)picolinonitrile

The preparation of 6-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)picolinonitrile was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 109 mg, as a yellow solid, Y: 70%. ESI-MS (M+H) + : 347.2.

Synthesis of 6-(6-(3-aminophenyl)-1H-indazol-1-yl)picolinonitrile

The preparation of 6-(6-(3-aminophenyl)-1H-indazol-1-yl)picolinonitrile was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine. 31 mg, as a yellow solid, Y: 31%. ESI-MS (M+H) + : 312.1. HPLC: 100.00%. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 8.80 (s, 1H), 8.57 (s, 1H), 8.35 (d, J=8.8 Hz, 1H), 8.25 (t, J=7.6 Hz, 1H), 7.99-7.97 (m, 2H), 7.56 (dd, J=8.4, 1.2 Hz, 1H), 7.18 (t, J=7.6 Hz, 1H), 6.91 (s, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.64 (dd, J=7.6, 1.2 Hz, 1H), 5.29 (br, 2H).

›Example 23. 3-(1-(4,6-dimethylpyridin-2-yl)-1H-indazol-6-yl)aniline

Synthesis of 6-bromo-1-(4,6-dimethylpyridin-2-yl)-1H-indazole

The preparation of 6-bromo-1-(4,6-dimethylpyridin-2-yl)-1H-indazole was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole. 70 mg, as a yellow solid, Y: 15%. ESI-MS (M+H) + : 302.2. 1 H NMR (400 MHz, CD 3 OD) δ: 9.08 (s, 1H), 8.12 (s, 1H), 7.64 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.36 (dd, J=8.4, 1.6 Hz, 1H), 6.87 (s, 1H), 2.61 (s, 3H), 2.40 (s, 3H).

Synthesis of 1-(4,6-dimethylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

The preparation of 1-(4,6-dimethylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 64 mg, as a yellow solid, Y: 80%. ESI-MS (M+H) + : 350.2.

Synthesis of 3-(1-(4,6-dimethylpyridin-2-yl)-1H-indazol-6-yl)aniline

The preparation of 3-(1-(4,6-dimethylpyridin-2-yl)-1H-indazol-6-yl)aniline was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine. 30 mg, as a yellow solid, Y: 52%. ESI-MS (M+H) + : 315.2. HPLC: 98.79%. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.06 (s, 1H), 8.17 (s, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.67 (s, 1H), 7.48 (dd, J=8.4, 1.6 Hz, 1H), 7.29 (d, J=7.6 Hz, 1H), 7.13 (d, J=7.2 Hz, 1H), 7.05 (t, J=2.0 Hz, 1H), 6.86 (s, 1H), 6.75-6.72 (m, 1H), 3.79 (s, 2H), 2.60 (s, 3H), 2.41 (s, 3H).

›Example 24. 3-(1-(5,6-dimethylpyridin-2-yl)-1H-indazol-6-yl)aniline

Synthesis of 6-bromo-1-(5,6-dimethylpyridin-2-yl)-1H-indazole

The preparation of 6-bromo-1-(5,6-dimethylpyridin-2-yl)-1H-indazole was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole. 30 mg, as a yellow solid, Y: 13%. ESI-MS (M+H) + : 302.2.

Synthesis of 1-(5,6-dimethylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

The preparation of 1-(5,6-dimethylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 28 mg, as a yellow solid, Y: 81%. ESI-MS (M+H) + : 350.2.

Synthesis of 3-(1-(5,6-dimethylpyridin-2-yl)-1H-indazol-6-yl)aniline

The preparation of 3-(1-(5,6-dimethylpyridin-2-yl)-1H-indazol-6-yl)aniline was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine. 15 mg, as a yellow solid, Y: 48%. ESI-MS (M+H) + : 315.2. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 8.97 (s, 1H), 8.20 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.50 (dd, J=8.4, 1.6 Hz, 1H), 7.21 (t, J=7.6 Hz, 1H), 7.09 (t, J=1.6 Hz, 1H), 7.03 (d, J=7.6 Hz, 1H), 6.75 (dd, J=7.6, 1.6 Hz, 1H), 2.59 (s, 3H), 2.34 (s, 3H).

›Example 25. 3-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)aniline

Synthesis of 6-bromo-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole

The preparation of 6-bromo-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole except the reaction was run at 200 for 1 h. 300 mg, as a yellow solid, Y: 22%. ESI-MS (M+H) + : 342.0. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.07 (s, 1H), 8.24 (d, J=8.8 Hz, 1H), 8.18 (s, 1H), 8.00 (t, J=7.6 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.54 (d, J=7.2 Hz, 1H), 7.44 (dd, J=8.8, 2.0 Hz, 1H).

Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole

The preparation of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 145 mg, as a yellow solid, Y: 85%. ESI-MS (M+H) + : 390.2.

Synthesis of 3-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)aniline

The preparation of 3-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)aniline was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole. 55 mg, as a yellow solid, Y: 42%. ESI-MS (M+H) + : 355.1. HPLC: 98.79%. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.16 (s, 1H), 8.26 (d, J=8.4 Hz, 1H), 8.22 (s, 1H), 7.99 (t, J=8.0 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.58 (dd, J=8.0, 1.6 Hz, 1H), 7.51 (d, J=7.6 Hz, 1H), 7.29 (t, J=8.0 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.09 (t, J=2.0 Hz, 1H), 6.74 (dd, J=8.0, 1.6 Hz, 1H), 3.79 (s, 2H).

›Example 27. 5-(1-(6-cyclopropylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine

Synthesis of 6-bromo-1-(6-cyclopropylpyridin-2-yl)-1H-indazole

The preparation of 6-bromo-1-(6-cyclopropylpyridin-2-yl)-1H-indazole was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole. 40 mg, as a yellow solid, Y: 18%. ESI-MS (M+H) + : 314.0.

Synthesis of 1-(6-cyclopropylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

The preparation of 1-(6-cyclopropylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 32 mg, as a yellow solid, Y: 70%. ESI-MS (M+H) + : 362.2.

Synthesis of 5-(1-(6-cyclopropylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine

The preparation of 5-(1-(6-cyclopropylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole. 12 mg, as a yellow solid, Y: 41%. ESI-MS (M+H) + : 328.1. HPLC: 100.00%. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.04 (s, 1H), 8.43 (d, J=1.6 Hz, 1H), 8.17 (s, 1H), 8.14 (d, J=2.4 Hz, 1H), 7.81-7.78 (m, 2H), 7.67 (t, J=8.0 Hz, 1H), 7.47 (dd, J=8.4, 1.6 Hz, 1H), 7.32 (dd, J=8.4, 2.8 Hz, 1H), 7.07 (d, J=7.6 Hz, 1H), 3.80 (br, 2H), 2.14-2.10 (m, 1H), 1.28-1.24 (m, 2H), 1.12-1.08 (m, 2H).

›Example 28. 5-(1-(6-cyclobutylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine

Synthesis of 6-bromo-1-(6-cyclobutylpyridin-2-yl)-1H-indazole

The preparation of 6-bromo-1-(6-cyclobutylpyridin-2-yl)-1H-indazole was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole. 140 mg, as a yellow solid, Y: 21%. ESI-MS (M+H) + : 328.0.

Synthesis of 1-(6-cyclobutylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

The preparation of 1-(6-cyclobutylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 100 mg, as a yellow solid, Y: 63%. ESI-MS (M+H) + : 376.2.

Synthesis of 5-(1-(6-cyclobutylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine

The preparation of 5-(1-(6-cyclobutylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole. 21 mg, as a yellow solid, Y: 23%. ESI-MS (M+H) + : 342.2. HPLC: 100.00%. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.22 (s, 1H), 8.37 (d, J=1.6 Hz, 1H), 8.11 (d, J=1.6 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.92 (s, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.32 (dd, J=8.4, 1.2 Hz, 1H), 7.26 (s, 1H), 7.15 (d, J=7.6 Hz, 1H), 3.80 (br, 2H), 3.75-3.70 (m, 1H), 2.48-2.39 (m, 4H), 2.12-1.97 (m, 2H).

›Example 29. 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)picolinonitrile

Synthesis of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)picolinonitrile

The preparation of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)picolinonitrile was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole. 120 mg, as a yellow solid, Y: 39%. ESI-MS (M+H) + : 313.1. HPLC: 94.59%. 1 H NMR (400 MHz, CD 3 OD) δ: 8.98 (s, 1H), 8.41-8.38 (m, 2H), 8.16 (d, J=1.6 Hz, 1H), 8.12 (d, J=8.4 Hz, 1H), 8.02 (d, J=2.4 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.44 (s, 1H).

›Example 30. 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)picolinic acid

Synthesis of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)picolinic acid

A mixture of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)picolinonitrile (60 mg, 0.19 mmol, 1.0 eq) and KOH (106 mg, 1.90 mmol, 10.0 eq) in EtOH/H 2 O (1 mL/1 mL) was stirred at 100° C. for 16 h. After cooling to rt, the mixture was adjusted pH=7 with 3 N HCl. After concentration, the residue was purified by pre-HPLC (CH 3 CN/0.5% TFA in H 2 O, 5%-95%) to give 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)picolinic acid as a white solid. 15 mg, Y: 24%. ESI-MS (M+H) + : 332.1. HPLC: 97.10%. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 9.45 (s, 1H), 8.57 (s, 1H), 8.32 (s, 1H), 8.23-8.20 (m, 2H), 8.07-7.99 (m, 2H), 7.98 (d, J=7.2 Hz, 1H), 7.68-7.66 (m, 2H).

›Example 31. 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)picolinamide

Synthesis of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)picolinamide

A mixture of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)picolinonitrile (65 mg, 0.21 mmol, 1.0 eq) and NaOH (17 mg, 0.42 mmol, 2.0 eq) in EtOH/H 2 O (1 mL/1 mL) was stirred at 50° C. for 4 h. After cooling to rt, the mixture was adjusted pH=7 with 3 N HCl. After concentration, the residue was purified by pre-HPLC (CH 3 CN/0.5% TFA in H 2 O, 5%-95%) to give 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)picolinamide as a white solid. 27 mg, Y: 39%. ESI-MS (M+H) + : 331.1. HPLC: 99.33%. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 8.94 (s, 1H), 8.54 (s, 1H), 8.22 (d, J=2.0 Hz, 1H), 8.19-8.17 (m, 2H), 8.07 (s, 1H), 8.02-7.98 (m, 2H), 7.90-7.59 (m, 2H), 7.61 (dd, J=8.4, 0.4 Hz, 1H), 7.29 (t, J=2.0 Hz, 1H), 5.45 (s, 2H).

›Example 32. 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-methylpicolinamide

Synthesis of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-methylpicolinamide

A mixture of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)picolinic acid (38 mg, 0.11 mmol, 1.0 eq), DIPEA (43 mg, 0.33 mmol, 3.0 eq) and HATU (65 mg, 0.17 mmol, 1.5 eq) in DMF (2 mL) was stirred at rt for 20 min, then, methylamine hydrochloride (CAS #593-51-1) (11 mg, 0.17 mmol, 1.5 eq) was added to the mixture. The mixture was stirred at rt for 16 h. The mixture was purified by pre-HPLC (CH 3 CN/0.5% NH 4 OH in H 2 O, 5%-95%) to give 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-methylpicolinamide as a white solid. 11 mg, Y: 28%). ESI-MS (M+H) + : 345.0. HPLC: 96.81%. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 8.98 (s, 1H), 8.65 (q, J=4.4 Hz, 1H), 8.54 (d, J=0.4 Hz, 1H), 8.27 (d, J=1.6 Hz, 1H), 8.18-8.16 (m, 2H), 8.02-7.99 (m, 2H), 7.87 (dd, J=6.0, 2.0 Hz, 1H), 7.61 (dd, J=8.0, 1.6 Hz, 1H), 7.32 (t, J=2.4 Hz, 1H), 5.43 (s, 2H), 2.93 (d, J=4.8 Hz, 3H).

›Example 33. 3-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)benzonitrile

Synthesis of 3-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)benzonitrile

The preparation of 3-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)benzonitrile was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole. 17 mg, as a yellow solid. Y: 21%. ESI-MS (M+H) + : 312.1. HPLC: 94.59%. 1 H NMR (400 MHz, CD 3 OD) δ: 8.34 (s, 1H), 8.19-8.15 (m, 2H), 8.11 (d, J=2.0 Hz, 1H), 7.97-7.95 (m, 3H), 7.77-7.74 (m, 2H), 7.53 (dd, J=8.4, 1.2 Hz, 1H), 7.40 (t, J=2.0 Hz, 1H).

›Example 34. 2-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-6-methylisonicotinonitrile

Synthesis of 2-(6-bromo-1H-indazol-1-yl)-6-methylisonicotinonitrile

The preparation of 2-(6-bromo-1H-indazol-1-yl)-6-methylisonicotinonitrile was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole. 80 mg, as a yellow solid, Y: 20%. ESI-MS (M+H) + : 313.0.

Synthesis of 2-methyl-6-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)isonicotinonitrile

The preparation of 2-methyl-6-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)isonicotinonitrile was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 62 mg, as a yellow solid, Y: 67%. ESI-MS (M+H) + : 361.2.

Synthesis of 2-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-6-methylisonicotinonitrile

The preparation of 2-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-6-methylisonicotinonitrile was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole. 17 mg, as a yellow solid, Y: 30%. ESI-MS (M+H) + : 327.1. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.05 (s, 1H), 8.35 (s, 1H), 8.14 (s, 1H), 8.13 (s, 1H), 8.01 (d, J=2.4 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.58 (dd, J=8.0, 1.6 Hz, 1H), 7.43-7.41 (m, 2H), 2.72 (s, 3H).

›Example 35. 2-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)isonicotinonitrile

Synthesis of 2-(6-bromo-1H-indazol-1-yl)isonicotinonitrile

The preparation of 2-(6-bromo-1H-indazol-1-yl)isonicotinonitrile was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole. 76 mg, as a yellow solid, Y: 23%. ESI-MS (M+H) + : 299.0.

Synthesis of 2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)isonicotinonitrile

The preparation of 2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)isonicotinonitrile was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 54 mg, as a yellow solid, Y: 62%. ESI-MS (M+H) + : 347.2.

Synthesis of 2-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)isonicotinonitrile

The preparation of 2-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)isonicotinonitrile was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole. 18 mg, as a yellow solid, Y: 37%. ESI-MS (M+H) + : 313.1. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.02 (s, 1H), 8.77 (dd, J=4.8, 0.4 Hz, 1H), 8.38 (s, 2H), 8.13 (d, J=1.6 Hz, 1H), 8.01 (d, J=2.4 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.59 (dd, J=8.4, 1.6 Hz, 1H), 7.45 (d, J=5.6 Hz, 1H), 7.44-7.43 (m, 1H).

›Example 36. 5-(1-(4-methylpyrimidin-2-yl)-1H-indazol-6-yl)pyridin-3-amine

Synthesis of 6-bromo-1-(4-methylpyrimidin-2-yl)-1H-indazole

The preparation of 6-bromo-1-(4-methylpyrimidin-2-yl)-1H-indazole was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole. 200 mg, as a yellow solid, Y: 46%. ESI-MS (M+H) + : 289.0.

Synthesis of 1-(4-methylpyrimidin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

The preparation of 1-(4-methylpyrimidin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 150 mg, as a yellow solid, Y: 64%. ESI-MS (M+H) + : 337.2.

Synthesis of 5-(1-(4-methylpyrimidin-2-yl)-1H-indazol-6-yl)pyridin-3-amine

The preparation of 5-(1-(4-methylpyrimidin-2-yl)-1H-indazol-6-yl)pyridin-3-amine was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole. 47 mg, as a yellow solid, Y: 37%. ESI-MS (M+H) + : 312.1. HPLC: 98.55%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.06 (s, 1H), 8.74 (d, J=5.2 Hz, 1H), 8.44 (s, 1H), 8.17 (d, J=1.2 Hz, 1H), 8.03 (d, J=2.0 Hz, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.63 (dd, J=8.4, 1.6 Hz, 1H), 7.46 (t, J=2.0 Hz, 1H), 7.28 (d, J=4.8 Hz, 1H), 2.69 (s, 3H).

›Example 37. 2-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)pyrimidine-4-carbonitrile

Synthesis of 5-bromo-N,N-bis(4-methoxybenzyl)pyridin-3-amine

To a solution of 5-bromopyridin-3-amine (CAS #13535-01-8) (1 g, 5.81 mmol) in DMF (10 mL) was added NaH (512 mg, 12.8 mmol, 2.2 eq) at 0° C. Then, PMBCl (2.09 g, 13.37 mmol, 2.3 eq) was added to the mixture. The mixture was stirred at rt for 2 h and diluted with water (50 mL). After filtration, the residue was purified by silica gel chromatography with PE/EA (10/1) as eluent to give 5-bromo-N,N-bis(4-methoxybenzyl)pyridin-3-amine as yellow oil. 1.4 g, Y: 58%. ESI-MS (M+H) + : 413.0.

Synthesis of (5-(bis(4-methoxybenzyl)amino)pyridin-3-yl)boronic acid

The preparation of (5-(bis(4-methoxybenzyl)amino)pyridin-3-yl)boronic acid was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 280 mg, as a yellow solid, Y: 61%. ESI-MS (M+H) + : 379.1.

Synthesis of 5-(1H-indazol-6-yl)-N,N-bis(4-methoxybenzyl)pyridin-3-amine

The preparation of 5-(1H-indazol-6-yl)-N,N-bis(4-methoxybenzyl)pyridin-3-amine was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole except palladiumtetrakis was used. 120 mg, as a yellow solid, Y: 36%. ESI-MS (M+H) + : 451.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 13.16 (s, 1H), 8.14 (d, J=1.2 Hz, 1H), 8.09 (s, 1H), 8.04 (d, J=2.8 Hz, 2H), 7.81 (d, J=8.0 Hz, 1H), 7.30-7.28 (m, 2H), 7.24 (d, J=8.4 Hz, 4H), 6.91 (d, J=8.4 Hz, 4H), 4.74 (s, 4H), 3.72 (s, 6H).

Synthesis of 2-(6-(5-(bis(4-methoxybenzyl)amino)pyridin-3-yl)-1H-indazol-1-yl)pyrimidine-4-carbonitrile

The preparation of 2-(6-(5-(bis(4-methoxybenzyl)amino)pyridin-3-yl)-1H-indazol-1-yl)pyrimidine-4-carbonitrile was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole. 80 mg, as yellow oil, Y: 54%. ESI-MS (M+H) + : 554.1.

Synthesis of 2-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)pyrimidine-4-carbonitrile

A solution of 2-(6-(5-(bis(4-methoxybenzyl)amino)pyridin-3-yl)-1H-indazol-1-yl)pyrimidine-4-carbonitrile (80 mg, 0.267 mmol) in TFA (5 mL) was stirred at 70° C. for 1 h. After concentration, the residue was purified by pre-HPLC (CH 3 CN/0.5% TFA in H 2 O, 5%-95%) to give 2-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)pyrimidine-4-carbonitrile as yellow oil. 14 mg, Y: 31%. ESI-MS (M+H) + : 313.1. HPLC: 98.15% 1 H NMR (400 MHz, CD 3 OD) δ: 9.03 (s, 1H), 8.91 (d, J=5.6 Hz, 1H), 8.56 (d, J=0.4 Hz, 1H), 8.34 (s, 1H), 8.31 (d, J=6.0 Hz, 1H), 8.10-8.07 (m, 2H), 8.00-7.99 (m, 1H), 7.74 (dd, J=8.4, 1.6 Hz, 1H).

›Example 38. 5-(1-(3-chloro-6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine

Synthesis of 6-bromo-1-(3-chloro-6-methylpyridin-2-yl)-1H-indazole

The preparation of 6-bromo-1-(3-chloro-6-methylpyridin-2-yl)-1H-indazole was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole. 80 mg, as a yellow solid, Y: 17%. ESI-MS (M+H) + : 322.0.

Synthesis of 1-(3-chloro-6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

The preparation of 1-(3-chloro-6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 70 mg, as a yellow solid, Y: 75%. ESI-MS (M+H) + : 370.1.

Synthesis of 5-(1-(3-chloro-6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine

The preparation of 5-(1-(3-chloro-6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole. 18 mg, as a yellow solid, Y: 28%. ESI-MS (M+H) + : 336.1. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 8.22 (d, J=0.8 Hz, 1H), 7.49 (d, J=1.6 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.86-7.82 (m, 2H), 7.58 (s, 1H), 7.40 (dd, J=8.8, 1.6 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.24 (t, J=2.4 Hz, 1H), 2.48 (s, 3H).

›Example 39. 5-(1-(4-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine

Synthesis of 6-bromo-1-(4-methylpyridin-2-yl)-1H-indazole

The preparation of 6-bromo-1-(4-methylpyridin-2-yl)-1H-indazole was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole. 150 mg, as a yellow solid, Y: 20%. ESI-MS (M+H) + : 288.0.

Synthesis of 1-(4-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

The preparation of 1-(4-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 131 mg, as a yellow solid, Y: 75%. ESI-MS (M+H) + : 336.2.

Synthesis of 5-(1-(4-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine

The preparation of 5-(1-(4-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole. 62 mg, as a yellow solid, Y: 52%. ESI-MS (M+H) + : 302.0. HPLC: 95.23%. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.04 (s, 1H), 8.40-8.39 (m, 2H), 8.21 (d, J=0.8 Hz, 1H), 8.13 (d, J=2.4 Hz, 1H), 7.90 (s, 1H), 7.83 (dd, J=8.4, 0.4 Hz, 1H), 7.46 (dd, J=8.0, 1.6 Hz, 1H), 7.32 (s, 1H), 7.00 (d, J=0.8 Hz, 1H), 3.83 (br, 2H), 2.46 (s, 3H).

›Example 40. 5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine

Synthesis of 6-bromo-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole

Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole

The preparation of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 500 mg, as a yellow solid, Y: 73%. ESI-MS (M+H) + : 390.2.

Synthesis of 5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine

The preparation of 5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole. 146 mg, as a yellow solid, Y: 64%. ESI-MS (M+H) + : 356.1. HPLC: 94.10%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.12 (s, 1H), 8.38 (s, 1H), 8.35 (d, J=8.4 Hz, 1H), 8.19-8.17 (m, 2H), 8.03 (d, J=2.4 Hz, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.61 (dd, J=8.4, 1.6 Hz, 1H), 7.44 (t, J=2.4 Hz, 1H).

›Example 41. 5-(3-(6-methylpyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-3-amine

Synthesis of N-((5-bromopyridin-2-yl)methyl)-6-methylpicolinamide

A mixture of (5-bromopyridin-2-yl)methanamine (CAS #173999-23-0) (250 mg, 1.34 mmol), 6-methylpicolinoyl chloride (CAS #126125-54-0) (208 mg, 1.34 mmol, 1.0 eq) and TEA (270 mg, 2.68 mmol, 2.0 eq) in DCM (10 mL) was stirred at rt for 16 h. After concentration, the residue was purified by silica gel chromatography with PE/EA (8/1) as eluent. 300 mg, as a yellow solid, Y: 73%. ESI-MS (M+H) + : 306.1.

Synthesis of 6-bromo-3-(6-methylpyridin-2-yl)imidazo[1,5-a]pyridine

A solution of N-((5-bromopyridin-2-yl)methyl)-6-methylpicolinamide (250 mg, 0.82 mmol) in POCl 3 (5 mL) was stirred at 90° C. for 3 h. After cooling down to rt, the mixture was poured into ice-water (30 mL) and stirred for 30 min. After filtration, the residue was purified by pre-TLC (PE/EA=10/1). 190 mg, as a yellow solid, Y: 67%. ESI-MS (M+H) + : 288.0. 1 H NMR (400 MHz, CDCl 3 ) δ: 10.28 (s, 1H), 8.16 (d, J=8.0 Hz, 1H), 7.70 (t, J=7.6 Hz, 1H), 7.61 (s, 1H), 7.44 (d, J=9.2 Hz, 1H), 7.11 (d, J=7.6 Hz, 1H), 6.93 (dd, J=9.6, 1.6 Hz, 1H), 2.67 (s, 3H).

Synthesis of 3-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine

The preparation of 3-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 180 mg, as a yellow solid, Y: 81%. ESI-MS (M+H) + : 336.2.

Synthesis of 5-(3-(6-methylpyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-3-amine

The preparation of 5-(3-(6-methylpyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-3-amine was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole. 17 mg, as a yellow solid, Y: 21%. ESI-MS (M+H) + : 301.9. HPLC: 96.34%. 1 H NMR (400 MHz, CD 3 OD) δ: 10.29 (s, 1H), 8.07 (d, J=1.6 Hz, 1H), 7.98-7.96 (m, 2H), 7.76 (d, J=8.0 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.58 (s, 1H), 7.25 (t, J=2.0 Hz, 1H), 7.21-7.17 (m, 2H), 2.62 (s, 3H).

›Example 42. 3-(3-(6-methylpyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)aniline

Synthesis of 3-(3-(6-methylpyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)aniline

The preparation of 3-(3-(6-methylpyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)aniline was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole. 16 mg, as a yellow solid, Y: 20%. ESI-MS (M+H) + : 301.0. HPLC: 97.85%. 1 H NMR (400 MHz, CDCl 3 ) δ: 10.33 (s, 1H), 8.14 (d, J=8.0 Hz, 1H), 7. 69 (t, J=7.6 Hz, 1H), 7.59-7.57 (m, 2H), 7.29 (d, J=8.0 Hz, 1H), 7.14 (dd, J=9.2, 1.6 Hz, 1H), 7.07 (d, J=7.6 Hz, 2H), 6.98 (t, J=1.6 Hz, 1H), 6.73 (dd, J=8.4, 2.0 Hz, 1H), 3.81 (br, 2H), 2.65 (s, 3H).

›Example 43. 5-(5-fluoro-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine

Synthesis of 6-bromo-5-fluoro-1-(6-methylpyridin-2-yl)-1H-indazole

A mixture of 4-bromo-2,5-difluorobenzaldehyde (CAS #357405-75-5) (220 mg, 1.0 mmol), 2-hydrazinyl-6-methylpyridine (CAS #5315-24-2) (129 g, 1.05 mmol, 1.05 eq) and K 2 CO 3 (2.5 eq) in DMSO (2 mL) was stirred at 130° C. for 3 h. The mixture was diluted with H 2 O (15 mL) and extracted with DCM (20 mL×2). The combined organic fractions were dried, concentrated and purified by silica gel chromatography with PE/EA (8/1) as eluent to give 6-bromo-5-fluoro-1-(6-methylpyridin-2-yl)-1H-indazole. 153 mg, as a white solid, Y: 50%. ESI-MS (M+H) + : 306.2, 308.2.

Synthesis of 5-fluoro-1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

The preparation of 5-fluoro-1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 100 mg, as a yellow solid, Y: 56%. ESI-MS (M+H) + : 354.2.

Synthesis of 5-(5-fluoro-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine

The preparation of 5-(5-fluoro-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole. 16 mg, as a yellow solid, Y: 19%. ESI-MS (M+H) + : 320.2. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 8.99 (d, J=6.4 Hz, 1H), 8.27 (s, 1H), 8.04-8.03 (m, 2H), 7.86-7.80 (m, 2H), 7.65 (d, J=10.0 Hz, 1H), 7.38-7.36 (m, 1H), 7.14 (d, J=6.8 Hz, 1H), 2.61 (s, 3H).

›Example 44. 5-(5-methyl-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine

Synthesis of 6-bromo-5-methyl-1-(6-methylpyridin-2-yl)-1H-indazole

The preparation of 6-bromo-5-methyl-1-(6-methylpyridin-2-yl)-1H-indazole was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole. 210 mg, as a yellow solid, Y: 30%. ESI-MS (M+H) + : 302.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.14 (s, 1H), 8.07 (s, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.70 (t, J=8.0 Hz, 1H), 7.60 (s, 1H), 7.02 (d, J=8.0 Hz, 1H), 2.66 (s, 3H), 2.53 (s, 3H).

Synthesis of 5-methyl-1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

The preparation of 5-methyl-1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 197 mg, as a yellow solid, Y: 81%. ESI-MS (M+H) + : 350.2.

Synthesis of 5-(5-methyl-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine

The preparation of 5-(5-methyl-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole. 45 mg, as a yellow solid, Y: 23%. ESI-MS (M+H) + : 316.1. HPLC: 96.91%. 1 H NMR (400 MHz, CD 3 OD) δ: 8.55 (s, 1H), 8.08 (s, 1H), 7.94 (d, J=2.8 Hz, 1H), 7.74 (d, J=2.0 Hz, 1H), 7.68-7.66 (m, 2H), 7.58 (s, 1H), 7.06 (t, J=2.0 Hz, 1H), 6.96 (d, J=8.0 Hz, 1H), 2.43 (s, 3H), 2.24 (s, 3H).

›Example 46. 6-(6-(6-(aminomethyl)pyridin-2-yl)-1H-indazol-1-yl)picolinonitrile

Synthesis of tert-butyl ((6-bromopyridin-2-yl)methyl)(2,4-dimethoxybenzyl)carbamate

To a mixture of 6-bromopicolinaldehyde (CAS #34160-40-2) (2.0 g, 10.81 mmol, 1.0 eq) and (2,4-dimethoxyphenyl)methanamine (CAS #20781-20-8) (1.81 g, 10.83 mmol, 1.0 eq) in THF (50 mL) was added NaBH(OAc) 3 (4.58 g, 21.62 mmol, 2.0 eq). The mixture was stirred at rt for 2 h. TEA (3.28 g, 32.43 mmol, 3.0 eq) and Boc 2 O (4.71 g, 21.62 mmol, 2.0 eq) were added into the mixture. The mixture was stirred at rt for 3 h. After concentration, the residue was purified by silica gel chromatography with PE/EA (6/1) as eluent to give tert-butyl ((6-bromopyridin-2-yl)methyl)(2,4-dimethoxybenzyl)carbamate. 1.51 g, as a white solid, Y: 32%. ESI-MS (M+H) + : 437.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 7.43 (t, J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.24-7.01 (m, 2H), 6.43 (d, J=8.0 Hz, 1H), 6.35 (d, J=2.4 Hz, 1H), 4.57-4.41 (m, 4H), 3.81 (s, 3H), 3.68 (s, 3H), 1.50-1.38 (m, 9H).

Synthesis of tert-butyl ((6-(1-(6-cyanopyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methyl)(2,4-dimethoxybenzyl)carbamate

The preparation of tert-butyl ((6-(1-(6-cyanopyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methyl)(2,4-dimethoxybenzyl)carbamate was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole. 350 mg, as a white solid, Y: 49%. ESI-MS (M+H) + : 577.2.

Synthesis of 6-(6-(6-(aminomethyl)pyridin-2-yl)-1H-indazol-1-yl)picolinonitrile

A solution of tert-butyl ((6-(1-(6-cyanopyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methyl)(2,4-dimethoxybenzyl)carbamate (350 mg, 0.61 mmol, 1.0 eq) in TFA (3 mL) was stirred at 70° C. for 0.5 h. After concentration, the residue was purified by pre-HPLC to give 6-(6-(6-(aminomethyl)pyridin-2-yl)-1H-indazol-1-yl)picolinonitrile as a white solid. (100 mg, Y: 50%). ESI-MS (M+H) + : 327.1. HPLC: 99.11%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.21 (s, 1H), 8.13 (d, J=0.8 Hz, 1H), 8.11 (d, J=8.8, 0.8 Hz, 1H), 7.92 (d, J=8.8, 7.6 Hz, 1H), 7.87 (d, J=8.4, 1.2 Hz, 1H), 7.78 (t, J=7.6 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.54 (dd, J=7.2, 0.4 Hz, 1H), 7.27 (d, J=7.6 Hz, 1H), 3.97 (s, 2H).

›Example 47. 6-(6-(6-(aminomethyl)pyridin-2-yl)-1H-indazol-1-yl)picolinamide

Synthesis of 6-(6-(6-(aminomethyl)pyridin-2-yl)-1H-indazol-1-yl)picolinamide

A mixture of 6-(6-(6-(aminomethyl)pyridin-2-yl)-1H-indazol-1-yl)picolinonitrile (51 mg, 0.16 mmol, 1.0 eq) and NaOH (13 mg, 0.32 mmol, 2.0 eq) in EtOH/H 2 O (3 mL/1 mL) was refluxed for 3 h. After concentration, the mixture was purified by pre-HPLC to give 6-(6-(6-(aminomethyl)pyridin-2-yl)-1H-indazol-1-yl)picolinamide as a white solid. (26 mg, Y: 48%). ESI-MS (M+H) + : 345.0. HPLC: 100.00%. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.48 (s, 1H), 8.26 (d, J=0.8 Hz, 1H), 8.24 (d, J=8.4, 1.2 Hz, 1H), 8.11 (d, J=7.6, 0.8 Hz, 1H), 8.03 (t, J=8.0 Hz, 1H), 7.94-7.87 (m, 2H), 7.81-7.73 (m, 2H), 7.29 (d, J=7.2 Hz, 1H), 6.06 (br, 2H), 4.08 (s, 2H).

›Example 48. (6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methanamine

Synthesis of 6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)picolinonitrile

The preparation of 6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)picolinonitrile was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole. 74 mg, as a white solid, Y: 35%. ESI-MS (M+H) + : 366.1.

Synthesis of (6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methanamine

The preparation of (6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methanamine was the same as that of 6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)picolinonitrile. 44 mg, as a white solid, Y: 59%. ESI-MS (M+H) + : 370.1. HPLC: 96.14%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.55 (s, 1H), 8.36-8.24 (m, 3H), 8.16-8.14 (m, 1H), 7.99-7.94 (m, 3H), 7.69-7.67 (m, 1H), 7.45-7.43 (m, 1H), 4.40 (s, 2H).

›Example 49. methyl 6-(5-aminopyridin-3-yl)-1-(6-cyanopyridin-2-yl)-1H-indazole-4-carboxylate · 1 of 2

Synthesis of methyl 6-bromo-1-(6-cyanopyridin-2-yl)-1H-indazole-4-carboxylate and methyl 6-bromo-2-(6-cyanopyridin-2-yl)-2H-indazole-4-carboxylate

The preparation of methyl 6-bromo-1-(6-cyanopyridin-2-yl)-1H-indazole-4-carboxylate and methyl 6-bromo-2-(6-cyanopyridin-2-yl)-2H-indazole-4-carboxylate was the same as that of 6-bromo-1-(6-methylpyridin-2-yl)-1H-indazole. 400 mg, as a yellow solid, Y: 48%. The mixture of methyl 6-bromo-1-(6-cyanopyridin-2-yl)-1H-indazole-4-carboxylate and methyl 6-bromo-2-(6-cyanopyridin-2-yl)-2H-indazole-4-carboxylate was difficult to be purified due to poor solubility. The mixture was directly used for next step. ESI-MS (M+H) + : 356.9.

Synthesis of methyl 1-(6-cyanopyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-4-carboxylate and methyl 2-(6-cyanopyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-4-carboxylate

The preparation of methyl 1-(6-cyanopyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-4-carboxylate and methyl 2-(6-cyanopyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-4-carboxylate was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 340 mg, as a yellow solid, Y: 75%. The mixture of methyl 1-(6-cyanopyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-4-carboxylate and methyl 2-(6-cyanopyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-4-carboxylate was directly used for next step without further purification. ESI-MS (M+H) + : 405.1.

Synthesis of methyl 6-(5-aminopyridin-3-yl)-1-(6-cyanopyridin-2-yl)-1H-indazole-4-carboxylate

The preparation of methyl 6-(5-aminopyridin-3-yl)-1-(6-cyanopyridin-2-yl)-1H-indazole-4-carboxylate was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole. The mixture of methyl 6-(5-aminopyridin-3-yl)-1-(6-cyanopyridin-2-yl)-1H-indazole-4-carboxylate and methyl 6-(5-aminopyridin-3-yl)-2-(6-cyanopyridin-2-yl)-2H-indazole-4-carboxylate was purified by silica gel chromatography with PE/EA (2/1) as eluent to give methyl 6-(5-aminopyridin-3-yl)-1-(6-cyanopyridin-2-yl)-1H-indazole-4-carboxylate and EA/MeOH (10/1) as eluent to give methyl 6-(5-aminopyridin-3-yl)-2-(6-cyanopyridin-2-yl)-2H-indazole-4-carboxylate. 18 mg of methyl 6-(5-aminopyridin-3-yl)-1-(6-cyanopyridin-2-yl)-1H-indazole-4-carboxylate, as a yellow solid, Y: 28%. ESI-MS (M+H) + : 371.1. HPLC: 93.60%. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 9.10 (s, 1H), 8.82 (d, J=0.4 Hz, 1H), 8.34 (dd, J=8.4, 0.4 Hz, 1H), 8.27 (t, J=8.0 Hz, 1H), 8.13-8.11 (m, 2H), 8.04 (d, J=2.4 Hz, 1H), 8.01 (dd, J=7.6, 0.8 Hz, 1H), 7.29 (t, J=2.4 Hz, 1H), 5.60 (s, 2H), 4.02 (s, 3H).

Example 50. methyl 6-(5-aminopyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylate

Synthesis of methyl 6-bromo-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylate and methyl 6-bromo-2-(6-(trifluoromethyl)pyridin-2-yl)-2H-indazole-4-carboxylate

The preparation of methyl 6-bromo-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylate and methyl 6-bromo-2-(6-(trifluoromethyl)pyridin-2-yl)-2H-indazole-4-carboxylate was the same as that of 6-bromo-1-(6-methylpyridin-2-yl)-1H-indazole. 950 mg, as a yellow solid, Y: 42%. The mixture of methyl 6-bromo-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylate and methyl 6-bromo-2-(6-(trifluoromethyl)pyridin-2-yl)-2H-indazole-4-carboxylate was difficult to be purified due to poor solubility. The mixture was directly used for next step. ESI-MS (M+H) + : 400.1.

Synthesis of methyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylate and methyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)-2H-indazole-4-carboxylate

The preparation of methyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylate and methyl 6-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)-2H-indazole-4-carboxylate was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 700 mg, as a yellow solid, Y: 79%. The mixture of methyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylate and methyl 6-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)-2H-indazole-4-carboxylate was directly used for next step without further purification. ESI-MS (M+H) + : 448.2.

Synthesis of methyl 6-(5-aminopyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylate

The preparation of methyl 6-(5-aminopyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylate was the same as that of 6-bromo-1-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-indazole. The mixture of methyl 6-(5-aminopyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylate and methyl 6-(5-aminopyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)-2H-indazole-4-carboxylate was purified by pre-HPLC (MeOH/H 2 O with 0.05% TFA as mobile phase from 5% to 95%) to give methyl 6-(5-aminopyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylate and 19-06-a. R f value of methyl 6-(5-aminopyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)-2H-indazole-4-carboxylate is more than that of methyl 6-(5-aminopyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylate.

methyl 6-(5-aminopyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylate: 20 mg, as a white solid, ESI-MS (M+H) + : 414.1, HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.37 (s, 1H), 8.78 (s, 1H), 8.36 (d, J=8.4 Hz, 1H), 8.26 (d, J=1.6 Hz, 1H), 8.21 (t, J=8.0 Hz, 1H), 8.16 (d, J=1.6 Hz, 1H), 8.04 (d, J=2.4 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.44 (t, J=2.4 Hz, 1H), 4.07 (s, 3H).

methyl 6-(5-aminopyridin-3-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)-2H-indazole-4-carboxylate: 15 mg, as a white solid, ESI-MS (M+H) + : 414.1, HPLC: 93.65%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.57 (d, J=0.8 Hz, 1H), 8.61 (d, J=8.0 Hz, 1H), 8.41-8.25 (m, 3H), 8.25 (d, J=1.6 Hz, 1H), 8.05 (s, 2H), 7.96 (d, J=7.2 Hz, 1H), 4.09 (s, 3H).

›Example 49. methyl 6-(5-aminopyridin-3-yl)-1-(6-cyanopyridin-2-yl)-1H-indazole-4-carboxylate · 2 of 2

Example 51. 6-(5-aminopyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylic acid

Synthesis of 6-(5-aminopyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylic acid

A mixture of methyl 6-(5-aminopyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylate (100 mg, 0.24 mmol, 1.0 eq) and LiOH.H 2 O (30 mg, 0.72 mmol, 3.0 eq) in THF/H 2 O (4 mL/1 mL) was stirred at rt for 16 h. The mixture was adjusted pH=6 with 1 N HCl and extracted with DCM (100 mL×2). The combined organic phase was washed with water (20 mL). After concentration, the residue was purified by pre-HPLC (MeOH/H 2 O as mobile phase from 5% to 95%) to give 6-(5-aminopyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylic acid. 67 mg, as a white solid, Y: 70%. ESI-MS (M+H) + : 400.1. HPLC: 98.77%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.41 (s, 1H), 8.86 (s, 1H), 8.40 (d, J=8.8 Hz, 1H), 8.32 (d, J=1.2 Hz, 1H), 8.29 (d, J=8.0 Hz, 1H), 8.25 (t, J=8.0 Hz, 1H), 8.08 (d, J=2.4 Hz, 1H), 7.96 (t, J=2.0 Hz, 1H), 7.75 (d, J=7.2 Hz, 1H).

›Example 52. 6-(5-aminopyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxamide

Synthesis of 6-(5-aminopyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxamide

The preparation of 6-(5-aminopyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxamide was the same as that of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-methylpicolinamide. 30 mg, as a yellow solid, Y: 50%. ESI-MS (M+H) + : 399.1. HPLC: 93.73%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.35 (s, 1H), 8.81 (s, 1H), 8.41 (d, J=8.8 Hz, 1H), 8.32 (d, J=0.8 Hz, 1H), 8.25 (t, J=8.0 Hz, 1H), 8.09-8.08 (m, 2H), 8.00 (t, J=2.0 Hz, 1H), 7.75 (d, J=7.6 Hz, 1H).

›Example 53. 5-(4-(aminomethyl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine

Synthesis of N-(5-(4-cyano-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-3-yl)-2,2,2-trifluoroacetamide

To a mixture of 6-(5-aminopyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxamide (50 mg, 0.13 mmol, 1.0 eq) and TEA (39 mg, 0.39 mmol, 3.0 eq) in DCM (4 mL) was added TFAA (55 mg, 0.26 mmol, 2.0 eq) at rt. The mixture was stirred at rt for 2 h. The mixture was diluted with water (5 mL) and DCM (10 mL). The organic phase was washed with brine (5 mL) and dried over Na 2 SO 4 . After filtration and concentration, 42 mg of N-(5-(4-cyano-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-3-yl)-2,2,2-trifluoroacetamide was obtained. Y: 68%. ESI-MS (M+H) + : 477.0. HPLC: 95.77%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.49 (s, 1H), 8.91 (d, J=2.4 Hz, 1H), 8.81 (d, J=1.6 Hz, 1H), 8.61 (s, 2H), 8.42 (d, J=8.8 Hz, 1H), 8.28 (t, J=7.6 Hz, 1H), 8.18 (d, J=1.6 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H).

Synthesis of 6-(5-aminopyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carbonitrile

A mixture of 6-(5-aminopyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carbonitrile (40 mg, 0.09 mmol, 1.0 eq) and K 2 CO 3 (25 mg, 0.18 mmol, 2.0 eq) in MeOH/H 2 O (4 mL/2 mL) was stirred at 60° C. for 2 h. After concentration, the residue was diluted with DCM (10 mL) and water (5 mL). The organic phase was concentrated and the residue was directly used for next step without further purification. 26 mg, as a yellow solid, Y: 75%. ESI-MS (M+H) + : 381.1.

Synthesis of 5-(4-(aminomethyl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine

The preparation of 5-(4-(aminomethyl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine was the same as that of 6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)picolinonitrile except THF was used as a solvent. 21 mg, as a yellow solid, Y: 80%. ESI-MS (M+H) + : 385.1. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.23 (s, 1H), 8.69 (s, 1H), 8.41 (d, J=8.8 Hz, 1H), 8.28-8.24 (m, 2H), 8.10 (s, 1H), 7.90 (s, 1H), 7.79 (s, 1H), 7.77 (d, J=7.6 Hz, 1H), 4.66 (s, 2H).

›Example 54. (6-(5-aminopyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-4-yl)methanol

Synthesis of (6-(5-aminopyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-4-yl)methanol

To a solution of methyl 6-(5-aminopyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylate (50 mg, 0.12 mmol, 1.0 eq) in MeOH (5 mL) was added NaBH 4 (9.0 mg, 0.24 mmol, 2.0 eq) at rt. The mixture reaction was at rt for 2 h. After concentration, the residue was purified by pre-HPLC (MeOH/H 2 O with 0.05% TFA as mobile phase from 5% to 95%) to give (6-(5-aminopyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-4-yl)methanol. 20 mg, as a yellow solid, Y: 52%. ESI-MS (M+H) + : 386.1. HPLC: 93.73%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.05 (s, 1H), 8.52 (d, J=1.2 Hz, 1H), 8.35 (d, J=8.8 Hz, 1H), 8.20 (d, J=8.0 Hz, 1H), 8.17 (s, 1H), 8.01 (d, J=2.8 Hz, 1H), 7.68 (d, J=7.2 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.60 (s, 1H), 7.44 (s, 1H), 5.08 (s, 2H).

›Example 55. 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine · 1 of 3

Synthesis of 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone

A mixture of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (275 mg, 0.82 mmol), 1-(6-bromopyridin-2-yl)ethanone (CAS #49669-13-8) (180 mg, 0.90 mmol, 1.1 eq), Pd(PPh 3 ) 4 (95 mg, 0.082 mmol, 0.1 eq) and K 2 CO 3 (226 mg, 1.64 mmol, 2.0 eq) in 1, 4-dioxane/H 2 O (5 mL/0.5 mL) was stirred at 110° C. for 2 h under N 2 . After concentration, the residue was purified by column chromatography (silica gel, PE/EA=8/1) to afford 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone as a yellow solid (200 mg, Y: 74%). ESI-MS (M+H) + : 330.1.

Synthesis of N-(4-methoxybenzyl)-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

A mixture of 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone (260 mg, 0.79 mmol), PMBNH 2 (162 mg, 1.18 mmol, 1.5 eq) and Ti(iPrO) 4 (168 mg, 1.58 mmol, 2.0 eq) in THF (10 mL) was stirred at 100° C. under mw for 2 h. After cooling to rt, NaBH 3 CN (98 mg, 1.58 mmol, 2.0 eq) was added into the mixture reaction. The mixture was stirred at 50° C. for 1 h. The mixture was poured into water (10 mL) and extracted with EA (20 mL). The organic phase was concentrated and the residue was purified by column chromatography (silica gel, PE/EA=6/1) to afford N-(4-methoxybenzyl)-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine as a yellow solid (180 mg, Y: 50%). ESI-MS (M+H) + : 450.1.

Synthesis of 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

A solution of N-(4-methoxybenzyl)-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine (70 mg, 0.19 mmol) in TFA (2 mL) was stirred at 80° C. for 16 h. After concentration, the residue was dissolved in EA (10 mL) and washed with saturated aqueous NaHCO 3 solution (10 mL) and brine (10 mL). The organics were dried (MgSO 4 ) and concentrated in vacuo. The crude product was purified by pre-HPLC (MeOH/H 2 O with 0.05% NH 4 OH as mobile phase from 5% to 95%) to give 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine. 40 mg, as a white solid, Y: 31%. ESI-MS (M+H) + : 330.1. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.64 (s, 1H), 8.20 (s, 1H), 7.99 (dd, J=8.8, 1.6 Hz, 1H), 7.86-7.82 (m, 2H), 7.76-7.71 (m, 3H), 7.25 (dd, J=4.4, 3.2 Hz, 1H), 7.03 (d, J=7.2 Hz, 1H), 4.27-4.22 (m, 1H), 2.69 (s, 3H), 1.55 (d, J=6.8 Hz, 3H).

Example 56. methyl 6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylate

Synthesis of methyl 6-(6-acetylpyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylate and methyl 6-(6-acetylpyridin-2-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)-2H-indazole-4-carboxylate

The preparation of methyl 6-(6-acetylpyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylate and methyl 6-(6-acetylpyridin-2-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)-2H-indazole-4-carboxylate was the same as that of 6-bromo-1-(6-methylpyridin-2-yl)-1H-indazole. The mixture of methyl 6-(6-acetylpyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylate and methyl 6-(6-acetylpyridin-2-yl)-2-(6-(trifluoromethyl)pyridin-2-yl)-2H-indazole-4-carboxylate was purified by silica gel chromatography with PE/EA (2/1) as eluent to give methyl 6-(6-acetylpyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylate. 400 mg, as a yellow solid, Y: 31%. ESI-MS (M+H) + : 441.1.

Synthesis of methyl 6-(6-(1-((4-methoxybenzyl)amino)ethyl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylate

The preparation of methyl 6-(6-(1-((4-methoxybenzyl)amino)ethyl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylate was the same as that of N-(4-methoxybenzyl)-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine. 285 mg, as a yellow solid, Y: 56%. ESI-MS (M+H) + : 562.1.

Synthesis of methyl 6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylate

The preparation of methyl 6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylate was the same as that of 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine. 38 mg, as a white solid, Y: 48%. ESI-MS (M+H) + : 442.1. HPLC: 96.49%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.68-9.65 (m, 1H), 8.59-8.54 (m, 2H), 8.19 (d, J=8.0 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.78-7.71 (m, 2H), 7.61 (d, J=7.2 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 4.11 (q, J=6.8 Hz, 1H), 3.96 (s, 3H), 1.45 (d, J=6.8 Hz, 3H).

Example 57. (6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-4-yl)methanol

Synthesis of (6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-4-yl)methanol

To a solution of methyl 6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylate (84 mg, 0.19 mmol, 1.0 eq) in THF (5 mL) was added LAH (43.0 mg, 1.14 mmol, 6.0 eq) at rt. The mixture reaction was at rt for 1 h. After concentration, the residue was purified by pre-HPLC (MeOH/H 2 O with 0.05% TFA as mobile phase from 5% to 95%) to give (6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-4-yl)methanol. 20 mg, as a white solid, Y: 25%. ESI-MS (M+H) + : 414.1. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.51 (s, 1H), 8.55 (s, 1H), 8.38 (d, J=8.0 Hz, 1H), 8.24 (s, 1H), 8.21 (t, J=8.0 Hz, 1H), 8.06-8.01 (m, 2H), 7.72 (d, J=7.6 Hz, 1H), 7.50 (dd, J=6.8, 2.0 Hz, 1H), 5.12 (s, 2H), 4.70 (q, J=6.8 Hz, 1H), 1.74 (d, J=6.8 Hz, 3H).

Example 58. 6-(6-(1-aminoethyl)pyridin-2-yl)-N,N-dimethyl-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxamide

Synthesis of 6-(6-(1-((4-methoxybenzyl)amino)ethyl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylic acid

The preparation of 6-(6-(1-((4-methoxybenzyl)amino)ethyl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylic acid was the same as that of 6-(5-aminopyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylic acid. 200 mg, as a white solid, Y: 68%. ESI-MS (M+H) + : 548.1.

›Example 55. 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine · 2 of 3

Synthesis of 6-(6-(1-((4-methoxybenzyl)amino)ethyl)pyridin-2-yl)-N,N-dimethyl-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxamide

The preparation of 6-(6-(1-((4-methoxybenzyl)amino)ethyl)pyridin-2-yl)-N,N-dimethyl-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxamide was the same as that of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-methylpicolinamide. 90 mg, as a yellow solid, Y: 56%. ESI-MS (M+H) + : 575.2.

Synthesis of 6-(6-(1-aminoethyl)pyridin-2-yl)-N,N-dimethyl-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxamide

The preparation of 6-(6-(1-aminoethyl)pyridin-2-yl)-N,N-dimethyl-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxamide was the same as that of 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine. 34 mg, as a white solid, Y: 48%. ESI-MS (M+H) + : 455.1. HPLC: 99.18%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.75 (s, 1H), 8.41-8.38 (m, 2H), 8.23 (t, J=8.0 Hz, 1H), 8.18 (d, J=1.2 Hz, 1H), 7.93-7.91 (m, 2H), 7.75 (d, J=7.6 Hz, 1H), 7.42 (dd, J=6.4, 2.0 Hz, 1H), 4.26 (q, J=6.4 Hz, 1H), 3.28 (s, 3H), 3.10 (s, 3H), 1.55 (d, J=6.8 Hz, 3H).

Example 59. 6-(6-(1-aminoethyl)pyridin-2-yl)-N-methyl-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxamide

Synthesis of 6-(6-(1-((4-methoxybenzyl)amino)ethyl)pyridin-2-yl)-N-methyl-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxamide

The preparation of 6-(6-(1-((4-methoxybenzyl)amino)ethyl)pyridin-2-yl)-N-methyl-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxamide was the same as that of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-methylpicolinamide. (Example 32) 102 mg, as a yellow solid, Y: 63%. ESI-MS (M+H) + : 561.2.

Synthesis of 6-(6-(1-aminoethyl)pyridin-2-yl)-N-methyl-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxamide

The preparation of 6-(6-(1-aminoethyl)pyridin-2-yl)-N-methyl-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxamide was the same as that of 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine. 54 mg, as a white solid, Y: 68%. ESI-MS (M+H) + : 441.1. HPLC: 99.59%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.78 (s, 1H), 8.75 (d, J=0.8 Hz, 1H), 8.58 (d, J=1.2 Hz, 1H), 8.42 (d, J=8.4 Hz, 1H), 8.27 (t, J=7.6 Hz, 1H), 8.09-8.07 (m, 2H), 7.76 (d, J=7.6 Hz, 1H), 7.54 (dd, J=5.6, 2.8 Hz, 1H), 4.73 (q, J=7.2 Hz, 1H), 3.08 (s, 3H), 1.75 (d, J=6.8 Hz, 3H).

Example 60. 6-(5-aminopyridin-3-yl)-N,N-dimethyl-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxamide

Synthesis of 6-(5-aminopyridin-3-yl)-N,N-dimethyl-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxamide

The preparation of 6-(5-aminopyridin-3-yl)-N,N-dimethyl-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxamide was the same as that of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-methylpicolinamide (Example 32). 32 mg, as a yellow solid, Y: 43%. ESI-MS (M+H) + : 427.1. HPLC: 99.74%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.23 (s, 1H), 8.38 (d, J=8.4 Hz, 1H), 8.37 (s, 1H), 8.23 (t, J=8.0 Hz, 1H), 8.17 (d, J=1.6 Hz, 1H), 8.03 (d, J=2.4 Hz, 1H), 7.73 (d, J=7.2 Hz, 1H), 7.65 (d, J=1.6 Hz, 1H), 7.44 (t, J=2.0 Hz, 1H), 3.26 (s, 3H), 3.09 (s, 3H).

Example 61. 6-(5-aminopyridin-3-yl)-N-methyl-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxamide

Synthesis of 6-(5-aminopyridin-3-yl)-N-methyl-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxamide

The preparation of 6-(5-aminopyridin-3-yl)-N-methyl-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxamide was the same as that of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-methylpicolinamide (Example 32). 20 mg, as a brown solid, Y: 28%. ESI-MS (M+H) + : 413.1. HPLC: 94.83%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.26 (s, 1H), 8.71 (s, 1H), 8.35 (d, J=8.4 Hz, 1H), 8.20-8.18 (m, 2H), 8.04 (d, J=2.4 Hz, 1H), 7.94 (d, J=1.2 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.45 (t, J=2.0 Hz, 1H), 3.04 (s, 3H).

Example 62. 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine

Synthesis of 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide

A solution of m-CPBA (4.7 g, 23.5 mmol, 1.2 eq, 85%) in DCM (25 mL) was added dropwise to a stirring solution of 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine (CAS #117890-55-8) (3.0 g, 19.6 mmol, 1.0 eq) in DCM (50 mL) and the resulting solution was allowed to stir at rt for 12 h. The reaction mixture was quenched with a saturated aqueous solution of Na 2 S 2 O 3 and the organic layer was separated. The aqueous phase was then extracted with DCM (3×30 mL), and the combined organic extracts were washed with aqueous NaHCO 3 , brine, dried over anhydrous Na 2 SO 4 and concentrated in vacuo to afford crude product as pale yellow solid (2.9 g, Y: 88%), which was used directly in the next step without further purification. ESI-MS (M+H) + : 170.0. 1 H NMR (400 MHz, CDCl 3 ) δ: 7.33 (d, J=7.8 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 3.31-3.13 (m, 2H), 3.12-2.96 (m, 2H), 2.31-2.16 (m, 2H).

Synthesis of 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate

In round bottom flask equipped with a condenser, 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (2.9 g, 17.2 mmol, 1.0 eq) was dissolved in acetic anhydride (10 mL) and heated at 100° C. for 4 h. The reaction mixture was allowed to cool and the solvent was removed under reduced pressure. The resulting residue was dissolved up in DCM, and washed successively with saturated aqueous solution of NaHCO 3 (20 mL) and brine. After drying over anhydrous Na 2 SO 4 , the solution was removed under reduce pressure to afford crude product 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate, which was used directly in the next step without further purification. ESI-MS (M+H) + : 212.0.

Synthesis of 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol

2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate was added to a 2 M solution of NaOH in MeOH (40 mL) and the mixture was stirred at rt for 12 h. The reaction mixture was extracted with DCM (3×40 mL), washed with brine and dried over anhydrous Na 2 SO 4 . After removing solvent under reduced pressure, the residue was purified by column chromatography (silica gel, PE/EA=4/1) to afford the compound 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol as off-white solid (1.1 g, Y: 38% for two steps). ESI-MS (M+H) + : 170.0. 1 H NMR (400 MHz, CDCl 3 ) δ: 7.53 (d, J=8.0 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 5.32-5.09 (m, 1H), 3.56 (br, 1H), 3.11-2.93 (m, 1H), 2.88-2.71 (m, 1H), 2.65-2.48 (m, 1H), 2.17-2.02 (m, 1H).

›Example 55. 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine · 3 of 3

Synthesis of 2-chloro-5H-cyclopenta[b]pyridin-7(6H)-one

To a stirred solution of oxalyl chloride (0.49 mL, 5.5 mmol, 1.1 eq) in DCM (12 mL) was slowly added DMSO (0.79 mL, 11.0 mmol, 2.2 eq) at −78° C., and the resulting mixture was stirred for 30 min at this temperature. A solution of 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (845 mg, 5.0 mmol, 1.0 eq) in DCM (10 mL) was added to this mixture slowly over 10 min, and then TEA (3.1 mL, 22.5 mmol, 4.5 eq) was added dropwise. The reaction mixture was allowed to warm slowly to rt and stirred at rt for 1 h, then quenched with water (10 mL). After extraction with DCM (3×20 mL), the organic layer was washed successively with HCl (10 mL, 1 M), saturated aqueous Na 2 CO 3 , and then brine. The organic layer was dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, PE/EA=2/1) to afford the compound 2-chloro-5H-cyclopenta[b]pyridin-7(6H)-one as off-white solid (600 mg, Y: 72%). ESI-MS (M+H) + : 168.0. 1 H NMR (400 MHz, CDCl 3 ) δ: 7.86 (d, J=8.2 Hz, 1H), 7.49 (d, J=8.2 Hz, 1H), 3.20-3.12 (m, 2H), 2.84-2.76 (m, 2H).

Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole

The preparation of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 550 mg, as a white solid, Y: 71%. ESI-MS (M+H) + : 390.2.

Synthesis of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one

6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole (550 mg, 1.41 mmol), 2-chloro-5H-cyclopenta[b]pyridin-7(6H)-one (262 mg, 1.56 mmol, 1.1 eq), Pd(PPh 3 ) 4 (162 mg, 0.14 mmol, 0.1 eq), K 2 CO 3 (389 mg, 2.82 mmol, 2.0 eq) were dissolved in 1,4-dioxane/H 2 O (1/1, 12 mL). The mixture was degassed with N 2 and heated to reflux for 4 h. The reaction mixture was cooled to rt and concentrated in vacuo. The residue was purified by column chromatography (silica gel, PE/EA=2/1) to afford the compound 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one as red solid (230 mg, Y: 41%). ESI-MS (M+H) + : 395.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.50 (s, 1H), 8.37 (dd, J=8.4, 1.5 Hz, 1H), 8.31-8.21 (m, 2H), 8.12 (d, J=8.2 Hz, 1H), 8.07-7.97 (m, 2H), 7.87 (d, J=8.4 Hz, 1H), 7.54 (d, J=7.5 Hz, 1H), 3.27-3.19 (m, 2H), 2.90-2.80 (m, 2H).

Synthesis of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one oxime

To a stirred solution of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one (120 mg, 0.3 mmol, 1.0 eq) in MeOH (10 mL) was added Hydroxyamine.HCl (CAS #5470-11-1) (42 mg, 0.6 mmol, 2.0 eq), and the resulting mixture was heated to reflux for 3 h. The reaction mixture was cooled to rt and concentrated in vacuo. The residue could be used in the next step without further purification (brown solid, 107 mg, Y: 86%). ESI-MS (M+H) + : 410.1.

Synthesis of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine

To a stirred solution of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one oxime (100 mg, 0.25 mmol, 1.0 eq) in MeOH/HOAc (1/1, 10 mL) was added Zn powder (82 mg, 1.25 mmol, 5.0 eq), and the resulting mixture was stirred at rt for 3 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was basified with aq. NaOH and purified by prep-HPLC (MeOH/H 2 O with 0.05% NH 4 OH as mobile phase from 5% to 95%) to afford the product as white solid (37 mg, Y: 38%). ESI-MS (M+H) + : 396.1. HPLC: 99.25%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.55 (s, 1H), 8.40-8.29 (m, 2H), 8.17 (t, J=8.0 Hz, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.84-7.73 (m, 2H), 7.67 (d, J=7.5 Hz, 1H), 4.39 (t, J=7.9 Hz, 1H), 3.11-3.00 (m, 1H), 3.00-2.85 (m, 1H), 2.69-2.54 (m, 1H), 1.94-1.81 (m, 1H).

Example 63. 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5,6,7,8-tetrahydroquinolin-8-amine

›Step 1. Synthesis of 2-chloro-5,6,7,8-tetrahydroquinoline 1-oxide

The preparation of 2-chloro-5,6,7,8-tetrahydroquinoline 1-oxide was the same as that of 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (Example 62). 900 mg, as a yellow solid, Y: 82%. ESI-MS (M+H) + : 184.1.

›Step 2. Synthesis of 2-chloro-5,6,7,8-tetrahydroquinolin-8-yl acetate

The preparation of 2-chloro-5,6,7,8-tetrahydroquinolin-8-yl acetate was the same as that of 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate. 500 mg, as yellow oil, Y: 45%. ESI-MS (M+H) + : 226.1. 1 H NMR (400 MHz, CD 3 OD) δ: 7.61 (d, J=7.6 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 5.81 (t, J=4.4 Hz, 1H), 3.12-2.84 (m, 1H), 2.80-2.72 (m, 1H), 2.16-2.01 (m, 5H), 1.93-1.81 (m, 2H).

›Step 3. Synthesis of 2-chloro-5,6,7,8-tetrahydroquinolin-8-ol

The preparation of 2-chloro-5,6,7,8-tetrahydroquinolin-8-ol was the same as that of 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol. 300 mg, as off-white solid, Y: 74%. ESI-MS (M+H) + : 184.1. 1 H NMR (400 MHz, CD 3 OD) δ: 7.45 (d, J=8.4 Hz, 1H), 7.15 (d, J=8.0 Hz, 1H), 4.55 (t, J=4.8 Hz, 1H), 2.76-2.59 (m, 2H), 1.95-1.80 (m, 3H), 1.75-1.62 (m, 1H).

›Step 4. Synthesis of 2-chloro-6,7-dihydroquinolin-8(5H)-one

The preparation of 2-chloro-6,7-dihydroquinolin-8(5H)-one was the same as that of 2-chloro-5H-cyclopenta[b]pyridin-7(6H)-one. 200 mg, as off-white solid, Y: 68%. ESI-MS (M+H) + : 182.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 7.93 (d, J=8.0 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 2.99 (t, J=6.0 Hz, 2H), 2.71-2.68 (m, 2H), 2.10-2.04 (m, 2H).

Step 5. Synthesis of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydroquinolin-8(5H)-one

The preparation of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydroquinolin-8(5H)-one was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one. 180 mg, as white solid, Y: 43%. ESI-MS (M+H) + : 409.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 9.44 (s, 1H), 8.62 (d, J=0.8 Hz, 1H), 8.34-8.29 (m, 2H), 8.16 (dd, J=8.4, 1.6 Hz, 1H), 8.10-8.02 (m, 3H), 7.86 (dd, J=6.0, 2.4 Hz, 1H), 3.07 (t, J=6.0 Hz, 2H), 2.79-2.75 (m, 2H), 2.17-2.11 (m, 2H).

Step 6. Synthesis of (E)-2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydroquinolin-8(5H)-one oxime

The preparation of (E)-2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydroquinolin-8(5H)-one oxime was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one oxime. 100 mg, as white solid, Y: 64%. ESI-MS (M+H) + : 424.1.

Step 7. Synthesis of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5,6,7,8-tetrahydroquinolin-8-amine

The preparation of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5,6,7,8-tetrahydroquinolin-8-amine was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine. 40 mg, as white solid, Y: 38%. ESI-MS (M+H) + : 410.1. 1 H NMR (400 MHz, CD 3 OD) δ: 9.58 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 8.24 (d, J=0.8 Hz, 1H), 8.05 (dd, J=8.4, 1.2 Hz, 1H), 8.00 (t, J=8.0 Hz, 1H), 7.85 (dd, J=8.4, 0.8 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.53 (d, J=7.2 Hz, 2H), 4.14-4.10 (m, 1H), 2.90-2.85 (m, 2H), 2.34-2.31 (m, 1H), 2.05-2.01 (m, 1H), 1.80-1.73 (m, 2H).

›Examples63

›Example 64. 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N,N-dimethylpicolinamide

Synthesis of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N,N-dimethylpicolinamide

A mixture of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)picolinic acid (100 mg, 0.30 mmol, 1.0 eq), DIPEA (116 mg, 0.90 mmol, 3.0 eq) and HATU (171 mg, 0.45 mmol, 1.5 eq) in DMF (2 mL) was stirred at rt for 20 min, then, dimethylamine (CAS #124-40-3) (1 M, in THF, 0.45 mL, 0.45 mmol, 1.5 eq) was added to the mixture. The mixture was stirred at rt for 16 h. The mixture was purified by pre-HPLC to give 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N,N-dimethylpicolinamide as a yellow solid. (25 mg, Y: 23%). ESI-MS (M+H) + : 359.1. HPLC: 97.92%., 1 H NMR (400 MHz, CD 3 OD) δ: 9.09 (s, 1H), 8.42 (s, 1H), 8.30 (d, J=1.2 Hz, 1H), 8.22 (d, J=7.6 Hz, 1H), 8.14-8.10 (m, 1H), 8.06-8.04 (m, 2H), 7.95-7.94 (m, 1H), 7.62 (dd, J=8.4, 1.6 Hz, 1H), 7.49 (d, J=7.6 Hz, 1H), 3.20 (s, 3H), 3.13 (s, 3H).

›Example 65. 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(2-hydroxyethyl)picolinamide

Synthesis of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(2-hydroxyethyl)picolinamide

The preparation of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(2-hydroxyethyl)picolinamide was the same as that of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N,N-dimethylpicolinamide. 18 mg, yellow solid. Y: 20%. ESI-MS (M+H) + : 375.1. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.02 (d, J=0.8 Hz, 1H), 8.44 (d, J=2.0 Hz, 2H), 8.31 (d, J=8.4, 0.8 Hz, 1H), 8.19-8.15 (m, 1H), 8.07-8.02 (m, 4H), 7.67 (dd, J=8.4, 1.6 Hz, 1H), 3.79 (t, J=4.8 Hz, 2H), 3.64 (t, J=4.8 Hz, 2H).

›Example 66. 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(3-hydroxypropyl)picolinamide

Synthesis of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(3-hydroxypropyl)picolinamide

The preparation of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(3-hydroxypropyl)picolinamide was the same as that of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N,N-dimethylpicolinamide. 27 mg, yellow solid. Y: 30%. ESI-MS (M+H) + : 389.1. HPLC: 97.38%. 1 H NMR (400 MHz, CD 3 OD) δ: 8.82 (s, 1H), 8.29 (s, 1H), 8.27 (s, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.99 (d, J=7.6 Hz, 1H), 7.98-7.96 (m, 1H), 7.91-7.89 (m, 2H), 7.82 (d, J=7.2 Hz, 1H), 7.50 (dd, J=8.0, 1.2 Hz, 1H), 3.54-3.47 (m, 4H), 1.75-1.71 (m, 2H).

›Example 67. 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(2-hydroxypropyl)picolinamide

Synthesis of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(2-hydroxypropyl)picolinamide

The preparation of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(2-hydroxypropyl)picolinamide was the same as that of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N,N-dimethylpicolinamide. 58 mg, yellow solid. Y: 51%. ESI-MS (M+H) + : 389.1. HPLC: 97.83%. 1 H NMR (400 MHz, CD 3 OD) δ: 8.52 (s, 1H), 8.19 (s, 1H), 8.12 (s, 1H), 7.99-7.93 (m, 2H), 7.86-7.82 (m, 2H), 7.76-7.73 (m, 2H), 7.39 (dd, J=8.4, 1.6 Hz, 1H), 3.88-3.84 (m, 1H), 3.53 (dd, J=14.0, 3.2 Hz, 1H), 3.17 (dd, J=13.6, 8.0 Hz, 1H), 1.11 (d, J=6.4 Hz, 3H).

Example 68. (6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)pyridin-2-yl)(3-hydroxyazetidin-1-yl)methanone

Synthesis of (6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)pyridin-2-yl)(3-hydroxyazetidin-1-yl)methanone

The preparation of (6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)pyridin-2-yl)(3-hydroxyazetidin-1-yl)methanone was the same as that of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N,N-dimethylpicolinamide. 22 mg, yellow solid. Y: 26%. ESI-MS (M+H) + : 387.1. HPLC: 97.48%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.06 (s, 1H), 8.42 (d, J=0.8 Hz, 1H), 8.34 (s, 1H), 8.24 (dd, J=8.4, 0.8 Hz, 1H), 8.14 (t, J=8.0 Hz, 1H), 8.06-8.04 (m, 3H), 7.81 (dd, J=7.6, 1.2 Hz, 1H), 7.65 (dd, J=8.0, 1.6 Hz, 1H), 4.70-4.62 (m, 2H), 4.59-4.50 (m, 2H), 4.07-4.03 (m, 1H).

›Example 69. 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(2-(dimethylamino)ethyl)picolinamide

Synthesis of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(2-(dimethylamino)ethyl)picolinamide

The preparation of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(2-(dimethylamino)ethyl)picolinamide was the same as that of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N,N-dimethylpicolinamide. 29 mg, yellow solid. Y: 31%. ESI-MS (M+H) + : 402.2. HPLC: 97.39%. 1 H NMR (400 MHz, CD 3 OD) δ: 8.95 (s, 1H), 8.46-8.45 (m, 2H), 8.29 (d, J=8.4 Hz, 1H), 8.22-8.17 (m, 1H), 8.08-8.05 (m, 4H), 7.67 (d, J=8.4 Hz, 1H), 3.90 (t, J=6.0 Hz, 2H), 3.43 (t, J=6.0 Hz, 2H), 3.01 (s, 6H).

›Example 70. 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(2-cyanoethyl)picolinamide

Synthesis of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(2-cyanoethyl)picolinamide

The preparation of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(2-cyanoethyl)picolinamide was the same as that of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N,N-dimethylpicolinamide. 55 mg, yellow solid. Y: 47%. ESI-MS (M+H) + : 384.1. HPLC: 96.87%. 1 H NMR (400 MHz, CD 3 OD) δ: 8.92 (s, 1H), 8.40 (s, 1H), 8.34 (d, J=1.2 Hz, 1H), 8.27 (dd, J=8.4, 0.8 Hz, 1H), 8.16 (t, J=8.0 Hz, 1H), 8.03-7.98 (m, 3H), 7.83-7.82 (m, 1H), 7.61 (dd, J=8.4, 1.2 Hz, 1H), 3.74 (t, J=6.4 Hz, 2H), 2.84 (t, J=6.4 Hz, 2H).

›Example 71. 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(3-cyanopropyl)picolinamide

Synthesis of 4-((2,4-dimethoxybenzyl)amino)butanenitrile

A mixture of 4-bromobutanenitrile (CAS #5332-06-9) (500 mg, 3.40 mmol, 1.0 eq), (2,4-dimethoxyphenyl)methanamine (CAS #20781-20-8) (1.14 g, 6.80 mmol, 2.0 eq) and Cs 2 CO 3 (2.21 g, 6.80 mmol, 2.0 eq) in ACN (10 mL) was stirred at 80° C. for 16 h. After concentration, the residue was purified by column chromatography on silica gel (PE/EA=6/1) to afford 4-((2,4-dimethoxybenzyl)amino)butanenitrile. 358 mg, as a yellow solid, Y: 45%. ESI-MS (M+H) + : 235.1. 1 H NMR (400 MHz, CD 3 OD) δ: 7.30 (d, J=8.8 Hz, 1H), 6.66 (d, J=2.4 Hz, 1H), 6.60 (dd, J=8.4, 2.4 Hz, 1H), 4.17 (s, 2H), 3.91 (s, 3H), 3.83 (s, 3H), 3.15-3.11 (m, 2H), 2.62 (t, J=7.2 Hz, 2H), 2.09-2.02 (m, 2H).

Synthesis of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(3-cyanopropyl)-N-(2,4-dimethoxybenzyl)picolinamide

The preparation of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(3-cyanopropyl)-N-(2,4-dimethoxybenzyl)picolinamide was the same as that of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N,N-dimethylpicolinamide. 62 mg, yellow solid. Y: 21%. ESI-MS (M+H) + : 548.2.

Synthesis of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(3-cyanopropyl)picolinamide

A solution of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(3-cyanopropyl)-N-(2,4-dimethoxybenzyl)picolinamide (62 mg, 0.11 mmol, 1.0 eq) in TFA (0.5 mL) was stirred at 70° C. for 0.5 h. After concentration, the residue was purified by pre-HPLC to give 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(3-cyanopropyl)picolinamide as a yellow solid. (15 mg, Y: 33%). ESI-MS (M+H) + : 398.1. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.00 (s, 1H), 8.43 (s, 1H), 8.38 (s, 1H), 8.28 (dd, J=8.4, 0.8 Hz, 1H), 8.17 (t, J=8.0 Hz, 1H), 8.067-8.05 (m, 2H), 7.99-7.97 (m, 2H), 7.64 (dd, J=8.0, 1.6 Hz, 1H), 3.59 (t, J=6.8 Hz, 2H), 2.53 (t, J=7.2 Hz, 2H), 1.98-1.94 (m, 2H).

›Example 72. N-(2-aminoethyl)-6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)picolinamide

Synthesis of N-(2-aminoethyl)-6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)picolinamide

The preparation of N-(2-aminoethyl)-6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)picolinamide was the same as that of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N,N-dimethylpicolinamide. 25 mg, yellow solid. Y: 24%. ESI-MS (M+H) + : 374.1. HPLC: 95.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 8.96 (s, 1H), 8.45 (d, J=0.4 Hz, 1H), 8.43 (d, J=1.2 Hz, 1H), 8.30 (dd, J=8.4, 0.8 Hz, 1H), 8.20 (t, J=8.0 Hz, 1H), 8.08-7.97 (m, 3H), 7.97 (s, 1H), 7.67 (dd, J=8.0, 1.2 Hz, 1H), 3.81 (t, J=6.0 Hz, 2H), 3.23 (t, J=6.0 Hz, 2H).

›Example 73. 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(cyanomethyl)picolinamide

Synthesis of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(cyanomethyl)picolinamide

The preparation of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(cyanomethyl)picolinamide was the same as that of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N,N-dimethylpicolinamide. 47 mg, yellow solid. Y: 38%. ESI-MS (M+H) + : 370.1. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 8.99 (s, 1H), 8.42 (d, J=0.8 Hz, 1H), 8.41 (d, J=1.2 Hz, 1H), 8.29 (dd, J=8.4, 0.8 Hz, 1H), 8.18 (t, J=8.0 Hz, 1H), 8.06-8.04 (m, 2H), 8.01-7.99 (m, 2H), 7.66 (dd, J=8.4, 1.6 Hz, 1H), 4.48 (s, 2H).

›Example 74. 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(2-(methylsulfonyl)ethyl)picolinamide

Synthesis of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(2-(methylsulfonyl)ethyl)picolinamide

The preparation of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(2-(methylsulfonyl)ethyl)picolinamide was the same as that of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N,N-dimethylpicolinamide. 25 mg, yellow solid. Y: 20%. ESI-MS (M+H) + : 437.1. HPLC: 96.20%. 1 H NMR (400 MHz, CD 3 OD) δ: 8.71 (s, 1H), 8.26 (d, J=0.4 Hz, 1H), 8.21 (d, J=0.4 Hz, 1H), 8.10 (dd, J=8.4, 1.2 Hz, 1H), 7.98 (t, J=8.0 Hz, 1H), 7.92-7.85 (m, 4H), 7.45 (dd, J=8.4, 1.6 Hz, 1H), 3.90-3.87 (m, 2H), 3.60-3.30 (m, 2H), 2.86 (s, 3H).

›Example 75. 3-(6-(5-aminopyridin-3-yl)imidazo[1,5-a]pyridin-3-yl)benzonitrile

Synthesis of N-((5-bromopyridin-2-yl)methyl)-3-cyanobenzamide

The preparation of N-((5-bromopyridin-2-yl)methyl)-3-cyanobenzamide was the same as that of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N,N-dimethylpicolinamide. 160 mg, yellow solid, Y: 55%. ESI-MS (M+H) + : 316.0. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.65 (d, J=2.0 Hz, 1H), 8.16 (d, J=1.6 Hz, 1H), 8.10 (dt, J=8.0, 1.2 Hz, 1H), 7.86 (dd, J=8.4, 2.8 Hz, 1H), 7.81 (dt, J=7.6, 1.2 Hz, 1H), 7.62-7.58 (m, 2H), 7.28 (d, J=8.0 Hz, 1H), 4.73 (d, J=5.2 Hz, 2H).

Synthesis of 3-(6-bromoimidazo[1,5-a]pyridin-3-yl)benzonitrile

A solution of N-((5-bromopyridin-2-yl)methyl)-3-cyanobenzamide (160 mg, 0.50 mmol, 1.0 eq) in POCl 3 (5 ml) was stirred at 90° C. for 3 h. After concentration, the residue was purified by silica gel chromatography with PE/EA (10/1) as eluent to give 3-(6-bromoimidazo[1,5-a]pyridin-3-yl)benzonitrile. 95 mg, yellow solid, Y: 63%. ESI-MS (M+H) + : 298.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.35 (d, J=0.8 Hz, 1H), 8.03 (t, J=1.2 Hz, 1H), 7.98 (dt, J=7.6, 1.2 Hz, 1H), 7.68 (dt, J=8.0, 1.2 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.56 (s, 1H), 7.38 (dd, J=9.6, 1.2 Hz, 1H), 6.81 (dd, J=9.6, 1.2 Hz, 1H).

Synthesis of 3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridin-3-yl)benzonitrile

The preparation of 3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridin-3-yl)benzonitrile was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 65 mg, as a white solid, Y: 58%. ESI-MS (M+H) + : 346.2.

Synthesis of 3-(6-(5-aminopyridin-3-yl)imidazo[1,5-a]pyridin-3-yl)benzonitrile

The preparation of 3-(6-(5-aminopyridin-3-yl)imidazo[1,5-a]pyridin-3-yl)benzonitrile was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine. 7 mg, as a yellow solid, Y: 12%. ESI-MS (M+H) + : 312.1. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 8.52 (d, J=0.8 Hz, 1H), 8.13 (s, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.98 (d, J=2.0 Hz, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.70-7.66 (m, 2H), 7.55 (s, 1H), 7.25 (t, J=2.0 Hz, 1H), 7.09 (dd, J=9.6, 1.2 Hz, 1H).

›Example 76. 6-(6-(5-aminopyridin-3-yl)imidazo[1,5-a]pyridin-3-yl)picolinonitrile

Synthesis of 6-((benzyloxy)carbonyl)picolinic acid

A mixture of pyridine-2,6-dicarboxylic acid (CAS #499-83-2) (8.12 g, 48.6 mmol, 1.0 eq) and Na 2 CO 3 (6.18 g, 58.3 mmol, 1.2 eq) in DMF (20 mL) was stirred at rt for 10 min. Then, BnBr (9.97 g, 58.3 mmol, 1.2 eq) was added into the mixture. The mixture was stirred at 60° C. for 3 h. The mixture was diluted with water (200 mL), adjusted pH=5-6 with 6 N HCl and extracted with EA (2×200 mL). The combined organic phase was washed with water (50 mL) and dried over Na 2 SO 4 . After filtration and concentration, the residue was purified by silica gel chromatography with DCM/MeOH (10/1) as eluent to give 6-((benzyloxy)carbonyl)picolinic acid as a yellow solid. 1.0 g, Y: 8%. ESI-MS (M+H) + : 258.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 8.08-8.03 (m, 2H), 7.96 (d, J=7.6 Hz, 1H), 7.50-7.49 (m, 2H), 7.43-7.36 (m, 3H), 5.40 (s, 2H).

Synthesis of benzyl 6-(chlorocarbonyl)picolinate

To a mixture of 6-((benzyloxy)carbonyl)picolinic acid (603 mg, 2.35 mmol, 1.0 eq) and DMF (cat.) in DCM (10 mL) was added (COCl) 2 (592 mg, 4.70 mmol, 2.0 eq) at rt. The mixture was stirred at rt for 2 h. After concentration, the residue was directly used for next step without further purification. 600 mg, yellow solid, Y: 93%. ESI-MS (M+H) + : 276.0.

Synthesis of benzyl 6-(((5-bromopyridin-2-yl)methyl)carbamoyl)picolinate

To a mixture of (5-bromopyridin-2-yl)methanamine (CAS #173999-23-0) (404 mg, 2.17 mmol, 1.0 eq) and TEA (438 mg, 4.34 mmol, 2.0 eq) in DCM (20 mL) was added benzyl 6-(((5-bromopyridin-2-yl)methyl)carbamoyl)picolinate (597 mg, 2.17 mmol, 1.0 eq) at rt. The mixture was stirred at rt for 2 h. After concentration, the residue was purified by silica gel chromatography with PE/EA (2/1) as eluent to give benzyl 6-(((5-bromopyridin-2-yl)methyl)carbamoyl)picolinate. 600 mg, yellow solid, Y: 65%. ESI-MS (M+H) + : 426.0.

Synthesis of benzyl 6-(6-bromoimidazo[1,5-a]pyridin-3-yl)picolinate

The preparation of benzyl 6-(6-bromoimidazo[1,5-a]pyridin-3-yl)picolinate was the same as that of 3-(6-bromoimidazo[1,5-a]pyridin-3-yl)benzonitrile. 380 mg, yellow solid, Y: 79%. ESI-MS (M+H) + : 408.0.

Synthesis of 6-(6-bromoimidazo[1,5-a]pyridin-3-yl)picolinic acid

A mixture of benzyl 6-(6-bromoimidazo[1,5-a]pyridin-3-yl)picolinate (380 mg, 0.94 mmol, 1.0 eq) and NaOH (301 mg, 7.52 mmol, 8.0 eq) in EtOH/H 2 O (10 mL/4 mL) was stirred at 60° C. for 3 h. After cooling to rt, the mixture was adjusted pH=6 with 3 N HCl and extracted with EA (3×100 mL). The combined organic phase was washed with brine (50 mL) and dried over Na 2 SO 4 . After filtration and concentration, the residue was directly used for next step without further purification. 250 mg, yellow solid, Y: 84%. ESI-MS (M+H) + : 318.0.

Synthesis of 6-(6-bromoimidazo[1,5-a]pyridin-3-yl)picolinamide

The preparation of 6-(6-bromoimidazo[1,5-a]pyridin-3-yl)picolinamide was the same as that of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N,N-dimethylpicolinamide. 240 mg, yellow solid, Y: 56%. ESI-MS (M+H) + : 317.0.

Synthesis of 6-(6-bromoimidazo[1,5-a]pyridin-3-yl)picolinonitrile

The preparation of 6-(6-bromoimidazo[1,5-a]pyridin-3-yl)picolinonitrile was the same as that of N-(5-(4-cyano-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-3-yl)-2,2,2-trifluoroacetamide. 200 mg, yellow solid, Y: 85%. ESI-MS (M+H) + : 299.0. 1 H NMR (400 MHz, CD 3 OD) δ: 10.04 (s, 1H), 8.58 (dd, J=8.4, 0.8 Hz, 1H), 7.94 (d, J=7.6 Hz, 1H), 7.70 (s, 1H), 7.64 (dd, J=7.6, 0.4 Hz, 1H), 7.52 (d, J=9.2 Hz, 1H), 7.07 (dd, J=9.2, 1.2 Hz, 1H).

Synthesis of 6-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridin-3-yl)picolinonitrile

The preparation of 6-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridin-3-yl)picolinonitrile was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 220 mg, yellow solid, Y: 71%. ESI-MS (M+H) + : 347.2

Synthesis of 6-(6-(5-aminopyridin-3-yl)imidazo[1,5-a]pyridin-3-yl)picolinonitrile

The preparation of 6-(6-(5-aminopyridin-3-yl)imidazo[1,5-a]pyridin-3-yl)picolinonitrile was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine. 13 mg, yellow solid, Y: 27%. ESI-MS (M+H) + : 313.1. HPLC: 99.55%. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 9.95 (s, 1H), 8.56 (dd, J=8.0, 0.4 Hz, 1H), 8.17 (t, J=8.0 Hz, 1H), 8.08 (d, J=2.0 Hz, 1H), 8.01-7.99 (m, 2H), 7.95 (dd, J=9.2, 0.8 Hz, 1H), 7.80 (d, J=0.8 Hz, 1H), 7.34 (dd, J=9.2, 1.2 Hz, 1H), 7.20 (t, J=2.0 Hz, 1H), 5.57 (s, 2H).

›Example 77. 6-(6-(5-aminopyridin-3-yl)imidazo[1,5-a]pyridin-3-yl)picolinamide

Synthesis of 6-(6-(5-aminopyridin-3-yl)imidazo[1,5-a]pyridin-3-yl)picolinamide

The preparation of 6-(6-(5-aminopyridin-3-yl)imidazo[1,5-a]pyridin-3-yl)picolinamide was the same as that of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)picolinamide. 8.1 mg, yellow solid, Y: 48%. ESI-MS (M+H) + : 331.1. HPLC: 95.29%. 1 H NMR (400 MHz, CD 3 OD) δ: 10.07 (s, 1H), 8.39 (d, J=8.0 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H), 8.11 (t, J=8.0 Hz, 1H), 8.05-8.01 (m, 2H), 7.84 (d, J=9.2 Hz, 1H), 7.70 (s, 1H), 7.43 (t, J=2.4 Hz, 1H), 7.33 (dd, J=9.2, 1.2 Hz, 1H).

›Example 78. 5-(3-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-3-amine

Synthesis of 6-(trifluoromethyl)picolinoyl chloride

The preparation of 6-(trifluoromethyl)picolinoyl chloride was the same as that of benzyl 6-(chlorocarbonyl)picolinate. 180 mg, yellow solid, Y: 92%. ESI-MS (M+H) + : 210.1.

Synthesis of N-((5-bromopyridin-2-yl)methyl)-6-(trifluoromethyl)picolinamide

The preparation of N-((5-bromopyridin-2-yl)methyl)-6-(trifluoromethyl)picolinamide was the same as that of benzyl 6-(((5-bromopyridin-2-yl)methyl)carbamoyl)picolinate. 140 mg, yellow solid, Y: 77%. ESI-MS (M+H) + : 360.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.73 (s, 1H), 8.67 (d, J=2.4 Hz, 1H), 8.41 (d, J=8.0 Hz, 1H), 8.08 (t, J=7.6 Hz, 1H), 7.85-7.81 (m, 2H), 7.30 (d, J=8.4 Hz, 1H), 4.78 (d, J=6.0 Hz, 2H).

Synthesis of 6-bromo-3-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,5-a]pyridine

The preparation of 6-bromo-3-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,5-a]pyridine was the same as that of 3-(6-bromoimidazo[1,5-a]pyridin-3-yl)benzonitrile. 90 mg, yellow solid, Y: 68%. ESI-MS (M+H) + : 342.1.

Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,5-a]pyridine

The preparation of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,5-a]pyridine was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 85 mg, yellow solid, Y: 65%. ESI-MS (M+H) + : 390.1.

Synthesis of 5-(3-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-3-amine

The preparation of 5-(3-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-3-amine was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine. 45 mg, yellow solid, Y: 48%. ESI-MS (M+H) + : 390.1. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 10.40 (s, 1H), 8.52 (d, J=8.4 Hz, 1H), 8.24 (d, J=2.0 Hz, 1H), 8.18 (t, J=8.0 Hz, 1H), 8.06 (d, J=2.4 Hz, 1H), 7.94-7.91 (m, 2H), 7.80-7.78 (m, 2H), 7.36 (dd, J=8.0, 1.2 Hz, 1H).

Example 79. 1-(6-(3-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)ethanamine

Synthesis of 1-(6-(3-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)ethanone

The preparation of 1-(6-(3-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)ethanone was the same as that of 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone. 200 mg, yellow solid, Y: 70%. ESI-MS (M+H) + : 381.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 10.76 (s, 1H), 8.59 (d, J=8.0 Hz, 1H), 8.06-7.97 (m, 4H), 7.83 (dd, J=9.2, 1.6 Hz, 1H), 7.74-7.69 (m, 2H), 7.61 (d, J=7.6 Hz, 1H), 2.86 (s, 3H).

Synthesis of (E)-1-(6-(3-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)ethanone oxime

The preparation of (E)-1-(6-(3-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)ethanone oxime was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one oxime. 80 mg, yellow solid, Y: 86%. ESI-MS (M+H) + : 398.1. HPLC: 95.37%. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 11.64 (br, 1H), 10.51 (d, J=0.4 Hz, 1H), 8.57 (d, J=8.0 Hz, 1H), 8.23 (t, J=8.0 Hz, 1H), 7.97-7.88 (m, 5H), 7.81-7.79 (m, 2H), 2.34 (s, 3H).

Synthesis of 1-(6-(3-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)ethanamine

The preparation of 1-(6-(3-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)ethanamine was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine. 55 mg, yellow solid, Y: 76%. ESI-MS (M+H) + : 384.2. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 10.62 (s, 1H), 8.41 (d, J=8.0 Hz, 1H), 8.07 (t, J=8.0 Hz, 1H), 7.81 (t, J=8.0 Hz, 1H), 7.74-7.73 (m, 2H), 7.70 (d, J=8.0 Hz, 2H), 7.62 (d, J=0.4 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 4.14 (q, J=6.8 Hz, 1H), 1.46 (d, J=6.8 Hz, 3H).

›Example 80. 2-(aminomethyl)-6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-4-amine

Synthesis of 2,6-dibromo-N,N-bis(4-methoxybenzyl)pyridin-4-amine

To a solution of 2,6-dibromopyridin-4-amine (CAS #39771-34-1) (2.0 g, 8.0 mmol, 1.0 eq) in DMF (10 mL) was added NaH (672 mg, 16.8 mmol, 2.1 eq) at rt. The mixture was stirred at rt for 10 min, then PMBCl (2.74 g, 17.6 mmol, 2.2 eq) was added into the mixture reaction. The mixture was stirred at rt for 3 h and diluted with water (80 mL). After filtration, the solid was directly used for next step without further purification. 3.2 g, as a white solid, Y: 86%. ESI-MS (M+H) + : 491.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 7.15 (d, J=8.4 Hz, 4H), 6.92 (d, J=8.8 Hz, 4H), 6.86 (s, 2H), 4.67 (s, 4H), 3.73 (s, 6H).

Synthesis of 4-(bis(4-methoxybenzyl)amino)-6-bromopicolinonitrile

To a solution of 2,6-dibromo-N,N-bis(4-methoxybenzyl)pyridin-4-amine (3.5 g, 7.14 mmol, 1.0 eq) in pyridine (10 mL) was added CuCN (636 mg, 7.14 mmol, 1.0 eq) at rt. The mixture was stirred at 100° C. for 16 h. After concentration, the residue was purified by silica gel column (PE/EA=10/1) to give 4-(bis(4-methoxybenzyl)amino)-6-bromopicolinonitrile as a white solid. 550 mg, Y: 19%. ESI-MS (M+H) + : 438.1 1 H NMR (400 MHz, CD 3 OD) δ: 7.05 (d, J=8.4 Hz, 4H), 6.91-6.88 (m, 6H), 4.56 (s, 4H), 3.82 (s, 6H).

Synthesis of 4-(bis(4-methoxybenzyl)amino)-6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)picolinonitrile

The preparation of 4-(bis(4-methoxybenzyl)amino)-6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)picolinonitrile was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine. 220 mg, as a yellow solid, Y: 31%. ESI-MS (M+H) + : 621.1.

Synthesis of 2-(aminomethyl)-N,N-bis(4-methoxybenzyl)-6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-4-amine

The preparation of 2-(aminomethyl)-N,N-bis(4-methoxybenzyl)-6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-4-amine was the same as that of 6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)picolinonitrile. 150 mg, as a yellow solid, Y: 89%. ESI-MS (M+H) + : 625.1. 1 H NMR (400 MHz, CD 3 OD) δ: 9.30 (s, 1H), 8.24-8.21 (m, 2H), 8.06 (t, J=8.0 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.56 (d, J=6.8 Hz, 1H), 7.10 (d, J=8.4 Hz, 4H), 7.02 (s, 1H), 6.79 (d, J=8.8 Hz, 4H), 6.68 (d, J=2.4 Hz, 1H), 4.65 (s, 4H), 3.73 (s, 2H), 3.68 (s, 6H).

Synthesis of N-((4-amino-6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methyl)-2,2,2-trifluoroacetamide

The preparation of N-((4-amino-6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methyl)-2,2,2-trifluoroacetamide was the same as that of 2-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)pyrimidine-4-carbonitrile. 60 mg, as a yellow solid, Y: 52%. ESI-MS (M+H) + : 481.1.

Synthesis of 2-(aminomethyl)-6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-4-amine

To a solution of N-((4-amino-6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methyl)-2,2,2-trifluoroacetamide (60 mg, 0.28 mmol, 1.0 eq) in MeOH (5 mL) was added K 2 CO 3 (116 mg, 0.84 mmol, 3.0 eq) at rt. The mixture was stirred at rt for 2 h. After filtration and concentration, the residue was purified by pre-HPLC (MeOH/H 2 O with 0.05% TFA as mobile phase from 5% to 95%) to give 2-(aminomethyl)-6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-4-amine as a yellow solid. 40 mg, Y: 83%. ESI-MS (M+H) + : 385.1. HPLC: 98.36%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.25 (s, 1H), 8.50 (s, 1H), 8.40 (d, J=8.4 Hz, 1H), 8.24 (t, J=8.0 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 7.77-7.73 (m, 2H), 7.11 (d, J=2.4 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 4.36 (s, 2H).

›Example 81. 2-(6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)pyridin-2-yl)acetonitrile

Synthesis of 6-bromo-1-(6-fluoropyridin-2-yl)-1H-indazole and 6-bromo-2-(6-fluoropyridin-2-yl)-2H-indazole

The preparation of 6-bromo-1-(6-fluoropyridin-2-yl)-1H-indazole and 6-bromo-2-(6-fluoropyridin-2-yl)-2H-indazole was the same as that of 6-bromo-1-(6-methylpyridin-2-yl)-1H-indazole. 600 mg, as a yellow solid, Y: 65%. The mixture of 6-bromo-1-(6-fluoropyridin-2-yl)-1H-indazole and 6-bromo-2-(6-fluoropyridin-2-yl)-2H-indazole was difficult to be separated and was directly used for next step. ESI-MS (M+H) + : 292.0, 294.0.

Synthesis of tert-butyl 2-(6-(6-bromo-1H-indazol-1-yl)pyridin-2-yl)-2-cyanoacetate

The preparation of tert-butyl 2-(6-(6-bromo-1H-indazol-1-yl)pyridin-2-yl)-2-cyanoacetate and tert-butyl 2-(6-(6-bromo-2H-indazol-2-yl)pyridin-2-yl)-2-cyanoacetate was the same as that of 6-bromo-1-(6-methylpyridin-2-yl)-1H-indazole. The mixture of tert-butyl 2-(6-(6-bromo-1H-indazol-1-yl)pyridin-2-yl)-2-cyanoacetate and tert-butyl 2-(6-(6-bromo-2H-indazol-2-yl)pyridin-2-yl)-2-cyanoacetate was purified by silica gel chromatography with PE/EA (5/1) as eluent to give tert-butyl 2-(6-(6-bromo-1H-indazol-1-yl)pyridin-2-yl)-2-cyanoacetate as a yellow solid (150 mg, Y: 31%) and PE/EA (1/1) as eluent to give tert-butyl 2-(6-(6-bromo-2H-indazol-2-yl)pyridin-2-yl)-2-cyanoacetate as a yellow solid (80 mg, Y: 17%). ESI-MS (M+H) + : 413.0, 415.0.

Synthesis of 2-(6-(6-bromo-1H-indazol-1-yl)pyridin-2-yl)acetonitrile

A solution of tert-butyl 2-(6-(6-bromo-1H-indazol-1-yl)pyridin-2-yl)-2-cyanoacetate (150 mg, 0.48 mmol, 1.0 eq) in TFA (1 mL)/DCM (3 mL) was stirred at rt for 16 h. After concentration, the residue was purified by pre-HPLC (CH 3 CN/H 2 O with 0.05% TFA as mobile phase from 5% to 95%) to give 2-(6-(6-bromo-1H-indazol-1-yl)pyridin-2-yl)acetonitrile as a yellow solid. 60 mg, Y: 40%. ESI-MS (M+H) + : 313.0, 315.0.

Synthesis of 2-(6-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)pyridin-2-yl)acetonitrile

The preparation of 2-(6-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)pyridin-2-yl)acetonitrile was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 36 mg, as a yellow solid, Y: 52%. ESI-MS (M+H) + : 361.1.

Synthesis of 2-(6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)pyridin-2-yl)acetonitrile

The preparation of 2-(6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)pyridin-2-yl)acetonitrile was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine. 14 mg, as a yellow solid, Y: 21%. ESI-MS (M+H) + : 327.1. HPLC: 100.00% 1 H NMR (400 MHz, CDCl 3 ) δ: 9.30 (s, 1H), 8.42 (d, J=1.6 Hz, 1H), 8.23 (s, 1H), 8.10 (d, J=2.0 Hz, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.86-7.82 (m, 2H), 7.74 (t, J=6.0 Hz, 1H), 7.63 (dd, J=8.4, 1.2 Hz, 1H), 7.09 (d, J=7.6 Hz, 1H), 4.06 (s, 2H), 3.92 (br, 2H).

›Example 82. 2-(6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)pyridin-2-yl)acetic acid

Synthesis of 2-(6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)pyridin-2-yl)acetic acid

The preparation of 2-(6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)pyridin-2-yl)acetic acid was the same as that of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)picolinic acid. 3.0 mg, as a yellow solid, Y: 5%. ESI-MS (M+H) + : 346.2. HPLC: 100.00% 1 H NMR (400 MHz, CD 3 OD) δ: 9.35 (s, 1H), 8.45 (s, 1H), 8.37 (s, 1H), 8.11 (s, 1H), 8.03-7.93 (m, 4H), 7.66 (dd, J=8.4, 0.8 Hz, 1H), 7.28 (d, J=7.6 Hz, 1H), 3.97 (s, 2H).

Example 209, 83 and 84. 1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

Synthesis of 1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone

The preparation of 1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine. 502 mg, as a white solid, Y: 80%. ESI-MS (M+H) + : 383.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.61 (s, 1H), 8.25 (d, J=8.4 Hz, 1H), 8.21 (s, 1H), 8.08-8.01 (m, 2H), 8.00-7.87 (m, 3H), 7.84 (d, J=8.4 Hz, 1H), 7.49 (d, J=7.5 Hz, 1H), 2.83 (s, 3H).

Synthesis of (E)-1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime

The preparation of (E)-1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one oxime. 631 mg, as white solid, Y: 76%. ESI-MS (M+H) + : 398.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 11.62 (s, 1H), 9.54 (s, 1H), 8.60 (d, J=0.6 Hz, 1H), 8.36-8.25 (m, 2H), 8.11 (dd, J=8.5, 1.4 Hz, 1H), 8.08-8.00 (m, 2H), 7.96 (t, J=7.7 Hz, 1H), 7.89 (dd, J=7.7, 0.9 Hz, 1H), 7.84 (d, J=7.0 Hz, 1H), 2.39 (s, 3H).

Synthesis of 1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

A solution of (E)-1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime (500 mg, 1.26 mmol, 1.0 eq) in NH 4 OH/MeOH/THF solution (1/5/5, 33 mL) was added Pd/C (50 mg). The mixture was stirred at rt under H 2 atmosphere for 48 h. The mixture was filtered and the filtrate was concentrated in vacuo to afford target compound 1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine as a white solid (410 mg, Y: 85%). ESI-MS (M+H) + : 384.1. HPLC: 100.00% 1 H NMR (400 MHz, CD 3 OD) δ: 9.56 (s, 1H), 8.30 (s, 1H), 8.28 (d, J=8.8 Hz, 1H), 8.11 (t, J=8.0 Hz, 1H), 8.00 (dd, J=8.4, 1.2 Hz, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.83-7.77 (m, 2H), 7.61 (d, J=7.6 Hz, 1H), 7.30 (dd, J=7.6, 1.6 Hz, 1H), 4.14 (q, J=6.8 Hz, 1H), 1.46 (d, J=6.4 Hz, 3H).

SFC (Chiralpak IC column, 4.6*250 mm 5 m, MeOH with 0.5% DEA, CO 2 flow rate=2.1, Co-Solvent Flow Rate=0.9, Detection wavelength=230 nm) t R =5.25 min, 6.22 min.

Example 83. 1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine—Isomer a

80 mg, as a yellow solid, ESI-MS (M+H) + : 384.2, HPLC: 100.00%. t R =5.25 min (Chiral HPLC). 1 H NMR (400 MHz, CD 3 OD) δ: 9.58 (s, 1H), 8.32 (d, J=0.8 Hz, 1H), 8.31 (d, J=8.8 Hz, 1H), 8.13 (t, J=8.0 Hz, 1H), 8.03 (dd, J=8.4, 1.2 Hz, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.84-7.81 (m, 2H), 7.64 (d, J=7.6 Hz, 1H), 7.33 (dd, J=7.2, 1.2 Hz, 1H), 4.17 (q, J=6.4 Hz, 1H), 1.49 (d, J=6.4 Hz, 3H).

Example 84. 1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine—Isomer b

80 mg, as a yellow solid, ESI-MS (M+H) + : 384.2, HPLC: 100.00%. t R =6.22 min (Chiral HPLC). 1 H NMR (400 MHz, CD 3 OD) δ: 9.56 (d, J=0.4 Hz, 1H), 8.30 (d, J=0.8 Hz, 1H), 8.28 (d, J=8.4 Hz, 1H), 8.11 (t, J=8.0 Hz, 1H), 8.01 (dd, J=8.8, 2.0 Hz, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.83-7.77 (m, 2H), 7.61 (d, J=7.6 Hz, 1H), 7.31 (dd, J=7.2, 1.6 Hz, 1H), 4.14 (q, J=6.8 Hz, 1H), 1.46 (d, J=6.4 Hz, 3H).

›Example 85. 3-amino-5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)benzoic acid

Synthesis of methyl 3-nitro-5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)benzoate

The preparation of methyl 3-nitro-5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)benzoate was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine. 163 mg, as a yellow solid, Y: 50%. ESI-MS (M+H) + : 443.1.

Synthesis of methyl 3-amino-5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)benzoate

A mixture of methyl 3-nitro-5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)benzoate (150 mg, 0.34 mmol, 1.0 eq), Raney Ni (30 mg) in MeOH (10 mL) was stirred at rt for 2 h under H 2 atmosphere. After filtration and concentration, the residue was directly used in the next step without further purification. 126 mg, as a white solid, Y: 90%. ESI-MS (M+H) + : 413.1.

Synthesis of 3-amino-5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)benzoic acid

A mixture of 3-amino-5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)benzoate (126 mg, 0.3 mmol, 1.0 eq), LiOH (37 mg, 1.5 mmol, 5.0 eq) in MeOH (5 mL)/MeOH (1 mL) was stirred at rt for 3 h. Then, pH value of the mixture was adjusted to 5-6. After filtration, 110 mg of 3-amino-5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)benzoic acid as a white solid was obtained. Y: 90%, ESI-MS (M+H) + : 399.1. 1 H NMR (400 MHz, CD 3 OD) δ: 9.11 (s, 1H), 8.31-8.25 (m, 3H), 8.10 (t, J=8.0 Hz, 1H), 7.92-7.87 (m, 2H), 7.75-7.74 (m, 1H), 7.60-7.57 (m, 2H).

›Example 86. 3-amino-N-(cyanomethyl)-5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)benzamide

Synthesis of 3-amino-N-(cyanomethyl)-5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)benzamide

The preparation of 3-amino-N-(cyanomethyl)-5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)benzamide was the same as that of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N,N-dimethylpicolinamide. 80 mg, as a white solid, Y: 70%. ESI-MS (M+H) + : 413.1. HPLC: 97.40%. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 9.13 (t, J=5.2 Hz, 1H), 8.96 (s, 1H), 8.59 (s, 1H), 8.34-8.31 (m, 2H), 8.03 (d, J=8.4 Hz, 1H), 7.84 (dd, J=6.0, 2.2 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.34 (s, 1H), 7.12 (s, 1H), 7.07 (s, 1H), 5.56 (s, 2H), 4.31 (d, J=5.6 Hz, 2H).

Example 87. 6-amino-N-(cyanomethyl)-4-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)picolinamide

Synthesis of 4-bromo-6-(methoxycarbonyl)picolinic acid

To a solution of dimethyl 4-bromopyridine-2,6-dicarboxylate (CAS #162102-79-6) (2.40 g, 8.8 mmol, 1.0 eq) in MeOH/DCM solution (10/1, 88 mL) was added KOH (896 mg, 8.0 mmol, 0.9 eq) at rt. The reaction mixture was stirred at rt for 3 h and Et 2 O (80 mL) was added thereto. The resulting white solid was filtered and then redissolved in water (50 mL). 2 M HCl solution (8 mL) was added. The mixture extracted with DCM (2×50 mL). The combined organic layers were washed with brine and dried over anhydrous Na 2 SO 4 . After removing the solvent, the residue as brown solid was used directly in the next step without further purification (1.0 g, Y: 44%). ESI-MS (M+H) + : 259.9. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.56 (d, J=1.7 Hz, 1H), 8.50 (d, J=1.7 Hz, 1H), 4.04 (s, 3H).

Synthesis of methyl 4-bromo-6-((tert-butoxycarbonyl)amino)picolinate

To a mixture of 4-bromo-6-(methoxycarbonyl)picolinic acid (1.25 g, 3.84 mmol, 1.0 eq), TEA (0.6 mL, 4.61 mmol, 1.2 eq), t-BuOH (8 mL) and 1,4-dioxane (20 mL) was added diphenylphosphoryl azide (1.27 g, 4.61 mmol, 1.2 eq) at rt. The reaction mixture was heated to reflux for 3 h and concentrated in vacuo. The residue was purified by silica gel column chromatography with PE/EA (6/1) as eluent to give methyl 4-bromo-6-((tert-butoxycarbonyl)amino)picolinate as a brown solid (793 mg, Y: 50%). ESI-MS (M+H) + : 331.0. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.42 (d, J=1.4 Hz, 1H), 7.93 (d, J=1.6 Hz, 1H), 7.65 (s, 1H), 3.98 (s, 3H), 1.51 (s, 9H).

Synthesis of methyl 6-((tert-butoxycarbonyl)amino)-4-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)picolinate

The preparation of methyl 6-((tert-butoxycarbonyl)amino)-4-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)picolinate was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine. 320 mg, as a white solid, Y: 43%. ESI-MS (M+H) + : 513.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 10.38 (s, 1H), 9.22 (s, 1H), 8.65 (s, 1H), 8.56 (d, J=1.3 Hz, 1H), 8.33 (d, J=6.1 Hz, 2H), 8.11 (dd, J=9.9, 4.8 Hz, 2H), 7.88-7.79 (m, 2H), 3.92 (s, 3H), 1.50 (s, 9H).

Synthesis of methyl 6-amino-4-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)picolinate

To a solution of methyl 6-((tert-butoxycarbonyl)amino)-4-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)picolinate (320 mg, 0.6 mmol, 1.0 eq) in DCM (10 mL) was added TFA (0.6 mL) at rt. The reaction mixture was stirred at rt for 2 h and then concentrated in vacuo. The residue as a yellow solid could be used directly in the next step without further purification (200 mg, Y: 78%). ESI-MS (M+H) + : 414.1.

Synthesis of 6-amino-4-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)picolinic acid

The preparation of 6-amino-4-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)picolinic acid was the same as that of 3-amino-5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)benzoic acid. 160 mg, as a white solid, Y: 83%. ESI-MS (M+H) + : 399.1. HPLC: 100.00%. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 9.11 (s, 1H), 8.65 (s, 1H), 8.36-8.30 (m, 2H), 8.11 (d, J=8.4 Hz, 1H), 7.87 (dd, J=5.1, 3.1 Hz, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.62 (s, 1H), 7.20 (s, 1H).

Synthesis of 6-amino-N-(cyanomethyl)-4-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)picolinamide

The preparation of 6-amino-N-(cyanomethyl)-4-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)picolinamide was the same as that of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N,N-dimethylpicolinamide. 64 mg, as a white solid, Y: 34%. ESI-MS (M+H) + : 437.1. HPLC: 93.37%. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.25 (s, 1H), 8.32-8.24 (m, 3H), 8.03 (t, J=8.0 Hz, 1H), 7.96 (d, J=1.3 Hz, 1H), 7.87 (d, J=8.3 Hz, 1H), 7.65 (dd, J=8.4, 1.4 Hz, 1H), 7.55 (d, J=7.5 Hz, 1H), 7.05 (d, J=1.3 Hz, 1H), 4.66 (br, 2H), 4.37 (d, J=6.0 Hz, 2H).

Example 88. 3-amino-N-(2-aminoethyl)-5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)benzamide

Synthesis of 3-amino-N-(2-aminoethyl)-5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)benzamide

The preparation of 3-amino-N-(2-aminoethyl)-5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)benzamide was the same as that of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N,N-dimethylpicolinamide. 15 mg, as a white solid, Y: 42%. ESI-MS (M+H) + : 441.2. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.10 (s, 1H), 8.26 (s, 1H), 8.24 (d, J=8.4 Hz, 1H), 8.08 (t, J=8.0 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.50 (dd, J=8.8, 1.2 Hz, 1H), 7.40 (s, 1H), 7.13 (d, J=1.6 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 3.43 (t, J=2.4 Hz, 2H), 2.85 (t, J=2.4 Hz, 2H).

›Example 89. 1-(3-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)phenyl)ethanamine

Synthesis of 1-(3-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)phenyl)ethanone

The preparation of 1-(3-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)phenyl)ethanone was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine. 320 mg, as a white solid, Y: 60%. ESI-MS (M+H) + : 382.1.

Synthesis of (Z)-1-(3-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)phenyl)ethanone oxime

The preparation of (Z)-1-(3-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)phenyl)ethanone oxime was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one oxime. 150 mg, as a yellow solid, Y: 72%. ESI-MS (M+H) + : 397.1.

Synthesis of 1-(3-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)phenyl)ethanamine

The preparation of 1-(3-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)phenyl)ethanamine was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine. 60 mg, as a white solid, Y: 41%. ESI-MS (M+H) + : 383.1. HPLC: 95.27%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.06 (s, 1H), 8.25-8.21 (m, 2H), 8.09-8.05 (m, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.68 (s, 1H), 7.60-7.53 (m, 3H), 7.41-7.35 (m, 2H), 4.07 (q, J=6.8 Hz, 1H), 1.43 (d, J=6.8 Hz, 3H).

›Example 90. 1-(5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-3-yl)ethanamine

Synthesis of 1-(5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-3-yl)ethanone

The preparation of 1-(5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-3-yl)ethanone was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine. 140 mg, as yellow solid, Y: 76%. ESI-MS (M+H) + : 383.1.

Synthesis of N-(2,4-dimethoxybenzyl)-1-(5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-3-yl)ethanamine

The preparation of N-(2,4-dimethoxybenzyl)-1-(5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-3-yl)ethanamine was the same as that of N-(4-methoxybenzyl)-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine. 140 mg, as yellow solid, Y: 71%. ESI-MS (M+H) + : 534.2.

Synthesis of 1-(5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-3-yl)ethanamine

The preparation of 1-(5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-3-yl)ethanamine was the same as that of 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine. 40 mg, as a yellow solid, Y: 42%. ESI-MS (M+H) + : 384.1, HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.25 (s, 1H), 9.02 (d, J=2.4 Hz, 1H), 8.73 (d, J=2.4 Hz, 1H), 8.44 (s, 1H), 8.39-8.34 (m, 2H), 8.22 (t, J=8.0 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.73 (t, J=8.2 Hz, 2H), 4.72 (q, J=6.6 Hz, 1H), 1.80 (d, J=6.8 Hz, 3H).

›Example 91. 1-(4-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

Synthesis of 4-bromo-N-methoxy-N-methylpicolinamide

To a solution of 4-bromopicolinic acid (CAS #30766-03-1) (1.01 g, 5.0 mmol, 1.0 eq), methoxymethylamine HCl salt (536 mg, 5.5 mmol, 1.1 eq) and N-methylmorpholine (2.02 g, 20 mmol, 4.0 eq) in DCM (20 mL) were added EDCI (959 mg, 5 mmol, 1.0 eq) and HOBT (676 mg, 5 mmol, 1.0 eq) in portions at 0° C. The reaction mixture was warmed up to rt and stirred for 12 h. The mixture was extracted with DCM (3×30 mL) and washed with brine. The combined organic phase was dried over Na 2 SO 4 and concentrated in vacuo. The crude mixture was purified by silica gel chromatography with PE/EA (10/1) as eluent to give 4-bromo-N-methoxy-N-methylpicolinamide. 545 mg, as colorless oil, Y: 44%. ESI-MS (M+H) + : 245.0.

Synthesis of 1-(4-bromopyridin-2-yl)ethanone

To a solution of 4-bromo-N-methoxy-N-methylpicolinamide (548 mg, 2.2 mmol, 1.0 eq) in anhydrous THF (25 mL) cooled to −78° C. was slowly added MeMgBr (3 M in THF, 1.43 mL, 4.4 mmol, 2.0 eq). After stirring at −78° C. for 2 h, the reaction mixture was quenched with aq. NH 4 Cl and extracted with EA (3×30 mL). The combined organic phase was dried over Na 2 SO 4 and concentrated in vacuo. The crude mixture was purified by silica gel chromatography with PE/EA (2/1) as eluent to give 1-(4-bromopyridin-2-yl)ethanone. 330 mg, as white solid, Y: 75%. ESI-MS (M+H) + : 200.0. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.50 (d, J=5.0 Hz, 1H), 8.20 (s, 1H), 7.74-7.51 (m, 1H), 2.72 (s, 3H).

Synthesis of 1-(4-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone

The preparation of 1-(4-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine. 280 mg, as pale yellow solid, Y: 52%. ESI-MS (M+H) + : 383.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.31 (s, 1H), 8.80 (d, J=5.1 Hz, 1H), 8.44 (d, J=1.7 Hz, 1H), 8.30-8.23 (m, 2H), 8.03 (t, J=7.9 Hz, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.85 (dd, J=5.1, 1.8 Hz, 1H), 7.68 (dd, J=8.3, 1.2 Hz, 1H), 7.55 (d, J=7.5 Hz, 1H), 2.81 (s, 3H).

Synthesis of N-(2,4-dimethoxybenzyl)-1-(4-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

The preparation of N-(2,4-dimethoxybenzyl)-1-(4-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine was the same as that of N-(4-methoxybenzyl)-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine. 200 mg, as brown oil, Y: 68%. ESI-MS (M+H) + : 534.2.

Synthesis of 1-(4-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

The preparation of 1-(4-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine was the same as that of 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine. 38 mg, as a white solid, Y: 35%. ESI-MS (M+H) + : 384.1, HPLC: 96.56%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.20 (s, 1H), 8.65 (d, J=5.2 Hz, 1H), 8.32 (s, 1H), 8.26 (d, J=8.5 Hz, 1H), 8.11 (t, J=8.0 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.75 (s, 1H), 7.69-7.64 (m, 2H), 7.61 (d, J=7.5 Hz, 1H), 4.59 (q, J=6.9 Hz, 1H), 1.63 (d, J=6.9 Hz, 3H).

›Example 92. 6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrazine-2-carbonitrile

Synthesis of 6-(6-bromopyrazin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole

The preparation of 6-(6-bromopyrazin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine. 300 mg, as a yellow solid, Y: 31%. ESI-MS (M+H) + : 419.9. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.57 (s, 1H), 8.97 (s, 1H), 8.79 (s, 1H), 8.30-8.28 (m, 2H), 8.07-8.04 (m, 2H), 7.93 (d, J=8.4 Hz, 1H), 7.58-7.55 (m, 1H).

Synthesis of 6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrazine-2-carbonitrile

A mixture of 6-(6-bromopyrazin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole (150 mg, 0.36 mmol, 1.0 eq), TBAF (281 mg, 1.08 mmol, 3.0 eq), TMSCN (107 mg, 1.08 mmol, 3.0 eq) in DMF (3 mL) was stirred at 100° C. for 1 h. After cooling to rt, the mixture was purified by pre-HPLC (MeOH/H 2 O with 0.05% NH 4 OH as mobile phase from 5% to 95%) to give 6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrazine-2-carbonitrile as a white solid. 50 mg, Y: 38%. ESI-MS (M+H) + : 367.1. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.61 (s, 1H), 9.48 (d, J=1.6 Hz, 1H), 9.36 (d, J=1.6 Hz, 1H), 8.69 (d, J=0.8 Hz, 1H), 8.34-8.33 (m, 2H), 8.23 (dd, J=9.2, 1.6 Hz, 1H), 8.16 (dd, J=9.2, 0.4 Hz, 1H), 7.90-7.87 (m, 1H).

›Example 93. (6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrazin-2-yl)methanamine

Synthesis of (6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrazin-2-yl)methanamine

A mixture of 6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrazine-2-carbonitrile (45 mg, 0.12 mmol, 1.0 eq) and Pd/C (5 mg) in THF/NH 3 .H 2 O (2 mL/0.5 mL) was stirred at rt under H 2 for 1 h. After filtration and concentration, the crude product was purified by pre-HPLC (MeOH/H 2 O with 0.05% NH 4 OH as mobile phase from 5% to 95%) to give (6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrazin-2-yl)methanamine as a white solid. 10 mg, Y: 22%. ESI-MS (M+H) + : 371.1. HPLC: 98.10%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.57 (s, 1H), 9.17 (s, 1H), 8.79 (s, 1H), 8.41 (s, 1H), 8.37 (d, J=8.4 Hz, 1H), 8.20 (t, J=8.0 Hz, 1H), 8.11 (dd, J=8.4, 1.2 Hz, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 4.18 (s, 2H).

›Example 94. 4-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidine-2-carbonitrile

Synthesis of 6-(2-chloropyrimidin-4-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole

The preparation of 6-(2-chloropyrimidin-4-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine. 390 mg, as a white solid, Y: 74%. ESI-MS (M+H) + : 376.0.

Synthesis of 4-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidine-2-carbonitrile

The preparation of 4-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidine-2-carbonitrile was the same as that of 6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrazine-2-carbonitrile. 40 mg, as a white solid, Y: 27%. ESI-MS (M+H) + : 367.1. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.76 (s, 1H), 9.15 (d, J=5.6 Hz, 1H), 8.68 (s, 1H), 8.47 (d, J=5.2 Hz, 1H), 8.34 (d, J=3.6 Hz, 2H), 8.22 (dd, J=8.4, 1.6 Hz, 1H), 8.15 (d, J=8.4 Hz, 1H), 7.90-7.88 (m, 1H).

›Example 95. (4-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-2-yl)methanamine

Synthesis of (4-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-2-yl)methanamine

The preparation of (4-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-2-yl)methanamine was the same as that of (6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrazin-2-yl)methanamine. 23 mg, as a white solid, Y: 28%. ESI-MS (M+H) + : 371.1. HPLC: 96.68%. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.69 (s, 1H), 8.74 (d, J=4.8 Hz, 1H), 8.30 (s, 1H), 8.26 (d, J=8.4 Hz, 1H), 8.10-8.07 (m, 2H), 7.89 (dd, J=8.4, 0.4 Hz, 1H), 7.83 (d, J=5.2 Hz, 1H), 7.63 (d, J=7.2 Hz, 1H), 4.06 (s, 2H).

›Example 96. 6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrazin-2-amine

Synthesis of 6-bromo-N-(2,4-dimethoxybenzyl)pyrazin-2-amine

A mixture of (2,4-dimethoxyphenyl)methanamine (CAS #20781-20-8) (668 mg, 4.0 mmol, 1.0 eq), K 2 CO 3 (1.1 g, 8.0 mmol, 2.0 eq) and 2,6-dibromopyrazine (CAS #23229-25-6) (1.42 g, 6.0 mmol, 1.5 eq) in DMF (10 mL) was stirred at 120° C. for 1.5 h. After cooling to rt, the mixture was poured into water (60 mL) and extracted with EA (2×60 mL). The combined organic phase was washed with brine (60 mL) and dried over Na 2 SO 4 . After filtration and concentration, the residue was purified by silica gel chromatography with PE/EA (2/1) as eluent to give 6-bromo-N-(2,4-dimethoxybenzyl)pyrazin-2-amine. 300 mg, as a yellow solid, Y: 23%. ESI-MS (M+H) + : 324.0. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.06 (s, 1H), 7.69 (s, 1H), 7.19 (d, J=8.4 Hz, 1H), 6.48-6.42 (m, 3H), 4.44 (s, 2H), 3.84 (s, 3H), 3.79 (s, 3H).

Synthesis of N-(2,4-dimethoxybenzyl)-6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrazin-2-amine

The preparation of N-(2,4-dimethoxybenzyl)-6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrazin-2-amine was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine. 250 mg, as a yellow solid, Y: 54%. ESI-MS (M+H) + : 507.2.

Synthesis of 6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrazin-2-amine

The preparation of 6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrazin-2-amine was the same as that of 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine. 32 mg, as a yellow solid, Y: 18%. ESI-MS (M+H) + : 357.1, HPLC: 93.27%. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 9.28 (d, J=0.8 Hz, 1H), 8.54-8.53 (m, 2H), 8.30-8.28 (m, 2H), 8.04 (d, J=1.6 Hz, 1H), 7.96 (d, J=0.8 Hz, 2H), 7.84-7.82 (m, 1H), 6.77 (br, 2H).

›Example 97. 6-(6-(pyrrolidin-2-yl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole

Synthesis of 2-bromo-6-(3,4-dihydro-2H-pyrrol-5-yl)pyridine

To a solution of ethyl 6-bromopicolinate (CAS #21190-88-5) (1.0 g, 4.3 mmol, 1.0 eq) and N-vinylpyrrolidinone (533 mg, 4.8 mmol, 1.1 eq) in 30 mL of THF was added NaH (3.44 g, 8.6 mmol, 60% dispersion in mineral oil, 2.0 eq) in one portion. The mixture was refluxed for 2 h and then cooled to rt. Conc. HCl (10 mL) diluted with 20 mL of H 2 O was added thereto and the mixture was heated under reflux for 12 h. The solution was made basic with concentrated aqueous NaOH (ice-bath cooling), and then extracted with DCM (2×40 mL). The organics were washed with brine (20 mL), dried over Na 2 SO 4 and concentrated in vacuo. The crude mixture was purified by silica gel chromatography with PE/EA (4/1) as eluent to give 2-bromo-6-(3,4-dihydro-2H-pyrrol-5-yl)pyridine. 360 mg, as off-white solid, Y: 29%. ESI-MS (M+H) + : 225.0. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.08 (d, J=7.6 Hz, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.51 (d, J=7.5 Hz, 1H), 4.18-4.08 (m, 2H), 3.15-3.01 (m, 2H), 2.10-1.99 (m, 2H).

Synthesis of 2-bromo-6-(pyrrolidin-2-yl)pyridine

To a solution of 2-bromo-6-(3,4-dihydro-2H-pyrrol-5-yl)pyridine (360 mg, 1.6 mmol, 1.0 eq) in MeOH/HOAc (20 mL, 4/1) was added NaBH 4 (152 mg, 4.0 mmol, 2.5 eq) at −78° C. After warming to rt, most of the solvent was removed with a rotary evaporator. The residue was purified by silica gel chromatography with PE/EA (2/1) as eluent to give 2-bromo-6-(pyrrolidin-2-yl)pyridine. 298 mg, as white solid, Y: 82%. ESI-MS (M+H) + : 226.0.

Synthesis of tert-butyl 2-(6-bromopyridin-2-yl)pyrrolidine-1-carboxylate

To a solution of 2-bromo-6-(pyrrolidin-2-yl)pyridine (250 mg, 1.1 mmol, 1.0 eq) in 10 mL of DCM was added (Boc) 2 O (1.2 g, 5.5 mmol, 5.0 eq). The reaction mixture was stirred at rt for 12 h and then concentrated in vacuo. The residue was purified by silica gel chromatography with PE/EA (10/1) as eluent to give tert-butyl 2-(6-bromopyridin-2-yl)pyrrolidine-1-carboxylate. 330 mg, as white solid, Y: 90%. ESI-MS (M+H) + : 327.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 7.54-7.44 (m, 1H), 7.34 (d, J=7.7 Hz, 1H), 7.13 (d, J=7.7 Hz, 1H), 4.89-4.78 (m, 1H), 3.68-3.54 (m, 2H), 2.45-2.31 (m, 1H), 2.04-1.95 (m, 1H), 1.93-1.83 (m, 2H), 1.23 (s, 9H).

Synthesis of tert-butyl 2-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)pyrrolidine-1-carboxylate

The preparation of tert-butyl 2-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)pyrrolidine-1-carboxylate was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine. 240 mg, as off-white solid, Y: 47%. ESI-MS (M+H) + : 510.2. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.57 (s, 1H), 8.33-8.20 (m, 2H), 8.09 (d, J=8.4 Hz, 1H), 8.01 (t, J=8.0 Hz, 1H), 7.85 (d, J=8.3 Hz, 1H), 7.81-7.70 (m, 2H), 7.54 (d, J=7.5 Hz, 1H), 7.22-7.13 (m, 1H), 5.01 (dd, J=8.0, 4.0 Hz, 1H), 3.78-3.60 (m, 2H), 2.50-2.39 (m, 1H), 2.26-2.13 (m, 1H), 1.98-1.87 (m, 2H), 1.22 (s, 9H).

Synthesis of 6-(6-(pyrrolidin-2-yl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole

To a solution of tert-butyl 2-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)pyrrolidine-1-carboxylate (255 mg, 0.5 mmol, 1.0 eq) in 10 mL of DCM was added TFA (0.55 mL, 7.5 mmol, 15 eq). The mixture was stirred at rt for 12 h and then concentrated in vacuo. The residue was purified by pre-HPLC (ACN/H 2 O with 0.05% TFA as mobile phase from 5% to 95%) to afford the product 6-(6-(pyrrolidin-2-yl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole. 220 mg, as white solid, Y: 84%. ESI-MS (M+H) + : 410.2. HPLC: 97.60%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.11 (s, 1H), 8.07 (d, J=8.8 Hz, 1H), 8.03-7.96 (m, 2H), 7.95-7.83 (m, 2H), 7.76-7.65 (m, 2H), 7.50-7.34 (m, 2H), 4.94 (t, J=7.3 Hz, 1H), 3.67-3.48 (m, 2H), 2.68-2.53 (m, 1H), 2.29-2.11 (m, 3H).

Example 98. 6-(6-(1-methylpyrrolidin-2-yl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole

Synthesis of 6-(6-(1-methylpyrrolidin-2-yl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole

To a mixture of 6-(6-(pyrrolidin-2-yl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole (125 mg, 0.30 mmol) and HCHO (aq., excess) in MeOH (30 mL) was added NaBH(OAc) 3 (318 mg, 1.50 mmol, 5.0 eq) at rt. The mixture was stirred at rt for 2 h. After concentration, the residue was purified by pre-HPLC (MeCN/H 2 O with 0.05% TFA as mobile phase from 5% to 95%) to give 6-(6-(1-methylpyrrolidin-2-yl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole as a pale yellow solid (80 mg, Y: 62%). ESI-MS (M+H) + : 424.2. HPLC: 98.13%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.17 (s, 1H), 8.17 (s, 1H), 8.09-8.00 (m, 2H), 8.01-7.87 (m, 2H), 7.82-7.70 (m, 2H), 7.54-7.42 (m, 2H), 4.71 (t, J=8.1 Hz, 1H), 4.01-3.87 (m, 1H), 3.47-3.35 (m, 1H), 2.96 (s, 3H), 2.75-2.62 (m, 1H), 2.40-2.21 (m, 3H).

›Example 99. 1-(6-(3-(6-methylpyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)ethanamine

Synthesis of N-((5-bromopyridin-2-yl)methyl)-6-methylpicolinamide

The preparation of N-((5-bromopyridin-2-yl)methyl)-6-methylpicolinamide was the same as that of benzyl 6-(((5-bromopyridin-2-yl)methyl)carbamoyl)picolinate. 420 mg, yellow solid, Y: 73%. ESI-MS (M+H) + : 306.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.85 (s, 1H), 8.65 (d, J=2.0 Hz, 1H), 8.02 (d, J=7.6 Hz, 1H), 7.79 (dd, J=8.4, 2.4 Hz, 1H), 7.74 (t, J=7.6 Hz, 1H), 7.30-7.28 (m, 2H), 4.75 (d, J=6.0 Hz, 2H), 2.59 (s, 3H).

Synthesis of 6-bromo-3-(6-methylpyridin-2-yl)imidazo[1,5-a]pyridine

The preparation of 6-bromo-3-(6-methylpyridin-2-yl)imidazo[1,5-a]pyridine was the same as that of 3-(6-bromoimidazo[1,5-a]pyridin-3-yl)benzonitrile. 312 mg, yellow solid, Y: 79%. ESI-MS (M+H) + : 288.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 10.28 (s, 1H), 8.12 (d, J=8.0 Hz, 1H), 7.69 (t, J=8.0 Hz, 1H), 7.59 (s, 1H), 7.43 (dd, J=9.6, 0.8 Hz, 1H), 7.10 (d, J=7.2 Hz, 1H), 6.91 (dd, J=9.6, 1.6 Hz, 1H), 2.67 (s, 3H).

Synthesis of 3-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine

The preparation of 3-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 273 mg, yellow solid, Y: 75%. ESI-MS (M+H) + : 336.1.

Synthesis of 1-(6-(3-(6-methylpyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)ethanone

The preparation of 1-(6-(3-(6-methylpyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)ethanone was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine. 120 mg, yellow solid, Y: 45%. ESI-MS (M+H) + : 329.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 10.88 (d, J=1.2 Hz, 1H), 8.19 (d, J=8.4 Hz, 1H), 8.03-8.01 (m, 1H), 7.97-7.95 (m, 2H), 7.72 (t, J=7.6 Hz, 1H), 7.66-7.63 (m, 3H), 7.12 (d, J=8.0 Hz, 1H), 2.89 (s, 3H), 2.70 (s, 3H).

Synthesis of (E)-1-(6-(3-(6-methylpyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)ethanone oxime

The preparation of (E)-1-(6-(3-(6-methylpyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)ethanone oxime was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one oxime. 94 mg, yellow solid, Y: 75%. ESI-MS (M+H) + : 344.1.

Synthesis of 1-(6-(3-(6-methylpyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)ethanamine

The preparation of 1-(6-(3-(6-methylpyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)ethanamine was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine. 65 mg, yellow solid, Y: 72%. ESI-MS (M+H) + : 330.2. HPLC: 98.32%. 1 H NMR (400 MHz, CD 3 OD) δ: 10.73 (d, J=1.2 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.80 (t, J=8.0 Hz, 1H), 7.72 (t, J=8.0 Hz, 1H), 7.68-7.65 (m, 2H), 7.60 (dd, J=9.2, 1.2 Hz, 1H), 7.52 (d, J=0.4 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.15 (d, J=7.2 Hz, 1H), 4.13 (q, J=6.8 Hz, 1H), 2.62 (s, 3H), 1.47 (d, J=6.8 Hz, 3H).

›Example 100. 6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-amine

Synthesis of 6-bromo-1-(6-methylpyridin-2-yl)-1H-indazole-4-carboxylic acid and 6-bromo-2-(6-methylpyridin-2-yl)-2H-indazole-4-carboxylic acid

The preparation of 6-bromo-1-(6-methylpyridin-2-yl)-1H-indazole-4-carboxylic acid and 6-bromo-2-(6-methylpyridin-2-yl)-2H-indazole-4-carboxylic acid was the same as that of 6-bromo-1-(6-methylpyridin-2-yl)-1H-indazole. 810 mg, as a light brown solid, Y: 60%. The mixture of of 6-bromo-1-(6-methylpyridin-2-yl)-1H-indazole-4-carboxylic acid and 6-bromo-2-(6-methylpyridin-2-yl)-2H-indazole-4-carboxylic acid was difficult to be purified due to poor solubility. The mixture was directly used for next step. ESI-MS (M+H) + : 332.9.

Synthesis of tert-butyl (6-bromo-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate and tert-butyl (6-bromo-2-(6-methylpyridin-2-yl)-2H-indazol-4-yl)carbamate

A mixture of 6-bromo-1-(6-methylpyridin-2-yl)-1H-indazole-4-carboxylic acid and 6-bromo-2-(6-methylpyridin-2-yl)-2H-indazole-4-carboxylic acid (350 mg, 1.1 mmol, 1.0 eq), DPPA (413 mg, 1.5 mmol, 1.5 eq) and TEA (165 mg, 1.5 mmol, 1.5 eq) in t-BuOH (15 mL) and anhydrous toluene (15 mL) was stirred at rt for 16 h and then refluxed for 8 h. After concentration, the crude product was purified by column chromatography on silica gel (PE/EA=10/1) to give a mixture of tert-butyl (6-bromo-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate and tert-butyl (6-bromo-2-(6-methylpyridin-2-yl)-2H-indazol-4-yl)carbamate as a white solid. 230 mg, Y: 54%. ESI-MS (M+H) + : 403.1

Synthesis of tert-butyl (1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-4-yl)carbamate and tert-butyl (2-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-4-yl)carbamate

The preparation of tert-butyl (1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-4-yl)carbamate and tert-butyl (2-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-4-yl)carbamate was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 206 mg, as a white solid, Y: 80%. The mixture of tert-butyl (1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-4-yl)carbamate and tert-butyl (2-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-4-yl)carbamate was directly used for next step without further purification. ESI-MS (M+H) + : 451.1.

Synthesis of tert-butyl (6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate

The preparation of tert-butyl (6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate was the same as that of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine. The mixture of tert-butyl (6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate and tert-butyl (6-(6-acetylpyridin-2-yl)-2-(6-methylpyridin-2-yl)-2H-indazol-4-yl)carbamate was purified by silica gel chromatography with PE/EA (5/1) as eluent to give tert-butyl (6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate and PE/EA (1/1) as eluent to give tert-butyl (6-(6-acetylpyridin-2-yl)-2-(6-methylpyridin-2-yl)-2H-indazol-4-yl)carbamate as a yellow solid (66 mg, Y: 33%). tert-butyl (6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate, as a yellow solid, 52 mg, Y: 26%. ESI-MS (M+H) + : 444.2. 1 H NMR (400 MHz, CDCl 3 ) □: 9.47 (s, 1H), 8.43 (s, 1H), 8.23 (d, J=0.8 Hz, 1H), 8.10 (dd, J=7.6, 0.8 Hz, 1H), 8.01 (dd, J=7.6, 0.8 Hz, 1H), 7.93 (t, J=8.0 Hz, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.75 (t, J=8.0 Hz, 1H), 7.06 (d, J=7.6 Hz, 1H), 6.93 (s, 1H), 2.93 (s, 3H), 2.69 (s, 3H), 1.55 (s, 9H).

Synthesis of (Z)-tert-butyl (6-(6-(1-(hydroxyimino)ethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate

The preparation of (Z)-tert-butyl (6-(6-(1-(hydroxyimino)ethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one oxime. 105 mg, as white solid, Y: 80%. ESI-MS (M+H) + : 459.1.

Synthesis of tert-butyl (6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate

The preparation of tert-butyl (6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine. 72 mg, as white solid, Y: 53%. ESI-MS (M+H) + : 445.1.

Synthesis of 6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-amine

To a solution of tert-butyl (6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate (72 mg, 0.16 mmol, 1.0 eq) in DCM (5 mL) was added TFA (1 mL). The mixture was stirred at rt for 1 h. After concentration, the residue was purified by prep-HPLC (CH 3 CN/H 2 O with 0.05% TFA as mobile phase from 5% to 95%) to give 6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-amine as a yellow solid. 32 mg, Y: 57%. ESI-MS (M+H) + : 345.1. HPLC: 98.64%. 1 H NMR (400 MHz, CD 3 OD) δ: 8.78 (s, 1H), 8.36 (s, 1H), 7.87-7.76 (m, 4H), 7.35 (d, J=7.6 Hz, 1H), 7.21 (d, J=0.8 Hz, 1H), 7.13 (dd, J=6.0, 2.4 Hz, 1H), 4.22 (q, J=6.4 Hz, 1H), 2.66 (s, 3H), 1.54 (d, J=6.8 Hz, 3H).

›Example 101. 6-(6-(1-aminoethyl)pyridin-2-yl)-N-methyl-1-(6-methylpyridin-2-yl)-1H-indazol-4-amine · 1 of 2

Synthesis of tert-butyl (6-bromo-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)(methyl)carbamate and tert-butyl (6-bromo-2-(6-methylpyridin-2-yl)-2H-indazol-4-yl)(methyl)carbamate

To a mixture of tert-butyl (6-bromo-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)(methyl)carbamate and tert-butyl (6-bromo-2-(6-methylpyridin-2-yl)-2H-indazol-4-yl)(methyl)carbamate (650 mg, 1.60 mmol, 1.0 eq) in anhydrous THF (10 mL) was added NaH (39 mg, 1.60 mmol, 1.0 eq) at rt. The mixture was stirred at rt for 5 min, then MeI (273 mg, 1.92 mmol, 1.2 eq) was added into the mixture. The mixture was stirred at 40° C. for 1 h. After concentration, the residue was purified by column chromatography on silica gel (PE/EA=10/1) to give a mixture of tert-butyl (6-bromo-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)(methyl)carbamate and tert-butyl (6-bromo-2-(6-methylpyridin-2-yl)-2H-indazol-4-yl)(methyl)carbamate as a white solid. 439 mg, Y: 65%. ESI-MS (M+H) + : 417.2.

Synthesis of tert-butyl methyl(1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-4-yl)carbamate and tert-butyl methyl(2-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-4-yl)carbamate

The preparation of tert-butyl methyl(1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-4-yl)carbamate and tert-butyl methyl(2-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-4-yl)carbamate was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 465 mg, as a white solid, Y: 80%. The mixture of tert-butyl methyl(1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-4-yl)carbamate and tert-butyl methyl(2-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-4-yl)carbamate was directly used for next step without further purification. ESI-MS (M+H) + : 465.1.

Synthesis of tert-butyl (6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)(methyl)carbamate

The preparation of tert-butyl (6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)(methyl)carbamate was the same as tert-butyl (6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate. 142 mg, as a yellow solid, Y: 31%. ESI-MS (M+H) + : 458.1. HPLC: 93.37%. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.52 (s, 1H), 8.07 (s, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.97 (d, J=7.6 Hz, 1H), 7.89 (t, J=8.0 Hz, 1H), 7.81-7.79 (m, 2H), 7.69 (t, J=7.6 Hz, 1H), 7.00 (d, J=7.6 Hz, 1H), 3.41 (s, 3H), 2.84 (s, 3H), 2.63 (s, 3H), 1.37 (s, 9H).

Synthesis of (Z)-tert-butyl (6-(6-(1-(hydroxyimino)ethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)(methyl)carbamate

The preparation of (Z)-tert-butyl (6-(6-(1-(hydroxyimino)ethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)(methyl)carbamate was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one oxime. 126 mg, as white solid, Y: 86%. ESI-MS (M+H) + : 473.2. HPLC: 98.82%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.62 (s, 1H), 8.19 (s, 1H), 7.97 (d, J=7.6 Hz, 1H), 7.93-7.82 (m, 5H), 7.17 (d, J=6.4 Hz, 1H), 3.47 (s, 3H), 2.70 (s, 3H), 2.49 (s, 3H), 1.46 (s, 9H).

Synthesis of tert-butyl (6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)(methyl)carbamate

The preparation of (6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)(methyl)carbamate was the same as 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine. 103 mg, as white solid, Y: 65%. ESI-MS (M+H) + : 458.2

Synthesis of 6-(6-(1-aminoethyl)pyridin-2-yl)-N-methyl-1-(6-methylpyridin-2-yl)-1H-indazol-4-amine

The preparation of 6-(6-(1-aminoethyl)pyridin-2-yl)-N-methyl-1-(6-methylpyridin-2-yl)-1H-indazol-4-amine was the same as 6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-amine. 33 mg, as yellow solid, Y: 87%. ESI-MS (M+H) + : 359.2. HPLC: 100.00%. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 8.79 (s, 1H), 8.51 (s, 1H), 8.45 (br, 2H), 8.04-7.98 (m, 2H), 7.87 (d, J=8.0 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.50 (dd, J=5.6, 2.8 Hz, 1H), 7.17 (d, J=7.6 Hz, 1H), 7.03 (s, 1H), 4.66-4.63 (m, 1H), 2.99 (s, 3H), 2.64 (s, 3H), 1.61 (d, J=7.2 Hz, 3H).

Example 102. 6-(6-(1-aminoethyl)pyridin-2-yl)-N,N-dimethyl-1-(6-methylpyridin-2-yl)-1H-indazol-4-amine

Synthesis of 6-bromo-1-(6-methylpyridin-2-yl)-1H-indazol-4-amine and 6-bromo-2-(m-tolyl)-2H-indazol-4-amine

The preparation of 6-bromo-1-(6-methylpyridin-2-yl)-1H-indazol-4-amine and 6-bromo-2-(m-tolyl)-2H-indazol-4-amine was the same as 6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-amine. 340 mg, as a light brown solid, Y: 85%. ESI-MS (M+H) + : 303.1.

Synthesis of 6-bromo-N,N-dimethyl-1-(6-methylpyridin-2-yl)-1H-indazol-4-amine and 6-bromo-N,N-dimethyl-2-(6-methylpyridin-2-yl)-2H-indazol-4-amine

The preparation of 6-bromo-N,N-dimethyl-1-(6-methylpyridin-2-yl)-1H-indazol-4-amine and 6-bromo-N,N-dimethyl-2-(6-methylpyridin-2-yl)-2H-indazol-4-amine was the same as tert-butyl (6-bromo-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)(methyl)carbamate. 250 mg, as white solid, Y: 67%. ESI-MS (M+H) + : 331.2.

Synthesis of N,N-dimethyl-1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-4-amine and N,N-dimethyl-2-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-4-amine

The preparation of N,N-dimethyl-1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-4-amine and N,N-dimethyl-2-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-4-amine was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 246 mg, as a white solid, Y: 86%. The mixture of N,N-dimethyl-1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-4-amine and N,N-dimethyl-2-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-4-amine was directly used for next step without further purification. ESI-MS (M+H) + : 379.1.

›Example 101. 6-(6-(1-aminoethyl)pyridin-2-yl)-N-methyl-1-(6-methylpyridin-2-yl)-1H-indazol-4-amine · 2 of 2

Synthesis of 1-(6-(4-(dimethylamino)-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone and 1-(6-(4-(dimethylamino)-2-(6-methylpyridin-2-yl)-2H-indazol-6-yl)pyridin-2-yl)ethanone

The preparation of 1-(6-(4-(dimethylamino)-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone was the same as tert-butyl (6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate. 67 mg, as a yellow solid, Y: 28%. ESI-MS (M+H) + : 372.1. HPLC: 100.00%. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.04 (s, 1H), 8.26 (s, 1H), 8.00 (d, J=8.0 Hz, 1H), 8.01 (d, J=7.2 Hz, 1H), 7.93 (t, J=8.0 Hz, 1H), 7.85 (d, J=7.6 Hz, 1H), 7.73 (t, J=7.6 Hz, 1H), 7.26 (s, 1H), 7.04 (d, J=7.6 Hz, 1H), 3.27 (s, 6H), 2.90 (s, 3H), 2.68 (s, 3H).

Synthesis of (Z)-1-(6-(4-(dimethylamino)-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime

The preparation of (Z)-1-(6-(4-(dimethylamino)-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one oxime. 51 mg, as white solid, Y: 81%. ESI-MS (M+H) + : 387.2. HPLC: 100.00% 1 H NMR (400 MHz, CD 3 OD) δ: 9.05 (s, 1H), 8.41 (s, 1H), 7.95-7.79 (m, 5H), 7.27 (d, J=0.8 Hz, 1H), 7.16-7.13 (m, 1H), 3.26 (s, 6H), 2.67 (s, 3H), 2.47 (s, 3H).

Synthesis of 6-(6-(1-aminoethyl)pyridin-2-yl)-N,N-dimethyl-1-(6-methylpyridin-2-yl)-1H-indazol-4-amine

The preparation of 6-(6-(1-aminoethyl)pyridin-2-yl)-N,N-dimethyl-1-(6-methylpyridin-2-yl)-1H-indazol-4-amine was the same as 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine. 42 mg, as a yellow solid, Y: 63%. ESI-MS (M+H) + : 373.3. HPLC: 100.00%. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 9.00 (s, 1H), 8.59 (s, 1H), 8.49 (br, 2H), 8.05-8.01 (m, 2H), 7.90 (t, J=8.0 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.51 (dd, J=8.4, 0.4 Hz, 1H), 7.24 (s, 1H), 7.20 (d, J=7.2 Hz, 1H), 4.67-4.63 (m, 1H), 3.26 (s, 6H), 2.65 (s, 3H), 1.61 (d, J=6.8 Hz, 3H).

›Example 103. N-(6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)acetamide

Synthesis of 1-(6-(4-amino-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone

The preparation of 1-(6-(4-amino-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone was the same as 6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-amine. 140 mg, as a yellow solid, Y: 80%. ESI-MS (M+H) + : 344.1.

Synthesis of N-(6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)acetamide

To a mixture of 1-(6-(4-amino-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone (95 mg, 0.28 mmol, 1.0 eq) and TEA (86 mg, 0.84 mmol, 3.0 eq) in THF (5 mL) was added AcCl (44 mg, 0.56 mmol, 2.0 eq). The mixture was stirred at rt for 1 h. After concentration, the residue was purified by pre-HPLC (CH 3 CN/H 2 O with 0.05% TFA as mobile phase from 5% to 95%) to give N-(6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)acetamide as a white solid. 65 mg, Y: 61%. ESI-MS (M+H) + : 386.1.

Synthesis of (Z)—N-(6-(6-(1-(hydroxyimino)ethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)acetamide

The preparation of (Z)—N-(6-(6-(1-(hydroxyimino)ethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)acetamide was the same as 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one oxime. 70 mg, as a white solid, Y: 85%. ESI-MS (M+H) + : 401.1.

Synthesis of N-(6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)acetamide

The preparation of N-(6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)acetamide was the same as 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine. 52 mg, as a white solid, Y: 72%. ESI-MS (M+H) + : 387.2. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.40 (s, 1H), 8.44 (d, J=0.8 Hz, 2H), 7.91 (t, J=7.6 Hz, 1H), 7.86-7.83 (m, 3H), 7.40 (d, J=7.6 Hz, 1H), 7.16 (dd, J=6.0, 2.0 Hz, 1H), 4.30 (q, J=6.8 Hz, 1H), 2.68 (s, 3H), 2.32 (s, 3H), 1.57 (d, J=6.8 Hz, 3H).

›Example 104. 1-(6-(4-(aminomethyl)-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine · 1 of 2

Synthesis of 6-bromo-1-(6-methylpyridin-2-yl)-1H-indazole-4-carboxamide and O-(6-bromo-2-(6-methylpyridin-2-yl)-2H-indazole-4-carbonyl)hydroxylamine

The preparation of 6-bromo-1-(6-methylpyridin-2-yl)-1H-indazole-4-carboxamide and O-(6-bromo-2-(6-methylpyridin-2-yl)-2H-indazole-4-carbonyl)hydroxylamine was the same as that of 6-bromo-1-(6-methylpyridin-2-yl)-1H-indazole-4-carboxamide and O-(6-bromo-2-(6-methylpyridin-2-yl)-2H-indazole-4-carbonyl)hydroxylamine. 1.5 g, as a yellow solid, Y: 60%. The mixture of 36-bromo-1-(6-methylpyridin-2-yl)-1H-indazole-4-carboxamide and O-(6-bromo-2-(6-methylpyridin-2-yl)-2H-indazole-4-carbonyl)hydroxylamine was difficult to be purified due to poor solubility. The mixture was directly used for next step. ESI-MS (M+H) + : 331.1.

Synthesis of 6-bromo-1-(6-methylpyridin-2-yl)-1H-indazole-4-carbonitrile and 6-bromo-2-(6-methylpyridin-2-yl)-2H-indazole-4-carbonitrile

The preparation of 6-bromo-1-(6-methylpyridin-2-yl)-1H-indazole-4-carbonitrile and 6-bromo-2-(6-methylpyridin-2-yl)-2H-indazole-4-carbonitrile was the same as that of N-(5-(4-cyano-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-3-yl)-2,2,2-trifluoroacetamide. 596 mg, as a white solid, Y: 42%. The mixture of 6-bromo-1-(6-methylpyridin-2-yl)-1H-indazole-4-carbonitrile and 6-bromo-2-(6-methylpyridin-2-yl)-2H-indazole-4-carbonitrile was difficult to be purified due to poor solubility. The mixture was directly used for next step. ESI-MS (M+H) + : 313.1.

Synthesis of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-4-carbonitrile and 2-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-4-carbonitrile

The preparation of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-4-carbonitrile and 2-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-4-carbonitrile was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 523 mg, as a white solid, Y: 76%. The mixture of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-4-carbonitrile and 2-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-4-carbonitrile was difficult to be purified due to poor solubility. The mixture was directly used for next step. ESI-MS (M+H) + : 361.1.

Synthesis of of 6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole-4-carbonitrile and 6-(6-acetylpyridin-2-yl)-2-(6-methylpyridin-2-yl)-2H-indazole-4-carbonitrile

The preparation of 6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole-4-carbonitrile and 6-(6-acetylpyridin-2-yl)-2-(6-methylpyridin-2-yl)-2H-indazole-4-carbonitrile was the same as that of tert-butyl (6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate. 262 mg, as a white solid, Y: 51%. The mixture of 6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole-4-carbonitrile and 6-(6-acetylpyridin-2-yl)-2-(6-methylpyridin-2-yl)-2H-indazole-4-carbonitrile was difficult to be purified due to poor solubility. The mixture was directly used for next step. ESI-MS (M+H) + : 354.1.

Synthesis of (Z)-6-(6-(1-(hydroxyimino)ethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole-4-carbonitrile and (Z)-6-(6-(1-(hydroxyimino)ethyl)pyridin-2-yl)-2-(6-methylpyridin-2-yl)-2H-indazole-4-carbonitrile

The preparation of (Z)-6-(6-(1-(hydroxyimino)ethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole-4-carbonitrile and (Z)-6-(6-(1-(hydroxyimino)ethyl)pyridin-2-yl)-2-(6-methylpyridin-2-yl)-2H-indazole-4-carbonitrile was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one oxime. 208 mg, as a white solid, Y: 76%. The mixture of (Z)-6-(6-(1-(hydroxyimino)ethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole-4-carbonitrile and (Z)-6-(6-(1-(hydroxyimino)ethyl)pyridin-2-yl)-2-(6-methylpyridin-2-yl)-2H-indazole-4-carbonitrile was difficult to be purified due to poor solubility. The mixture was directly used for next step. ESI-MS (M+H) + : 369.1.

Synthesis of 6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole-4-carbonitrile and 6-(6-(1-aminoethyl)pyridin-2-yl)-2-(6-methylpyridin-2-yl)-2H-indazole-4-carbonitrile

The preparation of 6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole-4-carbonitrile and 6-(6-(1-aminoethyl)pyridin-2-yl)-2-(6-methylpyridin-2-yl)-2H-indazole-4-carbonitrile was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine. 208 mg, as a white solid, Y: 43%. The mixture of 6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole-4-carbonitrile and 6-(6-(1-aminoethyl)pyridin-2-yl)-2-(6-methylpyridin-2-yl)-2H-indazole-4-carbonitrile was difficult to be purified due to poor solubility. The mixture was directly used for next step. ESI-MS (M+H) + : 355.1.

Synthesis of 1-(6-(4-(aminomethyl)-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine and 1-(6-(4-(aminomethyl)-2-(6-methylpyridin-2-yl)-2H-indazol-6-yl)pyridin-2-yl)ethanamine

The preparation of 1-(6-(4-(aminomethyl)-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine and 1-(6-(4-(aminomethyl)-2-(6-methylpyridin-2-yl)-2H-indazol-6-yl)pyridin-2-yl)ethanamine was the same as that of 02-04. The mixture of 1-(6-(4-(aminomethyl)-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine and 1-(6-(4-(aminomethyl)-2-(6-methylpyridin-2-yl)-2H-indazol-6-yl)pyridin-2-yl)ethanamine was purified by pre-HPLC (MeOH/H 2 O with 0.05% TFA as mobile phase from 5% to 95%) to give.

1-(6-(4-(aminomethyl)-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

5 mg, as a yellow oil, ESI-MS (M+H) + : 359.1, t R =2.57 min, HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.60 (s, 1H), 8.45 (s, 1H), 8.20 (s, 1H), 7.98-7.92 (m, 2H), 7.81-7.75 (m, 2H), 7.42 (dd, J=7.2, 1.2 Hz, 1H), 7.01 (d, J=6.8 Hz, 1H), 4.62 (q, J=6.8 Hz, 1H), 4.54 (s, 2H), 2.61 (s, 3H), 1.64 (d, J=7.2 Hz, 3H).

›Example 104. 1-(6-(4-(aminomethyl)-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine · 2 of 2

1-(6-(4-(aminomethyl)-2-(6-methylpyridin-2-yl)-2H-indazol-6-yl)pyridin-2-yl)ethanamine

4 mg, as a yellow oil, ESI-MS (M+H) + : 359.1, t R =2.47 min, HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.44 (s, 1H), 8.57 (s, 1H), 8.00-7.96 (m, 3H), 7.93-7.84 (m, 2H), 7.38 (d, J=7.2 Hz, 1H), 7.27 (d, J=7.2 Hz, 1H), 4.61 (q, J=6.8 Hz, 1H), 4.48 (s, 2H), 2.55 (s, 3H), 1.62 (d, J=7.2 Hz, 3H).

Example 105. N-((6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)methyl)acetamide

Synthesis of tert-butyl (1-(6-(4-cyano-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)carbamate and tert-butyl (1-(6-(4-cyano-2-(6-methylpyridin-2-yl)-2H-indazol-6-yl)pyridin-2-yl)ethyl)carbamate

To a mixture of tert-butyl (1-(6-(4-cyano-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)carbamate and tert-butyl (1-(6-(4-cyano-2-(6-methylpyridin-2-yl)-2H-indazol-6-yl)pyridin-2-yl)ethyl)carbamate (120 mg, 0.34 mmol, 1.0 eq) and TEA (51.4 mg, 0.51 mmol, 1.5 eq) in DCM (20 mL) was added (Boc) 2 O (88 mg, 0.41 mmol, 1.2 eq) at rt. The mixture was stirred at rt for 2 h and diluted with water (10 mL). The organic phase was washed with brine and dried over Na 2 SO 4 . After filtration and concentration, the residue was directly used for next step without further purification. 123 mg, as yellow oil, Y: 80%. ESI-MS (M+H) + : 455.1.

Synthesis of tert-butyl (1-(6-(4-(aminomethyl)-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)carbamate and tert-butyl (1-(6-(4-(aminomethyl)-2-(6-methylpyridin-2-yl)-2H-indazol-6-yl)pyridin-2-yl)ethyl)carbamate

The preparation of tert-butyl (1-(6-(4-(aminomethyl)-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)carbamate and tert-butyl (1-(6-(4-(aminomethyl)-2-(6-methylpyridin-2-yl)-2H-indazol-6-yl)pyridin-2-yl)ethyl)carbamate was the same as that of 5-(4-(aminomethyl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine. 100 mg, as yellow oil, ESI-MS (M+H) + : 459.1.

Synthesis of N-((6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)methyl)acetamide and N-((6-(6-(1-aminoethyl)pyridin-2-yl)-2-(6-methylpyridin-2-yl)-2H-indazol-4-yl)methyl)acetamide

The preparation of N-((6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)methyl)acetamide was the same as that of N-(6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)acetamide. The mixture of N-((6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)methyl)acetamide and N-((6-(6-(1-aminoethyl)pyridin-2-yl)-2-(6-methylpyridin-2-yl)-2H-indazol-4-yl)methyl)acetamide was purified by pre-HPLC (MeOH/H 2 O with 0.05% TFA as mobile phase from 5% to 95%).

N-((6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)methyl)acetamide: 9.8 mg, as a yellow oil, ESI-MS (M+H) + : 401.1, t R =1.15 min, HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.53 (s, 1H), 8.44 (s, 1H), 8.10 (s, 1H), 8.04-8.02 (m, 2H), 7.89-7.84 (m, 2H), 7.49 (dd, J=5.6, 2.4 Hz, 1H), 7.19 (dd, J=6.0, 1.6 Hz, 1H), 4.82 (s, 2H), 4.71 (q, J=6.8 Hz, 1H), 2.70 (s, 3H), 2.04 (s, 3H), 1.74 (d, J=6.8 Hz, 3H).

N-((6-(6-(1-aminoethyl)pyridin-2-yl)-2-(6-methylpyridin-2-yl)-2H-indazol-4-yl)methyl)acetamide: 4.9 mg, as a yellow oil, ESI-MS (M+H) + : 401.1, t R =1.07 min, HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.35 (s, 1H), 8.47 (s, 1H), 8.06-7.92 (m, 5H), 7.46 (d, J=7.6 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 4.76 (s, 2H), 4.70 (q, J=6.8 Hz, 1H), 2.66 (s, 3H), 2.04 (s, 3H), 1.72 (d, J=7.2 Hz, 3H).

›Example 106. 1-(6-(4-chloro-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

Synthesis of 6-bromo-4-chloro-1-(6-methylpyridin-2-yl)-1H-indazole

The preparation of 6-bromo-4-chloro-1-(6-methylpyridin-2-yl)-1H-indazole was the same as that of 6-bromo-1-(6-methylpyridin-2-yl)-1H-indazole. 200 mg, as a white solid, Y: 24%. ESI-MS (M+H) + : 321.9. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.02 (d, J=1.2 Hz, 1H), 8.21 (d, J=0.8 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.74 (t, J=8.0 Hz, 1H), 7.40 (d, J=1.6 Hz, 1H), 7.07 (d, J=7.2 Hz, 1H), 2.66 (s, 3H).

Synthesis of 4-chloro-1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

The preparation of 4-chloro-1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 185 mg, as a yellow solid, Y: 80%. ESI-MS (M+H) + : 370.1.

Synthesis of 1-(6-(4-chloro-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone

The preparation of 1-(6-(4-chloro-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone was the same as that of tert-butyl (6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate. 85 mg, as a white solid, Y: 47%. ESI-MS (M+H) + : 362.9. HPLC: 98.26% 1 H NMR (400 MHz, CDCl 3 ) δ: 9.56 (s, 1H), 8.24 (s, 1H), 8.01-7.97 (m, 3H), 7.90 (t, J=8.0 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.70 (t, J=8.0 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 2.84 (s, 3H), 2.63 (s, 3H).

Synthesis of (Z)-1-(6-(4-chloro-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime

The preparation of (Z)-1-(6-(4-chloro-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one oxime. 80 mg, as a yellow solid, Y: 90%. ESI-MS (M+H) + : 378.0. HPLC: 100.00% 1 H NMR (400 MHz, CD 3 OD) δ: 9.66 (s, 1H), 8.36 (s, 1H), 8.09 (d, J=1.2 Hz, 1H), 7.98-7.84 (m, 5H), 7.21 (d, J=6.8 Hz, 1H), 2.70 (s, 3H), 2.49 (s, 3H).

Synthesis of 1-(6-(4-chloro-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

The preparation of 1-(6-(4-chloro-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine. 50 mg, as a white solid, Y: 65%. ESI-MS (M+H) + : 364.2. HPLC: 100.00% 1 H NMR (400 MHz, CD 3 OD) δ: 9.38 (s, 1H), 8.17 (s, 1H), 7.92 (s, 1H), 7.89 (t, J=8.0 Hz, 1H), 7.73-7.69 (m, 3H), 7.32 (d, J=7.6 Hz, 1H), 7.06 (t, J=4.0 Hz, 1H), 4.14 (q, J=6.8 Hz, 1H), 2.57 (s, 3H), 1.48 (d, J=6.8 Hz, 3H).

›Example 107. 1-(6-(4-cyclopropyl-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

Synthesis of 1-(6-(4-iodo-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone

A mixture of tert-butyl (6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate (1.1 g, 2.5 mmol, 1.0 eq) and conc. HCl (30 mL) was stirred at rt for 30 min. Then the mixture was cooled down to 0° C. and NaNO 2 (190 mg, 2.75 mmol, 1.1 eq) was added into the mixture. The mixture was stirred at 0° C. for 15 min and a solution of potassium iodide (4.2 g, 25 mmol, 10 eq) in 100 mL of water was added. The mixture was stirred at rt for 16 h. After concentration, the residue was purified by silica gel chromatography with PE/EA (1/1) as eluent to give 1-(6-(4-iodo-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone as a brown solid. (550 mg, Y: 49%). ESI-MS (M+H) + : 455.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.62 (s, 1H), 8.33 (d, J=1.2 Hz, 1H), 8.02 (s, 1H), 8.01-7.93 (m, 2H), 7.92-7.85 (m, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.68 (t, J=7.6 Hz, 1H), 7.00 (d, J=7.6 Hz, 1H), 2.83 (s, 3H), 2.61 (s, 3H).

Synthesis of 1-(6-(4-cyclopropyl-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone

A mixture of 1-(6-(4-iodo-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone (70 mg, 0.15 mmol, 1.0 eq), cyclopropylboronic acid (CAS #411235-57-9) (16 mg, 0.18 mmol, 1.2 eq), Pd 2 dba 3 (14 mg, 0.015 mmol, 0.1 eq), xantphos (17 mg, 0.03 mmol, 0.2 eq) and K 3 PO 4 (95 mg, 0.45 mmol, 3.0 eq) in dry toluene (5 mL) was stirred at 100° C. for 16 h under N 2 atmosphere. After concentration, the residue was purified by column chromatography on silica gel (PE/EA=5/1) to give 1-(6-(4-cyclopropyl-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone as a light yellow solid. 30 mg, Y: 53%. ESI-MS (M+H) + : 369.2. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.43 (s, 1H), 8.29 (s, 1H), 7.97 (dd, J=7.6, 0.8 Hz, 1H), 7.93 (dd, J=7.6, 0.8 Hz, 1H), 7.86 (t, J=8.0 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.67 (t, J=7.2 Hz, 1H), 7.54 (s, 1H), 6.96 (d, J=7.6 Hz, 1H), 2.83 (s, 3H), 2.61 (s, 3H), 2.33-2.28 (m, 1H), 1.12-1.07 (m, 2H), 0.96-0.92 (m, 2H).

Synthesis of (Z)-1-(6-(4-cyclopropyl-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime

The preparation of (Z)-1-(6-(4-cyclopropyl-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one oxime. 27 mg, as a white solid, Y: 86%. ESI-MS (M+H) + : 384.2.

Synthesis of 1-(6-(4-cyclopropyl-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

The preparation of 1-(6-(4-cyclopropyl-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine. 14 mg, as a yellow solid, Y: 66%. ESI-MS (M+H) + : 370.3. HPLC: 97.95%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.35 (s, 1H), 8.49 (s, 1H), 8.03-7.98 (m, 2H), 7.88-7.83 (m, 2H), 7.72 (s, 1H), 7.47 (dd, J=5.2, 2.8 Hz, 1H), 7.18 (t, J=1.2 Hz, 1H), 4.71 (q, J=6.8 Hz, 1H), 2.69 (s, 3H), 2.51-2.44 (m, 1H), 1.73 (d, J=6.8 Hz, 3H), 1.22-1.18 (m, 2H), 1.08-1.05 (m, 2H).

Example 108. 1-(6-(1-(6-methylpyridin-2-yl)-4-(prop-1-en-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

Synthesis of 1-(6-(1-(6-methylpyridin-2-yl)-4-(prop-1-en-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone

The preparation of 1-(6-(1-(6-methylpyridin-2-yl)-4-(prop-1-en-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone was the same as that of tert-butyl (6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate. 103 mg, as a light yellow solid, Y: 34%. ESI-MS (M+H) + : 369.2. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.64 (s, 1H), 8.36 (s, 1H), 8.09 (d, J=7.6 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.98-7.93 (m, 2H), 7.88 (d, J=8.0 Hz, 1H), 7.75 (t, J=8.0 Hz, 1H), 7.06 (d, J=7.2 Hz, 1H), 5.53 (s, 1H), 5.46 (s, 1H), 2.91 (s, 3H), 2.70 (s, 3H), 2.38 (s, 3H).

Synthesis of (Z)-1-(6-(1-(6-methylpyridin-2-yl)-4-(prop-1-en-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime

The preparation of (Z)-1-(6-(1-(6-methylpyridin-2-yl)-4-(prop-1-en-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one oxime. 95 mg, as a yellow solid, Y: 89%. ESI-MS (M+H) + : 384.2.

Synthesis of 1-(6-(1-(6-methylpyridin-2-yl)-4-(prop-1-en-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

The preparation of 1-(6-(1-(6-methylpyridin-2-yl)-4-(prop-1-en-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine. 47 mg, as a white solid, Y: 52%. ESI-MS (M+H) + : 370.2. HPLC: 95.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.43 (s, 1H), 8.26 (d, J=0.8 Hz, 1H), 7.84 (s, 1H), 7.83-7.70 (m, 4H), 7.29 (dd, J=7.2, 0.4 Hz, 1H), 7.03 (dd, J=6.4, 0.8 Hz, 1H), 5.42 (s, 1H), 5.38-5.37 (m, 1H), 4.11 (q, J=6.8 Hz, 1H), 2.56 (s, 3H), 2.28 (s, 3H), 1.45 (d, J=6.8 Hz, 3H).

›Example 109. 1-(6-(4-ethyl-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

Synthesis of 1-(6-(1-(6-methylpyridin-2-yl)-4-((trimethylsilyl)ethynyl)-1H-indazol-6-yl)pyridin-2-yl)ethanone

A mixture of 1-(6-(4-iodo-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone (150 mg, 0.33 mmol, 1.0 eq), ethynyltrimethylsilane CAS #1066-54-2 (49 mg, 0.5 mmol, 1.5 eq), Pd(PPh 3 ) 2 Cl 2 (23 mg, 0.033 mmol, 0.1 eq) and CuI (6 mg, 0.033 mmol, 0.1 eq) in Et 3 N (15 mL) was stirred at 70° C. for 3 h under N 2 atmosphere. After concentration, the residue was purified by column chromatography on silica gel (PE/EA=10/1) to give 1-(6-(1-(6-methylpyridin-2-yl)-4-((trimethylsilyl)ethynyl)-1H-indazol-6-yl)pyridin-2-yl)ethanone as a white solid. 90 mg, Y: 64%. ESI-MS (M+H) + : 425.2. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.63 (s, 1H), 8.21 (s, 1H), 8.02 (d, J=1.2 Hz, 1H), 7.98-7.93 (m, 2H), 7.86 (t, J=7.6 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.66 (t, J=7.6 Hz, 1H), 6.97 (d, J=7.6 Hz, 1H), 2.84 (s, 3H), 2.59 (s, 3H), 0.28 (s, 9H).

Synthesis of 1-(6-(4-ethynyl-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone

A mixture of 1-(6-(1-(6-methylpyridin-2-yl)-4-((trimethylsilyl)ethynyl)-1H-indazol-6-yl)pyridin-2-yl)ethanone (196 mg, 0.46 mmol, 1.0 eq) and K 2 CO 3 (63 mg, 0.46 mmol, 1.5 eq) in MeOH/DCM (15 mL/15 mL) was stirred at 25° C. for 1 h. The mixture was diluted with DCM (100 mL) and washed with H 2 O (30 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EA=5/1) to give 1-(6-(4-ethynyl-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone as a white solid. 116 mg, Y: 73%. ESI-MS (M+H) + : 353.2. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.75 (s, 1H), 8.35 (s, 1H), 8.16 (d, J=1.2 Hz, 1H), 8.09-8.04 (m, 2H), 7.97 (t, J=7.6 Hz, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.76 (t, J=7.6 Hz, 1H), 7.07 (d, J=7.6 Hz, 1H), 3.45 (s, 1H), 2.92 (s, 3H), 2.69 (s, 3H).

Synthesis of (Z)-1-(6-(4-ethynyl-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime

The preparation of (Z)-1-(6-(4-ethynyl-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one oxime. 103 mg, as a white solid, Y: 80%. ESI-MS (M+H) + : 368.2.

Synthesis of 1-(6-(4-ethynyl-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

The preparation of 1-(6-(4-ethynyl-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine. 89 mg, as a yellow solid, Y: 72%. ESI-MS (M+H) + : 354.2. HPLC: 99.40%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.61 (s, 1H), 8.38 (s, 1H), 8.36 (s, 1H), 8.07-8.03 (m, 2H), 7.88-7.85 (m, 2H), 7.51-7.49 (m, 1H), 7.18 (dd, J=6.4, 0.8 Hz 1H), 4.71 (q, J=6.8 Hz, 1H), 4.01 (s, 1H), 2.71 (s, 3H), 1.73 (d, J=6.4 Hz, 3H).

Synthesis of 1-(6-(4-ethyl-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

A mixture of 1-(6-(4-ethynyl-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine (80 mg, 0.23 mmol, 1.0 eq) and Pd/C (8 mg) in MeOH (5 mL) was stirred at rt for 16 h under H 2 . After filtration and concentration, the residue was purified by pre-HPLC (MeOH/H 2 O with 0.05% TFA as mobile phase from 5% to 95%) to give 1-(6-(4-ethyl-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine as a yellow solid. 60 mg, Y: 74%. ESI-MS (M+H) + : 358.2. HPLC: 98.83%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.40 (s, 1H), 8.40 (s, 1H), 8.04-7.99 (m, 3H), 7.88-7.82 (m, 2H), 7.47 (dd, J=6.0, 2.8 Hz, 1H), 7.17 (d, J=6.0 Hz, 1H), 4.70 (q, J=6.8 Hz, 1H), 3.14 (q, J=7.6 Hz, 2H), 2.70 (s, 3H), 1.74 (d, J=6.4 Hz, 3H), 1.48 (t, J=7.6 Hz, 3H).

›Example 110. 1-(6-(4-isopropyl-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

Synthesis of 1-(6-(4-isopropyl-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

The preparation of 1-(6-(4-isopropyl-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine was the same as that of 1-(6-(4-ethyl-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine. 22 mg, as a yellow solid, Y: 62%. ESI-MS (M+H) + : 372.2. HPLC: 96.42%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.33 (s, 1H), 8.32 (s, 1H), 7.81-7.73 (m, 5H), 7.29 (d, J=7.6 Hz, 1H), 7.04 (t, J=6.0 Hz, 1H), 4.14 (q, J=6.4 Hz, 1H), 3.44-3.40 (m, 1H), 2.57 (s, 3H), 1.45 (d, J=6.8 Hz, 3H), 1.41 (t, J=6.4 Hz, 6H).

Example 111. 1-(6-(1-(6-methylpyridin-2-yl)-4-(trifluoromethyl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

Synthesis of 1-(6-(1-(6-methylpyridin-2-yl)-4-(trifluoromethyl)-1H-indazol-6-yl)pyridin-2-yl)ethanone

To a solution of 1-(6-(4-iodo-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone (80 mg, 0.18 mmol, 1.0 eq) in DMF (10 mL) were added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (CAS #680-15-9) (338 mg, 1.76 mmol, 10.0 eq), DIPEA (227 mg, 1.76 mmol, 10.0 eq), CuI (84 mg, 0.44 mmol, 2.5 eq) at rt. The mixture was stirred at 85° C. for 16 h under N 2 atmosphere. After concentration, the residue was purified by column chromatography on silica gel (PE/EA=2/1) to give 1-(6-(1-(6-methylpyridin-2-yl)-4-(trifluoromethyl)-1H-indazol-6-yl)pyridin-2-yl)ethanone as a yellow solid. 31 mg, Y: 45%. ESI-MS (M+H) + : 397.2. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.94 (s, 1H), 8.36 (s, 1H), 8.33 (s, 1H), 8.10 (dd, J=8.0, 1.2 Hz, 1H), 8.06 (dd, J=7.6, 1.2 Hz, 1H), 7.99 (t, J=8.0 Hz, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.78 (t, J=8.0 Hz, 1H), 7.10 (d, J=7.2 Hz, 1H), 2.91 (s, 3H), 2.70 (s, 3H).

Synthesis of (Z)-1-(6-(1-(6-methylpyridin-2-yl)-4-(trifluoromethyl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime

The preparation of (Z)-1-(6-(1-(6-methylpyridin-2-yl)-4-(trifluoromethyl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one oxime. 26 mg, as a white solid, Y: 81%. ESI-MS (M+H) + : 412.2.

Synthesis of 1-(6-(1-(6-methylpyridin-2-yl)-4-(trifluoromethyl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

The preparation of 1-(6-(1-(6-methylpyridin-2-yl)-4-(trifluoromethyl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine. 15 mg, as a yellow solid, Y: 60%. ESI-MS (M+H) + : 398.2. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.88 (s, 1H), 8.58 (s, 1H), 8.43 (s, 1H), 8.13-8.06 (m, 2H), 7.95-7.88 (m, 2H), 7.55 (dd, J=7.2, 0.8 Hz, 1H), 7.25 (d, J=6.8 Hz, 1H), 4.73 (q, J=6.8 Hz, 1H), 2.73 (s, 3H), 1.74 (d, J=6.8 Hz, 3H).

Example 112. methyl 6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole-4-carboxylate

Synthesis of methyl 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-4-carboxylate and methyl 2-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-4-carboxylate

The preparation of methyl 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-4-carboxylate and methyl 2-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-4-carboxylate was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 1.1 g, as a yellow solid, Y: 72%. The mixture of methyl 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-4-carboxylate and methyl 2-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-4-carboxylate was difficult to be purified due to poor solubility. The mixture was directly used for next step. ESI-MS (M+H) + : 394.1.

Synthesis of methyl 6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole-4-carboxylate

The preparation of methyl 6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole-4-carboxylate was the same as that of tert-butyl (6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate. The mixture was purified by silica gel chromatography with PE/EA (2/1) as eluent to give methyl 6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole-4-carboxylate and EA as eluent to give methyl 6-(6-acetylpyridin-2-yl)-2-(6-methylpyridin-2-yl)-2H-indazole-4-carboxylate as a yellow solid.

methyl 6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole-4-carboxylate, as a yellow solid, 300 mg, Y: 33%. ESI-MS (M+H) + : 387.1. 1 H NMR (400 MHz, CDCl 3 ) □ δ: 10.05 (s, 1H), 8.76 (s, 1H), 8.73 (d, J=1.6 Hz, 1H), 8.15 (dd, J=8.0, 1.2 Hz, 1H), 8.06 (dd, J=8.0, 1.2 Hz, 1H), 8.00 (t, J=7.6 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.75 (t, J=8.0 Hz, 1H), 7.09 (d, J=7.6 Hz, 1H), 4.10 (s, 3H), 2.93 (s, 3H), 2.63 (s, 3H).

Synthesis of (Z)-methyl 6-(6-(1-(hydroxyimino)ethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole-4-carboxylate

The preparation of (Z)-methyl 6-(6-(1-(hydroxyimino)ethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole-4-carboxylate was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one oxime. 255 mg, as white solid, Y: 82%. ESI-MS (M+H) + : 402.1.

Synthesis of methyl 6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole-4-carboxylate

The preparation of methyl 6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole-4-carboxylate was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine. 72 mg, as white solid, Y: 52%. ESI-MS (M+H) + : 388.2. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) □ δ: 9.46 (d, J=1.2 Hz, 1H), 8.53 (d, J=1.6 Hz, 1H), 8.34 (d, J=0.8 Hz, 1H), 7.87 (t, J=8.0 Hz, 1H), 7.65 (d, J=7.2 Hz, 1H), 7.62 (t, J=8.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H), 6.98 (d, J=7.2 Hz, 1H), 4.61 (q, J=6.4 Hz, 1H), 3.91 (s, 3H), 2.49 (s, 3H), 1.65 (d, J=6.8 Hz, 3H).

›Example 113. 6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole-4-carboxylic acid

Synthesis of 6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole-4-carboxylic acid

The preparation of 6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole-4-carboxylic acid was the same as that of 6-(5-aminopyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylic acid. 60 mg, as white solid, Y: 60%. ESI-MS (M+H) + : 374.2. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) □ δ: 9.84 (s, 1H), 8.86 (d, J=2.0 Hz, 1H), 8.72 (s, 1H), 8.07-8.05 (m, 2H), 7.88-7.84 (m, 2H), 7.53 (dd, J=6.0, 3.2 Hz, 1H), 7.20 (d, J=6.8 Hz, 1H), 4.73 (q, J=6.8 Hz, 1H), 2.71 (s, 3H), 1.75 (d, J=6.8 Hz, 3H).

›Example 114. 6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)methanol

Synthesis of (6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)methanol

The preparation of (6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)methanol was the same as that of (6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-4-yl)methanol. 17 mg, as a yellow solid, Y: 43%. ESI-MS (M+H) + : 360.2. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.53 (s, 1H), 8.43 (d, J=0.8 Hz, 1H), 8.05 (s, 1H), 7.95-7.90 (m, 2H), 7.87-7.81 (m, 2H), 7.41 (dd, J=6.0, 2.8 Hz, 1H), 7.16 (dd, J=6.4, 1.2 Hz, 1H), 5.08 (s, 2H), 4.38 (q, J=6.8 Hz, 1H), 2.69 (s, 3H), 1.61 (d, J=6.8 Hz, 3H).

Example 115. 6-(6-(1-aminoethyl)pyridin-2-yl)-N-methyl-1-(6-methylpyridin-2-yl)-1H-indazole-4-carboxamide

Synthesis of 6-(6-(1-aminoethyl)pyridin-2-yl)-N-methyl-1-(6-methylpyridin-2-yl)-1H-indazole-4-carboxamide

The preparation of 6-(6-(1-aminoethyl)pyridin-2-yl)-N-methyl-1-(6-methylpyridin-2-yl)-1H-indazole-4-carboxamide was the same as that of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-methylpicolinamide (Example 32). 22 mg, as a brown solid, Y: 49%. ESI-MS (M+H) + : 387.3. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.81 (s, 1H), 8.64 (d, J=0.8 Hz, 1H), 8.43 (d, J=1.6 Hz, 1H), 7.97-7.92 (m, 2H), 7.89-7.83 (m, 2H), 7.43 (dd, J=6.4, 2.0 Hz, 1H), 7.18 (d, J=6.4 Hz, 1H), 4.33 (q, J=6.8 Hz, 1H), 3.06 (s, 3H), 2.69 (s, 3H), 1.59 (d, J=6.8 Hz, 3H).

›Example 116. N-methyl-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

Synthesis of N-methyl-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

The preparation of N-methyl-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine was the same as that of N-(4-methoxybenzyl)-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine. 180 mg, as a white solid, Y: 34%. ESI-MS (M+H) + : 344.2.

Example 117 and 118. N-methyl-1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

Synthesis of N-methyl-1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

The preparation of N-methyl-1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine was the same as that of N-(4-methoxybenzyl)-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine. 120 mg, as a white solid, Y: 29%. ESI-MS (M+H) + : 398.2.

SFC (Column: IC, 4.6*250 mm 5 μm, IPA:MTBE=1:1 (1% DEA), CO 2 flow rate=2.25, Co-Solvent Flow Rate=0.75, Detection wavelength=214 nm) t R =6.58 min, 7.32 min.

Isomer a: 20 mg, as a yellow solid, ESI-MS (M+H) + : 398.2, HPLC: 98.13%. t R =6.58 min (Chiral HPLC). 1 H NMR (400 MHz, CD 3 OD) δ: 9.61 (s, 1H), 8.37 (s, 1H), 8.35 (d, J=8.8 Hz, 1H), 8.18 (t, J=8.0 Hz, 1H), 8.06 (dd, J=8.4, 1.2 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.90-7.88 (m, 2H), 7.68 (d, J=7.6 Hz, 1H), 7.37 (dd, J=6.8, 1.2 Hz, 1H), 3.91 (q, J=6.8 Hz, 1H), 2.34 (s, 3H), 1.50 (d, J=6.4 Hz, 3H). (Example 117)

Isomer b: 25 mg, as a yellow solid, ESI-MS (M+H) + : 398.2, HPLC: 98.13%. t R =7.32 min (Chiral HPLC). 1 H NMR (400 MHz, CD 3 OD) δ: 9.52 (s, 1H), 8.28 (s, 1H), 8.27 (d, J=8.8 Hz, 1H), 8.10 (t, J=8.0 Hz, 1H), 8.00 (dd, J=8.8, 1.6 Hz, 1H), 7.88-7.79 (m, 3H), 7.61 (d, J=7.2 Hz, 1H), 7.34 (dd, J=6.4, 2.8 Hz, 1H), 3.90 (q, J=6.8 Hz, 1H), 2.34 (s, 3H), 1.49 (d, J=6.8 Hz, 3H). (Example 118)

›Example 119. 1-(6-(1-(6-cyclopropylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

Synthesis of 1-(6-(1-(6-bromopyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone

The preparation of 1-(6-(1-(6-bromopyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone was the same as that of 6-bromo-1-(6-methylpyridin-2-yl)-1H-indazole. The mixture of 1-(6-(1-(6-bromopyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone and 1-(6-(2-(6-bromopyridin-2-yl)-2H-indazol-6-yl)pyridin-2-yl)ethanone was purified by pre-TLC (PE/EA=5/1) to give 1-(6-(1-(6-bromopyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone and 1-(6-(2-(6-bromopyridin-2-yl)-2H-indazol-6-yl)pyridin-2-yl)ethanone. R f value of 1-(6-(1-(6-bromopyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone is more than that of 1-(6-(2-(6-bromopyridin-2-yl)-2H-indazol-6-yl)pyridin-2-yl)ethanone.

1-(6-(1-(6-bromopyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone, 80 mg, as a yellow solid, Y: 15%. ESI-MS (M+H) + : 393.0, 395.0.

1-(6-(2-(6-bromopyridin-2-yl)-2H-indazol-6-yl)pyridin-2-yl)ethanone, 27 mg, as a yellow solid, Y: 5%. ESI-MS (M+H) + : 393.0, 395.0.

Synthesis of 1-(6-(1-(6-cyclopropylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone

A mixture of 1-(6-(1-(6-bromopyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone (80 mg, 0.20 mmol, 1.0 eq), cyclopropylboronic acid (CAS #411235-57-9) (26 mg, 0.30 mmol, 1.5 eq), tricyclohexyl phosphine (56 mg, 0.02 mmol, 0.1 eq), K 3 PO 4 (74 mg, 0.35 mmol, 3.5 eq), Pd(OAc) 2 (3 mg, 0.01 mmol, 0.05 eq) in toluene (2 mL)/H 2 O (0.2 mL) was stirred at 110° C. for 16 h under N 2 . After concentration, the residue was purified by silica gel chromatography with PE/EA (4/1) as eluent to give 1-(6-(1-(6-cyclopropylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone. 40 mg, as a yellow solid, Y: 44%. ESI-MS (M+H) + : 355.1.

Synthesis of (Z)-1-(6-(1-(6-cyclopropylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime

The preparation of (Z)-1-(6-(1-(6-cyclopropylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one oxime. 30 mg, as a yellow solid, Y: 72%. ESI-MS (M+H) + : 370.2.

Synthesis of 1-(6-(1-(6-cyclopropylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

The preparation of 1-(6-(1-(6-cyclopropylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine. 8.2 mg, as a yellow solid, Y: 28%. ESI-MS (M+H) + : 356.2. HPLC: 100.00%. 1 H NMR (500 MHz, CD 3 OD) δ: 9.34 (s, 1H), 8.18 (s, 1H), 7.91 (dd, J=7.5, 0.5 Hz, 1H), 7.83-7.80 (m, 2H), 7.71 (d, J=7.5 Hz, 1H), 7.67 (dd, J=7.5, 1.0 Hz, 1H), 7.63 (t, J=7.5 Hz, 1H), 7.27 (d, J=7.5 Hz, 1H), 7.07 (d, J=7.0 Hz, 1H), 4.20 (q, J=6.5 Hz, 1H), 2.16-2.12 (m, 1H), 1.49 (d, J=6.5 Hz, 3H), 1.27-1.09 (m, 2H), 1.07-1.04 (m, 2H).

Example 120. 1-(6-(1-(6-ethylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine Synthesis of 2-bromo-6-ethylpyridine

To a solution of 2-bromo-6-methylpyridine (CAS #5315-25-3) (2.0 g, 11.7 mmol, 1.0 eq) in THF (10 mL) was added LDA (12.3 mL, 12.3 mmol, 1.05 eq) at −78° C. After stirring at −78° C. for 1 h, CH 3 I (1.8 g, 12.3 mmol, 1.05 eq) was added to the mixture. The mixture was stirred at rt for 3 h. The mixture was quenched with sat. NH 4 Cl (2 mL), diluted with water (50 mL) and extracted with EA (2×100 mL). The combined organic phase was washed with brine and dried over Na 2 SO 4 . After concentration, the residue was purified by silica gel chromatography with PE/EA (20/1) as eluent to give 2-bromo-6-ethylpyridine. 1.0 g, as a yellow solid, Y: 46%. ESI-MS (M+H) + : 185.9, 187.9.

Synthesis of 6-bromo-1-(6-ethylpyridin-2-yl)-1H-indazole

The preparation of 6-bromo-1-(6-ethylpyridin-2-yl)-1H-indazole was the same as that of 6-bromo-1-(6-methylpyridin-2-yl)-1H-indazole. The mixture of 6-bromo-1-(6-ethylpyridin-2-yl)-1H-indazole and 6-bromo-2-(6-ethylpyridin-2-yl)-2H-indazole was purified by pre-TLC (PE/EA=10/1) to give 41-02-0002 and 6-bromo-2-(6-ethylpyridin-2-yl)-2H-indazole. R f value of 6-bromo-1-(6-ethylpyridin-2-yl)-1H-indazole is more than that of 6-bromo-2-(6-ethylpyridin-2-yl)-2H-indazole.

6-bromo-1-(6-ethylpyridin-2-yl)-1H-indazole, 230 mg, as a yellow solid, Y: 26%. ESI-MS (M+H) + : 302.0, 304.0.

6-bromo-2-(6-ethylpyridin-2-yl)-2H-indazole, 170 mg, as a yellow solid, Y: 19%. ESI-MS (M+H) + : 302.0, 304.0.

Synthesis of 1-(6-ethylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

The preparation of 1-(6-ethylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 216 mg, as a yellow solid, Y: 81%. ESI-MS (M+H) + : 350.2.

Synthesis of 1-(6-(1-(6-ethylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone

The preparation of 1-(6-(1-(6-ethylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone was the same as that of tert-butyl (6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate. 120 mg, as a white solid, Y: 57%. ESI-MS (M+H) + : 343.2. HPLC: 95.58%. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.71 (s, 1H), 8.23 (s, 1H), 8.09-8.02 (m, 3H), 7.95 (t, J=8.0 Hz, 1H), 7.90-7.87 (m, 2H), 7.77 (t, J=8.0 Hz, 1H), 7.06 (d, J=7.6 Hz, 1H), 2.98 (q, J=7.6 Hz, 2H), 2.89 (s, 3H), 1.48 (t, J=7.6 Hz, 3H).

Synthesis of (E)-1-(6-(1-(6-ethylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime

The preparation of (E)-1-(6-(1-(6-ethylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one oxime. 100 mg, as a white solid, Y: 87%. ESI-MS (M+H) + : 358.2. HPLC: 100.00% 1 H NMR (400 MHz, CD 3 OD) δ: 9.66 (s, 1H), 8.27 (s, 1H), 8.02 (dd, J=8.4, 1.2 Hz, 1H), 7.92-7.81 (m, 6H), 7.14 (dd, J=6.4, 1.2 Hz, 1H), 2.97 (q, J=7.6 Hz, 2H), 2.47 (s, 3H), 1.46 (t, J=7.6 Hz, 3H).

Synthesis of 1-(6-(1-(6-ethylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

The preparation of 1-(6-(1-(6-ethylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine. 55 mg, as a white solid, Y: 64%. ESI-MS (M+H) + : 344.2. HPLC: 100.00% 1 H NMR (400 MHz, CD 3 OD) δ: 9.56 (s, 1H), 8.20 (s, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.80-7.73 (m, 4H), 7.30 (d, J=7.2 Hz, 1H), 7.06 (d, J=6.4 Hz, 1H), 4.13 (q, J=7.6 Hz, 1H), 2.89 (q, J=7.6 Hz, 2H), 1.46-1.40 (m, 6H).

›Example 121. 1-(6-(1-(6-isopropylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

Synthesis of 6-bromo-1-(6-isopropylpyridin-2-yl)-1H-indazole

The preparation of 6-bromo-1-(6-isopropylpyridin-2-yl)-1H-indazole was the same as that of 6-bromo-1-(6-methylpyridin-2-yl)-1H-indazole. The mixture of 6-bromo-1-(6-isopropylpyridin-2-yl)-1H-indazole and 6-bromo-2-(6-isopropylpyridin-2-yl)-2H-indazole was purified by pre-TLC (PE/EA=10/1) to give 6-bromo-1-(6-isopropylpyridin-2-yl)-1H-indazole and 6-bromo-2-(6-isopropylpyridin-2-yl)-2H-indazole. R f value of 6-bromo-1-(6-isopropylpyridin-2-yl)-1H-indazole is more than that of 6-bromo-2-(6-isopropylpyridin-2-yl)-2H-indazole.

6-bromo-1-(6-isopropylpyridin-2-yl)-1H-indazole, 200 mg, as a yellow solid, Y: 23%. ESI-MS (M+H) + : 316.0, 318.0.

6-bromo-2-(6-isopropylpyridin-2-yl)-2H-indazole, 180 mg, as a yellow solid, Y: 21%. ESI-MS (M+H) + : 316.0, 318.0.

Synthesis of 1-(6-isopropylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

The preparation of 1-(6-isopropylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole was the same as that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 100 mg, as a yellow solid, Y: 72%. ESI-MS (M+H) + : 364.2.

Synthesis of 1-(6-(1-(6-isopropylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone

The preparation of 1-(6-(1-(6-isopropylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone was the same as that of tert-butyl (6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate. 45 mg, as a white solid, Y: 46%. ESI-MS (M+H) + : 357.2. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.67 (s, 1H), 8.24 (s, 1H), 8.09-8.02 (m, 3H), 7.90 (d, J=7.6 Hz, 1H), 7.83 (d, J=8.0 Hz, 2H), 7.71 (t, J=8.0 Hz, 1H), 7.01 (d, J=7.2 Hz, 1H), 3.17-3.10 (m, 1H), 2.87 (s, 3H), 1.39 (d, J=7.6 Hz, 6H).

Synthesis of (E)-1-(6-(1-(6-isopropylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime

The preparation of (E)-1-(6-(1-(6-isopropylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one oxime. 41 mg, as a yellow solid, Y: 87%. ESI-MS (M+H) + : 372.1.

Synthesis of 1-(6-(1-(6-isopropylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

The preparation of 1-(6-(1-(6-isopropylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine. 30 mg, as a yellow solid, Y: 76%. ESI-MS (M+H) + : 358.2. HPLC: 100.00% 1 H NMR (400 MHz, CD 3 OD) δ: 9.62 (s, 1H), 8.25 (s, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.89-7.79 (m, 5H), 7.37 (d, J=7.2 Hz, 1H), 7.12 (d, J=6.8 Hz, 1H), 4.24 (q, J=6.4 Hz, 1H), 3.19-3.15 (m, 1H), 1.52 (d, J=6.8 Hz, 3H), 1.46 (d, J=6.8 Hz, 6H).

›Example 122. 1-(6-(1-(pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

Synthesis of 1-(6-(1-(pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone

The preparation of 1-(6-(1-(pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone was the same as that of tert-butyl (6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate. 200 mg, as a white solid, Y: 57%. ESI-MS (M+H) + : 315.1. HPLC: 100.00%.

1 H NMR (400 MHz, CDCl 3 ) δ: 9.52 (s, 1H), 8.52 (dd, J=5.2, 1.2 Hz, 1H), 8.18 (s, 1H), 8.07-8.01 (m, 3H), 7.96 (dd, J=7.6, 0.8 Hz, 1H), 7.89 (t, J=8.0 Hz, 1H), 7.83 (d, J=9.2 Hz, 1H), 7.79 (dd, J=8.4, 1.6 Hz, 1H), 7.13 (dd, J=6.4, 0.8 Hz, 1H), 2.82 (s, 3H).

Synthesis of (E)-1-(6-(1-(pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime

The preparation of (E)-1-(6-(1-(pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one oxime. 140 mg, as a yellow solid, Y: 81%. ESI-MS (M+H) + : 330.1. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.45 (s, 1H), 8.50 (d, J=4.0 Hz, 1H), 8.21 (s, 1H), 8.01-7.97 (m, 2H), 7.88-7.76 (m, 5H), 7.19 (dd, J=7.2, 1.2 Hz, 1H), 2.36 (s, 3H).

Synthesis of 1-(6-(1-(pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

The preparation of 1-(6-(1-(pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine. 100 mg, as yellow oil, Y: 80%. ESI-MS (M+H) + : 316.1. HPLC: 100.00% 1 H NMR (400 MHz, CD 3 OD) δ: 9.26 (s, 1H), 8.44 (dd, J=4.4, 0.8 Hz, 1H), 8.13 (s, 1H), 7.92-7.87 (m, 2H), 7.80-7.78 (m, 1H), 7.77-7.63 (m, 3H), 7.24 (d, J=7.6 Hz, 1H), 7.12 (dd, J=7.2, 5.2 Hz, 1H), 4.10 (q, J=6.8 Hz, 1H), 1.45 (d, J=6.8 Hz, 3H).

›Example 123. (6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol

Synthesis of 6-(6-(6-acetylpyridin-2-yl)-1H-indazol-1-yl)picolinonitrile

The preparation of 6-(6-(6-acetylpyridin-2-yl)-1H-indazol-1-yl)picolinonitrile was the same as that of tert-butyl (6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate. 200 mg, as a white solid, Y: 68%. ESI-MS (M+H) + : 340.1. HPLC: 92.68%. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.72 (s, 1H), 8.63 (d, J=0.8 Hz, 1H), 8.40 (d, J=8.0 Hz, 1H), 8.37 (d, J=8.8 Hz, 1H), 8.27 (d, J=7.6 Hz, 1H), 8.25 (d, J=7.2 Hz, 1H), 8.21-8.15 (m, 2H), 8.09 (d, J=8.4 Hz, 1H), 7.99 (t, J=8.0 Hz, 1H), 2.86 (s, 3H).

Synthesis of methyl 6-(6-(6-acetylpyridin-2-yl)-1H-indazol-1-yl)picolinate

A solution of 6-(6-(6-acetylpyridin-2-yl)-1H-indazol-1-yl)picolinonitrile (180 mg, 0.53 mmol, 1.0 eq) in MeOH (50 mL)/H 2 SO 4 (2 mL) was refluxed for 16 h. After concentration, the residue was dissolved in DCM (100 mL) and adjusted pH=8 with 3 N NaOH solution. The organic phase was concentrated and the residue was purified by silica gel chromatography with PE/EA (1/1) as eluent to give methyl 6-(6-(6-acetylpyridin-2-yl)-1H-indazol-1-yl)picolinate. 118 mg, as a yellow solid, Y: 60%. ESI-MS (M+H) + : 373.1.

Synthesis of (E)-methyl 6-(6-(6-(1-(hydroxyimino)ethyl)pyridin-2-yl)-1H-indazol-1-yl)picolinate

The preparation of (E)-methyl 6-(6-(6-(1-(hydroxyimino)ethyl)pyridin-2-yl)-1H-indazol-1-yl)picolinate was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one oxime. 83 mg, as a white solid, Y: 68%. ESI-MS (M+H) + : 388.2. HPLC: 98.46%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.86 (s, 1H), 8.34 (s, 1H), 8.30 (d, J=8.4 Hz, 1H), 8.24 (dd, J=8.8, 1.6 Hz, 1H), 8.12 (t, J=8.0 Hz, 1H), 8.07 (dd, J=5.6, 4.0 Hz, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.92-7.90 (m, 2H), 4.07 (s, 3H), 2.46 (s, 3H).

Synthesis of methyl 6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)picolinate

The preparation of methyl 6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)picolinate was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine. 56 mg, as a white solid, Y: 80%. ESI-MS (M+H) + : 374.1.

Synthesis of (6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol

The preparation of (6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol was the same as that of (6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-4-yl)methanol. 40 mg, as a white solid, Y: 77%. ESI-MS (M+H) + : 346.2. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.78 (s, 1H), 8.32 (s, 1H), 8.16 (dd, J=8.4, 1.2 Hz, 1H), 8.08 (d, J=7.2 Hz, 1H), 8.03-7.94 (m, 4H), 7.47 (d, J=7.6 Hz, 1H), 7.36 (t, J=4.0 Hz, 1H), 4.89 (s, 2H), 4.71 (q, J=6.8 Hz, 1H), 1.73 (d, J=7.2 Hz, 3H).

›Example 124. 1-(4-methyl-6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

Synthesis of 6-chloro-N-methoxy-N,4-dimethylpicolinamide

The preparation of 6-chloro-N-methoxy-N,4-dimethylpicolinamide was the same as that of 4-bromo-N-methoxy-N-methylpicolinamide. 600 mg, as a yellow solid, Y: 48%. ESI-MS (M+H) + : 215.1.

Synthesis of 1-(6-chloro-4-methylpyridin-2-yl)ethanone

The preparation of 1-(6-chloro-4-methylpyridin-2-yl)ethanone was the same as that of 1-(4-bromopyridin-2-yl)ethanone. 400 mg, as a yellow solid, Y: 84%. ESI-MS (M+H) + : 170.0.

1 H NMR (400 MHz, CDCl 3 ) δ: 7.78 (s, 1H), 7.34 (s, 1H), 2.70 (s, 3H), 2.42 (s, 3H).

Synthesis of 1-(4-methyl-6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone

The preparation of 1-(4-methyl-6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone was the same as that of tert-butyl (6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate. 250 mg, as a yellow solid, Y: 82%. ESI-MS (M+H) + : 343.1. 1 H NMR (400 MHz, CD 3 OD) δ: 9.74 (s, 1H), 8.23 (s, 1H), 8.01 (dd, J=8.4, 0.8 Hz, 1H), 7.90-7.86 (m, 4H), 7.75 (t, J=7.6 Hz, 1H), 7.05 (d, J=7.2 Hz, 1H), 2.90 (s, 3H), 2.70 (s, 3H), 2.53 (s, 3H).

Synthesis of (Z)-1-(4-methyl-6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime

The preparation of (Z)-1-(4-methyl-6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one oxime. 220 mg, as a yellow solid, Y: 84%. ESI-MS (M+H) + : 358.2.

Synthesis of 1-(4-methyl-6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

The preparation of 1-(4-methyl-6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine. 140 mg, as a yellow solid, Y: 76%. ESI-MS (M+H) + :344.1. HPLC: 98.81%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.50 (s, 1H), 8.18 (s, 1H), 7.87 (dd, J=6.8, 1.2 Hz, 1H), 7.79 (d, J=6.8 Hz, 1H), 7.74-7.71 (m, 2H), 7.56 (s, 1H), 7.14 (s, 1H), 7.04 (d, J=5.6 Hz, 1H), 4.08 (q, J=5.2 Hz, 1H), 2.59 (s, 3H), 2.40 (s, 3H), 1.47 (d, J=5.2 Hz, 3H).

Example 125. 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-4-(trifluoromethyl)pyridin-2-yl)ethanamine

Synthesis of 6-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole

The preparation of 6-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole was the same as that of tert-butyl (6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate. 300 mg, as a yellow solid, Y: 36%. ESI-MS (M+H) + : 389.1.

Synthesis of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-4-(trifluoromethyl)picolinonitrile

A mixture of 6-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole (300 mg, 0.77 mmol, 1.0 eq), Zn(CN) 2 (179 mg, 1.54 mmol, 2.0 eq) and Pd(PPh 3 ) 4 (92 mg, 0.08 mmol, 0.1 eq) in DMF (5 mL) was stirred at 95° C. for 16 h. After cooling down to rt, the mixture was diluted with water (50 mL) and extracted with EA (3×60 mL). The combined organic phase was washed with brine and dried over Na 2 SO 4 . After filtration and concentration, the residue was purified by column chromatography on silica gel (PE/EA=5/1) to give 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-4-(trifluoromethyl)picolinonitrile as a brown solid. 480 mg, Y: 79%. ESI-MS (M+H) + : 380.2. 1 H NMR (400 MHz, CD 3 OD) δ: 9.67 (s, 1H), 8.30 (s, 1H), 8.24 (s, 1H), 8.02 (dd, J=8.4, 2.0 Hz, 1H), 7.85-7.91 (m, 3H), 7.76 (t, J=8.0 Hz, 1H), 7.06 (t, J=7.6 Hz, 1H), 2.70 (s, 3H).

Synthesis of 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-4-(trifluoromethyl)pyridin-2-yl)ethanamine

To a solution of 6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-4-(trifluoromethyl)picolinonitrile (92 mg, 0.24 mmol, 1.0 eq) in anhydrous THF was added MeMgBr (1 M in THF solution, 0.7 mmol, 0.7 ml) at rt. The mixture was stirred at rt for 3 h under N 2 . The mixture was added to a solution of NaBH 4 (45 mg, 1.2 mmol, 5.0 eq) in MeOH (20 mL) at rt. The mixture was stirred at rt for 1 h, quenched with H 2 O (30 mL) and extracted by DCM (4×30 mL). The combined organic phase was washed with brine (30 mL) and dried over Na 2 SO 4 . After filtration and concentration, the residue was purified by prep-HPLC (MeOH/H 2 O with 0.05% NH 4 OH as mobile phase from 5% to 95%) to give 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-4-(trifluoromethyl)pyridin-2-yl)ethanamine as a white solid. 54 mg, Y: 56%. ESI-MS (M+H) + : 398.2. HPLC: 95.86%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.71 (s, 1H), 8.34 (s, 1H), 8.31 (s, 1H), 8.22 (dd, J=8.4, 1.2 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.90-7.84 (m, 3H), 7.18 (d, J=6.4 Hz, 1H), 4.84 (q, J=6.8 Hz, 1H), 2.71 (s, 3H), 1.77 (d, J=7.2 Hz, 3H).

›Example 126. 6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)picolinamide

Synthesis of 6-(6-(6-acetylpyridin-2-yl)-1H-indazol-1-yl)picolinamide

The preparation of 6-(6-(6-acetylpyridin-2-yl)-1H-indazol-1-yl)picolinamide was the same as that of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)picolinamide. 120 mg, as a yellow solid, Y: 48%. ESI-MS (M+H) + : 358.1.

Synthesis of (E)-6-(6-(6-(1-(hydroxyimino)ethyl)pyridin-2-yl)-1H-indazol-1-yl)picolinamide

The preparation of (E)-6-(6-(6-(1-(hydroxyimino)ethyl)pyridin-2-yl)-1H-indazol-1-yl)picolinamide was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one oxime. 100 mg, as yellow oil, Y: 79%. ESI-MS (M+H) + : 373.1. 1 H NMR (400 MHz, CD 3 OD) δ: 9.41 (s, 1H), 8.38 (s, 1H), 8.28 (d, J=8.0 Hz 1H), 8.17 (t, J=8.0 Hz, 1H), 8.11 (dd, J=8.4, 1.2 Hz, 1H), 8.03 (d, J=8.0 Hz 1H), 8.01-7.97 (m, 2H), 7.90 (s, 1H), 7.89 (d, J=7.2 Hz 1H), 2.45 (s, 3H).

Synthesis of 6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)picolinamide

The preparation of 6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)picolinamide was the same as that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine. 43 mg, as a yellow solid, Y: 44%. ESI-MS (M+H) + : 359.2. HPLC: 100.00% 1 H NMR (400 MHz, CD 3 OD) δ: 9.45 (s, 1H), 8.38 (s, 1H), 8.25 (d, J=8.4 Hz, 1H), 8.21 (dd, J=8.4, 1.2 Hz, 1H), 8.15 (t, J=7.6 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 8.02 (d, J=7.6 Hz, 1H), 8.00-7.97 (m, 2H), 7.49 (d, J=7.6 Hz, 1H), 4.71 (q, J=6.8 Hz, 1H), 1.73 (d, J=6.8 Hz, 3H).

›Example 127. 1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propan-1-amine

Synthesis of 1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propan-1-amine

To a solution of 6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)picolinonitrile (180 mg, 0.49 mmol, 1.0 eq) in anhydrous toluene was added EtMgBr (1 M in THF solution, 0.6 mmol, 0.6 ml) at rt. The mixture was stirred at 100° C. for 20 min under microwave. After cooling to rt, the mixture was added to a solution of NaBH 4 (28 mg, 0.74 mmol, 1.5 eq) in MeOH (20 mL) at 0° C. The mixture was stirred at rt for 30 min, quenched with H 2 O (30 mL) and extracted by DCM (4×30 mL). The combined organic phase was washed with brine (30 mL) and dried over Na 2 SO 4 . After filtration and concentration, the residue was purified by prep-HPLC (MeOH/H 2 O with 0.05% NH 4 OH as mobile phase from 5% to 95%) to give 1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propan-1-amine as a yellow solid. 29 mg, Y: 15%. ESI-MS (M+H) + : 398.1. HPLC: 93.13%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.62 (d, J=0.4 Hz, 1H), 8.36 (s, 1H), 8.35 (d, J=8.0 Hz, 1H), 8.17 (t, J=8.0 Hz, 1H), 8.06 (dd, J=8.4, 1.2 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.90-7.84 (m, 2H), 7.68 (d, J=7.2 Hz, 1H), 7.34 (dd, J=6.8, 2.0 Hz, 1H), 3.94 (t, J=6.8 Hz, 1H), 1.98-1.86 (m, 2H), 0.94 (d, J=7.2 Hz, 3H).

Example 128. cyclopropyl(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methanamine

Synthesis of cyclopropyl(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methanamine

The preparation of cyclopropyl(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methanamine was the same as that of 1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propan-1-amine. 83 mg, as brown oil, Y: 37%. ESI-MS (M+H) + : 410.2. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.62 (s, 1H), 8.36 (s, 1H), 8.35 (d, J=7.6 Hz, 1H), 8.17 (t, J=8.0 Hz, 1H), 8.09 (dd, J=8.4, 1.2 Hz, 1H), 7.94 (dd, J=8.4, 0.8 Hz, 1H), 7.92-7.88 (m, 2H), 7.68 (d, J=7.6 Hz, 1H), 7.41 (dd, J=6.4, 2.4 Hz, 1H), 3.33 (d, J=6.8 Hz, 1H), 1.29-1.27 (m, 1H), 0.72-0.70 (m, 1H), 0.58-0.43 (m, 3H).

›Example 129. 2-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propan-2-amine

Synthesis of 2-(6-bromopyridin-2-yl)propan-2-ol

To a solution of 1-(6-bromo-pyridin-2-yl)-ethanone (4.0 g, 20 mmol) in anhydrous THF (50 mL) at 0° C. was added a solution of methyl magnesium bromide (3.0 M, 8.0 mL, 24 mmol, 1.2 eq) in THF dropwise over 20 min. The mixture was stirred at rt for 16 h, quenched with H 2 O (30 mL) and extracted by EA (4×30 mL). The organic phase was washed with brine (30 mL) and dried over Na 2 SO 4 . After filtration and concentration, the residue was directly used for next step without further purification. 4.2 g, Y: 98%. ESI-MS (M+H) + : 216.0

Synthesis of N-(2-(6-bromopyridin-2-yl)propan-2-yl)acetamide

To a solution of 2-(6-bromopyridin-2-yl)propan-2-ol (2.0 g, 9.26 mmol) in MeCN (30 mL) was added BF 3 -Et 2 O (3.7 mL, 23.1 mmol, 2.5 eq) at rt. The mixture was refluxed for 16 h. After cooling to rt, the mixture was neutralized with 5 N NaOH and extracted with DCM (100 mL). The organic phase was washed with brine (30 mL) and dried over Na 2 SO 4 . After filtration and concentration, the residue was purified by column chromatography (silica gel, PE/EA=1/1) to afford the compound N-(2-(6-bromopyridin-2-yl)propan-2-yl)acetamide (860 mg, Y: 36%). ESI-MS (M+H) + : 257.0

Synthesis of N-(2-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propan-2-yl)acetamide

The preparation of N-(2-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propan-2-yl)acetamide was the same as that of tert-butyl (6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate. 100 mg, as a white solid, Y: 46%. ESI-MS (M+H) + : 440.1

Synthesis of 2-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propan-2-amine

A mixture of N-(2-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propan-2-yl)acetamide (100 mg, 0.23 mmol) in conc. HCl (5 mL) was refluxed for 16 h. After concentration, the residue was basified with sat. NaHCO 3 and extracted with DCM (3×30 mL). The combined organic layers were washed with brine and dried over Na 2 SO 4 . After filtration and concentration, the residue was purified by prep-HPLC (MeOH/H 2 O with 0.05% NH 4 OH as mobile phase from 5% to 95%) to give 2-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propan-2-amine as a brown solid. 70 mg, Y: 77%. ESI-MS (M+H) + : 398.2. HPLC: 100.00%. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.55 (s, 1H), 8.21 (d, J=8.4 Hz, 1H), 8.17 (s, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.93 (t, J=8.0 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.73-7.70 (m, 2H), 7.46 (d, J=8.4 Hz, 1H), 7.37-7.35 (m, 1H), 2.29 (br, 2H), 1.56 (s, 6H).

›Example 130. 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanol

Synthesis of 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone

The preparation of 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone was the same as that of tert-butyl (6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate. 100 mg, as a yellow solid. Y: 68%. ESI-MS (M+H) + : 329.1.

Synthesis of 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanol

To a solution of 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone (100 mg, 0.3 mmol, 1.0 eq) in MeOH (2 mL) was added NaBH 4 (23 mg, 0.6 mmol, 2.0 eq) at rt. The mixture was stirred at rt for 1 h. After concentration, the residue was purified by Pre-HPLC (MeOH/H 2 O with 0.05% NH 4 OH as mobile phase from 5% to 95%) to give 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanol as a yellow solid. 60 mg, Y: 60%. ESI-MS (M+H) + : 331.1. HPLC: 98.98%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.51 (s, 1H), 8.23 (s, 1H), 7.93-7.77 (m, 6H), 7.50 (d, J=7.6 Hz, 1H), 7.10-7.08 (m, 1H), 4.96 (q, J=6.8 Hz, 1H), 2.63 (s, 3H), 1.58 (d, J=6.4 Hz, 3H).

›Example 131. cyclopropyl(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methanamine

Synthesis of cyclopropyl(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methanamine

The preparation of cyclopropyl(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methanamine was the same as that of 1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propan-1-amine. 167 mg, as a yellow solid, Y: 45%. ESI-MS (M+H) + : 356.2. HPLC: 96.74%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.42 (s, 1H), 8.17 (s, 1H), 8.06 (dd, J=8.0, 0.8 Hz, 1H), 7.89 (s, 1H), 7.88 (d, J=1.2 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.71-7.68 (m, 2H), 7.42-7.40 (m, 1H), 7.03 (dd, J=6.0, 2.0 Hz, 1H), 3.79 (d, J=6.0 Hz, 1H), 2.56 (s, 3H), 1.31-1.29 (m, 1H), 0.79-0.62 (m, 4H).

›Example 132. 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-amine

Synthesis of 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-amine

The preparation of 1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-amine was the same as that of 1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propan-1-amine. 7.9 mg, as yellow oil, Y: 18%. ESI-MS (M+H) + : 358.2. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.50 (s, 1H), 8.18 (s, 1H), 7.88 (dd, J=8.4, 1.6 Hz, 1H), 7.81-7.69 (m, 5H), 7.23 (dd, J=7.2, 1.6 Hz, 1H), 7.03 (dd, J=6.8, 1.2 Hz, 1H), 3.94 (t, J=6.0 Hz, 1H), 2.57 (s, 3H), 1.86-1.67 (m, 2H), 1.37-1.21 (m, 2H), 0.86 (t, J=6.8 Hz, 3H).

›Example 134. 1-(6-(1-(4-methylthiazol-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

Synthesis of 2-(6-bromo-1H-indazol-1-yl)-4-methylthiazole

The preparation of 2-(6-bromo-1H-indazol-1-yl)-4-methylthiazole was the similar to that of 6-bromo-1-(6-methylpyridin-2-yl)-1H-indazole. 200 mg, as a brown solid, Y: 32%. ESI-MS (M+H) + : 294.0. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.78 (s, 1H), 8.06 (s, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.36 (dd, J=8.5, 1.5 Hz, 1H), 6.55 (s, 1H), 2.42 (s, 3H).

Synthesis of 4-methyl-2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)thiazole

The preparation of 4-methyl-2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)thiazole was the similar to that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 180 mg, as a pale yellow solid, Y: 78%. ESI-MS (M+H) + : 342.1.

Synthesis of 1-(6-(1-(4-methylthiazol-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone

The preparation of 1-(6-(1-(4-methylthiazol-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone was the similar to that of tert-butyl (6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate. 114 mg, as a white solid, Y: 56%. ESI-MS (M+H) + : 335.1. HPLC: 98.62%. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.44 (s, 1H), 8.22 (s, 1H), 8.18-8.07 (m, 2H), 8.04 (d, J=6.9 Hz, 1H), 7.97 (t, J=7.7 Hz, 1H), 7.89 (d, J=8.4 Hz, 1H), 6.64 (s, 1H), 2.90 (s, 3H), 2.51 (s, 3H).

Synthesis of (Z)-1-(6-(1-(4-methylthiazol-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime

The preparation of (Z)-1-(6-(1-(4-methylthiazol-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime was the similar to that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one oxime. 75 mg, as a white solid, Y: 72%. ESI-MS (M+H) + : 350.1. HPLC: 94.61%. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 11.63 (s, 1H), 9.50 (s, 1H), 8.54 (s, 1H), 8.16 (dd, J=8.5, 1.3 Hz, 1H), 8.10 (d, J=7.6 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.97 (t, J=7.8 Hz, 1H), 7.90 (d, J=7.6 Hz, 1H), 7.08 (d, J=1.0 Hz, 1H), 2.45 (s, 3H), 2.41 (s, 3H).

Synthesis of 1-(6-(1-(4-methylthiazol-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

The preparation of 1-(6-(1-(4-methylthiazol-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine was the similar to that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine. 30 mg, as a white solid, Y: 45%. ESI-MS (M+H) + : 336.1. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.17 (s, 1H), 8.18 (s, 1H), 8.05-7.90 (m, 1H), 7.89-7.70 (m, 3H), 7.30 (d, J=6.6 Hz, 1H), 6.73 (s, 1H), 4.28-4.03 (m, 1H), 2.38 (s, 3H), 1.44 (d, J=6.7 Hz, 3H).

›Example 135. 1-(6-(1-(5-methylthiazol-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

Synthesis of 2-(6-bromo-1H-indazol-1-yl)-5-methylthiazole

The preparation of 2-(6-bromo-1H-indazol-1-yl)-5-methylthiazole was the similar to that of 6-bromo-1-(6-methylpyridin-2-yl)-1H-indazole. 200 mg, as a brown solid, Y: 33%. ESI-MS (M+H) + : 294.0. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.81 (s, 1H), 8.11 (s, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.42 (dd, J=8.5, 1.6 Hz, 1H), 7.26 (s, 1H), 2.48 (d, J=1.2 Hz, 3H).

Synthesis of 5-methyl-2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)thiazole

The preparation of 5-methyl-2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)thiazole was the similar to that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 187 mg, as a pale yellow solid, Y: 80%. ESI-MS (M+H) + : 342.1.

Synthesis of 1-(6-(1-(5-methylthiazol-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone

The preparation of 1-(6-(1-(5-methylthiazol-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone was the similar to that of tert-butyl (6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate. 114 mg, as a white solid, Y: 62%. ESI-MS (M+H) + : 335.1. HPLC: 100.00%. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.25 (s, 1H), 8.22-8.10 (m, 3H), 8.06-8.00 (m, 1H), 7.97 (d, J=7.7 Hz, 1H), 7.89 (d, J=8.5 Hz, 1H), 7.30 (d, J=1.3 Hz, 1H), 2.88 (s, 3H), 2.50 (d, J=1.2 Hz, 3H).

Synthesis of (Z)-1-(6-(1-(5-methylthiazol-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime

The preparation of (Z)-1-(6-(1-(5-methylthiazol-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime was the similar to that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one oxime. 79 mg, as a white solid, Y: 82%. ESI-MS (M+H) + : 350.1. HPLC: 100.00%. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 11.63 (s, 1H), 9.50 (s, 1H), 8.54 (s, 1H), 8.16 (dd, J=8.5, 1.3 Hz, 1H), 8.10 (d, J=7.6 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.97 (t, J=7.8 Hz, 1H), 7.90 (d, J=7.6 Hz, 1H), 7.08 (d, J=1.0 Hz, 1H), 2.45 (s, 3H), 2.41 (s, 3H).

Synthesis of 1-(6-(1-(5-methylthiazol-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

The preparation of 1-(6-(1-(5-methylthiazol-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine was the similar to that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine. 30 mg, as a white solid, Y: 75%. ESI-MS (M+H) + : 336.1. HPLC: 100.00%. H NMR (400 MHz, CD 3 OD) δ: 9.04 (s, 1H), 8.17 (s, 1H), 8.00 (dd, J=8.4, 1.4 Hz, 1H), 7.86-7.74 (m, 3H), 7.29 (dd, J=6.3, 2.2 Hz, 1H), 7.24 (d, J=1.3 Hz, 1H), 4.11 (q, J=6.7 Hz, 1H), 2.39 (d, J=1.2 Hz, 3H), 1.42 (d, J=6.7 Hz, 3H).

›Example 136. 1-(6-(1-(2-methylthiazol-4-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

Synthesis of 6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

To a mixture of 6-bromo-1H-indazole (CAS #79762-54-2) (750 mg, 3.83 mmol, 1.0 eq) in THF (15 mL), DHP (2.8 g, 7.66 mmol, 2.0 eq) and TsOH (132 mg, 0.77 mmol, 0.2 eq) were added. The mixture was stirred at 60° C. for 12 h. The solvent was removed in vacuo. The residue was diluted with ethyl acetate (50 mL) and washed with H 2 O (10 mL×3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EA=10/1) to give 6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole as a yellow solid. 783 mg, Y: 73%. ESI-MS (M+H) + : 281.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 7.92 (s, 1H), 7.72 (s, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.21 (dd, J=8.4, 1.6 Hz, 1H), 5.60 (dd, J=9.2, 2.8 Hz, 1H), 3.98-3.95 (m, 1H), 3.72-3.65 (m, 1H), 2.48-2.45 (m, 1H), 2.10-1.99 (m, 2H), 1.72-1.48 (m, 3H).

Synthesis of 1-(tetrahydro-2H-pyran-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

The preparation of 1-(tetrahydro-2H-pyran-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole was the similar to that of 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 734 mg, as a yellow solid, Y: 80%. ESI-MS (M+H) + : 329.2.

Synthesis of 1-(6-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone

The preparation of 1-(6-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone was the similar to that of tert-butyl (6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate. 503 mg, as a yellow solid, Y: 62%. ESI-MS (M+H) + : 322.1.

Synthesis of 1-(6-(1H-indazol-6-yl)pyridin-2-yl)ethanone

A solution of 1-(6-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone (503 mg, 1.57 mmol, 1.0 eq) in DCM (2 mL)/TFA (2 mL) was stirred at rt for 16 h. The solvent was removed in vacuo. The residue was adjusted to pH=8 with saturated NaHCO 3 solution and then purified by column chromatography on silica gel (PE/EA=3/1) to give 1-(6-(1H-indazol-6-yl)pyridin-2-yl)ethanone as a white solid. 268 mg, Y: 72%. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.31 (d, J=0.8 Hz, 1H), 8.15 (s, 1H), 8.03-8.01 (m, 2H), 7.96-7.90 (m, 3H), 2.87 (s, 3H).

Synthesis of 1-(6-(1-(2-methylthiazol-4-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone

A mixture of 47-SM04 (237 mg, 1.0 mmol), 298694-30-1 (248 mg, 1.4 mmol, 1.4 eq), K 3 PO 4 (424 mg, 2.0 mmol, 2.0 eq) and trans-N,N′-Dimethylcyclohexane-1,2-diamine (28 mg, 0.2 mmol, 0.2 eq) in toluene (5 mL) was stirred at 110° C. for 16 h under N 2 . After concentration, the residue was purified by column chromatography on silica gel (PE/EA=3/1) to give 1-(6-(1-(2-methylthiazol-4-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone as a white solid. 150 mg, Y: 45%. ESI-MS (M+H) + : 335.1.

Synthesis of (Z)-1-(6-(1-(2-methylthiazol-4-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime

The preparation of (Z)-1-(6-(1-(2-methylthiazol-4-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime was the similar to that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one oxime. 156 mg, as a white solid, Y: 100%. ESI-MS (M+H) + : 350.1.

Synthesis of 1-(6-(1-(2-methylthiazol-4-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

The preparation of 1-(6-(1-(2-methylthiazol-4-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine was the similar to that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine. 55 mg, as a yellow solid, Y: 75%. ESI-MS (M+H) + : 336.1. HPLC: 95.88%. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.00 (s, 1H), 8.12 (s, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.71-7.65 (m, 2H), 7.19-7.18 (m, 2H), 4.19 (q, J=6.4 Hz, 1H), 2.77 (s, 3H), 2.05 (br, 2H), 1.47 (d, J=6.8 Hz, 3H).

›Example 137. 1-(6-(1-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

Synthesis of 1-(6-(1-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone

The preparation of 1-(6-(1-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone was the similar to that of 1-(6-(1-(2-methylthiazol-4-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone. 166 mg, as a yellow solid, Y: 53%. ESI-MS (M+H) + : 318.1. 1 H NMR (400 MHz, CD 3 OD) δ: 9.11 (s, 1H), 8.27 (s, 1H), 8.25 (d, J=8.0 Hz, 1H), 8.13-7.95 (m, 4H), 7.71 (d, J=2.0 Hz, 1H), 6.61 (d, J=2.4 Hz, 1H), 4.01 (s, 3H), 2.86 (s, 3H).

Synthesis of (Z)-1-(6-(1-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime

The preparation of (Z)-1-(6-(1-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime was the similar to that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one oxime. 155 mg, as a white solid, Y: 89%. ESI-MS (M+H) + : 333.1.

Synthesis of 1-(6-(1-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

The preparation of 1-(6-(1-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine was the similar to that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine. 97 mg, as a yellow solid, Y: 66%. ESI-MS (M+H) + : 319.2. HPLC: 99.84%. 1 H NMR (400 MHz, CD 3 OD) δ: 8.76 (s, 1H), 8.09-8.07 (m, 1H), 7.83-7.81 (m, 1H), 7.73-7.65 (m, 3H), 7.53-7.51 (m, 1H), 7.20-7.18 (m, 1H), 6.45 (d, J=2.8 Hz, 1H), 4.03 (q, J=6.4 Hz, 1H), 2.85 (s, 3H), 1.36 (d, J=6.8 Hz, 3H).

›Example 138. 1-(6-(1-(1-methyl-1H-imidazol-4-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

Synthesis of 1-(6-(1-(1-methyl-1H-imidazol-4-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone

The preparation of 1-(6-(1-(1-methyl-1H-imidazol-4-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone was the similar to that of 1-(6-(1-(2-methylthiazol-4-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone. 200 mg, as a yellow solid, Y: 32%. ESI-MS (M+H) + : 318.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.99 (s, 1H), 8.15 (d, J=0.8 Hz, 1H), 8.10 (dd, J=8.0, 1.2 Hz, 1H), 8.07 (dd, J=8.4, 1.6 Hz, 1H), 7.99 (dd, J=8.0, 1.2 Hz, 1H), 7.92 (t, J=7.6 Hz, 1H), 7.87 (dd, J=8.8, 0.8 Hz, 1H), 7.45 (d, J=1.2 Hz, 1H), 7.21 (d, J=2.0 Hz, 1H), 3.80 (s, 3H), 2.86 (s, 3H).

Synthesis of (Z)-1-(6-(1-(1-methyl-1H-imidazol-4-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime

The preparation of (Z)-1-(6-(1-(1-methyl-1H-imidazol-4-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime was the similar to that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one oxime. 167 mg, as a white solid, Y: 80%. ESI-MS (M+H) + : 333.1.

Synthesis of 1-(6-(1-(1-methyl-1H-imidazol-4-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

The preparation of 1-(6-(1-(1-methyl-1H-imidazol-4-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine was the similar to that of 2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine. 103 mg, as a yellow solid, Y: 64%. ESI-MS (M+H) + : 319.1. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 8.49 (s, 1H), 8.13-8.11 (m, 1H), 7.91-7.88 (m, 1H), 7.81-7.79 (m, 1H), 7.74-7.70 (m, 2H), 7.62-7.59 (m, 1H), 7.32-7.24 (m, 2H), 4.08 (q, J=6.8 Hz, 1H), 3.75 (s, 3H), 1.40 (d, J=6.8 Hz, 3H).

›Example 139. (2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)thiazol-4-yl)methanamine

Synthesis of 2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)thiazole-4-carbonitrile

The preparation of 2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)thiazole-4-carbonitrile was the similar to that of tert-butyl (6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate. 60 mg, as a yellow solid, Y: 31%. ESI-MS (M+H) + : 317.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.57 (s, 1H), 8.23 (d, J=0.7 Hz, 1H), 8.03 (s, 1H), 7.94 (dd, J=8.4, 1.5 Hz, 1H), 7.90-7.83 (m, 2H), 7.80-7.72 (m, 1H), 7.08 (d, J=7.4 Hz, 1H), 2.71 (s, 3H).

Synthesis of (2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)thiazol-4-yl)methanamine

To a solution of 2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)thiazole-4-carbonitrile (59 mg, 0.19 mmol, 1.0 eq) in THF/NH 4 OH (2 mL/0.5 mL) was added Raney-Ni (6 mg) at rt. The mixture was stirred at rt for 2 h under H 2 . After filtration and concentration, the residue was purified by prep-HPLC (MeOH/H 2 O with 0.05% NH 4 OH as mobile phase from 5% to 95%) to afford (2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)thiazol-4-yl)methanamine as a pale yellow solid. 12 mg, Y: 20%. ESI-MS (M+H) + : 321.1. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.29 (s, 1H), 8.12 (s, 1H), 7.81-7.65 (m, 4H), 7.29 (s, 1H), 7.02-6.96 (m, 1H), 3.90 (s, 2H), 2.54 (s, 3H).

›Example 140. (2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)thiazol-5-yl)methanamine

Synthesis of 2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)thiazole-5-carbonitrile

The preparation of 2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)thiazole-5-carbonitrile was the similar to that of tert-butyl (6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate. 87 mg, as a yellow solid, Y: 22%. ESI-MS (M+H) + : 317.1.

Synthesis of (2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)thiazol-5-yl)methanamine

The preparation of (2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)thiazol-5-yl)methanamine was the similar to that of (2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)thiazol-4-yl)methanamine. 14 mg, as a pale green solid, Y: 20%. ESI-MS (M+H) + : 321.1. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.40 (s, 1H), 8.19 (s, 1H), 7.90-7.68 (m, 5H), 7.05 (d, J=5.8 Hz, 1H), 4.40 (s, 2H), 2.58 (s, 3H).

›Example 141. (R)-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

Synthesis of (R,E)-N-(1-(6-bromopyridin-2-yl)ethylidene)-2-methylpropane-2-sulfinamide

To a solution of 1-(6-bromopyridin-2-yl)ethanone (4.00 g, 20.0 mmol, 1.0 eq) and (R)-2-methylpropane-2-sulfinamide (2.42 g, 20.0 mmol, 1.0 eq) in THF (80 mL) was added Ti(OEt) 4 (9.12 g, 40.0 mmol, 2.0 eq) at room temperature. The mixture was stirred at 70° C. for 16 h. After cooling down to room temperature, the mixture was diluted with water (200 mL) and extracted with DCM (2×200 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After concentration, the residue was purified by silica gel chromatography with PE/EA (10/1) as eluent to give (R,E)-N-(1-(6-bromopyridin-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (4.83 g, yield: 80%) as a yellow solid. ESI-MS (M+H) + : 303.0. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.06 (d, J=7.6 Hz, 1H), 7.63-7.54 (m, 2H), 2.81 (s, 3H), 1.30 (s, 9H).

Synthesis of (R)—N—((R)-1-(6-bromopyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide

To a solution of (R,E)-N-(1-(6-bromopyridin-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (4.40 g, 14.5 mmol, 1.0 eq) in THF (60 mL) was added NaBH 4 (1.65 g, 43.5 mmol, 3.0 eq) at −50° C. The mixture was warmed to room temperature over 3 h. The mixture was diluted with EA (200 mL) and washed with water (2×100 mL). The organics were dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by silica gel chromatography with PE/EA (2/1) as eluent to give (R)—N—((R)-1-(6-bromopyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (2.2 g, yield: 51%) as a white solid. ESI-MS (M+H) + : 305.1, 307.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 7.76 (t, J=8.6 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 5.84 (d, J=8.0 Hz, 1H), 4.41-4.37 (m, 1H), 1.41 (d, J=6.8 Hz, 3H), 1.13 (s, 9H).

the R configuration was confirmed according

to specific optical activity (Ref. Heterocycles 2000, 52, 719-732)

Synthesis of (R)-2-methyl-N—((R)-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)propane-2-sulfinamide

A mixture of (R)—N—((R)-1-(6-bromopyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (185 mg, 0.6 mmol, 1.0 eq), 1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (201 mg, 0.6 mmol, 1.0 eq) and K 2 CO 3 (167 mg, 1.2 mmol, 2.0 eq) in 1, 4-dioxane/H 2 O (5 mL/0.5 mL) was stirred while purging N 2 at room temperature for 10 min. To this system was added Pd(dppf)Cl 2 (44 mg, 0.06 mmol, 0.1 eq) and heated to 110° C. for 2 h. The mixture was diluted with EA (50 mL), washed with water (50 mL) and brine (50 mL). The organics were dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by silica gel chromatography with PE/EA (3/1) as eluent to give (R)-2-methyl-N—((R)-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)propane-2-sulfinamide (132 mg, yield: 51%) as a white solid. ESI-MS (M+H) + : 434.1.

Synthesis of (R)-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

To a solution of (R)-2-methyl-N—((R)-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)propane-2-sulfinamide (132 mg, 0.3 mmol, 1.0 eq) in EA (3 mL) was added. conc. HCl (cat.). The mixture was stirred for 0.5 h at room temperature. The resulting mixture was adjusted to pH=7-8 with sat NaHCO 3 and extracted with EA (2×50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration and concentration, the residue was purified by pre-HPLC (MeCN/H 2 O with 0.05% NH 4 OH as mobile phase from 5% to 95%) to give (R)-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine as a white solid (72 mg, yield: 73%). ESI-MS (M+H) + : 330.0. HPLC: 94.94%. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.63 (s, 1H), 8.29 (s, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.92-7.84 (m, 5H), 7.39 (d, J=6.4 Hz, 1H), 7.15 (d, J=6.4 Hz, 1H), 4.25-4.23 (m, 1H), 2.69 (s, 3H), 1.55 (d, J=6.4 Hz, 3H).

›Example 142. (S)-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

Synthesis of (R)—N—((S)-1-(6-bromopyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide

To a solution of (R,E)-N-(1-(6-bromopyridin-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (3.4 g, 11.3 mmol, 1.0 eq) in THF (30 mL) was added L-selectride (34 mL, 34 mmol, 3.0 eq) at 0° C. The mixture was stirred at 0° C. for 3 h. The mixture was quenched with NH 4 Cl (aq.) (5 mL) and extracted with EA (2×100 mL). The organics were dried (MgSO 4 ) and concentrated in vacuo. The residue was dissolved in DCM (5 mL) and a white solid was precipitated out while PE (100 mL) was added into the solution. After filtration, the white solid (R)—N—((S)-1-(6-bromopyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide was dried in vacuo. 1.5 g, yield: 44%. ESI-MS (M+H) + : 305.1, 307.1. 1 H NMR (400 MHz, CD 3 OD) δ: 7.68 (t, J=8.0 Hz, 1H), 7.49-7.45 (m, 2H), 4.56 (q, J=6.8 Hz, 1H), 1.59 (d, J=6.8 Hz, 3H), 1.23 (s, 9H).

the s configuration was confirmed according

to specific optical activity

(Ref. Organometallics 2010, 29, 3563{umlaut over ( )}C3570)

Synthesis of (R)-2-methyl-N—((S)-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)propane-2-sulfinamide

The preparation of (R)-2-methyl-N—((S)-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)propane-2-sulfinamide was similar to that of (R)-2-methyl-N—((R)-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)propane-2-sulfinamide to give 200 mg as a white solid, Y: 66%. ESI-MS (M+H) + : 434.2. 1 H NMR (400 MHz, CD 3 OD) δ: 9.60 (s, 1H), 8.30 (s, 1H), 8.01 (dd, J=8.4, 1.2 Hz, 1H), 7.94-7.84 (m, 5H), 7.47 (dd, J=7.2, 1.2 Hz, 1H), 7.16 (dd, J=6.4, 1.6 Hz, 1H), 4.74 (q, J=6.8 Hz, 1H), 2.70 (s, 3H), 1.76 (d, J=7.2 Hz, 3H), 1.24 (s, 9H).

Synthesis of (S)-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine

The preparation of (S)-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine was similar to that of (R)-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine to give 60 mg as a yellow solid, Y: 61%. ESI-MS (M+H) + : 330.1. HPLC: 94.21%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.38 (s, 1H), 8.05 (d, J=6.0 Hz, 1H), 7.79-7.77 (m, 1H), 7.69-7.57 (m, 5H), 7.19 (d, J=7.2 Hz, 1H), 6.91 (d, J=6.8 Hz, 1H), 4.04 (q, J=6.8 Hz, 1H), 2.46 (s, 3H), 1.39 (d, J=6.8 Hz, 3H).

Example 143. (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol

›Step 1. Synthesis of 2-bromo-6-(((tert-butyldimethylsilyl)oxy)methyl)pyridine

To a mixture of (6-bromopyridin-2-yl)methanol (CAS #33674-96-3) (1.87 g, 0.01 mol, 1.0 eq) and imidazole (1.36 g, 0.02 mmol, 2.0 eq) in DMF (10 mL) was added TBSCl (2.25 g, 0.015 mol, 1.5 eq) at rt. The mixture was stirred at room temperature for 1 h. The mixture was diluted with water (50 mL) and extracted with EA (3×20 mL). The combined organic phases were washed with brine (10 mL) and dried over Na 2 SO 4 . After filtration and concentration, the residue was purified by column chromatography (silica gel, PE/EA=50/1) to give 2-bromo-6-(((tert-butyldimethylsilyl)oxy)methyl)pyridine as yellow oil (2.35 g, Y: 78%). ESI-MS (M+H) + : 302.1.

›Step 2. Synthesis of 6-bromo-1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazole

A mixture of 2-bromo-6-(((tert-butyldimethylsilyl)oxy)methyl)pyridine (1 g, 3.32 mmol), 6-bromo-1H-indazole (CAS #79762-54-2) (0.651 g, 3.32 mmol, 1.0 eq), K 3 PO 4 (1.41 g, 6.64 mmol, 2.0 eq), CuI (63 mg, 0.33 mmol, 0.1 eq) and trans-N,N′-dimethylcyclohexane-1,2-diamine (93 mg, 0.66 mmol, 0.2 eq) in toluene (1 mL) was stirred at 110° C. for 16 h under N 2 . After concentration, the residue was purified by column chromatography on silica gel (PE/EA=10/1) to give the mixture of 6-bromo-1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazole and 6-bromo-2-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-2H-indazole (the ratio 9/1) as a yellow solid. 0.91 g, Y: 65%. ESI-MS (M+H) + : 418.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.03 (s, 1H), 8.15 (s, 1H), 7.87-7.84 (m, 2H), 7.62 (d, J=8.8 Hz, 1H), 7.40-7.37 (m, 2H), 4.93 (s, 2H), 1.00 (s, 9H), 0.20 (s, 6H).

Step 3. Synthesis of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

A mixture of 6-bromo-1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazole and 6-bromo-2-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-2H-indazole (0.83 g, 1.99 mmol), pinacol diborane (CAS #73183-34-3) (0.531 g, 2.09 mmol, 1.05 eq) and CH 3 COOK (0.39 g, 3.98 mmol, 2.0 eq) in 1, 4-dioxane (15 mL) was stirred while purging N 2 at room temperature for 10 min. To this system was added Pd(dppf)Cl 2 (0.326 g, 0.4 mmol, 0.1 eq) and heated to 90° C. for 2 h. The mixture was diluted with EA (50 mL) and washed with saturated aqueous NaHCO 3 solution (20 mL) and brine (20 mL). The organics were dried (Na 2 SO 4 ) and concentrated in vacuo. The crude mixture was purified by silica gel chromatography with PE/EA (10/1) as eluent to give 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole and 2-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (the ratio 9/1). 0.74 g, as a yellow solid, Y: 80%. ESI-MS (M+H) + : 466.2.

Step 4. Synthesis of (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide

A mixture of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole and 2-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (0.74 g, 1.59 mmol), (R)—N—((S)-1-(6-bromopyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (0.532 g, 1.75 mmol, 1.1 eq) and K 2 CO 3 (0.439 g, 3.18 mmol, 2.0 eq) in 1, 4-dioxane/H 2 O (10 mL/1 mL) was stirred while purging N 2 at room temperature for 10 min. To this system was added Pd(dppf)Cl 2 (0.131 g, 0.16 mmol, 0.1 eq) and heated to 110° C. for 2 h. The mixture was diluted with EA (50 mL) and washed with saturated aqueous NaHCO 3 solution (10 mL) and brine (10 mL). The organic phase was dried (Na 2 SO 4 ) and concentrated in vacuo. The residue was purified by silica gel chromatography with PE/EA (3/1) as eluent to give (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide. 0.313 g, as a yellow solid, Y: 35%. ESI-MS (M+H) + : 564.2. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.43 (s, 1H), 8.22 (s, 1H), 8.00 (dd, J=8.4, 1.2 Hz, 1H), 7.93-7.84 (m, 3H), 7.79-7.75 (m, 2H), 7.40 (d, J=7.2 Hz, 1H), 7.29 (dd, J=6.8, 1.2 Hz, 1H), 5.30 (s, 2H), 4.98-4.95 (m, 1H), 4.05 (d, J=6.8 Hz, 1H), 1.76 (d, J=6.8 Hz, 3H), 1.22 (s, 9H), 0.99 (s, 9H), 0.17 (s, 6H).

›Step 5. Synthesis of (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol

A solution of (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (0.358 g, 0.636 mmol) in HCl/dioxane was stirred at room temperature for 1 h. After concentration, the residue was dissolved in THF (4 mL), adjusted pH=8 with 3 N NaOH and extracted with EA (10 mL). The organic phase was washed with water (4 mL), brine (4 mL) and dried over Na 2 SO 4 . After filtration and concentration, the residue was purified by prep-HPLC (MeOH/H 2 O with 0.05% NH 4 OH as mobile phase from 5% to 95%) to give (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol as a white solid. (0.127 g, Y: 58%). ESI-MS (M+H) + : 346.1. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.61 (s, 1H), 8.28 (s, 1H), 7.81 (dd, J=8.4, 0.8 Hz, 1H), 7.95-7.86 (m, 5H), 7.39-7.36 (m, 2H), 4.86 (s, 2H), 4.21 (q, J=6.4 Hz, 1H), 1.54 (d, J=6.8 Hz, 3H).

SFC (AD-H column, 4.6*250 mm 5 μm, MeOH with 0.1% DEA, CO 2 flow rate=1.95, Co-Solvent Flow Rate=1.05), t R =2.88 min.

›Example 144. (R)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol

Synthesis of (R)—N—((R)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide

The preparation of (R)—N—((R)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide was similar to that of (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide to give 120 mg as a white solid, Y: 38%. ESI-MS (M+H) + : 564.2.

Synthesis of (R)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol

The preparation of (R)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol was similar to that of (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol to give 44 mg as a white solid, Y: 60%. ESI-MS (M+H) + : 346.1. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.66 (s, 1H), 8.31 (d, J=0.4 Hz, 1H), 8.05 (dd, J=8.4, 1.2 Hz, 1H), 7.98-7.88 (m, 5H), 7.42-7.38 (m, 2H), 4.87 (s, 2H), 4.29 (q, J=6.8 Hz, 1H), 1.57 (d, J=6.8 Hz, 3H).

SFC (AD-H column, 4.6*250 mm 5 μm, MeOH with 0.1% DEA, CO 2 flow rate=2.1, Co-Solvent Flow Rate=0.9), t R =4.08 min.

Example 145. (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol

›Step 1. Synthesis of 6-bromo-N-methoxy-N-methylpicolinamide

To a solution of 6-bromopicolinic acid (CAS #21190-87-4) (0.6 g, 2.98 mmol, 1.0 eq), N,O-dimethylhydroxylamine hydrochloride (CAS #6638-79-5) (0.319 g, 3.28 mmol, 1.1 eq) and TEA (1.2 g, 11.9 mmol, 4.0 eq) in DCM (30 mL) were added EDCI (0.57 g, 2.98 mmol, 1.0 eq) and HOBT (0.403 g, 2.98 mmol, 1.0 eq) in portions at 0° C. The reaction mixture was warmed up to room temperature and stirred for 12 h. The mixture was extracted with DCM (3×10 mL) and washed with brine. The combined organic phase was dried over Na 2 SO 4 and concentrated in vacuo. The crude mixture was purified by silica gel chromatography with PE/EA (10/1) as eluent to give 6-bromo-N-methoxy-N-methylpicolinamide. 0.436 g, as colorless oil, Y: 60%. ESI-MS (M+H) + : 245.0.

›Step 2. Synthesis of 1-(6-bromopyridin-2-yl)butan-1-one

To a solution of 6-bromo-N-methoxy-N-methylpicolinamide (0.4 g, 1.63 mmol, 1.0 eq) in THF (5 mL) was slowly added n-PrMgBr (2.45 mL, 2.45 mmol, 1.5 eq, 1 M in THF) at −78° C. for 30 min. The mixture was warmed to room temperature and stirred at rt for 4 h. The mixture was quenched with NH 4 Cl (aq.) (2 mL) and extracted with EA (2×10 mL). The combined organic phase was washed with brine and dried over Na 2 SO 4 . After filtration and concentration, the residue was purified by silica gel chromatography with PE/EA (10/1) as eluent to give 1-(6-bromopyridin-2-yl)butan-1-one. 0.22 g, as colorless oil, Y: 60%. ESI-MS (M+H) + : 228.0.

›Step 3. Synthesis of (R,E)-N-(1-(6-bromopyridin-2-yl)butylidene)-2-methylpropane-2-sulfinamide

To a solution of 1-(6-bromopyridin-2-yl)butan-1-one (Example 145, Step 2, 0.2 g, 0.88 mmol, 1.0 eq) and (R)-2-methylpropane-2-sulfinamide (CAS #196929-78-9) (0.107 g, 0.88 mmol, 1.0 eq) in THF (2 mL) was added Ti(OEt) 4 (0.4 g, 1.76 mmol, 2.0 eq) at room temperature. The mixture was stirred at 70° C. for 16 h. After cooling down to rt, the mixture was diluted with water (10 mL) and extracted with DCM (2×10 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After concentration, the residue was purified by silica gel chromatography with PE/EA (10/1) as eluent to give (R,E)-N-(1-(6-bromopyridin-2-yl)butylidene)-2-methylpropane-2-sulfinamide (0.183 g, Y: 69%) as a yellow solid. ESI-MS (M+H) + : 331.0.

›Step 4. Synthesis of (R)—N—((R)-1-(6-bromopyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide

To a solution of (R,E)-N-(1-(6-bromopyridin-2-yl)butylidene)-2-methylpropane-2-sulfinamide (66 mg, 0.2 mmol, 1.0 eq) in THF (2 mL) was added NaBH 4 (22 mg, 0.6 mmol, 3.0 eq) at −50° C. The mixture was warmed to room temperature over 2 h. The mixture was diluted with EA (10 mL) and washed with water (2×5 mL). The organics were dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by prep-HPLC (MeCN/H 2 O with 0.05% NH 4 OH as mobile phase from 5% to 95%) to give (R)—N—((R)-1-(6-bromopyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide (30 mg, Y: 45%) as colorless oil. ESI-MS (M+H) + : 333.1.

›Step 5. Synthesis of (R)—N—((S)-1-(6-bromopyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide

To a solution of (R)—N—((R)-1-(6-bromopyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide (76 mg, 0.23 mmol, 1.0 eq) in THF (4 mL) was added L-Selectride (0.7 mL, 0.69 mmol, 3.0 eq) at 0° C. The mixture was stirred at 0° C. for 3 h. The reaction was quenched with NH 4 Cl (aq) (2 mL) and extracted with EA (2×4 mL). The combined organic phase was washed with brine and dried over Na 2 SO 4 . After filtration and concentration, the residue was dissolved in DCM (0.5 mL) and a white solid was precipitated out while PE (10 mL) was added into the solution. After filtration, the white solid (R)—N—((S)-1-(6-bromopyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide was dried in vacuo. 35 mg, Y: 46%. ESI-MS (M+H) + : 333.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 7.51 (t, J=8.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.22 (d, J=7.6 Hz, 1H), 4.46-4.41 (m, 1H), 1.92-1.85 (m, 2H), 1.38-1.24 (m, 2H), 1.18 (s, 9H), 0.92 (t, J=7.2 Hz, 3H).

Step 6. Synthesis of (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide

The preparation of (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide was similar to that of (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide to give 0.32 g as a white solid, Y: 51%. ESI-MS (M+H) + : 592.2.

›Step 7. Synthesis of (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol

The preparation of (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol was similar to that of (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol to give 0.1 g as a white solid, Y: 49%. ESI-MS (M+H) + : 374.1. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.62 (s, 1H), 8.29 (s, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.96-7.86 (m, 5H), 7.41-7.33 (m, 2H), 4.87 (s, 2H), 4.04 (t, J=6.8 Hz, 1H), 1.95-1.80 (m, 2H), 1.49-1.27 (m, 2H), 0.98 (t, J=6.8 Hz, 3H).

›Examples3

›Example 146. (R)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol

Synthesis of (R)—N—((R)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide

The preparation of (R)—N—((R)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide was similar to that of (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide to give 210 mg as a white solid, Y: 46%. ESI-MS (M+H) + : 592.2.

Synthesis of (R)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol

The preparation of (R)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol was similar to that of (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol to give 90 mg as a white solid, Y: 68%. ESI-MS (M+H) + : 374.1. HPLC: 100.00%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.61 (s, 1H), 8.29 (s, 1H), 8.01 (dd, J=8.8, 1.2 Hz, 1H), 7.95-7.86 (m, 5H), 7.40-7.32 (m, 2H), 4.86 (s, 2H), 4.04 (t, J=6.8 Hz, 1H), 1.95-1.80 (m, 2H), 1.49-1.27 (m, 2H), 0.97 (t, J=6.8 Hz, 3H).

Example 200. 1-(6-methylpyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-7-amine

›Example 200 was synthesized according to the procedures described herein

ESI-MS (M+H) + : 302.1.

1 H NMR (400 MHz, CD 3 OD) δ: 9.06 (s, 1H), 8.26 (s, 1H), 8.13 (d, J=1.6 Hz, 1H), 7.98 (d, J=2.4 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.83-7.77 (m, 2H), 7.51 (d, J=8.4 Hz, 1H), 7.41 (t, J=2.0 Hz, 1H), 7.11 (d, J=6.0 Hz, 1H), 2.63 (s, 3H).

Examples 201 to 323 can be synthesized according to the procedures described herein. In particular, Examples 201, 202, 203, 204, 205, 206, 209, 210, 211, 212, 213, 216, 220, 221, 228, 229, 230, 231, 232, 235, 236, 237, 239, 241, 242, 243, 244, 247, 248, 249, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 294, 296, 297, 298, 299, 300, 301, 304, 305, 306, 308, 310, 312, 313, 314, 315, 318, 320, 322, 323 were synthesized similar to that of example 146. Examples 207, 240, and 321 were synthesized similar to that of example 106. Examples 208, 214, 215, and 217 were synthesized similar to that of example 105. Examples 218 and 219 were synthesized similar to that of example 106. Examples 222, 223, 224, 275, 276, 293, 302, 311, and 317 were synthesized similar to that of example 99. Examples 225, 226, 227, 233, 234 were synthesized similar to that of example 103. Examples 245, 246, 250, 251, and 307 were synthesized similar to that of example X (4-position ethoxy methoxy). Examples 295, 303, and 319 were synthesized similar to that of example X (4-position aryl). Example 309 was synthesized similar to that of example 114. Example 316 was synthesized similar to that of example 104.

Example 324. (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(piperidin-1-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide

›Step 1 Synthesis of 4-bromo-2,6-difluorobenzaldehyde

To a solution of 1-bromo-3,5-difluorobenzene (Cas No. 461-96-1, 210 g, 1.09 mol, 1.0 eq) in anhydrous THF (1000 mL), LDA/THF (545 mL, 1.09 mol, 1.0 eq, 2 M) was added slowly under nitrogen atmosphere at −78° C. The reaction solution was stirred for 2 h at −78° C., and then anhydrous DMF (79.6 g, 1.09 mol, 1.0 eq) was added dropwise. The reaction was stirred for 15 min at −78° C. and then a solution of AcOH in ethyl acetate (1/1, 300 mL) was added to adjusted pH=4-5 at −78° C. The reaction mixture was stirred at rt for 15 min, concentrated under reduced pressure, diluted with ethyl acetate (1000 mL) and washed with brine (600 mL×2). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and recrystallized from n-hexane to give the title compound (106 g, yield: 44%) as a light yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ: 10.29 (s, 1H), 7.23 (s, 1H), 7.21 (s, 1H); ESI-MS (M+H) + : 220.9, 222.9.

›Step 2 Synthesis of 4-bromo-2-fluoro-6-methoxybenzaldehyde

To a solution of 4-bromo-2,6-difluorobenzaldehyde (106 g, 482 mmol, 1.0 eq) in methanol (150 mL), MeONa (26.0 g, 482 mmol, 1.0 eq) was added at rt. The reaction mixture was stirred for 2 h at 60° C. and concentrated under reduced pressure. The residue was purified by silica gel column (PE/EA=10/1) to give 4-bromo-2-fluoro-6-methoxybenzaldehyde (69 g, yield: 62%) as a light yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ: 10.36 (s, 1H), 6.97-6.94 (m, 2H), 3.95 (s, 3H); ESI-MS (M+H) + : 232.9, 234.9.

›Step 3 Synthesis of 4-bromo-2-fluoro-6-hydroxybenzaldehyde

To a solution of 4-bromo-2-fluoro-6-methoxybenzaldehyde (69 g, 297 mmol, 1.0 eq) in DCM (800 mL) was added BBr 3 (223 g, 891 mmol, 3.0 eq) at −60° C. The reaction mixture was stirred at −60° C. for 3 h, quenched with water (300 mL) and extracted with DCM (2×300 mL). The combined organic phase was washed with brine and dried over Na 2 SO 4 . After filtration and concentration, the residue was directly used for next step without further purification. ESI-MS (M+H) + : 218.9, 220.9.

›Step 5 Synthesis of 4-bromo-2-fluoro-6-((4-methoxybenzyl)oxy)benzaldehyde

To a solution of 4-bromo-2-fluoro-6-hydroxybenzaldehyde (50 g, 229 mmol, 1.0 eq) and K 2 CO 3 (63 g, 458 mmol, 2.0 eq) in DMF (100 mL) was added PMBCl (43 g, 275 mmol, 1.2 eq) at rt. The reaction mixture was stirred at rt for 16 h and diluted with water (600 mL). After filtration, the yellow solid was washed with water and dried in vacuo. 50 g, Y: 65%. ESI-MS (M+H) + : 339.0, 341.0.

›Step 6 Synthesis of 6-bromo-4-((4-methoxybenzyl)oxy)-1H-indazole

A mixture of 4-bromo-2-fluoro-6-((4-methoxybenzyl)oxy)benzaldehyde (50 g, 148 mmol, 1.0 eq) and NH 2 NH 2 .H 2 O (22 g, 444 mmol, 3.0 eq) in DMSO (100 mL) was stirred at 135° C. for 2 h. The mixture was diluted with water (600 mL). After filtration, the yellow solid was purified by column chromatography (silica gel, PE/EA=4/1) to give 6-bromo-4-((4-methoxybenzyl)oxy)-1H-indazole as a yellow solid (34.4 g, Y: 70%). ESI-MS (M+H) + : 333.1, 335.1.

›Step 7 Synthesis of (6-(6-bromo-4-((4-methoxybenzyl)oxy)-1H-indazol-1-yl)pyridin-2-yl)methanol · 1 of 2

A mixture of 6-bromo-4-((4-methoxybenzyl)oxy)-1H-indazole (20 g, 60 mmol, 1.0 eq), (6-bromopyridin-2-yl)methanol Cas No. 33674-96-3 (13.5 g, 72 mmol, 1.2 eq), CuBr (858 mg, 6 mmol, 0.1 eq), K 3 PO 4 (25.4 g, 120 mmol, 2.0 eq) and Cas. No. 61798-24-1 (1.7 g, 12 mmol, 0.2 eq) in toluene (200 mL) was stirred at 110° C. for 4 h under N 2 . After concentration, the residue was purified by column chromatography (silica gel, PE/EA=2/1) to give (6-(6-bromo-4-((4-methoxybenzyl)oxy)-1H-indazol-1-yl)pyridin-2-yl)methanol as a yellow solid (7.9 g, Y: 30%). ESI-MS (M+H) + : 440.1, 442.1.

Step 8 Synthesis of 6-bromo-1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-((4-methoxybenzyl)oxy)-1H-indazole

To a mixture of (6-(6-bromo-4-((4-methoxybenzyl)oxy)-1H-indazol-1-yl)pyridin-2-yl)methanol (2.35 g, 5.36 mmol, 1.0 eq) and imidazole (729 mg, 10.72 mmol, 2.0 eq) in DMF (30 mL) was added TBSCl (1.21 g, 8.04 mmol, 1.5 eq) at rt. The mixture was stirred at rt for 2 h. The mixture was diluted with water (300 mL) and extracted with EA (3×100 mL). The combined organic phases were washed with brine (100 mL) and dried over Na 2 SO 4 . After filtration and concentration, the residue was purified by column chromatography (silica gel, PE/EA=5/1) to give 6-bromo-1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-((4-methoxybenzyl)oxy)-1H-indazole as a yellow solid (2.34 g, Y: 79%). ESI-MS (M+H) + : 554.1.

Step 9 Synthesis of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-((4-methoxybenzyl)oxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

A mixture of 6-bromo-1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-((4-methoxybenzyl)oxy)-1H-indazole (2.34 g, 4.23 mmol, 1.0 eq), Cas. No. 73183-34-3 (1.13 g, 4.44 mmol, 1.05 eq) and CH 3 COOK (622 mg, 6.35 mmol, 1.5 eq) in 1, 4-dioxane (50 mL) was stirred while purging N 2 at rt for 10 min. To this system was added Pd(dppf)Cl 2 (343 mg, 0.42 mmol, 0.1 eq) and heated to 90° C. for 2 h. The mixture was diluted with EA (300 mL) and washed with saturated aqueous NaHCO 3 solution (100 mL) and brine (200 mL). The organics were dried (Na 2 SO 4 ) and concentrated in vacuo. The residue was purified by silica gel chromatography with PE/EA (5/1) as eluent to give 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-((4-methoxybenzyl)oxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. 2.11 g, as a yellow solid, Y: 83%. ESI-MS (M+H) + : 602.3.

Step 10 Synthesis of (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-((4-methoxybenzyl)oxy)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide

A mixture of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-((4-methoxybenzyl)oxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (2.11 g, 3.51 mmol, 1.0 eq), (R)—N—((S)-1-(6-bromopyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide (Example 145 step 5, 1.17 g, 3.51 mmol, 1.0 eq) and K 2 CO 3 (969 mg, 7.02 mmol, 2.0 eq) in 1, 4-dioxane/H 2 O (30 mL/1.0 mL) was stirred while purging N 2 at rt for 10 min. To this system was added Pd(dppf)Cl 2 (286 mg, 0.35 mmol, 0.1 eq) and heated to 110° C. for 16 h. The mixture was diluted with EA (400 mL) and washed with saturated aqueous NaHCO 3 solution (100 mL) and brine (100 mL). The organics were dried (Na 2 SO 4 ) and concentrated in vacuo. The crude mixture was purified by column chromatography (silica gel, PE/EA=2/1) to give (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-((4-methoxybenzyl)oxy)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide as a yellow solid (1.48 g, Y: 58%). ESI-MS (M+H) + : 728.4.

Step 11 Synthesis of (R)—N—((S)-1-(6-(4-hydroxy-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide

A solution of (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-((4-methoxybenzyl)oxy)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide (1.48 g, 2.03 mmol, 1.0 eq) in DCM/TFA (10 mL/3 mL) was stirred at rt for 2 h. After concentration, the residue was adjusted pH=7-8 with saturated sodium bicarbonate solution and extracted with DCM (40 mL). The organic phase was washed with brine and dried over Na 2 SO 4 . After filtration and concentration, the residue was directly used for next step without further purification. 730 mg, Y: 73%. ESI-MS (M+H) + : 494.2.

Step 12 Synthesis of (R)—N—((S)-1-(6-(4-((tert-butyldimethylsilyl)oxy)-1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide

To a mixture of (R)—N—((S)-1-(6-(4-hydroxy-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide (730 mg, 1.48 mmol, 1.0 eq) and imidazole (302 mg, 4.44 mmol, 3.0 eq) in DMF (10 mL) was added TBSCl (489 mg, 3.26 mmol, 2.2 eq) at rt. The mixture was stirred at rt for 2 h. The mixture was diluted with water (100 mL) and extracted with EA (3×50 mL). The combined organic phases were washed with brine (100 mL) and dried over Na 2 SO 4 . After filtration and concentration, the residue was purified by column chromatography (silica gel, PE/EA=2/1) to give (R)—N—((S)-1-(6-(4-((tert-butyldimethylsilyl)oxy)-1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide as a yellow solid (800 mg, Y: 75%). ESI-MS (M+H) + : 722.4.

Step 13 Synthesis of (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-hydroxy-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide

A mixture of (R)—N—((S)-1-(6-(4-((tert-butyldimethylsilyl)oxy)-1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide (800 mg, 1.11 mmol, 1.0 eq), Cs 2 CO 3 (721 mg, 2.22 mmol, 2.0 eq) in DMF (10 mL) was stirred at rt for 2 h. The mixture was diluted with water (60 mL) and extracted with EA (90 mL). The organic phase was washed with brine and dried over Na 2 SO 4 . After filtration and concentration, the residue was purified by silica gel chromatography with PE/EA (1/2) as eluent to give (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-hydroxy-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide. 600 mg, as a yellow solid, Y: 89%. ESI-MS (M+H) + : 608.3.

›Step 7 Synthesis of (6-(6-bromo-4-((4-methoxybenzyl)oxy)-1H-indazol-1-yl)pyridin-2-yl)methanol · 2 of 2

Step 14 Synthesis of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-(6-((S)-1-((R)-1,1-dimethylethylsulfinamido)butyl)pyridin-2-yl)-1H-indazol-4-yl trifluoromethanesulfonate

A mixture of (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-hydroxy-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide (607 mg, 1.0 mmol, 1.0 eq), Cas. No. 37595-74-7 (1.43 g, 4.0 mmol, 4.0 eq) and Et 3 N (404 mg, 4.0 mmol, 4.0 eq) in THF (20 mL) was stirred at 70° C. for 3 h. After cooling down to rt, the mixture was poured into H 2 O (50 mL) and extracted with DCM (50 mL×3). The combined organic fractions were dried, filtrated, concentrated and purified by silica gel chromatography with PE/EA (1/1) as eluent to give 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-(6-((S)-1-((R)-1,1-dimethylethylsulfinamido)butyl)pyridin-2-yl)-1H-indazol-4-yl trifluoromethanesulfonate. 600 mg, as a yellow solid, Y: 82%. ESI-MS (M+H) + : 740.3.

Step 15. Synthesis of (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(piperidin-1-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide

A mixture of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-(6-((S)-1-((R)-1,1-dimethylethylsulfinamido)butyl)pyridin-2-yl)-1H-indazol-4-yl trifluoromethanesulfonate (300 mg, 0.42 mmol, 1.0 eq), piperidine (CAS No. 110-89-4, 35 mg, 0.42 mmol, 1.0 eq), Pd 2 (dba) 3 (38 mg, 0.042 mmol, 0.1 eq), BINAP (26 mg, 0.042 mmol, 0.1 eq) and Cs 2 CO 3 (409 mg, 1.26 mmol, 3.0 eq) in toluene (10 mL) was stirred at 110° C. for 16 h. After concentration, the residue was purified by silica gel chromatography with PE/EA (1/1) as eluent to give (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(piperidin-1-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide. 80 mg, as a yellow solid, Y: 29%. ESI-MS (M+H) + : 675.4.

Step 16 Synthesis of (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(piperidin-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol

The preparation of (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(piperidin-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol was similar to that of (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol (Example 143) to give 34 mg as a yellow solid, Y: 61%. ESI-MS (M+H) + : 457.3. HPLC: 98%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.32 (s, 1H), 8.33 (s, 1H), 8.04-7.95 (m, 4H), 7.52 (s, 1H), 7.42 (d, J=7.6 Hz, 1H), 7.36 (dd, J=6.4, 2.8 Hz, 1H), 4.86 (s, 2H), 4.53 (t, J=6.8 Hz, 1H), 3.44-3.42 (m, 4H), 2.08-1.97 (m, 2H), 1.94-1.89 (m, 4H), 1.77-1.73 (m, 2H), 1.48-1.38 (m, 2H), 1.01 (t, J=6.8 Hz, 3H).

The following examples were prepared as described in example 324 using the appropriate amine in place of piperidine (CAS No. 110-89-4)

Example 352

›Step 1. Synthesis of 2-bromo-6-fluoro-4-hydroxybenzaldehyde

To a solution of 2-bromo-6-fluoro-4-methoxybenzaldehyde (21 g, 90 mmol, 1.0 eq) in DCM (100 mL) was added BBr 3 (46 g, 180 mmol, 2.0 eq) slowly at −78° C. The reaction mixture was stirred at rt for 2 h. The reaction was quenched with H 2 O (50 mL). The mixture was filtrated and the precipitate was washed with DCM (200 mL×2). The filtrate was washed with H 2 O (100 mL×2). The organic fraction was dried (Na 2 SO 4 ), filtrated and concentrated to give 2-bromo-6-fluoro-4-hydroxybenzaldehyde (13.0 g, Y: 66%) as yellow oil. ESI-MS (M+H) + : 219.0.

›Step 2. Synthesis of 2-bromo-6-fluoro-4-((4-methoxybenzyl)oxy)benzaldehyde

To a mixture of 2-bromo-6-fluoro-4-hydroxybenzaldehyde (13.0 g, 60 mmol, 1.0 eq) and K 2 CO 3 (16.6 g, 120 mmol, 2.0 eq) in DMF (110 mL) was added p-Methoxybenzyl chloride (PMBCl, 11.2 g, 72 mmol, 1.2 eq) slowly at 0° C. The reaction mixture was stirred for 16 h at rt. Then H 2 O (100 mL) was added to the mixture and stirred at rt for 30 min. The precipitate was collected by filtration and washed with H 2 O (100 mL×2) and PE (100 mL×2) to give 2-bromo-6-fluoro-4-((4-methoxybenzyl)oxy)benzaldehyde (17 g, Y: 84%) as a yellow solid. ESI-MS (M+H) + : 339.0.

›Step 3. Synthesis of 4-bromo-6-((4-methoxybenzyl)oxy)-1H-indazole

To a stirred solution of 2-bromo-6-fluoro-4-((4-methoxybenzyl)oxy)benzaldehyde (17 g, 50.3 mmol, 1.0 eq) in DMSO (100 mL) was added hydrazine monohydrate (7.5 g, 151 mmol, 3.0 eq). The reaction mixture was stirred at 130° C. for 2 h. After cooling down to rt, the reaction solution was diluted with water (500 mL) and stirred at rt for 30 min. The precipitate was collected by filtration and washed with water (50 mL×2) and PE (50 mL×2) to give 4-bromo-6-((4-methoxybenzyl)oxy)-1H-indazole (13 g, Y: 78%) as a light yellow solid. ESI-MS (M+H) + : 333.0.

›Step 4. Synthesis of (6-(4-bromo-6-((4-methoxybenzyl)oxy)-1H-indazol-1-yl)pyridin-2-yl)methanol · 1 of 2

A mixture of 4-bromo-6-((4-methoxybenzyl)oxy)-1H-indazole (13 g, 39 mmol, 1.0 eq), (6-bromopyridin-2-yl)methanol (CAS No. 33674-96-3, 8.8 g, 47 mmol, 1.2 eq), CuBr (560 mg, 3.9 mmol, 0.1 eq), N,N′-Dimethyl-1,2-cyclohexanediamine (CAS No. 61798-24-1, 1.1 g, 7.8 mmol, 0.2 eq) and K 3 PO 4 (16.6 g, 78 mmol, 2.0 eq) in 1,4-dioxane (120 mL) was stirred at 90° C. for 4 h under nitrogen atmosphere. After cooling down to rt, the mixture was filtrated and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=4/1) to give (6-(4-bromo-6-((4-methoxybenzyl)oxy)-1H-indazol-1-yl)pyridin-2-yl)methanol (6 g, Y: 36%) as a light yellow solid. ESI-MS (M+H) + : 440.1.

Step 5. Synthesis of 4-bromo-1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-((4-methoxybenzyl)oxy)-1H-indazole

A mixture of (6-(4-bromo-6-((4-methoxybenzyl)oxy)-1H-indazol-1-yl)pyridin-2-yl)methanol (6 g, 13.6 mmol, 1.0 eq), tert-butyldimethylsilyl chloride (TBSCl, 2.5 g, 16.4 mmol, 1.2 eq) and imidazole (1.85 g, 27.2 mmol, 2.0 eq) in DMF (50 mL) was stirred at 30° C. for 16 h. The reaction solution was diluted with water (200 mL) and stirred at rt for 30 min. The precipitate was collected by filtration and washed with water (50 mL×2) and PE (50 mL×2) to give 4-bromo-1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-((4-methoxybenzyl)oxy)-1H-indazole (6.3 g, Y: 83%) as a light yellow solid. ESI-MS (M+H) + : 554.2. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.33 (s, 1H), 8.07 (s, 1H), 7.89-7.82 (m, 2H), 7.42-7.36 (m, 3H), 7.17 (d, J=2.0 Hz, 1H), 6.64 (d, J=8.4 Hz, 2H), 5.12 (s, 2H), 4.89 (s, 2H), 3.82 (s, 3H), 0.99 (s, 9H), 0.17 (s, 6H).

Step 6. Synthesis of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-((4-methoxybenzyl)oxy)-4-(1H-pyrazol-1-yl)-1H-indazole

A mixture of 4-bromo-1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-((4-methoxybenzyl)oxy)-1H-indazole (600 mg, 1.1 mmol, 1.0 eq), 288-13-1 (738 mg, 11 mmol, 10 eq), CuI (105 mg, 0.55 mmol, 0.5 eq), N,N′-Dimethyl-1,2-cyclohexanediamine (CAS No. 61798-24-1, 31 mg, 0.2 mmol, 0.2 eq) and K 3 PO 4 (460 mg, 2.2 mmol, 2.0 eq) in 1, 4-dioxane (5 mL) was stirred at 90° C. for 16 h under nitrogen atmosphere. After cooling down to rt, the mixture was filtrated and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=2/1) to give 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-((4-methoxybenzyl)oxy)-4-(1H-pyrazol-1-yl)-1H-indazole (520 mg, Y: 86%) as a light yellow solid. ESI-MS (M+H) + : 542.3.

Step 7. Synthesis of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(1H-pyrazol-1-yl)-1H-indazol-6-ol

To a solution of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-((4-methoxybenzyl)oxy)-4-(1H-pyrazol-1-yl)-1H-indazole (520 mg, 0.96 mmol, 1.0 eq) in DCM (3 mL) was added slowly TFA (3 mL). Then the mixture was stirred at rt for 1 h. The mixture was diluted with DCM (10 mL) and adjusted pH=7 with NaOH(aq). The mixture was extracted with DCM (30 mL×2). The combined organic fractions were washed with brine (50 mL x 2), dried, filtrated and concentrated to give 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(1H-pyrazol-1-yl)-1H-indazol-6-ol (350 mg, Y: 86%) as a light yellow solid. ESI-MS (M+H) + : 422.1.

Step 8. Synthesis of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(1H-pyrazol-1-yl)-1H-indazol-6-yl trifluoromethanesulfonate

A mixture of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(1H-pyrazol-1-yl)-1H-indazol-6-ol (350 mg, 0.83 mmol, 1.0 eq), N-phenyl-bis(trifluoromethanesulfonimide) (CAS No. 37595-74-7, 1.2 g, 3.3 mmol, 4.0 eq) and TEA (340 mg, 3.3 mmol, 4.0 eq) in THF (50 mL) was stirred at 70° C. for 4 h. After cooling to rt, the reaction solution was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=2/1) to give 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(1H-pyrazol-1-yl)-1H-indazol-6-yl trifluoromethanesulfonate (430 mg, Y: 94%) as a light yellow solid. ESI-MS (M+H) + : 554.1.

Step 9. Synthesis of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(1H-pyrazol-1-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

A mixture of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(1H-pyrazol-1-yl)-1H-indazol-6-yl trifluoromethanesulfonate (430 mg, 0.78 mmol, 1.0 eq), Bis(pinacolato)diboron (CAS No. 73183-34-3, 210 mg, 0.82 mmol, 1.05 eq) and CH 3 COOK (160 mg, 1.6 mmol, 2.0 eq) in 1, 4-dioxane (5 mL) was stirred while purging N 2 at rt for 10 min. To this system was added Pd(dppf)Cl 2 (70 mg, 0.08 mmol, 0.1 eq) and heated to 90° C. for 16 h. The mixture was diluted with EtOAc (50 mL) and washed with brine (50 mL×2). The organic was dried (Na 2 SO 4 ) and concentrated to give 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(1H-pyrazol-1-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole which was used for next step without further purification. 330 mg, as a brown solid, Y: 80%. ESI-MS (M+H) + : 532.3.

Step 10. Synthesis of (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(1H-pyrazol-1-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide

A mixture of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(1H-pyrazol-1-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (330 mg, 0.62 mmol, 1.0 eq), (R)—N—((S)-1-(6-bromopyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (Example 142, Step 1, 283 mg, 0.93 mmol, 1.5 eq) and K 2 CO 3 (171 mg, 1.24 mmol, 2.0 eq) in 1,4-dioxane/H 2 O (5 mL/0.5 mL) was stirred while purging N 2 at rt for 10 min. To this system was added Pd(dppf)Cl 2 (57 mg, 0.06 mmol, 0.1 eq) and heated to 110° C. for 16 h. After concentration, the residue was purified by silica gel column chromatography (PE/EA=2/1) to give (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(1H-pyrazol-1-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (200 mg, Y: 51%) as a yellow solid. ESI-MS (M+H) + : 630.3.

›Step 4. Synthesis of (6-(4-bromo-6-((4-methoxybenzyl)oxy)-1H-indazol-1-yl)pyridin-2-yl)methanol · 2 of 2

Step 11. Synthesis of (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(1H-pyrazol-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol

To a solution of —((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(1H-pyrazol-1-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (200 mg, 0.32 mmol, 1.0 eq) in DCM (3 mL) was added slowly 4 M HCl in 1,4-dioxane (1 mL, excess). Then the mixture was stirred at rt for 1 h. After concentration, the residue was purified by prep-HPLC (CH 3 CN/H 2 O with 0.05% TFA as mobile phase from 5% to 95%) to give (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(1H-pyrazol-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol. 34 mg, as a yellow solid, Y: 26%. ESI-MS (M+H) + : 412.1. HPLC: 100%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.73-9.70 (m, 1H), 8.73 (d, J=5.2 Hz, 1H), 8.54 (d, J=2.0 Hz, 1H), 8.41 (s, 1H), 8.14-7.89 (m, 5H), 7.47 (d, J=8.0 Hz, 1H), 7.37-7.33 (m, 1H), 6.65 (d, J=1.6 Hz, 1H), 4.86 (s, 2H), 4.72-4.67 (m, 1H), 1.69 (d, J=6.8 Hz, 3H).

The preparation of the following was similar to that of Example 352 using the appropriate heterocycle in place of pyrazole

Example 357. (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol

Step 1. Synthesis of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-(6-((S)-1-((R)-1,1-dimethylethylsulfinamido)ethyl)pyridin-2-yl)-1H-indazol-4-yl trifluoromethanesulfonate

To a mixture of (S)-6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-ol (derived similar to that of Example 324 step 13 ((R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-hydroxy-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide) utilizing (R)—N—((S)-1-(6-bromopyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide in step 10) (600 mg, 1.0 mmol, 1.0 eq) and Et 3 N (419 mg, 4.0 mmol, 4.0 eq) in THF (30 mL) was added N-phenyl-bis(trifluoromethanesulfonimide) (CAS No. 37595-74-7, 1.5 g, 4.0 mmol, 4.0 eq) at rt. The mixture was stirred at 70° C. for 3 h. After concentration, the residue was purified by column chromatography (silica gel, PE/EA=3/1) to afford 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-(6-((S)-1-((R)-1,1-dimethylethylsulfinamido)ethyl)pyridin-2-yl)-1H-indazol-4-yl trifluoromethanesulfonate as brown oil (520 mg, Y: 83%). ESI-MS (M+H) + : 712.2. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.47 (s, 1H), 8.28 (s, 1H), 8.01 (s, 1H), 7.96-7.89 (m, 2H), 7.82 (t, J=8.0 Hz, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.46 (d, J=6.8 Hz, 1H), 7.34 (d, J=7.6 Hz, 1H), 4.96 (s, 2H), 4.77-4.73 (m, 1H), 4.07 (d, J=6.8 Hz, 1H), 1.73 (d, J=6.8 Hz, 3H), 1.20 (s, 9H), 0.99 (s, 9H), 0.17 (s, 6H).

Step 2. Synthesis of (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide

The preparation of (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide was similar to that of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(1H-pyrazol-1-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (Example 352, Step 9) to give 326 mg as a yellow solid, Y: 81%. ESI-MS (M+H) + : 690.3

Step 3. Synthesis of (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide

The preparation of (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide was similar to that of (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(1H-pyrazol-1-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (Example 352, Step 10) to give 150 mg as a yellow solid, Y: 52%. ESI-MS (M+H) + : 644.3. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.21 (s, 1H), 8.71 (s, 1H), 8.13 (s, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.72-7.60 (m, 3H), 7.33 (d, J=2.4 Hz, 1H), 7.23 (d, J=7.6 Hz, 1H), 7.12 (dd, J=7.2, 1.6 Hz, 1H), 6.64 (d, J=2.4 Hz, 1H), 4.80 (s, 2H), 4.59 (q, J=6.8 Hz, 1H), 3.89 (s, 3H), 1.60 (d, J=6.8 Hz, 3H), 1.06 (s, 9H), 0.82 (s, 9H), 0.00 (s, 6H).

Step 4. Synthesis of (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol

The preparation of (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol was similar to that of (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(1H-pyrazol-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol (Example 352, Step 11) to give 61 mg as a yellow solid, Y: 70%. ESI-MS (M+H) + : 426.0. HPLC: 100%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.70 (s, 1H), 8.82 (s, 1H), 8.48 (d, J=1.2 Hz, 1H), 8.13 (d, J=7.6 Hz, 1H), 8.03 (t, J=8.0 Hz, 1H), 7.98-7.95 (m, 2H), 7.76 (d, J=2.4 Hz, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.40-7.32 (m, 1H), 6.99 (d, J=2.0 Hz, 1H), 4.89 (s, 2H), 4.73 (q, J=6.8 Hz, 1H), 4.07 (s, 3H), 1.75 (d, J=6.8 Hz, 3H).

The following examples were prepared similar to Example 357 by Suzuki coupling using the appropriate halogenated heterocycle in place of 3-Bromo-1-methyl-1H-pyrazole and/or (R)—N—((S)-1-(6-bromopyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (Example 142, Step 1 and boranate in place of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole and/or (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide

›Examples3

›Example 395

Step 1. Synthesis of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-((4-methoxybenzyl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

A mixture of 4-bromo-1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-((4-methoxybenzyl)oxy)-1H-indazole (Example 352, step 5) (3.5 g, 6.3 mmol, 1.0 eq), 73183-34-3 (1.68 g, 6.6 mmol, 1.05 eq) and CH 3 COOK (1.23 g, 12.6 mmol, 2.0 eq) in 1, 4-dioxane (100 mL) was stirred while purging N 2 at rt for 10 min. To this system was added Pd(dppf)Cl 2 (576 mg, 0.63 mmol, 0.1 eq) and heated to 90° C. for 16 h. The mixture was diluted with EA (100 mL) and washed with saturated aqueous NaHCO 3 solution (100 mL) and brine (100 mL). The organic phase was dried (Na 2 SO 4 ) and concentrated to give 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-((4-methoxybenzyl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole which was used for next step without further purification. 3.0 g, as a brown solid, Y: 80%. ESI-MS (M+H) + : 602.3.

Step 2. Synthesis of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-((4-methoxybenzyl)oxy)-4-(1-methyl-1H-pyrazol-3-yl)-1H-indazole

A mixture of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-((4-methoxybenzyl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (3.0 g, 5.0 mmol, 1.0 eq), 3-bromo-1-methyl-1H-pyrazole (151049-87-5) (880 mg, 5.5 mmol, 1.1 eq) and K 2 CO 3 (1.38 g, 10.0 mmol, 2.0 eq) in 1, 4-dioxane/H 2 O (100 mL/5 mL) was stirred while purging N 2 at rt for 10 min. To this system was added Pd(dppf)Cl 2 (458 mg, 0.5 mmol, 0.1 eq) and heated to 110° C. for 16 h. The mixture was diluted with EA (100 mL) and washed with saturated aqueous NaHCO 3 solution (100 mL) and brine (100 mL). The organics were dried (Na 2 SO 4 ) and concentrated in vacuo. The crude mixture was purified by silica gel chromatography using PE/EA (1/1) as eluent to give 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-((4-methoxybenzyl)oxy)-4-(1-methyl-1H-pyrazol-3-yl)-1H-indazole. 1.75 g, as a yellow solid, Y: 62%. ESI-MS (M+H) + : 556.2.

Step 3. Synthesis of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-6-ol

To a solution of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-((4-methoxybenzyl)oxy)-4-(1-methyl-1H-pyrazol-3-yl)-1H-indazole (1.75 g, 3.15 mmol, 1.0 eq) in DCM (50 mL) was added TFA (10 mL). The mixture was stirred at rt for 2 h. The reaction was quenched with saturated NaOH solution. The mixture was extracted with DCM (50 mL×3). The combined organics were dried and concentrated to give 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-6-ol which was used for next step without further purification. 1.2 g, as a yellow solid, Y: 85%. ESI-MS (M+H) + : 436.2. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.72 (s, 1H), 8.64 (s, 1H), 7.75-7.69 (m, 2H), 7.32-7.22 (m, 3H), 6.55 (s, 1H), 4.74 (s, 2H), 3.87 (s, 3H), 0.82 (s, 9H), 0.00 (s, 6H).

Step 4. Synthesis of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-6-yl trifluoromethanesulfonate

A mixture of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-6-ol (1.2 g, 2.76 mmol, 1.0 eq), Cas No 37595-74-7 (3.94 g, 11.04 mmol, 4.0 eq) and TEA (1.11 g, 11.04 mmol, 4.0 eq) in THF (50 mL) was stirred at 70° C. for 3 h. After concentration, the residue was purified by silica gel chromatography using PE/EA (5/1) as eluent give 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-6-yl trifluoromethanesulfonate. 900 mg, as a yellow solid, Y: 45%. ESI-MS (M+H) + : 568.2. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.90 (s, 1H), 8.82 (s, 1H), 7.94 (d, J=7.6 Hz, 1H), 7.89-7.87 (m, 1H), 7.50-7.46 (m, 2H), 7.29-7.26 (m, 1H), 6.73 (d, J=2.0 Hz, 1H), 4.92 (s, 2H), 4.05 (s, 3H), 1.00 (s, 9H), 0.18 (s, 6H).

Step 5. Synthesis of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(1-methyl-1H-pyrazol-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

The preparation of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(1-methyl-1H-pyrazol-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole was similar to that of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-((4-methoxybenzyl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (Example 395, Step 1) to give 600 mg as a brown solid, Y: 72%. ESI-MS (M+H) + : 546.3.

Synthesis of (S)-tert-butyl (4-((tert-butyldimethylsilyl)oxy)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)carbamate

The preparation of (S)-tert-butyl (4-((tert-butyldimethylsilyl)oxy)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)carbamate was similar to that of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-((4-methoxybenzyl)oxy)-4-(1-methyl-1H-pyrazol-3-yl)-1H-indazole using (S)-tert-butyl (1-(6-bromopyridin-2-yl)-4-((tert-butyldimethylsilyl)oxy)butyl)carbamate from Example 396 to give 230 mg as a yellow solid, Y: 60%. ESI-MS (M+H) + : 798.5.

Synthesis of (S)-4-amino-4-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol

The preparation of (S)-4-amino-4-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol was similar to that of (S)-4-amino-4-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol (Example 484, Step 2) to give 107 mg as a yellow solid, Y: 63%. ESI-MS (M+H) + : 470.2. HPLC: 100%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.70 (s, 1H), 8.82 (s, 1H), 8.47 (s, 1H), 8.14 (d, J=8.0 Hz, 1H), 8.09-7.89 (m, 3H), 7.77 (d, J=2.0 Hz, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.44-7.27 (m, 1H), 7.00 (d, J=2.0 Hz, 1H), 4.90 (s, 2H), 4.63 (t, J=6.8 Hz, 1H), 4.08 (s, 3H), 3.66 (t, J=6.4 Hz, 2H), 2.23-2.16 (m, 2H), 1.87-1.47 (m, 2H).

›Example 396

Synthesis of 1-(6-bromopyridin-2-yl)-4-methoxybutan-1-one

To a solution of 6-bromo-N-methoxy-N-methylpicolinamide (2.5 g, 10.2 mmol, 1.0 eq) in THF (20 mL) was added (3-methoxypropyl)magnesium bromide (15.3 mL (2M in THF), 30.6 mmol, 3.0 eq) at −78° C. The mixture was stirred at −78° C. for 2 h. Then saturated ammonium chloride aqueous solution (10 mL) was added to quench the reaction and the mixture was extracted with EA (3×50 mL). The organic phase was washed with brine and dried over Na 2 SO 4 . After filtration and concentration, the residue was purified by column chromatography (silica gel, PE/EA=6/1) to give 1-(6-bromopyridin-2-yl)-4-methoxybutan-1-one (2.0 g, yield: 76%) as light yellow oil. ESI-MS (M+H) + : 258.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 7.98 (dd, J=7.2, 1.2 Hz, 1H), 7.76-7.55 (m, 2H), 3.48 (t, J=6.4 Hz, 2H), 3.32 (s, 3H), 3.27 (t, J=7.2 Hz, 2H), 2.09-1.90 (m, 2H).

Synthesis of (R,E)-N-(1-(6-bromopyridin-2-yl)-4-methoxybutylidene)-2-methylpropane-2-sulfinamide

To a solution of 1-(6-bromopyridin-2-yl)-4-methoxybutan-1-one (2.0 g, 7.8 mmol, 1.0 eq) and (R)-(+)-2-Methyl-2-propanesulfinamide (CAS No. 196929-78-9, 1.1 g, 9.4 mmol, 1.2 eq) in THF (20 mL) was added Ti(OEt) 4 (3.6 g, 15.6 mmol, 2.0 eq) at rt. The mixture was stirred at 70° C. for 16 h. After cooling down to rt, the mixture was diluted with water (200 mL) and extracted with EA (50 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4 . After concentration, the residue was purified by silica gel chromatography with PE/EA (8/1) as eluent to give (R,E)-N-(1-(6-bromopyridin-2-yl)-4-methoxybutylidene)-2-methylpropane-2-sulfinamide (1.8 g, yield: 64%) as a yellow solid. ESI-MS (M+H) + : 361.1.

Synthesis of (R)—N—((S)-1-(6-bromopyridin-2-yl)-4-methoxybutyl)-2-methylpropane-2-sulfinamide

To a solution of (R,E)-N-(1-(6-bromopyridin-2-yl)-4-methoxybutylidene)-2-methylpropane-2-sulfinamide (1.8 g, 5.0 mmol, 1.0 eq) in THF (50 mL) was added L-selectride (15 mL, 15 mmol, 3.0 eq) at −78° C. The mixture was stirred at −78° C. for 3 h. The mixture was diluted with DCM (80 mL) and then Na 2 SO 4 .10H 2 O was added to quench the reaction. After filtration and concentration, the residue was recrystallized by (DCM/PE=1/100) to give (R)—N—((S)-1-(6-bromopyridin-2-yl)-4-methoxybutyl)-2-methylpropane-2-sulfinamide (1.1 g, yield: 61%) as a white solid. ESI-MS (M+H) + : 363.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 7.50 (t, J=8.0 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.25 (d, J=7.2 Hz, 1H), 4.47 (q, J=6.4 Hz, 1H), 4.16 (d, J=6.0 Hz, 1H), 3.41-3.36 (m, 2H), 3.30 (s, 3H), 2.04-1.93 (m, 2H), 1.69-1.58 (m, 2H), 1.19 (s, 9H).

Synthesis of (S)-tert-butyl (1-(6-bromopyridin-2-yl)-4-hydroxybutyl)carbamate

To a solution of (R)—N—((S)-1-(6-bromopyridin-2-yl)-4-methoxybutyl)-2-methylpropane-2-sulfinamide (1.1 g, 3.0 mmol, 1.0 eq) in THF (50 mL) was added BBr 3 (0.6 mL, 6.0 mmol, 2.0 eq) at −78° C. The mixture was stirred at −78° C. to rt for 16 h. Then Boc 2 O (1.3 g, 6.0 mmol, 2.0 eq), NaOH (480 mg, 12.0 mmol, 4.0 eq) and H 2 O (20 mL) was added to the mixture. The mixture was stirred at 50° C. for 3 h. After cooling down to rt, the mixture was extracted with EA (30 mL×3). The combined organic fractions were dried, filtrated and concentrated. The residue was purified by silica gel chromatography (PE/EA=4/1) to give (S)-tert-butyl (1-(6-bromopyridin-2-yl)-4-hydroxybutyl)carbamate (370 mg, yield: 35%) as brown oil. ESI-MS (M+H) + : 345.1.

Synthesis of (S)-tert-butyl (1-(6-bromopyridin-2-yl)-4-((tert-butyldimethylsilyl)oxy)butyl)carbamate

The preparation of (S)-tert-butyl (1-(6-bromopyridin-2-yl)-4-((tert-butyldimethylsilyl)oxy)butyl)carbamate was similar to that of 4-bromo-1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-((4-methoxybenzyl)oxy)-1H-indazole (Example 352, Step 5) to give 380 mg, as a yellow solid, Y: 77%. ESI-MS (M+H) + : 459.2.

Synthesis of (S)-tert-butyl (4-((tert-butyldimethylsilyl)oxy)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)carbamate

The preparation of (S)-tert-butyl (4-((tert-butyldimethylsilyl)oxy)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)carbamate was similar to that of (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(1H-pyrazol-1-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (Example 352, Step 10) using the borate from Example 145, Step 3 to give 270 mg, as a yellow solid, Y: 63%. ESI-MS (M+H) + : 718.5. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.43 (s, 1H), 8.20 (s, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.96-7.78 (m, 3H), 7.74 (d, J=4.0 Hz, 2H), 7.39 (d, J=7.2 Hz, 1H), 7.19 (t, J=4.0 Hz, 1H), 5.84 (d, J=8.4 Hz, 1H), 4.97 (s, 2H), 4.85-4.82 (m, 1H), 3.76-3.36 (m, 2H), 2.09-1.83 (m, 2H), 1.60-1.53 (m, 2H), 1.42 (s, 9H), 0.98 (s, 9H), 0.84 (s, 9H), 0.15 (s, 6H), 0.00 (s, 6H).

Synthesis of (S)-4-amino-4-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol

To a solution of (S)-tert-butyl (4-((tert-butyldimethylsilyl)oxy)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)carbamate (270 mg, 0.38 mmol, 1.0 eq) in DCM (10 mL) was added conc. HCl (0.5 mL). The mixture was stirred at rt for 30 min. The solvent was removed in vacuo. The resulting mixture was diluted with DMF (3 mL) and adjusted to pH=7-8 with sodium hydroxide aqueous solution. The mixture was purified by prep-HPLC (MeOH/H 2 O with 0.05% NH 4 OH as mobile phase from 0% to 100%) to give (S)-4-amino-4-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol (95 mg, yield: 65%) as a white solid. ESI-MS (M+H) + : 390.3. HPLC: 96%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.65 (s, 1H), 8.31 (s, 1H), 8.10-7.84 (m, 6H), 7.49-7.29 (m, 2H), 4.88 (s, 2H), 4.10 (t, J=6.8 Hz, 1H), 3.61 (t, J=6.8 Hz, 2H), 2.21-1.82 (m, 2H), 1.82-1.36 (m, 2H).

Example 397. (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyrazin-2-yl)methanol

›Step 1. Synthesis of methyl 6-(6-bromo-1H-indazol-1-yl)pyrazine-2-carboxylate

The preparation of methyl 6-(6-bromo-1H-indazol-1-yl)pyrazine-2-carboxylate was similar to that of (6-(4-bromo-6-((4-methoxybenzyl)oxy)-1H-indazol-1-yl)pyridin-2-yl)methanol (Example 352, Step 4) to give 1.1 g as a yellow solid, Y: 36%. ESI-MS (M+H) + : 333.0. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.61 (s, 1H), 9.21 (s, 1H), 9.17 (s, 1H), 8.28 (s, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.52 (dd, J=8.4, 1.2 Hz, 1H), 4.15 (s, 3H).

›Step 2. Synthesis of (6-(6-bromo-1H-indazol-1-yl)pyrazin-2-yl)methanol

The preparation of (6-(6-bromo-1H-indazol-1-yl)pyrazin-2-yl)methanol was similar to that of (6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-4-yl)methanol (Example 57) to give 1.0 g as a yellow solid, Y: 82%. ESI-MS (M+H) + : 305.0.

›Step 3. Synthesis of 6-bromo-1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyrazin-2-yl)-1H-indazole

The preparation of 6-bromo-1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyrazin-2-yl)-1H-indazole was similar to that of 4-bromo-1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-((4-methoxybenzyl)oxy)-1H-indazole (Example 352, Step 5) to give 830 mg as a yellow solid, Y: 60%. ESI-MS (M+H) + : 419.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.29 (s, 1H), 8.93 (s, 1H), 8.63 (s, 1H), 8.21 (s, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.44 (dd, J=8.8, 1.6 Hz, 1H), 4.98 (s, 2H), 1.01 (s, 9H), 0.19 (s, 6H).

Step 4. Synthesis of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyrazin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

The preparation of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyrazin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole was similar to that of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(1H-pyrazol-1-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (Example 352, Step 9) to give 310 mg as a yellow solid, Y: 82%. ESI-MS (M+H) + : 467.3.

Step 5. Synthesis of (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyrazin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide

The preparation of (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyrazin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide was similar to that of (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(1H-pyrazol-1-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (Example 352, Step 10) to give 180 mg as a yellow solid, Y: 48%. ESI-MS (M+H) + : 565.3.

›Step 6. Synthesis of (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyrazin-2-yl)methanol

The preparation of (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyrazin-2-yl)methanol was similar to that of (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(1H-pyrazol-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol (Example 352, Step 11) to give 60 mg as a white solid, Y: 54%. ESI-MS (M+H) + : 347.2. HPLC: 100%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.57 (s, 1H), 9.25 (s, 1H), 8.56 (s, 1H), 8.39 (s, 1H), 8.08 (d, J=8.4 Hz, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.89 (d, J=4.8 Hz, 2H), 7.39 (t, J=4.0 Hz, 1H), 4.92 (s, 2H), 4.25 (q, J=6.8 Hz, 1H), 1.55 (d, J=6.8 Hz, 3H).

The following were synthesized in a similar fashion to Example 397 using the appropriate pyridyl bromide.

Example 400 (S)-(4-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol

›Step 1. Synthesis of (4-(6-bromo-1H-indazol-1-yl)pyridin-2-yl)methanol

A mixture of 6-Bromo-1H-indazole (CAS No. 79762-54-2, 1.5 g, 7.6 mmol, 1.0 eq), 4-Bromo-2-pyridinemethanol (CAS No. 131747-45-0, 1.85 g, 9.9 mmol, 1.3 eq), CuI (285 mg, 1.5 mmol, 0.2 eq), K 3 PO 4 (3.2 g, 15.2 mmol, 2.0 eq) and 61798-24-1 (426 mg, 3.0 mmol, 0.4 eq) in 1,4-dioxane (15 mL) was stirred at 110° C. for 16 h. After concentration, the residue was purified by silica gel chromatography using PE/EA (3/1) as eluent to give (4-(6-bromo-1H-indazol-1-yl)pyridin-2-yl)methanol as a yellow solid. 750 mg, Y: 32%. ESI-MS (M+H) + : 304.1

›Step 2. Synthesis of 6-bromo-1-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-4-yl)-1H-indazole

To a solution of (4-(6-bromo-1H-indazol-1-yl)pyridin-2-yl)methanol (750 mg, 2.5 mmol, 1.0 eq) in DCM (10 mL) was added TBSCl (750 mg, 5.0 mmol, 2.0 eq) and imidazole (340 mg, 5.0 mmol, 2.0 eq). The mixture was stirred at rt for 2 h. After concentration, the residue was purified by silica gel chromatography using PE/EA (5/1) as eluent to give 6-bromo-1-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-4-yl)-1H-indazole. 750 mg, as a white solid, Y: 67%. ESI-MS (M+H) + : 418.1.

Step 3. Synthesis of 1-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

A mixture of 6-bromo-1-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-4-yl)-1H-indazole (700 mg, 1.7 mmol, 1.0 eq), Bis(pinacolato)diboron (CAS No. 73183-34-3, 475 mg, 1.9 mmol, 1.1 eq) and CH 3 COOK (333 mg, 3.4 mmol, 2.0 eq) in 1,4-dioxane (10 mL) was stirred while purging N 2 at rt for 10 min. To this system was added Pd(dppf)Cl 2 (90 mg, 0.1 mmol, 0.1 eq) and heated to 90° C. for 16 h. The mixture was diluted with EtOAc (50 mL) and washed with and brine (50 mL×2). The organic phase was dried (Na 2 SO 4 ) and concentrated to give 1-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole which was used for next step without further purification. 620 mg, as a brown solid, Y: 80%. ESI-MS (M+H) + : 466.3.

Step 4. Synthesis of (R)—N—((S)-1-(6-(1-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-4-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide

A mixture of 1-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (520 mg, 1.1 mmol, 1.0 eq), (R)—N—((S)-1-(6-bromopyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide (Example 145, Step 5, 402 mg, 1.2 mmol, 1.1 eq) and K 2 CO 3 (304 mg, 2.2 mmol, 2.0 eq) in 1,4-dioxane/H 2 O (10 mL/1 mL) was stirred while purging N 2 at rt for 10 min. To this system was added Pd(dppf)Cl 2 (92 mg, 0.1 mmol, 0.1 eq) and heated to 110° C. for 16 h. After concentration, the residue was purified by silica gel chromatography using PE/EA (1/1) as eluent to give (R)—N—((S)-1-(6-(1-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-4-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide. 300 mg, as a brown solid, Y: 38%. ESI-MS (M+H) + : 592.3.

›Step 5. Synthesis of (S)-(4-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol

To a solution of (R)—N—((S)-1-(6-(1-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-4-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide (200 mg, 0.34 mmol, 1.0 eq) in DCM (5 mL) was added conc. HCl (0.3 mL). Then the mixture was stirred at rt for 1 h. After concentration, the residue was purified by prep-HPLC (CH 3 CN/H 2 O with 0.05% NH 4 HCO 3 as mobile phase from 5% to 95%) to afford the product (S)-(4-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol. 56 mg, as a white solid, Y: 30%. ESI-MS (M+H) + : 374.3. HPLC: 100%. 1 H NMR (400 MHz, CD 3 OD) δ: 8.78 (s, 1H), 8.62 (s, 1H), 8.42-8.40 (m, 1H), 8.19 (s, 1H), 8.07-7.90 (m, 5H), 7.38 (d, J=7.6 Hz, 1H), 4.83 (s, 2H), 4.16 (t, J=6.8 Hz, 1H), 1.94-1.82 (m, 2H), 1.47-1.31 (m, 2H), 0.98 (t, J=7.2 Hz, 3H).

›Examples4

›Example 401 (S)-(4-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyrimidin-2-yl)methanol

Synthesis of (R)-2-methyl-N-((1S)-1-(6-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)propane-2-sulfinamide

To a solution of 6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (2.9 g, 10.36 mmol, 1.0 eq) in dry 1,4-dioxane (100 mL) were added bis(pinacolato)diboron (3.2 g, 12.43 mmol, 1.2 eq), KOAc (3.05 g, 31.07 mmol, 3.0 eq) and Pd(dppf)Cl 2 DCM (846 mg, 1.04 mmol, 0.1 eq). The mixture was stirred at 100° C. under N 2 for 2 h. After cooling down to rt, H 2 O (10 mL), K 2 CO 3 (4.3 g, 31.07 mmol, 3.0 eq), Pd(dppf)Cl 2 DCM (846 mg, 1.04 mmol, 0.1 eq) and (R)—N—((S)-1-(6-bromopyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide (Example 145, Step 5, 3.44 g, 10.36 mmol, 1.0 eq) were added to the mixture. The mixture was stirred at 120° C. under N 2 for further 2 h. The mixture was diluted with water (200 mL) and extracted with EA (50 mL×3). The combined organic fractions were dried (Na 2 SO 4 ), filtrated, concentrated and purified by silica gel chromatography (PE/EA=5/1) to give the title compound. 3.5 g, as a yellow solid, Y: 75%. ESI-MS (M+H) + : 455.2. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.26 (d, J=13.2 Hz, 1H), 8.07 (s, 1H), 7.84-7.80 (m, 4H), 7.20 (d, J=6.4 Hz, 1H), 5.84 (dd, J=9.6, 2.4 Hz, 1H), 4.59-4.54 (m, 1H), 4.28-4.22 (m, 1H), 4.08-4.05 (m, 1H), 3.85-3.78 (m, 1H), 2.68-2.61 (m, 1H), 2.20-2.11 (m, 2H), 2.03-1.97 (m, 2H), 1.70-1.64 (m, 2H), 1.43-1.32 (m, 2H), 1.20 (s, 9H), 0.95 (t, J=7.2 Hz, 3H).

Synthesis of (R)—N—((S)-1-(6-(1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide

To a solution of (R)-2-methyl-N-((1S)-1-(6-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)propane-2-sulfinamide (3.5 g, 7.71 mmol, 1.0 eq) in DCM (100 mL) was added TFA (2.9 mL, 4.4 g, 38.55 mmol, 5.0 eq). The mixture was stirred at rt for 2 h and adjusted pH=7 with sat. NaHCO 3 . The residue was extracted with EtOAc (50 mL×3). The combined organic fractions were dried (Na 2 SO 4 ), filtrated and concentrated in vacuo to give (R)—N—((S)-1-(6-(1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide which was used for next step without further purification. 2.5 g, Y: 88%. ESI-MS (M+H) + : 371.2. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.23 (s, 1H), 8.11 (s, 1H), 7.83-7.80 (m, 2H), 7.75-7.68 (m, 2H), 7.20 (d, J=7.2 Hz, 1H), 4.58-4.53 (m, 1H), 4.24-4.23 (m, 1H), 1.99-1.96 (m, 2H), 1.52-1.32 (m, 2H), 1.20 (s, 9H), 0.92 (t, J=7.2 Hz, 3H).

Synthesis of (R)—N—((S)-1-(6-(1-(2-chloropyrimidin-4-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide

A solution of (R)—N—((S)-1-(6-(1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide (2.5 g, 6.76 mmol, 1.0 eq) in dry DMF (100 mL) cooled to 0° C. was treated with NaH (60%, 540 mg, 13.51 mmol, 2.0 eq) in portions. After stirring at rt for 2 h, 2,4-dichloropyrimidine (1.2 g, 8.11 mmol, 1.2 eq) was added and the mixture was stirred at rt for 4 h. The mixture was quenched with water and extracted with EA (50 mL×3). The combined organic layers were dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography (PE/EA=3/1) to afford (R)—N—((S)-1-(6-(1-(2-chloropyrimidin-4-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide. 2.0 g, as a white solid, Y: 61%. ESI-MS (M+H) + : 483.2.

Synthesis of methyl 4-(6-(6-((S)-1-((R)-1,1-dimethylethylsulfinamido)butyl)pyridin-2-yl)-1H-indazol-1-yl)pyrimidine-2-carboxylate

To a solution of (R)—N—((S)-1-(6-(1-(2-chloropyrimidin-4-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide (2.0 g, 4.15 mmol, 1.0 eq) in MeOH (100 mL) were added Pd(dppf)Cl 2 DCM (380 mg, 0.42 mmol, 0.1 eq) and Et 3 N (838 mg, 8.30 mmol, 2.0 eq). The mixture was stirred under an atmosphere of 20 atm CO at 100° C. for 24 h. After concentration, the residue was purified by chromatography (PE/EA=1/1) to give methyl 4-(6-(6-((S)-1-((R)-1,1-dimethylethylsulfinamido)butyl)pyridin-2-yl)-1H-indazol-1-yl)pyrimidine-2-carboxylate. 1.1 g, as a white solid, Y: 52%. ESI-MS (M+H) + : 507.2. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.89 (s, 1H), 8.91 (d, J=6.0 Hz, 1H), 8.32 (s, 1H), 7.42 (dd, J=8.0, 1.2 Hz, 1H), 8.13 (d, J=5.6 Hz, 1H), 7.95-7.80 (m, 3H), 7.23 (d, J=7.2 Hz, 1H), 4.57-4.54 (m, 1H), 4.44-4.42 (m, 1H), 4.16 (s, 3H), 2.08-2.01 (m, 2H), 1.52-1.32 (m, 2H), 1.16 (s, 9H), 0.95 (t, J=7.2 Hz, 3H).

Synthesis of (R)—N—((S)-1-(6-(1-(2-(hydroxymethyl)pyrimidin-4-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide

To a suspension of methyl 4-(6-(6-((S)-1-((R)-1,1-dimethylethylsulfinamido)butyl)pyridin-2-yl)-1H-indazol-1-yl)pyrimidine-2-carboxylate (500 mg, 0.99 mmol, 1.0 eq) in MeOH (50 mL) at 0° C. was added NaBH 4 (113 mg, 2.96 mmol, 3.0 eq). The reaction mixture was stirred at rt for 2 h. The solvent was removed by evaporation, and then the residue was diluted with water (100 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried (Na 2 SO 4 ), concentrated and purified by prep-TLC (DCM/MeOH=20/1) to afford (R)—N—((S)-1-(6-(1-(2-(hydroxymethyl)pyrimidin-4-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide. 300 mg, as a white solid, Y: 64%. ESI-MS (M+H) + : 479.2. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.73 (s, 1H), 8.73 (d, J=5.6 Hz, 1H), 8.23 (s, 1H), 8.03-8.01 (m, 1H), 7.90-7.85 (m, 2H), 7.79-7.78 (m, 2H), 7.24-7.22 (m, 1H), 4.99 (d, J=4.4 Hz, 2H), 4.56-4.52 (m, 2H), 4.19-4.17 (m, 1H), 2.09-2.04 (m, 2H), 1.45-1.24 (m, 2H), 1.18 (s, 9H), 0.95 (t, J=7.2 Hz, 3H).

Synthesis of (S)-(4-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyrimidin-2-yl)methanol

The preparation of (S)-(4-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyrimidin-2-yl)methanol was similar to that of (S)-(4-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol (Example 400, Step 5) using 1,4-dioxane in place of DCM to give 220 mg as a yellow solid, Y: 70%. ESI-MS (M+H) + : 375.2. HPLC: 100%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.58 (s, 1H), 8.89 (d, J=7.2 Hz, 1H), 8.73 (s, 1H), 8.45-8.41 (m, 2H), 8.16-8.06 (m, 3H), 7.54 (d, J=7.2 Hz, 1H), 5.23 (s, 2H), 4.61 (t, J=6.8 Hz, 1H), 2.11-2.04 (m, 2H), 1.51-1.39 (m, 2H), 1.04 (t, J=7.2 Hz, 3H).

›Example 402 (S)-(3-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)phenyl)methanol

Synthesis of (3-(6-bromo-1H-indazol-1-yl)phenyl)methanol

The preparation of (3-(6-bromo-1H-indazol-1-yl)phenyl)methanol was similar to that of (4-(6-bromo-1H-indazol-1-yl)pyridin-2-yl)methanol (Example 400, Step 1) to give 680 mg as a yellow solid, Y: 14%. ESI-MS (M+H) + : 303.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.17 (s, 1H), 7.90 (s, 1H), 7.71-7.65 (m, 2H), 7.60 (d, J=8.0 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.34 (dd, J=8.4, 1.2 Hz, 1H), 4.82 (d, J=4.4 Hz, 2H).

Synthesis of 6-bromo-1-(3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-1H-indazole

The preparation of 6-bromo-1-(3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-1H-indazole was similar to that of 6-bromo-1-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-4-yl)-1H-indazole (Example 400, Step 2) to give 850 mg as a white solid, Y: 90%. ESI-MS (M+H) + : 417.1.

Synthesis of 1-(3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

The preparation of 1-(3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole was similar to that of 1-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (Example 400, Step 3) to give 600 mg as a brown solid, Y: 63%. ESI-MS (M+H) + : 465.2.

Synthesis of (R)—N—((S)-1-(6-(1-(3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide

The preparation of (R)—N—((S)-1-(6-(1-(3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide was similar to that of (R)—N—((S)-1-(6-(1-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-4-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide (Example 400, Step 4) to give 450 mg as a yellow solid, Y: 59%. ESI-MS (M+H) + : 591.3.

Synthesis of (S)-(3-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)phenyl)methanol

The preparation of (S)-(3-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)phenyl)methanol was similar to that of (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyrazin-2-yl)methanol (Example 397, Step 6) to give 150 mg as a white solid, Y: 52%. ESI-MS (M+H) + : 373.2. HPLC: 100%. 1 H NMR (400 MHz, CD 3 OD) δ: 8.53 (s, 1H), 8.29 (s, 1H), 8.04 (dd, J=8.4, 1.2 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.96-7.91 (m, 2H), 7.81 (s, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.57 (t, J=8.0 Hz, 1H), 7.41-7.38 (m, 2H), 4.73 (s, 2H), 4.49 (t, J=6.8 Hz, 1H), 2.04-1.89 (m, 2H), 1.46-1.30 (m, 2H), 0.96 (t, J=7.6 Hz, 3H).

›Example 403 (S)-(2-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyrimidin-4-yl)methanol

Synthesis of methyl 2-(6-bromo-1H-indazol-1-yl)pyrimidine-4-carboxylate

To a solution of 6-bromo-1H-indazole (Cas No. 79762-54-2, 400 mg, 2.04 mmol, 1.0 eq) in DMF (6 mL) was added NaH (90 mg, 2.24 mmol, 1.1 eq) at 0° C. After stirring at 0° C. for 15 min, Methyl 2-chloropyrimidine-4-carboxylate (CAS No. 149849-94-5, 352 mg, 2.04 mmol, 1.0 eq) dissolving in DMF (2 mL) was added and the reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into H 2 O (40 mL) and stirred at rt for 15 min. The precipitate was collected by filtration and dried to give methyl 2-(6-bromo-1H-indazol-1-yl)pyrimidine-4-carboxylate. 400 mg, as a yellow solid, Y: 59%. ESI-MS (M+H) + : 333.0.

Synthesis of (2-(6-bromo-1H-indazol-1-yl)pyrimidin-4-yl)methanol

To a solution of methyl 2-(6-bromo-1H-indazol-1-yl)pyrimidine-4-carboxylate (300 mg, 0.9 mmol, 1.0 eq in THF (15 mL) was added LiBH 4 (1.8 mL, 1.8 mmol, 2.0 eq) dropwised at −78° C. After stirring at −78° C. for 5 min, the reaction was quenched with sat. NH 4 Cl solution. The mixture was filtrated and the filtrate was extracted with EA (30 mL×3). The combined organic phases were dried and concentrated to give (2-(6-bromo-1H-indazol-1-yl)pyrimidin-4-yl)methanol. 110 mg, as a yellow solid, Y: 48%. ESI-MS (M+H) + : 305.0.

Synthesis of 6-bromo-1-(4-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)-1H-indazole

The preparation of 6-bromo-1-(4-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)-1H-indazole was similar to that of 6-bromo-1-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-4-yl)-1H-indazole (Example 400, Step 2) to give 140 mg as a white solid, Y: 92%. ESI-MS (M+H) + : 419.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.02 (s, 1H), 8.83 (d, J=5.2 Hz, 1H), 8.27 (s, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.47-7.44 (m, 2H), 4.95 (s, 2H), 0.92 (s, 9H), 0.08 (s, 6H).

Synthesis of 1-(4-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

The preparation of 1-(4-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole was similar to that of 1-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (Example 400, Step 3) to give 120 mg as a brown solid, Y: 77%. ESI-MS (M+H) + : 467.2.

Synthesis of (R)—N—((S)-1-(6-(1-(4-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide

The preparation of (R)—N—((S)-1-(6-(1-(4-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide was similar to that of (R)—N—((S)-1-(6-(1-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-4-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide (Example 400, Step 4) to give 100 mg as yellow oil, Y: 66%. ESI-MS (M+H) + : 593.3.

Synthesis of (S)-(2-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyrimidin-4-yl)methanol

The preparation of (S)-(2-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyrimidin-4-yl)methanol was similar to that of (S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyrazin-2-yl)methanol (Example 397, Step 6) to give 58 mg as a white solid, Y: 70%. ESI-MS (M+H) + : 375.2. HPLC: 100%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.57 (s, 1H), 8.86 (d, J=4.8 Hz, 1H), 8.44 (s, 1H), 8.22 (d, J=8.4 Hz, 1H), 8.09-7.98 (m, 3H), 7.48-7.46 (m, 2H), 4.87 (s, 2H), 4.58 (t, J=6.8 Hz, 1H), 2.11-2.03 (m, 2H), 1.51-1.41 (m, 2H), 1.04 (t, J=7.2 Hz, 3H).

Example 404. (S)-(6-(6-(4-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol

›Step 1. Synthesis of 2-bromo-N-methoxy-N-methylisonicotinamide

To a solution of 2-Bromopyridine-4-carboxylic acid (CAS no. 66572-56-3, 6.1 g, 30 mmol, 1.0 eq) in dichloromethane (100 mL) were added N,O-dimethylhydroxylamine hydrochloride (CAS No. 6638-79-5, 3.5 g, 36 mmol, 1.2 eq), HATU (17.0 g, 45 mmol, 1.5 eq) and DIEA (12.4 mL, 75 mmol, 2.5 eq). The mixture was stirred at room temperature for 16 h under N 2 atmosphere. The mixture was diluted with dichloromethane (200 mL) and washed with water (80 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtrated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA=2/1) to give 2-bromo-N-methoxy-N-methylisonicotinamide (6.3 g, Y: 85%) as colorless oil. ESI-MS (M+1) + : 247.0, 245.0.

›Step 2. Synthesis of 1-(2-bromopyridin-4-yl)butan-1-one

To a mixture of 2-bromo-N-methoxy-N-methylisonicotinamide (2.5 g, 10.2 mmol, 1.0 eq) in anhydrous THF (60 mL) was added propylmagnesium bromide (2.0 M in THF, 7.7 mL, 15.3 mmol, 1.5 eq) at 0° C. under N 2 atmosphere. The mixture was stirred at rt for 2 h. The reaction was quenched with saturated aqueous ammonium chloride (40 mL). The mixture was extracted with ethyl acetate (50 mL×2). The organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA=5/1) to give 1-(2-bromopyridin-4-yl)butan-1-one (1.9 g, Y: 81%) as colorless oil. ESI-MS (M+1) + : 228.0, 230.0. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.55 (d, J=5.2 Hz, 1H), 7.91 (s, 1H), 7.69 (dd, J=5.2, 1.2 Hz, 1H), 2.94 (t, J=7.2 Hz, 2H), 1.82-1.72 (m, 2H), 1.03 (t, J=7.2 Hz, 3H).

›Step 3. Synthesis of (R,E)-N-(1-(2-bromopyridin-4-yl)butylidene)-2-methylpropane-2-sulfinamide

To a solution of 1-(2-bromopyridin-4-yl)butan-1-one (1.9 g, 8.4 mmol, 1.0 eq) in THF (60 mL) was added (R)-2-methylpropane-2-sulfinamide (CAS No. 196929-78-9, 1.2 g, 10.1 mmol, 1.2 eq) and titanium ethoxide (3.5 mL, 16.8 mmol, 2.0 eq). The mixture was stirred at 70° C. for 16 h under N 2 atmosphere. After cooling down to rt, the mixture was diluted with ethyl acetate (200 mL), and water (100 mL) was added. Then the mixture was filtered and washed with ethyl acetate (50 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtrated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA=2/1) to give (R,E)-N-(1-(2-bromopyridin-4-yl)butylidene)-2-methylpropane-2-sulfinamide (2.3 g, Y: 85%) as yellow oil. ESI-MS (M+1) + : 331.0, 333.0. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.47 (d, J=5.2 Hz, 1H), 7.78 (s, 1H), 7.57 (dd, J=4.0 Hz, 1H), 3.27-3.07 (m, 2H), 1.71-1.59 (m, 2H), 1.33 (s, 9H), 1.05 (t, J=7.2 Hz, 3H).

›Step 4. Synthesis of (R)—N—((S)-1-(2-bromopyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide

To a solution of (R,E)-N-(1-(2-bromopyridin-4-yl)butylidene)-2-methylpropane-2-sulfinamide (2.3 g, 7.0 mmol, 1.0 eq) in anhydrous THF (100 mL) was added L-selectride (1.0 M in THF, 21.0 mL, 21.0 mmol, 3.0 eq) at −78° C. under N 2 atmosphere. The mixture was stirred at rt for 3 h. The reaction was quenched with saturated aqueous ammonium chloride (60 mL). The mixture was extracted with ethyl acetate (50 mL×2). The combined organic layers were dried over anhydrous sodium sulfate, filtrated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA=2/1) to give (R)—N—((S)-1-(2-bromopyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide (1.4 g, Y: 62%) as colorless oil. ESI-MS (M+1) + : 333.0, 335.0. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.33 (d, J=5.2 Hz, 1H), 7.43 (s, 1H), 7.19 (d, J=5.2 Hz, 1H), 4.38 (t, J=6.4 Hz, 1H), 3.39 (br, 1H), 1.81-1.69 (m, 2H), 1.37-1.21 (m, 2H), 1.21 (s, 9H), 0.95 (t, J=7.2 Hz, 3H).

Step 5. Synthesis of (S)—N—((S)-1-(2-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide

To a solution of (R)—N—((S)-1-(2-bromopyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide (490 mg, 1.5 mmol, 1.0 eq) in 1,4-dioxane/H 2 O (20 mL/1.0 mL) were added 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole, (Example 143, Step 3) 698 mg, 1.5 mmol, 1.0 eq), Pd(dppf) 2 Cl 2 (122 mg, 0.15 mmol, 0.1 eq), K 2 CO 3 (414 mg, 3.0 mmol, 2.0 eq). The mixture was stirred at 110° C. for 16 h under N 2 atmosphere. After concentration, the residue was purified by silica gel column chromatography (PE/EA=5/1) to give (S)—N—((S)-1-(2-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide (595 mg, Y: 68%) as yellow oil. ESI-MS (M+1) + : 592.3. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.38 (s, 1H), 8.72 (d, J=4.8 Hz, 1H), 8.22 (s, 1H), 7.94-7.85 (m, 4H), 7.78 (s, 1H), 7.42 (d, J=7.2 Hz, 1H), 7.24 (d, J=4.8 Hz, 1H), 4.98 (s, 2H), 4.52 (t, J=5.6 Hz, 1H), 3.45 (s, 1H), 1.90-1.83 (m, 2H), 1.42-1.25 (m, 2H), 1.22 (s, 9H), 1.00 (s, 9H), 0.99 (t, J=7.2 Hz, 3H), 0.17 (s, 6H).

›Step 6. Synthesis of (S)-(6-(6-(4-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol · 1 of 3

To a solution of (S)—N—((S)-1-(2-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide (590 mg, 1.0 mmol, 1.0 eq) in dichloromethane (30 mL) was added 4.0 M HCl in 1,4-dioxane (3 mL). The mixture was stirred at rt for 1 h. Then the solution was filtered and washed with dichloromethane to get (S)-(6-(6-(4-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol (400 mg, Y: 97%) as a yellow solid. ESI-MS (M+1) + : 374.2. HPLC: 95%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.64 (s, 1H), 9.03 (d, J=7.0 Hz, 1H), 8.59 (s, 1H), 8.49 (s, 1H), 8.21 (d, J=8.4 Hz, 1H), 8.13 (d, J=5.6 Hz, 1H), 8.07-8.01 (m, 2H), 7.92 (d, J=8.4 Hz, 1H), 7.44 (d, J=6.8 Hz, 1H), 4.91 (s, 2H), 4.81 (t, J=7.2 Hz, 1H), 2.17-2.09 (m, 2H), 1.55-1.40 (m, 2H), 1.07 (t, J=7.2 Hz, 3H).

Example 405 and 406 (S)-(6-(6-(2-(1-aminobutyl)pyrimidin-4-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol and (R)-(6-(6-(2-(1-aminobutyl)pyrimidin-4-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol

Synthesis of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-(2-chloropyrimidin-4-yl)-1H-indazole

To a solution of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (Example 143, Step 3) (1.8 g, 3.87 mmol, 1.0 eq) in 1,4-dioxane/H 2 O (40 mL/5 mL) were added 2,4-dichloropyrimidine (692 mg, 4.65 mmol, 1.2 eq), Pd(dppf)Cl 2 DCM (316 mg, 0.387 mmol, 0.1 eq) and K 2 CO 3 (1.6 g, 11.61 mmol, 3.0 eq). The mixture was stirred at 120° C. under N 2 for 4 h. After cooling down to rt, the mixture was diluted with water (100 mL) and extracted with EA (50 mL×3). The combined organic fractions were washed with brine, dried and evaporated. The residue was purified by chromatography (PE/EA=3/1) to give 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-(2-chloropyrimidin-4-yl)-1H-indazole (920 mg, Y: 53%) as a white solid. ESI-MS (M+H) + : 452.2. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.66 (s, 1H), 8.70 (d, J=5.2 Hz, 1H), 8.25 (s, 1H), 8.01-7.99 (m, 1H), 7.93-7.87 (m, 3H), 7.78 (d, J=5.2 Hz, 1H), 7.44 (d, J=7.2 Hz, 1H), 5.01 (s, 2H), 1.01 (s, 9H), 0.19 (s, 6H).

Synthesis of 4-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidine-2-carbonitrile

To a stirred solution of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-(2-chloropyrimidin-4-yl)-1H-indazole (1.6 g, 3.55 mmol, 1.0 eq) in DMSO (30 mL) were added DABCO (80 mg, 0.71 mmol, 0.2 eq), NaCN (209 mg, 4.26 mmol, 1.2 eq) and drop-wise addition of H 2 O (10 mL). The resulting solution was stirred at 50° C. for 16 h. After consumption of starting material by TLC, the reaction mixture was diluted with water (100 mL) and extracted with EA (50 mL×3). Combined organic layers were dried over Na 2 SO 4 , filtered, evaporated and purified by chromatography (PE/EA=2/1) to give 4-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidine-2-carbonitrile (1.2 g, Y: 77%) as a white solid. ESI-MS (M+H) + : 443.2. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.70 (s, 1H), 8.90 (d, J=5.2 Hz, 1H), 8.26 (s, 1H), 8.04-8.01 (m, 2H), 7.94-7.90 (m, 3H), 7.45 (d, J=7.2 Hz, 1H), 5.01 (s, 2H), 1.01 (s, 9H), 0.19 (s, 6H).

Synthesis of 1-(4-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-2-yl)butan-1-one

To a solution of 4-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidine-2-carbonitrile (900 mg, 2.04 mmol, 1.0 eq) in dry THF (50 mL) was added n-PrMgCl (1 M, 4.1 mL, 4.07 mmol, 2.0 eq). The mixture was refluxed under N 2 for 1 h. After cooling down to rt, the reaction was quenched with water (10 mL) and extracted with EA (30 mL×3). The combined organic fractions were washed with brine, dried, filtrated and evaporated. The residue was purified by chromatography (PE/EA=1/1) to give 1-(4-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-2-yl)butan-1-one (260 mg, Y: 26%) as colorless oil. ESI-MS (M+H) + : 488.2. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.68 (s, 1H), 9.01 (d, J=5.2 Hz, 1H), 8.26 (s, 1H), 8.12-8.09 (m, 1H), 7.96-7.88 (m, 4H), 7.44 (d, J=7.2 Hz, 1H), 5.00 (s, 2H), 3.37 (t, J=7.2 Hz, 2H), 1.91-1.86 (m, 2H), 1.07 (t, J=7.2 Hz, 3H), 1.00 (s, 9H), 0.18 (s, 6H).

Synthesis of (R,E)-N-(1-(4-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-2-yl)butylidene)-2-methylpropane-2-sulfinamide

To a solution of 1-(4-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-2-yl)butan-1-one (260 mg, 0.53 mmol, 1.0 eq) in THF (50 mL) was added (R)-2-methylpropane-2-sulfinamide (388 mg, 3.20 mmol, 6.0 eq) and Ti(OEt) 4 (1.22 g, 5.34 mmol, 10.0 eq). The mixture was refluxed for 7 days. After cooling down to rt, the mixture was diluted with EA (20 mL) and washed with H 2 O (20 mL×2) and brine. The organic was dried (Na 2 SO 4 ) and concentrated in vacuo. The crude mixture was purified by silica gel chromatography (PE/EA=2/1) to give (R,E)-N-(1-(4-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-2-yl)butylidene)-2-methylpropane-2-sulfinamide (30 mg, Y: 10%) as a white solid. ESI-MS (M+H) + : 591.3.

Synthesis of (R)—N—((S)-1-(4-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-2-yl)butyl)-2-methylpropane-2-sulfinamide and (R)—N—((R)-1-(4-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-2-yl)butyl)-2-methylpropane-2-sulfinamide

The preparation of (R)—N—((S)-1-(4-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-2-yl)butyl)-2-methylpropane-2-sulfinamide and (R)—N—((R)-1-(4-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-2-yl)butyl)-2-methylpropane-2-sulfinamide were similar to that of (R)—N—((S)-1-(2-bromopyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide (Example 404, Step 4) to give (R)—N—((S)-1-(4-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-2-yl)butyl)-2-methylpropane-2-sulfinamide (16 mg, Y: 53%) and (R)—N—((R)-1-(4-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-2-yl)butyl)-2-methylpropane-2-sulfinamide (11 mg, Y: 37%) as separated by preparative TLC (PE/EA=1/1). ESI-MS (M+H) + : 593.3.

›Step 6. Synthesis of (S)-(6-(6-(4-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol · 2 of 3

Synthesis of (S)-(6-(6-(2-(1-aminobutyl)pyrimidin-4-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol

The preparation of (S)-(6-(6-(2-(1-aminobutyl)pyrimidin-4-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol was similar to that of (S)-(6-(6-(4-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol (Example 404, Step 6) to give 7 mg as a yellow solid, Y: 90%. ESI-MS (M+H) + : 375.2. HPLC: 100%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.81 (s, 1H), 8.83 (d, J=5.6 Hz, 1H), 8.25 (s, 1H), 8.10-8.08 (m, 1H), 8.01 (d, J=5.6 Hz, 1H), 7.91-7.87 (m, 3H), 7.29-7.28 (m, 1H), 4.80 (s, 2H), 4.52 (t, J=6.8 Hz, 1H), 2.12-1.96 (m, 2H), 1.46-1.40 (m, 2H), 0.94 (t, J=7.2 Hz, 3H).

Synthesis of (R)-(6-(6-(2-(1-aminobutyl)pyrimidin-4-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol

The preparation of (R)-(6-(6-(2-(1-aminobutyl)pyrimidin-4-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol was similar to that of (S)-(6-(6-(4-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol (Example 404, Step 6) to give 4 mg as a yellow solid, Y: 53%. ESI-MS (M+H) + : 375.2. HPLC: 100%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.81 (s, 1H), 8.83 (d, J=5.6 Hz, 1H), 8.25 (s, 1H), 8.10-8.08 (m, 1H), 8.01 (d, J=5.6 Hz, 1H), 7.91-7.87 (m, 3H), 7.29-7.28 (m, 1H), 4.80 (s, 2H), 4.52 (t, J=6.8 Hz, 1H), 2.12-1.96 (m, 2H), 1.46-1.40 (m, 2H), 0.94 (t, J=7.2 Hz, 3H).

Example 407 and 408 (S)-(6-(6-(6-(1-aminobutyl)pyrazin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol and (R)-(6-(6-(6-(1-aminobutyl)pyrazin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol

Synthesis of 1-(6-bromopyrazin-2-yl)butan-1-one

To a solution of 2,6-dibromopyrazine (CAS #23229-25-6, 1.5 g, 6.3 mmol, 1.0 eq) in anhydrous diethyl ether (30 mL) was added n-BuLi (2.4 M in THF, 2.6 mL, 6.3 mmol, 1.0 eq) at −78° C. under N 2 atmosphere. The mixture was stirred at −78° C. for 20 min. Then 623-42-7 (640 mg, 6.3 mmol, 1.0 eq) in anhydrous diethyl (5.0 mL) was added to the solution. After stirred at −78° C. for 30 min, the mixture was warmed to rt and stirred at rt for 1 h. Then the mixture was diluted with ethyl acetate (100 mL), and water (40 mL) was added. The aqueous layer was extracted with ethyl acetate (30 mL×2). The combined organic layers were dried over anhydrous sodium sulfate, filtrated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA=5/1) to give 1-(6-bromopyrazin-2-yl)butan-1-one (450 mg, Y: 31%) as a yellow solid. ESI-MS (M+1) + : 229.0, 231.0.

1 H NMR (400 MHz, CDCl 3 ) δ: 9.13 (s, 1H), 8.86 (s, 1H), 3.16 (t, J=7.2 Hz, 2H), 1.81-1.72 (m, 2H), 1.04 (t, J=7.2 Hz, 3H).

Synthesis of (R,E)-N-(1-(6-bromopyrazin-2-yl)butylidene)propane-2-sulfinamide

The preparation of (R,E)-N-(1-(6-bromopyrazin-2-yl)butylidene)propane-2-sulfinamide was similar to that of (R,E)-N-(1-(2-bromopyridin-4-yl)butylidene)-2-methylpropane-2-sulfinamide (Example 404, Step 3) to give 425 mg as a yellow solid, Y: 65%. ESI-MS (M+H) + : 332.0, 334.0. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.15 (s, 1H), 8.73 (s, 1H), 3.43-3.22 (m, 2H), 1.74-1.50 (m, 2H), 1.30 (s, 9H), 1.05 (t, J=7.2 Hz, 3H).

Synthesis of (R)—N—((R)-1-(6-bromopyrazin-2-yl)butyl)-2-methylpropane-2-sulfinamide and (R)—N—((S)-1-(6-bromopyrazin-2-yl)butyl)-2-methylpropane-2-sulfinamide

The preparation of the mixture of (R)—N—((R)-1-(6-bromopyrazin-2-yl)butyl)-2-methylpropane-2-sulfinamide and (R)—N—((S)-1-(6-bromopyrazin-2-yl)butyl)-2-methylpropane-2-sulfinamide was similar to that of (R)—N—((S)-1-(2-bromopyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide (Example 404, Step 4) to give 340 mg as yellow oil, Y: 80%. ESI-MS (M+H) + : 334.0, 336.0.

Synthesis of (R)—N—((R)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyrazin-2-yl)butyl)-2-methylpropane-2-sulfinamide and (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyrazin-2-yl)butyl)-2-methylpropane-2-sulfinamide

The preparation of the title compounds was similar to that of (S)—N—((S)-1-(2-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide (Example 404, Step 5) to give (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyrazin-2-yl)butyl)-2-methylpropane-2-sulfinamide (300 mg, Y: 50%) and (R)—N—((R)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyrazin-2-yl)butyl)-2-methylpropane-2-sulfinamide (260 mg, Y: 43%) as a yellow solid. ESI-MS (M+H) + : 593.3. (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyrazin-2-yl)butyl)-2-methylpropane-2-sulfinamide: 1 H NMR (400 MHz, CDCl 3 ) δ: 9.46 (s, 1H), 9.08 (s, 1H), 8.55 (s, 1H), 8.25 (s, 1H), 8.04 (dd, J=8.4, 1.6 Hz, 1H), 7.96-7.87 (m, 3H), 7.44 (d, J=8.8 Hz, 1H), 4.97 (s, 2H), 4.70-4.65 (m, 1H), 4.13 (s, 1H), 2.10-2.03 (m, 2H), 1.46-1.25 (m, 2H), 1.21 (s, 9H), 1.00 (s, 9H), 0.99 (t, J=7.6 Hz, 3H), 0.18 (s, 6H). (R)—N—((R)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyrazin-2-yl)butyl)-2-methylpropane-2-sulfinamide: 1 H NMR (400 MHz, CDCl 3 ) δ: 9.41 (s, 1H), 9.05 (s, 1H), 8.55 (s, 1H), 8.24 (s, 1H), 7.99-7.86 (m, 4H), 7.44 (d, J=7.2 Hz, 1H), 4.96 (s, 2H), 4.76 (d, J=7.6 Hz, 1H), 4.60-4.54 (m, 1H), 2.04-1.88 (m, 2H), 1.50-1.39 (m, 2H), 1.21 (s, 9H), 0.99 (s, 9H), 0.97 (t, J=7.6 Hz, 3H), 0.17 (s, 6H).

Synthesis of (S)-(6-(6-(6-(1-aminobutyl)pyrazin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol (Example 407)

The preparation of (S)-(6-(6-(6-(1-aminobutyl)pyrazin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol was similar to that of (S)-(6-(6-(4-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol (Example 404, Step 6) to give 190 mg as a yellow solid, Y: 91%. ESI-MS (M+H) + : 375.2. HPLC: 100%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.76 (s, 1H), 9.36 (s, 1H), 8.75 (s, 1H), 8.40 (s, 1H), 8.22 (d, J=8.4 Hz, 1H), 8.07-8.01 (m, 3H), 7.45 (d, J=6.0 Hz, 1H), 4.92 (s, 2H), 4.77 (t, J=7.2 Hz, 1H), 2.15-2.06 (m, 2H), 1.58-1.39 (m, 2H), 1.07 (t, J=7.2 Hz, 3H).

Synthesis of (R)-(6-(6-(6-(1-aminobutyl)pyrazin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol (Example 408)

›Step 6. Synthesis of (S)-(6-(6-(4-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol · 3 of 3

The preparation of (R)-(6-(6-(6-(1-aminobutyl)pyrazin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol was similar to that of (S)-(6-(6-(4-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol (Example 404, Step 6) to give 160 mg as a yellow solid, Y: 88%. ESI-MS (M+H) + : 375.2. HPLC: 100%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.76 (s, 1H), 9.36 (s, 1H), 8.75 (s, 1H), 8.41 (s, 1H), 8.22 (d, J=8.8 Hz, 1H), 8.09-8.03 (m, 3H), 7.45 (d, J=6.4 Hz, 1H), 4.92 (s, 2H), 4.77 (t, J=7.2 Hz, 1H), 2.15-2.09 (m, 2H), 1.58-1.41 (m, 2H), 1.07 (t, J=7.2 Hz, 3H).

Example 409 (S)-4-amino-4-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-4-methoxy-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol

Synthesis of (S)-tert-butyl (4-((tert-butyldimethylsilyl)oxy)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-methoxy-1H-indazol-6-yl)pyridin-2-yl)butyl)carbamate

›Step 1. Synthesis of 6-bromo-4-methoxy-1H-indazole

To a stirred solution of 4-bromo-2-fluoro-6-methoxybenzaldehyde (Example 324, Step 2; 16.5 g, 70.8 mmol) in DMSO (100 mL) was added hydrazine monohydrate (7.1 g, 141 mmol, 2.0 eq). The reaction mixture was stirred at 140° C. for 6 h. After cooled to rt, the reaction solution was diluted with water (100 mL). The precipitate was collected by filtration and washed with water (10 mL×2) to give 6-bromo-4-methoxy-1H-indazole (15.8 g, Y: 98%) as a light yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.10 (s, 1H), 7.27 (s, 1H), 6.61 (d, J=1.2 Hz, 1H), 3.96 (s, 3H); ESI-MS (M+H) + : 229.0.

›Step 4. Synthesis of (6-(6-bromo-4-methoxy-1H-indazol-1-yl)pyridin-2-yl)methanol

A mixture of 6-bromo-4-methoxy-1H-indazole (11.8 g, 52.0 mmol), (6-bromopyridin-2-yl)methanol (11.7 g, 62.4 mmol, 1.2 eq), CuBr (744 mg, 5.2 mmol, 0.1 eq), N,N′-Dimethyl-1,2-cyclohexanediamine (CAS No. 61798-24-1, 1.5 g, 10.4 mmol, 0.2 eq) and K 3 PO 4 (22.0 g, 104.0 mmol, 2.0 eq) in toluene (300 mL) was stirred at 100° C. for 16 h under nitrogen atmosphere. After cooled to rt, the solution was filtered by Celite and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (PE/EA, 6:1) to give (6-(6-bromo-4-methoxy-1H-indazol-1-yl)pyridin-2-yl)methanol (8.5 g, Y: 49%) as a light yellow solid. ESI-MS (M+H) + : 336.1, 338.1.

Step 5. Synthesis of 6-bromo-1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-methoxy-1H-indazole

The preparation of 6-bromo-1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-methoxy-1H-indazole was similar to that of 4-bromo-1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-((4-methoxybenzyl)oxy)-1H-indazole (Example 352, Step 5) to give 677 mg as a white solid, Y: 76%. ESI-MS (M+H) + : 448.1.

Step 6. Synthesis of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

The preparation of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole was similar to that of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(1H-pyrazol-1-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (Example 352, Step 9) to give 600 mg as a yellow solid, Y: 80%. ESI-MS (M+H) + : 496.2.

The preparation of (S)-tert-butyl (4-((tert-butyldimethylsilyl)oxy)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-methoxy-1H-indazol-6-yl)pyridin-2-yl)butyl)carbamate was similar to that of (S)—N—((S)-1-(2-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide (Example 404, Step 5) to give 120 mg as a yellow solid, Y: 23%. ESI-MS (M+H) + : 748.5.

Synthesis of (S)-4-amino-4-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-4-methoxy-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol

The preparation of (S)-4-amino-4-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-4-methoxy-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol was similar to that of (S)-(6-(6-(4-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol (Example 404, Step 6) to give 53 mg as a yellow solid, Y: 63%. ESI-MS (M+H) + : 420.1. HPLC: 100%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.29 (s, 1H), 8.32 (s, 1H), 8.09 (d, J=7.2 Hz, 1H), 8.04-7.94 (m, 3H), 7.57 (s, 1H), 7.48 (d, J=7.2 Hz, 1H), 7.43-7.30 (m, 1H), 4.88 (s, 2H), 4.61 (t, J=6.8 Hz, 1H), 4.15 (s, 3H), 3.65 (t, J=6.4 Hz, 2H), 2.22-2.14 (m, 2H), 1.70-1.61 (m, 2H).

Example 410 (S)-4-amino-4-(6-(4-ethoxy-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol

›Step 1. Synthesis of 4-bromo-2-ethoxy-6-fluorobenzaldehyde

A mixture of 4-bromo-2-fluoro-6-hydroxybenzaldehyde (Cas No. 1427438-90-1, 50.0 g, 0.23 mmol, 1.0 eq), K2CO3 (63.5 g, 0.46 mmol, 2.0 eq) and EtI (43.0 g, 0.28 mmol, 1.2 eq) in DMF (80 mL) was stirred at 60° C. for 16 h. After cooling to rt, the mixture was poured into water (500 mL). After filtration, the yellow solid was directly used for next step without purification. (42.4 g, Y: 75%). ESI-MS (M+H) + : 246.9.

›Step 2. Synthesis of 6-bromo-4-ethoxy-1H-indazole

The preparation of 6-bromo-4-ethoxy-1H-indazole was similar to that of 6-bromo-4-methoxy-1H-indazole (Example 409, Step 1) to give 28 g as a yellow solid, Y: 68%. ESI-MS (M+H) + : 240.9. 1 H NMR (400 MHz, CDCl 3 ) δ: 10.90 (br, 1H), 8.13 (s, 1H), 7.24 (s, 1H), 6.58 (s, 1H), 4.18 (q, J=6.8 Hz, 2H), 1.51 (t, J=6.8 Hz, 3H).

›Step 3. Synthesis of (6-(6-bromo-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol · 1 of 3

A mixture of 6-bromo-4-ethoxy-1H-indazole (7.0 g, 29 mmol, 1.0 eq), (6-bromopyridin-2-yl)methanol (CAS #33674-96-3, 7 g, 38 mmol, 1.3 eq), CuI (1.1 g, 5.8 mmol, 0.2 eq), K 3 PO 4 (12 g, 58 mmol, 2.0 eq) and 61798-24-1 (1.7 g, 12 mmol, 0.4 eq) in 1,4-dioxane (60 mL) was stirred at 110° C. for 24 h. After concentration, the residue was purified by silica gel chromatography using PE/EA (4/1) as eluent to give (6-(6-bromo-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol as a white solid. 1.5 g, Y: 13%. ESI-MS (M+H) + : 348.1.

Step 4. Synthesis of 6-bromo-1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-ethoxy-1H-indazole

To a solution of (6-(6-bromo-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol (1.5 g, 4.3 mmol, 1.0 eq) in DMF (8 mL) was added TBSCl (1.3 g, 8.6 mmol, 2.0 eq) and imidazole (585 mg, 8.6 mmol, 2.0 eq). The mixture was stirred at rt for 3 h. The mixture was poured into H 2 O (30 mL). The precipitate was collected by filtration and washed with water to give 6-bromo-1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-ethoxy-1H-indazole as a yellow solid. 1.3 g, Y: 65%. ESI-MS (M+H) + : 462.1.

Step 5. Synthesis of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-ethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

A mixture of 6-bromo-1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-ethoxy-1H-indazole (500 mg, 1.09 mmol, 1.0 eq), Bis(pinacolato)diboron (CAS No. 73183-34-3, 289 mg, 1.14 mmol, 1.05 eq) and CH 3 COOK (214 mg, 2.18 mmol, 2.0 eq) in 1, 4-dioxane (10 mL) was stirred while purging N 2 at rt for 10 min. To this system was added Pd(dppf)Cl 2 (90 mg, 0.1 mmol, 0.1 eq) and heated to 90° C. for 16 h. The mixture was diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO 3 solution (50 mL) and brine (50 mL). The organics were dried (Na 2 SO 4 ) and concentrated to give 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-ethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole which was used for next step without further purification. 400 mg, as a brown solid, Y: 80%. ESI-MS (M+H) + : 510.2.

Step 6. Synthesis of (S)-tert-butyl (4-((tert-butyldimethylsilyl)oxy)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-ethoxy-1H-indazol-6-yl)pyridin-2-yl)butyl)carbamate

The preparation of (S)-tert-butyl (4-((tert-butyldimethylsilyl)oxy)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-ethoxy-1H-indazol-6-yl)pyridin-2-yl)butyl)carbamate was similar to that of (S)—N—((S)-1-(2-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide (Example 404, Step 5) to give 130 mg as a yellow solid, Y: 33%. ESI-MS (M+H) + : 762.3.

Step 7. Synthesis of (S)-4-amino-4-(6-(4-ethoxy-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol

The preparation of (S)-4-amino-4-(6-(4-ethoxy-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol was similar to that of (S)-(6-(6-(4-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol (Example 404, Step 6) to give 62 mg as a yellow solid, Y: 83%. ESI-MS (M+H) + : 434.2. HPLC: 100%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.28 (s, 1H), 8.33 (s, 1H), 8.09-7.95 (m, 4H), 7.55 (s, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.38 (d, J=7.6 Hz, 1H), 4.88 (s, 2H), 4.61 (t, J=7.2 Hz, 1H), 4.42 (q, J=6.8 Hz, 2H), 3.65 (t, J=6.0 Hz, 2H), 2.21-2.13 (m, 2H), 1.70-1.58 (m, 5H).

Example 411 and 412 (S)-(6-(6-(4-(1-aminoethyl)pyrimidin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol and (R)-(6-(6-(4-(1-aminoethyl)pyrimidin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol

Synthesis of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-(4-(1-ethoxyvinyl)pyrimidin-2-yl)-1H-indazole

The preparation of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-(4-(1-ethoxyvinyl)pyrimidin-2-yl)-1H-indazole was similar to that of (S)—N—((S)-1-(2-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide (Example 404, Step 5) to give 500 mg as a yellow solid, Y: 56%. ESI-MS (M+H) + : 488.1.

Synthesis of 1-(2-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-yl)ethanone

A solution of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-(4-(1-ethoxyvinyl)pyrimidin-2-yl)-1H-indazole (500 mg, 1.03 mmol, 1.0 eq) in conc. HCl (1 mL)/THF (10 mL) was stirred at rt for 3 h. After concentration, the residue was directly used for next step without further purification. 300 mg, as a yellow solid, Y: 85%. ESI-MS (M+H) + : 346.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.93 (s, 1H), 9.08 (d, J=4.4 Hz, 1H), 8.49 (d, J=8.4 Hz, 1H), 8.27 (s, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.92-7.86 (m, 2H), 7.80 (d, J=4.8 Hz, 1H), 7.20 (d, J=7.6 Hz, 1H), 4.94 (s, 2H), 2.92 (s, 3H).

Synthesis of (R,E)-N-(1-(2-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-yl)ethylidene)-2-methylpropane-2-sulfinamide

The preparation of (R,E)-N-(1-(2-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-yl)ethylidene)-2-methylpropane-2-sulfinamide was similar to that of (R,E)-N-(1-(2-bromopyridin-4-yl)butylidene)-2-methylpropane-2-sulfinamide (Example 404, Step 3) to give 305 mg as a yellow solid, Y: 78%. ESI-MS (M+H) + : 449.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.92 (s, 1H), 8.96 (d, J=5.2 Hz, 1H), 8.47 (d, J=8.4 Hz, 1H), 8.26 (s, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.90-7.86 (m, 3H), 7.21 (d, J=7.2 Hz, 1H), 4.93 (s, 2H), 3.05 (s, 3H), 1.38 (s, 9H).

Synthesis of (R)—N—((S)-1-(2-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-yl)ethyl)-2-methylpropane-2-sulfinamide and (R)—N—((R)-1-(2-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-yl)ethyl)-2-methylpropane-2-sulfinamide

The preparation of (R)—N—((S)-1-(2-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-yl)ethyl)-2-methylpropane-2-sulfinamide and (R)—N—((R)-1-(2-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-yl)ethyl)-2-methylpropane-2-sulfinamide was similar to that of (R)—N—((S)-1-(2-bromopyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide (Example 404, Step 4). (R)—N—((S)-1-(2-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (140 mg) and (R)—N—((R)-1-(2-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (40 mg) were separated by by prep-TLC (PE/EA=1/1). ESI-MS (M+H) + : 451.1.

›Step 3. Synthesis of (6-(6-bromo-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol · 2 of 3

(R)—N—((S)-1-(2-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (t R : 6.31 min)

1 H NMR (400 MHz, CDCl 3 ) δ: 10.09 (s, 1H), 8.81 (d, J=4.8 Hz, 1H), 8.44-8.41 (m, 1H), 8.25 (d, J=0.8 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.89-7.84 (m, 2H), 7.19-7.17 (m, 2H), 4.96 (s, 2H), 4.66-4.61 (m, 1H), 4.17-4.15 (m, 1H), 3.72-3.68 (m, 1H), 1.75 (d, J=6.4 Hz, 3H), 1.20 (s, 9H).

(R)—N—((R)-1-(2-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (t R : 4.18 min)

1 H NMR (400 MHz, CDCl 3 ) δ: 9.96 (s, 1H), 8.83 (d, J=5.2 Hz, 1H), 8.38 (d, J=4.8 Hz, 1H), 8.25 (s, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.88-7.85 (m, 2H), 7.25 (s, 1H), 7.18 (d, J=7.2 Hz, 1H), 4.94 (s, 2H), 4.66-4.60 (m, 1H), 4.13 (t, J=4.4 Hz, 1H), 3.75-3.72 (m, 1H), 1.64 (d, J=6.8 Hz, 3H), 1.25 (s, 9H).

Synthesis of (S)-(6-(6-(4-(1-aminoethyl)pyrimidin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol (Example 411)

The preparation of (S)-(6-(6-(4-(1-aminoethyl)pyrimidin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol was similar to that of (S)-(6-(6-(4-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol (Example 404, Step 6) to give 98 mg as a yellow solid, Y: 68%. ESI-MS (M+H) + : 347.1. HPLC: 99%. 1 H NMR (400 MHz, CD 3 OD) δ: 10.07 (s, 1H), 8.91 (d, J=5.2 Hz, 1H), 8.45 (d, J=8.4 Hz, 1H), 8.27 (s, 1H), 7.91-7.87 (m, 3H), 7.46 (d, J=5.2 Hz, 1H), 7.33-7.31 (m, 1H), 4.86 (s, 2H), 4.70 (q, J=6.8 Hz, 1H), 1.69 (d, J=6.8 Hz, 3H).

Synthesis of (R)-(6-(6-(4-(1-aminoethyl)pyrimidin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol (Example 412)

The preparation of (R)-(6-(6-(4-(1-aminoethyl)pyrimidin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol was similar to that of (S)-(6-(6-(4-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol (Example 404, Step 6) to give 34 mg as a yellow solid, Y: 83%. ESI-MS (M+H) + : 347.1. HPLC: 97% 1 H NMR (400 MHz, CD 3 OD) δ: 10.02 (s, 1H), 8.92 (d, J=7.6 Hz, 1H), 8.47 (t, J=1.2 Hz, 1H), 8.26 (s, 1H), 7.89-7.82 (m, 3H), 7.48 (d, J=7.2 Hz, 1H), 7.32 (d, J=7.2 Hz, 1H), 4.88 (s, 2H), 4.74 (q, J=6.8 Hz, 1H), 1.73 (d, J=6.8 Hz, 3H).

Example 413 and 414 (S)-(6-(6-(4-(1-aminobutyl)pyrimidin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol and (R)-(6-(6-(4-(1-aminobutyl)pyrimidin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol

Synthesis of 2-chloro-N-methoxy-N-methylpyrimidine-4-carboxamide

The preparation of 2-chloro-N-methoxy-N-methylpyrimidine-4-carboxamide was similar to that of 6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-methylpicolinamide (Example 32) to give 400 mg as yellow oil, Y: 55%. ESI-MS (M+H) + : 202.1.

Synthesis of 2-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)-N-methoxy-N-methylpyrimidine-4-carboxamide

The preparation of 2-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)-N-methoxy-N-methylpyrimidine-4-carboxamide was similar to that of (S)—N—((S)-1-(2-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide (Example 404, Step 5) to give 550 mg as a yellow solid, Y: 55%. ESI-MS (M+H) + : 505.2.

Synthesis of 1-(2-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-yl)butan-1-one

The preparation of 1-(2-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-yl)butan-1-one was similar to that of 1-(2-bromopyridin-4-yl)butan-1-one (Example 404, step 2) to give 90 mg as a white solid, Y: 17%. ESI-MS (M+H) + : 488.2. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.75 (s, 1H), 8.91 (d, J=4.8 Hz, 1H), 8.29 (dd, J=8.4, 1.6 Hz, 1H), 8.08 (d, J=0.8 Hz, 1H), 7.78-7.70 (m, 3H), 7.63 (d, J=5.2 Hz, 1H), 7.27 (dd, J=7.2, 0.8 Hz, 1H), 4.85 (s, 2H), 3.22 (t, J=7.2 Hz, 2H), 1.73-1.67 (m, 2H), 0.91 (t, J=7.2 Hz, 3H), 0.83 (s, 9H), 0.00 (s, 6H).

Synthesis of (R,E)-N-(1-(2-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-yl)butylidene)-2-methylpropane-2-sulfinamide

The preparation of (R,E)-N-(1-(2-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-yl)butylidene)-2-methylpropane-2-sulfinamide was similar to that of (R,E)-N-(1-(2-bromopyridin-4-yl)butylidene)-2-methylpropane-2-sulfinamide (Example 404, Step 3) to give 120 mg as a yellow solid, Y: 30%. ESI-MS (M+H) + : 591.3. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.88 (s, 1H), 8.96 (d, J=5.2 Hz, 1H), 8.42 (dd, J=8.4, 1.2 Hz, 1H), 8.24 (s, 1H), 7.93-7.81 (m, 4H), 7.43 (d, J=6.8 Hz, 1H), 5.01 (s, 2H), 3.68-3.49 (m, 2H), 1.84-1.75 (m, 2H), 1.37 (s, 9H), 1.06 (t, J=7.2 Hz, 3H), 1.00 (s, 9H), 0.18 (s, 6H).

Synthesis of (R)—N—((S)-1-(2-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-yl)butyl)-2-methylpropane-2-sulfinamide and (R)—N—((R)-1-(2-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-yl)butyl)-2-methylpropane-2-sulfinamide

The preparation of (R)—N—((S)-1-(2-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-yl)butyl)-2-methylpropane-2-sulfinamide and (R)—N—((R)-1-(2-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-yl)butyl)-2-methylpropane-2-sulfinamide was similar to that of (R)—N—((S)-1-(2-bromopyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide (Example 404, Step 4). (R)—N—((S)-1-(2-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-yl)butyl)-2-methylpropane-2-sulfinamide (40 mg) and (R)—N—((R)-1-(2-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-yl)butyl)-2-methylpropane-2-sulfinamide (30 mg) were separated by chiral resolution. ESI-MS (M+H) + : 593.3.

(R)—N—((S)-1-(2-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-yl)butyl)-2-methylpropane-2-sulfinamide (t R : 4.6 min)

1 H NMR (400 MHz, CD 3 OD) δ: 9.67 (s, 1H), 8.67 (d, J=5.2 Hz, 1H), 8.22-8.19 (m, 1H), 8.10 (s, 1H), 7.78-7.70 (m, 3H), 7.25-7.22 (m, 2H), 4.81 (s, 2H), 4.34 (t, J=7.2 Hz, 1H), 1.88-1.79 (m, 2H), 1.39-1.17 (m, 2H), 1.01 (s, 9H), 0.83-0.79 (m, 12H), 0.00 (s, 6H).

›Step 3. Synthesis of (6-(6-bromo-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol · 3 of 3

(R)—N—((R)-1-(2-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-yl)butyl)-2-methylpropane-2-sulfinamide (t R : 3.46 min)

1 H NMR (400 MHz, CD 3 OD) δ: 9.63 (s, 1H), 8.64 (d, J=5.2 Hz, 1H), 8.18 (dd, J=8.4, 1.2 Hz, 1H), 8.05 (s, 1H), 7.78-7.59 (m, 3H), 7.30 (d, J=5.2 Hz, 1H), 7.20 (d, J=6.8 Hz, 1H), 6.74 (s, 1H), 4.79 (s, 2H), 4.30-4.26 (m, 1H), 1.81-1.73 (m, 2H), 1.38-1.25 (m, 2H), 1.22 (s, 9H), 0.81 (s, 12H), 0.00 (s, 6H).

Synthesis of (R)-(6-(6-(4-(1-aminobutyl)pyrimidin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol (Example 414)

The preparation of (R)-(6-(6-(4-(1-aminobutyl)pyrimidin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol was similar to that of (S)-(6-(6-(4-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol (Example 404, Step 6) to 20 mg as a yellow solid, Y: 81%. ESI-MS (M+H) + : 375.2. HPLC: 100%. 1 H NMR (400 MHz, CD 3 OD) δ: 10.00 (s, 1H), 8.84 (d, J=4.8 Hz, 1H), 8.43 (dd, J=8.4, 1.6 Hz, 1H), 8.34 (s, 1H), 7.99-7.94 (m, 3H), 7.45-7.41 (m, 2H), 4.91 (s, 2H), 4.04 (t, J=6.8 Hz, 1H), 1.99-1.81 (m, 2H), 1.57-1.38 (m, 2H), 1.01 (t, J=7.2 Hz, 3H).

Synthesis of (S)-(6-(6-(4-(1-aminobutyl)pyrimidin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol (Example 413)

The preparation of (S)-(6-(6-(4-(1-aminobutyl)pyrimidin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol was similar to that of (S)-(6-(6-(4-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol (Example 404, Step 6) to give 25 mg as a yellow solid, Y: 75%. ESI-MS (M+H) + : 375.2. HPLC: 100%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.83 (s, 1H), 8.74 (d, J=5.2 Hz, 1H), 8.30 (dd, J=8.4, 1.2 Hz, 1H), 8.20 (s, 1H), 7.90-7.79 (m, 3H), 7.34 (d, J=6.8 Hz, 1H), 7.30 (d, J=5.2 Hz, 1H), 4.83 (s, 2H), 3.95 (t, J=6.8 Hz, 1H), 1.91-1.72 (m, 2H), 1.48-1.28 (m, 2H), 0.96 (t, J=7.2 Hz, 3H).

Example 415 and 416 1-(6-(6-(6-((S)-1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanol—Peak 1 and 1-(6-(6-(6-((S)-1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanol—Peak 2

›Step 1. Synthesis of 1-(6-(6-bromo-1H-indazol-1-yl)pyridin-2-yl)ethanone

The preparation of 1-(6-(6-bromo-1H-indazol-1-yl)pyridin-2-yl)ethanone was similar to that of (4-(6-bromo-1H-indazol-1-yl)pyridin-2-yl)methanol (Example 400, Step 1) to give 1.65 g as a yellow solid, Y: 27%. ESI-MS (M+H) + : 316.0.

Step 2. Synthesis of 1-(6-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanone

The preparation of 1-(6-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanone was similar to that of 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-ethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (Example 410, Step 5) to give 1.73 g (crude) as a yellow solid. ESI-MS (M+H) + : 364.2.

Step 3. Synthesis of (R)—N—((S)-1-(6-(1-(6-acetylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide

The preparation of (R)—N—((S)-1-(6-(1-(6-acetylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide was similar to that of (S)—N—((S)-1-(2-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide (Example 404, Step 5) to give 2.0 g as a yellow solid, Y: 50% (two steps). ESI-MS (M+H) + : 462.2. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.57 (s, 1H), 8.33 (d, J=8.4 Hz, 1H), 8.27 (s, 1H), 8.05-7.99 (m, 2H), 7.95-7.89 (m, 2H), 7.81-7.79 (m, 2H), 7.34-7.29 (m, 1H), 5.31-5.29 (m, 1H), 2.99 (s, 3H), 1.69 (d, J=6.4 Hz, 3H), 1.23 (s, 9H).

Step 4. Synthesis of (R)—N-((1S)-1-(6-(1-(6-(1-hydroxyethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide

To a solution of (R)—N—((S)-1-(6-(1-(6-acetylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (2.0 g, 4.33 mmol, 1.0 eq) in MeOH (30 mL) was added NaBH 4 (320 mg, 8.66 mmol, 2.0 eq) at rt. The mixture was stirred at rt for 2 h. After concentration, the residue was dissolved in DCM (50 mL) and washed with water (15 mL). The organic phase washed with brine and dried over Na 2 SO 4 . After filtration and concentration, the residue was directly used for next step without further purification. 1.23 g, as a yellow solid, Y: 85%. ESI-MS (M+H) + : 464.2.

›Step 5. Synthesis of 1-(6-(6-(6-((S)-1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanol

The preparation of 1-(6-(6-(6-((S)-1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanol was similar to that of (S)-(6-(6-(4-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol (Example 404, Step 6) to give 450 mg as a yellow solid, Y: 47%. ESI-MS (M+H) + : 360.2.

Step 6. Chiral Resolution of 1-(6-(6-(6-((S)-1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanol

SFC (Chiralpak IC column, 4.6*250 mm 5 m, MeOH with 0.1% NH 4 OH, CO 2 flow rate=1.65, Co-Solvent Flow Rate=1.35). t R =3.66 min, 4.86 min.

1-(6-(6-(6-((S)-1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanol—Peak 1 (104 mg) and 1-(6-(6-(6-((S)-1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanol—Peak 2 (138 mg) were separated by chiral resolution from 1-(6-(6-(6-((S)-1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanol (450 mg).

1-(6-(6-(6-((S)-1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanol—Peak 1

1 H NMR (400 MHz, CD 3 OD) δ: 9.64 (s, 1H), 8.28 (s, 1H), 8.03 (dd, J=8.4, 2.8 Hz, 1H), 7.97-7.87 (m, 5H), 7.44-7.39 (m, 2H), 5.05 (q, J=6.4 Hz, 1H), 4.26 (q, J=6.8 Hz, 1H), 1.68 (d, J=6.4 Hz, 3H), 1.54 (d, J=6.8 Hz, 3H). ESI-MS (M+H) + : 360.2. HPLC: 100%.

1-(6-(6-(6-((S)-1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanol—Peak 2

1 H NMR (400 MHz, CD 3 OD) δ: 9.63 (s, 1H), 8.30 (s, 1H), 8.01 (dd, J=8.4, 1.6 Hz, 1H), 7.95-7.84 (m, 5H), 7.42-7.37 (m, 2H), 5.02 (q, J=6.8 Hz, 1H), 4.21 (q, J=6.8 Hz, 1H), 1.69 (d, J=6.8 Hz, 3H), 1.53 (d, J=6.8 Hz, 3H). ESI-MS (M+H) + : 360.2. HPLC: 100%.

Example 417 and 418 1-(6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanol-Peak 1 1-(6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanol-Peak 2

Synthesis of (R)—N—((S)-1-(6-(1-(6-acetylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide

The preparation of (R)—N—((S)-1-(6-(1-(6-acetylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide was similar to that of (S)—N—((S)-1-(2-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide (Example 415, Step 2) to give 600 mg as a yellow solid, Y: 43% (two steps). ESI-MS (M+H) + : 490.2.

Synthesis Preparation of (R)—N-((1S)-1-(6-(1-(6-(1-hydroxyethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide

The preparation of (R)—N-((1S)-1-(6-(1-(6-(1-hydroxyethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide was similar to that of (R)—N-((1S)-1-(6-(1-(6-(1-hydroxyethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (Example 415/416, Step 4) to give 500 mg as a yellow solid, Y: 83%. ESI-MS (M+H) + : 492.2.

Synthesis of 1-(6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanol

The preparation of 1-(6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanol was similar to that of (S)-(6-(6-(4-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol (Example 404, Step 6) to give 350 mg as a yellow solid, Y: 89%. ESI-MS (M+H) + : 388.2.

Chiral Resolution of 1-(6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanol

SFC (Chiralpak IC column, 4.6*250 mm 5 m, MeOH with 0.1% NH 4 OH, CO 2 flow rate=2.25, Co-Solvent Flow Rate=0.75). t R =5.26 min, 6.11 min.

1-(6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanol—Peak 1 (149 mg) and 1-(6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanol—Peak 2 (61 mg) were separated by chiral resolution from 1-(6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanol (350 mg).

1-(6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanol—Peak 1

1 H NMR (400 MHz, CD 3 OD) δ: 9.57 (s, 1H), 8.24 (s, 1H), 7.94-7.80 (m, 6H), 7.40-7.38 (m, 1H), 7.31-7.28 (m, 1H), 5.01 (q, J=6.4 Hz, 1H), 3.99 (t, J=6.8 Hz, 1H), 1.88-1.78 (m, 2H), 1.66 (d, J=6.4 Hz, 3H), 1.43-1.27 (m, 2H), 0.95 (t, J=7.2 Hz, 3H). ESI-MS (M+H) + : 388.2. HPLC: 98.34%.

1-(6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanol—Peak 2

1 H NMR (400 MHz, CD 3 OD) δ: 9.62 (s, 1H), 8.29 (s, 1H), 8.00-7.68 (m, 6H), 7.43-7.40 (m, 1H), 7.35-7.32 (m, 1H), 5.03 (q, J=6.4 Hz, 1H), 4.02 (t, J=6.8 Hz, 1H), 1.91-1.80 (m, 2H), 1.68 (d, J=6.8 Hz, 3H), 1.44-1.30 (m, 2H), 0.94 (t, J=7.2 Hz, 3H). ESI-MS (M+H) + : 388.2. HPLC: 100%.

›Example 419

Synthesis of Deutero (R)—N—((S)-1-(6-bromopyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide

To a solution of (R,E)-N-(1-(6-bromopyridin-2-yl)butylidene)-2-methylpropane-2-sulfinamide (2.3 g, 7.0 mmol, 1.0 eq) and D 2 O (1.5 g, excess) in THF (10 mL) was added NaBD 4 (882 mg, 21.0 mmol, 3.0 eq) at rt. The mixture was stirred at rt for 2 h. The reaction was quenched with NH 4 Cl (aq.) and extracted with DCM (20 mL×3). The combined organic fractions were dried and concentrated. The residue was recrystallized from PE/DCM (10/1) to give the title compound. 350 mg, as a white solid, Y: 15%. ESI-MS (M+H) + : 333.9. 1 H NMR (400 MHz, CDCl 3 ) δ: 7.50 (t, J=7.6 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.21 (d, J=7.2 Hz, 1H), 3.84 (br, 1H), 1.90-1.85 (m, 2H), 1.37-1.22 (m, 2H), 1.18 (s, 9H), 0.91 (t, J=7.2 Hz, 3H).

Synthesis of Deutero (R)—N—((S)-1-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide

A mixture of Deutero (R)—N—((S)-1-(6-bromopyridin-2-yl)butyl)-2-methylpropane-2-sulfinamide (200 mg, 0.6 mmol, 1.0 eq), 1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (CAS No. 54-14-0003, (Example 143, Step 3) 335 mg, 0.72 mmol, 1.2 eq) and K 2 CO 3 (170 mg, 1.2 mmol, 2.0 eq) in 1,4-dioxane/H 2 O (10 mL/1 mL) was stirred while purging N 2 at rt for 10 min. To this system was added Pd(dppf)Cl 2 (50 mg, 0.06 mmol, 0.1 eq) and heated to 110° C. for 2 h. After concentration, the residue was purified by silica gel chromatography using PE/EA (1/1) as eluent to give the title compound. 290 mg, as a yellow solid, Y: 81%. ESI-MS (M+H) + : 593.3.

Synthesis of deutero (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol

To a solution of the starting material (290 mg, 0.49 mmol, 1.0 eq) in DCM (3 mL) was added slowly 4 M HCl in 1,4-dioxane (1.0 mL, excess). Then the mixture was stirred at rt for 1 h. After concentration, the residue was dissolved in THF, adjusted pH=7-8 and extracted with EA (2×50 mL). The combined organic phase was washed with brine and dried over Na 2 SO 4 . After filtration and concentration, the residue was purified by prep-HPLC (CH 3 CN/H 2 O with 0.05% TFA as mobile phase from 5% to 95%) to give the title compound. 110 mg, as a yellow solid, Y: 60%. ESI-MS (M+H) + : 375.0. HPLC: 100%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.74 (s, 1H), 8.29 (s, 1H), 8.10 (dd, J=8.4, 0.8 Hz, 1H), 8.05-7.91 (m, 5H), 7.41 (d, J=7.6 Hz, 1H), 7.33 (t, J=8.0 Hz, 1H), 4.85 (s, 2H), 2.07-1.97 (m, 2H), 1.48-1.35 (m, 2H), 0.99 (t, J=7.2 Hz, 3H).

Example 420 (6-(6-(8-amino-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol

›Step 1. Synthesis of 2-chloro-8-methyl-5,6,7,8-tetrahydroquinolin-8-ol

To a solution of 2-chloro-6,7-dihydroquinolin-8(5H)-one (Example 63, Step 4, 630 mg, 3.5 mmol, 1.0 eq) in THF (10 mL) was slowly added CH 3 MgBr (2 M in hexane, 2.6 mL, 5.3 mmol, 1.5 eq) at −78° C. After stirring at rt for 4 h, the reaction was quenched with NH 4 Cl (aq.). The mixture was extracted with EA (20 mL×3). The combined organic phases were dried, filtrated and concentrated. The residue was purified by column chromatography on silica gel (PE/EA=10/1) to give 2-chloro-8-methyl-5,6,7,8-tetrahydroquinolin-8-ol as colorless oil. 300 mg, Y: 44%. ESI-MS (M+H) + : 198.1.

›Step 2. Synthesis of 8-azido-2-chloro-8-methyl-5,6,7,8-tetrahydroquinoline

To a round bottom flask equipped was added InBr 3 (54 mg, 0.15 mmol, 0.1 eq) in DCM (10 mL) was added C 3 H 9 SiN 3 (350 mg, 3.0 mmol, 2.0 eq) under N 2 . 2-chloro-8-methyl-5,6,7,8-tetrahydroquinolin-8-ol (300 mg, 1.5 mmol, 1.0 eq) in DCM (10 mL) was added to this mixture dropwise. The mixture was stirred at 25° C. for 16 h and concentrated. The residue was purified by column chromatography on silica gel (PE/EA=50/1) to give 8-azido-2-chloro-8-methyl-5,6,7,8-tetrahydroquinoline as yellow oil. 200 mg, Y: 52%. ESI-MS (M+H) + : 223.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 7.31 (d, J=8.0 Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 2.75-2.61 (m, 2H), 2.00-1.71 (m, 4H), 1.66 (s, 3H).

›Step 3. Synthesis of 2-chloro-8-methyl-5,6,7,8-tetrahydroquinolin-8-amine

To a mixture of 8-azido-2-chloro-8-methyl-5,6,7,8-tetrahydroquinoline (120 mg, 0.54 mmol, 1.0 eq) in THF/H 2 O (10 mL/0.5 mL) was added PPh 3 (425 mg, 1.6 mmol, 3.0 eq). The mixture was stirred at rt for 16 h. Then it was used directly in the next step without further purification. ESI-MS (M+H) + : 197.1.

›Step 4. Synthesis of tert-butyl (2-chloro-8-methyl-5,6,7,8-tetrahydroquinolin-8-yl)carbamate · 1 of 2

To a mixture of 2-chloro-8-methyl-5,6,7,8-tetrahydroquinolin-8-amine (0.54 mmol, 1.0 eq) in THF (5 mL) was added (Boc) 2 O (177 mg, 0.81 mmol, 1.5 eq) and TEA (164 mg, 1.62 mmol, 3.0 eq). The mixture was stirred at rt for 2 h. After concentration, the residue was purified by column chromatography on silica gel (PE/EA=10/1) to give tert-butyl (2-chloro-8-methyl-5,6,7,8-tetrahydroquinolin-8-yl)carbamate as colorless oil. 300 mg (crude), ESI-MS (M+H) + : 297.1.

Step 5. Synthesis of tert-butyl (2-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)-8-methyl-5,6,7,8-tetrahydroquinolin-8-yl)carbamate

The preparation of tert-butyl (2-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)-8-methyl-5,6,7,8-tetrahydroquinolin-8-yl)carbamate was similar to that of (S)—N—((S)-1-(2-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide (Example 404, Step 5) to give 100 mg as a yellow solid, Y: 27%. ESI-MS (M+H) + : 600.3.

Step 6. Synthesis of (6-(6-(8-amino-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol

The preparation of (6-(6-(8-amino-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol was similar to that of (S)-(6-(6-(4-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol (Example 404, Step 6) to give 5 mg as a yellow solid, Y: 15%. ESI-MS (M+H) + : 386.1. HPLC: 97%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.54 (s, 1H), 8.18 (s, 1H), 7.94-7.91 (m, 1H), 7.86-7.85 (m, 2H), 7.81-7.79 (m, 1H), 7.70-7.68 (m, 1H), 7.52-7.50 (m, 1H), 7.30-7.28 (m, 1H), 4.86 (s, 2H), 2.80 (t, J=5.6 Hz, 2H), 2.02-1.85 (m, 4H), 1.52 (s, 3H).

Example 421 (6-(6-(8-amino-8-propyl-5,6,7,8-tetrahydroquinolin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol

Synthesis of 2-chloro-8-propyl-5,6,7,8-tetrahydroquinolin-8-ol

The preparation of 2-chloro-8-propyl-5,6,7,8-tetrahydroquinolin-8-ol was similar to that 2-chloro-8-methyl-5,6,7,8-tetrahydroquinolin-8-ol (Example 420, Step 1) to give 880 mg as colorless oil, Y: 42%. ESI-MS (M+H) + : 226.1.

Synthesis of 8-azido-2-chloro-8-propyl-5,6,7,8-tetrahydroquinoline

The preparation of 8-azido-2-chloro-8-propyl-5,6,7,8-tetrahydroquinoline was similar to that of 8-azido-2-chloro-8-methyl-5,6,7,8-tetrahydroquinoline (Example 420, Step 2) to give 880 mg as yellow oil, Y: 72%. ESI-MS (M+H) + : 251.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 7.38 (d, J=8.0 Hz, 1H), 7.15 (d, J=8.0 Hz, 1H), 2.80-2.62 (m, 2H), 2.25-2.17 (m, 1H), 2.06-1.77 (m, 5H), 1.48-1.36 (m, 1H), 1.28-1.16 (m, 1H), 0.97 (t, J=7.2 Hz, 3H).

Synthesis of 2-chloro-8-propyl-5,6,7,8-tetrahydroquinolin-8-amine

The preparation of 2-chloro-8-propyl-5,6,7,8-tetrahydroquinolin-8-amine was similar to that of 2-chloro-8-methyl-5,6,7,8-tetrahydroquinolin-8-amine (Example 420, Step 3). ESI-MS (M+H) + : 225.1.

Synthesis of tert-butyl (2-chloro-8-propyl-5,6,7,8-tetrahydroquinolin-8-yl)carbamate

The preparation of tert-butyl (2-chloro-8-propyl-5,6,7,8-tetrahydroquinolin-8-yl)carbamate was similar to that of tert-butyl (2-chloro-8-methyl-5,6,7,8-tetrahydroquinolin-8-yl)carbamate (Example 404, Step 4) to give 200 mg as colorless oil, Y: 22% for two steps. ESI-MS (M+H) + : 325.1.

Synthesis of tert-butyl (2-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)-8-propyl-5,6,7,8-tetrahydroquinolin-8-yl)carbamate

The preparation of tert-butyl (2-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)-8-propyl-5,6,7,8-tetrahydroquinolin-8-yl)carbamate was similar to that of (S)—N—((S)-1-(2-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide (Example 404, Step 5) to give 230 mg as a yellow solid, Y: 45%. ESI-MS (M+H) + : 628.2.

Synthesis of (6-(6-(8-amino-8-propyl-5,6,7,8-tetrahydroquinolin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol

The preparation of (6-(6-(8-amino-8-propyl-5,6,7,8-tetrahydroquinolin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol was similar to that of (S)-(6-(6-(4-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol (Example 404, Step 6) to give 73 mg as a white solid, Y: 56%. ESI-MS (M+H) + : 414.2. HPLC: 100%. 1 H NMR (400 MHz, CD 3 OD) δ: 9.60 (s, 1H), 8.27 (s, 1H), 8.03-7.87 (m, 4H), 7.76 (d, J=8.4 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.41-7.39 (m, 1H), 4.88 (s, 2H), 2.89-2.85 (m, 2H), 2.17-2.12 (m, 1H), 2.05-1.82 (m, 5H), 1.54-1.45 (m, 1H), 1.31-1.23 (m, 1H), 0.93 (t, J=7.2 Hz, 3H).

Example 422 (S)-(6-(6-(6-(amino(cyclobutyl)methyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol

Synthesis of (6-bromopyridin-2-yl)(cyclobutyl)methanone

To a solution of 2,6-Dibromopyridine (CAS No. 626-05-1 (6.0 g, 25.3 mmol, 1.0 eq) in dry THF (30 mL) at −78° C. was added n-BuLi (1 M in THF, 25.3 mL, 25.3 mmol, 1.0 eq) dropwise. After stirring at −78° C. for 10 min, N-methoxy-N-methylcyclobutanecarboxamide (CAS No. 640768-72-5, 3.62 g, 25.3 mmol, 1.0 eq) in THF (10 mL) was added and the reaction mixture was stirred at −78° C. for 2 h. The reaction mixture was quenched with saturated aqueous NH 4 Cl (10 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo and purified by silica gel column chromatography (PE/EA=5/1) to obtain (6-bromopyridin-2-yl)(cyclobutyl)methanone (3.5 g, Y: 58%) as colorless oil. ESI-MS (M+1): 240.1.

Synthesis of (R,E)-N-((6-bromopyridin-2-yl)(cyclobutyl)methylene)-2-methylpropane-2-sulfinamide

The preparation of (R,E)-N-((6-bromopyridin-2-yl)(cyclobutyl)methylene)-2-methylpropane-2-sulfinamide was similar to that of (R,E)-N-(1-(2-bromopyridin-4-yl)butylidene)-2-methylpropane-2-sulfinamide (Example 404, Step 3) to give 2.0 g as a yellow solid, Y: 40%. ESI-MS (M+1): 343.1.

Synthesis of (R)—N—((S)-(6-bromopyridin-2-yl)(cyclobutyl)methyl)-2-methylpropane-2-sulfinamide

The preparation of (R)—N—((S)-(6-bromopyridin-2-yl)(cyclobutyl)methyl)-2-methylpropane-2-sulfinamide was similar to that of (R)—N—((S)-1-(2-bromopyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide (Example 404, Step 4) to give 1.0 g as a white solid, Y: 50%. ESI-MS (M+1): 345.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 7.50 (t, J=7.6 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.19 (d, J=7.2 Hz, 1H), 3.76-3.74 (m, 1H), 2.80-2.78 (m, 1H), 1.83-1.80 (m, 1H), 1.77-1.74 (m, 6H), 1.17 (s, 9H).

›Step 4. Synthesis of tert-butyl (2-chloro-8-methyl-5,6,7,8-tetrahydroquinolin-8-yl)carbamate · 2 of 2

Synthesis of (R)—N—((S)-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)(cyclobutyl)methyl)-2-methylpropane-2-sulfinamide

The preparation of (R)—N—((S)-(6-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)(cyclobutyl)methyl)-2-methylpropane-2-sulfinamide was similar to that of (S)—N—((S)-1-(2-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide (Example 404, Step 5) to give 320 mg as light yellow oil, Y: 61%. ESI-MS (M+1): 604.2.

Synthesis of (S)-(6-(6-(6-(amino(cyclobutyl)methyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol

The preparation of (S)-(6-(6-(6-(amino(cyclobutyl)methyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol was similar to that of (S)-(6-(6-(4-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol (Example 404, Step 6) to give 200 mg as a white solid, Y: 75%. ESI-MS (M+H) + : 386.1. HPLC: 100%. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 9.60 (s, 1H), 8.51 (s, 1H), 8.39 (s, 2H), 8.23-8.20 (m, 1H), 8.09-8.01 (m, 4H), 7.89 (d, J=8.4 Hz, 1H), 7.49 (d, J=7.2 Hz, 1H), 7.42 (d, J=7.6 Hz, 1H), 5.65 (br, 1H), 4.80 (s, 2H), 4.51-4.47 (m, 1H), 2.82 (d, J=8.4 Hz, 1H), 2.11-1.75 (m, 6H).

Example 423 (S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol

Step 1. Synthesis of tert-butyl 4-(1-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridi

›Tables in the description — 4

Example	Name	Structure
201	2-(1-(6-methylpyridin-2-yl)- 1H-indazol-6- yl)isonicotinamide
202	N,N-dimethyl-5-(1-(6- methylpyridin-2-yl)-1H- indazol-6-yl)pyridin-3-amine
203	1-(6-methylpyridin-2-yl)-6- (5-(pyrrolidin-1-yl)pyridin-3- yl)-1H-indazole
204	6-methyl-5-(1-(6- methylpyridin-2-yl)-1H- indazol-6-yl)pyridin-3-amine
205	5-(1-(6-cyclopentylpyridin-2- yl)-1H-indazol-6-yl)pyridin- 3-amine
206	5-(1-(6-methylpyridin-2-yl)- 1H-indazol-6-yl)-3,4- dihydroisoquinolin-1(2H)- one
207	1-(6-(4-fluoro-1-(6- (trifluoromethyl)pyridin-2- yl)-1H-indazol-6-yl)pyridin- 2-yl)ethanone
208	N-(5-(4-cyano-1-(6- (trifluoromethyl)pyridin-2- yl)-1H-indazol-6-yl)pyridin- 3-yl)-2,2,2- trifluoroacetamide
209	1-(6-(1-(6- (trifluoromethyl)pyridin-2- yl)-1H-indazol-6-yl)pyridin- 2-yl)ethanamine
210	2-(1-(6- (trifluoromethyl)pyridin-2- yl)-1H-indazol-6-yl)-5H- cyclopenta[b]pyridin-7(6H)- one
211	6-(1-(6- (trifluoromethyl)pyridin-2- yl)-1H-indazol-6- yl)picolinonitrile
212	2-(1-(6- (trifluoromethyl)pyridin-2- yl)-1H-indazol-6-yl)-6,7- dihydroquinolin-8(5H)-one
213	6-amino-4-(1-(6- (trifluoromethyl)pyridin-2- yl)-1H-indazol-6-yl)picolinic acid
214	6-(6-(1-aminoethyl)pyridin- 2-yl)-1-(6-methylpyridin-2- yl)-1H-indazole-4- carbonitrile
215	1-(6-(4-(aminomethyl)-2-(6- methylpyridin-2-yl)-2H- indazol-6-yl)pyridin-2- yl)ethanamine
216	N,N-dimethyl-1-(6-(1-(6- (trifluoromethyl)pyridin-2- yl)-1H-indazol-6-yl)pyridin- 2-yl)ethanamine
217	N-((6-(6-(1- aminoethyl)pyridin-2-yl)-2- (6-methylpyridin-2-yl)-2H- indazol-4- yl)methyl)acetamide
218	1-(6-(4-chloro-1-(6- methylpyridin-2-yl)-1H- indazol-6-yl)pyridin-2- yl)ethanone
219	(Z)-1-(6-(4-chloro-1-(6- methylpyridin-2-yl)-1H- indazol-6-yl)pyridin-2- yl)ethanone oxime
220	N,N-dimethyl-1-(6-(1-(6- methylpyridin-2-yl)-1H- indazol-6-yl)pyridin-2- yl)ethanamine
221	N,N-dimethyl-1-(6-(1-(6- (trifluoromethyl)pyridin-2- yl)-1H-indazol-6-yl)pyridin- 2-yl)ethanamine
222	1-(6-(3-(6- (trifluoromethyl)pyridin-2- yl)imidazo[1,5-a]pyridin-6- yl)pyridin-2-yl)ethanamine
223	1-(6-(3-(6- (trifluoromethyl)pyridin-2- yl)imidazo[1,5-a]pyridin-6- yl)pyridin-2-yl)ethanamine
224	(Z)-1-(6-(3-(6- (trifluoromethyl)pyridin-2- yl)imidazo[1,5-a]pyridin-6- yl)pyridin-2-yl)ethanone oxime
225	tert-butyl (6-(6- acetylpyridin-2-yl)-1-(6- methylpyridin-2-yl)-1H- indazol-4- yl)(methyl)carbamate
226	(Z)-tert-butyl (6-(6-(1- (hydroxyimino)ethyl)pyridin- 2-yl)-1-(6-methylpyridin-2- yl)-1H-indazol-4- yl)(methyl)carbamate
227	(Z)-1-(6-(4-(methylamino)-1- (6-methylpyridin-2-yl)-1H- indazol-6-yl)pyridin-2- yl)ethanone oxime
228	1-(6-(1-(6-ethylpyridin-2-yl)- 1H-indazol-6-yl)pyridin-2- yl)ethanone
229	1-(6-(1-(pyridin-2-yl)-1H- indazol-6-yl)pyridin-2- yl)ethanone
230	(E)-1-(6-(1-(pyridin-2-yl)- 1H-indazol-6-yl)pyridin-2- yl)ethanone oxime
231	2-(aminomethyl)-6-(1-(6- methylpyridin-2-yl)-1H- indazol-6-yl)pyridin-4-amine
232	N,N-dimethyl-1-(6-(1-(6- methylpyridin-2-yl)-1H- indazol-6-yl)pyridin-2- yl)ethanamine
233	1-(6-(4-(dimethylamino)-1- (6-methylpyridin-2-yl)-1H- indazol-6-yl)pyridin-2- yl)ethanone
234	(E)-1-(6-(4-(dimethylamino)- 1-(6-methylpyridin-2-yl)-1H- indazol-6-yl)pyridin-2- yl)ethanone oxime
235	(E)-1-(6-(1-(6-ethylpyridin- 2-yl)-1H-indazol-6- yl)pyridin-2-yl)ethanone oxime
236	6-(6-(6-acetylpyridin-2-yl)- 1H-indazol-1- yl)picolinonitrile
237	(E)-methyl 6-(6-(6-(1- (hydroxyimino)ethyl)pyridin- 2-yl)-1H-indazol-1- yl)picolinate
239	1-(6-(1-(4-methylthiazol-2- yl)-1H-indazol-6-yl)pyridin- 2-yl)ethanone
240	1-(6-(4-fluoro-1-(6- (trifluoromethyl)pyridin-2- yl)-1H-indazol-6-yl)pyridin- 2-yl)ethanamine
241	(S)-1-(6-(1-(6-methylpyridin- 2-yl)-1H-indazol-6- yl)pyridin-2-yl)ethanamine
242	1-(3-fluoro-6-(1-(6- methylpyridin-2-yl)-1H- indazol-6-yl)pyridin-2- yl)ethanamine
243	methyl 3-amino-6-(1-(6- methylpyridin-2-yl)-1H- indazol-6-yl)picolinate
244	2,2,2-trifluoro-1-(6-(1-(6- methylpyridin-2-yl)-1H- indazol-6-yl)pyridin-2- yl)ethanol
245	1-(6-(4-ethoxy-1-(6- methylpyridin-2-yl)-1H- indazol-6-yl)pyridin-2- yl)ethanamine
246	1-(6-(4-methoxy-1-(6- methylpyridin-2-yl)-1H- indazol-6-yl)pyridin-2- yl)ethanamine
247	3-amino-3-(6-(1-(6- methylpyridin-2-yl)-1H- indazol-6-yl)pyridin-2- yl)propan-1-ol
248	6-(1-(6-methylpyridin-2-yl)- 1H-indazol-6- yl)picolinamide
249	2-(6-(1-(6-methylpyridin-2- yl)-1H-indazol-6-yl)pyridin- 2-yl)acetonitrile
250	6-(6-(1-aminoethyl)pyridin- 2-yl)-1-(6-methylpyridin-2- yl)-1H-indazol-4-ol
251	1-(6-(4- (cyclopropylmethoxy)-1-(6- methylpyridin-2-yl)-1H- indazol-6-yl)pyridin-2- yl)ethanamine
252	(4-(1-(6-methylpyridin-2-yl)- 1H-indazol-6-yl)thiazol-2- yl)methanamine
253	N-((6-(1-(6-methylpyridin-2- yl)-1H-indazol-6-yl)pyridin- 2-yl)methyl)acetamide
254	2-(6-(1-(6-methylpyridin-2- yl)-1H-indazol-6-yl)pyridin- 2-yl)ethanamine
255	1-(6-(1-(6-methylpyridin-2- yl)-1H-indazol-6-yl)-3- (trifluoromethyl)pyridin-2- yl)ethanamine
256	2-(1-aminoethyl)-6-(1-(6- methylpyridin-2-yl)-1H- indazol-6-yl)pyridin-4-amine
257	(1-methyl-4-(1-(6- methylpyridin-2-yl)-1H- indazol-6-yl)-1H-imidazol-2- yl)methanol
258	2-amino-2-(6-(1-(6- methylpyridin-2-yl)-1H- indazol-6-yl)pyridin-2- yl)acetonitrile
259	2,2,2-trifluoro-1-(6-(1-(6- methylpyridin-2-yl)-1H- indazol-6-yl)pyridin-2- yl)ethanamine
260	3-amino-3-(6-(1-(6- methylpyridin-2-yl)-1H- indazol-6-yl)pyridin-2- yl)propanoic acid
261	methyl 3-amino-3-(6-(1-(6- methylpyridin-2-yl)-1H- indazol-6-yl)pyridin-2- yl)propanoate
262	1-(6-(1-(6-methylpyridin-2- yl)-1H-indazol-6-yl)pyridin- 2-yl)cyclopropanamine
263	1-(6-(1-(6-methylpyridin-2- yl)-1H-indazol-6-yl)pyridin- 2-yl)propan-1-amine
264	(R)-1-(6-(1-(6- methylpyridin-2-yl)-1H- indazol-6-yl)pyridin-2- yl)butan-1-amine
265	(S)-1-(6-(1-(6-methylpyridin- 2-yl)-1H-indazol-6- yl)pyridin-2-yl)butan-1- amine
266	1-(3-chloro-6-(1-(6- methylpyridin-2-yl)-1H- indazol-6-yl)pyridin-2- yl)ethanamine
267	2-amino-2-(6-(1-(6- methylpyridin-2-yl)-1H- indazol-6-yl)pyridin-2- yl)acetamide
268	1-(6-(1-(6- (trifluoromethyl)pyridin-2- yl)-1H-indazol-6-yl)pyridin- 2-yl)butan-1-amine
269	6-(6-(6-(1- aminopropyl)pyridin-2-yl)- 1H-indazol-1- yl)picolinamide
270	2-(1-aminoethyl)-6-(1-(6- (trifluoromethyl)pyridin-2- yl)-1H-indazol-6-yl)pyridin- 4-amine
271	2-amino-2-(6-(1-(6- methylpyridin-2-yl)-1H- indazol-6-yl)pyridin-2- yl)ethanol
272	methyl 2-amino-2-(6-(1-(6- methylpyridin-2-yl)-1H- indazol-6-yl)pyridin-2- yl)acetate
273	2-amino-2-(6-(1-(6- methylpyridin-2-yl)-1H- indazol-6-yl)pyridin-2- yl)acetic acid
274	6-(6-(6-(1- aminobutyl)pyridin-2-yl)- 1H-indazol-1- yl)picolinamide
275	1-(6-(3-(6-methylpyridin-2- yl)imidazo[1,5-a]pyridin-6- yl)pyridin-2-yl)propan-1- amine
276	1-(6-(3-(6-methylpyridin-2- yl)imidazo[1,5-a]pyridin-6- yl)pyridin-2-yl)butan-1- amine
278	2-(6-(6-(6-(1- aminoethyl)pyridin-2-yl)-1H- indazol-1-yl)pyridin-2- yl)propan-2-ol
279	1-(6-(1-(6- (methoxymethyl)pyridin-2- yl)-1H-indazol-6-yl)pyridin- 2-yl)ethanamine
280	(6-(6-(6-(1- aminobutyl)pyridin-2-yl)- 1H-indazol-1-yl)pyridin-2- yl)methanol
281	1-(3-methyl-6-(1-(6- methylpyridin-2-yl)-1H- indazol-6-yl)pyridin-2- yl)ethanamine
282	1-(6-(1-(4-methylthiophen-2- yl)-1H-indazol-6-yl)pyridin- 2-yl)ethanamine
283	1-(6-(1-(6-propylpyridin-2- yl)-1H-indazol-6-yl)pyridin- 2-yl)ethanamine
284	1-(6-(6-(6-(1- aminoethyl)pyridin-2-yl)-1H- indazol-1-yl)pyridin-2- yl)ethanol
285	(4-(1-(6-methylpyridin-2-yl)- 1H-indazol-6-yl)oxazol-2- yl)methanamine
286	1-(6-(1-(6-(tert- butyl)pyridin-2-yl)-1H- indazol-6-yl)pyridin-2- yl)ethanamine
287	1-(6-(1-(6- (aminomethyl)pyridin-2-yl)- 1H-indazol-6-yl)pyridin-2- yl)ethanamine
288	2-(6-(6-(6-(1- aminoethyl)pyridin-2-yl)-1H- indazol-1-yl)pyridin-2-yl)-2- methylpropanenitrile
289	1-(6-(1-(6-(2- (methylsulfonyl)propan-2- yl)pyridin-2-yl)-1H-indazol- 6-yl)pyridin-2-yl)ethanamine
290	1-(6-(6-(6-(1- aminoethyl)pyridin-2-yl)-1H- indazol-1-yl)pyridin-2- yl)cyclopropanecarbonitrile
291	(6-(6-(6- (aminomethyl)pyridin-2-yl)- 1H-indazol-1-yl)pyridin-2- yl)methanol
292	2-(6-(6-(6-(1- aminoethyl)pyridin-2-yl)-1H- indazol-1-yl)pyridin-2- yl)propan-2-amine
293	1-(6-(3-(6-ethylpyridin-2- yl)imidazo[1,5-a]pyridin-6- yl)pyridin-2-yl)ethanamine
294	(6-(6-(6-(1- aminopropyl)pyridin-2-yl)- 1H-indazol-1-yl)pyridin-2- yl)methanol
295	1-(6-(4-(1H-imidazol-2-yl)- 1-(6-methylpyridin-2-yl)-1H- indazol-6-yl)pyridin-2- yl)ethanamine
296	1-(6-(1-(4-methylpyrimidin- 2-yl)-1H-indazol-6- yl)pyridin-2-yl)ethanamine
297	1-(6-(1-(4- (trifluoromethyl)pyrimidin-2- yl)-1H-indazol-6-yl)pyridin- 2-yl)ethanamine
298	2-(6-(1-(6-methylpyridin-2- yl)-1H-indazol-6-yl)pyridin- 2-yl)propan-2-amine
299	1-(1-methyl-4-(1-(6- methylpyridin-2-yl)-1H- indazol-6-yl)-1H-imidazol-2- yl)ethanol
300	(1-methyl-4-(1-(6- methylpyridin-2-yl)-1H- indazol-6-yl)-1H-imidazol-2- yl)methanamine
301	2-(6-(6-(6-(1- aminoethyl)pyridin-2-yl)-1H- indazol-1-yl)pyridin-2-yl)-2- methylpropanamide
302	(6-(6-(6-(1- aminoethyl)pyridin-2- yl)imidazo[1,5-a]pyridin-3- yl)pyridin-2-yl)methanol
303	1-(6-(1-(6-methylpyridin-2- yl)-4-(thiazol-2-yl)-1H- indazol-6-yl)pyridin-2- yl)ethanamine
304	1-(6-(1-(6-methylpyridin-2- yl)-1H-indazol-6-yl)pyridin- 2-yl)cyclobutanecarbonitrile
305	1-(1-methyl-4-(1-(6- methylpyridin-2-yl)-1H- indazol-6-yl)-1H-imidazol-2- yl)ethanamine
306	1-(6-methylpyridin-2-yl)-6- (pyridin-2-yl)-1H-indazole
307	(6-(6-(6-(1- aminoethyl)pyridin-2-yl)-4- methoxy-1H-indazol-1- yl)pyridin-2-yl)methanol
308	2-(1-(6-methylpyridin-2-yl)- 1H-indazol-6-yl)-6,7,8,9- tetrahydro-5H- cyclohepta[b]pyridin-9- amine
309	(6-(6-(1-aminoethyl)pyridin- 2-yl)-1-(6- (hydroxymethyl)pyridin-2- yl)-1H-indazol-4- yl)methanol
310	1-(4-(1-(6-methylpyridin-2- yl)-1H-indazol-6-yl)thiazol- 2-yl)ethanamine
311	1-(6-(8-chloro-3-(6- (trifluoromethyl)pyridin-2- yl)imidazo[1,5-a]pyridin-6- yl)pyridin-2-yl)ethanamine
312	1-(6-(1-(6-methylpyridin-2- yl)-1H-indazol-6-yl)pyridin- 2-yl)cyclobutanecarboxamide
313	1-(6-methylpyridin-2-yl)-6- (6-(3,3,3- trifluoropropyl)pyridin-2-yl)- 1H-indazole
314	2-(6-(6-(6-(1- aminoethyl)pyridin-2-yl)-1H- indazol-1-yl)pyridin-2- yl)ethanol
315	1-(6-(1-(4,6-dimethylpyridin- 2-yl)-1H-indazol-6- yl)pyridin-2-yl)ethanamine
316	6-(6-(1-aminoethyl)pyridin- 2-yl)-1-(6- (hydroxymethyl)pyridin-2- yl)-N-methyl-1H-indazole-4- carboxamide
317	1-(6-(8-fluoro-3-(6- (trifluoromethyl)pyridin-2- yl)imidazo[1,5-a]pyridin-6- yl)pyridin-2-yl)ethanamine
318	(S)-(6-(6-(6-(1- aminopropyl)pyridin-2-yl)- 1H-indazol-1-yl)pyridin-2- yl)methanol
319	1-(6-(1-(6-methylpyridin-2- yl)-4-(1H-pyrazol-3-yl)-1H- indazol-6-yl)pyridin-2- yl)ethanamine
320	(4-(1-(6-methylpyridin-2-yl)- 1H-indazol-6-yl)thiazol-2- yl)methanol
321	(6-(6-(6-(1- aminoethyl)pyridin-2-yl)-4- fluoro-1H-indazol-1- yl)pyridin-2-yl)methanol
322	(R)-(6-(6-(6-(1- aminopropyl)pyridin-2-yl)- 1H-indazol-1-yl)pyridin-2- yl)methanol
323	6-(1-methyl-1H-imidazol-4- yl)-1-(6-methylpyridin-2-yl)- 1H-indazole

IC50	Compounds
+++	18, 22, 25, 27, 29, 31, 36, 37, 40, 41, 42, 47, 48, 49, 50, 51, 52, 54, 55,
	56, 57, 59, 61, 63, 72, 76, 78, 79, 80, 83, 84, 85, 86, 88, 89, 90, 99,
	100, 101, 102, 106, 108, 112, 114, 115, 117, 118, 119, 120, 121, 123,
	124, 126, 127, 128, 129, 131, 132, 141, 142, 143, 144, 145, 146, 200,
	209, 214, 216, 221, 222, 223, 231, 240, 241, 242, 245, 246, 247, 250,
	256, 257, 261, 263, 264, 265, 268, 269, 270, 271, 273, 274, 275, 276,
	278, 279, 280, 281, 283, 284, 286, 290, 291, 293, 294, 295, 297, 302,
	303, 304, 307, 309, 310, 311, 312, 314, 316, 317, 318, 319, 321, 322,
	324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337,
	338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 352,
	353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366,
	367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380,
	381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394,
	395, 396, 398, 399, 401, 402, 403, 405, 406, 407, 408, 409, 410, 411,
	413, 414, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427,
	428, 429, 430, 432, 433, 435, 436, 437, 438, 439, 440, 441, 442, 443,
	444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457,
	458, 459, 460, 461, 463, 464, 466, 467, 468, 469, 471, 473, 474, 475,
	476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489,
	490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502 503,
	504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517,
	518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 531, 532,
	533, 535, 536, 537, 538, 539, 542, 543, 544, 545, 546, 569, 570, 572,
	573, 574, 575, 576, 577, 578, 579, 580, 582, 583, 584, 586, 587, 588,
	589, 590, 591, 592, 594, 595, 596, 597, and 598.
++	1, 4, 6, 8, 9, 13, 14, 20, 21, 30, 32, 33, 34, 35, 39, 43, 46, 53, 58, 64,
	65, 66, 68, 71, 77, 81, 87, 91, 96, 97, 103, 105, 107, 109, 110, 111,
	113, 116, 122, 125, 130, 134, 135, 136, 137, 138, 139, 140, 202, 204,
	220, 228, 232, 234, 244, 248, 249, 251, 252, 254, 255, 258, 259, 260,
	262, 266, 267, 272, 287, 288, 298, 301, 305, 306, 308, 320, 323, 351,
	397, 400, 404, 415, 431, 465, 470, 530, 540, 541, 548, 551, 557, 559,
	561, 563, 564, 565, 566, 567, 571, 581, and 585.
+	2, 3, 5, 10, 11, 12, 15, 16, 17, 23, 24, 26, 28, 38, 44, 60, 62, 67, 69, 70,
	73, 74, 75, 82, 92, 93, 94, 95, 98, 104, 138, 203, 207, 211, 213, 215,
	217, 218, 219, 225, 227, 229, 233, 235, 243, 253, 282, 285, 289, 292,
	296, 299, 300, 313, 315, 412, 462, 472, 549, 550, 560, 562, and 568.
greater than 10 μM	201, 205, 206, 208, 210, 212, 224, 226, 230, 236, 237, and 239

EC50	Compounds
†††	324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336,
	337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349,
	354, 355, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367,
	368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 397, 398, 399,
	411, 413, 414, 415, 416, 418, 422, 423, 425, 427, 436, 437, 438,
	439, 442, 443, 445, 446, 447, 451, 453, 454, 456, 457, 458, 463,
	464, 473, 474, 475, 476, 483, 485, 486, 487, 488, 489, 490, 491,
	492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504,
	505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517,
	518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530,
	531, 532, 533, 535, 536, 537, and 538.
††	350, 356, 378, 379, 380, 381, 444, 448, 450, 452, 539, 540, 541,
	542, 543, 544, 545, 546, 548, 549, and 550.
†

Day

	−1	0	1	2	3	4	5	6	7
Bi-daily dosing with	X	IRI	X		X		X		Endpoint
an IRAK4 inhibitor or
vehicle

description truncated at 500,000 characters

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Claims as granted

6 claims

Classifications

13 codes

IPC · International Patent Classification

Section A — Human necessities

A61P19/02
A61P13/12
A61K31/416
A61K31/44
A61K31/437

Section C — Chemistry; metallurgy

C07D471/04
C07D413/14
C07D417/14
C07D401/12
C07D405/14
C07D487/04
C07B59/00
C07D401/14

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Venkataraman Balasubramanian

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