IRAK4 INHIBITING AGENTS

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Patent Application No. 62/280962, filed January 20, 2016, the entire contents of which are hereby incorporated by reference.

TECHNICAL FIELD

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

BACKGROUND

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 Inter leukin- 1 receptor (IL-1R), Interleukin-18 receptor (IL-18R), and To 11- 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-IR (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) IRAKI, Biologically, IRAK4 has been demonstrated to play a critical role in innate immunity.

SUMMARY

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;

Ring C is a 3- to 6-membered carbocyclyl,

n is 1, 2, or 3;

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 Ci _-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, halo, -CN, -C(R ^la )=NR(OR ^la ), - C(R ^la )=N(R ^la ), -C(0)R ^la , -C(0) ₂ R ^la , -C(0)N(R ^la ) ₂ , -N0 ₂ , -N(R ^la ) ₂ , -N(R ^la )C(0)R ^la , - N(R ^la )C(0) ₂ R ^la , -N(R ^la )C(0)N(R ^la ) ₂ , -N(R ^la )S(0) ₂ R ^la , -OR ^la , -OC(0)R ^la , - OC(0)N(R ^la ) ₂ , -SR ^la , -S(0)R ^la , -S(0) ₂ R ^la , -S(0)N(R ^la ) ₂ , and -S(0) ₂ N(R ^la ) ₂ , wherein said Ci- ₆ alkyl, C _2-6 alkenyl, and C _2-6 alkynyl are optionally substituted with one or more R ¹⁰ ;

R ^la in each occurrence is independently selected from H or Ci- ₆ alkyl wherein said Ci- ₆ alkyl in each occurrence are optionally and independently substituted with one or more R ¹⁰ ;

R ¹⁰ in each occurrence is independently selected from 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 , -N0 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 Ci- ₆ alkyl, wherein said

Ci- ₆ alkyl is optionally substituted with one or more halo; R is selected from H, Ci- 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(0)R ^2a , - C(0) ₂ R ^2a , -C(0)N(R ^2a ) ₂ , -N0 ₂ , -N(R ^2a ) ₂ , -N(R ^2a )C(0)R ^2a , -N(R ^2a )C(0) ₂ R ^2a , - N(R ^2a )C(0)N(R ^2a ) ₂ , -N(R ^2a )S(0) ₂ R ^2a , -OR ^2a , -OC(0)R ^2a , -OC(0)N(R ^2a ) ₂ , -SR ^2a , - S(0)R ^2a , -S(0) ₂ R ^2a , -S(0)N(R ^2a ) ₂ , and -S(0) ₂ N(R ^2a ) ₂ , wherein said Ci _-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 Ci- ₆ alkyl, wherein said Ci- 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 Ci- 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 , -N0 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 ^20a , -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 Ci _-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 Ci- ₆ alkyl, wherein said

Ci- ₆ alkyl is optionally substituted with R 25 ;

R ²⁵ is selected from halo and -OR ^25a ;

R ^25a is selected from H and Ci- ₆ alkyl;

R is selected from Ci- 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(0)R ^3a , - C(0) ₂ R ^3a , -C(0)N(R ^3a ) ₂ , -N0 ₂ , -N(R ^3a ) ₂ , -N(R ^3a )C(0)R ^3a , -N(R ^3a )C(0) ₂ R ^3a , - N(R ^3a )C(0)N(R ^3a ) ₂ , -N(R ^3a )S(0) ₂ R ^3a , -OR ^3a , -OC(0)R ^3a , -OC(0)N(R ^3a ) ₂ , -SR ^3a , -

S(0)R ^3a , -S(0) ₂ R ^3a , -S(0)N(R ^3a ) ₂ , and -S(0) ₂ N(R ^3a ) ₂ , wherein said Ci _-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, Ci- ₆ alkyl, 3- to 6-membered

carbocyclyl, and 3- to 6-membered heterocyclyl, wherein said Ci- 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 Ci- 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 , -N0 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 Ci _-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, 3-6 membered carbocyclyl, 3- to 6-membered heterocyclyl in each occurrence are optionally and independently substituted with one or more R 35 ;

R ^30a in each occurrence is independently selected from H and wherein Ci- ₄ alkyl is optionally substituted with one or more 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 _h alky!

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.

DETAILED DESCRIPTION

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 in ention is a compound of Formula (II):

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 in ention is a compound of Formula (III):

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 in ention 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), R ¹ is selected from Ci _-6 alkyl, halo, -CN, -C(0)R ^la , -C(0) ₂ R ^la , - C(0)N(R ^la ) ₂ , -N0 ₂ , -N(R ^la ) ₂ , -N(R ^la )C(0)R ^la , -N(R ^la )C(0) ₂ R ^la , -N(R ^la )C(0)N(R ^la ) ₂ , -OR ^la , - OC(0)R ^la , -OC(0)N(R ^la ) ₂ , and -SR ^la , wherein said Ci _-6 alkyl is optionally substituted with one to four R ¹⁰ ;

R ^la in each occurrence is independently selected from H or Ci- ₆ alkyl wherein said Ci- ₆ alkyl in each occurrence are optionally and independently substituted with one or to four R ¹⁰ ;

R ¹⁰ in each occurrence is independently selected from halo, -CN, -C(O)R ^10a , -C(O) ₂ R ^10a , -C(O)N(R ^10a ) ₂ , -N0 ₂ , -N(R ^10a ) ₂ , -N(R ^10a )C(O)R ^10a , -N(R ^10a )C(O) ₂ R ^10a , -OR ^10a , -OC(O)R ^10a , - OC(O)N(R ^10a ) ₂ , and -SR ^10a ; and

R ^10a in each occurrence is independently selected from H and Ci- ₆ alkyl, wherein said Ci- ₆ alkyl is optionally substituted with one to four halo, wherein said Ci- ₆ alkyl is optionally substituted with one to three halo, wherein the values of the other variables are as defined for the first, 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 R ¹ is selected from Ci- ₆ alkyl, halo, -OR ^la , wherein said Ci- ₆ alkyl are optionally substituted with one to three R ¹⁰ ;

R ^la in each occurrence is independently selected from H or Ci- ₆ alkyl wherein said Ci- ₆ alkyl in each occurrence are optionally and independently substituted with one to three R ¹⁰ ;

R ¹⁰ in each occurrence is independently selected from halo or -OR ^10a ; and

R ^10a in each occurrence is independently selected from H and C _1-6 alkyl, wherein said Ci- ₆ alkyl is optionally substituted with one to three halo, wherein the values of the other variables are as defined for the first, fifth, sixth, seventh, eighth, ninth, tenth and eleventh embodiments.

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 OH or -CH ₂ OH, wherein the values of the other variables are as defined for the first, 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 n is 2 and R ¹ is halo, wherein the values of the other variables are as defined for the first, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, and twelfth

embodiments.

In a fifteenth embodiment of the invention, the compound is represented by the formula (I), (II), (III), or (IV), wherein Ring C is cyclobutyl, wherein the values of the other variables are as defined for the first, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, and fourteenth embodiments.

In a sixteenth embodiment of the invention, the compound is represented by the formula (I), (II), (III), or (IV), wherein Ring C is cyclopentyl; wherein the values of the other variables are as defined for the first, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, and fourteenth embodiments.

In a seventeenth embodiment of the invention, the compound is represented by the formula (I), (II), (III), or (IV), R 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(0)R ^2a , -C(0) ₂ R ^2a , -C(0)N(R ^2a ) ₂ , -N0 ₂ , -N(R ^2a ) ₂ , - N(R ^2a )C(0)R ^2a , -N(R ^2a )C(0) ₂ R ^2a , -N(R ^2a )C(0)N(R ^2a ) ₂ , -OR ^2a , -OC(0)R ^2a , and -OC(0)N(R ^2a ) ₂ , wherein said Ci- 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 Ci- ₄ alkyl, wherein said

Ci- 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 Ci- ₆ alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C3 _-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 Ci- ₆ alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C3 _-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 Ci- ₄ alkyl, wherein said Ci- 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 Ci- ₄ alkyl, wherein the values of the other variables are as defined for the first, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, 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 eighteenth embodiment of the invention, the compound is represented by the formula (I), (II), (III), or (IV), R ² is H, Ci _-4 alkyl, C _2-4 alkenyl, halo, -C(0) ₂ R ^2a , -C(0)N(R ^2a ) ₂ ,- N(R ^2a ) _2, N(R ^2a )C(0)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 Ci- 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;

R ^2a in each occurrence is independently selected from H and Ci- ₄ alkyl, wherein said Q. ₄ alkyl is optionally substituted with cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl; and

R ^20a in each occurrence is independently selected from H and Ci- ₄ alkyl, wherein the values of the other variables are as defined for the first, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, and seventeenth embodiments.

In a nineteenth embodiment of the invention, the compound is represented by the formula (I), (II), (III), or (IV), R ² is H or -OR ^2a ; R ^2a in each occurrence is independently selected from H and Ci- ₄ alkyl, wherein said Ci- ₄ alkyl is optionally substituted with one to three halo, wherein the values of the other variables are as defined for the first, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, and eighteenth embodiments.

In a twentieth embodiment of the invention, the compound is represented by the formula (I), (II), (III), or (IV), wherein p is 1 or 2;

each R is independently selected from Ci- ₆ alkyl, C3- 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(0)R ^3a , -C(0) ₂ R ^3a , -C(0)N(R ^3a ) ₂ , -N(R ^3a ) ₂ , - N(R ^3a )C(0)R ^3a , -N(R ^3a )C(0) ₂ R ^3a , -N(R ^3a )C(0)N(R ^3a ) ₂ , -OR ^3a , -OC(0)R ^3a , -OC(0)N(R ^3a ) ₂ , - SR ^3a , -S(0)R ^3a , -S(0) ₂ R ^3a , -S(0)N(R ^3a ) ₂ , and -S(0) ₂ N(R ^3a ) ₂ , wherein said Ci _-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, Ci- 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 Ci- 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 ;

R 30 in each occurrence is independently selected from Ci- 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 , - 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 Ci- ₆ alkyl, 3-6 membered carbocyclyl, 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 Ci- ₆ alkyl, wherein Ci- 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 Ci- ₆ alkyl, wherein the values of the other variables are as defined for the first, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, 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 in each occurrence is independently selected from

Ci _-4 alkyl, -CN, halo, C(0) ₂ R ^3a , C(0)N(R ^3a ) ₂ , -N(R ^3a ) ₂ , cyclopropyl, cyclobutyl, and -C(0)R ^3a , wherein said Ci _-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(0)N(R ^3a ) ₂ , and -OR ^3a ;

R ^3a in each occurrence is independently selected from H, Ci _-4 alkyl, and azetidinyl, wherein said Ci _-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 Ci _-4 alkyl, wherein the values of the other variables are as defined for the first, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth and twentieth embodiments.

In a twenty-second embodiment of the invention, the compound is represented by the formula (I), (II), (III), or (IV), R is selected from Ci _-4 alkyl and cyclopropyl, each of which is optionally substituted with one to three groups selected from halo, -OR ^3a , and -CN; and R ^3a in each occurrence is independently selected from H and Ci _-4 alkyl wherein the values of the other variables are as defined for the first, 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 the compound is represented by the formula structural formula

, or a pharmaceutically acceptable salt thereof, wherein R ¹ is F, OH or -CH ₂ OH;

Ring C is cyclobutyl or cyclopentyl;

Ring A is pyridinyl or pyrazinyl;

Ring B is pyridinyl, pyrazinyl, or pyrimidinyl;

R ² is H or -OR ^2a ;

R ^2a is H or Ci _-4 alkyl, wherein the Ci _-4 alkyl is optionally substituted with one to three halo;

R is Ci- ₄ alkyl or (C ₃ -C ₆ )cycloalkyl, wherein said Ci- ₄ alkyl or (C ₃ -C ₆ )cycloalkyl is optionally substituted with one to three groups independently selected from halo, -OR ^3a or -CN and

R ^3a in each occurrence is independently selected form H and Ci- ₄ alkyl.

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

In a twenty-fifth embodiment of the invention, there is provided a compound selected from:

cis- (S)-(6-(6-(6-(amino(3-(hydroxymethyl)cyclobutyl)methyl)pyrid in-2-yl)- lH-indazol- 1- yl)pyridin-2-yl)methanol;

(R)-(6-(6-(6-(amino(3-(hydroxymethyl)cyclobutyl)methyl)py ridin-2-yl)-lH-indazol-l- yl)pyridin-2-yl)methanol;

trans-(S)-(6-(6-(6-(amino(3-(hydroxymethyl)cyclobutyl)met hyl)pyridin-2-yl)-lH-indazol-l- yl)pyridin-2-yl)methanol;

cis-3-((S)-amino(6-(l-(6-(hydroxymethyl)pyridin-2-yl)-lH- indazol-6-yl)pyridin-2- yl)methyl)cyclobutanol;

(6-(6-(6-((R)-amino((cis-3-(tert-butyldimethylsilyloxy)cy clobutyl)methyl)pyridin-2-yl)-lH- indazo 1- 1 - yl)pyridin-2- y 1) methano 1;

trans-3-((S)-amino(6-(l-(6-(hydroxymethyl)pyridin-2-yl)-l H-indazol-6-yl)pyridin-2- yl)methyl)cyclobutanol;

trans-3-((R)-amino(6-(l-(6-(hydroxymethyl)pyridin-2-yl)-l H-indazol-6-yl)pyridin-2- yl)methyl)cyclobutanol;

(lR,3S)-3-((S)-amino(6-(l-(4-(hydroxymethyl)pyrimidin-2-y l)-lH-indazol-6-yl)pyridin-2- yl)methyl)cyclobutanol;

cis 3-((S)-amino(6-(l-(6-(hydroxymethyl)pyrazin-2-yl)-lH-indazol -6-yl)pyridin-2- yl)methyl)cyclobutanol;

(lR,3S)-3-((S)-amino(6-(l-(6-(trifluoromethyl)pyridin-2-y l)-lH-indazol-6-yl)pyridin-2- yl)methyl)cyclobutanol;

(lR,3S)-3-((S)-amino(6-(l-(4-ethylpyrimidin-2-yl)-lH-inda zol-6-yl)pyridin-2- yl)methyl)cyclobutanol;

(lR,3s)-3-((S)-amino(6-(l-(6-ethylpyridin-2-yl)-lH-indazo l-6-yl)pyridin-2- yl)methyl)cyclobutanol; (lR,3s)-3-((S)-amino(6-(l-(4-(trifluorom

yl)methyl)cyclobutanol;

cis-3-((S)-amino(6-(l-(6-(difluoromethyl)pyridin-2-yl)-lH -indazol-6-yl)pyridin-2- yl)methyl)cyclobutanol;

(lR,3s)-3-((S)-amino(6-(l-(6-ethylpyrazin-2-yl)-lH-indazo l-6-yl)pyridin-2- yl)methyl)cyclobutanol;

(lR,3s)-3-((S)-amino(6-(l-(6-(fluoromethyl)pyridin-2-yl)- lH-indazol-6-yl)pyridin-2- yl)methyl)cyclobutanol;

cis-3-((S)-amino(6-(l-(6-(hydroxymethyl)pyridin-2-yl)-lH- indazol-6-yl)pyrazin-2- yl)methyl)cyclobutanol;

cis-3-((S)-amino(6-(l-(6-(fluoromethyl)pyridin-2-yl)-lH-i ndazol-6-yl)pyrazin-2- yl)methyl)cyclobutanol;

cis-3-((S)-amino(6-(l-(6-(trifluoromethyl)pyridin-2-yl)-l H-indazol-6-yl)pyrazin-2- yl)methyl)cyclobutanol;

l-(6-(6-(6-((S)-amino(cis-3-hydroxycyclobutyl)methyl)pyri din-2-yl)-lH-indazol-l-yl)pyridin-2- yl)cyclopropanecarbonitrile;

3-(amino(6-(l-(6-(hydroxymethyl)pyridin-2-yl)-lH-indazol- 6-yl)pyridin-2- yl)methyl)cyclopentanol;

(lR,3s)-3-((S)-amino(6-(4-(2,2-difluoroethoxy)-l-(6-(hydr oxymethyl)pyridin-2-yl)-lH-indazol-

6-yl)pyridin-2-yl)methyl)cyclobutanol;

(lR,3s)-3-((lS)-amino(6-(l-(4-(l-hydroxyethyl)pyrimidin-2 -yl)-lH-indazol-6-yl)pyridm^

yl)methyl)cyclobutanol;

(S)-(6-(6-(6-(amino(3,3-difluorocyclobutyl)methyl)pyridin -2-yl)-lH-indazol-l-yl)pyridin-2- yl) methanol;

(R)-(6-(6-(6-(amino(3,3-difluorocyclobutyl)methyl)pyridin-2- yl)-lH-indazol-l-yl)pyridin-2- yl) methanol;

(S)-(2-(6-(6-(amino(3,3-difluorocyclobutyl)methyl)pyridin-2- yl)-lH-indazol-l-yl)pyrimidin-4- yl) methanol;

(S)-(3,3-difluorocyclobutyl)(6-(l-(6-(fluoromethyl)pyridin-2 -yl)-lH-indazol-6-yl)pyridin-2- y 1) methanamine ;

(S)-(3,3-difluorocyclobutyl)(6-(l-(6-(difluoromethyl)pyridin -2-yl)-lH-indazol-6-yl)pyridin-2- y 1) methanamine ;

(S)-(6-(6-(6-(amino(l-fluorocyclobutyl)methyl)pyridin-2-yl)- lH-indazol-l-yl)pyridin-2- yl) methanol; (R)-(6-(6-(6-(amino(l-fluorocyclobutyl)methyl)pyridin-2-yl)- lH-indazol-l-yl)pyridin-2- yl) methanol;

(R)-(6-(6-(6-(amino(3,3-difluorocyclobutyl)methyl)pyridin-2- yl)-4-ethoxy-lH-indazol-l- yl)pyridin-2-yl)methanol;

(S)-(6-(6-(6-(amino(3,3-difluorocyclobutyl)methyl)pyridin -2-yl)-4-ethoxy-lH-indazol-l- yl)pyridin-2-yl)methanol;

3-((S)-amino(6-(l-(6-(difluoromethyl)pyridin-2-yl)-lH-ind azol-6-yl)pyridin-2- yl)methyl)cyclobutan- l-ol;

3-((S)-amino(6-(l-(6-ethylpyridin-2-yl)-lH-indazol-6-yl)p yridin-2-yl)methyl)cyclobutan-l-ol; (R)-(6-(6-(6-(amino(l-fluorocyclobutyl)methyl)pyridin-2-yl)- lH-indazol-l-yl)pyridin-2- yl) methanol;

(S)-(6-(6-(6-(amino(l-fluorocyclobutyl)methyl)pyridin-2-yl)- lH-indazol-l-yl)pyridin-2- yl) methanol;

(S)-3-(amino(6-(l-(6-methoxypyridin-2-yl)-lH-indazol-6-yl)py ridin-2-yl)methyl)cyclobutan-l- ol;

3-((S)-amino(6-(l-(6-(fluoromethyl)pyridin-2-yl)- lH-indazol-6-yl)pyridin-2-yl)methyl)-l- methylcyclobutan- l-ol;

3-((S)-amino(6-(l-(6-(difluoromethyl)pyridin-2-yl)-lH-ind azol-6-yl)pyridin-2-yl)methyl)-l- methylcyclobutan- l-ol;

(S)-(6-(l-(6-(difluoromethyl)pyridin-2-yl)-lH-indazol-6-y l)pyridin-2-yl)(3- methoxycyclobutyl)methanamine;

3-((S)-amino(6-(l-(6-(fluoromethyl)pyridin-2-yl)- lH-indazol-6-yl)pyridin-2-yl)methyl)-l- methylcyclobutan- l-ol;

(S)-(6-(l-(6-(difluoromethyl)pyridin-2-yl)-lH-indazol-6-y l)pyridin-2-yl)((lR,3S)-3- methoxycyclobutyl)methanamine;

(S)-(6-(l-(6-(fluoromethyl)pyridin-2-yl)-lH-indazol-6-yl) pyridin-2-yl)(l- methylcyclobutyl)methanamine; and

(S)-3-(amino(6-(l-(6-(fluoromethyl)pyridin-2-yl)- lH-indazol-6-yl)pyridin-2- yl)methyl)cyclobutane-l-carbonitrile;

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, "Ci- 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 or spiro 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, a- ketoglutarate, or a-glycerophosphate. Inorganic salts may also be formed, including

hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.

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(cyclo alkyl) 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, trimethamine, 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 optic ally- 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. 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, CD 14 mediated sepsis, non-CD 14 mediated sepsis, inflammatory bowel disease, Behcet's syndrome, ankylosing spondylitis, sarcoidosis, and gout. In particular, the inflammatory bowel disease is selected from Crohn's disease and ulcerative colitis.

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 Waldenstrom'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 particular, the neurodegenerative disease is selected from Alzheimer's disease (AD), Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis (ALS). Dementia is characterized by memory loss and other intellectual abilities of the patient serious enough to interfere with daily life. AD accounts for 60 to 80 percent of dementia cases. AD is a progressive disease and the dementia symptoms gradually worsen over a number of years. Survival rates for AD patients can range from four to 20 years, depending on age and other health conditions. AD has no current cure.

Increased IRAK-4 expression and activity has been found to be associated with AD. In particular, an immunohistochemical analysis revealed an increased presence of IRAK-4 in the astrocytes and microglia of post-mortem AD brain tissue as compared to post-mortem non-AD brain tissue indicating that IRAK-4 protein kinase activity is increased in AD patients. (See Hoozemans, J.J.M. et al, "Increased IRAK-4 Kinase Activity in Alzheimer's Disease; IRAK- 1/4 Inhibitor I Prevents Pro-inflammatory Cytokine Secretion but not the Uptake of Amyloid Beta by Primary Human Glia", Clin Cell Immunol 2014, 5:4, the teachings of which are incorporated herein by reference.)

In vitro functional assays showed that an IRAK- 1/4 inhibitor I reduced the

lipopolysaccharide-induced secretion of monocyte chemotactic protein- 1 (MCP-1) by primary human microglia and the interleukin- Ιβ-induced secretion of MCP-1 and interleukin 6 by primary human astrocytes. In contrast, the in vitro uptake of amyloid β (Αβ) by astrocytes and microglia is not affected by IRAK- 1/4 inhibition. Thus, selective inhibition of IRAK- 1/4 inhibits a pro-inflammatory response without affecting the uptake of Αβ by glial cells, indicating that the IRAK signaling pathway is a potential target for modulating neuroinflammation in AD. (See

Hoozemans, J.J.M. et al, "Increased IRAK-4 Kinase Activity in Alzheimer's Disease; IRAK- 1/4 Inhibitor I Prevents Pro-inflammatory Cytokine Secretion but not the Uptake of Amyloid Beta by Primary Human Glia", Clin Cell Immunol 2014, 5:4, the teachings of which are incorporated herein by reference.)

The loss of microglial IRAK4 function blocks microglial inflammatory responses and the generation of reactive oxygen species in vitro. In an AD murine model that lacks any

endogenous IRAK4 kinase activity, loss of IRAK4 function in vivo reduced amyloid burden at later ages, reduced gliosis, altered microglial phenotype including altered expression of interferon regulator factor (IRF) transcription factors, and restored normal behavior. Further, loss of IRAK4 function in vivo also promoted amyloid clearance mechanisms, including elevated expression of insulin-degrading enzyme, (see Cameron, B. et al., "Loss of Interleukin Receptor- Associated Kinase 4 Signaling Suppresses Amyloid Pathology and Alters Microglial Phenotype in a Mouse Model of Alzheimer's Disease," The Journal of Neuro science, October 24, 2012 · 32(43): 15112-15123, the teachings of which are incorporated herein by reference). 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.

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 ant i- 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, transmuco sally, 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, transmuco sally, 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 no n- toxic surfactants.

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.

Example 1. (S)-(6-(6-(6-(amino(3-(hydroxymethyl)cyclobutyl)methyl)pyrid in-2-yl)- lH-indazol-l-yl)pyridin-2-yl)methanol

Step 1. Synthesis of methyl 3-methylenecyclobutanecarboxylate

To a mixture of 3-methylenecyclobutanecarboxylic acid (4 g, 35.7 mmol, 1.0 eq) and K ₂ C0 ₃ (7.4 g, 53.5 mmol, 1.5 eq) in DMF (50 mL) was added CH ₃ I (10.1 g, 71.4 mmol, 2.0 eq). The reaction mixture was stirred at rt for 16 h. The mixture was diluted with Et ₂ 0 (100 mL) and washed with water (50 mL X 3). The organic phase was dried over Na ₂ S0 _4. After filtration and concentration, 4.04 g of methyl 3-methylenecyclobutanecarboxylate as yellow oil was obtained. Y: 90%. ESI-MS (M+H) ⁺ : 127.0. 1H NMR (400 MHz, CDC1 ₃ ) S: 4.82-4.79 (m, 2H), 3.70 (s, 3H), 3.13-3.11 (m, 1H), 3.09-2.97 (m, 2H), 2.94-2.89 (m, 2H).

Step 2. Synthesis of methyl 3-(hydroxymethyl)cyclobutanecarboxylate

To a solution of methyl 3-methylenecyclobutanecarboxylate (5.3 g, 42.4 mmol, 1.0 eq) in THF (30 mL) was added BH ₃ (12.6 mL, 12.6 mmol, 0.3 eq, 1 M) dropwise at 0 °C. Then the reaction mixture was warmed to rt and stirred for 4 h. MeOH (15 mL) was added and the mixture was stirred for 30 min at 0 °C. NaOH (4.2 mL, 3M) and H ₂ 0 ₂ (1.4 g, 42.4 mmol, 1.0 eq) were added and stirred at 0 °C for 1 h. The mixture was quenched with water (30 mL) and extracted with Et ₂ 0 (60 mL X 2). The combined organic phases were dried over Na ₂ S0 _4. After filtration and concentration, 3.3 g of methyl 3-(hydroxymethyl)cyclobutanecarboxylate as yellow oil was obtained. Y: 54%. ESI-MS (M+H) ⁺ : 145.0. 1H NMR (400 MHz, CD ₃ OD) δ: 3.69 (s, 1.3H), 3.67 (s, 1.7H), 3.59 (s, 0.4H), 3.58 (s, 0.5H), 3.50 (s, 0.4H), 3.48 (s, 0.5H), 3.12-3.03 (m, 1H), 2.48- 2.38 (m, 1H), 2.35-2.22 (m, 2H), 2.08- 1.94 (m, 2H).

Step 3. Synthesis of methyl 3-((tert- butyldimethylsilyloxy)methyl)cyclobutanecarboxylate

To a mixture of methyl 3-(hydroxymethyl)cyclobutanecarboxylate (3.3 g, 22.9 mmol, 1.0 eq) and imidazole (3.1 g, 45.8 mmol, 2.0 eq) in DMF (50 mL) was added TBSC1 (4.1 g, 27.5 mmol, 1.2 eq). The mixture was stirred at rt for 4 h. Then the mixture was diluted with EA (100 mL) and washed with water (100 mL X 3). The combined organic phases were dried over Na ₂ S0 _4. After filtration and concentration, the residue was purified by silica gel chromatography with PE/EA (10/1) as eluent to give methyl 3-((tert- butyldimethylsilyloxy)methyl)cyclobutanecarboxylate as yellow oil (5.3 g, Y: 90%). ESI-MS (M+H) ⁺ : 259.1. 1H NMR (400 MHz, CDC1 ₃ ) S: 3.68 (s, 1.3H), 3.66 (s, 1.7H), 3.60 (s, 0.4H), 3.59 (s, 0.4H), 3.53 (s, 0.5H), 3.51 (s, 0.5H), 3.10-3.06 (m, 0.4H), 3.03-2.94 (m, 0.6H), 2.51-2.28 (m, 1H), 2.34-2.24 (m, 1H), 2.20-2.17 (m, 1H), 2.08-2.00 (m, 2H), 0.87 (s, 4H), 0.85 (s, 5H), 0.04 (s, 2.5H), 0.03 (s, 3.5H).

Step 4. Synthesis of (6-bromopyridin-2-yl)(3-((tert- butyldimethylsilyloxy)methyl)cyclobutyl)methanone

To a solution of 2,6-dibromopyridine (9.8 g, 42 mmol, 2.0 eq) in Et ₂ 0 (200 mL) was added n-BuLi (16.8 mL, 42 mmol, 2.0 eq, 2.5 M) dropwise at -78 °C. The mixture was stirred at -78 °C for 30 min. Then methyl 3-((tert-butyldimethylsilyloxy)methyl)cyclobutanecarboxylate (5.3 g, 10.5 mmol, 1.0 eq) was added at -78 °C and the mixture was stirred for 30 min. Then the mixture was quenched with NH ₄ C1 (sat.). The mixture was extracted with EA (200 mL X 2). The combined organic phases were dried over Na ₂ S04. After filtration and concentration, the residue was purified by silica gel chromatography with PE/EA (20/1) as eluent to give (6-bromopyridin- 2-yl)(3-((tert-butyldimethylsilyloxy)methyl)cyclobutyl)metha none as yellow oil (2.1 g, Y: 27%). ESI-MS (M+H) ⁺ : 384.1.

Step 5. Synthesis of (R,E)-N-((6-bromopyridin-2-yl)(3-((tert- butyldimethylsilyloxy)methyl)cyclobutyl)methylene)-2-methylp ropane-2-sulfinamide (PI and P2)

To a mixture of (6-bromopyridin-2-yl)(3-((tert- butyldimethylsilyloxy)methyl)cyclobutyl)methanone (2.1 g, 5.48 mmol, 1.0 eq) and (R)-2- methylpropane-2-sulfinamide (995 mg, 8.22 mmol, 1.5 eq) in THF (50 mL) was added Ti(OEt)4 (3.10 g, 10.96 mmol, 2.0 eq). The reaction mixture was stirred at 70 °C for 16 h. After concentration, the residue was purified by silica gel chromatography with PE/EA (20/1) as eluent to give (R,E)-N-((6-bromopyridin-2-yl)(3-((tert- butyldimethylsilyloxy)methyl)cyclobutyl)methylene)-2-methylp ropane-2-sulfinamide (PI) (400 mg, Y: 31%) as yellow oil and (R,E)-N-((6-bromopyridin-2-yl)(3-((tert- butyldimethylsilyloxy)methyl)cyclobutyl)methylene)-2-methylp ropane-2-sulfinamide (P2) (600 mg, Y: 46%) as yellow oil. ESI-MS (M+H) ⁺ : 487.2.

Step 6. Synthesis of (R)-N-((S)-(6-bromopyridin-2-yl)(3-((tert- butyldimethylsilyloxy)methyl)cyclobutyl)methyl)-2-methylprop ane-2-sulfinamide (P2) and (R)-N-((R)-(6-bromopyridin-2-yl)(3-((tert- butyldimethylsilyloxy)methyl)cyclobutyl)methyl)-2-methylprop ane-2-sulfinamide P2)

To a solution of (R,E)-N-((6-bromopyridin-2-yl)(3-((tert- butyldimethylsilyloxy)methyl)cyclobutyl)methylene)-2-methylp ropane-2-sulfinamide (P2) (600 mg, 1.23 mmol, 1.0 eq) in THF (15 mL) was added L-selectride (3.69 mL, 3.0 eq, 1M) dropwise at -78 °C. Then the mixture was warmed to rt and stirred for 1 h. Then the mixture was quenched with NH ₄ CI (sat.). The mixture was extracted with EA (20 mL X 2). The combined organic phases were dried over Na ₂ S0 ₄ . After filtration and concentration, the residue was purified by silica gel chromatography with PE/EA (8/1) as eluent to give (R)-N-((S)-(6-bromopyridin-2- yl)(3-((tert-butyldimethylsilyloxy)methyl)cyclobutyl)methyl) -2-methylpropane-2-sulfinamide (P2) as a white solid (235 mg, Y: 36%) and (R)-N-((R)-(6-bromopyridin-2-yl)(3-((tert- butyldimethylsilyloxy)methyl)cyclobutyl)methyl)-2-methylprop ane-2-sulfinamide (P2) (120 mg, Y: 18%) as a yellow solid. ESI-MS (M+H) ⁺ : 489.2.

Step 7. Synthesis of (6-(6-bromo-lH-indazol-l-yl)pyridin-2-yl)methanol

A mixture of 6-bromo-lH-indazole (79762-54-2) (3.2 g, 16.3 mmol, 1.0 eq), (6- bromopyridin-2-yl)methanol (33674-96-3) (3.66 g, 19.6 mmol, 1.2 eq), Cul (620 mg, 3.26 mmol, 0.2 eq), K ₃ PO ₄ (6.9 g, 32.6 mmol, 2.0 eq) and N,N'-Dimethyl-cyclohexane-l,2-diamine (61798- 24-1) (930 mg, 6.52 mmol, 0.4 eq) in 1,4-dioxane (50 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 (6-(6-bromo-lH-indazol-l-yl)pyridin-2-yl)methanol as a yellow solid. 2.42 g, Y: 49%. ESI-MS (M+H) ⁺ : 304.1.

Step 8. Synthesis of 6-bromo-l-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2 - yl)-lH-indazole

To a solution of (6-(6-bromo-lH-indazol-l-yl)pyridin-2-yl)methanol (2.42 g, 8.0 mmol, 1.0 eq) in DCM (50 mL) was added TBSC1 (1.8 g, 12.0 mmol, 1.5 eq), imidazole (1.09 g, 16.0 mmol, 2.0 eq). The mixture was stirred at rt for 2 h. After filtration, the filtrate was concentrated and purified by silica gel chromatography using PE/EA (5/1) as eluent to give 6-bromo-l-(6- (((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-lH-indaz ole. 2.73 g, as a white solid, Y:

82%. ESI-MS (M+H) ⁺ : 418.1.

Step 9. Synthesis of l-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazole

Y: 70%

A mixture of 6-bromo-l-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2 -yl)-lH- indazole (834 mg, 2.0 mmol, 1.0 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (73183-34-3) (610 mg, 2.4 mmol, 1.2 eq) and CH ₃ COOK (294 mg, 3.0 mmol, 1.5 eq) in 1,4- dioxane (20 mL) was stirred while purging N ₂ at rt for 10 min. To this system was added

Pd(dppf)Cl ₂ (180 mg, 0.2 mmol, 0.1 eq) and heated to 90 °C for 2 h. The mixture was diluted with EA (50 mL), washed with and brine (50 mL) and was dried over Na ₂ S0 ₄ . After filtration and concentration, the residue was purified by silica gel chromatography using PE/EA (5/1) as eluent to give l-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-( 4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-indazole. 651 mg, as a white solid, Y: 70%. ESI-MS (M+H) ⁺ : 466.2.

Step 10. Synthesis of (R)-N-((S)-(3-((tert- butyldimethylsily loxy)methyl)cyclobutyl) (6- ( 1 - (6- ((tert- butyldimethylsilyloxy)methyl)pyridin-2-yl)-lH-indazol-6-yl)p yridin-2-yl)methyl)-2- methylpropane-2-sulfinamide (P2)

To a reaction mixture of (R)-N-((S)-(6-bromopyridin-2-yl)(3-((tert- butyldimethylsilyloxy)methyl)cyclobutyl)methyl)-2-methylprop ane-2-sulfinamide (P2) (Step 6)

(235 mg, 0.48 mmol, 1.0 eq), l-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-( 4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazole (246 mg, 0.48 mmol, 1.0 eq) and K ₂ C0 ₃ (133 mg, 0.96 mmol, 2.0 eq) in dioxane (4 mL) and H ₂ 0 (0.3 mL) was added Pd(dppf)Cl ₂ (40 mg, 0.04 mmol, 0.1 eq). The reaction mixture was stirred at 110 °C for 2 h under N ₂ . After concentration, the residue was purified by silica gel chromatography with PE/EA (2/1) as eluent to give (R)-N-((S)-(3-((tert-butyldimethylsilyloxy)methyl)cyclobutyl )(6-(l-(6-((tert- butyldimethylsilyloxy)methyl)pyridin-2-yl)-lH-indazol-6-yl)p yridin-2-yl)methyl)-2- methylpropane-2- sulfanamide (P2) as yellow oil (163 mg, Y: 42%). ESI-MS (M+H) ⁺ : 748.4

Step 11. Synthesis of (S)-(6-(6-(6-(amino(3- (hydroxymethyl)cyclobutyl)methyl)pyridin-2-yl)-lH-indazol-l- yl)pyridin-2-yl)methanol (P2, H

To a solution of (R)-N-((S)-(3-((tert-butyldimethylsilyloxy)methyl)cyclobutyl )(6-(l-(6- ((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-lH-indazol -6-yl)pyridin-2-yl)methyl)-2- methylpropane-2-sulfinamide (P2) (165 mg, 0.22 mmol, 1.0 eq) in DCM (5 mL) was added HCl in dioxane (1 mL, 4M). The mixture was stirred at rt for 2 h. After filtration, 70 mg of (S)-(6-(6- (6-(amino(3-(hydroxymethyl)cyclobutyl)methyl)pyridin-2-yl)-l H-indazol-l-yl)pyridin-2- yl)methanol (P2, HCl) as a white solid was obtained. Y: 70%. ESI-MS (M+H) ⁺ : 416.2. HPLC: 100% 1H NMR (400 MHz, CD ₃ OD) δ: 9.60 (s, 1H), 8.35 (s, 1H), 8.13-7.94 (m, 6H), 7.47 (d, = 7.6 Hz, 1H), 7.40 (d, = 6.8 Hz, 1H), 4.93 (s, 2H), 4.50-4.47 (m, 1H), 3.50 (d, = 5.6 Hz, 2H), 2.83-2.77 (m, 1H), 2.44-2.31 (m, 2H), 1.96-1.78 (m, 3H).

Example 2 (R)-(6-(6-(6-(amino(3-(hydroxymethyl)cyclobutyl)methyl)pyrid in-2-yl)- lH-indazol-l-yl)pyridin-2-yl)methanol

Step 1. Synthesis of (R)-N-((R)-(3-((tert-butyldimethylsilyloxy)methyl)cyclobutyl )(6- (l-(6-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-lH-i ndazol-6-yl)pyridin-2- yl)methyl)-2-methylpropane-2-sulfinamide (P2)

The preparation of (R)-N-((R)-(3-((tert-butyldimethylsilyloxy)me

(6-((tert-butyldimethylsilyloxy)methyl)p

methylpropane-2-sulfinamide (P2) was similar to that of (R)-N-((S)-(3-((tert- butyldimethylsilyloxy)methyl)cyclobutyl)(6-(l-(6-((tert-buty ldimethylsilyloxy)methyl)pyridin-2- yl)-lH-indazol-6-yl)pyridin-2-yl)methyl)-2-methylpropane-2-s ulfinamide (P2) (Example 1, Step 10) to give 95 mg as yellow oil, Y: 52%. ESI-MS (M+H) ⁺ : 748.4.

Step 2. Synthesis of (R)-(6-(6-(6-(amino(3- (hydroxymethyl)cyclobutyl)methyl)pyridin-2-yl)-lH-indazol-l- yl)pyridin-2-yl)methanol (P2, H

The preparation of (R)-(6-(6-(6-(amino(3-(hydroxymethyl)cyclobutyl)methyl)pyrid in-2- yl)-lH-indazol-l-yl)pyridin-2-yl)methanol (P2, HC1) was similar to that of (S)-(6-(6-(6- (amino(3-(hydroxymethyl)cyclobutyl)methyl)pyridin-2-yl)-lH-i ndazol-l-yl)pyridin-2- yl)methanol (P2, HC1) (Example 1, Step 11) to give 20 mg as a yellow solid, Y: 35%. ESI-MS (M+H) ⁺ : 416.2. HPLC: 80% 1H NMR (400 MHz, CD ₃ OD) δ: 9.60 (s, 1H), 8.39 (s, 1H), 8.15- 8.00 (m, 6H), 7.49 (d, = 7.6 Hz, 1H), 7.44 (d, = 6.8 Hz, 1H), 4.92 (s, 2H), 4.50-4.48 (m, 1H), 3.51 (d, = 5.6 Hz, 2H), 2.84-2.78 (m, 1H), 2.46-2.30 (m, 2H), 1.98-1.79 (m, 3H).

Example 3 (S)-(6-(6-(6-(amino(3-(hydroxymethyl)cyclobutyl)methyl)pyrid in-2-yl)- lH-indazol-l-yl)pyridin-2-yl)methanol

Step 1. Synthesis of (R)-N-((S)-(6-bromopyridin-2-yl)(3-((tert- butyldimethylsilyloxy)methyl)cyclobutyl)methyl)-2-methylprop ane-2-sulfinamide (PI)

The preparation of (R)-N-((S)-(6-bromopyridin-2-yl)(3-((tert- butyldimethylsilyloxy)methyl)cyclobutyl)methyl)-2-methylprop ane-2-sulfinamide (PI) was similar to that of (R)-N-((S)-(6-bromopyridin-2-yl)(3-((tert- butyldimethylsilyloxy)methyl)cyclobutyl)methyl)-2-methylprop ane-2-sulfinamide (P2) and (R)- N-((R)-(6-bromopyridin-2-yl)(3-((tert-butyldimethylsilyloxy) methyl)cyclobutyl)methyl)- methylpropane-2-sulfinamide (P2) (Example 1, Step 6)to give 250 mg of the title compound as yellow oil, Y: 52%, and a smaller amount of (R)-N-((R)-(6-bromopyridin-2-yl)(3-((tert- butyldimethylsilyloxy)methyl)cyclobutyl)methyl)-2-methylprop ane-2-sulfinamide (PI). ESI-MS (M+H) ⁺ : 489.2.

Step 2. Synthesis of (R)-N-((S)-(3-((tert-butyldimethylsilyloxy)methyl)cyclobutyl )(6- (l-(6-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-lH-i ndazol-6-yl)pyridin-2- yl)methyl)-2-methylpropane-2-sulfinamide (PI)

The preparation of (R)-N-((S)-(3-((tert-butyldimethylsilyloxy)methyl)cyclobutyl )(6-(l- (6-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-lH-inda zol-6-yl)pyridin-2-yl)methyl)-2- methylpropane-2-sulfinamide (PI) was similar to that of (R)-N-((S)-(3-((tert- butyldimethylsilyloxy)methyl)cyclobutyl)(6-(l-(6-((tert-buty ldimethylsilyloxy)methyl)pyridin-2- yl)-lH-indazol-6-yl)pyridin-2-yl)methyl)-2-methylpropane-2-s ulfinamide (P2) (Example 1, Step 10) to give 200 mg as yellow oil. Y: 36%. ESI-MS (M+H) ⁺ : 748.4

Step 3. Synthesis of (S)-(6-(6-(6-(amino(3- (hydroxymethyl)cyclobutyl)methyl)pyridin-2-yl)-lH-indazol-l- yl)pyridin-2-yl)methanol

The preparation of (S)-(6-(6-(6-(amino(3-(hydroxymethyl)cyclobutyl)methyl)pyrid in-2- yl)-lH-indazol-l-yl)pyridin-2-yl)methanol (PI, HC1) was similar to that of (S)-(6-(6-(6- (amino(3-(hydroxymethyl)cyclobutyl)methyl)pyridin-2-yl)-lH-i ndazol-l-yl)pyridin-2- yl)methanol (P2, HC1) (Example 1, Step 11) to give 19 mg as a yellow solid. Y: 70%. ESI-MS (M+H) ⁺ : 416.2. HPLC: 100% 1H NMR (400 MHz, CD ₃ OD) δ: 9.56 (s, 1H), 8.38 (s, 1H), 8.14- 8.04 (m, 5H), 7.98 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.43 (d, J = 6.8 Hz, 1H), 4.91 (s, 2H), 4.63-4.60 (m, 1H), 3.60 (d, J = 6.8 Hz, 2H), 3.00-2.93 (m, 1H), 2.46-2.42 (m, 1H), 2.31- 2.26 (m, 1H), 2.19-2.10 (m, 2H), 1.82- 1.76 (m, 1H).

Example 4 czs-3-((S)-amino(6-(l-(6-(hydroxymethyl)pyridin-2-yl)- yl)pyridin-2-yl)methyl)cyclobutanol

Step 1. Synthesis of czs-methyl 3-hydroxycyclobutanecarboxylate

To a solution of methyl 3-oxocyclobutanecarboxylate (15 g, 117.2 mmol) in MeOH was added NaBH ₄ (6.7 g, 175.8 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 h. The solvent was removed and the residue was diluted with water (100 mL), extracted with EA (100 mL X 3). The combined organic layers were washed with brine (100 mL) and dried over Na ₂ S0 ₄ . After filtration and concentration, 12.5 g of czs-methyl 3 -hydro xycyclobutanecarboxy late was obtained as colorless oil, which was used in the next step without further purification. Y: 82%. ESI-MS (M+H) ⁺ : 131.1. 1H NMR (400 MHz, CDC1 ₃ ) S: 4.20-4.19 (m, 1H), 3.69 (s, 3H), 2.64-2.56 (m, 3H), 2.24-2.14 (m, 3H).

Step 2. Synthesis of (czs-methyl 3-(tert- butyldimethylsilyloxy)cyclobutanecarboxylate

Y: 77%

To a solution of czs-methyl 3-hydroxycyclobutanecarboxylate (12 g, 92.3 mmol) in DMF (150 mL) were added imidazole (12.6 g, 184.6 mmol) and TBSCI (16.6 g, 110.8 mmol). The mixture was stirred at rt for 16 h. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine, dried, evaporated and purified by silica gel chromatography with PE/EA (50/1) as eluent to give cis- methyl 3-(tert-butyldimethylsilyloxy)cyclobutanecarboxylate (17 g, Y: 77%) as colorless oil. ESI-MS (M+H) ⁺ : 245.1. 1H NMR (400 MHz, CDC1 ₃ ) S: 4.11-4.09 (m, 1H), 3.64 (s, 3H), 2.50- 2.42 (m, 3H), 2.18-2.14 (m, 2H), 0.84 (s, 9H), 0.05 (s, 6H). Step 3. Synthesis of (6-bromopyridin-2-yl)(cz ^' s- 3-(tert- butyldimethylsilyloxy)cyclobutyl)methanone

Y: 23%

To a solution of 2,6-dibromopyridine (8.3 g, 35 mmol, 1.0 eq) in dry ether (150 mL) at - 78 °C was added n-BuLi (2.5 M, 14 mL, 35 mmol, 1.0 eq) dropwise. The mixture was stirred at - 78 °C for 30 min and then czs-methyl 3-(tert-butyldimethylsilyloxy)cyclobutanecarboxylate (8.5 g, 35 mmol, 1.0 eq) was added. The mixture was stirred at this temperature for further 1.5 h, quenched with sat. NH ₄ C1, extracted with EA (50 mL x 3). The combined organic fractions were washed with brine, dried, evaporated and purified by silica gel chromatography with PE/EA (20/1) as eluent to give (6-bromopyridin-2-yl)(cz5-3-(tert- butyldimethylsilyloxy)cyclobutyl)methanone as colorless oil. 3.0 g, Y: 23%, ESI-MS (M+H) ⁺ : 370.1, 372.1. 1H NMR (400 MHz, CDC1 ₃ ) S: 8.01-7.99 (m, 1H), Ί .10-1.62 (m, 2H), 4.39-4.31 (m, 1H), 3.90-3.81 (m, 1H), 2.62-2.54 (m, 2H), 2.26-2.16 (m, 2H), 0.89 (s, 9H), 0.06 (s, 6H).

Step 4. Synthesis of (R)-N-((6-bromopyridin-2-yl)((czs- 3-(tert- butyldimethylsilyloxy)cyclobutyl)methylene)-2-methylpropane- 2-sulfinamide

To a solution of ( ?)-(+)-2-methyl-2-propanesulfinamide (1.18 g, 9.76 mmol, 1.2 eq) and (6-bromopyridin-2-yl)(cis-3-(tert-butyldimethylsilyloxy)cycl obutyl)methanone (3.0 g, 8.13 mmol, 1.0 eq) in THF (100 mL) was added Ti(OEt) ₄ (5.3 g, 16.26 mmol, 2.0 eq). The mixture was stirred at 60 °C for 16 h. After concentration, the residue was purified by silica gel chromatography with PE/EA (3/1) as eluent to afforded (R)-N-((6-bromopyridin-2-yl)(cz5-3- (tert-butyldimethylsilyloxy)cyclobutyl)methylene)-2-methylpr opane-2-sulfinamide (1.2 g, Y: 31%) as yellow oil and (R)-N-((6-bromopyridin-2-yl)(3-(tert- butyldimethylsilyloxy)cyclobutylidene)methyl)-2-methylpropan e-2-sulfinamide (900 mg, Y: 23%) as yellow oil. ESI-MS (M+H) ⁺ : 473.1, 475.1. 1H NMR (400 MHz, CDC1 ₃ ) S: 7.60-7.48 (m, 3H), 4.18-4.13 (m, 1H), 3.61-3.16 (m, 1H), 2.59-2.56 (m, 2H), 2.21-2.14 (m, 2H) , 1.27 (s, 9H) , 0.88 (s, 9H) , 0.04 (s, 6H). Step 5. Synthesis of (R)-N-((S)-(6-bromopyridin-2-yl)(cw-3-(tert- butyldimethylsilyloxy)cyclobutyl)methyl)-2-methylpropane-2-s ulfinamide and (R)-N-((R)- (6-bromopyridin-2-yl)(cw-3-(tert-butyldimethylsilyloxy)cyclo butyl)methyl)-2- methylpropane-2-sulfinamide

To a solution of (R)-N-((6-bromopyridin-2-yl)(cz5-3-(tert- butyldimethylsilyloxy)cyclobutyl)methylene)-2-methylpropane- 2-sulfinamide (1.2 g, 2.54 mmol, 1.0 eq) in dry THF (50 mL) was added L-Selectride (1.0 M in THF, 7.6 mL, 7.63 mmol, 3.0 eq) at -78 °C. Then the mixture was stirred at -78 °C for 2 h. The reaction was quenched with saturated NH ₄ C1 solution and dried over Na ₂ S0 ₄ . After filtration and concentration, the residue was purified by silica gel chromatography with PE/EA (5/1) as eluent to give (R)-N-((S)-(6- bromopyridin-2-yl)(cz5-3-(tert-butyldimethylsilyloxy)cyclobu tyl)methyl)-2-methylpropane-2- sulfinamide (550 mg, Y: 46%) as a white solid and (R)-N-((R)-(6-bromopyridin-2-yl)(cz5-3-(tert- butyldimethylsilyloxy)cyclobutyl)methyl)-2-methylpropane-2-s ulfinamide (380 mg, Y: 32%) as a white solid. ESI-MS (M+H) ⁺ : 475.1, 477.1.

(R)-N-((S)-(6-bromopyridin-2-yl)(cz5-3-(tert-butyldimethylsi lyloxy)cyclobutyl)methyl)- 2-methylpropane-2-sulfinamide: 1H NMR (400 MHz, CDC1 ₃ ) S: 7.49 (t, = 7.6 Hz, IH), 7.36 (dd, J = 8.0 Hz, 0.8 Hz, IH), 7.17 (dd, 7 = 8.0 Hz, 0.8 Hz, IH), 4.31-4.27 (m, IH), 4.10-4.03 (m, IH), 3.89-3.88 (m, IH), 2.59-2.50 (m, IH), 2.23-2.16 (m, IH), 2.09-2.04 (m, IH), 1.90-1.83 (m, IH), 1.73-1.62 (m, IH), 1.17 (s, 9H) , 0.86 (s, 9H), 0.02 (s, 6H).

(R)-N-((R)-(6-bromopyridin-2-yl)(cz5-3-(tert-butyldimethylsi lyloxy)cyclobutyl)methyl)- 2-methylpropane-2-sulfinamide: 1H NMR (400 MHz, CDC1 ₃ ) S: 7.50-7.46 (m, IH), 7.36-7.34 (m, IH), 7.19-7.17 (m, IH), 4.61-4.59 (m, IH), 4.31-4.17 (m, IH), 4.08-4.05 (m, IH), 2.39-2.31 (m, IH), 2.15-2.05 (m, 2H), 1.83-1.76 (m, 2H), 1.26 (s, 9H) , 0.87 (s, 9H) , 0.02 (s, 6H).

Step 6. Synthesis of (R)-N-((S)-(cw-3-(tert-butyldimethylsilyloxy)cyclobutyl)(6-( l-(6- ((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-lH-indazol -6-yl)pyridin-2-yl)methyl)-2- methylpropane-2-sulfinamide

Y: 76%

To a solution of (R)-N-((S)-(6-bromopyridin-2-yl)((cz5-3-(tert- butyldimethylsilyloxy)cyclobutyl)methyl)-2-methylpropane-2-s ulfinamide (220 mg, 0.46 mmol, 1.0 eq) and l-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-( 4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-indazole (Example 1, Step 9, 216 mg, 0.46 mmol, 1.0 eq) in 1,4- dioxane/H ₂ 0 (20/1, 21 mL) were added Pd(dppf)Cl ₂ DCM (38 mg, 0.046 mmol, 0.1 eq) and K ₂ C0 ₃ (192 mg, 1.39 mmol, 3.0 eq). The mixture was stirred at 110 °C under N ₂ for 2 h. After cooling to rt, the mixture was diluted with water (100 mL) and extracted with EA (30 mL x 3). The combined organic fractions were washed with brine, dried and evaporated. The residue was purified by pre-TLC (PE/EA=1/1) to give (R)-N-((S)-(cz ^' s-3-(tert- butyldimethylsilyloxy)cyclobutyl)(6-(l-(6-((tert-butyldimeth ylsilyloxy)methyl)pyridin-2-yl)-lH- indazol-6-yl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinam ide (260 mg, Y: 76%) as a white solid. ESI-MS (M+H) ⁺ : 734.4. 1H NMR (400 MHz, CDC1 ₃ ) S: 9.33 (s, 1H), 8.22 (s, 1H), 8.08- 8.06 (m, 1H), 7.93-7.84 (m, 3H), 7.79-7.74 (m, 2H), 7.41-7.39 (m, 1H), 7.20-7.17 (m, 1H), 4.97 (s, 2H), 4.44-4.40 (m, 1H), 4.29-4.27 (m, 1H), 4.12-4.05 (m, 1H), 2.65-2.59 (m, 1H), 2.32-2.26 (m, 1H), 2.14-2.05 (m, 1H), 1.98-1.92 (m, 1H), 1.84-1.77 (m, 1H), 1.17 (s, 9H), 0.99 (s, 9H), 0.86 (s, 9H) , 0.17 (s, 6H), 0.02 (s, 6H).

Step 7. Synthesis of cw-3-((S)-amino(6-(l-(6-(hydroxymethyl)pyridin-2-yl)-lH- indazo -6-yl)pyridin-2-yl)methyl)cyclobutanol (HC1)

To a solution of (R)-N-((S)-(cz5-3-(tert-butyldimethylsilyloxy)cyclobutyl)(6- (l-(6-((tert- butyldimethylsilyloxy)methyl)pyridin-2-yl)-lH-indazol-6-yl)p yridin-2-yl)methyl)-2- methylpropane-2-sulfinamide (260 mg, 0.355 mmol) in DCM (10 mL) was added HCl/dioxane (4 M, 1 mL) at rt. The mixture was stirred at rt for 1 h. The precipitate was filtered and washed with DCM, dried in vacuo to give cz5-3-((S)-amino(6-(l-(6-(hydroxymethyl)pyridin-2-yl)-lH- indazol-6-yl)pyridin-2-yl)methyl)cyclobutanol (HC1) (150 mg, Y: 97%) as a yellow solid. ESI- MS (M+H) ⁺ : 402.2, HPLC: 100%. 1H NMR (400 MHz, CD ₃ OD) δ: 9.75 (s, 1H), 8.35 (s, 1H), 8.15-8.09 (m, 2H), 8.03-7.96 (m, 4H), 7.45-7.38 (m, 2H), 4.94 (s, 2H), 4.49-4.47 (m, 1H), 4.16- 4.13 (m, 1H), 2.65-2.59 (m, 1H), 2.42-2.28 (m, 1H), 2.27-2.22 (m, 1H), 1.97-1.86 (m, 2H).

Example 5. (6-(6-(6-((R)-amino((cw-3-(tert- butyldimethylsilyloxy)cyclobutyl)methyl)pyridin-2-yl)-lH-ind azol-l-yl)pyridin-2- yl)methanol

Step 1. Synthesis of (R)-N-((R)-(cw-3-(tert-butyldimethylsilyloxy)cyclobutyl)(6-( l-(6- ((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-lH-indazol -6-yl)pyridin-2-yl)methyl)-2- methylpropane-2-sulfinamide

The preparation of (R)-N-((R)-(cz5-3-(tert-butyldimethylsilyloxy)cyclobutyl)(6- (l-(6- ((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-lH-indazol -6-yl)pyridin-2-yl)methyl)-2- methylpropane-2-sulfinamide was similar to that of (R)-N-((S)-(3-((tert- butyldimethylsilyloxy)methyl)cyclobutyl)(6-(l-(6-((tert-buty ldimethylsilyloxy)methyl)pyridin-2- yl)-lH-indazol-6-yl)pyridin-2-yl)methyl)-2-methylpropane-2-s ulfinamide (P2) (Example 1, Step 10) to give 110 mg as a white solid. Y: 37%. ESI-MS (M+H) ⁺ : 734.4. 1H NMR (400 MHz, CDC1 ₃ ) S: 9.29 (s, 1H), 8.22 (s, 1H), 8.02-8.00 (m, 1H), 7.93-7.83 (m, 3H), 7.79-7.74 (m, 2H), 7.41-7.39 (m, 1H), 7.22-7.20 (m, 1H), 5.26-5.25 (m, 1H), 4.96 (s, 2H), 4.41-4.37 (m, 1H), 4.13- 4.08 (m, 1H), 2.38-2.33 (m, 1H), 2.21-2.14 (m, 2H), 1.95-1.85 (m, 2H), 1.29 (s, 9H), 0.99 (s, 9H), 0.88 (s, 9H) , 0.17 (s, 6H), 0.02 (s, 6H). Step 2. Synthesis of (cis)-3-((R)-amino(6-(l-(6-(hydroxymethyl)pyridin-2-yl)-lH- indazol- -yl)pyridin-2-yl)methyl)cyclobutan-l-ol hydrochloride

The preparation of (6-(6-(6-((R)-amino(cz5-3-(tert- butyldimethylsilyloxy)cyclobutyl)methyl)^

(HCl) was similar to that of (S)-(6-(6-(6-(amino(3-(hydroxymethyl)cyclobutyl)methyl)pyrid in-2- yl)-lH-indazol-l-yl)pyridin-2-yl)methanol (P2, HCl) (Example 1, Step 11) to give 65 mg as a yellow solid. Y: 95%. ESI-MS (M+H) ⁺ : 402.2. 1H NMR (400 MHz, CD ₃ OD) δ: 9.75 (s, IH), 8.37-8.36 (m, IH), 8.16-8.10 (m, 2H), 8.04-7.97 (m, 4H), 7.45-7.38 (m, 2H), 4.94 (s, 2H), 4.49- 4.47 (m, IH), 4.18-4.11 (m, IH), 2.65-2.59 (m, IH), 2.42-2.28 (m, IH), 2.27-2.22 (m, IH), 1.97- 1.86 (m, 2H).

Example 6. trans-3-((S)-amino(6-(l-(6-(hydroxymethyl)pyridin-2-yl)-lH-i ndazol-6- yl)pyridin-2-yl)methyl)cyclobutanol

Step 1. Synthesis of trans-methyl 3-(tert- butyldimethylsilyloxy)cyclobutanecarboxylate

The preparation of trans-methyl 3-(tert-butyldimethylsilyloxy)cyclobutanecarboxylate was similar to that of methyl 3-((tert-butyldimethylsilyloxy)methyl)cyclobutanecarboxylate (Example 1, Step 3) to give 9.5 g as colorless oil, Y: 84%. ESI-MS (M+H) ⁺ : 245.1. 1H NMR (400 MHz, CDC1 ₃ ) S: 4.53-4.50 (m, IH), 3.69 (s, 3H), 2.98-2.93 (m, IH), 2.53-2.48 (m, 2H), 2.56-2.18 (m, 3H), 0.88 (s, 9H), 0.05 (s, 6H). Step 2. Synthesis of (6-bromopyridin-2-yl)(trans-3-(tert

butyldimethylsilyloxy)cyclobutyl)methanone

The preparation of (6-bromopyridin-2-yl)(iran5-3-(tert- butyldimethylsilyloxy)cyclobutyl)methanone was similar to that of (6-bromopyridin-2-yl)(3- ((tert-butyldimethylsilyloxy)methyl)cyclobutyl)methanone (Example 1, Step 4) to give 6.0 g as colorless oil, purity: 50%, Y: 20%. ESI-MS (M+H) ⁺ : 370.1.

Step 3. Synthesis of (R)-N-((6-bromopyridin-2-yl)(3-(tert- butyldimethylsilyloxy)cyclobutylidene)methyl)-2-methylpropan e-2-sulfinamide

The preparation of (R)-N-((6-bromopyridin-2-yl)(3-(tert- butyldimethylsilyloxy)cyclobutylidene)methyl)-2-methylpropan e-2-sulfinamide was similar to that of (R,E)-N-((6-bromopyridin-2-yl)(3-((tert- butyldimethylsilyloxy)methyl)cyclobutyl)methylene)-2-methylp ropane-2-sulfinamide (Example 1, Step 5) (PI and P2) to give 3.5 g as colorless oil, which was used in the Step 4 without further purification. Y: 91%. ESI-MS (M+H) ⁺ : 472.1, 474.1.

Step 4. Synthesis of (R)-N-((S)-(6-bromopyridin-2-yl)(trans-3-(tert- butyldimethylsilyloxy)cyclobutyl)methyl)-2-methylpropane-2-s ulfinamide and (R)-N-((R)- (6-bromopyridin-2-yl)(trans-3-(tert-butyldimethylsilyloxy)cy clobutyl)methyl)-2- methylpropane-2-sulfinamide

The preparation of (R)-N-((S)-(6-bromopyridin-2-yl)(/rans-3-(tert- butyldimethylsilyloxy)cyclobutyl)methyl)-2-methylpropane-2-s ulfinamide and (R)-N-((R)-(6- bromopyridin-2-yl)(iran5-3-(tert-butyldimethylsilyloxy)cyclo butyl)methyl)-2-methylpropane-2- sulfinamide was similar to that of (R)-N-((6-bromopyridin-2-yl)(3-((tert- butyldimethylsilyloxy)methyl)cyclobutyl)methylene)-2-methylp ropane-2-sulfinamide (PI and P2, Example 1, Step 6) The residue was purified by chiral-HPLC (column: AS-H; Co-Solvent: IPA; Rt: (R)-N-((S)-(6-bromopyridin-2-yl)(irans-3-(tert- butyldimethylsilyloxy)cyclobutyl)methyl)-2-methylpropane-2-s ulfinamide, 5.55 min, ((R)-N- ((S)-(6-bromopyridin-2-yl)(iran5-3-(tert-butyldimethylsilylo xy)cyclobutyl)methyl)-2- methylpropane-2-sulfinamide, 3.13 min) to give (R)-N-((S)-(6-bromopyridin-2-yl)(iran5-3-(tert- butyldimethylsilyloxy)cyclobutyl)methyl)-2-methylpropane-2-s ulfinamide (560 mg, Y: 16%) and ((R)-N-((R)-(6-bromopyridin-2-yl)(iran5-3-(tert-butyldimethy lsilyloxy)cyclobutyl)methyl)- 2-methylpropane-2-sulfinamide (150 mg, Y: 4%) as white solid. ESI-MS (M+H) ⁺ : 475.1, 477.1.

(R)-N-((S)-(6-bromopyridin-2-yl)(iran5-3-(tert- butyldimethylsilyloxy)cyclobutyl)methyl)-2-methylpropane-2-s ulfinamide: 1H NMR (400 MHz, CDCls) S: 7.51 (t, 7 = 7.6 Hz, 1H), 7.37 (dd, 7 = 7.6 Hz, 0.8 Hz, 1H), 7.20 (d, 7 = 7.6 Hz, 1H), 4.38-4.31 (m, 2H), 3.75-3.73 (m, 1H), 2.68-2.64 (m, 1H), 2.40-2.35 (m, 1H), 2.19-2.06 (m, 2H), 1.99- 1.95 (m, 1H), 1.16 (s, 9H) , 0.86 (s, 9H), 0.02 (s, 6H).

(R)-N-((R)-(6-bromopyridin-2-yl)(iran5-3-(tert- butyldimethylsilyloxy)cyclobutyl)methyl)-2-methylpropane-2-s ulfinamide: 1H NMR (400 MHz, CDCI ₃ ) S: 7.49 (t, 7 = 7.6 Hz, 1H), 7.35 (d, 7 = 7.6 Hz, 1H), 7.19 (d, 7 = 7.6 Hz, 1H), 4.34-4.31 (m, 1H), 4.23-4.20 (m, 1H), 2.64-2.59 (m, 1H), 2.31-2.26 (m, 1H), 2.08- 1.97 (m, 3H), 1.26 (s, 9H) , 0.85 (s, 9H) , 0.01 (s, 6H).

Step 5. Synthesis of (R)-N-((S)-(trans-3-(tert-butyldimethylsilyloxy)cyclobutyl)( 6-(l- (6-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-lH-inda zol-6-yl)pyridin-2-yl)methyl)- 2-methylpropane-2-sulfinamide

Y: 78%

The preparation of (R)-N-((S)-(iran5-3-(tert-butyldimethylsilyloxy)cyclobutyl)( 6-(l- (6-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)- lH-indazol-6-yl)pyridin-2-yl)methyl)-2- methylpropane-2-sulfinamide was similar to that of (R)-N-((S)-(3-((tert- butyldimethylsilyloxy)methyl)cyclobutyl)(6-(l-(6-((tert-buty ldimethylsilyloxy)methyl)pyridin-2- yl)- lH-indazol-6-yl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfi namide (P2) (Example 1, Step

10) to give 180 mg as a white solid. Y: 78%. ESI-MS (M+H) ⁺ : 734.4. 1H NMR (400 MHz,

CDCI ₃ ) S: 9.33 (s, 1H), 8.22 (s, 1H), 8.08-8.06 (m, 1H), 7.93-7.84 (m, 3H), 7.78-7.77 (m, 2H), 7.40 (d, J = 7.6 Hz, IH), 7.24-7.22 (m, IH), 4.96 (s, 2H), 4.53-4.49 (m, IH), 4.30-4.26 (m, IH), 4.14-4.07 (m, IH), 2.81-2.77 (m, IH), 2.49-2.44 (m, IH), 2.26-2.17 (m, 2H), 2.04- 1.98 (m, IH), 1.16 (s, 9H), 0.99 (s, 9H), 0.84 (s, 9H) , 0.17 (s, 6H), 0.02 (s, 6H).

Step 6. Synthesis of trans-3-((S)-amino(6-(l-(6-(hydroxymethyl)pyridin-2-yl)-lH- indazol- -yl)pyridin-2-yl)methyl)cyclobutanol (HC1)

The preparation of iran5-3-((S)-amino(6-(l-(6-(hydroxymethyl)pyridin-2-yl)- lH-indazol- 6-yl)pyridin-2-yl)methyl)cyclobutanol (HC1) was similar to that of (S)-(6-(6-(6-(amino(3- (hydroxymethyl)cyclobutyl)methyl)pyridin-2-yl)- lH-indazol- l-yl)pyridin-2-yl)methanol (P2, HC1) (Example 1, Step 11) to give 100 mg as a white solid. Y: 93%. ESI-MS (M+H) ⁺ : 402.2. 1H NMR (400 MHz, CO ₃ OO) S: 9.72 (s, IH), 8.35 (s, IH), 8.16-8.11 (m, 2H), 8.05-7.97 (m, 4H), 7.51-7.49 (m, IH), 7.42-7.409 (m, IH), 4.94 (s, 2H), 4.59-4.56 (m, IH), 4.33-4.27 (m, IH), 3.03- 2.96 (m, IH), 2.54-2.47 (m, IH), 2.39-2.24 (m, 2H), 2.04- 1.97 (m, IH).

Example 7. trans-3-((R)-amino(6-(l-(6-(hydroxymethyl)pyridin-2-yl)-lH-i ndazol- 6-yl)pyridin-2-yl)methyl)cyclobutanol

Step 1. Synthesis of (R)-N-((R)-(trans-3-(tert-butyldimethylsilyloxy)cyclobutyl)( 6-(l- (6-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-lH-inda zol-6-yl)pyridin-2-yl)methyl)- 2-methylpropane-2-sulfinamide

The preparation of (R)-N-((R)-((iran5-3-(tert-butyldimethylsilyloxy)cyclobutyl) (6-(l- (6-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)- lH-indazol-6-yl)pyridin-2-yl)methyl)-2- methylpropane-2-sulfinamide was similar to that of (R)-N-((S)-(3-((tert- butyldimethylsilyloxy)methyl)cyclobutyl)(6-(l-(6-((tert-buty ldimethylsilyloxy)methyl)pyridin-2- yl)- lH-indazol-6-yl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfi namide (P2) (Example 1, Step 10) to give 115 mg as a white solid. Y: 50%. ESI-MS (M+H) ⁺ : 734.4. 1H NMR (400 MHz, CDC1 ₃ ) S: 9.29 (s, 1H), 8.21 (s, 1H), 8.02-8.00 (m, 1H), 7.93-7.83 (m, 3H), 7.79-7.73 (m, 2H), 7.41-7.39 (m, 1H), 7.24-7.22 (m, 1H), 5.24-5.22 (m, 1H), 4.96 (s, 2H), 4.42-4.31 (m, 2H), 2.77- 2.70 (m, 1H), 2.37-2.31 (m, 1H), 2.24-2.19 (m, 1H), 2.12-2.01 (m, 2H), 1.28 (s, 9H), 0.99 (s, 9H), 0.85 (s, 9H) , 0.17 (s, 6H), 0.02 (s, 6H).

Step 2. Synthesis of trans-3-((R)-amino(6-(l-(6-(hydroxymethyl)pyridin-2-yl)-lH- indazol-6-yl)pyridin-2-yl)methyl)cyclobutanol (HC1)

The preparation of iran5-3-((R)-amino(6-(l-(6-(hydroxymethyl)pyridin-2-yl)- lH- indazol-6-yl)pyridin-2-yl)methyl)cyclobutanol (HC1) was similar to that of (S)-(6-(6-(6- (amino(3-(hydroxymethyl)cyclobutyl)methyl)pyridin-2-yl)- lH-indazol- l-yl)pyridin-2- yl)methanol (P2, HC1) (Example 1, Step 11) to give 65 mg as a yellow solid. Y: 95%. ESI-MS (M+H) ⁺ : 402.2. 1H NMR (400 MHz, CO ₃ OO) S: 9.75 (s, 1H), 8.35 (s, 1H), 8.15-8.10 (m, 2H), 8.04-7.96 (m, 4H), 7.50-7.48 (m, 1H), 7.40-7.38 (m, 1H), 4.92 (s, 2H), 4.57-4.55 (m, 1H), 4.29- 4.27 (m, 1H), 3.01-2.97 (m, 1H), 2.51-2.48 (m, 2H), 2.37-2.26 (m, 2H), 2.04-2.00 (m, 1H).

Example 8 (lR,3S)-3-((S)-amino(6-(l-(4-(hydroxymethyl)pyrimidin-2

indazol-6-yl)pyridin-2-yl)methyl)cyclobutanol

Step 1. methyl 2-(6-bromo-lH-indazol-l-yl)pyrimidine-4-carboxylate

To a solution of 6-bromo- lH-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) dissolved 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 0 (40 mL) and stirred at rt for 15 min. The precipitate was collected by filtration and dried to give methyl 2-(6-bromo-lH-indazol-l-yl)pyrimidine-4- carboxylate. 400 mg, as a yellow solid, Y: 59%. ESI-MS (M+H) ⁺ : 333.0.

Step 2. Synthesis of (2-(6-bromo-lH-indazol-l-yl)pyrimidin-4-yl)methanol

To a solution of methyl 2-(6-bromo-lH-indazol-l-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) dropwise at -78 °C. After stirring at -78 °C for 5 min, the reaction was quenched with sat. NH ₄ C1 solution. The mixture was filtrated and the filtrate was extracted with EA (30 mL x 3). The combined organic phases were dried and concentrated to give (2-(6-bromo-lH-indazol-l-yl)pyrimidin-4- yl)methanol. 110 mg, as a yellow solid, Y: 48%. ESI-MS (M+H) ⁺ : 305.0.

Step 3. Synthesis of 6-bromo-l-(4-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidin -2- yl)-lH-indazole

The preparation of 6-bromo-l-(4-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidin -2-yl)- lH-indazole was similar to that of methyl 3-((tert- butyldimethylsilyloxy)methyl)cyclobutanecarboxylate (Example 1, Step 3) to give 140 mg as a white solid, Y: 92%. ESI-MS (M+H) ⁺ : 419.1. 1H NMR (400 MHz, CDC1 ₃ ) S: 9.02 (s, 1H), 8.83 (d, = 5.2 Hz, 1H), 8.27 (s, 1H), 7.65 (d, = 8.4 Hz, 1H), 7.47-7.44 (m, 2H), 4.95 (s, 2H), 0.92 (s, 9H), 0.08 (s, 6H).

Step 4. Synthesis of l-(4-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)-6 - (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazole

Y: 77%

The preparation of l-(4-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)-6 -(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazole was similar to that of l-(6-(((tert- butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-(4,4,5,5-tetra methyl-l,3,2-dioxaboro lH-indazole (Example 1, Step 9) to give 120 mg as a brown solid, Y: 77%. ESI-MS (M+H) ⁺ : 467.2.

Step 5. Synthesis of (R)-N-((S)-((ls,3R)-3-(tert-butyldimethylsilyloxy)cyclobutyl )(6- (l-(4-((tert-butyldimethylsilyloxy)methyl)pyrimidin-2-yl)-lH -indazol-6-yl)pyridin-2- yl)methyl)-2-methylpropane-2-sulfinamide

a reaction mixture of (R)-N-((S)-(6-bromopyridin-2-yl)((ls,3R)-3-(tert- butyldimethylsilyloxy)cyclobutyl)methyl)-2-methylpropane-2-s ulfinamide (Example 4, Step 5) 60 mg, 0.12 mmol, 1.0 eq), l-(4-((tert-butyldimethylsilyloxy)methyl)pyrimidin-2-yl)-6-( 4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazole from previous step 65 mg, 0.14 mmol, 1.1 eq) and K ₂ CO ₃ (33 mg, 0.24 mmol, 2.0 eq) in dioxane (3 mL) and H ₂ 0 (0.3 mL) was added

Pd(dppf)Cl ₂ (10 mg, 0.01 mmol, 0.1 eq). The reaction mixture was stirred at 90 °C for 16 h under N ₂ . After cooling to rt, the reaction mixture was concentrated and the residue was purified by silica gel using PE/EA (2/1) as eluent to give (R)-N-((S)-((ls,3R)-3-(tert- butyldimethylsilyloxy)cyclobutyl)(6-(l-(4-((tert-butyldimeth ylsilyloxy)methyl)pyrimidin-2-yl)- lH-indazol-6-yl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfi namide as yellow oil (45 mg, Y: 48%). ESI-MS (M+H) ⁺ : 735.4.

Synthesis of (lR,3s)-3-((S)-amino(6-(l-(4-(hydroxymethyl)pyrimidin-2-yl)- lH- indazol-6-yl)pyridin-2-yl)methyl)cyclobutanol (TFA)

A solution of (R)-N-((S)-((ls,3R)-3-(tert-butyldimethylsilyloxy)cyclobutyl )(6-(l-(4- ((tert-butyldimethylsilyloxy)methyl)pyrimidin-2-yl)-lH-indaz ol-6-yl)pyridin-2-yl)methyl)-2- methylpropane-2-sulfinamide (45 mg, 0.06 mmol, 1.0 eq) in DCM (3 mL) was added HCI in dioxane (0.5 mL, 4M). The mixture was stirred at rt for 2 h. After filtration and concentration, the residue was purified by HPLC-preparation (0.05%TFA in H ₂ 0/CH ₃ CN = 0%- 100%) to give (lR,3s)-3-((S)-arnino(6-(l-(4-(hydroxymethyl)pyrimidin-2-yl) - lH-indazol-6-yl)pyridin-2- yl)methyl)cyclobutanol (TFA) (15 mg, Y: 64%) as a white solid. ESI-MS (M+H) ⁺ : 403.2.

HPLC: 100% 1H NMR (400 MHz, CD ₃ OD) δ: 9.56 (s, IH), 8.91 (s, IH), 8.52 (s, IH), 8.26 (d, 7 = 8.4 Hz, IH), 8.10 (d, 7 = 7.6 Hz, IH), 8.05-8.01 (m, 2H), 7.54 (s, IH), 7.47 (d, 7 = 7.6 Hz, IH), 4.94 (s, 2H), 4.52-4.50 (m, IH), 4.18-4.11 (m, IH), 2.66-2.59 (m, IH), 2.41-2.33 (m, IH), 2.30- 2.22 (m, IH), 1.98- 1.88 (m, 2H).

Example 9 cis 3-((S)-amino(6-(l-(6-(hydroxymethyl)pyrazin-2-yl)-lH-indazol -6- yl)pyridin-2-yl)methyl)cyclobutanol

Step 1. Synthesis of methyl 6-(6-bromo-lH-indazol-l-yl)pyrazine-2-carboxylate

40155-34-8 toluene, 110°C, 16 h

Y: 36%

The preparation of methyl 6-(6-bromo- lH-indazol- l-yl)pyrazine-2-carboxylate was similar to that of (6-(6-bromo- lH-indazol- l-yl)pyridin-2-yl)methanol (Example 1, Step 7) to give 1.1 g as a yellow solid, Y: 36%. ESI-MS (M+H) ⁺ : 333.0. 1H NMR (400 MHz, CDC1 ₃ ) S: 9.61 (s, IH), 9.21 (s, IH), 9.17 (s, IH), 8.28 (s, IH), 7.71 (d, 7 = 8.4 Hz, IH), 7.52 (dd, 7 = 8.4, 1.2 Hz, IH), 4.15 (s, 3H).

Step 2. Synthesis of (6-(6-bromo-lH-indazol-l-yl)pyrazin-2-yl)methanol

The preparation of (6-(6-bromo- lH-indazol- l-yl)pyrazin-2-yl)methanol was similar to that of (2-(6-bromo- lH-indazol- l-yl)pyrimidin-4-yl)methanol (Example 8, Step 2) to give 1.0 g as a yellow solid, Y: 82%. ESI-MS (M+H) ⁺ : 305.0. Step 3. Synthesis of 6-bromo-l-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyrazin-2 - yl)-lH-indazole

The preparation of 6-bromo- l-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyrazin-2-yl)- lH- indazole was similar to that of methyl 3-((tert- butyldimethylsilyloxy)methyl)cyclobutanecarboxylate (Example 1, Step 3) to give 830 mg as a yellow solid, Y: 60%. ESI-MS (M+H) ⁺ : 419.1. 1H NMR (400 MHz, CDC1 ₃ ) S: 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 l-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyrazin-2-yl)-6-

(4,4,5,5-tetrameth l-l,3,2-dioxaborolan-2-yl)-lH-indazole

90 °C, 16 h

Y: 82%

The preparation of l-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyrazin-2-yl)-6-( 4,4,5,5- tetramethyl- l,3,2-dioxaborolan-2-yl)- lH-indazole was similar to that of l-(6-(((tert- butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-(4,4,5,5-tetra methyl- l,3,2-dioxaborolan-2-yl)- lH-indazole (Example 1, 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)-(czs 3-(tert-butyldimethylsilyloxy)cyclobutyl)(6-(l-(6- ((tert-butyldimethylsilyloxy)methyl)pyrazin-2-yl)-lH-indazol -6-yl)pyridin-2-yl)methyl)-2- methylpropane-2-sulfinamide

Y: 57%

A mixture of l-(6-((tert-butyldimethylsilyloxy)methyl)pyrazin-2-yl)-6-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazole from in previous step 115 mg, 0.25 mmol, 1.0 eq), (R)-N-((S)-(6-bromopyridin-2-yl)((cz5-3-(tert-butyldimethyls ilyloxy)cyclobutyl)methyl)-2- methylpropane-2-sulfinamide (Example 4, Step 5) 120 mg, 0.25 mmol, 1.0 eq) and K ₂ CO ₃ (70 mg, 0.5 mmol, 2.0 eq) in 1, 4-dioxane/H ₂ 0 (4/1, 10 mL) was stirred while purging N ₂ at rt for 10 min. To this system was added Pd(dppf)Cl ₂ (25 mg, 0.03 mmol, 0.1 eq) and heated to 110 °C for 2 h. After concentrated, the mixture was purified by silica gel chromatography using PE/EA (2/1) as eluent to give (R)-N-((S)-(cz ^' s -3-(tert-butyldimethylsilyloxy)cyclobutyl)(6-(l-(6-((tert- butyldimethylsilyloxy)methyl)pyrazin-2-yl)-lH-indazol-6-yl)p yridin-2-yl)methyl)-2- methylpropane-2- sulfanamide as a yellow solid. 100 mg, Y: 57%, ESI-MS (M+H) ⁺ : 735.4.

Step 6. Synthesis of cis 3-((S)-amino(6-(l-(6-(hydroxymethyl)pyrazin-2-yl)-lH- indazol- -yl)pyridin-2-yl)methyl)cyclobutanol

To a solution of (R)-N-((S)-(cz5 -3-(tert-butyldimethylsilyloxy)cyclobutyl)(6-(l-(6-((tert- butyldimethylsilyloxy)methyl)pyrazin-2-yl)-lH-indazol-6-yl)p yridin-2-yl)methyl)-2- methylpropane-2-sulfinamide (100 mg, 0.14 mmol, 1.0 eq) in DCM (3 mL) was added

HCl/Dioxane (4 M, 0.5 mL, excess). The mixture was stirred at rt for 1 h. After concentration, the residue was dissolved in THF, adjusted pH =7-8 with NaHC0 ₃ solution and extracted with

EA (50 mL x2). The combined organic phase was washed with brine and dried over Na ₂ S0 ₄ .

After filtration and concentration, the residue was purified by prep-HPLC (CH ₃ CN/0.05% TFA in H ₂ 0 = 0%~100%) to give cis -3-((S)-amino(6-(l-(6-(hydroxymethyl)pyrazin-2-yl)-lH- indazol-6-yl)pyridin-2-yl)methyl)cyclobutanol as a yellow solid. 30 mg, Y: 43%, ESI-MS (M+H) ⁺ : 403.2. HPLC: 100%. 1H NMR (400 MHz, CD ₃ OD) δ: 9.62 (s, 1H), 9.24 (s, 1H), 8.54 (s, 1H), 8.39 (s, 1H), 8.17 (dd, 7 = 8.4, 0.8 Hz, 1H), 8.07-7.96 (m, 3H), 7.43 (d, 7 = 7.6 Hz, 1H), 4.93 (s, 2H), 4.47 (d, 7 = 9.6 Hz, 1H), 4.15-4.10 (m, 1H), 2.63-2.58 (m, 1H), 2.40-2.20 (m, 2H), 1.95-1.85 (m, 2H).

Example 10 (lR,3S)-3-((S)-amino(6-(l-(6-(trifluoromethyl)pyridin-2-yl)- lH- indazol-6-yl)pyridin-2-yl)methyl)cyclobutanol

Step 1. Synthesis of 6-bromo-l-(6-(trifluoromethyl)pyridin-2-yl)-lH-indazole

The preparation of 6-bromo-l-(6-(trifluoromethyl)pyridin-2-yl)-lH-indazole was similar to that of methyl 2-(6-bromo-lH-indazol-l-yl)pyrimidine-4-carboxylate (Example 8, Step 1). 600 mg, as a yellow solid, Y: 34 %. ESI-MS (M+H) ⁺ : 342.0.

Step 2. Synthesis of 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(6- (trifluoromethyl)pyridin-2-yl)-lH-indazole

dioxane, 90 °C, 2 h

Y: 73 %

The preparation of 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(6- (trifluoromethyl)pyridin-2-yl)-lH-indazole was the same as that of l-(6-(((tert- butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-(4,4,5,5-tetra methyl-l,3,2-dioxaborolan-2-yl)- lH-indazole (Example 1, Step 9). 500 mg, as a yellow solid, Y: 73 %. ESI-MS (M+H) ⁺ : 390.2. Step 3 Synthesis of (R)-N-((S)-(6-bromopyridin-2-yl)((ls,3R)-3- hydroxycyclobutyl)methyl)-2-methylpropane-2-sulfinamide

To a solution of (R)-N-((S)-(6-bromopyridin-2-yl)((ls,3R)-3-((tert- butyldimethylsilyl)oxy)cyclobutyl)methyl)-2-methylpropane-2- sulfinamide (example 4 step 5) (12 g, 25.3 mmol) in THF (200 ml) was added TBAF (6.6 g, 25.3 mmol, 1.0 eq) at rt. The mixture was stirred at rt for 2 h. The mixture was quenched with NaHC0 ₃ (aq.) and extracted with DCM (100 mL x 3). The organic s were washed with brine, dried, concentrated under reduced pressure. The residue was purified by silica gel chromatography with DCM/MeOH (40/1) to QCP-15087909-01 as a off-white solid (5.2 g; Y: 57%). ESI-MS (M+H) ⁺ : 361.1. 1H NMR (400 MHz, CDC1 ₃ ) S: 7.50 (t, = 7.6 Hz, 1H), 7.37(d, = 7.6 Hz, 1H), 7.17 (d, = 7.6 Hz, 1H), 4.34 (t, = 7.2 Hz, 1H), 4.15-4.08 (m, 2H), 2.57-2.51 (m, 1H), 2.32-2.22 (m, 3H), 1.89-1.77 (m, 1H), 1.19 (s, 9H). Step 4. Synthesis of (R)-N-((S)-((ls,3R)-3-hydroxycyclobutyl)(6-(l-(6-

(trifluoromethyl)pyridin-2-yl)-lH-indazol-6-yl)pyridin-2- yl)methyl)-2-methylpropane-2- sulfinamide

The preparation of (R)-N-((S)-((ls,3R)-3-hydroxycyclobutyl)(6-(l-(6- (trifluoromethyl)pyridin-2-yl)-lH-indazol-6-yl)pyridin-2-yl) methyl)-2-methylpropane-2- sulfinamide was similar to that of (R)-N-((S)-(cz5 3-(tert-butyldimethylsilyloxy)cyclobutyl)(6-(l- (6-((tert-butyldimethylsilyloxy)methyl)pyrazin-2-yl)-lH-inda zol-6-yl)pyridin-2-yl)methyl)-2- methylpropane-2- sulfinamide (Example 9, Step 5) to give 110 mg as a yellow solid. Y: 72%, ESI-MS (M+H) ⁺ : 544.2. Step 5. Synthesis of (lR,3s)-3-((S)-amino(6-(l-(6-(trifluoromethyl)pyridin-2-yl)- lH- indazol- -yl)pyridin-2-yl)methyl)cyclobutanol

The preparation of (lR,3s)-3-((S)-amino(6-(l-(6-(trifluoromethyl)pyridin-2-yl)- lH- indazol-6-yl)pyridin-2-yl)methyl)cyclobutanol was similar to that of cis 3-((S)-amino(6-(l-(6- (hydroxymethyl)pyrazin-2-yl)- lH-indazol-6-yl)pyridin-2-yl)methyl)cyclobutanol (Example 9, Step 6) to give 85 mg (HCI salt) as a yellow solid. Y: 88%, ESI-MS (M+H) ⁺ : 440.2. HPLC: 100%. 1H NMR (400 MHz, CD ₃ OD) δ: 9.54 (s, 1H), 8.41 (s, 1H), 8.37 (d, = 8.8 Hz, 1H), 8.25-8.20 (m, 2H), 8.05-7.99 (m, 3H), 7.72 (d, J = 7.6 Hz, 1H), 7.46 (dd, J = 6.8, 1.6 Hz, 1H), 4.46 (d, J = 9.6 Hz, 1H), 4.18-4.11 (m, 1H), 2.66-2.59 (m, 1H), 2.45-2.36 (m, 1H), 2.28-2.20 (m, 1H), 1.97- 1.85 (m, 2H).

Example 11 (lR,3S)-3-((S)-amino(6-(l-(4-ethylpyrimidin-2-yl)-lH-indazol -6- yl)pyridin-2-yl)methyl)cyclobutanol

Step 1. Synthesis of 6-bromo-l-(4-ethylpyrimidin-2-yl)-lH-indazole

Y: 91 %

To a solution of 6-bromo- lH-indazole (2.5 g, 12.7 mmol, 1.0 eq) in dry DMF (10 mL) was slowly added NaH (560 mg, 14.0 mmol, 1.1 eq) at rt. After stirring at rt for 10 min, 2- chloro-4-ethylpyrimidine (2.0 g, 14.0 mmol, 1.1 eq) was added to the mixture. Then the mixture was stirred at 130 °C for 4 h under N ₂ atmosphere. After cooling down to rt, the mixture was diluted with H ₂ 0 (50 mL) and stirred at rt for 10 min. The precipitate was collected by filtration and was purified by silica gel chromatography (PE/EA = 3/1) to give 6-bromo- l-(4- ethylpyrimidin-2-yl)- lH-indazole as a yellow solid. 3.5 g, Y: 91%. ESI-MS (M+H) ⁺ : 303.1. 1H NMR (400 MHz, CDC1 ₃ ) S: 9.06 (s, 1H), 8.69 (d, J = 5.2 Hz, 1H), 8.26 (s, 1H), 7.64 (d, / = 8.4 Hz, 1H), 7.42 (d, / = 8.0 Hz, 1H), 7.07 (d, / = 5.2 Hz, 1H), 2.96 (q, = 7.6 Hz, 2H), 1.43 (t, / = 7.6 Hz, 3H).

Step 2. Synthesis of l-(4-ethylpyrimidin-2-yl)-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-indazole

Y: 76%

A mixture of 6-bromo-l-(4-ethylpyrimidin-2-yl)-lH-indazole (170 mg, 0.56 mmol, 1.0 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (150 mg, 0.59 mmol, 1.05 eq) and CH ₃ COOK (110 mg, 1.12 mmol, 2.0 eq) in 1,4-dioxane (20 mL) was stirred while purging N ₂ at rt for 10 min. To this system was added Pd(dppf)Cl ₂ (51 mg, 0.06 mmol, 0.1 eq) and heated to 110 °C for 16 h. The mixture was diluted with EA (50 mL) and washed with brine (50 mL). The organic phase was dried (Na ₂ S0 ₄ ) and concentrated to give l-(4-ethylpyrimidin-2-yl)-6-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazole, which was used for Step 3 without further purification. 150 mg, as a brown solid, Y: 76%. ESI-MS (M+H) ⁺ : 351.2.

Step 3. Synthesis of (R)-N-((S)-(6-(l-(4-ethylpyrimidin-2-yl)-lH-indazol-6- yl)pyridin-2-yl)((ls,3R)-3-hydroxycyclobutyl)methyl)-2-methy lpropane-2-sulfinamide

Y: 35%

The preparation of (R)-N-((S)-(6-(l-(4-ethylpyrimidin-2-yl)-lH-indazol-6-yl)pyr idin-2- yl)((ls,3R)-3-hydroxycyclobutyl)methyl)-2-methylpropane-2-su lfinamide was similar to that of (R)-N-((S)-((ls,3R)-3-hydroxycyclobutyl)(6-(l-(6-(trifluorom ethyl)pyridin-2-yl)-lH-indazol-6- yl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (Example 10, Step 4) to give 50 mg as a yellow solid. Y: 35%, ESI-MS (M+H) ⁺ : 505.2. Step 4. Synthesis of (lR,3s)-3-((S)-amino(6-(l-(4-ethylpyrimidin-2-yl)-lH-indazol -6- yl)pyridin-2-yl)methyl)cyclobutanol

The preparation of (lR,3s)-3-((S)-amino(6-(l-(4-ethylpyrimidin-2-yl)- lH-indazol-6- yl)pyridin-2-yl)methyl)cyclobutanol was similar to that of cis 3-((S)-amino(6-(l-(6-

(hydroxymethyl)pyrazin-2-yl)- lH-indazol-6-yl)pyridin-2-yl)methyl)cyclobutanol (Example 9, Step 6) to give 20 mg as a yellow solid (TFA salt). Y: 50%, ESI-MS (M+H) ⁺ : 401.2, HPLC: 100%. 1H NMR (400 MHz, CD ₃ OD) δ: 9.45 (s, 1H), 8.75 (s, 1H), 8.44 (s, 1H), 8.22 (d, = 8.4 Hz, 1H), 8.05-7.98 (m, 3H), 7.45 (d, J = 6.4 Hz, 1H), 7.29 (s, 1H), 4.49 (d, J = 9.2 Hz, 1H), 4.18- 4.11 (m, 1H), 3.01 (q, = 7.6 Hz, 2H), 2.66-2.58 (m, 1H), 2.41-2.21 (m, 2H), 1.97- 1.87 (m, 2H), 1.52 (t, 7 = 7.6 Hz, 3H).

Example 12. (lR,3s)-3-((S)-amino(6-(l-(6-ethylpyridin-2-yl)-lH-indazol-6 - yl)pyridin-2-yl)methyl)cyclobutanol

Step 1. Synthesis of 2-bromo-6-ethylpyridine

5315-25-3 Y: 46%

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 CI (2 mL), diluted with water (50 mL) and extracted with EA (2 x 100 mL). The combined organic phase was washed with brine and dried over Na ₂ S0 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. Step 2. Synthesis of 6-bromo-l-(6-ethylpyridin-2-yl)-lH-indazole

The preparation of 6-bromo- l-(6-ethylpyridin-2-yl)-lH-indazole was similar to that of 6- bromo-l-(4-ethylpyrimidin-2-yl)-lH-indazole (Example 11, Step 1). The mixture of 6-bromo-l- (6-ethylpyridin-2-yl)-lH-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- l-(6-ethylpyridin-2-yl)-lH-indazole is more than that of 6-bromo- 2-(6-ethylpyridin-2-yl)-2H-indazole.

6-bromo- l-(6-ethylpyridin-2-yl)-lH-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.

Step 3. Synthesis of l-(6-ethylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-indazole

90 °C, 2 h

Y: 81 %

The preparation of l-(6-ethylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxabo rolan-2- yl)-lH- indazole was similar to that of l-(4-ethylpyrimidin-2-yl)-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-indazole (Example 11, Step 2). 216 mg, as a yellow solid, Y: 81%. ESI- MS (M+H) ⁺ : 350.2. Step 4. Synthesis of (R)-N-((S)-(6-(l-(6-ethylpyridin-2-yl)-lH-indazol-6-yl)pyrid in-2- yl)((ls, -3-hydroxycyclobutyl)methyl)-2-methylpropane-2-sulfinamide

Y: 75%

The preparation of (R)-N-((S)-(6-(l-(6-ethylpyridin-2-yl)- lH-indazol-6-yl)pyridin-2- yl)((ls,3R)-3-hydroxycyclobutyl)methyl)-2-methylpropane-2-su lfinamide was similar to that of (R)-N-((S)-((ls,3R)-3-hydroxycyclobutyl)(6-(l-(6-(trifluorom ethyl)pyridin-2-yl)- lH-indazol-6- yl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (Example 10, Step 4) to give 100 mg as a yellow solid, Y: 75%. ESI-MS (M+H) ⁺ : 504.2.

Step 5. Synthesis of (lR,3s)-3-((S)-amino(6-(l-(6-ethylpyridin-2-yl)-lH-indazol-6 - yl)pyridin-2-yl)methyl)cyclobutanol

The preparation of (lR,3s)-3-((S)-amino(6-(l-(6-ethylpyridin-2-yl)- lH-indazol-6- yl)pyridin-2-yl)methyl)cyclobutanol was similar to that of cis 3-((S)-amino(6-(l-(6- (hydroxymethyl)pyrazin-2-yl)- lH-indazol-6-yl)pyridin-2-yl)methyl)cyclobutanol (Example 9, Step 6) to give 35 mg as a white solid, Y: 56%. ESI-MS (M+H) ⁺ : 400.2. HPLC: 100%. 1H NMR (400 MHz, CD ₃ OD) δ: 9.63 (s, 1H), 8.30 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.94-7.84 (m, 5H), 7.34-7.31 (m, 1H), 7.17 (d, J = 6.4 Hz, 1H), 4.10-4.03 (m, 1H), 3.93 (d, 7 = 8.4 Hz, 1H), 3.00 (q, J = 7.6 Hz, 2H), 2.58-2.52 (m, 1H), 2.23-2.11 (m, 2H), 1.87- 1.74 (m, 2H), 1.52 (t, J = 8.0 Hz, 3H). Example 13 (lR,3s)-3-((S)-amino(6-(l-(4-(trifluoromethyl)pyrimidin-2-yl )-lH- indazol-6-yl)pyridin-2-yl)methyl)cyclobutanol

Step 1. Synthesis of 6-bromo-l-(4-(trifluoromethyl)pyrimidin-2-yl)-lH-indazole

The preparation of 6-bromo- l-(4-(trifluoromethyl)pyrimidin-2-yl)- lH-indazole was similar to that of 6-bromo- l-(4-ethylpyrimidin-2-yl)- lH-indazole (Example 11, Step 1) to give 400 mg as a yellow solid. Y: 58%. ESI-MS (M+H) ⁺ : 343.1. 1H NMR (400 MHz, CDC1 ₃ ) S: 9.10 (d, J = 4.8 Hz, 1H), 8.97 (s, 1H), 8.33 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.59-7.41 (m, 2H).

Step 2. Synthesis of 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(4- (trifluoromethyl)pyrimidin-2-yl)-lH-indazole

1 ,4-dioxane, 90 °C, 4 h

Y: 83%

The preparation of 6-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)- l-(4- (trifluoromethyl)pyrimidin-2-yl)- lH-indazole was similar to that of l-(4-ethylpyrimidin-2-yl)-6- (4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)- lH-indazole (Example 11, Step 2) to give 380 mg as a white solid. Y: 83%. ESI-MS (M+H) ⁺ : 391.2.

Step 3. Synthesis of (R)-N-((S)-((ls,3R)-3-hydroxycyclobutyl)(6-(l-(4- (trifluoromethyl)pyrimidin-2-yl)-lH-indazol-6-yl)pyridin-2-y l)methyl)-2-methylpropane-2- sulfinamide

To a solution of 6-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)- l-(4-

(trifluoromethyl)pyrimidin-2-yl)- lH-indazole (108 mg, 0.28 mmol, 1.0 eq) and (R)-N-((S)-(6- bromopyridin-2-yl)((ls,3R)-3-hydroxycyclobutyl)methyl)-2-met hylpropane-2-sulfinamide Example 10 step 3) 100 mg, 0.28 mmol, 1.0 eq) in l,4-dioxane/H ₂ 0 (10/1, 22 mL) were added

Pd(dppf)Cl ₂ DCM (23 mg, 0.028 mmol, 1.0 eq) and K ₂ C0 ₃ (115 mg, 0.83 mmol, 3.0 eq). The mixture was stirred at 110 °C under N ₂ for 16 h. After cooling to rt, diluted with water (100 mL) and extracted with EA (30 mL x 3). The combined organic fractions were washed with brine, dried and evaporated. The residue was purified by pre-TLC (DCM/MeOH = 30/1) to give (R)-N- ((S)-((ls,3R)-3-hydroxycyclobutyl)(6-(l-(4-(trifluoromethyl) pyrimidin-2-yl)- lH-indazol-6- yl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (40 mg, Y: 29%) as a yellow solid. ESI- MS (M+H) ⁺ : 545.2.

Step 4. Synthesis of (lR,3s)-3-((S)-amino(6-(l-(4-(trifluoromethyl)pyrimidin-2-yl )- lH-indazol-6-yl)pyridin-2-yl)methyl)cyclobutanol

To a solution of (R)-N-((S)-((ls,3R)-3-hydroxycyclobutyl)(6-(l-(4- (trifluoromethyl)pyrimidin-2-yl)- lH-indazol-6-yl)pyridin-2-yl)methyl)-2-methylpropane-2- sulfinamide (40 mg, 0.073 mmol, 1.0 eq) in DCM (10 mL) was added 4 M HCI/dioxane (2 mL, excess). The mixture was stirred at rt for 1 h. The precipitate was filtered and washed with DCM, dried in vacuo to give (lR,3s)-3-((S)-amino(6-(l-(4-(trifluoromethyl)pyrimidin-2-yl )- lH- indazol-6-yl)pyridin-2-yl)methyl)cyclobutanol (25 mg, Y: 71%) as a yellow solid. ESI-MS (M+H) ⁺ : 441.2. HPLC: 100%. 1H NMR (400 MHz, CO ₃ OO) S: 9.41 (s, 1H), 9.29-9.16 (m, 1H), 8.61-8.51 (m, 1H), 8.28 (d, J = 8.4 Hz, 1H), 8.04-8.03 (m, 3H), 7.83-7.77 (m, 1H), 7.50-7.45 (m, 1H), 4.49 (d, J = 9.2 Hz, 1H), 4.18-4.11 (m, 1H), 2.67-2.59 (m, 1H), 2.43-2.37 (m, 1H), 2.28- 2.21 (m, 1H), 1.98- 1.86 (m, 2H).

Example 14 cw-3-((S)-amino(6-(l-(6-(difluoromethyl)pyridin-2-yl)-lH-ind azol-6- yl)pyridin-2-yl)methyl)cyclobutanol

Step 2. Synthesis of 6-(6-bromo-lH-indazol-l-yl)picolinaldehyde

N,N'-Dimethyl-1 ,2-cyclohexanediamine (0.4 eq)

1 ,4-dioxane, 1 10 °C, 16 h

Y: 44% To a mixture of 6-bromo-lH-indazole (3 g, 15.3 mmol, 1.0 eq), 6-bromopicolinaldehyde (5.6 g, 30.6 mmol, 2.0 eq) and Ν,Ν'-Dimethyl- 1,2-cyclohexanediamine (852 mg, 6 mmol, 0.4 eq) in 1,4-dioxane (50 mL) were added Cul (570 mg, 3 mmol, 0.2 eq) and K ₃ PO ₄ (6.5 g, 30.6 mmol, 2.0 eq). The mixture was stirred at 110 °C for 16 h under N ₂ . After concentration, the residue was purified by silica gel chromatography with PE/EA (10/1) as eluent to give 6-(6-bromo-lH- indazol-l-yl)picolinaldehyde (2 g, Y: 44%) as a yellow solid. ESI-MS (M+H) ⁺ : 302.1.

Step 2. Synthesis of 6-bromo-l-(6-(difluoromethyl)pyridin-2-yl)-lH-indazole

To a solution of 6-(6-bromo-lH-indazol-l-yl)picolinaldehyde (2 g, 6.6 mmol, 1.0 eq) in DCM (30 mL) was slowly added DAST (3.2 g, 19.8 mmol, 3.0 eq) at -78 °C. The mixture was stirred from -78 °C to rt for 4 h. The reaction was quenched by pouring it into ice water and by washing the organic layer thoroughly with saturated sodium bicarbonate solution, followed by water. The solution was evaporated under reduced pressure to give 6-bromo-l-(6- (difluoromethyl)pyridin-2-yl)-lH-indazole (1.5 g, Y: 70%) as a brown solid. ESI-MS (M+H) ⁺ : 324.1.

Step 3. Synthesis of l-(6-(difluoromethyl)pyridin-2-yl)-6-(4,4,5,5-tetramethyl-l, 3,2- dioxaborolan-2-yl)-lH-indazole

Y: 59%

A mixture of 6-bromo-l-(6-(difluoromethyl)pyridin-2-yl)-lH-indazole (1.5 g, 4.6 mmol, 1.0 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.2 g, 4.9 mmol, 1.05 eq) and CH ₃ COOK (902 mg, 9.2 mmol, 2.0 eq) in 1,4-dioxane (20 mL) was stirred while purging N ₂ at rt for 10 min. To this system was added Pd(dppf)Cl ₂ (375 mg, 0.46 mmol, 0.1 eq) and heated to 110 °C for 16 h. After concentration, the residue was purified by silica gel chromatography with PE/EA (100/1) as eluent to give l-(6-(difluoromethyl)pyridin-2-yl)-6-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-lH-indazole (1 g, Y: 59%) as a yellow solid. ESI-MS (M+H) ⁺ : 372.1. 1H NMR (400 MHz, CDC1 ₃ ) S: 9.23 (s, 1H), 8.21 (s, 1H), 8.15 (d, = 8.0 Hz, 1H), 7.96 (t, = 8.0 Hz, 1H), 7.77 (d, / = 8.0 Hz, 1H), 7.71 (d, = 8.0 Hz, 1H), 7.49 (d, = 7.6 Hz, 1H), 6.93-6.65 (m, 1H), 1.40 (s, 12H).

Step 4. Synthesis of (R)-N-((S)-(6-(l-(6-(dinuoromethyl)pyridin-2-yl)-lH-indazol- 6- yl)pyridin-2-yl)(cw-3-hydroxycyclobutyl)methyl)-2-methylprop ane-2-sulfinamide

The preparation of (R)-N-((S)-(6-(l-(6-(difluoromethyl)pyridin-2-yl)-lH-indazol -6- yl)pyridin-2-yl)(cz5-3-hydroxycyclobutyl)methyl)-2-methylpro pane-2-sulfinamide was similar to that of (R)-N-((S)-((ls,3R)-3-hydroxycyclobutyl)(6-(l-(6-(trifluorom ethyl)pyridin-2-yl)-lH- indazol-6-yl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinam ide (Example 10, Step 4)to give 110 mg as a yellow solid, Y: 52%. ESI-MS (M+H) ⁺ : 526.2.

Step 5. Synthesis of cw-3-((S)-amino(6-(l-(6-(difluoromethyl)pyridin-2-yl)-lH- indazol- -yl)pyridin-2-yl)methyl)cyclobutanol

The preparation of cz5-3-((S)-amino(6-(l-(6-(difluoromethyl)pyridin-2-yl)-lH-in dazol-6- yl)pyridin-2-yl)methyl)cyclobutanol was similar to that of (lR,3s)-3-((S)-amino(6-(l-(4-

(trifluoromethyl)pyrimidin-2-yl)-lH-indazol-6-yl)pyridin- 2-yl)methyl)cyclobutanol (Example 13, Step 4) to give 39 mg as a white solid, Y: 44%. ESI-MS (M+H) ⁺ : 422.1. HPLC: 100%. 1H NMR (400 MHz, CD ₃ OD) δ: 9.63 (s, 1H), 8.34 (s, 1H), 8.22 (d, = 8.4 Hz, 1H), 8.11 (t, = 8.0 Hz, 1H), 8.06 (d, = 8.4 Hz, 1H), 7.95-7.89 (m, 3H), 7.55 (d, = 7.6 Hz, 1H), 7.33-7.31 (m, 1H), 7.08-6.80 (m, 1H), 4.11-4.04 (m, 1H), 3.95 (d, = 9.2 Hz, 1H), 2.59-2.55 (m, 1H), 2.24- 2.12 (m, 2H), 1.88-1.76 (m, 2H). Example 15 (lR,3s)-3-((S)-amino(6-(l-(6-ethylpyrazin-2-yl)-lH-indazol-6 - yl)pyridin-2-yl)methyl)cyclobutanol

Ste 1. Synthesis of 2-chloro-6-ethylpyrazine

To a solution of 2,6-dichloropyrazine (4.0 g, 27.0 mmol, 1.0 eq) and Iron acetylacetonate

(477 mg, 1.35 mmol, 0.05 eq) in THF/NMP (20 mL/2 mL) was slowly added EtMgBr (1.0 M in THF, 32.4 mL, 32.4 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 3 h. The mixture was quenched with H ₂ 0 (50 mL) and extracted with EA (50 mL x 3). The combined organic fractions were dried over Na ₂ S0 ₄ , filtrated and concentrated. The residue was purified by silica gel chromatography (PE/EA = 8/1) to give 2-chloro-6-ethylpyrazine (520 mg, Y: 14%) as brown oil. ESI-MS (M+H) ⁺ : 143.1. 1H NMR (400 MHz, CDC1 ₃ ) S: 8.43 (s, 1H), 8.37 (s, 1H), 2.84 (q, = 7.6 Hz, 2H), 1.34 (t, = 7.6 Hz, 3H).

Step 2. Synthesis of 6-bromo-l-(6-ethylpyrazin-2-yl)-lH-indazole

A mixture of 2-chloro-6-ethylpyrazine (520 mg, 3.7 mmol, 1.0 eq), 6-bromo- lH-indazole

(798 mg, 4.1 mmol, 1.1 eq) and NaH (164 mg, 4.1 mmol, 1.1 eq) in DMF (10 mL) was stirred while purging N ₂ at 120 °C for 2 h. The mixture was diluted with EA (100 mL) and washed with H ₂ 0 (50 mL x 3). The organic phase was dried over Na ₂ S0 ₄ . After filtration and concentration, the residue was purified by silica gel chromatography (PE/EA = 10/1) to give 6-bromo- l-(6- ethylpyrazin-2-yl)- lH-indazole (620 mg, Y: 56%) as a yellow solid. ESI-MS (M+H) ⁺ : 303.1. 1H NMR (400 MHz, CDC1 ₃ ) S: 9.20 (s, 1H), 9.03 (s, 1H), 8.34 (s, 1H), 8.20 (s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.43 (d, / = 8.4 Hz, 1H), 2.97 (q, J = 7.6 Hz, 2H), 1.48 (t, J = 7.6 Hz, 3H).

Step 3. Synthesis of l-(6-ethylpyrazin-2-yl)-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-indazole

A mixture of 6-bromo-l-(6-ethylpyrazin-2-yl)-lH-indazole (250 mg, 0.83 mmol, 1.0 eq),

4,4,4',4 ^, ,5,5,5 ^, ,5 ^, -octamethyl-2,2'-bi(l,3,2-dioxaborolane) (221 mg, 0.87 mmol, 1.05 eq) and CH ₃ COOK (122 mg, 1.25 mmol, 1.5 eq) in 1, 4-dioxane (30 mL) was stirred while purging N ₂ at rt for 10 min. To this system was added Pd(dppf)Cl ₂ (65 mg, 0.08 mmol, 0.1 eq) and heated to 90 °C for 16 h. After concentration, the residue was purified by silica gel chromatography

(PE/EA=10/1) to give l-(6-ethylpyrazin-2-yl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxabo rolan-2-yl)- lH-indazole (240 mg, Y: 83%) as a yellow solid. ESI-MS (M+H) ⁺ : 351.2.

Step 4. Synthesis of (R)-N-((S)-(6-(l-(6-ethylpyrazin-2-yl)-lH-indazol-6-yl)pyrid in-2- yl)((ls, -3-hydroxycyclobutyl)methyl)-2-methylpropane-2-sulfinamide

A mixture of l-(6-ethylpyrazin-2-yl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxabo rolan-2-yl)-lH- indazole (240 mg, 0.69 mmol, 1.0 eq), (R)-N-((S)-(6-bromopyridin-2-yl)((ls,3R)-3- hydroxycyclobutyl)methyl)-2-methylpropane-2-sulfinamide (Example 10, Step 3) 247 mg, 0.69 mmol, 1.0 eq) and K ₂ C0 ₃ (190 g, 1.38 mmol, 2.0 eq) in 1, 4-dioxane/H ₂ 0 (30 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, 0.07 mmol, 0.1 eq) and heated to 110 °C for 4 h. After concentration, the residue was purified by silica gel chromatography (EA) to give (R)-N-((S)-(6-(l-(6-ethylpyrazin-2-yl)-lH-indazol-6- yl)pyridin-2-yl)(( 1 s,3R)-3-hydroxycyclobutyl)methyl)-2-methylpropane-2-sulfinam ide (200 mg, Y: 58%) as a yellow solid. ESI-MS (M+H) ⁺ : 505.2.

Step 5. Synthesis of (lR,3s)-3-((S)-amino(6-(l-(6-ethylpyrazin-2-yl)-lH-indazol-6 - yl)pyridin-2-yl)methyl)cyclobutanol

To a solution of (R)-N-((S)-(6-(l-(6-ethylpyrazin-2-yl)-lH-indazol-6-yl)pyrid in-2- yl)((ls,3R)-3-hydroxycyclobutyl)methyl)-2-methylpropane-2-su lfinamide (200 mg, 0.4 mmol,

1.0 eq) in DCM (10 mL) was added HC1 in dioxane (1 mL, 4 M, excess). The mixture was stirred at rt for 30 min. After concentration, the residue was dissolved in THF, adjusted pH =7-8 with NaOH solution and extracted with EA (3 X 60 mL). The combined organic phase was washed with brine and dried over Na ₂ S04. After filtration and concentration, the residue was purified by prep-HPLC (CH ₃ CN/0.05% NH ₄ OH in H ₂ 0 = 0%- 100%) to give (lR,3s)-3-((S)- amino(6-(l-(6-ethylpyrazin-2-yl)- lH-indazol-6-yl)pyridin-2-yl)methyl)cyclobutanol (64 mg, Y: 40%) as a white solid. ESI-MS (M+H) ⁺ : 401.2. HPLC: 100%. 1H NMR (400 MHz, CD ₃ OD) δ: 9.53 (s, 1H), 9.17 (s, 1H), 8.38 (d, J = 4.0 Hz, 2H), 8.08 (d, J = 8.4 Hz, 1H), 7.97-7.87 (m, 3H), 7 ^' .37 '-7.35 (m, 1H), 4.11-4.04 (m, 1H), 3.99 (d, J = 8.4 Hz, 1H), 3.05 (q, = 7.6 Hz, 2H), 2.60- 2.53 (m, 1H), 2.24-2.13 (m, 2H), 1.89- 1.75 (m, 2H), 1.56 (t, = 7.6 Hz, 3H).

Example 16 (lR,3s)-3-((S)-amino(6-(l-(6-(fluoromethyl)pyridin-2-yl)-lH- indazol-6- yl)pyridin-2-yl)methyl)cyclobutanol

Step 1. Synthesis of 6-bromo-l-(6-(fluoromethyl)pyridin-2-yl)-lH-indazole

To a solution of (6-(6-bromo- lH-indazol- l-yl)pyridin-2-yl)methanol (Example 1, Step 7, 1.0 g, 3.3 mmol, 1.0 eq) in DCM (100 mL) was added DAST (1.6 g, 9.9 mmol, 3.0 eq) at -78°C. The mixture was warmed to rt and stirred for 2 h. After concentration, the residue was purified by silica gel chromatography using PE/EA (5/1) as eluent to give 6-bromo- l-(6- (fluoromethyl)pyridin-2-yl)- lH-indazole (640 mg, Y: 64%) as a yellow solid. ESI-MS (M+H) ⁺ : 306.0. 1H NMR (400 MHz, CDCL3) S: 8.99 (s, 1H), 8.15 (s, 1H), 7.98 (d, = 8.4 Hz, 1H), 7.89 (t, = 7.6 Hz, 1H), 7.62 (d, = 8.4 Hz, 1H), 7.39 (d, = 8.4 Hz, 1H), 7.33 (d, = 7.2 Hz, 1H), 5.60 (d, = 47.2 Hz, 2H).

Step 2. Synthesis of l-(6-(fluoromethyl)pyridin-2-yl)-6-(4,4,5,5-tetramethyl-l,3, 2- dioxaborolan-2- l -lH-indazole

A mixture of 6-bromo- l-(6-(fluoromethyl)pyridin-2-yl)- lH-indazole (320 mg, 1.05 mmol, 1.0 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (320 mg, 1.26 mmol,

1.2 eq) and CH ₃ COOK (155 mg, 1.58 mmol, 1.5 eq) in dioxane (6 mL) was stirred while purging

N ₂ at rt for 10 min. To this system was added Pd(dppf)Cl ₂ (82 mg, 0.1 mmol, 0.1 eq) and heated to 90 °C for 16 h. The mixture was diluted with EA (20 mL) and washed with brine (20 mL). The organic was dried over Na ₂ S04. After filtration and concentration, 260 mg of l-(6- (fluoromethyl)pyridin-2-yl)-6-(4,4,5,5-tetramethyl-l,3,2-dio xaborolan-2-yl)-lH-indazole as brown oil was obtained which was used for next step without further purification. Y: 70%. ESI- MS (M+H) ⁺ : 354.1.

Step 3. Synthesis of (R)-N-((S)-(6-(l-(6-(nuoromethyl)pyridin-2-yl)-lH-indazol-6- yl)pyridin-2-yl)((ls,3R)-3-hydroxycyclobutyl)methyl)-2-methy lpropane-2-sulfinamide

N _2, 1 ,4-dioxane/H ₂ 0, 110 °C, 16 h

Y:70%

A mixture of l-(6-(fluoromethyl)pyridin-2-yl)-6-(4,4,5,5-tetramethyl-l,3, 2-dioxaborolan- 2-yl)-lH-indazole (65 mg, 0.18 mmol, 1.0 eq), (R)-N-((S)-(6-bromopyridin-2-yl)((ls,3R)-3- hydroxycyclobutyl)methyl)-2-methylpropane-2-sulfinamide (Example 10, step 3, 65 mg, 0.18 mmol, 1.0 eq) and K ₂ C0 ₃ (50 mg, 0.36 mmol, 2.0 eq) in 1, 4-dioxane/H ₂ 0 (4/1, 5 mL) was stirred while purging N ₂ at rt for 10 min. To this system was added Pd(dppf)Cl ₂ (16 mg, 0.02 mmol, 0.1 eq) and heated to 110 °C for 2 h. The mixture was purified by silica gel

chromatography using PE/EA (1/1) as eluent to give (R)-N-((S)-(6-(l-(6-(fluoromethyl)pyridin- 2-yl)-lH-indazol-6-yl)pyridin-2-yl)((ls,3R)-3-hydroxycyclobu tyl)methyl)-2-methylpropane-2- sulfinamide as a yellow solid. 65 mg, Y: 70%. ESI-MS (M+H) ⁺ : 508.2.

Step 4. Synthesis of (lR,3s)-3-((S)-amino(6-(l-(6-(fluoromethyl)pyridin-2-yl)-lH- indazol-6-yl)pyridin-2-yl)methyl)cyclobutanol

a solution of (R)-N-((S)-(6-(l-(6-(fluoromethyl)pyridin-2-yl)-lH-indazol-6 -yl)pyridin-2- yl)((ls,3R)-3-hydroxycyclobutyl)methyl)-2-methylpropane-2-su lfinamide (65 mg, 0.13 mmol, 1.0 eq) in DCM (5 mL) was added HCl in dioxane (0.4 mL, excess). The mixture was stirred at rt for 30 min. The solvent was removed in vacuo. The residue was dissolved in THF, adjusted pH =7-8 with NaOH solution and extracted with EA (100 mL x 2). The combined organic phase was washed with brine and dried over Na2S04. After filtration and concentration, the residue was purified by prep-HPLC (CH ₃ CN/0.05% NH ₄ OH in H ₂ 0 = 0%-100%) to give (lR,3s)-3-((S)- amino(6-(l-(6-(fluoromethyl)pyridin-2-yl)-lH-indazol-6-yl)py ridin-2-yl)methyl)cyclobutanol as a yellow solid. 9 mg, Y: 18%, ESI-MS (M+H) ⁺ : 404.1. HPLC: 100%. 1H NMR (400 MHz, CD ₃ OD) S: 9.57 (s, 1H), 8.30 (s, 1H), 8.05-7.97 (m, 3H), 7.92-7.85 (m, 3H), 7.37 (d, J = 6.8 Hz, 1H), 7.31 (t, J = 4.0 Hz, 1H), 5.61 (d, J = 47.2 Hz, 1H), 4.08-4.04 (m, 1H), 3.93 (d, / = 8.4 Hz, 1H), 2.55-2.53 (m, 1H), 2.21-2.13 (m, 2H), 1.84-1.76 (m, 2H).

Example 17 cw-3-((S)-amino(6-(l-(6-(hydroxymethyl)pyridin-2-yl)-lH-inda zol-6- yl)pyrazin-2-yl)methyl)cyclobutanol

Step 1. Synthesis of (czs-3-(tert-butyldimethylsilyloxy)cyclobutyl)methanol

LiAIH ₄ (1 .2 eq)

ether, 0 °C, 2 h

Y: 52%

To a solution of czs-methyl 3-(tert-butyldimethylsilyloxy)cyclobutanecarboxylate

(Example 4, Step 2, 98 g, 0.402 mol) in ether (100 mL) was added a suspension of L1AIH ₄ (18.3 g, 0.482 mol, 1.2 eq) in dry ether (500 mL) dropwise at 0 °C. The mixture solution was stirred at 0 °C for 2 h, then quenched with H ₂ 0 (18 mL), 15% NaOH (18 mL) and H ₂ 0 (55 mL), then dried over Na ₂ S0 ₄ . The solution was filtered and concentrated in vacuo to give (cis- 3- (tert- butyldimethylsilyloxy)cyclobutyl)methanol (45 g, Y: 52%) as colorless oil. ESI-MS (M+H) ⁺ : 217.2. 1H NMR (400 MHz, CDC1 ₃ ) S: 4.16-4.10 (m, 1H), 3.59 (t, J = 5.6 Hz, 2H), 2.37-2.30 (m, 2H), 1.95-1.91 (m, 1H), 1.69-1.62 (m, 2H), 1.43-1.41 (m, 1H), 0.88 (s, 9H) , 0.04 (s, 6H).

Step 2. Synthesis of czs-3-(tert-butyldimethylsilyloxy)cyclobutanecarbaldehyde

To a solution of (cz5-3-(tert-butyldimethylsilyloxy)cyclobutyl)methanol (60 g, 0.278 mol) in DCM (500 mL) was added Dess-Martin periodane (236 g, 0.556 mol, 2.0 eq) at 0° C. The mixture was stirred at rt under nitrogen for 4 h. The mixture was washed with brine, dried over Na ₂ S0 ₄ , filtered, and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography with PE/EA (10/1) to give czs- 3- (tert- butyldimethylsilyloxy)cyclobutanecarbaldehyde as colorless oil (38 g, Y: 60%). ESI-MS (M+H) ⁺ : 215.2. 1H NMR (400 MHz, CDC1 ₃ ) S: 9.64 (d, = 2.8 Hz, 1H), 4.30-4.23 (m, 1H), 2.64-2.55 (m, 1H), 2.46-2.41 (m, 2H), 2.19-2.11 (m, 2H), 0.89 (s, 9H), 0.06 (s, 6H).

Step 3. Synthesis of (R)-N-((cis-3-(tert-butyldimethylsilyloxy)cyclobutyl)methyle ne)- 2-methylpropane-2-sulfinamide

To a solution of cz5-3-(tert-butyldimethylsilyloxy)cyclobutanecarbaldehyde (27 g, 0.126 mol) in THF (300 mL) were added (7?)-2-methylpropane-2-sulfinamide (18.3 g, 0.151 mol, 1.2 eq) and Ti(OEt) ₄ (58 g, 0.252 mol, 2.0 eq) at rt. The mixture was stirred at 60 °C for 16 h. The residue was purified by silica gel chromatography with PE/EA (5/1) to give (R)-N-((cz5-3-(tert- butyldimethylsilyloxy)cyclobutyl)methylene)-2-methylpropane- 2-sulfinamide as colorless oil. 27.5 g; Y: 69%. ESI-MS (M+H) ⁺ : 318.2. 1H NMR (400 MHz, CDC1 ₃ ) S: 8.05 (d, = 4.8 Hz, 1H), 4.28-4.24 (m, 1H), 2.82-2.80 (m, 1H), 2.56-2.49 (m, 2H), 2.14-2.08 (m, 2H), 1.20 (s, 9H) , 0.89 (s, 9H) , 0.05 (s, 6H).

Step 4. Synthesis of (R)-N-((S)-(6-bromopyrazin-2-yl)(cis-3-(tert- butyldimethylsilyloxy)cyclobutyl)methyl)-2-methylpropane-2-s ulfinamide

To a solution of 2,6-dibromopyrazine (750 mg, 3.18 mmol, 2.0 eq) in dry Et ₂ 0 (50 mL) was added n-BuLi (2.5 M, 1.3 mL, 3.18 mmol, 2.0 eq) at -78 °C. The mixture was stirred at -78 °C for 30 min. Then (R)-N-((cis-3-(tert-butyldimethylsilyloxy)cyclobutyl)methyle ne)-2- methylpropane-2-sulfinamide (507 mg, 1.60 mmol, 1.0 eq) was added into the mixture and the mixture was stirred for another 1 h at -78 °C. The reaction was quenched with H ₂ 0 (20 mL) and extracted with EA (50 mL x 2). The combined organic phase was washed with brine and dried over Na ₂ S0 ₄ . After filtration and concentration, the residue was purified by silica gel chromatography using PE/EA (1/1) as eluent to give (R)-N-((S)-(6-bromopyrazin-2-yl)(cis-3- (tert-butyldimethylsilyloxy)cyclobutyl)methyl)-2-methylpropa ne-2-sulfinamide as yellow oil. 280 mg, Y: 37%. ESI-MS (M+H) ⁺ : 476.1. Step 5. Synthesis of (R)-N-((S)-(czs -3-(tert-butyldimethylsilyloxy)cyclobutyl)(6-(l-(6- ((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-lH-indazol -6-yl)pyrazin-2-yl)methyl)-2- methylpropane-2-sulfinamide

The preparation of (R)-N-((S)-(cz5-3-(tert-butyldimethylsilyloxy)cyclobutyl)(6- (l-(6- ((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-lH-indazol -6-yl)pyrazin-2-yl)methyl)-2- methylpropane-2-sulfinamide was similar to that of (R)-N-((S)-(6-(l-(6-(fluoromethyl)pyridin-2- yl)-lH-indazol-6-yl)pyridin-2-yl)((ls,3R)-3-hydroxycyclobuty l)methyl)-2-methylpropane-2- sulfinamide (Example 16, Step 3) to give 170 mg as a yellow solid, Y: 48%. ESI-MS (M+H) ⁺ : 735.4.

Step 6. Synthesis of cw-3-((S)-amino(6-(l-(6-(hydroxymethyl)pyridin-2-yl)-lH- indazol- -yl)pyrazin-2-yl)methyl)cyclobutanol

The preparation of cz5-3-((S)-amino(6-(l-(6-(hydroxymethyl)pyridin-2-yl)-lH-ind azol-6- yl)pyrazin-2-yl)methyl)cyclobutanol was similar to that of (lR,3s)-3-((S)-amino(6-(l-(6- (fluoromethyl)pyridin-2-yl)- lH-indazol-6-yl)pyridin-2-yl)methyl)cyclobutanol (Example 16, Step 4) to give 80 mg as a yellow solid, Y: 86%, ESI-MS (M+H) ⁺ : 403.2. HPLC: 100%. 1H NMR (400 MHz, CD ₃ OD) δ: 9.63-9.60 (m, IH), 9.07-9.06 (m, IH), 8.54 (s, IH), 8.27-8.25 (m, IH), 8.02-8.00 (m, IH), 7.91-7.87 (m, 3H), 7.37-7.36 (m, IH), 4.84 (s, 2H), 4.13-4.02 (m, 2H), 2.62-2.54 (m, IH), 2.27-2.13 (m, 2H), 1.90-1.75 (m, 2H). Example 18 cw-3-((S)-amino(6-(l-(6-(fluoromethyl)pyridin-2-yl)-lH-indaz ol-6- yl)pyrazin-2-yl)methyl)cyclobutanol

Step 1. Synthesis of (R)-N-((S)-(cw-3-(tert-butyldimethylsilyloxy)cyclobutyl)(6-( l-(6-

(fluoromethyl)pyridin-2-yl)-lH-indazol-6-yl)pyrazin-2-yl) methyl)-2-methylpropane-2- sulfinamide (containing

A mixture of l-(6-(fluoromethyl)pyridin-2-yl)-6-(4,4,5,5-tetramethy 1-1,3, 2-dioxaborolan- 2-yl)-lH-indazole (Example 16, Step 2, 150 mg, 0.42 mmol, 1.0 eq), (R)-N-((S)-(6- bromopyrazin-2-yl)(cis-3-(tert-butyldimethylsilyloxy)cyclobu tyl)methyl)-2-methylpropane-2- sulfinamide (Example 17, Step 4, 240 mg, 0.51 mmol, 1.0 eq) and K ₂ CO ₃ (116 mg, 0.84 mmol, 2.0 eq) in l,4-dioxane/H ₂ 0 (4/1, 10 mL) was stirred while purging N ₂ at rt for 10 min. To this system was added Pd(dppf)Cl ₂ (77 mg, 0.04 mmol, 0.1 eq) and heated to 90 °C for 16 h under N ₂ atmosphere. After concentration, the residue was purified by silica gel chromatography using PE/EA (2/1) as eluent to give (R)-N-((S)-(cz5-3-(tert-butyldimethylsilyloxy)cyclobutyl)(6- (l-(6- (fluoromethyl)pyridin-2-yl)-lH-indazol-6-yl)pyrazin-2-yl)met hyl)-2-methylpropane-2- sulfinamide (containing 15% trans isomer). 166 mg, as a yellow solid, Y: 63%. ESI-MS (M+H) ⁺ : 623.2.

Step 2. Synthesis of cw-3-((S)-amino(6-(l-(6-(fluoromethyl)pyridin-2-yl)-lH-indaz ol- -yl)pyrazin-2-yl)methyl)cyclobutanol

containing 15% trans isomer

To a solution of (R)-N-((S)-(cz5-3-(tert-butyldimethylsilyloxy)cyclobutyl)(6- (l-(6- (fluoromethyl)pyridin-2-yl)-lH-indazol-6-yl)pyrazin-2-yl)met hyl)-2-methylpropane-2- sulfinamide (containing 15% trans isomer) (166 mg, 0.27 mmol, 1.0 eq) in DCM (5 mL) was added slowly HCl/l,4-dioxane (4 M, 0.5 mL, excess). Then the mixture was stirred at rt for 20 min. After filtration, the residue was purified by prep-HPLC (CH ₃ CN/0.05% TFA in H ₂ 0 = 0%~100%) and prep-chiral HPLC to give cz5-3-((S)-amino(6-(l-(6-(fluoromethyl)pyridin-2-yl)- lH-indazol-6-yl)pyrazin-2-yl)methyl)cyclobutanol. 21 mg, as a yellow solid, Y: 19%. ESI-MS (M+H) ⁺ : 405.2. HPLC: 100%.

Preparative-SFC conditions Instrument: Gilson-281, Column: WHELK, Mobile phase: Hexane (0.1% DEA)/Ethanol (0.1% DEA) = 80/20, Flow rate: 50 mL/min, Detection

wavelength: 214&254 nm, Cycle time: 32 min, Sample solution: 80 mg dissolved in 5 mL Methanol, Injection volume: 0.5 mL

1H NMR (400 MHz, CD ₃ OD) δ: 9.63 (s, 1H), 9.28 (s, 1H), 8.68 (s, 1H), 8.36 (s, 1H),

8.15 (d, 7 = 8.4 Hz, 1H), 8.07-7.99 (m, 3H), 7.40 (d, 7 = 6.8 Hz, 1H), 5.65 (d, 7 = 44.0 Hz, 2H), 4.62 (d, 7 = 9.6 Hz, 1H), 4.14 (t, 7 = 7.6 Hz, 1H), 2.64-2.60 (m, 1H), 2.41-2.24 (m, 2H), 2.01- 1.86 (m, 2H). Example 19 cw-3-((S)-amino(6-(l-(6-(trifluoromethyl)pyridin-2-yl)-lH-in dazol-6- yl)pyrazin-2-yl)methyl)cyclobutanol

Step 1. Synthesis of (R)-N-((S)-(cw-3-(tert-butyldimethylsilyloxy)cyclobutyl)(6-( l-(6- (trifluoromethyl)pyridin-2-yl)-lH-indazol-6-yl)pyrazin-2-yl) methyl)-2-methylpropane-2- sulfinamide (containing 15% trans isomer)

The preparation of (R)-N-((S)-(cz5-3-(tert-butyldimethylsilyloxy)cyclobutyl)(6- (l-(6- (trifluoromethyl)pyridin-2-yl)-lH-indazol-6-yl)pyrazin-2-yl) methyl)-2-methylpropane-2- sulfinamide (containing 15% trans isomer) was similar to that of (R)-N-((S)-(cz5-3-(tert- butyldimethylsilyloxy)cyclobutyl)(6-(l-(6-(fluoromethyl)pyri din-2-yl)-lH-indazol-6-yl)pyrazin- 2-yl)methyl)-2-methylpropane-2-sulfinamide (Example 18, Step 1) (containing 15% trans isomer) to give 112 mg as yellow oil, Y: 47%. ESI-MS (M+H) ⁺ : 659.3. Step 2. Synthesis of cw-3-((S)-amino(6-(l-(6-(trifluoromethyl)pyridin-2-yl)-lH- indazo -6-yl)pyrazin-2-yl)methyl)cyclobutanol

containing 15% trans isomer

The preparation of cz5-3-((S)-amino(6-(l-(6-(trifluoromethyl)pyridin-2-yl)-lH-i ndazol-6- yl)pyrazin-2-yl)methyl)cyclobutanol was similar to that of cz ^' 5-3-((S)-amino(6-(l-(6-

(fluoromethyl)pyridin-2-yl)- lH-indazol-6-yl)pyrazin-2-yl)methyl)cyclobutanol (Example 18, Step 2) and purified by prep-chiral HPLC to give 15 mg as a yellow solid, Y: 20%. ESI-MS (M+H) ⁺ : 441.2.

Preparative-SFC conditions Instrument: Gilson-281, Column: CE-3, Mobile Phase: n- Hexane (0.1% DEA)/EtOH (0.1% DEA) = 80/20, Flow rate: 50 mL/min, Wavelength: 214 & 254 nm

Example 20 l-(6-(6-(6-((S)-amino(cis-3-hydroxycyclobutyl)methyl)pyridin -2-yl)-lH- indazol-l-yl)pyridin-2-yl)cyclopropanecarbonitrile

Step 1. Synthesis of l-(6-(6-bromo-lH-indazol-l-yl)pyridin-2- yl)cyclopropanecarbonitrile

N,N'-Dimethyl-1 ,2-cyclohexanediamine (0.4 eq)

1 ,4-dioxane, 1 10 °C, 16 h

Y: 50%

A mixture of l-(6-bromopyridin-2-yl)cyclopropanecarbonitrile (300 mg, 1.35 mmol, 1.0 eq), 6-bromo-lH-indazole (263 mg, 1.35 mmol, 1.0 eq), K ₃ PO ₄ (572 mg, 2.7 mmol, 2.0 eq), CuBr (39 mg, 0.27 mmol, 0.2 eq) and N,N'-Dimethyl-l,2-cyclohexanediamine (48 mg, 0.54 mmol, 0.4 eq ) in 1,4-dioxane (20 mL) was stirred at 110 °C for 16 h under N ₂ atmosphere. After concentration, the residue was purified by silica gel chromatography using PE/EA (5/1) as eluent to give l-(6-(6-bromo-lH-indazol-l-yl)pyridin-2-yl)cyclopropanecarbo nitrile. 230 mg, as a yellow solid, Y: 50%. ESI-MS (M+H) ⁺ : 339.0 Step 2. Synthesis of l-(6-(6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- indazol- -yl)pyridin-2-yl)cyclopropanecarbonitrile

Y: 67%

A mixture of l-(6-(6-bromo-lH-indazol-l-yl)pyridin-2-yl)cyclopropanecarbo nitrile (230 mg, 0.68 mmol, 1.0 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (207 mg, 0.82 mmol, 1.2 eq) and KOAc (133 mg, 1.36 mmol, 2.0 eq) in 1,4-dioxane (20 mL) was stirred while purging N ₂ at rt for 10 min. To this system was added Pd(dppf)Cl ₂ (62 mg, 0.068 mmol, 0.1 eq) and heated to 110 °C for 2 h. The mixture was diluted with EtOAc (50 mL) and washed with H ₂ 0 (50 mL) and brine (50 mL). The organic was dried (Na ₂ S0 ₄ ) and concentrated in vacuo to give l-(6-(6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-ind azol-l-yl)pyridin-2- yl)cyclopropanecarbonitrile. 175 mg as a yellow solid, Y: 67%. ESI-MS (M+H) ⁺ : 387.2.

Step 3. Synthesis of (R)-N-((S)-(6-(l-(6-(l-cyanocyclopropyl)pyridin-2-yl)-lH- indazol-6-yl)pyridin-2-yl)((ls,3R)-3-hydroxycyclobutyl)methy l)-2-methylpropane-2- sulfinamide

Y: 53%

A mixture of l-(6-(6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-ind azol-l- yl)pyridin-2-yl)cyclopropanecarbonitrile (175 mg, 0.45 mmol, 1.0 eq), (R)-N-((S)-(6- bromopyridin-2-yl)(cis-3-hydroxycyclobutyl)methyl)-2-methylp ropane-2-sulfinamide (Example 10, Step 3, 162 mg, 0.45 mmol, 1.0 eq) and K ₂ C0 ₃ (124 mg, 0.9 mmol, 2.0 eq) in 1,4- dioxane/H ₂ 0 (20 mL/1 mL) was stirred while purging N ₂ at rt for 10 min. To this system was added Pd(dppf)Cl ₂ (41 mg, 0.045 mmol, 0.1 eq) and heated to 110 °C for 4 h. The mixture was diluted with EtOAc (50 mL) and washed with brine (50 mL). The organic was dried (Na ₂ S0 ₄ ) and concentrated in vacuo. The crude mixture was purified by silica gel chromatography using PE/EA (1/1) as eluent to give (R)-N-((S)-(6-(l-(6-(l-cyanocyclopropyl)pyridin-2-yl)-lH- indazol-6-yl)pyridin-2-yl)((ls,3R)-3-hydroxycyclobutyl)methy l)-2-methylpropane-2- sulfinamide. 130 mg, as a yellow solid, Y: 53%. ESI-MS (M+H) ⁺ : 541.2.

Step 4. Synthesis of l-(6-(6-(6-((S)-amino(cis-3-hydroxycyclobutyl)methyl)pyridin -2- -lH-indazol-l-yl)pyridin-2-yl)cyclopropanecarbonitrile

179-02

To a solution of (R)-N-((S)-(6-(l-(6-(l-cyanocyclopropyl)pyridin-2-yl)-lH-ind azol-6- yl)pyridin-2-yl)(( 1 s,3R)-3-hydroxycyclobutyl)methyl)-2-methylpropane-2-sulfinam ide (130 mg, 0.24 mmol, 1.0 eq) in DCM (10 mL) was added 4M HC1 in 1,4-dioxane (0.5 mL, excess). The mixture was stirred at rt for 10 min. The solvent was removed in vacuo. The residue was purified by prep-HPLC (CH ₃ CN/0.05% NH ₄ HC0 ₃ in H ₂ 0 = 0%-100%) to give l-(6-(6-(6-((S)- amino(cis-3-hydroxycyclobutyl)methyl)pyridin-2-yl)-lH-indazo l-l-yl)pyridin-2- yl)cyclopropanecarbonitrile. 28 mg as a white solid, Y: 27%. ESI-MS (M+H) ⁺ : 437.2. HPLC: 100%. 1H NMR (400 MHz, CD ₃ OD) δ: 9.19 (s, IH), 8.20 (s, IH), 7.95-7.89 (m, 2H), 7.86-7.80 (m, 3H), 7.75 (t, = 7.6 Hz, IH), 7.37 (d, = 7.6 Hz, IH), 7.23 (d, = 7.6 Hz, IH), 3.98-3.91 (m, IH), 3.88-3.86 (m, IH), 2.46-2.43 (m, IH), 2.10-2.04 (m, 2H), 1.96-1.93 (m, 2H), 1.84-1.83 (m, 2H), 1.79-1.60 (m, 2H).

Examples 21, 22, and 23 3-(amino(6-(l-(6-(hydroxymethyl)pyridin-2-yl)-lH- indazol-6-yl)pyridin-2-yl)methyl)cyclopentanol-A, 3-(amino(6-(l-(6- (hydroxymethyl)pyridin-2-yl)-lH-indazol-6-yl)pyridin-2-yl)me thyl)cyclopentanol-B and 3- (amino(6-(l-(6-(hydroxymethyl)pyridin-2-yl)-lH-indazol-6-yl) pyridin-2- yl)methyl)cyclopentanol-C

Step 1. Synthesis of methyl 3-hydroxycyclopentanecarboxylate

To a solution of methyl 3-oxocyclopentanecarboxylate (5.0 g, 35.2 mmol, 1.0 eq) in MeOH (10 mL) was slowly added NaBH ₄ (2.0 g, 52.8 mmol, 1.5 eq) at 0 °C. Then the mixture was stirred at 0 °C for 1 h. The reaction was quenched with H ₂ 0 (5 mL). The mixture was extracted with DCM (30 mL x 3). The combined organics were dried over Na ₂ S0 ₄ , filtrated and concentrated. The residue was purified by silica gel chromatography (PE/EA = 4/1) to give methyl 3-hydroxycyclopentanecarboxylate (3.1 g, Y: 61%) as a white solid. ESI-MS (M+H) ⁺ : 145.1.

Step 2. Synthesis of methyl 3-(tert-butyldimethylsilyloxy)cyclopentanecarboxylate

To a solution of methyl 3-hydroxycyclopentanecarboxylate (3.1 g, 21.5 mmol, 1.0 eq) THF (40 mL), TBSCI (6.5 g, 43 mmol, 2.0 eq) and imidazole (2.9 g, 43 mmol, 2.0 eq) was added. The mixture was stirred at rt for 16 h. The solvent was removed in vacuo. The residue was purified by silica gel chromatography (PE/EA = 10/1) to give methyl 3-(tert- butyldimethylsilyloxy)cyclopentanecarboxylate (2.3 g, Y: 43%) as light yellow oil. ESI-MS (M+H) ⁺ : 259.1.

Step 3. Synthesis of (3-(tert-butyldimethylsilyloxy)cyclopentyl)methanol

To a solution of methyl 3-(tert-butyldimethylsilyloxy)cyclopentanecarboxylate (2.0 g, 7.8 mmol, 1.0 eq) in THF (40 mL) was added L1AIH ₄ (356 mg, 9.3 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction was quenched with Na ₂ SO ₄ .10H ₂ O and the mixture was filtrated. The filtrate was extracted with EA (40 mL x 3). The combined organic fractions were dried over Na ₂ S0 ₄ , filtrated and concentrated. The residue was purified by silica gel chromatography (PE/EA = 4/1) to give (3-(tert-butyldimethylsilyloxy)cyclopentyl)methanol (1.2 g, Y: 67%) as a white solid. ESI-MS (M+H) ⁺ : 231.2.

Step 4. Synthesis of 3-(tert-butyldimethylsilyloxy)cyclopentanecarbaldehyde

To a solution of (3-(tert-butyldimethylsilyloxy)cyclopentyl)methanol (1.2 g, 5.2 mmol, 1.0 eq) in DCM (30 mL) was added Dess-Martin (4.4 g, 10.4 mmol, 2.0 eq). The mixture was stirred at rt for 2 h. The solvent was removed in vacuo. The residue was purified by silica gel chromatography (PE/EA = 10/1) to give 3-(tert-butyldimethylsilyloxy)cyclopentanecarbaldehyde (800 mg, Y: 67%) as a light yellow solid. ESI-MS (M+H) ⁺ : 229.2.

Step 5. Synthesis of (15R,Z)-N-((3-(tert- butyldimethylsilyloxy)cyclopentyl)methylene)-2-methylpropane -2-sulfinamide

A mixture of 3-(tert-butyldimethylsilyloxy)cyclopentanecarbaldehyde (800 mg, 3.5 mmol, 1.0 eq), (R)-2-methylpropane-2-sulfinamide (508 mg, 4.2 mmol, 1.2 eq) and Ti(OEt) ₄ (1.6 g, 7.0 mmol, 2.0 eq) in THF (50 mL) was stirred while purging N ₂ at 70 °C for 16 h. The mixture was diluted with H ₂ 0 (50 mL) and extracted with EA (50 mL x 3). The organic phases were washed with H ₂ 0 (60 mL) and brine (60 mL) and dried over Na ₂ S0 ₄ . After concentration, the residue was purified by silica gel chromatography (PE/EA = 8/1) to give (15R,Z)-N-((3-(tert- butyldimethylsilyloxy)cyclopentyl)methylene)-2-methylpropane -2-sulfinamide (640 mg, Y: 55%) as yellow oil. ESI-MS (M+H) ⁺ : 332.2.

Step 6. Synthesis of (2R)-N-((6-bromopyridin-2-yl)(3-(tert- butyldimethylsilyloxy)cyclopentyl)methyl)-2-methylpropane-2- sulfinamide

To a solution of 2,6-dibromopyridine (920 mg, 3.9 mmol, 1.0 eq) in Et ₂ 0 (60 mL) was added n-BuLi (2.4 M in hexane, 1.6 mL, 3.9 mmol, 1.0 eq) at -78 °C. After stirring at -78 °C for 30 min, (15R,Z)-N-((3-(tert-butyldimethylsilyloxy)cyclopentyl)methyl ene)-2-methylpropane-2- sulfinamide (640 mg, 1.95 mmol, 0.5 eq) was added and the reaction was stirred for further 3 h at -78 °C. The reaction was quenched with H ₂ 0 (40 mL) and the mixture was extracted with EA (50 mL x 3). The combined organic fractions were dried over Na ₂ S0 ₄ , filtrated and concentrated. The residue was purified by silica gel chromatography (PE/EA = 1/1) to give (2R)-N-((6- bromopyridin-2-yl)(3-(tert-butyldimethylsilyloxy)cyclopentyl )methyl)-2-methylpropane-2- sulfinamide (340 mg, Y: 36%) as a yellow solid. ESI-MS (M+H) ⁺ : 489.2. Step 7. Synthesis of (32R)-N-((3-(tert-butyldimethylsilyloxy)cyclopentyl)(6-(l-(6 - ((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-lH-indazol -6-yl)pyridin-2-yl)methyl)-2- methylpropane-2-sulfinamide

The preparation of (32R)-N-((3-(tert-butyldimethylsilyloxy)cyclopentyl)(6-(l-(6 -((tert- butyldimethylsilyloxy)methyl)pyridin-2-yl)-lH-indazol-6-yl)p yridin-2-yl)methyl)-2- methylpropane-2-sulfinamide was similar to that of (R)-N-((S)-(6-(l-(6-(l- cyanocyclopropyl)pyridin-2-yl)-lH-indazol-6-yl)pyridin-2-yl) ((ls,3R)-3- hydroxycyclobutyl)methyl)-2-methylpropane-2-sulfinamide (Example 20, Step 3) to give 190 mg as a yellow solid, Y: 37%. ESI-MS (M+H) ⁺ : 748.4.

Step 8. Synthesis of 3-(amino(6-(l-(6-(hydroxymethyl)pyridin-2-yl)-lH-indazol-6- yl)pyridin-2-yl)methyl)cyclopentanol-A, 3-(amino(6-(l-(6-(hydroxymethyl)pyridin-2-yl)- lH-indazol-6-yl)pyridin-2-yl)methyl)cyclopentanol-B and 3-(amino(6-(l-(6- (hydroxymethyl)pyridin-2-yl)-lH-indazol-6-yl)pyridin-2-yl)me thyl)cyclopentanol-C

To a solution of (32R)-N-((3-(tert-butyldimethylsilyloxy)cyclopentyl)(6-(l-(6 -((tert- butyldimethylsilyloxy)methyl)pyridin-2-yl)-lH-indazol-6-yl)p yridin-2-yl)methyl)-2- methylpropane-2-sulfinamide (190 mg, 0.25 mmol, 1.0 eq) in DCM (10 mL) was added HCl in dioxane (1 mL, excess). The mixture was stirred at rt. for 30 min. The mixture was adjusted to pH = 7 with NaOH (aq). The solvent was removed in vacuo. The residue was purified by prep- HPLC (CH ₃ CN/0.05% NH ₄ OH in H ₂ 0 = 0%-100%) to give 3-(amino(6-(l-(6- (hydroxymethyl)pyridin-2-yl)-lH-indazol-6-yl)pyridin-2-yl)me thyl)cyclopentanol-A, 3- (amino(6-(l-(6-(hydroxymethyl)pyridin-2-yl)-lH-indazol-6-yl) pyridin-2- yl)methyl)cyclopentanol-B and 3-(amino(6-(l-(6-(hydroxymethyl)pyridin-2-yl)-lH-indazol-6- yl)pyridin-2-yl)methyl)cyclopentanol-C.

3-(amino(6-(l-(6-(hydroxymethyl)pyridin-2-yl)-lH-indazol-6-y l)pyridin-2- yl)methyl)cyclopentanol-A: 17 mg, Y: 16%, as a white solid. ESI-MS (M+H) ⁺ : 416.2. HPLC: 100%. 1H NMR (400 MHz, CD ₃ OD) δ: 9.69 (s, 1H), 8.32 (s, 1H), 8.05 (dd, J = 8.4, 1.2 Hz, 1H), 8.00-7.89 (m, 5H), 7.41-7.36 (m, 2H), 4.89 (s, 2H), 4.73-4.34 (m, 1H), 3.96 (d, J = 8.4 Hz, 1H), 2.81-2.74 (m, 1H), 2.01-1.92 (m, 2H), 1.78-1.42 (m, 4H).

3-(amino(6-(l-(6-(hydroxymethyl)pyridin-2-yl)-lH-indazol-6-y l)pyridin-2- yl)methyl)cyclopentanol-B: 15 mg, Y: 14%, as colorless oil. ESI-MS (M+H) ⁺ : 416.2. HPLC: 100%.

1H NMR (400 MHz, CD ₃ OD) δ: 9.68 (s, 1H), 8.32 (s, 1H), 8.04 (d, = 8.4 Hz, 1H), 8.00- 7.88 (m, 5H), 7.42-7.36 (m, 2H), 4.89 (s, 2H), 4.31-4.21 (m, 1H), 4.04-4.01 (m, 1H), 2.58-2.52 (m, 1H), 2.25-2.16 (m, 1H), 1.91-1.42 (m, 5H).

3-(amino(6-(l-(6-(hydroxymethyl)pyridin-2-yl)-lH-indazol-6-y l)pyridin-2- yl)methyl)cyclopentanol-C: 6.9 mg, Y: 6%, as a white solid. ESI-MS (M+H) ⁺ : 416.2. HPLC: 100%.

1H NMR (400 MHz, CD ₃ OD) δ: 9.68 (s, 1H), 8.32 (s, 1H), 8.04 (dd, J = 8.4, 1.2 Hz, 1H), 8.00-7.88 (m, 5H), 7.42-7.35 (m, 2H), 4.89 (s, 2H), 4.29-4.25 (m, 1H), 3.87 (d, J = 8.4 Hz, 1H), 2.77-2.70 (m, 1H), 2.17-1.98 (m, 2H), 1.68-1.42 (m, 4H).

Example 24 (lR,3s)-3-((S)-amino(6-(4-(2,2-dinuoroethoxy)-l-(6- (hydroxymethyl)pyridin-2-yl)-lH-indazol-6-yl)pyridin-2-yl)me thyl)cyclobutanol

Ste 1. Synthesis of 4-bromo-2 6-difluorobenzaldehyde

Y: 44%

To a solution of l-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 x 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. 1H NMR (400 MHz, CDC1 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. 1H NMR (400 MHz, CDC1 ₃ ) S: 10.36 (s, 1H), 6.97-6.94 (m, 2H), 3.95 (s, 3H); ESI-MS (M+H) ⁺ : 232.9, 234.9

Ste 3. Synthesis of 6-bromo-4-methoxy-lH-indazole

To a stirred solution of 4-bromo-2-fluoro-6-methoxybenzaldehyde (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 x 2) to give 6-bromo-4-methoxy-lH-indazole (15.8 g, Y: 98%) as a light yellow solid. 1H NMR (400 MHz, CDC1 ₃ ) S: 8.10 (s, 1H), 7.27 (s, 1H), 6.61 (d, = 1.2 Hz, 1H), 3.96 (s, 3H); ESI-MS (M+H) ⁺ : 229.0.

Step 4. Synthesis of (6-(6-bromo-4-methoxy-lH-indazol-l-yl)pyridin-2-yl)methanol

Tol, 1 10 °C, 16 h

Y: 49%

A mixture of 6-bromo-4-methoxy-lH-indazole (Cas No. 885519-21-1, 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),N,N'-Dimethyl-l,2-cyclohexanediamine (CAS No. 61798-24-1, 1.5 g, 10.4 mmol) and

K ₃ PO ₄ (22.0 g, 104.0 mmol) in toluene (300 mL) was stirred at 110 °C for 16 h under nitrogen atmosphere. After cooling to rt, the solution was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc, 6: 1) to give the product as a light yellow solid (8.5 g, 49%).

ES (+) MS m/e = 336/338 (M+l)

Step 5. Synthesis of 6-bromo-l-(6-(hydroxymethyl)pyridin-2-yl)-lH-indazol-4-ol

To a suspension of (6-(6-bromo-4-methoxy-lH-indazol-l-yl)pyridin-2-yl)methanol (8.0 g, 24.0 mmol) in DCM (100 mL) was added 3 M BBr ₃ in DCM (24 mL, 72.0 mmol) slowly at 0 °C. The reaction mixture was stirred for 6 h at rt. The reaction was quenched with MeOH (50 mL) and the product was collected by filtration and washed with MeOH (5 mL x 2) to give the title compound (6.2 g, 80%) as a yellow solid. ES (+) MS m/e = 321/323 (M+l)

Step 6. Synthesis of 6-bromo-4-((tert-butyldimethylsilyl)oxy)-l-(6-(((tert- butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-lH-indazole

To a solution of 6-bromo-l-(6-(hydroxymethyl)pyridin-2-yl)-lH-indazol-4-ol (6.0 g, 18.75 mmol) in THF (150 mL) were added TBSCI (14.1 g, 93.75 mmol), lH-imidazole (6.4 g, 93.75 mmol) and DMAP (230 mg, 1.88 mmol). The mixture was stirred at rt for 6 h, diluted with H ₂ 0 (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (200 mL x 2), dried over anhydrous Na ₂ S0 ₄ , concentrated under reduced pressure to give the product (8.7 g, 85%) as a yellow solid. ES (+) MS m/e = 548/550 (M+l) Step 7. Synthesis of 6-bromo-l-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2 - yl)-lH-indazol-4-ol

To a solution of 6-bromo-4-((tert-butyldimethylsilyl)oxy)-l-(6-(((tert- butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-lH-indazole (8.0 g, 14.6 mmol) in MeCN (200 mL) were added CS ₂ CO ₃ (4.8 g, 14.6 mmol). The mixture was stirred at rt for 5 h, filtered through Celite before concentrating the filtrate in vacuo. The residue was purified by flash

chromatography (silica gel, PE / EtOAc, 4: 1) to give 6-bromo-l-(6-(((tert- butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-lH-indazol-4-ol (5.7 g, 90%) as a light yellow solid. 1H NMR (400 MHz, d ₆ -DMSO) δ 8.48 (s, 1H), 8.21 (s, 1H), 7.84-7.82 (m, 2H), 7.39-7.36 (m, 1H), 6.70 (d, J = 1.2 Hz, 1H), 4.92 (s, 2H), 1.00 (s, 9H), 0.08 (s, 6H). ES (+) MS m/e = 434/436 (M+l)

Step 8. Synthesis of 6-bromo-l-(6-((tert-butyldimethylsilyloxy)methyl)pyridin-2-y l)- 4-(2,2-difluoroethoxy)-lH-indazole

To a solution of 6-bromo-l-(6-((tert-butyldimethylsilyloxy)methyl)pyridin-2-y l)-lH- indazol-4-ol (500 mg, 1.15 mmol, 1.0 eq) in DMF (3 mL) was added 2-bromo-l,l-difluoroethane (331 mg, 2.30 mmol, 2.0 eq) and K ₂ CO ₃ (317 mg, 2.30 mmol, 2.0 eq). The mixture was stirred at 70 °C for 2 h in a sealed tube. After cooling down to rt, the mixture was diluted with EA (20 mL) and washed with H ₂ 0 (20 mL x 2). The organic was dried (Na ₂ S0 ₄ ) and concentrated in vacuo. The crude mixture was purified by silica gel chromatography using PE/EA (5/1) as eluent to give 6-bromo-l-(6-((tert-butyldimethylsilyloxy)methyl)pyridin-2-y l)-4-(2,2-difluoroethoxy)-lH- indazole as a yellow solid. 373 mg Y: 65%. ESI-MS (M+H) ⁺ : 498.1. Step 9. Synthesis of l-(6-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-4-(2, 2- difluoroethoxy)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-lH-indazole

The preparation of l-(6-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-4-(2, 2- difluoroethoxy)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-lH-indazole was similar to that of l-(6-(6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-ind azol-l-yl)pyridin-2- yl)cyclopropanecarbonitrile (Example 20, Step 2) to give 280 mg as yellow oil, Y: 71%. ESI-MS (M+H) ⁺ : 546.2.

Step 10. Synthesis of (R)-N-((S)-(3-(tert-butyldimethylsilyloxy)cyclobutyl)(6-(l-( 6- ((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-4-(2,2-dif luoroethoxy)-lH-indazol-6- yl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide

The preparation of (R)-N-((S)-(3-(tert-butyldimethylsilyloxy)cyclobutyl)(6-(l-( 6-((tert- butyldimethylsilyloxy)methyl)pyridin-2-yl)-4-(2,2-difluoroet hoxy)-lH-indazol-6-yl)pyridin-2- yl)methyl)-2-methylpropane-2-sulfinamide was similar to that of (R)-N-((S)-(6-(l-(6-(l- cyanocyclopropyl)pyridin-2-yl)-lH-indazol-6-yl)pyridin-2-yl) ((ls,3R)-3- hydroxycyclobutyl)methyl)-2-methylpropane-2-sulfinamide (Example 20, Step 3) to give 140 mg as a yellow solid, Y: 53%. ESI-MS (M+H) ⁺ : 814.3. Step 11. Synthesis of (lR,3s)-3-((S)-amino(6-(4-(2,2-difluoroethoxy)-l-(6- (hydroxymethyl)pyridin-2-yl)-lH-indazol-6-yl)pyridin-2-yl)me thyl)cyclobutanol

The preparation of (lR,3s)-3-((S)-amino(6-(4-(2,2-difluoroethoxy)-l-(6- (hydro xymethyl)pyridin-2-yl)-lH-indazol-6-yl)pyridin-2-yl)methyl)c yclobutanol was similar to that of l-(6-(6-(6-((S)-amino(cis-3-hydroxycyclobutyl)methyl)pyridin -2-yl)-lH-indazol-l- yl)pyridin-2-yl)cyclopropanecarbonitrile (Example 20, Step 4) to give 55 mg as a white solid, Y: 66%. ESI-MS (M+H) ⁺ : 482.2. HPLC: 100%. 1H NMR (400 MHz, CD ₃ OD) δ: 9.19 (s, 1H), 8.29 (s, 1H), 7.97-7.84 (m, 4H), 7.51 (s, 1H), 7.40 (d, J = 1.2 Hz, 1H), 7.33-7.31 (m, 1H), 6.36 (tt, J = 14.8, 3.6 Hz, 1H), 4.86 (s, 2H), 4.62-4.54 (m, 2H), 4.12-4.05 (m, 1H), 3.93 (d, / = 8.4 Hz, 1H), 2.61-2.53 (m, 1H), 2.24-2.12 (m, 2H), 1.88-1.75 (m, 2H).

Example 25 (lR,3s)-3-((lS)-amino(6-(l-(4-(l-hydroxyethyl)pyrimidin-2-yl )-lH- indazol-6-yl)pyridin-2-yl)methyl)cyclobutanol

Step 1. Synthesis of 2-(6-bromo-lH-indazol-l-yl)-N-methoxy-N-methylpyrimidine-4- carboxamide

To a solution of 6-bromo-lH-indazole (3.0 g, 15.3 mmol, 1.0 eq) in DMF (10 mL) was added NaH (60% in oil, 612 mg, 15.3 mmol, 1.0 eq) at rt. The mixture was stirred at rt for 10 min. Then 2-chloro-N-methoxy-N-methylpyrimidine-4-carboxamide (3.7 g, 18.4 mmol, 1.2 eq) was added into the mixture. The mixture was stirred at rt for 1 h. The mixture was poured into water (60 mL). After filtration, the yellow solid was dried in vacuo. 2.3 g, Y: 42%. ESI-MS (M+H) ⁺ : 362.1. Step 2. Synthesis of l-(2-(6-bromo-lH-indazol-l-yl)pyrimidin-4-yl)ethanone

To a solution of 2-(6-bromo-lH-indazol-l-yl)-N-methoxy-N-methylpyrimidine-4- carboxamide (2.3 g, 6.37 mmol, 1.0 eq) in THF (20 mL) was added MeMgBr (2 M, 4.8 mL, 9.60 mmol, 1.5 eq) at -78 °C. The mixture was stirred at -78 °C for 1 h. The mixture was quenched with water and extracted with DCM (3 X 80 mL). The combined organic phase was washed with brine and dried over Na ₂ S0 ₄ . After filtration and concentration, the residue was recrystallized from EA. l-(2-(6-bromo-lH-indazol-l-yl)pyrimidin-4-yl)ethanone. 1.37 g, as a yellow solid, Y: 68%, ESI-MS (M+H) ⁺ : 317.1.

Step 3. Synthesis of l-(2-(6-bromo-lH-indazol-l-yl)pyrimidin-4-yl)ethanol

To a solution of l-(2-(6-bromo-lH-indazol-l-yl)pyrimidin-4-yl)ethanone (1.37 g, 4.33 mmol, 1.0 eq) in MeOH/THF (10 mL/10 mL) was added NaBH ₄ (329 mg, 8.66 mmol, 2.0 eq) at rt. The mixture was stirred at rt for 10 min. After concentration, the residue was dissolved in MeOH (5 mL) and diluted with water (30 mL). After filtration, the white solid was dried in vacuo. 909 mg, Y: 66%. ESI-MS (M+H) ⁺ : 319.1.

Step 4. Synthesis of 6-bromo-l-(4-(l-(tert-butyldimethylsilyloxy)ethyl)pyrimidin- 2- yl)-lH-indazole

To a solution of l-(2-(6-bromo-lH-indazol-l-yl)pyrimidin-4-yl)ethanol (909 mg, 2.86 mmol, 1.0 eq) in DCM (20 mL) was added imidazole (389 mg, 5.72 mmol, 2.0 eq) and TBSCI

(515 mg, 3.43 mmol, 1.2 eq) at rt. The mixture was stirred at rt for 2 h. The mixture was quenched with water and extracted with DCM (3 X 80 mL). The combined organic phase was washed with brine and dried over Na ₂ S0 ₄ . After filtration and concentration, the residue was purified by silica gel chromatography using PE/EA (4/1) as eluent to give 6-bromo-l-(4-(l-(tert- butyldimethylsilyloxy)ethyl)pyrimidin-2-yl)-lH-indazole as a yellow solid. 988 mg, Y: 80%, ESI-MS (M+H) ⁺ : 433.2.

Step 5. Synthesis of l-(4-(l-(tert-butyldimethylsilyloxy)ethyl)pyrimidin-2-yl)-6- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazole

BS

Y: 70%

A mixture of 6-bromo-l-(4-(l-(tert-butyldimethylsilyloxy)ethyl)pyrimidin- 2-yl)-lH- indazole (180 mg, 0.41 mmol, 1.0 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (130 mg, 0.50 mmol, 1.2 eq) and KOAc (80 mg, 0.82 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 (30 mg, 0.04 mmol, 0.1 eq) and heated to 90 °C for 16 h. The mixture was diluted with EA (50 mL) and washed with brine (50 mL). The organic was dried (Na ₂ S0 ₄ ) and concentrated in vacuo to give l-(4-(l-(tert-butyldimethylsilyloxy)ethyl)pyrimidin-2-yl)-6- (4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-indazole. 140 mg, as a yellow solid, Y: 70%. ESI-MS (M+H) ⁺ : 481.2.

Step 6. Synthesis of (R)-N-((S)-((ls,3R)-3-(tert-butyldimethylsilyloxy)cyclobutyl )(6- (l-(4-((tert-butyldimethylsilyloxy)methyl)pyrimidin-2-yl)-lH -indazol-6-yl)pyridin-2- yl)methyl)-2-methylpropane-2-sulfinamide

The preparation of (R)-N-((lS)-((ls,3R)-3-(tert-butyldimethylsilyloxy)cyclobuty l)(6- (l-(4-(l-(tert-butyldimethylsilyloxy)ethyl)pyrimidin-2-yl)-l H-indazol-6-yl)pyridin-2-yl)methyl)- 2-methylpropane-2-sulfinamide was similar to that of (R)-N-((S)-(6-(l-(6-(l- cyanocyclopropyl)pyridin-2-yl)-lH-indazol-6-yl)pyridin-2-yl) ((ls,3R)-3- hydroxycyclobutyl)methyl)-2-methylpropane-2-sulfinamide (Example 20, Step 3) to give 110 mg as yellow oil, Y: 59%. ESI-MS (M+H) ⁺ : 749.4. Step 7. Synthesis of (lR,3s)-3-((lS)-amino(6-(l-(4-(l-hydroxyethyl)pyrimidin-2-yl )- lH-indazol-6-yl)pyridin-2-yl)methyl)cyclobutanol (TFA)

The preparation of (lR,3s)-3-((lS)-amino(6-(l-(4-(l-hydroxyethyl)pyrimidin-2-yl )- lH- indazol-6-yl)pyridin-2-yl)methyl)cyclobutanol (TFA) was similar to that of l-(6-(6-(6-((S)- amino(cis-3-hydroxycyclobutyl)methyl)pyridin-2-yl)- lH-indazol- l-yl)pyridin-2- yl)cyclopropanecarbonitrile (Example 20, Step 4) to give 15 mg as a yellow solid, Y: 65%. ESI- MS (M+H) ⁺ : 417.2. HPLC: 100% 1H NMR (400 MHz, CD ₃ OD) δ: 9.67 (s, 0.5H), 9.58 (s, 0.5H), 8.89 (t, J = 4.8 Hz, 1H), 9.48 (s, 1H), 8.26-8.22 (m, 1H), 8.11-8.08 (m, 1H), 8.04-8.00 (m, 2H), 7.52-7.49 (m, 1H), 7.44 (d, J = 7.6 Hz, 1H), 5.07-5.03 (m, 1H), 4.49-4.47 (m, 1H), 4.16- 4.12 (m, 1H), 2.64-2.60 (m, 1H), 2.39-2.36 (m, 2H), 1.97- 1.87 (m, 2H), 1.66- 1.64 (m, 3H).

Example 26 (5)-(6-(6-(6-(amino(3,3-difluorocyclobutyl)methyl)pyridin-2- yl)-lH- indazol-l-yl)pyridin-2-yl)methanol

Step 1. Synthesis of (6-bromopyridin-2-yl)(3,3-difluorocyclobutyl)methanol

To a suspension of 2,6-dibromopyridine (6.39 g, 27.0 mmol) in Et ₂ 0 (200 mL) at -78 °C was added a 2.5 M solution of n-butyllithium in hexanes (9.9 mL, 25 mmol). After 30 min, 3,3- difluorocyclobutanecarbaldehyde (2.7 g, 22 mmol) in Et ₂ 0 was added. After 15 min, the reaction was allowed to warm to - 10 °C over 30 minutes then quenched by addition of saturated NH ₄ C1. The layers were separated and the aqueous layer was extracted once with diethyl ether. The combined ether layers were washed with brine, dried over MgS0 ₄ , filtered, and concentrated. The residue was purified over Si0 ₂ (80 g, 10-30% EtOAc in heptane) to afford (6-bromopyridin- 2-yl)(3,3-difluorocyclobutyl)methanol (4.9 g, 78%). LCMS (ESI+) 278.0 (M+H) ⁺ . 1H NMR (400 MHz, CDCI ₃ ) δ 7.53-7.62 (m, IH), 7.42 (d, 7=8.03 Hz, IH), 7.24 (d, 7=7.53 Hz, IH), 4.71 (d, 7=4.77 Hz, IH), 2.45-2.76 (m, 4H), 2.29-2.45 (m, IH)

Ste 2. Synthesis of (6-bromopyridin-2-yl)(3,3-difluorocyclobutyl)methanone

To a solution of (6-bromopyridin-2-yl)(3,3-difluorocyclobutyl)methanol (4.64 g, 16.7 mmol) in CH ₂ CI ₂ (100 niL) was added Dess-Martin periodinane (8.5 g, 20.0 mmol) as a solid. The reaction was stirred at room temperature for 1.5h then water (3.0 mL) was added. The reaction was stirred for an hour then 10% sodium thiosulfate/sat NaHC0 ₃ was added and stirred for lh. The organic phase was separated and dried over MgS0 ₄ , filtered, and concentrated. The residue was purified over S1O ₂ (40 g, 0-5% EtOAc in heptane) to afford (6-bromopyridin-2- yl)(3,3-difluorocyclobutyl)methanone (3.914 g, 85%). LCMS (ESI+) 276.0 (M+H) ⁺ . 1H NMR (400 MHz, CDC1 ₃ ) δ 8.04 (dd, 7=1.25, 7.28 Hz, IH), 7.66-7.76 (m, 2H), 4.21 (m, IH), 4.06-4.16 (m, IH), 2.81-2.97 (m, 4H)

Step 3. Synthesis of (R)-N-((6-bromopyridin-2-yl)(3,3- difluorocyclobutyl)methylene)-2-methylpropane-2-sulfinamide

(6-bromopyridin-2-yl)(3,3-difluorocyclobutyl)methanone (3.94 g, 14.27 mmol) in anhydrous THF (50 mL) was treated with ( ?)-(+)-2-methyl-2-propanesulfinamide (2.27 g, 18.6 mmol) and titanium tetraethyloxide (8.43 mL, 28.5 mmol). The mixture was heated to 60 °C overnight and subsequently cooled to room temperature and quenched with water (5.0 mL) and EtOAc (50 mL). The suspension was filtered through Celite, rinsed with EtOAc and concentrated in vacuo. The residue was purified over Si0 ₂ (24 g, 30-40% EtOAc in heptane) to afford ( ?)-N-((6-bromopyridin-2-yl)(3,3-difluorocyclobutyl)methylene )-2-methylpropane-2- sulfinamide (2.10 g, 38.8%). LCMS (ESI+) 379.0 (M+H) ⁺ . 1H NMR (400 MHz, CDC1 ₃ ) δ 7.60- 7.67 (m, IH), 7.50-7.59 (m, 2H), 3.59-3.68 (m, IH), 2.74-3.14 (m, 4H), 1.27- 1.32 (m, 9H). Step 4. Synthesis of (R)-N-((5)-(6-bromopyridin-2-yl)(3,3- difluorocyclobutyl)methyl)-2-methylpropane-2-sulfinamide & (R)-N-((/f)-(6-bromopyridin- -yl)(3,3-difluorocyclobutyl)methyl)-2-methylpropane-2-sulfin amide

To a solution of ( ?)-N-((6-bromopyridin-2-yl)(3,3-difluorocyclobutyl)methylene )-2- methylpropane-2-sulfinamide (2.10 g, 5.5 mmol) in anhydrous THF (50 mL) at -78 °C was added a solution of L-Selectride (1.0 M in THF, 11.0 mmol, 11 mL) dropwise over 20 minutes. The reaction was allowed to stir at -78 °C for lh. The reaction was quenched by addition of saturated NH ₄ C1. The mixture was diluted with EtOAc and the layers were separated. The organic phase was washed with brine, dried over MgS04, filtered, and concentrated in vacuo. The residue was purified over S1O ₂ (24 g, 0-60% EtOAc in heptane) to afford a mixture of diastereomers (1.025 g; 48%). The diastereomers were separated using reverse phase HPLC (Column: Waters Sunfire C18 OBD 50x100mm, 5um. Solvent system: 30% to 60% (B, acetonitrile) over 15 minutes (A, H ₂ 0) (flow rate: 80mL/min). Modifier: 0.1% formic acid). Peak 1, ( ?)-N-((5)-(6-bromopyridin-2-yl)(3,3-difluorocyclobutyl)methy l)-2-methylpropane-2- sulfinamide (0.578 g). LCMS (ESI+) 381.0 (M+H) ⁺ . 1H NMR (400 MHz, CDC1 ₃ ) δ 7.52-7.57 (m, 1H), 7.40-7.43 (m, 1H), 7.22 (d, 7=7.53 Hz, 1H), 4.35 (d, 7=8.78 Hz, 1H), 2.72-2.83 (m, 2H), 2.59-2.68 (m, 2H), 2.31-2.41 (m, 1H), 1.18 (s, 9H). Peak 2, (tf)-N-((tf)-(6-bromopyridin-2- yl)(3,3-difluorocyclobutyl)methyl)-2-methylpropane-2-sulfina mide (0.438 g). LCMS (ESI+) 381.0 (M+H) ⁺ . 1H NMR (400 MHz, CDC1 ₃ ) δ 7.49-7.57 (m, 1H), 7.40 (dd, 7=0.75, 8.03 Hz, 1H), 7.25 (dd, 7=0.75, 7.53 Hz, 1H), 4.65 (br d, 7=8.28 Hz, 1H), 4.28 (t, 7=7.53 Hz, 1H), 2.43-2.67 (m, 4H), 2.27-2.42 (m, 1H), 1.28 (s, 9H).

Step 5. Synthesis of (R)-N-((5)-(6-(l-(6-(((tert-butyldimethylsilyl)oxy)methyl)py ridin- 2-yl)-lH-indazol-6-yl)pyridin-2-yl)(3,3-difluorocyclobutyl)m ethyl)-2-methylpropane-2- sulfinamide

suspension of l-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-( 4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)- lH-indazole (Example 1, Step 9, 0.110 g, 0.236 mmol), K ₂ C0 ₃ (0.0816 g, 0.590 mmol), ( ?)-N-((5)-(6-bromopyridin-2-yl)(3,3-difluorocyclobutyl)methy l)-2- methylpropane-2-sulfinamide (Example 26, Step 4, 0.075 g, 0.20 mmol), and Pd(dppf)Cl ₂ (8.0 mg, 0.010 mmol) in dioxane (0.66 mL) and water (0.22 mL) were purged with nitrogen for 15 minutes then warmed to 110 °C for 2 h. The mixture was cooled to room temperature, adsorbed onto silica and purified over Si0 ₂ (12 g, 50- 100% EtOAc in heptane) to provide ( ?)-N-((5)-(6- (l-(6-(((ieri-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)- lH-indazol-6-yl)pyridin-2-yl)(3,3- difluorocyclobutyl)methyl)-2-methylpropane-2-sulfinamide (0.056 g; 44%). LCMS (ESI+) 640.3 (M+H) ⁺ . 1H NMR (400 MHz, CDC1 ₃ ) δ 9.34 (s, IH), 8.24 (s, IH), 8.02 (dd, 7=1.51, 8.53 Hz, IH), 7.85-7.97 (m, 3H), 7.82 (d, 7=4.02 Hz, 2H), 7.42 (d, 7=7.28 Hz, IH), 7.24 (t, 7=4.27 Hz, IH), 4.96 (s, 2H), 4.46-4.56 (m, IH), 4.37 (br s, IH), 2.65-2.92 (m, 3H), 2.46-2.58 (m, 2H), 1.18 (s, 9H), 1.00 (s, 9H), 0.17 (s, 6H).

Step 6. Synthesis of (5)-(6-(6-(6-(amino(3,3-difluorocyclobutyl)methyl)pyridin-2- yl)- -indazol-l-yl)pyridin-2-yl)methanol

To a solution of ( ?)-N-((5)-(6-(l-(6-(((ieri-butyldimethylsilyl)oxy)methyl)pyr idin-2-yl)- lH-indazol-6-yl)pyridin-2-yl)(3,3-difluorocyclobutyl)methyl) -2-methylpropane-2-sulfinamide

(0.056 g, 0.088 mmol) in CH ₂ C1 ₂ (2 mL) was added a solution of hydrogen chloride (4.0 M in dioxane, 0.650 mL, 2.60 mmol). The resulting mixture was stirred at room temperature for 2h. The mixture was diluted with Et ₂ 0 and stirred at room temperature for 30 min. The resulting precipitate was filtered to provide (5)-(2-(6-(6-(amino(3,3-difluorocyclobutyl)methyl)pyridin-2- yl)- lH-indazol- l-yl)pyrimidin-4-yl)methanol (0.028 g; 76%). LCMS (ESI+) 422.2 (M+H) ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.59 (m, 1H), 8.55 (br s, 3H), 8.51 (d, 7=1.00 Hz, 1H), 8.23 (dd, 7=1.51, 8.5 Hz, 1H), 8.07 (m, 4H), 7.90 (dd, 7=0.75, 8.03 Hz, 1H), 7.56 (dd, 7=0.88, 7.40 Hz, 1H), 7.42 (dd, 7=0.88, 7.40 Hz, 1H), 5.65 (m, 1H), 4.79 (s, 2H), 4.64 (m, 1H), 2.74(m, 4H).

Example 27 (R)-(6-(6-(6-(amino(3,3-difluorocyclobutyl)methyl)pyridin-2- yl)-lH- indazol-l-yl)pyridin-2-yl)methanol

Step 1. Synthesis of (R)-N-((R)-(6-(l-(6-(((tert- butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-lH-indazol-6-yl) pyridin-2-yl)(3,3- difluorocyclobutyl)methyl)-2-methylpropane-2-sulfinamide

A suspension of l-(6-(((ieri-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-( 4,4,5,5- tetramethyl- l,3,2-dioxaborolan-2-yl)- lH-indazole (Example 1, Step 9, 0.110 g, 0.236 mmol), K ₂ C0 ₃ (81.6 mg, 0.590 mmol), (tf)-N-((tf)-(6-bromopyridin-2-yl)(3,3- difluorocyclobutyl)methyl)-2-methylpropane-2-sulfinamide (Example 26, step 4, 0.075 g, 0.20 mmol), Pd(dppf)Cl ₂ (8.0 mg, 0.010 mmol) in dioxane (0.66 mL) and water (0.22 mL) were purged with nitrogen for 15 minutes then warmed to 70 °C for 2 h. The mixture was cooled to room temperature, adsorbed onto silica and purified over Si0 ₂ (12 g, 50- 100% EtOAc:heptane) to provide ( ?)-N-(( ?)-(6-(l-(6-(((ieri-butyldimethylsilyl)oxy)methyl)pyridin-2- yl)- lH-indazol-6- yl)pyridin-2-yl)(3,3-difluorocyclobutyl)methyl)-2-methylprop ane-2-sulfinamide (0.100 g; 79%). LCMS (ESI+) 640.3 (M+H) ⁺ . 1H NMR (400 MHz, CDC1 ₃ ) δ 9.27-9.31 (m, 1H), 8.23 (d, 7=0.75 Hz, 1H), 7.74-8.04 (m, 6H), 7.42 (dd, 7=1.13, 7.15 Hz, 1H), 7.29 (dd, 7=1.00, 7.28 Hz, 1H), 5.23-5.50 (m, 1H), 4.96 (s, 2H), 4.49 (br t, 7=6.65 Hz, 1H), 2.73 (br s, 1H), 2.47-2.67 (m, 4H), 1.30 (s, 9H), 1.00 (s, 9H), 0.17 (s, 6H). Step 2. Synthesis of (R)-(6-(6-(6-(amino(3,3-difluorocyclobutyl)methyl)pyridin-2- -indazol-l-yl)pyridin-2-yl)methanol

To a solution of ( ?)-N-(( ?)-(6-(l-(6-(((ie^butyldimethylsilyl)oxy)methyl)pyridin-2-yl )- lH- indazol-6-yl)pyridin-2-yl)(3,3-difluorocyclobutyl)methyl)-2- methylpropane-2-sulfinamide (0.100 g, 0.156 mmol) in CH ₂ Cl ₂ (4 mL) was added a solution of hydrogen chloride (4.0 M in dioxane, 1.16 mL, 4.64 mmol). The resulting mixture was stirred at room temperature for 2h. The mixture was diluted with Et ₂ 0 and stirred at room temperature for 30 min. The resulting precipitate was filtered to provide ( ?)-(2-(6-(6-(amino(3,3-difluorocyclobutyl)methyl)pyridin-2- yl)- lH-indazol- l-yl)pyrimidin-4-yl)methanol (0.040 g; 61%). LCMS (ESI+) 422.1 (M+H) ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.57-9.61 (m, IH), 8.57 (br s, 3H), 8.51 (d, 7=1.00 Hz, IH), 8.23 (dd, 7=1.51, 8.53 Hz, IH), 7.99-8.14 (m, 4H), 7.89 (dd, 7=0.75, 8.03 Hz, IH), 7.56 (dd, 7=0.88, 7.40 Hz, IH), 7.42 (dd, 7=0.88, 7.40 Hz, IH), 5.57-5.71 (m, IH), 4.79 (s, 2H), 4.58-4.70 (m, IH), 2.64-2.84 (m, 4H).

Example 28 (5)-(2-(6-(6-(amino(3,3-difluorocyclobutyl)methyl)pyridin-2- yl)-lH- indazol-l-yl)pyrimidin-4-yl)methanol

Step 1. Synthesis of (R)-N-((5)-(6-(l-(4-(((tert- butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)-lH-indazol-6-y l)pyridin-2-yl)(3,3- difluorocyclobutyl)methyl)-2-methylpropane-2-sulfinamide

A suspension of l-(4-(((ie^butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)-6-( 4,4,5,5- tetramethyl- l,3,2-dioxaborolan-2-yl)- lH-indazole (Example 8, Step 4, 0.110 g, 0.236 mmol), K ₂ CO ₃ (81.6 mg, 0.590 mmol), (tf)-N-((S)-(6-bromopyridin-2-yl)(3,3- difluorocyclobutyl)methyl)-2-methylpropane-2-sulfinamide (Example 26, Step 4, 0.075 g, 0.20 mmol), and Pd(dppf)Cl ₂ (8.0 mg, 0.010 mmol) in dioxane (0.66 mL) and water (0.22 mL) were purged with nitrogen for 15 min then warmed to 110 °C for 2 h. The mixture was cooled to room temperature adsorbed onto silica and purified over S1O ₂ (12 g, 50- 100% EtOAc:heptane) to provide ( ?)-N-((5)-(6-(l-(4-(((ieri-butyldimethylsilyl)oxy)methyl)pyr imidin-2-yl)- lH-indazol-6- yl)pyridin-2-yl)(3,3-difluorocyclobutyl)methyl)-2-methylprop ane-2-sulfinamide (0.111 g; 88%). LCMS (ESI+) 641.1 (M+H) ⁺ . 1H NMR (400 MHz, CDC1 ₃ ) δ 9.33-9.45 (m, IH), 8.80-8.91 (m, IH), 8.32-8.40 (m, IH), 7.78-8.04 (m, 4H), 7.48 (d, 7=5.02 Hz, IH), 7.27-7.37 (m, IH), 4.98 (s, 2H), 4.48-4.64 (m, IH), 2.47-2.90 (m, 5H), 1.31 (s, 9H), 1.00 (s, 9H), 0.17 (d, 7=0.75 Hz, 6H).

Step 2. Synthesis of (5)-(2-(6-(6-(amino(3,3-difluorocyclobutyl)methyl)pyridin-2- yl)- -indazol-l-yl)pyrimidin-4-yl)methanol

To a solution of ( ?)-N-((5)-(6-(l-(4-(((ieri-butyldimethylsilyl)oxy)methyl)pyr imidin-2-yl)- lH- indazol-6-yl)pyridin-2-yl)(3,3-difluorocyclobutyl)methyl)-2- methylpropane-2-sulfinamide (0.111 g, 0.173 mmol) in CH ₂ C1 ₂ (2 mL) was added a solution of hydrogen chloride (4.0 M in dioxane , 0.650 mL, 2.60 mmol). The resulting mixture was stirred at room temperature for 2h. The mixture was diluted with Et ₂ 0 and stirred at room temperature for 30 min. The resulting precipitate was filtered to provide (5)-(2-(6-(6-(amino(3,3-difluorocyclobutyl)methyl)pyridin-2- yl)- lH-indazol- l-yl)pyrimidin-4-yl)methanol (0.069 g; 94%). LCMS (ESI+) 423.1 (M+H) ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.43 (d, 7=0.75 Hz, IH), 8.93 (d, 7=5.02 Hz, IH), 8.72 (br s, 4H), 8.53 (d, 7=0.75 Hz, IH), 8.27 (dd, 7=1.51, 8.28 Hz, IH), 7.99-8.17 (m, 3H), 7.51-7.62 (m, 2H), 4.75 (s, 2H), 4.59-4.68 (m, IH), 2.58-2.92 (m, 4H), 2.52-2.59 (m, IH).

Example 29 (S)-(3,3-difluorocyclobutyl)(6-(l-(6-(fluoromethyl)pyridin-2 -yl)-lH- indazol-6-yl)pyridin-2-yl)methanamine

Synthesis of (S)-(3,3-difluorocyclobutyl)(6-(l-(6-(fluoromethyl)pyridin-2 -yl)- lH- indazo 1- 6- yl)pyridin-2- y 1) methanamine

Preparation of the title compound was similar to that of Example 26 except that l-(6- (fluoromethyl)pyridin-2-yl)-6-(4,4,5,5-tetramethyl-l,3,2-dio xaborolan-2-yl)-lH-indazole (Example 16, Step 2) in place of l-(6-(((ieri-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazole and was purified by HPLC to give the title compound as a TFA salt (58 mg, 80%). LCMS: RT 1.26 min.; MH+ 424.0; 1H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.48 - 8.66 (m, 3H), 8.21 (dd, J = 1.25, 8.53 Hz, 1H), 7.96 - 8.17 (m, 5H), 7.56 (d, J = 7.28 Hz, 1H), 7.46 (d, J = 7.28 Hz, 1H), 5.60 - 5.83 (m, 2H), 4.65 (br. s., 1H), 2.59 - 2.87 (m, 5H). Example 30 (S)-(3,3-difluorocyclobutyl)(6-(l-(6-(difluoromethyl)pyridin -2-yl)-lH- indazo 1- 6- yl)pyridin-2- y 1) methanamine

Synthesis of (S)-(3,3-difluorocyclobutyl)(6-(l-(6-(difluoromethyl)pyridin -2-yl)-lH- indazo -6-yl)pyridin-2-yl)methanamine

Preparation of the title compound was similar to that of example 26 except that l-(6-

(difluoromethyl)pyridin-2-yl)-6-(4,4,5,5-tetramethyl-l,3, 2-dioxaborolan-2-yl)-lH-indazole (Example 14, Step 3) in place of l-(6-(((ieri-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazole and was purified by HPLC to give the title compound as a TFA salt (58 mg, 65%). LCMS: RT 1.29 min.; MH+ 442.0; 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.59 (s, 3H), 8.16 - 8.32 (m, 3H), 8.01 - 8.13 (m, 3H), 7.66 (d, J = 6.53 Hz, 1H), 7.57 (dd, J = 1.88, 6.40 Hz, 1H), 7.01 - 7.40 (m, 1H), 4.64 (br. s., 1H), 2.56 - 2.87 (m, 5H).

Example 31 and 32 (5)-(6-(6-(6-(amino(l-fluorocyclobutyl)methyl)pyridin-2-yl)- lH- indazol-l-yl)pyridin-2-yl)methanol & ( ?)-(6-(6-(6-(amino(l-fluorocyclobutyl)methyl)pyridin-2- yl)- lH-indazol- l-yl)pyridin-2-yl)methanol

Step 1. Synthesis of 1-fluoro-N-methoxy-N-methylcyclobutane-l-carboxamide

Λ/,Ο-dimethylhydroxylamine hydrochloride

HATU (3.55 g, 9.32 mmol) and N, 0-dimethylhydroxylamine hydrochloride (0.908 g, 9.32 mmol) were suspended in CH ₂ CI ₂ (32 mL). N,N-Diisopropylethylamine (3.52 mL, 25.4 mmol) was added followed by a solution of 1-fluorocyclobutanecarboxylic acid (1.00 g, 8.47 mmol) in CH ₂ CI ₂ (10 mL). The mixture was stirred at room temperature for 16 h. The solution was concentrated in vacuo and the residue was partitioned between CH ₂ CI ₂ (200 mL) and saturated NH ₄ CI (100 mL). The aqueous layer was extracted with CH ₂ CI ₂ (200 mL) and the combined organics were dried over Na ₂ S0 ₄ and then concentrated. The residue was purified by silica gel chromatography to afford 1-fluoro-N-methoxy-N-methyl-cyclobutanecarboxamide (0.744 g, 54%). 1H NMR (400 MHz, CDC1 ₃ ) δ 3.70 (s, 3H), 3.20-3.23 (m, 3H), 2.68 (m, 2H), 2.25-2.51 (m, 2H), 1.81-1.99 (m, 1H), 1.52-1.72 (m, 1H).

Step 2. Synthesis of (6-bromopyridin-2-yl)(l-fluorocyclobutyl)methanone

To a suspension of 2,6-dibromopyridine (1.09 g, 4.62 mmol) in Et ₂ 0 (23mL) at -78 °C was added a solution of n-butyl lithium (2.5 M in hexanes, 2.03 mL, 5.08 mmol). After 30 min, 1-fluoro-N-methoxy-N-methyl-cyclobutanecarboxamide (0.744 g, 4.62 mmol) in Et ₂ 0 (5 mL) was added. After 15 minutes, the reaction was allowed to warm to -10 °C over 30 min then quenched by addition of saturated NH ₄ C1. The layers were separated and the aqueous layer was extracted once with diethyl ether. The combined ether layers were washed with brine, dried over MgS0 ₄ , filtered, and concentrated. The residue was purified over S1O ₂ (80 g, 10-30% EtOAc in heptane) to afford (6-bromo-2-pyridyl)-(l-fluorocyclobutyl)methanone (0.55 g, 46%). 1H NMR (400 MHz, CDCI3) δ 7.93 (dd, =0.75, 7.28 Hz, 1H), 7.69-7.75 (m, 1H), 7.63-7.68 (m, 1H), 2.82-3.03 (m, 2H), 2.51-2.73 (m, 2H), 2.00-2.17 (m, 1H), 1.83-1.98 (m, 1H).

Step 3. Synthesis of (/f)-N-((6-bromopyridin-2-yl)(l-fluorocyclobutyl)methylene)- 2- methylpropane-2-sulfinamide

A solution of (6-bromo-2-pyridyl)-(l-fluorocyclobutyl)methanone (0.276 g, 1.07 mmol) in anhydrous THF (5.3 mL) was treated with ( ?)-(+)-2-methyl-2-propanesulfinamide (0.260 g, 2.14 mmol) and titanium tetraisopropoxide (1.27 mL, 4.28 mmol). The mixture was heated to 70 °C for 4h. The mixture was cooled to room temperature and quenched by addition of water (1 mL) and EtOAc (20 mL). The suspension was filtered through Celite and rinsed with EtOAc. The residue was purified over Si0 ₂ (80 g, 10-30% EtOAc in heptane) to afford (R)- N-[(6-bromo-2-pyridyl)-(l-fluorocyclobutyl)methylene]-2-meth yl-propane-2-sulfinamide (0.122 g, 32% yield). 1H NMR (400 MHz, CDC1 ₃ ) δ 7.53-7.61 (m, 1H), 7.47-7.52 (m, 1H), 7.35 (td, 7=1.13, 7.53 Hz, 1H), 2.80-3.03 (m, 2H), 2.43-2.69 (m, 2H), 1.94-2.08 (m, 1H), 1.74- 1.89 (m, 1H), 1.31 (s, 9H).

Step 4. Synthesis of (/f)-N-((6-bromopyridin-2-yl)(l-fluorocyclobutyl)methyl)-2- methylpropane-2-sulfinamide

To a solution of ( ?)-N-[(6-bromo-2-pyridyl)-(l-fluorocyclobutyl)methylene]-2-m ethyl- propane-2-sulfinamide (0.122 g, 0.338 mmol) in THF (1.69 mL) at -78 °C was added a solution of L-Selectride (1.0 M in THF, 0.675 mL, 0.675 mmol) dropwise. The mixture was stirred for 60 minutes at -78 °C, and then quenched by addition of saturated NH ₄ C1. The mixture was extracted with EtOAc, dried over MgS0 ₄ , filtered, and concentrated. The residue was purified over Si0 ₂ (12 g, 20- 100% EtOAc in heptane) to provide a mixture of diastereomeric products (38.00 mg, 31%). 1H NMR (400 MHz, CDC1 ₃ ) δ 7.49-7.59 (m, 2H), 7.39-7.45 (m, 2H), 7.30-7.38 (m, 2H), 5.00 (d, 7=8.28 Hz, 1H), 4.60-4.71 (m, 1H), 4.50 (dd, 7=8.41, 18.20 Hz, 1H), 4.18 (br d, 7=6.02 Hz, 1H), 2.09-2.66 (m, 8H), 1.82- 1.96 (m, 2H), 1.51- 1.66 (m, 2H), 1.29 (s, 9H), 1.20 (s, 9H).

Step 5. Synthesis of (R)-N-((6-(l-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridi n-2- yl)-lH-indazol-6-yl)pyridin-2-yl)(l-fluorocyclobutyl)methyl) -2-methylpropane-2- sulfinamide

A suspension of tert-butyl-dimethyl-[[6-[6-(4,4,5,5-tetramethyl- l,3,2-dioxaborokn-2-yl)indazol- l-yl]-2-pyridyl]methoxy] silane (0.096 g, 0.206 mmol), K ₂ C0 ₃ (0.086 g, 0.619 mmol), ( ?)-N-((6- bromopyridin-2-yl)(l-fluorocyclobutyl)methyl)-2-methylpropan e-2-sulfinamide (0.075 g, 0.206 mmol), and Pd(dppf)Cl ₂ (0.015 g, 0.02 mmol) in dioxane (0.4 mL) and water (0.12 mL) were purged with nitrogen for 15 minutes then warmed to 110 °C for 2 hours. The mixture was cooled to room temperature, adsorbed onto silica and purified over Si0 ₂ (12 g, 50- 100% EtOAc in heptane) to provide desired product as a mixture of diastereomers (0.082 mg, 64%). LCMS (ESI+) 622.3 (M+H) ⁺ . 1H NMR (400 MHz, CDC1 ₃ ) δ 9.38 (s, 1H), 9.29-9.35 (m, 1H), 8.23 (dd, =0.75, 3.77 Hz, 2H), 7.75-8.08 (m, 15H), 7.35-7.48 (m, 5H), 5.60 (br d, =7.78 Hz, 1H), 4.94- 5.02 (m, 5H), 4.82-4.94 (m, 1H), 4.53-4.81 (m, 2H), 2.16-2.78 (m, 9H), 1.81-2.10 (m, 9H), 1.58 (qd, =8.86, 17.85 Hz, 4H), 1.30 (s, 10H), 1.21 (s, 12H), 0.98- 1.02 (m, 21H), 0.17 (d, =2.76 Hz, 14H).

Step 6. Synthesis of (5)-(6-(6-(6-(amino(l-fluorocyclobutyl)methyl)pyridin-2-yl)- lH- indazol-l-yl)pyridin-2-yl)methanol & (/?)-(6-(6-(6-(amino(l- fluorocyclobutyl)methyl)pyridin-2-yl)-lH-indazol-l-yl)pyridi n-2-yl)methanol

To a solution of ( ?)-N-((6-(l-(6-(((ieri-butyldimethylsilyl)oxy)methyl)pyridin -2-yl)- lH- indazol-6-yl)pyridin-2-yl)(l-fluorocyclobutyl)methyl)-2-meth ylpropane-2-sulfinamide (0.082 g, 0.131 mmol) in CH ₂ CI ₂ (0.7 mL) was added a solution of hydrogen chloride (4.0 M in dioxane , 0.70 mL, 2.80 mmol). The resulting mixture was stirred at room temperature for 2h. The mixture was diluted with Et ₂ 0 and stirred at room temperature for 30 min. The resulting precipitate was filtered to provide a mixture of enantiomers. The enantiomers were isolated using chiral SFC (column: CHIRALPAK AD-H 30x250mm, 5um. Co-solvent: 25% ethanol with 0.1% DEA in C0 ₂ (flow rate: lOOmL/min) 120bar). Peak 1 : (8.90 mg, 17%). LCMS (ESI+) 404.2 (M+H) ⁺ . 1H NMR (400 MHz, METHANOL-d ₄ ) δ 9.57 (td, 7=0.75, 1.51 Hz, IH), 8.27 (d, 7=1.00 Hz, IH), 7.86-8.02 (m, 6H), 7.47 (d, 7=7.03 Hz, IH), 7.36-7.41 (m, IH), 4.84 (s, 2H), 4.25 (d, 7=19.33 Hz, IH), 2.46-2.71 (m, 2H), 2.12-2.44 (m, 2H), 1.74- 1.86 (m, IH), 1.20- 1.32 (m, IH). Peak 2: (12.00 mg, 23%). LCMS (ESI+) 404.2 (M+H) ⁺ . 1H NMR (400 MHz, METHANOL-d ₄ ) δ 9.56 (s, IH), 8.27 (s, IH), 7.81-8.05 (m, 6H), 7.47 (d, 7=7.03 Hz, IH), 7.38 (dd, 7=2.76, 5.77 Hz, IH), 4.83 (s, 2H), 4.24 (d, 7=19.33 Hz, IH), 2.46-2.72 (m, 2H), 2.13-2.44 (m, 2H), 1.73- 1.87 (m, IH), 1.18- 1.32 (m, IH).

Example 33 Synthesis of (R)-(6-(6-(6-(amino(3,3-difluorocyclobutyl)methyl)pyridin-2- yl)-4-ethoxy- lH-indazol- l-yl)pyridin-2-yl)methanol

Using a sequence of steps similar to that described in example 24 except that 6-bromo-4- ethoxy- lH-indazole was used instead of 6-bromo-4-methoxy- lH-indazole was used in Step 4 and (R)-N-((R)-(6-bromopyridin-2-yl)(3,3-difluorocyclobutyl)meth yl)-2-methylpropane-2- sulfinamide (Example 26, Step 4) was used in place of (R)-N-((S)-(6-bromopyridin-2-yl)(cis-3- hydroxycyclobutyl)methyl)-2-methylpropane-2-sulfinamide in Step 10 to give the title compound. 1H NMR (400 MHz, DMSO- ) δ ppm 9.09 - 9.17 (m, 1 H) 8.74 (br s, 3 H) 8.43 (d, 7=0.8 Hz, 1 H) 8.08 - 8.16 (m, 1 H) 7.95 - 8.07 (m, 2 H) 7.87 (dd, 7=8.2, 0.6 Hz, 1 H) 7.62 (d, 7=1.0 Hz, 1 H) 7.57 (d, 7=7.5 Hz, 1 H) 7.41 (dd, 7=7.5, 0.8 Hz, 1 H) 4.77 (s, 2 H) 4.62 (br s, 1 H) 4.38 - 4.49 (m, 2 H) 2.56 - 2.95 (m, 4 H) 1.51 (t, 7=7.0 Hz, 3 H). LCMS (M+H) = 466.2. HPLC purity >99% Example 34 Synthesis of (S)-(6-(6-(6-(amino(3,3-difluorocyclobutyl)methyl)pyridin-2- yl)-4-ethoxy- lH-indazol- l-yl)pyridin-2-yl)methanol

Using a sequence of steps similar to that described in example 24 except that 6-bromo-4- ethoxy-lH-indazole was used instead of 6-bromo-4-methoxy-lH-indazole was used in Step 4 and (R)-N-((S)-(6-bromopyridin-2-yl)(3,3-difluorocyclobutyl)meth yl)-2-methylpropane-2- sulfinamide (Example 26, Step 4) was used in place of (R)-N-((S)-(6-bromopyridin-2-yl)(cis-3- hydroxycyclobutyl)methyl)-2-methylpropane-2-sulfinamide in Step 10 to give the title compound . 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.09 - 9.17 (m, 1 H) 8.74 (br s, 3 H) 8.43 (d, 7=0.8 Hz, 1 H) 8.08 - 8.16 (m, 1 H) 7.95 - 8.07 (m, 2 H) 7.87 (dd, 7=8.2, 0.6 Hz, 1 H) 7.62 (d, 7=1.0 Hz, 1 H) 7.57 (d, 7=7.5 Hz, 1 H) 7.41 (dd, 7=7.5, 0.8 Hz, 1 H) 4.77 (s, 2 H) 4.62 (br s, 1 H) 4.38 - 4.49 (m, 2 H) 2.56 - 2.95 (m, 4 H) 1.51 (t, 7=7.0 Hz, 3 H). LCMS (M+H) = 466.2. HPLC purity 98.7%.

Example 35 Synthesis of Additional Compounds

The following compounds were synthesized according to the procedures generally described herein.

a) 3-((S)-amino(6-(l-(6-(difluoromethyl)pyridin-2-yl)-lH-indazo l-6-yl)pyridin-2- yl)methyl)cyclobutan- l-ol

b) 3-((S)-amino(6 l-(6-ethylpyridin-2-yl)-lH-indazol-6-yl)pyridin-2- yl)methyl)cyclobutan- l-ol

c) (R)-(6-(6 6-(amino(l-fluorocyclobutyl)methyl)pyridin-2-yl)-lH-indazol- l-yl)pyridin- 2-yl)methanol

(35c)

d) (S)-(6-(6-(6-(amino(l-fluorocyclobutyl)methyl)pyridin-2-yl)- lH-indazol-l-yl)pyridin- 2-yl)methanol

(35d)

e) (S)-3 amino(6-(l-(6-methoxypyridin-2-yl)-lH-indazol-6-yl)pyridin-2 - yl)methyl)cyclobutan- l-ol

f) 3-((S)-amino(6-(l-(6-(fluoromethyl)pyridin-2-yl)-lH-indazol- 6-yl)pyridin-2- yl)methyl)- 1 -methylcyclobutan- 1 -ol

g) 3 (S)-amino(6-(l-(6-(difluoromethyl)pyridin-2-yl)-lH-indazol-6 -yl)pyridin-2- yl)meth - 1 -methylcyclobutan- 1 -ol

h) (S)-(6-(l-(6-(difluoromethyl)pyridin-2-yl)-lH-indazol-6-yl)p yridin-2-yl)(3- methox cyclobutyl)methanamine

i) 3-((S)-amino(6-(l-(6-(fluoromethyl)pyridin-2-yl)- lH-indazol-6-yl)pyridin-2- yl)methyl)- 1 -methylcyclobutan- l-ol

j) (S)-(6-(l-(6-(difluoromethyl)pyridin-2-yl)-lH-indazol-6-yl)p yridin-2-yl)((lR,3S)-3- methoxycyclobutyl)methanamine

(35j) k) (S)-(6-(l-(6-(fluoromethyl)pyridin-2-yl)-lH-indazol-6-yl)pyr idin-2-yl)(l- methylcyclobutyl)methanamine

1) (S)-3-(amino(6-(l-(6-(fluoromethyl)pyridin-2-yl)-lH-indazol- 6-yl)pyridin-2- yl)meth l)cyclo butane- 1 -carbonitrile

Example 36

Biochemical Assay: The biochemical assay is in a AlphaScreen format. The kinase reaction is based on the IRAK-4 phosphorylation of a biotin labeled peptide. The phosphopeptide is incubated with anti-phospho threonine antibody as well as streptavidin- and protein A-coated beads. Binding of the protein-A coated beads to the antibody and the streptavidin beads to the peptide, leads to an energy transfer from one bead to the other, ultimately producing a luminescent/fluorescent signal.

Generally, the kinase reaction is carried out at InM IRAK4, 1.6 μΜ peptide, 1 mM ATP in reaction buffer 50 mM Hepes, 60 mM NaCl, 5 mM MgCl ₂ , 0.25 mM MnCl ₂ , 2 mM DTT,

0.01% BSA, 0.01% Tween-20) for 3.5 h at RT.

The compounds described herein were tested for in the above biochemical assay. The results are provided below, wherein the compound number corresponds to the numbers set forth in the examples above, "+" represents an IC50 of less than 10 uM, but greater than 1 uM, "++" represents an IC50 of less than or equal to 1 uM but greater than 0.1 uM, and a "+++" represents an IC50 of less than or equal to 0.1 uM. IC50 Compounds

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35a, 35b, 35c, 35d, 35f, 35g and

+++

35h

++ 11, 18, 35e and 35i

+

greater than ΙΟμΜ

Cell-based Assay: The cell-based assays is based on IL-6 ELISA quantification. Briefly, A549 cells are cultured in DMEM with 10% FBS medium. When cells reach 80% confluence they are trypsin treated and seeded 180ul/well in 96- well plate at 2.5X10 ^A 4 cells /well. Then, 20ul of compound serial dilutions (starting at lOuM, 10 points) are added to the cell plate;

incubate for 30 min at 37C and stimulated with 2ng/ml human IL-lbeta 37C, 5% C0 ₂ overnight. The next day lOOul of cell supernatant per well are analyzed on a Human IL-6 Quantikine ELISA kit from R&D Systems.

The compounds described herein were tested for in the above biochemical and cell-based assays. The results are provided below, wherein the compound number corresponds to the numbers set forth in the examples above, "†" represents an EC50 of greater than 10 uM, "††" represents an EC50 of equal to or less than 10 uM but greater than 1 uM, and "†††" represents an EC50 of equal to or less than 1 uM.