EA040817B1 - Benzoazepine Analogs as Inhibiting Agents for Bruton's Tyrosine Kinase - Google Patents

Description

Related Applications

This application claims priority by date of filing under 35 U.S.C. §119(e), pursuant to U.S. Provisional Application No. 62/485745, filed April 14, 2017, the entire contents of which are hereby incorporated by reference.

Technical field

Certain agents are provided that inhibit Bruton's tyrosine kinase (Btk), as well as methods for the preparation and use of such agents.

State of the art

Protein kinases are a large multigene family of more than 500 proteins that play an essential role in the development and treatment of a number of human oncological, neurological and immunological diseases. The Tec family kinases are non-receptor tyrosine kinases that consist of five members (Tec (a tyrosine kinase expressed in hepatocellular carcinoma), Btk (Bruton's tyrosine kinase), Itk (interleukin-2 (IL-2) inducible T-cell kinase, also known as Emt or Tsk), Rlk (resting lymphocyte kinase, also known as Txk), and Bmx (bone marrow tyrosine kinase gene on chromosome X, also known as Etk)) and which are primarily expressed in hematopoietic cells, although Bmx and Tec expression have been found in endothelial cells. and liver cells. The Tec family kinases (Itk, Rlk and Tec) are expressed in T cells and all are activated downstream of the T cell receptor (TCR). Btk is an downstream mediator of B cell receptor (BCR) signaling that is involved in the regulation of B cell activation, proliferation and differentiation. More specifically, Btk contains a PH domain that binds phosphatidylinositol-(3,4,5)-trisphosphate (PIP3). Binding of PIP3 causes phosphorylation of phospholipase C (PLCy) by Btk kinase, which in turn leads to hydrolysis of PIP2 with the formation of two second messengers, inositol triphosphate (IP3) and diacylglycerol (DAG), which activate PKC protein kinase, which then induces additional B-cell signaling. Mutations that disable the enzymatic activity of Btk lead to the development of XLA syndrome (X-linked agammaglobulinemia), a primary immunodeficiency. Given the critical importance that the Tes family kinases have on both B cell and T cell signaling, the Tes family kinases are of interest from an autoimmune disorder perspective.

Therefore, there is a great need in the art for effective Btk inhibitors.

The essence of the invention

The invention relates to a compound represented by the following formula:

Η N=N ⁰ r^N

L if

H or a pharmaceutically acceptable salt thereof.

The invention also relates to a compound represented by the following formula:

its pharmaceutically acceptable salt and crystalline forms.

In addition, the invention relates to a pharmaceutical composition for inhibition of Bruton's tyrosine kinase and a method of treating a disorder responsive to inhibition of Bruton's tyrosine kinase in a subject, comprising administering to the subject the compounds and crystalline forms of the invention.

Brief description of graphic materials

In FIG. 1 shows the powder X-ray diffraction pattern (XRD) of the crystalline form A (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4 -yl)-2-(oxetan-3-yl)-2,3,4,5tetrahydro-1 H-benzo[c]azepin-5-yl)-1 H-1,2,3-triazole-4-carboxamide .

In FIG. Figure 2 shows profiles of differential scanning calorimetry (DSC) and thermography.

- 1 040817 vimetric analysis (TGA) for crystalline form A yl)-2-(oxetan-3 -yl)-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-5 -yl)-1 H1,2,3-triazole-4-carboxamide.

In FIG. 3A shows the ¹³ C-NMR spectrum for a solution of crystalline form A(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro1 H-benzo[c]azepin-5-yl)-1 H-1,2,3-triazole-4-carboxamide.

In FIG. 3B shows the ¹³ C-NMR spectrum for crystalline form A in the solid state.

In FIG. 4 shows the powder X-ray diffraction pattern (XRD) of the crystalline form G(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4 -yl)-2-(oxetan-3-yl)-2,3,4,5tetrahydro-1 H-benzo[c]azepin-5-yl)-1 H-1,2,3-triazole-4-carboxamide .

In FIG. 5 shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) profiles for G(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1Hpyrazol-4-yl )amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-5-yl)-1 H1,2,3 -triazole-4-carboxamide.

In FIG. 6A depicts the ¹³ C-NMR spectrum of a solution of crystal form G(R)-1-(tert-butyl)N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4 -yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1Hbenzo [c]azepin-5-yl)-1 H-1,2,3-triazole-4-carboxamide.

In FIG. 6B depicts the ¹³ C-NMR spectrum for crystalline form G in the solid state.

Detailed description of the invention

The compounds, or pharmaceutically acceptable salts thereof, described herein exhibit activity as Btk modulators. In particular, the compounds or pharmaceutically acceptable salts thereof described herein are Btk inhibitors.

The first embodiment of the invention is a compound of formula (I):

^R4

Formula (I) or a pharmaceutically acceptable salt, wherein Ring A is a 5-membered monocyclic hereroaryl containing 3 heteroatoms independently selected from N, O, and S, said 5-membered monocyclic heteroaryl being optionally substituted with one or more R ¹ ;

Q ¹ , Q ² and Q ³ are each independently selected from O, N(R ² ) and CH-R ³ , with at least two of Q ¹ , Q ² and Q ³ being CR ³ ;

W is selected from CH and N;

Y is selected from CH and N;

R ¹ at each occurrence is independently selected from C _1-6 -alkyl and 3-5 membered carbocyclyl, said C _1-6 alkyl and 3-5 membered carbocyclyl being optionally substituted with one or more R ¹⁰ ;

R ¹⁰ at each occurrence is independently selected from halogen, -CN, C _1-6 alkyl, and 3-5 membered carbocyclyl;

R ² is selected from H, C1-6-α-kyl, C2-6-α-alkenyl, C2-6-alkynyl, 4-6-membered monocyclic carbocyclyl, 4-6-membered monocyclic heterocyclyl, -CN, -C(O)R ^2a , -C(O)2R ^2a , -C(O)N(R ^2a )2, S(O)2R ^2a and -S(O)2N(R ^2a ) ₂ , wherein said C _1-6 -αkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, 4-6-membered monocyclic carbocyclyl and 4-6-membered monocyclic heterocyclyl are optionally substituted with one or more R ²⁰ ;

R ^2a is in each case independently selected from H, C _1-6 -αkyl, C _2-6 -αlkenyl, C _2-6 -αkynyl, 4-6 membered monocyclic carbocyclyl and 4-6 membered monocyclic heterocyclyl, wherein

- 2 040817 said C1-6-alkyl, _C2-6 -alkenyl, _C2-6 -alkynyl, 4-6 membered monocyclic carbocyclyl and 4-6 membered monocyclic heterocyclyl are in each occurrence optionally and independently substituted with one or more R ²⁰ ;

R ²⁰ is independently selected from C ₁ _ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, 4-6 membered monocyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, halogen, -CN, -C (O)R ^20a , -C(O)2R ^20a , -C(O)N(R ^20a )2, -N(R ^20a )2, -N(R ^20a )C(O)R ^20a , -N( R ^20a )C(O)2R ^20a ,

-N(R ^20a )C(O)N(R ^20a )2, -N(R ^20a )S(O)2R ^20a , -OR ^20a , -OC(O)R ^20a , -OC(O)N(R ^20a )2, -SR ^20a , -S(O)R ^20a , -S(O)2R ^20a , -S(O)N(R ^20a )2 and -S(O)2N(R ^20a )2;

R ^20a is in each case independently selected from H, C ₁ . ₆ -alkyl, C ₂ . ₆ -alkenyl, C ₂ . ₆ -alkynyl, 4-6 membered monocyclic carbocyclyl and 4-6 membered monocyclic heterocyclyl;

R ³ is selected from H, C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 4-6 membered monocyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, halogen, -CN, -C(O) R ^3a , -C(O)2R ^3a , -C(O)N(R ^3a )2, -N(R ^3a )2, -N(R ^3a )C(O)R ^3a , -N(R ^3a ) C(O)2R ^3a , -N(R ^3a )C(O)N(R ^3a )2, -N(R ^3a )S(O)2R ^3a , -OR ^3a , -OC(O)R ^3a , - OC(O)N(R ^3a )2, -SR ^3a , -S(O)R ^3a , -S(O)2R ^3a , -S(O)N(R ^3a )2 and -S(O)2N( R ^3a )2, wherein said C1-6alkyl, _{C2_6} alkenyl, _{C2_6} alkynyl, 4-6 membered monocyclic carbocyclyl and 4-6 membered monocyclic heterocyclyl are optionally substituted with one _or more R ³⁰ ;

R ^{3a is} in each case independently selected from H, C ₁ _ ₆ -alkyl, C ₂ . ₆ -alkenyl, C ₂ . ₆ -alkynyl, 4-6-membered monocyclic carbocyclyl and 4-6-membered monocyclic heterocyclyl, wherein said C ₁ . ₆ -alkyl, C ₂ . ₆ -alkenyl, C ₂ . ₆ -alkynyl, 4-6 membered monocyclic carbocyclyl and 4-6 membered monocyclic heterocyclyl are each optionally and independently substituted with one or more R ³⁰ ;

R ³⁰ is in each case independently selected from H, C ₁ . ₆ -alkyl, C ₂ . ₆ -alkenyl, C ₂ . _6- alkynyl, 4-6-membered monocyclic carbocyclyl, 4-6-membered monocyclic heterocyclyl, halogen, -CN, -C(O)R ^30a , -C(O)2R ^30a , -C(O)N(R ^30a )2 , -N(R ^30a )2, -N(R ^30a )C(O)R ^30a , -N(R ^30a )C(O)2R ^30a , -N(R ^30a )C(O)N(R ^30a ) 2, -N(R ^30a )S(O)2R ^30a , -OR ^30a , -OC(O)R ^30a , -OC(O)N(R ^30a )2, -SR ^3Oa , -S(O)R ^30a , -S(O)2R ^30a , -S(O)N(R ^30a )2 and -S(O)2N(R ^30a )2;

R ^30a is in each case independently selected from H, C ₁ . ₆ -alkyl, C ₂ . ₆ -alkenyl, C ₂ . ₆ -alkynyl, 4-6 membered monocyclic carbocyclyl and 4-6 membered monocyclic heterocyclyl;

R ⁴ is selected from H and C ₁ _ ₆ alkyl, said C ₁ _ ₆ alkyl being optionally substituted with one or more halogens;

R ⁵ is selected from H and C ₁ _ ₆ alkyl, said C ₁ _ ₆ alkyl being optionally substituted with one or more halogens;

R ⁶ is selected from H and C ₁ . ₆ -alkyl, and the specified C ₁ . ₆ -alkyl is optionally substituted with one or more halogens;

or R ⁵ and R ⁶ together with the atoms to which they are attached form a ring containing one or two heteroatoms selected from O, N and S, the ring being optionally substituted with one or more R ⁵⁰ ; And

R ⁵⁰ is C ₁ _ ₆ alkyl.

The invention also provides a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

In one embodiment, the invention is a method of treating a Btk inhibition responsive disorder in a subject, comprising administering to said subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof.

The invention also includes the use of at least one compound described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disorder responsive to Btk inhibition. Also provided is a compound described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disorder responsive to Btk inhibition.

Other features and advantages will become apparent from the following detailed description of several embodiments of the invention, as well as from the appended claims.

In a second embodiment of the present invention, the compound is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein Q ¹ , Q ² and Q ³ are each independently CH-R ³ and other variables are defined in the first embodiment.

In a third embodiment of the present invention, the compound is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein Q ² is N(R ² ), Q ¹ and Q ³ are each independently CH-R ³ , and definitions of the other variables are given in the first embodiment of the invention.

In a fourth embodiment of this invention, the compound is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein Q ³ is N(R ² ), Q ¹ and Q ² are each independently CH-R ³ , and definitions of the other variables are given in the first variant of rea

- 3 040817 lysis of the invention.

In a fifth embodiment of the present invention, the compound is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein each Q ¹ is O, each Q ² and Q ³ are independently CH-R ³ , and definitions of other variables are given in the first embodiment of the invention .

In a sixth embodiment of this invention, the compound is represented by formula (I) or a pharmaceutically acceptable salt thereof, W is CH, and definitions of other variables are given in the first, second, third, fourth or fifth embodiment of the invention.

In a seventh embodiment of the present invention, the compound is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein Y is N and other variables are defined in the first, second, third, fourth, fifth or sixth embodiment.

In an eighth embodiment of the present invention, the compound of the present invention is represented by any of the following formulas:

- 4 040817

or its pharmaceutically acceptable salt, and definitions of other variables are given in the first embodiment of the invention.

In the ninth embodiment of this invention, the compound is represented by formulas (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V') or its pharmaceutically acceptable salt, wherein ring A is selected from 1,2,3-oxadiazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1 ,2,4-thiadiazole, 1,2,3-triazole and 1,2,4-triazole, each of which is optionally substituted with one or two R ¹ ; and definitions of other variables are given in the first, second, third, fourth, fifth, sixth, seventh or eighth embodiment of the invention.

In the tenth embodiment of this invention, the compound is represented by formulas (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V') or its a pharmaceutically acceptable salt, wherein ring A is represented by one of the following formulas:

and definitions of other variables are given in the first, second, third, fourth, fifth, sixth, seventh or eighth embodiment of the invention.

In the eleventh embodiment of this invention, the compound is represented by formulas (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or its pharmaceutically acceptable salt, and

R1 is in each case independently selected from C ₁ . ₆ -alkylα and C ₃ . ₅ -cycloalkyl, and the specified

- 5 040817

C _1-6 alkyl and C3-5 cycloalkyl are optionally substituted with one to three R ¹⁰ ;

R ¹⁰ at each occurrence is independently selected from halogen, -CN and C _1-6 alkyl; and definitions of other variables are given in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiment of the invention.

In the twelfth embodiment of this invention, the compound is represented by formulas (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V') or its pharmaceutically acceptable salt, and

R ¹ at each occurrence is independently C _1-4 alkyl, cyclopropyl and cyclobutyl, said C _1-4 alkyl, cyclopropyl and cyclobutyl being optionally substituted with one to three R ¹⁰ ;

R ¹⁰ in each occurrence is independently selected from halogen, -CN and C ₁ . ₃ -alkyl; and definitions of other variables are given in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiment of the invention.

In the thirteenth embodiment of this invention, the compound is represented by formulas (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or its pharmaceutically acceptable salt, and

R ¹ in each case independently selected from -C(CH ₃ ) ₃ , -CH(CH ₃ )2, -C(CH ₃ )2CHF2, -C(CH ₃ )2CF ₃ , -C(CH ₃ )2CH2F, - C(CH ₃ )2CN, 1-methylcyclopropyl, cyclobutyl, and 3,3-difluorocyclobutyl, and other variables are defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment.

In the fourteenth embodiment of this invention, the compound is represented by formulas (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V') or its a pharmaceutically acceptable salt, wherein R ¹ is -C(CH ₃ ) ₃ ; and definitions of other variables are given in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiment of the invention.

In the fifteenth embodiment of this invention, the compound is represented by formulas (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V') or its pharmaceutically acceptable salt, and

R ² is selected from H, C1.6-alkyl, C4.6-cycloalkyl, saturated 4-6 membered monocyclic heteropicyl, -C(O)R ^2a , -C(O)2R ^2a and -S(O)2R ^2a , and these C1. ₆ -alkyl, C _4-6 -cycloalkyl and saturated 4-6-membered monocyclic heterocyclyl are optionally substituted with one to three R ²⁰ ;

R ^{2a is} in each case independently selected from H, C ₁ . ₆ -alkyl, C _4-6 -alkyl and saturated 4-6-membered monocyclic heterocyclyl, and these C ₁ . ₆ -alkyl, 4-6 membered monocyclic carbocyclyl and saturated 4-6 membered monocyclic heterocyclyl are each optionally and independently substituted with one or more R ²⁰ ;

R ²⁰ is in each case independently selected from C ₁ . ₆ -alkyl, C _4-6 -cycloalkyl, saturated 4-6 membered monocyclic heterocyclyl, halogen, -CN, -N(R ^20a )2 and -OR ^20a ;

R ^20a is in each case independently selected from H or C ₁ . ₆ -alkyl;

and definitions of other variables are given in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment.

In the sixteenth embodiment of this invention, the compound is represented by formulas (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V') or its pharmaceutically acceptable salt, and

R ² is selected from H, C1.6-alkyl, C4-6-cycloalkyl selected from cyclobutyl, cyclopentyl and cyclohexyl, saturated 4-6-membered monocyclic heterocyclyl selected from azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl , oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl and dioxanyl, -C(O)R ^2a , -C(O)2R ^2a and -S(O) 2R ^2a , with said C1. ₆ -alkyl, C ₄ - ₆ -cycloalkyl and saturated 4-6-membered monocyclic heterocyclyl are optionally substituted with one to three R ²⁰ ;

R ^2a is C ₁ . ₆ -alkyl, optionally and independently substituted with one to three R ²⁰ ;

R ²⁰ is in each case independently selected from C ₁ . ₃ -alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, halogen, -N(R ^20a )2 and -OR ^20a ;

R ^20a is at each occurrence independently H or C ₁ _ ₃ alkyl; and definitions of other variables are given in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth or fifteenth embodiment.

In the seventeenth embodiment of this invention, the compound is represented by formulas (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V') or its pharmaceutically acceptable salt, and

R ² is selected from H, C1.6-alkyl, cyclobutyl, cyclopentyl and cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, -C(O)R ^2a , -C(O)2R ^2a and -S(O)2R ^2a , and these C1. ₆ -alkyl, piclobutyl, cyclopentyl and cyclohexyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl are optionally substituted with one to three R ²⁰ ;

R ^2a is C ₁ . ₆ -alkyl optionally substituted with one R ²⁰ ;

R ²⁰ at each occurrence is independently selected from C1.3-alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, halogen, -N(R ^20a )2 and -OR ^20a ;

R ^20a is at each occurrence independently H and methyl;

- 6 040817 definitions of other variables are given in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth or fifteenth embodiment of the invention.

In the eighteenth embodiment of this invention, the compound is represented by formulas (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V') or its a pharmaceutically acceptable salt, wherein R ² is selected from -H, -SO ₂ CH ₃ , -C(=O)OC(CH ₃ ) ₃ , -C(=O)CH ₂ N(CH ₃ ) ₂ , -CH3, - CH ₂ CH ₃ , -CH ₂ CH ₂ OH,

-CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH(CH3)OH, -CH2C(CH3)2OH,

-CH ₂ CH ₂ CH ₂ OH, -CH ₂ CHF ₂ ,

-CH2CF3

and definitions of other variables are given in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment.

In the nineteenth embodiment of this invention, the compound is represented by formulas (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V') or its a pharmaceutically acceptable salt, wherein R ² is selected from -CH2CHF2, -CH2CF3, -CH2CH2OH, -CH2CH(CH3)OH, -CH2CH2OCH3, and D

In the twentieth embodiment of this invention, the compound is represented by formulas (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V') or its pharmaceutically acceptable salt, and

R ³ is selected from H, C1_6-alkyl, C4-6-cycloalkyl, saturated 4-6-membered monocyclic heteropicyl, halogen, -OR ^3a , -OC(O)R ^3a , -OC(O)N(R ^3a )2 and -SR ^3a , wherein said _{C1_6} alkyl, _{C4_6} cycloalkyl and saturated _4-6 membered monocyclic heterocyclyl are optionally substituted with one to three R ³⁰ ;

R ^3a is independently in each occurrence H or _{C1_6} alkyl, said _{C1_6} alkyl in each occurrence being optionally and independently substituted with one R ³⁰ ;

R ³⁰ at each occurrence is independently selected from _C1-6 alkyl;

and definitions of other variables are given in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth and nineteenth embodiments.

In the twenty-first embodiment of this invention, the compound is represented by formulas (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharmaceutically acceptable salt thereof, R ³ being selected from H, halo and -OR ^3a ; R ^3a is independently H or _{C1_3} alkyl; and definitions of other variables are given in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth and nineteenth embodiments of the invention.

In the twenty-second embodiment of this invention, the compound is represented by formulas (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V') or its pharmaceutically acceptable salt, and R ³ selected from H, -F and -OH; and definitions of other variables are given in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth and nineteenth embodiments of the invention.

In the twenty-third embodiment of this invention, the compound is represented by formulas (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V') or its pharmaceutically acceptable salt, and R ⁴ represents H or C1_ ₃ -alkyl, optionally substituted with one to three fluorines; and definitions of the other variables are given in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, and twenty second embodiment of the invention.

In the twenty-fourth embodiment of this invention, the compound is represented by formulas (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V') or its pharmaceutically acceptable salt, and R ⁴ represents H or methyl; and definitions of the other variables are given in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, and twenty second embodiment of the invention.

In the twenty-fifth embodiment of this invention, the compound is represented by formulas (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V') or its pharmaceutically acceptable salt, and R ⁵ represents H or C1_ ₃ -alkyl, optionally substituted with one to three fluorines; and definitions of the other variables are given in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty second, twenty-third and twenty-fourth embodiments of the invention.

In the twenty-sixth embodiment of this invention, the compound is represented by the formulas

- 7 040817 (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V') or a pharmaceutically acceptable salt thereof, wherein R ⁵ is H, methyl, ethyl or isopropyl; and definitions of the other variables are given in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty second, twenty-third and twenty-fourth embodiments of the invention.

In the twenty-seventh embodiment of this invention, the compound is represented by formulas (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V') or its pharmaceutically acceptable salt, and R ⁶ represents H or ^.s-alkyl, optionally substituted with one to three fluorines; and definitions of the other variables are given in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty second, twenty-third, twenty-fourth, twenty-fifth and twenty-sixth embodiments of the invention.

In the twenty-eighth embodiment of this invention, the compound is represented by formulas (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V') or its pharmaceutically acceptable salt, and R ⁶ represents H, methyl or trifluoromethyl; and definitions of the other variables are given in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty second, twenty-third, twenty-fourth, twenty-fifth or twenty-sixth embodiment of the invention.

In the twenty-ninth embodiment of this invention, the compound is represented by formulas (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V') or a pharmaceutically acceptable salt thereof, wherein R ⁵ and R ⁶ together with the atoms to which they are attached form a 5-6 membered saturated heterocyclic ring containing one or two heteroatoms selected from O, N and S, the ring being optionally substituted with one R ⁵⁰ ;

R ⁵⁰ is C ₁ .3-alkyl; and definitions of the other variables are given in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty second, twenty-third and twenty-fourth embodiments of the invention. In a particular embodiment, the 5-6 membered saturated heterocyclic ring is pyrrolidine, piperazine, or N-methylpiperazine.

In the thirtieth embodiment of this invention, the compound is represented by the following formulas:

- 8 040817

(IVA); OG or its pharmaceutically acceptable salt, where ring A is represented by one of the following formulas:

R ¹ is C _1-6 alkyl;

R ² is C _1-6 -αkyl, oxetanyl, tetrahydrofuranyl or tetrahydropyranyl, said C _1-6 -alkyl being optionally substituted with one to three R ²⁰ ;

R ²⁰ is at each occurrence independently halogen or —OR ^20a ;

R ^20a is H or C _1-3 -αkyl;

R ³ is H; And

R ⁵ is H or C _1-3 alkyl.

In the thirty-first embodiment of this invention, the compound is represented by formulas (IIA), (IVA), (VA), (IIA'), (IVA') or (VA') or its pharmaceutically acceptable salt, and R ¹ represents tert-butyl , and definitions of other variables are given in the thirtieth embodiment of the invention.

In the thirty-second embodiment of this invention, the compound is represented by formulas (IIA) or (IIA'), or a pharmaceutically acceptable salt thereof, wherein R ² is ^v , -CH2CHF2, -CH2CF3, -CH2CH2OH, -CH2CH2OCH3 or -CH2C(CH3)OH , and definitions of other variables are given in the thirtieth or thirty-first embodiment of the invention.

- 9 040817

In the thirty-third embodiment of this invention, the compound is represented by formulas (IVA) - (IVA'), or its pharmaceutically acceptable salt, and R ³ represents H, and the definitions of other variables are given in the thirtieth or thirty-first embodiment of the invention.

In a thirty-fourth embodiment of this invention, the compound is represented by formulas (IIA), (IVA), (VA), (IIA'), (IVA') or (VA') or a pharmaceutically acceptable salt thereof, wherein R ⁵ is methyl or isopropyl , and definitions of other variables are given in the thirtieth, thirty-first, thirty-second or thirty-third embodiment of the invention.

In the thirty-fifth embodiment of the present invention, the compound of the present invention is selected from

5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1Hbenzo [b]azepin-1-yl)-1,2,4-oxadiazole-3-carbocamide, (8)-5-(tert-butyl)-K-(7-(2-((1-methyl-1Н- pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro1H-benzo[b]azepin-1-yl)-1,2,4-oxadiazol-3-carboxamide, (K )-5-(tert-butyl)-M-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro1H -benzo[d]azepin-1 -yl)-1,2,4-oxadiazole-3-carboxamide,

5-(tert-butyl)-M-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2 ,3,4,5tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide, (K)-5-(tert-butyl)-N-(8-( 2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)2,3,4,5-tetrahydro-1H-benzo [c] azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide, (8)-5-(tert-butyl)-M-(8-(2-((1-methyl-1H-pyrazole-4 -yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4- oxadiazole-3-carboxamide,

5-(tert-butyl)-M-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3, 4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide, (K)-5-(tert-butyl)-M-(2-(2 -hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4,5-tetrahydro-1H-benzo[c]azepin-5 -yl)-1,2,4-oxadiazole-3-carboxamide, (8)-5-(tert-butyl)-M-(2-(2-hydroxyethyl)-8-(2-((1-methyl- 1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide ,

5-(tert-butyl)-M-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(methylsulfonyl)2,3,4 ,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide, (K)-5-(tert-butyl)-L1-(8-(2- ((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(methylsulfonyl)2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl) -1,2,4-oxadiazol-3-carboxamide, (8)-5-(tert-butyl)-M-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine -4-yl)-2-(methylsulfonyl)2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,

5-(tert-butyl)-M-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4yl)-2,3,4 ,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,

- 10 040817 (K)-5-(tert-butyl)-M-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine 4 -yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide, (S)-5-(tert-butyl) -N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin4-yl)-2,3,4,5-tetrahydro-1H -benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,

5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2 ,3,4,5tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide, (K)-5-(tert-butyl)-M-(8-( 2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)2,3,4,5-tetrahydro-1H-benzo[c] azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide, (8)-5-(tert-butyl)-M-(8-(2-((1-ethyl-1H-pyrazole-4 -yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4- oxadiazol-3-carboxamide,

5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran4-yl) -2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl1)-1,2,4-oxadiazole-3-carboxamide, (K)-5-(tert-butyl)-K- (8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2Hpyran-4-yl)-2,3,4,5-tetrahydro -1H-benzo[c]azepin-5-yl1)-1,2,4-oxadiazole-3-carboxamide, (8)-5-(tert-butyl)-M-(8-(2-((1- methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2Hpyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5 -yl)-1,2,4-oxadiazole-3-carboxamide,

5-(tert-butyl)-M-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)2, 3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide, (I)-5-(tert-butyl)-M-(8- (2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo [c] azepin-5-yl)-1,2,4-o xadiazol-3-carboxamide, (8)-5-(tert-butyl)-M-(8-(2-((1,5-dimethyl-1H- pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4- o xadiazol-3-carboxamide, 5-(tert-butyl)-M-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydrofuran -3yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,

5-(tert-butyl)-KG-((K)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((I)tetrahydrofuran -3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-KG -((I)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((8)tetrahydrofuran-3-yl)-2.3 ,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-KG-((8)-8-( 2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((K)tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H- benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,

5-(tert-butyl)-M-((8)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((8)tetrahydrofuran -3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,

5-(tert-butyl)-M-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl) 2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazol-3-carboxamide, (I)-5-(tert-butyl)-KG- (8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2trifluoroethyl)-2,3,4,5-tetrahydro- 1H -benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide, (8)-5-(tert-butyl)-M-(8-(2-((1-methyl- 1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2trifluoroethyl)-2,3,4,5-tetrahydro- 1H-benzo[c]azepin-5-yl)- 1,2,4-oxadiazole-3-carboxamide,

5-(tert-butyl)-L1-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran4-yl) -2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (I)-5-(tert-butyl)-KG- (8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2Hpyran-4-yl)-2,3,4,5-tetrahydro -1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

- 11 040817 (8)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro -2Hpyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2 ,3,4,5tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (K)-5-(tert-butyl)-N-(8-( 2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)2,3,4,5-tetrahydro-1H-benzo [c] azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (8)-5-(tert-butyl)-M-(8-(2-((1-methyl-1H-pyrazole-4 -yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4- oxadiazole-2-carboxamide,

5-(tert-butyl)-M-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(methylsulfonyl)2,3,4, 5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (K)-5-(tert-butyl)-K-(8-(2-( (1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(methylsulfonyl)

2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (8)-5-(tert-butyl)-M-( 8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(methylsulfonyl)

2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-(2-(2-hydroxyethyl)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2.3, 4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (K)-5-(tert-butyl)-M-(2-(2 -hydroxyethyl)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5- yl)-1,3,4-oxadiazole-2-carboxamide, (8)-5-(tert-butyl)-M-(2-(2-hydroxyethyl)-8-(2-((1-isopropyl-1Н -pyrazol-4-yl)amino)pyrimidin-4yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)2, 3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (K)-5-(tert-butyl)-M-(8- (2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3yl)-2,3,4,5-tetrahydro-1H-benzo[c] azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (8)-5-(tert-butyl)-M-(8-(2-((1-isopropyl-1H-pyrazole-4 -yl)amino)pyrimidin-4-yl)-2-(oxetan-3yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole -2-carboxamide,

5-(tert-butyl)-M-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl) 2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (K)-5-(tert-butyl)-K-( 8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2trifluoroethyl)-2,3,4,5-tetrahydro- 1H- benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (8)-5-(tert-butyl)-M-(8-(2-((1-methyl-1Н -pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2trifluoroethyl)-2,3,4,5-tetrahydro- 1H-benzo[c]azepin-5-yl)-1 ,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3, 4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (K)-5-(tert-butyl)-M-(2-(2 -hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4,5-tetrahydro-1H-benzo[c]azepin-5 -yl)-1,3,4-oxadiazole-2-carboxamide, (8)-5-(tert-butyl)-M-(2-(2-hydroxyethyl)-8-(2-((1-methyl- 1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4,5-tetrahydro- 1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide ,

5-(tert-butyl)-M-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydrofuran-3yl)-2,3 ,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-K-((K)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((K)tetrahydrofuran -3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

- 12 040817

5-(tert-butyl)-K-(^)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((8)tetrahydrofuran- 3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-KG-((8)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((K)tetrahydrofuran -3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-((8)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((8)tetrahydrofuran -3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-(2-(2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3, 4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-((K)-2-((8)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine4- yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-((K)-2-((K)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine 4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-((8)-2-((K)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine4- yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-((8)-2-((8)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine4- yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-(2-((8)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4yl)-2 ,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-(2-((K)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4yl)-2 ,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-((K)-2-((K)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine 4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-((8)-2-((8)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine4- yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-LT-((8)-2-((K)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin4- yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2 ,3,4,5tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide, (R)-1-(tert-butyl)-M-(8-( 2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)2,3,4,5-tetrahydro-1H-benzo [c] azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide, (8)-1-(tert-butyl)-M-(8-(2-((1-ethyl-1H-pyrazole -4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1, 2,3-triazole-4-carboxamide,

-(tert-butyl)-M-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)2.3 ,4,5-tetrahydro-1Н-benzo[c]azepin-5-yl)-1Н-1,2,3-triazole-4-carboxamide, (R)-l-(τpetτ-butyl)-N-(8 -(2-((l-isopropyl-lH-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oκcetan-3yl)-2,3,4,5-tetrahydro-1H-benzo[c ]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide, (8)-1-(tert-butyl)-M-(8-(2-((1-isopropyl-1H- pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1, 2,3-triazole-4-carboxamide,

-(tert-butyl)-M-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydrofuran-3yl)-2.3 ,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide, l-(τpeτ-byτyl)-N-((5R)-8 -(2-((l-methyl-lH-pyrazol-4-yl)amino)pyrimidin-4-yl)-2(tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[ c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,

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-(tert-butyl)-N-((K)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydrofuran3-yl)- 2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(tert-butyl)-K-((K)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((8)tetrahydrofuran -3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(tert-butyl)-M-((8)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((8)tetrahydrofuran -3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(tert-butyl)-K-((8)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((H)tetrahydrofuran -3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(tert-butyl)-M-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2 ,3,4,5tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide, (R)-1-(tert-butyl)-M-(8 -(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)2,3,4,5-tetrahydro-1H-benzo [ c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide, (8)-1-(tert-butyl)-M-(8-(2-((1-methyl-1H -pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H- 1,2,3-triazole-4-carboxamide,

1-(tert-butyl)-M-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl) 2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide, (H)-1-(tert-butyl)-K -(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2trifluoroethyl)-2,3,4,5-tetrahydro- 1H-benzo[c]azepin-5-yl)- 1H-1,2,3-triazole-4-carboxamide, (8)-1-(tert-butyl)-M-(8-(2-((1 -methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2trifluoroethyl)-2,3,4,5-tetrahydro- 1H-benzo [c]azepin-5 - yl)- 1H-1,2,3-triazole-4-carboxamide,

1-(tert-butyl)-M-(2-(2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3, 4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(tert-butyl)-M-((H)-2-((H)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine4- yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(tert-butyl)-L1-((K)-2-((8)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin4- yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(tert-butyl)-M-((8)-2-((H)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine4- yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(tert-butyl)-M-((8)-2-((8)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin4- yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,

-(tert-butyl)-M-(2-(2-methoxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4 ,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide, (H)-1-(tert-butyl)-M-(2-( 2-methoxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4,5-tetrahydro-1H-benzo [c]azepin- 5-yl)-1H-1,2,3-triazole-4-carboxamide, (8)-1-(tert-butyl)-M-(2-(2-methoxyethyl)-8-(2-((1 -methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3- triazole-4-carboxamide,

5-(tert-butyl)-M-(2-(2,2-difluoroethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2, 3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (H)-5-(tert-butyl)-M-(2- (2,2-difluoroethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4,5-tetrahydro-1H-benzo[c ]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (8)-5-(tert-butyl)-M-(2-(2,2-difluoroethyl)-8-(2- ((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4 -oxadiazole-2-carboxamide,

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5-(tert-butyl)-KG-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5Hbenzo [7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide, (K)-5-(tert-butyl)-KG-(2-(2-((1-methyl-1Н- pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide, (8 )-5-(tert-butyl)-KG-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro5H -benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide,

KG-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene 5 -yl)-5 -(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide, (K)-K-(2-(2-((1-methyl-1H-pyrazol-4-yl )amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5Hbenzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide , (8)-KG-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5Hbenzo[7] annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide,

5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5Hbenzo [7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide, (K)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H- pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5Hbenzo[7]annulen-5-yl)-1,2,4-oxadiazol-3-carboxamide, (8 )-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro -5Hbenzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide,

5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5Hbenzo [7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide, (K)-5-(tert-butyl)-KG-(2-(2-((1-methyl-1Н- pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro 5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazol-2-carboxamide, (8 )-5-(tert-butyl)-KG-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro5Н -benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide,

3-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5Hbenzo [7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide, (K)-3-(tert-butyl)-KG-(2-(2-((1-methyl-1Н- pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide, (8 )-3-(tert-butyl)-KG-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro5H -benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide,

5-(tert-butyl)-KG-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydrobenzo[b]oxepin -5-yl)-1,3,4-oxadiazole-2-carboxamide, (K)-5-(tert-butyl)-KG-(8-(2-((1-methyl-1H-pyrazole-4- yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydrobenzo[b]oxepin-5-yl)-1,3,4-oxadiazol-2-carboxamide, (8)-5-(tert-butyl )-KG-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydrobenzo[b]oxepin-5-yl)- 1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-KG-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydrobenzo[b]oxepin -5-yl)-1,2,4-oxadiazole-2-carboxamide, (K)-5-(tert-butyl)-M-(8-(2-((1-methyl-1H-pyrazole-4- yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydrobenzo[b]oxepin-5-yl)-1,2,4-oxadiazol-2-carboxamide, (8)-5-(tert-butyl )-KG-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydrobenzo[b]oxepin-5-yl)- 1,2,4-oxadiazole-2-carboxamide,

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5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5Hcyclo hepta[c]pyridin-9-yl)-1,3,4-oxadiazol-2-carboxamide

W)-5-(tert-butyl)-K-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9- tetrahydro 5H-cyclohepta[c]pyridin-9-yl)-1,3,4-oxadiazole-2-carboxamide, (8)-5-(tert-butyl)-M-(3-(2-((1-methyl -1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro 5H-cyclohepta[c]pyridin-9-yl)-1,3,4-oxadiazol-2-carboxamide ,

5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5Hcyclohepta [c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamide, (K)-5-(tert-butyl)-K-(3-(2-((1-methyl-1H- pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro5H-cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazol-3-carboxamide, (8 )-5-(tert-butyl)-M-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro5H -cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamide,

1-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5Hcyclohepta [c]pyridin-9-yl)-1H-1,2,3-triazole-4-carboxamide, (R)-l-(τpeτ-byτyl)-N-(3-(2-((l-methyl- lH-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-teτpahydro-5Hcyclohepta[c]pyridin-9-yl)-1H-1,2,3-triazol-4- carboxamide, (8)-1-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6.7.8 ,9-tetrahydro-5Hcyclohepta[c]pyridin-9-yl)-1H-1,2,3-triazole-4-carboxamide,

5-(tert-butyl)-M-(3-(2-hydroxyethyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3, 4,5-tetrahydro-1H-benzo[c1]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (K)-5-(tert-butyl)-M-(3-(2 -hydroxyethyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4,5-tetrahydro-1H-benzo[c1]azepin-1 -yl)-1,3,4-oxadiazole-2-carboxamide, (8)-5-(tert-butyl)-M-(3-(2-hydroxyethyl)-7-(2-((1-methyl- 1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4,5-tetrahydro-1H-benzo[c1]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide ,

5-(tert-butyl)-M-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(methylsulfonyl)2,3,4, 5-tetrahydro-1H-benzo[c1]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (K)-5-(tert-butyl)-N-(7-(2-( (1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3 -(methylsulfonyl) 2,3,4,5-tetrahydro-1H-benzo[c1]azepin-1-yl)- 1,3,4-oxadiazol-2-carboxamide, (8)-5-(tert-butyl)-M-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin- 4-yl)-3-(methylsulfonyl) 2,3,4,5-tetrahydro-1H-benzo[c1]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(oxetan-3-yl)-2 ,3,4,5tetrahydro-1H-benzo[b]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (K)-5-(tert-butyl)-N-(7-( 2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(oxetan-3-yl)2,3,4,5-tetrahydro-1H-benzo[c1] azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (8)-5-(tert-butyl)-M-(7-(2-((1-methyl-1H-pyrazole-4 -yl)amino)pyrimidin-4-yl)-3-(oxetan-3-yl)2,3,4,5-tetrahydro-1H-benzo[c1]azepin-1-yl)-1,3,4- oxadiazole-2-carboxamide,

5-(tert-butyl)-M-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(tetrahydrofuran-3yl)-2, 3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-((K)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-((S)tetrahydrofuran -3-yl)-2,3,4,5-tetrahydro-1H-benzo[c1]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, 5-(tert-butyl)-K -(II)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3 -((R)tetrahydrofuran-3-yl)-2.3, 4,5-tetrahydro-1H-benzo[c1]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,

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5-(tert-butyl)-M-((8)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-((8)tetrahydrofuran -3-yl)-2,3,4,5-tetrahydro-1H-benzo[c1]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-((8)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-((K)tetrahydrofuran -3-yl)-2,3,4,5-tetrahydro-1H-benzo[c1]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-(3-(2-hydroxy-2-methylpropyl)-7-(2-((1-methyl-1H-pyrazol-4yl)amino)pyrimidin-4-yl)-2 ,3,4,5-tetrahydro-1H-benzo[c1]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (K)-5-(tert-butyl)-N-(3 -(2-hydroxy-2-methylpropyl)-7-(2-((1-methyl-1H-pyrazol-4yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo [c1]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (8)-5-(tert-butyl)-M-(3-(2-hydroxy-2-methylpropyl)-7 -(2-((1-methyl-1H-pyrazol-4yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c1]azepin-1-yl)-1, 3,4-oxadiazole-2-carboxamide,

1-(tert-butyl)-K-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1Hbenzo [c!]azepin-1-yl)-1H-1,2,3-triazole-4-carboxamide, (R)-1 -(tert-butyl)-M-(7-(2-((1-methyl - 1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro1H-benzo[c!]azepin-1-yl)-1H-1,2,3-triazol- 4-carboxamide, (8)-1-(tert-butyl)-M-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3 ,4,5-tetrahydro1H-benzo[c!]azepin-1-yl)-1H-1,2,3-triazole-4-carboxamide,

-(tert-butyl)-M-(3-methyl-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydro- 1H-benzo[b]azepin-1-yl)- 1H-1,2,3-triazole-4-carboxamide, (R)-l-(τpet-butyl)-N-(3-methyl-7-(2 -((l-methyl-lH-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydro-1H-benzo [c!]azepin-1 -yl)- 1H-1, 2,3-triazole-4-carboxamide, (8)-1-(tert-butyl)-M-(3-methyl-7-(2-((1-methyl-1H-pyrazol-4-yl)amino) pyrimidin-4-yl)-2,3,4,5tetrahydro-1H-benzo[c!]azepin-1-yl)-1H-1,2,3-triazole-4-carboxamide,

-(tert-butyl)-M-(3 -(2-hydroxyethyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4 ,5-tetrahydro-1H-benzo[c1]azepin-1-yl)-1H-1,2,3-triazole-4-carboxamide, (R)-1-(tert-butyl)-M-(3-( 2-hydroxyethyl)-7 -(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4,5-tetrahydro-1H-benzo[c1]azepin- 1-yl)-1H-1,2,3-triazole-4-carboxamide, (S)-l -(tert-butyl)-M-(3 -(2-hydroxyethyl)-7-(2-(( 1 -methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4,5-tetrahydro-1H-benzo[c1]azepin-1-yl)-1H-1,2,3- triazole-4-carboxamide,

5-(tert-butyl)-M-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl) 2,3,4,5-tetrahydro- 1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazol-3-carboxamide, (R)-5-(τpet-butyl)-N- (8-(2-((l-methyl-lH-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2trifluoroethyl)-2,3,4,5-tetrahydro- 1H -benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide, (8)-5-(tert-butyl)-M-(8-(2-((1-methyl- 1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2trifluoroethyl)-2,3,4,5-tetrahydro- 1H-benzo[c]azepin-5-yl)- 1,2,4-oxadiazole-3-carboxamide,

5-(tert-butyl)-M-(2-(2-(dimethylamino)acetyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4 yl)-2 ,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide, (R)-5-(τpet-butyl)-N-(2 -(2-(dimethylamino)acetyl)-8-(2-((l-methyl-lH-pyrazol-4yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[ c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide, (8)-5-(tert-butyl)-M-(2-(2-(dimethylamino)acetyl)-8-( 2-((1-methyl-1H-pyrazol-4yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2, 4-oxadiazole-3-carboxamide,

M-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro1H-benzo [c]azepin-5-yl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,3,4-oxadiazol-2-carboxamide,

- 17 040817 (R)-M-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3, 4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,3,4-oxadiazole-2carboxamide, (8) -LH-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydro-1H- benzo[c]azepin-5-yl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,3,4-oxadiazol-2carboxamide,

N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1Hbenzo[c]azepine -5 -yl) -5- (1,1,1 -trifluoro-2-methylpropan-2 -yl) -1,3,4-oxadiazol-2-carboxamide, (K) -M - (2-methyl- 8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)-5 -(1,1,1 -trifluoro-2-methylpropan-2 -yl)-1,3,4-oxadiazol-2-carboxamide, (8)-M-(2-methyl-8-(2-(( 1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)-5-(1,1,1 -trifluoro-2-methylpropan-2 -yl)-1,3,4-oxadiazol-2-carboxamide,

5-(1,1-difluoro-2-methylpropan-2-yl)-M-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2 (oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (R)-5-( l, 1-difluoro-2-methylpropan-2-yl)-M-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl) 2-(oxetan- 3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (S)-5-( 1.1 -difluoro-2-methylpropan-2-yl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl) 2-(oxetan-3 - yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(1,1-difluoro-2-methylpropan-2-yl)-N-(2-(2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4yl)amino)pyrimidine- 4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, 5-(1,1-difluoro-2 -methylpropan-2-yl)-K-(2-((8)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4yl)amino)pyrimidin-4-yl)-2 ,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (R)-5-(l, 1-difluoro-2-methylpropane -2-yl)-K-(2-((8)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4yl)amino)pyrimidin-4-yl)-2,3 ,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (R)-5-(1,1-difluoro-2-methylpropan-2 -yl)-T4-(2-((K)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4yl)amino)pyrimidin-4-yl)-2,3,4 ,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazol-2-carboxamide, (8)-5-(1,1-difluoro-2-methylpropan-2-yl )-K-(2-((K)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4yl)amino)pyrimidin-4-yl)-2,3,4,5 -tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (8)-5-(1,1-difluoro-2-methylpropane -2-yl)-K-(2-((8)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4yl)amino)pyrimidin-4-yl)-2,3 ,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(1-fluoro-2-methylpropan-2-yl)-M-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2(oxetane -3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (R)-5-(1- fluoro-2-methylpropan-2-yl)-M-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2(oxetan-3-yl) -2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (8)-5-(1-fluoro-2-methylpropane -2-yl)-M-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2(oxetan-3-yl)-2.3, 4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, 5-(1-fluoro-2-methylpropan-2-yl)-N-( 2-(2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c] azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, 5-(1-fluoro-2-methylpropan-2-yl)-K-(2-((8)-2-hydroxypropyl)- 8-(2-((1-methyl-1H-pyrazol-4yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1 ,3,4-oxadiazole-2-carboxamide, (R)-5-(1-fluoro-2-methylpropan-2-yl)-N-(2-((8)-2-hydroxypropyl)-8-(2 -((1-methyl-1H-pyrazole-4i l)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

- 18 040817 (K)-5-(1-fluoro-2-methylpropan-2-yl)-K-(2-((K)-2-hydroxypropyl)-8-(2-((1-methyl-1H -pyrazol-4yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, ( 8)-5-(1-fluoro-2-methylpropan-2-yl)-K-(2-((K)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4yl )amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (8)-5 -(1-fluoro-2-methylpropan-2-yl)-M-(2-((8)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4yl)amino)pyrimidine -4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-cyclobutyl-M-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydro-1H-benzo [c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (K)-5-cyclobutyl-M-(2-methyl-8-(2-((1-methyl-1H- pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (8 )-5-cyclobutyl-M-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydro-1H -benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(2-cyanopropan-2-yl)-M-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3 ,4,5 tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (R)-5-(2-cyanopropan-2-yl)-C- (2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4,5-tetrahydro- 1H-benzo [c]azepin- 5-yl)-1,3,4-oxadiazole-2-carboxamide, (S)-5-(2-cyano-propan-2-yl)-C-(2-methyl-8-(2-((1- methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazol-2 -carboxamide,

5-(2-cyanopropan-2-yl)-C-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4 yl)- 2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (Н)-5-(2-cyanopropan-2-yl) -N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H- benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (8)-5-(2-cyanopropan-2-yl)-M-(2-(2-hydroxyethyl)- 8-(2-((1-methyl-1H-pyrazol-4yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1 ,3,4-oxadiazol-2-carboxamide, 1-isopropyl-C-(8-(2-((1-methyl-III-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetane -3-yl)-2,3,4,5tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide, (R)-1-isopropyl-N -(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)2,3,4,5-tetrahydro-1H -benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide, (8)-1-isopropyl-C-(8-(2-((1-methyl-1H- pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1 ,2,3-tr iazole-4-carboxamide,

1-cyclobutyl-C-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4 ,5tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide, (R)-1-cyclobutyl-N-(8-(2-(( 1 - methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl) -1H-1,2,3-triazol-4-carboxamide, (8)-1-cyclobutyl-M-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4 -yl)-2-(oxetan-3-yl)2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,

5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2 ,3,4,5tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-thiadiazole-2-carboxamide, (I)-5-(tert-butyl)-M-(8-( 2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)2,3,4,5-tetrahydro-1H-benzo [c] azepin-5-yl)-1,3,4-thiadiazole-2-carboxamide, (8)-5-(tert-butyl)-M-(8-(2-((1-methyl-1H-pyrazole-4 -yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4- thiadiazole-2-carboxamide,

- 19 040817

-(tert-butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4yl)-2,3,4, 5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-5-carboxamide, (K)-3-(tert-butyl)-N-(2-(3-hydroxycyclobutyl )-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin 4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5- yl)-1,2,4-oxadiazole-5-carboxamide, (S)-3 -(tert-butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H -pyrazol-4-yl)amino)pyrimidin4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-5-carboxamide,

1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1Hbenzo [c] azepin-5 -yl) - 1H-1,2,3 -triazo l-4-carboxamide, (R) -1- (tert-butyl) -KG - (8- (2- (( 1-methyl -1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazol-4 -carboxamide, (8)-1-(tert-butyl)-M-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2.3, 4,5-tetrahydro1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(tert-butyl)-N-(2-ethyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydro -1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide, (I)-1-(trst-butyl)-M-(2-ethyl-8-( 2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1, 2,3-triazole-4-carboxamide, (8)-1-(tert-butyl)-M-(2-ethyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino) pyrimidin-4-yl)-2,3,4,5tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,

-(tert-butyl)-M-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4yl)-2,3,4, 5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide, (R)-l-(τpeτ-byτyl)-N-(2-(3 -hydroκcicyclobutyl)-8-(2-((l-methyl-lH-pyrazol-4-yl)amino)pyrimidin 4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5 -yl)-1H-1,2,3-triazole-4-carboxamide, (S)-l -(tert-butyl)-M-(2-(3-hydroxycyclobutyl)-8-(2-(( 1 - methyl-1H-pyrazol-4-yl)amino)pyrimidin4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazol- 4-carboxamide,

1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran4-yl) -2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide, (R)-1 -(tert-butyl)- M-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2Hpyran-4-yl)-2,3,4,5 -tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide, (8)-1-(tert-butyl)-N-(8-(2- ((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2Hpyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c ]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(tert-butyl)-M-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3, 4,5-tetrahydro-1Н-benzo[c]azepin-5-yl)-1Н-1,2,3-triazole-4-carboxamide, (R)-l-(τpetτ-byτyl)-N-(2- (2-hydroxyethyl)-8-(2-((l-methyl-lH-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide, (8)-1-(tert-butyl)-M-(2-(2-hydroxyethyl)-8-(2-(( 1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3 -triazole-4-carboxamide, l-(τpet-butyl)-N-(2-((R)-2-hydroκcyppopyl)-8-(2-((l-methyl-lH-pyrazol-4-yl)amino )pyrimidin-4yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide, (R)-1 -( trst-butyl)-M-(2-((I)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin4-yl)-2.3, 4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide, (R)-l-(τpeτ-butyl)-N-(2- ((S)-2-hydroxypyrimidin4-yl)-8-(2-((l-methyl-lH-pyrazol-4-yl)amino)pyrimidin4-yl)-2,3,4,5-tetrahydro-1H-benzo[ c]azepin-5-yl)-1H- 1,2,3-triazole-4-carboxamide,

- 20 040817 (8)-1-(tert-butyl)-N-(2-((K)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino )pyrimidin4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide, (8)-1-( tert-butyl)-M-(2-((8)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin4-yl)-2.3, 4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,

5-(tert-butyl)-N-(2-(2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3, 4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,

5-(tert-butyl)-M-(2-((K)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4yl)-2 ,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide, (K)-5-(tert-butyl)-M-(2 -((K)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin4-yl)-2,3,4,5-tetrahydro-1H-benzo [c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide, (K)-5-(tert-butyl)-M-(2-((8)-2-hydroxypropyl)-8 -(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1, 2,4-oxadiazole-3-carboxamide, (8)-5-(tert-butyl)-M-(2-((K)-2-hydroxypropyl)-8-(2-((1-methyl-1H- pyrazol-4-yl)amino)pyrimidin4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide, (8 )-5-(tert-butyl)-M-(2-((8)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin4-yl) -2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,

5-(tert-butyl)-M-(2-(2-methoxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2.3, 4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide, (K)-5-(tert-butyl)-M-(2-(2 -methoxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4,5-tetrahydro-1H-benzo[c]azepin-5 -yl)-1,2,4-oxadiazole-3-carboxamide, (8)-5-(tert-butyl)-M-(2-(2-methoxyethyl)-8-(2-((1-methyl- 1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide ,

5-(tert-butyl)-M-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydrofuran-3yl)-2,3 ,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-KG-((K)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((K)tetrahydrofuran -3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, 5-(tert-butyl)-Y -((K)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)tetrahydrofuran-3-yl)-2.3 ,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, 5-(tert-butyl)-N-((8)-8-( 2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((K)tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H- benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, 5-(tert-butyl)-M-((8)-8-(2-((1-methyl-1H -pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((8)tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl )-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4yl)-2,3,4 ,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (K)-5-(tert-butyl)-M-(2-(3- hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin 4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5 -yl)-1,3,4-oxadiazole-2-carboxamide, (8)-5-(tert-butyl)-M-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl- 1H-pyrazol-4-yl)amino)pyrimidin4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-(2-ethyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydro -1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (K)-5-(tert-butyl)-M-(2-ethyl-8-(2- ((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4- oxadiazole-2-carboxamide,

- 21 040817 (8)-5-(tert-butyl)-M-(2-ethyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)- 2,3,4,5tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-(2-(2-hydroxy-2-methylpropyl)-8-(2-((1-methyl-1H-pyrazol-4yl)amino)pyrimidin-4-yl)-2 ,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, 5-tert-butyl-1,3,4-oxadiazol-2 -carboxylic acid {(R)-2 -(2-hydroxy-2-methylpropyl)-8-[2-(1 methyl-1H-pyrazol-4-ylamino)-pyrimidin-4-y1]-2,3,4 ,5-tetrahydro-1H-2-benzazepin-5-yl}-amide, (8)-5-(tert-butyl)-N-(2-(2-hydroxy-2-methylpropyl)-8-(2- ((1-methyl-1H-pyrazol-4yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4- oxadiazole-2-carboxamide,

5-(tert-butyl)-M-(2-(3-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3, 4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazol-2-carboxamide, (K)-5-(tert-butyl)-M-(2-( 3-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5 -yl)-1,3,4-oxadiazole-2-carboxamide, (8)-5-(tert-butyl)-M-(2-(3-hydroxypropyl)-8-(2-((1-methyl- 1H-pyrazol-4-yl)amino)pyrimidin-4yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

N-(8-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1Hbenzo [c ] azepin-5 -yl) -5 - (tert-butyl) -1,3,4-oxadiazol-2-carboxamide, (K) -K- (8- (2- ((1H-pyrazol-4-yl )amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)-5-(tert-butyl)-1 ,3,4-oxadiazol-2-carboxamide, (8)-K-(8-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3- yl)-2,3,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)-5-(tert-butyl)-1,3,4-oxadiazol-2-carboxamide, (K)-5 -(tert-butyl)-K-(8-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-2( 2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (8)-5-(tert-butyl )-K-(8-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-2(2-hydroxyethyl)- 2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-(8-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-2 -(2hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (K)-1-(tert-butyl )-K-(8-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-2(2-hydroxyethyl)- 2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide, (8)-1-(tert-butyl)-K -(8-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-2(2-hydroxyethyl)-2.3 ,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(tert-butyl)-N-(8-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-2 -(2hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,

M-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1Hbenzo[c]azepine -5 -yl) -5 - (1 -methylcyclopropyl) -1,3,4-oxadiazol-2-carboxamide, (K) -M- (2-methyl-8- (2- ((1-methyl-1H -pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)-5-(1-methylcyclopropyl)-1,3,4 -oxadiazol-2-carboxamide, (8)-M-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3 ,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)-5-(1-methylcyclopropyl)-1,3,4-oxadiazol-2-carboxamide,

5-(tert-butyl)-M-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydrofuran-3-yl)2, 3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazol-2-carboxamide, 5-(tert-butyl)-N-((K)-8 -(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((K)tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro- 1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

- 22 040817

5-(tert-butyl)-K-((K)-8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((8)tetrahydrofuran -3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-N-((8)-8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((K)tetrahydrofuran -3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-N-((8)-8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((8)tetrahydrofuran -3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-K-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)2.3, 4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (K)-5-(tert-butyl)-M-(8-(2 -((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)2,3,4,5-tetrahydro-1H-benzo[c]azepin-5 -yl)-1,3,4-oxadiazole-2-carboxamide, (8)-5-(tert-butyl)-M-(8-(2-((1-ethyl-1H-pyrazol-4-yl) amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide ,

5-(tert-butyl)-M-(2-methyl-8-(2-((1-methyl-1H-parizol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydro -1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (K)-5-(tert-butyl)-M-(2-methyl-8-(2- ((1-methyl-1H-parizol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4- oxadiazole-2-carboxamide, (8)-5-(tert-butyl)-M-(2-methyl-8-(2-((1-methyl-III-parizol-4-yl)amino)pyrimidin-4- yl)-2,3,4,5tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)2, 3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (K)-5-(tert-butyl)-M-(8- (2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo [c] azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (8)-5-(tert-butyl)-M-(8-(2-((1,5-dimethyl-1H-pyrazole -4-yl)amino)pyrimidin-4-yl)-2-(2hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole -2-carboxamide,

1-(tert-butyl)-LH-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)2, 3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide, (K)-1-(tert-butyl)-M-( 8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[ c]azepin-5-yl)- 1H-1,2,3-triazole-4-carboxamide, (8)-1-(tert-butyl)-M-(8-(2-((1,5-dimethyl -1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2hydroxyethyl)-2,3,4,5-tetrahydro- 1H-benzo[c]azepin-5-yl)- 1H-1 ,2,3-triazole-4-carboxamide,

5-(tert-butyl)-M-(8-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl) 2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide, (K)-5-(tert-butyl)-K-( 8-(2-((1,3-dimethyl-1Н-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)2,3,4,5-tetrahydro- 1Н -benzo[c]azepin-5-yl)-1,2,4-oxadiazol-3-carboxamide, (8)-5-(tert-butyl)-M-(8-(2-((1,3 -dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl )-1,2,4-oxadiazol-3-carboxamide,

-(tert-butyl)-M-(8-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)2 ,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide, (K)-1-(tert-butyl)-bg- (8-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)2,3,4,5-tetrahydro- 1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide, (8)-1-(tert-butyl)-M-(8-(2-((1 ,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)2,3,4,5-tetrahydro-1H-benzo[c]azepin-5 -yl)-1H-1,2,3-triazole-4-carboxamide,

- 23 040817

5-(tert-butyl)-M-(8-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)2, 3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazol-3-carboxamide, (K)-5-(tert-butyl)-M-(8 -(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c ]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide, (8)-5-(tert-butyl)-M-(8-(2-((1,3-dimethyl-1Н- pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4- oxadiazole-3-carboxamide, 1-(tert-butyl)-M-(2-(2-hydroxyethyl)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl) 2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide, (R)-1-(tert-butyl) -M-(2-(2-hydroxyethyl)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4 yl)-2,3,4,5-tetrahydro- 1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide, (8)-1-(tert-butyl)-M-(2-(2-hydroxyethyl)- 8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4yl)-2,3,4,5-tetrahydro-1H-benzo[c] azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide,

5-(tert-butyl)-M-(2-(cyclopropylmethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4, 5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (K)-5-(tert-butyl)-M-(2-(cyclopropylmethyl)- 8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1 ,3,4-oxadiazole-2-carboxamide, (8)-5-(tert-butyl)-M-(2-(cyclopropylmethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl )amino)pyrimidin-4yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-(8-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2trifluoromethyl) -2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (K)-5-(tert-butyl)-M- (8-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2trifluoromethyl)-2,3,4,5-tetrahydro -1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (8)-5-(tert-butyl)-M-(8-(2-((1, 3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2trifluoromethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5 -yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5Hbenzo [7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide, (K)-5-(tert-butyl)-KG-(2-(2-((1-methyl-1Н- pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazol-2-carboxamide, (8 )-5-(tert-butyl)-M-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro5H -benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide,

N-(2-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)- 5 (tert-butyl) -1,2,4-oxadiazole-3 -carboxamide, (K) -K- (2- (2- ((1H-pyrazol-4-yl) amino) pyrimidin-4-yl) - 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5yl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide, (8)-R-(2- (2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annu len-5yl)-5-(tert-butyl )-1,2,4-oxadiazole-3-carboxamide,

5-(tert-butyl)-M-(2-(2-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)amino)pyrimidine 4- yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide, (K)-5-(tert-butyl)- K-(2-(2-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3yl)amino)pyrimidin-4-yl)-6,7,8,9 -tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide, (8)-5-(tert-butyl)-N-(2-(2-(( 5-methyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-3yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7] annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide,

- 24 040817

N-(2-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)- 5(tert-butyl)-1,3,4-oxadiazol-2-carboxamide, (K)-K-(2-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl) -6,7,8,9-tetrahydro-5H-benzo[7]annulen-5yl)-5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamide, (8)-K-(2 -(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5yl)-5-(tert-butyl )-1,3,4-oxadiazole-2-carboxamide,

1-(tert-butyl)-K-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5Hbenzo [7]annulen-5-yl)-1H-1,2,3-triazole-4-carboxamide, (R)-1 -(tert-butyl)-N-(2-(2-(( 1 -methyl- 1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro5H-benzo[7]annulen-5-yl)-1H-1,2,3-triazol-4- carboxamide, (8)-1-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6.7.8 ,9-tetrahydro5H-benzo[7]annulen-5-yl)-1H-1,2,3-triazole-4-carboxamide,

5-(tert-butyl)-4-methyl-H-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9tetrahydro -5H-benzo[7]annulen-5-yl)-4H-1,2,4-triazole-3-carboxamide, (K)-5-(tert-butyl)-4-methyl-K-(2-( 2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9tetrahydro-5H-benzo[7]annulen-5-yl)-4H-1, 2,4-triazole-3-carboxamide, (8)-5-(tert-butyl)-4-methyl-K-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino) pyrimidin-4-yl)-6,7,8,9tetrahydro-5H-benzo[7]annulen-5-yl)-4H-1,2,4-triazole-3-carboxamide,

2-isopropyl-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5Hbenzo[7]annulene -5-yl)-2H-1,2,3-triazol-4-carboxamide, (K)-2-isopropyl-i-(2-(2-((1-methyl-1H-pyrazol-4-yl) amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H benzo[7]annulen-5-yl)-2H-1,2,3-triazole-4-carboxamide, (8)- 2-isopropyl-i-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5Hbenzo[7]annulene -5-yl)-2H-1,2,3-triazole-4-carboxamide,

5-(tert-butyl)-M-(8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9tetrahydro -5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-N-((88)-8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6.7 ,8,9tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-N-((8K)-8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6.7 ,8,9tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-N-((5K,88)-8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6 ,7,8,9tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-N-((58.8K)-8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6 ,7,8,9tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-N-((5K,8K)-8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6 ,7,8,9tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-N-((58.88)-8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6 ,7,8,9tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide,

M-(8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5Hbenzo[7] annulene -5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-carboxamide,

N-((88)-8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5Hbenzo [7] annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide,

- 25 040817

N-((8K)-8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5Hbenzo [7] annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide,

N-((5K,88)-8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro -5Hbenzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide,

N-((58.8K)-8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro -5Hbenzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide,

N-((58.88)-8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro -5Hbenzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide,

N-((58.8K)-8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro -5Hbenzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide,

M-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen5-yl )-5 -(1-methylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide, (K)-M-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino )pyrimidin-4-yl)-6,7,8,9-tetrahydro-5Hbenzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide, ( 8)-M-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5Hbenzo[7]annulen- 5-yl)-5-(1-methylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1Hbenzo [c] azepin-5-yl) -1,3,4-oxadiazol-2-carboxamide, (K)-5-(tert-butyl)-M-(8-(2-((1-methyl-1H -pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazol-2-carboxamide, (8)-5-(tert-butyl)-M-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5 -tetrahydro1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazol-2-carboxamide, 5-cyclobutyl-M-(2-(2-hydroxyethyl)-8-(2-((1 -methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazol -2-carboxamide, (K)-5-cyclobutyl-M-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl )2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazol-2-carboxamide, (8)-5-cyclobutyl-K-(2- (2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazol-2-carboxamide,

5-(tert-butyl)-M-(2-(2-ethoxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3 ,4,5tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (K)-5-(tert-butyl)-M-(2-(2- ethoxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4,5-tetrahydro-1H-benzo [c]azepin-5- yl)-1,3,4-oxadiazol-2-carboxamide, (8)-5-(tert-butyl)-M-(2-(2-ethoxyethyl)-8-(2-((1-methyl- 1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4,5-tetrahydro- 1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazol-2- carboxamide,

5-(tert-butyl)-M-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1Hbenzo [d] azepin-1 -yl)-1,3,4-oxadiazol-2-carboxamide, (K)-5-(tert-butyl)-M-(7-(2-((1-methyl-1H -pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazol-2-carboxamide, (8)-5-(tert-butyl)-I -(7-(2-((1 -methyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4, 5-tetrahydro1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazol-2-carboxamide,

-(tert-butyl)-M-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(oxetan-3-yl)-2, 3,4,5tetrahydro-1H-benzo[b]azepin-1-yl)-1H-1,2,3-triazole-4-carboxamide,

- 26 040817 (R)-1-(tert-butyl)-M-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(oxetane -3-yl)2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)-1H-1,2,3-triazole-4-carboxamide, (8)-1-(tert -butyl)-M-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(oxetan-3-yl)2,3,4, 5-tetrahydro-1H-benzo[b]azepin-1-yl)-1H-1,2,3-triazole-4-carboxamide,

5-(tert-butyl)-M-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydrofuran-3yl)-2,3 ,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-thiadiazole-2-carboxamide,

5-(tert-butyl)-K-((H)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((H)tetrahydrofuran -3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-thiadiazole-2-carboxamide,

5-(tert-butyl)-K-((H)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((8)tetrahydrofuran -3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-thiadiazole-2-carboxamide,

5-(tert-butyl)-K-((8)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((H)tetrahydrofuran -3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-thiadiazole-2-carboxamide,

5-(tert-butyl)-M-((8)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((8)tetrahydrofuran -3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-thiadiazole-2-carboxamide,

5-(tert-butyl)-M-(3-methyl-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydro -1H-benzo[b]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (K)-5-(tert-butyl)-M-(3-methyl-7-(2- ((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydro-1H-benzo[b]azepin-1-yl)-1,3,4- oxadiazole-2-carboxamide, (8)-5-(tert-butyl)-M-(3-methyl-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)-2,3,4,5tetrahydro-1H-benzo [b]azepin-1 -yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5Hbenzo [7]annulen-5-yl)-1,3,4-thiadiazole-2-carboxamide, (K)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H- pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro 5H-benzo[7]annulen-5-yl)-1,3,4-thiadiazole-2-carboxamide, ( 8)-5-(tert-butyl)-M-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9- tetrahydro 5H-benzo[7]annulen-5-yl)-1,3,4-thiadiazole-2-carboxamide,

5-(tert-butyl)-M-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl) 2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide, tert-butyl-1-(5-(tert-butyl)- 1,3,4-oxadiazol-2-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4yl)amino)pyrimidin-4-yl)-1,2,4,5-tetrahydro-3N -benzo[b]aze pin-3-carboxylate, (I)-tert-butyl-1 -(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-7-(2-( (1-methyl-1H-pyrazol-4yl)amino)pyrimidin-4-yl)-1,2,4,5-tetrahydro-3H-benzo[c!]azepin-3-carboxylate, (8)-tert-butyl -1-(5-(tert-butyl)-1,3,4-oxadiazol-2-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4yl)amino)pyrimidin-4-yl) -1,2,4,5-tetrahydro-3H-benzo[d]aze pin-3-carboxylate,

5-(tert-butyl)-M-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(2,2,2-trifluoroethyl) 2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (Н)-5-(tert-butyl)-K-( 7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(2,2,2trifluoroethyl)-2,3,4,5-tetrahydro- 1H- benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (8)-5-(tert-butyl)-M-(7-(2-((1-methyl-1H -pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(2,2,2trifluoroethyl)-2,3,4,5-tetrahydro- 1H-benzo [d]azepin-1 -yl)-1 ,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-(3-(2-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl) 2.3 ,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,

- 27 040817

5-(tert-butyl)-N-(3-((8)-2-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4yl)-2 ,3,4,5-tetrahydro-1H-benzo[c1]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (K)-5-(tert-butyl)-M-(3 -((8)-2-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin4-yl)-2,3,4,5-tetrahydro-1H-benzo [c1]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (8)-5-(tert-butyl)-M-(3-((8)-2-hydroxypropyl)-7 -(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin4-yl)-2,3,4,5-tetrahydro-1H-benzo[c1]azepin-1-yl)-1, 3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-(3-((K)-2-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4yl)-2 ,3,4,5-tetrahydro-1H-benzo[c1]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (K)-5-(tert-butyl)-M-(3 -((K)-2-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin4-yl)-2,3,4,5-tetrahydro-1H-benzo [c1]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (8)-5-(tert-butyl)-LT-(3-((K)-2-hydroxypropyl)-7 -(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin4-yl)-2,3,4,5-tetrahydro-1H-benzo[c1]azepin-1-yl)-1, 3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(tetrahydro-2H-pyran 4- yl)-2,3,4,5-tetrahydro-1H-benzo[c1]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (K)-5-(tert-butyl)- N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(tetrahydro-2Hpyran-4-yl)-2,3,4,5 -tetrahydro-N-benzo[c1]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (8)-5-(tert-butyl)-M-(7-(2-(( 1-methyl-III-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(tetrahydro-2Hpyran-4-yl)-2,3,4,5-tetrahydro-III-benzo[c1]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-(3 -(3-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3, 4,5-tetrahydro-N-benzo[c1]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (8)-5-(tert-butyl)-M-(3-(3 -hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1- yl)-1,3,4-oxadiazole-2-carboxamide, (K)-5-(tert-butyl)-M-(3-(3-hydroxypropyl)-7-(2-((1-methyl-1H -pyrazol-4-yl)amino)pyrimidin-4yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(3,3-difluorocyclobutyl)-bT-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4, 5-tetrahydro-N-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (K)-5-(3,3-difluorocyclobutyl)-M-(2-methyl- 8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4,5-tetrahydro-III-benzo [c]azepin-5-yl)- 1,3,4-oxadiazole-2-carboxamide, (8)-5-(3,3-difluorocyclobutyl)-N-(2-methyl-8-(2-((1-methyl-1H-pyrazole-4- yl)amino)pyrimidin-4-yl)2,3,4,5-tetrahydro-III-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(3,3-difluorocyclobutyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-III-pyrazol-4yl)amino)pyrimidin-4-yl)-2,3 ,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (K)-5-(3,3-difluorocyclobutyl)-K-(2 -(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide, (8)-5-(3,3-difluorocyclobutyl)-N-(2-(2-hydroxyethyl)-8-(2-(( 1-methyl-1H-pyrazol-4yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazol- 2-carboxamide,

5-(tert-butyl)-N-(8-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-2 -(2hydroxyethyl)-2,3,4,5-tetrahydro-N-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide, (R)-5-(tert-butyl )-K-(8-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-2(2-hydroxyethyl)- 2,3,4,5-tetrahydro-N-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide, (8)-5-(tert-butyl)-N-( 8-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-2(2-hydroxyethyl)-2,3,4 ,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide,

- 28 040817

5-(tert-butyl)-N-(8-hydroxy-2-(2-((1-methyl-III-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9tetrahydro -5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide, (K.)-5-(tert-butyl)-M-(8-hydroxy-2-(2 -((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4 -oxadiazole-2-carboxamide, (8)-5-(tert-butyl)-N-(8-hydroxy-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4 -yl)-6,7,8,9tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(tert-butyl)-M-(2-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro5H -benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide, (K)-5-(tert-butyl)-M-(2-(2-((1,5- dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazol-3 - carboxamide, (8)-5-(tert-butyl)-M-(2-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6.7 ,8,9tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide,

5-(tert-butyl)-M-(2-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)6, 7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide, (K)-5-(tert-butyl)-M-(2- (2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)6,7,8,9-tetrahydro-5H-benzo[7 ]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide, (8)-5-(tert-butyl)-M-(2-(2-((5,6-dihydro-4H- pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4 -oxadiazole-3-carboxamide,

5-(tert-butyl)-M-(2-(2-((1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)6,7,8, 9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide, (K)-5-(tert-butyl)-M-(2-(2-( (1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)- 1,2,4-oxadiazole-3-carboxamide, (8)-5-(tert-butyl)-M-(2-(2-((1-methyl-5-(trifluoromethyl)-1H-pyrazole-4- yl)amino)pyrimidin-4-yl)6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazol-3-carboxamide,

1-(tert-butyl)-M-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5Hbenzo [7]annulen-5-yl)-1H-1,2,3-triazole-4-carboxamide, (R)-1-(tert-butyl)-M-(2-(2-((1-methyl- 1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5Hbenzo[7]annulen-5-yl)-1H-1,2,3-triazol-4- carboxamide, (8)-1-(tert-butyl)-M-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6.7.8 ,9-tetrahydro-5Hbenzo[7]annulen-5-yl)-1H-1,2,3-triazole-4-carboxamide,

M-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro1H-benzo [c]azepin-5-yl)-5-(1-methylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide, (K)-M-(2-(2-hydroxyethyl)-8-(2 -((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydro-1H-benzo[c]azepin-5-yl)-5-(1- methylcyclopropyl)-1,3,4-oxadiazol-2-carboxamide, (8)-M-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino )pyrimidin-4-yl)-2,3,4,5tetrahydro-1H-benzo[c]azepin-5-yl)-5-(1-methylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide, or its pharmaceutically acceptable salt.

The present invention also provides a crystalline form of (R)-1-(tert-butyl)-N-(8-(2-((1methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2- (oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin5-yl)-1H-1,2,3-triazole-4-carboxamide (compound 27):

- 29 040817

As used herein, the term crystalline refers to a solid form having a crystalline structure, with the individual molecules having a highly homogeneous, regular, closed chemical configuration.

Form A.

In one embodiment, this invention also provides a crystalline form A (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4 -yl)-2-(oxetan-3-yl)-2,3,4,5tetrahydro-1 H-benzo[c]azepin-5 -yl)-1H-1,2,3-triazole-4-carboxamide.

In one aspect, crystalline form A is characterized by at least three, at least four, or at least five peaks in an X-ray powder diffraction (XRD) pattern at 2θ angles selected from 5.7°, 7.9°, 9.7°, 18.2°, 19.0° and 22.4°. In one aspect, crystalline form A is characterized by peaks in the powder x-ray diffraction pattern (PGD) at 2θ angles selected from 5.7°, 7.9°, 9.7°, 18.2°, 19.0°, and 22.4° . In some embodiments, the peaks for crystalline Form A described above have a relative intensity of at least 5%, at least 10%, or at least 15%. In another aspect, crystalline form A is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, or at least nineteen peaks on the PXR at 2θ angles selected from 4.3°, 5.7°, 7.9°, 8.7°, 9.7°, 11.9°, 13.1°, 14.8°, 15.2°, 16.1°, 17.0°, 17.8°, 18.2°, 19.0°, 20.5°, 21.2°, 22.4°, 22.8°, 23.8° and 25.6°.

As used herein, the term relative intensity refers to the ratio of the intensity of the peak in question to the intensity of the largest peak.

In another aspect, crystalline form A has a diffraction pattern (XRD) substantially the same as the diffraction pattern (XRD) shown in FIG. 1.

In another aspect, crystalline form A has a differential scanning calorimetry (DSC) profile substantially the same as the DSC profile depicted in FIG. 2. In particular, crystalline form A on the DSC profile is characterized by the temperature of the beginning of decomposition at 175.6°C±2°C. In one embodiment of the invention, crystalline form A has a melting point of 186°C±2°C.

In one aspect, crystalline Form A has a TGA profile substantially the same as the TGA profile depicted in FIG. 2. In particular, the TGA profile indicates that crystalline form A is a hydrate.

As used herein, the term hydrate refers to a crystalline solid adduct containing (R)-1-(tert-butyl-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin- 4-yl)-2(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide and either a stoichiometric or non-stoichiometric amount of water incorporated into the crystal structure Techniques known in the art for determining the amount of water present include, for example, TGA and Karl Fischer analysis.

In another aspect, crystalline Form A has a solid state ¹³ C-NMR spectrum substantially the same as that shown in FIG. 3B. In one embodiment of the invention, crystalline form A has chemical shifts at 143.7 ppm and/or 134.4 ppm on the ¹³ C-NMR spectrum for the solid. Form A spectrum shows broader signals without clear double signals. Based on the spectrum of form A, it can be assumed that there are two independent molecules with different geometries. In another embodiment of the invention, crystalline form A is characterized by chemical shifts in the 13C-NMR spectrum shown in table. 3.

In some embodiments, crystalline Form A is characterized by, for example, XRD, DSC, TGA, or ¹³ C-NMR as described above, or any combination thereof. In one embodiment of the invention, crystalline form A is characterized by VRD only or VRD in combination with one or more of DSC, TGA and 13C-NMR described above.

In some embodiments, crystalline Form A is at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5% or 99.9% pure. Form A purity is determined by dividing the mass

- 30 040817 of crystalline form A in a composition containing the compound )-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-III-benzo[c]azepin-5-yl)1H-1,2,3-triazole-4-carboxamide, total the mass of the compound in the composition. In one embodiment, this invention provides a composition comprising the compound (R)-1-(tert-butyl)-N-(8-(2-((1methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl )-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5yl)-1H-1,2,3-triazole-4-carboxamide, with at least at least 70, 80, 85, 90, 95, 97, 99, 99.5, or 99.9% by weight of the compound in the composition is the crystalline form A of the compound.

In one embodiment, this invention provides a process for preparing crystalline form A(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin- 4-yl)-2-(oxetan-3-yl)2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide . Such methods include, for example, the formation of crystalline Form A from a suspension containing (R)-1-(tert-butyl)-N-(8-(2((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine -4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin5-yl)-1H-1,2,3-triazole-4-carboxamide and ethanol (EtOH). In one embodiment, the method includes stirring a suspension containing (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4yl)amino)pyrimidin-4-yl )-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-5-yl)-1 H-1,2,3-triazole4-carboxamide and EtOH at room temperature for 1 hour to 1 week, such as 1, 2, 3, 4, 5, 10, 15, 24 or 48 hours.

Form G.

In one embodiment, this invention provides a crystalline form of G(R)-1(tert-butyl)-K-(8-(2-(( 1 -methyl-1 H-pyrazol-4-yl)amino)pyrimidin-4- yl)-2-(oxetan-3-yl)-2,3,4,5tetrahydro-1 H-benzo[c]azepin-5-yl)-1 H-1,2,3-triazole-4-carboxamide.

In one aspect, crystalline form G is characterized by at least three, at least four, or at least five peaks in an X-ray powder diffraction (XRD) pattern at 2θ angles selected from 3.6°, 8.9°, 10.9°, 12.6°, 20.2° and 21.8°. In one aspect, crystalline form G is characterized by peaks on PGD at 2θ angles selected from 3.6°, 8.9°, 10.9°, 12.6°, 20.2°, and 21.8°. In some embodiments, the peaks for crystalline Form G described above have a relative intensity of at least 5%, at least 10%, or at least 15%. In another aspect, crystalline form G is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, or at least thirteen peaks on a PDP at 2θ angles selected from 3.6°, 8.9°, 11.0°, 12.6°, 14.5°, 15.4°, 16.3°, 18.4°, 20.2°, 21.8°, 23.4° and 25.4°, 26.8° and 34.2°. In another embodiment of the invention, the crystalline form G is characterized by peaks on the XRD at angles 2θ selected from 3.6°, 8.9°, 11.0°, 12.6°, 14.5°, 15.4°, 16, 3°, 18.4°, 20.2°, 21.8°, 23.4°, 25.4°, 26.8° and 34.2°.

In another aspect, crystalline form G has a diffraction pattern (XRD) substantially the same as the diffraction pattern (XRD) shown in FIG. 4.

In one aspect, crystalline form G has a DSC profile substantially the same as the DSC profile depicted in FIG. 5. In particular, the crystalline form G on the DSC profile is characterized by a decomposition onset temperature of 215.4°C±2°C. In another embodiment of the invention form G is characterized by a melting point of 217°C±2°C.

In one aspect, crystalline form G has a TGA profile substantially the same as the TGA profile depicted in FIG. 5. In particular, the TGA profile indicates that crystalline form G is an anhydrate.

As used herein, anhydrate means that the crystalline form contains essentially no water in the crystal lattice, for example, contains less than 1% by weight, as determined, for example, using TGA analysis or other quantitative analysis.

In another aspect, crystalline Form G has a 13C-NMR solid state spectrum substantially the same as that shown in FIG. 6B. In one embodiment, solid state crystalline form G has chemical shifts at 147.0 ppm, 146.0 ppm, and/or 140.6 ppm on the 13C-NMR spectrum. The form G spectrum shows peak splitting (double signals) in the aromatics regions when compared to the resolution 13C-NMR spectrum, suggesting the existence of two independent molecules in the asymmetric unit. In another embodiment of the invention, the crystalline form G is characterized by chemical shifts in the spectrum of 13C-NMR for the solid shown in table. 3.

In some embodiments, crystalline Form G is at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5% or 99.9% pure. The purity of form G is determined by dividing the mass of the crystalline form G in the composition containing the compound (R)-1-(tert-butyl)-N-(8-(2-((1-methyl1H-pyrazol-4-yl)amino)pyrimidine -4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)1H-1,2,3-triazol-4- carboxamide, based on the total weight of the compound in the composition. In one embodiment, this invention provides a composition comprising the compound (R)-1-(tert-butyl)-N-(8-(2-((1-31 040817 methyl-1H-pyrazol-4-yl)amino)pyrimidine -4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5yl)-1H-1,2,3-triazole-4-carboxamide , wherein at least 70, 80, 85, 90, 95, 97, 99, 99.5 or 99.9% by weight of the compound in the composition is the crystalline form G of the compound.

In one embodiment, this invention provides a process for preparing the crystalline form G(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin- 4-yl)-2-(oxetan-3-yl)2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide . Such methods include, for example, the formation of crystalline form G from a suspension containing (R)-1-(tert-butyl)-N-(8-(2((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine -4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin5-yl)-1H-1,2,3-triazole-4-carboxamide and isopropyl acetate (IPAc). In one embodiment, the method includes stirring a suspension containing (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1Hpyrazol-4-yl)amino)pyrimidin-4-yl )-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H1,2,3-triazole-4-carboxamide and isopropyl acetate (IPAc ) at elevated temperature (for example, from 30°C to 70°C, from 4°C to 60°C, from 45°C to 55°C or at 50°C) for 1 hour to 1 week, for example in within 1, 2, 3, 4, 5, 10, 15, 24 or 48 hours.

Alternatively, crystalline Form G is prepared by a process comprising the steps of (i) removing at least a portion of the dichloromethane by distillation from a mixture containing (R)-1(tert-butyl)-K-(8-(2-(( 1 - methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5tetrahydro-1H-benzo[c]azepin-5-yl) -1H-1,2,3-triazole-4-carboxamide and dichloromethane; (ii) adding isopropyl acetate (IPAc) to the mixture; (iii) heating the IPAc-containing mixture to an elevated temperature (eg, 50°C to 70°C, 55°C to 65°C, or 60°C) followed by cooling to near room temperature (eg, 20°C). C) in order to obtain a suspension containing the compound and IPAC; and (iv) isolating crystalline Form G from the suspension. In one embodiment, steps (i) and (ii) are repeated one or more times (eg two, three, four or five times). In one embodiment, steps (i) and (ii) are repeated until substantially all of the dichloromethane (e.g., at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% by volume) will not be removed. In one embodiment of the invention, heating and cooling in step (iii) is repeated once or more (eg, two, three, four, five, ten, fifteen, twenty or more times).

It should be understood that the XRD 2θ values for crystalline form A and crystalline form G vary slightly from one instrument to another and depend on differences in sample preparation. Therefore, the positions of the peaks on the XRD for crystalline form A and crystalline form G should not be considered as absolute, and they can vary within ±0.2°.

As contemplated herein, substantially the same diffraction pattern (XRD) as shown in FIG. 1, practically the same diffraction pattern (XRD) as shown in FIG. 4 is essentially the same as that shown in FIG. 3B or substantially the same as that shown in FIG. 6B means that, for comparison purposes, at least 80%, at least 90%, or at least 95% of the peaks depicted in FIG. 1, 4, 3B and 6B are present. It should be further understood that, for purposes of comparison, some deviations in peak positions from those depicted in FIG. 1 and FIG. 4, namely ±0.2°. Likewise, for purposes of comparison, some deviations in peak positions from those depicted in FIG. 3V and 6V, namely ±0.5 ppm.

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

Alkenyl refers to an unsaturated hydrocarbon group that is linear or branched and has at least one carbon-carbon double bond. Alkenyl groups with 2 to 6 carbon atoms are preferred. Alkenyl groups contain 1, 2 or 3 or more carbon-carbon double bonds. Examples of alkenyl groups include ethenyl, npropenyl, isopropenyl, n-but-2-enyl, n-hex-3-enyl and the like.

Alkynyl refers to an unsaturated hydrocarbon group that is linear or branched and has at least one carbon-carbon triple bond. C 2 to C 6 alkynyl groups are preferred. Alkynyl groups contain 1, 2 or 3 or more carbon-carbon triple bonds. Examples of alkynyl groups include ethynyl, npropynyl, n-but-2-ynyl, n-hex-3-ynyl, and the like.

The number of carbon atoms in a group is indicated herein by the prefix C _x _ _xx , where x and xx are integers. For example, _C1 . ₄ -alkyl is an alkyl group which contains from 1 to 4 carbon atoms.

Halogen or halo is fluorine, chlorine, bromine or iodine.

As used herein, the term heterocyclyl refers to saturated or non-saturated

- 32 040817 a closed, monocyclic or bicyclic (for example, fused, bridged or spiro ring system) ring system, which contains from 3 to 10 ring members or, in particular, from 3 to 8 ring members, from 3 to 7 ring members, from 3 up to 6 ring members or 5 to 7 ring members or 4 to 7 ring members at least one of which is a heteroatom and up to 4 of which (e.g. 1, 2, 3 or 4) are heteroatoms, wherein the heteroatoms independently selected from O, S, and N, and wherein C is oxidized (eg, C(O)), N is oxidized (eg, N(O)) or quaternary, and S is optionally oxidized to a sulfoxide or sulfone. Unsaturated heterocyclic rings include heteroaryl rings. As used herein, the term heteroaryl refers to an aromatic 5 to 6 membered monocyclic ring system containing 1 to 4 heteroatoms independently selected from O, S, and N, where N is oxidized (e.g., N(O)) or quaternary, and S is optionally oxidized to a sulfoxide or sulfone. In one embodiment, the heterocyclyl is a 3-7 membered saturated monocyclic ring or a 3-6 membered saturated monocyclic ring, a 5-7 membered saturated monocyclic ring, or a 4-6 membered saturated monocyclic ring. In one embodiment, the heterocyclyl is a 3-7 membered monocyclic or 3-6 membered monocyclic or 4-6 membered monocyclic ring or a 5-7 membered monocyclic ring. In another embodiment, the heterocyclyl is a 6-7 membered bicyclic ring. In yet another embodiment of the invention, the heterocyclyl is a 4-7 membered monocyclic non-aromatic ring. In another embodiment of the invention, the heterocyclyl is a 6-8 membered spiro or bicyclic ring with a bridged group. The heterocyclic group is attached to a heteroatom or carbon atom. Примеры гетероциклилов включают, но не ограничиваются ими, азиридинил, оксиранил, тииранил, оксазиридинид, азетидинил, оксетанил, тиетанил, пирролидинил, тетрагидрофуранил, тиоланил, имидазолидинил, пиразолидинил, оксазолидинил, изоксазолидинил, тиазолидинил, изотиазолидинил, диоксоланил, дитиоланил, оксатиоланил, пиперидинил, тетрагидропиранил , thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, trithianyl, azepanyl, oxepanil, thiepanyl, dihydrofuranyl, imidazolinyl, dihydropyranyl and heteroaryl rings including azetyl, thioethyl, 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, dioxynyl, dithienyl, oxathianyl, triazinepinyl, tetrazinyl, tetrazinyl, , thiepinil, diazepinil and thiazepinil, and the like.

As used herein, the term fused ring system is a ring system that has two rings, each independently selected from carbocyclyl or heterocyclyl, with the two ring structures sharing two adjacent ring-forming atoms. The fused ring system contains 9 to 12 ring members.

As used herein, the term bridged ring system is a ring system that has a carbocyclic or heterocyclic ring, wherein two non-adjacent atoms in the ring are connected (bridged) by one or more (preferably one to three) atoms selected from C, N, O or S. Bridged ring system has 6 to 8 ring members.

As used herein, the term spiro ring system is a ring system that has two rings each independently selected from carbocyclyl or heterocyclyl, with the two ring structures sharing one ring-forming atom. The spiro ring system has 5 to 8 ring members.

In another embodiment, the heterocyclyl is a 4-6 membered monocyclic heterocyclyl. Examples of the 4-6 membered monocyclic heterocyclic ring system include, but are not limited to, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanylpera, oxathiolanyl, piperidinyl, tetrahydropyranyl, , morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, dihydrofuranyl, imidazolinyl, dihydropyranyl, pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, tetrazolyl, tetrazolyl , pyranyl, thiopyranil, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxynyl, dithiinyl, oxathianyl, triazinyl and tetrazinyl.

In another embodiment, the heterocyclyl is a 4-6 membered monocyclic heterocyclyl. Examples of the 4-6 membered monocyclic heterocyclic ring system include, but are not limited to, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, thianylpyranyl, piperazinil, morpholinyl, thiomorpholinyl, dioxanil and dithienyl. In one embodiment, the saturated 4-6 membered monocyclic heterocyclyl includes, but is not limited to, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydro furanyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidi

- 33 040817 nil, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl or dioxynyl. In another embodiment, the saturated 4-6 membered monocyclic heterocyclyl is oxetanyl, tetrahydro furanyl, or tetrahydropyranyl.

As used herein, the term carbocyclyl refers to saturated or unsaturated, monocyclic or bicyclic hydrocarbon groups of 3 to 7 carbon atoms, 3 to 5, 3 to 6, 4 to 6, or 5 to 7 carbon atoms. The term carbocyclyl encompasses cycloalkyl groups and aromatic groups. The term carbocyclyl refers to fully saturated monocyclic, bicyclic or hydrocarbon spiro groups of 3 to 7 carbons, 3 to 6 carbons, or 5 to 7 carbons. Exemplary monocyclic carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclobutadienyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl, phenyl, and cycloheptatrienyl. Exemplary bicyclic carbocyclic 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 2,6,6trimethylbicyclo[3.1.1]heptyl, spiro[2.2]pentanyl and spiro[3.3]heptanyl. In one embodiment, the carbocyclyl is a 4-6 membered monocyclic carbocyclyl. In another embodiment, the carbocyclyl is a 3-5 membered monocyclic carbocyclyl. In one embodiment, the carbocyclyl is C ₄ - ₆ -cycloalkyl. In another embodiment, the carbocyclyl is cyclobutyl, cyclopentyl, or cyclohexyl.

In cases where a compound provided herein is sufficiently basic or acidic to form stable non-toxic acid or base salts, it is appropriate to prepare and administer the compounds as pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids that form a physiologically acceptable anion, such as tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate or αglycerophosphate. Inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate and carbonate salts.

Pharmaceutically acceptable salts are prepared by standard procedures well known in the art, for example by reacting a sufficiently basic compound, namely an amine, with an appropriate acid to produce a physiologically acceptable anion. Alkali metal (eg sodium, potassium or lithium) or alkaline earth metal (eg calcium) salts of carboxylic acids can also be prepared.

Pharmaceutically acceptable base addition salts are prepared from inorganic and organic bases. Inorganic base salts include, but are not limited to, sodium, potassium, lithium, ammonium, calcium or magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary or tertiary amines, namely alkylamines, dialkylamines, trialkylamines, substituted alkylamines, di(substituted alkyl)amines, tri(substituted alkyl)amines, alkenylamines, dialkenylamines, trialkenylamines, substituted alkenylamines, di(substituted alkenyl)amines, tri(substituted alkenyl)amines, cycloalkylamines, di(cycloalkyl)amines, tri(cycloalkyl)amines, substituted cycloalkylamines, disubstituted cycloalkylamines, trisubstituted cycloalkylamines, cycloalkenylamines, di(cycloalkenyl)amines, tri(cycloalkenyl)amines, substituted cycloalkenylamines, disubstituted cycloalkenylamines, trisubstituted cycloalkenylamines, arylamines, diarylamines, triarylamines, heteroarylamines, diheteroarylamines, triheteroarylamines, heterocycloalkylamines, diheterocycloalkylamines, triheterocycloalkylamines, or mixed di- and triamines, wherein at least two substituents on the amine are different and are alkyl substituted by alkyl l, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl or heterocycloalkyl and the like. Also included are amines in which two or three substituents together with the nitrogen of the amine form a heterocycloalkyl or heteroaryl group. Non-limiting examples of amines include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, trimetamine, 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 are useful, for example, amides of carboxylic acids, including carboxamides, lower alkyl carboxamides or dialkyl carboxamides, and the like.

The compounds or their pharmaceutically acceptable salts described herein contain one or more asymmetric centers in the molecule. For the purposes of this disclosure, any structure that does not establish stereochemistry is intended to encompass all of the various stereoisomers (e.g., diastereomers and enantiomers) in pure or substantially pure form, as well as mixtures thereof (namely, racemic mixtures or enantiomerically enriched mixtures). In the art

- 34 040817 it is well known how to obtain such optically active forms (for example, separation of racemic forms using recrystallization techniques, synthesis from optically active starting materials, chiral synthesis or chromatographic separation using a chiral stationary phase).

If a specific stereoisomer of a compound is indicated by a name or structure, then 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%. Stereochemical purity means the weight percent of the target stereoisomer based on the combined weight of all stereoisomers.

When a specific enantiomer of a compound is indicated by name or structure, then 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%. Stereochemical purity means the weight percent of the target enantiomer based on the combined weight of all stereoisomers.

Where the stereochemistry of a disclosed compound is named or indicated by a structure, and the named or indicated structure encompasses more than one stereoisomer (eg, as in the case of diastereomeric pairs), one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is meant to be included. It should be further understood that the stereoisomeric purity of the named or designated stereoisomers is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%. Stereochemical purity means the weight percent of the target stereoisomers encompassed by the name or structure, relative to the combined weight of all stereoisomers.

Where the target compound has a name or structure without indicating stereochemistry and the compound has a single chiral center, the name or structure is to be understood to encompass one enantiomer of the compound in pure or substantially pure form, as well as mixtures thereof (namely, racemic mixtures of the compound and mixtures enriched in one enantiomer relative to its corresponding optical isomer).

If the target compound has a name or is designated by a structure without specifying the stereochemistry, and, for example, the compound has at least two chiral centers, the name or structure should be understood to cover one stereoisomer in pure or substantially pure form, as well as mixtures thereof (namely, mixtures of stereoisomers; and mixtures of stereoisomers enriched in one or more stereoisomers relative to the other(s) stereoisomer(s)).

The disclosed compounds exist in tautomeric forms or mixtures, and isolated individual tautomers are contemplated. Additionally, some compounds exhibit polymorphism.

In one embodiment, the compounds of the invention, or pharmaceutically acceptable salts thereof, contain deuterium.

Another embodiment of the invention is a pharmaceutical composition containing 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 are used to reduce the activity of Btk, or otherwise affect the properties and/or behavior of Btk, such as stability, phosphorylation, kinase activity, interactions with other proteins, and the like.

In some embodiments of this invention, methods are provided for reducing Btk enzymatic activity. In some embodiments of the invention, such methods include contacting Btk with an effective amount of a Btk inhibitor. Therefore, the present invention further provides methods for inhibiting Btk enzymatic activity by contacting Btk with a Btk inhibitor of the present invention.

In one embodiment, a method for treating a Btk inhibition responsive disorder in a subject is provided, comprising administering to said subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof.

In one embodiment, the invention provides methods for treating autoimmune diseases, inflammatory diseases, and cancer in a subject in need thereof, comprising administering to said subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof.

The term autoimmune disorders includes diseases or disorders involving an inappropriate immune response to native antigens, namely acute disseminated encephalomyelitis (ADEM), Addison's disease, alopecia areata, antiphospholipid antibody syndrome (AAS), autoimmune hemolytic anemia, autoimmune hepatitis, bullous pemphigoid (BP) , celiac disease, dermatomyositis, type 1 diabetes mellitus, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, lupus erythematosus, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anemia , polymyositis, primary biliary cirrhosis, Sjögren's syndrome, temporal arteritis and Wegener's granulomatosis. The term inflammatory diseases includes diseases and disorders

- 35 040817 diseases, including acute and chronic inflammations, namely, allergies, asthma, prostatitis, glomerulonephritis, pelvic inflammatory disease (PID), inflammatory bowel disease (IBD, eg Crohn's disease, ulcerative colitis), reperfusion injury, rheumatoid arthritis, transplant rejection and vasculitis. In some embodiments, this invention provides methods for treating rheumatoid arthritis or lupus. In some embodiments of this invention, methods for the treatment of multiple sclerosis are provided.

The term cancer includes diseases or disorders involving abnormal cell growth and/or proliferation, such as glioma, thyroid cancer, breast cancer, lung cancer (eg, small cell lung cancer, non-small cell lung cancer), gastric cancer, gastrointestinal stromal tumors , pancreatic cancer, bile duct cancer, ovarian cancer, endometrial cancer, prostate cancer, renal cell carcinoma, lymphoma (eg, anaplastic large cell lymphoma), leukemia (eg, acute myeloid leukemia, T-cell leukemia, chronic lymphocytic leukemia), multiple myeloma, malignant mesothelioma, malignant melanoma, and colon cancer (eg, colorectal cancer with high microsatellite instability). In some embodiments, this invention provides methods for treating leukemia or lymphoma.

As used herein, the terms subject or patient are used interchangeably and refer to the mammal in need of treatment, such as domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats, and the like) and laboratory animals (eg rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment.

Used in this document, the term treatment refers to obtaining the target pharmacological and/or philological effect. The effect is therapeutic, which includes achieving, in part or almost completely, one or more of the following results: partial or complete reduction in the extent of the disease, disorder or syndrome; reducing or improving a clinical symptom or score associated with the disorder; or slowing, inhibiting or reducing the likelihood of progression of a disease, disorder or syndrome.

An effective dose of a compound provided herein, or a pharmaceutically acceptable salt thereof, administered to a subject is 10 μg to 500 mg.

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

Therefore, a compound or a pharmaceutically acceptable salt thereof as described herein is administered systemically, eg orally, in combination with a pharmaceutically acceptable carrier, namely an inert diluent or an assimilable edible carrier. They are enclosed in hard or soft shell gelatin capsules, compressed into tablets, or administered directly with the patient's food. For oral therapeutic administration, a compound or a pharmaceutically acceptable salt thereof described herein is combined with one or more excipients and administered as ingestible tablets, buccal tablets, lozenges, capsules, tinctures, suspensions, syrups or capsules, and the like. Such compositions and preparations should contain at least about 0.1% of the active ingredient. The percentage of composition and formulation can, of course, vary, and is typically in the range of about 2 to about 60% by weight of the particular unit dosage form. The amount of active compound in such a therapeutically useful composition is such as to obtain an effective dosage level.

Tablets, lozenges, pills, capsules and the like include the following: a binder, namely gum tragacanth, gum arabic, corn starch or gelatin; filler, namely dicalcium phosphate; a disintegrating agent for tablets, namely corn starch, potato starch, alginic acid and the like; a lubricant, namely magnesium stearate; or a sweetener, namely sucrose, fructose, lactose or aspartame; or fragrance.

The active compound is also administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts are prepared in water, optionally mixed with a non-toxic surfactant.

Typical pharmaceutical dosage forms for injection or infusion include sterile aqueous solutions or dispersions, or sterile powders containing the active ingredient, adapt

- 36 040817 approved for the extemporaneous preparation of sterile injection or infusion solutions or dispersions. In all cases, the final dosage form must be sterile, fluid and stable under the conditions of manufacture and storage.

Sterile injectable solutions are prepared by incorporating the active compound in the required amount in a suitable solvent with various other necessary ingredients listed above, followed by filtered sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum or freeze-drying techniques, which result in a powder of the active ingredient plus any additional target ingredient found in solutions previously sterilized by filtration.

Typical solid carriers include finely divided solids, namely talc, clay, microcrystalline cellulose, silicon dioxide, alumina and the like. Suitable liquid carriers include water, alcohols or glycols, or mixtures of water and alcohols/glycols, in which the compounds or their pharmaceutically acceptable salts described herein are dissolved or dispersed to an effective level, optionally with non-toxic surfactants.

Suitable dosages of a compound or its pharmaceutically acceptable salts described herein are determined by comparing their in vitro activity and in vivo activity in animal models. Methods for extrapolating effective dosages in mice and other animals to humans are known in the art; for example, see US Pat. No. 4,938,949, which is incorporated herein by reference in its entirety.

The amount of a compound or a pharmaceutically acceptable salt thereof described herein required for use in treatment varies not only with the particular salt chosen, but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and ultimately depends on the assessment of the attending physician. However, as a rule, the dose is in the range from about 0.1 to about 10 mg/kg of body weight per day.

A compound or a pharmaceutically acceptable salt thereof described herein is generally administered as a unit dosage form, for example, containing 0.01 to 10 mg or 0.05 to 1 mg of the active ingredient per unit dosage form. In some embodiments of the invention, a dose of 5 mg/kg or less is appropriate.

The required dose is usually in the form of a single dose or divided doses administered at suitable intervals.

The disclosed method includes a kit containing a compound, or a pharmaceutically acceptable salt thereof, described herein, and an instruction that describes the introduction into a cell or subject of a compound or a pharmaceutically acceptable salt thereof, described herein, or a composition containing a compound or a pharmaceutically acceptable salt thereof. salt described in this document. This should be considered to cover other embodiments of kits known to those skilled in the art, namely kits containing a (sterile) solvent for dissolving or dispersing in suspension a compound or a pharmaceutically acceptable salt thereof described herein or a composition prior to administration to a cell. or the subject of a compound or a pharmaceutically acceptable salt thereof described herein, or a composition. In some embodiments of the invention, the subject is a human.

Examples

LC-MS Methods: Samples are analyzed on a Waters Acquity UPLC WEN C18 1.7 μM 2.1x50 mm instrument, instrument number 186002350, MS mode: MS: ESI+ scan range 100-1000 daltons. Registration using a photodiode array 210-400 nm. The technique used is a linear gradient from 95% water/5% MeCN (initial conditions) to 5% H ₂ O/95% MeCN in 1 min, holding 5% H ₂ O/95% MeCN to 1.3 min at 0, 7 ml/min in 0.1% trifluoroacetic acid (0.1% v/v) and 0.5 µl injection volume.

SFC separation: Each separation is performed under the conditions shown in the examples below, including column name/instrument number, separation method, SFC system backpressure regulator setting, flow rate, wavelength registration, sample injection volume, sample concentration, and sample diluent.

Example 1 5-(tert-Butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydro- 1 H-benzo[d]azepin-1-yl)-1,2,4-oxadiazole-3-carbocamide.

- 37 040817

1. Synthesis of N-(3-bromophenethyl)-4-methylbenzenesulfonamide.

Triethylamine ( _{2.02 g} , 20 mmol) and TsCl (2.18 g, 11 .5 mmol). The mixture was stirred at rt for 2 h, diluted with NaOH (1H, 100 ml) and extracted with CH ₂ Cl ₂ (100 ml). The organic layer was washed with water (100 ml), brine (100 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo to give N-(3-bromopheneethyl)-4-methylbenzenesulfonamide (3.5 g, yield: 100%) as yellow oily liquid. ESI-MS (M+H)+: 354.0. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.69 (d, J=8.0 Hz, 2H), 7.34 (d, J=8.4 Hz, 1H), 7.30 (d, J=8.0Hz, 2H), 7.17(t, J=1.6Hz, 1H), 7.13(t, J=8.0Hz, 1H), 7.03-7.02(m, 1H) , 4.52 (t, J=6.0 Hz, 1H), 3.22-3.17 (m, 2H), 2.73 (t, J=6.8 Hz, 2H), 2.45 ( s, 3H).

2. Synthesis of ethyl 2-(N-(3-bromophenethyl)-4-methylphenylsulfonamido)acetate.

K ₂ CO ₃ ( _19.3 g, 140 mmol) and _ethyl- 2-bromoacetate (3.67 g, 22 mmol). The mixture is stirred at 60° C. for 12 hours, cooled to rt, and the salt is filtered off. The resulting filtrate was concentrated in vacuo to give ethyl 2-(N-(3-bromopheneethyl)-4-methylphenylsulfonamido)acetate (8.78 g, yield: 100%) as a yellow oil. ESI-MS (M+H)+: 440.0. 1H-NMR (400 MHz, CDCl ₃ ) δ: 7.70 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.4 Hz, 1H), 7.28 (d, J=8.0 Hz, 2H), 7.14 (t, J=7.6 Hz, 1H), 7.10-7.08 (m, 2H), 4.08 (q, J=7.6 Hz, 2H), 3.98 (s, 2H), 3.44 (t, J=7.6 Hz, 2H), 2.85 (t, J=7.2 Hz, 2H), 2.42 ( s, 3H), 1.19 (t, J=7.2 Hz, 3H).

3. Synthesis of 2-(N-(3-bromophenethyl)-4-methylphenylsulfonamido)acetic acid.

NaOH (1.6 g, 40 mmol). The reaction mixture was stirred at rt for 12 h. The solvent was then reduced and the pH of the residue was adjusted to 3 with HCl (1N). The mixture is extracted with EtOAc (100 mlx3). The organic layer was dried over (Na ₂ SO ₄ ) and concentrated in vacuo to give 2-(N-(3-bromophenethyl)-4-methylphenylsulfonamido)acetic acid (8.2 g, yield: 100%). ESI-MS (M+H)+: 412.0. 1H-NMR (400 MHz, CDCl ₃ ) δ: 7.69 (d, J=8.0 Hz, 2H), 7.34 (d, J=7.6 Hz, 1H), 7.29 (d, J=8.4Hz, 2H), 7.22(s, 1H), 7.14(t, J=8.0Hz, 1H), 7.08-7.06(m, 1H), 4, 00 (s, 2H), 3.45 (t, J=7.6 Hz, 2H), 2.83 (t, J=7.6 Hz, 2H), 2.42 (s, 3H).

4. Synthesis of 7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-one.

- 38 040817

_{SOCl 2 (} 11.9 g, ₁₀₀ mmol) DMF (cat.). The reaction mixture was stirred at 40° C. for 1 hour. The solvent was then removed under reduced pressure and dried in vacuo for 2 hours. The residue was dissolved in CH ₂ Cl ₂ (100 ml) and cooled in an ice bath. AlCl ₃ (10.56 g, 80 mmol) was added and the mixture was stirred at 0° C. to rt for 12 h. The mixture was poured into conc.

HCl (20 ml) and extracted with EtOAc (100 mlx2). The organic layer was washed with water (100 ml), brine (100 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a residue which was purified by silica gel column chromatography (petroleum ether: EtOAc=4:1) to give 7-bromo-3-tosyl-2,3,4,5-tetrahydro-N-benzo[d]azepin-1-one as a yellow solid (1.88 g, yield: 24%). ESI-MS (M+H)+: 394.1. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.42 (d, J=8.4 Hz, 2H), 7.38 (dd, J=8.4, 1.6 Hz, 1H), 7 .31-7.29 (m, 2H), 7.14 (d, J=8.0 Hz, 2H), 4.21 (s, 2H), 3.68 (t, J=6.8 Hz, 2H), 2.93 (t, J=7.2 Hz, 2H), 2.39 (s, 3H).

5. Synthesis of 7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-amine.

The synthesis of 7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-amine is analogous to example 2. The residue is purified using silica gel column chromatography (CH ₂ Cl ₂ : MeOH= 20:1) to give 7-bromo-3-tosyl-2,3,4,5-tetrahydro-N-benzo[d]azepine-1-amine as a yellow solid (154 mg, yield: 64%) . ESI-MS (M+H)+: 395.1. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.66 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.31 (dd , J=8.4, 1.6Hz, 1H), 7.27 (d, J=1.6Hz, 1H), 7.18 (d, J=8.4Hz, 1H), 4.12 -4.40(m, 1H), 3.42-3.36(m, 2H), 3.19-3.12(m, 2H), 2.96-2.89(m, 2H), 2 .41 (s, 3H).

6. Synthesis of 7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-amine.

A mixture of 7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-amine (1.2 g, 3.04 mmol) in HBr/HOAc (33%, 20 ml) stirred at 70° C. for 12 h. After cooling, the mixture was diluted with EtOAc (60 ml) and the resulting precipitate was filtered and dried in vacuo to give 7-bromo-3-tosyl2,3,4,5-tetrahydro-1H- benzo[d]azepine-1-amine (870 mg, yield: 71%) as a white solid. ESI-MS (M+H)+: 241.1. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.65-7.63 (m, 2H), 7.25 (d, J=8.8 Hz, 1H), 5.175.14 (m, 1H) , 3.84-3.80(m, 1H), 3.69-3.65(m, 1H), 3.44-3.40(m, 2H), 3.27-3.14(m, 2H).

7. Synthesis of tert-butyl-1-amino-7-bromo-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate.

To a mixture of 7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-amine (680 mg, 1.7 mmol) and triethylamine (515 mg, 5.1 mmol ) in CH ₂ Cl ₂ (10 ml) add Boc ₂ O (333 mg, 1.0 mmol). reaction mixture

- 39 040817 stirred at rt for 2 h. After dilution with CH ₂ Cl ₂ (100 ml), the organic layer was washed with water (30 ml) and brine (30 ml), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to obtaining tert-butyl 1-amino-7-bromo-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate (450 mg, yield: 77%) as a yellow oily liquid. ESI-MS (M+H)+: 341.0. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.31 (d, J=8.0 Hz, 1H), 7.26 (s, 1H), 7.19-7.11 (m, 1H) , 4.17-4.10 (m, 1H), 3.83-3.66 (m, 2H), 3.48-3.45 (m, 1H), 3.373.14 (m, 2H), 2 .78-2.73 (m, 1H), 1.47 (s, 9H).

8. Synthesis of tert-butyl-7-bromo-1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-4,5-dihydro-1Нbenzo[d]azepin-3(2Н )-carboxylate.

Br

(COCl) 2 (COCl) ₂ (COCl) _{2 (} 567 mg, 4.5 mmol) and DMF (cat.). The mixture is stirred at room temperature for 1 hour. The mixture is concentrated. The residue was dried in vacuo, then dissolved in CH ₂ Cl ₂ (10 ml) and 1-amino-7-bromo-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate (408 mg, 1.5 mmol) and triethylamine (454 mg, 4.5 mmol). The mixture was stirred at rt for 12 h and diluted with CH ₂ Cl ₂ (100 ml). The organic phase is washed with water (50 ml) and brine (50 ml) and concentrated. The residue was purified by silica gel column chromatography (PE (petroleum ether): EtOAc (ethyl acetate)=4:1) to obtain t-butyl-7-bromo-1-(5-(t-butyl)-1,2,4 -oxadiazole-3-carboxamido)-4,5-dihydro-Nbenzo[d]azepine-3(2H)-carboxylate (290 mg, yield: 38%) as a white solid. IEMS (M+H-56)+: 437.0. ¹ H-NMR (400 MHz, CD3OD) δ: 7.42-7.38 (m, 2H), 7.26 (d, J=7.6 Hz, 1H), 5.39 (d, J=5 .2 Hz, 1H), 4.14-4.08 (m, 1H), 4.01-3.87 (m, 1H), 3.75-3.70 (m, 2H), 3.56- 3.46 (m, 1H), 3.24-3.15 (m, 1H), 3.00-2.91 (m, 1H), 1.48 (s, 9H), 1.38 (s, 9H).

9. Synthesis of 2-chloro-4-methoxypyrimidine.

To a solution of 2,4-dichloropyrmidine (7.5 g, 50 mmol) in MeOH (80 ml) at 0° C. was added a solution of NaOMe (2.84 g, 52.5 mmol) in MeOH (20 ml) dropwise. The reaction mixture was stirred at 0°C for 2 hours.

The reaction mixture is concentrated in vacuo to give the crude product. The crude product is poured into 150 ml of water. The aqueous phase is extracted with EtOAc (100 ml). The organic layer was dried with Na2SO4 and concentrated in vacuo to give 2-chloro-4-methoxypyrimidine (5.9 g, yield: 82%) as a light yellow solid. ESI-MS (M+H)+: 145.0. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.27 (d, J=6.0 Hz, 1H), 6.65 (d, J=6.0 Hz, 1H), 3.99 (s , 3H).

10. Synthesis of 4-methoxy-N-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-amine.

^NS 'LC (1.0 eq.) ^9

АА__А Pd ₂ (dba) ₃ (0.02 eq.), S-Phos (0.04 w*

Cs ₂ CO ₃ (3.0 f.), dioxene, 120 ^b C, 4h n

To a solution of 2-chloro-4-methoxypyrimidine (120 g, 0.83 mol) in dioxane (2 L) was added 1-methyl-1H-pyrazol-4-amine hydrochloride (111 g, 0.83 mol), Cs ₂ CO ₃ (0.83 kg, 2.5 mol), S-Phos (13.3 g, 0.03 mol) nPd ₂ (dba) ₃ (16.7 g, 0.02 mol). The reaction mixture was stirred at 120° C. under N2 for 4 hours. The reaction mixture was cooled to room temperature and water (4 L) was added. The layers are separated and the aqueous phase is extracted with EtOAc (3x2 L). The combined organic layers are washed with brine (3 L), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column chromatography (PE: EtOAc=5:1 to 1:1) to give 4-methoxy-N-(1-methyl-N-pyrazol-4yl)-pyrimidin-2-amine (73 g , yield: 43%) as a tan solid.

- 40 040817

ESI-MS (M+H)+: 205.8.

11. Synthesis of 4-chloro-Ni(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-amine.

HBr (11.2 L, 38% aqueous) was added to 4-methoxy-Ni(1-methyl-III-pyrazol-4-yl)pyrimidin-2-amine (1.4 kg, 6.8 mol). The reaction mixture is heated to 100° C. and stirred at this temperature for 2 hours. The reaction mixture is concentrated and then POCl ₃ (11.2 L) is added. The reaction mixture is heated to 100° C. and stirred at this temperature for 16 hours. The reaction mixture is cooled to room temperature and concentrated. Water (10 L) was added to the residue and the pH of the solution was adjusted to pH=14 with aqueous NaOH (4M). The main aqueous phase is extracted with EtOAc (3x10 L). The combined organic layers are washed with brine (9 l), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column chromatography (PE: EtOAc=5:1 to 2:1) to give 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-amine in as a white solid (770 g, yield: 54%). ESI-MS (M+H)+: 210.0.

12. Synthesis of tert-butyl-1-(5-(tert-butyl)-1,2,4-oxadiazol-3-carboxamido)-7-(2-((1-methyl-1Hpyrazol-4-yl)amino) pyrimidin-4-yl)-4,5-dihydro-1H-benzo[d]azepin-3(2H)-carboxylate

To a mixture of tert-butyl-7-bromo-1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-4,5-dihydro-1Hbenzo[d]azepin-3(2H) -carboxylate (510 mg, 1.03 mmol) and PinB-BPin (263 mg, 1.0 mmol) in dry 1,4-dioxane (10 ml) under N ₂ KOAc (303 mg, 3.09 mmol ) and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (81 mg, 0.1 mmol). The mixture was stirred at 100° C. under N ₂ for 12 h. ), K2CO3 (213 mg, 1.54 mmol) and H ₂ O (2.5 ml). The mixture was stirred at 100° C. under N ₂ for 12 hours. After cooling, the mixture was concentrated and purified by silica gel column chromatography (CH ₂ Cl ₂ : PE: EtOAc=1:1:1) to give t-butyl-1 -(5-(tert-butyl)-1,2,4-oxadiazol-3-carboxamido)-7-(2((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)- 4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate (250 mg, yield: 41%) as a yellow solid. ESI-MS (M+H)+: 588.2. ¹ H-NMR (400 MHz, CD3OD) δ: 8.41 (d, J=4.8 Hz, 1H), 7.99-7.98 (m, 3H), 7.64 (s, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.21 (d, J=5.2 Hz, 1H), 5.54-5.47 (m, 1H), 4.18-4 .05 (m, 1H), 3.97-3.90 (m, 4H), 3.87-3.76 (m, 2H), 3.65-3.57 (m, 1H), 3.153.11 (m, 1H), 1.49 (s, 9H), 1.39 (s, 9H).

13. Synthesis of 5 -(tert-butyl)-N-(7-(2-((1-methyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5 - tetrahydro-1 H-benzo[d]azepin-1-yl)-1,2,4-oxadiazole-3-carbocamide.

To a solution of TFA (1 ml) in CH ₂ Cl ₂ (2 ml) was added tert-butyl-1-(5-(tert-butyl)-1,2,4-oxadiazole-3carboxamido)-7-(2-(( 1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[d]azepine 3(2H)-carboxylate (230 mg, 0.39 mmol). The mixture was stirred at rt for 1 h, then concentrated and purified by preparative HPLC (CH ₃ CN/water NH4HCO3 0.05% as mobile phase) to give 5-(tert-butyl)-N-(7-(2-( ( 1 -methyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H

- 41 040817 benzo[d]azepin-1-yl)-1,2,4-oxadiazole-3-carbocamide (120 mg, yield: 58%). ESI-MS (M+H)+: 488.3. 1HNMR (400 MHz, CD3OD) δ: 8.37-8.35 (m, 1H), 7.95 (s, 1H), 7.91-7.88 (m, 2H), 7.63 (s, 1H), 7.46 (d, J=7.6Hz, 1H), 7.15 (d, J=4.8Hz, 1H), 5.34 (d, J=7.2Hz, 1H) , 3.95 (s, 3H), 3.24-3.19 (m, 1H), 3.11-3.08 (m, 3H), 2.992.94 (m, 2H), 1.49 (s , 9H).

Example 2 (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetane3 -yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide (compound 2).

Method 1.

1. Obtaining ethyl ester of 3-(3-bromobenzylamino)propionic acid.

Triethylamine (60.7 g, 0.6 mol) and NaCNBH ₃ (56.5 g, 0.9 mol). The resulting mixture was stirred at rt for 4 h. The reaction mixture was concentrated in vacuo and the residue was diluted with water (600 ml). The mixture is extracted with EtOAc (3x500 ml). The combined organic layer was washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give 3-(3-bromobenzylamino)propionic acid ethyl ester (46.5 g, yield: 54%) as an oil light yellow liquid. ¹ H-NMR (DMSO-d ₆ , 300 MHz): δ 7.52 (s, 1H), 7.40 (d, J=7.5 Hz, 1H), 7.31-7.25 (m, 2H), 4.04 (q, J=7.2 Hz, 2H), 3.67 (s, 2H), 2.69 (t, J=7.2 Hz, 2H), 2.42 (t, J=6.9 Hz, 2H), 1.17 (t, J=6.9 Hz, 3H).

2. Preparation of 3-[(3-bromobenzyl)-(toluene-4-sulfonylamino]propionic acid ethyl ester

To a solution of 3-(3-bromobenzylamino)propionic acid ethyl ester (45.6 g, 0.16 mol) in pyridine (500 ml) was added TosCl (61.0 g, 0.32 mol) at rt. The reaction mixture was stirred at 120° C. for 16 hours. To obtain a crude product, the solvent was removed in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether: EtOAc=10:1 to 5:1) to give 3-[(3-bromobenzyl)-(toluene-4-sulfonyl)amino]propionic acid ethyl ester (61 g. yield: 88%) as light yellow oily liquid. ¹ H-NMR (DMSO^ ₆ , 300 MHz): δ 7.74 (d, J=8.4 Hz, 2H), 7.49-7.41 (m, 4H), 7.31 (d, J =5.1 Hz, 2H), 4.33 (s, 2H), 3.93 (q, J=7.2 Hz, 2H), 3.32 (t, J=7.2 Hz, 2H), 2.41 (s, 3H), 2.36 (t, J=6.9 Hz, 2H), 1.10 (t, J=6.9 Hz, 3H).

3. Preparation of 3-[(3-bromobenzyl)-(toluene-4-sulfonyl)amino]propionic acid.

To a solution of 3-[(3-bromobenzyl)-(toluene-4-sulfonyl)amino]propionic acid ethyl ester (60.0 g, 0.14 mol) in a mixed solvent of EtOH (600 ml) and H ₂ O (60 ml) add NaOH (11.2 g, 0.28 mol) in portions; the reaction solution was stirred at 60° C. for 4 hours. The reaction solution was cooled to 0° C. and acidified to pH=5 with concentrated HCl. The solution was concentrated in vacuo to give a residue which was extracted with EtOAc (3x150 ml). The organic layer was dried with Na ₂ SO ₄ , filtered and concentrated in vacuo to give 3-[(3-bromobenzyl)-(toluene-4sulfonyl)amino]propionic acid (45.2 g, yield: 78.6%) as a solid white substances. ¹ H-NMR (DMSO-de, 300 MHz): δ 12.28 (br, 1H), 7.74 (d, J=8.1 Hz, 2H), 7.49-7.41 (m, 4H ), 7.32 (d, J=5.1 Hz,

- 42 040817

2H), 4.33 (s, 2H), 3.29 (t, J=6.9 Hz, 2H), 2.41 (s, 3H), 2.27 (t, J=7.5 Hz, 2H).

4. Preparation of 3-[(3-bromobenzyl)-(toluene-4-sulfonyl)amino]propionyl chloride.

To a solution of 3-[(3-bromobenzyl)-(toluene-4-sulfonyl)amino]propionic acid (45.2 g, 0.11 mol) in CH ₂ Cl ₂ (1000 ml) was added portionwise DMF (1 ml) and dropwise oxalyl chloride (27.9 g, 0.22 mol). The reaction solution was stirred at 55° C. for 2 hours. The mixture was concentrated in vacuo to give crude 3-[(3-bromobenzyl)-(toluene-4-sulfonyl)amino]propionyl chloride (47.2 g, yield: 99%) in in the form of a black oily liquid, which is used in the next step without further purification.

5. Preparation of 8-bromo-2-(toluene-4-sulfonyl)-1,2,3,4-tetrahydrobenzo[c]azepin-5-one.

AlCl _{3 ( 29} .3 g, 0.22 mol). The reaction mixture was stirred at 55° C. for 2 hours. The reaction mixture was poured into freezing water (1.2 L) and extracted (500 ml). The organic layer was concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: EtOAc=5:1 to 2:1) to give 8-bromo-2-(toluene-4-sulfonyl)-1,2,3,4tetrahydrobenzo[c]azepine- 5-one (35 g, yield: 81%) as a white solid. ¹ H-NMR (DMSO-d6, 300 MHz): δ 7.65 (d, J=8.4 Hz, 3H), 7.60-7.51 (m, 2H), 7.36 (d, J = 8.1 Hz, 2H), 4.68 (s, 2H), 3.42 (t, J=9.2 Hz, 2H), 2.96 (t, J=6.3 Hz, 2H), 2.37 (s, 3H).

6. Preparation of [8-bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1Hbenzo[c]azepinp-5-yl]carbamic acid tert-butyl ester.

To& 1,NH ₄ OAc/EtOH Jos

ΙΊΤ' NaBHjCN^

2. BoCjO

DXM, EtjN NM _ъ 'Sun

To a solution of 8-bromo-2-(toluene-4-sulfonyl)-1,2,3,4-tetrahydrobenzo[c]azepin-5-one (32.0 g, 0.08 mol) in EtOH (600 ml) NH ₄ OAC (18.5 g, 0.24 mol) and NaCNBH ₃ (14.9 g, 0.24 mol) are added in portions at rt. The reaction mixture was then stirred at 95° C. for 16 hours. The mixture was poured into freezing water (500 ml) and then the EtOH was removed in vacuo. The residue is extracted with CH ₂ Cl ₂ (3x500 ml). The combined solvent is concentrated. The residue was redissolved in CH ₂ Cl ₂ (300 ml) and triethylamine (12.2 g, 0.12 mol) and (Boc) ₂ O (34.6 g, 0.12 mol) were added at rt. The reaction mixture was stirred at rt for 4 h and then concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: EtOAc=8:1 to 2:1) to give tert-butyl ester [8-bromo-2-(toluene-4sulfonyl)-2,3,4,5-tetrahydro -1H-benzo[c]azepinp-5-yl]carbamic acid (16.7 g, yield: 42%) as a white solid. ¹ H-NMR (DMSO-d ₆ , 300 MHz): δ 7.62-7.51 (m, 2H), 7.47 (d, J=9.9 Hz, 1H), 7.41-7, 34 (m, 3H), 7.10 (d, J=8.4 Hz, 1H), 4.81-4.74 (m, 1H), 4.53 (d, J=15.0 Hz, 1H ), 4.28 (d, J=15.3 Hz, 1H), 3.64-3.57 (m, 1H), 3.41-3.30 (m, 1H), 2.35 (s, 3H), 1.85-1.77(m, 1H), 1.69-1.63(m, 1H), 1.36(s, 9H).

7. Preparation of 8-bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-ylamine.

HN _x H ₂ N' Boc

[8-Bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl]carbamic acid tert-butyl ester solution (14.8 g, 0. 03 mol) in HCl/EtOAc (150 ml) was stirred at 25°C for 4 h. The resulting solid was filtered and washed with MeOH and Et ₂ O to obtain

- 43 040817 prepared 8-bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-ylamine (10.5 g, yield: 89%) as a white solid. 1H-NMR (DMSO-d ₆ , 300 MHz): δ 8.79 (br, 3H), 7.64-7.58 (m, 3H), 7.53 (s, 1h), 7.36 (d , J=8.4 Hz, 2H), 7.15 (d, J=8.4 Hz, 1H), 4.71-4.61 (m, 2H), 4.31 (d, J=15, 3 Hz, 1H), 3.82 (d, J=18.3 Hz, 1H), 2.38 (s, 3H), 2.14-2.07 (m, 1H), 1.77-1, 71(m, 1H). LC-MS: m/z 395.0/397.0 [M+H]+.

8. Synthesis of 8-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-amine.

A solution of 8-bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-ylamine (2.00 g, 5.06 mmol) in HBr ( 33% solution in acetic acid, 20 ml) was heated to 50° C. for 12 hours. After cooling to rt, the mixture was diluted with EtOAc (50 ml). The white solid was collected by filtration and dried in vacuo to give the crude finished 8-bromo-2,3,4,5-tetrahydro-1Hbenzo[c]azepine-5-amine (1.66 g, yield: 82%) which immediately applied to the next step. ESI-MS (M+H)+ 241.1. 1H-NMR (400 MHz, CD3OD) δ: 7.72-7.55 (m, 2H), 7.18 (d, J=8.4 Hz, 1H), 4.99-4.98 (m, 1H), 4.51 (d, J=14.4 Hz, 1H), 4.39 (d, J=14.4 Hz, 1H), 3.62-3.49 (m, 2H), 2, 38-2.24 (m, 1H), 2.16-2.00 (m, 1H).

9. Synthesis of tert-butyl 5-amino-8-bromo-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate.

In a solution of 8-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-amine (640 mg, 1.60 mmol) and triethylamine (490 mg, 4.8 mmol) in CH ₂ Cl ₂ (20 ml) was added (Boc) ₂ O (314 mg, 1.44 mmol). The mixture was stirred at rt for 1 h. After dilution with CH ₂ Cl ₂ (100 ml), the mixture was washed with brine (20 mlx2). The organic phase is concentrated in vacuo and the residue is purified by preparative HPLC (CH3CN/H2O with 0.05% NH3-H2O as mobile phase) to give t-butyl-5-amino-8-bromo-4,5-dihydro-1Hbenzo[ c]azepine-2(3H)-carboxylate as a colorless oily liquid (364 mg, yield: 67%). IEMS (M+H)+: 341.1.

10. Preparation of tert-butyl-8-bromo-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-4,5-dihydro1 H-benzo[c]azepine-2( 3H)-carboxylate.

Synthesis of tert-butyl-8-bromo-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-4,5-dihydro-1Hbenzo[c]azepine-2(3H)- carboxylate is similar to the synthesis of tert-butyl-7-bromo-1-(5-(tert-butyl)-1,2,4oxadiazole-3-carboxamido)-4,5-dihydro-1H-benzo[d]azepin-3(2Н )-carboxylate from example 1, step 8. The crude product was purified by preparative HPLC (CH3CN/H2O with 0.05% NH4HCO3 as mobile phase) to give t-butyl-8-bromo-5-(5-(t-butyl) -1,2,4-oxadiazole-3-carboxamido)-4,5dihydro-1H-benzo[c]azepine-2(3H)-carboxylate as a yellow solid (4.5 g, yield: 70%). ESI-MS (M+H)+: 493.3.

11. Preparation of tert-butyl-5-(5-(tert-butyl)-1,2,4-oxadiazol-3-carboxamido)-8-(2-((1-methyl-1Hpyrazol-4-yl)amino) pyrimidin-4-yl)-4,5-dihydro-1H-benzo[c]azepin-2(3H)-carboxylate.

- 44 040817

(1.2 equiv)

Pd(dppf)Cl2(O.O5 equiv) K2CO3 (2.0 equiv) dioxene/H^O, 100°C, 2 h

Synthesis of tert-butyl-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4yl)amino)pyrimidine- 4-yl)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate is similar to the synthesis of tert-butyl-1-(5-(tert-butyl)-1,2,4-oxadiazole-3 - carboxamido)-7-(2-((1-methyl-1 H-pyrazol-4-yl)amino)pyrmidin4-yl)-4,5-dihydro-1H-benzo[d]azepin-3(2H)-carboxylate from example 1, step 12. The crude product was purified by silica gel column chromatography (EtOAc/MeOH=15:1) to give tert-butyl-5(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido )-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4yl)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate as yellow solid (1.2 g, yield: 28%). ESI-MS (M+H)+: 588.3. ¹ H-NMR (400 MHz, CD3OD) δ: 8.43-8.38 (m, 1H), 8.11-7.95 (m, 3H), 7.67-7.48 (m, 2H) , 7.25-7.24(m, 1H), 5.67-5.63(m, 1H), 4.84-4.77(m, 1H), 4.55-4.50(m, 1H), 4.17-4.09 (m, 1H), 3.94-3.88 (m, 3H), 3.64-3.54 (m, 1H), 2.11-2.08 ( m, 2H), 1.43-1.34 (m, 9H), 1.22 (s, 9H).

12. Preparation of 5-(tert-butyl)-K-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydro- 1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide.

Into a solution of tert-butyl-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1Hpyrazol-4-yl)amino)pyrimidine -4-yl)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate (600 mg, 1.0 mmol) in CH ₂ Cl ₂ (5 ml) add TFA (5 ml) ; the mixture is stirred for 1 h at rt. After concentration, the crude product (440 mg, yield: 85%) was used in the next step without further purification. ESI-MS (M+H)+: 488.3.

13. Preparation of 5-(tert-butyl)-K-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2(oxetan-3-yl) -2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide.

To a solution of 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydro-1H -benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide (180 mg, 0.36 mmol) and dihydrofuran-3(2H)-one (132 mg, 1.8 mmol) in MeOH (20 ml) NaBH ₃ CN (66 mg, 1.08 mmol) and ZnCl ₂ (246 mg, 1.8 mmol) are added. The mixture was stirred at rt for 16 h. After concentration and dilution with water (30 ml), the mixture was extracted with EtOAc (80 mlx2). The combined organic layers are washed with H2O

- 45 040817 (60 ml) and concentrate. The crude product was purified by preparative HPLC (CH3CN/H2O with 0.05% NH4HCO3 as mobile phase) to give 5-(t-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4yl) amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole3- carboxamide as a yellow solid (114 mg, yield: 49%). ESI-MS (M+H)+: 544.3. ¹ H-NMR (400 MHz, CD3OD) δ: 8.30 (d, J=5.2 Hz, 1H), 7.92-7.85 (m, 3H), 7.51 (s, 1H), 7.35 (d, J=8.4Hz, 1H), 7.11 (d, J=5.2Hz, 1H), 5.50 (d, J=9.6Hz, 1H), 4, 67-4.55 (m, 4H), 3.84-3.70 (m, 3H), 3.80 (s, 3H), 2.95-2.89 (m, 1H), 2.76- 2.72 (m, 1H), 2.15-2.12 (m, 1H), 1.95-1.92 (m, 1H), 1.40 (s, 9H).

14. Preparation of (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2(oxetan- 3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide.

5-(tert-Butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2 ,3,4,5tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide was separated by SFC (OD-H (2x25 cm), 30% methanol/CO2 , 100 bar, 60 ml/min, 220 nm, input, vol.: 1.5 ml, 9 mg/ml, methanol), which gives 34.8 mg of peak 1 (chemical purity 99%, ee >99%) and 37.1 mg peak 2 (chemical purity 99%, ee >99%).

Peak 2 means {(K)-8-[2-(1-methyl-1H-pyrazol-4-ylamino)-pyrimidin-4-yl]-2-oxetan-3-yl-2,3,4,5tetrahydro- 1H-2-benzazepin-5-yl}-5-tert-butyl-1,2,4-oxadiazole-3-carboxylic acid amide: LCMS: Rt 0.88 min, m/z 544.00. ¹ H-NMR (400 MHz, methanol-OO δ: 8.40 (d, J=5.02 Hz, 1H), 7.87-8.09 (m, 3H), 7.63 (s, 1H) , 7.45 (d, J=8.28 Hz, 1H), 7.20 (d, J=5.27 Hz, 1H), 5.60 (s, 1H), 4.55 - 4.77 ( m, 4H), 3.89 (s, 3H), 3.75-3.85 (m, 3H), 2.75-3.10 (m, 2H), 1.89-2.42 (m, 2H ), 1.51 (s, 9H).

Method 2.

1. Chiral resolution of tert-butyl-5-amino-8-bromo-4,5-dihydro-1H-benzo[c]azepine-2(3H)carboxylate to obtain the compound tert-butyl-(R)-5-amino- 8-bromo-1,3,4,5-tetrahydro-2Hbenzo[c]azepine-2-carboxylate with (11bS)-4-hydroxydinaphyto[2,1-d:1',2'-f][1,3 ,2]dioxaosphepin-4-oxide (1:1).

MeOH (4.8 L) is added to tert-butyl 5-amino-8-bromo-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate (800 g, 2.34 mol) and (S)-(-)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (816.6 g, 2.34 mol). The mixture is stirred at 25° C. for 30 minutes and a yellow suspension forms. The suspension is stirred under reflux (70°C) to obtain a yellow solution. The reaction mixture was concentrated to dryness and IPAC (3.44 L) was added. The reaction mixture is heated to 70° C. and stirred at this temperature for 3 hours. The reaction mixture is cooled to room temperature and an additional portion of IPAc (3.44 L) is added. The reaction mixture is stirred at room temperature for 16 hours. The suspension is filtered on a centrifuge and the precipitate is washed three times, each time with 7 volumes of IPAC. The wet cake is quickly dried to give the compound tert-butyl-(R)-5-amino-8-bromo-1,3,4,5-tetra-hydro-2H-benzo[c]azepine-2-carboxylate with (11bS)4- hydroxydinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin-4-oxide (1:1) (515 g, yield: 64% [assuming

- 46 040817 maximum recovery 50%], 91.3% ee) as a white solid. The recrystallization process is repeated to increase it to 97.2%.

2. Preparation of tert-butyl-(R)-8-bromo-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-1,3,4,5tetrahydro-2H-benzo [c]azepine-2-carboxylate.

TEA (3.0 equiv), DCM, ct, 2 h

To a solution of sodium 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylate (800 mg, 4.0 mmol) and oxalyl chloride (2.0 g, 16 mmol) in CH ₂ Cl ₂ (10 ml ) add DMF (cat.). The mixture is stirred at room temperature for 2 hours and then concentrated twice with CH ₂ Cl ₂ . The residue was diluted with CH ₂ Cl ₂ (20 ml) and the compound tert-butyl-(R)-5-amino-8-bromo-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2carboxylate with ( 11bR)-4-hydroxydinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin-4-oxide (1:1) (2.0 g, 3.0 mmol) and triethylamine (900 mg, 9.0 mmol). The mixture is stirred at room temperature for 2 hours and concentrated. The crude product is purified by silica chromatography (PE: EtOAc=2:1) to give tert-butyl-(R)-8-bromo-5-(5-(tert-butyl)-1,2,4-oxadiazole- 3-carboxamido)1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate as a yellow solid (1.2 g, yield: 80%). ESI-MS (M+Na)+: 515.1. ¹ H-NMR (400 MHz, CDCb) δ: 7.48-7.36 (m, 2H), 7.24-7.18 (m, 1H), 5.61-5.50 (m, 1H) , 4.70-4.51(m, 1H), 4.38-4.29(m, 1H), 4.05-3.85(m, 1H), 3.53-3.48(m, 1H), 2.24-2.16(m, 2H), 1.48(s, 9H), 1.40-1.37(m, 9H).

3. Synthesis of tert-butyl-(R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1Hpyrazole-4- yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate.

Pd(dpprf)Cl2(O,O5 equiv)

K ₂ C0j(2,O equiv) dioxene/Н _g О, 100 °C, 2 h

Synthesis of tert-butyl-(R)-5-(5-(tert-butyl)-1,2,4-oxadiazol-3-carboxamido)-8-(2-((1-methyl-1Hpyrazol-4-yl) amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate is similar to the synthesis of tert-butyl-1-(5-(tert-butyl)-1,2 ,4-oxadiazol-3-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4yl)amino)pyrmidin-4-yl)-4,5-dihydro-N-benzo[d]azepin- 3(2H)-carboxylate from example 1, step 12. The crude material was purified by silica chromatography (EtOAc:MeOH=15:1) to give tert-butyl-(R)-5-(5-(tert-butyl) -1,2,4-oxadiazol-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro- 2H-benzo[c]azepine-2-carboxylate as a yellow solid (1.5 g, yield: 43%). ESI-MS (M+H)+: 588.3.

4. Synthesis of (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrmidin-4-yl)-2,3, 4,5tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide.

- 47 040817

Into a solution of tert-butyl-(R)-5-(5-(tert-butyl)-1,2,4-oxadiazol-3-carboxamido)-8-(2-((1-methyl-1Hpyrazol-4-yl )amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate (1.4 g, 2.3 mmol) in CH ₂ Cl ₂ (10 ml ) add TFA (10 ml). The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the crude product (1.0 g, yield: 81%) was used in the next step without further purification. ESI-MS (M+H)+: 488.3.

5. Synthesis of (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2(oxetan- 3-yl)-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide (I-RP33).

Synthesis of (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3yl )-2,3,4,5-tetrahydro-N-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide is similar to the synthesis of 5(tert-butyl)-N-(8- (2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5tetrahydro-1H-benzo[c] azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide described in Method 1, Step 13 above. The crude material was purified by silica gel chromatography (EtOAc:MeOH=20:1) to give (R) -5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)2 ,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide as a yellow solid (746 mg, yield: 67%). ESI-MS (M+H)+: 544.3. ¹ H-NMR (400 MHz, CD ₃ OD) δ: 8.42 (d, J=5.2 Hz, 1H), 8.03-7.96 (m, 3H), 7.63 (s, 1H ), 7.48 (d, J=8.0Hz, 1H), 7.23 (d, J=5.2Hz, 1H), 5.61 (d, J=9.6Hz, 1H), 4.78-4.67 (m, 4H), 3.96-3.82 (m, 3H), 3.90 (s, 3H), 3.06-3.02 (m, 1H), 2, 89-2.80 (m, 1H), 2.29-2.22 (m, 1H), 2.07-2.03 (m, 1H), 1.52 (s, 9H).

Example 3 5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin4-yl)-2, 3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide (compound 3).

To a solution of 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydro-1H -benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide (200 mg, 0.41 mmol) in CH3CN (20 ml) 2-iodoethanol (141 mg, 0.82 mmol) is added ) and K ₂ CO ₃ (170 mg, 1.23 mmol). The mixture was stirred at 80° C. for 2 hours. The mixture was diluted with EtOAc (100 ml), washed with water (60 ml) and concentrated. The crude product was purified by preparative HPLC (CH3CN/H2O with 0.05% NH ₄ HCO ₃ as mobile phase) to give 5-(t-butyl)-N-(2-(2-hydroxyethyl)-8-(2-( (1-methyl-1H-pyrazol-4yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole -3-carboxamide

- 48 040817 as a yellow solid (90 mg, yield: 32%). ESI-MS (M+H)+: 532.3. 1H-NMR (400 MHz, CD3OD) δ: 8.43 (d, J=5.2 Hz, 1H), 8.04-8.00 (m, 3H), 7.64 (s, 1H), 7 .47 (d, J=8.0Hz, 1H), 7.25 (d, J=5.0Hz, 1H), 5.60 (d, J=9.6Hz, 1H), 4.22 -4.10 (m, 2H), 3.91 (s, 3H), 3.75 (t, J=6.0 Hz, 2H), 3.28-3.21 (m, 2H), 2.692, 65 (m, 2H), 2.31-2.27 (m, 1H), 2.00-1.97 (m, 1H), 1.53 (s, 9H).

Example 4 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2(methylsulfonyl)-2.3 ,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide (compound 4).

Synthesis of 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(methylsulfonyl)2,3,4 ,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide is similar to the synthesis of 5-(tert-butyl)-N-(8-(2-((1-metul -1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(methylsulfonyl)-2,3,4,5-tetrahydro1H-benzo[c]azepin-5-yl)-1,3,4 -oxadiazole-2-carboxamide in Example 15. The crude product was purified by preparative HPLC (CH ₃ CN/H ₂ O with 0.05% NH ₄ HCO ₃ as mobile phase) to give 5(tert-butyl)-N-(8 -(2-((1-methyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(methylsulfonyl)-2,3,4,5tetrahydro-1H-benzo[c]azepin- 5-yl)-1,2,4-oxadiazole-3-carboxamide as a yellow solid (98 mg, yield: 60%). ESI-MS (M+H)+: 566.2. ¹ H-NMR (400 MHz, CDQ3) δ: 8.45 (d, J=4.8 Hz, 1H), 8.02 (s, 1H), 7.94-7.92 (m, 2H), 7.57-7.48 (m, 3H), 7.07 (d, J=5.2 Hz, 1H), 6.96 (s, 1H), 5.72 (t, J=8.8 Hz , 1H), 4.85-4.81 (m, 1H), 4.57-4.53 (m, 1H), 4.03-3.97 (m, 1H), 3.93 (s, 3H ), 3.66-3.63 (m, 1H), 2.74 (s, 3H), 2.392.21 (m, 2H), 1.49 (s, 9H).

Example 5 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3yl)- 2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide (compound 5).

In a solution of 5-(tert-butyl)-N-(8-(2-((1-methyl-1 H-purazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydro- 1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide (180 mg, 0.36 mmol) and dihydrofuran-3(2H)-one (132 mg, 1.8 mmol ) in MeOH (20 ml) NaBH ₃ CN (66 mg, 1.08 mmol) and ZnCl ₂ (246 mg, 1.8 mmol) are added. The mixture was stirred at rt for 16 h. After concentration and dilution with water (30 ml), the mixture was extracted with EtOAc (80 mlx2). The combined organic layers are washed with H2O (60 ml) and concentrated. The crude product was purified by preparative HPLC (CH ₃ CN/H ₂ O with 0.05% NH4HCO3 as mobile phase) to give 5-(tert-butyl)-N-(8-(2-((1-methyl-1H- pyrazol-4yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2, 4-oxadiazole 3-carboxamide as a yellow solid (114 mg, yield: 49%). ESI-MS (M+H)+: 544.3. ¹ H-NMR (400 MHz, CD3OD) δ: 8.30 (d, J=5.2 Hz, 1H), 7.92-7.85 (m, 3H), 7.51 (s, 1H), 7.35 (d, J=8.4Hz, 1H), 7.11 (d, J=5.2Hz, 1H), 5.50 (d, J=9.6Hz, 1H), 4, 67-4.55 (m, 4H), 3.84-3.70 (m, 3H), 3.80 (s, 3H), 2.95-2.89 (m, 1H), 2.76- 2.72 (m, 1H), 2.15-2.12 (m, 1H), 1.95-1.92 (m, 1H), 1.40 (s, 9H).

Example 6 5-(tert-butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)- 2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide (compound 6).

- 49 040817

Synthesis of 5-(tert-butyl)-Ni(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-N-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3 ,4,5-tetrahydro-1 H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide is similar to the synthesis of 5-(tert-butyl)-N-(8-(2- ((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)2,3,4,5-tetrahydro-III-benzo[c]azepin- 5-yl)-1,2,4-oxadiazole-3-carboxamide in Example 5. The crude product was purified by silica gel chromatography (EtOAc:MeOH=10:1) to give 5-(tert-butyl)-N-(2- (3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydro-1H-benzo[c]azepin- 5-yl)-1,2,4-oxadiazole-3-carboxamide as a yellow solid (102 mg, yield: 53%). ESI-MS (M+H)+: 557.7. ¹ H-NMR (400 MHz, CD3OD) δ: 8.29 (d, J=5.2 Hz, 1H), 7.87 (s, 3H), 7.50 (s, 1H), 7.32 ( d, J=8.8Hz, 1H), 7.09 (d, J=5.6Hz, 1H), 5.45 (d, J=10.0Hz, 1H), 3.86-3, 78 (m, 3H), 3.75 (s, 3H), 3.09-3.06 (m, 1H), 2.80-2.74 (m, 1H), 2.50-2.39 ( m, 3H), 2.14-2.05 (m, 1H), 1.88-1.85 (m, 1H), 1.72-1.69 (m, 2H), 1.41 (s, 9H).

Example 7 5-(tert-Butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3yl)- 2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide (compound 7).

1. Synthesis of 4-methoxy-N-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-amine.

The synthesis of 4-methoxy-N-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-amine is similar to the synthesis of 4-methoxy-N(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine in example 1, step 10. The crude material was purified by silica gel chromatography (PE:EtOAc=1:1) to give 4-methoxy-N-(1-ethyl-1H-pyrazol-4yl)pyrimidin-2-amine (420 mg, yield: 43%) as a yellowish brown solid. ESI-MS(M+H)+: 220.1.

2. Synthesis of 4-chloro-N-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-amine.

HBr (5 ml, 48% aqueous) was added to 4-methoxy-N-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-amine (420 mg, 1.9 mmol). The reaction mixture is heated to 100° C. and stirred at this temperature for 2 hours. The reaction mixture is concentrated and then POCl ₃ (5 ml) is added. The reaction mixture is heated to 100° C. and stirred at this temperature for 16 hours. The reaction mixture is cooled to room temperature and poured into water cooled to freezing point. The pH of the solution was adjusted to pH=8 with aqueous NaOH (5 M). The main aqueous phase is extracted with EtOAc (2x30 ml). The combined organic layers are washed with brine (100 ml), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel chromatography (PE:EtOAc=1:1) to give

- 50 040817 4-Chloro-N-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-amine as a white solid (220 mg, yield: 51%) ESI-MS (M+H) )+: 224.1.

3. Synthesis of tert-butyl-5-(5-(tert-butyl)-1,2,4-oxadiazol-3-carboxamido)-8-(2-((1-ethyl-1 H-pyrazol4-yl)amino )pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate.

Pd(tippf)CI ₂ (0.05 eq.)

K ₂ CO ₂ (2.0 eq.) dioxane 80 ° C _; 2h

To a mixture of tert-butyl-8-bromo-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-1,3,4,5-tetrahydro2H-benzo[d]azepine- 2-carboxylate (560 mg, 1.13 mmol) and PinB-BPin (288 mg, 1.10 mmol) in dry 1,4-dioxane (11 mL) under N2 atmosphere, KOAc (332 mg, 3.39 mmol) was rapidly added and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (89 mg, 0.11 mmol).

The mixture was stirred at 100° C. under N2 for 12 h. ₂ CO ₃ (312 mg, 2.26 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (89 mg, 0.11 mmol) and H ₂ O (2.5 ml). The mixture was stirred under N2 at 80° C. for 2 hours. After cooling, the mixture was concentrated and purified by silica gel column chromatography (PE:EIAc=3:1) to give tert-butyl-5-(5-(tert-butyl )-1,2,4-oxadiazol-3-carboxamido)8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5- tetrahydro-2H-benzo[c]azepine-2carboxylate (200 mg, yield: 29%) as a yellow solid. ESI-MS (M+H)+: 602.2.

4. Preparation of 5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydro- 1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide.

Into a solution of tert-butyl-5-(5-(tert-butyl)-1,2,4-oxadiazol-3-carboxamido)-8-(2-((1-ethyl-1 H-pyrazol4-yl)amino) pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate (200 mg, 0.33 mmol) in CH ₂ Cl ₂ (5 ml) TFA (5 ml); the mixture is stirred for 1 h at rt. After concentration, the crude product (166 mg, yield: 100%) was used in the next step without further purification. ESI-MS (M+H)+: 502.7.

5. Synthesis of 5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3yl)- 2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide (I-RP1).

Into a solution of 5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5

- 51 040817 tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide (166 mg, 0.33 mmol) and dihydrofuran-3(2H)-one (119 mg , 1.65 mmol) in MeOH (18 ml) was added NaBH ₃ CN (21 mg, 0.33 mmol) and ZnCl ₂ (90 mg, 0.66 mmol). The mixture was stirred at rt for 3 h. After concentration and dilution with water (30 ml), the mixture was extracted with EtOAc (80 mlx2). The combined organic layers are washed with H2O (60 ml) and concentrated. The crude product was purified by preparative TLC (CH ₂ Cl ₂ : MeOH=20:1) to give 5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino )pyrimidin-4-yl)-2-(oxetan-3yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide as a yellow solid (60 mg, yield: 32%). ESI-MS (M+H)+: 557.7. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.42 (d, J=5.2 Hz, 2H), 7.90 (s, 1H), 7.85 (d, J=8.0 Hz , 1H), 7.79 (s, 1H), 7.57-7.53 (m, 2H), 7.04 (d, J=5.2 Hz, 1H), 5.71 (t, J= 8.4 Hz, 1H), 4.82-4.66 (m, 4H), 4.17 (q, J=7.2 Hz, 2H), 3.91-3.72 (m, 3H), 2.99-2.92(m, 1H), 2.63-2.58(m, 1H), 2.40-2.34(m, 1H), 2.15-2.07(m, 1H ), 1.51 (t, J=7.6 Hz, 3H), 1.45 (s, 9H).

Example 8 5-(tert-Butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro2H-pyran-4 -yl)-2,3,4,5-tetrahydro-N-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide (compound 8).

Synthesis of 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro2H-pyran-4-yl )-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide is similar to the synthesis of 5-(tert-butyl)-N-(8 -(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2Hpyran-4-yl)-2,3,4,5-tetrahydro-N -benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide in Example 12, step 4. The crude product was purified by preparative HPLC (CH3CN/H2O with 0.05% NH4HCO3 as mobile phase) to obtain 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4- yl)-2,3,4,5-tetrahydro-N-benzo[c]azepin-5-yl)1,2,4-oxadiazole-3-carboxamide as yellow solid (20 mg, yield: 14% ). ESI-MS (M+H)+: 572.3. ¹ H-NMR (400 MHz, CD3OD) δ: 8.30 (s, 1H), 7.91-7.86 (m, 3H), 7.53 (s, 1H), 7.36 (d, J =8.0 Hz, 1H), 7.10 (d, J=5.6 Hz, 1H), 5.48 (d, J=9.2 Hz, 1H), 4.19-3.88 (m , 4H), 3.78 (s, 3H), 3.30-3.21 (m, 2H), 3.163.03 (m, 2H), 2.67-2.62 (m, 1H), 2, 16-2.11 (m, 1H), 1.96-1.83 (m, 3H), 1.64-1.52 (m, 2H), 1.38 (s, 9H).

Example 9 (R)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2- (2hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide (compound 9).

1. Synthesis of tert-butyl-(R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(4,4,5,5-tetramethyl1,3, 2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate.

- 52 040817

A mixture of tert-butyl-(R)-8-bromo-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-1,3,4,5-tetrahydro2H-benzo[c ]azepine-2-carboxylate (1.2 mg, 2.43 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3 ,2dioxaborolane) (650 mg, 2.56 mmol), KOAc (477 mg, 4.86 mmol) and Pd(dppf)Cl ₂ -DCM (196 mg, 0.24 mmol) in 30 ml of 1,4-dioxane are stirred under nitrogen atmosphere at 90°C for 2 h. After cooling to room temperature, the mixture was diluted with EtOAc (200 ml), washed with water (50 mlx2), dried with Na ₂ SO ₄ and concentrated to obtain tert-butyl-(R)- 5-(5-(tert-butyl)-1,2,4-oxadiazol-3-carboxamido)-8(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 ,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate, which is used in the next step without further purification. ESI-MS (M+H)+: 541.3.

2. Synthesis of tert-butyl-(R)-5-(5-(tert-butyl)-1,2,4-oxadiazol-3-carboxamido)-8-(2-chloropyrimidin4-yl)-1,3,4 ,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate.

A mixture of tert-butyl-(R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(4,4,5,5-tetramethyl1,3,2- dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate (1.31 g, 2.43 mmol), 2,4 dichloropyrimidine (344 mg, 2.31 mmol), Pd(dppf)Cl ₂ (196 mg, 0.24 mmol) and K2CO3 (672 mg, 4.86 mmol) in 20 ml dioxane/H ₂ O (4:1) are stirred under N2 atmosphere at 90°C for 12 hours. After removing the solvent, the residue was purified by silica gel chromatography (CH ₂ Cl ₂ : MeOH=20:1) to obtain tert-butyl-(R)-5-(5-(tert-butyl)-1,2,4- oxadiazole-3-carboxamido)-8-(2-chloropyrmidin-4-yl)-1,3,4,5tetrahydro-2H-benzo[c]azepine-2-carboxylate as yellow solid (900 mg, yield: 70% in two stages). ESI-MS (M+H) ⁺ : 527.2.

3. Synthesis of tert-butyl-(R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1,5-dimethyl1H-pyrazole- 4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate.

Pd ₂ (dba) ₃ (OD eq) Ξ-Phos (OD eq) Cs ₂ CO ₃ (2.0 eq) dioxep 100 C, 2 h

A mixture of tert-butyl-(R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-chloropyrmidin-4yl)-1,3,4,5 -tetrahydro-2H-benzo[c]azepine-2-carboxylate (900 mg, 1.71 mmol), 1,5-dimethyl-1H-pyrazole4-amine (228 mg, 2.05 mmol), Cs ₂ CO ₃ ( 1.11 g, 3.42 mmol), Pd ₂ (dba) ₃ (157 mg, 0.17 mmol) and S-Phos (140 mg, 0.34 mmol) in 15 ml of 1,4-dioxane are stirred under atmosphere nitrogen at 100°C for 2 hours. The mixture was diluted with EtOAc (200 ml) and washed with water (60 mlx2). The organic phase is dried with Na ₂ SO ₄ and concentrated. The crude product is purified by silica gel chromatography (DCM/MeOH=20:1) to give t-butyl-(R)-5-(5-(t-butyl)-1,2,4-oxadiazole-3-carboxamido)-8 -(2-((1,5-dimethyl-1H-pyrazol4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate in the form yellow solid (110 mg, yield: 11%). ESI-MS (M+H) ⁺ : 602.3. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.39

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8.38 (m, 1H), 7.93-7.90 (m, 2H), 7.67 (s, 1H), 7.46-7.44 (m, 2H), 7.05 (d, J=4.2 Hz, 1H), 6.48-6.41 (m, 1H), 5.69-5.59 (m, 1H), 4.81-4.66 (m, 1H), 4 .50-4.41 (m, 1H), 4.10-4.03 (m, 1H), 3.81 (s, 3H), 3.61-3.52 (m, 1H), 2.23 (s, 3H), 2.20-2.16 (m, 2H), 1.40 (s, 9H), 1.34-1.30 (m, 9H).

4. Synthesis of (R)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-

2,3,4,5-tetrahydro-1 H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide.

Synthesis of (R)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3, 4,5tetrahydro-1 H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide is similar to the synthesis of 5-(tert-butyl)N-(8-(2-(( 1 - methyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)1,2,4-oxadiazole -3-carboxamide in example 2. The crude material is used further without further purification. ESI-MS (M+H)+: 502.2.

5. Synthesis of (R)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2- (2hydroxyethyl)-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-5 -yl)-1,2,4-oxadiazole-3-carboxamide.

Synthesis of (R)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2hydroxyethyl )-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide is similar to the synthesis of 5-(tert-butyl)-N-(2 -(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4,5-tetrahydro-1H-benzo[c] azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide in Example 3. The crude material was purified by silica gel chromatography (CH ₂ Cl ₂ :MeOH=10:1) to give (R)-5-(tert-butyl )-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5tetrahydro -1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide as a yellow solid (43 mg, yield: 42%). ESI-MS (M+H) ⁺ : 546.3. ¹ H-NMR (400 MHz, CD3OD) δ: 8.32 (d, J=5.2 Hz, 1H), 8.00-7.98 (m, 2H), 7.60 (s, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.23 (d, J=5.2 Hz, 1H), 5.58-5.56 (m, 1H), 4.16-4 .10 (m, 2H), 3.82 (s, 3H), 3.73 (t, J=6.0 Hz, 2H), 3.30-3.21 (m, 2H), 2.67- 2.65 (m, 2H), 2.30-2.27 (m, 1H), 2.25 (s, 3H), 2.02-1.96 (m, 1H), 1.52 (s, 9H).

Example 10 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2(tetrahydrofuran-3-yl) -2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide (compound 10).

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Synthesis of 5-(tert-butyl)-Sch8-(2-((1-methyl-N-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydrofuran3-yl)-2,3,4 ,5-tetrahydro-III-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide as described in example 7, step 3. The crude product was purified by preparative HPLC (CH ₃ CN/H ₂ O with 0.05% NH ₄ HCO ₃ as mobile phase) to obtain 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4yl)amino)pyrimidine-4 -yl)-2-(tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4oxadiazole-3-carboxamide as a solid yellow (97 mg, yield: 57%). ESI-MS (M+H)+: 558.3. ¹ H-NMR (400 MHz, CD3OD) δ: 8.43 (d, J=5.2 Hz, 1H), 8.04-7.99 (m, 3H), 7.64-7.63 (m , 1H), 7.48 (d, J=8.0 Hz, 1H), 7.24 (d, J=5.2 Hz, 1H), 5.61 (d, J=9.6 Hz, 1H ), 4.10-3.91 (m, 4H), 3.90 (s, 3H), 3.78-3.71 (m, 2H), 3.36-3.10 (m, 3H), 2.33-2.20 (m, 2H), 2.06-1.96 (m, 2H), 1.52 (s, 9H).

Example 11 (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2 ,2,2trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide (compound 11).

Η

1. Synthesis of tert-butyl-(R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1Hpyrazole-4- yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate.

Pd(dpprf)Cl2 (0.05 equiv) K ₂₀₆₃ (2.0 equiv) dioxene/H ₂ O, 100°C, 2 h

Synthesis of tert-butyl-(R)-5-(5-(tert-butyl)-1,2,4-oxadiazol-3-carboxamido)-8-(2-((1-methyl-1Hpyrazol-4-yl) amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate is similar to the synthesis of tert-butyl-1-(5-(tert-butyl)-1,2 ,4-oxadiazol-3-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4yl)amino)pyrmidin-4-yl)-4,5-dihydro-1H-benzo[d]azepine- 3(2H)-carboxylate in example 1, step 12. The crude material was purified by silica gel chromatography (EtOAc:MeOH=15:1) to give tert-butyl-(R)-5-(5-(tert-butyl) -1,2,4-oxadiazol-3-carboxamido)-8-(2-((1-methyl-1Hpyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro- 2H-benzo[c]azepine-2-carboxylate as a yellow solid (1.5 g, yield: 43%). ESI-MS (M+H) ⁺ : 588.3.

2. Synthesis of (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrmidin-4-yl)-2,3, 4,5tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide.

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Into a solution of tert-butyl-(R)-5-(5-(tert-butyl)-1,2,4-oxadiazol-3-carboxamido)-8-(2-((1-methyl-1Hpyrazol-4-yl )amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate (1.4 g, 2.3 mmol) in CH2C12 (10 mL) TFA was added (10 ml). The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the crude product (1.0 g, yield: 81%) was used in the next step without further purification. ESI-MS (M+H)+: 488.3.

3. Synthesis of (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2 ,2,2trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide.

In a solution of (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4 ,5-tetrahydro-N-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide (75 mg, 0.15 mmol) in CH3CN (5 ml) was added 2,2,2-( trifluoroethyl) trifluoromethanesulfonate (60 mg, 0.3 mmol) and DIPEA (34 mg, 0.3 mmol). The mixture is stirred at 80°C for 2 hours in the microwave. The mixture was concentrated and purified by preparative TLC (DCM/MeOH=10:1) to give (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1Hpyrazol-4-yl)amino )pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)1,2,4-oxadiazol- 3-carboxamide as a yellow solid (45 mg, yield: 58%). ESI-MS (M+H)+: 570.2. ¹ H-NMR (400 MHz, CD3OD) δ: 8.30 (d, J=5.6 Hz, 1H), 7.92-7.86 (m, 3H), 7.50 (s, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.10 (d, J=5.6 Hz, 1H), 5.48-5.50 (m, 1H), 4.26-4 .22 (m, 1H), 4.02-3.98 (m, 1H), 3.78 (s, 3H), 3.32-3.27 (m, 1H), 3.21-3.17 (m, 1H), 3.05-2.98 (m, 2H), 2.17-2.07 (m, 1H), 1.91-1.82 (m, 1H), 1.40 (s , 9H).

Example 12 4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide (compound 12).

1. Preparation of tert-butyl-8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-4,5-dihydro1 H-benzo[c]azepine-2( 3H)-carboxylate.

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To a solution of 5-(tert-butyl)-1,3,4-oxadiazole-2-potassium carboxylate (1.4 g, 6.7 mmol) and HATU (3.2 g, 8.4 mmol) in DMF (20 ml) add triethylamine (1.69 g, 16.8 mmol) and tert-butyl-5-amino-8-bromo-4,5dihydro-1H-benzo[c]azepine-2(3H)-carboxylate (1.9 g, 5.6 mmol). The mixture was stirred at rt for 4 h. After dilution with water (80 ml), the mixture was extracted with EtOAc (100 mlx2). The combined organic layers are washed with brine (80 ml), dried and concentrated. The crude product was purified by silica gel column chromatography (PE/MeOH=2:1) to give tert-butyl-8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-4, 5-dihydro-N-benzo[c]azepine-2(3H)-carboxylate as a yellow solid (1.8 g, yield: 62%). ESI-MS (M+H-56)+: 437.3. ¹ H-NMR (400 MHz, CD ₃ OD) δ: 7.51-7.43 (m, 2H), 7.28-7.26 (m, 1H), 5.52-5.45 (m, 1H), 4.65-4.61 (m, 1H), 4.43-4.39 (m, 1H), 4.15-4.09 (m, 1H), 3.65-3.43 ( m, 1H), 2.08-2.03 (m, 2H), 1.50 (s, 9H), 1.43-1.42 (m, 9H).

2. Preparation of tert-butyl-5-(5-(tert-butyl)-1,3,4-oxadiazol-2-carboxamido)-8-(2-((1-methyl-1Hpyrazol-4-yl)amino) pyrimidin-4-yl)-4,5-dihydro-1H-benzo[c]azepin-2(3H)-carboxylate.

Pd(dppf)Cl2(O,O5 equiv) K ₂ CO _E (2.0 equiv) d&xen/H ₂ O, 80°C, 16h

A mixture of tert-butyl-8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-4,5-dihydro-1Hbenzo[c]azepine-2(3H)- carboxylate (1.6 g, 3.2 mmol), PinB-BPin (802 mg, 3.84 mmol), KOAc (640 mg, 6.4 mmol) and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (130 mg, 0.16 mmol) in 20 ml of dry 1,4-dioxane was stirred under nitrogen at 80°C for 16 h. yl) pyrimidine-2-amine (802 mg, 3.84 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (130 mg, 0.16 mmol), K ₂ CO ₃ (1.3 g, 9, 6 mmol) and H2O (5 ml), and the resulting mixture was stirred at 80°C for another 16 hours. The mixture was diluted with EtOAc (200 ml), washed with water (80 mlx2), dried with Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel column chromatography (EtOAc/MeOH=20:1) to give t-butyl-5-(5-(t-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2 -((1-methyl-1H-pyrazol-4yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate as a yellow solid (1 .4 g, yield: 86%). ESI-MS (M+H)+: 588.3. ¹ H-NMR (400 MHz, CD3OD) δ: 8.42-8.38 (m, 1H), 8.11-7.95 (m, 3H), 7.66-7.50 (m, 2H) , 7.24-7.21(m, 1H), 5.64-5.62(m, 1H), 4.85-4.47(m, 2H), 3.93-3.88(m, 1H), 3.57-3.54 (m, 1H), 2.12-2.10 (m, 2H), 1.51 (s, 9H), 1.43-1.34 (m, 9H) .

3. Preparation of 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydro- 1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide.

In a solution of tert-butyl-5 - (5 - (tert-butyl) - 1,3,4-oxadiazol-2-carboxamido) -8- (2- (( 1 -methyl-1H- 57 040817 pyrazol-4-yl )amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate (600 mg, 1.02 mmol) in CH ₂ C1 ₂ (5 ml) TFA is added (5 ml). The mixture was stirred at rt for 1 hour. After removing the solvent, the residue was dried in vacuo to give the title product (460 mg, yield: 80%) and used in the next step without further purification. ESI-MS (M+N): 488.3.

4. Synthesis of 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro2H-pyran-4 -yl)-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-5 -yl)-1,3,4-oxadiazole-2-carboxamide.

NaEHjCN (5.0 equiv)

CHjCOOH (cat)

MeOH, 50 °C, 4h

In a solution of 5 - (tert-butyl) ^ - (8- (2- (( 1 -methyl-1 H-pyrazol-4-yl) amino) pyrimidin-4-yl) -2,3,4,5 tetrahydro- 1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide (170 mg, 0.35 mmol) and dihydropyran-4-one (175 mg, 1.75 mmol) in MeOH (30 ml) add NaBH ₃ CN (112 mg, 1.75 mmol) and CH ₃ COOH (cat.). The mixture is stirred at 50° C. for 4 hours. After cooling to rt, the mixture is adjusted to pH=8 with concentrated NH ₄ OH. After concentration, the crude product was purified by preparative HPLC (CH ₃ CN/H ₂ O with 0.05% NH ₄ HCO ₃ as mobile phase) to give 5-(tert-butyl)-N-(8-(2-(( 1-methyl -111-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-211-pyran-4-yl)2,3,4,5-tetrahydro-1H-benzo[c]azepin- 5-yl)-1,3,4-oxadiazole-2-carboxamide as a yellow solid (24 mg, yield: 9%). ESI-MS (M+H) ⁺ : 572.3. 'H-NMR (400 MHz, CD ₃ OD) δ: 8.29 (d, J=5.2 Hz, 1H), 7.91-7.85 (m, 3H), 7.53 (s, 1H ), 7.36 (d, J=8.0Hz, 1H), 7.10 (d, J=5.6Hz, 1H), 5.44 (d, J=9.2Hz, 1H), 4.08-3.86 (m, 4H), 3.78 (s, 3H), 3.28-3.20 (m, 3H), 3.08-3.01 (m, 1H), 2, 63-2.57 (m, 1H), 2.14-2.09 (m, 1H), 1.94-1.76 (m, 3H), 1.63-1.49 (m, 2H), 1.38(s, 9H).

Example 13 5-(tert-butyl)-N-(8-(2-((1-methyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan3-yl) -2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide (compound 13).

NaBH ₃ CN (5.0 equiv)

ZnCl ₂ (10.0 equiv)

MeOH, ct, 16 h

Synthesis of 5-(tert-butyl)-N-(8-(2-((1-methyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl) 2,3,4,5-tetrahydro-1 H-benzo [c]azepin-5 -yl)-1,3,4-oxadiazole-2-carboxamide is similar to the synthesis of 5 (tert-butyl)-N-(8-( 2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)2,3,4,5-tetrahydro-1H- benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide in Example 8. The crude product was purified by preparative HPLC (CH ₃ CN/H ₂ O with 0.05% NH ₄ HCO ₃ as mobile phase) to obtain 5 - (tert-butyl) -X- (8- (2- (( 1 -methyl-1 H-pyrazol-4-yl) amino) pyrimidin-4-yl) -2- (oxetan- 3 yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide as a yellow solid (59 mg, yield: 33%). ESI-MS (M+H) ⁺ : 544.2. 'H-NMR (400 MHz, CD ₃ OD) δ: 8.29 (d, J=5.2 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.86 ( s, 1H), 7.83 (s, 1H), 7.51 (s, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.09 (d, J=5.2 Hz, 1H), 5.46 (d, J=10.0 Hz, 1H), 4.65-5.55 (m, 4H), 3.83-3.67 (m, 3H), 3.77 (s, 3H), 2.96-2.93 (m, 1H), 2.79-2.73 (m, 1H), 2.13-2.10 (m, 1H), 1.93-1 .90 (m, 1H), 1.38 (s, 9H).

Example 14 (K)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2(oxetan- 3-yl)-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide (compound 14a) and (8)-5 -(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)2.3 ,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide (compound 14b).

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Method 1.

14а 14b {8-[2-((1-methyl-1Н-pyrazol-4-yl)amino)pyrimidin-4-yl]-2-oxetan-3-yl-2,3,4,5-tetrahydro-1Н 5-tert-Butyl-1,3,4-oxadiazole-2-carboxylic acid -2-benzazepin-5-yl}-amide was resolved with SFC (OD-H (2x25 cm), 30% methanol (0.1% DEA) /CO ₂ , 100 bar, 65 ml/min, 220 nm, input, vol.: 0.5 ml, 4 mg/ml, methanol) which gives 93 mg of peak 1 (chemical purity 99%, ee >99%) and 97 mg peak 2 (chemical purity 99%, ee >99%).

Peak 1 means {(R)-8-[2-(1-methyl-1H-pyrazol-4-ylamino)pyrimidin-4-yl]-2-oxetan-3-yl-2,3,4,5tetrahydro-1H 5-tert-Butyl-1,3,4-oxadiazole-2-carboxylic acid -2-benzazepin-5-yl}-amide: LCMS: Rt 0.84 min, m/z 544.2. ¹ H-NMR (400 MHz, methanol-d ₄ ) 8.41 (br. s., 1H), 7.84-8.14 (m, 3H), 7.63 (br. s., 1H), 7.47 (t, J=7.56 Hz, 1H), 7.21 (d, J=10.04 Hz, 1H), 5.57 (d, J=9.29 Hz, 1H), 4, 61 - 4.80 (m, 4H), 3.66 - 4.07 (m, 6H), 3.05 (br. s., 1H), 2.88 (d, J=9.04 Hz, 1H ), 2.23 (br. s., 1H), 2.05 (br. s., 1H), 1.50 (d, J=2.89 Hz, 9H).

Peak 2 means {(8)-8-[2-(1-methyl-1H-pyrazol-4-ylamino)pyrimidin-4-yl]-2-oxetan-3-yl-2,3,4,5tetrahydro-1H 5-tert-Butyl-1,3,4-oxadiazole-2-carboxylic acid-2-benzazepin-5-yl}-amide: LCMS: Rt 0.84 min, m/z 544.2. ¹ H-NMR (400 MHz, methanol-d ₄ ) 8.42 (d, J=5.02 Hz, 1H), 7.86-8.14 (m, 3H), 7.63 (s, 1H) , 7.48 (d, J=8.09 Hz, 1H), 7.22 (d, J=5.27 Hz, 1H), 5.58 (d, J=9.73 Hz, 1H), 4 .59 - 4.81 (m, 4H), 3.73 - 4.05 (m, 6H), 3.05 (br. s., 1H), 2.89 (br. s., 1H), 2 .23 (br. s., 1H), 2.06 (d, J=5.52 Hz, 1H), 1.50 (s, 9H).

Method 2.

1. Synthesis of tert-butyl-(R)-8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-1,3,4,5tetrahydro-2H-benzo [c]azepine-2-carboxylate.

To a solution of (R)-5-amino-8-bromo-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate (3.1 g, 4.5 mmol) and triethylamine (910 mg, 9.0 mmol) in DCM (100 mL) add HATU (2.6 g, 6.8 mmol) and 5-(tert-butyl)1,3,4-oxadiazole-2-potassium carboxylate (1.12 g, 5.4 mmol). The mixture was stirred at rt for 2 h. Water (100 ml) was then added and the mixture was extracted with DCM (2x100 ml). The combined organic layers are dried and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc=4:1) to give (R)-8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2carboxamido)-1 ,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate as a white solid (1.8 g, yield: 82%). ESI-MS (M+H)+: 493.1.

2. Synthesis of tert-butyl-(R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(4,4,5,5-tetramethyl1,3, 2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate.

A mixture of tert-butyl-(R)-8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-1,3,4,5-tetrahydro2H-benzo[c ]azepine-2-carboxylate (1.8 g, 3.65 mmol), bis (pinocolate) diborone (975 mg, 3.84 mmol), KOAc (715 mg, 7.30 mmol) and Pd (dppf) Cl ₂ -DCM (293 mg, 0.36 mmol) in 30 ml of 1,4-dioxane is stirred in

- 59 040817 nitrogen atmosphere at 90°C for 2 hours After cooling, the mixture is diluted with EtOAc (200 ml), washed with water (2x50 ml), dried with Na ₂ SO ₄ and concentrated. Crude product tert-butyl-(R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)-1,3,4,5tetrahydro-2H-benzo[c]azepine-2-carboxylate is used in the next step without purification. ESI-MS (M+H)+: 541.3.

3. Synthesis of tert-butyl-(R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-methyl-1Hpyrazole-4- yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate.

A mixture of tert-butyl-(R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(4,4,5,5-tetramethyl-1,3, 2dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate (4.85 g, 8.98 mmol), 4-χλορ-Ν(1-methyl- N-pyrazol-4-yl)pyrimidin-2-amine (1.88 g, 8.98 mmol), Pd(dppf)Cl ₂ (734 mg, 0.9 mmol) and K ₂ CO ₃ (2.48 g , 18 mmol) in dioxane/H ₂ O (4:1, 20 ml) was degassed and stirred under N2 at 100° C. for 2 h. After concentrating the reaction mixture, the residue was purified by chromatography on silica gel (EtOAc: PE=2:1 ) to obtain tert-butyl-(R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2((1-methyl-1H-pyrazole-4 -yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate as yellow solid (3.4 g, yield: 51%) . ESI-MS (M+H)+: 588.3.

4. Synthesis of (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3, 4,5tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide.

Into a solution of tert-butyl-(R)-5-(5-(tert-butyl)-1,3,4-oxadiazol-2-carboxamido)-8-(2-((1-methyl-1Hpyrazol-4-yl )amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate (3.4 g, 5.79 mmol) in DCM (10 mL) TFA was added (4 ml). The resulting solution was stirred at room temperature for 2 hours. After concentrating the reaction mixture, the residue was dissolved in MeOH (10 ml) and adjusted to pH=8 with aqueous ammonia. Then water (20 ml) was added and the mixture was extracted with DCM/MeOH solutions (20:1, 30 mlx3). The organic phase is dried and concentrated to give (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-N-pyrazol-4-yl)amino)pyrimidin-4-yl)- 2,3,4,5-tetrahydro-Nbenzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide as yellow solid (2.47 g, yield: 88%), which is used in the next step without further purification. ESI-MS (M+H)+: 488.2.

5. Synthesis of (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2(oxetan- 3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide (I-RP38).

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To a solution of (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4 ,5tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide (1.5 g, 3.08 mmol) and oxetan-3-one (1.1 g, 15.4 mmol) in MeOH (30 ml) are added NaBH ₃ CN (970 mg, 15.4 mmol) and ZnCl ₂ (4.2 g, 30.8 mmol). The resulting mixture was stirred at room temperature for 4 hours. After dilution with H ₂ O (20 ml), the mixture was extracted with DCM/MeOH solutions (20:1, 20 mlx3). The combined organic layers are dried and concentrated. The residue was purified by silica gel chromatography (DCM: MeOH=50:1 to 20:1) to obtain (R)-5-(t-butyl)-N-(8-(2-((1-methyl-1H-pyrazole -4-yl)amino)pyrimidin-4-yl)-2-(oxetan3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4 -oxadiazole-2-carboxamide as a yellow solid (1.1 g, yield: 58%). ESI-MS (M+H)+: 544.3. J-NMR (400 MHz, CDCl ₃ ) δ: 8.42 (d, J=5.2 Hz, 1H), 8.32 (br, 1H), 7.86-7.78 (m, 3H), 7.53-7.26(m, 2H), 7.15(s, 1H), 7.05-7.03(m, 1H), 5.62(t, J=8.4Hz, 1H) , 4.75-4.67(m, 4H), 3.94-3.85(m, 6H), 3.02-2.96(m, 1H), 2.75-2.70(m, 1H), 2.35-2.31 (m, 1H),

2.14-2.07 (m, 1H), 1.47 (s, 9H).

Example 15 5-(t-butyl)-M-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2(methylsulfonyl)-2.3 ,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide (compound 15).

In a solution of 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydro-1H -benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide (100 mg, 0.20 mmol) in CH ₂ Cl ₂ (20 ml) MsCl (34 mg, 0.3 mmol) and triethylamine (61 mg, 0.60 mmol). The mixture was stirred at rt for 2 h. The mixture was diluted with CH ₂ Cl ₂ (100 ml), washed with brine (60 ml) and concentrated. The crude product was purified by preparative HPLC (CH3CN/H2O with 0.05% NH ₄ HCO ₃ as mobile phase) to give 5-(t-butyl)-N-(8-(2-((1-methyl-1H-pyrazole -4-yl)amino)pyrimidin-4-yl)-2(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazol- 2-carboxamide as a yellow solid (130 mg, yield: 87%). ESI-MS (M+H)+: 566.3. 'H-NMR (400 MHz,

DMSO-de) δ: 10.01 (d, J=7.6 Hz, 1H), 9.57 (s, 1H), 8.49 (d, J=5.2 Hz, 1H), 8.07 (s, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.99 (br, 1H), 7.50 (s, 1H), 7.47 (d, J=8, 4 Hz, 1H), 7.27 (d, J=5.2 Hz, 1H), 5.56-5.51 (m, 1H), 4.75-4.70 (m, 1H), 4, 60-4.56 (m, 1H), 3.86-3.84 (m, 1H), 3.83 (s, 3H), 3.61-3.58 (m, 1H), 2.80 ( s, 3H), 2.15-2.09 (m, 2H), 1.43 (s, 9H).

Example 16 (R)-5-(t-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-isopropyl-1H-pyrazol-4yl)amino)pyrimidin-4-yl )-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide (compound 16).

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1. Synthesis of tert-butyl-(R)-8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-1,3,4,5tetrahydro-2H-benzo [c]azepine-2-carboxylate.

To a solution of tert-butyl-(R)-5-amino-8-bromo-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate (3.1 g, 4.5 mmol) and triethylamine (910 mg, 9.0 mmol) in DCM (100 ml) add HATU (2.6 g, 6.8 mmol) and 5-(tert-butyl)-1,3,4-oxadiazole-2-carboxylate potassium (1.12 g, 5.4 mmol). The mixture was stirred at rt for 2 h. Water (100 ml) was then added and the mixture was extracted with DCM (2x100 ml). The combined organic layers are dried and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc=4:1) to give (R)-8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole2-carboxamido)-1 ,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate as a white solid (1.8 g, yield: 82%). ESI-MS (M+H)+: 493.1.

2. Synthesis of tert-butyl-(R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(4,4,5,5-tetramethyl1,3, 2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate.

A mixture of tert-butyl-(R)-8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-1,3,4,5tetrahydro-2H-benzo[c ]azepine-2-carboxylate (1.8 g, 3.65 mmol), bis (pinocolate) diborone (975 mg, 3.84 mmol), KOAc (715 mg, 7.30 mmol) and Pd (dppf) Cl ₂ -DCM (293 mg, 0.36 mmol) in 30 ml of 1,4-dioxane was stirred under nitrogen at 90°C for 2 h. After cooling to rt, the mixture was diluted with EtOAc (200 ml), washed with water (2x50 ml) , dried with Na ₂ SO ₄ and concentrated. The crude product is tert-butyl-(R)5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate is used in the next step without purification. IEMS (M+H)+: 541.3.

3. Synthesis of tert-butyl-(R)-5-(5-(tert-butyl)-1,3,4-oxadiazol-2-carboxamido)-8-(2-chloropyrimidin4-yl)-1,3,4 ,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate.

- 62 040817

A mixture of tert-butyl-(R)-5-(5-(tert-butyl)-1,3,4-oxadiαzol-2-carboxamido)-8-(4,4,5,5-tetramethyl1,3,2- dilxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate, 2,4-dichloropyrimidine (648 mg, 4.38 mmol), K ₂ CO ₃ (1 .0 g, 7.30 mmol) and Pd(dppf)Cl ₂ -DCM (293 mg, 0.36 mmol) in 30 ml of 1,4dioxane and 6 ml of water were stirred under nitrogen at 90° C. for 12 h. The mixture was diluted with EtOAc (200 ml) and washed with water (2x60 ml). The organic phase is dried with Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel column chromatography (DCM/MeOH=20:1) to give tert-butyl-(R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)- 8-(2-chloropyrimidin-4-yl)1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate as yellow solid (1.3 g, yield: 67% for two stages). ESI-MS (M+H)+: 527.2.

4. Synthesis of tert-butyl-(R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-isopropyl1H-pyrazole-4- yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate.

Synthesis of tert-butyl-(R)-5-(5-(tert-butyl)-1,3,4-oxadiazol-2-carboxamido)-8-(2-((1-isopropyl-1Hpyrazol-4-yl) amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate is similar to the synthesis of tert-butyl-(R)-5-(5-(tert-butyl) -1,2,4-oxadiazol-3-carboxamido)-8-(2-((1,5-dimethyl-1Hpyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5- tetrahydro-2H-benzo[c]azepine-2-carboxylate (Example 9, step 3). The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether=3:1) to give t-butyl-(R)-5-(5-(t-butyl)-1,3,4-oxadiazole-2carboxamido)-8 -(2-((1-isopropyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2Hbenzo[c]azepine-2-carboxylate in the form of a solid yellow substance (280 mg, yield: 78%). ESI-MS (M+H) ⁺ : 616.3.

5. Synthesis of (R)-5-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4 ,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide.

Synthesis of (R)-5-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-nyrαzol-4-yl)amino)pyrimidin-4-yl)-2,3,4, 5tetrahydro-1H-benzo[c]αzepin-5-yl)-1,3,4-oxadiαzol-2-carboxamide is similar to the synthesis of (R)-5-(tert-butyl)N-(8-(2-((1 ,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)1,2,4- oxadiazole-3-carboxamide (example 9, step 4). Crude (R)-5-(tert-butyl)-N-(8-(2-((1isopropyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5 -tetrahydro-1 H-benzo[c]azepin-5-yl)-1,3,4oxadiazole-2-carboxamide as a yellow solid (240 mg) was used in the next step without further purification. ESI-MS (M+H) ⁺ : 516.3.

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6. Synthesis of (R)-5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4 -yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide.

In a solution of (R)-5-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4, 5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide (240 mg, 0.47 mmol) and 2-iodoethanol (200 mg, 1.17 mmol) in 10 ml CH3CN add K2CO3 (195 mg, 1.41 mmol). The resulting mixture was stirred at 80° C. for 24 hours. After dilution with H ₂ O (20 ml), the mixture was extracted with DCM/MeOH solutions (20:1, 3x40 ml). The combined organic layers are dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by preparative TLC (DCM/MeOH=10:1) to give (R)-5-(tert-butyl)-N-(2-(2hydroxyethyl)-8-(2-((1-isopropyl-III-pyrazole -4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-Thbenzo[c]azepin-1,3,4-oxadiazole-2-carboxamide as a yellow solid (108 mg , yield: 42%) ESE-MS (M+H)+: 560.3 ¹ H-NMR (400 MHz, CD3OD) δ: 8.37 (d, J=5.2 Hz, 1H), 8 .03 (s, 1H), 7.98-7.95 (m, 2H), 7.66 (s, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.17( d, J=5.2Hz, 1H), 5.55(d, J=9.6Hz, 1H), 4.54-4.37(m, 1H), 4.17-4.04(m , 2H), 3.71 (t, J=6.0 Hz, 2H), 3.30-3.17 (m, 2H), 2.29-2.25 (m, 2H), 2.29- 2.25 (m, 1H), 1.99-1.95 (m, 1H), 1.52 (d, J=6.4 Hz, 6H), 1.49 (s, 9H).

Example 17 (R)-5-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazole-4-yl)amino)pyrimidin-4-yl)-2(oxetan- 3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide (compound 17).

A mixture of (R)-5-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4, 5tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide (220 mg, 0.43 mmol), oxetan-3one (157 mg, 2.15 mmol), NaBH ₃ CN (135 mg, 2.15 mmol) and ZnCl ₂ (585 mg, 4.30 mmol) in 10 ml MeOH was stirred at rt for 16 h. The mixture was diluted with EtOAc (150 ml) and washed with water (50 ml x 2). The organic phase is dried with Na ₂ SO ₄ and concentrated. The crude product is purified by silica chromatography (DCM:MeOH=15:1) to give (R)-5-(tert-butyl)-N-(8-(2-((1-isopropyl-1Hpyrazol-4-yl )amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4oxadiazol-2 -carboxamide as a yellow solid (146 mg, yield: 60%). ESI-MS (M+H)+: 572.3. ¹ H-NMR (400 MHz, CDCL3) δ: 8.42 (d, J=5.2 Hz, 1H), 8.05-7.97 (m, 3H), 7.67 (s, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 5.59-5.57 (m, 1H), 4.87-4 .66 (m, 4H), 4.53-4.50 (m, 1H), 3.98-3.81 (m, 3H), 3.09-3.03 (m, 1H), 2.92 -2.86(m, 1H), 2.29-2.20(m, 1H), 2.07-2.03(m, 1H), 1.54-1.51(m, 15H)

Example 18 (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-nurazol-4-yl)amino)pyrimidin-4-yl)-2-(2 ,2,2trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide (compound 18).

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1. Synthesis of tert-butyl-(R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-methyl-1Hpyrazole-4- yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate.

A mixture of tert-butyl-(R)-5-(5-(tert-butyl)-1,3,4-oxadiαzol-2-carboxamido)-8-(4,4,5,5-tetramethyl-1,3, 2dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate (4.85 g, 8.98 mmol), 4-chloro-N(1-methyl- 1H-pyrazol-4-yl)pyrimidin-2-amine (1.88 g, 8.98 mmol), Pd(dppf)Cl ₂ (734 mg, 0.9 mmol) and K ₂ CO ₃ (2.48 g , 18 mmol) in dioxane/H ₂ O (4:1, 20 ml) was degassed and stirred under N2 at 100° C. for 2 h. ) to obtain tert-butyl-(R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)8-(2-((1-methyl-III-pyrazole-4 -yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2carboxylate as a yellow solid (3.4 g, yield: 51%). ESI-MS (M+H)+: 588.3.

2. Synthesis of (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3, 4,5tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide.

Into a solution of tert-butyl-(R)-5-(5-(tert-butyl)-1,3,4-oxadiazol-2-carboxamido)-8-(2-((1-methyl-1Hpyrazol-4-yl )amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate (3.4 g, 5.79 mmol) in DCM (10 mL) TFA was added (4 ml). The resulting solution was stirred at room temperature for 2 hours. After concentrating the reaction mixture, the residue was dissolved in MeOH (10 ml) and adjusted to pH=8 with aqueous ammonia. Then water (20 ml) was added and the mixture was extracted with DCM/MeOH solutions (20:1, 30 mlx3). The organic phase is dried and concentrated to give crude (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl) -2,3,4,5tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide as yellow solid (2.47 g, yield: 88%) , which is used in the next step without further purification. IEMS (M+H)+: 488.2.

3. Synthesis of (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2 ,2,2trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide.

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To a solution of (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4 ,5tetrahydro-N-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide (1.5 g, 3.1 mmol) and DIPEA (800 mg, 6.2 mmol) in CH3CN (30 ml) 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.1 g, 4.7 mmol) was added. The mixture was stirred at 50° C. for 12 hours. After dilution with water (100 ml), the mixture was extracted

DXM (100 mlx3). The combined organic layers are washed with brine (100 ml), dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product is purified by silica gel chromatography (DCM:MeOH=10:1) to give (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4yl )amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4oxadiazole -2-carboxamide as a yellow solid (1.2 g, yield: 68%). ESI-MS (M+H)+: 570.2. ¹ H-NMR (400 MHz, CD3OD) δ: 8.31 (d, J=5.2 Hz, 1H), 7.94-7.88 (m, 3H), 7.51 (s, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.12 (d, J=5.2 Hz, 1H), 5.49-5.47 (m, 1H), 4.27-4 .23 (m, 1H), 4.04-4.00 (m, 1H), 3.78 (s, 3H), 3.33-3.24 (m, 2H), 3.04-2.98 (m, 2H), 2.14-2.05 (m, 1H), 1.87-1.84 (m, 1H), 1.40 (s, 9H).

Example 19 5-(t-butyl)-N-(2-(2-hydroxyethyl)-8-(2-(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4yl))-2 ,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide (compound 19).

Synthesis of 5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4yl)-2,3,4 ,5-tetrahydro-N-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide is similar to the synthesis of 5(tert-butyl)-N-(2-(2-hydroxyethyl)-8 -(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydro-1H-benzo[c]azepin-5-yl)-1, 2,4-oxadiazole-3-carboxamide in Example 3. The crude product was purified by preparative HPLC (CH3CN/H2O with 0.05% NH ₄ HCO ₃ as mobile phase) to give 5-(tert-butyl)-N-(2 -(2-hydroxyethyl)-8-(2-(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide as a yellow solid (165 mg, yield: 84%). ESI-MS (M+H)+: 532.2. ¹ H-NMR (400 MHz, CD3OD) δ: 8.42 (d, J=5.2 Hz, 1H), 8.03-8.00 (m, 3H), 7.64 (s, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.23-7.22 (m, 1H), 5.58 (d, J=9.6 Hz, 1H), 4.21-4 .09 (m, 2H), 3.90 (s, 3H), 3.74 (t, J=5.6 Hz, 2H), 3.20-3.18 (m, 2H), 2.70- 2.62 (m, 2H), 2.30-2.28 (m, 1H), 2.00-1.98 (m, 1H), 1.52 (s, 9H).

Example 20 5-(tert-butyl)-N-((R)-8-(2-((1-methyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-( (R)tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide (compound 20).

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1. Synthesis of (S)-tetrahydrofuran-3-yltrifluoromethanesulfonate.

Tf ₂ O (1.1 eq), pyridine (1.2 eq)

DCM -10 ^a s, 0.5 h

Tf ₂ O (1.8 d, 6.3 mmol). The mixture was stirred at -10° C. for 0.5 h. The mixture was quenched with 2 N HCl. The organic layer is separated, dried over Na ₂ SO ₄ and filtered. The resulting solution of (S)-tetrahydrofuran-3-yltrifluoromethanesulfonate in DCM is used in the next step. ESI-MS (M+H)+: 221.0.

2. Synthesis of 5-(tert-butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(( R) tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide.

To a solution of (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4 ,5tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide (1.7 g, 3.5 mmol) in THF (24 ml) and DMF (3 ml) at -78° C., KHMDS (5.2 ml, 5.2 mmol, 1 M solution) was added dropwise. The solution was stirred under nitrogen at -78° C. for 0.5 h. Then, a solution of (S)tetrahydrofuran-3-yltrifluoromethanesulfonate (from the previous step) was added dropwise. The mixture was stirred at room temperature for 16 hours. After dilution with water (40 ml), the mixture was extracted with DCM (40 mlx3). The combined organic layers are washed with brine (60 ml), dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product is purified by silica gel chromatography (DCM: MeOH=10:1) to give 5-(tert-butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazole-4 -yl)amino)pyrimidin-4yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3 ,4-oxadiazole-2carboxamide as a yellow solid (448 mg, yield: 23%). ESI-MS (M+H) ⁺ : 558.3. 1H NMR (400 MHz, DMSO-d6) δ: 9.82-9.80 (m, 1H), 9.51 (s, 1H), 8.47 (d, J=4.8 Hz, 1H), 7 .99-7.95 (m, 3H), 7.55 (s, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.28 (d, J=5.2 Hz, 1H), 5.43-5.38 (m, 1H), 4.06-3.99 (m, 2H), 3.83-3.80 (m, 5H), 3.63-3.50 ( m, 2H), 3.10-3.05 (m, 3H), 2.22-2.02 (m, 2H), 1.85-1.82 (m, 2H), 1.42 (s, 9H).

Example 21 5-(tert-Butyl)-N-((R)-2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4yl)amino)pyrimidine -4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide (compound 21).

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To a solution of (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4 (S)-2-methyloxirane (S)-2-methyloxirane is added (29 µl, 0.42 mmol) and cesium carbonate (135 mg, 0.42 mmol). The mixture is stirred at 60° C. for 16 hours. The reaction mixture is cooled to room temperature and filtered. The filtrate is concentrated and the crude product is purified by silica gel chromatography (DCM:MeOH=10:1) to give 5-(t-butyl)-N-((R)-2-((S)-2-hydroxypropyl)-8 -(2-((1methyl-III-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-III-benzo[c]azepin-5-yl)-1, 3,4oxadiazole-2-carboxamide as a yellow solid (50 mg, yield: 44%). ESI-MS (M+H)+: 546.0. ¹ H-NMR (400 MHz, methanol^) δ: 8.41 (d, J=5.3 Hz, 1H), 8.07-8.02 (m, 2H), 7.97 (s, 1H) , 7.63 (s, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.22 (d, J=5.3 Hz, 1H), 5.62-5.53 ( m, 1H), 4.33-4.10 (m, 2H), 4.04-3.95 (m, 1H), 3.89 (s, 3H), 3.33-3.27 (m, 2H), 2.58-2.46(m, 2H), 2.38-2.23(m, 1H), 2.07-1.95(m, 1H), 1.48(s, 9H) , 1.15 (d, J=6.3 Hz, 3H).

Example 22 5-(tert-butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(( S)tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide (compound 22).

1. Synthesis of (R)-tetrahydrofuran-3-yltrifluoromethanesulfonate.

Tf ₂ O (1J eq \ pyridine (1.2 eq) with ______________________________ LJ IG

DCM -10 °C, 0.5 h

The synthesis of (R)-tetrahydrofuran-3-yltrifluoromethanesulfonate is similar to that of (S)tetrahydrofuran-3-yltrifluoromethanesulfonate in Example 20, step 1. The resulting DCM solution is used in the next step. ESI-MS (M+H) ⁺ : 221.0.

2. Synthesis of 5-(tert-butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(( S)tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide (IRP58).

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Synthesis of 5-(tert-butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S) tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-III-benzo[c]azepin-5-yl)-1,3,4-oxadiazol-2-carboxamide is similar to the synthesis of 5-(tert-butyl) -N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-ul)-2-((R)tetrahydrofuran-3-yl)-2 ,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide in Example 20, step 2. The crude product is purified by silica gel chromatography (DCM :MeOH=10:1) to obtain 5-(tert-butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl )-2-((S)tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-N-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide in as a yellow solid (50 mg, yield: 38%). ESI-MS (M+H)+: 558.1. ¹ H-NMR (400 MHz, methanol-d4) δ: 8.38 (d, J=5.3 Hz, 1H), 8.03-7.95 (m, 3H), 7.60 (s, 1H ), 7.45 (d, J=8.5 Hz, 1H), 7.19 (d, J=5.3 Hz, 1H), 5.56 (brd, J=9.3 Hz, 1H), 4.12-4.01 (m, 2H), 4.01-3.90 (m, 2H), 3.88 (s, 3H), 3.79-3.68 (m, 2H), 3, 29-3.21(m, 1H), 3.20-3.09(m, 1H), 2.33-2.11(m, 2H), 2.09-1.90(m, 2H), 1.48(s, 9H).

Example 23 1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan3-yl)- 2,3,4,5-tetrahydro-N-benzo[c]azepin-5-yl)-1,2,3-triazole-4-carboxamide (compound 23).

Η Ν=Ν ⁰ ί^Ν

Γ if L. N—,

N\

H

1. Preparation of tert-butyl-8-bromo-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-1,3,4,5tetrahydro-2H-benzo[c ]azepine-2-carboxylate.

Into a solution of tert-butyl-8-bromo-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-1,3,4,5tetrahydro-2H-benzo[c] azepine-2-carboxylate (556 mg, 3.06 mmol) in CH ₂ Cl ₂ (10 ml) HATU (1.16 g, 3.06 mmol) and DIPEA (592 mg, 4.6 mmol) are added. The mixture was stirred at rt for 1 h after which 1-(tert-butyl)-M-1,2,3-triazole-4-carboxylic acid (1.04 g, 3.06 mmol) was added. The mixture was stirred at rt for 12 h. The mixture was diluted with CH ₂ Cl ₂ (200 ml), washed with water (100 ml), brine (100 ml), dried and concentrated. The crude product is purified by silica gel chromatography (P€;E1OAc=1:1) to give tert-butyl-8-bromo-5-(1-(tert-butyl)-N-1,2,3-triazole-4carboxamido )-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate (1.1 g, yield: 73%) as a yellow solid. ESI-MS (M+H)+: 492.1. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.17 (s, 1H), 7.35-7.33 (m, 2H), 7.21 (d, J=8.0 Hz, 1H) , 5.52-5.42(m, 1H), 4.54-4.34(m, 2H), 4.04-3.86(m, 1H), 3.65-3.55(m, 1H), 2.80 (s, 9H), 2.10-2.07 (m, 2H), 1.41 (s, 9H).

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2. Preparation of 5-(1-(tert-butyl)-III-1,2,3-triazole-4-carboxamido)-8-(2-((1-ethyl-III-pyrazol-4yl)amino)pyrimidine- 4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate.

Pd(dppf)CI ₂ (0=.05 eq)

K ₂ CO3 (2.0 eq) dioxane/H2O, IO °C, 2h

Synthesis of 5-(1-(tert-butyl)-N-1,2,3-triazole-4-carboxamido)-8-(2-((1-ethyl-1 H-pyrazol-4-yl)amino)pyrimidine -4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate is similar to the synthesis of tert-butyl-5(5-(tert-butyl)-1,2,4-oxadiazole -3-carboxamido)-8-(2-((1-methyl-III-pyrazol-4-yl)amino)pyrmidin-4yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine- 2-carboxylate in Example 7. The crude product was purified by silica gel column chromatography (CH2Cl2:MeOH=20:1) to give 5-(1-(tert-butyl)-N-1,2,3-triazole-4-carboxamido) -8-(2-((1-ethyl-1H-pyrazole-4-ul)amino)pyrimidin-4-ul)-1,3,4,5tetrahydro-2H-benzo[c]azepine-2-carboxylate in the form yellow solid (170 mg, yield: 35%). ESI-MS (M+H)+: 601.2.

3. Preparation of 1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydro- 1 H-benzo[c]azepin-5-yl)-1 H-1,2,3-triazole-4-carboxamide.

Synthesis of 1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydro-1H- benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide is similar to the synthesis of 5-(tert-butyl)-N-8-(2-((1-ethyl-1H-pyrazole-4 -yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin5-yl)-1,2,4-oxadiazole-3-carboxamide in Example 7. Crude product (135 mg, yield: 95%) was used in the next step without further purification. ESI-MS (M+H)+: 501.2.

4. Preparation of 1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan3-yl)- 2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-ul)-1H-1,2,3-triazole-4-carboxamide.

Synthesis of 1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)2 ,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide is similar to the synthesis of 5(tert-butyl)-N-8-(2 -((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-ul)-2,3,4,5tetrahydro-1H-benzo[c]azepine- 5-yl)-1,2,4-oxadiazole-3-carboxamide in Example 7. Crude pro

- 70 040817 The product is purified by silica gel column chromatography (EtOAc: MeOH=10:1) to give 1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazole-4- yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3- triazole-4-carboxamide in the form of a yellow solid (67 mg, yield: 45%). ESI-MS (M+H)+: 556.7. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 9.48 (s, 1H), 9.02 (d, J=8.8 Hz, 1H), 8.76 (s, 1H), 8 .46 (d, J=5.2 Hz, 1H), 7.97-7.91 (m, 3H), 7.56 (s, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.25 (d, J=5.2 Hz, 1H), 5.47-5.43 (m, 1H), 4.61-1.47 (m, 4H), 4.13-4 .08 (m, 2H), 3.88-3.65 (m, 3H), 2.90-2.78 (m, 2H), 2.15-2.06 (m, 1H), 1.88 -1.82 (m, 1H), 1.65 (s, 9H), 1.36 (t, J=7.2 Hz, 3H).

Example 24 (R)-1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2(oxetan- 3 -yl)-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-5 -yl)-1 H-1,2,3-triazole-4-carboxamide (compound 24a) and (S )-1 -(tert-butyl)-N-(8-(2-((1-ethyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl )2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide (compound 24b).

1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2 ,3,4,5tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide is subjected to separation using SFC (2.1x25.0 cm (S,S) Whelk0-1, 58% methanol with 0.5% isopropylamine/CO ₂ , 120 bar, 85 mL/min, 230 nm, methanol) giving 23 mg of peak 1 (99% chemical purity, ee >99%) and 24 mg peak 2 (chemical purity 99%, ee >99%).

Peak 1 is (R)-1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2(oxetan- 3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]αzepin-5-yl)-1H-1,2,3-triαzol-4-carboxamide: LCMS: Rt 4.0 min, m/z 557.20. ¹ H-NMR (400 MHz, methanol^) δ ppm 8.51 (s, 1H), 8.40 (d, J=5.27 Hz, 1H), 8.05-7.92 (m, 3H) , 7.64 (s, 1H), 7.47 (d, J=8.28 Hz, 1H), 7.21 (d, J=5.27 Hz, 1H), 5.57 (brd, J= 9.04 Hz, 1H), 4.78-4.71 (m, 1H), 4.714.65 (m, 3H), 4.17 (q, J=7.28 Hz, 2H), 4.01- 3.91 (m, 1H), 3.91-3.78 (m, 2H), 3.15-2.98 (m, 1H), 2.88 (ddd, J=12.99 Hz, 9, 60 Hz, 3.51 Hz, 1H), 2.36-2.14 (m, 1H), 2.11-1.87 (m, 1H), 1.73 (s, 9H), 1.46 ( t, J=7.28 Hz, 3H).

Peak 2 is (S)-1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2(oxetan- 3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide: LCMS: Rt 5.3 min, m/z 557.00. ¹ H-NMR (400 MHz, methanol-bd) δ ppm 8.51 (s, 1H), 8.40 (d, J=5.27 Hz, 1H), 8.06-7.92 (m, 3H ), 7.64(s, 1H), 7.47 (d, J=8.03 Hz, 1H), 7.21 (d, J=5.27 Hz, 1H), 5.57 (brd, J =9.29 Hz, 1H), 4.77-4.70 (m, 1H), 4.70-4.63 (m, 2H), 4.17 (q, J=7.28 Hz, 2H) , 4.05-3.91 (m, 1H), 3.91-3.76 (m, 2H), 3.15-2.98 (m, 1H), 2.89 (ddd, J=12, 8Hz, 9.7Hz, 3.6Hz, 1H), 2.40-2.13(m, 1H), 2.12-1.87(m, 1H), 1.74(s, 9H) , 1.47 (t, J=7.28 Hz, 3H).

Example 25 (R)-1-(tert-butyl)-N-(8-(2-((1-isopropyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2(oxetane -3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide (compound 25).

1. Synthesis of tert-butyl-(R)-5-(1-(tert-butyl)- 1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-isopropyl1H-pyrazole- 4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate.

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dioxene. 100 °C, 2h

Synthesis of tert-butyl-(R)-5-( 1 -(tert-butyl)-1Н-1,2,3-triazole-4-carboxamido)-8-(2-(( 1 -isopropyl- 1Hpyrazole-4- yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate is similar to the synthesis of tert-butyl-(R)-5-(5-(tert- butyl)-1,2,4-oxadiazol-3-carboxamido)-8-(2-((1,5-dimethyl-1Hpyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4, 5-tetrahydro-2H-benzo[c]azepine-2-carboxylate (Example 9, step 3). The crude material is purified by silica gel chromatography (EIAc:PE=4:1) to give tert-butyl-(R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4- carboxamido)-8-(2-((1-isopropyl-1 Hpyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2- carboxylate as a yellow solid (520 mg, yield: 56%). ESI-MS (M+H)+: 615.3.

2. Synthesis of (R)-1-(m-ret-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4 ,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide.

Synthesis of (R)-1-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrαzol-4-yl)amino)pyrimidin-4-yl)-2,3,4, 5tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide is similar to the synthesis of (R)-5-(tert-butyl)N-(8-(2 -((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)1, 2,4-oxadiazole-3-carboxamide (example 9, step 4). The crude product is isolated as a yellow solid and used in the next step without further purification (420 mg, yield: 96%). ESI-MS (M+H)+: 515.3.

3. Synthesis of (R)-1 -(m-ret-butyl)-N-(8-(2-((1-isopropyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2- ( oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]αzepin-5-yl)-1H-1,2,3-triazole-4-carboxamide (I-RP35).

Synthesis of (R)-1-(m-ret-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2(oxetan-3- yl)-2,3,4,5-tetrahydro-1 H-benzo[c]αzepin-5-yl)-1H-1,2,3-triazole-4-carboxamide is similar to the synthesis of (R)-5-(mret -butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3yl)-2,3,4,5 -tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide in Example 17 Purify the crude material by silica gel chromatography (DCM:MeOH=20:1) to give (R )-1(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)- 2,3,4,5

- 72 040817 tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide as a yellow solid (116 mg, yield: 51%). ESI-MS (M+H)+: 571.2. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.42 (d, J=4.8 Hz, 1H), 8.17 (s, 1H), 8.07 (d, J=8.8 Hz , 1H), 7.94 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.77 (s, 1H), 7.57 (s, 1H), 7.48 (d, J=8.0Hz, 1H), 7.11 (s, 1H), 7.03 (d, J=5.2Hz, 1H), 5.64 (t, J=8.0Hz , 1H), 4.78-4.68 (m, 4H), 4.53-4.45 (m, 1H), 3.91-3.80 (m, 3H), 3.04-2.99 (m, 1H), 2.82-2.79 (m, 1H), 2.27-2.23 (m, 1H), 2.10-2.05 (m, 1H), 1.70 (s , 9H), 1.55 (s, 3H), 1.52 (s, 3H).

Example 26 1-(tert-butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(( R) tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide (compound 26a) and 1-(tert-butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)tetrahydrofuran -3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide (compound 26b).

Η Η

26a 26b

1. Synthesis of tert-butyl-(R)-8-bromo-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-1,3,4,5tetrahydro-2H -benzo[c]azepine-2-carboxylate.

Synthesis of tert-butyl-(R)-8-bromo-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-1,3,4,5tetrahydro-2H-benzo [c]azepine-2-carboxylate is similar to the synthesis of 8-bromo-5-(5-(tert-butyl)-1,3,4oxadiazole-2-carboxamido)-4,5-dihydro-1H-benzo[c]azepine- 2(3H)-carboxylate in Example 12, Step 1. The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether=1:2) to give tert-butyl-(R)-8-bromo-5-(1-( tert-butyl)-1H-1,2,3-triazole-4-carboxamido)1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate as a yellow solid (2.3 d, yield: 95%). ESI-MS (M+H)+: 492.2.

2. Synthesis of tert-butyl-(R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(4,4,5,5-tetramethyl1, 3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate.

Synthesis of tert-butyl-(R)-5-(1-(tert-butyl)-1H-1,2,3-triαzol-4-carboxamido)-8-(4,4,5,5-tetramethyl1,3, 2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate is similar to the synthesis of tert-butyl-(R)-5-(5-(tert-butyl)-1 ,2,4-triazole-3-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-1,3,4,5-tetrahydro-2H-benzo[ c]azepine-2-carboxylate in example 9, step 1. The crude product is used in the next step without purification. ESI-MS (M+H)+: 540.3.

3. Synthesis of tert-butyl-(R)-5 -(1 -(tert-butyl)- 1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-methyl- 1Hppyrazole- 4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate.

- 73 040817

Into a solution of tert-butyl-(R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(4,4,5,5-tetramethyl1,3 ,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate (5.4 g, 10.0 mmol) in dioxane/H ₂ O (100 ml) add 4-chloro-Y-(1-megyl-Y-nirazol-4-yl)nirimidin-2-amine (2.1 g, 10.0 mmol), K ₂ CO ₃ (2.8 g, 20 .0 mmol) and Pd(dppf)Cl ₂ (0.4 g, 0.5 mmol). The mixture was stirred at 100° C. under nitrogen for 16 hours. After cooling to rt, the mixture was concentrated and purified by silica gel column chromatography (petroleum ether/EtOAc=1:3) to give tert-butyl-(R)-5-(1 -(tert-butyl)-III-1,2,3-triazol-4-carboxamido)-8-(2-((1-methyl-III-ppyrazol-4-yl)amino)pyrimidin-4-yl)1,3 ,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate as a yellow solid (3.2 g, yield: 55%). ESI-MS (M+H)+: 586.7. ¹ H-NMR (400 MHz, CDC^) δ: 8.42 (s, 1H), 8.19 (s, 1H), 8.02-7.87 (m, 3H), 7.68 (s, 1H), 7.54-7.49 (m, 2H), 7.06 (d, J=5.2 Hz, 1H), 5.63-5.58 (m, 1H), 4.83-4 .67 (m, 1H), 4.51-4.47 (m, 1H), 4.02-4.00 (m, 1H), 3.93 (s, 3H), 3.65-3.62 (m, 1H), 2.14-2.12 (m, 2H), 1.72 (s, 9H), 1.41-1.38 (m, 9H).

4. Synthesis of (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3, 4,5tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide.

Into a solution of tert-butyl-(R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-methyl-1Hpyrazole-4 -yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate (3.2 g, 5.5 mmol) in DCM (30 ml) add TFA (30 ml). The mixture was stirred at rt for 3 h. The solvent was removed. The crude product was dissolved in MeOH (30 ml)/water (20 ml). The mixture was basified with NH ₄ OH to pH=8-9 and extracted with DCM (3x50 ml). The combined organic layers are washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give (R)-1-(tert-butyl)-N-(8-(2-((1methyl-III-pyrazol-4-yl) amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-III-benzo[c]azepin-5-yl)-III-1,2,3triazole-4-carboxamide as a gray solid ( 2.6 g, yield: 98%). ESI-MS (M+H)+: 486.7.

5. Synthesis of 1-(tert-butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(( R)tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide and 1(tert- butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3yl)- 2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide.

26a 26b

In a solution of (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4 ,5tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide (500 mg, 1.0 mmol) in MeOH (30 ml) dihydrofuran-3(2H )-one (258 mg, 3.0 mmol), ZnCl ₂ (682 mg, 5.0 mmol) and NaBH ₃ CN (189 mg, 3.0 mmol). The mixture was stirred at 50° C. for 16 hours. The mixture was concentrated and purified by silica gel column chromatography (DCM/MeOH=20/1 to 15/1) to give a race

- 74 040817 of the mic product in the form of a yellow solid (542 mg, yield: 79%).

-(Ίret-Bugyl)-N-((R)-8-(2-((1-methyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)- tetrahydrofuran3-yl)-2,3,4,5-tetrahydro-III-benzo[c]azepin-5-yl)-III-1,2,3-triazole-4-carboxamide (154 mg) and 1-(tert -butyl)N-((R)-8-(2-((1-methyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3 - yl)-2,3,4,5tetrahydro-III-benzo[c]azepin-5-yl)-III-1,2,3-triazole-4-carboxamide (167 mg) was separated by chiral separation. ESI-MS (M+H)+: 557.3.

Isomer 1: ¹ H-NMR (400 MHz, CD3OD) δ: 8.53 (s, 1H), 8.42 (d, J=5.2 Hz, 1H), 8.05-7.99 (m, 3H), 7.64 (s, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.23 (d, J=5.2 Hz, 1H), 5.58 (d, J=10.4 Hz, 1H), 4.16-4.09 (m, 2H), 4.02-3.96 (m, 2H), 3.90 (s, 3H), 3.79-3 .71 (m, 2H), 3.31-3.24 (m, 2H), 3.15-3.10 (m, 1H), 2.31-2.17 (m, 2H), 2.07 -1.97 (m, 2H), 1.74 (s, 9H).

Isomer 2: ¹ H-NMR (400 MHz, CD ₃ OD) δ: 8.43 (s, 1H), 8.30 (d, J=5.2 Hz, 1H), 7.95-7.86 ( m, 3H), 7.67 (s, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.13 (d, J=5.2 Hz, 1H), 5.47 ( d, J=9.6 Hz, 1H), 4.00 (br, 2H), 3.93-3.85 (m, 2H), 3.85 (s, 3H), 3.69-3.58 (m, 2H), 3.28-3.22 (m, 1H), 3.17-2.97 (m, 2H), 2.21-2.01 (m, 2H), 1.99-1 .80 (m, 2H), 1.63 (s, 9H).

Example 27a. (R)-1 -(tert-butyl)-Sch8-(2-((1-methyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan3-yl)-2 ,3,4,5-tetrahydro-III-benzo[c]azepin-5-yl)-III-1,2,3-triazole-4-carboxamide (compound 27).

In a solution of (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4 ,5tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide (500 mg, 1.0 mmol) in MeOH (30 ml) add oxetan-3-one (216 mg, 3.0 mmol), ZnCl ₂ (682 mg, 5.0 mmol) and NaBH ₃ CN (189 mg, 3.0 mmol). The mixture was stirred at 50° C. for 3 hours. The mixture was concentrated and the crude material was purified by silica gel chromatography (CH ₂ Cl ₂ :MeOH ranging from 20:1 to 15:1) to give (R)-1-(tert-butyl )-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5tetrahydro -1H-benzo[c]azepin-5-yl)-N-1,2,3-triazole-4-carboxamide as a yellow solid (307 mg, yield: 55%). ESI-MS (M+H)+: 542.7. ¹ H-NMR (400 MHz, CD ₃ OD) δ: 8.54 (s, 1H), 8.42 (d, J=5.6 Hz, 1H), 8.04-7.98 (m, 3H ), 7.71 (s, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.24 (d, J=5.2 Hz, 1H), 5.59 (d, J =9.2 Hz, 1H), 4.79-4.75 (m, 1H), 4.71-4.69 (m, 3H), 4.00-3.83 (m, 6H), 3, 09-3.05 (m, 1H), 3.94-2.88 (m, 1H), 2.29-2.21 (m, 1H), 2.07-2.04 (m, 1H), 1.75(s, 9H).

Example 27b. (R)-1-(tert-butyl)-N-(8-(2-((1-(methyl-d ₃ )-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2( oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide 1.

Synthesis of 1 -(methyl-d ₃ )-1 H-pyrazole-4-amine.

A mixture of 4-nitro-1-pyrazole (5.0 g, 44 mmol) and d6-dimethyl sulfate (10.0 g, 75.7 mmol) in 1 M NaOH in water (50.0 ml) was heated to 35°C during the night. The solid formed is filtered off, washed with water and dried (Na ₂ SO ₄ ) to give 1-d ₃ -methyl-4-nitro-1-pyrazole as a white crystalline solid (3.9 g, yield: 68%). LCMS: RT 0.36 min; MH+ 131.1; 1H NMR (400 MHz, DMSO-d6) δ: 8.84 (s, 1H), 8.23 (s, 1H).

2. Synthesis of 1-(methyl-d ₃ )-4-nitro-1H-pyrazole.

10% Pd on carbon

L N- _C D ₃ . LN-CDa o ₂ m^ * h,n

A solution of 1-d ₃ -methyl-4-nitro-1-pyrazole (3.9 g, 30 mmol) in EtOH (50.0 ml) was degassed with nitrogen, then 10% palladium on carbon (0.32 g, 0. 30 mmol). The mixture was placed under a hydrogen atmosphere and stirred at rt for 2 h. The mixture was concentrated and the filtrate was concentrated in vacuo to give the crude 1-d ₃ -methyl-N-pyrazol-4-amine as an oily liquid (2.9 g, yield : 96%),

- 75 040817 which is used in the next step without further purification.

3. Synthesis of 4-methoxy-N-( 1 -(methyl-d ₃ )-1 H-pyrazol-4-yl)pyrimidin-2-amine.

J^N-CDa

H ₂ N (1.0 g)

Pd^idbaJj (0.02 eq), S-Phos (0.04 eq), CSjCOg (3.0 eq), dioxane, sample. cold, 4 pm

To a solution of 2-chloro-4-methoxypyrimidine (9.4 g, 65.1 mol) in 1,4-dioxane (0.3 L) was added 1-methyld ₃ -1H-pyrazole-4-amine (8.5 g, 85 mmol), Cs ₂ CO ₃ (63.6 g, 195 mol), S-Phos (13.3 g, 0.03 mol) and Pd ₂ (dba) ₃ (16.7 g, 0.02 mol). The reaction mixture was stirred at reflux under N2 for 16 hours. The reaction mixture was cooled to room temperature and the mixture was filtered through a plug of silica gel and washed with EtOAc (500 ml). The combined filtrates are concentrated in vacuo. The crude material was purified by silica gel chromatography (heptane:EtOAc=100:0 to 0:100) to give 4-methoxy-N-(1-(methyl-d ₃ )-1H-pyrazol-4-yl)pyrimidin-2- amine (9.2 g, yield: 68%) as a light yellow solid. ESI-MS (M+H)+: 209.1. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.10 (d, J=5.7 Hz, 1H), 7.77 (s, 1H), 7.51 (s, 1H), 6.13 (d, J=5.7 Hz, 1H), 3.94 (s, 3H).

4. Synthesis of 4-chloro-N-(1-(methyl-d ₃ )-1H-pyrazol-4-yl)pyrimidin-2-amine.

HBr (90 ml _, 38%- ny water). The reaction mixture is heated to 100° C. and stirred at this temperature for 3 h. The reaction mixture is cooled to room temperature and concentrated in vacuo, azeotropically distilled with toluene (3x100 ml) and dried at 50° C. overnight to give the HBr salt (16 g) as a yellow/brown solid. The salt is then dissolved in POCl ₃ (250 ml) and heated to 100° C. for 36 hours. The reaction mixture is cooled to room temperature and concentrated in vacuo, azeotropically distilled with toluene (3x100 ml); the resulting residue was diluted with EtOAc (500 ml) and water (100 ml) and the layer separated. The aqueous layer was extracted with EtOAc (3x100 ml), the combined organic layers were washed with brine (200 ml), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a residue which was triturated with EtOAc/heptanes (1:1) to give 4 -chloro-N-(1-(methyl-d ₃ )-1H-pyrazol-4-yl)pyrimidin-2-amine as a white solid (7.4 g, yield: 80%). ESI-MS (M+H) ⁺ : 213.0.

5. Synthesis of tert-butyl-(R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-(methyl-d ₃ )1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine 2-carboxylate.

Into a solution of tert-butyl-(R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(4,4,5,5tetramethyl-1,3 ,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate (4.6 g, 8.5 mmol) in 1,4-dioxane (100 ml) and water (20 ml) was added 4-chloro-N-(1-methyl-d ₃ )-1H-pyrazol-4yl)pyrimidin-2-amine (1.8 g, 8.5 mmol), K2CO3 (2 .4 g, 17 mmol) and Pd(dppf)Cl ₂ (0.7 g, 0.85 mmol). The mixture was stirred at 100° C. under nitrogen for 16 hours. After cooling to rt, the mixture was diluted with EtOAc (300 ml) and washed with saturated brine (100 ml). The aqueous layer is extracted with EtOAc (3x100 ml), the organic phases are combined, dried (Na2SO4), filtered and concentrated in vacuo to obtain a residue. The crude material was purified by silica gel column chromatography (heptanes/EtOAc gradient=100:0 to 0:100) to give t-butyl-(R)-5-(1-(t-butyl)-1H-1,2,3 -triazol-4carboxamido)-8-(2-((1-(methyl-d ₃ )-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2Hbenzo [c]azepine-2-carboxylate as a yellow solid (3.2 g, yield: 55%). ESI-MS (M+H) ⁺ : 590.4.

6. Synthesis of (R)-1-(tert-butyl)-N-(8-(2-((1-(methyl-d ₃ )-1H-pyrazol-4-yl)amino)pyrimidin-4-yl) -

2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide.

- 76 040817

In a solution of tert-butyl-(R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-methyl-d ₃ ) 1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-carboxylate (3.2 g, 5.5 mmol) in CH ₂ Cl ₂ (40 ml) TFA (40 ml) was added. The mixture was stirred at rt for 3 h. The solvent was removed and the crude material was redissolved in MeOH (30 ml)/water (20 ml). The mixture was basified with NH ₄ OH to pH=8-9 and extracted with CH ₂ Cl ₂ (3x100 ml). The combined organic layers are washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give (R)-1-(tert-butyl)-N-(8-(2-((1-methyl- d ₃ )-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)-1H-1,2,3- triazole-4-carboxamide as a yellow solid (3.0 g, yield: 86%). ESI-MS (M+H)+: 490.2.

7. (R)-1-(tert-butyl)-N-(8-(2-((1-(methyl-d ₃ )-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)- 2-(oxetan-3ul)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide.

(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-d ₃ )-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2.3 ,4,5tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide (2.6 g, 15.9 mmol) was dissolved in MeOH (160 ml) and treated with oxetan-3-one (1.15 g, 16.0 mmol), ZnCl ₂ (3.6 g, 26.5 mmol) and NaBH ₃ CN (1.0 mg, 15.9 mmol). The mixture was stirred at 50° C. for 16 h, concentrated in vacuo and the crude material was purified by silica gel chromatography (CH ₂ Cl ₂ :MeOH=100:10 gradient) to give a yellow solid, which was further purified by dissolving in MeOH (100 ml) and CH ₂ Cl ₂ (500 ml) and washed with water (100 ml) and saturated brine (100 ml); the organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give (R)-1(tert-butyl)-N-(8-(2-((1-methyl-d ₃ )-1H- pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-ul)-2,3,4,5tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1, 2,3-triazole-4-carboxamide as a yellow solid (2.32 g, 67%, yield: 55%). ESI-MS (M+H)+: 546.3. ¹ H-NMR (400 MHz, DMSO^) δ: 9.46 (s, 1H), 8.98 (d, J=8.3 Hz, 1H), 8.74 (s, 1H), 8.46 (d, J=5.6 Hz, 1H), 7.95 (m, 3H), 7.54 (s, 1H), 7.38 (d, J=8.1 Hz, 1H), 7.25 (d, J=5.2Hz, 1H), 5.45(m, 1H), 4.61-4.47(m, 4H), 3.86(m, 1H), 3.78(m, 1H), 3.67 (m, 1H), 2.93 (m, 1H), 2.77 (m, 1H), 2.12 (m, 1H), 1.86 (m, 1H), 1, 66(s, 9H).

Example 27c. Preparation of crystalline form A and crystalline form G of compound 27.

Compound (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4, 5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide (1200 g, 2.47 mol) was charged into a 20 liter reactor at room temperature (25° C.), then load 24 l of 1,2-dichloromethane at 25°C. Oxetan-3-one (534 g, 24.7 mol), NaBH(OAc) ₃ (523 g, 2.47 mol) and AcOH (24 ml, 0.17 eq.) are added to the solution. Additional NaBH(OAc) ₃ (1046 g, 4.94 mol) was added in portions to the reactor at room temperature. The mixture is stirred at 25° C. for 16 hours. Freezing water (12 kg) is slowly added to the reactor at room temperature. The organic layer is separated and the aqueous solution is extracted with dichloromethane three times (3x12 L). The combined organic layers are washed with brine (20 L), dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was purified by silica gel chromatography (CH ₂ Cl ₂ :MeOH=20:1) to give (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazole- 4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2, 3-triazole-4-carboxamide (compound 27).

Purified compound 27 (950 g) and EtOH (5 L) were stirred vigorously for 4 h, and the suspension was filtered and washed with 1 L of EtOH. The resulting wet cake was dried in vacuo at 45° C. for ∼24 h until a constant weight was obtained to obtain crystalline form A (960 g, yield:

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85.7%, purity 99%).

300.2 mg of crystalline form A is weighed into a 20 ml glass ampoule, after which 6 ml of isopropyl acetate (IPAc) is added to obtain a suspension. The sample is stirred on a magnetic stirrer at 50°C at a speed of ~1000 rpm for three days. Three days later, the solids are separated by filtration and then dried at room temperature in vacuo for 5 hours to obtain crystalline form G.

Alternatively, 15 volumes of dichloromethane (mL/g) is added to 2.1 g of crystalline Form A. The resulting mixture is distilled using a Dean-Stark trap under atmospheric conditions TjT _r =20 K and T _jmax =110° C., where T _j = jacket temperature, T _r = reaction mixture/reactor temperature and T _jmax = maximum jacket temperature. 5 ml or 2 volumes of dichloromethane are removed, after which 2 volumes of isopropyl acetate (IPAc) are added. The distillation is continued under conditions of T _j -T _r =40K and T _jmax =110°C to remove 10 ml or 5 volumes of solvent(s). Then 5 volumes of IPAc are added, followed by continuous distillation to remove another 10 ml or 5 volumes of solvent(s). 5 volumes of IPAc are added, followed by an additional 30 ml of IPAc. The resulting mixture is stirred and the temperature is cycled over the weekend from 20° C. to 60° C. to obtain a slurry, and form G is isolated from the slurry.

Powder x-ray diffraction

The crystal structure of the compound was examined using an XRD-D8 X-ray powder diffractometer using Cu Ka radiation (Brucker, Madison, Wisconsin). The device is equipped with a long, sharp-focus X-ray tube. The voltage and current are set to 40 kV and 40 mA, respectively. The divergence slit and the diffusion slit are set to 1°, and the receiving slit is set to 0.15 mm. The diffracted radiation is registered by the Lynxeye detector. A continuous θ-2θ scan is applied at 1.6°/min from 3 to 42° 2θ. The sample is prepared for analysis by placing it on a zero background plate.

The powder x-ray diffraction pattern (XRD) of crystalline Form A is shown in FIG. 1, and the main peaks are given in table. 1. An X-ray powder diffraction pattern (XRD) of crystalline Form G is shown in FIG. 4, and the main peaks are given in table. 2.

Table 1. List of PRD peaks for crystalline form A

Angle 20 Pure Intensity Relative intensity 4.31 53.6 0.08 5.68 700.9 1.00 7.94 247.9 0.35 8.73 136.1 0.19 9.65 176.0 0.25 11.89 168.3 0.24 13.05 91.4 0.13 14.79 118.9 0.17 15.17 61.7 0.09 16.08 171.5 0.24 4.31 53.6 0.08 5.68 700.9 1.00 7.94 247.9 0.35 8.73 136.1 0.19

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9.65 176.0 0.25 16.96 164.8 0.24 17.82 132.6 0.19 18.21 488.1 0.70 19.02 208.4 0.30 20.45 143.8 0.21 21.23 116.4 0.17 16.96 164.8 0.24 22.42 248.8 0.35 22.80 79.2 0.11 23.79 136.4 0.19 25.61 103.5 0.15

Table 2. List of PRD peaks for crystalline form G

Angle 20 Pure Intensity Relative intensity 3.62 1071.5 0.58 8.92 96.8 0.05 10.96 184.5 0.10 12.59 206.5 0.11 14.53 81.6 0.04 15.41 252.1 0.14 16.33 133.3 0.07 18.44 294.9 0.16 20.18 701.1 0.38 21.79 1860.2 1.00 23.36 205.8 0.11 25.40 502.9 0.27 26.78 34.5 0.02 34.18 28.8 0.02

Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA)

The thermal properties of the compound are examined using a Discovery Differential Scanning Calorimeter (DSC) (TA Installations) and a Discovery Thermogravimetric Analyzer (TGA) (TA Instruments). The sample is placed in a closed aluminum crucible for DSC analysis and in an open aluminum crucible for TGA analysis. Thermal analysis is carried out with a linear gradient from 25° C. to 300° C. at 10° C./min for both DSC and TGA studies. Differential scanning calorimetry (DSC) analysis of crystalline form A shows that form A has an onset temperature of 175.6° C. and a melting point of 186° C. (FIG. 2).

DSC analysis of crystalline form G shows that form G has an onset temperature of 215.4°C and a melting point of 217.3°C (FIG. 5).

TGA analysis for form A of compound 27 shows a weight loss of 3.16%, indicating that form A is a hydrate (FIG. 3).

TGA analysis of form G of compound 27 showed no weight loss to melt, indicating that form G was anhydrous (FIG. 5).

NMR for solid state

¹³ C-NMR CR/CMS (Cross Polarization/Magic Angle Rotation) solid state spectrum was obtained on a Tecmag Redstone spectrometer at 363 MHz at Spectral Data Services of Champaign, IL. Each sample is placed in a 7 mm (OD) zirconium rotor closed with a kel-F plug for subsequent data acquisition. All three samples fill the rotor approximately

- 79 040817 fault. The ¹³ C-NMR spectrum with RI/VMF was acquired using a Doty XC 7 mm RI/VMF probe at an observation frequency of 91 MHz (rotation 7 kHz, pulse width 1H 5.0 µs, spectrum width 29.8 kHz, time of investigation 0.0344 s, pulse width 1111 2 ms, relaxation delay 5.0 s, number of scans 1296). The spectrum is referenced to the chemical shift of an external glycinecarbonyl carbon sample at 176 ppm and processed with Nuts (line broadening 10 Hz). The list of peaks and the spectrum overlay were processed using MNOVA.

¹³ Solid state RI/MFA C-NMR for Form A and Form G is depicted in FIG. 3B and FIG. 6B, respectively. Diagnostic chemical shifts are given in table. 3.

Table 3. Diagnostic chemical shifts by ¹³ C-NMR with PP/VMF _____________________ for solid forms of compound 27_________________________________

Peak assignment* Form A (ppm) Form G (ppm) carbonyl 163.2 163.6 163.2 159.5 157.9 159.4 156.2 (shoulder) 147.0 143.7 146.0 142.5 (shoulder) 141.5 135.8 140.6 134.4 137.1 132.3 136.0 aromatic hydrocarbons 130.5 130.2 129.6 125.9 126.9 125.0 124.7 120.7 123.6 105.9 106.1 104.4 105.1 77.4 77.7 75.9 76.8 60.7 75.5 59.5 61.4 55.9 60.9 51.6 58.2 aliphatic hydrocarbons 50.3 54.4 39.5 51.7 37.9 49.9 35.2 40.0 30.1 37.3 29.1 30.0

*This is a preliminary assignment based on chemical structure and chemical shift calculations using ChemDraw, and ¹³ C-NMR spectra in DMSO solution

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Example 28 (R)-1-(t-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2 ,2,2trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide (compound 28).

In a solution of (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4 ,5tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide (200 mg, 0.4 mmol) in CH3CN (5 ml) was added 2,2,2 -trifluoroethyl trifluoromethanesulfonate (190 mg, 0.6 mmol). The mixture was stirred at 50° C. for 12 hours. After concentrating the reaction mixture, the residue was purified by silica gel chromatography (PE:EUAc=1:1) to obtain (R)-1-(tert-butyl)-N-(8-(2 -((1-methyl-1H-pyrazol-4yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c] azepin-5-yl)-1H-1,2,3triazole-4-carboxamide as a yellow solid (85 mg, yield: 36%). ESI-MS (M+H)+: 569.3. ¹ H-NMR (400 MHz, CD3OD) δ: 8.54 (s, 1H), 8.42 (d, J=5.2 Hz, 1H), 8.03-7.99 (m, 3H), 7.61 (s, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.22 (d, J=5.2 Hz, 1H), 5.60-5.57 (m , 1H), 4.39-4.35 (m, 1H), 4.17-4.12 (m, 1H), 3.89 (s, 3H) 3.43-3.32 (m, 2H) , 3.16-3.09 (m, 2H), 2.24-2.20 (m, 1H), 1.98-1.94 (m, 1H), 1.74 (s, 9H).

Example 29 1-(tert-butyl)-N-((R)-2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4yl)amino)pyrimidine -4-yl)-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-5 -yl)-1H-1,2,3-triazole-4-carboxamide (compound 29).

In a solution of (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4 ,5tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide (250 mg, 0.51 mmol) in EtOH (5 ml) add (R)-2 -methyloxirane (58 mg, 1.0 mmol). The mixture was stirred at 50° C. for 24 hours. After concentration, the residue was purified by silica gel column chromatography (petroleum ether/EtOAc=1:2) to give 1-(tert-butyl)-N-((R)-2-(( R)-2-hydroxypropyl)-8-(2-((1-methyl-1Hpyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c] azepin-5-yl)-1H-1,2,3-triazole-4carboxamide as a white solid (110 mg, yield: 40%). ESI-MS (M+H)+: 545.3. 1H NMR (400 MHz, CD3OD) δ: 8.42 (s, 1H), 8.28 (d, J=5.2 Hz, 1H), 7.93-7.84 (m, 3H), 7.52 (s, 1H), 7.35 (d, J=8.8 Hz, 1H), 7.09 (d, J=5.2 Hz, 1H), 5.46 (d, J=10 Hz, 1H ), 4.13-4.00 (m, 2H), 3.92-3.87 (m, 1H), 3.78 (s, 3H) 3.213.12 (m, 2H), 2.40-2 .32 (m, 2H), 2.17-2.13 (m, 1H), 1.89-1.84 (m, 1H), 1.62 (s, 9H), 1.02 (d, J =6.0 Hz, 3H).

Example 30 1-(tert-Butyl)-N-((R)-2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4yl)amino)pyrimidine -4-yl)-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-5 -yl)-1H-1,2,3-triazole-4-carboxamide (compound 30).

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Synthesis of 1-(tert-butyl)-N-((R)-2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine -4-yl)-2,3,4,5-tetrahydro-III-benzo[c]azepin-5-yl)-III-1,2,3-triazole-4-carboxamide is similar to the synthesis of 1-(tert-butyl )-N-((R)-2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2 ,3,4,5-tetrahydro-III-benzo[c]azepin-5-yl)-III-1,2,3-triazole-4-carboxamide (Example 29). The crude product was purified by preparative TLC (DCM/MeOH=10:1) to give 1-(tert-butyl)-N-((R)-2-((S)-2-hydroxypropyl)-8-(2-((1- methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydro-III-benzo[c]azepin-5-yl)-III-1,2,3-triazol- 4-carboxamide as a yellow solid (97 mg, yield: 44%). ESI-MS (M+H)+: 545.3. ¹ H-NMR (400 MHz, CD3OD) δ: 8.54 (s, 1H), 8.41 (d, J=5.2 Hz, 1H), 8.01-7.97 (m, 3H), 7.63 (s, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.22 (d, J=5.6 Hz, 1H), 5.57 (d, J=9 .6 Hz, 1H), 4.23-4.20 (m, 1H), 4.12-4.07 (m, 1H), 4.02-3.97 (m, 1H), 3.90 ( s, 3H), 3.30-3.28 (m, 1H), 3.26-3.19 (m, 1H), 2.47-2.45 (m, 2H), 2.31-2, 22 (m, 1H), 2.01-1.97 (m, 1H), 1.74 (s, 9H), 1.16 (d, J=6.4 Hz, 3H).

Example 31 (R)-1-(t-butyl)-N-(2-(2-methoxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin4-yl )-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triαzol-4-carboxamide (compound 31).

In a solution of (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4 ,5tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide (140 mg, 0.29 mmol) in MeOH (10 ml) 1-bromo-2 is added -methoxyethane (121 mg, 0.87 mmol) and K ₂ CO ₃ (120 mg, 0.87 mmol). The mixture was stirred at 80° C. for 16 hours. After dilution with water (20 ml), the mixture was extracted with CH ₂ Cl ₂ (30 mlx2). The combined organic layers are washed with H2O (20 mlx2), dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by preparative TLC (DCM:MeOH=20:1) to give (R)-1-(tert-butyl)-N-(2-(2-methoxyethyl)-8-(2-((1-methyl- 1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-N-1,2,3-triazol-4 α-carboxamide as a yellow solid (66 mg, yield: 42%). ESI-MS (M+H) ⁺ : 545.1. ¹ H-NMR (400 MHz, CDQ3) δ: 8.41 (d, J=5.2 Hz, 1H), 8.18 (s, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.90 (s, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.80 (s, 1H), 7.53 (s, 1H), 7.46 ( d, J=8.0 Hz, 1H), 7.04 (d, J=5.2 Hz, 1H), 6.97 (s, 1H), 5.60 (t, J=8.8 Hz, 1H), 4.19-4.07 (m, 2H), 3.91 (s, 3H), 3.57 (t, J=5.6 Hz, 2H), 3.37 (s, 3H), 3.32-3.26(m, 1H), 3.19-3.15(m, 1H), 2.78-2.69(m, 2H), 2.24-2.20(m, 1H ), 2.02-1.99 (m, 1H), 1.70 (s, 9H).

Example 32 (R)-5-(tert-butyl)-N-(2-(2,2-difluoroethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine -4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiαzol-2-carboxamide (compound 32).

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To a solution of (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4 ,5tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide (105 mg, 0.21 mmol) in CH ₃ CN (8 ml) add 1,1-difluoro -2-iodoethane (23 µl, 0.26 mmol) and potassium carbonate (89 mg, 0.64 mmol). The mixture is stirred at 80° C. for 18 hours. The reaction mixture is cooled to room temperature and filtered. The filtrate was concentrated and the crude product was purified by preparative HPLC (CH ₃ CN/H ₂ O with 0.05% TFA as mobile phase) to give (R)-5-(tert-butyl)-N-(2-(2.2 -difluoroethyl)-8-(2-((1-methyl-1Hpyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1 H-benzo[c]azepin-5 -yl)-1,3,4-oxadiazole-2-carboxamide as a yellow solid (30 mg, yield: 25%). ESI-MS (M+H)+: 552.0. 1H NMR (400 MHz, methanol^) δ: 8.42 (d, J=5.3 Hz, 1H), 8.23 (d, J=8.4 Hz, 1H), 8.19 (s, 1H) , 7.95 (s, 1H), 7.687.65 (m, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.30 (d, J=5.5 Hz, 1H) , 6.40 (tt, J=53.5 Hz, 3.6 Hz, 1H), 5.70 (dd, J=9.8 Hz, 2.5 Hz, 1H), 4.83 (br d, J=14.3Hz, 1H), 4.67(brd, J=14.3Hz, 1H), 3.90(s, 3H), 3.83-3.67(m, 2H), 3, 59 (dt, J=15.0 Hz, 3.4 Hz, 2H), 2.52-2.31 (m, 2H), 1.49 (s, 9H).

Example 33 5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9tetrahydro- 5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide (compound 33).

1. Synthesis of (E)-5-(3-bromophenyl)pent-4-enoic acid.

To a solution of (3-carboxypropyl)triphenylphosphonium bromide (12.87 g, 30 mmol, 1.0 eq.) in dry DMSO (50 ml) at 0°C was added NaH (3 g, 75 mmol, 2.5 eq. ). The reaction mixture was stirred at room temperature for 30 minutes, after which 3-bromobenzaldehyde (5.5 g, 30 mmol, 1.0 eq.) was added dropwise. The mixture was stirred at room temperature for another 2 h and then poured into water (200 ml) and extracted with EtOAc (100 ml). The aqueous solution was acidified with concentrated HCl and extracted with EtOAc (200 mlx3). The combined organic layers are washed with brine (100 mlx3). The organic layer is dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc=2:1) to obtain (E)-5-(3-bromophenyl)pent-4-enoic acid (4.4 g, yield: 58%) as yellow oily liquid. ESI-MS (M+H)+: 254.9. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.48 (s, 1H), 7.33 (d, J=7.6 Hz, 1H), 7.23 (d, J=8.0 Hz , 1H), 7.15 (t, J=8.0 Hz, 1H), 6.39-6.35 (m, 1H), 6.23-6.19 (m,

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1H), 2.55-2.53 (m, 4H).

2. Synthesis of 5-(3-bromophenyl)pentenoic acid.

PtO ₂ (200 mg, 10 %). The mixture was stirred under a hydrogen atmosphere for 1 hour. The catalyst was filtered off and the resulting filtrate was concentrated to give the title compound 5-(3-bromophenyl)pentenoic acid (2.1 g, yield: 87%) as a yellow solid, which was used in the next step. without additional cleaning. ESI-MS (M+H)+: 256.9. ¹ H-NMR (400 MHz, CD3OD) δ: 7.24 (s, 1H), 7.21-7.18 (m, 1H), 7.06-7.03 (m, 2H), 2.50 (t, J=6.8 Hz, 2H), 2.20 (t, J=6.8 Hz, 2H), 1.53-1.51 (m, 4H).

3. Synthesis of 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one.

A mixture of 5-(3-bromophenyl)pentenoic acid (2.1 g, 8.2 mmol, 1.0 eq.) and PFA (5 ml) was stirred for 1 hour at 130°C. After cooling, the mixture was basified to pH= 7~8 with NaOH (1H). The mixture is extracted with EtOAc (200 ml x 2). The combined organic layers were concentrated and purified by preparative HPLC (gradient: 5% B increased to 95% B, A: 0.5% NH ₃ in water, B: CH ₃ CN) to give 2-bromo-6,7,8,9 -tetrahydro-5H-benzo[7]annulen-5-one (1.1 g, yield: 56%) as a colorless oily liquid. ESI-MS (M+H)+: 239.0. ¹ H-NMR (400 MHz, CDCi ₃ ) δ: 7.59 (d, J=8.4 Hz, 1H), 7.43 (dd, J=8.4, 2.0 Hz, 1H), 7 .38 (s, 1H), 2.89 (t, J=6.8 Hz, 2H), 2.72 (t, J=6.0 Hz, 2H), 1.90-1.79 (m, 4H).

4. Synthesis of 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ol.

NaBH ₄ (144 mg, 3.8 mmol, 1.5 eq.) and then stirred at room temperature for 1 hour. After evaporation of the solvent, the residue was purified by silica gel column chromatography (EtOAc/hexane=1:5) to give 2-bromo -6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ol (600 mg, yield: 99%) as a white solid. ESI-MS (M+H-17) ⁺ : 222.9. ¹ H-NMR (400 MHz, CDCl3) δ: 7.34-7.30 (m, 2H), 7.24 (s, 1H), 4.88-4.86 (m, 1H), 2.88 -8.82(m, 1H), 2.70-2.63(m, 1H), 2.08-2.00(m, 2H), 1.81-1.72(m, 4H).

5. Synthesis of 5-azido-2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulene.

Br Br

A solution of 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ol (600 mg, 2.5 mmol, 1.0 eq.) in toluene (10 ml) was cooled in ice bath under N2 atmosphere and treated with one portion of DPPA (2.06 g, 7.5 mmol, 3.0 eq.) followed by the addition of DBU (1.14 g, 7.5 mmol, 3.0 eq.). The reaction temperature is maintained at 0°C for 1 h, and then warmed to room temperature for 12 h. The mixture is diluted with EtOAc (100 ml) and washed with 2 N HCl (2x50 ml) and brine, and the organic layer is dried over Na ₂ SO ₄ , filtered, then concentrated. The crude product was purified by silica gel column chromatography (PE eluting) to give 5-azido-2-bromo-6,7,8,9-tetrahydro-5Hbenzo[7]annulene (350 mg, yield: 45%) as a yellow oily liquid colors. ESI-MS (M+HN ₃ ) ⁺ : 223.0. ¹ H-NMR (400 MHz, CDCh) δ: 7.31-7.29 (m, 2H), 7.15 (d, J=8.0 Hz, 1H), 4.72 (t, J=5 .2 Hz, 1H),

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2.99-2.92(m, 1H), 2.70-2.64(m, 1H), 2.08-2.00(m, 1H), 1.90-1.59(m, 5H ).

6. Synthesis of 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-amine.

To a solution of 5-azido-2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulene (375 mg, 1.4 mmol, 1.0 eq.) in THF (5 ml) and H ₂ O (0.5 ml) add PPh ₃ (741 mg, 2.8 mmol, 2.0 eq.). The mixture was stirred at room temperature for 12 hours. The mixture was acidified to pH=1 with HCl (1 N) and extracted with EtOAc (100 ml). The separated aqueous layer was made basic to pH=10 with NaOH (1H). The resulting precipitate was collected and dried to give 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-amine (360 mg, yield: 100%) as a white solid. ESI-MS (M+H-17)+: 222.9.

7. Synthesis of (2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate.

To a mixture of tert-butyl-(2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate (360 mg, 1.5 mmol, 1.0 eq.) in CH ₂ Cl ₂ (5 ml) and triethylamine (303 mg, 3.0 mmol, 2.0 eq.) add Boc ₂ O (394 mg, 1.8 mmol, 1.2 eq.). The mixture was stirred at room temperature for 2 hours. After dilution

EtOAc (100 ml) the mixture was washed with water (100 ml x 2). The organic layer was concentrated and purified by silica gel column chromatography (PE:EIAc=30:1) to give (2-bromo-6,7,8,9tetrahydro-5H-benzo[7]annulen-5-yl)carbamate (310 mg, yield: 61%) as a white solid. EER-MS (M-55): 284.0. ¹ H-NMR (400 MHz, CDCI3) δ: 7.29-7.23 (m, 2H), 7.10 (d, J=8.0 Hz, 1H), 4.924.82 (m, 2H), 2.84-2.75 (m, 2H), 1.88-1.83 (m, 5H), 1.44 (s, 9H).

8. Synthesis of tert-butyl-(2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate.

The synthesis of tert-butyl-(2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate is similar to the synthesis of 4-(2-chloropyrimidine- 4-yl)-2-methylbenzylcarbamate. The mixture was concentrated and purified by silica gel column chromatography (PE:EtOAc=4:1) to give t-butyl(2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo [7]annulen-5-yl)carbamate (200 mg, yield: 66%) as a white solid. ESI-MS (M+H)+: 374.1.

9. Synthesis of tert-butyl-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro5H-benzo[7] annulen-5-yl) carbamate.

tert-Butyl-(2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate mixture (500 mg, 1.34 mmol) , 1-methyl-N-pyrazole-4-amine (195 mg, 2.01 mmol), Pd ₂ (dba) ₃ (120 g, 0.13 mmol), Sphos (111 mg, 0.27 mmol) and Cs2CO3 (870 mg, 2.68 mmol) in 1,4-dioxane (12 mL) was stirred under N2 at 100° C. for 6 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated. os

- 85 040817 tar is purified by silica gel column chromatography (EtOAc) to give tert-butyl-(2-(2-((1methyl-N-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8, 9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate as a white solid (480 mg, yield: 83%). ESI-MS (M+H)+: 435.3. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.46 (d, J=5.2 Hz, 1H), 7.88-7.80 (m, 3H), 7.38-6.85 ( m, 4H), 4.97-4.94 (m, 2H), 3.85 (s, 3H), 2.962.94 (m, 2H), 1.93-1.64 (m, 6H), 1 .47 (s, 9H).

10. Synthesis of 4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-N-(1-methyl-1H-pyrazol-4yl)pyrimidin-2 - amine.

Η

A mixture of tert-butyl-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5Hbenzo[7]annulen- 5-yl)carbamate (240 mg, 0.55 mmol) in TFA (4.0 ml) and CH ₂ Cl ₂ (4.0 ml) was stirred at rt for 2 h. The reaction mixture was then concentrated to give compound 4- (5-amino6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (250 mg, crude) as a yellow oily liquid, which is used in the next step without further purification. ESI-MS (M+H)+: 335.3

11. Synthesis of 5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9tetrahydro- 5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide.

Synthesis of 5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9tetrahydro-5Н- benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide is similar to the synthesis of 8-bromo-5-(5 (tert-butyl)-1,2,4-oxadiazole-3-carboxamido) -4,5-dihydro-1H-benzo[d]azepine-2(3H)-carboxylate in Example 2. The residue was purified by preparative HPLC (CH3CN/H2O with 0.05% NH4HCO3 as mobile phase) to give 5-(tert -butyl)-N-(2-(2-((1-methyl-N-pyrazol-4-yl)amino)pyrimidin-4-yl)6,7,8,9-tetrahydro-5H-benzo[7] annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide as a yellow solid (120 mg, yield: 42%). ESI-MS (M+H)+: 487.3. ¹ H-NMR (400 MHz, CD3OD) δ: 8.43 (d, J=5.2 Hz, 1H), 7.98-7.96 (m, 2H), 7.51-7.30 (m , 3H), 6.74 (d, J=2.4 Hz, 1H), 5.44 (d, J=10.0 Hz, 1H), 3.83 (s, 3H), 3.09-3 .03 (m, 2H), 2.10-1.43 (m, 6H), 1.54 (s, 9H).

Example 34 (R)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5Hbenzo[ 7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide (compound 34).

H

1. Synthesis of (R,Z)-5-((1-phenylethyl)imino)-6,7,8,9-tetrahydro-5H-bnzo[7]annulen-2-ol.

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Suspension of a mixture of 2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (Herdman C.A. et al., Stractural interrogation of benzosuberen-based inhibitors of tubulin polymerization, Bioorganic & Medical Chemistry, 23(24), 7497-7520, 2015) (10 g, 57 mmol), (R)-(+)-α-methylbenzylamine (9.0 g, 74 mmol) and p-toluenesulfonic acid (0.48 g, 2, 84 mmol) in 150 ml of toluene is heated under reflux in a Dean-Stark apparatus. After 16 hours, the Dean-Stark apparatus was removed and reflux continued until ~80 ml of toluene had been distilled, during which time a solid crystallized. The mixture is cooled to 0° C., kept at 0° C. for 2 h, and then filtered to obtain (R,Z) 5-((1-phenylethyl)imino)-6,7,8,9-tetrahydro-5H- bknzo[7]annulen-2-ol as a yellow-brown solid (after drying 13.5 g, yield: 85%). The crude product is used in the next step without further purification.

2. Synthesis of (R)-5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-ol acetate.

A suspension of (R,Z)-5-((1-phenylethyl)imino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-ol (13.5 g, 48 mmol) in 10 :1 EtOAc/MeOH (148 ml) cooled to -5°C. Solid NaBH4 (5.45 g, 144 mmol) was added in portions while maintaining the temperature below 5°C. The mixture is stirred at -5° C. for 40 minutes. After 1 h, water (135 ml) was added followed by 5N HCl until pH ~6. The layers are separated and the aqueous phase is extracted with 135 ml of EtOAc. The combined organic layers are washed with brine (100 ml), dried (Na ₂ SO ₄ ) and filtered to obtain a solution of (R)-5-(((R)-1-phenylethyl)amino)-6,7,8,9-tetrahydro5H -benzo[7]annulen-2-ol, which is used further.

To a solution of (R)-5-(((R)-1-phenylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-ol (48 mmol) in EtOAc (~ 185 ml) add acetic acid (5.8 g, 96 mmol). The solution is then concentrated and used further.

MeOH (200 ml) was added followed by 10% Pd/C (1.4 g, 10% by weight). The mixture is stirred under H ₂ (50 psi) at 55° C. for 16 hours. The mixture is filtered and the filtrate is concentrated. Methyl tert-butyl ether (100 ml) was added followed by petroleum ether (100 ml). The mixture is stirred at 25° C. for 2 hours and filtered. After drying at 50°C, (R)-5-amino-6,7,8,9tetrahydro-5H-benzo[7]annulen-2-ol acetate (9.9 g, yield: 87% over three steps) is isolated.

3. Synthesis of (R)-(2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate.

SPLA

OH OH

Aqueous _NaHCO (1H, 100 ml, 100 mmol) followed by Boc ₂ O (13.7 g, 63 mmol). The mixture was stirred at rt overnight. Add EtOAc (150 ml) and the layers are separated. The aqueous layer was extracted with EtOAc (150 ml). The combined organic layers are dried (Na ₂ SO ₄ ), filtered and concentrated. MTBE (150 ml) was added followed by petroleum ether (150 ml). After stirring for 2 hours, the mixture is filtered and the filtrate is concentrated to give an oily liquid. The crude material was purified by silica gel column chromatography to give (R)-(2-hydroxy-6,7,8,9tetrahydro-5H-benzo[7]annulen-5-yl)carbamate as a white solid (7.8 g , yield: 67%, ee: 98.5%). ¹ H-NMR (400 MHz, DMSO^) δ: 9.06 (s, 1H), 7.29-7.27 (m, 1H), 6.94 (d, J=8.8 Hz, 1H) , 6.49 (s, 2H), 4.48 (m, 1H), 2.65 (brs, 2H), 1.99-1.64 (m, 4H), 1.48-1.25 (m , 11H).

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4. Synthesis of (R)-5-((tert-butoxycarbonyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2yltrifluoromethanesulfonate.

To a solution of (R)-(2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate (1.0 mg, 3.6 mmol) and pyridine (570 mg , 7.2 mmol) in DCM (30 ml) at 0°C add Tf ₂ O (1.5 g, 5.4 mmol). The mixture was stirred at 0° C. for 1 hour. After dilution with water (20 ml), the mixture was extracted with DCM (3x40 ml). The combined organic layers are washed with aqueous NaHSO ₄ (0.5 N, 20 ml) to bring the aqueous layer to pH=5-6, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product is used in the next step without further purification. ESI-MS (M+H)+: 410.1. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.31 (d, J=8.8 Hz, 1H), 7.07-7.00 (m, 2H), 4.93-4.88 ( m, 2H), 2.89-2.82 (m, 2H), 1.91-1.68 (m, 6H), 1.45 (s, 9H).

5. Synthesis of tert-butyl-(R)-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9tetrahydro-5H- benzo[7]annulen-5-yl)carbamate.

Synthesis of tert-butyl-(R)-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro5H-benzo[ 7]annulen-5-yl)carbamate is similar to the synthesis of tert-butyl-5-(5-(tert-butyl)-1,2,4-oxadiazole-3carboxamido)-8-(2-((1-methyl-III- pyrazol-4-yl)amino)pyrmidin-4-yl)-4,5-dihydro-III-benzo[c]azepine 2(3H)-carboxylate (Example 2, step 11). The crude product was purified by silica gel column chromatography (DCM/MeOH=20:1) to give tert-butyl-(R)-(2-(2-((1-methyl-1H-pyrazol-4yl)amino)pyrimidin-4- yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate as a yellow solid (420 mg, yield: 68%). ESI-MS (M+H)+: 435.2. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.418.37 (m, 1H), 7.88-7.77 (m, 3H), 7.55-7.36 (m, 4H), 7, 05 (d, J=5.2 Hz, 1H), 5.09-5.01 (m, 1H), 3.90 (s, 3H), 2.93-2.91 (m, 2H), 2 .18-2.17 (m, 1H), 1.91-1.82 (m, 5H), 1.28-1.24 (m, 9H).

6. Synthesis of (R)-4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-N-(1-methyl-1H-pyrazol-4yl) )pyrimidine-2-amine.

Synthesis of (R)-4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-N-(1-methyl-1H-pyrazol-4yl)pyrimidine- 2-amine is similar to the synthesis of 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4yl)amino)pyrimidin-4-yl)-2,3,4,5 - tetrahydro-1 H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide described in Example 2, step 12. The crude product was used in the next step without further purification. ESI-MS (M+H)+: 335.2

7. Synthesis of ethyl-(Z)-2-amino-2-(((1-methylcyclopropane-1-carbonyl)oxy)imino)acetate.

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SH ₂ ^ΗΟ Ν ^Λ _γ °^ (COCl) ₂ (2 eq) 9 ⁰ o 2

K ------ (/у __- /sA,N _4n A/

DKhK1.kt, 16h Δ TEA 0 eq), DKhM1. kg, 2 h

To a solution of 1-methylcyclopropane-1-carboxylic acid (2 g, 20 mmol) in DCM (50 ml) was added (COCl) ₂ (5 g, 40 mmol). The mixture was stirred at rt for 16 h and then concentrated to give the intermediate acyl chloride. A solution of the acyl chloride intermediate in DCM (20 mmol). The reaction mixture is stirred at rt for 2 h, washed with water, dried with Na ₂ SO ₄ , concentrated to give ethyl-(Z)-2-amino-2-(((1-methylcyclopropane-1carbonyl)oxy)imino)acetate as white solid (3.0 g, yield: 63%). ESI-MS (M+H)+: 215.1.

8. Synthesis of ethyl 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate.

A solution of ethyl-(Z)-2-amino-2-(((1-methylcyclopropane-1-carbonyl)oxy)imino)acetate (3.0 g, 14 mmol) in AcOH (20 ml) was stirred at 100°C in for 2 h and then concentrated. The residue was diluted with DCM (20 ml), washed with saturated NaHCO ₃ solution (3x10 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc=10:1) to give ethyl 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate as a yellow solid (1. 1 g, yield: 52%). ESI-MS (M+H) ⁺ : 197.1.

9. Synthesis of 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-potassium carboxylate.

Ethyl 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate (1.0 g, 5.0 mmol) and KOH (308 mg, 5.5 mmol) are dissolved in EtOH/H ₂ O (4 :1, 20 ml). The reaction mixture was stirred at rt for 12 h and then concentrated to give potassium 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate as a yellow solid (1.1 g, yield: 95 %). ESI-MS (M+H) ⁺ : 169.1.

10. Synthesis of N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5Hbenzo[7]annulen- 5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide (I-IM_6).

In a solution of 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-potassium carboxylate (123 mg, 0.6 mmol), DIPEA (232 mg, 0.75 mmol) and HATU (342 mg, 0. 9 mmol) in DxM (5 ml) add (R)-4-(5-amino-6,7,8,9tetrahydro-5H-benzo[7]annulen-2-yl)-N-(1-methyl-1H -pyrazol-4-yl)pyrimidin-2-amine (150 mg, 0.50 mmol). The mixture was stirred at rt for 1 h. After dilution with water (60 ml), the mixture was extracted with DCM (80 mlx2). The combined organic layers are dried and concentrated. The crude product was purified by preparative HPLC to give (R)-N-(2-(2-((1-methyl-1H-pyrazol-4yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro- 5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4oxadiazole-3-carboxamide as a white solid (60 mg, yield: 30%). ESI-MS (M+H) ⁺ : 485.2. ¹ H-NMR (400 MHz, CD3OD) δ: 8.40 (d, J=5.2 Hz, 1H), 7.97 (s, 1H), 7.98-7.93 (m, 2H), 7.66 (s, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.21 (d, J=5.2 Hz, 1H), 5.43 (d, J=10 Hz, 1H), 3.90 (s, 3H), 3.09-3.02 (m, 2H), 2.09

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1.86 (m, 5H), 1.64 (s, 3H), 1.54-1.45 (m, 3H), 1.21-1.18 (m, 2H).

Example 35 (R)-5-(t-butyl)-N-(2-(2-((1-methyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6.7 ,8,9tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide (compound 35).

1. Synthesis of tert-butyl-(R)-(2-(2-chloropyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5yl)carbamate.

The synthesis of tert-butyl-(R)-(2-(2-chloropyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5yl)carbamate is similar to the synthesis of tert-butyl-1 -(5-(tert-butyl)-1,2,4-oxadiazol-3-carboxamido)-7-(2((1-methyl-1 H-pyrazol-4-yl)amino)pyrmidin-4-yl) -4,5-dihydro-1 H-benzo[d]azepine-3(2H)-carboxylate (example 1, step 12). The crude product was purified by silica gel column chromatography (MeOH/EtOAc=1/50) to give tert-butyl-(R)-(2-(2-chloropyridin-4-yl)-6,7,8,9-tetrahydro-5Hbenzo [7]annulen-5-yl)carbamate as a yellow solid (350 mg, yield: 44%). ESI-MS (M+H)+: 373.2.

2. Synthesis of tert-butyl-(R)-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro5Н- benzo[7]annulen-5-yl)carbamate.

In a solution of tert-bugyl-(R)-(2-(2-chloropyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5yl)carbamate (400 mg, 1, 1 mmol) in dioxane (20 ml) add 1-methyl-1H-pyrazol-4-amine (210 mg, 2.1 mmol), Pd ₂ (dba) ₃ (100 mg, 0.11 mmol), SPhos (45 mg, 0.11 mmol) and Cs ₂ CO ₃ (680 mg, 2.1 mmol). The mixture is heated to 100° C. for 2 hours and concentrated. The crude product was purified by silica gel column chromatography (MeOH/EtOAc=1/50) to give tert-butyl-(R)-(2-(2-((1-methyl-N-pyrazol4-yl)amino)pyridin-4- yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate (330 mg, yield: 71%) as a yellow solid. ESI-MS (M+H) ⁺ : 434.2.

3. Synthesis of (R)-4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-N-(1-methyl-1H-pyrazol-4yl) pyridine-2-amine.

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Synthesis of (R)-4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-N-(1-methyl-1H-pyrazol-4yl)pyridine- 2-amine is similar to the synthesis of 5-(tert-butyl)-N-(7-(2-((1-methyl-N-pyrazol-4yl)amino)pyrimidin-4-yl)-2,3,4,5- tetrahydro-1H-benzo[d]azepin-1-yl)-1,2,4-oxadiazole-3-carbocamide (example 1, step 13). Crude product (R)-4-(5-Amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)Ni(1-methyl-III-pyrazol-4-yl)pyridine -2-amine as a yellow solid (200 mg, yield: 79%). ESI-MS (M+H)+: 334.2.

4. Synthesis of (R)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6.7, 8,9tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide (I-IM_65).

Synthesis of (R)-5-(tert-bugyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)α-mino)pyridin-4-yl)-6,7,8, 9 tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazol-3-carboxamide is similar to the synthesis of N-(2-(2-((1methyl-1H-pyrazol-4-yl)amino )pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide described in Example 34, Step 10. The mixture was purified by preparative HPLC (CH3CN/H2O with 0.05% NH3H2O as mobile phase) to give (R)-5-(tert-butyl)-N-(2-(2-(( 1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5Нbenzo[7]annulen-5-yl)-1,2,4-oxadiazol- 3-carboxamide as a yellow solid (100 mg, yield: 88%). ESI-MS (M+H)+: 486.3. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.17-8.16 (m, 1H), 7.61 (s, 1H), 7.48 (s, 1H), 7.43-7, 41 (m, 1H), 7.36-7.30 (m, 3H), 6.87-6.86 (m, 1H), 6.71 (s, 1H), 6.22-6.18 ( m, 1H), 5.44-5.40 (m, 1H), 3.91 (s, 3H), 3.01-2.89 (m, 2H), 2.05-1.93 (m, 4H), 1.82-1.78 (m, 2H), 1.49 (s, 9H).

Example 36 (R)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6.7, 8,9tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide (compound 36a).

1. Synthesis of (R)-1-(tert-butyl)-N-(8-(2-chloropyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5yl) - 1H-1,2,3-triazole-4-carboxamide.

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Synthesis of (R)-1-(tert-butyl)-N-(8-(2-chloropyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5yl)- 1H -1,2,3-triazole-4-carboxamide is similar to the synthesis of (R)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1Hpyrazol-4-yl)amino) pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide (Example 9, step 4). The crude product is used in the next step without purification. ESI-MS (M+H)+: 427.2.

2. Synthesis of (R)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6.7, 8,9tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide (compound 36а) and (S)S-(tert-butyl)-N-(2-(2- ((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5Hbenzo[7]annulen-5-yl)-1,3,4- oxadiazole-2-carboxamide (compound 36b).

36а 36b -1,2,4-oxadiazole-5-carboxylic acid (76 mg) is subjected to separation using SFC (IA 2x (2x15 cm), 30% ethanol/CO ₂ , 100 bar, 70 ml/min, 220 nm, input, vol: 1 ml, 5 mg/ml, ethanol) which gives 43 mg of peak 1 (99% chemical purity, >99% ee) and 36 mg of peak 2 (99% chemical purity, >99% ee).

Peak 1 is (R)-5-(t-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)6,7,8 ,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide: LCMS: Rt 1.23 min, m/z 487.00. 1H-NMR (400 MHz, methanol^) 8.41 (d, J=5.27 Hz, 1H), 7.96 (d, J=11.80 Hz, 3H), 7.66 (s, 1H) , 7.43 (d, J=8.53Hz, 1H), 7.22 (d, J=5.27Hz, 1H), 5.43 (d, J=9.29Hz, 1H), 3 .90 (s, 3H), 2.96 - 3.24 (m, 2H), 1.74 - 2.25 (m, 5H), 1.51 (s, 9H), 1.28 - 1.43 ( m, 1H).

Peak 2 is (Z)-5-(t-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)6,7,8 ,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide: LCMS: Rt 1.23 min, m/z 487.00. 1H-NMR (400 MHz, methanol^) 8.40 (d, J=5.27 Hz, 1H), 7.96 (d, J=12.05 Hz, 3H), 7.66 (s, 1H) , 7.43 (d, J=8.53 Hz, 1H), 7.22 (d, J=5.27 Hz, 1H), 5.44 (s, 1H), 3.90 (s, 3H) , 2.93-3.21(m, 2H), 1.78-2.23(m, 5H), 1.51(s, 9H), 1.31(s, 1H).

Example 37 5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide (compound 37)

In a solution of 3-tert-butyl-1,2,4-oxadiazole-5-carboxylic acid (1.0 mg, 0.60 mmol), N,N,N',N'tetramethyl-O-(7-azabenzotriazole- 1-yl)uronium hexafluorophosphate (273 mg, 0.72 mmol) and 4-(5-amino6,7,8,9-tetrahydro-5H-benzo[7]annylen-2-yl)-N-(1-methyl -1H-pyrazol-4-yl)pyrimidin-2-amine (200 mg, 0.6 mmol) in Ν,N-dimethylformamide (2.3 ml) was added Ν,N-diisopropylethylamine (0.42 ml, 2.4 mmol). The reaction mixture was stirred at rt overnight and quenched with MeOH. After preparative treatment

- 92 040817

HPLC gives 3-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9tetrahydro-5H -benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide as a solid (186 mg, yield: 64%). LCMS: Rt 1.38 min, m/z 487.1. ¹ H-NMR (400 MHz, methanol-d4) 8.29 (br. s., 1H), 7.97 8.09 (m, 2H), 7.94 (s, 1H), 7.68 (br s., 1H), 7.43 (d, J=8.78 Hz, 2H), 5.41 (d, J=9.79 Hz, 1H), 3.92 (s, 3H), 2, 87 3.18 (m, 2H), 1.70-2.29 (m, 5H), 1.45 (s, 10H).

Example 38 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydrobenzo[ b]oxepin-5-yl)-1,3,4-oxadiazole-2-carboxamide (compound 38).

1. Synthesis of methyl 4-(3-bromophenoxy)butanoate.

He

DMF, rt up to 95 °C, 1.5 h

K ₂ CO 3 (5.52 g, _5.52 g, 40.0 mmol). The mixture was stirred at rt for 0.5 h and then heated with stirring at 90° C. for 1 h. After dilution with EtOAc (200 ml), the mixture was washed with water (3x50 ml), dried and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc=10:1) to give methyl 4-(3-bromophenoxy)butanoate as a white liquid (5.2 g, yield: 96%). ESI-MS (M+H) ⁺ : 273.1.

2. Synthesis of 4-(3-bromophenoxy)butonic acid.

NaOH (3.0 eq)

MeOH, 65 °C, 1h

HE

To a solution of methyl 4-(3-bromophenoxy)butanoate (4.9 g, 19 mmol) in MeOH (40 ml) and H2O (40 ml) was added NaOH (2.3 g, 57 mmol). The mixture is stirred at 65° C. for 1 hour. The solvent is then concentrated under reduced pressure. The pH of the residue was adjusted to 3 with HCl (1 N). The mixture is extracted with EtOAc (3x100 mlx3). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain 4-(3-bromophenoxy)butanoic acid (4.8 g, yield: 98%). The crude product is used in the next step without further purification. ESI-MS (M+H)+: 259.1. 1H NMR (400 MHz, CDCl ₃ ) δ: 7.24-7.20 (m, 1H), 7.10-7.08 (m, 2H), 6.93 (d, J=9.6 Hz, 1H ), 3.97 (t, J=6.4 Hz, 2H), 2.35 (t, J=7.2 Hz, 2H), 1.92-1.88 (m, 2H).

3. Synthesis of 8-bromo-3,4-dihydrobenzo[b]oxepin-5(2Н)-one.

bg

OH 1 SOCI ₂ (2.0 eq), DMF (cat.) DCM, rt, 1 h

2, A1C1 _E (1D eq), DCM 0°C to rt, 1 h

Vg

To a solution of 4-(3-bromophenoxy)butanoic acid (1.82 g, 7.04 mmol) in DCM (35 ml) was added SOCl ₂ (1.67 g, 14 mmol) and DMF (cat.). The reaction mixture was stirred at 40° C. for 1 hour. The solvent was then removed under reduced pressure and dried in vacuo for 2 hours. The residue was dissolved in DCM (35 ml) and cooled in an ice bath. AlCl ₃ (1.02 g, 80 mmol) was added and the mixture was stirred at 0° C. to rt for 12 h. The mixture was poured into conc. HCl (10 ml) and extracted with EtOAc (2x50 ml). The organic layers are washed with water (50 ml) and brine (50 ml) and dried over sodium sulfate. After concentration under reduced pressure, the crude product was purified by silica gel column chromatography (petroleum ether/EtOAc=4:1) to give 8-bromo-3.4

- 93 040817 dihydrobenzo[b]oxepin-5(2H)-one in the form of a white solid (1.2 g, yield: 71%). ESI-MS (M+H)+: 241.1. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.64 (d, J=8.8 Hz, 1H), 7.27-7.23 (m, 2H), 4.25 (t, J= 6.8 Hz, 2H), 2.89 (t, J=7.2 Hz, 2H), 2.25-2.18 (m, 2H).

4. Synthesis of 8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-amine.

NH ₄ OAc (7.63 g, 100 mmol) and NaBH ₃ CN (3.15 g, 50 mmol). The mixture is stirred at 80° C. for 4 hours. After cooling, the mixture is basified to pH>12 with NaOH (1H). The mixture is extracted

DXM (250 mlx2). The combined organic layers are dried and concentrated. The resulting residue was purified by silica gel column chromatography (DCM:MeOH=20:1) to give 8-bromo2,3,4,5-tetrahydrobenzo[b]oxepin-5-amine as a white solid (900 mg, yield : 75%). ESI-MS (M+H-NH ₃ )+: 225.1.

5. Synthesis of N-(8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-5-(tert-butyl)-1,3,4-oxadiazole-2carboxamide.

5-tert-butyl -1,3,4-oxadiazole-2-potassium carboxylate (557 mg, 2.68 mmol, 1.2 eq.), HATU (1.3 g, 3.35 mmol, 1.5 eq.) and triethylamine ( 863 mg, 6.69 mmol, 3.0 eq.). The mixture was stirred at rt for 2 h. The solution was diluted with EtOAc (150 ml) and washed with water (50 ml and brine (2x50 ml). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated on a rotary evaporator. The residue was purified by chromatography with reverse phase (CH3CN/H2O with 0.05% NH3-H2O as mobile phase) to give N-(8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-5-( tert-butyl)-1,3,4oxadiazole-2-carboxamide (210 mg, yield: 30%) as light yellow solid IEMS (M+H)+: 394.1.

6. Preparation of 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydrobenzo[ b]oxepin-5-yl)-1,3,4-oxadiazole-2-carboxamide.

In a mixture of N-(8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-5-(tert-butyl)-1,3,4-oxadiazole-2carboxamide (393 mg, 1 .00 mmol) and PinB-BPin (263 mg, 1.1 mmol) in dry 1,4-dioxane (10 ml) under N2 atmosphere, add KOAc (196 mg, 2.0 mmol) and Pd(dppf)Cl ₂ - DCM (81 mg, 0.1 mmol). The mixture was stirred under N2 at 100° C. for 2 h. (276 mg, 2.0 mmol) and H ₂ O (2.5 ml). The mixture was stirred under N2 at 100° C. for 2 hours. After cooling, the mixture was concentrated and purified by silica gel column chromatography (DCM/MeOH=20:1) to give 5-(tert-butyl)-N-(8

- 94 040817 (2-((1-methyl-1H-n-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1, 3,4oxadiazole-2-carboxamide as a yellow solid (50 mg, yield: 21%). ESI-MS (M+H)+: 489.2. ¹ H-NMR (400 MHz, CD ₃ OD) δ: 8.26 (d, J=5.2 Hz, 1H), 7.82 (s, 1H), 7.69-7.64 (m, 2H ), 7.51 (s, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.02 (d, J=5.2 Hz, 1H), 5.35-5.32 (m, 1H), 4.14-4.10 (m, 1H), 3.83-3.80 (m, 1H), 3.76 (s, 3H), 2.00-1.98 (m , 4H), 1.36 (s, 9H).

Example 39 Synthesis of 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2,3,4,5- tetrahydrobeio[b]oxepin-5-yl)-1,2,4-oxadiazole-2-carboxamide (compound 39).

1. Synthesis of carboxamide.

N-(8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-5-(tert-butyl)-1,2,4-oxadiazol-2-

The synthesis of N-(8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide is similar to the synthesis of (R )-8-bromo-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-1,3,4,5tetrahydro-2H-benzo[c]azepine-2-carboxylate in Example 2, Method 2, Step 2 Purify the crude material by silica gel chromatography (PE:EtOAc=3:1) to give N-(8-6pom-2,3,4,5tetrahydrobenzo[b]oxepin-5-yl)- 5-(tert-butyl)-1,2,4-oxadiazole-2-carboxamide (610 mg, yield: 85%) as a light yellow solid. ESI-MS (M+H)+: 394.1.

2. Preparation of 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5tetrahydrobenzo[ b]oxepin-5-yl)-1,2,4-oxadiazole-2-carboxamide.

In a mixture of N-(8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-5-(tert-butyl)-1,2,4-oxadiazole-2carboxamide (135 mg, 0 .34 mmol) and PinB-BPin (96 mg, 0.38 mmol) in dry 1,4-dioxane (3 ml) under N2 atmosphere, add KOAc (68 mg, 0.69 mmol) and Pd(dppf)Cl ₂ - DCM (24 mg, 0.03 mmol). The mixture was stirred under N2 at 100° C. for 2 h. (95 mg, 0.69 mmol) and H ₂ O (0.8 ml). The mixture was stirred under N ₂ at 100° C. for 2 hours. After cooling, the mixture was concentrated and purified by silica gel chromatography (DCM:MeOH=20:1) to give 5-(tert-butyl)-N-(8( 2-((1-methyl-N-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,2,4oxadiazol- 2-carboxamide as a yellow solid (77 mg, yield: 46%). ESI-MS (M+H)+: 489.2. ¹ H-NMR (400 MHz, CD3OD) δ: 8.35 (d, J=5.2 Hz, 1H), 7.91 (s, 1H), 7.78-7.73 (m, 2H), 7.62(s,

- 95 040817

1H), 7.38 (d, J=8.4 Hz, 1H), 7.10 (d, J=5.6 Hz, 1H), 5.46-5.44 (m, 1H), 4, 18-4.15 (m, 1H), 3.98-3.95 (m, 1H), 3.86 (s, 3H), 2.10-2.02 (m, 4H), 1.48 ( s, 9H).

Example 40 5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9tetrahydro- 5H-cyclohepta[c]pyridin-9-yl)-1,3,4-oxadiazole-2-carboxamide (compound 40).

1. Synthesis of 3-chlorocyclohept-2-en-1-one.

O O (soan ^ ekHdmFOLek) JL

X / ⁰ DCM» O °C, 30 min ^C|

Oxalyl chloride (24, 4 g, 0.19 mol). After stirring at 0°C for 30 min, the reaction mixture was washed with water (3x500 ml). The aqueous phase is then extracted with diethyl ether (4x300 ml). The combined DCM and diethyl ether phases were dried over MgSO ₄ and concentrated to give 3-chlorocyclohept-2-en-1-one (crude, 22.8 g, used in next step) as a brown oil. ESI-MS (M+H)+: 145.1.

2. Synthesis of 2-cyano-2-(3-oxocyclohept-1-en-1-yl)acetamide.

NaH (2D eq), DMF

About °C, 30 min, kg, 30 min

To a solution of 2-cyanoacetamide (26.9 g, 0.32 mol) in DMF (300 ml) at 0° C. was added NaH (60% in mineral oil, 14.1 g, 0.35 mol) in one portion. After stirring at 0° C. for 30 minutes, a solution of 3-chlorocyclohept-2-en-1-one (22.8 g, 0.16 mol) in DMF (100 ml) was added dropwise. The reaction mixture is stirred at room temperature for 30 minutes and the DMF is removed under reduced pressure. The residue is dissolved in water (350 ml). The solution was washed with ethyl acetate (4x150 ml), adjusted to pH 2-3 with 3.0 N aqueous HCl and extracted with 10% MeOH/DCM (6x300 ml). The combined extracts of the latter are dried over MgSO ₄ and concentrated. The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether=4:1) to give 2-cyano-2-(3oxocyclohept-1-en-1-yl)acetamide as a yellow oil (22.0 g, yield : 73% for two stages). ESI-MS (M+H) ⁺ : 193.1.

3. Synthesis of 3,9-dioxo-3,5,6,7,8,9-hexahydro-2H-cyclohepta[c]pyridine-4-carbonitrile.

CN DMF, 50°C, 4h GN

DMF- DMA (22.8 ml, 0.17 mol). The reaction mixture is stirred at 50° C. for 4 hours and concentrated under reduced pressure. The resulting brown oily liquid was dissolved in aqueous NaOH (1.0 N, 200 ml), washed with chloroform (5x150 ml) and acidified slowly at 0° C. with HCl (6.0 N) to pH 2-3. The brown solid 3,9-dioxo3,5,6,7,8,9-hexahydro-2H-cyclohepta[c]pyridine-4-carbonitrile (17.0 g, yield: 74%) was collected by filtration and dried in vacuo . ESI-MS (M+H) ⁺ : 203.1. 1 H-NMR (400 MHz, CDCl ₃ ) δ: 8.16 (s, 1H), 3.17-3.14 (m, 2H), 2.77-2.74 (m, 2H), 2.04 -2.00 (m, 2H), 1.90-1.87 (m, 2H).

4. Synthesis of 5,6,7,8-tetrahydro-2H-cyclohepta[c]pyridine-3,9-dione.

- 96 040817

A solution of 3,9-dioxo-3,5,6,7,8,9-hexahydro-2H-cyclohepta[c]pyridine-4-carbonitrile (17.0 g, 0.084 mol) in 50% concentrated sulfuric acid ( 100 ml) is stirred at 140°C for 12 hours. The reaction mixture is slowly neutralized at 0°C with 50% sodium hydroxide to pH 7-8. Water is removed under reduced pressure. The residue is dissolved in warm chloroform and the insoluble solid is removed by filtration. The filtrate was concentrated and purified by silica gel column chromatography (DCM/MeOH=20:1) to give 5,6,7,8-tetrahydro-2H-cyclohepta[c]pyridine-3,9-dione as a yellow solid (9 .5 g, yield: 63%). ESI-MS (M+H)+: 178.1.

5. Synthesis of 9-amino-2,5,6,7,8,9-hexahydro-3H-cyclohepta[c]pyridin-3-one.

ABOUT

NH^OAc {20.0 eq), NaBH ₃ CN (3.0 eq)

i-PrOH, 80 °C, 8 h

Mixture of 5,6,7,8-tetrahydro-2H-cyclohepta[c]pyridine-3,9-dione (7.0 g, 39.5 mmol), NH ₄ OAc (60.8 g, 790.0 mmol) and NaBH ₃ CN (7.4 g, 118.5 mmol) in i-PrOH (150 ml) heated to 80°C for 8 h and cooled to rt. The solution is used in the next step without purification. ESI-MS (M+H)+: 179.2.

6. Synthesis of tert-butyl-(3-oxo-3,5,6,7,8,9-hexahydro-2H-cyclohepta[c]pyridin-9-yl)carbamate.

NaHCO ₃ (aqueous, 50 ml), THF (50 ml) and Boc ₂ O (17.2 g, 79.0 mmol) are added to the previous solution. The mixture was stirred at rt for 6 h. After concentration and dilution with water (100 ml), the mixture was extracted with DCM (3x200 ml). The combined organic layers are washed with brine (200 ml), dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by silica gel column chromatography (DCM/MeOH=20:1) to give tert-butyl-(3-oxo-3,5,6,7,8,9hexahydro-2H-piclogepta[c]pyridin-9-yl )carbamate as a yellow solid (6.2 g, yield: 56% over two steps). ESI-MS (M+H)+: 279.2. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.25 (s, 1H), 6.35 (s, 1H), 5.30 (brs, 1H), 2.65-2.63 (m, 2H), 1.86-1.76(m, 4H), 1.45(s, 9H), 1.39-1.35(m, 2H).

7. Synthesis of 9-((tert-butoxycarbonyl)amino)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-3yltrifluoromethanesulfonate.

To a solution of tert-butyl-(3-oxo-3,5,6,7,8,9-hexahydro-2H-cyclohepta[c]pyridin-9-yl)carbamate (6.2 g, 22.3 mmol) and triethylamine (6.8 g, 66.9 mmol) in DCM (150 ml) at 0° C. Tf ₂ O (9.4 g, 33.5 mmol) was added dropwise. The mixture was stirred for 1 hour. The solution was diluted with water (150 ml) and extracted with DCM (2x200 ml). The combined organic layers are washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/MeOH=4:1) to give 9-((tert-butoxycarbonyl)amino)-6,7,8,9-tetrahydro-5Hcyclohepta[c]pyridin-3-yltrifluoromethanesulfonate in as a yellow solid (5.7 g, yield: 63%). ESI-MS (M+H)+: 411.1.

8. Synthesis of tert-butyl-(3-(1-ethoxyvinyl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9yl)carbamate.

- 97 040817

PQ(OAc) _g (0.1 eq), DPFP (0.4 eq) TEA (3.0 eq), DMF, 70°C, 24 h sealed tube

9-((tert-Butoxycarbonyl)amino)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-3-yltrifluoromethanesulfonate mixture (2.4 g, 5.85 mmol), tributyl(1-ethoxyvinyl) )stannate (4.3 g, 11.7 mmol), triethylamine (1.8 g, 17.6 mmol), Pd(OAc)2 (131 mg, 0.58 mmol) and DPFP (903 mg, 2.34 mmol) in 50 ml of DMF was stirred under nitrogen at 70°C for 2 h in a sealed tube. The mixture is diluted

EtOAc (200 ml) and washed with water (3x100 ml). The organic phase is dried with Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc=4:1) to give tert-butyl-(3-(1-ethoxyvinyl)-6,7,8,9-tetrahydro-5Hcyclohepta[c]pyridine-9- yl)carbamate as a yellow solid (1.0 g, yield: 51%). IEMS (M+H)+: 333.2.

9. Synthesis of 1-(9-amino-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-3-yl)ethan-1-one.

To a solution of tert-butyl-(3-(1-ethoxyvinyl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9yl)carbamate (1.0 g, 3.0 mmol) in THF ( 30 ml) HCl (1 ml, 6.0 mmol) was added dropwise. The mixture was stirred at rt for 1 h. The solution was used in the next step without purification. ESI-MS (M+H)+: 205.1.

10. Synthesis of tert-butyl-(3-acetyl-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamate.

The synthesis of tert-butyl-(3-acetyl-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamate is similar to the synthesis of tert-butyl-(3-oxo-3,5,6, 7,8,9-hexahydro-2H-cyclohepta[c]pyridin-9-yl)carbamate (Example 40, step 6). The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc=4:1) to give tert-butyl-(3-acetyl-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9yl)carbamate in as a yellow solid (550 mg, yield: 60% for two steps). ESI-MS (M+H)+: 305.2. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.54 (s, 1H), 7.78 (s, 1H), 4.99-4.97 (m, 2H), 2.91-2, 90 (m, 2H), 2.70 (s, 3H), 1.94-1.74 (m, 4H), 1.62-1.60 (m, 2H), 1.45 (s, 9H) .

11. Synthesis of tert-butyl-(3-(3-dimethylamino)acryloyl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin9-yl)carbamate.

Solution of tert-butyl-(3-acetyl-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamate (550 mg, 1.8 mmol) in DMF-DMA (10 ml) stirred at 100°C for 2 hours. After concentration, the crude product was purified by reverse phase chromatography (CH ₃ CN/0.05% NH3.H2O in water) to give tert-butyl-(3-(3-dimethylamino)acryloyl) -6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9yl)carbamate (380 mg, yield: 61%). ESI-MS (M+H)+: 360.2.

12. Synthesis of 1-(1-methyl-1H-pyrazole-4-ul)guanidine hydrochloride.

To a solution of 1-methyl-1H-pyrazole-4-amine (500 mg, 5 mmol, 1.0 eq.)

- 98 040817 anamide (273 g, 6.5 mmol, 1.3 eq.) and conc. HCl (1 ml). The reaction mixture is stirred at 100° C. for 12 hours. The solvent is removed under reduced pressure. The residue is crystallized from the cosolvent MeOH and Et2O. 1-(1-methyl-1H-pyrazol-4-yl)guanidine hydrochloride (600 mg, yield: 55%) is obtained as a yellow solid. ESI-MS (M+H)+: 140.1. ¹ H-NMR (400 MHz, CD ₃ OD) δ: 7.78 (s, 1H), 7.48 (s, 1H), 3.91 (s, 3H).

13. Synthesis of tert-butyl-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro5H-cyclohepta[c] pyridin-9-yl) carbamate.

EUN. 90 °C, 12h

A mixture of 1-(1-methyl-1H-pyrazol-4-yl)guanidine hydrochloride (588 mg, 4.23 mmol), K2CO3 (1.2 g, 8.46 mmol) and triethylamine (855 mg, 8.46 mmol ) in EtOH (10 ml) was stirred at rt for 1 h, then tert-butyl-(3-(3-dimethylamino)acryloyl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridine9- yl)carbamate (380 mg, 1.06 mmol) and the mixture heated to 90° C. for 12 h. After concentration, the crude product was purified by reverse phase HPLC (CH ₃ CN/0.05% NH3.H2O in water) to obtaining tert-butyl-(3-(2-((1-methyl-N-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-pyclohepta[c]pyridine- 9-yl)carbamate (240 mg, yield: 52%). ESI-MS (M+H)+: 436.2. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.57 (s, 1H), 8.50 (d, J=5.2 Hz, 1H), 8.08 (s, 1H), 7.85 (s, 1H), 7.66 (d, J=5.6 Hz, 1H), 7.60 (s, 1H), 6.92 (s, 1H), 5.00 (br, 2H), 3 .92 (s, 3H), 2.97-2.90 (m, 2H), 2.01-1.82 (m, 5H), 1.51-1.46 (m, 10H).

14. Synthesis of 3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5Hcyclohepta[c]pyridin-9-amine .

Into a solution of tert-butyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro5H-cyclohepta[c]pyridine- 9-amine (240 mg, 0.55 mmol) in DCM (5 ml) was added with TFA (5 ml). The mixture was stirred at rt for 1 h. After concentration, the residue was basified with NaHCO ₃ (aq) and extracted with DCM (3x30 ml), dried and concentrated to give 3-(2-((1-methyl-N-pyrazol-4yl)amino) pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridine-9-amine as yellow solid (170 mg, yield: 92%, used in next step without further purification ). ESI-MS (M+H)+: 336.2.

15. Synthesis of 5 - (tert-butyl) -N- (3 - (2- (( 1 -methyl-1 H-pyrazol-4-yl) amino) pyrimidin-4-yl) -6,7,8,9 - tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,3,4-oxadiazole-2-carboxamide (I-IM_29).

Into a solution of 3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5Hcyclohepta[c]pyridin-9-amine ( 80 mg, 0.24 mmol) and triethylamine (49 mg, 0.48 mmol) in DCM (5 ml) add HATU (182 mg, 0.48 mmol) and 5-(tert-butyl)-1,3,4 -oxadiazole-2-potassium carboxylate (75 mg,

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0.36 mmol). The mixture was stirred at rt for 3 h. Water (30 ml) was then added and the mixture was extracted with DCM (2x50 ml). The combined organic layers are dried and concentrated. The crude product was purified by silica gel column chromatography (DCM/MeOH=10:1) to give 5-(tert-butyl)-N(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine -4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9yl)-1,3,4-oxadiazole-2-carboxamide as yellow solid (60 mg, yield: 51%). IEMS (M+H)+: 487.9. ¹ H-NMR (400 MHz, CD3OD) δ: 8.52 (s, 1H), 8.49 (d, J=5.2 Hz, 1H), 8.22 (s, 1H), 7.97 ( s, 1H), 7.66 (s, 1H), 7.54 (d, J=5.2 Hz, 1H), 5.47-5.45 (m, 1H), 3.90 (s, 3H ), 3.08-3.06 (m, 2H), 2.13-1.98 (m, 5H), 1.51-1.49 (m, 10H).

Example 41 (R)-5-(t-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6.7, 8,9tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,3,4-oxadiazole-2-carboxamide (compound 41).

5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5Hcyclohepta [c]pyridin-9-yl)-1,3,4-oxadiazole-2-carboxamide (216 mg, 0.44 mmol) is separated by chiral SFC (CHIRALPAK AS-H 30x250 mm, 5 µm; co-solvent: 20 % methanol + 0.1% DEA in CO ₂ (flow rate: 100 g/min); system back pressure: 120 bar) to obtain (R)-5(tert-butyl)-N-(3-(2-( (1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5Hcyclohepta[c]pyridin-9-yl)-1,3,4-oxadiazole -2-carboxamide (93 mg, yield: 43%) as a white solid. ESI-MS (M+H) ⁺ : 488.1. ¹ H-NMR (400 MHz, CD3OD) δ: ppm 8.52 (s, 1H), 8.49 (d, J=5.1 Hz, 1H), 8.22 (s, 1H), 7.97 (s, 1H), 7.65 (s, 1H), 7.55 (d, J=5.0 Hz, 1H), 5.46 (brd, J=9.5 Hz, 1H), 3.90 (s , 3 H), 3.07 (brt, J=4.4 Hz, 2H), 2.12 (br d, J=8.8 Hz, 2H), 1.91 - 2.05 (m, 3 H), 1.44 - 1.57 (m, 10H).

Example 42 (R)-5-(t-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6.7, 8,9tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamide (compound 42a) and (S)-5(tert-butyl)-N-(3-( 2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,2, 4-oxadiazole-3-carboxamide (compound 42b).

42a 42b

1. Synthesis of 5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9tetrahydro- 5H-cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamide.

Synthesis of 5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9tetrahydro-5Н- cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamide is similar to the synthesis of 5(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazole-4 -yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H

- 100 040817 cyclohepta[c]pyridin-9-yl)-1,3,4-oxadiazole-2-carboxamide (example 40, step 15). The filtrate was purified by silica gel column chromatography (DCM/MeOH=10:1) to obtain 5-(tert-butyl)-N-(3-(2-((1methyl-1H-pyrazol-4-yl)amino)pyrimidin-4 -yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)1,2,4-oxadiazole-3-carboxamide as yellow solid (55 mg, yield: 47 %). ESI-MS (M+H)+: 487.9. ¹ H-NMR (400 MHz, CD3OD) δ: 8.50 (s, 1H), 8.49 (d, J=5.6 Hz, 1H), 8.21 (s, 1H), 7.97 ( s, 1H), 7.66 (s, 1H), 7.54 (d, J=5.2 Hz, 1H), 5.49-5.47 (m, 1H), 3.90 (s, 3H ), 3.08-3.06 (m, 2H), 2.12-1.97 (m, 5H), 1.521.50 (m, 10H).

2. Synthesis of (R)-5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6.7, 8,9tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamide (I-IM_31) and (S)-S-(tert-butyl)-N-(3-( 2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,2, 4-oxadiazole-3-carboxamide (compound 42).

42a 42b

5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5Hcyclohepta [c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamide (40 mg, 0.08 mmol) was separated by chiral SFC (CHIRALPAK AS-H 30x250 mm, 5 µm; co-solvent: 30 % methanol + 0.1% DEA in CO ₂ (flow rate: 100 g/min); system back pressure: 120 bar) to obtain (R)-5-(tert-butyl)-N(3-(2-( (1-methyl-N-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)1,2,4- oxadiazole-3-carboxamide (11 mg, yield: 27%) and (S)-5-(tert-butyl)-N-(3-(2-((1-methyl-N-pyrazol4-yl)amino)pyrimidine -4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3carboxamide (10 mg, yield: 26%) as solid white substances.

(R ): IES-MS (M+H) ⁺ : 488.1. ¹ H-NMR (400 MHz, CD3OD) δ: 8.51 (s, 1H), 8.49 (s, 1H), 8.22 (s, 1H), 7.97 (s, 1H), 7, 65 (s, 1H), 7.55 (d, J=5.1 Hz, 1H), 5.48 (br d, J=9.3 Hz, 1H), 3.90 (s, 3 H), 3.01 - 3.11 (m, 2H), 1.90 - 2.14 (m, 5H), 1.50 - 1.53 (m, 9H).

(S): ESI-MS (M+H) ⁺ : 488.1. ¹ H-NMR (400 MHz, CD3OD) δ: 8.50 - 8.51 (m, 1H), 8.48 (s, 1H), 8.21 (s, 1H), 7.96 (s, 1H ), 7.65 (s, 1H), 7.53-7.56 (m, 1H), 5.47 (br d, J=9.5 Hz, 1H), 3.89 (s, 3H), 3.02 - 3.13 (m, 2H), 1.91 - 2.16 (m, 5H), 1.50 - 1.52 (m, 10H).

Example 43 1-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9tetrahydro- 5H-cyclohepta[c]pyridin-9-yl)-1H-1,2,3-triazole-4-carboxamide (compound 43).

1. Synthesis of tert-butyl-(3-(2-chloropyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9yl)carbamate.

dioxene / H ₂ O, 60¾. 4 h

Synthesis of tert-butyl-(3-(2-chloropyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridine-9

- 101 040817 yl) carbamate is similar to the synthesis of tert-butyl-1 - (5- (tert-butyl) -1,2,4-oxadiazole-3-carboxamido) -7- (2 ((1-methyl-1H-pyrazole- 4-yl)amino)pyrmidin-4-yl)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate (Example 1, step 12). The crude product is purified by silica gel chromatography (petroleum ether/EtOAc=3:1) to give t-butyl-(3-(2-chloropyridin-4-yl)-6,7,8,9-tetrahydro-5H-pyclohepta[c]pyridine -9-yl)carbamate as a yellow solid (170 mg, yield: 42%). ESI-MS (M+H)+: 374.2.

2. Synthesis of tert-butyl-(3-(2-((1-methyl-III-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5Hcyclohepta[c] pyridin-9-yl) carbamate.

Synthesis of tert-butyl-(3-(2-((1-methyl-III-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-pyclohepta[c]pyridine- 9-yl)carbamate is similar to the synthesis of (R)-(2-(2-((1-methyl-1H-pyrazol-4yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5Н- benzo[7]annulen-5-yl)carbamate (example 35, step 2). The crude product was purified by silica gel column chromatography (PE/EtOAc=1:1) to give tert-butyl-(3-(2-((1-methyl-III-pyrazol-4-yl)amino)pyridin-4-yl) -6,7,8,9-tetrahydro-5H-pyclohepta[c]pyridin-9-yl)carbamate as a yellow solid (140 mg, yield: 71%). ESI-MS (M+H)+: 435.2.

3. Synthesis of 9-amine.

Synthesis of (3-(2-((1-methyl-III-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9- amine is similar to the synthesis of 5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro- 1H-benzo[d]azepin-1-yl)-1,2,4-oxadiazole-3-carbocamide (Example 1, step 13) Crude product (3-(2-((1-methyl-1H-pyrazole- 4-yl)amino)pyridin-4-yl)6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-amine was obtained as a yellow solid (100 mg, yield: 94%). ESI-MS (M+H)+: 335.2.

4. Synthesis of 1-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9- tetrahydro 5H-cyclohepta[c]pyridin-9-yl)-1H-1,2,3-triazole-4-carboxamide.

Synthesis of 1-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro5Н- cyclohepta[c]pyridin-9-yl)-1H-1,2,3-triazole-4-carboxamide is similar to the synthesis of 5-(tert-butyl)-N(3-(2-((1-methyl-1H-pyrazole -4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin9-yl)-1,3,4-oxadiazole-2-carboxamide in example 40, step 15. The crude product is purified by silica gel chromatography (DCM/MeOH=15:1) to give 1-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazole

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solid yellow substance (46 mg, yield: 32%). ESI-MS (M+H)+: 486.3. 1H NMR (400 MHz, CD3OD) δ: 8.53-8.49 (m, 2H), 8.16 (d, J=5.2 Hz, 1H), 7.92 (s, 1H), 7.69 (s, 1H), 7.51 (s, 1H), 7.20-7.17 (m, 2H), 5.45-5.43 (m, 1H), 3.89 (s, 3H), 3.08-3.06 (m, 2H), 2.14-2.00 (m, 5H), 1.74 (s, 9H), 1.591.50 (m, 1H).

Examples 44-154.

The following compounds were synthesized according to procedures similar to those described in examples 1-43._________________________________________________________________________________

Information No. chemical name Structure Ή-NMR and MC 44 (8)-5-(tert-butyl)-N-(7-(2((1-methyl-1H-pyrazo l-4 yl)amino)pyrimidin-4 yl) -2,3,4,5-tetrahydro -1Нbenzo[d]azepin-1 -yl)1,2,4-oxadiazole-3carboxamide Ν'θ / λ /λΑ ( 1 Ίι^ ^Ν ' O An HIL n— N N' ^X ^ ^/ H LCMS: Rt 0.89 min, m/z 488.00. ΉNMR (400 MHz, METHANOL-b ₄ )6: 8.38 (d, J= 5.27 Hz, 1H), 7.83-8.04 (m, 3H), 7.64 (s, 1H), 7.47 (d, J= 7.97 Hz, 1H), 7.19 (s, 1H), 5.34 (d, J= 6.46 Hz, 1H), 3.89 (s, 3H), 2.81 - 3.28 (m, 6H), 1.43 - 1.54 (m, 9H). 45 (H)-5-(tert-butyl)-N-(7-(2((1-methyl-1H-pyrazo l-4 yl)amino)pyrimidin-4 yl)-2,3,4,5-tetrahydro -1Нbenzo[d]azepin-1 -yl)1,2,4-oxadiazole-3carboxamide nQ / ^HN ^\ sN d. / V \ 0 An HI /. N—N H LCMS: Rt=0.89 min, m/z 488.00. ΉNMR (400 MHz, METAHOJI-d ₄ )6: 8.32-8.46 (m, 1H), 7.89-8.05 (m, 3H), 7.64 (s, 1H), 7.48 (d, J = 7.97 Hz, 1H), 7.19 (d, J = 5.33 Hz, 1H), 5.34 (d, J = 6.46 Hz, 1H), 3.89 (s , 3H), 2.91 - 3.28 (m, 6H), 1.45 - 1.55 (m, 9H). 46 5 - (tert-butyl) -N- (3 - (2 hydroxyethyl) -7 - (2- (( 1 methyl- 1H -pyrazol-4 yl) amino) pyrimidin-4 yl) -2,3,4,5- tetrahydro-1Hbenzo[d]azepin-1 -yl)- 1,3,4-oxadiazo l-2carboxamide HU \ n-n v / Ή-NMR (400 MHz, CD ₃ OD)6: 8.288.26 (m, 1H), 7.85-7.76 (m, 3H), 7.52 (s, 1H), 7.40-7, 37 (m, 1H), 7.08-7.05 (m, 1H), 5.15-5.12 (m, 1H), 3.77 (s, 3H), 3.65-3.62 ( m, 2H), 3.14-3.12 (m, 2H), 2.94-2.91 (m, 2H), 2.74-2.65 (m, 3H), 2.61-2, 57 (m, 1H), 1.34 (s, 9H). ESI-MS (M+H) ⁺ : 532.3.

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47 5-(tert-butyl)-I-(7-(2-((1methyl-1H-pyrazol-4 yl)amino)pyrimidin-4 yl)-3-(methylsulfonyl)2,3,4,5-tetrahydro -1Нbenzo[d]azepin-1 -yl)1,3,4-oxadiazol-2 carboxamide °V° N'N _χ o* χχ Ή-NMR (400 MHz, CD3OD)d: 8.41 (d, J = 5.6 Hz, 1H), 7.99-7.93 (m, 3H), 7.65 (s, 1H), 7 .56 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 5.2 Hz, 1H), 5.47-5.45 (m, 1H), 4.00-3, 95 (m, 1Ή), 3.90 (s, 3H), 3.82-3.78 (m, 1H), 3.65-3.61 (m, 1Ή), 3.44-3.37 ( m, 2H), 3.22-3.17 (m, 1H), 2.90 (s, 3H), 1.47 (s, 9H). ESI-MS (M+Hf: 566.2. 48 5 - (tert-butyl) -N- (7- (2 ( (1 -methyl- 1H-pyrazo l-4 yl) amino) pyrimidin-4 yl) -3 - (oxetan-3 -yl) 2.3, 4,5-tetrahydro-1Нbenzo[d]azepin-1-yl)1,3,4-oxadiazol-2carboxamide Z/k about Xj A r\- HIMR (400 MHz, CD ₃ OD)6: 8.29 (d, J = 5.2 Hz, 1H), 7.85-7.80 (m, 3H), 7.52 (s, 1H), 7 .41 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 4.8 Hz, 1H), 5.16-5.15 (m, 1H), 4.62-4, 58 (m, 3H), 4.55-4.51 (m, 1H), 3.78 (s, 3H), 3.70-3.66 (m, 1H), 3.203.15 (m, 1H) , 2.98-2.93(m, 1H), 2.882.83(m, 1H), 2.70-2.66(m, 1H), 2.472.44(m, 1H), 2.35-2 .29 (m, 1H), 1.35 (s, 9H). ESI-MS (M+H) ⁺ : 544.3. 49 5-(tert-butyl)-I- (7- (2- (( 1 methyl- 1H -pyrazol-4 yl) amino) pyrimidin-4 yl) -3 - (tetrahydrofuran-3 yl) -2,3,4 ,5-tetrahydro-1Нbenzo[d]azepin-1-yl)1,3,4-oxadiazol-2carboxamide 0 ^N 'k\/ A XX HNRMR (400 MHz, CD ₃ OD)5: 8.39 (d, J = 5.6 Hz, 1H), 7.96 (s, 1H), 7.94 (dd, J = 8.0, 2, 0 Hz, 1H), 7.89 (s, 1H), 7.64 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 5, 2 Hz, 1H), 5.24-5.22 (m, 1H), 4.013.96 (m, 1H), 3.89 (s, 3H), 3.87-3.83 (m, 1H), 3.80-3.70(m, 2H), 3.53-3.49(m, 1H), 3.29-3.20(m, 2H), 3.15-2.97(m, 2H ), 2.82-2.62 (m, 2H), 2.15-2.10 (m, 1H), 1.98-1.91 (m, 1H), 1.46 (s, 9H). ESI-MS (M+H) ⁺ : 558.3. 50 5 -(tert-butyl) -N-(3 -(2hydroxy-2-methylpropyl)7-(2-((1-methyl-1Hpyrazol-4yl)amino)pyrimidin-4 yl)-2,3,4,5 -tetrahydro-1Hbenzo [d]azepin-1 -yl)- 1,3,4-oxadiazo l-2carboxamide HO / k \, Η N-N ji vz \ 1 ΖχΖ o XJ Xn k Ji L H Ή-NMR (400 MHz, CD ₃ OD)6: 8.40 (d, J = 4.8 Hz, 1H), 7.97-7.89 (m, 3H), 7.64 (s, 1H) , 7.51 (d, J = 8.0, 2.0 Hz, 1H), 7.20-7.19 (m, 1H), 5.22-5.20 (m, 1H), 3.89 (s, 3H), 3.29-3.21 (m, 3H), 3.053.00 (m, 1H), 2.93-2.90 (m, 1H), 2.772.72 (m, 1H), 2.60 (s, 2H), 1.46 (s, 9H), 1.32-1.31 (m, 6H). ESI-MS (M+H) ⁺ : 560.3.

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51 l-(mpem-6ymwi)-N-(7-(2((1-methyl-1H-pyrayl-4yl)amino)pyrimidin-4yl)-2,3,4,5-tetrahydro1H-benzo[<1]azepine -1-yl)1H-1,2,3-triazole-4carboxamide ⁿ / I N -NN O O' rV Ή-NMR (400 MHz, CD ₃ OD)6: 8.48 (s, 1H), 8.40 (d, J = 5.6 Hz, 1H), 7.98-7.93 (m, 3H) , 7.65 (br, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.21 (d, J = 5.2 Hz, 1H), 5.355.34 (m, 1H) , 3.90 (s, 3H), 3.28-2.99 (m, 6H), 1.73 (s, 9H). ESI-MS (M+H) ⁺ : 487.2. 52 1 -(tert-butyl)-\ ^T -(3methyl- 7-(2-((1-methyl1H-pyrazol-4yl)amino)pyrimidin-4yl)-2,3,4,5-tetrahydro1H-benzo[<1 ]azepin-1-yl)1H-1,2,3-triazole-4carboxamide \ n ^N =4 / NN ιίι ⁰ oc χο ^Ν Ή-NMR (400 MHz, CD ₃ OD)6: 8.45 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H), 7.98-7.92 (m, 3H) , 7.65 (s, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 5.2 Hz, 1H), 5.335.31 (m, 1H) , 3.90 (s, 3H), 3.31-3.26 (m, 1H), 3.11-3.05 (m, 2H), 2.92-2.59 (m, 3H), 2 .51 (s, 3H), 1.72 (s, 9H). ESI-MS (M+H) ⁺ : 501.3. 53 l-(mpem-6ymiLi)-N-(3-(2hydroxyethyl)-7-(2-((1methyl-1H-pyrazol-4yl)amino)pyrimidin-4yl)-2,3,4,5-tetrahydro1H-benzo [4]azepin-1-yl)1Н-1,2,3-triazole-4carboxamide ^none rv/ 0 Λ Ή-NMR (400 MHz, CD ₃ OD)6: 8.44 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H), 7.98-7.91 (m, 3H) , 7.65 (s, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.21 (d, J = 5.2 Hz, 1H), 5.215.25 (m, 1H) , 3.90 (s, 3H), 3.79-3.76 (m, 2H), 3.19-3.02 (m, 4H), 2.86-2.64 (m, 4H), 1 .71 (s, 9H). ESI-MS (M+H) ⁺ : 531.3. 54 5-(tert-butyl)-I-(8-(2-((1methyl-1H-pyrazol-4 yl)amino)pyrimidin-4 yl)-2-(2,2,2-trifluoroethyl)2,3, 4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)1,2,4-oxadiazole-3carboxamide O'χν ESI-MS (M+H) ⁺ : 570.2. Ή-NMR (400 MHz, CD ₃ OD)6: 8.31 (d, J = 4.8 Hz, 1H), 7.93-7.88 (m, 3H), 7.50 (s, 1H) , 7.37 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 4.8 Hz, 1H), 5.51 (d, J = 10.0 Hz, 1H), 4.264 .22 (m, 1H), 4.02-3.98 (m, 1H), 3.48 (s, 3H), 3.30-3.27 (m, 2H), 3.05-2.98 (m, 2H), 2.13-2.08 (m, 1H), 1.85-1.82 (m, 1H), 1.41 (s, 9H). 55 5 -(tert-butyl) -N-(2-(2(dimethylamino)acetyl)-8(2-((1-methyl-1H-pyrazol4-yl)amino)pyrimidin-4yl)-2,3,4, 5-tetrahydro-1Hbenzo[c]azepin-5-yl)1,2,4-oxadiazole-3carboxamide ΛχΧ Λ jO ESI-MS (M+H) ⁺ : 573.3. Ή-NMR (400 MHz, CD ₃ OD)6: 8.33-8.29 (m, 1H), 8.10 (s, 1H), 8.02-7.86 (m, 2H), 7.567, 34 (m, 2H), 7.15-7.12 (m, 1H), 5.615.50 (m, 1H), 5.03-4.94 (m, 2H), 4.774.36 (m, 1H) , 4.16-4.13(m, 1H), 4.043.99(m, 3H), 3.83-3.35(m, 2H), 3.103.05(m, 2H), 2.17-2 .12 (m, 6H), 1.42 (s, 9H).

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56 ^(2-(2-hydroxyethyl)-8(2-((1-methyl-1H-pyrazol4-yl)amino)pyrimidin-4yl)-2,3,4,5-tetrahydro1H-benzo[c]azepin-5 -yl)5-(1,1,1-trifluoro-2methylpropan-2-yl)-1,3,4oxadiazole-2carboxamide _n -n | HO—, H /1 \V_L- Ύ ' Ga ГΗ ESI-MS (M+H) ⁺ : 586.3. Ή-NMR (400 MHz, CD ₃ OD)6: 8.43 (d, J = 5.2 Hz, 1H), 8.05 (s, 1H), 8.03-8.00 (m, 2H) , 7.65 (s, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 5.2 Hz, 1H), 5.59-5.57 ( m, 1H), 4.64 (br, 1H), 4.17-4.15 (m, 2H), 3.91 (s, 3H), 3.75 (t, J = 6.0 Hz, 2H ), 3.26-3.16 (m, 1H), 2.72-2.61 (m, 2H), 2.34-2.25 (m, 1H), 2.02-1.97 (m , 1H), 1.76 (s, 6H). 57 N-(2-methyl-8-(2-((1-methyl1H-pyrazol-4yl)amino)pyrimidin-4 yl)-2,3,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl) -5 (1,1,1 -trifluoro-2 methylpropan-2-yl) -1,3,4oxadiazole-2-carboxamide N-CH I h 'and ΛΧνΑΙΛτ -N G Y ° CF ₃ C / L ⁰ ΊΟ il N r^N [1 Y 1 N - NH ESI-MS (M+H) ⁺ : 556.2. Ή-NMR (400 MHz, CDC1 ₃ )6: 8.52 (br, 1H), 8.42 (d, J = 5.2 Hz, 1H), 7.87 (s, 1H), 7.85- 7.81 (m, 2H), 7.55 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.05 (d, J = 5.2 Hz, 1H), 6.91 (s, 1H), 5.61-5.56 (m, 1H), 3.94-3.92 (m, 5H), 3.14-3.07 (m, 1H), 2, 85-2.80(m, 1H), 2.52(s, 3H), 2.36-2.28(m, 1H), 2.11-2.03(m, 1H), 1.71( s, 6H). 58 (R)-5 -(1,1-difluoro-2 methylpropan-2-yl)-K-(8(2-((1-methyl-1H-pyrazol4-yl)amino)pyrimidin-4yl) -2-( oxetan-3 -yl) 2,3,4,5-tetrahydro-1Hbenzo [c] azepin-5 -yl1) 1,3,4-oxadiazol-2-carboxamide E AF . _t4 η p VT « ^N Ϋ O L if L n— H ESI-MS (M+H) ⁺ : 580.2. Ή-NMR (400 MHz, CD ₃ OD)5: 8.42 (d, J = 5.2 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.99-7 .98 (m, 2H), 7.64 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 5.2 Hz, 1H), 6 .15 (t, J = 55.6 Hz, 1H), 5.60-5.56 (m, 1H), 4.78-4.75 (m, 1H), 4.70-4.66 (m , 3H), 3.98-3.94 (m, 1H), 3.90 (s, 3H), 3.883.79 (m, 2H), 3.09-3.06 (m, 1H), 2.932, 87 (m, 1H), 2.30-2.20 (m, 1H), 2.072.04 (m, 1H), 1.60 (s, 6H). 59 5-(1,1-difluoro-2methylpropan-2-yl)-M-(2((8)-2-hydroxypropyl)-8(2-((1-methyl-1H-pyrazol4-yl)amino)pyrimidin- 4yl)-2,3,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)1,3,4-oxadiazol-2carboxamide k ΝΛ \/-f ήΟ ⁷ ESI-MS (M+H) ⁺ : 582.3. Ή-NMR (400 MHz, CD ₃ OD)6: 8.42 (d, J = 5.2 Hz, 1H), 8.03-8.00 (m, 3H), 7.64 (s, 1H) , 7.48-7.46 (m, 1H), 7.23 (d, J = 5.2 Hz, 1H), 6.15 (t, J = 55.6 Hz, 1H), 5.57 ( d, J = 9.6 Hz, 1H), 4.23-4.19 (m, 1H), 4.134.06 (m, 1H), 4.00-3.96 (m, 1H), 3.91 (s, 3H), 3.26-3.20 (m, 2H), 2.44 (d, J = 6.0 Hz, 2H), 2.31-2.25 (m, 1H), 1.991, 95 (m, 1H), 1.60 (s, 6H), 1.16 (d, J = 6.0 Hz, 3H).

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60 5-(1-fluoro-2-methylpropan2-yl)-I-(8-(2-((1-methyl1H-pyrazol-4yl)amino)pyrimidin-4 yl) -2-(oxetan-3-yl) 2 ,3,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)1,3,4-oxadiazol-2carboxamide n ⁿ V^NI /G N ХхЧ ° ή An i*N L if .n— N H ESI-MS (M+H) ⁺ : 562.3. Ή-NMR (400 MHz, CD ₃ OD)6: 8.29 (d, J = 5.6 Hz, 1H), 8.21 (s, 1H), 7.91-7.89 (m, 1H) , 7.86-7.83 (m, 2H), 7.35 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 5.6 Hz, 1H), 5.46 ( d, J = 9.6 Hz, 1H), 4.75-4.57 (m, 1H), 4.564.55 (m, 4H), 4.43 (s, 1H), 3.85-3.66 (m, 6H), 2.96-2.92 (m, 1H), 1.94-1.91 (m, 1H), 1.41 (d, J = 2.0 Hz, 6H), 1, 19 (m, 2H). 61 5 -(1-Fluoro-2-methylpropan2-yl)-I-(2-((8)-2hydroxypropyl)-8-(2-((1methyl-1H-pyrazol-4 yl)amino)pyrimidin-4 yl )-2,3,4,5-tetrahydro-1Hbenzo [c] azepin-5 -yl)- 1,3,4-oxadiazo l-2carboxamide T o z uhhd iz o=/ H Uch! r ESI-MS (M+H) ⁺ : 564.3. Ή-NMR (400 MHz, CD ₃ OD): 8.31-8.29 (m, 1H), 7.89-7.88 (m, 3H), 7.55 (s, 1H), 7.387.36 (m, 1H), 7.11-7.10 (m, 1H), 5.485.46 (m, 1H), 4.53 (d, J = 47.2 Hz, 2H), 4.11-3, 86 (m, 3H), 3.81 (s, 3H), 3.213.14 (m, 2H), 2.35-2.17 (m, 3H), 1.891.87 (m, 1H), 1.44 (s, 6H), 1.07-1.03 (m, 3H). 62 5-uuicio6ymu:i-N-(2methyl-8-(2-((1-methyl1H-pyrazole-4- yl)amino)pyrimidin-4yl)-2,3,4,5-tetrahydro1H-benzo[c]azepin-5-yl)1,3,4-oxadiazole-2carboxamide h ° An ^n |l IL n— N N'^ ⁷ H ESI-MS (M+H) ⁺ : 500.3. Ή-NMR (400 MHz, CD ₃ OD)6: 8.31-8.28 (m, 1H), 7.92-7.86 (m, 3H), 7.52 (s, 1H), 7.357, 33 (m, 1H), 7.12-7.08 (m, 1H), 5.43 (d, J = 10.0 Hz, 1H), 4.00-3.98 (m, 1H), 3 .82-3.79(m, 2H), 3.77(s, 3H), 3.082.95(m, 2H), 2.45-2.38(m, 4H), 2.28(s, 3H ), 2.15-1.89 (m, 4H). 63 5-(2-cyanopropan-2-yl)1U-(2-methyl-8-(2-((1methyl-1H-pyrazol-4yl)amino)pyrimidin-4yl)-2,3,4,5-tetrahydro1H- benzo[c]azepin-5-yl)1,3,4-oxadiazole-2carboxamide \ CN /—k H O-/ Ow Tj ⁰ X ^x N L if £ N N'^' ⁷ H ESI-MS (M+H) ⁺ : 513.6. Ή-NMR (400 MHz, CDC1 ₃ )6: 8.59-8.58 (m, 1H), 8.41 (d, J = 5.2 Hz, 1H), 7.85-7.81 (m , 3H), 7.53 (s, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.04 (d, J = 5.2 Hz, 1H), 5.58 (t , J = 8.0 Hz, 1H), 3.93-3.92 (m, 1H), 3.90 (s, 3H), 3.13-3.06 (m, 1H), 2.86- 2.80 (m, 1H), 2.51 (s, 3H), 2.35-2.28 (m, 1H), 2.10-2.03 (m, 2H), 1.91 (s, 6H).

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64 5-(2-cyanopropan-2-yl)-N(2-(2-hydroxyethyl)-8-(2((1-methyl-1H-pyrazo l-4 yl)amino)pyrimidin-4 yl)-2, 3,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)1,3,4-oxadiazol-2carboxamide \ cm /—\ ⁿ Ra /—ι/ - ^Ν IO-/ '1 / Uch V Г ν ρ=Ν if Ν Ν^^ ⁷ Η EER-MS (M+H) ⁺ : 543.6. Ή-NMR (400 MHz, CD ₃ OD)6: 8.40 (d, J = 5.2 Hz, 1H), 8.01-7.98 (m, 3H), 7.64 (s, 1H) , 7.47 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 5.2 Hz, 1H), 5.57 (d, J = 9.6 Hz, 1H), 4.204 .11 (m, 2H), 3.90 (s, 3H), 3.75-3.72 (m, 2H), 3.28-3.20 (m, 2H), 2.68-2.63 (m, 2H), 2.31-2.27 (m, 1H), 2.01-1.97 (m, 1H), 1.94 (s, 6H). 65 1-isopropyl ^-(8-(2-((1 methyl-1 H-pyrazol-4yl)amino)pyrimidin-4yl)-2-(oxetan-3-yl)2,3,4,5-tetrahydro-1Hbenzo [c]azepin-5-yl)-1H- 1,2,3-triazole-4carboxamide . __ Η Ν=Ν γ Ι^Ν Ρ=Ν L if L Ν Ν ⁷ ^ ⁷ Η ESI-MS (M+H) ⁺ : 529.2. Ή-NMR (400 MHz, flMCO-d ₆ )5: 9.49 (s, 1H), 9.05 (d, J = 8.0 Hz, 1H), 8.74 (s, 1H), 8, 46 (d, J = 5.2 Hz, 1H), 8.03-7.81 (m, 3H), 7.54 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H ), 7.25 (d, J = 5.2 Hz, 1H), 5.44 (t, J = 9.6 Hz, 1H), 5.00-4.80 (m, 1H), 4.59 (t, J = 6.4 Hz, 1H), 4.56-4.41 (m, 3H), 3.93-3.59 (m, 6H), 2.98-2.70 (m, 2H ), 2.19-2.03 (m, 1H), 1.90-1.77 (m, 1H), 1.54 (d, J = 6.8 Hz, 6H). 66 1-cyclobutyl-M-(8-(2-((1methyl-1H-pyrazol-4yl)amino)pyrimidin-4yl)-2-(oxetan-3-yl)~ 2,3,4,5-tetrahydro-1Hbenzo [c]azepin-5-yl)-1H1,2,3-triazole-4carboxamide Η Ν=Ν γ f^N r=N L if 1. v— Η ESI-MS (M+H) ⁺ : 540.7. Ή-NMR (400 MHz, flMCO-d ₆ )5: 9.49 (s, 1H), 9.07 (d, J = 8.4 Hz, 1H), 8.81 (s, 1H), 8, 47 (d, J = 5.2 Hz, 1H), 7.97-7.94 (m, 2H), 7.90 (s, 1H), 7.53 (s, 1H), 7.37 (d , J = 8.0 Hz, 1H), 7.26 (d, J = 5.2 Hz, 1H), 5.44 (t, J = 9.6 Hz, 1H), 5.25-5.16 (m, 1H), 4.59 (t, J = 6.4 Hz, 1H), 4.54-4.47 (m, 3H), 3.88-3.62 (m, 2H), 3, 68 (s, 3H), 2.932.90 (m, 1H), 2.81-2.76 (m, 1H), 2.742.72 (m, 1H), 2.60-2.48 (m, 4H) , 2.142.06 (m, 1H), 1.92-1.83 (m, 3H). 67 5-(tert-butyl)-M-(8-(2-((1methyl-1H-pyrazol-4 yl)amino)pyrimidin-4 yl) -2-(oxetan-3-yl) 2,3,4, 5-tetrahydro-1Hbenzo[c]azepin-5-yl)1,3,4-thiadiazol-2 carboxamide Μ-Ν / ί^Ν L if Η ESI-MS (M+H) ⁺ : 560.0. Ή-NMR (400 MHz, CDC1 ₃ )6: 8.42 (d, J = 5.2 Hz, 1H), 8.33 (d, J = 8.4 Hz, 1H), 7.87 (s, 1H), 7.86 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.77 (d, J = 1.6 Hz, 1H), 7.53 (s, 1H), 7 .49 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 5.2 Hz, 1H), 6.95 (s, 1H), 5.62-5.58 (m, 1H), 4.774.68 (m, 4H), 3.92-3.86 (m, 6H), 3.042.97 (m, 1H), 2.81-2.75 (m, 1H), 2.32 -

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2.26 (m, 1H), 2.13-2.06 (m, 1H), 1.51 (s, 9H). 68 3-(tert-butyl)-N-(2-(3-hydroxycyclobutyl)-8(2-((1-methyl-III-pyrazol4-yl)amino)pyrimidin-4yl)-2,3,4,5-tetrahydro -1Hbenzo [c]azepin-5 -yl)1,2,4-oxadiazole-5carboxamide o-'H \/ r \u003d ^N ί l b - ESI-MS (M+H) ⁺ : 558.3. s-NMR (400 MHz, CDC1 ₃ )5: 8.61 (br, 1H), 8.43 (d, J = 4.8 Hz, 1H), 7.85-7.82 (m, 3H), 7.55 (s, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 4.2 Hz, 1H), 7.02 (s, 1H), 5.61 (t, J = 8.0 Hz, 1H), 4.07-3.73 (m, 6H), 3.153.06 (m, 1H), 2.73-2.49 (m, 3H) , 2.372.30 (m, 1H), 2.12-1.85 (m, 4H), 1.39 (s, 9H). 69 l-(mpem-6ymwi)-N-(8-(2((1-methyl-1H-pyrazol-4yl)amino)pyrimidin-4yl)-2,3,4,5-tetragi dro1H-benzo[c]azepine -5-yl)1H-1,2,3-triazole-4carboxamide I IZ Os/ b h 1 ESI-MS (M+H) ⁺ : 487.2. s-NMR (400 MHz, CDC1 ₃ )5: 8.40 (d, J = 5.2 Hz, 1H), 8.19 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.89 (s, 1H), 7.84-7.81 (m, 2H), 7.517.47 (m, 2H), 7.03 (d, J = 5.2 Hz, 1H), 5.63 (t, J = 9.2 Hz, 1H), 4.16-4.14 (m, 2H), 3.90 (s, 3H), 3.42-3.32 (m, 2H) , 2.10-2.08 (m, 2H), 1.71 (s, 9H). 70 1 -(tert-butyl)-I-(2-ethyl8-(2-((1-methyl-1Hpyrazol-4yl)amino)pyrimidin-4 yl)-2,3,4,5-tetrahydro-1Hbenzo [c] azepin-5-yl)- 1H1,2,3-triazole-4carboxamide ^, ___, ^H n=n ESI-MS (M+H) ⁺ : 514.8. s-NMR (400 MHz, CDC1 ₃ )5: 8.41 (d, J = 5.2 Hz, 1H), 8.17 (s, 1H), 7.91 (s, 1H), 7.84- 7.24 (m, 2H), 7.53 (s, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.04 (d, J = 5.2 Hz, 2H), 6.95 (s, 1H), 5.61 (t, J = 9.2 Hz, 1H), 4.02 (s, 2H), 3.91 (s, 3H), 3.31-3.22 (m, 1H), 3.02-2.98 (m, 1H), 2.66-2.60 (m, 2H), 2.28-2.21 (m, 1H), 2.06-2 .02 (m, 1H), 1.67 (s, 9H), 1.20 (t, J = 7.2 Hz, 3H). 71 l-(mpem-6ymwi)-N-(8-(2((1-methyl-1 H-pyrazol-4yl)amino)pyrimidin-4yl)-2-(oxetan-3-yl)2,3,4, 5-tetrahydro-1Hbenzo[c]azepin-5-yl)-1H1,2,3-triazole-4carboxamide H N=N Yr r^N r=N L if L n— H ESI-MS (M+H) ⁺ : 542.7. s-NMR (400 MHz, CD ₃ OD)5: 8.52 (s, 1H), 8.42 (d, J = 5.6 Hz, 1H), 8.02 (d, J = 7.6 Hz , 1H), 7.98-7.97 (m, 2H), 7.64 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 4.4 Hz, 1H), 5.60-5.57 (m, 1H), 4.76 (t, J = 6.4 Hz, 1H), 4.71-4.69 (m, 3H), 3.99-3.82(m, 6H), 3.10-3.05(m, 1H), 2.92-2.86(m, 1H), 2.27-2.18(m, 1H ), 2.07-2.02 (m, 1H), 1.74 (s, 9H).

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72 1 -(tert-butyl)-I-(2-(3-hydroxycyclobutyl)-8(2-((1-methyl-1H-pyrazol4-yl)amino)pyrimidin-4yl)-2,3,4,5-tetrahydro -1Hbenzo[c]azepin-5-yl)-1H1,2,3-triazole-4carboxamide Η N=N Η θ r/ 'V” Ν o Sj^N^ ⁷ H EER-MS (M+H) ⁺ : 556.7. Ή-NMR (400 MHz, CDC1 ₃ )6: 8.41 (d, J = 5.2 Hz, 1H), 8.17 (s, 1H), 7.88 (s, 1H), 7.817.78 ( m, 2H), 7.54 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.04-7.02 (s, 2H), 5.59 (t, J = 8.4 Hz, 1H), 4.03-3.79 (m, 6H), 3.193.13 (m, 1H), 2.76-2.63 (m, 4H), 2.312.25 (m, 1H), 2.15-1.93 (m, 3H), 1.68 (s, 9H). 73 1 - (tert-butyl ) -N- (8- (2- (( 1 methyl- 1H -pyrazol-4 yl) amino) pyrimidin-4 yl) -2- (tetrahydrofuran-3 yl) -2,3,4, 5-tetrahydro -1Hbenzo[c]azepin-5-yl)-1H1,2,3-triazole-4carboxamide o —\ ⁿ n=n then Λ ^Ν^Ν^^ ⁷ Η ESI-MS (M+H) ⁺ : 556.7. Ή-NMR (400 MHz, CD ₃ OD)6: 8.47 (s, 1H), 8.38 (d, J = 5.2 Hz, 1H), 7.98-7.95 (m, 3H) , 7.62 (d, J = 5.2 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.17 (d, J = 5.2 Hz, 1H), 5 .57-5.55 (m, 1H), 4.09-3.94 (m, 4H), 3.89 (s, 3H), 3.78-3.70 (m, 2H), 3.28 -3.06 (m, 3H), 2.32-1.94 (m, 4H), 1.74 (s, 9H). 74 1-(tert-butyl)-N-(8-(2-((1methyl-1H-pyrazol-4 yl)amino)pyrimidin-4 yl)-2-(tetrahydro-2Hpyran-4-u l)-2 ,3,4,5 tetrahydro-1Hbenzo[c]azepin-5-yl)-1H1,2,3-triazole-4carboxamide /--, _ Η ν=ν ⁰ Y-ι/ 0 Α χν ^Ν^Ν^ ⁷ Η ESI-MS (M+H) ⁺ : 570.7. Ή-NMR (400 MHz, CDC1 ₃ )6: 8.41 (d, J = 4.8 Hz, 1H), 8.22 (d, J = 10.0 Hz, 1H), 8.16 (s, 1H), 7.88 (s, 1H), 7.83-7.80 (m, 2H), 7.50 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.04 (d, J = 5.2 Hz, 1H), 6.93 (s, 1H), 5.65 (t, J = 8.4 Hz, 1H), 4.10-4.05 (m , 4H), 3.91 (s, 3H), 3.44-3.37 (m, 2H), 3.19-3.16 (m, 1H), 3.10-3.05 (m, 1H ), 2.86-2.81 (m, 1H), 2.31-2.26 (m, 1H), 2.10-2.04 (m, 1H), 1.95-1.70 (m , 4H), 1.69 (s, 9H). 75 1 -(tert-butyl)-N-(8-(2-((1methyl-1H-pyrazol-4 yl)amino)pyrimidin-4yl)-2-(2,2,2-trifluoroethyl)2,3 ,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)-1H1,2,3-triazole-4carboxamide η Ν=Ν "Ο. ΐ' O? χν Η ESI-MS (M+H) ⁺ : 568.7. Ή-NMR (400 MHz, CDC1 ₃ )6: 8.42 (d, J = 5.2 Hz, 1H), 8.18 (s, 1H), 7.91 (s, 1H), 7.87 ( d, J = 7.6 Hz, 1H), 7.83 (s, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.51 (s, 1H), 7.48 ( d, J = 8.0 Hz, 1H), 7.05 (d, J = 5.2 Hz, 1H), 7.02 (s, 1H), 5.61 (t, J = 8.4 Hz, 1H), 4.33-4.12 (m, 2H), 3.91 (s, 3H), 3.413.35 (m, 2H), 3.10-3.03 (m, 2H), 2.222.14 (m, 1H), 2.03-1.97 (m, 1H), 1.71 (s, 9H).

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76 1 -(tert-butyl)-N-(2-(2hydroxyethyl)-8-(2-((1 methyl-1H-pyrazol-4 yl)amino)pyrimidin-4 yl)-2,3,4,5- tetrahydro-1Hbenzo[c]azepin-5-yl)- 1H1,2,3-triazole-4carboxamide Η N=N l if IT n—- H ESI-MS (M+H) ⁺ : 531.3. Ή-NMR (400 MHz, CDC1 ₃ )6: 8.50 (br, 1H), 8.41 (d, J = 5.2 Hz, 1H), 8.16 (s, 1H), 7.88 ( s, 1H), 7.83-7.80 (m, 2H), 7.54 (s, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 5.2 Hz, 1H), 6.91 (s, 1H), 5.61 (t, J = 8.8 Hz, 1H), 4.14-4.03 (m, 2H), 3.92 (s, 3H), 3.803.79 (m, 2H), 3.29-3.26 (m, 1H), 3.993.96 (m, 1H), 2.80-2.77 (m, 2H), 2.302.27 (m, 1H), 2.08-2.01 (m, 1H), 1.70 (s, 9H). 77 1 - (tert-butyl) -N- (2- ((R) -2 hydroxypropyl) -8- (2- (( 1 methyl- 1H -pyrazol-4 yl) amino) pyrimidin-4 yl) -2.3 ,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)- 1H1,2,3-triazole-4carboxamide _ H n= ⁿ , , but-/ \ 1 // \ \ o L £ L F- H ESI-MS (M+H) ⁺ : 544.3. Ή-NMR (400 MHz, flMCO-d ₆ )5: 9.50 (s, 1H), 9.00 (d, J = 7.2 Hz, 1H), 8.75 (s, 1H), 8, 45 (d, J = 5.2 Hz, 1H), 7.95 (s, 3H), 7.53 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7, 25 (d, J = 5.2 Hz, 1H), 5.46-5.42 (m, 1H), 4.35-3.94 (m, 3H), 3.82-3.76 (m, 4H), 3.31-3.13 (m, 2H), 2.36-2.11 (m, 3H), 1.79-1.73 (m, 1H), 1.65 (s, 9H) , 1.03 (t, J = 5.2 Hz, 3H). 78 5-(mpem-6ymwi)-N-(2- ((K)-2-hydroxypropyl)-8(2-((1-methyl-1H-pyrazol4-yl)amino)pyrimidin-4yl)-2,3,4,5-tetrahydro1H-benzo[c]azepin-5 -yl)1,2,4-oxadiazole-Scarboxamide h N-q r^N r=L Г if L n— H ESI-MS (M+H) ⁺ : 546.3. Ή-NMR (400 MHz, CD ₃ OD)6: 8.42 (d, J = 5.2 Hz, 1H), 8.03-7.99 (m, 3H), 7.64 (s, 1H) , 7.46 (d, J = 7.2 Hz, 1H), 7.24-7.22 (m, 1H), 5.61-5.58 (m, 1H), 4.22-3.98 (m, 3H), 3.91 (s, 3H), 3.28-3.21 (m, 2H), 2.47-2.26 (m, 3H), 1.97-1.94 (m , 1H), 1.52 (s, 9H), 1.16-1.28 (m, 3H). 79 5 - (tert-butyl) -N- (2- (2 methoxyethyl) -8- (2- (( 1 methyl- 1H -pyrazol-4 yl) amino) pyrimidin-4 yl) -2,3,4,5- tetrahydro-1Hbenzo[c]azepin-5-yl)1,2,4-oxadiazole-3carboxamide ^x os IZ i Г ESI-MS (M+H) ⁺ : 545.7. Ή-NMR (400 MHz, CD ₃ OD)6: 8.43 (d, J = 5.2 Hz, 1H), 8.05-8.03 (m, 2H), 7.99 (s, 1H) , 7.65 (s, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 5.6 Hz, 1H), 5.59 (d, J = 10.0 Hz, 1H), 4.22-4.11 (m, 2H), 3.90 (s, 3H), 3.61 (t, J = 5.6 Hz, 2H), 3.36 ( s, 3H), 3.27-3.15 (m, 2H), 2.77-2.69 (m, 2H), 2.31-2.25 (m, 1H), 2.00-1, 97(m, 1H), 1.53(s, 9H).

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80 5-(tert-butyl)-I-(8-(2-((1methyl-1H-pyrazol-4 yl)amino)pyrimidin-4 yl)-2-(tetrahydrofuran-3yl)-2,3,4,5 -tetrahydro-1Hbenzo[c]azepin-5-yl)1,3,4-oxadiazol-2carboxamide A ¹ 4° J ) \u003d O ZI ό EER-MS (M+H) ⁺ : 558.3. Ή-NMR (400 MHz, CD ₃ OD)6: 8.42 (d, J = 5.2 Hz, 1H), 8.04-7.99 (m, 3H), 7.64-7.63 ( m, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 5.2 Hz, 1H), 5.59 (d, J = 10.0 Hz, 1H), 4.10-3.91 (m, 4H), 3.90 (s, 3H), 3.793.70 (m, 2H), 3.32-3.12 (m, 3H), 2.302.18 (m , 2H), 2.05-1.97 (m, 2H), 1.51 (s, 9H). 81 5 -(tert-butyl) -N-(2-(3-hydroxycyclobutyl)-8(2-((1-methyl-1H-pyrazol4-yl)amino)pyrimidin-4yl)-2,3,4,5-tetrahydro -1Hbenzo [c] azepin-5 -yl) - 1,3,4-oxadiazo l-2carboxamide ^N Vv ^uy^ αγ- ESI-MS (M+H) ⁺ : 558.2. Ή-NMR (400 MHz, CD ₃ OD)6: 8.42 (d, J = 5.2 Hz, 1H), 8.03-8.01 (m, 3H), 7.63 (s, 1H) , 7.47 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 5.2 Hz, 1H), 5.56-5.54 (m, 1H), 3.98- 3.87 (m, 6H), 3.25-3.21 (m, 1H), 2.96-2.91 (m, 1H), 2.64-2.18 (m, 4H), 2, 02-1.83 (m, 3H), 1.51 (s, 9H). 82 (K)-5-(tert-butyl)-N-(2-(3hydroxycyclobutyl)-8(2-((1-methyl-1H-pyrazol4-yl)amino)pyrimidin-4yl)-2,3,4, 5-tetrahydro-1Hbenzo[c]azepin-5-yl)1,3,4-oxadiazol-2carboxamide ν-ν \/ Ό LCMS: Rt 2.9 min, m/z 558.00. ΉNMR (400 MHz, METAHO4-d ₄ )6: 8.41 (d, J = 5.3 Hz, 1H), 8.07-7.94 (m, 3H), 7.65-7.59 (m , 1H), 7.50-7.43 (m, 1H), 7.22 (d, J = 5.3 Hz, 1H), 5.54 (br d, J = 9.5 Hz, 1H), 4.58 (s, 1H), 4.07-3.94 (m, 2H), 3.92-3.82 (m, 4H), 3.29-3.18 (m, 1H), 3. 04-2.78 (m, 1H), 2.66-2.50 (m, 2H), 2.37-2.10 (m, 1H), 2.10-1.94 (m, 1H), 1.88-1.79(m, 2H), 1.49(s, 9H), 0.98-0.79(m, 1H). 83 5 -(tert-butyl) -N-(2 -ethyl8-(2-((1-methyl-1Hpyrazole-4- yl)amino)pyrimidin-4 yl)-2,3,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)1,3,4-oxadiazol-2carboxamide Η Ν-Ν /--Ν-'Ν Λ G hA, ° ίο r^N [if L N- η ESI-MS (M+H) ⁺ : 516.2. Ή-NMR (400 MHz, CD ₃ OD)6: 8.41 (d, J = 5.2 Hz, 1H), 8.04-7.98 (m, 3H), 7.64 (s, 1H) , 7.47 (d, J = 7.6 Hz, 1H), 7.21 (d, J = 5.2 Hz, 1H), 5.56-5.54 (m, 1H), 4.07 ( s, 2H), 3.90 (s, 3H), 3.30-3.07 (m, 2H), 2.61-2.55 (m, 2H), 2.28-2.00 (m, 2H), 1.51 (s, 9H), 1.19 (t, J = 7.2 Hz, 3H).

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84 (R) -5 - (tert-butyl) -N- (2 ethyl-8 - (2- (( 1 -methyl- 1Hpyrazol-4yl) amino) pyrimidin-4 yl) -2,3,4,5-tetrahydro -1Hbenzo[c]azepin-5-yl)1,3,4-oxadiazol-2carboxamide O* LCMS: Rt 2.7 min, m/z 516.10. ΉNMR (400 MHz, METAHOL-d ₄ )δ: 8.38 (d, J = 5.3 Hz, 1H), 8.02-7.98 (m, 2H), 7.96 (s, 1H), 7.62 (s, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 5.3 Hz, 1H), 5.53 (br d, J = 9.3Hz, 1H), 4.05(s, 2H), 3.87(s, 3H), 3.29-3.22(m, 1H), 3.09(ddd, J=13.3 Hz, 10.4 Hz, 2.9 Hz, 1H), 2.64-2.50(m, 2H), 2.31-2.17(m, 1H), 2.09-1.91(m , 1H), 1.49 (s, 9H), 1.17 (t, J = 7.2 Hz, 3H). 85 (8)-5-(tert-butyl)-I-(2ethyl-8 -(2-((1-methyl-1Hpyrazol-4yl)amino)pyrimidin-4 yl)-2,3,4,5-tetrahydro- 1Hbenzo[c]azepin-5-yl)1,3,4-oxadiazol-2carboxamide O' LCMS: Rt 3.9 min, m/z 516.10. ΉNMR (400 MHz, METAHOJl-d ₄ )5: 8.39 (d, J = 5.3 Hz, 1H), 8.04-7.98 (m, 2H), 7.96 (s, 1H), 7.62 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 5.3 Hz, 1H), 5.54 (d, J = 9 .3 Hz, 1H), 4.07 (s, 2H), 3.88 (s, 3H), 3.29-3.20 (m, 1H), 3.10 (ddd, J = 13.2 Hz , 10.5 Hz, 2.6 Hz, 1H), 2.66-2.50 (m, 2H), 2.25 (dtd, J = 14.0 Hz, 10.4 Hz, 3.4 Hz, 1H), 2.01 (dt, J = 14.4 Hz, 2.3 Hz, 1H), 1.49 (s, 9 H), 1.18 (t, J = 7.2 Hz, 3H). 86 5-(mpem-6ymwi)-N-(2-((S)2-hydroxypropyl)-8-(2((1-methyl-1H-pyraul-4yl)amino)pyrimidin-4yl)-2,3,4 ,5-tetrahydro1H-benzo[c]azepin-5-yl)1,3,4-oxadiazole-2carboxamide ηN-N , Vjo r^N r^N L if Ln-. H ESI-MS (M+H) ⁺ : 546.3. Ή-NMR (400 MHz, CD ₃ OD)6: 8.33 (d, J = 5.2 Hz, 1H), 7.94-7.90 (m, 3H), 7.61 (d, J = 2.0 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.11 (dd, J = 5.2, 1.6 Hz, 1H), 5.55-5.52 ( m, 1H), 4.12-3.93(m, 3H), 3.87(s, 3H), 3.23-3.18(m, 2H), 2.42-2.37(m, 2H), 2.24-2.22(m, 1H), 1.93-1.91(m, 1H), 1.48(s, 9H), 1.13-1.09(m, 3H) . 87 5-(tert-butyl)-N-(2-((R)-2hydroxypropyl)-8-(2-((1 methyl-1H-pyrazol-4 yl)amino)pyrimidin-4 yl)-2,3, 4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)1,3,4-oxadiazol-2carboxamide H N-N J! r^N r=N L if Ln— H ESI-MS (M+H) ⁺ : 545.7. Ή-NMR (400 MHz, CD ₃ OD)5: 8.30-8.28 (m, 1H), 7.91-7.69 (m, 3H), 7.52 (s, 1H), 7, 36 (d, J = 8.4 Hz, 1H), 7.11 (s, 1H), 5.46 (d, J = 10.0 Hz, 1H), 4.11-3.85 (m, 3H ), 3.79 (s, 3H), 3.10-3.06 (m, 2H), 2.33-2.14 (m, 3H), 1.86-1.83 (m, 1H), 1.39 (s, 9H), 1.05-1.00 (m, 3H).

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88 5 - (tert-butyl) -N- (2- (2 hydroxy-2 -methylpropyl) 8- (2- ((1-methyl-1Hpyrazol-4yl) amino) pyrimidin-4 yl) -2,3,4, 5-tetrahydro-1Hbenzo[c]azepin-5-yl)1,3,4-oxadiazol-2 carboxamide b °b / g ESI-MS (M+H) ⁺ : 559.7. Ή-NMR (400 MHz, CD ₃ OD)5: 8.27-8.25 (m, 1H), 7.84-7.81 (m, 3H), 7.52 (s, 1H), 7.347, 33 (m, 1H), 7.07-7.05 (m, 1H), 5.46 (d, J = 10.0 Hz, 1H), 4.11-3.97 (m, 2H), 3 .77 (s, 3H), 3.21-3.17 (m, 2H), 2.372.27 (m, 2H), 2.13-2.12 (m, 1H), 1.841.80 (m, 1H ), 1.38 (s, 9H), 1.09 (s, 6H). 89a {(R)-2-(2-hydroxy-2methylppopyl)-8-[2-(lmethyl-1H-pyrazol-4 ylamino)-pyrimidine-4 at 1] -2,3,4,5-tetrahydro -1H 2 -benzazepin-5 -yl} -5-tert-butyl-1,3,4oxadiazole-2-carboxylic acid-amide Ν'Ί \/ An δ |1 4 1 Ν— ^Ν And LCMS: Rt 0.87 min, m/z 560.3. ΉNMR (400 MHz, METHANOL ₄ )0: 8.42 (br. sn 1H), 7.90 - 8.13 (m, 3H), 7.64 (s, 1H), 7.47 (d , J = 8.03 Hz, 1H), 7.22 (br. S., 1H), 5.58 (d, J = 9.79 Hz, 1H), 4.07 4.34 (m, 2H) , 3.90 (s, 3H), 2.45 (q, J = 14.31Hz, 2H), 2.18-2.32 (m, 3H), 1.95 (d, J = 13.80Hz , 1H), 1.50 (s, 9H), 1.22 (br. sn 6H). 89b (8)-5-(tert-butyl)-M-(2-(2hydroxy-2-methylpropyl)8-(2-((1-methyl-1Hpyrazole-4- yl)amino)pyrimidin-4 yl)-2,3,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)1,3,4-oxadiazol-2carboxamide V n yL / ΗοΑχ 1 P ° 'o Αν H J n— H LCMS: Rt 0.87 min, m/z 560.3. ΉNMR (400 MHz, METHANOL ₄ )0: 8.43 (br. sn 1H), 8.02 (s, 3H), 7.64 (s, 1H), 7.47 (d, J = 8 .03 Hz, 1H), 7.23 (br. sn 1H), 5.58 (d, J = 9.54 Hz, 1H), 4.05 4.38 (m, 2H), 3.90 ( s, 3H), 2.45 (q, J = 14.06 Hz, 2H), 2.27 (d, J = 2.51 Hz, 1H), 1.95 (d, J = 13.80 Hz, 1H), 1.50 (s, 9H), 1.21 (s, 6H). 90 5-(tert-butyl)-N-(2-(3 hydroxypropyl)-8-(2-((1 methyl-1H-pyrazol-4 yl)amino)pyrimidin-4 yl)-2,3,4,5 -tetrahydro-1Hbenzo[c]azepin-5-yl)1,3,4-oxadiazol-2carboxamide An r=N L If L. n— N N H ESI-MS (M+H) ⁺ : 545.7. Ή-NMR (400 MHz, CD ₃ OD)5: 8.29 (d, J = 5.2 Hz, 1H), 7.91-7.88 (m, 2H), 7.85 (s, 1H) , 7.53 (s, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 5.2 Hz, 1H), 5.46-5.42 ( m, 1H), 4.02-3.93 (m, 2H), 3.78 (s, 3H), 3.51 (t, J = 6.0 Hz, 2H), 3.20-3.15 (m, 1H), 3.04-3.00 (m, 1H), 2.53-2.47 (m, 2H), 2.19-2.11 (m, 1H), 1.90-1 .87 (m, 1H), 1.74-1.68 (m, 2H), 1.38 (s, 9H).

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91 5-(tert-butyl)-I-(8-(2-((1methyl-1H-pyrazol-4 yl)amino)pyrimidin-4 yl)-2-(2,2,2-trifluoroethyl)2,3, 4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)1,3,4-oxadiazol-2carboxamide ΓΧχν ESI-MS (M+H) ⁺ : 570.2. Ή-NMR (400 MHz, CDC1 ₃ )6: 8.37 (d, J = 5.2 Hz, 1H), 7.83-7.76 (m, 4H), 7.46 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 6.99 (d, J = 5.2 Hz, 1H), 6.85 (s, 1H), 5.56-5.52 (m , 1H), 4.234.19 (m, 1H), 4.08-4.04 (m, 1H), 3.85 (s, 3H), 3.28-3.04 (m, 4H), 2, 23-2.18 (m, 1H), 2.02-1.95 (m, 1H), 1.40 (s, 9H). 92 N-(8-(2-((1H-pyrazol-4yl)amino)pyrimidin-4yl)-2-(oxetan-3-yl) 2,3,4,5-tetrahydro-1Hbenzo[c]azepin-5 -yl)-5 (tert-butyl)-1,3,4oxadiazole-2-carboxamide Η Ν-Ν L if νη Η ESI-MS (M+H) ⁺ : 530.3. Ή-NMR (400 MHz, DMSOD ₆ )6: 9.83 (d, J = 8.4 Hz, 1H), 9.47 (s, 1H), 8.47 (d, J = 8.8 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.96 (s, 1H), 7.91 (s, 1H), 7.65 (s, 1H), 7.39 ( d, J = 8.0 Hz, 1H), 7.27 (d, J = 5.2 Hz, 2H), 5.40 (t, J = 9.6 Hz, 1H), 4.58 (t, J = 6.4 Hz, 1H), 4.52-4.45 (m, 3H), 3.90-3.62 (m, 3H), 2.95-2.92 (m, 1H), 2 .83-2.77 (m, 1H), 2.13-2.05 (m, 1H), 1.88-1.85 (m, 1H), 1.42 (s, 9H). 93 (K)-5-(tert-butyl)-N-(8-(2((5,6-dihydro-4H- pyrrolo[1,2-b]pyrazol-3 yl)amino)pyrimidin-4 yl)-2-(2-hydroxyethyl)2,3,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)1, 3,4-oxadiazol-2-carboxamide L if % ^Ν Ν YJ ESI-MS (M+H) ⁺ : 557.7. Ή-NMR (400 MHz, CD ₃ OD)6: 8.36 (d, J = 5.2 Hz, 1H), 8.04-8.02 (m, 2H), 7.69 (s, 1H) , 7.48 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 5.2 Hz, 1H), 5.60-5.57 (m, 1H), 4.294.13 ( m, 4H), 3.77 (t, J = 6.0 Hz, 2H), 3.35-3.33 (m, 2H), 2.95 (t, J = 7.2 Hz, 2H), 2.78-2.76(m, 2H), 2.66-2.62(m, 2H), 2.34-2.28(m, 1H), 2.08-2.01(m, 1H ), 1.50 (s, 9H). 94 (R)-l-(mpem-6ymwi)-N-(8(2-((5,6-dugudpo-4Hnuppolo[l,2-b]nupazol-3yl)amino)pyrimidin-4yl)-2-(2 -hydroxyethyl)2,3,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)-1H1,2,3-triazole-4carboxamide Ν=N 1 η /—]—O Xx Ν I n V- ^J ESI-MS (M+H) ⁺ : 556.7. Ή-NMR (400 MHz, CD ₃ OD)6: 8.45 (s, 1H), 8.27 (d, J = 5.2 Hz, 1H), 7.91-7.87 (m, 2H) , 7.59 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.14 (d, J = 5.6 Hz, 1H), 5.49 (d, J = 9.6 Hz, 1H), 4.13-3.99 (m, 4H), 3.65 (t, J = 6.0 Hz, 2H), 3.20-3.05 (m, 2H), 2.86 (t, J = 7.2 Hz, 2H), 2.62-2.52 (m, 4H), 2.21-2.17 (m, 1H), 1.93-1.89 ( m, 1H), 1.65 (s, 9H).

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95 N-(2-methyl-8-(2-((1-methyl1H-pyrazol-4yl)amino)pyrimidin-4 yl)-2,3,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl) -5 -(1 methylcyclopropyl) -1,3,4oxadiazole-2-carboxamide O Γ^Ν L N— Η EER-MS (M+H) ⁺ : 530.2. Ή-NMR (400 MHz, CD ₃ OD)6: 8.39 (d, J = 5.2 Hz, 1H), 8.00-7.97 (m, 3H), 7.63 (s, 1H) , 7.44 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 5.6 Hz, 1H), 5.53 (d, J = 10.0 Hz, 1H), 4.184 .06 (m, 2H), 3.90 (s, 3H), 3.73 (t, J = 6.0 Hz, 2H), 3.28-3.19 (m, 2H), 2.672.62 ( m, 2H), 2.28-2.24 (m, 1H), 1.981.95 (m, 1H), 1.61 (s, 3H), 1.45-1.42 (m, 2H), 1 .13-1.10 (m, 2H). 96 5-(tert-butyl)-I-(8-(2-((1ethyl-1H-pyrazol-4 yl)amino)pyrimidin-4 yl)-2-(tetrahydrofuran-3yl)-2,3,4,5 -tetrahydro-1Hbenzo[c]azepin-5-yl)1,3,4-oxadiazol-2carboxamide Ν-4 1 _ο _. .___ Η II \\_J 1 Π ^υ ο ΊΟ r^N r= ^N , L If L. ν—< Ν ' Η ESI-MS (M+H) ⁺ : 572.3. Ή-NMR (400 MHz, CD ₃ OD)6: 8.42 (d, J = 5.2 Hz, 1H), 8.05-8.03 (m, 3H), 7.65 (s, 1H) , 7.48 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 5.2 Hz, 1H), 5.60-5.57 (m, 1H), 4.21- 3.97 (m, 6H), 3.78-3.70 (m, 2H), 3.32-3.14 (m, 3H), 2.33-1.96 (m, 4H), 1, 51-1.47 (m, 12H). 97 5-(tert-butyl)-I-((K)-8-(2((1-ethyl-1H-pyrazo l-4 yl)amino)pyrimidin-4 yl)-2-((R*)tetrahydrofuran -3 -yl) 2,3,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)1,3,4-oxadiazol-2carboxamide LCMS: Rt 0.90 min, m/z 572.10. ΉNMR (300 MHz, METAHOR-d ₄ )0: 8.41 (d, J = 5.3 Hz, 1H), 8.07-7.98 (m, 3H), 7.65 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.22 (d, J = 5.3 Hz, 1H), 5.56 (br d, J = 9.1 Hz, 1H), 4 .58 (s, 1H), 4.23-4.07 (m, 4H), 4.13-3.90 (m, 2H), 3.82-3.63 (m, 2H), 3.27 -3.05 (m, 2H), 2.42-2.11 (m, 2H), 2.11-1.90 (m, 2H), 1.51-1.43 (m, 12H). 98 5-(tert-butyl)-I-(8-(2-((1ethyl-1H-pyrazol-4 yl)amino)pyrimidin-4 yl)-2-(2-hydroxyethyl)2,3,4,5- tetrahydro-1Hbenzo[c]azepin-5-yl)1,3,4-oxadiazol-2carboxamide ,___. Η Ν-Ν ί^Ν L Ji L. v-—/ Η ESI-MS (M+H) ⁺ : 545.7. Ή-NMR (400 MHz, CD ₃ OD)6: 8.42 (d, J = 5.2 Hz, 1H), 8.04-8.02 (m, 3H), 7.66 (s, 1H) , 7.47 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 5.2 Hz, 1H), 5.58-5.56 (m, 1H), 4.23- 4.10 (m, 4H), 3.74 (t, J = 6.0 Hz, 1H), 3.253.22 (m, 2H), 2.71-2.63 (m, 2H), 2.322.27 (m, 1H), 2.02-1.98 (m, 1H), 1.401.47 (m, 12H).

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99 5 - (tert-butyl) -N- (2 methyl-8 - (2- (( 1 -methyl- 1Hparizol-4yl)amino)pyrimidin-4 yl) -2,3,4,5-tetrahydro-1Hbenzo [c ] azepin-5 -yl)- 1,3,4-oxadiazo l-2carboxamide S/S ⁰ D N Η IL Ν— Ν N ESI-MS (M+H) ⁺ : 502.2. Ή-NMR (400 MHz, CD ₃ OD)6: 8.43 (d, J = 5.2 Hz, 1H), 8.07-8.05 (m, 2H), 7.99 (s, 1H) , 7.65 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 5.6 Hz, 1H), 5.56 (d, J = 9.6 Hz, 1H), 4.13-4.09 (m, 1H), 3.97-3.93 (m, 1H), 3.90 (s, 3H), 3.21-3.18 (m, 1H), 3.10-3.05 (m, 1H), 2.42 (s, 3H), 2.30-2.26 (m, 1H), 2.05-2.01 (m , 1H), 1.52 (s, 9H). 100 (K)-5-(tert-butyl)-I-(8-(2((1,5-dimethyl-1H-pyrazol4-yl)amino)pyrimidin-4yl)-2-(2-hydroxyethyl)2,3 ,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)1,3,4-oxadiazol-2carboxamide I / A ESI-MS (M+H) ⁺ : 545.7. Ή-NMR (400 MHz, CD ₃ OD)6: 8.32 (d, J = 5.2 Hz, 1H), 8.01-7.99 (m, 2H), 7.60 (s, 1H) , 7.44 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 5.6 Hz, 1H), 5.57-5.54 (m, 1H), 4.21- 4.07 (m, 2H), 3.82 (s, 3H), 3.73 (t, J = 6.0 Hz, 2H), 3.30-3.21 (m, 2H), 2.68 -2.63(m, 2H), 2.30-2.27(m, 1H), 2.24(s, 3H), 2.01-1.96(m, 1H), 1.51(s , 9H). 101 (R)-l-(mpem-6ymwi)-N-(8(2-((1,5-dumemul-lHnupazol-4yl)amino)pyrimidin-4yl)-2-(2-hydroxyethyl)2,3,4 ,5-tetrahydro-1Hbenzo[c]azepin-5-yl)-1H1,2,3-triazole-4carboxamide Г N r=N L If .L n— N H1 ESI-MS (M+H) ⁺ : 544.7. ^X H-NMR (400 MHz, CDC1 ₃ )6: 8.47 (br, 1H), 8.36 (d, J = 5.2 Hz, 1H), 8.16 (s, 1H), 7.807.78 (m, 2H), 7.67 (s, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.02 (d, J = 5.2 Hz, 1H), 6.45 (s, 1H), 5.59 (t, J = 8.8 Hz, 1H), 4.12-4.02 (m, 2H), 3.81 (s, 3H), 3.773.68 (m, 2H), 3.28-3.24 (m, 1H), 2.992.96 (m, 1H), 2.79-2.76 (m, 2H), 2.332.26 (m, 1H), 2.22 (s, 3H), 2.08-2.01 (m, 1H), 1.70 (s, 9H). 102 (K)-5-(tert-butyl)-I-(8-(2((1,3-dimethyl-1H-pyrazol4-yl)amino)pyrimidin-4yl)-2-(oxetan-3-yl) 2 ,3,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)1,2,4-oxadiazole-3carboxamide , — H N-q L if n— H ESI-MS (M+H) ⁺ : 558.3. Ή-NMR (400 MHz, CD ₃ OD)6: 8.38 (d, J = 5.6 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.95 (s , 1H), 7.84 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 5.2 Hz, 1H), 5.61 (d , J = 9.2 Hz, 1H), 4.76 (t, J = 6.4 Hz, 1H), 4.70-4.66 (m, 3H), 3.96-3.81 (m, 3H), 3.84 (s, 3H), 3.08-3.02 (m, 1H), 2.872.81 (m, 1H), 2.27-2.24 (m, 1H), 2.22 (s, 3H), 2.07-2.03 (m, 1H), 1.15 (s, 9H).

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103 (I)-1-(tert-butyl)-I-(8-(2((1,3-dimethyl-1H-pyrazol4-yl)amino)pyrimidin-4yl) -2-(oxetan-3-yl) 2 ,3,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)- 1H1,2,3-triazole-4carboxamide and N=N I θ\/~N 1 ' ABOUT ifj (1 N 4=4 [1 G L N— ESI-MS (M+H) ⁺ : 557.3. Ή-NMR (400 MHz, CD ₃ OD)6: 8.53 (s, 1H), 8.37 (d, J = 5.2 Hz, 1H), 8.00 (d, J = 7.6 Hz , 1H), 7.95 (s, 1H), 7.84 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 5.6 Hz , 1H), 5.59 (d, J = 9.6 Hz, 1H), 4.76 (t, J = 6.4 Hz, 1H), 4.70-4.67 (m, 3H), 3 .98-3.81 (m, 3H), 3.84 (s, 3H), 3.08-3.05 (m, 1H), 2.92-2.87 (m, 1H), 2.27 -2.21 (m, 1H), 2.19 (s, 3H), 2.06-2.03 (m, 1H), 1.74 (s, 9H). 104 (R)-5-(tert-butyl)-I-(8-(2((1,3-dimethyl-1H-pyrazol4-yl)amino)pyrimidin-4yl)-2-(2-hydroxyethyl)2.3 ,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)1,2,4-oxadiazole-3carboxamide N-0 i a- NN^ ⁷ H ESI-MS (M+H) ⁺ : 546.3. Ή-NMR (400 MHz, CD ₃ OD)6: 8.37 (d, J = 4.8 Hz, 1H), 8.01 (s, 1H), 8.00 (d, J = 8.4 Hz , 1H), 7.85 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 5.6 Hz, 1H), 5.59 (d , J = 9.6 Hz, 1H), 4.21-4.08 (m, 2H), 3.85 (s, 3H), 3.74 (t, J = 6.0 Hz, 2H), 3.273 .17 (m, 2H), 2.71-2.63 (m, 2H), 2.302.25 (m, 1H), 2.22 (s, 3H), 1.99-1.96 (m, 1H ), 1.52 (s, 9H). 105 (R)-1 -(tert-butyl)-I-(2-(2hydroxyethyl)-8-(2-((1isopropyl-1H-pyrazol-4yl)amino)pyrimidin-4 yl)-2,3,4 ,5-tetrahydro-1Hbenzo[c]azepin-5-yl)- 1H1,2,3-triazole-4carboxamide ESI-MS (M+H) ⁺ : 559.3. Ή-NMR (400 MHz, CDC1 ₃ )6: 8.51 (br, 1H), 8.41 (d, J = 4.8 Hz, 1H), 8.17 (s, 1H), 7.95 ( s, 1H), 7.83-7.82 (m, 2H), 7.56 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.15 (s, 1H ), 7.02 (d, J = 5.2 Hz, 1H), 5.61 (t, J = 8.0 Hz, 1H), 4.53-4.46 (m, 1H), 4.14 -4.02(m, 2H), 3.79-3.70(m, 2H), 3.29-3.24(m, 1H), 2.98-2.95(m, 1H), 2 .79-2.77 (m, 2H), 2.32-2.27 (m, 1H), 2.06-2.03 (m, 1H), 1.68 (s, 9H), 1.55 (d, J = 6.4 Hz, 6H). 106 5 -(tert-butyl) -N-((R) -2((I)-2-hydroxypropyl)-8(2-((1-methyl-1H-pyrazol4-yl)amino)pyrimidin-4yl)-2 ,3,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)- 1,3,4-oxadiazo l-2carboxamide N-Λ \/ An |l J L N— ESI-MS (M+H) ⁺ : 546.3. Ή-NMR (400 MHz, CD ₃ OD)5: 8.39 (d, J = 5.2 Hz, 1H), 8.00-7.97 (m, 3H), 7.64 (s, 1H) , 7.45 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 5.2 Hz, 1H), 5.57-5.55 (m, 1H), 4.214.09 ( m, 2H), 3.99-3.97(m, 1H), 3.90(s, 3H), 3.28-3.23(m, 2H), 2.40-2.37(m, 2H), 2.28-2.25 (m, 1H), 1.97-1.94

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(m, 1H), 1.48 (s, 9H), 1.13-1.12 (m, 3H). 107 (R)-5-(mpem-6ymwi)-N-(2(cyclopropylmethyl)-8(2-((1-methyl-1H-pyrazol4-yl)amino)pyrimidin-4yl)-2,3,4,5 -tetrahydro1H-benzo[c]azepin-5-yl)1,3,4-oxadiazole-2carboxamide πχΐ ESI-MS (M+H) ⁺ : 542.1. Ή-NMR (300 MHz, METHANOL-a ₄ )6: 8.45 (d, J = 5.3 Hz, 1H), 8.28-8.23 (m, 2H), 7.92 (s, 1H ), 7.70-7.61 (m, 2H), 7.28 (d, J = 5.7 Hz, 1H), 5.72 (br s, 1H), 4.83-4.72 (m , 2H), 3.89 (s, 3H), 3.87-3.67 (m, 2H), 3.25-3.14 (m, 1H), 2.46 (br s, 2H), 1 .50 (s, 10H), 1.32-1.17 (m, 1H), 0.85 (br s, 2H), 0.52 (br s, 2H). 108 1-(tert-butyl)-I-((8)-8-(2((1-methyl-1H-pyrazol-4 yl)amino)pyrimidin-4yl)-2-((8*)- tetrahydrofuran-3-yl) 2,3,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)- 1H1,2,3-triazole-4carboxamide N=!\ \/ AC ©A LCMS: Rt 0.82 min, m/z 557.00. ΉNMR (400 MHz, MET ANOL-d ,) 5:8.51 (s, 1H), 8.41 (d, J = 5.4 Hz, 1H), 8.118.00 (m, 2H), 7.97 (s , 1H), 7.67-7.58 (m, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 5.3 Hz, 1H), 5 .66-5.54 (m, 1H), 4.58 (br s, 1H), 4.28-4.108 (m, 2H), 4.03 (td, J = 8.7 Hz, 3.8 Hz , 1H), 3.993.93 (m, 1H), 3.89 (s, 3H), 3.86-3.70 (m, 2H), 3.47-3.38 (m, 1H), 3, 27-3.17(m, 1H), 2.37-2.17(m, 2H), 2.16-1.96(m, 2H), 1.73(m, 9H). 109 1 -(mpem-6ymwi)-N-((S)-8(2-((1-methyl-1H-pyrazol4-yl)amino)pyrimidin-4wi)-2-((R*)tetrahydrofuran-3-yl )2,3,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)-1H1,2,3-triazole-4carboxamide G* 1 LCMS: Rt 0.82 min, m/z 557.10. ΉNMR (400 MHz, MET ANOL-d,) 5:8.51 (s, 1H), 8.46-8.37 (m, 1H), 8.09-8.00 (m, 2H), 7.99 ( s, 1H), 7.65-7.58 (m, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 5.3 Hz, 1H), 5.59 (br d, J = 9.5 Hz, 1H), 4.58 (s, 1H), 4.26-4.12 (m, 2H), 4.07-3.94 (m, 2H ), 3.89 (s, 3H), 3.863.71 (m, 2H), 3.46-3.37 (m, 1H), 3.263.19 (m, 1H), 2.36-2.16 ( m, 2H), 2.ΜΙ.95 (m, 2H), 1.73 (s, 9H). 110 (I)-5-(trst-butyl)-M-(8-(2((1,3-dimethyl-1H-pyrazol4-yl)amino)pyrimidin-4yl)-2-(2,2,2trifluoromethyl)- 2,3,4,5tetrahydro- 1Hbenzo[c]azepin-5-yl)- N'N \/ XX [A n va HJL n— ^N N ESI-MS (M+H) ⁺ : 584.3. Ή-NMR (400 MHz, CD ₃ OD)5: 8.38 (d, J = 5.2 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.98 (s , 1H), 7.84 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 5.6 Hz, 1H), 5.59 (d , J = 9.6 Hz, 1H), 4.37-4.34 (m, 1H), 4.134.10 (m, 1H), 3.84 (s, 3H), 3.46-3.41

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1,3,4-oxadiazo l-2carboxamide (m, 2H), 3.15-3.08 (m, 2H), 2.25-2.17 (m, 1H), 2.22 (s, 3H), 1.97-1.93 (m , 1H), 1.51 (s, 9H). 111 5-(tert-butyl)-N-(2-(2-((1methyl- 1H-pyrazol-4 yl)amino)pyrimidin-4 yl)-6,7,8,9-tetrahydro-5Hbenzo [7] annulene -5 -yl) 1,3,4-oxadiazol-2carboxamide N'4 / Ι^Ί ° Αν Η IL ^Ν Ν LCMS: Rt 1.23 min; (M+H) ^+487.0 . 3H-NMR (400 MHz, METHANOL-a ₄ )6: 9.70 (br. sn 1H), 8.34 (d, J = 5.77 Hz, 1H), 8.02 (s, 2H), 7.97 (s, 1H), 7.69 (s, 1H), 7.47 (d, J = 8.53 Hz, 1H), 7.41 (s, 1H), 5.44 (t, J = 8.28 Hz, 1H), 3.93 (s, 3H), 2.87 - 3.22 (m, 2H), 1.77 - 2.28 (m, 4H), 1.51 (s, 11H). 112 I-(2-(2-((1H-pyrazol-4yl)amino)pyrimidin-4 yl)-6,7,8,9-tetrahydro-5Hbenzo[7]annulen-5-yl)-5 (tert-butyl )-1,2,4oxadiazo l-3-carboxamide ο Αν π-νη n ι JL/ ⁿ Η ESI-MS (M+H) ⁺ : 473.1. W-NMR (400 MHz, CD ₃ OD)6: 8.41 (d, J = 5.2 Hz, 1H), 8.07 (br, 1H), 7.96-7.95 (m, 2H) , 7.76 (br, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 5.6 Hz, 1H), 5.44 (d, J = 9.6Hz, 1H), 3.06-3.03(m, 2H), 2.10-1.91(m, 5H), 1.53(s, 9H), 1.49-1.46 (m, 1H). 113 5-(tert-butyl)-I-(2-(2-((5methyl-4,5,6,7tetrahydropyrazolo[1,5a]pyrazin-3yl)amino)pyrimidin-4yl)-6.7, 8,9-tetrahydro-5Hbenzo[7]annulen-5-yl) 1,2,4-oxadiazole-3carboxamide ,___ ₄ Η Ν-Ο , \ 1 1Q ^O Α ^ν Η I ^Ν κγ ) \ ESI-MS (M+H) ⁺ : 542.2. W-NMR (400 MHz, CD ₃ OD)6: 8.34 (d, J = 5.2 Hz, 1H), 7.94-7.91 (m, 2H), 7.70 (s, 1H) , 7.38 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 5.6 Hz, 1H), 5.45-5.42 (m, 1H), 4.23- 4.21 (m, 2H), 3.67 (s, 2H), 3.02-2.99 (m, 4H), 2.49 (s, 3H), 2.06-1.92 (m, 5H), 1.54 (s, 9H), 1.51-1.42 (m, 1H). 114 N-(2-(2-((1H-pyrazol-4yl)amino)pyrimidin-4 yl)-6,7,8,9-tetrahydro-5Hbenzo[7]annulen-5-yl)-5 (tert-butyl )-1,3,4oxadiazole-2-carboxamide ,___„ Η Ν-Ν , \ 1 ιΓ^ο/^' (a ESI-MS (M+H) ⁺ : 472.7. W-NMR (400 MHz, DMSO-b ₆ )5: 12.46 (s, 1H), 9.89 (d, J = 8.0 Hz, 1H), 9.45 (s, 1H), 8, 45 (d, J = 5.2 Hz, 1H), 7.96-7.91 (m, 3H), 7.63-7.62 (m, 1H), 7.37 (d, J = 8, 0 Hz, 1H), 7.24 (d, J = 5.2 Hz, 1H), 5.28-5.24 (m, 1H), 2.97-2.96 (m, 2H), 2, 00-1.77(m, 5H), 1.42(s, 9H), 1.33-1.30(m, 1H).

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115 1 -(tert-butyl)-N-(2-(2-((1methyl-1Н-pyrazol-4 yl)amino)pyrimidin-4yl)-6,7,8,9-tetrahydro-5Нbenzo [7] annulen-5-yl) - 1H1,2,3-triazole-4carboxamide XX. O XN L if J. N— H ESI-MS (M+H) ⁺ : 486.2. Ή-NMR (400 MHz, CDC1 ₃ )6: 8.39 (d, J = 5.2 Hz, 1H), 8.16 (s, 1H), 7.90 (s, 1H), 7.81 ( s, 1H), 7.79 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.54 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.05 (d, J = 5.2 Hz, 1H), 6.91 (s, 1H), 5.46-5.42 (m, 1H), 3.91 (s, 3H ), 3.043.01 (m, 2H), 2.05-1.88 (m, 6H), 1.72 (s, 9H). 116 5 -(tert-butyl) -4 -methyl-N (2-(2-((1-methyl- Spirazol-4yl)amino)pyrimidin-4yl)-6,7,8,9-tetrahydro-5Нbenzo [7 ]annulen-5-yl)-4H1,2,4-triazole-3carboxamide l 1 /=O ZI ESI-MS (M+H) ⁺ : 500.3. Ή-NMR (400 MHz, CD ₃ OD)6: 8.27 (d, J = 5.2 Hz, 1H), 7.85-7.81 (m, 3H), 7.53 (s, 1H) , 7.30 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 5.2 Hz, 1H), 5.26-5.24 (m, 1H), 4.04 ( s, 3H), 3.77 (s, 3H), 2.95-2.93 (m, 2H), 1.97-1.79 (m, 5H), 1.36-1.33 (m, 1H), 1.30 (s, 9H). 117 2-isopropyl-N-(2-(2-((1methyl-1H-pyrazol-4 yl)amino)pyrimidin-4 yl)-6,7,8,9-tetrahydro-5Нbenzo[7]annulen-5-yl ) -2H1,2,3-triazole-4carboxamide /-l J £ W / Υγ ^N \ tS ⁰ L if J. N— H ESI-MS (M+H) ⁺ : 472.2. Ή-NMR (400 MHz, CDC1 ₃ )6: 8.41 (d, J = 5.2 Hz, 1H), 8.06 (s, 1H), 7.87-7.81 (m, 3H), 7.55 (s, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.20-7.18 (m, 1H), 7.06 (d, J = 5.2 Hz , 1H), 6.99 (s, 1H), 5.45-5.41 (m, 1H), 4.91-4.85 (m, 1H), 3.91 (s, 3H), 3, 08-2.96 (m, 2H), 2.03-1.86 (m, 5H), 1.67-1.66 (m, 1H), 1.63 (d, J = 6.8 Hz, 6H). 118a* * Racemic mixture 5(tert-butyl)-N-((5I,88)-8fluoro-2-(2-((1-methyl-1Hpyrazol-4yl)amino)pyrimidin-4yl)-6,7,8,9 -tetrahydro-5Hbenzo[7]annulen-5-yl) 1,3,4-oxadiazol-2carboxamide and 5-(tert-butyl)-N-((58.8K)-8-fluoro2-(2-((1- methyl-1Hpyrazol-4yl) amino) pyrimidin-4 yl) -6,7,8,9-tetrahydro-5Hbenzo [7] annulen-5 -yl) - Λχχ + N-N i A ESI-MS (M+H) ⁺ : 505.2. Ή-NMR (400 MHz, CDC1 ₃ )0: 8.44 (d, J = 5.2 Hz, 1H), 7.90-7.88 (m, 3H), 7.60 (d, J = 7 .6 Hz, 1H), 7.55 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 5.2 Hz, 1H), 6, 91 (s, 1H), 5.38 (d, J = 8.0 Hz, 1H), 4.91 (d, J = 47.2 Hz, 1H), 3.92 (s, 3H), 3, 45-3.29 (m, 2H), 2.32-2.20 (m, 3H), 2.00-1.93 (m, 1H), 1.48 (s, 9H).

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1,3,4-oxadiazol-2- carboxamide 118b* Racemic mixture 5- G- Ν-Ν / a>4- Ή-NMR (400 MHz, CDC1 ₃ )5: 8.44 (d, J * (tert-butyl) -Y - ((5K, 8K) -8- ⁰ / = 5.2 Hz, 1H), 7.92-7.88 (m, 3H), 7.56- fluorine-2-(2-(( 1 -methyl- 1Н- V 7.54 (m, 2H), 7.40 (d, J = 8.0 Hz, 1H), pyrazole-4- yl)amino)pyrimidine-4 - A N G 7.07 (d, J = 5.2 Hz, 1H), 6.89 (s, 1H), 5.40 (d, J = 9.6 Hz, 1H), 4.70 (d, J = 48 .0 yl)-6,7,8,9-tetrahydro-5H- + Hz, 1H), 3.92 (s, 3H), 3.45-3.28 (m, benzo[7]annulen-5-yl) - 2H), 2.37-2.30(m, 1H), 2.22-2.17(m, 1,3,4-oxadiazol-2-carboxamide and 5-(tert-butyl)-N-((58.88)-8-fluoro2-(2-((1-methyl-1Hpyrazol-4yl)amino)pyrimidin-4yl) -6,7,8,9-tetrahydro-5Hbenzo [7 J annulen-5 -yl) 1,3,4-oxadiazol-2-carboxamide ^F *\ Al La N G G 2H), 1.95-1.92 (m, 1H), 1.49 (s, 9H). Racemic N- Η N-0 ESI-MS (M+H) ⁺ : 503.2. Ή-NMR (400 ((5K,88)-8-fluoro-2-(2-((1- F-h »Ν MHz, CDC1 ₃ )6: 8.44 (d, J = 5.2 Hz, 1H), methyl-1H-pyrazole-4 - ο 7.90-7.88 (m, 3H), 7.55 (s, 1H), 7.40- yl)amino)pyrimidine-4 - 7.35 (m, 2H), 7.07 (d, J = 5.2 Hz, 1H), yl)-6,7,8,9-tetrahydro-5Hbenzo [7] annulen-5 -yl) -5 - N 'Ν D /G Ν— 6.87 (s, 1H), 5.42 (d, J = 8.0 Hz, 1H), 4.90 (d, J = 48.8 Hz, 1H), 3.92 (s, 3H), (1-methylcyclopropyl)1,2,4-oxadiazol-3 - + Η 3.39-3.33(m, 2H), 2.33-2.17(m, 3H), 1.95-1.92 (m, 1H), 1.61 (s, 3H), 1.53- carboxamide and N((58.8R)-8-fluoro-2-(2-((1methyl-1H-pyrazole-4 - 1.50 (m, 2H), 1.12-1.09 (m, 2H).

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yl)amino)pyrimidine-4 - Η N'O // yl)-6,7,8,9-tetrahydro-5H- F'-( / benzo [7] annulen-5 -yl) -5 (1-methylcyclopropyl) - VxA about Χχ 1,2,4-oxadiazole-3- An carboxamide k Jk χ N N H J.N— 120** Racemic N- H N-0 ESI-MS (M+H) ⁺ : 503.2. Ή-NMR (400 ((58.88)-8-fluoro-2-(2-((1- F— /— N / MHz, CDC1 ₃ )6: 8.44 (d, J = 5.6 Hz, 1H), methyl-1H-pyrazole-4 - kx-k O χ J 7.91-7.87(m, 3H), 7.55(s, 1H), 7.36- yl)amino)pyrimidine-4 - 7.30 (m, 2H), 7.07 (d, J = 5.2 Hz, 1H), yl)-6,7,8,9-tetrahydro-5H- /A ^N 6.87 (s, 1H), 5.43 (d, J = 8.4 Hz, 1H), benzo[7]annulen-5-yl)-5- k Jk x N N J.N— 4.67 (d, J = 47.2 Hz, 1H), 3.92 (s, 3H), (1-methylcyclopropyl)- H 3.45-3.26 (m, 2H), 2.34-2.17 (m, 3H), 1,2,4-oxadiazole-3carboxamide and N- H /---- N-0 Λ ΑΑδ 1.94-1.91 (m, 1H), 1.63 (s, 3H), 1.55- 1.53(m, 2H), 1.13-1.12(m, 2H). ((5K,8K)-8-fluoro-2-(2-((1methyl-1H-pyrazol-4 yl)amino)pyrimidine-4 - Fn.· k/k about χχ N/A,' ^N ~ yl)-6,7,8,9-tetrahydro-5H- A^N A x benzo [7] annulen-5 -yl) -5 (1-methylcyclopropyl) 1,2,4-oxadiazole-3-carboxamide N N H 121 1-(tert-butyl)-N-((5P)-8- ,--- ^4H N=N ESI-MS (M+H) ⁺ : 557.3. Ή-NMR (400 (2-(( 1 -methyl-1H-pyrazole- w MHz, CD ₃ OD)6: 8.53 (s, 1H), 8.42 (d, J 4-yl)amino)pyrimidine-4- I = 5.2 Hz, 1H), 8.05-7.99 (m, 3H), 7.64 yl)-2-(tetrahydrofuran-3- a L' ^N ~~ (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.23 (d, yl)-2,3,4,5-tetrahydro-1H- N' N H J = 5.2 Hz, 1H), 5.58 (d, J = 10.4 Hz, benzo [c] azepin-5 -yl)- 1H- 1H), 4.16-4.09 (m, 2H), 4.02-3.96 (m, 1,2,3-triazole-4- 2H), 3.90 (s, 3H), 3.79-3.71 (m, 2H), carboxamide 3.31-3.24(m, 2H), 3.15-3.10(m, 1H), 2.31-2.17(m, 2H), 2.07-1.97(m, 2H ), 1.74 (s, 9H).

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122 (I)-N-(2-(2-((1-methyl-1Hpyrazol-4yl)amino)pyrimidin-4 yl)-6,7,8,9-tetrahydro-5Hbenzo[7]annulen-5-yl) -5(1-methylcyclopropyl)1,3,4-oxadiazol-2carboxamide Η 9* A - ^Ν \ / ΑχΑ o An L if .1 n— NH ESI-MS (M+H) ⁺ : 485.2. Ή-NMR (400 MHz, CD ₃ OD)6: 8.39 (d, J = 5.2 Hz, 1H), 7.97-7.92 (m, 3H), 7.65 (s, 1H) , 7.40 (d, J = 8.8 Hz, 1H), 7.20 (d, J = 5.2 Hz, 1H), 5.42-5.39 (m, 1H), 3.89 ( s, 3H), 3.07-3.02 (m, 2H), 2.10-1.86 (m, 5H), 1.62 (s, 3H), 1.47-1.43 (m, 3H), 1.13-1.10 (m, 2H). 123 5-(tert-butyl)-N-(8-(2-((1methyl-1H-pyrazol-4 yl)amino)pyrimidin-4 yl)-2,3,4,5-tetrahydro-1Hbenzo [c]azepine -5 -yl)1,3,4-oxadiazol-2carboxamide and NN _; /—V ^N \/\ / 7 — HN I P ⁰ / 0 y An /^n NH ESI-MS (M+H) ⁺ : 488.3. Ή-NMR (400 MHz, CD ₃ OD)6: 8.40 (d, J = 5.6 Hz, 1H), 8.02-7.98 (m, 3H), 7.64 (s, 1H) , 7.47 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 5.2 Hz, 1H), 5.60-5.58 (m, 1H), 4.12 ( s, 2H), 3.89 (s, 3H), 3.39-3.37 (m, 1H), 3.28-3.21 (m, 2H), 2.15-2.09 (m, 2H), 1.51(s, 9H). 124* 5-(tert-butyl)-N-((I)-8-(2((1-ethyl-1H-pyrazo l-4 yl)amino)pyrimidin-4 yl)-2-((8*)- tetrahydrofuran-3-yl) 2,3,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)1,3,4-oxadiazol-2carboxamide O-\ /— ₄ H NN LK/ ν Ga X^- ⁷ H LCMS: Rt 0.90 min, m/z 572.10. ΉNMR (300 MHz, METHANOL ₄ )5: 8.41 (d, J = 5.3 Hz, 1H), 8.07-7.98 (m, 3H), 7.65 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.22 (d, J = 5.3 Hz, 1H), 5.56 (br d, J = 9.1 Hz, 1H), 4 .58 (s, 1H), 4.23-4.09 (m, 4H), 4.00-3.92 (m, 2H), 3.78-3.69 (m, 2H), 3.27 -3.05 (m, 2H), 2.36-2.20 (m, 2H), 2.16-1.91 (m, 2H), 1.51-1.43 (m, 12H). 125 K-(2-(2-hydroxyethyl)-8(2-((1-methyl-1H-pyrazol4-yl)amino)pyrimidin-4yl)-2,3,4,5-tetrahydro-1Hbenzo[c]azepin- 5 -yl)-5 -(1 methylcyclopropyl) -1,3,4oxadiazole-2-carboxamide I 0 Οχ): A t -A ESI-MS (M+H) ⁺ : 530.2. Ή-NMR (400 MHz, CD ₃ OD)6: 8.39 (d, J = 5.2 Hz, 1H), 8.00-7.97 (m, 3H), 7.63 (s, 1H) , 7.44 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 5.6 Hz, 1H), 5.53 (d, J = 10.0 Hz, 1H), 4.184 .06 (m, 2H), 3.90 (s, 3H), 3.73 (t, J = 6.0 Hz, 2H), 3.28-3.19 (m, 2H), 2.672.62 ( m, 2H), 2.28-2.24 (m, 1H), 1.981.95 (m, 1H), 1.61 (s, 3H), 1.45-1.42 (m, 2H), 1 .13-1.10 (m, 2H).

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126 5-cyclobutyl-I-(2-(2hydroxyethyl)-8-(2-((1methyl-1H-pyrazol-4 yl)amino)pyrimidin-4 yl)-2,3,4,5-tetrahydro-1Hbenzo [ c] azepin-5 -yl) 1,3,4-oxadiazol-2-carboxamide ⁿ °—. n ρΎ-ΖΝ y O Χ ⁴ ΝΗ EER-MS (M+H) ⁺ : 529.7. Ή-NMR (400 MHz, CDC1 ₃ )6: 8.80 (br, 1H), 8.43 (d, J = 5.2 Hz, 1H), 7.87 (s, 1H), 7.84- 7.81 (m, 2H), 7.55 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.05 (d, J = 5.2 Hz, 1H), 6.90 (s, 1H), 5.59 (t, J = 8.0 Hz, 1H), 4.134.04 (m, 2H), 3.91 (s, 3H), 3.81-3.69 (m, 3H), 3.27-3.20 (m, 1H), 2.96-2.91 (m, 1H), 2.81 (t, J = 4.8 Hz, 2H), 2.522, 32 (m, 5H), 2.17-2.02 (m, 3H), 1.60 (s, 9H). 127 (R) -5 -(tert-butyl) -N- (2- (2ethoxyethyl) -8- (2- (( 1 methyl- 1H -pyrazol-4 yl) amino) pyrimidin-4 yl) -2.3, 4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)1,3,4-oxadiazol-2carboxamide ,---. Η Ν-Ν -α γ [Μ Χ^ΝΝ^Ν^^ ⁷ Η ESI-MS (M+H) ⁺ : 560.1. Ή-NMR (300 MHz, METAHOL-d ₄ )δ: 8.39 (d, J=5.3 Hz, 1H), 8.02-7.95 (m, 3H), 7.62 (s, 1H ), 7.45 (d, J=7.9 Hz, 1H), 7.19 (d, J=5.3 Hz, 1H), 5.54 (br d, J=9.1 Hz, 1H) , 4.15 (d, J=4.9 Hz, 2H), 3.88 (s, 3H), 3.62 (t, J=5.7 Hz, 2H), 3.50 (q, J= 6.8 Hz, 2H), 3.26 - 3.14 (m, 2H), 2.76 - 2.63 (m, 2H), 2.34 - 2.19 (m, 1H), 2.05 -1.92 (m, 1H), 1.50 -1.47 (m, 9H), 1.16 (t, J=7.0 Hz, 3H). 128 (I)-5-(tert-butyl)-I-(7-(2((1-methyl-1H-pyrazo l-4 yl)amino)pyrimidin-4 yl) -3 -(oxetan-3 -yl) 2,3,4,5-tetrahydro-1Нbenzo[d]azepin-1-yl)1,3,4-oxadiazol-2carboxamide ο Αν Υ' [I v χ, v— Η LCMS: Rt 0.87 min, m/z 544.2. ΉNMR (400 MHz, METHANOL^4)5: 8.39 (br. s., 1H), 7.81-8.04 (m, 3H), 7.64 (br. sn. 1H), 7.50 (d, J = 8.03 Hz, 1H), 7.17 (s, 1H), 5.25 (d, J = 6.53 Hz, 1H), 4.53 - 4.78 (m, 4H) , 3.90 (br. s., 3H), 3.67 - 3.83 (m, 1H), 2.20 - 3.28 (m, 6H), 1.37 - 1.66 (m, 9H ). 129 5-(tert-butyl)-I-(7-(2-((1 methyl-1H-pyrazol-4 yl)amino)pyrimidin-4 yl) -2,3,4,5-tetrahydro -1Hbenzo [d] azepin-1-yl)1,3,4-oxadiazol-2carboxamide II Ο~ ν \ / Π Ν 1^1 ° LX Χ^ Ν— Ή^Ή^^ ⁷ Η ESI-MS (M+H) ⁺ : 488.00. Ή-NMR (400 MHz, DMSO-b ₆ )6: 10.15 (d, J=8.0 Hz, 1H), 9.53 (s, 1H), 9.21 (br s, 2H), 8 .49 (d, J=5.3 Hz, 1H), 8.09 - 7.99 (m, 2H), 7.91 (s, 1H), 7.57 (br s, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.27 (d, J=5.3 Hz, 1H), 5.62 (br t, J=8.4 Hz, 1H), 3.82 ( s, 3H), 3.61 - 3.47 (m, 2H), 3.44 - 3.21 (m, 3H), 3.13 (br d, J=9.0 Hz, 1H), 1, 43(s, 9H).

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130 1 - (tert-butyl) -I - (7- (2- (( 1 methyl- 1H -pyrazol-4 yl) amino) pyrimidin-4 yl) -3 - (oxetan-3 -yl) 2,3,4 ,5-tetrahydro-1Нbenzo[d]azepin-1-yl)- 1Н1,2,3-triazole-4carboxamide Η N=N /О-N f ' _N / ОО о An L if L n— NN^^ ⁷ H ESI-MS (M+H) ⁺ : 543.3. Ή-NMR (400 MHz, CD ₃ OD)6: 8.44 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H), 7.98-7.92 (m, 3H) , 7.65 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 5.2 Hz, 1H), 5.29-5.27 ( m, 1H), 4.81-4.65 (m, 4H), 3.90 (s, 3H), 3.863.79 (m, 1H), 3.10-2.87 (m, 4H), 2.572 .37 (m, 2H), 1.72 (s, 9H). 131 5-(tert-butyl)-I-(8-(2-((1methyl-1H-pyrazol-4 yl)amino)pyrimidin-4 yl)-2-(tetrahydrofuran-3yl)-2,3,4,5 -tetrahydro-1Hbenzo[c]azepin-5-yl)1,3,4-thiadiazol-2 carboxamide An L if L n— H ESI-MS (M+H) ⁺ : 574.0. Ή-NMR (400 MHz, CDC1 ₃ )6: 8.42 (d, J = 5.2 Hz, 1H), 8.38 (brs, 1H), 7.89-7.81 (m, 3H), 7.53 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 5.2 Hz, 1H), 6.96 (s, 1H), 5.62-5.56(m, 1H), 4.09-3.92(m, 4H), 3.91(s, 3H), 3.81-3.73(m, 2H), 3, 48-3.40 (m, 1H), 3.23-3.08 (m, 1H), 2.99-2.95 (m, 1H), 2.35-2.28 (m, 1H), 2.19-2.06 (m, 2H), 2.00-1.95 (m, 1H), 1.51 (s, 9H). 132 5 - (tert-butyl) -N- (3 methyl-7 - (2- (( 1 -methyl-1Hpyrazol-4yl)amino)pyrimidin-4 yl) -2,3,4,5-tetrahydro-1Hbenzo [d ] azepin-1 -yl)- 1,3,4-oxadiazo l-2carboxamide \ u 0"Ί Λ \ / Π N ⁰ TO [An r=\ L if J. N— H ESI-MS (M+H) ⁺ : 502.1. 133 (8)-5-(tert-butyl)-I-(8-(2((1-mstyl- 1H-pyrazo l-4 yl)amino)pyrimidin-4 yl) -2-(oxetan-3 -yl) 2,3,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)1,2,4-oxadiazole-3carboxamide lA o T / G N rr-N L if NN^^ ⁷ H ESI-MS (M+H) ⁺ : 544.0. Ή-NMR (400 MHz, METAHOJI-d4)6: 8.40 (d, J = 5.02 Hz, 1H), 7.87 - 8.09 (m, 3H), 7.63 (s, 1H) , 7.45 (d, J = 8.28 Hz, 1H), 7.20 (d, J = 5.27 Hz, 1H), 5.60 (s, 1H), 4.55 4.77 (m , 4H), 3.89 (s, 3H), 3.75 - 3.85 (m, 3H), 2.75 - 3.10 (m, 2H), 1.89 - 2.42 (m, 2H ), 1.51 (s, 9H). 134 (8)-5-(tert-butyl)-N-(2-(3hydroxycyclobutyl)-8(2-((1-methyl-1H-pyrazol4-yl)amino)pyrimidin-4yl)-2,3,4, 5-tetrahydro-1Hbenzo [c] azepin-5 -yl)- and NN HO-/\Ky / Π o u- Yf^N LIT An- H LCMS: Rt 4.5 min, m/z 558.00. ΉNMR (400 MHz, METAHOR-d ₄ )6: 8.41 (d, J=5.3 Hz, 1H), 8.03-7.98 (m, 3H), 7.62 (s, 1H), 7.47 - 7.45 (m, 1H), 7.22 (d, J=5.3 Hz, 1H), 5.58 - 5.48 (m, 1H), 4.58 (br s, 1H ), 3.99 (br s, 1H), 3.89 (s, 3H), 3.25 - 3.21 (m, 1H), 2.97 - 2.91 (m,

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1,3,4-oxadiazo l-2carboxamide 1H), 2.63 - 2.52 (m, 2H), 2.25 - 2.15 (m, 2H), 2.05 - 1.98 (m, 1H), 1.87 - 1.79 ( m, 2H), 1.49 (s, 9H), 0.97-0.86 (m, 1H). 135 5-(tert-butyl)-N-(2-(2-((1methyl- 1H-pyrazol-4 yl)amino)pyrimidin-4 yl)-6,7,8,9-tetrahydro-5Hbenzo [7] annulene -5 -yl) 1,3,4-thiadiazol-2 carboxamide IZ ο=ζ A <1 Z g ¹ A ESI-MS (M+H) ⁺ : 503.2. Ή-NMR (400 MHz, CDC1 ₃ )6: 8.40 (d, J = 5.2 Hz, 1H), 7.89-7.80 (m, 4H), 7.54 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 5.2 Hz, 1H), 6.92 (s, 1H), 5.41-5.39 (m , 1H), 3.91 (s, 3H), 3.03-3.00 (m, 2H), 2.00-1.84 (m, 6H), 1.53 (s, 9H). 136 5-(tert-butyl)-N-((8)-2((8)-2-hydroxypropyl)-8(2-((1-methyl-1H-pyrazol4-yl)amino)pyrimidin-4yl)-2 ,3,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)1,3,4-oxadiazol-2carboxamide BUT-/ .__. Η V / \.·>Ν _Χ Λ Ν / \ ο ΑΑ Αν r=h 1 if £, ν - NN Η LCMS: Rt 0.85 min, m/z 546.3. ΉNMR (400 MHz, METAHOJl-d4)6: 8.41 (br. s" 1H), 7.91 - 8.12 (m, 3H), 7.64 (br. s" 1H), 7.46 ( d, J = 7.53 Hz, 1H), 7.20 (br. sn 1H), 5.57 (d, J = 9.79 Hz, 1H), 4.08 - 4.36 (m, 2H ), 4.00 (br. S., 1H), 3.83 - 3.92 (m, 3H), 3.47 - 3.75 (m, 4H), 3.28 (br. s., 2H ), 2.37 - 2.62 (m, 2H), 2.26 (br. sn 1H), 1.84 - 2.07 (m, 1H), 1.50 (s, 9H), 0, 95 - 1.24 (m, 4H). 137 (8)-5-(tert-butyl)-I-(8-(2((1-methyl-1H-pyrazo l-4 yl)amino)pyrimidin-4 yl)-2-(2,2,2- trifluoroethyl)2,3,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)1,2,4-oxadiazole-3carboxamide ^{f F 0} An £ A. ^N ~ H LCMS: Rt 1.36 min, m/z 570.3. ΉNMR (400 MHz, METAHOJl-d4)6: 8.40 (br. s" 1H), 7.98 (d, J = 5.27 Hz, 3H), 7.62 (br. s" 1H), 7 .46 (br. s" 1H), 7.18 (br. s" 1H), 5.60 (d, J = 8.78 Hz, 1H), 4.26 - 4.45 (m, 1H), 4.02 - 4.20 (m, 1H), 3.89 (br. s" 3H), 3.39 (br. s" 1H), 3.11 (br. s" 2H), 2.24 ( br. s" 1H), 1.97 (br. s" 1H), 1.52 (s, 9H). 138* 5-(trst-butyl)-M-((8)-8-(2((1-ethyl-1H-pyrazo l-4 yl)amino)pyrimidin-4 yl)-2-((R*)tetrahydrofuran- 3-yl)2,3,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)1,3,4-oxadiazol-2carboxamide O\, /—\ AND N-N OK/ \ A F o P° An. L if L N-/ ''N N'^' H LCMS: Rt 0.90 min, m/z 572.0. ΉNMR (300 MHz, METAHOJl-d4)6: 8.41 (d, >5.3 Hz, 1H), 8.07 - 7.97 (m, 3H), 7.65 (s, 1H), 7, 48 (d, >7.6 Hz, 1H), 7.22 (d, >5.3 Hz, 1H), 5.56 (br d, >8.7 Hz, 1H), 4.58 (s, 1H), 4.22 - 4.08 (m, 4H), 4.03 - 3.92 (m, 2H), 3.78 - 3.69 (m, 2H), 3.27 - 3.07 ( m, 2H), 2.36-2.14 (m, 2H), 2.06-1.91 (m, 2H), 1.53-1.43 (m, 12H).

- 127 040817

139* 5-(tert-butyl)-I-((8)-8-(2((1-ethyl-1H-pyrazo l-4 yl)amino)pyrimidin-4 yl)-2-((8*)tetrahydrofuran- 3-yl)2,3,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)1,3,4-oxadiazol-2carboxamide O\ /--K Η NN L ) ⁿ vA Kz V Λ π o Αν γ^ν / L ϊ L Ν-γ Η LCMS: Rt 0.90 min, m/z 572.0. ΉNMR (300 MHz, METAHOJI-d4)6: 8.41 (d, J=5.3 Hz, 1H), 8.04 - 8.01 (m, 3H), 7.63 (s, 1H), 7 .47 (d, J=7.6 Hz, 1H), 7.23 (d, J=5.3 Hz, 1H), 5.57 (br d, J=8.7 Hz, 1H), 4, 58 (s, 1H), 4.23 - 4.10 (m, 4H), 4.04 - 3.93 (m, 2H), 3.78 - 3.70 (m, 2H), 3.25 - 3.07(m, 2H), 2.35-2.13(m, 2H), 2.07-1.90(m, 2H), 1.51-1.43(m, 12H). 140 tert-butyl-1 -(5 -(tert-butyl)-!,3,4-oxadiazole-2carboxamido)-7-(2-((1 methyl-1H-pyrazol-4 yl)amino)pyrimidin-4 yl)-1 ,2,4,5-tetrahydro-3Hbenzo[d]azepine-3 carboxylate ΟοΥ \ / Π Ν СхХ ο Αν L if £ ν— Η ESI-MS (M+H) ⁺ : 588.10. δ-NMR (400 MHz, CHLOROFORM-d) δ: 8.44 (d, J=5.3 Hz, 1H), 7.94 - 7.79 (m, 3H), 7.62 - 7.50 ( m, 2H), 7.06 (d, J=5.3 Hz, 1H), 6.92 (s, 1H), 5.46 - 5.30 (m, 1H), 4.48 (brs, 1H ), 4.37-4.18 (m, 1H), 3.92 (s, 3H), 3.44 (brd, J=13.3 Hz, 1H), 3.31-3.11 (m, 2H), 3.05 (brdd, J=6.5, 13.6 Hz, 1H), 1.56-1.33 (m, 18H). 141 (8)-5-(tert-butyl)-I-(7-(2((1-methyl-1H-pyrazo l-4 yl)amino)pyrimidin-4 yl) -3 -(oxetan-3 -yl) 2,3,4,5-tetrahydro-1Нbenzo[d]azepin-1-yl)1,3,4-oxadiazol-2carboxamide °~7 ΑΑ, ° Αν ρ=ν [1 J Ν—Ν Ν^^ ⁷ Η LCMS: Rt 0.87 min, m/z 544.3. ΉNMR (400 MHz, METAHOJI-d4)6: 8.39 (d, J = 5.02 Hz, 1H), 7.85 - 8.03 (m, 3H), 7.64 (s, 1H), 7 .51 (d, J = 8.03 Hz, 1H), 7.18 (d, J = 5.27 Hz, 1H), 5.26 (d, J = 6.78 Hz, 1H), 4.72 (d, J = 7.28 Hz, 4H), 3.89 (s, 3H), 3.79 (d, J = 6.27 Hz, 1H), 2.21 - 3.29 (m, 6H) , 1.47 (s, 9H). 142 5-(tert-Butyl)-N-(7-(2-((1methyl-1H-pyrazol-4 yl)amino)pyrimidin-4 yl)-3-(2,2,2-trifluoroethyl)2,3 ,4,5-tetrahydro-1Hbenzo[d]azepin-1-yl)- 1,3,4-oxadiazo l-2carboxamide ° Αν pY Η Τ ν— N Η ESI-MS (M+H) ⁺ : 570.3. s-NMR (400 MHz, CD ₃ OD)6: 8.29 (d, J = 5.2 Hz, 1H), 7.85-7.79 (m, 3H), 7.52 (s, 1H) , 7.41 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 5.2 Hz, 1H), 5.14-5.13 (m, 1H), 3.78 ( s, 3H), 3.36-3.23 (m, 3H), 3.15-3.09 (m, 2H), 3.01-2.92 (m, 2H), 2.86-2, 81 (m, 1H), 1.35 (s, 9H).

- 128 040817

143 5-(tert-butyl)-N-(3-((8)-2hydroxypropyl)-7-(2-((1 methyl-1H-pyrazol-4 yl)amino)pyrimidin-4 yl)-2,3, 4,5-tetrahydro-1Нbenzo[d]azepin-1-yl)1,3,4-oxadiazol-2carboxamide BUT Η NN /Λ/Νχ Ji Y-U \ / » ⁰ L if L n— H ESI-MS (M+H) ⁺ : 546.3. Ή-NMR (400 MHz, CDC1 ₃ )6: 8.95-8.79 (m, 1H), 8.41 (d, J = 5.2 Hz, 1H), 7.87-7.78 (m , 3H), 7.56-7.54 (m, 2H), 7.04 (d, J = 5.2 Hz, 1H), 6.97 (s, 1H), 5.18-5.14 ( m, 1H), 3.92-3.91(m, 1H), 3.90(s, 3H), 3.392.43(m, 8H), 1.43(s, 9H), 1.23-1 .21 (m, 3H). 144 5-(tert-butyl)-N-(3-((K)-2hydroxypropyl)-7-(2-((1 methyl-1H-pyrazol-4 yl)amino)pyrimidin-4 yl)-2.3, 4,5-tetrahydro-1Нbenzo[d]azepin-1-yl)1,3,4-oxadiazol-2carboxamide HO S'llll H NN _z ⁿ ^vn _x 'll y/ \ / II ⁰ x o L if N— NN^ ⁷ H ESI-MS (M+H) ⁺ : 546.3. Ή-NMR (400 MHz, CD ₃ OD)6: 8.40 (d, J = 4.8 Hz, 1H), 7.97-7.90 (m, 3H), 7.64 (s, 1H) , 7.51 (d, J = 8.0, 2.0 Hz, 1H), 7.20-7.18 (m, 1H), 5.26-5.24 (m, 1H), 4.01 -3.98(m, 1H), 3.90(s, 3H), 3.27-3.21(m, 2H), 3.14-3.03(m, 2H), 2.85-2 .80 (m, 1H), 2.70-2.56 (m, 3H), 1.46 (s, 9H), 1.26-1.23 (m, 3H). 145 5-(tert-butyl)-N-(7-(2-((1 methyl-1H-pyrazol-4 yl)amino)pyrimidin-4 yl) -3 -(tetrahydro-2Hpyran-4 -u l)-2 ,3,4,5 tetrahydro-1Нbenzo[d]azepin-1-yl)1,3,4-oxadiazol-2carboxamide \i ⁿ rVV 95° CX X ⁿ ' ⁿ - N N' ^X ^ ^/ H ESI-MS (M+H) ⁺ : 572.3. Ή-NMR (400 MHz, CDC1 ₃ ) δ: 9.02 (d, J = 7.2 Hz, 1H), 8.41 (d, J = 5.2 Hz, 1H), 7.87 (s, 1H), 7.81 (dd, J = 8.0, 1.6 Hz, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.53 (s, 1H), 7.03 (d, J = 5.2 Hz, 1H), 6.98 (s, 1H), 5.11-5.08 (m, 1H ), 4.054.02 (m, 2H), 3.91 (s, 3H), 3.41-3.25 (m, 5H), 2.92-2.67 (m, 4H), 1.76- 1.63(m, 4H), 1.42(s, 9H). 146 5-(tert-butyl)-N-(3 -(3 hydroxypropyl)-7-(2-((1 methyl-1H-pyrazol-4 yl)amino)pyrimidin-4 yl)-2,3,4,5 -tetrahydro-1Нbenzo[d]azepin-1-yl)1,3,4-oxadiazol-2carboxamide Oh H N-N /α,ν J/ \ 1 ° \ 4/¼ o Xn f^N L if H ESI-MS (M+H) ⁺ : 545.7. Ή-NMR (400 MHz, CDC1 ₃ )6: 9.02 (d, J = 6.8 Hz, 1H), 8.40 (d, J = 5.2 Hz, 1H), 7.89-7, 76 (m, 3H), 7.57-7.52 (m, 3H), 7.03 (d, J = 5.2 Hz, 1H), 5.13-5.10 (m, 1H), 3 .94-3.84 (m, 5H), 3.32-3.15 (m, 3H), 2.90-2.67 (m, 5H), 2.45-2.42 (m, 1H) , 1.83-1.81 (m, 2H), 1.43 (s, 9H). 147 5-(3,3- difluorocyclobutyl) -N- (2 methyl-8 - (2- (( 1 -methyl-1Hpyrazol-4yl) amino) pyrimidin-4 yl) -2,3,4,5-tetrahydro-1H- Η IL /XF Xn r=N L if n— n n''^ ⁷ H ESI-MS (M+H) ⁺ : 536.2. Ή-NMR (400 MHz, CDC1 ₃ ) δ: 8.43-8.42 (m, 2H), 7.87 (s, 1H), 7.85-7.82 (m, 2H), 7.55 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.05 (d, J = 5.2 Hz, 1H), 6.94 (s, 1H), 5.60 -5.56(m, 1H), 3.98-3.88(m, 5H), 3.69-3.61(m,

- 129 040817

benzo[c]azepin-5-yl)1,3,4-oxadiazol-2carboxamide 1H), 3.13-3.05 (m, 5H), 2.87-2.81 (m, 1H), 2.52 (s, 3H), 2.36-2.28 (m, 1H) , 2.10-2.03 (m, 1H). 148 5-(3,3difluorocyclobutyl) -N-(2(2-hydroxyethyl)-8-(2-((1methyl-1H-pyrazol-4yl)amino)pyrimidin-4yl)-2,3,4,5 -tetrahydro-1Hbenzo[c]azepin-5-yl)1,3,4-oxadiazol-2carboxamide Η NN ° ° ^F An r=N [ If n— NH ESI-MS (M+H) ⁺ : 566.2. Ή-NMR (400 MHz, CDC1 ₃ )6: 8.88 (br, 1H), 8.42 (d, J = 5.2 Hz, 1H), 7.85 (s, 1H), 7.84- 7.81 (m, 2H), 7.54 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.05-7.02 (m, 2H), 5.61 -5.57 (m, 1H), 4.12-4.03 (m, 2H), 3.91 (s, 3H), 3.81-3.60 (m, 3H), 3.38-3 .04 (m, 6H), 2.95-2.78 (m, 3H), 2.39-2.31 (m, 1H), 2.12-2.05 (m, 1H). 149 (K)-5-(tert-butyl)-N-(8-(2((5,6-dihydro-4H- pyrrolo[1,2-b]pyrazol-3 yl)amino)pyrimidin-4 yl)-2-(2-hydroxyethyl)2,3,4,5-tetrahydro-1Hbenzo[c]azepin-5-yl)1, 2,4-oxadiazole-Scarboxamide H N=( ?o HO-/ \ / IT N X An r^N L If H \—' ESI-MS (M+H) ⁺ : 558.2. Ή-NMR (400 MHz, CD ₃ OD)6: 8.35 (d, J = 5.2 Hz, 1H), 7.99-7.97 (m, 2H), 7.69 (s, 1H) , 7.42 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 5.2 Hz, 1H), 5.59-5.55 (m, 1H), 4.16- 4.10 (m, 4H), 3.74 (t, J = 6.0 Hz, 2H), 3.273.13 (m, 2H), 2.96 (t, J = 7.2 Hz, 2H), 2.67-2.62 (m, 4H), 2.33-2.24 (m, 1H), 2.00-1.96 (m, 1H), 1.52 (s, 9H). 150 5-(tert-butyl)-N-(8hydroxy-2-(2-((1-methyl1H-pyrazol-4yl)amino)pyrimidin-4 yl)-6,7,8,9-tetrahydro-5Hbenzo [7] annulen-5-yl) 1,3,4-oxadiazol-2carboxamide H NN /--\^-N. // Λ / but-( Y TV> C/C ⁰ ON [A L if n— NN ^x ^ ^/ H ESI-MS (M+H) ⁺ : 503.2. Ή-NMR (400 MHz, CDC1 ₃ )5: 8.74 (d, J = 4.8 Hz, 1H), 7.88-7.85 (m, 3H), 7.76-7.59 (m , 1H), 7.54 (s, 1H), 7.39-7.37 (m, 1H), 7.057.03 (m, 2H), 5.41-5.37 (m, 1H), 4.144, 09 (m, 1H), 3.91 (s, 3H), 3.89-3.84 (m, 1H), 3.26-3.19 (m, 2H), 2.24-1.96 ( m, 4H), 1.49-1.44 (m, 9H). 151 (R) -5 - (tert-butyl) -N- (2- (2 ( (1,5-dimethyl- 1H-pyrazol4-yl) amino) pyrimidin-4yl) -6,7,8,9-tetrahydro- 5Hbenzo[7]annulen-5-yl) 1,2,4-oxadiazole-3carboxamide .—. Η N-0 / An // \ 1 //'N ^z \A O ⁰ An r=4 L if L n— NH \ ESI-MS (M+H) ⁺ : 501.3. Ή-NMR (400 MHz, CD ₃ OD)5: 8.31 (d, J = 5.2 Hz, 1H), 7.93-7.91 (m, 2H), 7.60 (s, 1H) , 7.38 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 5.2 Hz, 1H), 5.44 (d, J = 10.0 Hz, 1H), 3 .82 (s, 3H), 3.10-2.97 (m, 2H), 2.25 (s, 3H), 2.09-1.86 (m, 5H), 1.54 (s, 9H ), 1.491.43 (m, 1H).

- 130 040817

152 (R) -5 -(tert-butyl) -N-(2-(2((5,6-dihydro-4H- pyrrolo[1,2-b]pyrazol-3 yl)amino)pyrimidin-4 yl)-6,7,8,9-tetrahydro-5Hbenzo[7]annulen-5-yl) 1,2,4-oxadiazol- 3 carboxamide y—. Η NO \ 1 l/'N' ^Z V\ Ca xO NNX 7 H \__1 ESI-MS (M+H) ⁺ : 513.3. Ή-NMR (500 MHz, DMSO-a ₆ )5: 9.57 (a, J=7.94 Hz, 1H), 9.06 (s, 1H), 8.40 (a, J=5.49 Hz, 1H), 7.93 - 7.84 (m, 2H), 7.62 (br s, 1H), 7.32 (a, J=7.94 Hz, 1H), 7.21 (a, J=4.88Hz, 1H), 5.26(t, J=8.85Hz, 1H), 4.05(t, J=7.33Hz, 2H), 3.17(s, 4H) , 2.97-2.91(m, 2H), 2.91-2.83(m, 2H), 2.54-2.51(m, 2H), 1.99-1.89(m, 3H), 1.88-1.68(m, 2H), 1.46(s, 9H), 1.36-1.26(m, 1H). 153 (R) -5 - (tert-butyl) -N- (2- (2 ( (1 -methyl-5 (trifluoromethyl) -1H pyrazol-4yl) amino) pyrimidin-4 yl) -6,7,8,9 -tetrahydro-5Hbenzo [7] annulen-5 -yl) 1,2,4-oxadiazol-3 carboxamide / \-Ν _χ __A \ 1 / Г ' ⁿ xp ⁰ Г N r=N LX Y N^ NNY H [ f ESI-MS (M+H) ⁺ : 555.3. Ή-NMR (500 MHz, DMSO-a ₆ )6: 9.56 (a, J=8.55 Hz, 1H), 8.93 (s, 1H), 8.43 (a, J=5.49 Hz, 1H), 7.89 (s, 1H), 7.86 (da, J=8.2, 1.5 Hz, 1H), 7.79 (s, 1H), 7.37 - 7.28 (m, 2H), 5.25 (br t, J=8.85 Hz, 1H), 3.95 (s, 3 H), 2.99 - 2.86 (m, 2H), 1.99 - 1.88 (m, 3H), 1.86-1.71 (m, 2H), 1.46 (s, 9H), 1.35-1.25 (m, 1H). 154 (R)-1 -(tert-butyl)-M-(2-(2((1-methyl-1H-pyrazo l-4 yl)amino)pyridin-4-yl)6,7,8,9-tetrahydro -5Нbenzo [7] annulen-5 -yl) - 1Н1,2,3-triazole-4carboxamide ,___. Η N=N x5° A XV N^N^^ ⁷ N ESI-MS (M+H) ⁺ : 485.3, Ή-NMR (400 MHz, CDC1 ₃ )6: 8.17-8.15 (m, 1H), 7.66 (a, J = 8.4 Hz, 1H), 7.61(s, 1H), 7.47(s, 1H), 7.37-7.30(m, 3H), 6.87-6.86(m, 1H), 6 .70 (s, 1H), 6.13-6.09 (m, 1H), 5.41-5.38 (m, 1H), 3.91 (s, 3H), 3.032.92 (m, 2H ), 2.03-1.93 (m, 4H), 1.871.84 (m, 1H), 1.71 (s, 9H), 1.63-1.55 (m, 1H).

^ means that the stereochemistry at the chiral center is specified arbitrarily ** means that the relative stereochemistry at the two chiral centers for the racemic mixture is specified arbitrarily, i.e., the trans or cis configuration at one chiral center relative to the other chiral center is specified arbitrarily

Example 155 BTK Kinase In Vitro Assay: BTK-POLYGAT-LS ASSAY.

The purpose of the in vitro BTK assay is to determine the activity of a compound against BTK by measuring the IC ₅₀ . Compound inhibition is measured after monitoring the amount of phosphorylated fluorescein labeled polyGAT peptide (Invitrogen PV3611) in the presence of active BTK enzyme (Upstate 14-552), ATP and an inhibitor. The reaction with BTK kinase was carried out in a black 96-well plate (costar 3694). In a typical assay, 24 pc aliquots of the ATP/peptide master mix (final concentration; ATP 10 μM, polyGAT 100 nM) in kinase buffer (10 mM TrisHCl pH 7.5, 10 mM MgCl ₂ , 200 μM Na ₃ PO) are added to each well. ₄ , 5 mM DHT, 0.01% Triton X-100 and 0.2 mg/ml casein). Next, 1 cl of a 4x diluted (40X) titer of compound in 100% DMSO solvent is added, followed by 15 µl of the BTK enzyme mixture in 1X kinase buffer (final concentration of 0.25 nM). The sample for analysis is incubated for 30 minutes, after which it is stopped with 28 ml of a 50 mm EDTA solution. Aliquots (5 μl) of the kinase reaction mixture are transferred to a low volume white 384-well plate (Coming 3674) and 5 pl of 2X detection buffer (Invitrogen PV3574 with 4 nM TbPY20 antibody, Invitrogen PV3552) is added. The plate is covered and incubated for 45 minutes at room temperature. Time resolved fluorescence (TFR) was measured on a Molecular Devices M5 (excitation 332 nm; emission 488 nm; fluorescein emission 518 nm). IC ₅₀ values are calculated by a four-parameter approximation, with 100% enzyme activity determined using control DMSO and 0% activity using control EDTA.

In table. 1 shows the activities of selected compounds according to this invention in the analysis of ki

- 131 040817 called VTK in vitro, and the number of each connection corresponds to the numbers of compounds given in examples 1-154 in this document.

' denotes an IC ₅₀ equal to 1000 nm or less than more than 10 nm;

denotes an IC50 of 10 nM or less and greater than 1 nM; and “ttt” denotes an IC ₅₀ of 1 nM or less.

Table 1

ICso (nM) Connection No. tgt 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14a, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24a, 25, 26a, 26b, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36a, 37, 38, 39, 40, 41, 42a, 44, 54, 55, 58, 59, 68, 70, 71, 72, 73, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 86, 87, 88, 89a, 90, 91, 92, 93, 96, 97, 98, 99, 101, 102, 105, 106, 107, 111, 112, 114, 117, 119a, 116, 121, 122, 124, 125, 127, 135, 149, 150, 152, 153, η 43, 45, 46, 47, 49, 48, 50, 51, 52, 53, 56, 57, 60, 61, 62, 63, 64, 65, 66, 67, 69, 74, 94, 95, 100, 103, SW, 113, 115, 123, 126, 128, 129, 130, 131, ΐ 14b, 24b, 36b, 85, 89b, 108, 109, 132, 133, 134, 136, 137, 138, 139, 141

Example 156 In vitro PD assay in human whole blood.

Heparinized human venous blood was obtained from Bioreclamation, Inc. or SeraCare Life Sciences and transported overnight. Whole blood is aliquoted into a 96-well plate and serial dilutions of test compound in DMSO or drug-free DMSO are added. The final concentration of DMSO in all wells is 0.1%. The plate is incubated at 37°C for 30 minutes. Lysis buffer containing protease and phosphatase inhibitors is added to drug-containing samples and one DMSO-only sample (+PPi, high control), and lysis buffer containing protease inhibitors is added to other DMSO-only samples (-PPi, low control). All samples of lysed whole blood are subjected to complete absorption of the WTK and the method of detection of phosphotyrosine, described in US20160311802, incorporated herein by reference. Extracorporeal life support (ECL) values are plotted in Prism and a best fit curve with maximum and minimum limits determined by the high and low +PPi and -PPi controls is used to estimate the concentration of test compound, which by interpolation results in a 50% signal inhibition. ECL.

In table. 2 shows the activities of selected compounds of this invention in the BTK kinase assay, with the number of each compound corresponding to the compound numbers given in Examples 1-154 described herein.

' denotes an IC ₅₀ equal to 10,000 nM or less and more than 500 nM;

Ή denotes an IC ₅₀ equal to or less than 500 nM and greater than 100 nM; and ttt is an IC ₅₀ of 100 nM or less.

table 2

ICso (nM) Connection No. ttt 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14a, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24a, 25, 26a, 26b, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36a, 37, 39, 40, 41, 42a, 44, 56, 58, 60, 62, 63, 64, 65, 67, 68, 71, 72, 73, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 86, 87, 88, 89a, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 104, 105, 106, 107, 110, 111, 112, 113, 114, 119a, 120, 121, 122, 123, 124, 125, 126, 152, 38, 42b, 45, 46, 47, 48, 49, 51, 52, 53, 57, 59, 61, 66, 69, 70, 74, 102, 103, 115, 117, 118a, 118b, 127, 128, 129, 130, 131, 132, t 14b, 24b, 36b, 43, 50, 85, 89b, 108, 109, 116, 133, 134, 135, 136, 137, 138, 139, 140, 141, 153,

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Claims (7)

CLAIM 1. A compound represented by the following formula: or a pharmaceutically acceptable salt thereof. 2. A compound represented by the following formula: or a pharmaceutically acceptable salt thereof. 3. Crystal form A (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4yl)-2-(oxetane -3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide specified in claim 2, and the crystalline form is characterized by at least three powder x-ray diffraction (PXRD) peaks at 2θ angles selected from 5.7°, 7.9°, 9.7°, 18.2°, 19.0° and 22.4°. 4. Crystal form G (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4yl)-2-(oxetane -3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide specified in claim 2, and the crystalline form is characterized by at least three PXRD peaks at 2θ angles selected from 3.6°, 8.9°, 10.9°, 12.6°, 20.2° and 21.8°. 5. A pharmaceutical composition for inhibiting Bruton's tyrosine kinase, comprising (i) a compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, (ii) a crystalline form A according to claim 3 or (iii) a crystalline form G according to claim 4, and pharmaceutically acceptable excipient. 6. A method of treating a Bruton's tyrosine kinase inhibition responsive disorder in a subject, comprising administering to said subject an effective amount of (i) a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, (ii) a crystalline form A of claim 3, or (iii) crystalline form G according to claim 4, characterized in that the disorder is an autoimmune disorder. 7. The method of claim 6 wherein the autoimmune disorder is multiple sclerosis.