Benzazepine analogs as inhibitors of bruton's tyrosine kinase

Abstract

To provide compounds for treating a disease responsive to inhibition of Bruton's tyrosine kinase.SOLUTION: For example, the invention provides compounds of the formula in the figure, or pharmaceutically acceptable salts thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] Related Applications This application claims the benefit under 35 U.S.C. §119(e) of the filing date of U.S. Provisional Application No. 62 / 485,745, filed April 14, 2017, the entire contents of which are incorporated herein by reference.

[0002] Certain agents that inhibit Bruton's tyrosine kinase (Btk) are provided, as well as methods for making and using such agents. [Background technology]

[0003] Protein kinases are a large multigene family of over 500 proteins that play important roles in the development and treatment of numerous human diseases in oncology, neurology and immunology. Tec kinases are non-receptor tyrosine kinases consisting of five members (Tec (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 (myeloid tyrosine kinase gene on the X chromosome; also known as Etk)) and are expressed primarily in hematopoietic cells, although expression of Bmx and Tec has been detected in endothelial cells and hepatic cells. Tec kinases (Itk, Rlk and Tec) are expressed in T cells and are all activated downstream of the T cell receptor (TCR). Btk is a downstream mediator of B cell receptor (BCR) signaling involved in regulating B cell activation, proliferation and differentiation. More specifically, Btk contains a PH domain that binds phosphatidylinositol (3,4,5)-triphosphate (PIP3). PIP3 binding induces Btk to phosphorylate phospholipase C (PLCy), which in turn hydrolyzes PIP2 to generate two second messengers, inositol triphosphate (IP3) and diacylglycerol (DAG), which activates the protein kinase PKC, which then induces additional B cell signaling. Mutations that abolish Btk enzymatic activity cause XLA syndrome (X-linked agammaglobulinemia), a primary immune deficiency. Given the important role that Tec kinase plays in both B and T cell signaling, Tec kinase is a target of interest for autoimmune disorders.

[0004] Thus, there is a great need in the art for effective inhibitors of Btk. Summary of the Invention

[0005] A first embodiment of the present invention relates to a compound of formula (I):

[0006] [ka]

[0007] or a pharma- ceutically acceptable salt thereof, Ring A is a 5-membered monocyclic heteroaryl containing three heteroatoms independently selected from N, O, and S, said 5-membered monocyclic heteroaryl being selected from one or more R 1 is optionally substituted with; Q 1 , Q 2 , and Q 3 are independently O, N(R 2 ), and CH-R 3 Selected from Q 1 , Q 2 , and Q 3 At least two of the 3 and; W is selected from CH and N; Y is selected from CH and N; R 1 is, in each case independently, C 1-6 alkyl and 3- to 5-membered carbocyclyl, 1-6 Alkyl and 3- to 5-membered carbocyclyl are each independently selected from one or more R 10 is optionally substituted with; R 10 is, in each occurrence, independently, halo, -CN, C 1-6 selected from alkyl, and 3- to 5-membered carbocyclyl; R 2 , H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 4-6 membered monocyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, -CN, -C(O)R 2a , -C(O) 2 R 2a , -C(O)N(R 2a ) 2 , -S(O) 2 R 2a , and -S(O) 2 N(R 2a )2 C is selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl are each independently selected from the group consisting of one or more R 20 is optionally substituted with; R 2a is, in each case independently, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each may have one or more R 20 is optionally independently substituted with; R 20 is, in each case independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 4-6 membered monocyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, halo, -CN, -C(O)R 20a , -C(O) 2 R 20a , -C(O)N(R 20a ) 2 , -N(R 20a ) 2 , -N(R 20a )C(O)R 20a , -N(R 20a )C(O) 2 R 20a , -N(R 20a )C(O)N(R 20a ) 2 , -N(R 20a )S(O) 2 R 20a , -OR 20a , -OC(O)R 20a , -OC(O)N(R 20a ) 2 , -SR 20a , -S(O)R 20a , -S(O) 2 R20a , -S(O)N(R 20a ) 2 , and -S (O) 2 N(R 20a ) 2 Selected from; R 20a is, in each case independently, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 selected from alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 3 , H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 4-6 membered monocyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, halo, -CN, -C(O)R 3a , -C(O) 2 R 3a , -C(O)N(R 3a ) 2 , -N(R 3a ) 2 , -N(R 3a )C(O)R 3a , -N(R 3a )C(O) 2 R 3a , -N(R 3a )C(O)N(R 3a ) 2 , -N(R 3a )S(O) 2 R 3a , -OR 3a , -OC(O)R 3a , -OC(O)N(R 3a ) 2 , -SR 3a , -S(O)R 3a , -S(O) 2 R 3a , -S(O)N(R 3a ) 2 , and -S(O) 2 N(R 3a ) 2 C is selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl are each independently selected from the group consisting of one or more R 30 is optionally substituted with; R 3a is, in each case independently, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each may have one or more R 30 is optionally independently substituted with; R 30 is, in each case independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 4-6 membered monocyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, halo, -CN, -C(O)R 30a , -C(O) 2 R 30a , -C(O)N(R 30a ) 2 , -N(R 30a ) 2 , -N(R 30a )C(O)R 30a , -N(R 30a )C(O) 2 R 30a , -N(R 30a )C(O)N(R 30a ) 2 , -N(R 30a )S(O) 2 R 30a , -OR 30a , -OC(O)R 30a , -OC(O)N(R 30a ) 2 , -SR 30a , -S(O)R 30a , -S(O) 2 R 30a , -S(O)N(R 30a ) 2 , and -S(O) 2 N(R30a ) 2 Selected from; R 30a is, in each case independently, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 selected from alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 4 H and C 1-6 alkyl, 1-6 The alkyl is optionally substituted with one or more halo; R 5 H and C 1-6 alkyl, 1-6 The alkyl is optionally substituted with one or more halo; R 6 H and C 1-6 alkyl, 1-6 The alkyl is optionally substituted with one or more halo; or R 5 and R 6 together with the atom to which they are attached form a ring containing 1 or 2 heteroatoms selected from O, N, and S, which ring is joined by one or more R 50 is optionally substituted with; R 50 is C 1-6 (alkyl).

[0008] The present invention also provides pharmaceutical compositions comprising at least one compound described herein, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

[0009] In one embodiment, the invention is a method of treating a disorder responsive to inhibition of Btk in a subject, comprising administering to the subject an effective amount of at least one compound described herein, or a pharma- ceutically acceptable salt thereof.

[0010] The present invention also includes the use of at least one compound as described herein, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disorder responsive to inhibition of Btk. Also provided are pharma- ceutically acceptable salts thereof.

[0011] Other features or advantages will be apparent from the following detailed description of several embodiments, and further from the appended claims. [Brief description of the drawings]

[0012] [Figure 1] FIG. 1 illustrates a powder X-ray diffraction (PXRD) pattern for crystalline form A of (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. [Diagram 2] FIG. 1 illustrates the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) profiles of crystalline form A of (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. [Diagram 3] FIG. 3A shows the solution 13C NMR spectrum of crystalline form A of (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. FIG. 3B shows the solid state 13C NMR spectrum of crystalline form A. [Figure 4]FIG. 1 illustrates a powder X-ray diffraction (PXRD) pattern for crystalline form G of (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. [Diagram 5] FIG. 1 illustrates the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) profiles of crystalline form G of (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. [Figure 6] FIG. 6A shows the solution C NMR spectrum of crystalline form G of (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. FIG. 6B shows the solid state C NMR spectrum of crystalline form G. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Detailed Description The compounds described herein or their pharma- ceutically acceptable salts may have activity as Btk modulators. In particular, the compounds described herein or their pharma- ceutically acceptable salts may be Btk inhibitors.

[0014] In a second embodiment of the present invention, the compound is represented by formula (I), or a pharma- ceutically acceptable salt thereof, 1 , Q 2 and Q 3 are each independently CH-R 3and the definitions of the other variables are as defined in the first embodiment).

[0015] In a third embodiment of the present invention, the compound is represented by formula (I): (In the formula, Q 2 is N(R 2 ), and Q 1 and Q 3 are each independently CH-R 3 and the definitions of the other variables are as defined in the first embodiment).

[0016] In a fourth embodiment of the present invention, the compound is represented by formula (I), or a pharma- ceutically acceptable salt thereof, 3 is N(R 2 ), and Q 1 and Q 2 are each independently CH-R 3 and the definitions of the other variables are as defined in the first embodiment).

[0017] In a fifth embodiment of the present invention, the compound is represented by formula (I), or a pharma- ceutically acceptable salt thereof, 1 is O and Q 2 and Q 3 are each independently CH-R 3 and the definitions of the other variables are as defined in the first embodiment).

[0018] In a sixth embodiment of the present invention, the compound is represented by formula (I), or a pharma- ceutically acceptable salt thereof, wherein W is CH; and the other variables are as defined in the first, second, third, fourth, or fifth embodiment.

[0019] In a seventh embodiment of the present invention, the compound is represented by formula (I), or a pharma- ceutically acceptable salt thereof, wherein Y is N; and the other variables are as defined in the first, second, third, fourth, fifth, or sixth embodiment.

[0020] In an eighth embodiment of the invention, the compound of the invention has the following formula:

[0021] [ka]

[0022] or any one of its pharma- ceutically acceptable salts; the definitions of the variables are as defined in the first embodiment.

[0023] In a ninth embodiment of the present invention, the compound is represented by formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharma- ceutically acceptable salt thereof, 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 selected from one or two R 1 and optionally substituted with: ; the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh or eighth embodiment.

[0024] In a tenth embodiment of the present invention, the compound is represented by formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharma- ceutically acceptable salt thereof, wherein ring A is represented by the following formula:

[0025] [ka]

[0026] the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh or eighth embodiment.

[0027] In an eleventh embodiment of the present invention, the compound is represented by formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharma- ceutically acceptable salt thereof, wherein: R 1 is, in each case independently, C 1-6 Alkyl or C 3-5 cycloalkyl; 1-6 Alkyl and C 3-5 Cycloalkyl is one to three R 10 is optionally substituted with; R 10 is, in each occurrence, independently, halo, -CN and C 1-6 alkyl; The definitions of the other variables are represented by the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiment).

[0028] In a twelfth embodiment of the present invention, the compound is represented by formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharma- ceutically acceptable salt thereof, wherein: R 1 is, in each case independently, C 1-4 alkyl, cyclopropyl, or cyclobutyl; 1-4 Alkyl, cyclopropyl and cyclobutyl have 1 to 3 R 10 is optionally substituted with; R 10 is, in each occurrence, independently, halo, -CN and C 1-3 alkyl; The definitions of the other variables are represented by the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiment).

[0029] In a thirteenth embodiment of the present invention, the compound is represented by formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharma- ceutically acceptable salt thereof, wherein: R 1is, independently in each occurrence, -C(CH 3 ) 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 2 CHF 2 , -C(CH 3 ) 2 CF 3 , -C(CH 3 ) 2 CH 2 F, -C(CH 3 ) 2 CN, 1-methylcyclopropyl, cyclobutyl, and 3,3-difluorocyclobutyl; definitions of the other variables are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 8, 9 or 10 embodiment).

[0030] In a fourteenth embodiment of the present invention, the compound is of formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharma- ceutically acceptable salt thereof, wherein R 1 is -C(CH 3 ) 3 and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiment.

[0031] In a fifteenth embodiment of the present invention, the compound is represented by formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharma- ceutically acceptable salt thereof, wherein: R 2 , H, C 1-6 Alkyl, C 4-6 Cycloalkyl, saturated 4-6 membered monocyclic heterocyclyl, -C(O)R 2a , -C(O) 2 R 2a , and -S(O) 2 R 2a C is selected from 1-6 Alkyl, C 4-6Cycloalkyl and saturated 4- to 6-membered monocyclic heterocyclyl are each independently one to three R 20 is optionally substituted with; R 2a is, in each case independently, H, C 1-6 Alkyl, C 4-6 alkyl, and saturated 4-6 membered monocyclic heterocyclyl, 1-6 Alkyl, 4- to 6-membered monocyclic carbocyclyl, and saturated 4- to 6-membered monocyclic heterocyclyl each may have one or more R 20 is optionally independently substituted with; R 20 is, in each case independently, C 1-6 Alkyl, C 4-6 Cycloalkyl, saturated 4-6 membered monocyclic heterocyclyl, halo, -CN, -N(R 20a ) 2 , and -OR 20a Selected from; R 20a is, in each occurrence, independently, H or C 1-6 is alkyl; The definitions of the other variables are represented by the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth or fourteenth embodiments).

[0032] In a sixteenth embodiment, the compound has formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharma- ceutically acceptable salt thereof, wherein: R 2 , H, C 1-6 C selected from alkyl, cyclobutyl, cyclopentyl and cyclohexyl 4-6saturated 4-6 membered monocyclic heterocyclyl selected from cycloalkyl, 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) 2 R 2a , and -S(O) 2 R 2a C is selected from 1-6 Alkyl, C 4-6 Cycloalkyl and saturated 4- to 6-membered monocyclic heterocyclyl are each independently one to three R 20 is optionally substituted with; R 2a 1 to 3 R 20 C optionally independently substituted with 1-6 is alkyl; R 20 is, in each case independently, C 1-3 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, halo, -N(R 20a ) 2 , and -OR 20a Selected from; R 20a is, in each occurrence, independently, H or C 1-3 is alkyl; Definitions of the other variables are represented by the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth or fifteenth embodiments).

[0033] In a seventeenth embodiment of the present invention, the compound is of formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharmaceutical composition thereof. A commercially acceptable salt thereof, R 2 , H, C 1-6Alkyl, cyclobutyl, cyclopentyl and cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, -C(O)R 2a , -C(O) 2 R 2a , and -S(O) 2 R 2a C is selected from 1-6 Alkyl, cyclobutyl, cyclopentyl and cyclohexyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl are each independently one to three R 20 is optionally substituted with; R 2a is one R 20 C optionally substituted with 1-6 is alkyl; R 20 is, in each case independently, C 1-3 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, halo, -N(R 20a ) 2 , and -OR 20a Selected from; R 20a is, independently in each occurrence, H or methyl; Definitions of the other variables are represented by the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth or fifteenth embodiments).

[0034] In an eighteenth embodiment of the present invention, the compound is of formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharma- ceutically acceptable salt thereof, 2 -H, -SO 2 CH 3 , -C(=O)OC(CH 3 ) 3 , -C(=O)CH 2 N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 OH, -CH2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 3 , -CH 2 CH(CH 3 )OH, -CH 2 C(CH 3 ) 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CHF 2 , -CH 2 CF 3 ,

[0035] [ka]

[0036] and wherein the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth or fifteenth embodiment.

[0037] In a nineteenth embodiment of the present invention, the compound is of formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharma- ceutically acceptable salt thereof, wherein R 2 is -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 OH, -CH 2 CH(CH 3 )OH, -CH 2 CH 2 OCH 3 ,

[0038] [ka]

[0039] (selected from the group consisting of

[0040] In a twentieth embodiment of the present invention, the compound is represented by formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharma- ceutically acceptable salt thereof, wherein: R 3 , H, C 1-6 Alkyl, C 4-6 Cycloalkyl, saturated 4-6 membered monocyclic heterocyclyl, halo, -OR 3a , -OC(O)R 3a , -OC(O)N(R 3a ) 2 , and -SR 3a C is selected from 1-6 Alkyl, C 4-6 Cycloalkyl and saturated 4- to 6-membered monocyclic heterocyclyl are each independently one to three R 30 is optionally substituted with; R 3a is, in each occurrence, independently, H or C 1-6 alkyl, 1-6 Al Kill is one R in each case. 30 is optionally independently substituted with; R 30 is, in each case independently, C 1-6 alkyl; Definitions of the other variables are represented by the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, seventeenth, eighteenth, or nineteenth embodiments).

[0041] In a twenty-first embodiment of the present invention, the compound is of formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharma- ceutically acceptable salt thereof, 3 H, halo, and -OR 3a Selected from; R 3a are independently H or C 1-3alkyl; and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, seventeenth, eighteenth, or nineteenth embodiment.

[0042] In a twenty-second embodiment of the present invention, the compound is of formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharma- ceutically acceptable salt thereof, 3 is selected from H, -F, and -OH; the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, seventeenth, eighteenth, or nineteenth embodiment.

[0043] In a twenty-third embodiment of the present invention, the compound is of formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharma- ceutically acceptable salt thereof, wherein R 4 is H or C optionally substituted with 1 to 3 fluoro 1-3 alkyl; and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first or twenty-second embodiment).

[0044] In a twenty-fourth embodiment of the present invention, the compound is of formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharma- ceutically acceptable salt thereof, wherein R 4 is H or methyl; and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, or twenty-second embodiment).

[0045] In a twenty-fifth embodiment of the present invention, the compound is of formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharma- ceutically acceptable salt thereof, wherein R 5 is H or C optionally substituted with 1 to 3 fluoro 1-3 alkyl; and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third or twenty-fourth embodiment.

[0046] In a twenty-sixth embodiment of the present invention, the compound is of formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharma- ceutically acceptable salt thereof, 5 is H, methyl, ethyl, or isopropyl; definitions of the other variables are as defined in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, or 24th embodiment).

[0047] In a twenty-seventh embodiment of the present invention, the compound is of formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharma- ceutically acceptable salt thereof, wherein R 6 is H or C optionally substituted with 1 to 3 fluoro 1-3 alkyl; and the definitions of the other variables are as defined in the 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26 embodiment.

[0048] In a twenty-eighth embodiment of the present invention, the compound is of formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharma- ceutically acceptable salt thereof, wherein R 6 is H, methyl, or trifluoromethyl; and the definitions of the other variables are as defined in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, or 26th embodiment).

[0049] In a twenty-ninth embodiment of the present invention, the compound is of formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharma- ceutically acceptable salt thereof, wherein R 5 and R 6 together with the atom to which they are attached form a 5-6 membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from O, N, and S, which ring is bound to one R 50 Optionally substituted with; R 50 is C 1-3 and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, or twenty-fourth embodiment. In a more specific embodiment, the 5- to 6-membered saturated heterocyclic ring is pyrrolidine, piperazine, or N-methylpiperazine.

[0050] In a 30th embodiment of the present invention, the compound has the following formula:

[0051] [ka]

[0052] or a pharma- ceutically acceptable salt thereof, Ring A has the formula:

[0053] [ka]

[0054] represented by one of; R 1 is C 1-6 is alkyl; R 2 is C 1-6 alkyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl, 1-6 Alkyl is one to three R 20 is optionally substituted with; R 20 is, for each occurrence independently, halo or -OR 20a and; R 20a is H or C 1-3 is alkyl; R 3 is H; R 5 is H or C 1-3 is an alkyl group.

[0055] In a thirty-first embodiment of the present invention, the compound is represented by formula (IIA), (IVA), (VA), (IIA′), (IVA′), or (VA′), or a pharma- ceutically acceptable salt thereof, 1 is tert-butyl; the definitions of the other variables are as defined in the 30th embodiment.

[0056] In a thirty-second embodiment of the present invention, the compound is of formula (IIA) or (IIA′), or a pharma- ceutically acceptable salt thereof, 2 teeth,

[0057] [ka]

[0058] -CH 2 CHF 2 , -CH2 CF 3 , -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , or -CH 2 C(CH 3 )OH; the definitions of the other variables are as defined in the 30th or 31st embodiment).

[0059] In a thirty-third embodiment of the present invention, the compound is represented by formula (IVA)-(IVA′), or a pharma- ceutically acceptable salt thereof, 3 is H; the definitions of the other variables are as defined in the 30th or 31st embodiment.

[0060] In a thirty-fourth embodiment of the present invention, the compound is represented by formula (IIA), (IVA), (VA), (IIA'), (IVA'), or (VA'), or a pharma- ceutically acceptable salt thereof, wherein R 5 is methyl or isopropyl; the definitions of the other variables are as defined in the 30th, 31st, 32nd or 33rd embodiment.

[0061] In a thirty-fifth embodiment of the present invention, the compound of the present invention is 5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,2,4-oxadiazole-3-carboxamide, (S)-5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,2,4-oxadiazole-3-carboxamide, (R)-5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-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)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide, (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, (S)-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-(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, (R)-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, (S)-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, 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, (R)-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, (S)-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, 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, (R)-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, (S)-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, 5-(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)-1,2,4-oxadiazole-3-carboxamide, (R)-5-(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)-1,2,4-oxadiazole-3-carboxamide, (S)-5-(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)-1,2,4-oxadiazole-3-carboxamide, 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, (R)-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, (S)-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, 5-(tert-butyl)-N-(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, (R)-5-(tert-butyl)-N-(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, (S)-5-(tert-butyl)-N-(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, 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, 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)-1,2,4-oxadiazole-3-carboxamide, 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)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-((S)-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)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-((S)-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)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(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 (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethylene) (ethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide, (S)-5-(tert-butyl)-N-(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, 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)-1,3,4-oxadiazole-2-carboxamide, (R)-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)-1,3,4-oxadiazole-2-carboxamide, (S)-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)-1,3,4-oxadiazole-2-carboxamide, 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, (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, (S)-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, 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)-1,3,4-oxadiazole-2-carboxamide (R)-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)-1,3,4-oxadiazole-2-carboxamide, (S)-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)-1,3,4-oxadiazole-2-carboxamide, 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 (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, (S)-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, 5-(tert-butyl)-N-(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 (R)-5-(tert-butyl)-N-(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, (S)-5-(tert-butyl)-N-(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, 5-(tert-butyl)-N-(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 (R)-5-(tert-butyl)-N-(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, (S)-5-(tert-butyl)-N-(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 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)-1,3,4-oxadiazole-2-carboxamide, (R)-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)-1,3,4-oxadiazole-2-carboxamide, (S)-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)-1,3,4-oxadiazole-2-carboxamide, 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)-1,3,4-oxadiazole-2-carboxamide, 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, 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, 5-(tert-butyl)-N-((S)-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, 5-(tert-butyl)-N-((S)-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-(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)-N-((R)-2-((S)-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)-N-((R)-2-((R)-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)-N-((S)-2-((R)-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)-N-((S)-2-((S)-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)-N-(2-((S)-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)-N-(2-((R)-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)-N-((R)-2-((R)-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)-N-((S)-2-((S)-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)-N-((S)-2-((R)-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)-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)-1,2,4-oxadiazole-3-carboxamide, (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]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide (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 1-(tert-butyl)-N-(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)-1H-1,2,3-triazole-4-carboxamide, (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-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide, (S)-1-(tert-butyl)-N-(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)-1H-1,2,3-triazole-4-carboxamide, 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-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide, 1-(tert-butyl)-N-((5R)-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)-1H-1,2,3-triazole-4-carboxamide, 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, 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, 1-(tert-butyl)-N-((S)-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, 1-(tert-butyl)-N-((S)-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, 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, (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, (S)-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, 1-(tert-butyl)-N-(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, (R)-1-(tert-butyl)-N-(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, (S)-1-(tert-butyl)-N-(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, 1-(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)-1H-1,2,3-triazole-4-carboxamide, 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-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide, 1-(tert-butyl)-N-((R)-2-((S)-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)-N-((S)-2-((R)-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)-N-((S)-2-((S)-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)-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)-1H-1,2,3-triazole-4-carboxamide, (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)-1H-1,2,3-triazole-4-carboxamide, (S)-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)-1H-1,2,3-triazole-4-carboxamide, 5-(tert-butyl)-N-(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, (R)-5-(tert-butyl)-N-(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, (S)-5-(tert-butyl)-N-(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, 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)-1,2,4-oxadiazole-3-carboxamide, (R)-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)-1,2,4-oxadiazole-3-carboxamide, (S)-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)-1,2,4-oxadiazole-3-carboxamide, N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide (R)—N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide, (S)—N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[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-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide, (R)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide, (S)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[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-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide, (R)-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-oxadiazole-2-carboxamide, (S)-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-oxadiazole-2-carboxamide, 3-(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)-1,2,4-oxadiazole-5-carboxamide, (R)-3-(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)-1,2,4-oxadiazole-5-carboxamide, (S)-3-(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)-1,2,4-oxadiazole-5-carboxamide, 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (S)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,2,4-oxadiazole-2-carboxamide, (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,2,4-oxadiazole-2-carboxamide, (S)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,2,4-oxadiazole-2-carboxamide, 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)-1,3,4-oxadiazole-2-carboxamide, (R)-5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5 H-cyclohepta[c]pyridin-9-yl)-1,3,4-oxadiazole-2-carboxamide, (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)-1,3,4-oxadiazole-2-carboxamide, 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, (R)-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, (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, 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, (R)-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, (S)-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, 5-(tert-butyl)-N-(3-(2-hydroxyethyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (R)-5-(tert-butyl)-N-(3-(2-hydroxyethyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (S)-5-(tert-butyl)-N-(3-(2-hydroxyethyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, 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[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (R)-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[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (S)-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[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide 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[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (R)-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[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (S)-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[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, 5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, 5-(tert-Butyl)-N-((R)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide 5-(tert-Butyl)-N-((R)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide 5-(tert-butyl)-N-((S)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide 5-(tert-Butyl)-N-((S)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide 5-(tert-butyl)-N-(3-(2-hydroxy-2-methylpropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (R)-5-(tert-butyl)-N-(3-(2-hydroxy-2-methylpropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (S)-5-(tert-butyl)-N-(3-(2-hydroxy-2-methylpropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, 1-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[b]pyridine Zo[d]azepin-1-yl)-1H-1,2,3-triazole-4-carboxamide, (R)-1-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1H-1,2,3-triazole-4-carboxamide, (S)-1-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1H-1,2,3-triazole-4-carboxamide, 1-(tert-butyl)-N-(3-methyl-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1H-1,2,3-triazole-4-carboxamide, (R)-1-(tert-butyl)-N-(3-methyl-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1H-1,2,3-triazole-4-carboxamide, (S)-1-(tert-butyl)-N-(3-methyl-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1H-1,2,3-triazole-4-carboxamide, 1-(tert-butyl)-N-(3-(2-hydroxyethyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1H-1,2,3-triazole-4-carboxamide, (R)-1-(tert-butyl)-N-(3-(2-hydroxyethyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1H-1,2,3-triazole-4-carboxamide, (S)-1-(tert-butyl)-N-(3-(2-hydroxyethyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-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-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide, (R)-5-(tert-butyl)-N-(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 (S)-5-(tert-butyl)-N-(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 5-(tert-butyl)-N-(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-(tert-butyl)-N-(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, (S)-5-(tert-butyl)-N-(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, 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)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,3,4-oxadiazole-2-carboxamide, (R)—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)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,3,4-oxadiazole-2-carboxamide, (S)—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)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,3,4-oxadiazole-2-carboxamide, N-(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)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,3,4-oxadiazole-2-carboxamide, (R)—N-(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)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,3,4-oxadiazole-2-carboxamide, (S)—N-(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)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,3,4-oxadiazole-2-carboxamide, 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, (R)-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, (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-4-yl)amino)pyrimidin-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)-N-(2-((S)-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, (R)-5-(1,1-difluoro-2-methylpropan-2-yl)-N-(2-((S)-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, (R)-5-(1,1-difluoro-2-methylpropan-2-yl)-N-(2-((R)-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, (S)-5-(1,1-difluoro-2-methylpropan-2-yl)-N-(2-((R)-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, (S)-5-(1,1-difluoro-2-methylpropan-2-yl)-N-(2-((S)-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-(1-fluoro-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, (R)-5-(1-fluoro-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 (S)-5-(1-fluoro-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-fluoro-2-methylpropan-2-yl)-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)-1,3,4-oxadiazole-2-carboxamide, 5-(1-fluoro-2-methylpropan-2-yl)-N-(2-((S)-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, (R)-5-(1-fluoro-2-methylpropan-2-yl)-N-(2-((S)-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, (R)-5-(1-fluoro-2-methylpropan-2-yl)-N-(2-((R)-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, (S)-5-(1-fluoro-2-methylpropan-2-yl)-N-(2-((R)-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, (S)-5-(1-fluoro-2-methylpropan-2-yl)-N-(2-((S)-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-cyclobutyl-N-(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-cyclobutyl-N-(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-cyclobutyl-N-(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, 5-(2-cyanopropan-2-yl)-N-(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)-N-(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-cyanopropan-2-yl)-N-(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, 5-(2-cyanopropan-2-yl)-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)-1,3,4-oxadiazole-2-carboxamide, (R)-5-(2-cyanopropan-2-yl)-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)-1,3,4-oxadiazole-2-carboxamide, (S)-5-(2-cyanopropan-2-yl)-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)-1,3,4-oxadiazole-2-carboxamide, 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, (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, (S)-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, 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-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-triazole-4-carboxamide, (S)-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-triazole-4-carboxamide, 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-thiadiazole-2-carboxamide (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-thiadiazole-2-carboxamide, (S)-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-thiadiazole-2-carboxamide, 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, (R)-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)pyrimidin-4-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-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide, (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, (S)-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, 1-(tert-butyl)-N-(2-ethyl-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, (R)-1-(tert-butyl)-N-(2-ethyl-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, (S)-1-(tert-butyl)-N-(2-ethyl-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)-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)-1H-1,2,3-triazole-4-carboxamide, (R)-1-(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)-1H-1,2,3-triazole-4-carboxamide, (S)-1-(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)-1H-1,2,3-triazole-4-carboxamide, 1-(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)-1H-1,2,3-triazole-4-carboxamide, (R)-1-(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)-1H-1,2,3-triazole-4-carboxamide, (S)-1-(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)-1H-1,2,3-triazole-4-carboxamide, 1-(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)-1H-1,2,3-triazole-4-carboxamide, (R)-1-(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)-1H-1,2,3-triazole-4-carboxamide, (S)-1-(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)-1H-1,2,3-triazole-4-carboxamide, 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-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide (R)-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-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide, (R)-1-(tert-butyl)-N-(2-((S)-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, (S)-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-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide, (S)-1-(tert-butyl)-N-(2-((S)-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, 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)-N-(2-((R)-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, (R)-5-(tert-butyl)-N-(2-((R)-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, (R)-5-(tert-butyl)-N-(2-((S)-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, (S)-5-(tert-butyl)-N-(2-((R)-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, (S)-5-(tert-butyl)-N-(2-((S)-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)-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)-1,2,4-oxadiazole-3-carboxamide, (R)-5-(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)-1,2,4-oxadiazole-3-carboxamide, (S)-5-(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)-1,2,4-oxadiazole-3-carboxamide, 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)-1,3,4-oxadiazole-2-carboxamide, 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, 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, 5-(tert-butyl)-N-((S)-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, 5-(tert-butyl)-N-((S)-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-(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, (R)-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)-1,3,4-oxadiazole-2-carboxamide, (S)-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)-1,3,4-oxadiazole-2-carboxamide, 5-(tert-butyl)-N-(2-ethyl-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-(tert-butyl)-N-(2-ethyl-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-(tert-butyl)-N-(2-ethyl-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)-N-(2-(2-hydroxy-2-methylpropyl)-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-1,3,4-oxadiazole-2-carboxylic acid {(R)-2-(2-hydroxy-2-methyl-propyl)-8-[2-(1-methyl-1H-pyrazol-4-ylamino)-pyrimidin-4-yl]-2,3,4,5-tetrahydro-1H-2-benzazepin-5-yl}-amide, (S)-5-(tert-butyl)-N-(2-(2-hydroxy-2-methylpropyl)-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)-N-(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-oxadiazole-2-carboxamide, (R)-5-(tert-butyl)-N-(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-oxadiazole-2-carboxamide, (S)-5-(tert-butyl)-N-(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-oxadiazole-2-carboxamide N-(8-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamide, (R)—N-(8-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamide, (S)—N-(8-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamide, (R)-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)-1,3,4-oxadiazole-2-carboxamide, (S)-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)-1,3,4-oxadiazole-2-carboxamide, 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)-1,3,4-oxadiazole-2-carboxamide, (R)-1-(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)-1H-1,2,3-triazole-4-carboxamide, (S)-1-(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)-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-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide, N-(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)-5-(1-methylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide, (R)—N-(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)-5-(1-methylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide, (S)—N-(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)-5-(1-methylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide, 5-(tert-butyl)-N-(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-oxadiazole-2-carboxamide, 5-(tert-butyl)-N-((R)-8-(2-((1-ethyl-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, 5-(tert-butyl)-N-((R)-8-(2-((1-ethyl-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-((S)-8-(2-((1-ethyl-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, 5-(tert-butyl)-N-((S)-8-(2-((1-ethyl-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-(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, (R)-5-(tert-butyl)-N-(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, (S)-5-(tert-butyl)-N-(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)-N-(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-(tert-butyl)-N-(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-(tert-butyl)-N-(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, 5-(tert-butyl)-N-(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, (R)-5-(tert-butyl)-N-(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, (S)-5-(tert-butyl)-N-(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, 1-(tert-butyl)-N-(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, (R)-1-(tert-butyl)-N-(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, (S)-1-(tert-butyl)-N-(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, 5-(tert-butyl)-N-(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, (R)-5-(tert-butyl)-N-(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, (S)-5-(tert-butyl)-N-(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, 1-(tert-butyl)-N-(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, (R)-1-(tert-butyl)-N-(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, (S)-1-(tert-butyl)-N-(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, 5-(tert-butyl)-N-(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-oxadiazole-3-carboxamide, (R)-5-(tert-butyl)-N-(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-oxadiazole-3-carboxamide, (S)-5-(tert-butyl)-N-(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-oxadiazole-3-carboxamide, 1-(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)-1H-1,2,3-triazole-4-carboxamide, (R)-1-(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)-1H-1,2,3-triazole-4-carboxamide, (S)-1-(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)-1H-1,2,3-triazole-4-carboxamide, 5-(tert-butyl)-N-(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, (R)-5-(tert-butyl)-N-(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, (S)-5-(tert-butyl)-N-(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, 5-(tert-butyl)-N-(8-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl) (1H-benzo[c]azepin-5-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide, (R)-5-(tert-butyl)-N-(8-(2-((1,3-dimethyl-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, (S)-5-(tert-butyl)-N-(8-(2-((1,3-dimethyl-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, 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-oxadiazole-2-carboxamide, (R)-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-oxadiazole-2-carboxamide, (S)-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-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, (R)—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, (S)—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, 5-(tert-butyl)-N-(2-(2-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide, (R)-5-(tert-butyl)-N-(2-(2-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide, (S)-5-(tert-butyl)-N-(2-(2-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-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)-1,3,4-oxadiazole-2-carboxamide, (R)—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-oxadiazole-2-carboxamide, (S)-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-oxadiazole-2-carboxamide, 1-(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)-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-tetrahydro-5H-benzo[7]annulen-5-yl)-1H-1,2,3-triazole-4-carboxamide, (S)-1-(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)-1H-1,2,3-triazole-4-carboxamide, 5-(tert-butyl)-4-methyl-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-4H-1,2,4-triazole-3-carboxamide, (R)-5-(tert-butyl)-4-methyl-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-4H-1,2,4-triazole-3-carboxamide, (S)-5-(tert-butyl)-4-methyl-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-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-5H-benzo[7]annulen-5-yl)-2H-1,2,3-triazole-4-carboxamide, (R)-2-isopropyl-N-(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, (S)-2-isopropyl-N-(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, 5-(tert-butyl)-N-(8-fluoro-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, 5-(tert-butyl)-N-((8S)-8-fluoro-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, 5-(tert-butyl)-N-((8R)-8-fluoro-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, 5-(tert-butyl)-N-((5R,8S)-8-fluoro-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, 5-(tert-butyl)-N-((5S,8R)-8-fluoro-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, 5-(tert-butyl)-N-((5R,8R)-8-fluoro-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, 5-(tert-butyl)-N-((5S,8S)-8-fluoro-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, N-(8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide, N-((8S)-8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide, N-((8R)-8-Fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide N-((5R,8S)-8-Fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide N-((5S,8R)-8-Fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide N-((5S,8S)-8-Fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide N-((5S,8R)-8-Fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide, (R)—N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide, (S)—N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide, 5-(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)-1,3,4-oxadiazole-2-carboxamide, (R)-5-(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)-1,3,4-oxadiazole-2-carboxamide, (S)-5-(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)-1,3,4-oxadiazole-2-carboxamide, 5-cyclobutyl-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)-1,3,4-oxadiazole-2-carboxamide, (R)-5-cyclobutyl-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)-1,3,4-oxadiazole-2-carboxamide, (S)-5-cyclobutyl-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)-1,3,4-oxadiazole-2-carboxamide, 5-(tert-butyl)-N-(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-oxadiazole-2-carboxamide, (R)-5-(tert-butyl)-N-(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-oxadiazole-2-carboxamide, (S)-5-(tert-butyl)-N-(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-oxadiazole-2-carboxamide, 5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (R)-5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (S)-5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, 1-(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[d]azepin-1-yl)-1H-1,2,3-triazole-4-carboxamide, (R)-1-(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[d]azepin-1-yl)-1H-1,2,3-triazole-4-carboxamide, (S)-1-(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[d]azepin-1-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-(tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-thiadiazole-2-carboxamide, 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-thiadiazole-2-carboxamide, 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-thiadiazole-2-carboxamide, 5-(tert-butyl)-N-((S)-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-thiadiazole-2-carboxamide, 5-(tert-butyl)-N-((S)-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-thiadiazole-2-carboxamide, 5-(tert-butyl)-N-(3-methyl-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (R)-5-(tert-butyl)-N-(3-methyl-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (S)-5-(tert-butyl)-N-(3-methyl-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, 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, (R)-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 Mido, (S)-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, 5-(tert-butyl)-N-(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-oxadiazole-2-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate, (R)-tert-butyl 1-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate, (S)-tert-butyl 1-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate, 5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (R)-5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (S)-5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, 5-(tert-butyl)-N-(3-(2-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, 5-(tert-butyl)-N-(3-((S)-2-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (R)-5-(tert-butyl)-N-(3-((S)-2-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (S)-5-(tert-butyl)-N-(3-((S)-2-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, 5-(tert-butyl)-N-(3-((R)-2-hydroxypropyl)-7-( 2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (R)-5-(tert-butyl)-N-(3-((R)-2-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (S)-5-(tert-butyl)-N-(3-((R)-2-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, 5-(tert-butyl)-N-(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[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (R)-5-(tert-butyl)-N-(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[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (S)-5-(tert-butyl)-N-(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[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, 5-(tert-butyl)-N-(3-(3-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (S)-5-(tert-butyl)-N-(3-(3-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, (R)-5-(tert-butyl)-N-(3-(3-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,3,4-oxadiazole-2-carboxamide, 5-(3,3-difluorocyclobutyl)-N-(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-(3,3-difluorocyclobutyl)-N-(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-(3,3-difluorocyclobutyl)-N-(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, 5-(3,3-Difluorocyclobutyl)-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)-1,3 ,4-oxadiazole-2-carboxamide, (R)-5-(3,3-difluorocyclobutyl)-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)-1,3,4-oxadiazole-2-carboxamide, (S)-5-(3,3-difluorocyclobutyl)-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)-1,3,4-oxadiazole-2-carboxamide, 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, (R)-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, (S)-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, 5-(tert-butyl)-N-(8-hydroxy-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, (R)-5-(tert-butyl)-N-(8-hydroxy-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, (S)-5-(tert-butyl)-N-(8-hydroxy-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, 5-(tert-butyl)-N-(2-(2-((1,5-dimethyl-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, (R)-5-(tert-butyl)-N-(2-(2-((1,5-dimethyl-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, (S)-5-(tert-butyl)-N-(2-(2-((1,5-dimethyl-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, 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-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide, (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-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide, (S)-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-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(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, (R)-5-(tert-butyl)-N-(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, (S)-5-(tert-butyl)-N-(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, 1-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[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)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1H-1,2,3-triazole-4-carboxamide, (S)-1-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1H-1,2,3-triazole-4-carboxamide, 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)-5-(1-methylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide, (R)-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)-5-(1-methylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide, and (S)—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)-5-(1-methylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide, or a pharma- ceutically acceptable salt thereof.

[0062] The present invention also provides a crystalline form of (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 (Compound 27):

[0063] [ka]

[0064] As used herein, the term "crystalline" refers to a solid form having a crystal structure, in which the individual molecules have a highly uniform, regular, fixed chemical structure.

[0065] Form A In one embodiment, the present invention provides crystalline Form A of (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.

[0066] In one aspect, crystalline form A is characterized by at least three, at least four, or at least five X-ray powder diffraction (PXRD) peaks at 2θ angles selected from 5.7°, 7.9°, 9.7°, 18.2°, 19.0°, and 22.4°. In one embodiment, crystalline form A is characterized by X-ray powder diffraction peaks at 2θ angles selected from 5.7°, 7.9°, 9.7°, 18.2°, 19.0°, and 22.4°. In some embodiments, the peaks described above for crystalline form A have a relative intensity of at least 5%, at least 10%, or at least 15%. In another embodiment, crystalline form A is characterized by at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or at least 19 PXRD peaks 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°.

[0067] As used herein, the term "relative intensity" refers to the ratio of the peak intensity for a peak of interest to the peak intensity for the largest peak.

[0068] In another embodiment, crystalline form A has a PXRD pattern substantially the same as the PXRD pattern shown in FIG.

[0069] In one aspect, crystalline form A has a differential scanning calorimetry (DSC) profile substantially the same as the DSC profile shown in Figure 2. In particular, crystalline form A is characterized by an onset temperature at 175.6°C ± 2°C in the DSC profile. In one embodiment, crystalline form A has a melting temperature of 186°C ± 2°C.

[0070] In one embodiment, crystalline form A has a TGA profile substantially the same as the TGA profile shown in FIG. In particular, the TGA profile indicates that crystalline form A is a hydrate.

[0071] As used herein, "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 stoichiometric or non-stoichiometric amounts of water incorporated within the crystal structure. Techniques known in the art for determining the amount of water present include, for example, TGA and Karl Fischer (KF) analysis.

[0072] In another embodiment, crystalline form A is a solid form substantially similar to that shown in FIG. 3B. 13 In one embodiment, crystalline form A has a solid C NMR spectrum. 13 The crystalline form A is characterized by chemical shifts at 143.7 ppm and / or 134.4 ppm in the C NMR spectrum. The spectrum of form A shows broad signals without obvious overlapping signals. The spectrum of form A also suggests that there may be two independent molecules with different geometric structures. In another embodiment, the crystalline form A is the solid form shown in Table 3. 13 It is characterized by chemical shifts in the C NMR spectrum.

[0073] In some embodiments, crystalline form A can be determined by, for example, PXRD, DSC, TGA or 13 In one embodiment, crystalline form A is characterized by PXRD alone or by DSC, TGA and / or a combination thereof. 13 Characterized by PXRD combined with one or more of NMR.

[0074] In some embodiments, the crystalline form A is at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5% or 99.9% pure. The purity of form A is determined by dividing the weight of crystalline form A in a composition comprising the compound (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 by the total weight of the compound in the composition. In one embodiment, the invention provides a composition comprising the compound (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, wherein at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5% or 99.9% by weight of the compound in the composition is crystalline form A of the compound.

[0075] In one embodiment, the present invention provides a method for preparing crystalline form A of (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 a method, for example, includes forming crystalline form A from a slurry including (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 ethanol (EtOH). In one embodiment, the method includes forming crystalline form A from a slurry including (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)- The method comprises stirring a slurry containing 2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide and EtOH at room temperature for 1 hour to 1 week, for example, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 10 hours, 15 hours, 24 hours, or 48 hours.

[0076] Form G In one embodiment, the present invention provides crystalline form G of (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.

[0077] In one aspect, crystalline form G is characterized by at least three, at least four, or at least five PXRD peaks at 2θ angles selected from 3.6°, 8.9°, 10.9°, 12.6°, 20.2°, and 21.8°. In one embodiment, crystalline form G is characterized by PXRD peaks at 2θ angles selected from 3.6°, 8.9°, 10.9°, 12.6°, 20.2°, and 21.8°. In some embodiments, the peaks described above for crystalline form G have a relative intensity of at least 5%, at least 10%, or at least 15%. In another embodiment, 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 PXRD peaks 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°, 25.4°, 26.8°, and 34.2°. In another embodiment, crystalline form A is characterized by PXRD peaks 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°, 25.4°, 26.8°, and 34.2°.

[0078] In another embodiment, crystalline form G has a PXRD pattern substantially the same as the PXRD pattern shown in FIG.

[0079] In one embodiment, crystalline form G has a DSC profile substantially the same as the DSC profile shown in Figure 5. In particular, crystalline form G is characterized by an onset temperature in the DSC profile at 215.4°C ± 2°C. In another embodiment, crystalline form G has a melting temperature of 217°C ± 2°C.

[0080] In one embodiment, crystalline form G has a TGA profile substantially similar to the TGA profile shown in Figure 5. In particular, the TGA profile indicates that crystalline form G is anhydrous.

[0081] "Anhydrous," as used herein, means that the crystalline form is substantially free of water within the crystal lattice, e.g., contains less than 1% water by weight as determined by TGA analysis or other quantitative analysis.

[0082] In another embodiment, crystalline form G is a solid form substantially similar to that shown in FIG. 6B. 13 In one embodiment, crystalline form G is a solid 13 Form G is characterized by chemical shifts at 147.0 ppm, 146.0 ppm and / or 140.6 ppm in the C NMR spectrum. 13 When compared with the C NMR spectrum, it shows a splitting of peaks (double signals) in the aromatic region, which is the asymmetric unit. In another embodiment, crystalline form G is a solid form as shown in Table 3. 13 It is characterized by chemical shifts in the C NMR spectrum.

[0083] In some embodiments, the 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 weight of crystalline form G in a composition comprising the compound (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 by the total weight of the compound in the composition. In one embodiment, the invention provides a composition comprising the compound (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, wherein at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5% or 99.9% by weight of the compound in the composition is crystalline form G of the compound.

[0084] In one embodiment, the present invention provides a method for preparing crystalline form G of (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 a method includes, for example, forming crystalline form G from a slurry 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 isopropyl acetate (IPAc). In one embodiment, the method comprises stirring a slurry 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 isopropyl acetate (IPAc) at an elevated temperature (e.g., 30° C. to 70° C., 40° C. to 60° C., 45° C. to 55° C., or 50° C.) for a period of time ranging from 1 hour to 1 week, e.g., 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 10 hours, 15 hours, 24 hours, or 48 hours.

[0085] Alternatively, crystalline form G may be prepared by a process comprising the steps of: (i) removing at least a portion of the dichloromethane from a mixture 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 dichloromethane by distillation; (ii) adding isopropyl acetate (IPAc) to the mixture; (iii) heating the mixture containing IPAc to an elevated temperature (e.g., 50° C. to 70° C., 55° C. to 65° C. or 60° C.) followed by cooling to about room temperature (e.g., 20° C.) to form a slurry containing the compound and IPAc; and (iv) isolating crystalline form G from the slurry. In one embodiment, steps (i) and (ii) may be repeated one or more times (e.g., two, three, four, or five times). In one embodiment, steps (i) and (ii) may be repeated one or more times to remove substantially all (e.g., at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% by volume) of the dichloromethane. In one embodiment, the heating and cooling in step (iii) may be repeated one or more times (e.g., 2, 3, 4, 5, 10, 15, 20, or more times).

[0086] The 2θ values ​​of the PXRD patterns for crystalline form A or crystalline form G may vary slightly from instrument to instrument and may depend on variations in sample preparation. Therefore, the PXRD peak positions for crystalline form A or crystalline form G should not be construed as absolute and may vary by ±0.2°.

[0087] As intended herein, "PXRD pattern substantially the same as that shown in FIG. 1," "PXRD pattern substantially the same as that shown in FIG. 4," "substantially the same as that shown in FIG. 3B," or "substantially the same as that shown in FIG. 6B" means that, for purposes of comparison, at least 80%, at least 90%, or at least 95% of the peaks shown in FIG. 1, FIG. 4, FIG. 3B, and FIG. 6B are present. It is further understood that, for purposes of comparison, some variation in peak positions from those shown in FIG. 1 and FIG. 4 is permitted, e.g., ±0.2°. Similarly, for purposes of comparison, some variation in peak positions from those shown in FIG. 3B and FIG. 6B is permitted, e.g., ±0.5 ppm.

[0088] 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, alkyl contains 6 to 20 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl.

[0089] "Alkenyl" refers to an unsaturated hydrocarbon group that may be linear or branched and has at least one carbon-carbon double bond. Alkenyl groups having 2 to 6 carbon atoms may be preferred. Alkenyl groups may contain 1, 2, or 3 or more carbon-carbon double bonds. Examples of alkenyl groups include ethenyl, n-propenyl, iso-propenyl, n-but-2-enyl, n-hex-3-enyl, and the like.

[0090] "Alkynyl" refers to an unsaturated hydrocarbon group that may be linear or branched and has at least one carbon-carbon triple bond. Alkynyl groups having 2 to 6 carbon atoms may be preferred. Alkynyl groups may contain 1, 2, or 3 or more carbon-carbon triple bonds. Examples of alkynyl groups include ethynyl, n-propynyl, n-but-2-ynyl, n-hex-3-ynyl, and the like.

[0091] The number of carbon atoms in a group is indicated herein by the prefix "C x-xx (wherein x and xx are integers). For example, "C 1-4 "Alkyl" is an alkyl group having 1 to 4 carbon atoms.

[0092] "Halogen" or "halo" can be fluoro, chloro, bromo or iodo.

[0093] As used herein, the term "heterocyclyl" refers to a saturated or unsaturated monocyclic or bicyclic (e.g., fused, bridged, or spiro) ring system having 3 to 10 ring members, or in particular 3 to 8 ring members, 3 to 7 ring members, 3 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 four of which (e.g., 1, 2, 3, or 4) can be heteroatoms, the heteroatoms being independently selected from O, S, and N, where C can be oxidized (e.g., C(O)), N can be oxidized (e.g., N(O)) or quaternized, and S can be optionally oxidized to sulfoxide or sulfone. Unsaturated heterocyclic rings include heteroaryl rings. As used herein, the term "heteroaryl" refers to an aromatic 5- or 6-membered monocyclic ring system having 1-4 heteroatoms independently selected from O, S, and N, where N may be oxidized (e.g., N(O)) or quaternized, and S may be optionally oxidized to sulfoxide or sulfone. In one embodiment, the heterocyclyl is a 3- to 7-membered saturated monocyclic or a 3- to 6-membered saturated monocyclic or a 5- to 7-membered saturated monocyclic ring, or a 4- to 6-membered saturated monocyclic ring. In one embodiment, the heterocyclyl is a 3- to 7-membered monocyclic or a 3- to 6-membered monocyclic or a 4- to 6-membered monocyclic ring. In another embodiment, the heterocyclyl is a 6- or 7-membered bicyclic ring. In yet another embodiment, the heterocyclyl is a 4- to 7-membered monocyclic non-aromatic ring. In another embodiment, the heterocyclyl is a 6-8 membered spiro or bridged bicyclic ring.The heterocyclyl group may be attached at a heteroatom or a carbon atom.Examples of heterocyclyls include aziridinyl, oxiranyl, thiiranyl, oxaziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, trithianyl, azepanyl, oxepanyl, thiepanyl, dihydrofuranyl, imidazolinyl, dihydropyranyl, nyl, and heteroaryl rings (including, but not limited to, azetyl, thiethyl, pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, oxathiaryl, triazinyl, tetrazinyl, azepinyl, oxepinyl, thiepinyl, diazepinyl, and thiazepinyl).

[0094] The term "fused ring system," as used herein, refers to a ring system having two rings, each of which is independently selected from carbocyclyl or heterocyclyl, and the two ring structures share two adjacent ring atoms. The fused ring system may have 9 to 12 ring members.

[0095] The term "bridged ring system," as used herein, is a ring system having a carbocyclyl or heterocyclyl ring in which two non-adjacent atoms of the ring are connected (bridged) by one or more (preferably 1-3) atoms selected from C, N, O, or S. The bridged ring system can have 6-8 ring members.

[0096] The term "spiro ring system," as used herein, refers to a ring system having two rings, each of which is independently selected from carbocyclyl or heterocyclyl, and the two ring structures have one ring atom in common. Spiro ring systems have 5 to 8 ring members.

[0097] In one embodiment, the heterocyclyl is a 4-6 membered monocyclic heterocyclyl. Examples of 4-6 membered monocyclic heterocyclic ring systems include azetidinyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, dihydrofuranyl, imidazolinyl, dihydropyranyl, pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, and the like. Examples of aryl include, but are not limited to, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, oxathianyi, triazinyl, and tetrazinyl.

[0098] In another embodiment, the heterocyclyl is a saturated 4-6 membered monocyclic heterocyclyl. Examples of saturated 4-6 membered monocyclic heterocyclic ring systems include, but are not limited to, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, and dithiinyl. In one embodiment, the saturated 4-6 membered monocyclic heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, or dioxinyl. In another embodiment, the saturated 4-6 membered monocyclic heterocyclyl is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.

[0099] As used herein, the term "carbocyclyl" refers to a saturated or unsaturated monocyclic or bicyclic hydrocarbon group 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 "cycloalkyl" refers to a fully saturated monocyclic or bicyclic or spiro hydrocarbon group of 3 to 7 carbon atoms, 3 to 6 carbon atoms, or 5 to 7 carbon atoms. Exemplary monocyclic carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopenentyl, cyclohexenyl, cycloheptenyl, cyclobutadienyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl, phenyl, and cycloheptatrienyl. Exemplary bicyclic carbocyclyl groups include bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, tricyclo[2.2.1.0]cyclopentyl, tricyclo[2.2.1.1]cyclopent ... 2,6 ]heptanyl, 6,6-dimethylbicyclo[3.1.1]heptyl, or 2,6,6-trimethylbicyclo[3.1.1]heptyl, spiro[2.2]pentanyl, and spiro[3.3]heptanyl. In one embodiment, the carbocyclyl is a 4-6 membered monocyclic carbocyclyl. In another embodiment, the carbocyclyl is a 3-5 membered carbocyclyl. In one embodiment, the carbocyclyl is a C 4-6≠ In yet another embodiment, the carbocyclyl is cyclobutyl, cyclopentyl or cyclohexyl.

[0100] When the compounds provided herein are sufficiently basic or acidic to form stable non-toxic acid or base salts, it may be 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 physiologically acceptable anions, such as tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate, or α-glycerophosphate. Inorganic salts, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate, may also be formed.

[0101] Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example, by reacting a sufficiently basic compound, such as an amine, with a suitable acid to give a physiologically acceptable anion. Alkali metal (e.g., sodium, potassium or lithium) or alkaline earth metal (e.g., calcium) salts of carboxylic acids can also be prepared. It can be made.

[0102] Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts from inorganic bases can include, but are not limited to, sodium, potassium, lithium, ammonium, calcium or magnesium salts. Salts derived from organic bases include primary, secondary or tertiary amines, such as 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 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, where at least two of the substituents on the amine can be different and can be alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, or heterocycloalkyl, etc. Also included are amines where two or three of the substituents, together with the amino nitrogen, form a heterocycloalkyl or heteroaryl group. Non-limiting examples of amines may include isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, trimethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purine, piperazine, piperidine, morpholine, or N-ethylpiperidine, and the like.Other carboxylic acid derivatives may be useful, such as carboxylic acid amides, including carboxamides, lower alkyl carboxamides, or dialkyl carboxamides.

[0103] The compounds described herein or their pharma- ceutically acceptable salts may contain one or more asymmetric centers in the molecule. According to the present disclosure, any structure that does not specify stereochemistry should be understood to include all various stereoisomers (e.g., diastereomers and enantiomers) in pure or substantially pure form, and mixtures thereof (such as racemic mixtures or enantiomerically enriched mixtures). Methods for preparing such optically active forms (e.g., resolution of racemic forms by recrystallization techniques, synthesis from optically active starting materials by chiral synthesis, or chromatographic separation using chiral stationary phases) are well known in the art.

[0104] When a particular stereoisomer of a compound is indicated by name or structure, the stereochemical purity of the compound is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5% or 99.9%. "Stereochemical purity" means the percent by weight of the desired stereoisomer based on the combined weight of all stereoisomers.

[0105] When a particular enantiomer of a compound is designated by name or structure, the stereochemical purity of the compound is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5% or 99.9%. "Stereochemical purity" means the percent by weight of the desired enantiomer based on the combined weight of all stereoisomers.

[0106] When the stereochemistry of a disclosed compound is named or depicted by a structure, and the named or depicted structure encompasses multiple stereoisomers (e.g., as a diastereomeric pair), it is understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. It is further understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5% or 99.9%. Stereoisomeric purity is the weight percent of the desired stereoisomer encompassed by the name or structure relative to the combined weight of all stereoisomers.

[0107] Where a disclosed compound is named or depicted by structure without indicating stereochemistry, and the compound has one chiral center, it is understood that the name or structure encompasses one enantiomer of the compound in pure or substantially pure form, and mixtures thereof, including racemic mixtures of the compounds, and mixtures in which one enantiomer is enriched relative to its corresponding optical isomer.

[0108] Where a disclosed compound is named or depicted by structure without indicating stereochemistry, for example, where the compound has at least two chiral centers, it is understood that the name or structure encompasses one stereoisomer in pure or substantially pure form, as well as mixtures thereof, including mixtures of stereoisomers and mixtures of stereoisomers where one or more stereoisomers are enriched relative to the other(s).

[0109] The disclosed compounds may exist in tautomeric forms and mixtures, and separate individual tautomers are contemplated. Also, some compounds may exhibit polymorphism.

[0110] In one embodiment, the compound of the invention or a pharma- ceutically acceptable salt thereof comprises deuterium.

[0111] Another embodiment is a pharmaceutical composition comprising at least one compound described herein, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable carrier.

[0112] The compounds described herein, or pharma- ceutically acceptable salts thereof, can be 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, etc.

[0113] In some embodiments, the present invention provides methods of reducing Btk enzymatic activity. In some embodiments, such methods include contacting Btk with an effective amount of a Btk inhibitor. Thus, the present invention further provides methods of inhibiting Btk enzymatic activity by contacting Btk with a Btk inhibitor of the present invention.

[0114] One embodiment of the present invention includes a method of treating a disorder responsive to inhibition of Btk in a subject, comprising administering to the subject an effective amount of at least one compound described herein, or a pharma- ceutically acceptable salt thereof.

[0115] In one embodiment, the present invention provides a method of treating autoimmune disorders, inflammatory disorders, and cancer in a subject in need thereof, comprising administering to the subject an effective amount of at least one compound described herein, or a pharma- ceutically acceptable salt thereof.

[0116] The term "autoimmune disorders" includes acute disseminated encephalomyelitis (ADEM), Addison's disease, and prolapse. These include diseases or disorders involving an inappropriate immune response to natural antigens, such as alopecia, antiphospholipid syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, bullous pemphigoid (BP), celiac disease, dermatomyositis, type 1 diabetes, 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, Sjogren's syndrome, temporal arteritis, and Wegener's granulomatosis. The term "inflammatory disorder" includes diseases or disorders involving acute or chronic inflammation, such as allergies, asthma, prostatitis, glomerulonephritis, pelvic inflammatory disease (PID), inflammatory bowel disease (IBD, e.g., Crohn's disease, ulcerative colitis), reperfusion injury, rheumatoid arthritis, transplant rejection, and vasculitis. In some embodiments, the invention provides methods of treating rheumatoid arthritis or lupus. In some embodiments, the invention provides methods of treating multiple sclerosis.

[0117] The term "cancer" includes diseases or disorders involving abnormal cell growth and / or proliferation, such as glioma, thyroid cancer, breast cancer, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer), gastric cancer, gastrointestinal stromal tumor, pancreatic cancer, bile duct cancer, ovarian cancer, endometrial cancer, prostate cancer, renal cell carcinoma, lymphoma (e.g., anaplastic large cell lymphoma), leukemia (e.g., acute myeloid leukemia, T-cell leukemia, chronic lymphocytic leukemia), multiple myeloma, malignant mesothelioma, malignant melanoma, and colon cancer (e.g., microsatellite instability high colon carcinoma). In some embodiments, the present invention provides a method of treating leukemia or lymphoma.

[0118] As used herein, the terms "subject" and "patient" may be used interchangeably and refer to a mammal in need of treatment, such as companion animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Typically, the subject is a human in need of treatment.

[0119] As used herein, the term "treating" or "treatment" refers to obtaining a desired pharmacological and / or physiological effect. The effect may be therapeutic, including partially or substantially achieving one or more of the following results: partially or totally reducing the severity of a disease, disorder or syndrome; improving or ameliorating clinical symptoms or indicators associated with a disorder; or delaying, inhibiting or reducing the likelihood of progression of a disease, disorder or syndrome.

[0120] An effective dose of a compound provided herein, or a pharma- ceutically acceptable salt thereof, to be administered to a subject can be from 10 μg to 500 mg.

[0121] Administering the compounds described herein, or pharmaceutically acceptable salts thereof, to a mammal includes any suitable delivery method. Administering the compounds described herein, or pharmaceutically acceptable salts thereof, to a mammal includes administering the compounds described herein, or pharmaceutically acceptable salts thereof, to a mammal topically, enterally, parenterally, transdermally, transmucosally, via inhalation, intracapsularly, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally, or intravitreally. Administering the compounds described herein, or pharmaceutically acceptable salts thereof, to a mammal also includes administering a compound that metabolizes to the compounds described herein, or pharmaceutically acceptable salts thereof, on or in the mammal's body, to a mammal topically, enterally, parenterally, transdermally, transmucosally, via inhalation, intracapsularly, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally, or intravitreally.

[0122] Thus, the compounds described herein, or a pharma- ceutically acceptable salt thereof, can be administered in combination with a pharma- ceutically acceptable vehicle, such as, for example, an inert diluent or an assimilable edible carrier. , may be administered systemically, for example, orally. They may be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or directly integrated with the food of the patient's diet. For oral therapeutic administration, the compounds described herein or pharma-ceutically acceptable salts thereof may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, or wafers, and the like. Such compositions and preparations should contain at least about 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions may be such that an effective dosage level will be obtained.

[0123] The tablets, troches, pills, capsules and the like may contain the following: a binder such as tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid, etc.; a lubricant such as magnesium stearate; a sweetening agent or flavoring agent such as sucrose, fructose, lactose or aspartame.

[0124] The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.

[0125] Exemplary pharmaceutical dosage forms for injection or infusion may include sterile aqueous solutions or dispersions or sterile powders containing the active ingredient adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.

[0126] Sterile injectable solutions can be prepared by incorporating the required amount of active compound in a suitable solvent with various other ingredients as listed above, as needed, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred preparation method can be vacuum drying and freeze-drying technology, which can produce a powder of the active ingredient and any additional desired ingredients present in the previously sterile-filtered solution.

[0127] Exemplary solid carriers may include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, etc. Useful liquid carriers include water, alcohols or glycols or water-alcohol / glycol blends in which the compounds described herein or pharma- ceutically acceptable salts thereof can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.

[0128] The useful dosage of the compounds described herein or their pharma-ceutically acceptable salts can be 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; see, for example, U.S. Patent No. 4,938,949 (incorporated by reference in its entirety).

[0129] The amount of the compounds described herein or pharma- ceutically acceptable salts thereof required for therapeutic use may vary depending on the particular salt selected, as well as the route of administration, the nature of the condition being treated, and the age and condition of the patient, and may ultimately be at the discretion of the attending physician or clinician. In general, however, dosages may range from about 0.1 to about 10 mg / kg body weight per day.

[0130] The compounds described herein or pharma- ceutically acceptable salts thereof may be, for example, in unit dosage forms. It may be conveniently administered in a unit dosage form containing from 0.01 to 10 mg, or from 0.05 to 1 mg, of active ingredient, in some embodiments, a dose of 5 mg / kg or less may be suitable.

[0131] The desired dose may conveniently be presented as a single dose or as divided doses administered at appropriate intervals.

[0132] The disclosed method may include a kit comprising a compound described herein or a pharma- ceutically acceptable salt thereof and instructional material describing administering a compound described herein or a pharma- ceutically acceptable salt thereof or a composition comprising a compound described herein or a pharma- ceutically acceptable salt thereof to a cell or subject. This should be construed to include other embodiments of kits known to those skilled in the art, such as kits comprising a solvent (such as sterile) for dissolving or suspending a compound described herein or a pharma- ceutically acceptable salt thereof prior to administering a compound described herein or a pharma- ceutically acceptable salt thereof or a composition to a cell or subject. In some embodiments, the subject may be a human.

[0133] Example LCMS Method: Samples were analyzed on a Waters Acquity UPLC BEH C18 1.7uM 2.1x50mm, part number 186002350 machine, MS mode: MS:ESI+ scan range 100-1000 Daltons. PDA detection 210-400nm. The method used was 95% water / 5% MeCN (initial state) in 1 min, followed by 5% H2O in 1 min. 2 Linear gradient to O / 95% MeCN, 5% H in 0.1% trifluoroacetic acid (0.1% v / v) at 0.7 ml / min up to 1.3 min 2 Maintenance was O / 95% MeCN and injection volume was 0.5 uL.

[0134] SFC Separations: Each separation was performed under the conditions specified in the examples below, including column name / part number, separation method, backpressure controller setting on the SFC system, flow rate, detection wavelength, injection volume, sample concentration, and sample diluent.

[0135] Example 1: 5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,2,4-oxadiazole-3-carboxamide

[0136] [ka]

[0137] 1. Synthesis of N-(3-bromophenethyl)-4-methylbenzenesulfonamide

[0138] [ka]

[0139] CH 2 Cl 2 To a mixture of 2-(3-bromophenyl)ethanamine (2 g, 10 mmol) in TsCl (10 mL) was added triethylamine (2.02 g, 20 mmol) and TsCl (2.18 g, 11.5 mmol) at 0 °C. The mixture was stirred at room temperature for 2 h, diluted with NaOH (1N, 100 mL) and dissolved in CH 2 Cl 2 (100 mL). The organic layer was washed with water (100 mL), brine (100 mL) and dried (Na 2 SO 4 ) and concentrated in vacuo to give N-(3-bromophenethyl)-4-methylbenzenesulfonamide (3.5 g, yield: 100%) as a yellow oil. 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 = 8.0 Hz, 2H), 7.17 (t, J = 1.6 Hz, 1H), 7.13 (t, J = 8.0 Hz, 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).

[0140] 2. Synthesis of ethyl 2-(N-(3-bromophenethyl)-4-methylphenylsulfonamido)acetate

[0141] [ka]

[0142] (CH 3 ) 2 To a mixture of N-(3-bromophenethyl)-4-methylbenzenesulfonamide (7.2 g, 20 mmol) in CO (80 mL), 2 CO 3 (19.3 g, 140 mmol) and ethyl 2-bromoacetate (3.67 g, 22 mmol) were added. The mixture was stirred at 60° C. for 12 h, cooled to room temperature, and the salts were filtered off. The filtrate was concentrated in vacuo to give ethyl 2-(N-(3-bromophenethyl)-4-methylphenylsulfonamido)acetate (8.78 g, yield: 100%) as a yellow oil. ESI-MS (M+H) + :440.0. 1 H NMR (400 MHz, CDCl 3 ) δ : 7.70 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 H z, 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).

[0143] 3. Synthesis of 2-(N-(3-bromophenethyl)-4-methylphenylsulfonamido)acetic acid

[0144] [ka]

[0145] EtOH (40 mL) and H 2 To a solution of ethyl 2-(N-(3-bromophenethyl)-4-methylphenylsulfonamide)acetate (8.78 mg, 20 mmol) in 2H2O (40 mL) was added NaOH (1.6 g, 40 mmol). The reaction mixture was stirred at room temperature for 12 h. The solvent was then reduced and the residue was adjusted to pH = 3 with HCl (1N). The mixture was extracted with EtOAc (100 mL x 3). The organic layer was washed with (Na 2 SO 4 ) and concentrated in vacuo to give 2-(N-(3-bromophenethyl)-4-methylphenylsulfonamido)acetic acid as a yellow solid (8.2 g, yield: 100%). ESI-MS (M+H) + :412.0. 1 H 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 = 8.4 Hz, 2H), 7.22 (s, 1H), 7.14 (t, J = 8.0 Hz, 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).

[0146] 4. Synthesis of 7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-one

[0147] [ka]

[0148] CH 2 Cl 2 A solution of 2-(N-(3-bromophenethyl)-4-methylphenylsulfonamido)acetic acid (8.2 g, 20 mmol) in 100 mL of SOCl 2 (11.9 g, 100 mmol) and DMF (catalyst) were added. The reaction mixture was stirred at 40° C. for 1 h. The solvent was then removed under reduced pressure and dried in vacuum for 2 h. The residue was dissolved in CH 2 Cl 2 (100 mL) and cooled in an ice bath. 3 (10.56 g, 80 mmol) was added and the mixture was stirred at 0 °C to room temperature for 12 h. The mixture was poured into concentrated HCl (20 mL) and extracted with EtOAc (100 mL x 2). 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 (petroleum ether: EtOAc = 4:1) to give 7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-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).

[0149] 5. Synthesis of 7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-amine

[0150] [ka]

[0151] The synthesis of 7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-amine was similar to that in Example 2. The residue was purified by silica gel column (CH 2 Cl 2 :MeOH=20:1) to give 7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-amine as a yellow solid (154 mg, yield: 64%). ESI-MS (M+H) + :395.1. 1 H.N.M. R (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, 1.6 Hz, 1H), 7.27 (d, J = 1.6 Hz, 1H), 7.18 (d, J = 8.4 Hz, 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).

[0152] 6. Synthesis of 7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-amine

[0153] [ka]

[0154] 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) was 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 under vacuum to give 7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-amine (870 mg, yield: 71%) as a white solid. ESI-MS (M+H) + :241.1. 1 HN MR (400 MHz, CDCl 3 ) δ: 7.65-7.63 (m, 2H), 7.25 (d, J = 8.8 Hz, 1H), 5.17-5.14 (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).

[0155] 7. Synthesis of tert-butyl 1-amino-7-bromo-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate

[0156] [ka]

[0157] CH 2 Cl 2 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 10 mL of Boc 2 C.O (333 mg, 1.0 mmol) was added. The mixture was stirred at room temperature for 2 h. 2 Cl 2 After dilution with (100 mL), the organic layer was washed with water (30 mL) and brine (30 mL), dried (Na2 SO 4 ), filtered and concentrated in vacuo to give tert-butyl 1-amino-7-bromo-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate (450 mg, yield: 77%) as a yellow oil. 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), 3.37-3.14 (m, 2H), 2.78-2.73 (m , 1H), 1.47 (s, 9H).

[0158] 8. Synthesis of tert-butyl 7-bromo-1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate

[0159] [ka]

[0160] CH 2 Cl 2 To a mixture of potassium 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylate (358 mg, 1.5 mmol) in (10 mL) (COCl) 2 (567 mg, 4.5 mmol) and DMF (catalyst) were added at 0° C. The mixture was stirred at room temperature for 1 h. The mixture was concentrated. The residue was dried in vacuum and then extracted with CH 2 Cl 2 (10 mL) and tert-butyl 1-amino-7-bromo-4,5-dihydrochloride. Doro-1H-benzo[d]azepine-3(2H)-carboxylate (408 mg, 1.5 mmol) and triethylamine (454 mg, 4.5 mmol) were added. The mixture was stirred at room temperature for 12 h and then cooled to 5° C. 2 Cl 2 (100 mL). The organic phase was washed with water (50 mL) and brine (50 mL) and concentrated. The residue was purified by silica gel column (PE (petroleum ether): EtOAc (ethyl acetate) = 4:1) to give tert-butyl 7-bromo-1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate (290 mg, yield: 38%) as a white solid. ESI-MS (M+H-56) + :437.0. 1 H NMR (400 MHz, CD 3 OD) 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).

[0161] 9. Synthesis of 2-chloro-4-methoxypyrimidine

[0162] [ka]

[0163] A solution of 2,4-dichloropyrimidine (7.5 g, 50 mmol) in MeOH (80 mL) was added dropwise to a solution of NaOMe (2.84 g, 52.5 mmol) in MeOH (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was concentrated in vacuo to give the crude product. The crude product was poured into 150 mL of water. The aqueous phase was extracted with EtOAc (100 mL). The organic layer was washed with Na2 SO 4 and concentrated in vacuo to give 2-chloro-4-methoxypyrimidine (5.9 g, yield: 82%) as a pale 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).

[0164] 10. Synthesis of 4-methoxy-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine

[0165] [ka]

[0166] A solution of 2-chloro-4-methoxypyrimidine (120 g, 0.83 mol) in dioxane (2 L) was diluted with 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) and Pd 2 (dba) 3 (16.7 g, 0.02 mol) was added. The reaction mixture was heated at 120 °C with N 2 The reaction mixture was stirred at room temperature for 4 hours. ) was added. The layers were separated and the aqueous phase was extracted with EtOAc (3×2 L). The combined organic layers were washed with brine (3 L), dried (Na 2 SO 4 ) and concentrated. The crude material was purified by silica gel chromatography (PE:EtOAc=5:1 to 1:1) to give 4-methoxy-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (73 g, yield: 43%) as a brown solid. ESI-MS (M+H) + :205.8.

[0167] 11. Synthesis of 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine

[0168] [ka]

[0169] To 4-methoxy-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (1.4 kg, 6.8 mol) was added HBr (11.2 L, 38% aqueous solution). The reaction mixture was heated to 100° C. and stirred at that temperature for 2 hours. The reaction mixture was concentrated and then diluted with POCl. 3 (11.2 L) was added. The reaction mixture was heated to 100° C. and stirred at that temperature for 16 h. The reaction mixture was 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 (4 M). The basic aqueous phase was extracted with EtOAc (3×10 L). The combined organic layers were washed with brine (9 L), dried (Na 2 SO 4 ) and concentrated. The crude material was purified by silica gel chromatography (PE: EtOAc = 5: 1 to 2: 1) to give 4-chloro-N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine as a white solid (770 g, yield: 54%). ESI-MS (M + H) + :210.0.

[0170] 12. Synthesis of tert-butyl 1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate

[0171] [ka]

[0172] To a mixture of tert-butyl 7-bromo-1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate (510 mg, 1.03 mmol) and PinB-BPin (263 mg, 1.0 mmol) in dry 1,4-dioxane (10 mL), KOAc (303 mg, 3.09 mmol) and Pd(dppf)Cl 2 ·CH 2 Cl 2 (81 mg, 0.1 mmol) 2 The mixture was heated at 100 °C under N 2 The mixture was stirred under reduced pressure for 12 hours. After cooling, 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (237 mg, 1.13 mmol), K 2 CO 3 (213 mg, 1.54 mmol) and H 2 O (2.5 mL) was added. The mixture was heated at 100 °C for 2 h at 37 °C. 2 The mixture was stirred under reduced pressure for 12 h. After cooling, the mixture was concentrated and purified by silica gel column (CH 2 Cl 2 Purification by PE:EtOAc=1:1:1) gave tert-butyl 1-(5-(tert-butyl)-1,2,4-oxadiazole-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, CD 3 OD) 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), 3.15-3.11 (m, 1H), 1.49 (s, 9H), 1.39 (s, 9H).

[0173] 13. Synthesis of 5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,2,4-oxadiazole-3-carboxamide

[0174] [ka]

[0175] CH 2 Cl 2 To a solution of TFA (1 mL) in TFA (2 mL) was added tert-butyl 1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-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 room temperature for 1 h, then concentrated and purified by preparative HPLC (CH as mobile phase). 3 CN / Water NH 4 HCO 3 0.05%) to give 5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,2,4-oxadiazole-3-carboxamide (120 mg, yield: 58%). ESI-MS (M+H) + :488.3. 1 H.N.M. R (400 MHz, CD 3OD) 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 = 7.6 Hz, 1H), 7.15 (d, J = 4.8 Hz, 1H), 5.34 (d, J = 7.2 Hz, 1H), 3.95 (s, 3H), 3.24-3.19 (m, 1H), 3.11-3.08 (m, 3H), 2.99- 2.94 (m, 2H), 1.49 (s, 9H).

[0176] Example 2. (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 (compound 2)

[0177] [ka]

[0178] Method 1: 1. Preparation of 3-(3-bromo-benzylamino)-propionic acid ethyl ester

[0179] [ka]

[0180] A solution of ethyl 3-aminopropanoate (46.0 g, 0.3 mol) and 3-bromobenzaldehyde (55.5 g, 0.3 mol) in MeOH (1.2 L) was diluted with triethylamine (60.7 g, 0.6 mol) and NaCNBH 3(56.5 g, 0.9 mol) was added portionwise. The resulting mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated in vacuo and the residue was diluted with water (600 mL). The mixture was extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (100 mL) and anhydrous Na 2 SO 4 It was dried at 40° C., filtered and concentrated in vacuo to give 3-(3-bromo-benzylamino)-propionic acid ethyl ester (46.5 g, yield: 54%) as a pale yellow oil. 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).

[0181] 2. Preparation of 3-[(3-bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionic acid ethyl ester

[0182] [ka]

[0183] To a solution of 3-(3-bromo-benzylamino)-propionic acid ethyl ester (45.6 g, 0.16 mol) in pyridine (500 mL) was added TosCl (61.0 g, 0.32 mol) at room temperature. The reaction mixture was stirred at 120 °C for 16 h. The solvent was removed in vacuum to give the crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: EtOAc = 10: 1 to 5: 1) to give 3-[(3-bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionic acid ethyl ester (61 g, yield: 88%) as a pale yellow oil. 1 H NMR (DMSO-d 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).

[0184] 3. Preparation of 3-[(3-bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionic acid

[0185] [ka]

[0186] EtOH (600 mL) and H 2 To a solution of 3-[(3-bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionic acid ethyl ester (60.0 g, 0.14 mol) in a mixture of 2,3-dichloro-3,4-tetrahydrofuran (1,100 mL) and 1,2,3-tetrahydrofuran (1,100 mL) was added NaOH (11.2 g, 0.28 mol) in portions and the reaction solution was stirred at 60° C. for 4 h. The reaction solution was cooled to 0° C. and acidified to pH=5 with concentrated HCl. The solvent was concentrated in vacuo to give a residue, which was extracted with EtOAc (3×150 mL). The organic layer was washed with Na 2 SO 4 It was dried at 40° C., filtered and concentrated in vacuo to give 3-[(3-bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionic acid (45.2 g, yield: 78.6%) as a white solid. 1 H NMR (DMSO-d 6 , 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, 2H), 4.33 (s, 2H), 3.29 (t, J = 6.9 H z, 2H), 2.41 (s, 3H), 2.27 (t, J = 7.5 Hz, 2H ).

[0187] 4. Preparation of 3-[(3-bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionyl chloride

[0188] [ka]

[0189] CH 2 Cl 2 To a solution of 3-[(3-bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionic acid (45.2 g, 0.11 mol) in DMF (1000 mL) was added dropwise in portions with DMF (1 mL) and oxalyl chloride (27.9 g, 0.22 mol). The reaction solution was stirred at 55° C. for 2 h. The mixture was concentrated in vacuo to give crude 3-[(3-bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionyl chloride (47.2 g, yield: 99%) as a black oil, which was used in the next step without further purification.

[0190] 5. Preparation of 8-bromo-2-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-benzo[c]azepin-5-one

[0191] [ka]

[0192] Anhydrous CH 2 Cl 2 A solution of 3-[(3-bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionyl chloride (47.0 g, 0.11 mol) in (1200 mL) of AlCl 3(29.3 g, 0.22 mol) was added portionwise at room temperature. The reaction mixture was stirred at 55° C. for 2 h. The reaction mixture was poured into ice water (1.2 L) and extracted with (500 mL). The organic layer was concentrated in vacuo to give the crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: EtOAc = 5: 1 to 2: 1) to give 8-bromo-2-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-benzo[c]azepin-5-one (35 g, yield: 81%) as a white solid. 1 H NMR (DMSO-d 6 , 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).

[0193] 6. Preparation of [8-bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl]-carbamic acid tert-butyl ester

[0194] [ka]

[0195] A solution of 8-bromo-2-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-benzo[c]azepin-5-one (32.0 g, 0.08 mol) in EtOH (600 mL) was treated with NH 4 OAc (18.5 g, 0.24 mol) and NaCNBH 3 (14.9 g, 0.24 mol) was added portionwise at room temperature. The reaction mixture was then stirred at 95° C. for 16 h. The mixture was poured into ice water (500 mL) and then EtOH was removed in vacuo. The residue was dissolved in CH 2 Cl 2 (3×500 mL). The combined solvents were concentrated. The residue was CH 2 Cl 2 (300 mL) and triethylamine (12.2 g, 0.12 mol) and (Boc) 2 0 (34.6 g, 0.12 mol) was added at room temperature. The mixture was stirred at room temperature for 4 h and then concentrated in vacuo to give the crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: EtOAc = 8: 1 to 2: 1) to give [8-bromo-2- (toluene-4-sulfonyl) -2,3,4,5-tetrahydro-1H-benzo [c] azepin-5-yl] -carbamic acid tert-butyl ester (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), 1.3 6 (s, 9H).

[0196] 7. Preparation of 8-bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-ylamine

[0197] [ka]

[0198] A solution of [8-bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl]-carbamic acid tert-butyl ester (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 purified by elution with MeOH and Et 2 Washing with O gave the product 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. 1 H 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 / z395.0 / 397.0[M+H] + .

[0199] 8. Synthesis of 8-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-amine

[0200] [ka]

[0201] 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 at 50° C. for 12 h. After cooling to room temperature, the mixture was diluted with EtOAc (50 mL). The white solid was collected by filtration and dried in vacuum to give the crude product 8-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-amine (1.66 g, yield: 82%), which was used directly in the next step. ESI-MS (M+H) + 241.1. 1 H NMR (400 MHz, CD 3 OD) 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, 1 H).

[0202] 9. Synthesis of tert-butyl 5-amino-8-bromo-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate

[0203] [ka]

[0204] CH 2 Cl 2 To 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 (20 mL) (Boc) 2 C.O (314 mg, 1.44 mmol) was added. The mixture was stirred at room temperature for 1 h. 2 Cl 2After dilution with (100 mL), the mixture was washed with brine (20 mL × 2). The organic phase was concentrated in vacuo, and the residue was purified by preparative HPLC (0.05% NH 3 .H 2 CH with O 3 CN / H 2 0) to give tert-butyl 5-amino-8-bromo-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate as a colorless oil (364 mg, yield: 67%). ESI-MS (M+H) + :341.1.

[0205] 10. Preparation of tert-butyl 8-bromo-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate

[0206] [ka]

[0207] The synthesis of tert-butyl 8-bromo-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate was similar to that of tert-butyl 7-bromo-1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate in Example 1, step 8. The crude product was purified by preparative HPLC (0.05% NH as mobile phase). 4 HCO 3 CH with 3 CN / H 2 0) to give tert-butyl 8-bromo-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate as a yellow solid (4.5 g, yield: 70%). ESI-MS (M+H) + :493.3.

[0208] 11. Preparation of tert-butyl 5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate

[0209] [ka]

[0210] The synthesis of tert-butyl 5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate was carried out in the same manner as in Example 1, Step 12, for the synthesis of tert-butyl 1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate. 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-4-yl)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate as a yellow solid (1.2 g, yield: 28%). ESI-MS (M+H) + :588.3. 1 H NMR (400 MHz, CD 3 OD) 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).

[0211] 12. Preparation of 5-(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)-1,2,4-oxadiazole-3-carboxamide

[0212] [ka]

[0213] CH 2 Cl 2 To a solution of tert-butyl 5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate (600 mg, 1.0 mmol) in (5 mL) was added TFA (5 mL) and the mixture was stirred at room temperature for 1 h. After concentration, the crude product (440 mg, yield: 85%) was used in the next step without further purification. ESI-MS (M+H) + :488.3.

[0214] 13. Preparation 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-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide

[0215] [ka]

[0216] To a solution of 5-(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)-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) was added NaBH 3 CN (66 mg, 1.08 mmol) and ZnCl 2 (246 mg, 1.8 mmol) was added. The mixture was stirred at room temperature for 16 h. After concentration and dilution with water (30 mL), the mixture was extracted with EtOAc (80 mL×2). The combined organic layers were diluted with H 2 The crude product was purified by preparative HPLC (0.05% NH as mobile phase). 4 HCO 3 CH with 3 CN / H 2 0) to give 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 (114 mg, yield: 49%). ESI-MS (M+H) + :544.3. 1 H NMR (400 MHz, CD 3 OD) δ: 8.30 (d, J = 5.2 Hz, 1H), 7. 92-7.85 (m, 3H), 7.51 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 5.2 Hz, 1H), 5.50 (d , J = 9.6 Hz, 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), 1.9 5-1.92 (m, 1H), 1.40 (s, 9H).

[0217] 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

[0218] [ka]

[0219] 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 was separated by SFC (OD-HO (2 × 25 cm), 30% methanol / CO 2 , 100 bar, 60 mL / min, 220 nm, injection volume: 1.5 mL, 9 mg / mL, methanol) yielding 34.8 mg of peak-1 (chemical purity 99%, ee > 99%) and 37.1 mg of peak-2 (chemical purity 99%, ee > 99%).

[0220] Peak 2 was assigned as 5-tert-butyl-1,2,4-oxadiazole-3-carboxylic acid {(R)-8-[2-(1-methyl-1H-pyrazol-4-ylamino)-pyrimidin-4-yl]-2-oxetan-3-yl-2,3,4,5-tetrahydro-1H-2-benzazepin-5-yl}-amide: LCMS: Rt 0.88 min, m / z 544.00. 1H NMR (400 MHz, methanol-d4) δ 8.40 ( d, J = 5.02 Hz, 1H), 7.87 - 8.09 (m, 3H), 7.6 3 (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).

[0221] Method 2 1. Chiral Resolution of tert-Butyl (R)-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-4,5-Dihydro-1H-Benzo[c]azepine-2(3H)-Carboxylate and (11bS)-4-Hydroxydinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepine 4-Oxide (1:1)

[0222] [ka]

[0223] To tert-butyl 5-amino-8-bromo-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate (800 g, 2.34 mol) was added MeOH (4.8 L) and (S)-(-)-1,1'-binaphthyl-2,2'-diylhydrogenphosphate (816.6 g, 2.34 mol). The mixture was stirred at 25°C for 30 min to form a yellow slurry. The slurry was stirred at reflux (70°C) to give a yellow solution. The mixture was concentrated to dryness and IPAc (3.44 L) was added. The mixture was heated to 70°C and stirred at that temperature for 3 h. The reaction mixture was cooled to room temperature and an additional portion of IPAc was added. (3.44 L) was added. The reaction mixture was stirred continuously at room temperature for 16 h. The slurry was filtered by centrifugation and the cake was washed three times (each with 7 volumes of IPAc). The wet cake was briefly dried to give tert-butyl (R)-5-amino-8-bromo-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate compound and (11bS)-4-hydroxydinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepine 4-oxide (1:1) (515 g. Yield: 64% ([50% assumed maximum recovery], 91.3% ee) as a white solid. The recrystallization process can be repeated to increase the ee to 97.2%.

[0224] 2. Preparation of 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

[0225] [ka]

[0226] CH 2 Cl 2To a solution of potassium 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylate (800 mg, 4.0 mmol) and oxalyl chloride (2.0 g, 16 mmol) in DMF (10 mL) was added DMF (catalyst). The mixture was stirred at room temperature for 2 h and then CH 2 Cl 2 The residue was concentrated twice with CH 2 Cl 2 (20 mL) and tert-butyl (R)-5-amino-8-bromo-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate and (11bR)-4-hydroxydinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepine 4-oxide (1:1) (2.0 g, 3.0 mmol) and triethylamine (900 mg, 9.0 mmol) were added. The mixture was stirred at room temperature for 2 h and concentrated. The crude product was purified by silica gel chromatography (PE: EtOAc = 2: 1) to give tert-butyl (R)-8-bromo-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide)-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, CDCl 3 ) 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).

[0227] 3. Synthesis of tert-butyl (R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

[0228] [ka]

[0229] The synthesis of tert-butyl (R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate was similar to that of tert-butyl 1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-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-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-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.

[0230] 4. Synthesis of (R)-5-(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)-1,2,4-oxadiazole-3-carboxamide

[0231] [ka]

[0232] CH 2 Cl 2 tert-Butyl (R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate (1.4 g, 2.3 To a solution of 1.0 mmol) was added TFA (10 mL). The mixture was stirred at room temperature for 1 h. 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.

[0233] 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)-1,2,4-oxadiazole-3-carboxamide (I-RP33)

[0234] [ka]

[0235] The 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)-1,2,4-oxadiazole-3-carboxamide was similar to that 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-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide described above in Method 1, Step 13. 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, Y: 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 = 8.0 Hz, 1H), 7.23 (d, J = 5.2 Hz, 1H), 5.61 (d, J = 9.6 Hz, 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).

[0236] Example 3. 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 (compound 3)

[0237] [ka]

[0238] CH 3 A solution of 5-(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)-1,2,4-oxadiazole-3-carboxamide (200 mg, 0.41 mmol) in CN (20 mL) was added with 2-iodoethanol (141 mg, 0.82 mmol) and K 2 CO 3 (170 mg, 1.23 mmol) was added. The mixture was stirred at 80° C. for 2 h. The mixture was diluted with EtOAc (100 mL), washed with water (60 mL) and concentrated. The crude product was purified by preparative HPLC (0.05% NH 4 HCO 3 CH with 3 CN / H 2 0) 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]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide as a yellow solid (90 mg, yield: 32%). ESI-MS (M+H) + :532.3. 1 H NMR (400 MHz, CD 3 OD) δ: 8.43 (d, J = 5.2 Hz, 1H), 8.04-8.00 (m, 3H), 7.64 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 5.0 Hz, 1H), 5.60 (d, J = 9.6 Hz, 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), 2.69-2.65 (m, 2H), 2.31-2.27 (m, 1H), 2.00-1.97 (m, 1H), 1 .53 (s, 9H).

[0239] 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)

[0240] [ka]

[0241] The 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 was similar to that 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)-1,3,4-oxadiazole-2-carboxamide in Example 15. The crude product was purified by preparative HPLC (0.05% NH as mobile phase). 4 HCO 3 CH with 3 CN / H2 0) to give 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 as a yellow solid (98 mg, yield: 60%). ESI-MS (M+H) + :566.2. 1 HN MR (400 MHz, CDCl 3 ) δ: 8.45 (d, J = 4.8 Hz, 1 H), 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), 2.39-2.21 (m, 2H), 1.49 (s, 9H).

[0242] Example 5. 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 (compound 5)

[0243] [ka]

[0244] To a solution of 5-(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)-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) was added NaBH 3 CN (66 mg, 1.08 mmol) and ZnCl 2 (246 mg, 1.8 mmol) was added. The mixture was stirred at room temperature for 16 h. After concentration and dilution with water (30 mL), the mixture was extracted with EtOAc (80 mL×2). The combined organic layers were diluted with H 2 The crude product was purified by preparative HPLC (0.05% NH as mobile phase). 4 HCO 3 CH with 3 CN / H 2 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetanediol) (1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide was obtained as a yellow solid (114 mg, yield: 49%). ESI-MS (M+H) + :544.3. 1 H NMR (400 MHz, CD 3 OD) δ: 8.30 (d, J = 5.2 Hz, 1H), 7. 92-7.85 (m, 3H), 7.51 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 5.2 Hz, 1H), 5.50 (d , J = 9.6 Hz, 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), 1.9 5-1.92 (m, 1H), 1.40 (s, 9H).

[0245] 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)

[0246] [ka]

[0247] The synthesis of 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 was similar to that 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-1H-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)-2,3,4,5-tetrahydro-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, CD 3OD) δ: 8.29 (d, J = 5.2 Hz, 1H), 7.87 (s, 3H), 7.50 (s, 1H), 7.32 (d, J = 8.8 Hz, 1H), 7.09 (d, J = 5.6 Hz, 1H), 5.45 (d, J = 10.0 Hz, 1H), 3.86-3.78 (m, 3H), 3.75 (s, 3H), 3.09-3.06 (m, 1H), 2.80-2.74 (m, 1 H), 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).

[0248] Example 7. 5-(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)-1,2,4-oxadiazole-3-carboxamide (compound 7)

[0249] [ka]

[0250] 1. Synthesis of 4-methoxy-N-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-amine

[0251] [ka]

[0252] The synthesis of 4-methoxy-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine was similar to that 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-4-yl)pyrimidin-2-amine (420 mg, yield: 43%) as a brown solid. ESI-MS (M+H) + :220.1.

[0253] 2. Synthesis of 4-chloro-N-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-amine

[0254] [ka]

[0255] To 4-methoxy-N-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-amine (420 mg, 1.9 mmol) was added HBr (5 mL, 48% aqueous solution). The reaction mixture was heated to 100° C. and stirred at that temperature for 2 hours. The reaction mixture was concentrated and then diluted with POCl. 3 (5 mL) was added. The reaction mixture was heated to 100° C. and stirred at that temperature for 16 h. The reaction mixture was cooled to room temperature and poured into ice water. The pH of the solution was adjusted to 1.2 with aqueous NaOH (5 The pH was adjusted to 8 with 1×M. The basic aqueous phase was extracted with EtOAc (2×30 mL). The combined organic layers were 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 4-chloro-N-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-amine as a white solid (220 mg, yield: 51%). ESI-MS (M+H) + :224.1.

[0256] 3. Synthesis of tert-butyl 5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

[0257] [ka]

[0258] A mixture of tert-butyl 8-bromo-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate (560 mg, 1.13 mmol) and PinB-BPin (288 mg, 1.10 mmol) in dry 1,4-dioxane (11 mL) was diluted with KOAc (332 mg, 3.39 mmol) and Pd(dppf)Cl 2 ·CH 2 Cl 2 (89 mg, 0.11 mmol) 2 The mixture was heated at 100 °C for 12 h under N 2 After cooling, 4-chloro-N-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-amine (301 mg, 1.35 mmol), K 2 CO 3 (312mg, 2.26mmol), Pd(dppf)Cl 2 ·CH 2 Cl 2 (89 mg, 0.11 mmol) and H 2 O (2.5 mL) was added. The mixture was heated at 80 °C for 2 h with N 2After cooling, the mixture was concentrated and purified by silica gel column (PE: EtOAc = 3: 1) to give tert-butyl 5- (5- (tert-butyl) -1, 2, 4-oxadiazole-3-carboxamido) -8- (2- ( (1-ethyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1, 3, 4, 5-tetrahydro-2H-benzo [c] azepine-2-carboxylate (200 mg, yield: 29%) as a yellow solid. ESI-MS (M + H) + :602.2.

[0259] 4. Preparation of 5-(tert-butyl)-N-(8-(2-((1-ethyl-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

[0260] [ka]

[0261] CH 2 Cl 2 To a solution of tert-butyl 5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate (200 mg, 0.33 mmol) in (5 mL) was added TFA (5 mL) and the mixture was stirred at room temperature for 1 h. After concentration, the crude product (166 mg, yield: 100%) was used in the next step without further purification. ESI-MS (M+H) + :502.7.

[0262] 5. Synthesis of 5-(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)-1,2,4-oxadiazole-3-carboxamide (I-RP1)

[0263] [ka]

[0264] To a solution of 5-(tert-butyl)-N-(8-(2-((1-ethyl-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 (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) was added. The mixture was stirred at room temperature for 3 h. After concentration and dilution with water (30 mL), the mixture was extracted with EtOAc (80 mL×2). The combined organic layers were diluted with H 2 The mixture was washed with O (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-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole- The 3-carboxamide was obtained 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).

[0265] Example 8. 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 (compound 8)

[0266] [ka]

[0267] 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 was similar to that 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)-1,3,4-oxadiazole-2-carboxamide in Example 12, step 4. The crude product was purified by preparative HPLC (0.05% NH as mobile phase). 4 HCO 3 CH with 3 CN / H 2 0) to give 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 as a yellow solid (20 mg, yield: 14%). ESI-MS (M+H) + :572.3. 1 H NMR (400 MHz, CD 3 OD) 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), 3.16-3.03 (m, 2H), 2.67-2.62 (m, 1H), 2.16-2.11 (m, 1H), 1.96-1.83 (m, 3 H), 1.64-1.52 (m, 2H), 1.38 (s, 9H).

[0268] Example 9. (R)-5-(tert-butyl)-N-(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 (Compound 9)

[0269] [ka]

[0270] 1. Synthesis of tert-butyl (R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-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

[0271] [ka]

[0272] 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 (1.2 g, 2.43 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (650 mg, 2.56 mmol), KOAc (477 mg, 4.86 mmol) and Pd(dppf)Cl in 30 mL of 1,4-dioxane. 2 The mixture was stirred at 90° C. for 2 h under nitrogen. After cooling to room temperature, the mixture was diluted with EtOAc (200 mL), washed with water (50 mL×2), and diluted with Na 2 SO 4and concentrated to give tert-butyl (R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-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 was used in the next step without further purification. ESI-MS (M+H). + :541.3.

[0273] 2. tert-Butyl (R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide)-8-(2-chloropyrimidin-4-yl)-1,3 Synthesis of ,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

[0274] [ka]

[0275] 20 mL of dioxane / H 2 tert-Butyl (R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-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 (1.31 g, 2.43 mmol), 2,4-dichloropyrimidine (344 mg, 2.31 mmol), Pd(dppf)Cl in O(4:1) 2 (196 mg, 0.24 mmol) and K 2 CO 3 A mixture of (672 mg, 4.86 mmol) was incubated at 90 °C for 12 h with N 2 After removing the solvent, the residue was purified by silica gel chromatography (CH 2 Cl 2:MeOH=20:1) to give tert-butyl (R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-chloropyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate as a yellow solid (900 mg, yield: 70% for two steps). ESI-MS (M+H) + :527.2.

[0276] 3. Synthesis of tert-butyl (R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

[0277] [ka]

[0278] tert-Butyl (R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-chloropyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate (900 mg, 1.71 mmol), 1,5-dimethyl-1H-pyrazol-4-amine (228 mg, 2.05 mmol), Cs in 15 mL of 1,4-dioxane 2 CO 3 (1.11g, 3.42mmol), Pd 2 (dba) 3 A mixture of S-Phos (157 mg, 0.17 mmol) and S-Phos (140 mg, 0.34 mmol) was stirred at 100° C. for 2 h under nitrogen. The mixture was diluted with EtOAc (200 mL) and washed with water (60 mL×2). The organic phase was diluted with Na 2 SO 4The crude product was purified by silica gel chromatography (DCM / MeOH=20:1) to give tert-butyl (R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate as a yellow solid (110 mg, yield: 11%). ESI-MS (M+H) + :602.3. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.39-8.38 (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, 1 H), 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).

[0279] 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-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide

[0280] [ka]

[0281] 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 was similar to that of 5-(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)-1,2,4-oxadiazole-3-carboxamide in Example 2. The crude material was carried forward without further purification. ESI-MS (M+H) + :502.2.

[0282] 5. Synthesis of (R)-5-(tert-butyl)-N-(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

[0283] [ka]

[0284] The synthesis of (R)-5-(tert-butyl)-N-(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 was similar to that 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)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide as a yellow solid (43 mg, 42% yield). ESI-MS (M+H) + :546.3. 1 H NMR (400 MHz, CD 3 OD) 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), 3.3 0-3.21 (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).

[0285] 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)

[0286] [ka]

[0287] The synthesis of 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 was similar to that described in Example 7, step 3. The crude material was purified by preparative HPLC (0.05% NH as mobile phase). 4 HCO 3 CH with 3 CN / H 2 0) to give 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 as a yellow solid (97 mg, yield: 57%). ESI-MS (M+H) + :558.3. 1 H NMR (400 MHz, CD 3 OD) 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 H z, 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).

[0288] Example 11. (R)-5-(tert-butyl)-N-(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 (Compound 11)

[0289] [ka]

[0290] 1. tert-Butyl (R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide)-8-(2-((1-methyl-1H-pyrazole-4 Synthesis of (4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

[0291] [ka]

[0292] The synthesis of tert-butyl (R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate was similar to that of tert-butyl 1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-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-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-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.

[0293] 2. Synthesis of (R)-5-(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)-1,2,4-oxadiazole-3-carboxamide

[0294] [ka]

[0295] CH 2 Cl 2To a solution of tert-butyl (R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate (1.4 g, 2.3 mmol) in (10 mL) was added TFA (10 mL). The mixture was stirred at room temperature for 1 h. 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.

[0296] 3. Synthesis of (R)-5-(tert-butyl)-N-(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

[0297] [ka]

[0298] CH 3To 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-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide (75 mg, 0.15 mmol) in CN (5 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (60 mg, 0.3 mmol) and DIPEA (34 mg, 0.3 mmol). The mixture was stirred at 80° C. for 2 h under 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-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 as a yellow solid (45 mg, yield: 58%). ESI-MS (M+H) + :570.2. 1 H NMR (400 MHz, CD 3 OD) δ: 8.30 (d, J = 5.6 Hz, 1H), 7.9 2-7.86 (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).

[0299] Example 12. 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)-1,3,4-oxadiazole-2-carboxamide (compound 12)

[0300] [ka]

[0301] 1. Preparation of tert-butyl 8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamide)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate

[0302] [ka]

[0303] To a solution of potassium 5-(tert-butyl)-1,3,4-oxadiazole-2-carboxylate (1.4 g, 6.7 mmol) and HATU (3.2 g, 8.4 mmol) in DMF (20 mL) was added triethylamine (1.69 g, 16.8 mmol) and tert-butyl 5-amino-8-bromo-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate (1.9 g, 5.6 mmol). The mixture was stirred at room temperature for 4 h. After dilution with water (80 mL), the mixture was extracted with EtOAc (100 mL x 2). The combined organics were washed with brine (80 mL), dried and concentrated. The crude product was purified by silica gel column chromatography (PE / EtOAc=2:1) ​​to give tert-butyl 8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamide)-4,5-dihydro-1H-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).

[0304] 2. Preparation of tert-butyl 5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate

[0305] [ka]

[0306] tert-Butyl 8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamide)-4,5-dihydro-1H-benzo[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 in 20 mL of dry 1,4-dioxane. 2 ·CH 2 Cl 2 (130 mg, 0.16 mmol) was stirred at 80 °C for 16 h under nitrogen. After the mixture was cooled to room temperature, 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (802 mg, 3.84 mmol), Pd(dppf)Cl 2 ·CH 2 Cl 2 (130mg, 0.16mmol), K 2 CO 3(1.3 g, 9.6 mmol), and H 2 O (5 mL) was added and the resulting mixture was stirred at 80° C. for an additional 16 h. The mixture was diluted with EtOAc (200 mL) and washed with water (80 mL×2) and sodium 2 SO 4 The crude product was purified by silica gel column chromatography (EtOAc / MeOH=20:1) to give tert-butyl 5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)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 , CD 3 OD) 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), 3.9 3-3.88 (m, 1H), 3.57-3.54 (m, 1H), 2.12-2.10 (m, 2H), 1.51 (s, 9H), 1.43-1.34 (m, 9H)

[0307] 3. Preparation of 5-(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)-1,3,4-oxadiazole-2-carboxamide

[0308] [ka]

[0309] CH 2 Cl2 To a solution of tert-butyl 5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate (600 mg, 1.02 mmol) in (5 mL) was added TFA (5 mL). The mixture was stirred for 1 h at room temperature. After removal of the solvent, the residue was dried in vacuum to give the title crude product (460 mg, yield: 80%), which was used in the next step without further purification. ESI-MS (M+H) + :488.3.

[0310] 4. 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)-1,3,4-oxadiazole-2-carboxamide

[0311] [ka]

[0312] To a solution of 5-(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)-1,3,4-oxadiazole-2-carboxamide (170 mg, 0.35 mmol) and dihydro-pyran-4-one (175 mg, 1.75 mmol) in MeOH (30 mL) was added NaBH 3 CN (112 mg, 1.75 mmol) and CH 3 COOH (catalyst) was added. The mixture was stirred at 50° C. for 4 h. After cooling to room temperature, the mixture was diluted with concentrated NH 4 The pH was adjusted to 8 with OH. After concentration, the crude product was purified by preparative HPLC (0.05% NH 4 HCO 3 CH with 3 CN / H2 0) to give 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)-1,3,4-oxadiazole-2-carboxamide as a yellow solid (24 mg, yield: 9%). ESI-MS (M+H) + :572.3. 1 H NMR (40 0MHz, 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 = 8.0 Hz, 1H), 7.10 (d, J = 5.6 Hz, 1H), 5.44 (d , J = 9.2 Hz, 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), 1.9 4-1.76 (m, 3H), 1.63-1.49 (m, 2H), 1.38 (s, 9H).

[0313] Example 13. 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 13)

[0314] [ka]

[0315] 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-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide was similar to that 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 (0.05% NH as mobile phase). 4 HCO 3 CH with 3 CN / H 2 0) to give 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 as a yellow solid (59 mg, yield: 33%). ESI-MS (M+H) + :544.2. 1 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), 7.3 6 (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).

[0316] Example 14. (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetane-3 (S)-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). Method 1

[0317] [ka]

[0318] 5-tert-Butyl-1,3,4-oxadiazole-2-carboxylic acid {8-[2-(1-methyl-1H-pyrazol-4-ylamino)-pyrimidin-4-yl]-2-oxetan-3-yl-2,3,4,5-tetrahydro-1H-2-benzazepin-5-yl}-amide (264 mg) was separated by SFC (OD-H (2 × 25 cm), 30% methanol (0.1% DEA) / CO 2 , 100 bar, 65 mL / min, 220 nm, injection volume: 0.5 mL, 4 mg / mL, methanol) yielding 93 mg of peak-1 (chemical purity >99%, ee >99%) and 97 mg of peak-2 (chemical purity >99%, ee >99%).

[0319] Peak 1 was assigned as 5-tert-butyl-1,3,4-oxadiazole-2-carboxylic acid {(R)-8-[2-(1-methyl-1H-pyrazol-4-ylamino)-pyrimidin-4-yl]-2-oxetan-3-yl-2,3,4,5-tetrahydro-1H-2-benzazepin-5-yl}-amide: LCMS: Rt 0.84 min, m / z 544.2. 1 H NMR (400 MHz, methanol-d 4 ) δ 8.41 (b rs, 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).

[0320] Peak 2 was assigned as 5-tert-butyl-1,3,4-oxadiazole-2-carboxylic acid {(S)-8-[2-(1-methyl-1H-pyrazol-4-ylamino)-pyrimidin-4-yl]-2-oxetan-3-yl-2,3,4,5-tetrahydro-1H-2-benzazepin-5-yl}-amide: LCMS: Rt 0.84 min, m / z 544.2. 1 H NMR (400 MHz, methanol-d 4 ) δ 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, 9 H).

[0321] Method 2 1. Synthesis of tert-butyl (R)-8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

[0322] [ka]

[0323] 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) was added HATU (2.6 g, 6.8 mmol) and potassium 5-(tert-butyl)-1,3,4-oxadiazole-2-carboxylate (1.12 g, 5.4 mmol). The mixture was stirred at room temperature for 2 h. Water (100 mL) was then added and the mixture was extracted with DCM (2 x 100 mL). The combined organics were dried and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc=4:1) to give tert-butyl (R)-8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamide)-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.

[0324] 2. Synthesis of 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

[0325] [ka]

[0326] tert-Butyl (R)-8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate (1.8 g, 3.65 mmol), bis(pinocolato)diboron (975 mg, 3.84 mmol), KOAc (715 mg, 7.30 mmol) and Pd(dppf)Cl in 30 mL of 1,4-dioxane 2 A mixture of DCM (293 mg, 0.36 mmol) was stirred at 90° C. for 2 h under nitrogen. After cooling to room temperature, the mixture was diluted with EtOAc (200 mL), washed with water (2×50 mL), and diluted with Na 2 SO 4 The 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)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate was used in the next step without purification. ESI-MS (M+H) + :541.3.

[0327] 3. Synthesis of tert-butyl (R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

[0328] [ka]

[0329] Dioxane / H 2 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 (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 in O (4:1, 20 mL). 2 (734 mg, 0.9 mmol) and K 2 CO 3 A mixture of (2.48 g, 18 mmol) was degassed and cooled to 100 °C with N for 2 h. 2 After stirring under atmospheric pressure, the reaction mixture was concentrated and the residue was purified by silica gel chromatography (EtOAc:PE=2:1) ​​to give tert-butyl (R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate as a yellow solid (3.4 g, yield: 51%). ESI-MS (M+H) + :588.3.

[0330] 4. Synthesis of (R)-5-(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)-1,3,4-oxadiazole-2-carboxamide

[0331] [ka]

[0332] To a solution of tert-butyl (R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-methyl-1H-pyrazol-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) was added TFA (4 mL). The resulting solution was stirred at room temperature for 2 h. After concentration of the reaction mixture, the residue was dissolved in MeOH (10 mL) and adjusted to pH=8 with aqueous ammonia. Water (20 mL) was then added and the mixture was extracted with DCM / MeOH solution (20:1, 30 mL×3). The organic phase was dried and concentrated to give crude (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide as a yellow solid (2.47 g, yield: 88%), which was used in the next step without further purification. ESI-MS (M+H) + :488.2.

[0333] 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)

[0334] [ka]

[0335] To 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-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) was added NaBH 3 CN (970 mg, 15.4 m mol) and ZnCl 2 (4.2 g, 30.8 mmol) was added. The resulting mixture was stirred at room temperature for 4 hours. 2 After dilution with 20 mL of HO, the mixture was extracted with DCM / MeOH solution (20:1, 20 mL x 3). The combined organic layers were dried and concentrated. The residue was purified by silica gel chromatography (DCM:MeOH = 50:1 to 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)-1,3,4-oxadiazole-2-carboxamide as a yellow solid (1.1 g, yield: 58%). ESI-MS (M+H) + :544.3. 1 H 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 = 8.4 Hz, 1H), 4.75-4.67 (m, 4H), 3.94-3.85 (m, 6H), 3.02-2.96 (m, 1H), 2.75-2.70 (m, 1 H), 2.35-2.31 (m, 1H), 2.14-2.07 (m, 1H), 1 .47 (s, 9H).

[0336] Example 15. 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)-1,3,4-oxadiazole-2-carboxamide (compound 15)

[0337] [ka]

[0338] CH 2 Cl 2 To a solution of 5-(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)-1,3,4-oxadiazole-2-carboxamide (100 mg, 0.20 mmol) in (20 mL) was added MsCl (34 mg, 0.3 mmol) and triethylamine (61 mg, 0.60 mmol). The mixture was stirred at room temperature 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 (0.05% NH 4 HCO 3 CH with 3 CN / H 2 0) to give 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)-1,3,4-oxadiazole-2-carboxamide as a yellow solid (130 mg, yield: 87%). ESI-MS (M+H) + :566.3. 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0339] Example 16. (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 (compound 16)

[0340] [ka]

[0341] 1. Synthesis of tert-butyl (R)-8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

[0342] [ka]

[0343] 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) was added HATU (2.6 g, 6.8 mmol) and potassium 5-(tert-butyl)-1,3,4-oxadiazole-2-carboxylate (1.12 g, 5.4 mmol). The mixture was stirred at room temperature for 2 h. Water (100 mL) was then added and the mixture was extracted with DCM (2 x 100 mL). The combined organics were dried and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc=4:1) to give tert-butyl (R)-8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamide)-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.

[0344] 2. Synthesis of 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

[0345] [ka]

[0346] tert-Butyl (R)-8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate (1.8 g, 3.65 mmol), bis(pinocolato)diboron (975 mg, 3.84 mmol), KOAc (715 mg, 7.30 mmol) and Pd(dppf)Cl in 30 mL of 1,4-dioxane 2A mixture of DCM (293 mg, 0.36 mmol) was stirred at 90° C. for 2 h under nitrogen. After cooling to room temperature, the mixture was diluted with EtOAc (200 mL), washed with water (2×50 mL), and diluted with Na 2 SO 4 The 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)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate was used in the next step without purification. ESI-MS (M+H) + :541.3.

[0347] 3. Synthesis of 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

[0348] [ka]

[0349] 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, 2,4-dichloropyrimidine (648 mg, 4.38 mmol), K 2 CO 3 (1.0g, 7. 30mmol) and Pd(dppf)Cl 2 A mixture of DCM (293 mg, 0.36 mmol) was stirred at 90° C. for 12 h under nitrogen. The mixture was diluted with EtOAc (200 mL) and washed with water (2×60 mL). The organic phase was washed with Na 2 SO 4The 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-carboxamide)-8-(2-chloropyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate as a yellow solid (1.3 g, yield: 67% for two steps). ESI-MS (M+H) + :527.2.

[0350] 4. Synthesis of tert-butyl (R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

[0351] [ka]

[0352] The synthesis of tert-butyl (R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate was similar to that of tert-butyl (R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1,5-dimethyl-1H-pyrazol-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 tert-butyl (R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate as a yellow solid (280 mg, yield: 78%). ESI-MS (M+H) + :616.3.

[0353] 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

[0354] [ka]

[0355] The 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 was similar to that 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 (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 as a yellow solid (240 mg) was used in the next step without further purification. ESI-MS (M+H) + :516.3.

[0356] 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

[0357] [ka]

[0358] 10 mL of CH 3 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 CN was diluted with K 2 CO3 (195 mg, 1.41 mmol) was added. The resulting mixture was stirred at 80° C. for 24 h. 2 O(20 After dilution with 1 mL of DCM / MeOH (20:1, 3×40 mL), the mixture was extracted with DCM / MeOH (20:1, 3×40 mL). The combined organic layers were 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-(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 as a yellow solid (108 mg, yield: 42%). ESI-MS (M+H) + :560.3. 1 H NMR (400 MHz, CD 3 OD) 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 = 5.2 Hz, 1H), 5.55 (d, J = 9.6 Hz, 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).

[0359] Example 17. (R)-5-(tert-butyl)-N-(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 (compound 17)

[0360] [ka]

[0361] (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 (220 mg, 0.43 mmol), oxetan-3-one (157 mg, 2.15 mmol), NaBH 3 CN (135 mg, 2.15 mmol) and ZnCl 2 (585 mg, 4.30 mmol) was stirred at room temperature for 16 h. The mixture was diluted with EtOAc (150 mL) and washed with water (50 mL x 2). The organic phase was washed with Na 2 SO 4 The crude product was purified by silica gel chromatography (DCM:MeOH=15:1) to give (R)-5-(tert-butyl)-N-(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 as a yellow solid (146 mg, yield: 60%). ESI-MS (M+H) + :572.3. 1 H NMR (400 MHz, CDCl 3 ) 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)

[0362] Example 18. (R)-5-(tert-butyl)-N-(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 (Compound 18)

[0363] [ka]

[0364] 1. Synthesis of tert-butyl (R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

[0365] [ka]

[0366] Dioxane / H 2tert-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 (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 in O (4:1, 20 mL). 2 (734 mg, 0.9 mmol) and K 2 CO 3 A mixture of (2.48 g, 18 mmol) was degassed and cooled to 100 °C with N for 2 h. 2 After concentration of the reaction mixture, the residue was purified by silica gel chromatography (EtOAc:PE=2:1) ​​to give tert-butyl (R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamide)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-yl. The carboxylate was obtained as a yellow solid (3.4 g, yield: 51%). ESI-MS (M+H) + :588.3.

[0367] 2. Synthesis of (R)-5-(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)-1,3,4-oxadiazole-2-carboxamide

[0368] [ka]

[0369] To a solution of tert-butyl (R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-methyl-1H-pyrazol-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) was added TFA (4 mL). The resulting solution was stirred at room temperature for 2 h. After concentration of the reaction mixture, the residue was dissolved in MeOH (10 mL) and adjusted to pH=8 with aqueous ammonia. Water (20 mL) was then added and the mixture was extracted with DCM / MeOH solution (20:1, 30 mL×3). The organic phase was dried and concentrated to give crude (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide as a yellow solid (2.47 g, yield: 88%), which was used in the next step without further purification. ESI-MS (M+H) + :488.2.

[0370] 3. Synthesis of (R)-5-(tert-butyl)-N-(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

[0371] [ka]

[0372] CH 3To 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-1H-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 CN (30 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.1 g, 4.7 mmol). The mixture was stirred at 50° C. for 12 h. After dilution with water (100 mL), the mixture was extracted with DCM (100 mL×3). The combined organic layers were washed with brine (100 mL), dried (Na 2 SO 4 ), filtered and concentrated. The crude product was purified by silica gel chromatography (DCM:MeOH=10:1) to give (R)-5-(tert-butyl)-N-(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 as a yellow solid (1.2 g, yield: 68%). ESI-MS (M+H) + :570.2. 1 H.N.M. R (400 MHz, CD 3 OD) 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).

[0373] Example 19. 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)-1,3,4-oxadiazole-2-carboxamide (compound 19)

[0374] [ka]

[0375] 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)-1,3,4-oxadiazole-2-carboxamide was similar to that 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 3 in Example 3. The crude product was purified by preparative HPLC (0.05% NH as mobile phase). 4 HCO 3 CH with 3 CN / H 2 0) 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]azepin-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, CD 3 OD) 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).

[0376] Example 20. 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 (compound 20)

[0377] [ka]

[0378] 1. Synthesis of (S)-Tetrahydrofuran-3-yl trifluoromethanesulfonate

[0379] [ka]

[0380] To a solution of (S)-tetrahydrofuran-3-ol (500 mg, 5.7 mmol) and pyridine (538 mg, 6.8 mmol) in DCM (15 mL) at -10 °C, Tf 2 O (1.8 g, 6.3 mmol) was added. The mixture was stirred at -10°C for 0.5 h. The mixture was quenched with 2N HCl solution. The organic layer was separated and washed with Na 2 SO 4The resulting solution of (S)-tetrahydrofuran-3-yl trifluoromethanesulfonate in DCM was used in the next step. ESI-MS (M+H) + :221.0.

[0381] 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

[0382] [ka]

[0383] To 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-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) was added KHMDS (5.2 mL, 5.2 mmol, 1 M solution) dropwise at −78° C. The solution was stirred under nitrogen at −78° C. for 0.5 h. Then, a solution of (S)-tetrahydrofuran-3-yl trifluoromethanesulfonate (from the previous step) was added dropwise. The mixture was stirred at room temperature for 16 h. After dilution with water (40 mL), the mixture was extracted with DCM (40 mL×3). The combined organic layers were washed with brine (60 mL) and dried (Na 2 SO 4), filtered and concentrated. The crude product was purified by silica gel chromatography (DCM:MeOH=10:1) to give 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 as a yellow solid (448 mg, yield: 23%). ESI-MS (M+H) + :558.3. 1 H NMR (400 MHz, DMSO-d 6 ) 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, 1 H), 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), 3.83-380 (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).

[0384] Example 21. 5-(tert-butyl)-N-((R)-2-((S)-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 (compound 21)

[0385] [ka]

[0386] To 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-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide (101 mg, 0.21 mmol) in MeOH (7 mL) was added (S)-2-methyloxirane (29 μL, 0.42 mmol) and cesium carbonate (135 mg, 0.42 mmol). The mixture was stirred at 60° C. for 16 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and the crude product was purified by silica gel chromatography (DCM:MeOH=10:1) to give 5-(tert-butyl)-N-((R)-2-((S)-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 as a yellow solid (50 mg, yield: 44%). ESI-MS (M+H) + :546.0. 1 H NMR (400MHz, methanol-d 4 ) 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), 7.2 2 (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).

[0387] 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-1H-benzo[c]azepiperidin (5-phenyl-1,3,4-oxadiazole-2-carboxamide) (compound 22)

[0388] [ka]

[0389] 1. Synthesis of (R)-Tetrahydrofuran-3-yl trifluoromethanesulfonate

[0390] [ka]

[0391] The synthesis of (R)-tetrahydrofuran-3-yl trifluoromethanesulfonate) was similar to that of (S)-tetrahydrofuran-3-yl trifluoromethanesulfonate) in Example 20, step 1. The resulting DCM solution was used in the next step. ESI-MS (M+H) + :221.0.

[0392] 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 (I-RP58)

[0393] [ka]

[0394] The 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 was carried out in Example 20, Step 2. The crude product was purified by silica gel chromatography (DCM:MeOH=10:1) to give 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 as a yellow solid (50 mg, yield: 38%). ESI-MS (M+H) + :558.1. 1 H NMR (400MHz, methanol-d 4 ) 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 ( br d, 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).

[0395] Example 23. 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 (compound 23)

[0396] [ka]

[0397] 1. Preparation of tert-butyl 8-bromo-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamide)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

[0398] [ka]

[0399] CH 2 Cl 2 To a solution of tert-butyl 8-bromo-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamide)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate (556 mg, 3.06 mmol) in (10 mL) was added HATU (1.16 g, 3.06 mmol) and DIPEA (592 mg, 4.6 mmol). The mixture was stirred at room temperature for 1 h before adding 1-(tert-butyl)-1H-1,2,3-triazole-4-carboxylic acid (1.04 g, 3.06 mmol). The mixture was stirred at room temperature 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 was purified by silica gel column (PE: EtOAc = 1:1) to give tert-butyl 8-bromo-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamide)-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).

[0400] 2. Preparation of tert-butyl 5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

[0401] [ka]

[0402] The synthesis of tert-butyl 5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate was similar to that of tert-butyl 5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate in Example 7. The crude product was purified by silica gel column chromatography (CH 2 Cl 2 :MeOH=20:1) to obtain tert-butyl 5-(1-(tert-butyl) -1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate was obtained as a yellow solid (170 mg, Y: 35%). ESI-MS (M+H) + :601.2.

[0403] 3. Preparation of 1-(tert-butyl)-N-(8-(2-((1-ethyl-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

[0404] [ka]

[0405] The synthesis of 1-(tert-butyl)-N-(8-(2-((1-ethyl-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 was similar to that of 5-(tert-butyl)-N-(8-(2-((1-ethyl-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 7. The crude product (135 mg, yield: 95%) was used in the next step without further purification. ESI-MS (M+H) + :501.2.

[0406] 4. Preparation 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

[0407] [ka]

[0408] The 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 was similar to that of 5-(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)-1,2,4-oxadiazole-3-carboxamide in Example 7. The crude product was purified by silica gel column chromatography (EtOAc:MeOH=10:1) to give 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 as a yellow solid (67 mg, yield: 45%). ESI-MS (M+H) + :556.7. 1 HN MR (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, 1 H), 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 H z, 3H).

[0409] 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-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide (compound 24a) and (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 (compound 24b)

[0410] [ka]

[0411] 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 (50 mg) was subjected to SFC separation (2.1 × 25.0 cm (S,S) Whelk 0-1, 58% methanol / water with 0.5% isopropylamine). CO 2 , 120 bar, 85 mL / min, 230 nm, methanol) yielding 23 mg of peak-1 (chemical purity 99%, ee>99%) and 24 mg of peak-2 (chemical purity 99%, ee=99%).

[0412] Peak 1 was assigned as (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]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide: LCMS: Rt 4.0 min, m / z 557.20.1 H NMR (400 MHz, methanol-d 4 ) 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 (br d, J = 9.04 Hz, 1H), 4.78-4.71 (m, 1H), 4.71-4.65 (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).

[0413] Peak 2 was assigned as (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-d 4 ) 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 (br d, 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 = 12.8 Hz, 9. 7 Hz, 3.6 Hz, 1H), 2.40-2.13 (m, 1H), 2.12-1.87 (m, 1H), 1.74 (s, 9H), 1.47 (t, J=7.28 H z, 3H).

[0414] Example 25. (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-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 25)

[0415] [ka]

[0416] 1. Synthesis of tert-butyl (R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

[0417] [ka]

[0418] The synthesis of tert-butyl (R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate was similar to that of tert-butyl (R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate (Example 9, step 3). The crude material was purified by silica gel chromatography (EtOAc:PE=4:1) to give tert-butyl (R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate as a yellow solid (520 mg, yield: 56%). ESI-MS (M+H) + :615.3.

[0419] 2. Synthesis of (R)-1-(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)-1H-1,2,3-triazole-4-carboxamide

[0420] [ka]

[0421] The synthesis of (R)-1-(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)-1H-1,2,3-triazole-4-carboxamide was similar to that 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 in Example 9, step 4. The crude product was isolated as a yellow solid and used in the next step without further purification (420 mg, yield: 96%). ESI-MS (M+H) + :515.3.

[0422] 3. Synthesis of (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-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide (I-RP35)

[0423] [ka]

[0424] The synthesis of (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-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide was similar to that of (R)-5-(tert-butyl)-N-(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 in Example 17. The crude material was purified by silica gel chromatography. The residue was purified by 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-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 = 8.0 Hz, 1H), 7.11 (s, 1H), 7.03 (d, J = 5.2 Hz, 1H), 5.64 (t, J = 8.0 Hz, 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, 1 H), 2.27-2.23 (m, 1H), 2.10-2.05 (m, 1H), 1 .70 (s, 9H), 1.55 (s, 3H), 1.52 (s, 3H).

[0425] 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)

[0426] [ka]

[0427] 1. Synthesis of 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

[0428] [ka]

[0429] The synthesis of 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 was similar to that of tert-butyl 8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-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-carboxamide)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate as a yellow solid (2.3 g, yield: 95%). ESI-MS (M+H) + :492.2.

[0430] 2. Synthesis of tert-butyl (R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

[0431] [ka]

[0432] The synthesis of tert-butyl (R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate was similar to the synthesis of tert-butyl (R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-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 described in Example 9, step 1. The crude product was used in the next step without purification. ESI-MS (M+H) + :540.3.

[0433] 3. Synthesis of tert-butyl (R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

[0434] [ka]

[0435] Dioxane / H 2 To a solution of tert-butyl (R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate (5.4 g, 10.0 mmol) in 2O (100 mL) was added 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (2.1 g, 10.0 mmol) and stirred at 4°C for 1 h. 2 CO 3 (2.8 g, 20.0 mmol) and Pd(dppf)Cl 2(0.4 g, 0.5 mmol) was added. The mixture was stirred at 100° C. for 16 h under nitrogen. After cooling to room temperature, 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)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-methyl-1H-pyrazol-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 , CDCl 3 ) 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).

[0436] 4. Synthesis of (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

[0437] [ka]

[0438] To a solution of tert-butyl (R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-methyl-1H-pyrazol-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) was added TFA (30 mL). The mixture was stirred at room temperature for 3 h. The solvent was removed. The crude was dissolved in MeOH (30 mL) / water (20 mL). The mixture was diluted with NH 4 The mixture was basified with OH to pH = 8-9 and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine and 2 SO 4 Drying at 40° C., filtering and concentrating gave (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 as a grey solid (2.6 g, yield: 98%). ESI-MS (M+H) + :486.7.

[0439] 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-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide

[0440] [ka]

[0441] A solution of (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 (500 mg, 1.0 mmol) in MeOH (30 mL) was diluted with 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) was added. The mixture was stirred at 50° C. for 16 h. The mixture was concentrated and purified by silica gel column chromatography (DCM / MeOH=20 / 1 to 15 / 1) to give the racemic product as a yellow solid (542 mg, yield: 79%).

[0442] 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 (154 mg) and 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 (167 mg) was isolated by chiral resolution. ESI-MS (M+H) + :557.3.

[0443] Isomer 1: 1 H NMR (400 MHz, CD 3 OD) 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, 2 H), 2.07-1.97 (m, 2H), 1.74 (s, 9H).

[0444] 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, 1 H), 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).

[0445] Example 27a. (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 (Compound 27)

[0446] [ka]

[0447] To a solution of (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 (500 mg, 1.0 mmol) in MeOH (30 mL) was added oxetan-3-one (216 mg, 3.0 mmol), ZnCl 2 (682 mg, 5.0 mmol) and NaBH 3 CN (189 mg, 3.0 mmol) was added. The mixture was stirred at 50° C. for 3 h. The mixture was concentrated and the crude material was purified by silica gel chromatography (CH gradient from 20:1 to 15:1). 2 Cl 2 :MeOH) to obtain (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-tetrahydrofuran -1H-Benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide was obtained 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, 1 H), 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).

[0448] Example 27b. (R)-1-(tert-butyl)-N-(8-(2-((1-(methyl-d3)-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-d3)-1H-pyrazol-4-amine

[0449] [ka]

[0450] A mixture of 4-nitro-1-pyrazole (5.0 g, 44 mmol) and d6-dimethylsulfate (10.0 g, 75.7 mmol) in 1 M aqueous NaOH (50.0 mL) was heated at 35° C. overnight. The solid formed was filtered, washed with water, and dried (Na 2 SO 4 ) to give l-d3-methyl-4-nitro-1-pyrazole as white crystals (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).

[0451] 2. Synthesis of 1-(methyl-d3)-4-nitro-1H-pyrazole

[0452] [ka]

[0453] A solution of 1-d3-methyl-4-nitro-1-pyrazole (3.9 g, 30 mmol) in EtOH (50.0 mL) was degassed with nitrogen followed by the addition of 10% palladium on carbon (0.32 g, 0.30 mmol). The mixture was placed under an atmosphere of hydrogen and stirred at room temperature for 2 h. The mixture was filtered and the filtrate was concentrated in vacuo to give l-(d3-methyl-lH-pyrazol-4-amine as an oil (2.9 g, yield: 96%), which was used in the next step without further purification.

[0454] 3. Synthesis of 4-methoxy-N-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-2-amine

[0455] [ka]

[0456] A solution of 2-chloro-4-methoxypyrimidine (9.4 g, 65.1 mmol) in 1,4-dioxane (0.3 L) was diluted with 1-methyl-d3-1H-piazol-4-amine (8.5 g, 85 mmol), Cs 2 CO 3 (63.6g, 195mmol), S-Phos (13.3g, 0.03mol) and Pd 2 (dba) 3 (16.7 g, 0.02 mol) was added. The reaction mixture was refluxed and N 2 The mixture was stirred under reduced pressure for 16 h. The reaction mixture was cooled to room temperature and the mixture was filtered through a silica gel pad and washed with EtOAc (500 mL). The combined filtrates were 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-d3)-1H-pyrazol-4-yl)pyrimidin-2-amine (9.2 g, yield: 68%) as a pale 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).

[0457] 4. Synthesis of 4-chloro-N-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-2-amine

[0458] [ka]

[0459] To 4-methoxy-N-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-2-amine (9.1 g, 43.7 mmol) was added HBr (90 mL, 38% aqueous solution). The reaction mixture was heated to 100 °C and stirred at that temperature for 3 h. The reaction mixture was cooled to room temperature, concentrated in vacuo, azeotroped with toluene (3 x 100 mL), and dried at 50 °C overnight to give the HBr salt (16 g) as a yellow / brown solid. The salt was then dissolved in POCl 3 (250 mL) and heated to 100° C. for 36 h. The reaction mixture was cooled to room temperature, concentrated in vacuo, and azeotroped with toluene (3×100 mL). The resulting residue was diluted with EtOAc (500 mL) and water (100 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (3×100 mL) and 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 purified with EtOAc / heptane (1:1) to give 4-chloro-N-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-2-amine as a white solid (7.4 g, yield: 80%). ESI-MS (M+H) + :213.0.

[0460] 5. tert-Butyl (R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamide)-8-(2-((1-(methyl-d3)-1H-pi Synthesis of pyrazol-4-ylaminopyrimidin-4-yl-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate

[0461] [ka]

[0462] To a solution of tert-butyl (R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(4,4,5,5-tetramethyl-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-d3)-1H-pyrazol-4-yl)pyrimidin-2-amine (1.8 g, 8.5 mmol), and the resulting mixture was cooled to 5° C. for 1 h. 2 CO 3 (2.4 g, 17 mmol) and Pd(dppf)Cl 2 (0.7 g, 0.85 mmol) was added. The mixture was stirred at 100° C. for 16 h under nitrogen. After cooling to room temperature, the mixture was diluted with EtOAc (300 mL) and washed with saturated brine (100 mL). The aqueous layer was extracted with EtOAc (3×100 mL) and the organics were combined and dried (Na 2 SO 4 ), filtered and concentrated in vacuo to give a residue. The crude material was purified by silica gel column chromatography (gradient heptane / EtOAc = 100:0 to 0:100) to give tert-butyl (R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-(methyl-d3)-1H-pyrazol-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) + :590.4.

[0463] 6. Synthesis of (R)-1-(tert-butyl)-N-(8-(2-((1-(methyl-d3)-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

[0464] [ka]

[0465] CH 2 Cl 2 tert-Butyl (R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-(methyl-d3)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1, To a solution of 3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate (3.2 g, 5.5 mmol) was added TFA (40 mL). The mixture was stirred at room temperature for 3 h. The solvent was removed and the crude material was redissolved in MeOH (30 mL) / water (20 mL). The mixture was diluted with NH 4 Basify with OH to pH=8-9 and CH 2 Cl 2 (3×100 mL). The combined organic layers were washed with brine (100 mL) and 2 SO 4 Drying at 40° C., filtering and concentrating in vacuo afforded (R)-1-(tert-butyl)-N-(8-(2-((1-(methyl-d3)-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 as a yellow solid (3.0 g, yield: 86%). ESI-MS (M+H) + :490.2.

[0466] 7. (R)-1-(tert-butyl)-N-(8-(2-((1-(methyl-d3)-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.

[0467] [ka]

[0468] (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-d3)-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 (2.6 g, 15.9 mmol) was dissolved in MeOH (160 mL) and oxetan-3-one (1.15 g, 16.0 mmol), ZnCl 2 (3.6 g, 26.5 mmol) and NaBH 3 The mixture was stirred at 50° C. for 16 h, concentrated in vacuo, and the crude material was purified by silica gel chromatography (gradient CH 2 Cl 2 :MeOH 100:10) to give a yellow solid, which was then purified by distillation with MeOH (100 mL) and CH 2 Cl 2 (500 mL), washed with water (100 mL) and saturated brine (100 mL), the organic layer separated and dried (Na 2 SO 4 ), filtered and concentrated in vacuo to give (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-d3)-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 as a yellow solid (2.32 g, 67% yield: 55%). ESI-MS (M+H) +:546.3.

[0469] 1 H NMR (400 MHz, DMSO-d 6 ) 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, 1 H), 7.38 (d, J = 8.1 Hz, 1H), 7.25 (d, J = 5.2 Hz, 1H), 5.45 (m, 1H), 4.61-4.47 (m, 4H), 3 .86 (m, 1H), 3.78 (m, 1H), 3.67 (m, 1H), 2.9 3 (m, 1H), 2.77 (m, 1H), 2.12 (m, 1H), 1.86 (m, 1H), 1.66 (s, 9H).

[0470] Example 27c. Preparation of Crystal Form A and Crystal Form G of Compound 27 The 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 added to a 20 L reactor at room temperature (25° C.), followed by 24 L of 1,2-dichloroethane at 25° C. The solution was added with oxetan-3-one (534 g, 24.7 mol), NaBH(OAc) 3 (523 g, 2.47 mol), and AcOH (24 mL, 0.17 equiv.) were added. 3 (1046 g, 4.94 mol) was added to the reactor at room temperature in one portion. The mixture was stirred at 25° C. for 16 h. Ice water (12 kg) was added slowly to the reactor at room temperature. The organic layer was separated and the aqueous layer was extracted three times with dichloromethane (3×12 L). The combined organic layers were washed with brine (20 L) and diluted with Na2 SO 4 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-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 27).

[0471] Purified compound 27 (950 g) and EtOH (5 L) were vigorously stirred for 4 h, the slurry was filtered and washed with 1 L of EtOH, and the resulting wet cake was dried under vacuum at 45° C. for about 24 h until a constant weight was reached to obtain crystalline form A (960 g, 85.7% yield, 99% purity).

[0472] 300.2 mg of crystalline form A was weighed into a 20 mL glass vial, followed by the addition of 6 mL of isopropyl acetate (IPAc) for suspension. The sample was magnetically stirred at 50° C. at a speed of about 1000 rpm for 3 days. After 3 days, the solid was isolated by filtration and then dried under vacuum at room temperature for about 5 hours to produce crystalline form G.

[0473] Alternatively, 2.1 g of crystalline form A was charged with 15 volumes of dichloromethane (mL / g). j -T r = 20K and T jmax =110℃ (in the formula, T j = jacket temperature, T r = reaction / reactor temperature and T jmax Distill under atmospheric conditions using a Dean-Stark trap under conditions of T = maximum jacket temperature). Remove 5 mL or 2 volumes of dichloromethane, followed by the addition of 2 volumes of isopropyl acetate (IPAc). Continue distilling until 10 mL or 5 volumes of solvent(s) have been removed. j -T r =40K and T jmaxDistillation was continued under conditions of C = 110°C. 5 volumes of IPAc were then added, followed by continued distillation to remove an additional 10 mL or 5 volumes of solvent(s). 5 volumes of IPAc were added, followed by an additional 30 mL of IPAc. The resulting mixture was stirred and the temperature cycled from 20°C to 60°C over the weekend to form a slurry from which Form G was isolated.

[0474] Powder X-ray diffraction The crystallinity of the compounds was investigated using an XRD-D8 X-ray powder diffractometer (Bruker, Madison, WI) using Cu Ka radiation. The instrument was equipped with a long microfocus X-ray tube. The tube voltage and current were set at 40 kV and 40 mA, respectively. The divergence and scattering slits were set at 1°, and the receiving slit was set at 0.15 mm. The diffracted radiation was , and detection by a Lynxeye detector. A θ-2θ continuous scan at 1.6° / min from 3 to 42° 2θ was used. Samples were prepared for analysis by placing them on a zero background plate.

[0475] The powder X-ray diffraction (PXRD) pattern of crystalline form A is shown in Figure 1, and the major peaks are listed in Table 1. The PXRD pattern of crystalline form G is shown in Figure 4, and the major peaks are listed in Table 2.

[0476] [Table 1]

[0477] [Table 2]

[0478] Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) The thermal properties of the compounds were investigated using a Discovery Differential Scanning Calorimeter (DSC) (TA Instruments) and a Discovery Thermogravimetric Analyzer (TGA) (TA Instruments). Samples were sealed in closed aluminum DSC pans for DSC analysis and in open aluminum pans for TGA analysis. For both DSC and TGA studies, thermal analysis was performed with a linear gradient from 25°C to 300°C at 10°C per minute.

[0479] Differential scanning calorimetry (DSC) analysis of crystalline form A shows that it has an onset temperature at 175.6° C. and a melting temperature at 186° C. (FIG. 2).

[0480] DSC analysis of crystalline form G shows that it has an onset temperature at 215.4° C. and a melting temperature at 217.3° C. (FIG. 5).

[0481] TGA analysis of Form A of compound 27 showed a weight loss of 3.16%, implying that Form A is a hydrate (Figure 3).

[0482] TGA analysis of compound 27 form G showed no weight loss upon melting, implying that form A is anhydrous (Figure 5).

[0483] solid state NMR 13 C CP / MAS (cross polarization / magic angle spinning) solid-state NMR spectra were acquired on a 363 MHz Tecmag Redstone spectrometer from Spectral Data Services, Champaign, IL. Each sample was packed into a 7 mm (OD) zirconia rotor closed with a Kel-F end cap for subsequent data acquisition. All three samples filled the rotor approximately halfway. 13 C CP / MAS NMR spectra were recorded using a Doty XC 7mm CP / MAS NMR spectrometer at a frequency of 91 MHz. Acquired on a / MAS probe (spin 7kZz, 1H pulse width 5.0 μs, spectral width 29.8 kHz, acquisition time 0.0344 s, CP pulse width 2 ms, relaxation delay 5.0 s, number of scans 1296). Spectra were referenced to the chemical shift of an external sample of the glycine carbonyl carbon at 176 ppm and processed using Nuts (10 Hz line broadening). Spectral peak enumeration and overlay are processed using MNOVA.

[0484] Regarding Form A and Form G 13 The C CP / MAS solid-state NMR is shown in Figures 3B and 6B, respectively. Diagnostic chemical shifts are listed in Table 3.

[0485] [Table 3]

[0486] Example 28. (R)-1-(tert-butyl)-N-(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]azepine-5 -yl)-1H-1,2,3-triazole-4-carboxamide (compound 28)

[0487] [ka]

[0488] CH 3To a solution of (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 (200 mg, 0.4 mmol) in CN (5 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (190 mg, 0.6 mmol). The mixture was stirred at 50° C. for 12 h. After concentration of the reaction mixture, the residue was purified by silica gel chromatography (PE: EtOAc = 1: 1) to give (R)-1- (tert-butyl)-N- (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 as a yellow solid (85 mg, yield: 36%). ESI-MS (M + H) + :569.3. 1 H NMR (400 MHz, CD 3 O.D. 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).

[0489] Example 29. 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-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide (compound 29)

[0490] [ka]

[0491] To a solution of (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 (250 mg, 0.51 mmol) in EtOH (5 mL) was added (R)-2-methyloxirane (58 mg, 1.0 mmol). The mixture was stirred at 50° C. for 24 h. After concentration, the residue was purified by silica gel column (petroleum ether / EtOAc=1:2) to give 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-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide as a white solid (110 mg, yield: 40%). ESI-MS (M+H) + :545.3. 1 H.N.M. R (400 MHz, CD 3 OD) 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. 21-3.12 (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).

[0492] Example 30. 1-(tert-butyl)-N-((R)-2-((S)-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 (compound 30)

[0493] [ka]

[0494] The synthesis of 1-(tert-butyl)-N-((R)-2-((S)-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 was similar to that 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-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide (Example 29). The crude 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)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide as a yellow solid (97 mg, yield: 44%). ESI-MS (M+H) + :545.3. 1 H NMR (400 MHz, CD 3 OD) 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 H z, 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).

[0495] Example 31. (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)-1H-1,2,3-triazole-4-carboxamide (compound 31)

[0496] [ka]

[0497] To a solution of (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 (140 mg, 0.29 mmol) in MeOH (10 mL) was added 1-bromo-2-methoxyethane (121 mg, 0.87 mmol) and K 2 CO 3 (120 mg, 0.87 mmol) was added. The mixture was stirred at 80 °C for 16 h. After dilution with water (20 mL), the mixture was diluted with CH 2 Cl 2 (30 mL x 2). The combined organic layers were extracted with H 2 Wash with 20 mL of HO (20 mL × 2) and dry (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)-1H-1,2,3-triazole-4-carboxamide as a yellow solid (66 mg, yield: 42%). ESI-MS (M+H) + :545.1. 1H NMR (400 MHz, CDCl 3 ) 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 H z, 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).

[0498] Example 32. (R)-5-(tert-butyl)-N-(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 (compound 32)

[0499] [ka]

[0500] CH 3To 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-1H-benzo[c]azepin-5-yl)-1,3,4-oxadiazole-2-carboxamide (105 mg, 0.21 mmol) in CN (8 mL) was added 1,1-difluoro-2-iodoethane (23 μL, 0.26 mmol) and potassium carbonate (89 mg, 0.64 mmol). The mixture was stirred at 80° C. for 18 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and the crude product was purified by preparative HPLC (CH with 0.05% TFA as mobile phase). 3 CN / H 2 0) to give (R)-5-(tert-butyl)-N-(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 as a yellow solid (30 mg, yield: 25%). ESI-MS (M+H) + :552.0. 1 H NMR (400MHz, methanol-d 4 ) δ: 8. 42 (d, J = 5.3 Hz, 1H), 8.23 ​​(d, J = 8.4 Hz, 1 H), 8.19 (s, 1H), 7.95 (s, 1H), 7.68-7.65 (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, 1 H), 5.70 (dd, J = 9.8 Hz, 2.5 Hz, 1H), 4.83 ( br d, J = 14.3 Hz, 1H), 4.67 (br d, J = 14.3 H z, 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)

[0501] Example 33. 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)-1,2,4-oxadiazole-3-carboxamide (compound 33)

[0502] [ka]

[0503] 1. Synthesis of (E)-5-(3-bromophenyl)pent-4-enoic acid

[0504] [ka]

[0505] To a solution of (3-carboxypropyl)triphenylphosphonium bromide (12.87 g, 30 mmol, 1.0 equiv) in dry DMSO (50 mL) was added NaH (3 g, 75 mmol, 2.5 equiv) portionwise at 0 °C. The reaction was stirred at room temperature for 30 min and then 3-bromobenzaldehyde (5.5 g, 30 mmol, 1.0 equiv) was added dropwise. The mixture was stirred at room temperature for an additional 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 mL x 3). The combined organic layers were washed with brine (100 mL x 3). The organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether / EtOAc=2:1) ​​to give (E)-5-(3-bromophenyl)pent-4-enoic acid (4.4 g, yield: 58%) as a yellow oil. ESI-MS (M+1) + :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, 1H), 2.55-2.53 (m, 4H).

[0506] Synthesis of 2.5-(3-bromophenyl)pentanoic acid

[0507] [ka]

[0508] A solution of (E)-5-(3-bromophenyl)pent-4-enoic acid (2.4 g, 9.4 mmol, 1.0 equiv.) in ethanol (20 mL) was added to PtO 2 (200 mg, 10%) was added. The mixture was stirred under hydrogen atmosphere for 1 h. The catalyst was filtered off and the resulting filtrate was concentrated to give the target compound 5-(3-bromophenyl)pentanoic acid (2.1 g, yield: 87%) as a yellow solid, which was used in the next step without further purification. ESI-MS (M+1) + :256.9. 1 H NMR (400 MHz, CD 3 OD) 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).

[0509] 3. Synthesis of 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one

[0510] [ka]

[0511] A mixture of 5-(3-bromophenyl)pentanoic acid (2.1 g, 8.2 mmol, 1.0 equiv) in PPA (5 ml) was stirred at 130 °C for 1 h. After cooling, the mixture was basified with NaOH (1 N) to pH = 7-8. The mixture was extracted with EtOAc (200 mL × 2). The combined organic layers were concentrated and purified by preparative HPLC (gradient: 5% B increasing to 95% B, A: 0.5% NH in water 3 , B:CH 3 Purification by ESI-MS (M+H) gave 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (1.1 g, yield: 56%) as a colorless oil. + :239.0. 1 H NMR (400 MHz, CDCl 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).

[0512] 4. Synthesis of 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ol

[0513] [ka]

[0514] A solution of 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (600 mg, 2.5 mmol, 1.0 equiv) in MeOH (10 mL) was treated with NaBH 4(144 mg, 3.8 mmol, 1.5 equiv) was added and then stirred at room temperature for 1 h. After evaporation of the solvent, the residue was purified by silica gel column (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, CDCl 3 ) 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).

[0515] 5. Synthesis of 5-azido-2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulene

[0516] [ka]

[0517] A solution of 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ol (600 mg, 2.5 mmol, 1.0 equiv.) in toluene (10 mL) was heated in an ice bath with N 2 The mixture was cooled under reduced pressure and treated with DPPA (2.06 g, 7.5 mmol, 3.0 equiv) in one portion followed by DBU (1.14 g, 7.5 mmol, 3.0 equiv). The reaction temperature was maintained at 0° C. for 1 h and then warmed to room temperature for 12 h. The mixture was diluted with EtOAc (100 mL) and washed with 2 N HCl (2×50 mL), brine and the organic layer was washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The crude product was purified by silica gel column (eluted with PE) to give 5-azido-2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulene (350 mg, yield: 45%) as a yellow oil. ESI-MS (M+HN 3) + :223.0. 1 H NMR (400 MHz, CDCl 3 ) δ: 7.31-7.29 (m, 2H), 7.15 (d, J = 8.0 Hz, 1H), 4.72 (t, J = 5.2 Hz, 1H), 2.99-2.92 (m, 1H), 2.70-2.64 (m, 1H), 2.08-2.00 (m, 1H), 1.90-1.59 (m, 5H).

[0518] 6. Synthesis of 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-amine

[0519] [ka]

[0520] THF (5 mL) and H 2 A mixture of 5-azido-2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulene (375 mg, 1.4 mmol, 1.0 equiv) in 20O (0.5 mL) was treated with PPh 3 (741 mg, 2.8 mmol, 2.0 equiv.) was added. The mixture was stirred at room temperature for 12 h. The mixture was acidified with HCl (1N) to pH=1 and extracted with EtOAc (100 mL). The separated aqueous layer was basified with NaOH (1N) to pH=10. The resulting precipitate was collected and dried to give 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-amine (360 mg, yield: 100%) as a white solid. ESI-MS (M+H-17) + :222.9.

[0521] 7. Synthesis of tert-butyl (2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate

[0522] [ka]

[0523] CH 2 Cl 2 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 equiv.) and triethylamine (303 mg, 3.0 mmol, 2.0 equiv.) in 1 mL of Boc 2 0 (394 mg, 1.8 mmol, 1.2 equiv.) was added. The mixture was stirred at room temperature for 2 h. After dilution with EtOAc (100 mL), the mixture was washed with water (100 mL x 2). The organic layer was concentrated and purified by silica gel column (PE: EtOAc = 30: 1) to give tert-butyl (2-bromo-6,7,8,9-tetrahydro-5H-benzo [7] annulen-5-yl) carbamate (310 mg, yield: 61%) as a white solid. ESI-MS (M-55): 284.0. 1 H NMR (400 MHz, CDCl 3 ) δ: 7.29-7.23 (m, 2H), 7.10 (d, J = 8.0 Hz, 1H), 4.92-4.82 (m, 2H), 2.84-2. 75 (m, 2H), 1.88-1.83 (m, 5H), 1.44 (s, 9H).

[0524] 8. Synthesis of tert-butyl (2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate

[0525] [ka]

[0526] The synthesis of tert-butyl (2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate was similar to that of tert-butyl 4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate. The mixture was concentrated and purified by silica gel column (PE:EtOAc=4:1) to give tert-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.

[0527] 9. Synthesis of tert-butyl (2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate

[0528] [ka]

[0529] tert-Butyl (2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate (500 mg, 1.34 mmol), 1-methyl-1H-pyrazol-4-amine (195 mg, 2.01 mmol), Pd 2 (dba) 3 (120mg, 0.13mmol), S-phos (111mg, 0.27mmol) and Cs 2 CO 3 A mixture of (870 mg, 2.68 mmol) was heated at 100 °C for 6 h in N 2The mixture was stirred under reduced pressure. The mixture was filtered through a pad of Celite and the filtrate was concentrated. The residue was purified by silica gel column (EtOAc) to give tert-butyl (2-(2-((1-methyl-1H-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), 2.96-2.94 (m, 2H), 1.93 -1.64 (m, 6H), 1.47 (s, 9H).

[0530] 10. Synthesis of 4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine

[0531] [ka]

[0532] TFA (4.0 mL) and CH 2 Cl 2A mixture of tert-butyl (2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate (240 mg, 0.55 mmol) in (4.0 mL) was stirred at room temperature for 2 hours. The reaction mixture was then concentrated to give the compound 4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (250 mg, crude) as a yellow oil, which was used in the next step without further purification. ESI-MS (M+H) + :335.3.

[0533] 11. Synthesis of 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)-1,2,4-oxadiazole-3-carboxamide

[0534] [ka]

[0535] The synthesis of 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)-1,2,4-oxadiazole-3-carboxamide was similar to that of tert-butyl 8-bromo-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide)-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate in Example 2. The residue was purified by preparative HPLC (0.05% NH as mobile phase). 4 HCO 3 CH with 3 CN / H 2O), and purified by 5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydrofuran. -5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide was obtained as a yellow solid (120 mg, yield: 42%). ESI-MS (M+H) + :487.3. 1 H NMR (400 MHz, CD 3 OD) 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), 3.09-3.0 3 (m, 2H), 2.10-1.43 (m, 6H), 1.54 (s, 9H).

[0536] Example 34. (R)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide (Compound 34)

[0537] [ka]

[0538] 1. Synthesis of (R,Z)-5-((1-phenylethyl)imino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-ol

[0539] [ka]

[0540] 2-Hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (Herdman CA et al., Structural interrogation of benzosuberen-based A slurry mixture of (R)-(+)-α-methylbenzylamine (10 g, 57 mmol), (R)-(+)-α-methylbenzylamine (9.0 g, 74 mmol), and p-toluenesulfonic acid (0.48 g, 2.84 mmol) was heated at reflux in a Dean-Stark apparatus. After 16 h, the Dean-Stark apparatus was removed and reflux was continued until approximately 80 mL of toluene had been distilled, during which time a solid had crystallized. The mixture was cooled to 0 °C and maintained at 0 °C for 2 h, then filtered. Filtered to give (R,Z)-5-((1-phenylethyl)imino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-ol as a brown solid (after drying-13.5 g, yield: 85%). The crude product was used in the next step without further purification.

[0541] 2. Synthesis of (R)-5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-ol acetate

[0542] [ka]

[0543] A slurry 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) was cooled to -5 °C. Solid NaBH 4(5.45 g, 144 mmol) was added portionwise while maintaining the temperature at 5° C. The mixture was stirred at −5° C. for 40 min. After 1 h, water (135 mL) was added, followed by 5N HCl to a pH of about 6. The layers were separated and the aqueous layer was extracted with 135 mL of EtOAc. The combined organics were washed with brine (100 mL), dried (Na 2 SO 4 ) and filtered to give a solution of (R)-5-(((R)-1-phenylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-ol which was carried forward.

[0544] 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 (approximately 185 mL) was added acetic acid (5.8 g, 96 mmol). The solution was then concentrated and carried forward.

[0545] MeOH (200 mL) was added, followed by 10% Pd / C (1.4 g, 10% wt%). The mixture was diluted with H 2 The mixture was stirred at 55° C. for 16 h under an atmosphere of 0.1% (50 psi). The mixture was filtered and the filtrate was concentrated. Methyl tert-butyl ether (100 mL) was added, followed by petroleum ether (100 mL). The mixture was stirred at 25° C. for 2 h and filtered. After drying at 50° C., (R)-5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-ol acetate was isolated (9.9 g for 3 steps, yield: 87%).

[0546] 3. Synthesis of tert-butyl (R)-(2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)carbamate

[0547] [ka]

[0548] A solution of (R)-5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-ol acetate (9.9 g, 42 mmol) in dioxane (50 mL) was diluted with NaHCO 3 Aqueous solution (1N, 100 mL, 100 mmol) was added, followed by Boc 2 2H2O (13.7 g, 63 mmol) was added. The mixture was stirred at room temperature overnight. EtOAc (150 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (150 mL). The combined organic layers were dried (Na 2 SO 4 The mixture was stirred for 2 h, filtered and concentrated. MTBE (150 mL) was added, followed by petroleum ether (150 mL). After stirring for 2 h, the mixture was filtered and the filtrate was concentrated to give an oil. The crude material was purified by silica gel chromatography to give tert-butyl (R)-(2-hydroxy-6,7,8,9-tetrahydro-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-d 6 ) 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 (br s, 2H), 1.99-1.64 (m, 4H), 1.48-1.25 (m, 11H).

[0549] 4. Synthesis of (R)-5-((tert-butoxycarbonyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate

[0550] [ka]

[0551] A solution of tert-butyl (R)-(2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate (1.0 g, 3.6 mmol) and pyridine (570 mg, 7.2 mmol) in DCM (30 mL) was diluted with Tf 2 HO (1.5 g, 5.4 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 1 h. After dilution with water (20 mL), the mixture was extracted with DCM (3 × 40 mL). The combined organic layers were washed with aqueous NaHSO4 (0.5 N, 20 mL) to adjust the aqueous layer to pH = 5-6, dried (Na 2 SO 4 ), filtered and concentrated. The crude product was used in the next step without further purification. ESI-MS (M+H) + :410.1. 1 H NMR (400 MH z, 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).

[0552] 5. Synthesis of tert-butyl (R)-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate

[0553] [ka]

[0554] The synthesis of tert-butyl (R)-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate was similar to that of tert-butyl 5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-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-4-yl)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: 8.41-8.37 (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, 1 H), 1.91-1.82 (m, 5H), 1.28-1.24 (m, 9H).

[0555] 6. Synthesis of (R)-4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine

[0556] [ka]

[0557] The synthesis of (R)-4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine was similar to 5-(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)-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.

[0558] 7. Synthesis of ethyl (Z)-2-amino-2-(((1-methylcyclopropane-1-carbonyl)oxy)imino)acetate

[0559] [ka]

[0560] To a solution of 1-methylcyclopropane-1-carboxylic acid (2 g, 20 mmol) in DCM (50 mL) (COCl) 2 (5 g, 40 mmol) was added. The mixture was stirred at room temperature for 16 h and then concentrated to give the intermediate acyl chloride. To a solution of ethyl (Z)-2-amino-2-(hydroxyimino)acetate (2.6 g, 20 mmol) and triethylamine (6 g, 60 mmol) in DCM (20 mL) was added a solution of the intermediate acyl chloride in DCM (20 mL). The reaction was stirred at room temperature for 2 h, washed with water and sodium hydroxide. 2 SO 4 The mixture was dried by hexanes and concentrated to give ethyl (Z)-2-amino-2-(((1-methylcyclopropane-1-carbonyl)oxy)imino)acetate as a white solid (3.0 g, yield: 63%). ESI-MS (M+H) + :215.1.

[0561] 8. Synthesis of ethyl 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate

[0562] [ka]

[0563] 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. for 2 h and then concentrated. The residue was diluted with DCM (20 mL) and saturated NaHCO 3 Solution (3×10 mL) and washed with Na 2 SO 4 The mixture was dried at 40° C. and concentrated. The residue was purified by silica gel column (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.

[0564] 9. Synthesis of potassium 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate

[0565] [ka]

[0566] Ethyl 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate (1.0 g, 5.0 mmol) and KOH (308 mg, 5.5 mmol) were dissolved in EtOH / H 2 2H 2 O (4:1, 20 mL). The reaction was stirred at room temperature 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.

[0567] 10.Synthesis of N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide (I-IM_6)

[0568] [ka]

[0569] To a solution of potassium 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate (123 mg, 0.6 mmol), DIPEA (232 mg, 0.75 mmol) and HATU (342 mg, 0.9 mmol) in DCM (5 mL) was added (R)-4-(5-amino-6,7,8,9-tetrahydro-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 room temperature for 1 h. After dilution with water (60 mL), the mixture was extracted with DCM (80 mL x 2). The combined organic layers were dried and concentrated. The crude product was purified by preparative HPLC to give (R)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide as a white solid (60 mg, yield: 30%). ESI-MS (M+H) + :485.2. 1 H NMR (400 MHz, CD 3 OD) 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), 2.09-1.86 ( m, 5H), 1.64 (s, 3H), 1.54-1.45 (m, 3H), 1.21-1.18 (m, 2H).

[0570] Example 35. (R)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide (Compound 35)

[0571] [ka]

[0572] 1. Synthesis of tert-butyl (R)-(2-(2-chloropyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate

[0573] [ka]

[0574] The synthesis of tert-butyl (R)-(2-(2-chloropyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate was similar to that of tert-butyl 1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-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-5H-benzo[7]annulen-5-yl)carbamate as a yellow solid (350 mg, yield: 44%). ESI-MS (M+H) + :373.2.

[0575] 2. Synthesis of tert-butyl (R)-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate

[0576] [ka]

[0577] A solution of tert-butyl (R)-(2-(2-chloropyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate (400 mg, 1.1 mmol) in dioxane (20 mL) was diluted with 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) was added. The mixture was heated to 100° C. for 2 h and concentrated. The crude was purified by silica gel column chromatography (MeOH / EtOAc=1 / 50) to give tert-butyl (R)-(2-(2-((1-methyl-1H-pyrazole-4- (yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate (330 mg, yield: 71%) was obtained as a yellow solid. ESI-MS (M+H) + :434.2.

[0578] 3. Synthesis of (R)-4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine

[0579] [ka]

[0580] The synthesis of (R)-4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine was similar to that of 5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)-1,2,4-oxadiazole-3-carboxamide (Example 1, step 13). The crude product (R)-4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine was obtained as a yellow solid (200 mg, yield: 79%). ESI-MS (M+H) + :334.2.

[0581] 4. Synthesis of (R)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide (I-IM_65)

[0582] [ka]

[0583] (R)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide The synthesis of this amide was similar to that of N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide described in Example 34, step 10. The mixture was purified by preparative HPLC (with 0.05% NH as the mobile phase). 3. H 2 CH with O 3 CN / H 2 0) to give (R)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-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, 2 H), 1.49 (s, 9H).

[0584] Example 36. (R)-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-oxadiazole-2-carboxamide (compound 36a)

[0585] [ka]

[0586] 1. Synthesis of (R)-1-(tert-butyl)-N-(8-(2-chloropyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide

[0587] [ka]

[0588] (R)-1-(tert-butyl)-N-(8-(2-chloropyrimidin-4-yl) 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 was similar to that 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 was used in the next step without purification. ESI-MS (M+H) + :427.2.

[0589] 2. Synthesis of (R)-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-oxadiazole-2-carboxamide (compound 36a) and (S)-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-oxadiazole-2-carboxamide (compound 36b)

[0590] [ka]

[0591] 3-tert-Butyl-1,2,4-oxadiazole-5-carboxylic acid {2-[2-(1-methyl-1H-pyrazol-4-ylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-benzocycloheptan-5-yl}-amide (76 mg) was subjected to SFC separation (IA2× (2×15 cm), 30% ethanol / CO 2 , 100 bar, 70 mL / min, 220 nm, injection volume: 1 mL, 5 mg / mL, ethanol) yielding 43 mg of peak-1 (chemical purity 99%, ee > 99%) and 36 mg of peak-2 (chemical purity 99%, ee > 99%).

[0592] Peak 1 was assigned as (R)-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-oxadiazole-2-carboxamide: LCMS: Rt 1.23 min, m / z 487.00. 1 H NMR (400 MHz, methanol-d4) δ 8.41 (d, J = 5.27 Hz, 1H), 7.96 (d, J = 11.80 Hz, 3H), 7.66 ( s, 1H), 7.43 (d, J = 8.53 Hz, 1H), 7.22 (d, J = 5.27 Hz, 1H), 5.43 (d, J = 9.29 Hz, 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).

[0593] Peak 2 was determined as (S)-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-oxadiazole-2 -Assigned as carboxamide: LCMS: Rt 1.23 min, m / z 487.00. 1 H NMR (400 MHz, methanol-d4) δ 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).

[0594] Example 37. 3-(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)-1,2,4-oxadiazole-5-carboxamide (compound 37)

[0595] [ka]

[0596] To a solution of 3-tert-butyl-1,2,4-oxadiazole-5-carboxylic acid (1.00 mg, 0.60 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (273 mg, 0.72 mmol) and 4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (200 mg, 0.6 mmol) in N,N-dimethylformamide (2.3 mL) was added N,N-diisopropylethylamine (0.42 mL, 2.4 mmol). The reaction was stirred at room temperature overnight and quenched with MeOH. After workup, preparative HPLC gave 3-(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)-1,2,4-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) δ: 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).

[0597] Example 38: 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,3,4-oxadiazole-2-carboxamide (compound 38)

[0598] [ka]

[0599] 1. Synthesis of methyl 4-(3-bromophenoxy)butanoate

[0600] [ka]

[0601] A solution of 3-bromophenol (3.44 g, 20.0 mmol) and methyl 4-bromobutanoate (4.32 g, 24.0 mmol) in DMF (20 mL) was diluted with K 2 CO 3 (5.52 g, 40.0 mmol) was added. The mixture was stirred at room temperature for 0.5 h and then heated at 90° C. with stirring for 1 h. After dilution with EtOAc (200 mL), the mixture was washed with water (3×50 mL), dried and concentrated. The crude product was purified by silica gel column chromatography (petroleum / 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.

[0602] 2. Synthesis of 4-(3-bromophenoxy)butanoic acid

[0603] [ka]

[0604] MeOH (40 mL) and H 2 To a solution of methyl 4-(3-bromophenoxy)butanoate (4.9 g, 19 mmol) in O (40 mL) was added NaOH (2.3 g, 57 mmol). The reaction mixture was stirred at 65° C. for 1 h. Then the solvent was concentrated under reduced pressure. The residue was adjusted to pH=3 with HCl (1N). The mixture was extracted with EtOAc (3×100 mL×3). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 4-(3-bromophenoxy)butanoic acid (4.8 g, yield: 98%). The crude product was used in the next step without further purification. ESI-MS (M+H) + :259.1. 1 H 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).

[0605] Synthesis of 3.8-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one

[0606] [ka]

[0607] A solution of 4-(3-bromophenoxy)butanoic acid (1.82 g, 7.04 mmol) in DCM (35 mL) was diluted with SOCl 2 (1.67 g, 14 mmol) and DMF (catalyst) were added. The reaction mixture was stirred at 40° C. for 1 h. The solvent was then removed under reduced pressure and dried in vacuum for 2 h. 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 room temperature for 12 h. The mixture was poured into concentrated HCl (10 mL) and extracted with EtOAc (2 x 50 mL). The organic layer was washed with water (50 mL), 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-dihydrobenzo[b]oxepin-5(2H)-one as 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).

[0608] Synthesis of 4.8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-amine

[0609] [ka]

[0610] A mixture of 8-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one (1.2 g, 5.0 mmol) in i-PrOH (50 mL) was treated with NH 4 OAc (7.63 g, 100 mmol) and NaBH 3CN (3.15 g, 50 mol) was added. The mixture was stirred at 80° C. for 4 h. After cooling, the mixture was basified with NaOH (1N) to pH>12. The mixture was extracted with DCM (250 mL×2). The combined organic layers were dried and concentrated. The resulting residue was purified by silica gel column (DCM:MeOH=20:1) to give 8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-amine as a white solid (900 mg, yield: 75%). ESI-MS (M+H-NH 3 ) + :225.1.

[0611] 5. N-(8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5- Synthesis of (5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamide

[0612] [ka]

[0613] To a solution of 8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-amine (500 mg, 2.23 mmol, 1.0 equiv) in DMF (20 mL) was added potassium 5-tert-butyl-1,3,4-oxadiazole-2-carboxylate (557 mg, 2.68 mmol, 1.2 equiv), HATU (1.3 g, 3.35 mmol, 1.5 equiv) and triethylamine (863 mg, 6.69 mmol, 3.0 equiv). The mixture was stirred at room temperature for 2 h. The solution was diluted with EtOAc (150 mL) and washed with water (50 mL), brine (2×50 mL). The organic layer was dried (Na 2 SO 4 The residue was purified by reverse phase chromatography (0.05% NH 3 .H 2 CH with O 3 CN / H 20) to give N-(8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamide (210 mg, yield: 30%) as a small amount of yellow solid. ESI-MS (M+H) + :394.1.

[0614] 6. Preparation of 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,3,4-oxadiazole-2-carboxamide

[0615] [ka]

[0616] To a mixture of N-(8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamide (393 mg, 1.00 mmol) and PinB-BPin (263 mg, 1.1 mmol) in dry 1,4-dioxane (10 mL), KOAc (196 mg, 2.0 mmol), Pd(dppf)Cl 2 DCM (81 mg, 0.1 mmol) was dissolved in N 2 The mixture was heated at 100 °C for 2 h under N 2 After cooling, 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (209 mg, 1.0 mmol), K 2 CO 3 (276 mg, 2.0 mmol) and H 2 O (2.5 mL) was added. The mixture was heated at 100 °C for 2 h with N 2After cooling, the mixture was concentrated and purified by silica gel column chromatography (DCM / MeOH=20:1) to give 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,3,4-oxadiazole-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).

[0617] Example 39. Synthesis of 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,2,4-oxadiazole-2-carboxamide (compound 39)

[0618] [ka]

[0619] 1. Synthesis of N-(8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-5-(tert-butyl)-1,2,4-oxadiazole-2-carboxamide

[0620] [ka]

[0621] The synthesis of N-(8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide was similar to that of tert-butyl (R)-8-bromo-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate in Example 2, Method 2, Step 2. The crude material was purified by silica gel chromatography (PE: EtOAc = 3: 1) to give N-(8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-5-(tert-butyl)-1,2,4-oxadiazole-2-carboxamide (610 mg, yield: 85%) as a small amount of yellow solid. ESI-MS (M+H) + :394.1.

[0622] 2. Preparation of 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,2,4-oxadiazole-2-carboxamide

[0623] [ka]

[0624] To a mixture of N-(8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-5-(tert-butyl)-1,2,4-oxadiazole-2-carboxamide (135 mg, 0.34 mmol) and PinB-BPin (96 mg, 0.38 mmol) in dry 1,4-dioxane (3 mL), KOAc (68 mg, 0.69 mmol) was added. mol), Pd(dppf)Cl 2 .DCM (24 mg, 0.03 mmol) was dissolved in N 2 The mixture was heated at 100 °C for 2 h under N2 After cooling, 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (71 mg, 0.34 mmol), K 2 CO 3 (95 mg, 0.69 mmol) and H 2 O (0.8 mL) was added. The mixture was heated at 100 °C for 2 h with N 2 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-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,2,4-oxadiazole-2-carboxamide as a yellow solid (77 mg, yield: 46%). ESI-MS (M+H) + :489.2. 1 H NMR (400 MHz, CD 3 OD) δ: 8.35 (d, J = 5.2 Hz, 1H), 7 .91 (s, 1H), 7.78-7.73 (m, 2H), 7.62 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 5.6 H z, 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).

[0625] Example 40. 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)-1,3,4-oxadiazole-2-carboxamide (compound 40)

[0626] [ka]

[0627] Synthesis of 1.3-chlorocyclohept-2-en-1-one

[0628] [ka]

[0629] To a solution of cycloheptane-1,3-dione (20.0 g, 0.16 mol) and DMF (11.6 g, 0.16 mol) in DCM (500 mL) was added oxalyl chloride (24.4 g, 0.19 mol) dropwise at 0° C. After stirring for 30 min at 0° C., the reaction mixture was washed with water (3×500 mL). The aqueous phase was then extracted with diethyl ether (4×300 mL). The combin...

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, Ring A is a 5-membered monocyclic heteroaryl containing three heteroatoms independently selected from N, O, and S, said 5-membered monocyclic heteroaryl being selected from one or more R １ optionally substituted with; Q １ , Q ２ , and Q ３ are each independently O, N(R ２ ), and CH-R ３ is selected from １ , Q ２ , and Q ３ At least two of the are C-R ３ and W is selected from CH and N; Y is selected from CH and N; R １ is, in each occurrence, independently １－６ alkyl and 3- to 5-membered carbocyclyl, １－６ Alkyl and 3- to 5-membered carbocyclyl are each independently one or more R １０ optionally substituted with; R １０ is, in each occurrence, independently, halo, -CN, C １－６ selected from alkyl, and 3- to 5-membered carbocyclyl; R ２ is H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 4- to 6-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, -CN, -C(O)R ２ａ , -C(O) ２ R ２ａ , -C(O)N(R ２ａ ) ２ , -S(O) ２ R ２ａ , and -S(O) ２ N (R ２ａ ) ２ and C is selected from １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl are each independently selected from the group consisting of one or more R ２０ optionally substituted with; R ２ａ is, in each occurrence, independently: H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each represent one or more R ２０ is optionally independently substituted with; R ２０ is, in each occurrence, independently １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 4- to 6-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halo, -CN, -C(O)R ２０ａ , -C(O) ２ R ２０ａ , -C(O)N(R ２０ａ ) ２ , -N(R ２０ａ ) ２ , -N(R ２０ａ ) C(O)R ２０ａ , -N(R ２０ａ ) C(O) ２ R ２０ａ , -N(R ２０ａ ) C(O)N(R ２０ａ ) ２ , -N(R ２０ａ ) S (O) ２ R ２０ａ , -OR ２０ａ , -OC(O)R ２０ａ , -OC(O)N(R ２０ａ ) ２ , -SR ２０ａ , -S(O)R ２０ａ , -S(O) ２ R ２０ａ , -S(O)N(R ２０ａ ) ２ , and -S(O) ２ N (R ２０ａ ) ２ Selected from: R ２０ａ is, in each occurrence, independently: H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ selected from alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R ３ is H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 4- to 6-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halo, -CN, -C(O)R ３ａ , -C(O) ２ R ３ａ , -C(O)N(R ３ａ ) ２ , -N(R ３ａ ) ２ , -N(R ３ａ ) C(O)R ３ａ , -N(R ３ａ ) C(O) ２ R ３ａ , -N(R ３ａ ) C(O)N(R ３ａ ) ２ , -N(R ３ａ ) S (O) ２ R ３ａ , -OR ３ａ , -OC(O)R ３ａ , -OC(O)N(R ３ａ ) ２ , -SR ３ａ , -S(O)R ３ａ , -S(O) ２ R ３ａ , -S(O)N(R ３ａ ) ２ , and -S(O) ２ N (R ３ａ ) ２ and C is selected from １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl are each independently selected from the group consisting of one or more R ３０ optionally substituted with; R ３ａ is, in each occurrence, independently: H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each represent one or more R ３０ is optionally independently substituted with; R ３０ is, in each occurrence, independently １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 4- to 6-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halo, -CN, -C(O)R ３０ａ , -C(O) ２ R ３０ａ , -C(O)N(R ３０ａ ) ２ , -N(R ３０ａ ) ２ , -N(R ３０ａ ) C(O)R ３０ａ , -N(R ３０ａ ) C(O) ２ R ３０ａ , -N(R ３０ａ ) C(O)N(R ３０ａ ) ２ , -N(R ３０ａ ) S (O) ２ R ３０ａ , -OR ３０ａ , -OC(O)R ３０ａ , -OC(O)N(R ３０ａ ) ２ , -SR ３０ａ , -S(O)R ３０ａ , -S(O) ２ R ３０ａ , -S(O)N(R ３０ａ ) ２ , and -S(O) ２ N (R ３０ａ ) ２ Selected from: R ３０ａ is, in each occurrence, independently: H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ selected from alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R ４ is H and C １－６ alkyl, １－６ The alkyl is optionally substituted with one or more halo; R ５ is H and C １－６ alkyl, １－６ The alkyl is optionally substituted with one or more halo; R ６ is H and C １－６ alkyl, １－６ The alkyl is optionally substituted with one or more halo; Or R ５ and R ６ together with the atom to which they are attached form a ring containing 1 or 2 heteroatoms selected from O, N, and S, said ring being joined by one or more R ５０ optionally substituted with; R ５０ is C １－６ (alkyl).

2. Q １ , Q ２ and Q. ３ are each independently CH-R ３ 2. The compound of claim 1, wherein:

3. Q ２ is N(R ２ ), and Q １ and Q. ３ are each independently CH-R ３ 2. The compound of claim 1, wherein:

4. Q ３ is N(R ２ ), and Q １ and Q. ２ are each independently CH-R ３ 2. The compound of claim 1, wherein:

5. Q １ is O and Q ２ and Q. ３ are each independently CH-R ３ 2. The compound of claim 1, wherein:

6. 6. The compound of any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, wherein W is CH.

7. The compound according to any one of claims 1 to 6, wherein Y is N, or a pharma- ceutically acceptable salt thereof.

8. The compound has the following formula: 【Chemistry 2】 2. The compound of claim 1, represented by one of: or a pharma- ceutically acceptable salt thereof.

9. The compound has the following formula: 【Chemistry 3】 2. The compound of claim 1, represented by one of: or a pharma- ceutically acceptable salt thereof.

10. Ring A is selected from 1,2,3-oxadiazole, 1,3,4-oxadiazole, 1,2,4-oxadizole, 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 selected from one or two R １ 10. The compound of any one of claims 1 to 9, optionally substituted with: or a pharma- ceutically acceptable salt thereof.

11. Ring A has the following formula: 【Chemistry 4】 10. The compound according to any one of claims 1 to 9, represented by one of:

12. R １ is, in each occurrence, independently １－６ Alkyl or C ３－５ cycloalkyl; １－６ Alkyl and C ３－５ Cycloalkyl is one to three R １０ optionally substituted with; R １０ is, in each occurrence, independently selected from halo, -CN and C １－６ 12. The compound of any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein: R is selected from the group consisting of alkyl, aryl, arylsulfates, arylalkyl, arylsulfates ...

13. R １ is, in each occurrence, independently １－４ alkyl, cyclopropyl, or cyclobutyl; １－４ Alkyl, cyclopropyl and cyclobutyl are each independently one to three R １ ０ optionally substituted with; R １０ is, in each occurrence, independently selected from halo, -CN and C １－３ The compound according to any one of claims 1 to 11, wherein the aryl group is selected from alkyl.

14. R １ is, in each occurrence, independently -C(CH ３ ) ３ , -CH(CH ３ ) ２ , -C(CH ３ ) ２ CHF ２ , -C(CH ３ ) ２ CF ３ , -C(CH ３ ) ２ CH ２ F, -C(CH ３ ) ２ 12. The compound of any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, selected from CN, 1-methylcyclopropyl, cyclobutyl, and 3,3-difluorocyclobutyl.

15. R １ is -C(CH ３ ) ３ 15. The compound of claim 14, which is: or a pharma- ceutically acceptable salt thereof.

16. R ２ is H, C １－６ Alkyl, C ４－６ Cycloalkyl, saturated 4-6 membered monocyclic heterocyclyl, -C(O)R ２ａ , -C(O) ２ R ２ａ , and -S(O) ２ R ２ａ and C is selected from １－６ Alkyl, C ４－６ Cycloalkyl and saturated 4- to 6-membered monocyclic heterocyclyl are each independently one to three R ２０ optionally substituted with; R ２ａ is, in each occurrence, independently: H, C １－６ Alkyl, C ４－６ alkyl, and saturated 4- to 6-membered monocyclic heterocyclyl; １－６ Alkyl, 4- to 6-membered monocyclic carbocyclyl, and saturated 4- to 6-membered monocyclic heterocyclyl each represent one or more R ２０ is optionally independently substituted with; R ２０ is, in each occurrence, independently １－６ Alkyl, C ４－６ Cycloalkyl, saturated 4-6 membered monocyclic heterocyclyl, halo, -CN, -N(R ２０ａ ) ２ , and -OR ２０ａ Selected from: R ２０ａ is, in each occurrence, independently, H or C １－６ is alkyl, 16. The compound according to any one of claims 1 to 15, or a pharma- ceutically acceptable salt thereof.

17. R ２ is H, C １－６ C selected from alkyl, cyclobutyl, cyclopentyl and cyclohexyl ４－６ saturated 4-6 membered monocyclic heterocyclyl selected from cycloalkyl, 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) ２ R ２ａ , and -S(O) ２ R ２ａ and C is selected from １－６ Alkyl, C ４－６ Cycloalkyl and saturated 4- to 6-membered monocyclic heterocyclyl are each independently one to three R ２０ optionally substituted with; R ２ａ is 1 to 3 R ２０ C optionally independently substituted with １－６ is alkyl; R ２０ is, in each occurrence, independently １－３ Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, halo, -N(R ２０ａ ) ２ , and -OR ２０ａ Selected from: R ２０ａ is, in each occurrence, independently, H or C １－３ is alkyl, 17. The compound of claim 16, or a pharma- ceutically acceptable salt thereof.

18. R ２ is H, C １－６ Alkyl, cyclobutyl, cyclopentyl and cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, -C(O)R ２ａ , -C(O) ２ R ２ａ , and -S(O) ２ R ２ａ and C is selected from １－６ Alkyl, cyclobutyl, cyclopentyl and cyclohexyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl are each independently one to three R ２０ optionally substituted with; R ２ａ is one R ２０ C optionally substituted with １－６ is alkyl; R ２０ is, in each occurrence, independently １－３ Alkyl, cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, halo, -N(R ２０ａ ) ２ , and -OR ２０ａ Selected from: R ２０ａ is, independently in each occurrence, H or methyl; 17. The compound of claim 16, or a pharma- ceutically acceptable salt thereof.

19. R ２ は、-H、-SO ２ CH ３ 、-C(=O)OC(CH ３ ) ３ 、-C(=O)CH ２ N(CH) ３ ) ２ 、-CH ３ 、-CH ２ CH ３ 、-CH ２ CH ２ OH、-H ２ CH ２ OCH ３ 、-CH ２ CH ２ OCH ２ CH ３ 、-CH ２ HH(H) ３ )OH、-H ２ C(CH) ３ ) ２ OH、-H ２ CH ２ CH ２ OH、-H ２ CHF ２ 、-CH ２ CF ３ 、 【Chemistry 5】 17. The compound of claim 16, selected from:

20. R ２ は、-CH ２ CHF ２ 、-CH ２ CF ３ 、-CH ２ CH ２ OH、-H ２ HH(H) ３ )OH、-H ２ CH ２ OCH ３ 、 【Chemistry 6】 17. The compound of claim 16, selected from:

21. R ３ is H, C １－６ Alkyl, C ４－６ Cycloalkyl, saturated 4-6 membered monocyclic heterocyclyl, halo, -OR ３ａ , -OC(O)R ３ａ , -OC(O)N(R ３ａ ) ２ , and -SR ３ａ and C is selected from １－６ Alkyl, C ４－６ Cycloalkyl and saturated 4- to 6-membered monocyclic heterocyclyl are each independently one to three R ３０ optionally substituted with; R ３ａ is, in each occurrence, independently, H or C １－６ alkyl, １－６ Alkyl is, in each case, one R ３０ is optionally independently substituted with; R ３０ is, in each occurrence, independently １－６ selected from alkyl, 21. The compound according to any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof.

22. R ３ is H, halo, and -OR ３ａ is selected from; ３ａ are independently H or C １－３ 22. The compound of claim 21, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

23. R ３ is selected from H, -F and -OH, or a pharma- ceutically acceptable salt thereof.

24. R ４ is H or C optionally substituted with 1 to 3 fluoro １－３ 24. The compound of any one of claims 1 to 23, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

25. R ４ is H or methyl, or a pharma- ceutically acceptable salt thereof.

26. R ５ is H or C optionally substituted with 1 to 3 fluoro １－３ 26. The compound of any one of claims 1 to 25, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

27. R ５ 27. The compound of claim 26, wherein is H, methyl, ethyl or isopropyl, or a pharma- ceutically acceptable salt thereof.

28. R ６ is H or C optionally substituted with 1 to 3 fluoro １－３ Alkyl, 28. The compound according to any one of claims 1 to 27, or a pharma- ceutically acceptable salt thereof.

29. R ６ 30. The compound of claim 28, or a pharma- ceutically acceptable salt thereof, wherein: is H, methyl or trifluoromethyl.

30. R ５ and R ６ together with the atom to which they are attached form a 5-6 membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from O, N, and S, said ring being bound to one R ５０ optionally substituted with; R ５０ is C １－３ 26. The compound of any one of claims 1 to 25, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

31. 31. The compound of claim 30, or a pharma- ceutically acceptable salt thereof, wherein said 5-6 membered saturated heterocyclic ring is pyrrolidine, piperazine or N-methylpiperazine.

32. The compound has the following formula: 【Chemistry 7】 or a pharma- ceutically acceptable salt thereof, Ring A has the following formula: 【Chemistry 8】 is represented by one of: R １ is C １－６ is alkyl; R ２ is C １－６ alkyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl, １－６ Alkyl is one to three R ２０ optionally substituted with; R ２０ is, for each occurrence, independently halo or -OR ２０ａ and R ２０ａ is H or C １－３ is alkyl; R ３ is H; R ５ is H or C １－３ is alkyl) 2. The compound of claim 1, represented by: or a pharma- ceutically acceptable salt thereof.

33. The compound has the following formula: 【Chemistry 9】 2. The compound of claim 1, represented by: or a pharma- ceutically acceptable salt thereof.

34. R １ is tert-butyl, or a pharma- ceutically acceptable salt thereof.

35. R ２ teeth, 【Chemistry 10】 -CH ２ CHF ２ , -CH ２ CF ３ , -CH ２ CH ２ OH, -CH ２ CH ２ OCH ３ , or -CH ２ C (CH ３ 35. The compound of claim 32, 33, or 34, or a pharma- ceutically acceptable salt thereof, wherein: R is 0, R is 1, R is 2, R is 3, or R is 4.

36. R ３ is H, or a pharma- ceutically acceptable salt thereof.

37. R ５ The compound according to any one of claims 32 to 36, or a pharma- ceutically acceptable salt thereof, wherein is methyl or isopropyl.

38. (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazo Crystal form A of)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide.

39. 39. The crystalline form A of claim 38, wherein 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°.

40. 39. The crystalline form A of claim 38, wherein the crystalline form is characterized by at least four PXRD peaks at 2θ angles selected from 5.7°, 7.9°, 9.7°, 18.2°, 19.0°, and 22.4°.

41. 39. The crystalline form A of claim 38, wherein the crystalline form is characterized by at least five PXRD peaks at 2θ angles selected from 5.7°, 7.9°, 9.7°, 18.2°, 19.0°, and 22.4°.

42. 39. The crystalline form A of claim 38, wherein the crystalline form is characterized by PXRD peaks at 2θ angles selected from 5.7°, 7.9°, 9.7°, 18.2°, 19.0°, and 22.4°.

43. 39. The crystalline form A of claim 38, wherein the crystalline form is characterized by PXRD peaks 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°.

44. 44. The crystalline form A of any one of claims 38 to 43, wherein the crystalline form A is characterized by a melting temperature of 186.0°C ± 2°C as determined by differential scanning calorimetry (DSC) analysis.

45. The crystalline form A of any one of claims 38 to 44, wherein the crystalline form has a DSC profile substantially the same as the DSC profile shown in Figure 2.

46. The crystalline form A according to any one of claims 38 to 45, wherein the crystalline form A is a hydrate.

47. 47. The crystalline form A of any one of claims 38 to 46, wherein the crystalline form A is at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5% or 99.9% pure.

48. Crystal form G of (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.

49. 49. The crystalline form G of claim 48, wherein 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°.

50. The crystalline forms are 3.6°, 8.9°, 10.9°, 12.6°, 20.2° and 21°.

49. The crystalline form G of claim 48, characterized by at least four PXRD peaks at 2θ angles selected from .8°.

51. 49. The crystalline form G of claim 48, wherein the crystalline form is characterized by PXRD peaks at 2θ angles selected from 3.6°, 8.9°, 10.9°, 12.6°, 20.2°, and 21.8°.

52. 49. The crystalline form G of claim 48, wherein the crystalline form is characterized by PXRD peaks 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°, 25.4°, 26.8°, and 34.2°.

53. 53. The crystalline form G of any one of claims 48 to 52, wherein the crystalline form G has a melting temperature of 217.3°C ± 2°C as determined by Differential Scanning Calorimetry (DSC) analysis.

54. The crystalline form G of any one of claims 48 to 53, wherein the crystalline form G has a DSC profile substantially the same as the DSC profile shown in Figure 5.

55. The crystalline form G according to any one of claims 48 to 54, wherein the crystalline form G is anhydrous.

56. 56. The crystalline form G of any one of claims 48 to 55, wherein the crystalline form G is at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5% or 99.9% pure.

57. 56. A pharmaceutical composition comprising: (i) a compound according to any one of claims 1 to 37, or a pharma- ceutically acceptable salt thereof; (ii) crystalline form A according to any one of claims 38 to 47; or (iii) crystalline form G according to any one of claims 48 to 56, and a pharma- ceutically acceptable excipient.

58. 57. A method of treating a disorder responsive to inhibition of Bruton's tyrosine kinase in a subject, comprising administering to the subject an effective amount of (i) a compound according to any one of claims 1 to 37, or a pharma- ceutically acceptable salt thereof, (ii) crystalline form A according to any one of claims 38 to 47, or (iii) crystalline form G according to any one of claims 48 to 56.

59. 59. The method of claim 58, wherein the disorder is an autoimmune disorder.

60. 60. The method of claim 59, wherein the autoimmune disorder is multiple sclerosis.

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