BTK inhibitors

Abstract

Compounds of formula (I) TIFF2023537065000456.tif8264 or a pharmaceutically acceptable salt thereof. 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , A 1 , A 2 , Q 1 , Q 2 , Q 3 , A, Z, m, and n are as defined herein. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, and a method of treating a disorder responsive to Bruton's tyrosine kinase inhibition using the compound, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition are provided.

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of the filing date under 35 U.S.C. §119(e) of U.S. Provisional Application No. 63 / 063,188, filed August 7, 2020, and U.S. Provisional Application No. 63 / 189,476, filed May 17, 2021, the entire contents of which are incorporated herein by reference.

[0002] Provided are certain agents that inhibit Bruton's tyrosine kinase (Btk), 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 many human diseases in oncology, neurology, and immunology. Tec kinases are non-receptor tyrosine kinases consisting of five members: Tec (a tyrosine kinase expressed in hepatocellular carcinoma), Btk (Bruton's tyrosine kinase), Itk (interleukin-2 (IL-2)-inducible T cell kinase; also known as Emt or Tsk), Rlk (resting lymphocyte kinase; also known as Txk), and Bmx (myeloid tyrosine kinase gene on chromosome X; also known as Etk). These kinases are primarily expressed in hematopoietic cells, although Bmx and Tec have been detected in endothelial and hepatic cells. Tec kinases (Itk, Rlk, and Tec) are expressed in T cells and are 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). Binding of PIP3 induces Btk to phosphorylate phospholipase C (PLCy), which hydrolyzes PIP2 to generate two second messengers, inositol triphosphate (IP3) and diacylglycerol (DAG), which activate the protein kinase PKC, which in turn induces further B cell signaling. Mutations that impair Btk enzymatic activity result in the primary immunodeficiency disorder XLA syndrome (X-linked agammaglobulinemia). Given that Tec kinase plays an important role in both B cell and T cell signaling, Tec kinase is an intended target in autoimmune disorders.

[0004] Therefore, 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 is a compound of formula (I) [ka] A compound represented by or a pharmaceutically acceptable salt thereof; A 1 and A 2 One of them is CR 6A and A 1 and A 2 The other is CR 6A or N, Q 1 is CR 6 and N, Q 2 is CR 6 and N, Q 3 is CR 6 and N, Q 1 , Q 2 , and Q 3 at most one of them is N, Ring A is one or more R 11 is a 4- to 8-membered monocyclic saturated or partially saturated heterocyclyl substituted with n is 0 or 1, m is 0 or 1, R 1 is -N(R 1a )2, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, 5- to 6-membered heteroaryl, 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl, 8- to 10-membered bicyclic heteroaryl, and 9- to 10-membered bicyclic aryl; R 1 The phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, 5- to 6-membered heteroaryl, 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl, and 9- to 10-membered bicyclic aryl each optionally may have one or more R 12 is replaced by R1a independently for each occurrence, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, phenyl, a 3- to 7-membered saturated or partially unsaturated carbocyclyl ring, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and a 5- to 6-membered heteroaryl; R 1a C, represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, 3- to 7-membered saturated or partially unsaturated carbocyclyl ring, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and 5- to 6-membered heteroaryl each optionally contain one or more R 12 is replaced by Or, two R on the same nitrogen 1a groups, together with their intervening atoms, form a ring selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl and 5- to 6-membered heteroaryl, and the ring optionally contains one or more R 12 is replaced by R 12 independently for each occurrence, a halogen, -OR 12a , -S(O)2R 12a , -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 4- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl; R 12 C, represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 4- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl each optionally contain one or more R 15 is replaced by R 12a is C optionally substituted with one or more halogens 1-6 is alkyl, R 15independently for each occurrence, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -CN, and -OR 15a is selected from R 15a is C 1-6 is alkyl, R 2 is H, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 is alkynyl, or Or, R 1 and R 2 together with their intervening atoms form ring B selected from 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl, 7-10 membered saturated or partially unsaturated bicyclic heterocyclyl, and 8-10 membered bicyclic heteroaryl, and ring B optionally contains one or more R 100 is replaced by R 100 independently for each occurrence, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 R is selected from alkynyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 4- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl, and halogen; 100 C, represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 4- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl each optionally contain one or more R 150 is replaced by R 150 independently at each occurrence, a halogen and -OR 150a is selected from R 150a is C 1-6 is alkyl, R 3 is H, halogen, -C(O)N(R 3a )2, -C(O)OR 3a , -C(O)R 3a , C 1-6Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, and R 3 C, represented by 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 each alkynyl is optionally substituted with one or more substituents selected from halogen and hydroxyl; R 3a independently for each occurrence, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, phenyl, a 3- to 7-membered saturated or partially unsaturated carbocyclyl ring, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, or a 5- to 6-membered heteroaryl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, 3- to 7-membered saturated or partially unsaturated carbocyclyl ring, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and 5- to 6-membered heteroaryl may optionally be joined by one or more R 30 is replaced by Or, two R on the same nitrogen 3a groups, together with their intervening atoms, form a ring selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl and 5- to 6-membered heteroaryl, and the ring optionally contains one or more R 30 is replaced by R 30 independently for each occurrence, a halogen, -OR 30a , -N(R 30a )2, -C(O)N(R 30a ), -C(O)R 30a , Oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 selected from alkynyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 4- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl; R 30a is H or C 1-6 is alkyl, R 4 is H, halogen, -NO2, -CN, -OR 4a , -SR 4a , -N(R 4a )2, -C(O)R 4a , -C(O)OR 4a , -S(O)R 4a , -S(O)2R 4a , -C(O)N(R 4a )2, -SO2N(R 4a )2, -OC(O)R 4a , -N(R 4a )C(O)R 4a , -N(R 4a )C(O)OR 4a , -N(R 4a )SO2R 4a , -OC(O)N(R 4a )2, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 alkynyl, 1-6 Alkyl, the C 2-6 Alkenyl and the C 2-6 Each alkynyl optionally contains one or more R 40 is replaced by R 4a is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, phenyl, 3- to 8-membered saturated or partially unsaturated carbocyclyl ring, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and 5- to 6-membered heteroaryl; 4a C, represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, 3- to 8-membered saturated or partially unsaturated carbocyclyl ring, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl, and 5- to 6-membered heteroaryl each optionally contain one or more R 40 is replaced by Or, two R on the same nitrogen 4agroups, together with their intervening atoms, form a ring selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl and 5- to 6-membered heteroaryl, and the ring optionally contains one or more R 40 is replaced by R 40 independently for each occurrence, a halogen, -OR 40a , -N(R 40a )2, -C(O)N(R 40a )2, -C(O)2R 40a , Oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 40 C, represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each optionally include one or more R 45 is replaced by R 40a is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each optionally include one or more R 45 is replaced by R 45 independently for each occurrence, C 1-6 Alkyl, halogen, and -OR 45a is selected from R 45a is H or C 1-6 Is it alkyl? Or, R 3 and R 4 together with the atoms between them form a ring C, ring C being selected from a 5- to 7-membered monocyclic carbocycle and a 5- to 7-membered monocyclic heterocycle, ring C optionally being selected from R300 is replaced by R 300 independently for each occurrence, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halogen, -C(O)R 300a , -OR 300a , and -S(O)R 300a Selected from R 300 C, represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each optionally include one or more R 350 is replaced by R 300a is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 300a C, represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each optionally include one or more R 350 is replaced by R 350 independently for each occurrence, C 1-6 Alkyl, halogen, -CN, C(O)R 350a , -C(O)N(R 350a )2, -C(R 350a )2N(R 350a )2, and -OR 350a is selected from R 350a is independently at each occurrence H or C optionally substituted with 1 to 3 halogens 1-6 is alkyl, R 5 H, -NHR 5s , or -NHC(O)R 5s is selected from R5a is H or C 1-6 is alkyl, R 6 and R 6A independently for each occurrence, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, -NO2, -CN, -OR 6a , -SR 6a , -N(R 6a )2, -C(O)R 6a , -C(O)OR 6a , -S(O)R 6a , -S(O)2R 6a , -C(O)N(R 6a )2, -SO2N(R 6a )2, -OC(O)R 6a , -N(R 6a )C(O)R 6a , -N(R 6a )C(O)OR 6a , -N(R 6a )SO2R 6a , and -OC(O)N(R 6a ) and R 6a is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 6a C, represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each optionally contain one or more R 60 is replaced by R 60 independently for each occurrence, a halogen, -OR 60a , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 60 C, represented by 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl may optionally be one or more R 65 is replaced by R 60a is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 60a C, represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each optionally contain one or more R 65 is replaced by R 65 independently for each occurrence, C 1-6 Alkyl, halogen, and -OR 65a is selected from R 65a is H or C 1-6 is alkyl, R 7 and R 8 are each independently H or halogen and C 1-6 C optionally substituted with one or more substituents independently selected from alkoxy 1-6 is alkyl, R 9 is H, C 1-6 Alkyl or C 3-6 is cycloalkyl, C 1-6 Alkyl is halogen and C 1-6 optionally substituted with one or more substituents independently selected from alkoxy, C 3-6 Cycloalkyl is C 1-6 Alkyl, halogen, C 1-6 Haloalkyl and C 1-6 optionally substituted with one or more substituents independently selected from alkoxy; or if m is 1, R 9 and R of ring A 11together with the intervening atoms, optionally halogen, -CN, -OH, C 1-6 Alkyl and C 1-6 forming a 4- to 7-membered monocyclic saturated or partially saturated heterocyclyl substituted with one or more substituents independently selected from alkoxy; Z is -C(=O)R 10 , -SO2R 10 , or -CN, R 10 is C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Alkylenyl oxide, or C 4-7 is cycloalkenyl, and R 10 C, represented by 2-6 Alkenyl is C 1-6 Alkyl, C 1-6 Alkoxy and -NR 10a R 10b and R 200 C, represented by 2-6 Alkynyl is C 1-6 Alkyl and C 1-6 optionally substituted with one or more substituents independently selected from alkoxy; 10 C, represented by 2-6 Alkylene oxides may have one or more C 1-6 optionally substituted with alkyl; R 10a and R 10b are each independently H or C 1-3 alkyl, or R 10a and R 10b together with the nitrogen atom to which they are attached, form halo and C 1-6 forming a 4- to 7-membered monocyclic saturated heterocyclyl optionally substituted with one or more substituents independently selected from alkyl; R 11 is independently H, halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6or two R independently selected from alkoxy 11 together with the same carbon atom to which they are attached to form a -C(=O)- group.

[0006] The present invention also provides pharmaceutical compositions comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0007] In one embodiment, the invention is a method for treating a disorder responsive to Btk inhibition in a subject, comprising administering to the subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0008] The present invention also includes the use of at least one compound described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disorder responsive to Btk inhibition. Also provided are compounds described herein, or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions described herein, for use in the treatment of a disorder responsive to Btk inhibition.

[0009] Other features or advantages will be apparent from the following detailed description of several embodiments, and from the appended claims. DETAILED DESCRIPTION OF THE INVENTION

[0010] The compounds described herein, or pharmaceutically acceptable salts thereof, can have activity as Btk modulators. In particular, the compounds described herein, or pharmaceutically acceptable salts thereof, can be Btk inhibitors.

[0011] In a second embodiment, the compound of the present invention is a compound of formula (I), or a pharmaceutically acceptable salt thereof: R 15 independently at each occurrence, a halogen and -OR 15a is selected from R 10 is C 2-6 Alkenyl, C 2-6 Alkynyl, or C 2-6 alkylenyl oxide, and R 10 C, represented by 2-6 Alkenyl is C 1-6 Alkyl, C 1-6 Alkoxy and -NR 10a R 10b and R 10 C, represented by 2-6 Alkynyl is C 1-6 Alkyl and C 1-6 optionally substituted with one or more substituents independently selected from alkoxy; 10 C, represented by 2-6 Alkylene oxides may have one or more C 1-6 optionally substituted with alkyl; R 10a and R 10b are each independently H or C 1-3 is alkyl, R 11 is independently H, halogen, -CN, -OH, C 1-6 Alkyl and C 1-6 or two R independently selected from alkoxy 11 together with the same carbon atom to which they are attached to form a -C(=O)- group, where the other variables are defined as in the first embodiment.

[0012] In a third embodiment, the compound of the present invention is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , and Q 3 is CR 6 and the definitions of the other variables are as defined in the first or second embodiment.

[0013] In a fourth embodiment, the compound of the present invention is a compound of formula (I), or a pharmaceutically acceptable salt thereof, 1is N and A 2 is CR 6A and the definitions of the other variables are as defined in the first, second, or third embodiment.

[0014] In a fifth embodiment, the compound of the present invention is a compound of formula (I), or a pharmaceutically acceptable salt thereof, 1 and A 2 Both are CR 6A and the definitions of the other variables are as defined in the first, second, or third embodiment.

[0015] In a sixth embodiment, the compound of the present invention has the formula (IIA) or the formula (IIB) [ka] A compound represented by or a pharmaceutically acceptable salt thereof, wherein the definitions of the variables are as defined in the first, second, third, fourth, or fifth embodiment.

[0016] In a seventh embodiment, the compound of the present invention is a compound of formula (I), (IIA), or (IIB), or a pharmaceutically acceptable salt thereof, wherein R 1 is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from O, N, and S, or a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from O, N, and S; R 1 The 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl and 5- to 6-membered heteroaryl represented by the formula: 10 and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, or sixth embodiment.

[0017] In an eighth embodiment, the compound of the present invention is a compound of formula (I), (IIA), or (IIB), or a pharmaceutically acceptable salt thereof, wherein R1 is one or two R 10 and the other variables are as defined in the first, second, third, fourth, fifth, sixth, or seventh embodiment.

[0018] In a ninth embodiment, the compound of the present invention is a compound of formula (I), (IIA), or (IIB), or a pharmaceutically acceptable salt thereof, wherein R 1 is a 5-membered heteroaryl selected from pyridinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and tetrazolyl, each of which is selected from one or two R 10 and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, or seventh embodiment.

[0019] In a tenth embodiment, the compound of the present invention is a compound of formula (I), (IIA), or (IIB), or a pharmaceutically acceptable salt thereof, wherein R 1 is expressed as follows: [ka] and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth and seventh embodiments.

[0020] In an eleventh embodiment, the compound of the present invention is a compound of formula (I), (IIA), or (IIB), or a pharmaceutically acceptable salt thereof, wherein R 1 is expressed as follows: [ka] and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, or seventh embodiment.

[0021] In a twelfth embodiment, the compound of the present invention is a compound of formula (I), (IIA), or (IIB), or a pharmaceutically acceptable salt thereof, wherein R 12 independently for each occurrence, a halogen, -OR 12a , -S(O)2R 12a , -CN, C 1-6 Alkyl, C 3-6 cycloalkyl, and phenyl; R 12 C, represented by 1-6 Alkyl, C 3-6 Cycloalkyl and phenyl each optionally contain 1 to 3 R 15 is replaced by R 12a independently for each occurrence, H and C 1-3 alkyl, and R 15 independently at each occurrence, a halogen and -OR 15a Selected from R 15a is H or C 1-3 alkyl, and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment.

[0022] In a thirteenth embodiment, the compound of the present invention is a compound of formula (I), (IIA), or (IIB), or a pharmaceutically acceptable salt thereof, wherein R 12 independently for each occurrence, a halogen, -OR 12a , -S(O)2R 12a , -CN, C 1-6 Alkyl, C 3-6 cycloalkyl, and phenyl; R 12 C, represented by 1-6 Alkyl, C 3-6 Cycloalkyl and phenyl each optionally contain 1 to 3 R 15 is replaced by R 12a independently for each occurrence, H and C 1-3alkyl, and R 15 independently for each occurrence, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, -CN, and -OR 15a Selected from R 15a is H or C 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, or eleventh embodiment.

[0023] In a fourteenth embodiment, the compound of the invention is a compound of formula (I), (IIA), or (IIB), or a pharmaceutically acceptable salt thereof, wherein R 12 is independently at each occurrence a C optionally substituted with 1 to 3 halogens; 1-6 alkyl or one or two C 1-3 C optionally substituted with alkyl 3-6 and cycloalkyl, and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or thirteenth embodiment.

[0024] In a fifteenth embodiment, the compound of the invention is a compound of formula (I), (IIA), or (IIB), or a pharmaceutically acceptable salt thereof, wherein R 12 is independently at each occurrence -CH3, -CF3, or -C(CH3)3, and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or twelfth embodiment.

[0025] In a sixteenth embodiment, the compound of the present invention is a compound of formula (I), (IIA), or (IIB), or a pharmaceutically acceptable salt thereof, wherein R 12 is, independently at each occurrence, -CH3, -CHF2, -CF3, -C(CH3)3, [ka] and the definitions of the other variables are as defined in the first, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, twelfth, or thirteenth embodiment.

[0026] In a seventeenth embodiment, the compound of the present invention is a compound of formula (I), (IIA), or (IIB), or a pharmaceutically acceptable salt thereof, wherein R 2 is H or C 1‐3 and 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, or sixteenth embodiment.

[0027] In an eighteenth embodiment, the compound of the invention is a compound of formula (I), (IIA), or (IIB), or a pharmaceutically acceptable salt thereof, wherein R 2 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, or seventeenth embodiment.

[0028] In a nineteenth embodiment, the compound of the present invention is a compound represented by formula (I), (IIA), or (IIB), or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are taken together with the atoms between them to form ring B, ring B being selected from 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, N, and S, 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from O, N, and S; 7-10 membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from O, N, and S, and 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from O, N, and S, and ring B being selected from one or two R 100and optionally substituted with the definitions of the other variables as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, or eighteenth embodiment.

[0029] In a twentieth embodiment, the compound of the present invention is a compound represented by formula (I), (IIA), or (IIB), or a pharmaceutically acceptable salt thereof, wherein ring B is a group represented by the following formula: [ka] and ring B is represented by one or two R 100 and optionally substituted with the definitions of the other variables as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or nineteenth embodiment.

[0030] In a twenty-first embodiment, the compound of the present invention is a compound of formula (I), (IIA), or (IIB), or a pharmaceutically acceptable salt thereof, wherein R 100 independently for each occurrence, C 1-6 Alkyl, C 3-6 Cycloalkyl, halogen, -CN, and -OR 100a Selected from C 1-6 Alkyl and C 3-6 Each cycloalkyl is optionally substituted with halogen and C 1-3 substituted with 1 to 3 substituents independently selected from alkyl; 100a independently for each occurrence, H, C 1-6 Alkyl, C 3-6 cycloalkyl, and 4-6 membered monocyclic heterocyclyl, 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, sixteenth, nineteenth, or twentieth embodiment.

[0031] In a twenty-second embodiment, the compound of the invention is a compound of formula (I), (IIA), or (IIB), or a pharmaceutically acceptable salt thereof, wherein R 100 is C 1-6 Alkyl or C 3-6 and cycloalkyl, 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, sixteenth, seventeenth, or twenty-first embodiment.

[0032] In a twenty-third embodiment, the compound of the invention is a compound of formula (I), (IIA), or (IIB), or a pharmaceutically acceptable salt thereof, wherein R 100 is independently at each occurrence -C(CH3)3, -CH2C(CH3)3, or cyclopropyl, 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, sixteenth, seventeenth, eighteenth, or twenty-second embodiment.

[0033] In a twenty-fourth embodiment, the compound of the invention is a compound of formula (I), (IIA), or (IIB), or a pharmaceutically acceptable salt thereof, wherein R 3 is H, 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, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, or twenty-third embodiment.

[0034] In a twenty-fifth embodiment, the compound of the invention is a compound of formula (I), (IIA), or (IIB), or a pharmaceutically acceptable salt thereof, wherein R 4 is H, halogen, -CN, -OR 4a , C 1-6 Alkyl, and C 3-6 cycloalkyl, R 4 C, represented by 1-6 Alkyl and C 3-6Each cycloalkyl is optionally substituted with 1 to 3 halogens, and R 4a is C optionally substituted with 1 to 3 halogens 1-4 and 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, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, or twenty-fourth embodiment.

[0035] In a 26th embodiment, the compound of the present invention is a compound of formula (I), (IIA), or (IIB), or a pharmaceutically acceptable salt thereof, wherein R 4 is H, halogen, -OR 4a and C optionally substituted with 1 to 3 halogens 1-6 alkyl, and R 4a is C optionally substituted with one or three halogens 1-4 and 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, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, or twenty-fifth embodiment.

[0036] In a 27th embodiment, the compound of the invention is a compound of formula (I), (IIA), or (IIB), or a pharmaceutically acceptable salt thereof, wherein R 4 is CH3, 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, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, or twenty-sixth embodiment.

[0037] In a 28th embodiment, the compound of the invention is a compound of formula (I), (IIA), or (IIB), or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4together with the atoms between them form ring C, ring C being selected from a 5- to 7-membered monocyclic carbocycle and a 5- to 7-membered monocyclic heterocycle, ring C optionally being selected from R 300 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, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, or twenty-third embodiment.

[0038] In a 29th embodiment, the compound of the invention is a compound of formula (I), (IIA), or (IIB), or a pharmaceutically acceptable salt thereof, wherein R 6 is H or halogen, 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, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, or twenty-eighth embodiment.

[0039] In a thirtieth embodiment, the compound of the invention is a compound of formula (I), (IIA), or (IIB), or a pharmaceutically acceptable salt thereof, wherein R 6 is H or F, 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, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, or twenty-ninth embodiment.

[0040] In a thirty-first embodiment, the compound of the invention is a compound of formula (I), (IIA), or (IIB), or a pharmaceutically acceptable salt thereof, wherein R 6Ais H, halogen, or CN, 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, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, or thirtieth embodiment.

[0041] In a thirty-second embodiment, the compound of the invention is a compound of formula (I), (IIA), or (IIB), or a pharmaceutically acceptable salt thereof, wherein R 5 is H or -NHR 5a and R 5a is H or C 1-3 and 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, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-first, or thirty-first embodiment.

[0042] In a thirty-third embodiment, the compound of the invention is a compound of formula (I), (IIA), or (IIB), or a pharmaceutically acceptable salt thereof, wherein R 5 is H, 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, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-first, or thirty-second embodiment.

[0043] In a thirty-fourth embodiment, the compound of the present invention is a compound of formula (I), (IIA), or (IIB), or a pharmaceutically acceptable salt thereof, wherein ring A optionally contains one or two R 11and 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, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-first, thirty-second, or thirty-third embodiment.

[0044] In a thirty-fifth embodiment, the compound of the invention is a compound of formula (I), (IIA), or (IIB), or a pharmaceutically acceptable salt thereof, wherein m is 1 and R 9 and one R 11 are taken together with their intervening atoms to form a 4- to 8-membered monocyclic saturated azacycle, 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, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-first, thirty-second, thirty-third, or thirty-fourth embodiment.

[0045] In a thirty-sixth embodiment, the compound of the invention is a compound of Formula (I), (IIA), or (IIB), or a pharmaceutically acceptable salt thereof, wherein the azaring is azetidine, pyrrolidine, piperidine, piperazine, azepane, or oxazepane, and the other variables are as defined in the thirty-fourth or thirty-fifth embodiment.

[0046] In a thirty-seventh embodiment, the compound of the invention is a compound of Formula (I), (IIA), or (IIB), or a pharmaceutically acceptable salt thereof, wherein m is 0, n is 0, and the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-second, thirty-third, thirty-fourth, or thirty-sixth embodiment.

[0047] In a thirty-eighth embodiment, the compound of the present invention has the formula: [ka] [ka] or a pharmaceutically acceptable salt thereof, X is O or CHR 11B and R 11A is H or R 11A and R 9 together with the atoms between them form a 4- to 6-membered saturated monocyclic azacycle; R 11B is H or R 11B and R 9 together with the atoms between them form a 4- to 6-membered saturated monocyclic azacycle; Y is CH or N; p is 0, 1, 2, 3, or 4; p1 is 0, 1, or 2; p2 is 0, 1, or 2; q1 is 0, 1, or 2, and if Y is N, q1 is not 0; q2 is 0, 1, or 2, provided that q1 and q2 cannot both be 0; S is 0, 1, or 2, 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, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, or thirty-seventh embodiment.

[0048] In a thirty-ninth embodiment, the compound of the invention is a compound represented by formula (IIIA), (IIIB), (IVA), (IVB), (VA), or (VB), or a pharmaceutically acceptable salt thereof, wherein p1 is 1 or 2, p2 is 0 or 1, q1 is 1 or 2, q2 is 1 or 2, and s is 1 or 2, and the other variables are as defined in the thirty-eighth embodiment.

[0049] In a fortieth embodiment, the compound of the present invention has the formula: [ka] [ka] [ka] [ka] A compound represented by or a pharmaceutically acceptable salt thereof, p1 is 1 or 2, s is 1 or 2, r1 is 1 or 2, X is 0 or CH2, 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, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, or thirty-eighth embodiment.

[0050] In a forty-first embodiment, the compound of the present invention is a compound represented by formula (I), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA), (VB), (VIA), (VIB), (VIIA), (VIIB), (VIIIA), (VIIIB), (IXA), (IXB), (XA), (XB), (XIA), (XIB), (XIIA), or (XIIB), or a pharmaceutically acceptable salt thereof; is 0, 1, or 2, 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, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, or fortieth embodiment.

[0051] In a forty-second embodiment, the compound of the present invention is a compound represented by formula (I), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA), (VB), (VIA), (VIB), (VIIA), (VIIB), (VIIIA), (VIIIB), (IXA), (IXB), (XA), (XB), (XIA), (XIB), (XIIA), or (XIIB), or a pharmaceutically acceptable salt thereof; p is 0, 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, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, or fortieth embodiment.

[0052] In a forty-third embodiment, the compound of the present invention is a compound represented by formula (I), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA), (VB), (VIA), (VIB), (VIIA), (VIIB), (VIIIA), (VIIIB), (IXA), (IXB), (XA), (XB), (XIA), (XIB), (XIIA), or (XIIB), or a pharmaceutically acceptable salt thereof, wherein p is 2 and two R 11 together with the same carbon atom to which they are attached form a —C(═O)— group, 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, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, or fortieth embodiment.

[0053] In a forty-fourth embodiment, the compound of the present invention is a compound represented by formula (I), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA), (VB), (VIA), (VIB), (VIIA), (VIIB), (VIIIA), (VIIIB), (IXA), (IXB), (XA), (XB), (XIA), (XIB), (XIIA), or (XIIB), or a pharmaceutically acceptable salt thereof; 9 is C 1‐3 Alkyl or C 3‐6 and cycloalkyl, 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, sixteenth, seventeenth, eighteenth, nineteenth, twenty, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, forty-first, forty-first, forty-second, or forty-third embodiment.

[0054] In a forty-fifth embodiment, the compound of the present invention is a compound represented by formula (I), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA), (VB), (VIA), (VIB), (VIIA), (VIIB), (VIIIA), (VIIIB), (IXA), (IXB), (XA), (XB), (XIA), (XIB), (XIIA), or (XIIB), or a pharmaceutically acceptable salt thereof; 9 is -CH3, -CH2CH3, or cyclopropyl, 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, sixteenth, seventeenth, eighteenth, nineteenth, twenty, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, forty-first, forty-second, forty-third, or forty-fourth embodiment.

[0055] In a forty-sixth embodiment, the compound of the present invention is a compound represented by formula (I), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA), (VB), (VIA), (VIB), (VIIA), (VIIB), (VIIIA), (VIIIB), (IXA), (IXB), (XA), (XB), (XIA), (XIB), (XIIA), or (XIIB), or a pharmaceutically acceptable salt thereof; 10 is C 1-6 Alkyl, C 1-6 Alkoxy, or -NR 10a R 10b C optionally replaced with 2-6 alkenyl, and R 10a and R 10b are each independently H or C 1-3 and 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, sixteenth, seventeenth, eighteenth, nineteenth, twenty, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, forty-first, forty-second, forty-third, forty-fifth, or forty-fifth embodiment.

[0056] In a forty-seventh embodiment, the compound of the present invention is a compound represented by formula (I), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA), (VB), (VIA), (VIB), (VIIA), (VIIB), (VIIIA), (VIIIB), (IXA), (IXB), (XA), (XB), (XIA), (XIB), (XIIA), or (XIIB), or a pharmaceutically acceptable salt thereof; 10is -CH=CH2, 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, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, forty-first, forty-second, forty-third, forty-fourth, forty-fifth, or forty-sixth embodiment.

[0057] In a forty-eighth embodiment, the compound of the present invention is a compound represented by formula (I), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA), (VB), (VIA), (VIB), (VIIA), (VIIB), (VIIIA), (VIIIB), (IXA), (IXB), (XA), (XB), (XIA), (XIB), (XIIA), or (XIIB), or a pharmaceutically acceptable salt thereof; 10 is one or more halo, C 1-6 Alkyl, C 1-6 Alkoxy, or -NR 10a R 10b C optionally replaced with 2-6 Alkenyl or C 4-7 is cycloalkenyl, and R 10a and R 10b are each independently H or C 1-3 alkyl or R 10a and R 10b taken together with the nitrogen atom to which they are attached form a 4-7 membered monocyclic saturated heterocyclyl optionally substituted with one or more substituents independently selected from halo and C alkyl, and the definitions of the other variables are as defined in the 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 45 embodiment.

[0058] In a forty-ninth embodiment, the compound of the present invention is a compound represented by formula (I), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA), (VB), (VIA), (VIB), (VIIA), (VIIB), (VIIIA), (VIIIB), (IXA), (IXB), (XA), (XB), (XIA), (XIB), (XIIA), or (XIIB), or a pharmaceutically acceptable salt thereof; 10 is -CH=CH2, CF=CH2, -CH=CHCF3 optionally substituted with halo or methyl; [ka] -CCH, -CCCH3, -cyclobutene, azetidino, morpholino, or piperazino, and the definitions of the other variables are as defined in the 48th embodiment.

[0059] In a 50th embodiment, the compound of the present invention is a compound represented by formula (I), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA), (VB), (VIA), (VIB), (VIIA), (VIIB), (VIIIA), (VIIIB), (IXA), (IXB), (XA), (XB), (XIA), (XIB), (XIIA), or (XIIB), or a pharmaceutically acceptable salt thereof; 1 is expressed as follows: [ka] is expressed as R 10 is independently at each occurrence a C optionally substituted with 1 to 3 halogens; 1-4 alkyl or optionally one or two C 1-3 Alkyl-substituted C 3‐6 is cycloalkyl, R 2 is H or C 1-3 is alkyl, R 3is H, R 4 is C 1-3 is alkyl, R 5 is H, R 6 is H or a halogen, R 6A is H, halogen, or CN, and the definitions of the other variables are as defined in the thirty-eighth, thirty-ninth, fortieth, forty-first, forty-second, forty-third, forty-fourth, forty-fifth, forty-sixth, or forty-seventh embodiment.

[0060] In a fifty-first embodiment, the compound of the present invention is a compound represented by formula (I), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA), (VB), (VIA), (VIB), (VIIA), (VIIB), (VIIIA), (VIIIB), (IXA), (IXB), (XA), (XB), (XIA), (XIB), (XIIA), or (XIIB), or a pharmaceutically acceptable salt thereof; R 1 is expressed as follows: [ka] R 10 is independently at each occurrence a C optionally substituted with 1 to 3 halogens; 1-4 alkyl or optionally one C 1‐3 is cyclopropyl substituted with alkyl; R 2 is H, R 3 is H, R 4 is -CH3, R 5 is H, R 6 is H or F, R 6A is H or CN, and the definitions of the other variables are as defined in the thirty-eighth, thirty-ninth, fortieth ...

[0061] 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, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl.

[0062] "Alkenyl" refers to an unsaturated hydrocarbon group having at least one carbon-carbon double bond, which may be straight-chain or branched. Alkenyl groups having 2 to 6 carbon atoms may be preferred. The alkenyl group may contain one or more. Examples of alkenyl groups include ethenyl, n-propenyl, isopropenyl, n-but-2-enyl, n-hex-3-enyl, and the like.

[0063] "Alkynyl" refers to an unsaturated hydrocarbon group having at least one carbon-carbon triple bond, which may be straight-chain or branched. Alkynyl groups having 2 to 6 carbon atoms may be preferred. The alkynyl group may contain one or more. Examples of alkynyl groups include ethynyl, n-propynyl, n-but-2-ynyl, n-hex-3-ynyl, and the like.

[0064] The number of carbon atoms in a group is indicated herein by the prefix "C x-xx " where x and xx are integers. For example, "C 1-4 "Alkyl" is an alkyl group having 1 to 6 carbon atoms.

[0065] "Halogen" or "halo" can be fluoro, chloro, bromo or iodo.

[0066] 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, particularly, 3 to 8, 3 to 7, 3 to 6, 5 to 7, 4 to 8, 4 to 7, 4 to 6, or 7 to 10 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, independently selected from O, S, and N, where C can be optionally oxidized (e.g., C(O)), N can be optionally oxidized (e.g., N(O)) or quaternized, and S can be optionally oxidized to sulfoxide and sulfone. Unsaturated heterocycles include heteroaryl rings. The heterocyclyl group is bonded to the rest of the compound of the present invention through a heteroatom or a carbon atom. The term azacyclic refers to a non-aromatic heterocyclyl having at least one nitrogen ring atom. Examples of azacyclic include, but are not limited to, morpholine.

[0067] In one embodiment, the heterocyclyl is a 3-7 membered monocyclic heterocyclyl (saturated or partially unsaturated (ie, non-aromatic)) having 1-2 heteroatoms selected from O, S, and N. Examples of 3- to 7-membered monocyclic heterocyclyl include, but are not limited to, aziridinyl, oxiranyl, thirranyl, 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, and dihydropyranyl. In one embodiment, the heterocyclyl is a 5- to 7-membered monocyclic heterocyclyl (saturated or partially unsaturated). Examples include 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, and dihydropyranyl.

[0068] In another embodiment, the heterocyclyl is a 4-6 membered monocyclic heterocyclyl (saturated or partially unsaturated) having 1-2 heteroatoms selected from O, S, and N. Examples of 4-6 membered monocyclic heterocycles include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, trithianyl, dihydrofuranyl, imidazolinyl, and dihydropyranyl.

[0069] In one embodiment, the heterocyclyl is a 4-6 membered monocyclic heterocyclyl (unsaturated, partially unsaturated or saturated) having 1-2 heteroatoms selected from O, S and N. Examples of 4-6 membered monocyclic heterocycles 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, pyrrolidinyl, and pyrrolidinyl. Examples of aryl include, but are not limited to, phenyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, oxathianyl, triazinyl, and tetrazinyl.

[0070] In another embodiment, heterocyclyl is a 5-7 membered monocyclic heterocyclyl (unsaturated, partially unsaturated or saturated) having 1-2 heteroatoms selected from O, S and N. Examples of 4-6 membered monocyclic heterocycles include 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 phenyl). or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, oxathianyl, triazinyl, and tetrazinyl, azepanyl, oxepanyl, and thiepanyl.

[0071] In another embodiment, the heterocyclyl is a 4-7 membered monocyclic heterocyclyl (saturated or partially unsaturated) having 1-2 heteroatoms selected from O, S, and N. Examples of 4-7 membered monocyclic heterocycles include, but are not limited to, 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, and dihydropyranyl.

[0072] In another embodiment, the heterocyclyl is a saturated 4-6 membered monocyclic heterocyclyl having 1-2 heteroatoms selected from O, S, and N. 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.

[0073] In one embodiment, the 4-6 membered monocyclic heterocyclyl is [ka] is selected from.

[0074] In another embodiment, the 4-6 membered monocyclic heterocyclyl is [ka] is selected from.

[0075] In one embodiment, the heterocyclyl is a 7-membered monocyclic heterocyclyl (saturated or partially unsaturated), such as a 7-membered monocyclic heterocyclyl having one heteroatom selected from O and N. Examples of 7-membered monocyclic heterocyclyls include, but are not limited to, azepanyl, azepinyl, oxepanyl, oxepinyl, thiepanyl, thiepinyl, diazepanyl, diazepinyl, and thiazepinyl.

[0076] In another embodiment, the heterocyclyl is a 7-10 membered bicyclic heterocyclyl. In yet another embodiment, the heterocyclyl is a 9-10 membered non-aromatic bicyclic heterocyclyl. In another embodiment, the heterocyclyl is a 9-10 membered fused non-aromatic bicyclic heterocyclyl. The heterocyclyl group is attached to the remainder of the compound of the invention at a heteroatom or carbon atom. In one embodiment, the 9-10 membered fused non-aromatic bicyclic heterocyclyl is: [ka] is selected from.

[0077] In another embodiment, heterocyclyl is [ka] and the like.

[0078] In another embodiment, the heterocyclyl is a 4-8 membered monocyclic saturated azacycle. Examples include azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, oxazepanyl, and imidazolinyl. In another embodiment, the heterocyclyl is a 4-6 membered monocyclic saturated azacycle. Examples include azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxazepanyl, and imidazolinyl.

[0079] As used herein, the term "aryl" refers to a carbocyclic (all carbon) aromatic monocyclic or bicyclic ring system containing 6 to 10 or 9 to 10 carbon atoms. Examples of 6- to 10-membered aryl groups include phenyl, naphthyl, and tetrahydronaphthyl. An example of a 9- to 10-membered bicyclic aryl group is naphthyl.

[0080] As used herein, the term "heteroaryl" refers to an aromatic 5-6 membered monocyclic or 7-10 membered bicyclic ring system having 1-4 heteroatoms independently selected from O, N, and S, wherein N can be oxidized (e.g., N(O)) or quaternized, and S can be optionally oxidized to sulfoxide and sulfone. Examples of 5-6 membered monocyclic heteroaryls include, but are not limited to, pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, and the like. In one embodiment, heteroaryl is a 5-membered heteroaryl. Examples of 5-membered heteroaryls include, but are not limited to, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadizolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and tetrazolyl. Examples of 8-10-membered bicyclic heteroaryls include, but are not limited to, dihydropyrrolopyrrolyl, indolyl, isoindolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, and purinyl.

[0081] As used herein, the term "carbocyclyl" refers to a saturated or unsaturated monocyclic or bicyclic hydrocarbon group of 3 to 10, 3 to 8, 3 to 7, 3 to 5, 3 to 6, 4 to 6, 5 to 7, or 7 to 10 carbon atoms. The term "carbocyclyl" encompasses cycloalkyl groups and aromatic groups (i.e., aryl). 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 bicyclic carbocyclyl groups include bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, spiro[2.2]pentanyl, and spiro[3.3]heptanyl.

[0082] As used herein, the term "cycloalkenyl" refers to a non-aromatic monocyclic hydrocarbon ring system having 4 to 7 ring atoms and at least one double bond between two adjacent carbon atoms. For example, "C4-7 cycloalkenyl" can refer to cyclobutene, cyclopentene, cyclohexene, or cycloheptene. In some cases, one double bond can be present in the ring structure. In other cases, more than one double bond can be present (e.g., [ka]

[0083] As used herein, the term "alkylene oxide" refers to an alkyl group in which the hydrogen atoms of each of two adjacent carbon atoms are replaced with an oxygen atom to bridge the two carbon atoms (e.g., an epoxide). Depending on the alkyl group, one or more substitutions may be present.

[0084] In one embodiment, the carbocyclyl is a 7- to 10-membered bicyclic carbocyclyl. Exemplary 7- to 10-membered bicyclic carbocyclyls include, but are not limited to, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, spiro[3.3]heptanyl, bicyclo[3.3.0]octanyl, bicyclo[2.2.2]octanyl, bicyclo[3.3.1]nonanyl, bicyclo[3.3.2]decanyl, decalinyl, and indanyl. In one embodiment, the carbocyclyl is a 3- to 7-membered monocyclic carbocyclyl. Exemplary 3- to 7-membered monocyclic carbocyclyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopenentyl, cyclohexenyl, cycloheptenyl, cyclobutadienyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl, phenyl, and cycloheptatrienyl. In one embodiment, the carbocyclyl is a 5- to 7-membered monocyclic carbocyclyl, such as, but not limited to, cyclopentyl, cyclohexyl, cycloheptyl, cyclopenentyl, cyclohexenyl, cycloheptenyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl, phenyl, or cycloheptatrienyl. In another embodiment, the carbocyclyl is a 4-6 membered monocyclic carbocyclyl such as, but not limited to, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopenentyl, cyclohexenyl, cyclobutadienyl, cyclopentadienyl, cyclohexadienyl, or phenyl. In another embodiment, the carbocyclyl is a 3-6 membered carbocyclyl such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopenentyl, cyclohexenyl, cyclobutadienyl, cyclopentadienyl, cyclohexadienyl, or phenyl.In another embodiment, the carbocyclyl is a 3-6 membered cycloalkyl such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In yet another embodiment, the carbocyclyl is phenyl. In yet another embodiment, the carbocyclyl is cyclopropyl.

[0085] As used herein, the term "fused ring system" refers to a ring system having two rings, each of which is independently selected from carbocyclyl or heterocyclyl, where the two ring structures share two adjacent ring atoms. In one embodiment, the fused ring system has 9 to 12 ring members.

[0086] As used herein, the term "bridged ring system" refers to a ring system having a carbocyclyl ring or a heterocyclyl ring in which two non-adjacent ring atoms are connected (bridged) by one or more (preferably 1 to 3) atoms selected from C, N, O, and S. In one embodiment, the bridged ring system has 6 to 8 ring members.

[0087] As used herein, the term "spiro ring system" refers to a ring system having two rings, each of which is independently selected from carbocyclyl or heterocyclyl, and the two rings share one ring atom in their structure. In one embodiment, the spiro ring system has 5 to 8 ring members.

[0088] When the compounds provided herein are sufficiently basic or acidic to form stable non-toxic acid or base salts, the preparation and administration of the compounds as pharmaceutically acceptable salts may be appropriate. Examples of pharmaceutically acceptable salts include 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 may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate.

[0089] Pharmaceutically acceptable salts may be obtained, for example, by reacting a sufficiently basic compound, such as an amine, with a suitable acid to provide a physiologically acceptable anion, using standard procedures well known in the art. Alkali metal (e.g., sodium, potassium, or lithium) or alkaline earth metal (e.g., calcium) salts of carboxylic acids can also be formed.

[0090] Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, or magnesium salts. Salts derived from organic bases include primary amines, secondary amines, 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 cyclo Examples of suitable amines include, but are not limited to, salts of alkenylamines, trisubstituted cycloalkenylamines, arylamines, diarylamines, triarylamines, heteroarylamines, diheteroarylamines, triheteroarylamines, heterocycloalkylamines, diheterocycloalkylamines, triheterocycloalkylamines, or mixed amines of diamines 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, taken together with the amino nitrogen, form a heterocycloalkyl or heteroaryl group.Non-limiting examples of amines include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, trimethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamine, theobromine, purine, piperazine, piperidine, morpholine, or N-ethylpiperidine. Other carboxylic acid derivatives, such as carboxylic acid amides, including carboxamides, lower alkylcarboxamides, or dialkylcarboxamides, may be useful.

[0091] The compounds described herein, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers within the molecule. In accordance with the present disclosure, any structure in which stereochemistry is not specified should be understood to encompass all of the 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 racemates by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using chiral stationary phases) are well known in the art.

[0092] When a particular stereoisomer 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 stereoisomer based on the combined weight of all stereoisomers.

[0093] When the stereochemistry of a disclosed compound is named or depicted in a structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in the case of a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. Furthermore, it is to be 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.

[0094] Where a disclosed compound is named or depicted by structure without indicating stereochemistry, and the compound has one chiral center, it should be understood that the name or structure encompasses one enantiomer of the compound in pure or substantially pure form, and mixtures thereof, such as racemic mixtures of the compounds and mixtures in which one enantiomer is enriched relative to its corresponding optical isomer.

[0095] Where a disclosed compound is named or depicted by structure without indicating stereochemistry, and for example, where the compound has at least two chiral centers, it is to be 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 stereoisomeric mixtures in which one or more stereoisomers are enriched relative to the other stereoisomer(s).

[0096] Compounds of the present disclosure may exist in tautomeric forms, and mixtures and separated individual tautomers are contemplated.

[0097] In one embodiment, the present invention provides a deuterated compound disclosed herein, where any or more positions occupied by hydrogen can contain an enrichment with deuterium above the natural abundance of deuterium. For example, one or more hydrogen atoms are replaced with deuterium at an abundance at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% deuterium incorporation), at least 3500 times (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 times (60% deuterium incorporation), at least 4500 times (67.5% deuterium incorporation), at least 5000 times (75% deuterium), at least 5500 times (82.5% deuterium incorporation), at least 6000 times (90% deuterium incorporation), at least 6333.3 times (95% deuterium incorporation), at least 6466.7 times (97% deuterium incorporation), at least 6600 times (99% deuterium incorporation), or at least 6633.3 times (99.5% deuterium incorporation) greater than the natural abundance of deuterium, which is 0.015%. In one embodiment, hydrogen is present at its natural abundance at all positions. The compounds described herein, or pharmaceutically acceptable salts thereof, may exist in tautomeric forms, and mixtures and separated individual tautomers are contemplated.

[0098] Another embodiment is a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0099] The compounds described herein, or pharmaceutically acceptable salts thereof, can be used to decrease the activity of Btk or to otherwise affect the properties and / or behavior of Btk, such as stability, phosphorylation, kinase activity, interactions with other proteins, etc.

[0100] In some embodiments, the present invention provides methods for reducing Btk enzymatic activity. In some embodiments, such methods include contacting Btk with an effective amount of a Btk inhibitor. Accordingly, the present invention further provides methods for inhibiting Btk enzymatic activity by contacting Btk with a Btk inhibitor of the present invention.

[0101] One embodiment of the present invention includes a method of treating a disorder responsive to Btk inhibition in a subject, comprising administering to the subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0102] In one embodiment, the present invention provides methods of treating autoimmune disorders, inflammatory diseases, 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0103] The term "autoimmune disorder" includes diseases or disorders involving an inappropriate immune response to natural antigens, such as acute disseminated encephalomyelitis (ADEM), Addison's disease, alopecia areata, antiphospholipid syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, bullous pemphigoid (BP), celiac disease, dermatomyositis, diabetes mellitus type 1, 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 disease" includes diseases or disorders involving acute or chronic inflammation, such as allergies, asthma, atopic dermatitis, 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 present invention provides methods of treating rheumatoid arthritis. In some embodiments, the present invention provides methods of treating multiple sclerosis. In some embodiments, the present invention provides methods of treating systemic lupus erythematosus. In some embodiments, the present invention provides methods of treating atopic dermatitis.

[0104] The term "cancer" includes diseases or disorders involving abnormal growth and / or proliferation of cells, 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 cancer). In some embodiments, the present invention provides methods of treating leukemia or lymphoma.

[0105] 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.), livestock (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.

[0106] As used herein, the terms "treating" or "treatment" refer to obtaining a desired pharmacological and / or physiological effect. The effect may be therapeutic, which includes partially or substantially achieving one or more of the following results: partially or completely reducing the severity of a disease, disorder, or syndrome; ameliorating or improving clinical symptoms or indicators associated with a disorder; or delaying, inhibiting, or reducing the likelihood of progression of a disease, disorder, or syndrome.

[0107] An effective dose of a compound provided herein, or a pharmaceutically acceptable salt thereof, to be administered to a subject can be from 10 μg to 500 mg.

[0108] Administering the compound described herein or its pharmaceutically acceptable salt to a mammal comprises any suitable delivery method.Administering the compound described herein or its pharmaceutically acceptable salt to a mammal comprises administering the compound described herein or its pharmaceutically acceptable salt to a mammal topically, enterally, parenterally, transdermally, transmucosally, by inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally, or intravitreally.Administering the compound described herein or its pharmaceutically acceptable salt to a mammal also comprises administering the compound that is metabolized to the compound described herein in or on the body surface of the mammal topically, enterally, parenterally, transdermally, transmucosally, by inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally, or intravitreally to a mammal.

[0109] Thus, the compounds described herein, or pharmaceutically acceptable salts thereof, may be administered systemically, e.g., orally, in combination with a pharmaceutically acceptable vehicle, such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly with the patient's food. For oral therapeutic administration, the compounds described herein, or pharmaceutically 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, wafers, or the like. Such compositions and preparations should contain at least about 0.1% of the active compound. The percentage of the compositions and preparations may, of course, vary 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.

[0110] Tablets, troches, pills, capsules, etc. may contain: 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, and the like; a lubricant such as magnesium stearate; or a sweetening or flavoring agent such as sucrose, fructose, lactose, or aspartame.

[0111] 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.

[0112] Exemplary pharmaceutical dosage forms for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders containing the active ingredient suitable 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.

[0113] Sterile injectable solutions can be prepared by combining the required amount of the active compound in an appropriate solvent with various other ingredients listed above, as needed, followed by filtered sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation can be vacuum drying and freeze-drying, which can yield a powder of the active ingredient plus any additional desired ingredients contained in a previously sterile-filtered solution.

[0114] Exemplary solid carriers can include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, etc. Useful liquid carriers include water, alcohols or glycols or blends of water and alcohols / glycols, in which the compounds described herein or pharmaceutically acceptable salts thereof can be dissolved or dispersed at effective levels, optionally with the use of nontoxic surfactants.

[0115] Useful dosages of the compounds described herein or their pharmaceutically acceptable salts can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; see, for example, U.S. Patent No. 4,938,949, incorporated by reference in its entirety.

[0116] The amount of the compound described herein or a pharmaceutically acceptable salt thereof required for therapeutic use will vary not only with the particular salt selected, but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and is ultimately left to the discretion of the attending physician or clinician. Generally, however, the dosage may range from about 0.1 to about 10 mg / kg body weight per day.

[0117] The compounds described herein, or pharmaceutically acceptable salts thereof, can be conveniently administered in unit dosage form, for example, containing 0.01 to 10 mg, or 0.05 to 1 mg of active ingredient per unit dosage form. In some embodiments, dosages of 5 mg / kg or less may be suitable.

[0118] The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals.

[0119] The disclosed methods may include kits containing a compound described herein or a pharmaceutically acceptable salt thereof, and instructional materials that can describe administering a compound described herein or a pharmaceutically acceptable salt thereof, or a composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, to a cell or a subject. This should be construed to include other embodiments of kits known to those of skill in the art, such as kits that include a solvent (e.g., sterile) for dissolving or suspending a compound described herein or a pharmaceutically acceptable salt thereof or a composition prior to administering the compound described herein or a pharmaceutically acceptable salt thereof or a composition to a cell or a subject. In some embodiments, the subject may be a human. [Example]

[0120] Synthesis of a compound of formula (I), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA), (VB), (VIA), (VIB), (VIIA), (VIIB), (VIIIA), (VIIIB), (IXA), (IXB), (XA), (XB), (XIA), (XIB), (XIIA), or (XIIB): Abbreviations and acronyms used herein include the following: AcOH means acetic acid Aq. means aqueous solution; Ar means argon Bn means benzyl Boc means tert-butoxycarbonyl BocO means di-tert-butyl dicarbonate, (BPin)2 means bis(pinacolato)diboron; br means wide area, n-BuOH means n-butanol t-BuOH means tert-butanol; n-BuLi means n-butyllithium; °C means degrees Celsius, CCl4 means carbon tetrachloride CHCl3 means chloroform, CDCl3 means deuterochloroform CDI means 1,1'-carbonyldiimidazole CO means carbon monoxide; CO2 means carbon dioxide, Cs2CO3 means cesium carbonate, CuBr means copper bromide CuCN means copper cyanide CuI means copper iodide; δ means the chemical shift d means double line, dd means double double line, DCM means dichloromethane DAST means (diethylamino)sulfur trichloride; DIPEA means N-ethyldiisopropylamine or N,N-diisopropylethylamine DEA means diethylamine DIAD means diisopropyl azodiformate DMAP means 4-(dimethylamino)pyridine DMF means N,N-dimethylformamide DMSO means dimethyl sulfoxide, DMSO-d6 means hexadeuterodimethyl sulfoxide; D2O means heavy water, EDC means N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; Et means ethyl, Et2O means ether, EtOH means ethanol EtOAc means ethyl acetate, Eq. means equivalent, g means grams HATU means N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide; HBr means hydrogen bromide HCl means hydrochloric acid HCO2H means formic acid, Hept means heptane 1 HNMR means proton nuclear magnetic resonance, H2O means water, HPLC means high pressure liquid chromatography h means hours, IPA stands for isopropyl alcohol K2CO3 means potassium carbonate, KF means potassium fluoride KI means potassium iodide KOAc means potassium acetate KOtBu means potassium tert-butoxide; KOH means potassium hydroxide K3PO4 means tripotassium phosphate L stands for liters LCMS means liquid chromatography mass spectrometry; LiOH means lithium hydroxide m means multiplet; M means mole, Me means methyl MeCN means acetonitrile MeI means methyl iodide MeOH means methanol MeOH-d4 means deuteromethanol, mg means milligrams MgSO4 means magnesium sulfate, MHz stands for megahertz mins means minutes, mL means milliliters mmol means millimoles, MnO2 means manganese(IV) oxide; MSm / z means a mass spectrum peak. M / V means mass-to-volume ratio, N2 means nitrogen; Na2CO3 means sodium carbonate, NaH means sodium hydride NaHCO3 means sodium bicarbonate NaI means sodium iodide; NaOH means sodium hydroxide NaOtBu means sodium tert-butoxide; Na2SO3 means sodium thiosulfate, Na2SO4 means sodium sulfate, NBS means N-bromosuccinimide NH3 means ammonia, NH4Cl means ammonium chloride; NH4HCO3 means ammonium bicarbonate NH4OH is ammonium hydroxide, Pd / C means palladium on carbon; Pd(t-Bu3P)2 means bis(tri-tert-butylphosphine)palladium(0); P(t-Bu)3PdG2 means chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II); Pd(OAc)2 means palladium acetate; Pd2(dba)3 means tris(dibenzylideneacetone)dipalladium(0); Pd(dppf)Cl2 means [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd(dppf)Cl2·DCM refers to the dichloromethane complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). Pd(dtbpf)Cl2 means [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II); Pd(PPh3)4 means tetrakis(triphenylphosphine)palladium(0); PE means petroleum ether POCl3 means phosphoryl chloride; i-PrOH means isopropanol PPh3 means triphenylphosphine PyBroP means bromotripyrrolidinophosphonium hexafluorophosphate q means quartet, Rt means retention time; rt means room temperature; RuPhos means 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; RuPhosPdG3 means (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate; s means single line, sat. means saturated, SCX stands for strong cation exchange SFC stands for supercritical fluid chromatography SiO2 means silicon dioxide; SOCl2 means thionyl chloride soln. means solution, t means triple line, TBDMS means tert-butyldimethylsilyl TBME means tert-butyl methyl ether TEA means triethylamine TFA means trifluoroacetic acid THF means tetrahydrofuran TLC means thin layer chromatography TMOS means tetramethyl orthosilicate TMS means trimethylsilyl T3P means 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide; TTBP means tri-tert-butylphosphonium tetrafluoroborate; μL means microliters μmol means micromolar.

[0121] Preparative HPLC conditions In the Examples section below, the following preparative HPLC method was used.

[0122] Method A1: Column: Welch Xtimate C18 150 x 25 mm x 5 μm Mobile phase A: MeCN Mobile phase B: H2O Adjustment agent: 10mM NH4HCO3 Gradient (organic %): % optimized for each example Flow rate: 25mL / min Grading time: 10 minutes Method A2: Column: Welch Xtimate CSH C18 150 x 50 mm x 5 μm Mobile phase A: MeCN Mobile phase B: H2O Adjuster: NH4OH, 10~90% Gradient (organic %): Optimized for each case Method B: Column: Agela Durashell C18 50 x 30 mm, 5 μm Mobile phase A: MeCN Mobile phase B: H2O Adjustment agent: 0.05% NH4OH + 10mM NH4HCO3 Gradient (organic %): Optimized for each case Flow rate: 25mL / min Method C: Column: Waters XSelect CSH OBD C18 150 x 19 mm, 5 μm Mobile phase A: MeCN Mobile phase B: H2O Regulator: NH3 Gradient (organic %): Optimized for each case Preparative SFC conditions Method D: Column: CHIRALPAK IB 3×250mm, 5μm Mobile phase B: 30% EtOH and 0.1% DEA in CO2 Flow rate: 100mL / min ABPR 120 bar, MBPR 40 psi, column temperature 40°C Common intermediate Intermediate 1: 1-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] 1. Synthesis of N-(4-bromo-2-methylbenzyl)-1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamide [ka] To a solution of 1-(tert-butyl)-1H-1,2,3-triazole-4-carboxylic acid (450 mg, 2.66 mmol), (4-bromo-2-methylphenyl)methanamine (585 mg, 2.93 mmol), and HATU (1.2 g, 3.19 mmol) in DMF (6.0 mL) was added TEA (1.1 mL, 7.98 mmol), and the reaction was stirred at 25 °C for 2 h. The reaction was concentrated in vacuo, and the residue was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over NaSO, filtered, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography eluting with PE / EtOAc (1 / 1 to 1 / 9) to give N-(4-bromo-2-methylbenzyl)-1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamide as a white solid (860 mg, 92% yield). LCMS m / z=352.8 (M+H)+.

[0123] 2. Synthesis of 1-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] A suspension of N-(4-bromo-2-methylbenzyl)-1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamide (860 mg, 2.45 mmol), (BPin) (1.5 g, 6.13 mmol), and KOAc (601 mg, 6.13 mmol) in dioxane (20 mL) was purged with N. Pd(dppf)Cl (179.2 mg, 0.245 mmol) was added, and the reaction was stirred under N at 90 °C for 2 h. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel chromatography eluting with PE / EtOAc (3 / 1) to give 1-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide as a white solid (900 mg, 92% yield). LCMS m / z=398.9 (M+H)+.

[0124] Intermediate 2: 3-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide [ka] 1. Synthesis of N-(4-bromo-2-methylbenzyl)-1-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide [ka] 3-(tert-Butyl)-1,2,4-oxadiazole-5-carboxylic acid (735 mg, 3.56 mmol) and HATU (1.45 g, 3.80 mmol) were slowly added to a solution of (4-bromo-2-methylphenyl)-methanamine (600 mg, 2.54 mmol) and DIPEA (983 mg, 7.61 mmol) in DCM (50 mL), and the reaction was stirred at 20 °C for 1 h. The mixture was concentrated in vacuo, and the crude product was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 0 to 1 / 1) to give N-(4-bromo-2-methylbenzyl)-1-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide as a yellow solid (553 mg, 61% yield). LCMS m / z = 351.4 (M+H)+.

[0125] 2. Synthesis of 1-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide [ka] Following a procedure similar to that described for Step 2 of Intermediate 1: 1-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide, N-(4-bromo-2-methylbenzyl)-1-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide was obtained as a yellow solid (365 mg, 46% yield) from N-(4-bromo-2-methylbenzyl)-1-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide. LCMS m / z=400.3 (M+H)+.

[0126] Intermediate 3: 5-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)isoxazole-3-carboxamide [ka] 1. Synthesis of N-(4-bromo-2-methylbenzyl)-5-(tert-butyl)isoxazole-3-carboxamide [ka] HATU (1.43 g, 3.75 mmol) was slowly added to a mixture of (4-bromo-2-methyl-phenyl)methanamine (500 mg, 2.50 mmol), DIPEA (646 mg, 5.0 mmol), and 5-(tert-butylisoxazole-3-carboxylic acid (381 mg, 2.25 mmol) in DCM (30 mL), and the reaction was stirred at 20 °C for 1 h. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 0 to 5 / 1) to give N-(4-bromo-2-methylbenzyl)-5-(tert-butyl)isoxazole-3-carboxamide (617 mg, 68% yield) as a yellow solid. LCMS m / z=351.1 (M+H)+.

[0127] Synthesis of 2,5-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)isoxazole-3-carboxamide [ka] Following a procedure similar to that described for Step 2 of Intermediate 1: 1-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide, N-(4-bromo-2-methylbenzyl)-5-(tert-butyl)isoxazole-3-carboxamide gave 5-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)isoxazole-3-carboxamide as a yellow solid (600 mg, 81% yield). LCMS m / z=399.3 (M+H)+.

[0128] Intermediate 4: N-methyl-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-6-(trifluoromethyl)nicotinamide [ka] 1. Synthesis of N-(4-bromo-2-methylbenzyl)-N-methyl-6-(trifluoromethyl)nicotinamide [ka] A mixture of 1-(4-bromo-2-methyl-phenyl)-N-methyl-methanamine (300 mg, 1.40 mmol), 6-(trifluoromethyl)pyridine-3-carboxylic acid (268 mg, 1.40 mmol), HATU (1.07 g, 2.80 mmol), and DIPEA (543 mg, 4.20 mmol) in DCM (5 mL) was stirred at room temperature for 16 h. The reaction mixture was filtered through Celite® and washed with DCM. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography eluting with heptane / EtOAc (100 / 0 to 1 / 1) to give N-(4-bromo-2-methylbenzyl)-N-methyl-6-(trifluoromethyl)nicotinamide (527 mg, 92% yield) as a white solid. LCMS m / z = 389.0 (M+H)+.

[0129] 2. Synthesis of N-methyl-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-6-(trifluoromethyl)nicotinamide [ka] A solution of N-(4-bromo-2-methylbenzyl)-N-methyl-6-(trifluoromethyl)nicotinamide (527 mg, 1.36 mmol), (BPin) (346 mg, 1.36 mmol), KOAc (401 mg, 4.08 mmol), and Pd(dppf)Cl·DCM (111 mg, 136 μmol) in dioxane (5 mL) was degassed and heated at 95 °C for 16 h. The cooled mixture was diluted with EtOAc and filtered through Celite®. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography eluting with heptane / EtOAc (100 / 0 to 0 / 100) to give N-methyl-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-6-(trifluoromethyl)nicotinamide (523 mg, 89% yield) as a gel. LCMS m / z=435.2 (M+H)+.

[0130] Intermediate 5: 5-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] 1. Synthesis of (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine hydrochloride [ka] A solution of tert-butyl (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (5.00 g, 14.4 mmol) in 4 M HCl / dioxane (100 mL) was stirred for 1 h at 20° C. The mixture was evaporated under reduced pressure to give (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine hydrochloride as a pale yellow solid (4.0 g, 98% yield), which was carried forward without further purification.

[0131] Synthesis of 2,5-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] To a solution of (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine hydrochloride (3.33 g, 11.8 mmol) in DCM (20 mL) was added 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylic acid (2.00 g, 11.8 mmol) and the solution was cooled to 0 °C. POCl (3.28 mL, 35.3 mmol) was added, followed by pyridine (5.69 mL, 70.5 mmol) and the reaction was stirred at 20 °C for 1 h. The reaction was poured into saturated aqueous NaHCO (300 mL) and the mixture was extracted with DCM (300 mL). The organic layer was washed with brine (200 mL), dried (NaSO), filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (5 / 1 to 1 / 1) to give 5-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide as a pale yellow oil (3.4 g, yield: 73%). 1 H NMR (400MHz CDCl3) δ:7.69-7.64 (m, 2H), 7.32 (d, 1H), 7.07 (br s, 1H), 4.68 (d, 2H), 2.38 (s, 3H), 1.46 (s, 9H), 1.35 (s, 12H).

[0132] Intermediate 6: 3-(Difluoromethyl)-1-methyl-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-pyrazole-4-carboxamide [ka] Intermediate 5, Step 1: To a solution of (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine hydrochloride (500 mg, 1.76 mmol) in DMF (10 mL) was added DIPEA (953 μL, 5.46 mmol) and the solution was stirred at room temperature for 5 minutes. 3-(Difluoromethyl)-1-methyl-pyrazole-4-carboxylic acid (620 mg, 3.52 mmol) and HATU (671 mg, 1.76 mmol) were added and the reaction was stirred at room temperature for 4 hours. The reaction mixture was partitioned between water and EtOAc and the layers were separated. The aqueous phase was extracted with EtOAc (2×) and the combined organic layers were washed with brine (50 mL) and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with EtOAc / heptane (0 / 100 to 6 / 4) to give 3-(difluoromethyl)-1-methyl-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-pyrazole-4-carboxamide (450 mg, 63% yield). LCMS m / z=406.2 (M+H)+.

[0133] Intermediate 7: 5-(tert-butyl)-N-(3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] Synthesis of 1,4-bromo-2-fluoro-3-methylaniline [ka] A solution of NBS (28.4 g, 160 mmol) in DCM was added dropwise to an ice-cold solution of 2-fluoro-3-methylaniline (20.0 g, 160 mmol) in DCM (200 mL), and the reaction was stirred at 20 °C for 5 h. The mixture was diluted with saturated aqueous Na2CO3 (100 mL), the layers were separated, and the aqueous phase was extracted with DCM (2 × 100 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with PE / EtOAc (10 / 1) to give 4-bromo-2-fluoro-3-methylaniline as a brown oil (32.0 g, crude). LCMS m / z = 205.8 (M+H)+.

[0134] Synthesis of 2,4-amino-3-fluoro-2-methylbenzonitrile [ka] CuCN (35.6 g, 397 mmol) was added to a solution of 4-bromo-2-fluoro-3-methylaniline (27 g, 132 mmol) in DMF (200 mL) under N and the reaction was stirred at 140 °C for 16 h. To the cooled reaction was added NH H O (300 mL), the mixture was filtered, and the filtrate was poured into H O (300 mL) and extracted with EtOAc (2 × 300 mL). The aqueous phase was extracted with EtOAc (2 × 300 mL), and the combined organic layers were dried (Na SO ), filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with PE / EtOAc (70 / 30) to give 4-amino-3-fluoro-2-methylbenzonitrile as a brown oil (15 g, 75% yield). LCMS m / z = 151.0 (M+H) +

[0135] Synthesis of 3,4-bromo-3-fluoro-2-methylbenzonitrile [ka] A solution of 4-amino-3-fluoro-2-methylbenzonitrile (15 g, 100 mmol) in MeCN (250 mL) was added to a solution of tert-butyl nitrite (17.8 mL, 150 mmol) and CuBr (21.5 g, 150 mmol) at 65° C., and the reaction was stirred under N at 65° C. for 3 h. The cooled mixture was filtered, the filtrate concentrated in vacuo, and the crude product purified by silica gel column chromatography eluting with PE / EtOAc (9 / 1) to give 4-bromo-3-fluoro-2-methylbenzonitrile as an orange solid (11.5 g, crude). 1 H NMR (400 MHz, CDCl3) δ: 7.51 (dd, 1H), 7.28 (dd, 1H), 2.52 (s, 3H).

[0136] 4. Synthesis of (4-bromo-3-fluoro-2-methylphenyl)methanamine [ka] To a solution of 4-bromo-3-fluoro-2-methylbenzonitrile (15.0 g, 70 mmol) in THF (150 mL) was added BH (10.5 mL, 105 mmol, 10 M in MeS solution) slowly at 25 °C. The reaction mixture was heated at 65 °C for 17 h. The mixture was quenched with MeOH (10 mL) and concentrated in vacuo to give crude (4-bromo-3-fluoro-2-methylphenyl)methanamine (15 g, crude), which was used directly in the next step without further purification.

[0137] 5. Synthesis of tert-butyl (4-bromo-3-fluoro-2-methylbenzyl)carbamate [ka] To a solution of (4-bromo-3-fluoro-2-methylphenyl)methanamine (14 g, 64 mmol) in DCM (100 mL) was added TEA (13 g, 128 mmol) and BocO (16.8 g, 77 mmol), and the mixture was stirred for 2 h at 25° C. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography with PE / EtOAc (50 / 1) to give tert-butyl (4-bromo-3-fluoro-2-methylbenzyl)carbamate as a white solid (12.0 g, 59%). 1 H NMR (400MHz, DMSO-d6) δ: 7.47 (dd, 1H), 7.37 (dd, 1H), 6.96 (d, 1H), 4.07 (d, 2H), 2.19 (d, 3H), 1.37 (s, 9H).

[0138] 6. Synthesis of tert-butyl (3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate [ka] To a solution of tert-butyl (4-bromo-3-fluoro-2-methylbenzyl)carbamate (10 g, 31 mmol) in dioxane (150 mL) was added (BPin) (9.6 g, 38 mmol) and KOAc (6.2 g, 63 mmol). Pd(dppf)Cl·DCM (2.1 g, 2.5 mmol) was added, and the reaction was stirred at 80 °C under N for 17 h. The reaction mixture was concentrated in vacuo, and the crude material was purified by silica gel column chromatography eluting with PE / EtOAc (20:1) to afford tert-butyl (3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate as a yellow solid (13.0 g, crude). LCMS m / z = 310.1 (M-tBu+H).

[0139] 7. Synthesis of (3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine hydrochloride [ka] To a solution of tert-butyl (3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (7.0 g, 19.16 mmol) in EtOAc (10 mL) and MeOH (5 mL) was added HCl (4 M, 13.2 mL) slowly and the reaction was stirred at 15 °C for 4 h. The mixture was evaporated under reduced pressure to give (3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine hydrochloride (6.0 g, crude) as a yellow solid which was carried forward without further purification. LCMS m / z=266.2 (M+H)+

[0140] 8. Synthesis of 5-(tert-butyl)-N-(3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] DIPEA (2.73 g, 21.2 mmol, 3.7 mL) was added to a suspension of (3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine hydrochloride (3.19 g, 10.6 mmol) and 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylic acid (1.50 g, 7.05 mmol) in anhydrous DMF (20 mL), and the mixture was cooled to 0 °C. T3P (5.83 g, 9.2 mmol, 50% purity) was added, the cooling bath was removed, and the reaction was stirred at 15 °C for 2 h. The reaction was quenched with water (30 mL), followed by the addition of EtOAc (30 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (40 mL). The combined organic layers were washed with water (50 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give a beige oil, which was purified by silica gel column chromatography (PE / EtOAc, 100 / 0 to 65 / 35) to give 5-(tert-butyl)-N-(3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (600 mg, 20% yield) as a viscous, pale yellow oil that solidified upon standing. LCMS m / z = 417.9 (M+H)+.

[0141] Example 1: 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] 1. Synthesis of tert-butyl (1-(4-chloropyridin-3-yl)piperidin-3-yl)(methyl)carbamate [ka] To a solution of 4-chloro-3-iodopyridine (200 mg, 835 μmol) in toluene (5 mL) was added tert-butyl methyl(piperidin-3-yl)carbamate (179 mg, 835 μmol), RuPhos Pd G3 (70 mg, 84 μmol), and NaOt-Bu (241 mg, 2.51 mmol), and the reaction was stirred at 110 °C under N for 10 h. The cooled reaction was concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE / EtOAc, 1 / 0 to 0 / 1) to afford tert-butyl (1-(4-chloropyridin-3-yl)piperidin-3-yl)(methyl)carbamate (170 mg, 62% yield) as a yellow oil. LCMS m / z = 326.3 (M+H)+.

[0142] 2. Synthesis of tert-butyl (1-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate [ka] To a solution of intermediate 1:1-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (200 mg, 502 μmol) in dioxane (6 mL) and water (1 mL) was added tert-butyl (1-(4-chloropyridin-3-yl)piperidin-3-yl)(methyl)carbamate (164 mg, 502 μmol), KPO (320 mg, 1.51 mmol), and Pd(dtbpf)Cl (33 mg, 50 μmol). The mixture was stirred under N at 80° C. for 2 h, then allowed to cool and concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc, 1 / 0 to 0 / 1) to give tert-butyl (1-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate (120 mg, 43% yield) as a colorless oil. LCMS m / z=562.6 (M+H)+.

[0143] 3. Synthesis of 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide hydrochloride [ka] To a solution of tert-butyl (1-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate (120 mg, 214 μmol) in DCM (2 mL) was added 4 M HCl / EtOAc (15 mL) and the reaction was stirred at 25° C. for 1 h. The mixture was evaporated under reduced pressure to give 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide hydrochloride (100 mg, crude) as a white solid. LCMS m / z=462.4 (M+H)+.

[0144] 4. Synthesis of 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] To a solution of 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide hydrochloride (100 mg, 217 μmol) in DCM (20 mL) was added DIPEA (76 μL, 433 μmol) and acryloyl chloride (18 μL, 217 μmol) and the reaction was stirred at 25° C. for 30 min. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC (Method A2, organic gradient 32-62%) to give 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide as a white solid (48 mg, 43% yield). LCMS m / z=516.3 (M+H)+. 1H NMR (500MHz, DMSO-d6) δ:8.97(s, 1H), 8.71(s, 1H), 8.34(s, 1H), 8.25(s, 1H), 7.55-7.14(m, 4H), 6.77-5.42(m, 3H), 4.54-4.41(m, 2H), 3.74-3.36(m, 1H), 3.19-2.64(m, 7H), 2.38(s, 3H), 1.72-1.51(m, 13H).

[0145] Example 2: 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)pyrrolidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] 1. Synthesis of tert-butyl (1-(4-chloropyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate [ka] According to the procedure described in Example 1, Step 1: (1-(4-chloropyridin-3-yl)piperidin-3-yl)(methyl)carbamate tert-butyl, 4-chloro-3-iodopyridine and methyl(pyrrolidin-3-yl)carbamate gave tert-butyl (1-(4-chloropyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate as a yellow solid (200 mg, 65% yield). LCMS m / z=312.2 (M+H)+.

[0146] 2. Synthesis of tert-butyl (1-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate [ka] To a solution of intermediate 1:1-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (200 mg, 502 μmol) in dioxane (20 mL) and water (2 mL) was added tert-butyl (1-(4-chloropyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate (172 mg, 552 μmol), KPO (320 mg, 1.51 mmol) at 20° C. Then, Pd(dtbpf)Cl (65 mg, 100 μmol) was added, and the mixture was stirred at 90° C. under N for 5 h. The cooled mixture was filtered and concentrated in vacuo. The crude was purified by column chromatography on silica gel eluting with PE / EtOAc (100 / 0 to 0 / 100) to give tert-butyl (1-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate (160 mg, 51% yield) as a yellow solid. LCMS m / z=548.4 (M+H)+.

[0147] 3. Synthesis of 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)pyrrolidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide hydrochloride [ka] A solution of tert-butyl (1-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate (160 mg, 257 μmol) in 4 M HCl / EtOAc (20 mL) was stirred at 20° C. for 1 h. The mixture was evaporated under reduced pressure to give 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)pyrrolidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide hydrochloride (130 mg, crude) as a white solid, which was used without further purification. LCMS m / z=448.3 (M+H)+.

[0148] 4. Synthesis of 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamide)pyrrolidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] To a solution of 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)pyrrolidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide hydrochloride (120 mg, 248 μmol) in DCM (30 mL) was added DIPEA (64 mg, 496 μmol) at 20° C. Acryloyl chloride (27 mg, 298 μmol) was added slowly and the reaction was stirred at 20° C. for 1 h. The mixture was poured into water (50 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (Method A2, organic gradient 30-60%) to give 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)pyrrolidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (44 mg, 35% yield) as a yellow solid. LCMS m / z=502.3 (M+H)+. 1H NMR (400MHz, DMSO-d6) δ:8.95 (s, 1H), 8.68 (s, 1H), 8.19 (s, 1H), 8.08 (d, 1H), 7.30-7.21 (m, 3H), 7.05 (d, 1H), 6.76-6.10 (m, 1H), 6.08-5.97 (m, 1H), 5.62 (s, 1H), 5.07-4.65 (m, 1H), 4.46 (d, 2H), 3.09-2.67 (m, 7H), 2.34 (s, 3H), 1.98-1.77 (m, 2H), 1.62 (s, 9H).

[0149] Example 3: N-(4-(3-(1-acryloyl-1,7-diazaspiro[4.4]nonan-7-yl)pyridin-4-yl)-2-methylbenzyl)-1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamide [ka] Synthesis of tert-butyl 1,7-(4-chloropyridin-3-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate [ka] To a solution of 4-chloro-3-iodopyridine (110 mg, 460 μmol) and tert-butyl 1,7-diazaspiro[4.4]nonane-1-carboxylate (80 mg, 354 μmol) in toluene (8 mL) was added RuPhos Pd G3 (44 mg, 53 μmol) and NaotBu (102 mg, 1.06 mmol) at 20 °C. The reaction was stirred at 110 °C under N for 5 h and then concentrated in vacuo. The crude product was purified by preparative TLC (PE / EtOAc = 1 / 3) to give tert-butyl 7-(4-chloropyridin-3-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate (75 mg, 63% yield) as a pale white solid. LCMS: m / z = 338.3 (M+H)+.

[0150] 2. Synthesis of tert-butyl 7-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate [ka] To a solution of intermediate 1:1-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (107 mg, 269 μmol) and tert-butyl 7-(4-chloropyridin-3-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate (70 mg, 207 μmol) in a mixture of dioxane (4 mL) and water (1 mL) was added KPO (88 mg, 414 mmol) and Pd(dtbpf)Cl (20 mg, 31 μmol) at 20° C. The reaction was stirred at 90° C. under N for 5 h, then allowed to cool and concentrated in vacuo. The crude product was purified by preparative TLC (EtOAc) to give tert-butyl 7-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate (75 mg, 63% yield) as a light gray solid. LCMS m / z=574.4 (M+H)+.

[0151] 3. Synthesis of trifluoroacetic acid of N-(4-(3-(1,7-diazaspiro[4.4]nonan-7-yl)pyridin-4-yl)-2-methylbenzyl)-1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamide [ka] To a solution of tert-butyl 7-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate (75 mg, 131 μmol) in DCM (20 mL) was added TFA (4 mL) and the reaction was stirred at 20° C. for 1 h. The reaction mixture was evaporated under reduced pressure to afford the trifluoroacetic acid of N-(4-(3-(1,7-diazaspiro[4.4]nonan-7-yl)pyridin-4-yl)-2-methylbenzyl)-1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamide (62 mg, crude) as a light brown oil. LCMS m / z=474.3 (M+H)+.

[0152] 4. Synthesis of N-(4-(3-(1-acryloyl-1,7-diazaspiro[4.4]nonan-7-yl)pyridin-4-yl)-2-methylbenzyl)-1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamide [ka] To a solution of N-(4-(3-(1,7-diazaspiro[4.4]nonan-7-yl)pyridin-4-yl)-2-methylbenzyl)-1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamide trifluoroacetic acid (62 mg, 131 μmol) and DIPEA (68 mg, 524 μmol) in DCM (35 mL) was added acryloyl chloride (15 mg, 170 μmol) and the reaction was stirred at 20° C. for 1 h. The reaction was quenched with MeOH (2 mL) and the mixture was concentrated in vacuo. The crude product was purified by preparative HPLC (Method A2, organic gradient 34-64%) to give N-(4-(3-(1-acryloyl-1,7-diazaspiro[4.4]nonan-7-yl)pyridin-4-yl)-2-methylbenzyl)-1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamide (38 mg, 50% yield) as an off-white solid. LCMS m / z=528.3 (M+H)+. 1HNMR (400MHz, DMSO-d6) δ:8.92(t, 1H), 8.67(s, 1H), 8.12-8.03(m, 2H), 7.28-7.20(m, 3H), 7.03(d, 1H), 6.51-6.44(m, 1H), 6.06-6.00(m, 1H), 5.59-5.55(m, 1H), 4.43(d, 2H), 3.49-3.43(m, 2H), 3.06-3.01(m, 2H), 2.64-2.55(m, 2H), 2.33(s, 3H), 1.83-1.48(m, 15H).

[0153] Example 4: N-(4-(3-(7-acryloyl-2,7-diazaspiro[4.4]nonan-2-yl)pyridin-4-yl)-2-methylbenzyl)-1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamide [ka] Synthesis of tert-butyl 1,7-(4-chloropyridin-3-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate [ka] A mixture of 4-chloro-3-iodopyridine (160 mg, 668 μmol), tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate (151 mg, 668 μmol), RuPhos Pd G3 (56 mg, 67 μmol), and NaOtBu (193 mg, 2.0 mmol) in toluene (4 mL) was purged with N for 5 min and heated at 100 °C for 2 h. The cooled mixture was concentrated in vacuo, and the residue was suspended in EtOAc, washed with HO (2×) and brine, and then concentrated in vacuo. The crude was purified by silica gel column chromatography eluting with EtOAc / heptane (0 / 100 to 60 / 40) to give tert-butyl 7-(4-chloropyridin-3-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (170 mg, 75% yield). LCMS m / z=338.1(M+H)+.

[0154] Synthesis of tert-butyl 2,7-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate [ka] To a solution of intermediate 1:1-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (236 mg, 592 μmol) in dioxane (4.2 mL) and water (700 μL) was added tert-butyl 7-(4-chloropyridin-3-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (200 mg, 592 μmol), KCO (246 mg, 1.78 mmol), and Pd(dtbpf)Cl (39 mg, 59 μmol), and the mixture was purged with N for 10 minutes and then sealed. The reaction was stirred under N at 90° C. for 5 hours, allowed to cool, and concentrated in vacuo. The residue was taken up in DCM, filtered and purified by silica gel column chromatography eluting with EtOAc / heptane (0 / 100 to 100 / 0) to give tert-butyl 7-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (100 mg, 29% yield). LCMS m / z=574.4 (M+H)+.

[0155] 3. Synthesis of N-(4-(3-(2,7-diazaspiro[4.4]nonan-2-yl)pyridin-4-yl)-2-methylbenzyl)-1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamide hydrochloride [ka] A solution of tert-butyl 7-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (100 mg, 175 μmol) in HCl (4 M, 437 μL) and MeOH (2 drops) was stirred at room temperature for 2 h. The reaction was evaporated under reduced pressure to give N-(4-(3-(2,7-diazaspiro[4.4]nonan-2-yl)pyridin-4-yl)-2-methylbenzyl)-1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamide hydrochloride (80 mg, crude), which was carried forward without further purification. LCMS m / z=474.3 (M+H)+.

[0156] 4. Synthesis of N-(4-(3-(7-acryloyl-2,7-diazaspiro[4.4]nonan-2-yl)pyridin-4-yl)-2-methylbenzyl)-1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamide [ka] To a solution of N-(4-(3-(2,7-diazaspiro[4.4]nonan-2-yl)pyridin-4-yl)-2-methylbenzyl)-1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamide hydrochloride (80 mg, 169 μmol) in THF (2 mL) was added DIPEA (109 mg, 845 μmol) and acryloyl chloride (31 mg, 338 μmol) and the reaction was stirred at 25° C. for 30 min. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography eluting with EtOAc / EtOH (100 / 0 to 75 / 25) to give the product N-(4-(3-(7-acryloyl-2,7-diazaspiro[4.4]nonan-2-yl)pyridin-4-yl)-2-methylbenzyl)-1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamide (61 mg, 68% yield). LCMS m / z=528.4 (M+H)+. 1H NMR (400MHz, CDCl3) δ:8.24-8.17(m, 2H), 8.14(dd, 1H), 7.48(br s, 1H), 7.36(d, 1H), 7.27-7.21(m, 2H), 7.06(dd, 1H), 6.51-6.33(m, 2H), 5.75-5.64(m, 1H), 4.70(d, 2H), 3.69-3.40(m, 4H), 3.00(s, 4H), 2.42(d, 3H), 2.01-1.76(m, 4H), 1.72(s, 9H).

[0157] Example 5: N-(4-(3-(7-acryloyl-2,7-diazaspiro[4.4]nonan-2-yl)pyridin-4-yl)-2-methylbenzyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide [ka] According to the steps described in Example 4, Step 1 of Example 4: tert-butyl 7-(4-chloropyridin-3-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate and intermediate 6: 3-(difluoromethyl)-1-methyl-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-pyrazole-4-carboxamide was used to obtain N-(4-(3-(7-acryloyl-2,7-diazaspiro[4.4]nonan-2-yl)pyridin-4-yl)-2-methylbenzyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide (61 mg, yield 63%). LCMS m / z=535.3 (M+H)+. 1H NMR (400MHz, CDCl3) δ:8.19-8.06(m, 3H),7.36-7.22(m, 1H), 7.19-7.07(m, 2H), 7.04-6.86(m, 2H), 6.34-6.14(m, 2H), 5.69-5.56(m, 1H), 4.82-4.67(m, 1H), 4.38-4.25(m, 1H), 3.87(s, 3H), 3.55-3.37(m, 2H), 3.36-3.21(m, 1H), 3.20-2.97(m, 3H), 2.82-2.70(m, 1H), 2.58-2.46(m, 1H), 2.30(d, 3H), 1.68-1.87(m, 4H).

[0158] Example 6: N-(4-(3-(6-acryloyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide [ka] Synthesis of tert-butyl 1,6-(4-chloropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ka] According to the procedure described in Example 4, Step 1: tert-butyl 7-(4-chloropyridin-3-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate, tert-butyl 6-(4-chloropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate was obtained as a pale oil from 4-chloro-3-iodopyridine and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate. LCMS m / z=310.0 (M+H)+.

[0159] Synthesis of tert-butyl 2,6-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ka] A mixture of tert-butyl 6-(4-chloropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (250 mg, 807 μmol), Intermediate 5: 5-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (483 mg, 1.21 mmol), KCO (446 mg, 3.23 mmol), and Pd(t-BuP) (41 mg, 81 μmol) in dioxane (6 mL) and water (1 mL) was purged with N for 5 minutes. The reaction was heated to 100 °C and stirred for 2 hours. The cooled reaction was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with (3 / 1 EtOAc:EtOH):heptane (0 / 100 to 75 / 25) to afford tert-butyl 6-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (299 mg, 68% yield) as an off-white solid. LCMS m / z=547.2 (M+H)+.

[0160] 3. Synthesis of N-(4-(3-(2,6-diazaspiro[3.3]heptan-2-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride [ka] A solution of tert-butyl 6-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (299 mg, 547 μmol) in MeOH (1.8 mL) and HCl / MeOH (1.25 M, 4.4 mL) was stirred at 50° C. for 6 h. The solution was evaporated under reduced pressure to give N-(4-(3-(2,6-diazaspiro[3.3]heptan-2-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride as a yellow solid (304 mg, 23% yield). LCMS m / z=447.1 (M+H)+.

[0161] 4. Synthesis of N-(4-(3-(6-acryloyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide [ka] To DCM (4.8 mL) and TEA (289 mg, 2.86 mmol) was added N-(4-(3-(2,6-diazaspiro[3.3]heptan-2-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride (69 mg, 143 μmol) and the mixture was stirred for 5 min. The solution was cooled in a dry ice and acetone bath, acryloyl chloride (65 mg, 715 μmol) was added dropwise, and the reaction was stirred for 15 min. The reaction mixture was directly purified by silica gel column chromatography with (3:1 EtOAc:EtOH):heptane (0 / 100 to 100 / 0) to give N-(4-(3-(6-acryloyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide (29 mg, 40% yield) as a pale yellow film. LCMS m / z=501.2 (M+H)+. 1H NMR (500MHz, MeOH-d4) δ:8.00(d, 1H), 7.85(s, 1H), 7.39(d, 1H), 7.30-7.24(m, 2H), 7.11(d, 1H), 6.31-6.15(m, 2H), 5.73-5.66(m, 1H), 4.64(s, 2H), 4.33(s, 2H), 4.08(s, 2H), 3.73(s, 4H), 2.44(s, 3H), 1.48(s, 9H).

[0162] Example 7: N-(4-(3-(2-acryloyl-2,6-diazaspiro[3.4]octan-6-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide [ka] Synthesis of tert-butyl 1,6-(4-chloropyridin-3-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate [ka] According to the procedure described in Example 4, Step 1: tert-butyl 7-(4-chloropyridin-3-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate, 4-chloro-3-iodopyridine and tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate were prepared as a pale oil (333 mg, 49% yield) from tert-butyl 6-(4-chloropyridin-3-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate. LCMS m / z=324.0 (M+H)+.

[0163] Synthesis of tert-butyl 2,6-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate [ka] tert-Butyl 6-(4-chloropyridin-3-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate and Intermediate 5: 5-(tert-butyl) according to the procedure described in Step 2 of Example 6: N-(4-(3-(6-acryloyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide tert-Butyl 6-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate was obtained from (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide. LCMS m / z=561.3 (M+H)+.

[0164] 3. Synthesis of N-(4-(3-(2,6-diazaspiro[3.4]octan-6-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide [ka] TFA (1.0 g, 8.85 mmol) was added to a solution of tert-butyl 6-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (496 mg, 885 μmol) in DCM (4.4 mL) and the reaction was stirred at room temperature for 18 hours. This material was passed through an SCX ion exchange column and washed with MeOH. The product was liberated by elution with 2M NH3 / MeOH and the filtrate evaporated to give N-(4-(3-(2,6-diazaspiro[3.4]octan-6-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide (368 mg, 90% yield) as a pale yellow oily solid. LCMS m / z=461.3 (M+H)+.

[0165] 4. Synthesis of N-(4-(3-(2-acryloyl-2,6-diazaspiro[3.4]octan-6-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide [ka] N-(4-(3-(2,6-diazaspiro[3.4]octan-6-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide was prepared according to the procedure described in Example 6, Step 4: N-(4-(3-(6-acryloyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide N-(4-(3-(2-acryloyl-2,6-diazaspiro[3.4]octan-6-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide and acryloyl chloride gave N-(4-(3-(2-acryloyl-2,6-diazaspiro[3.4]octan-6-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide as a pale yellow film. LCMS m / z=515.2 (M+H)+. 1H NMR (500MHz, DMSO-d6) δ:9.47-9.38(m, 1H), 8.16(s, 1H), 8.03(br d, 1H), 7.34-7.20(m, 2H), 7.05(br d, 1H), 6.27(br dd, 1H), 6.07(br dd, 1H), 5.64(br dd, 1H), 4.49(br d, 2H), 4.08(br s, 2H), 3.79(s, 2H), 3.24-3.14(m, 2H), 2.91(br t, 2H), 2.36(s, 3H), 1.98(br dd, 2H), 1.43(s, 9H).

[0166] Example 8: 1-(tert-butyl)-N-(2-methyl-4-(5-(3-(N-methylacrylamido)piperidin-1-yl)pyrimidin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] 1. Synthesis of tert-butyl (1-(4-methoxypyrimidin-5-yl)piperidin-3-yl)(methyl)carbamate [ka] According to the procedure described in Example 1, Step 1: (1-(4-chloropyridin-3-yl)piperidin-3-yl)(methyl)carbamate tert-butyl, 5-iodo-4-methoxypyrimidine and methyl(piperidin-3-yl)carbamate tert-butyl was obtained as a yellow oil (850 mg, 78% yield). LCMS m / z=323.5 (M+H)+.

[0167] Synthesis of 2.5-(3-(methylamino)piperidin-1-yl)pyrimidin-4-ol hydrobromide [ka] tert-Butyl (1-(4-methoxypyrimidin-5-yl)piperidin-3-yl)(methyl)carbamate (850 mg, 2.64 mmol) was added to HBr (20 mL, 40%) at 20° C., and the reaction was stirred at 80° C. for 2 hours. The mixture was evaporated under reduced pressure to give 5-(3-(methylamino)-piperidin-1-yl)pyrimidin-4-ol hydrobromide (550 mg, crude) as a yellow oil. LCMS m / z=209.3 (M+H)+.

[0168] 3. Synthesis of tert-butyl (1-(4-hydroxypyrimidin-5-yl)piperidin-3-yl)(methyl)carbamate [ka] To a solution of 5-(3-(methylamino)piperidin-1-yl)pyrimidin-4-ol (550 mg, 2.64 mmol) in DCM (30 mL) and MeOH (5 mL) was added DIPEA (682 mg, 5.28 mmol) and (Boc)2O (1.15 g, 5.28 mmol), and the reaction was stirred at 20 °C for 5 h. The reaction was concentrated in vacuo, and the residue was purified by silica gel column chromatography eluting with PE to EtOAc to give tert-butyl (1-(4-hydroxypyrimidin-5-yl)piperidin-3-yl)(methyl)carbamate as a yellow oil (500 g, 61% yield). LCMS m / z = 309.5 (M+H)+.

[0169] 4. Synthesis of tert-butyl (1-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyrimidin-5-yl)piperidin-3-yl)(methyl)carbamate [ka] To a solution of tert-butyl (1-(4-hydroxypyrimidin-5-yl)piperidin-3-yl)(methyl)carbamate (194 mg, 628 μmol) in dioxane (12 mL) was added TEA (191 mg, 1.88 mmol) and PyBroP (293 mg, 628 μmol), and the mixture was stirred at 20° C. for 2 h. Intermediate 1: 1-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (250 mg, 628 μmol), NaCO (200 mg, 1.88 mmol), Pd(PPh)Cl (44 mg, 63 μmol), and water (2 mL) were added and the mixture was stirred at 90 °C under N for 8 h. The cooled reaction was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with PE to EtOAc to give tert-butyl (1-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyrimidin-5-yl)piperidin-3-yl)(methyl)carbamate (170 mg, 48% yield) as a yellow oil which was carried forward without further purification.

[0170] 5. Synthesis of 1-(tert-butyl)-N-(2-methyl-4-(5-(3-(methylamino)piperidin-1-yl)pyrimidin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide hydrochloride [ka] According to the procedure described in Step 3 of Example 1: 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide hydrochloride, 1-(tert-butyl)-N-(2-methyl-4-(5-(3-(methylamino)piperidin-1-yl)pyrimidin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide hydrochloride was obtained as a white solid (140 mg, crude) from tert-butyl (1-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamide)methyl)-3-methylphenyl)pyrimidin-5-yl)piperidin-3-yl)(methyl)carbamate. LCMS m / z=463.3(M+H)+.

[0171] 6. Synthesis of 1-(tert-butyl)-N-(2-methyl-4-(5-(3-(N-methylacrylamido)piperidin-1-yl)pyrimidin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide was prepared according to a procedure similar to that described in Step 4 of Example 1: 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide 1-(tert-butyl)-N-(2-methyl-4-(5-(3-(N-methylacrylamido)piperidin-1-yl)pyrimidin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide hydrochloride and acryloyl chloride gave 1-(tert-butyl)-N-(2-methyl-4-(5-(3-(N-methylacrylamido)piperidin-1-yl)pyrimidin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide as a white solid (54 mg, 37% yield). LCMS m / z=517.3 (M+H)+. 1H NMR (400MHz, DMSO-d6) δ:8.99(s, 1H), 8.84(s, 1H), 8.74-8.69(m, 1H), 8.60-8.40(m, 1H), 7.96-7.86(m, 2H), 7.34(d, 1H), 6.79-6.33(m, 1H), 6.13-5.89(m, 1H), 5.70-5.56(m, 1H), 4.50(d, 2H), 4.19-3.86(m, 1H), 3.33-2.49(m, 7H), 2.40(s, 3H), 1.64(m, 13H).

[0172] Example 9: 1-(tert-butyl)-N-(2-methyl-4-(5-(3-(N-methylacrylamido)pyrrolidin-1-yl)pyrimidin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] Following the steps described in the synthesis of Example 8, 5-iodo-4-methoxypyrimidine and tert-butyl cyclopentyl(methyl)carbamate gave 1-(tert-butyl)-N-(2-methyl-4-(5-(3-(N-methylacrylamido)pyrrolidin-1-yl)pyrimidin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. The crude product was purified by preparative HPLC (Method A2, organic gradient 23-53%) to give a white solid. LCMS m / z=503.2 (M+H)+. 1 H NMR (400MHz, DMSO-d6) δ:8.95(s, 1H), 8.65(d, 2H), 8.35(s, 1H), 7.48-7.42(m, 2H), 7.27(d, 1H), 6.76-6.66(m, 1H), 6.03-5.80(m, 1H), 5.07-4.68(m, 1H), 4.46(d, 2H), 3.12-2.63(m, 8H), 2.34(s, 3H), 2.00-1.80(m, 2H), 1.61(s, 9H).

[0173] Example 10: 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)-2-oxopiperidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] 1. Synthesis of tert-butyl (1-(4-chloropyridin-3-yl)-2-oxopiperidin-3-yl)carbamate [ka] To a solution of 4-chloro-3-iodopyridine (500 mg, 2.09 mmol) in dioxane (6 mL) was added tert-butyl (2-oxopiperidin-3-yl)carbamate (447 mg, 2.09 mmol), CuI (159 mg, 836 μmol), CsCO (1.36 g, 4.18 mmol), and trans-N,N-dimethylcyclohexane-1,2-diamine (119 mg, 836 μmol), and the reaction was stirred under N at 90 °C for 10 h. The cooled mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography eluting with PE to EtOAc to give tert-butyl (1-(4-chloropyridin-3-yl)-2-oxopiperidin-3-yl)carbamate as a yellow oil (200 mg, 29% yield). LCMS m / z=326.2(M+H)+.

[0174] 2. Synthesis of tert-butyl (1-(4-chloropyridin-3-yl)-2-oxopiperidin-3-yl)(methyl)carbamate [ka] To a solution of tert-butyl (1-(4-chloropyridin-3-yl)-2-oxopiperidin-3-yl)carbamate (200 mg, 614 μmol) in THF (20 mL) was added NaH (49 mg, 1.23 mmol, 60% purity) at 0° C., and the mixture was stirred at 0° C. for 10 minutes. MeI (174 mg, 1.23 mmol) was added, the ice bath was removed, and the reaction mixture was stirred at 25° C. for 6 hours. The reaction was quenched with MeOH (2 mL) and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with PE to EtOAc to give tert-butyl (1-(4-chloropyridin-3-yl)-2-oxopiperidin-3-yl)(methyl)carbamate (160 mg, 77% yield) as a yellow oil. LCMS m / z=340.1 (M+H)+.

[0175] 3. Synthesis of tert-butyl (1-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)-2-oxopiperidin-3-yl)(methyl)carbamate [ka] The compound was obtained from tert-butyl (1-(4-chloropyridin-3-yl)-2-oxopiperidin-3-yl)(methyl)carbamate and intermediate 1: 1-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide according to the procedure described in Step 2 of Example 4: tert-butyl 7-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate. The crude product was purified by preparative TLC (EtOAc) to give tert-butyl (1-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)-2-oxopiperidin-3-yl)(methyl)carbamate (130 mg, 69% yield) as a yellow oil. LCMS m / z=576.4 (M+H)+.

[0176] 4. Synthesis of 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)-2-oxopiperidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide hydrochloride [ka] 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)-2-oxopiperidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide hydrochloride was obtained as a yellow solid from tert-butyl (1-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)-2-oxopiperidin-3-yl)(methyl)carbamate according to the procedure described in Step 3 of Example 1: 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide hydrochloride. LCMS m / z=476.3(M+H)+.

[0177] 5. Synthesis of 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)-2-oxopiperidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] The compound was obtained from acryloyl chloride and 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)-2-oxopiperidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide hydrochloride according to the procedure described in Example 1, Step 4: 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)-2-oxopiperidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. The crude was purified by preparative HPLC (Method A1, organic gradient 23-53%) to give 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)-2-oxopiperidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide as a white solid (35 mg, 32% yield). LCMS m / z=530.2 (M+H)+. 1H NMR (400MHz, DMSO-d6) δ:8.98(s, 1H), 8.71(s, 1H), 8.58-8.48(m, 2H), 7.47-7.32(m, 2H), 7.24-7.13(m, 2H), 6.81-6.52(m, 1H), 6.20-5.94(m, 1H), 5.75-5.56(m, 1H), 4.55-4.45(m, 2H), 3.64-3.48(m, 1H), 3.32-2.72(m, 5H), 2.39(s, 3H), 2.26-1.72(m, 4H), 1.64(s, 9H).

[0178] Example 11: 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)-2-oxopyrrolidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] 1. Synthesis of tert-butyl (1-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)-2-oxopyrrolidin-3-yl)(methyl)carbamate [ka] Following the steps 1-3 described in Example 10, the compound was obtained from 4-chloro-3-iodopyridine and tert-butyl (2-oxopyrrolidin-3-yl)carbamate. The crude product was purified by silica gel chromatography eluting with PE to EtOAc to produce tert-butyl (1-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)-2-oxopyrrolidin-3-yl)(methyl)carbamate as a yellow oil (170 mg, 40% yield). LCMS m / z=562.3 (M+H)+.

[0179] 2. Synthesis of 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)-2-oxopyrrolidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] The compound was obtained from tert-butyl (1-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)-2-oxopyrrolidin-3-yl)(methyl)carbamate according to the steps described in Steps 3 and 4 of Example 1. The crude was purified by preparative HPLC (Method A1, organic gradient 22-52%) to give 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)-2-oxopyrrolidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide as a white solid (58 mg, 37% yield). LCMS m / z=516.2 (M+H)+. 1 H NMR (500MHz, DMSO-d6) δ:9.02-8.96(m, 1H), 8.74-8.68(m, 1H), 8.61-8.54(m, 2H), 7.44(d, 1H), 7.34(d, 1H), 7.27-7.17(m, 2H), 6.77-6.66(m, 1H), 6.19-6.04(m, 1H), 5.75-5.64(m, 1H), 5.25-4.95(m, 1H), 4.47(d, 2H), 3.65-3.37(m, 2H), 3.31-2.71(m, 3H), 2.39-2.36(m, 3H), 2.30-2.10(m, 1H), 2.03-1.89(m, 1H), 1.64(s, 9H).

[0180] Example 12: 5-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] 1. Synthesis of tert-butyl (1-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate [ka] The compound was obtained from Step 1 of Example 1: tert-butyl (1-(4-chloropyridin-3-yl)piperidin-3-yl)(methyl)carbamate and Intermediate 5: 5-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide according to the procedure described in Step 2 of Example 4: tert-butyl 7-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate. The crude was purified by silica gel chromatography (Combiflash®) eluting with PE to EtOAc to give tert-butyl (1-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate (170 mg, 25% yield) as a yellow oil. LCMS m / z=563.3 (M+H)+.

[0181] Synthesis of 2,5-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride [ka] According to the procedure described in Step 3 of Example 1: 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide hydrochloride, 5-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride was obtained as a yellow oil (190 mg, crude) from tert-butyl (1-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate. LCMS m / z=463.3(M+H)+.

[0182] Synthesis of 3.5-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] Following the procedure described in Step 4 of Example 3, the compound was obtained from 5-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride and acryloyl chloride. The crude was purified by preparative HPLC (Method B, organic gradient 32-62%) to give 5-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide as a pale yellow solid (50 mg, 24% yield). LCMS m / z=539.4 (M+H)+. 1H NMR (500MHz, MeOH-d4) δ:8.32-8.21(m, 2H), 7.57-7.42(m, 3H), 7.27-7.25(m, 1H), 6.67-6.08(m, 2H), 5.72-5.67(m, 1H), 4.90-4.71(m, 2H), 4.69-3.77(m, 1H), 3.34-2.97(m, 2H), 2.83-2.72(m, 5H), 2.47(s, 3H), 2.06-1.67(m, 4H), 1.50(s, 9H).

[0183] Example 13: 3-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide [ka] 1. Synthesis of tert-butyl (1-(4-(4-((3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate [ka] According to the procedure described in Step 1 of Example 12: tert-butyl (1-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate, intermediate 2: 3-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole Azole-5-carboxamide and Step 1 of Example 1: tert-butyl (1-(4-chloropyridin-3-yl)piperidin-3-yl)(methyl)carbamate gave tert-butyl (1-(4-(4-((3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate as a yellow solid (345 mg, 68% yield). LCMS m / z=563.3 (M+H)+.

[0184] 2. Synthesis of 3-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride [ka] 3-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride was obtained from tert-butyl (1-(4-(4-((3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate according to the procedure described in Step 3 of Example 1: 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide hydrochloride. LCMS m / z=463.3 (M+H)+.

[0185] 3. Synthesis of 3-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide [ka] The compound was obtained from acryloyl chloride and 3-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride according to the procedure described in Example 2, Step 4: 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamide)pyrrolidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. The crude product was purified by preparative HPLC (Method B, organic gradient 39-69%) to give 3-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (75 mg, 28% yield) as a yellow solid. LCMS m / z=517.3 (M+H)+. 1 H NMR (400MHz, DMSO-d6) δ:9.83(s, 1H), 8.35(s, 1H), 8.26(s, 1H), 7.59-7.44(m, 2H), 7.40-7.35(m, 1H), 7.18(s, 1H), 6.90-5.88(m, 2H), 5.83-5.27(m, 1H), 4.50(s, 2H), 4.42-3.66(m, 1H), 3.13-2.62(m, 7H), 2.39(s, 3H), 1.70-1.47(m, 4H), 1.36(s, 9H).

[0186] Example 14: 5-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)isoxazole-3-carboxamide [ka] 1. Synthesis of tert-butyl (1-(4-(4-((5-(tert-butyl)isoxazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate [ka] According to the procedure described in Example 12, Step 1: tert-butyl (1-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate, intermediate 3: 5-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)isoxazoline From isoxazole-3-carboxamide and Step 1 of Example 1: tert-butyl (1-(4-chloropyridin-3-yl)piperidin-3-yl)(methyl)carbamate, tert-butyl (1-(4-(4-((5-(tert-butyl)isoxazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate was obtained as a yellow solid (300 mg, 55% yield). LCMS m / z=562.4 (M+H)+.

[0187] Synthesis of 2.5-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)isoxazole-3-carboxamide [ka] Following the procedure described in Steps 3 and 4 of Example 2, except that the preparative HPLC gradient was (41-71%), tert-butyl (1-(4-(4-((5-(tert-butyl)isoxazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate gave 5-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)isoxazole-3-carboxamide as a yellow solid (80 mg, 41% yield). LCMS m / z=516.3 (M+H)+. 1 H NMR (400MHz, DMSO-d6) δ:9.19-9.13(m, 1H), 8.31(s, 1H), 8.22(s, 1H), 7.51-7.42(m, 2H), 7.29(d, 1H), 7.14(s, 1H), 6.70-6.05(m, 2H), 6.01-5.52(m, 2H), 4.49-4.35(m, 2H), 3.65(m, 1H), 3.07-2.55(m, 7H), 2.34(s, 3H), 1.66-1.42(m, 4H), 1.30(s, 9H).

[0188] Example 15 (S)-1-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] 1. Synthesis of tert-butyl (S)-(1-(4-chloropyridin-3-yl)piperidin-3-yl)(methyl)carbamate [ka] A mixture of 4-chloro-3-iodopyridine (250 mg, 1.04 mmol), (S)-methyl(piperidin-3-yl)tert-butylcarbamate (200 mg, 933 μmol), RuPhos (40 mg, 85 μmol), RuPhos Pd G3 (78 mg, 85 μmol), and KOtBu (143 mg, 1.27 mmol) was purged with N2, degassed dioxane was added, and the resulting mixture was heated under reflux for 2 h. The cooled reaction mixture was diluted with EtOAc and filtered through Celite®. The filtrate was washed with water and brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting dark oil was purified by silica gel column chromatography eluting with EtOAc / EtOH (3:1) (0 / 100 to 50 / 50) in heptane to give (S)-tert-butyl(1-(4-chloropyridin-3-yl)piperidin-3-yl)(methyl)carbamate as a pale yellow oil (204 mg, 74% yield). LCMS m / z = 326.1 (M+H). + .

[0189] 2. Synthesis of tert-butyl (1-(tert-butyl)-1H-1,2,3-triazole-4-carbonyl)(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate [ka] To a solution of tert-butyl (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (406 mg, 1.17 mmol) in DMF (5 mL) was added NaH (94 mg, 2.34 mmol, 60% purity) at room temperature and the solution was stirred under N for 1 h. A solution of 1-tert-butyltriazole-4-carbonyl chloride (220 mg, 1.17 mmol) in DMF (1 mL) was added dropwise and the reaction was stirred for an additional 1 h. The reaction was quenched with water, diluted with EtOAc, and the layers were separated. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified by silica gel column chromatography eluting with EtOAc / EtOH (3:1) (0 / 100 to 60 / 40) in heptane to give tert-butyl (1-(tert-butyl)-1H-1,2,3-triazole-4-carbonyl)(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (433 mg, 74% yield) as a colorless oil. LCMS m / z = 399.2 (M-Boc+H)+.

[0190] 3. Synthesis of tert-butyl (S)-(1-(4-(4-((N-(tert-butoxycarbonyl)-1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate [ka] A mixture of (S)-tert-butyl(1-(4-chloropyridin-3-yl)piperidin-3-yl)(methyl)carbamate (75 mg, 229 μmol), (1-(tert-butyl)-1H-1,2,3-triazole-4-carbonyl)(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (120 mg, 241 μmol), KPO (97 mg, 459 μmol), and Pd(dtbpf)Cl (27 mg, 37 μmol) was purged with N. Dioxane (4.5 mL) and water (500 μL) were added via syringe, and the reaction was sealed and heated under reflux for 2 h. The cooled reaction was diluted with EtOAc and filtered through Celite®, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc / EtOH (3:1) (0 / 100 to 40 / 60) in heptane to give tert-butyl (S)-(1-(4-(4-((N-(tert-butoxycarbonyl)-1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate as a pale yellow oil (58 mg, 38% yield). LCMS m / z=562.2 (M-Boc+H)+.

[0191] 4. Synthesis of (S)-1-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] To a solution of tert-butyl (S)-(1-(4-(4-((N-(tert-butoxycarbonyl)-1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate (52 mg, 79 μmol) in DCM (3 mL) was added TFA (1.49 mg, 13.1 mmol) and the reaction was stirred at room temperature for 18 hours. The mixture was evaporated under reduced pressure and the residue was purified by silica gel column chromatography eluting with 5% NH4OH / MeOH (0 / 100 to 10 / 90) in DCM to give (S)-1-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (30 mg, 83% yield). LCMS m / z=462.2 (M+H)+. 1 H NMR (500MHz, CDCl3) δ:8.31-8.21(m, 2H), 8.15(s, 1H), 7.48(br t,1H), 7.39-7.31(m, 3H), 7.05(d, 1H), 5.41(br s, 1H), 4.68-4.53(m, 2H), 3.14(br d, 1H), 3.05(br d, 1H), 2.71-2.62(m, 1H), 2.55(br t, 1H), 2.47-2.39(m, 1H), 2.36(s, 3H), 2.14(s, 3H), 1.87(br dd, 1H), 1.63(s, 9H), 1.53-1.40(m, 1H), 1.37-1.25(m, 1H), 1.24-1.14(m, 1H).

[0192] 5. Synthesis of (S)-1-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] To a solution of (S)-1-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (30 mg, 64.99 μmol) and DIPEA (25.20 mg, 194.97 μmol) in DCM (1 mL) was added acryloyl chloride (7.35 mg, 81.24 μmol) at 0° C. and the reaction was stirred for 30 min. The reaction mixture was diluted with DCM (5 mL) and washed with saturated aqueous NH4Cl, water, and brine. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with MeOH / 5% NH4OH in DCM (0 / 100 to 15 / 85) to give (S)-1-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (21 mg, 62.67% yield) as an off-white solid. LCMS m / z=516.2 (M+H)+. 1 H NMR (500MHz, MeCN-d3) δ:8.33(br s, 1H), 8.24(br s, 1H), 8.05-7.78(m, 1H), 7.60-7.33(m, 3H), 7.15(br s,1H), 6.65-6.10(m, 1H), 6.10-5.95(m, 1H), 5.63-5.51(m, 1H), 4.76-4.45(m, 2H), 4.43-3.65(m, 1H), 3.30-2.95(m, 2H), 2.89-2.72(m, 3H), 2.68(br d,2H), 2.41(s, 3H), 2.15(s, 3H), 1.74(br s, 1H), 1.67(s, 9H), 1.63(br s, 1H).

[0193] Example 16: 1-(tert-butyl)-N-(4-(3-(3-(N-ethylacrylamido)piperidin-1-yl)pyridin-4-yl)-2-methylbenzyl)-1H-1,2,3-triazole-4-carboxamide [ka] 1. Synthesis of tert-butyl (1-(4-chloropyridin-3-yl)piperidin-3-yl)(ethyl)carbamate [ka] A mixture of tert-butyl N-ethyl-N-(3-piperidyl)carbamate (200 mg, 876 μmol), 4-chloro-3-iodopyridine (250 mg, 1.04 mmol), RuPhos Pd G3 (88 mg, 105 μmol), and NaOtBu (168 mg, 1.75 mmol) in toluene (4 mL) was degassed with N, the reaction vessel was sealed, and the mixture was stirred at 100 °C for 18 h. The cooled reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography eluting with EtOAc in heptane (0 / 100 to 50 / 50) to give tert-butyl (1-(4-chloropyridin-3-yl)piperidin-3-yl)(ethyl)carbamate (204.20 mg, 68.59% yield) as a colorless oil. LCMS m / z = 340.2 (M+H)+.

[0194] 2. Synthesis of 1-(tert-butyl)-N-(4-(3-(3-(N-ethylacrylamide)piperidin-1-yl)pyridin-4-yl)-2-methylbenzyl)-1H-1,2,3-triazole-4-carboxamide [ka] Following a procedure similar to that described in steps 2 to 4 of Example 4, the compound was obtained from tert-butyl (1-(4-chloropyridin-3-yl)piperidin-3-yl)(ethyl)carbamate and intermediate 1:1-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. The crude was purified by silica gel column chromatography eluting with EtOAc / heptane / MeOH (0 / 100 / 0 to 100 / 0 / 0 to 90 / 0 / 10) to give 1-(tert-butyl)-N-(4-(3-(3-(N-ethylacrylamido)piperidin-1-yl)pyridin-4-yl)-2-methylbenzyl)-1H-1,2,3-triazole-4-carboxamide (58 mg, 50% yield). LCMS m / z=530.4 (M+H)+. 1 H NMR (400MHz, MeOH-d4) δ:8.89-8.78(m, 1H), 8.48(s, 1H), 8.31-8.17(m, 2H),7.56-7.53(m, 1H), 7.53-7.40(m, 2H), 7.28-7.22(m, 1H), 6.67-5.97(m, 2H), 5.72-5.59(m, 1H), 4.73-4.58(m, 2H), 4.19-3.70(m, 1H)), 3.29-2.98(m, 3H), 2.93-2.73(m, 1H), 2.70-2.54(m, 1H), 2.45(s, 3H), 1.88-1.73(m, 2H), 1.72-1.70(m, 9H), 1.70-1.65(m, 1H), 1.63-1.51(m, 1H), 1.06(td, 3H).

[0195] Example 17: 1-(tert-butyl)-N-(4-(3-(3-(N-cyclopropylacrylamide)piperidin-1-yl)pyridin-4-yl)-2-methylbenzyl)-1H-1,2,3-triazole-4-carboxamide [ka] According to the steps described in Example 16, tert-butyl N-cyclopropyl-N-(3-piperidyl)carbamate and 4-chloro-3-iodopyridine gave 1-(tert-butyl)-N-(4-(3-(3-(N-cyclopropylacrylamide)piperidin-1-yl)pyridin-4-yl)-2-methylbenzyl)-1H-1,2,3-triazole-4-carboxamide as a colorless oil. LCMS m / z=542.4 (M+H)+. 1 H NMR (400MHz, MeOH-d4) δ:8.47(s, 1H), 8.25(s, 1H), 8.19(d, 1H), 7.59-7.54(m, 1H), 7.54-7.48(m, 1H), 7.46-7.40(m, 1H), 7.26-7.20(m, 1H), 6.94-6.75(m, 1H), 6.11(dd, 1H), 5.66-5.59(m, 1H), 4.70-4.59(m, 2H), 3.85-3.70(m, 1H), 3.18-3.10(m, 1H), 3.08(d, 2H), 2.68-2.59(m, 1H), 2.59-2.52(m, 1H), 2.46(s, 3H), 2.16-2.04(m, 1H),1.84-1.76(m, 1H), 1.75-1.66(m, 10H), 1.65-1.50(m, 1H), 0.89-0.77(m, 2H), 0.72-0.61(m, 1H), 0.51-0.41(m, 1H).

[0196] Example 18: 3-(tert-butyl)-N-(3-fluoro-2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide [ka] 1. Synthesis of tert-butyl (1-(4-(4-((3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)methyl)-2-fluoro-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate [ka] Following a procedure similar to that described in Step 1 of Example 12: tert-butyl (1-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate, 3-(tert-butyl)-N-(3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2 ,4-Oxadiazole-5-carboxamide and Step 1 of Example 1: tert-butyl (1-(4-chloropyridin-3-yl)piperidin-3-yl)(methyl)carbamate gave tert-butyl (1-(4-(4-((3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)methyl)-2-fluoro-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate as a yellow oil. LCMS m / z=581.3 (M+H)+.

[0197] 2. Synthesis of 3-(tert-butyl)-N-(3-fluoro-2-methyl-4-(3-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride [ka] According to the procedure described in Step 3 of Example 2: 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)pyrrolidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide hydrochloride, (1-(4-(4-((3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide)methyl)-2-fluoro-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate was converted to tert-butyl 3-(tert-butyl)-N-(3-fluoro-2-methyl-4-(3-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride as a yellow solid (170 mg, crude). LCMS m / z=481.3(M+H)+.

[0198] 3. Synthesis of 3-(tert-butyl)-N-(3-fluoro-2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide [ka] The compound was obtained from 3-(tert-butyl)-N-(3-fluoro-2-methyl-4-(3-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride and acryloyl chloride according to a procedure similar to that described in Step 4 of Example 1: 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamide)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. The crude was purified by preparative HPLC (Method A1, organic gradient 39-69%) to give 3-(tert-butyl)-N-(3-fluoro-2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (77 mg, 43% yield) as a yellow solid. LCMS m / z=535.3 (M+H)+. 1 H NMR (400MHz, DMSO-d6) δ:9.87(s, 1H), 8.42(s, 1H), 8.28(s, 1H), 7.38-7.22(m, 2H), 7.17(d, 1H), 6.71-5.92(m, 2H), 5.60(t, 1H), 4.53(s, 2H), 4.23-3.53(m, 1H), 2.97-2.71(m, 7H), 2.28(s, 3H), 1.65-1.35(m, 13H).

[0199] Example 19: 5-(tert-butyl)-N-(3-fluoro-2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] 1. Synthesis of tert-butyl (1-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-2-fluoro-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate [ka] The compound was obtained from Step 1 of Example 1: tert-butyl (1-(4-chloropyridin-3-yl)piperidin-3-yl)(methyl)carbamate (648 mg, 2.0 mmol) and Intermediate 7: 3-(tert-butyl)-N-(3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide according to a procedure similar to that described in Step 2 of Example 4: tert-butyl 7-(4-(4-((1-(tert-butyl)-1H-1,2,3-oxadiazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate. The crude was purified by silica gel column chromatography using (3:1 EtOAc:EtOH):heptane (0 / 100 to 100 / 0) to give tert-butyl (1-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-2-fluoro-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate (470 mg, 41% yield) as an off-white solid. LCMS m / z=581.3 (M+H)+.

[0200] Synthesis of 2,5-(tert-butyl)-N-(3-fluoro-2-methyl-4-(3-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride [ka] HCl / MeOH (1.25 M, 6.5 mL) was added to a solution of tert-butyl (1-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-2-fluoro-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate (470 mg, 809 μmol) in MeOH (2.7 mL) and the reaction was stirred at 50° C. for 6 h. The cooled reaction was evaporated under reduced pressure to give 5-(tert-butyl)-N-(3-fluoro-2-methyl-4-(3-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride (465 mg, crude) as a pale yellow solid. LCMS m / z=481.2(M+H)+.

[0201] Synthesis of 3.5-(tert-butyl)-N-(3-fluoro-2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] A solution of 5-(tert-butyl)-N-(3-fluoro-2-methyl-4-(3-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride (150 mg, 271 μmol), DCM (2.7 mL), and TEA (123 mg, 1.21 mmol) was cooled in a dry ice / acetone bath for 5 min. Acryloyl chloride (26 mg, 285 μmol) was added dropwise, and the reaction was stirred for 15 min. The reaction mixture was directly purified by silica gel column chromatography eluting with (3:1 EtOAc:EtOH):heptane (0 / 100 to 100 / 0) to give 5-(tert-butyl)-N-(3-fluoro-2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (104 mg, 72% yield) as a pale yellow film. LCMS m / z=535.2 (M+H)+. 1H NMR (500MHz, DMSO-d6) δ:9.58-9.39(m, 1H), 8.48-8.37(m, 1H), 8.27(br d,1H), 7.42-7.25(m, 1H), 7.23-7.13(m, 2H), 6.77-6.57(m, 1H), 6.16-5.90(m, 1H), 5.68-5.51(m, 1H), 4.60-4.42(m, 2H), 4.22(br s, 1H), 3.54(br s, 1H), 3.02-2.75(m, 4H), 2.71(br s, 2H), 2.28(s, 3H), 1.80-1.49(m, 3H), 1.43(s, 9H), 1.31-1.22(m, 1H).

[0202] Example 20: 5-(tert-butyl)-N-(2-methyl-4-(3-(3-((N-methylacrylamido)methyl)pyrrolidin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] 1. Synthesis of tert-butyl ((1-(4-chloropyridin-3-yl)pyrrolidin-3-yl)methyl)(methyl)carbamate [ka] A mixture of 4-chloro-3-iodopyridine (250 mg, 1.04 mmol), tert-butyl N-methyl-N-(pyrrolidin-3-ylmethyl)carbamate (245 mg, 1.14 mmol), KOtBu (233 mg, 2.08 mmol), and RuPhos Pd G3 (87 mg, 104 μmol) in dry, degassed toluene (4 mL) was stirred at 90 °C for 17 h under N. The cooled mixture was filtered through Celite®, washed with EtOAc, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with EtOAc / heptane (0 / 100 to 70 / 30) to give tert-butyl ((1-(4-chloropyridin-3-yl)pyrrolidin-3-yl)methyl)(methyl)carbamate (121 mg, 36% yield) as an oil. LCMS m / z=326.1(M+H)+.

[0203] 2. Synthesis of tert-butyl ((1-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)(methyl)carbamate [ka] A mixture of intermediate 5:5-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (191 mg, 479 μmol), tert-butyl ((1-(4-chloropyridin-3-yl)pyrrolidin-3-yl)methyl)(methyl)carbamate (120 mg, 368 μmol), and KCO (153 mg, 1.10 mmol) in dioxane (3 mL) and water (500 μL) was purged with N for 5 minutes. Pd(dtbpf)Cl (24 mg, 37 μmol) was added, and the reaction was heated at 90 °C for 18 hours. Additional Pd(dtbpf)Cl (24 mg, 37 μmol) was added and the reaction was stirred at 90° C. for an additional 24 h. The cooled reaction was diluted with water and EtOAc, filtered through Celite®, washed with EtOAc, and the layers were separated. The aqueous phase was extracted with EtOAc, and the combined organic extracts were dried (MgSO), filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc / heptane (0 / 100 to 100 / 0) to give tert-butyl ((1-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)(methyl)carbamate as a brown oil (22 mg, 11% yield). LCMS m / z=563.3 (M+H)+.

[0204] 3. Synthesis of tert-butyl ((1-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)(methyl)carbamate hydrochloride [ka] A solution of tert-butyl ((1-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)(methyl)carbamate (25 mg, 43 μmol) in 4 M HCl / dioxane (500 μL) was stirred at room temperature for 1 h and then evaporated under reduced pressure to give tert-butyl ((1-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)(methyl)carbamate hydrochloride (19 mg, crude) as a yellow solid. LCMS m / z=463.2 (M+H)+.

[0205] 4. Synthesis of 5-(tert-butyl)-N-(2-methyl-4-(3-(3-((N-methylacrylamido)methyl)pyrrolidin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] To tert-butyl ((1-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)(methyl)carbamate hydrochloride (19 mg, 35 μmol) in dry DMF (1 mL) was added DIPEA (23 mg, 177 μmol) at 0° C. Then, acryloyl chloride (6 mg, 71 μmol) was added dropwise and the resulting mixture was stirred at 0° C. for 15 min and quenched with saturated aqueous NaHCO3. The layers were separated and the organic phase was washed with brine (3 times). The combined aqueous layers were extracted with EtOAc and the combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH 96 / 4) to give 5-(tert-butyl)-N-(2-methyl-4-(3-(3-((N-methylacrylamido)methyl)pyrrolidin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide as an oil (2.60 mg, 13% yield). LCMS m / z=517.2 (M+H)+. 1 H NMR (500MHz, CDCl3) δ:8.21-8.16(m, 1H), 8.14-8.06(m, 1H), 7.38-7.29(m, 1H), 7.34-7.29(m, 1H), 7.26-7.20(m, 2H), 7.05-6.98(m, 1H), 6.57-6.41(m, 1H), 6.35-6.21(m, 1H), 5.72-5.57(m, 1H), 4.79-4.62(m, 2H)), 3.53-3.28(m, 2H), 3.13-2.90(m, 6H), 2.80-2.70(m, 1H), 2.54-2.44(m, 1H), 2.42-2.38(m, 3H), 2.02-1.88(m, 1H), 1.47(d, 10H).

[0206] Example 21: 5-(tert-butyl)-N-(2-methyl-4-(3-(3-((N-methylacrylamido)methyl)piperidin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] 1. Synthesis of tert-butyl ((1-(4-chloropyridin-3-yl)piperidin-3-yl)methyl)(methyl)carbamate [ka] According to the procedure described in Example 20, Step 1: tert-butyl ((1-(4-chloropyridin-3-yl)pyrrolidin-3-yl)methyl)(methyl)carbamate, tert-butyl ((1-(4-chloropyridin-3-yl)piperidin-3-yl)methyl)(methyl)carbamate was obtained from 4-chloro-3-iodopyridine and tert-butyl N-methyl-N-(piperidin-3-ylmethyl)carbamate as an oil. LCMS m / z=340.1 (M+H)+.

[0207] 2. Synthesis of tert-butyl ((1-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)methyl)(methyl)carbamate [ka] A mixture of intermediate 5:5-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (305 mg, 765 μmol), tert-butyl ((1-(4-chloropyridin-3-yl)piperidin-3-yl)methyl)(methyl)carbamate (200 mg, 588 μmol), and P(t-Bu)Pd G2 (30 mg, 59 μmol) in dioxane (2 mL) and water (400 μL) was purged with N2 for 5 minutes. K2CO3 (325 mg, 2.35 mmol) was added, and the reaction was heated to 90 °C for 2 days. The cooled reaction was diluted with EtOAc and water, and the layers were separated. The organic layer was washed with brine (3 times), the combined aqueous layers were extracted with EtOAc, and the combined organic extracts were dried (MgSO), filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc / heptane (0 / 100 to 100 / 0) to afford tert-butyl ((1-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)methyl)(methyl)carbamate (180 mg, 53% yield) as an off-white solid. LCMS m / z = 577.4 (M+H)+.

[0208] Synthesis of 3.5-(tert-butyl)-N-(2-methyl-4-(3-(3-((N-methylacrylamido)methyl)piperidin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] Following the procedure described in steps 3 and 4 of Example 20, tert-butyl ((1-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)methyl)(methyl)carbamate gave 5-(tert-butyl)-N-(2-methyl-4-(3-(3-((N-methylacrylamido)methyl)piperidin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide as an oil. LCMS m / z=531.3 (M+H)+. 1 H NMR (400 MHz, CDCl3) δ: 8.36-8.23 (m, 1H), 7.53-7.28 (m, 2H), 7.13 (br dd, 1H), 6.46 (br d, 1H), 6.38-6.24 (m, 1H), 6.42-6.22 (m, 1H), 6.21-6.10 (m, 1H), 5.88 (br d, 1H), 5.83-5.53 (m, 1H), 4.96-4.43 (m, 2H), 3.49-2.81 (m, 4H), 2.78-2.64 (m, 3H), 2.45-2.34 (m, 3H), 2.28-1.97 (m, 1H), 1.97-1.54 (m, 3H), 1.33-1.20 (m, 6H), 1.54-1.19 (m, 6H).

[0209] Example 22: (R)-1-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] 1. Synthesis of benzyl (R)-(1-(4-chloropyridin-3-yl)piperidin-3-yl)(methyl)carbamate [ka] A mixture of 4-chloro-3-iodopyridine (600 mg, 2.51 mmol), (R)-methyl(piperidin-3-yl)benzylcarbamate (571 mg, 2.30 mmol), KOtBu (352 mg, 3.14 mmol), RuPhos (98 mg, 209 μmol), and RuPhos Pd G3 (175 mg, 209 μmol) was purged with N. Dioxane (15 mL) was added via syringe, and the reaction was stirred at 95° C. for 3 h. The cooled mixture was diluted with EtOAc, filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with heptane / EtOAc (50 / 50) to give (R)-benzyl(1-(4-chloropyridin-3-yl)piperidin-3-yl)(methyl)carbamate (480 mg, 64% yield) as a yellow viscous gum. LCMS m / z=360.2 (M+H)+.

[0210] 2. Synthesis of benzyl (R)-(1-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate [ka] A mixture of (R)-(1-(4-chloropyridin-3-yl)piperidin-3-yl)(methyl)benzylcarbamate (480 mg, 1.33 mmol), Intermediate 1:1-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (583 mg, 1.46 mmol), K2CO3 (735 mg, 5.32 mmol), and Pd(dtbpf)Cl2 (130 mg, 200 μmol) was purged with N2. Dioxane (6 mL) and water (1.5 mL) were added, and the mixture was again purged with N2. The reaction was stirred at room temperature for 5 minutes and then heated at 90 °C for 3 hours. The cooled mixture was diluted with EtOAc, the mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / MeOH (100 / 1) to give (R)-(1-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)benzylcarbamate (280 mg, 32% yield) as a viscous yellow gum. LCMS m / z=596.4 (M+H)+.

[0211] 3. Synthesis of (R)-1-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] A solution of (R)-(1-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)benzylcarbamate (240 mg, 403 μmol) and 2,6-dimethylpyridine (6.48 mg, 60.4 mmol) in DCM (5 mL) was cooled in an ice bath. (Me)SiI (3.63 g, 18.1 mmol) was added dropwise via syringe and the reaction was allowed to warm to room temperature. 1 M HCl (50 mL) was added dropwise very carefully. EtOAc (80 mL) was added and the biphasic system was stirred at room temperature for 1 h. The phases were separated and the aqueous phase was basified by the very careful addition of KCO (solid) followed by extraction with EtOAc (2×). The combined organic extracts were dried, filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by SCX column eluted with TEA-MeOH to give (R)-1-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (95 mg, 46% yield) as a yellow gum. LCMS m / z=462.3 (M+H)+.

[0212] 4. Synthesis of (R)-1-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] To a solution of (R) 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (90 mg, 195 μmol) in THF (3 mL) was added TEA (39 mg, 390 μmol) followed by acryloyl chloride (35 mg, 390 μmol) and the reaction was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and the crude was purified by preparative HPLC (Method A2, organic gradient 10-95%) to give (R) 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (33 mg, 31% yield) as a white solid. LCMS m / z=516.3 (M+H)+. 1 H NMR (500MHz, CDCl3) δ : 8.37-8.25 (m, 2H), 8.20 (s, 1H), 7.67 (br s, 1H), 7.53-7.37 (m, 3H), 7.21-7.10 (m, 1H), 6.57-6.47 (m, 0.5 H), 6.31-6.14 (m, 1H), 5.99-5.90 (m, 0.5 H), 5.68-5.56 (m, 1H), 4.77-4.49 (m, 2H), 3.68 (br s, 1H), 3.24-3.11 (br s, 1H), 3.02 (br s, 1H), 2.96-2.78 (m, 3H), 2.77-2.58 (m, 2H), 2.42 (s, 3H), 1.81 (br s, 2H), 1.70 (s, 9H), 1.61 (br s, 2H).

[0213] Intermediate 8: tert-butyl 3-(4-(4-(aminomethyl)-3-methylphenyl)pyridin-3-yl)piperidine-1-carboxylate [ka] 1. Synthesis of 4-(3-bromopyridin-4-yl)-2-methylbenzonitrile [ka] To a solution of 3,4-dibromopyridine (12.0 g, 50.7 mmol), Pd(dppf)Cl (150 mg, 205 μmol), and KCO (9.01 g, 65.2 mmol) in dioxane (100 mL) and water (50 mL), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (5.0 g, 20.6 mmol) was added, and the reaction mixture was degassed under N. The reaction was stirred at 45 °C for 18 h. An additional 320 mg (437 μmol) of Pd(dppf)Cl was added, and the reaction was stirred at 50 °C for an additional 3 h. The cooled reaction was diluted with water (100 mL) and saturated aqueous NaHCO (100 mL), and the mixture was extracted with EtOAc (2 × 200 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was evaporated under reduced pressure. The residual brown oil was purified by silica gel column chromatography eluting with heptane / EtOAc (100 / 0 to 1 / 1). The resulting white solid was further purified by silica gel column chromatography eluting with DCM to give 4-(3-bromopyridin-4-yl)-2-methylbenzonitrile as a white solid (2.25 g, 40% yield). LCMS m / z = 274.9 (M+H)+. 1 H NMR (500MHz, DMSO-d6) δ: 8.90 (s, 1H), 8.68-8.62 (1H), 7.94 (d, 1H), 7.61-7.58 (m, 2H), 7.50 (d, 1H), 2.56 (s, 3H).

[0214] Synthesis of tert-butyl 2,4'-(4-cyano-3-methylphenyl)-5,6-dihydro-[3,3'-bipyridine]-1(2H)-carboxylate [ka] To 4-(3-bromopyridin-4-yl)-2-methylbenzonitrile (500 mg, 1.83 mmol) was added tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.0 g, 3.23 mmol), Pd(dppf)Cl (50 mg, 68 μmol), KCO (750 mg, 5.43 mmol), dioxane (5 mL), and water (3 mL). The reaction vessel was sealed and heated at 70 °C for 3 h. The cooled mixture was partitioned between EtOAc and water, and the layers were separated. The aqueous layer was extracted with EtOAc, and the combined organic extracts were evaporated under reduced pressure. The crude was purified by silica gel column chromatography eluting with EtOAc / heptane (1 / 1) to give tert-butyl 4'-(4-cyano-3-methylphenyl)-5,6-dihydro-[3,3'-bipyridine]-1(2H)-carboxylate (665 mg, crude), which was carried forward without further purification. LCMS m / z=376.2 (M+H)+. 1 H NMR (500MHz, DMSO-d6) δ: 8.63 (d, 1H), 8.50 (s, 1H), 7.97-7.75 (m, 1H), 7.70-7.44 (m, 2H), 7.42 (d, 1H), 5.99 (br s, 1H), 3.71-3.48 (m, 2H), 3.71-3.48 (m, 2H), 3.36 (s, 2H), 2.52 (s, 3H), 2.30-2.05 (m, 2H), 1.22 (br d, 9H).

[0215] 3. Synthesis of tert-butyl 3-(4-(4-(aminomethyl)-3-methylphenyl)pyridin-3-yl)piperidine-1-carboxylate [ka] A solution of tert-butyl 4'-(4-cyano-3-methylphenyl)-5,6-dihydro-[3,3'-bipyridine]-1(2H)-carboxylate (665 mg from the previous reaction) in 7.0 M NH3 / MeOH (6 mL) was added to a vial containing 10% Pd / C (700 mg, 658 μmol, 10% purity), and the vial was sealed. The vial was purged with N2 and then charged with H2 to 100 psi and stirred at room temperature for 18 h. The mixture was filtered through Celite®, washing through with EtOH (20 mL), and the filtrate was concentrated in vacuo. The resulting oil was purified by silica gel column chromatography eluting with diisopropylamine / EtOAc (0 / 100 to 5 / 95) to give tert-butyl 4'-(4-cyano-3-methylphenyl)-5,6-dihydro-[3,3'-bipyridine]-1(2H)-carboxylate as a pale yellow oil. LCMS m / z=382.2 (M+H)+. 1 H NMR (500MHz, DMSO-d6) δ: 8.67 (s, 1H), 8.45 (d, 1H), 7.48 (d, 1H), 7.19 (d, 1H), 7.14 (br d, 2H), 3.98-3.86 (m, 1H), 378-3.69 (m, 2H), 3.15-3.04 (m, 1H), 3.04-2.88 (m, 1H), 2.88-2.62 (m, 2H), 2.32 (s, 3H), 1.97-1.70 (m, 3H), 1.70-1.58 (m, 1H), 1.52-1.04 (m, 9H).

[0216] Intermediate 9: tert-butyl 4-(4-(4-(aminomethyl)-3-methylphenyl)pyridin-3-yl)piperidine-1-carboxylate [ka] 1. Synthesis of tert-butyl 4-(4-cyano-3-methylphenyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate [ka] Following the procedure described in Step 1 of Intermediate 8: 4-(3-Bromopyridin-4-yl)-2-methylbenzonitrile, 4-(3-bromopyridin-4-yl)-2-methylbenzonitrile and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate gave tert-butyl 4-(4-cyano-3-methylphenyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate as an oil (880 mg, 96% yield). LCMS m / z=376.2 (M+H)+. 1 H NMR (500MHz, DMSO-d6) δ: 8.60 (d, 1H), 8.50 (s, 1H), 7.84 (s, 1H), 7.59-7.52 (m, 1H), 7.47-7.41 (m, 1H), 7.41-7.35 (m, 1H), 5.78 (br s, 1H), 3.93 (s, 2H), 3.31-3.22 (m, 2H), 2.53 (s, 3H), 1.96-1.78 (m, 2H), 1.40 (br s, 9H).

[0217] 2. Synthesis of tert-butyl 4-(4-(4-(aminomethyl)-3-methylphenyl)pyridin-3-yl)piperidine-1-carboxylate [ka] A solution of tert-butyl 4-(4-cyano-3-methylphenyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (880 mg, 2.34 mmol) in 7.0 M NH3 / MeOH (7 mL) was added to a vial containing 10% Pd / C (500 mg, 470 μmol, 10% purity), and the vial was sealed. The vial was purged with N2, then charged with H2 to 100 psi and stirred at room temperature overnight. Additional Pd / C (200 mg, 10%) was added, and the reaction was stirred under an H2 atmosphere for an additional 72 hours. The mixture was filtered through Celite®, washing with EtOH (10 mL), and the filtrate was concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (eluting with 100% EtOAc to 13% EtOH in EtOAc with 1% diethylamine) to afford tert-butyl 4-(4-(4-(aminomethyl)-3-methylphenyl)pyridin-3-yl)piperidine-1-carboxylate as a gummy solid. 1 H NMR (500MHz, DMSO-d6) δ: 8.60 (s, 1H), 8.45-8.36 (m, 1H), 7.48 (d, 2H), 7.18-7.02 (m, 2H), 4.15-3.90 (m, 2H), 3.76 (s, 4H), 2.89-2.75 (m, 1H), 2.32 (s, 3H), 1.97-1.77 (m, 2H), 1.72-1.56 (m, 2H), 1.41 (s, 9H).

[0218] Intermediate 10: tert-butyl (1-(4-(4-(aminomethyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate [ka] Synthesis of 1.4-(3-chloropyridin-4-yl)-2-methylbenzonitrile [ka] A mixture of 4-bromo-3-chloropyridine (9.50 g, 49.4 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (9.70 g, 39.9 mmol), Pd(dppf)Cl (125 mg, 171 μmol), and KCO (17 g, 123 mmol) in dioxane (10 mL) and water (5 mL) was degassed with N, and the reaction was stirred at 65 °C for 3 h. The cooled reaction was washed with brine (150 mL), and the layers were separated. The aqueous phase was extracted with EtOAc (150 mL), and the combined organic layers were dried over NaSO, filtered through Celite®, washed with EtOAc (100 mL), and evaporated under reduced pressure. This material was purified by silica gel column chromatography eluting with heptane to EtOAc to give 4-(3-chloropyridin-4-yl)-2-methylbenzonitrile as a white solid (10.1 g, 100% yield). 1 H NMR (500MHz, DMSO-d6) δ: 8.79 (s, 1H), 8.64 (d, 1H), 7.94 (d, 1H), 7.64 (s, 1H), 7.58-7.49 (m, 2H), 2.56 (3H).

[0219] 2. Synthesis of tert-butyl (1-(4-(4-cyano-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate [ka] A mixture of 4-(3-chloropyridin-4-yl)-2-methylbenzonitrile (5.0 g, 21.9 mmol), RuPhos Pd G3 (750 mg, 897 μmol), and tert-butyl N-methyl-N-(3-piperidyl)carbamate (5.01 g, 23.4 mmol) in toluene (100 mL) was degassed with N. NaOtBu (5.0 g, 52.0 mmol) was added and the reaction was stirred at 100° C. for 3 h. The cooled reaction was diluted with MTBE (75 mL), and the mixture was stirred for 1 h and then filtered through Celite®. The filtrate was evaporated under reduced pressure, and the crude was purified by silica gel column chromatography eluting with heptane to EtOAc to give tert-butyl (1-(4-(4-cyano-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate as a yellow oil (5.77 g, 65% yield). 1 H NMR (500MHz, DMSO-d6) δ: 8.40 (br s, 1H), 8.31 (br d, 1H), 7.86 (br d, 1H), 7.75 (s, 1H), 7.70-7.55 (m, 1H), 7.25 (d, 1H), 3.91-3.58 (m, 3H), 3.08-2.92 (m, 2H), 2.91-2.76 (m, 2H), 2.61 (s, 3H), 2.54 (s, 3H), 1.72-1.55 (m, 2H), 1.36 (s, 9H).

[0220] 3. Synthesis of tert-butyl (1-(4-(4-cyano-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate [ka] A solution of tert-butyl (1-(4-(4-cyano-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate (5.77 g, 14.2 mmol) in IPA (75 mL) was divided into 15 reaction vials. Carbonylhydrido(tetrahydroborato)[bis(2-diphenylphosphinoethyl)amino]ruthenium(II) (Ru-MACHO-BH, 15 mg, 25.5 μmol) was added to each reaction vial, and the reactions were degassed with N. The reactions were charged with H to 95 psi and heated at 100° C. for 3 h. The cooled reactions were combined and concentrated in vacuo to give a dark brown oil which was purified by silica gel column chromatography eluting with EtOAc / EtOH (100 / 0 to 75 / 25) to give tert-butyl (1-(4-(4-cyano-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate as an oil (4.88 g, 84% yield). 1 H NMR (500MHz, DMSO-d6) δ: 8.33 (s, 1H), 8.24 (d, 1H), 7.53-7.38 (m, 3H), 7.18 (d, 1H), 3.74 (s, 2H), 3.07-2.89 (m, 2H), 2.85-2.72 (m, 2H), 2.66 (s, 3H), 2.49-2.37 (m,1H), 2.32 (s, 3H), 1.98-1.71 (m, 2H), 1.71-1.46 (m, 2H), 1.37 (s, 9H).

[0221] Example 23: N-(4-(3-(1-acryloylpiperidin-3-yl)pyridin-4-yl)-2-methylbenzyl)-1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamide [ka] 1. Synthesis of tert-butyl 3-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidine-1-carboxylate [ka] To a solution of intermediate 8: tert-butyl 3-(4-(4-(aminomethyl)-3-methylphenyl)pyridin-3-yl)piperidine-1-carboxylate (95 mg, 249 μmol) and 1-tert-butyltriazole-4-carboxylic acid (54 mg, 319 μmol) in toluene (2 mL) was added tetramethyl silicate (110 mg, 723 μmol). The reaction vial was sealed and heated at 100° C. for 18 h. The cooled reaction was diluted with DCM (5 mL) and purified directly by silica gel column chromatography eluting with heptane to EtOAc to afford tert-butyl 3-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidine-1-carboxylate (79 mg, 60% yield) as a crystalline solid. LCMS m / z=533.3(M+H)+. 1 H NMR (500MHz, DMSO-d6) δ: 9.00 (br s, 1H), 8.75-8.65 (m, 2H), 8.45 (d, 1H), 7.40-7.25 (m, 2H), 7.20 (br d, 2H), 4.55-4.43 (m, 2H), 3.98-3.55 (m, 4H), 3.05-2.89 (m, 1H), 2.83-2.66 (m, 2H), 2.39 (s, 3H), 1.93-1.71 (m, 2H), 1.65 (s, 9H), 1.44-1.09 (m, 9H).

[0222] 2. Synthesis of 1-(tert-butyl)-N-(2-methyl-4-(3-(piperidin-3-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide hydrochloride [ka] To tert-butyl 3-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidine-1-carboxylate (79 mg, 148 μmol) was added DCM (2 mL), MeOH (2 mL), and HCl (4 M, 1 mL), and the clear solution was allowed to stand at room temperature for 18 h. The mixture was concentrated to a small volume, diluted with EtOAc (10 mL), and evaporated under reduced pressure to give 1-(tert-butyl)-N-(2-methyl-4-(3-(piperidin-3-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide hydrochloride as an off-white solid (80 mg, crude). LCMS m / z=433.2 (M+H)+.

[0223] 3. Synthesis of N-(4-(3-(1-acryloylpiperidin-3-yl)pyridin-4-yl)-2-methylbenzyl)-1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamide [ka] A solution of 1-(tert-butyl)-N-(2-methyl-4-(3-(piperidin-3-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide hydrochloride (80 mg, 158 μmol) and TEA (110 μL, 791 μmol) in DCM (2 mL) was cooled to −70 °C. Acryloyl chloride (13 μL, 158 μmol) was added and the reaction was stirred for 15 min. NaHCO (5 mL) was added and the reaction was allowed to warm to room temperature. DCM (5 mL) was added, the phases were separated, and the aqueous layer was extracted with DCM (10 mL). The combined organic layers were dried over NaSO, filtered, and evaporated under reduced pressure. The crude product was dissolved in DMSO (2.3 mL), filtered through a 0.2 μm syringe filter, and purified by preparative HPLC (Method C, organic gradient: 5–55%). LCMS m / z=487.1(M+H)+. 1H NMR (500MHz, DMSO-d6) δ: 8.98 (br s, 1H), 8.77-8.66 (m, 2H), 8.51-8.39 (m, 1H), 7.37-7.24 (m, 1H), 7.24-7.11 (m, 3H), 6.87-6.37 (m, 1H), 6.11-5.89 (m, 1H), 5.69-5.47 (m, 1H), 4.56-4.37 (m, 3H), 4.11-3.96 (m, 1H), 3.24-3.05 (m, 1H), 2.83-2.69 (m, 1H), 2.67-2.58 (m, 1H), 2.43-2.27 (m, 3H), 2.01-1.67 (m, 3H), 1.64 (s, 9H), 1.36-1.13 (m, 1H).

[0224] Examples 24 and 25: (R)—N-(4-(3-(1-acryloylpiperidin-3-yl)pyridin-4-yl)-2-methylbenzyl)-1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamide and (S)—N-(4-(3-(1-acryloylpiperidin-3-yl)pyridin-4-yl)-2-methylbenzyl)-1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamide [ka] (arbitrarily assigned stereochemistry) N-(4-(3-(1-acryloylpiperidin-3-yl)pyridin-4-yl)-2-methylbenzyl)-1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamide (20 mg, 41 μmol) from Example 23 was separated by SFC (Method D) to produce (R)-N-(4-(3-(1-acryloylpiperidin-3-yl)pyridin-4-yl)-2-methylbenzyl)-1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamide and (S)-N-(4-(3-(1-acryloylpiperidin-3-yl)pyridin-4-yl)-2-methylbenzyl)-1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamide. The first peak (Example 24) eluted at a retention time (Rt) of 2.91 minutes (7.8 mg), and the second peak (Example 25) eluted at Rt of 3.36 minutes (7.5 mg).

[0225] Example 26: N-(4-(3-(1-acryloylpiperidin-3-yl)pyridin-4-yl)-2-methylbenzyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide [ka] 1. Synthesis of tert-butyl 3-(4-(3-methyl-4-((5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamido)methyl)phenyl)pyridin-3-yl)piperidine-1-carboxylate [ka] A mixture of intermediate 8: tert-butyl 3-(4-(4-(aminomethyl)-3-methylphenyl)pyridin-3-yl)piperidine-1-carboxylate (115 mg, 301 μmol), ethyl 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate (150 mg, 765 μmol), and tetramethyl silicate (250 mg, 1.64 mmol) in toluene (2 mL) was sealed in a vial and heated at 120° C. for 18 hours. The cooled reaction mixture was purified directly by silica gel column chromatography eluting with heptane to EtOAc to give tert-butyl 3-(4-(3-methyl-4-((5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamido)methyl)phenyl)pyridin-3-yl)piperidine-1-carboxylate (40 mg, 25% yield). LCMS m / z=532.2(M+H)+.

[0226] 2. Synthesis of N-(4-(3-(1-acryloylpiperidin-3-yl)pyridin-4-yl)-2-methylbenzyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide [ka] N-(4-(3-(1-acryloylpiperidin-3-yl)pyridin-4-yl)-2-methylbenzyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide was obtained from tert-butyl 3-(4-(3-methyl-4-((5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamido)methyl)phenyl)pyridin-3-yl)piperidine-1-carboxylate according to the procedure described in Steps 2 and 3 of Example 23. The compound was purified by preparative HPLC (Method C, organic gradient: 5-55%). LCMS m / z=486.1 (M+H)+. 1H NMR (500MHz, DMSO-d6) δ: 9.38 (br t, 1H), 8.72 (d, 1H), 8.53-8.42 (m, 1H), 7.36-7.26 (m, 1H), 7.24-7.10 (m, 3H), 6.81-6.41 (m, 1H), 6.11-5.89 (m, 1H), 5.69-5.49 (m, 1H), 4.51-4.35 (m, 3H), 4.03 (br d, 1H), 3.25-3.08 (m, 1H), 2.79-2.57 (m, 2H), 2.41-2.26 (m, 4H), 1.99-1.62 (m, 3H), 1.54 (s, 3H), 1.43-1.33 (m, 2H), 1.22-1.14 (m, 2H).

[0227] Examples 27 and 28: (R)—N-(4-(3-(1-acryloylpiperidin-3-yl)pyridin-4-yl)-2-methylbenzyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide and (S)—N-(4-(3-(1-acryloylpiperidin-3-yl)pyridin-4-yl)-2-methylbenzyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide [ka] Arbitrarily assigned stereochemistry N-(4-(3-(1-acryloylpiperidin-3-yl)pyridin-4-yl)-2-methylbenzyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide (10 mg, 21 μmol) from Example 26 was separated by SFC (Method D) to produce (R)-N-(4-(3-(1-acryloylpiperidin-3-yl)pyridin-4-yl)-2-methylbenzyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide and (S)-N-(4-(3-(1-acryloylpiperidin-3-yl)pyridin-4-yl)-2-methylbenzyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide. The first peak (Example 27) eluted at Rt=3.58 min (2.5 mg), and the second peak (Example 28) eluted at Rt=4.18 min (2.3 mg).

[0228] Example 29: N-(4-(3-(1-acryloylpiperidin-3-yl)pyridin-4-yl)-2-methylbenzyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide [ka] Intermediate 8: N-(4-(3-(1-acryloylpiperidin-3-yl)pyridin-4-yl)-2-methylbenzyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide was obtained from tert-butyl 3-(4-(4-(aminomethyl)-3-methylphenyl)pyridin-3-yl)piperidine-1-carboxylate and ethyl 3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxylate according to the steps described in Example 1, except that the compound was purified by preparative HPLC (Method C, organic gradient: 5-55%). LCMS m / z=486.1 (M+H)+. 1H NMR (500MHz, DMSO-d6) δ: 9.75 (br d, 1H), 8.72 (d, 1H), 8.53-8.40 (m, 1H), 7.43-7.27 (m, 1H), 7.27-7.11 (m, 3H), 6.81-6.44 (m, 1H), 6.13-5.87 (m, 1H), 5.73-5.44 (m, 1H), 4.56-4.36 (m, 3H), 4.11-3.94 (m, 1H), 3.25-3.06 (m, 1H), 2.81-2.57 (m, 2H), 2.43-2.31 (m, 4H), 2.02-1.64 (m, 3H), 1.48 (s, 3H), 1.22-1.14 (m, 2H), 0.99 (br s, 2H).

[0229] Examples 30 and 31: (R)—N-(4-(3-(1-acryloylpiperidin-3-yl)pyridin-4-yl)-2-methylbenzyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide and (S)—N-(4-(3-(1-acryloylpiperidin-3-yl)pyridin-4-yl)-2-methylbenzyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide [ka] Arbitrarily assigned stereochemistry N-(4-(3-(1-acryloylpiperidin-3-yl)pyridin-4-yl)-2-methylbenzyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide (15 mg, 31 μmol) from Example 29 was separated by SFC (Method D) to produce (R)-N-(4-(3-(1-acryloylpiperidin-3-yl)pyridin-4-yl)-2-methylbenzyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide and (S)-N-(4-(3-(1-acryloylpiperidin-3-yl)pyridin-4-yl)-2-methylbenzyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide. The first peak (Example 30) eluted at Rt=1.92 min (7.2 mg), and the second peak (Example 31) eluted at Rt=2.14 min (7.7 mg).

[0230] Example 32: N-(4-(3-(1-acryloylpiperidin-3-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)isoxazole-3-carboxamide [ka] Intermediate 8: N-(4-(3-(1-acryloylpiperidin-3-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)isoxazole-3-carboxamide was obtained from tert-butyl 3-(4-(4-(aminomethyl)-3-methylphenyl)pyridin-3-yl)piperidine-1-carboxylate and 5-(tert-butyl)isoxazole-3-carboxylic acid according to the steps described in Example 1. LCMS m / z=487.1 (M+H)+. 1H NMR (500MHz, DMSO-d6) δ: 9.21 (br d, 1H), 8.72 (d, 1H), 8.54-8.40 (m, 1H), 7.35-7.25 (m, 1H), 7.25-7.11 (m, 3H), 6.81-6.44 (m, 1H), 6.60 (s, 1H), 6.13-5.88 (m, 1H), 5.71-5.47 (m, 1H), 4.53-4.34 (m, 3H), 4.03 (br d, 1H), 3.61-3.41 (m, 1H), 3.26-3.04 (m, 1H), 2.81-2.58 (m, 1H), 2.41-2.18 (m, 3H), 2.00-1.78 (m, 2H), 1.78-1.66 (m, 1H), 1.33 (s, 9H), 1.28-1.14 (m, 1H).

[0231] Examples 33 and 34, (R)—N-(4-(3-(1-acryloylpiperidin-3-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)isoxazole-3-carboxamide and (S)—N-(4-(3-(1-acryloylpiperidin-3-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)isoxazole-3-carboxamide [ka] Arbitrarily assigned stereochemistry N-(4-(3-(1-acryloylpiperidin-3-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)isoxazole-3-carboxamide (10 mg, 21 μmol) from Example 32 was further purified by SFC (Method D) to produce (R)-N-(4-(3-(1-acryloylpiperidin-3-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)isoxazole-3-carboxamide and (S)-N-(4-(3-(1-acryloylpiperidin-3-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)isoxazole-3-carboxamide. The first peak (Example 33) eluted at Rt=2.35 min (4.8 mg), and the second peak (Example 34) eluted at Rt=2.68 min (4.9 mg).

[0232] Example 35: N-(4-(3-(1-acryloylpiperidin-4-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide [ka] 1. Synthesis of tert-butyl 4-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidine-1-carboxylate [ka] A solution of intermediate 9: tert-butyl 4-(4-(4-(aminomethyl)-3-methylphenyl)pyridin-3-yl)piperidine-1-carboxylate (100 mg, 0.26 mmol) in dioxane (2 mL) was added to ethyl 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylate (100 mg, 0.50 mmol) and the reaction was stirred at 90° C. for 20 hours. The cooled reaction was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with heptane to EtOAc to give tert-butyl 4-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidine-1-carboxylate (8 mg, 6% yield). LCMS m / z=534.2 (M+H)+.

[0233] Synthesis of 2,5-(tert-butyl)-N-(2-methyl-4-(3-(piperidin-4-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride [ka] A solution of tert-butyl 4-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidine-1-carboxylate (8 mg, 15 μmol) in MeOH (2 mL) and HCl (4 M, 500 μL) was left at room temperature for 18 h. The reaction was diluted with EtOAc (5 mL), evaporated under reduced pressure, and azeotroped with EtOAc to give 5-(tert-butyl)-N-(2-methyl-4-(3-(piperidin-4-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride (8 mg, crude) as a white solid. LCMS m / z=434.2 (M+H)+.

[0234] 3. Synthesis of N-(4-(3-(1-acryloylpiperidin-4-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide [ka] To 5-(tert-butyl)-N-(2-methyl-4-(3-(piperidin-4-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride (8 mg, 15 μmol) was added DCM (5 mL) and TEA (5 mg, 47 μmol) and the solution was cooled to below 0° C. Acryloyl chloride (1.4 mg, 15 μmol) was added and the reaction was stirred for 15 minutes, then NaHCO (5 mL) was added and the reaction was allowed to warm to room temperature. The phases were separated, the aqueous layer was extracted with DCM (5 mL) and the combined organic layers were evaporated under reduced pressure. The crude material was dissolved in DMSO (2.3 mL), filtered through a 0.2 μm syringe filter, and purified by preparative HPLC (Method C, organic gradient: 5-55%) to give N-(4-(3-(1-acryloylpiperidin-4-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide. LCMS m / z=488.2 (M+H)+. 1 H NMR (500 MHz, DMSO-d6) δ: 9.47 (br t, 1H), 8.65 (s, 1H), 8.45 (br d, 1H), 7.35 (br d, 1H), 7.25-7.12 (m, 3H), 6.89-6.67 (m, 1H), 6.19-6.02 (m, 1H), 5.76-5.57 (m, 1H), 4.66-4.41 (m, 3H), 4.26-4.00 (m, 1H), 3.03-2.81 (m, 2H), 2.47-2.41 (m,1H), 2.40 (s, 3H), 1.83-1.59 (m, 4H), 1.54-1.31 (m, 9H).

[0235] Example 36: N-(4-(3-(1-acryloylpiperidin-4-yl)pyridin-4-yl)-2-methylbenzyl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide [ka] Intermediate 9: tert-butyl 4-(4-(4-(aminomethyl)-3-methylphenyl)pyridin-3-yl)piperidine-1-carboxylate and ethyl 3-tert-butyl-1,2,4-oxadiazole-5-carboxylate gave N-(4-(3-(1-acryloylpiperidin-4-yl)pyridin-4-yl)-2-methylbenzyl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide according to the steps described in Example 35. The compound was purified by preparative HPLC (Method C, organic gradient: 5-55%) to give the title compound. LCMS m / z=488.1 (M+H)+. 1 H NMR (500 MHz, DMSO-d6) δ: 9.86 (s, 1H), 8.64 (s, 1H), 8.45 (br d, 1H), 7.39 (br d, 1H), 7.25-7.15 (m, 3H), 6.86-6.70 (m, 1H), 6.12 (s, 1H), 5.76-5.55 (m, 1H), 4.53 (br d, 3H), 4.23-4.03 (m, 1H), 3.02-2.82 (m, 2H), 2.45-2.43 (m, 1H), 2.40 (s, 3H), 1.82-1.56 (m, 4H), 1.47-1.27 (m, 9H).

[0236] Example 37: 2-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)oxazole-4-carboxamide [ka] 1. Synthesis of tert-butyl (1-(4-(4-((2-(tert-butyl)oxazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate [ka] To 2-(tert-butyl)oxazole-4-carboxylic acid (100 mg, 591 μmol) and Intermediate 10: tert-butyl (1-(4-(4-(aminomethyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate (120 mg, 292 μmol), DMF (1 mL), DIPEA (80 mg, 620 μmol), and T3P (376 mg, 590 μmol, 50% purity) were added and the reaction was stirred at room temperature for 20 hours. The reaction was diluted with EtOAc (5 mL), washed with NaHCO3 (10 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 5 mL), and the combined organic layers were evaporated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with heptane to EtOAc to give tert-butyl (1-(4-(4-((2-(tert-butyl)oxazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate as a clear oil (164 mg, 100% yield). LCMS m / z=562.3 (M+H)+.

[0237] 2. Synthesis of 2-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)benzyl)oxazole-4-carboxamide hydrochloride [ka] A solution of tert-butyl (1-(4-(4-((2-(tert-butyl)oxazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate (164 mg, 292 μmol) in 1.25 M HCl / MeOH (5.0 mL) was stirred at room temperature for 20 h. EtOAc (5 mL) was added, and the solution was concentrated in vacuo and azeotroped with EtOAc (10 mL) to give 2-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)benzyl)oxazole-4-carboxamide hydrochloride (164 mg, crude) as a white solid. LCMS m / z=462.2 (M+H)+.

[0238] 3. Synthesis of 2-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)oxazole-4-carboxamide [ka] A solution of 2-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)benzyl)oxazole-4-carboxamide hydrochloride (164 mg from the previous reaction) and TEA (213 μL, 1.53 mmol) in DCM (5 mL) was cooled to −10° C. Acryloyl chloride (25 μL, 307 μmol) was added, the reaction was stirred for 5 min, and then quenched with saturated aqueous NaHCO (10 mL), and the biphasic mixture was stirred vigorously while warming to room temperature. The layers were separated, and the aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic layers were concentrated in vacuo, and the residue was purified by silica gel column chromatography eluting with EtOAc / EtOH (100 / 0 to 75 / 25) to give 2-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)oxazole-4-carboxamide as a colorless glass-like solid (107 mg, 68% yield). LCMS m / z=516.2 (M+H)+. 1 H NMR (500MHz, DMSO-d6) δ: 8.54 (br d, 2H), 8.35 (s, 1H), 8.30-8.17 (m, 1H), 7.54 (br s, 2H), 7.37-7.27 (m, 1H), 7.23-7.11 (m, 1H), 6.18-6.04 (m, 1H), 6.00-5.87 (m, 1H), 5.72-5.54 (m, 1H), 4.57-4.34 (m, 2H), 3.68 (br s, 1H), 3.16-3.00 (m, 1H), 2.99-2.83 (m, 3H), 2.77-2.59 (m, 3H), 2.38 (s, 3H), 1.81-1.45 (m, 4H), 1.37 (s, 9H).

[0239] Examples 38 to 41 Following the steps described in Example 37, the compounds in the following table were prepared from Intermediate 10: tert-butyl (1-(4-(4-(aminomethyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate and the appropriate carboxylic acid. [Table 1-1] [Table 1-2] [Table 1-3] Example 42: 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-pyrazole-4-carboxamide [ka] 1. Synthesis of tert-butyl (1-(4-(4-((1-(tert-butyl)-1H-pyrazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate [ka] To a solution of 1-(tert-butyl)-1H-pyrazole-4-carboxylic acid (161 mg, 960 μmol) and Intermediate 10: tert-butyl (1-(4-(4-(aminomethyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate (130 mg, 318 μmol) in anhydrous DMF (0.5 mL) was added DIPEA (0.4 mL, 2.29 mmol) dropwise. T3P (50% solution in DMF, 1.1 mL, 1.85 mmol) was then added and the reaction was stirred at room temperature for 22 h. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3 and brine, and the aqueous layer was re-extracted with EtOAc (2×). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with heptane (3:1 EtOAc:EtOH) (5 / 95 to 30 / 70) to give tert-butyl (1-(4-(4-((1-(tert-butyl)-1H-pyrazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate as a yellow oil (27 mg, 15% yield). LCMS m / z=561.3 (M+H)+.

[0240] 2. Synthesis of 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-pyrazole-4-carboxamide hydrochloride [ka] A solution of tert-butyl (1-(4-(4-((1-(tert-butyl)-1H-pyrazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate (27 mg, 48 μmol) in MeOH (0.5 mL) and 1.25 M HCl / MeOH (0.5 mL) was stirred at room temperature for 19 h. The reaction was evaporated under reduced pressure to give 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-pyrazole-4-carboxamide hydrochloride as a pale yellow film (24 mg, crude) which was carried forward without further purification. LCMS m / z=461.2 (M+H)+.

[0241] 3. Synthesis of 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-pyrazole-4-carboxamide [ka] A solution of 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-pyrazole-4-carboxamide hydrochloride (24 mg, 48 μmol) in DCM (0.5 mL) was cooled to −25° C. and TEA (0.1 mL, 721 μmol) was added dropwise. After 5 min, acryloyl chloride (0.03 mL, 368 μmol) was added dropwise and the reaction was stirred for 10 min. The reaction was quenched with saturated aqueous NaHCO3, and the mixture was extracted with DCM (3×). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The crude was purified by preparative HPLC (Method A2, organic gradient 10-60%) to give 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-pyrazole-4-carboxamide as an off-white solid (3.3 mg, 13% yield). LCMS m / z=515.2 (M+H)+. 1H NMR (500MHz, CD2Cl2) δ : 8.42-8.21 (m, 2H), 8.16-7.89 (m, 2H), 7.57-7.05 (m, 4H), 6.54-5.86 (m, 2H), 5.50 (br d, 1H), 4.96-4.46 (m, 1H), 4.27 (br s, 1H), 3.72-3.24 (m, 1H), 2.83-2.59 (m, 5H), 2.39 (s, 3H), 2.30-1.84 (m, 2H), 1.79-1.50 (m, 14H).

[0242] Example 43: 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-imidazole-4-carboxamide [ka] The compound was obtained from 1-(tert-butyl)-1H-imidazole-4-carboxylic acid hydrochloride and Intermediate 10: tert-butyl (1-(4-(4-(aminomethyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate according to the steps described in Example 42. The crude product was purified by silica gel column chromatography eluting with 3:1 EtOAc / EtOH (15 / 85 to 35 / 65) in heptane to give 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-imidazole-4-carboxamide (27 mg, 59% yield) as a white solid. LCMS m / z=515.2 (M+H)+. 1H NMR (500MHz, DMSO-d6) δ: 8.39-8.21 (m, 3H), 7.87 (s, 1H), 7.56-7.43 (m, 2H), 7.31 (br d, 1H), 7.16 (br d, 1H), 6.71 (br dd, 1H), 6.09 (br dd, 1H), 5.97-5.58 (m, 3H), 4.56-4.31 (m, 3H), 3.68 (br s, 1H), 3.13-2.87 (m, 4H), 2.79-2.63 (m, 3H), 2.37 (s, 3H), 1.75-1.49 (m, 11H).

[0243] Example 44: 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-pyrazole-3-carboxamide [ka] 1. Synthesis of tert-butyl (1-(4-(4-((1-(tert-butyl)-1H-pyrazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate [ka] To a solution of 1-(tert-butyl)-pyrazole-3-carboxylic acid (136 mg, 808 μmol) and Intermediate 10: tert-butyl (1-(4-(4-(aminomethyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate (226 mg, 551 μmol) in anhydrous DMF (1 mL) at 0 °C was carefully added DIPEA (0.48 mL, 2.75 mmol), followed by careful addition of HATU (325 mg, 853 μmol). Upon complete addition, the reaction was allowed to warm to room temperature and stirred for 2.5 h. The reaction was diluted with EtOAc and washed sequentially with saturated aqueous NaHCO and brine, then the aqueous layer was re-extracted with EtOAc (2×). The combined organic extracts were dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with heptane (3:1 EtOAc:EtOH) (5 / 95 to 35 / 65) to give tert-butyl (1-(4-(4-((1-(tert-butyl)-1H-pyrazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate as a pale yellow solid (279 mg, 90% yield). LCMS m / z=561.3 (M+H)+.

[0244] 2. Synthesis of 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-pyrazole-3-carboxamide [ka] Following the procedure described in steps 2 and 3 of Example 42, tert-butyl (1-(4-(4-((1-(tert-butyl)-1H-pyrazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate gave 1-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)-1H-pyrazole-3-carboxamide as a white solid. LCMS m / z=515.2 (M+H)+.1 H NMR (500MHz, DMSO-d6) δ: 8.47-8.27 (m, 3H), 7.92 (d, 1H), 7.59-7.45 (m, 2H), 7.38-7.18 (m, 3H), 6.67 (d, 2H), 6.22-6.04 (m, 1H), 6.02-5.91 (m, 1H), 5.69-5.59 (m, 1H), 4.61-4.28 (m, 2H), 3.15-2.84 (m, 4H), 2.77-2.62 (m, 3H), 2.39 (s, 3H), 1.69 (br d, 1H), 1.65-1.54 (m, 11H).

[0245] Example 45: 5-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)oxazole-2-carboxamide [ka] The compound was obtained from potassium 5-(tert-butyl)oxazole-2-carboxylate and Intermediate 10: tert-butyl (1-(4-(4-(aminomethyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate according to the steps described in Example 44. The crude product was purified by silica gel column chromatography eluting with 3:1 EtOAc / EtOH (10 / 90 to 60 / 40) in heptane to give 5-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)oxazole-2-carboxamide (29 mg, 32% yield) as a white solid. LCMS m / z=516.2 (M+H)+. 1H NMR (500MHz, DMSO-d6) δ: 9.37-9.26 (m, 1H), 8.39-8.21 (m, 2H), 7.57-7.30 (m, 3H), 7.23-7.03 (m, 2H), 6.70 (br dd, 1H), 6.16-5.90 (m, 2H), 5.68-5.55 (m, 1H), 4.53-4.37 (m, 2H), 3.68 (br s, 1H), 3.13-2.90 (m, 3H), 2.82-2.62 (m, 3H), 2.38 (s, 3H), 1.89-1.80 (m, 13H).

[0246] Example 46: 3-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)isoxazole-5-carboxamide [ka] The compound was obtained from 3-(tert-butyl)oxazole-5-carboxylic acid and Intermediate 10: tert-butyl (1-(4-(4-(aminomethyl)-3-methylphenyl)pyridin-3-yl)piperidin-3-yl)(methyl)carbamate according to the steps described in Example 44. The crude product was purified by silica gel column chromatography eluting with 3:1 EtOAc / EtOH (5 / 95 to 30 / 70) in heptane to give 3-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)benzyl)isoxazole-5-carboxamide (91.2 mg, 57% yield) as a white solid. LCMS m / z=516.2 (M+H)+. 1H NMR (500MHz, DMSO-d6) δ: 9.39-9.28 (m, 1H), 8.38-8.22 (m, 2H), 7.61-7.45 (m, 2H), 7.34 (br d, 1H), 7.17 (br s, 2H), 6.78-5.90 (m, 2H), 5.70-5.49 (m, 1H), 4.55-4.37 (m, 2H), 3.74-3.41 (m, 1H), 3.13-2.96 (m, 1H), 2.91 (br s, 2H), 2.77-2.60 (m, 3H), 2.49-2.34 (m, 4H), 1.80-1.42 (m, 4H), 1.30 (s, 9H).

[0247] Example 47: 1-(tert-butyl)-N-(4-(3-cyano-5-((R)-3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)-3-fluoro-2-methylbenzyl)-1H-1,2,3-triazole-4-carboxamide [ka] 1. Synthesis of tert-butyl (R)-(1-(4-chloro-5-cyanopyridin-3-yl)piperidin-3-yl)(methyl)carbamate [ka] To a solution of 5-bromo-4-chloronicotinonitrile (200.00 mg, 919.75 μmol, 1.0 equiv) in toluene (40.00 mL) was added tert-butyl (R)-methyl(piperidin-3-yl)carbamate (197.10 mg, 919.75 μmol, 1.0 equiv) and t-BuONa (176.78 mg, 1.84 mmol, 2.0 equiv) at 15° C. Then, precatalyst (RuPhos) (153.85 mg, 183.95 μmol, 0.2 equiv) was added at 15° C. The mixture was stirred at 75° C. under N for 6 hours. LCMS showed that the starting material was consumed and the desired product was detected. The mixture was concentrated under vacuum to give a crude product, which was purified by silica gel column chromatography (PE / EA = 1 / 0 to 1 / 1) to give the title compound (170.00 mg, 314.96 μmol, 34.24% yield) as a yellow oil. LCMS m / z = 351.3 (M+H + ).

[0248] 2. Synthesis of tert-butyl ((3R)-1-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-2-fluoro-3-methylphenyl)-5-cyanopyridin-3-yl)piperidin-3-yl)(methyl)carbamate [ka] To a solution of 1-(tert-butyl)-N-(3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (169.68 mg, 407.59 μmol, 1.1 equiv) in a mixture of dioxane (4.00 mL) and water (0.6 mL) was added KPO (235.96 mg, 1.11 mmol, 3.0 equiv) and tert-butyl (R)-(1-(4-chloro-5-cyanopyridin-3-yl)piperidin-3-yl)(methyl)carbamate (130.00 mg, 370.54 μmol, 1.0 equiv) at 20 °C. Pd(dtbpf)Cl2 (48.30 mg, 74.11 μmol, 0.2 equiv) was then added to the mixture at 20 °C. The reaction was stirred under N2 at 20 °C for 2 h. LCMS showed that the starting material was consumed and the desired product was detected. The mixture was concentrated to give a crude, which was purified by preparative TLC to give the title compound (160.00 mg, 42.84% yield) as a yellow oil. LCMS: m / z = 605.3 (M+H + ).

[0249] 3. Synthesis of 1-(tert-butyl)-N-(4-(3-cyano-5-((R)-3-(methylamino)piperidin-1-yl)pyridin-4-yl)-3-fluoro-2-methylbenzyl)-1H-1,2,3-triazole-4-carboxamide [ka] To a solution of tert-butyl ((3R)-1-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-2-fluoro-3-methylphenyl)-5-cyanopyridin-3-yl)piperidin-3-yl)(methyl)carbamate (160.00 mg, 264.59 μmol, 1.0 equiv) in DCM (10.00 mL) was added HCl / EA (1 mL, 4 M) slowly at 20° C. The mixture was then stirred at 20° C. for 30 min. LCMS showed that the starting material was consumed and the desired product was detected. The mixture was concentrated under vacuum to give the title compound (130 mg, crude) as a yellow solid, which was used directly in the next step without further purification. LCMS: m / z=505.2 (M+H + ).

[0250] 4. Synthesis of 1-(tert-butyl)-N-(4-(3-cyano-5-((R)-3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)-3-fluoro-2-methylbenzyl)-1H-1,2,3-triazole-4-carboxamide [ka] To a solution of 1-(tert-butyl)-N-(4-(3-cyano-5-((R)-3-(methylamino)piperidin-1-yl)pyridin-4-yl)-3-fluoro-2-methylbenzyl)-1H-1,2,3-triazole-4-carboxamide (110 mg, 203.30 μmol, 1.0 equiv.) in DCM (20.00 mL) was added DIPEA (52.55 mg, 406.61 μmol, 2.0 equiv.) at 20° C. Then, acryloyl chloride (20.24 mg, 223.63 μmol, 1.1 equiv.) was added slowly to the mixture at 20° C. The mixture was then stirred at 20° C. for 30 minutes. LCMS showed that the starting material was consumed and the desired product was detected. The mixture was poured into water (50 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated in vacuo to give a crude product, which was purified by preparative HPLC (Column: Welch Xtimate C18 150 x 25 mm x 5 μm, Conditions: water (10 mM NHHCO)-ACN, Start B35, End B65, Gradient time (min): 10, 100% B Retention time (min): 2, Flow rate (mL / min): 25) to give the title compound (48.8 mg, Yield 42.97%, Purity 100.00%, Enantiomeric excess: 100.00%) as a yellow solid. LCMS: m / z = 559.4 (M+H + ). 1 H NMR (500MHz, DMSO-d6) δ ppm=9.15-9.03 (m, 1H), 8.81-8.56 (m, 3H), 7.44-7.20 (m, 2H), 6.70-5.93 (m, 2H), 5.77-5.59 (m, 1H), 4.65-4.47 (m, 2H), 4.17-3.44 (m, 1H), 2.95-2.53 (m, 7H), 2.30 (d, J=17.5 Hz, 3H), 1.65-1.51 (m, 12H), 1.29-1.12 (m, 1H).

[0251] Example 48: (R)-1-(tert-butyl)-N-(4-(3-cyano-5-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)-2-methylbenzyl)-1H-1,2,3-triazole-4-carboxamide [ka] 1. Synthesis of tert-butyl (R)-(1-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)-5-cyanopyridin-3-yl)piperidin-3-yl)(methyl)carbamate [ka] To a solution of 1-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (136.24 mg, 342.04 μmol, 1.0 equiv) in dioxane (10.00 mL) and water (2.00 mL) was added tert-butyl (R)-(1-(4-chloro-5-cyanopyridin-3-yl)piperidin-3-yl)(methyl)carbamate (120.00 mg, 342.04 μmol, 1.0 equiv) and KPO (217.81 mg, 1.03 mmol, 3.0 equiv) at 15 °C. Then, Pd(dtbpf)Cl2 (44.58 mg, 68.41 μmol, 0.2 equiv) was added at 15 °C. The mixture was stirred under N2 at 15 °C for 3 h. LCMS showed that the starting material was consumed and the desired product was detected. The mixture was filtered and concentrated in vacuo to give a crude, which was purified by preparative TLC (PE / EA=1 / 2) to give the title compound (120.00 mg, 32.89% yield) as a yellow oil. LCMS: m / z=587.5 (M+H + ).

[0252] 2. Synthesis of (R)-1-(tert-butyl)-N-(4-(3-cyano-5-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)-2-methylbenzyl)-1H-1,2,3-triazole-4-carboxamide [ka] A solution of tert-butyl (R)-(1-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)-5-cyanopyridin-3-yl)piperidin-3-yl)(methyl)carbamate (0.12 g, 204.52 μmol, 1.0 equiv) in DCM (20.00 mL) and HCl / EA (10 mL, 4 M) was stirred at 20° C. for 1 h. LCMS showed that the starting material was consumed and the desired product was detected. The mixture was concentrated in vacuo to give the title compound (0.08 mg, crude, hydrochloride salt) as a yellow solid, which was used directly in the next step without further purification. LCMS: m / z=487.4 (M+H + ).

[0253] 3. Synthesis of (R)-1-(tert-butyl)-N-(4-(3-cyano-5-(3-(N-methylacrylamido)piperidin-1-yl)pyridin-4-yl)-2-methylbenzyl)-1H-1,2,3-triazole-4-carboxamide [ka] To a solution of (R)-1-(tert-butyl)-N-(4-(3-cyano-5-(3-(methylamino)piperidin-1-yl)pyridin-4-yl)-2-methylbenzyl)-1H-1,2,3-triazole-4-carboxamide (80.00 mg, 152.94 μmol, hydrochloride, 1.0 equivalent) in DCM (10.00 mL) was added DIPEA (39.53 mg, 305.89 μmol, 2.0 equivalent) at 15° C. Then, compound acryloyl chloride (16.61 mg, 183.53 μmol, 1.2 equivalent) was added slowly to the mixture at 15° C. The mixture was then stirred at 15° C. for 1 hour. LCMS showed that the starting material was consumed and the desired product was detected. The mixture was poured into water (50 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated in vacuo to give a crude product, which was purified by preparative HPLC (Column: Welch Xtimate C18 150 x 25 mm x 5 μm, Conditions: water (10 mM NHHCO)-ACN, Start B34, End B64, Gradient time (min): 10, 100% B Retention time (min): 2, Flow rate (mL / min): 25) to give the title compound (42.3 mg, Yield 51.16%, Purity 100.00%, Enantiomeric excess: 100.00%) as a white solid. LCMS: m / z = 541.4 (M+H + ). 1 H NMR (400MHz, DMSO-d6) δ=9.00(s, 1H), 8.69-8.57 (m, 3H), 7.42-7.30 (m, 3H), 6.68-5.89 (m, 2H), 5.64-5.60 (m, 1H), 4.49-3.48 (m, 3H), 2.98-2.65 (m, 7H), 2.36 (s, 3H), 1.61-1.44 (m, 13H).

[0254] Example 49: N-(4-(3-(4-acryloylpiperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamide [ka] 1. Synthesis of tert-butyl 4-(4-chloropyridin-3-yl)piperazine-1-carboxylate [ka] A solution of 4-chloro-3-iodopyridine (200.00 mg, 0.835 mmol, 1.0 equiv.), tert-butyl piperazine-1-carboxylate (186.69 mg, 1.00 mmol, 1.2 equiv.), NaOtBu (240.81 mg, 2.51 mmol, 3.0 equiv.), and Pd-Ruphos-G3 (69.86 mg, 0.083 mmol, 0.1 equiv.) in toluene (8.00 mL) was purged with N2 for 1 min. The mixture was stirred at 100 °C for 4.5 h. LCMS showed that the starting material was completely consumed and a peak with the desired MS was detected. The solvent was removed to give a residue, which was purified by Combi-Flash eluting with 0% to 30% EtOAc in PE to give the title compound (150.00 mg, 54.28% yield) as a yellow oil. LCMS: m / z=298.1 (M+H + ).

[0255] 2. Synthesis of tert-butyl 4-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperazine-1-carboxylate [ka] A mixture of tert-butyl 4-(4-chloropyridin-3-yl)piperazine-1-carboxylate (150.00 mg, 0.503 mmol, 1.0 equiv), 1-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (220.70 mg, 0.554 mmol, 1.1 equiv), Pd(dtbpf)Cl (32.83 mg, 0.050 mmol, 0.1 equiv), and KCO (208.86 mg, 1.51 mmol, 3.0 equiv) in a mixture of dioxane (5.00 mL) and water (1.00 mL) was purged with N for 1 minute. The mixture was stirred at 90°C for 16 hours. LCMS showed that the starting material was completely consumed and a major peak with the desired MS was detected. The solvent was removed to give a residue, which was purified by Si chromatography eluting with 0% to 50% to 100% EtOAc in PE to give the title compound (260.00 mg, 82.21% yield) as a yellow solid. LCMS: m / z = 534.4 (M+H + ).

[0256] 3. Synthesis of 1-(tert-butyl)-N-(2-methyl-4-(3-(piperazin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] To a mixture of tert-butyl 4-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperazine-1-carboxylate (260.00 mg, 0.487 mmol, 1.0 equiv) in DCM (2.00 mL) was added HCl in EtOAc (4 M, 6.00 mL). The mixture was stirred at 25° C. for 1 h. LCMS showed that the starting material was completely consumed and a peak with the desired MS was detected. The reaction mixture was concentrated to give the title compound (200.00 mg, crude) as a yellow oil, which was used directly in the next step. LCMS: m / z=434.3 (M+H + ).

[0257] 4. Synthesis of N-(4-(3-(4-acryloylpiperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamide [ka] To a mixture of 1-(tert-butyl)-N-(2-methyl-4-(3-(piperazin-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (200.00 mg, 0.461 mmol, 1.0 equiv) and DIPEA (35.93 mg, 1.38 mmol, 3.0 equiv) in DCM (20.00 mL) was added acryloyl chloride (43.84 mg, 0.484 mmol, 1.05 equiv) at 0° C. The mixture was stirred at 0° C. for 2 minutes. LCMS showed that the starting material was completely consumed and a peak with the desired MS was detected. MeOH (2.00 mL) was added dropwise. The resulting mixture was stirred at 25° C. for 10 minutes. The solvent was removed to give a crude product, which was purified by preparative HPLC (column: Agela DuraShell C18 150 x 25 mm x 5 μm, conditions: water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN, start B29, end B59, gradient time (min) 14, 100% B retention time (min) 2, flow rate (mL / min) 25) to give the title compound (77.8 mg, yield 34.59%, purity 100.00%) as a pale yellow solid. LCMS: m / z = 488.4 (M+H + ). 1 H NMR (500MHz, MeOH-d4) δ ppm=8.50 (s, 1H), 8.28-8.22 (m, 2H), 7.61-7.55 (m, 2H), 7.44 (d, J=8.5 Hz, 1H), 7.30 (d, J=5.0 Hz, 1H), 6.77-6.70 (m, 1H), 6.23-6.18 (m, 1H), 5.76-5.73 (m, 1H), 4.67 (s, 2H), 3.65-3.55 (m, 4H), 2.98-2.89 (m, 4H), 2.47 (s, 3H), 1.73 (s, 9H). Example 50: N-(4-(5-(4-acryloylpiperazin-1-yl)pyrimidin-4-yl)-2-methylbenzyl)-1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamide [ka] 1. Synthesis of tert-butyl 4-(4-(tert-butoxy)pyrimidin-5-yl)piperazine-1-carboxylate [ka] A solution of 4-(tert-butoxy)-5-iodopyrimidine (400.00 mg, 1.44 mmol, 1.0 equiv.), tert-butyl piperazine-1-carboxylate (321.84 mg, 1.73 mmol, 1.2 equiv.), t-BuONa (276.77 mg, 2.88 mmol, 2.0 equiv.), and precatalyst (Ruphos) (120.44 mg, 144.00 μmol, 0.1 equiv.) in toluene (15.00 mL) was purged with N for 1 min. The reaction mixture was stirred under N at 90 °C for 6 h. LCMS showed the reaction was complete. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (PE / EA = 10 / 1 to 3 / 1) to give the title compound (456.00 mg, 84.72% yield) as a brown solid. LCMS: m / z=337.3 (M+H + ).

[0258] 2. Synthesis of tert-butyl 4-(4-hydroxypyrimidin-5-yl)piperazine-1-carboxylate [ka] A mixture of tert-butyl 4-(4-(tert-butoxy)pyrimidin-5-yl)piperazine-1-carboxylate (456.00 mg, 1.36 mmol, 1.0 equiv) in HOAc (10.00 mL) and dioxane (10.00 mL) was stirred at 90° C. for 2 hours. LCMS showed that several peaks were detected, and one peak with the desired MS was found. The reaction was concentrated to give the crude product, to which aqueous NaCO solution was added and the pH was adjusted to >7. The reaction was concentrated to give the crude product, which was purified by column chromatography (DCM:MeOH=10:1) to give the title compound (350.00 mg, 91.81% yield) as a yellow solid. LCMS: m / z=281.3 (M+H + ).

[0259] 3. Synthesis of tert-butyl 4-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyrimidin-5-yl)piperazine-1-carboxylate [ka] To a solution of tert-butyl 4-(4-hydroxypyrimidin-5-yl)piperazine-1-carboxylate (150.00 mg, 535.10 μmol, 1.0 equiv) in dioxane (3.00 mL) was added TEA (162.44 mg, 1.61 mmol, 3.0 equiv) and PyBrop (249.45 mg, 535.10 μmol, 1.0 equiv). The mixture was stirred at 20° C. for 2 hours. Then, 1-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (234.45 mg, 588.61 μmol, 1.1 equiv), NaCO (170.15 mg, 1.61 mmol, 3.0 equiv), Pd(PPh)Cl (37.56 mg, 53.51 μmol, 0.1 equiv), and water (500.17 μL) were added to the mixture and stirred at 90 °C under N for 8 h. LCMS showed that the starting material was consumed and the desired MS was detected. The solvent was removed in vacuo to give a residue. The residue was purified by silica gel chromatography (PE to EA) to give the title compound (200.00 mg, 55.93% yield) as a yellow oil. LCMS: m / z = 535.3 (M+H + ).

[0260] 4. Synthesis of 1-(tert-butyl)-N-(2-methyl-4-(5-(piperazin-1-yl)pyrimidin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] A mixture of tert-butyl 4-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyrimidin-5-yl)piperazine-1-carboxylate (200.00 mg, 374.08 μmol, 1.0 equiv) in HCl / EA (4 M, 15.00 mL) was stirred at 9° C. for 30 min. LCMS showed that the starting material was completely consumed. The crude material was concentrated under vacuum to give the title compound (115.00 mg, crude) as a yellow oil. LCMS: m / z=435.3 (M+H+ ).

[0261] 5. Synthesis of N-(4-(5-(4-acryloylpiperazin-1-yl)pyrimidin-4-yl)-2-methylbenzyl)-1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamide [ka] To 1-(tert-butyl)-N-(2-methyl-4-(5-(piperazin-1-yl)pyrimidin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (115.00 mg, 264.65 μmol, 1.0 equiv) and DIPEA (68.41 mg, 529.30 μmol, 2.0 equiv) in DCM (20.00 mL) was added acryloyl chloride (26.35 mg, 291.11 μmol, 1.1 equiv) dropwise at 0° C. The mixture was stirred at 0° C. for 5 minutes. LCMS showed that the starting material was completely consumed. MeOH (6 mL) was added dropwise. The resulting mixture was stirred at 8° C. for 10 minutes. The solvent was removed to give a residue, which was purified by preparative HPLC (column: Welch Xtimate C18 150 x 25 mm x 5 μm, conditions: water (10 mM NH4HCO3)-ACN, start B23, end B53, gradient time (min) 10, 100% B retention time (min) 2, flow rate (mL / min) 25) to give the title compound (41.10 mg, yield 31.79%, purity 100.00%) as a white solid. LCMS: m / z = 489.4 (M+H + ). 1 H NMR (500MHz, MeOH-d4) δ=8.83 (s, 1H), 8.50 (s, 2H), 7.95-7.90 (m, 2H), 7.47 (d, J=8.0 Hz, 1H), 6.75 (dd, J=10.5, 17.0 Hz, 1H), 6.22 (dd, J=2.0, 16.5 Hz, 1H), 5.76 (dd, J1=2.0, J2=10.5 Hz, 1H), 4.69 (s, 2H), 3.68 (s, 4H), 3.01-2.98 (m, 4H), 2.49 (s, 3H), 1.73 (s, 9H).

[0262] Example 51: (R)-1-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)azepan-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] 1. Synthesis of (R)-tert-butyl 3-(((benzyloxy)carbonyl)amino)azepane-1-carboxylate [ka] To a solution of (R)-tert-butyl 3-aminoazepane-1-carboxylate (800.00 mg, 3.73 mmol, 1.0 equiv) in DCM (50.00 mL) was added TEA (755.50 mg, 7.47 mmol, 2.0 equiv), and the mixture was cooled to -70 °C. CbzCl (955.24 mg, 5.60 mmol, 1.5 equiv) was then added to the mixture, and the mixture was stirred at -70 °C for 30 min. LCMS showed that a mass of product was observed. The reaction mixture was concentrated under vacuum to give a crude product, which was purified by column chromatography (PE / EA = 7 / 3) to give the title compound (1.20 g, 83.10% yield) as a clear oil. LCMS: m / z = 249.2 (M+H + -Boc).

[0263] 2. Synthesis of (R)-tert-butyl 3-(((benzyloxy)carbonyl)(methyl)amino)azepane-1-carboxylate [ka] To a solution of (R)-tert-butyl 3-(((benzyloxy)carbonyl)amino)azepane-1-carboxylate (1.20 g, 3.44 mmol, 1.0 equiv) in THF (50.00 mL) was added NaH (688.78 mg, 17.22 mmol, 5.0 equiv), and the mixture was stirred at 0 °C for 30 min. Then, MeI (3.47 g, 24.45 mmol, 7.11 equiv) was added to the mixture, and the mixture was stirred at 20 °C for 1 h. The instrument was quenched with NH3H2O. LCMS showed that a mass of product was observed. The mixture was quenched with MeOH (20.00 mL). The reaction mixture was concentrated under vacuum to give the crude, which was purified by column chromatography (PE / EA = 4 / 1) to give the title compound (1.20 g, 89.50% yield) as a clear oil. LCMS: m / z=363.3 (M+H + ).

[0264] 3. Synthesis of (R)-azepan-3-yl(methyl)benzylcarbamate [ka] To a solution of (R)-tert-butyl 3-(((benzyloxy)carbonyl)(methyl)amino)azepane-1-carboxylate (1.20 g, 3.31 mmol, 1.0 equiv) in DCM (20.00 mL) was added HCl / EA (4 M, 4.00 mL) and the mixture was stirred at 20° C. for 30 min. LCMS showed that a mass of product was observed. The mixture was concentrated under vacuum to give the title compound (980.00 mg, crude, hydrochloride salt) as a white solid. The compound was used in the next step without further purification. LCMS: m / z=263.2 (M+H + ).

[0265] 4. Synthesis of (R)-(1-(4-chloropyridin-3-yl)azepan-3-yl)(methyl)benzylcarbamate [ka] To a solution of (R)-benzyl azepan-3-yl(methyl)carbamate (500.00 mg, 1.67 mmol, hydrochloride salt, 1.0 equiv.) and 4-chloro-3-iodopyridine (479.84 mg, 2.00 mmol, 1.2 equiv.) in toluene (15.00 mL) was added t-BuONa (481.46 mg, 5.01 mmol, 3.0 equiv.). Precatalyst (Ruphos) (139.67 mg, 167.00 μmol, 0.1 equiv.) was then added to the mixture, and the mixture was stirred at 100° C. under N for 2 hours. LCMS showed that a mass of product was observed. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by column chromatography (PE / EA=1 / 1) to give the title compound (100.00 g, 14.41% yield) as a brown oil. LCMS: m / z=374.2 (M+H + ).

[0266] 5. (R)-1-(4-chloropyridin-3-yl)-N-methylazepan-3-amine [ka] To a solution of (R)-(1-(4-chloropyridin-3-yl)azepan-3-yl)(methyl)benzylcarbamate (100.00 mg, 267.47 μmol, 1.0 equiv) in DCM (10.00 mL) was added HBr / HOAc (1.00 mL, 33 wt%) and the mixture was stirred at 20° C. for 30 min. LCMS showed that a mass of product was observed. The mixture was concentrated under vacuum to give the title compound (60.00 mg, crude) as an orange oil. The compound was used in the next step without further purification. LCMS: m / z=240.1 (M+H + ).

[0267] 6. Synthesis of tert-butyl (R)-(1-(4-chloropyridin-3-yl)azepan-3-yl)(methyl)carbamate [ka] To a solution of (R)-1-(4-chloropyridin-3-yl)-N-methylazepan-3-amine (60.00 mg, 250.27 μmol, 1.0 equiv.) in DCM (20.00 mL) was added TEA (75.97 mg, 750.81 μmol, 3.0 equiv.). Then, (Boc)2O (109.24 mg, 500.54 μmol, 2.0 equiv.) was added to the mixture, and the mixture was stirred at 20° C. for 30 minutes. LCMS showed that a mass of product was observed. The reaction mixture was concentrated under vacuum to give a crude product, which was purified by column chromatography (PE / EA=7 / 3) to give the title compound (80.00 g, 89.35% yield) as a brown oil. LCMS: m / z=340.2 (M+H + ).

[0268] 7. (R)-(1-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)azepan-3-yl)(methyl)carbamate tert-Butyl [ka] To tert-butyl (R)-(1-(4-chloropyridin-3-yl)azepan-3-yl)(methyl)carbamate (70.00 mg, 205.97 μmol, 1.0 equiv) and 1-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-1,2,3-triazole-4carboxamide (98.45 mg, 247.16 μmol, 1.2 equiv) in dioxane (10.00 mL) was added water (999.89 uL). Then, K2CO3 (85.40 mg, 617.90 μmol, 3.0 equiv.) and Pd(dtbpf)Cl2 (13.42 mg, 20.60 μmol, 0.1 equiv.) were added to the mixture, and the mixture was stirred at 80 °C under N2 for 2 h. LCMS showed that a mass of product was observed. The reaction mixture was concentrated under vacuum to give a crude, which was purified by column chromatography (PE / EA = 1 / 4) to give the title compound (80.00 g, 49.25% yield) as a brown oil. LCMS: m / z = 576.4 (M+H + ).

[0269] 8. (R)-1-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)azepan-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] A solution of tert-butyl (R)-(1-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)azepan-3-yl)(methyl)carbamate (80.00 mg, 138.95 μmol, 1.0 equiv) in HCl / EA (4 M, 10.00 mL) was added and the mixture was stirred at 20° C. for 30 min. LCMS showed that a mass of product was observed. The mixture was concentrated under vacuum to give the title compound (70.00 mg, crude, hydrochloride salt) as a yellow solid. The compound was used in the next step without further purification. LCMS: m / z=476.4 (M+H + ).

[0270] 9. Synthesis of (R)-1-(tert-butyl)-N-(2-methyl-4-(3-(3-(N-methylacrylamido)azepan-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] To a solution of (R)-1-(tert-butyl)-N-(2-methyl-4-(3-(3-(methylamino)azepan-1-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (65.00 mg, 126.93 μmol, hydrochloride salt, 1.0 equiv.) in DCM (50.00 mL) was added DIPEA (49.21 mg, 380.79 μmol, 3.0 equiv.). Acryloyl chloride (13.79 mg, 152.32 μmol, 1.2 equiv.) was then added to the mixture, and the mixture was stirred at 20° C. for 30 minutes. LCMS showed that a mass of product was observed. The mixture was concentrated in vacuo to give a brown crude, which was purified by preparative HPLC (Column: Welch Xtimate C18 150 x 25 mm x 5 μm, Conditions: water (10 mM NH4HCO3)-ACN, Start B35, End B65, Gradient time (min): 10, 100% B Retention time (min): 2, Flow rate (mL / min) 25) to give the title product (36.00 mg, 52.42% yield) as a yellow solid. LCMS: m / z = 530.3 (M+H + ). 1H NMR (400MHz, DMSO-d6) δ ppm=8.94 (s, 1H), 8.70 (s, 1H), 8.49-8.43 (m, 1H), 8.21-8.13 (m, 1H), 7.36-7.22 (m, 3H), 7.12-7.05 (m, 1H), 6.67-6.59 (m, 1H), 6.11-5.98 (m, 1H), 5.66-5.58 (m, 1H), 4.54-3.85 (m, 3H), 3.33-3.10 (m, 3H), 3.03-2.90 (m, 1H), 2.76-2.56 (m, 3H), 2.36 (s, 3H), 1.63 (s, 11H), 1.57-1.26 (m, 4H).

[0271] Example 52: 1-(tert-butyl)-N-(2-methyl-4-(3-(6-(N-methylacrylamido)-1,4-oxazepan-4-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] Synthesis of tert-butyl 1,6-methylene-1,4-oxazepane-4-carboxylate [ka] To a solution of 3-chloro-2-(chloromethyl)prop-1-ene (5.00 g, 40.00 mmol, 1.0 equiv) in DMF (80.00 mL) was added NaH (3.63 g, 90.80 mmol, 60% purity, 2.27 equiv) at 0 °C. The mixture was stirred at 0 °C for 30 min. Then, tert-butyl (2-hydroxyethyl)carbamate (6.13 g, 38.00 mmol, 0.95 equiv) was added at 0 °C. The mixture was stirred at 20 °C for 2 h. LCMS showed that a mass of product was observed. The reaction was quenched by adding saturated NH4Cl (300 mL). The solvent was removed in vacuo, and the residue was extracted with EA (200 mL × 2). The organic layer was concentrated and purified by silica gel column (PE / EA=4 / 1) to give the title compound (4.30 g, yield 50.41%) as a colorless oil. LCMS: m / z=158.1 (M+H + -56).

[0272] Synthesis of tert-butyl 2,6-oxo-1,4-oxazepane-4-carboxylate [ka] To a solution of tert-butyl 6-methylene-1,4-oxazepane-4-carboxylate (4.30 g, 20.16 mmol, 1.0 equiv) in THF (60.00 mL) was added water (60.00 mL). 4. 2 (HO) (371.45 mg, 1.01 mmol, 0.05 equiv) and NaIO (9.96 g, 46.57 mmol, 2.31 equiv) were added to the mixture, and the mixture was stirred at 20 °C for 4 h. LCMS showed that mass of product was observed. The mixture was poured into EA (30 mL) and filtered to remove the solid. The mixture was poured into HO (30 mL) and extracted with EA (30 mL × 2). The combined organic layer was washed with brine (40 mL), dried over NaSO, and concentrated under vacuum to give the crude product, which was purified by silica gel column chromatography (PE / EA = 5 / 1) to give the title compound (4.15 g, 86.07% yield) as a yellow oil. LCMS: m / z = 160.1 (M+H + -56).

[0273] 3. Synthesis of tert-butyl 6-(methylamino)-1,4-oxazepane-4-carboxylate [ka] To a solution of tert-butyl 6-oxo-1,4-oxazepane-4-carboxylate (4.15 g, 19.28 mmol, 1.0 equiv) in MeOH (150.00 mL), methanamine hydrochloride (13.02 g, 192.80 mmol, 10.0 equiv) was added, and the mixture was stirred at 60 °C for 2 h. Sodium cyanoborohydride (6.06 g, 96.40 mmol, 5.0 equiv) was then added, and the mixture was stirred at 60 °C for 16 h. LCMS showed that product mass was observed. The mixture was concentrated in vacuo to give the crude, which was poured into water (100 mL) and extracted with EA (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na SO , filtered, and concentrated in vacuo to give the title compound (4.40 g, crude) as a yellow oil. The compound was used in the next step without further purification. LCMS: m / z=231.2 (M+H + ).

[0274] 4. Synthesis of tert-butyl 6-(((benzyloxy)carbonyl)(methyl)amino)-1,4-oxazepane-4-carboxylate [ka] To a solution of tert-butyl 6-(methylamino)-1,4-oxazepane-4-carboxylate (4.40 g, 19.11 mmol, 1.0 equiv.) in DCM (150.00 mL) was added TEA (3.87 g, 38.22 mmol, 2.0 equiv.). CbzCl (4.89 mg, 28.66 mmol, 1.5 equiv.) was then added to the mixture, and the mixture was stirred at 0° C. for 30 minutes. LCMS showed that a mass of product was observed. The reaction mixture was concentrated under vacuum to give a crude product, which was purified by column chromatography (PE / EA=4 / 1) to give the title compound (2.52 g, 34.38% yield) as a clear oil. LCMS: m / z=265.2 (M-Boc+H + ).

[0275] 5. Synthesis of benzyl methyl(1,4-oxazepan-6-yl)carbamate [ka] To a solution of tert-butyl 6-(((benzyloxy)carbonyl)(methyl)amino)-1,4-oxazepane-4-carboxylate (520.00 mg, 1.43 mmol, 1.0 equiv) in DCM (20.00 mL) was added HCl / EA (4 M, 4.00 mL) and the mixture was stirred at 20° C. for 3 h. LCMS showed that a mass of product was observed. The mixture was concentrated under vacuum to give the title compound (430.00 mg, crude, hydrochloride salt) as a clear oil. The compound was used in the next step without further purification. LCMS: m / z=265.3 (M+H + ).

[0276] 6. Synthesis of benzyl (4-(4-chloropyridin-3-yl)-1,4-oxazepan-6-yl)(methyl)carbamate [ka] To a solution of benzyl methyl(1,4-oxazepan-6-yl)carbamate (430.00 mg, 1.43 mmol, hydrochloride, 1.0 equiv.) and 4-chloro-3-iodopyridine (376.54 mg, 1.57 mmol, 1.1 equiv.) in toluene (12.00 mL) was added tBuONa (412.16 mg, 4.29 mmol, 3.0 equiv.). Precatalyst (Ruphos) (119.57 mg, 143.00 μmol, 0.1 equiv.) was then added to the mixture, and the mixture was stirred at 100° C. under N for 2 hours. LCMS showed that a mass of product was observed. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by column chromatography (PE / EA=1 / 1) to give the title compound (180.00 g, 29.47% yield) as a brown oil. LCMS: m / z=376.1 (M+H + ).

[0277] 7. Synthesis of 4-(4-chloropyridin-3-yl)-N-methyl-1,4-oxazepan-6-amine [ka] To a solution of benzyl (4-(4-chloropyridin-3-yl)-1,4-oxazepan-6-yl)(methyl)carbamate (180.00 mg, 478.91 μmol, 1.0 equiv) in DCM (10.00 mL) was added HBr / HOAc (1.00 mL, purity 33%) and the mixture was stirred at 20° C. for 30 min. LCMS showed that a mass of product was observed. The mixture was concentrated under vacuum to give the title compound (110.00 mg, crude) as an orange oil. The compound was used in the next step without further purification. LCMS: m / z=242.4 (M+H + ).

[0278] 8. Synthesis of tert-butyl (4-(4-chloropyridin-3-yl)-1,4-oxazepan-6-yl)(methyl)carbamate [ka] To a solution of 4-(4-chloropyridin-3-yl)-N-methyl-1,4-oxazepan-6-amine (110.00 mg, 455.07 μmol, 1.0 equiv.) in DCM (30.00 mL) was added TEA (138.15 mg, 1.37 mmol, 3.0 equiv.). Then, (Boc)2O (198.64 mg, 910.14 μmol, 2.0 equiv.) was added to the mixture, and the mixture was stirred at 20° C. for 30 minutes. LCMS showed that a mass of product was observed. The reaction mixture was concentrated under vacuum to give a crude product, which was purified by column chromatography (PE / EA=7 / 3) to give the title compound (140.00 g, 81.00% yield) as a brown oil. LCMS: m / z 342.1 (M+H + ).

[0279] 9. Synthesis of tert-butyl (4-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)-1,4-oxazepan-6-yl)(methyl)carbamate [ka] To tert-butyl (4-(4-chloropyridin-3-yl)-1,4-oxazepan-6-yl)(methyl)carbamate (130.00 mg, 380.31 μmol, 1.0 equiv.) and 1-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (151.48 mg, 380.31 μmol, 1.0 equiv.) in dioxane (10.00 mL) was added water (999.89 uL). Then, K2CO3 (157.69 mg, 1.14 mmol, 3.0 equiv.) and Pd(dtbpf)Cl2 (24.79 mg, 38.03 μmol, 0.1 equiv.) were added to the mixture, and the mixture was stirred at 85 °C under N2 for 2 h. LCMS showed that a mass of product was observed. The reaction mixture was concentrated under vacuum to give a crude product, which was purified by column chromatography (PE / EA = 1 / 4) to give the title compound (115.00 g, 47.11% yield) as a brown oil. LCMS: m / z = 578.4 (M+H + ).

[0280] 10. Synthesis of 1-(tert-butyl)-N-(2-methyl-4-(3-(6-(methylamino)-1,4-oxazepan-4-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] A solution of tert-butyl (4-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)-1,4-oxazepan-6-yl)(methyl)carbamate (115.00 mg, 199.06 μmol, 1.0 equiv) in HCl / EA (4 M, 20.00 mL) was stirred at 20° C. for 30 min. LCMS showed that a mass of product was observed. The mixture was concentrated under vacuum to give the title compound (95.00 mg, crude) as a yellow solid. The compound was used in the next step without further purification. LCMS: m / z=478.3 (M+H + ).

[0281] 11. Synthesis of 1-(tert-butyl)-N-(2-methyl-4-(3-(6-(N-methylacrylamido)-1,4-oxazepan-4-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] To a solution of 1-(tert-butyl)-N-(2-methyl-4-(3-(6-(methylamino)-1,4-oxazepan-4-yl)pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (95.00 mg, 198.91 μmol, 1.0 equiv.) in DCM (50.00 mL) was added DIPEA (77.12 mg, 596.73 μmol, 3.0 equiv.). Acryloyl chloride (21.60 mg, 238.69 μmol, 1.2 equiv.) was then added to the mixture, and the mixture was stirred at 20° C. for 30 minutes. LCMS showed that a mass of product was observed. The mixture was concentrated under vacuum to give a brown crude, which was purified by preparative HPLC (Column: Welch Xtimate C18 150 x 25 mm x 5 μm, Conditions: water (10 mM NH4HCO3)-ACN, Start B27, End B57, Gradient time (min): 10, 100% B Retention time (min) 2, Flow rate (mL / min) 25) to give the title compound (54.00 mg, Yield 51.06%, Purity 100.00%) as a yellow solid. LCMS: m / z = 532.5 (M+H + ). 1H NMR:(400MHz, DMSO-d6) δ ppm=9.00-8.90 (m, 1H), 8.68 (d, J=10.4 Hz, 1H), 8.45 (d, J=7.6 Hz, 1H), 8.25-8.21 (m, 1H), 7.48-7.27 (m, 3H), 7.18-7.12 (m, 1H), 6.65-6.04 (m, 1H), 5.96-5.85 (m, 1H), 5.67-5.48 (m, 1H), 4.48 (d, J=6.4 Hz, 2H), 3.89-3.80 (m, 1H), 3.78-3.36 (m, 4H), 3.29-3.01 (m, 4H), 2.89-2.73 (m, 3H), 2.39 (d, J=14.8 Hz, 3H), 1.63 (s, 9H).

[0282] Example 53: (S)-2-(tert-butyl)-N-(2-methyl-4-(3-(5-(N-methylacrylamido)-2-oxopiperidin-1-yl)pyridin-4-yl)benzyl)-2H-tetrazole-5-carboxamide and (R)-2-(tert-butyl)-N-(2-methyl-4-(3-(5-(N-methylacrylamido)-2-oxopiperidin-1-yl)pyridin-4-yl)benzyl)-2H-tetrazole-5-carboxamide [ka] Synthesis of tert-butyl (1-(4-chloropyridin-3-yl)-6-oxopiperidin-3-yl)carbamate [ka] To a solution of 4-chloro-3-iodopyridine (1.00 g, 4.18 mmol, 1.0 equiv) in dioxane (15.00 mL) was added tert-butyl (6-oxopiperidin-3-yl)carbamate (894.84 mg, 4.18 mmol, 1.0 equiv), CsCO (4.08 g, 12.53 mmol, 3.0 equiv), CuI (318.16 mg, 1.67 mmol, 0.4 equiv), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (237.62 mg, 1.67 mmol, 0.4 equiv) at 15 °C. The mixture was stirred at 110 °C under N2 for 10 h. LCMS showed the desired product was detected. The mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150 x 25 mm x 5 μm, conditions: water (10 mM NH4HCO3)-ACN, start B 16, end 46, gradient time (min) 10, 100% B retention time (min) 2, flow rate (mL / min): 25) to give the title compound (0.27 g, 19.84% yield) as a white solid. LCMS: m / z = 326.1 (M+H + ).

[0283] 1. Synthesis of tert-butyl (1-(4-chloropyridin-3-yl)-6-oxopiperidin-3-yl)(methyl)carbamate [ka] To a solution of tert-butyl (1-(4-chloropyridin-3-yl)-6-oxopiperidin-3-yl)carbamate (270 mg, 828.76 μmol, 1.0 equiv) in DMF (12.00 mL) was added NaH (49.72 mg, 1.24 mmol, 60% purity, 1.5 equiv) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes. Then, CHCl (15.94 g, 112.30 mmol, 135.51 equiv) was added to the reaction mixture. The ice bath was removed, and the reaction mixture was stirred at 0° C. for 30 minutes. LCMS showed the reaction was complete, and the reaction was quenched with HCl (0.2 mL, 1 M). The mixture was purified by preparative TLC (DCM / MeOH=10 / 1) to give the title compound (190 mg, yield 67.47%) as a yellow oil. LCMS: m / z=340.1 (M+H + ).

[0284] 2. Synthesis of tert-butyl (1-(4-(4-((2-(tert-butyl)-2H-tetrazole-5-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)-6-oxopiperidin-3-yl)(methyl)carbamate [ka] To a solution of 2-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-2H-tetrazole-5-carboxamide (223.26 mg, 559.13 μmol, 1.0 equiv) in dioxane (15.00 mL) and water (3.00 mL) was added tert-butyl (1-(4-chloropyridin-3-yl)-6-oxopiperidin-3-yl)(methyl)carbamate (190.00 mg, 559.13 μmol, 1.0 equiv) KCO (231.82 mg, 1.68 mmol, 3.0 equiv), and Pd(dtbpf)Cl (36.44 mg, 55.91 μmol, 0.1 equiv) at 15 °C. The mixture was stirred under N2 at 90°C for 2 hours. LCMS showed that the reaction was complete. The mixture was concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC (DCM / MeOH = 10 / 1) to give the title compound (200.00 mg, yield 62.03%) as a yellow oil. LCMS: m / z = 577.4 (M+H + ).

[0285] 4. Synthesis of 2-(tert-butyl)-N-(2-methyl-4-(3-(5-(methylamino)-2-oxopiperidin-1-yl)pyridin-4-yl)benzyl)-2H-tetrazole-5-carboxamide [ka] To a solution of tert-butyl (1-(4-(4-((2-(tert-butyl)-2H-tetrazole-5-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)-6-oxopiperidin-3-yl)(methyl)carbamate (200.00 mg, 346.81 μmol, 1.0 equiv) in DCM (15.00 mL) was added HCl / EA (8 mL, 4 M) at 15° C. The mixture was stirred at 15° C. for 1 h. LCMS showed the reaction was complete. The mixture was concentrated under vacuum to give the title compound (150 mg, crude, hydrochloride salt) as a yellow solid. LCMS: m / z=477.3 (M+H + ).

[0286] 5. Synthesis of 2-(tert-butyl)-N-(2-methyl-4-(3-(5-(N-methylacrylamido)-2-oxopiperidin-1-yl)pyridin-4-yl)benzyl)-2H-tetrazole-5-carboxamide [ka] To a solution of 2-(tert-butyl)-N-(2-methyl-4-(3-(5-(methylamino)-2-oxopiperidin-1-yl)pyridin-4-yl)benzyl)-2H-tetrazole-5-carboxamide (150.00 mg, 292.38 μmol, hydrochloride salt, 1.0 equiv) in DCM (20 mL) was added DIPEA (75.57 mg, 584.76 μmol, 2.0 equiv) and acryloyl chloride (26.46 mg, 292.38 mmol, 1.0 equiv) at 15° C. The mixture was stirred at 15° C. for 10 min. LCMS showed the reaction was complete. The mixture was quenched with MeOH (1 mL) and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150 x 25 mm x 5 μm, conditions: water (10 mM NH4HCO3)-ACN, start B23, end B53, gradient time (min): 15, 100% B retention time (min): 2, flow rate (mL / min): 25) to give the title compound (100 mg, yield 64.46%) as a yellow solid. LCMS: m / z = 531.3 (M+H + ).

[0287] 6. Synthesis of (S)-2-(tert-butyl)-N-(2-methyl-4-(3-(5-(N-methylacrylamido)-2-oxopiperidin-1-yl)pyridin-4-yl)benzyl)-2H-tetrazole-5-carboxamide and (R)-2-(tert-butyl)-N-(2-methyl-4-(3-(5-(N-methylacrylamido)-2-oxopiperidin-1-yl)pyridin-4-yl)benzyl)-2H-tetrazole-5-carboxamide [ka] 2-(tert-butyl)-N-(2-methyl-4-(3-(5-(N-methylacrylamido)-2-oxopiperidin-1-yl)pyridin-4-yl)benzyl)-2H-tetrazole-5-carboxamide (100.00 mg, 188.46 μmol, 1.0 equiv.) was purified by SFC (column: DAICEL CHIRALCEL OD-H (250 mm × 30 mm, 5 μm), conditions: 0.1% NH 3 H 2 O ETOH, start B45, end B45, flow rate (mL / min): 80) to obtain peak 1 (32.00 mg, 32.00% yield, 100.00% purity, enantiomeric excess: 98.36%) as a white solid. LCMS: m / z = 531.4 (M+H + ). 1 H NMR (500MHz, DMSO-d6) δ ppm=9.55 (s, 1H), 8.67-8.30 (m, 2H), 7.50-7.35 (m, 2H), 7.21 (s, 2H), 6.91-5.43 (m, 3H), 4.54 (s, 2H), 3.81-3.63 (m, 1H), 3.32-2.66 (m, 5H), 2.41 (s, 3H), 2.38-2.12 (m, 2H), 1.85-1.62 (m, 11H).

[0288] Peak 2 (32.90 mg, yield 32.90%, purity 100.00%, enantiomeric excess: 97.28%) was obtained as a white solid. LCMS: m / z = 531.4 (M+H + ). 1 H NMR (500MHz, DMSO-d6) δ ppm=9.56-9.50 (m, 1H), 8.62-8.42 (m, 2H), 7.50-7.36 (m, 2H), 7.21 (s, 2H), 6.87-5.46 (m, 3H), 4.54 (s, 2H), 3.80-3.62 (m, 1H), 3.32-2.67 (m, 5H), 2.41 (s, 3H), 2.38-2.11 (m, 2H), 1.85-1.68 (m, 11H). Example 54: tert-Butyl 3-[4-[4-[[(1-tert-butyltriazole-4-carbonyl)amino]methyl]-3-methyl-phenyl]-3-pyridyl]-3,6-diazabicyclo[3.2.1]octane-6-carboxylate [ka] Synthesis of tert-butyl 1,3-(4-chloro-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane-6-carboxylate [ka] 4-Chloro-3-iodo-pyridine (563.95 mg, 2.36 mmol), tert-butyl 3,6-diazabicyclo[3.2.1]octane-6-carboxylate (500.00 mg, 2.36 mmol), RuPhos Pd G3 (196.99 mg, 235.53 mmol), and sodium tert-butoxide (679.02 mg, 7.07 mmol) were dissolved in toluene (10.00 mL). The reaction was purged with nitrogen for 5 minutes and stirred at 100° C. for 16 hours. The cooled mixture was diluted with EtOAc, filtered through Celite, and the concentrated residue was purified by silica gel chromatography (HE / EA 0-100%) to give tert-butyl 3-(4-chloro-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane-6-carboxylate (443.00 mg, 1.37 mmol, 57.97% yield). LCMS: Rt = 0.83 min, m / z 324.1 (M+H). + ). 1H NMR (400MHz, CDCl3) δ 8.32 (d, J=5.27 Hz, 1H), 8.17 (t, J=5.52 Hz, 1H), 7.26 (d, J=5.02 Hz, 1H), 4.20 (t, J=4.77 Hz, 0.5H),4.07-4.11 (m, 0.5H), 3.76 (dd, J=4.27, 11.04 Hz, 1H), 3.55-3.69 (m, 1H), 3.36-3.48 (m, 1H), 3.27-3.36 (m, 1H), 3.15 (br d, J=10.29 Hz, 1H), 2.80 (t,J=11.29 Hz, 1H), 2.51 (br s, 1H), 1.95-2.04 (m, 1H), 1.72 (dd, J=5.02, 11.04 Hz, 1H), 1.47 (d, J=7.53 Hz, 9H).

[0289] 2. Synthesis of benzyl N-[[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]carbamate [ka] A solution of [2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanamine (1.18 g, 4.16 mmol, hydrochloride) in DCM (10.00 mL) was cooled to 0 °C, and Cbz chloride (709.67 mg, 4.16 mmol, 591.39 μL) was added, followed by the dropwise addition of TEA (1.26 g, 12.48 mmol, 1.73 mL). After 1 h, the mixture was filtered through Celite, and the concentrated residue was subjected to silica gel chromatography (HE / EA 0-50%) to give N-[[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]benzyl carbamate (1.04 g, 2.73 mmol, 65.57% yield). LCMS: Rt=1.01 min, m / z382.3(M+H + ).

[0290] 3. Synthesis of tert-butyl 3-(4-(4-((((benzyloxy)carbonyl)amino)methyl)-3-methylphenyl)pyridin-3-yl)-3,6-diazabicyclo[3.2.1]octane-6-carboxylate [ka] A solution of tert-butyl 3-(4-chloropyridin-3-yl)-3,6-diazabicyclo[3.2.1]octane-6-carboxylate (351.00 mg, 953.11 umol), benzyl N-[[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]carbamate (545.09 mg, 1.43 mmol), potassium carbonate (526.90 mg, 3.81 mmol), and palladium with tri-tert-butylphosphane (48.71 mg, 95.31 umol) in dioxane (4.20 mL) and water (700.21 uL) was degassed and heated to 100 °C for 16 hours. The cooled mixture was filtered through Celite, and the concentrated residue was purified by silica gel chromatography (HE / EA 0-100%) to give tert-butyl 3-(4-(4-(((benzyloxy)carbonyl)amino)methyl)-3-methylphenyl)pyridin-3-yl)-3,6-diazabicyclo[3.2.1]octane-6-carboxylate (254.00 mg, 468.06 μmol, 49.11% yield) as a white solid. LCMS: Rt = 0.89 min, m / z 543.3 (M+H). + ).

[0291] 4. Synthesis of tert-butyl 3-[4-[4-(aminomethyl)-3-methyl-phenyl]-3-pyridyl]-3,6-diazabicyclo[3.2.1]octane-6-carboxylate [ka] tert-Butyl 3-[4-[4-(benzyloxycarbonylaminomethyl)-3-methyl-phenyl]-3-pyridyl]-3,6-diazabicyclo[3.2.1]octane-6-carboxylate (254.00 mg, 468.06 umol), Pd / C (99.62 mg, 46.81 umol, 5% purity) in MeOH (5.00 mL) was added to acetic acid (56.21 mg, 936.12 umol, 53.53 uL) and stirred under 1 atmosphere of H2 for 16 hours. The concentrated residue was diluted with DCM, washed with saturated aqueous NaHCO3, dried over Na2SO4, and subjected to silica gel chromatography (DCM / MeOH 0-30%) to give tert-butyl 3-[4-[4-(aminomethyl)-3-methyl-phenyl]-3-pyridyl]-3,6-diazabicyclo[3.2.1]octane-6-carboxylate (230.00 mg, 562.98 μmol, 120.28% yield) as a yellow gel. LCMS: Rt = 0.70 min, m / z 409.3 (M+H) + ).

[0292] 5. Synthesis of tert-butyl 3-[4-[4-[[(1-tert-butyltriazole-4-carbonyl)amino]methyl]-3-methyl-phenyl]-3-pyridyl]-3,6-diazabicyclo[3.2.1]octane-6-carboxylate [ka] To tert-butyl 3-[4-[4-(aminomethyl)-3-methyl-phenyl]-3-pyridyl]-3,6-diazabicyclo[3.2.1]octane-6-carboxylate (80.00 mg, 195.82 μmol), 1-tert-butyltriazole-4-carboxylic acid (33.13 mg, 195.82 μmol) in DCM (2.00 mL) was added DIPEA (25.31 mg, 195.82 μmol, 34.20 μL) and HATU (74.65 mg, 195.82 μmol) and stirred at room temperature for 16 hours. The crude was subjected to Si gel chromatography (HE / EA 0-100%) to give tert-butyl 3-[4-[4-[[(1-tert-butyltriazole-4-carbonyl)amino]methyl]-3-methyl-phenyl]-3-pyridyl]-3,6-diazabicyclo[3.2.1]octane-6-carboxylate (43.90 mg, 78.43 μmol, 40.05% yield) as a gel. LCMS: Rt = 0.88 min, m / z 560.4 (M+H) + ).

[0293] 6. Synthesis of 1-tert-butyl-N-[[4-[3-(3,6-diazabicyclo[3.2.1]octan-3-yl)-4-pyridyl]-2-methyl-phenyl]methyl]triazole-4-carboxamide [ka] To tert-butyl 3-[4-[4-[[(1-tert-butyltriazole-4-carbonyl)amino]methyl]-3-methyl-phenyl]-3-pyridyl]-3,6-diazabicyclo[3.2.1]octane-6-carboxylate (43.90 mg, 78.43 μmol) in EtOAc (2.00 mL) was added HCl (4 M, 78.43 μL) and stirred at room temperature for 16 h. The crude was concentrated to give 1-tert-butyl-N-[[4-[3-(3,6-diazabicyclo[3.2.1]octan-3-yl)-4-pyridyl]-2-methyl-phenyl]methyl]triazole-4-carboxamide (38.40 mg, 77.41 μmol, 98.70% yield, hydrochloride salt) as a white solid, which was used directly in the next step. LCMS: Rt=0.63 min, m / z460.3(M+H+ ).

[0294] 7. Synthesis of 1-tert-butyl-N-[[2-methyl-4-[3-(6-prop-2-enoyl-3,6-diazabicyclo[3.2.1]octan-3-yl)-4-pyridyl]phenyl]methyl]triazole-4-carboxamide [ka] To 1-tert-butyl-N-[[4-[3-(3,6-diazabicyclo[3.2.1]octan-3-yl)-4-pyridyl]-2-methyl-phenyl]methyl]triazole-4-carboxamide (38.40 mg, 77.41 μmol, hydrochloride salt) in DCM (4.00 mL) was added TEA (15.67 mg, 154.82 μmol, 21.47 μL) and stirred for 5 minutes. After cooling to 0 °C, prop-2-enoyl chloride (8.41 mg, 92.89 μmol, 7.58 μL) was added and stirred for 5 minutes, followed by quenching with saturated aqueous NaHCO (10 mL). The organic layer was passed through a pad of anhydrous NaSO and concentrated. The residue was purified by Si gel chromatography (0-15% EtOAc / MeOH) to give 1-tert-butyl-N-[[2-methyl-4-[3-(6-prop-2-enoyl-3,6-diazabicyclo[3.2.1]octan-3-yl)-4-pyridyl]phenyl]methyl]triazole-4-carboxamide (7.00 mg, 12.95 μmol, 16.73% yield, 95% purity). LCMS: Rt = 0.56 min, m / z 514.3 (M+H) + ). 1H NMR (400MHz, CDCl3) δ ppm 8.41 (m, 1 H), 8.31 (m,1 H), 8.22 (m, 1 H), 7.46-7.73 (m, 1 H), 7.28-7.40 (m, 1 H), 7.23-7.26 (m, 1 H), 7.17-7.22 (m, 1 H), 7.07 (m, 1 H), 6.43-6.47 (m, 1 H), 5.99-6.36 (m, 1 H), 5.60-5.70 (m, 1 H), 4.57-4.80 (m, 2 H), 4.54 (t, J=4.39 Hz, 0.5 H), 4.02-4.06 (m, 0.5 H), 2.52-3.57 (m, 7H), 2.40-2.42 (m, 3H), 1.81-1.99 (m, 1H), 1.70-1.72 (m, 9H), 1.60-1.69 (m, 1H).

[0295] Example 55: 5-tert-butyl-N-[[2-methyl-4-[3-(6-prop-2-enoyl-3,6-diazabicyclo[3.2.1]octan-3-yl)-4-pyridyl]phenyl]methyl]isoxazole-3-carboxamide [ka] 1. Synthesis of tert-butyl 3-[4-[4-[[(5-tert-butylisoxazole-3-carbonyl)amino]methyl]-3-methyl-phenyl]-3-pyridyl]-3,6-diazabicyclo[3.2.1]octane-6-carboxylate [ka] To tert-butyl 3-[4-[4-(aminomethyl)-3-methyl-phenyl]-3-pyridyl]-3,6-diazabicyclo[3.2.1]octane-6-carboxylate (80.00 mg, 195.82 μmol), 5-tert-butylisoxazole-3-carboxylic acid (33.13 mg, 195.82 μmol) in DCM (2.00 mL) was added DIPEA (75.92 mg, 587.46 μmol, 102.59 μL) and HATU (149.31 mg, 391.64 μmol) and stirred at room temperature for 16 hours. The crude was subjected to Si gel chromatography (HE / EA 0-100%) to give tert-butyl 3-[4-[4-[[(5-tert-butylisoxazole-3-carbonyl)amino]methyl]-3-methyl-phenyl]-3-pyridyl]-3,6-diazabicyclo[3.2.1]octane-6-carboxylate (18.40 mg, 31.23 μmol, 15.95% yield, 95% purity). LCMS: Rt = 1.01 min, m / z 560.4 (M+H). + ).

[0296] 2,5-tert-butyl-N-[[4-[3-(3,6-diazabicyclo[3.2.1]octan-3-yl)-4-pyridyl]-2-methyl-phenyl]methyl]isoxazole-3-carboxamide [ka] To tert-butyl 3-[4-[4-[[(5-tert-butylisoxazole-3-carbonyl)amino]methyl]-3-methyl-phenyl]-3-pyridyl]-3,6-diazabicyclo[3.2.1]octane-6-carboxylate (18.40 mg, 32.87 μmol) in EtOAc (2.00 mL) was added HCl (4 M, 49.30 μL) and stirred at room temperature for 16 h. The crude was concentrated to give 5-tert-butyl-N-[[4-[3-(3,6-diazabicyclo[3.2.1]octan-3-yl)-4-pyridyl]-2-methyl-phenyl]methyl]isoxazole-3-carboxamide (17.00 mg, 34.27 μmol, 104.26% yield, hydrochloride salt) as a white solid, which was used directly in the next step. LCMS: Rt=0.74 min, m / z460.3(M+H + ).

[0297] 3,5-tert-butyl-N-[[2-methyl-4-[3-(6-prop-2-enoyl-3,6-diazabicyclo[3.2.1]octan-3-yl)-4-pyridyl]phenyl]methyl]isoxazole-3-carboxamide [ka] To 5-tert-butyl-N-[[4-[3-(3,6-diazabicyclo[3.2.1]octan-3-yl)-4-pyridyl]-2-methyl-phenyl]methyl]isoxazole-3-carboxamide (17.00 mg, 34.27 μmol, hydrochloride salt) in DCM (3.00 mL) was added TEA (6.94 mg, 68.54 μmol, 9.51 μL) and stirred for 5 minutes. After cooling to 0 °C, prop-2-enoyl chloride (3.72 mg, 41.12 μmol, 3.35 μL) was added, stirred for 5 minutes, and quenched with saturated aqueous NaHCO (10 mL). The organic layer was concentrated through an anhydrous NaSO pad. The residue was purified by Si gel chromatography (0-15% EtOAc / MeOH) to give 5-tert-butyl-N-[[2-methyl-4-[3-(6-prop-2-enoyl-3,6-diazabicyclo[3.2.1]octan-3-yl)-4-pyridyl]phenyl]methyl]isoxazole-3-carboxamide (5.20 mg, 9.62 μmol, 28.06% yield, 95% purity). LCMS: Rt = 0.65 min, m / z 514.3 (M+H) + ). 1 H NMR (400MHz, CDCl3) δ ppm 8.38-8.48 (m, 1 H), 8.28-8.36 (m, 1 H), 7.48-7.81 (m, 1 H), 7.29-7.37 (m, 1 H), 7.19-7.22 (m, 1 H), 7.15-7.18 (m, 1 H), 7.03-7.12 (m, 1 H), 6.48-6.49 (m, 1 H), 5.91-6.32 (m, 1 H), 5.52-5.78 (m, 1 H), 3.96-4.92 (m, 4 H), 2.94-3.48 (m, 5 H), 2.64-2.75 (m, 1H), 2.47-2.56 (m, 1H), 2.34-2.41 (m, 3H), 1.79-1.98 (m, 1H), 1.60-1.75 (m, 1H), 1.33-1.42 (m, 9H).

[0298] Example 56: 1-tert-butyl-N-[[4-[3-fluoro-5-[(3R)-3-[methyl(prop-2-enoyl)amino]-1-piperidyl]-4-pyridyl]-2-methyl-phenyl]methyl]triazole-4-carboxamide [ka] 1. Synthesis of tert-butyl N-[(3R)-1-(4-chloro-5-fluoro-3-pyridyl)-3-piperidyl]-N-methyl-carbamate [ka] A flask was charged with 3-bromo-4-chloro-5-fluoropyridine (50.00 mg, 237.61 μmol), tert-butyl N-methyl-N-[(3R)-3-piperidyl]carbamate (48.37 mg, 225.73 μmol), potassium tert-butoxide (53.32 mg, 475.22 μmol), and SPhosPd G3 (18.54 mg, 23.76 μmol). The flask was purged and refilled with N2 three times, followed by the addition of degassed dioxane (2.00 mL). The resulting mixture was heated to reflux until all starting material was consumed, as monitored by LCMS for 1 h. The concentrated crude was purified by column chromatography (12 g, SiO, 0-35% EtOAc / EtOH 3:1 in heptane) to give tert-butyl N-[(3R)-1-(4-chloro-5-fluoro-3-pyridyl)-3-piperidyl]-N-methyl-carbamate (38.00 mg, 110.52 μmol, 46.51% yield). LCMS: m / z 344.2 (M+H). + ).

[0299] 2. Synthesis of tert-butyl N-[(3R)-1-[4-[4-[[(1-tert-butyltriazole-4-carbonyl)amino]methyl]-3-methyl-phenyl]-5-fluoro-3-pyridyl]-3-piperidyl]-N-methyl-carbamate [ka] A flask was charged with tert-butyl N-[(3R)-1-(4-chloro-5-fluoro-3-pyridyl)-3-piperidyl]-N-methylcarbamate (38.00 mg, 110.52 µmol), 1-tert-butyl-N-[[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]triazole-4-carboxamide (48.42 mg, 121.57 µmol), potassium phosphate tripotassium (46.92 mg, 221.04 µmol), and Pd(dtbpf)Cl (10.80 mg, 16.58 µmol). The flask was purged and refilled with N three times, followed by the addition of pre-degassed water (100.00 µL) in dioxane (1.90 mL). The mixture was refluxed overnight, cooled to room temperature, diluted with EtOAc, washed with water, and the organic phase was separated and concentrated under reduced pressure. The residue was purified by column chromatography (12 g, SiO, 0-40% EtOAc / EtOH 3:1 in heptane) to give tert-butyl N-[(3R)-1-[4-[4-[[(1-tert-butyltriazole-4-carbonyl)amino]methyl]-3-methyl-phenyl]-5-fluoro-3-pyridyl]-3-piperidyl]-N-methyl-carbamate (31.50 mg, 54.34 μmol, 49.17% yield) as a pale yellow oil. LCMS: m / z 580.4 (M+H) + ).

[0300] 3. Synthesis of 1-tert-butyl-N-[[4-[3-fluoro-5-[(3R)-3-(methylamino)-1-piperidyl]-4-pyridyl]-2-methyl-phenyl]methyl]triazole-4-carboxamide [ka] To tert-butyl N-[(3R)-1-[4-[4-[[(1-tert-butyltriazole-4-carbonyl)amino]methyl]-3-methyl-phenyl]-5-fluoro-3-pyridyl]-3-piperidyl]-N-methyl-carbamate (31.50 mg, 54.34 umol) in DCM (2.00 mL) was added TFA (745.00 mg, 6.53 mmol, 500.00 uL) at 0° C. The resulting reaction mixture was stirred at that temperature for 30 minutes until the starting material was consumed. The volatiles were removed under reduced pressure and the resulting brown residue was purified by column chromatography (4 g of SiO, 0-15% MeOH in DCM (5% NHOH)) to afford the title compound 1-tert-butyl-N-[[4-[3-fluoro-5-[(3R)-3-(methylamino)-1-piperidyl]-4-pyridyl]-2-methyl-phenyl]methyl]triazole-4-carboxamide (25.00 mg, 52.13 μmol, 95.93% yield) as a pale yellow oil. LCMS: m / z 480.3 (M+H) + ).

[0301] 4. Synthesis of 1-tert-butyl-N-[[4-[3-fluoro-5-[(3R)-3-[methyl(prop-2-enoyl)amino]-1-piperidyl]-4-pyridyl]-2-methyl-phenyl]methyl]triazole-4-carboxamide [ka] To a solution of 1-tert-butyl-N-[[4-[3-fluoro-5-[(3R)-3-(methylamino)-1-piperidyl]-4-pyridyl]-2-methyl-phenyl]methyl]triazole-4-carboxamide (25.00 mg, 52.13 μmol) and DIPEA (20.21 mg, 156.39 μmol, 27.31 μL) in DCM (2.00 mL) and THF (500.00 μL) was added a solution of acryloyl chloride (5.90 mg, 65.16 μmol, 5.32 μL) in THF (100.10 μL) at 0 °C. After LCMS showed complete conversion of the starting material (30 min), the reaction mixture was diluted with DCM (5 mL), transferred to a separatory funnel, and washed with saturated aqueous NH4Cl, water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The concentrated residue was purified by column chromatography (12 g of SiO, 0-15% MeOH in DCM (5% NHOH)) to give the title compound 1-tert-butyl-N-[[4-[3-fluoro-5-[(3R)-3-[methyl(prop-2-enoyl)amino]-1-piperidyl]-4-pyridyl]-2-methyl-phenyl]methyl]triazole-4-carboxamide (13.00 mg, 24.36 μmol, 46.73% yield) as an off-white solid. LCMS: Rt=1.56 min, m / z=534.3 (M+H). + ). 1 H NMR (500MHz, MeOH-d4) δ 8.48 (s, 1H), 8.19 (br s, 1H), 8.14 (br d, J=7.33 Hz, 1H), 7.41-7.51 (m, 1H), 7.30-7.41 (m, 2H), 6.02-6.71 (m, 2H), 5.69 (td, J=3.36, 9.16 Hz, 1H), 4.86 (s, 2H), 4.58-4.75 (m, 2H), 3.59-4.36 (m, 1H), 3.02-3.22 (m, 2H), 2.50-2.96 (m, 5H), 2.44 (s, 3H), 1.73-1.85 (m, 1H), 1.70 (s, 9H), 1.40-1.69 (m, 2H).

[0302] Example 57: 5-(tert-butyl)-N-(4-(3-(4-(cyclobut-1-ene-1-carbonyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide [ka] 1. Synthesis of tert-butyl 4-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperazine-1-carboxylate [ka] To a solution of tert-butyl 4-(4-chloro-3-pyridyl)piperazine-1-carboxylate (5 g, 16.8 mmol) in dioxane (120 mL) and water (20 mL) were added potassium carbonate (6.96 g, 50.37 mmol) and 5-tert-butyl-N-[[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide (8.05 g, 20.2 mmol) at 20° C. Then, [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (2.19 g, 3.36 mmol) was added to the mixture at 20° C. The reaction was stirred at 90° C. for 12 hours under N. The mixture was concentrated in vacuo and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give tert-butyl 4-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperazine-1-carboxylate as a yellow oil (6 g, 63% yield). LCMS: m / z = 535.5 (M+H + ).

[0303] Synthesis of 2,5-(tert-butyl)-N-(2-methyl-4-(3-(piperazin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride [ka] To a solution of tert-butyl 4-[4-[4-[[(5-tert-butyl-1,2,4-oxadiazole-3-carbonyl)amino]methyl]-3-methyl-phenyl]-3-pyridyl]piperazine-1-carboxylate (2 g, 3.74 mmol) in DCM (200 mL) was added a solution of HCl in ethyl acetate (20 mL) at 20° C. The mixture was stirred at 20° C. for 30 minutes. The mixture was concentrated in vacuo to give a crude product, which was purified by preparative HPLC (column: Boston Uni C18 40 x 150 x 5 μm, conditions: water (0.05% HCl)-ACN, start B0, end B30; gradient time (min): 10, 100% B retention time (min): 2, flow rate (ml / min): 60) to give 5-tert-butyl-N-[[2-methyl-4-(3-piperazin-1-yl-4-pyridyl)phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide hydrochloride as a yellow solid (1.11 g, 63% yield). LCMS: m / z = 435.2 (M+H + ).

[0304] Synthesis of 3.5-(tert-butyl)-N-(4-(3-(4-(cyclobut-1-ene-1-carbonyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide [ka] A vial was charged with 5-tert-butyl-N-[[2-methyl-4-(3-piperazin-1-yl-4-pyridyl)phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide hydrochloride (55 mg, 117 μmol), cyclobutene-1-carboxylic acid (23 mg, 234 μmol), and DCM (1 mL). DIPEA (60 mg, 467 μmol, 81 μL) was then added, followed by T3P (186 mg, 292 μmol, 50% purity). After stirring overnight at room temperature, the mixture was diluted with water and extracted with ethyl acetate (×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated. The residual material was purified by acidic preparative HPLC (water (0.1% TFA)-ACN, starting with B10, ending with B95) to give a white solid after lyophilization. This material contained a small amount of impurity and was re-purified by basic preparative HPLC ((water (0.1% NHOH)-ACN, start B10, finish B90)) to give 5-tert-butyl-N-[[4-[3-[4-(cyclobutene-1-carbonyl)piperazin-1-yl]-4-pyridyl]-2-methyl-phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide as a white solid (3.3 mg, 5% yield). LCMS: m / z=515.5 (M+H). + ). 1 H NMR (DMSO-d6, 400MHz):δ=9.48 (dt, J=11.9, 6.1 Hz, 1H), 8.70 (m, 0.5H), 8.52 (m, 0.5H), 8.39-8.46 (m, 1H), 7.93 (d, J=6.3 Hz, 0.5H), 7.64-7.78 (m, 2.5H), 7.36-7.47 (m, 1H), 6.40-6.49 (m, 1H), 4.47-4.56 (m, 2H), 3.45-3.65 (br s, 2H), 3.02-3.15 (m, 1H), 2.93 (br d, J=4.0 Hz, 4H), 2.65-2.72 (m, 2H), 2.35-2.45 (m, 5H), 2.18-2.26 (m, 1H), 1.43 (s, 9H).

[0305] Example 58: (E)-5-(tert-butyl)-N-(2-methyl-4-(3-(4-(4,4,4-trifluorobut-2-enoyl)piperazin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] A flask was charged with 5-tert-butyl-N-[[2-methyl-4-(3-piperazin-1-yl-4-pyridyl)phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide hydrochloride (55 mg, 117 μmol), (E)-4,4,4-trifluorobut-2-enoic acid (33 mg, 234 μmol), and DCM (1 mL). DIPEA (60 mg, 467 μmol, 81 μL) was then added, followed by T3P (186 mg, 292 μmol, 50% purity). After stirring overnight at room temperature, the mixture was diluted with water and extracted with ethyl acetate (×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated. The residual material was purified by acidic preparative HPLC (10-95%): Rt = 8.8 min to afford (E)-5-(tert-butyl)-N-(2-methyl-4-(3-(4-(4,4,4-trifluorobut-2-enoyl)piperazin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate as a pale yellow solid (35 mg, 43% yield). LCMS: m / z = 557.5 (M+H + ). 1 H NMR (DMSO-d6, 400 MHz): δ=9.47 (t, J=6.0 Hz, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.44 (s, 1H), 7.64-7.72 (m, 3H), 7.31-7.42 (m, 2H), 6.71-6.80 (m, 1H), 4.51 (d, J=6.0 Hz, 2H), 3.44-3.54 (m, 2H), 2.96 (br s, 2H), 2.91 (br s, 2H), 2.41 (s, 3H) 1.43 (s, 9H).

[0306] Example 59: Synthesis of 5-(tert-butyl)-N-(2-methyl-4-(3-(4-(oxirane-2-carbonyl)piperazin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] To a solution of 5-(tert-butyl)-N-(2-methyl-4-(3-(piperazin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride (60 mg, 127 μmol) in DCM (15 mL) was added DIPEA (33 mg, 255 μmol) at 20° C. Then, oxirane-2-carboxylic acid (22 mg, 255 μmol) and HATU (97.13 mg, 254.78 μmol, 2.0 equiv.) were added slowly to the mixture at 20° C. The mixture was stirred at 20° C. for 5 hours. The mixture was poured into water (50 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give crude which was purified by preparative HPLC (Column: Welch Xtimate C18 150 x 25 mm x 5 μm, Conditions: water (10 mM NH4HCO3)-ACN, Start B33, End B63, Gradient time (min): 10, 100% B Retention time (min): 2, Flow rate (mL / min): 25) to give 5-(tert-butyl)-N-(2-methyl-4-(3-(4-(oxirane-2-carbonyl)piperazin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide as a yellow solid (22 mg, 34% yield). LCMS: m / z = M+H + :505.3. 1 H NMR:(400MHz, CDCl3) δ: 8.39-8.31 (m, 1H), 8.29 (s, 1H), 7.53-7.47 (m, 2H), 7.36 (d, J=7.6 Hz, 1H), 7.20-7.09 (m, 2H), 4.70 (d, J=6.0 Hz, 2H), 3.65-3.50 (m, 5H), 3.00-2.85 (m, 6H), 2.41 (s, 3H), 1.46 (s, 9H).

[0307] Example 60: Synthesis of 5-(tert-butyl)-N-(2-methyl-4-(3-(4-propioloylpiperazin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] The synthesis of 1,5-(tert-butyl)-N-(2-methyl-4-(3-(4-propioloylpiperazin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide was similar to that of 5-(tert-butyl)-N-(2-methyl-4-(3-(4-(oxirane-2-carbonyl)piperazin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide in Example 59. The crude material was purified by preparative HPLC (Column: Welch Xtimate C18 150 x 25 mm x 5 μm, Conditions: water (10 mM NH4HCO3)-ACN, Start B34, End B64, Gradient time (min) 10, Retention time 100% B (min) 2, Flow rate (mL / min) 25) to give 5-(tert-butyl)-N-(2-methyl-4-(3-(4-propioloylpiperazin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid (62 mg, 40% yield). LCMS: m / z=M+H + :487.3. 1 H NMR:(400MHz, DMSO-d6) δ=9.39 (t, J=6.0 Hz, 1H), 8.29-8.25 (m, 2H), 7.56-7.53 (m, 2H), 7.29 (d, J=8.0 Hz, 1H), 7.20 (d, J=4.8 Hz, 1H), 4.53 (s, 1H), 4.46 (d, J=6.0 Hz, 2H), 3.61-3.59 (m, 2H), 3.40-3.38 (m, 2H), 2.90-2.88 (m, 2H), 2.80-2.78 (m, 2H), 2.35 (s, 3H), 1.40 (s, 9H).

[0308] Example 61: Synthesis of (E)-5-(tert-butyl)-N-(4-(3-(4-(4-(dimethylamino)but-2-enoyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide [ka] 1. The synthesis of (E)-5-(tert-butyl)-N-(4-(3-(4-(4-(dimethylamino)but-2-enoyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide was similar to the synthesis of 5-(tert-butyl)-N-(2-methyl-4-(3-(4-(oxirane-2-carbonyl)piperazin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide in Example 59. The crude material was purified by preparative HPLC (Column: Welch Xtimate C18 150 x 25 mm x 5 μm, Conditions: water (10 mM NH4HCO3)-ACN, Start B31, End B61, Gradient time (min) 15, Retention time 100% B (min) 2, Flow rate (mL / min) 25) to give (E)-5-(tert-butyl)-N-(4-(3-(4-(4-(dimethylamino)but-2-enoyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid (34 mg, 39% yield). LCMS: m / z=M+H + :546.4. 1 H NMR:(500 MHz, DMSO-d6) δ ppm=9.43 (t, J=6.0 Hz, 1H), 8.30-8.27 (m, 2H), 7.59-7.56 (m, 2H), 7.32 (d, J=7.5 Hz, 1H), 7.22 (d, J=4.5 Hz, 1H), 6.59-6.56 (m, 2H), 4.49 (d, J=6.0 Hz, 2H), 3.48 (s, 4H), 2.99 (d, J=4.5 Hz, 2H), 2.83 (s, 4H), 2.38 (s, 3H), 2.12 (s, 6H), 1.43 (s, 9H).

[0309] Example 62: Synthesis of N-(4-(3-(4-(but-2-ynoyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide [ka] 1. The synthesis of N-(4-(3-(4-(but-2-ynoyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide was similar to the synthesis of 5-(tert-butyl)-N-(2-methyl-4-(3-(4-(oxirane-2-carbonyl)piperazin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide in Example 59. The crude material was purified by preparative HPLC (Column: Agela DuraShell C18 150 x 25 mm x 5 μm, Conditions: water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN, Start B35, End B65, Gradient time (min) 10, Retention time 100% B (min) 2, Flow rate (mL / min) 25) to give N-(4-(3-(4-(but-2-ynoyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide as a white solid (22 mg, 25% yield). LCMS: m / z = M+H + :501.4. 1 H NMR:(500 MHz, methanol-d4) δ=8.28-8.25 (m, 2H), 7.60-7.55 (m, 2H), 7.44 (d, J=8.5 Hz, 1H), 7.30 (d, J=5.0 Hz, 1H), 4.67 (s, 2H), 3.77-3.69 (m, 2H), 3.58-3.51 (m, 2H), 3.00-2.94 (m, 2H), 2.91 (t, J=5.0 Hz, 2H), 2.48 (s, 3H), 2.03 (s, 3H), 1.50 (s, 9H).

[0310] Example 63: Synthesis of N-(4-(3-(4-acryloylpiperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide [ka] To a solution of 5-(tert-butyl)-N-(2-methyl-4-(3-(piperazin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride (130 mg, 276 μmol) in DCM (20 mL) was added DIPEA (71 mg, 552 μmol) and acryloyl chloride (25 mg, 276 μmol) at 0° C. The mixture was stirred at 0° C. for 10 min. The mixture was quenched with MeOH (1 mL) and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150 x 25 mm x 5 μm, conditions: water (10 mM NH4HCO3)-ACN, start B32, end B62, gradient time (min) 15, 100% B retention time (min) 2, flow rate (mL / min) 25) to give N-(4-(3-(4-acryloylpiperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide as a white solid (34 mg, 25% yield). LCMS: m / z = M+H + :489.4. 1 H NMR:(500 MHz, DMSO-d6) δ ppm=9.43 (t, J=6.0 Hz, 1H), 8.32-8.26 (m, 2H), 7.60-7.56 (m, 2H), 7.33 (d, J=8.5 Hz, 1H), 7.22 (d, J=5.0 Hz, 1H), 6.77 (dd, J1=10.5 Hz, J2=17.0 Hz, 1H), 6.10 (dd, J1=2.5 Hz, J2=16.5 Hz, 1H), 5.69-5.63 (m, 1H), 4.49 (d, J=6.0 Hz, 2H), 3.50 (s, 4H), 2.84 (d, J=5.5 Hz, 4H), 2.38 (s, 3H), 1.43 (s, 9H).

[0311] Example 64: (E)-5-(tert-butyl)-N-(4-(3-(4-(4-(3-fluoroazetidin-1-yl)but-2-enoyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide [ka] 1. Synthesis of (E)-N-(4-(3-(4-(4-bromobut-2-enoyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide [ka] To a solution of 5-tert-butyl-N-[[2-methyl-4-(3-piperazin-1-yl-4-pyridyl)phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide hydrochloride (2.2 g, 4.7 mmol) in DCM (120 mL) was added DIPEA (1.8 g, 14 mmol, 2.4 mL) at 20° C. Then, (E)-4-bromobut-2-enoic acid (848 mg, 5.1 mmol) and HATU (2.0 g, 5.1 mmol) were added slowly to the mixture at 20° C. The mixture was stirred at 20° C. for 2 hours. The mixture was concentrated in vacuo to give N-[[4-[3-[4-[(E)-4-bromobut-2-enoyl]piperazin-1-yl]-4-pyridyl]-2-methyl-phenyl]methyl]-5-tert-butyl-1,2,4-oxadiazole-3-carboxamide as a yellow oil (2.7 g, crude), which was used directly in the next step without further purification. LCMS: m / z=M+H + :581.2, 583.2.

[0312] 2. Synthesis of (E)-5-(tert-butyl)-N-(4-(3-(4-(4-(3-fluoroazetidin-1-yl)but-2-enoyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide [ka] To a solution of (E)-N-(4-(3-(4-(4-bromobut-2-enoyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide (200 mg, 344 μmol) in DCM (30 mL) was added DIPEA (445 mg, 3.44 mmol) at 20° C. Then, 3-fluoroazetidine (959 mg, 8.60 mmol) was added to this mixture at 20° C. The mixture was then stirred at 20° C. for 2 hours. The mixture was poured into water (50 mL) and extracted with DCM (50 mL×3). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product. This material was purified by preparative HPLC (column: Phenomenex Synergi C18 150 x 30 mm x 4 μm, conditions: water (0.225% FA)-ACN, start B17, end B17, gradient time (min): 10, 100% B retention time (min): 2, flow rate (mL / min): 25) to give (E)-5-(tert-butyl)-N-(4-(3-(4-(4-(3-fluoroazetidin-1-yl)but-2-enoyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide as a yellow solid (33 mg, 16% yield). LCMS: m / z=M+H + :576.3. 1 H NMR:(400 MHz, methanol-d4) δ=8.26-8.20 (m, 2H), 7.58-7.52 (m, 2H), 7.40 (d, J=8.4 Hz, 1H), 7.27 (d, J=4.8 Hz, 1H), 6.66-6.52 (m, 2H), 4.62 (s, 2H), 4.01-3.44 (m, 11H), 2.93-2.85 (m, 4H), 2.44 (s, 3H), 1.47-1.45 (m, 9H).

[0313] Example 65: Synthesis of (E)-5-(tert-butyl)-N-(2-methyl-4-(3-(4-(4-(4-methylpiperazin-1-yl)but-2-enoyl)piperazin-1-yl))pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] To a solution of (E)-N-(4-(3-(4-(4-bromobut-2-enoyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide (200 mg, 344 μmol) in DCM (20 mL) was added 1-methylpiperazine (52 mg, 516 μmol) at 20° C. The mixture was stirred at 20° C. for 2 hours. The mixture was poured into water (50 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product. This material was purified by preparative HPLC (Column: Welch Xtimate C18 150 x 25 mm x 5 μm, Conditions: water (10 mM NH4HCO3)-ACN, Start B28, End B58, Gradient time (min): 10, 100% B retention time (min): 2, Flow rate (mL / min): 25) to give (E)-5-(tert-butyl)-N-(2-methyl-4-(3-(4-(4-(4-methylpiperazin-1-yl)but-2-enoyl)piperazin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide as a yellow solid (82 mg, 40% yield). LCMS: m / z=M+H + :601.4. 1H NMR:(400 MHz, methanol-d4) δ=8.28-8.23 (m, 2H), 7.59-7.54 (m, 2H), 7.47-7.39 (m, 1H), 7.29 (d, J=5.2 Hz, 1H), 6.81-6.69 (m, 1H), 6.65-6.54 (m, 1H), 4.65 (s, 2H), 3.57 (s, 4H), 3.18 (d, J=6.0 Hz, 2H), 2.92 (s, 4H), 2.75-2.22 (m, 14H), 1.48 (s, 9H).

[0314] Example 66: Synthesis of (E)-N-(4-(3-(4-(4-(azetidin-1-yl)but-2-enoyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide [ka] 1. The synthesis of (E)-N-(4-(3-(4-(4-(azetidin-1-yl)but-2-enoyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide was similar to the synthesis of (E)-5-(tert-butyl)-N-(2-methyl-4-(3-(4-(4-(4-methylpiperazin-1-yl)but-2-enoyl)piperazin-1-yl))pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide in Example 65. The crude material was purified by preparative HPLC (column: Phenomenex Synergi C18 150 x 30 mm x 4 μm, conditions: water (0.225% FA)-ACN, start B5, end B35, gradient time (min): 11, 100% B retention time (min): 2, flow rate (mL / min): 25) to give (E)-N-(4-(3-(4-(4-(azetidin-1-yl)but-2-enoyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide as a yellow solid (65 mg, 23% yield). LCMS: m / z=M+H+ :558.4. 1 H NMR:(400 MHz, methanol-d4) δ=8.43 (s, 1H), 8.26 (d, J=4.8 Hz, 1H), 7.60-7.54 (m, 2H), 7.42 (d, J=8.4 Hz, 1H), 7.29 (d, J=4.8 Hz, 1H), 6.77 (d, J=15.2 Hz, 1H), 6.59-6.48 (m, 1H), 4.64 (s, 2H), 4.07 (t, J=8.0 Hz, 4H), 3.88 (d, J=6.4 Hz, 2H), 3.59-3.57 (m, 4H), 2.95-2.92 (m, 4H), 2.55-2.44 (m, 5H), 1.49 (s, 9H).

[0315] Example 67: Synthesis of (E)-5-(tert-butyl)-N-(2-methyl-4-(3-(4-(4-morpholinobut-2-enoyl)piperazin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] 1. The synthesis of (E)-5-(tert-butyl)-N-(2-methyl-4-(3-(4-(4-morpholinobut-2-enoyl)piperazin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide was similar to that of (E)-5-(tert-butyl)-N-(2-methyl-4-(3-(4-(4-(4-methylpiperazin-1-yl)but-2-enoyl)piperazin-1-yl))pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide in Example 65. The crude material was purified by preparative HPLC (Column: Welch Xtimate C18 150 x 25 mm x 5 μm, Conditions: water (10 mM NH4HCO3)-ACN, Start B30, End B60, Gradient time (min): 10, 100% B retention time (min): 2, Flow rate (mL / min): 25) to give (E)-5-(tert-butyl)-N-(2-methyl-4-(3-(4-(4-morpholinobut-2-enoyl)piperazin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide as a yellow solid (79 mg, 31% yield). LCMS: m / z=M+H + :588.3. 1 H NMR: (400 MHz, MeOH-d4) δ: 8.27-8.22 (m, 2H), 7.60-7.55 (m, 2H), 7.45-7.39 (m, 1H), 7.28 (d, J=5.2 Hz, 1H), 6.80-6.69 (m, 1H), 6.64-6.54 (m, 1H), 4.64 (s, 2H), 3.73-3.66 (m, 4H), 3.57 (s, 4H), 3.17 (d, J=5.6 Hz, 2H), 2.96-2.90 (m, 4H), 2.49-2.41 (m, 7H), 1.49 (s, 9H).

[0316] Example 68: Synthesis of (E)-5-(tert-butyl)-N-(2-methyl-4-(3-(4-(4-(methylamino)but-2-enoyl)piperazin-1-yl)pyridin-4-yl))benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] 1. The synthesis of (E)-5-(tert-butyl)-N-(2-methyl-4-(3-(4-(4-(methylamino)but-2-enoyl)piperazin-1-yl)pyridin-4-yl))benzyl)-1,2,4-oxadiazole-3-carboxamide was similar to that of (E)-5-(tert-butyl)-N-(2-methyl-4-(3-(4-(4-(4-methylpiperazin-1-yl)but-2-enoyl)piperazin-1-yl))pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide in Example 65. The crude material was purified by preparative HPLC (Column: Welch Xtimate C18 150 x 25 mm x 5 μm, Conditions: water (10 mM NH4HCO3)-ACN, Start B30, End B60, Gradient time (min): 10, 100% B retention time (min): 2, Flow rate (mL / min): 25) to give (E)-5-(tert-butyl)-N-(2-methyl-4-(3-(4-(4-(methylamino)but-2-enoyl)piperazin-1-yl)pyridin-4-yl))benzyl)-1,2,4-oxadiazole-3-carboxamide as a yellow solid (91 mg, 49% yield). LCMS: m / z=M+H + :532.3. 1 HNMR:(400 MHz, MeOH-d4) δ: 8.28-8.23 (m, 2H), 7.63-7.58 (m, 2H), 7.45-7.42 (m, 1H), 7.29 (d, J=5.2 Hz, 1H), 6.81-6.67 (m, 1H), 6.64-6.47 (m, 1H), 4.64 (s, 2H), 3.58 (s, 4H), 3.43 (d, J=6.0 Hz, 2H), 2.96-2.90 (m, 4H), 2.45 (d, J=4.0 Hz, 6H), 1.49 (s, 9H).

[0317] Example 69: (E)-5-(tert-butyl)-N-(4-(3-cyano-5-(4-(4-(dimethylamino)but-2-enoyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide [ka] 1. Synthesis of tert-butyl 4-(4-chloro-5-cyanopyridin-3-yl)piperazine-1-carboxylate [ka] To a solution of 5-bromo-4-chloronicotinonitrile (300 mg, 1.38 mmol) in toluene (10 mL) were added tert-butyl piperazine-1-carboxylate (231 mg, 1.24 mmol) and sodium tert-butoxide (265 mg, 2.76 mmol) at 15° C. Then, precatalyst (Ruphos) (231 mg, 276 μmol) was added at 15° C. The mixture was stirred at 50° C. under N for 5 hours. The mixture was filtered and concentrated in vacuo to give the crude product. This material was purified by preparative HPLC (Column: Welch Xtimate C18 150 x 25 mm x 5 μm, Conditions: water (10 mM NH4HCO3)-ACN, Start B40, End B70, Gradient time (min) 10, Retention time 100% B (min) 2, Flow rate (mL / min) 25) to give tert-butyl 4-(4-chloro-5-cyanopyridin-3-yl)piperazine-1-carboxylate as a yellow solid (55 mg, 12% yield). LCMS: m / z = M+H + :323.3.

[0318] 2. Synthesis of tert-butyl 4-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)-5-cyanopyridin-3-yl)piperazine-1-carboxylate [ka] To a solution of tert-butyl 4-(4-chloro-5-cyanopyridin-3-yl)piperazine-1-carboxylate (50 mg, 155 μmol) in dioxane (5 mL) and water (1 mL) were added 5-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (62 mg, 155 μmol) and KPO (99 mg, 465 μmol) at 20° C. Then, Pd(dtbpf)Cl (20 mg, 31 μmol) was added at 20° C. The mixture was stirred under N at 20° C. for 3 hours. The mixture was filtered, and the filtrate was concentrated in vacuo. The crude material was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 0 to 2 / 1) to give tert-butyl 4-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)-5-cyanopyridin-3-yl)piperazine-1-carboxylate as a yellow solid (80 mg, 76% yield). LCMS: m / z=M+H + :560.5.

[0319] Synthesis of 3.5-(tert-butyl)-N-(4-(3-cyano-5-(piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride [ka] To a solution of tert-butyl 4-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)-5-cyanopyridin-3-yl)piperazine-1-carboxylate (80 mg, 143 μmol) in DCM (5 mL) was added a solution of HCl in ethyl acetate (4 M, 5 mL) and the reaction mixture was stirred at 20° C. for 1 h. The mixture was concentrated in vacuo to give 5-(tert-butyl)-N-(4-(3-cyano-5-(piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride as a yellow solid (65 mg, crude) which was carried forward without further purification. LCMS: m / z=M+H + :460.3.

[0320] 4. Synthesis of (E)-5-(tert-butyl)-N-(4-(3-cyano-5-(4-(4-(dimethylamino)but-2-enoyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide [ka] 5. The synthesis of (E)-5-(tert-butyl)-N-(4-(3-cyano-5-(4-(4-(dimethylamino)but-2-enoyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide was similar to that of (E)-5-(tert-butyl)-N-(4-(3-(4-(4-(dimethylamino)but-2-enoyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide in Example 61. The crude material was purified by preparative HPLC (Column: Welch Xtimate C18 150 x 25 mm x 5 μm, Conditions: water (10 mM NH4HCO3)-ACN, Start B35, End B65, Gradient time (min) 10, Retention time 100% B (min) 2, Flow rate (mL / min) 25) to give (E)-5-(tert-butyl)-N-(4-(3-cyano-5-(4-(4-(dimethylamino)but-2-enoyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide as a yellow solid (45 mg, 65% yield). LCMS: m / z=M+H + :571.4. 1 H NMR:(500 MHz, DMSO-d6) δ=9.50-9.47 (m, 1H), 8.74-8.67 (m, 1H), 8.59-8.54 (m, 1H), 7.48-7.39 (m, 3H), 6.62-6.52 (m, 2H), 4.54 (d, J=6.0 Hz, 2H), 3.39-3.37 (m, 4H), 2.99 (d, J=5.0 Hz, 2H), 2.83-2.81 (m, 4H), 2.41-2.36 (m, 3H), 2.12 (s, 6H), 1.44 (s, 9H).

[0321] Example 70: (E)-5-(tert-butyl)-N-(4-(3-cyano-5-(4-(4-(dimethylamino)but-2-enoyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)isoxazole-3-carboxamide [ka] 1. Synthesis of tert-butyl 4-(4-(4-((5-(tert-butyl)isoxazole-3-carboxamido)methyl)-3-methylphenyl)-5-cyanopyridin-3-yl)piperazine-1-carboxylate [ka] 2. The synthesis of tert-butyl 4-(4-(4-((5-(tert-butyl)isoxazole-3-carboxamido)methyl)-3-methylphenyl)-5-cyanopyridin-3-yl)piperazine-1-carboxylate was similar to the synthesis of tert-butyl 4-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)-5-cyanopyridin-3-yl)piperazine-1-carboxylate in Step 2 of Example 69. The crude material was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 0 to 2 / 1) to give tert-butyl 4-(4-(4-((5-(tert-butyl)isoxazole-3-carboxamido)methyl)-3-methylphenyl)-5-cyanopyridin-3-yl)piperazine-1-carboxylate as a yellow solid (100 mg, 61% yield). LCMS: m / z=M+H + :559.5.

[0322] Synthesis of 3.5-(tert-butyl)-N-(4-(3-cyano-5-(piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)isoxazole-3-carboxamide hydrochloride [ka] 4. The synthesis of 5-(tert-butyl)-N-(4-(3-cyano-5-(piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)isoxazole-3-carboxamide hydrochloride was similar to the synthesis of 5-(tert-butyl)-N-(4-(3-cyano-5-(piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride in Step 3 of Example 69. The reaction mixture was concentrated in vacuo to give crude 5-(tert-butyl)-N-(4-(3-cyano-5-(piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)isoxazole-3-carboxamide hydrochloride (80 mg, crude), which was carried forward without further purification. LCMS: m / z=M+H + :459.3.

[0323] 5. Synthesis of (E)-5-(tert-butyl)-N-(4-(3-cyano-5-(4-(4-(dimethylamino)but-2-enoyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)isoxazole-3-carboxamide [ka] 6. The synthesis of (E)-5-(tert-butyl)-N-(4-(3-cyano-5-(4-(4-(dimethylamino)but-2-enoyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)isoxazole-3-carboxamide was similar to the synthesis of (E)-5-(tert-butyl)-N-(4-(3-cyano-5-(4-(4-(dimethylamino)but-2-enoyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide in Step 4 of Example 69. The crude material was purified by preparative HPLC (Column: Welch Xtimate C18 150 x 25 mm x 5 μm, Conditions: water (10 mM NH4HCO3)-ACN, Start B38, End B68, Gradient time (min) 10, Retention time 100% B (min) 2, Flow rate (mL / min) 25) to give (E)-5-(tert-butyl)-N-(4-(3-cyano-5-(4-(4-(dimethylamino)but-2-enoyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)isoxazole-3-carboxamide as a yellow solid (41 mg, 48% yield). LCMS m / z=M+H + :570.4. 1 H NMR:(500 MHz, DMSO-d6) δ ppm=9.28-9.24 (m, 1H), 8.71 (s, 1H), 8.56 (s, 1H), 7.47-7.43 (m, 2H), 7.40-7.37 (m, 1H), 6.62-6.52 (m, 3H), 4.51 (d, J=6.0 Hz, 2H), 3.38-3.35 (m, 4H), 2.99 (d, J=5.0 Hz, 2H), 2.82 (s, 4H), 2.40 (s, 3H), 2.12 (s, 6H), 1.34 (s, 9H).

[0324] Example 71: (E)-5-(tert-butyl)-N-(4-(3-(4-(4-(dimethylamino)but-2-enoyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-N-methyl-1,2,4-oxadiazole-3-carboxamide [ka] 1. Synthesis of 1-(4-bromo-2-methylphenyl)-N-methylmethanamine [ka] To a solution of methylamine (4.97 g, 52.8 mmol, 7.10 mL) in MeOH (100 mL) was added 4-bromo-2-methyl-benzaldehyde (5.00 g, 25.1 mmol) in small portions. The reaction was stirred at 15 °C for 2 h, then NaBHCN (3.16 g, 50.2 mmol) was added in small portions to the mixture. The reaction mixture was continued to stir at 15 °C for 32 h. Water (1 mL) was added and the reaction mixture was concentrated in vacuo. The crude material was purified by silica gel chromatography (10% MeOH in DCM) to give 1-(4-bromo-2-methyl-phenyl)-N-methyl-methanamine as a semi-solid (3.0 g, 28% yield, 50% purity). This material was carried forward without further purification. LCMS m / z = M+H + :214.0.

[0325] 2. Synthesis of tert-butyl (4-bromo-2-methylbenzyl)(methyl)carbamate [ka] To a solution of 1-(4-bromo-2-methyl-phenyl)-N-methyl-methanamine (3.00 g, 14.0 mmol) in DCM (80 mL) was added DIPEA (5.43 g, 42.0 mmol, 7.34 mL). Then, tert-butoxycarbonyl tert-butyl carbonate (3.06 g, 14.0 mmol, 3.22 mL) was added slowly in small portions to the above mixture at 0 °C. The reaction mixture was stirred at 15 °C for 16 hours. The reaction solvent was concentrated to dryness to give a residue, which was purified by silica gel chromatography using 6% ethyl acetate in petroleum ether as an eluent to give tert-butyl N-[(4-bromo-2-methyl-phenyl)methyl]-N-methyl-carbamate as a clear oil (2.5 g, 54% yield). LCMS m / z = (M + Ht-Bu). +:257.9, 259.9.

[0326] 3. Synthesis of tert-butyl methyl(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate [ka] To a solution of tert-butyl N-[(4-bromo-2-methyl-phenyl)methyl]-N-methyl-carbamate (2.50 g, 7.96 mmol) in dioxane (50 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.22 g, 8.75 mmol) and KOAc (2.34 g, 23.9 mmol). Pd(dppf)Cl (291 mg, 398 μmol) was added to the mixture under nitrogen. The reaction was stirred at 85° C. for 16 hours. The solvent was concentrated to dryness to give a residue which was purified by silica gel chromatography using eluent (10% ethyl acetate in petroleum ether) to give tert-butyl N-methyl-N-[[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]carbamate as an oil (2.6 g, 74% yield). LCMS m / z=M+H + :362.2.

[0327] 4. Synthesis of N-methyl-1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine hydrochloride [ka] To a solution of tert-butyl methyl(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (300 mg, 830 μmol) in DCM (35 mL) was added a solution of HCl in ethyl acetate (4 M, 12 mL) at 25° C. The mixture was stirred at 25° C. for 30 minutes. The reaction mixture was concentrated to give N-methyl-1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine hydrochloride (200 mg, crude), which was used directly in the next step. LCMS: m / z=M+H + :262.2.

[0328] 5. Synthesis of 5-(tert-butyl)-N-methyl-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] To a solution of N-methyl-1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine hydrochloride (150 mg, 574 μmol) in DCM (35 mL) was added DIPEA (223 mg, 1.72 mmol) at 25° C. The mixture was stirred at 25° C. for 10 minutes. Then, 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylic acid (117 mg, 689 μmol) and HATU (263 mg, 689 μmol) were added. The mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated to give a crude product, which was purified by silica gel chromatography (petroleum ether / ethyl acetate=4 / 1) to give 5-(tert-butyl)-N-methyl-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide as a yellow oil (160 mg, 67% yield). LCMS: m / z=M+H + :414.3.

[0329] 6. Synthesis of tert-butyl 4-(4-(4-((5-(tert-butyl)-N-methyl-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperazine-1-carboxylate [ka] A mixture of 5-(tert-butyl)-N-methyl-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (140 mg, 339 μmol), tert-butyl 4-(4-chloropyridin-3-yl)piperazine-1-carboxylate (121 mg, 406 μmol), KCO (140 mg, 1.02 mmol), and Pd(dtbpf)Cl (22 mg, 34 μmol) in dioxane (3 mL) and water (0.6 mL) was purged with N for 3 minutes. The mixture was then stirred at 90° C. for 24 hours. The reaction mixture was concentrated to give crude material which was purified by silica gel chromatography (1:1 petroleum ether / ethyl acetate) to give tert-butyl 4-(4-(4-((5-(tert-butyl)-N-methyl-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperazine-1-carboxylate as a yellow oil (80 mg, 43% yield). LCMS: m / z=M+H + :549.3.

[0330] 7. Synthesis of 5-(tert-butyl)-N-methyl-N-(2-methyl-4-(3-(piperazin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride [ka] To a solution of tert-butyl 4-(4-(4-((5-(tert-butyl)-N-methyl-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperazine-1-carboxylate (80 mg, 146 μmol) in DCM (10 mL) was added a solution of HCl in ethyl acetate (4 M, 1.5 mL). The reaction mixture was stirred at 25° C. for 30 minutes. The reaction mixture was concentrated to give crude 5-(tert-butyl)-N-methyl-N-(2-methyl-4-(3-(piperazin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride (60 mg, crude), which was carried forward without further purification. LCMS: m / z=M+H + :449.2.

[0331] 8. Synthesis of (E)-5-(tert-butyl)-N-(4-(3-(4-(4-(dimethylamino)but-2-enoyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-N-methyl-1,2,4-oxadiazole-3-carboxamide [ka] To a solution of 5-(tert-butyl)-N-(2-methyl-4-(3-(piperazin-1-yl)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride (60 mg, 134 μmol) in DCM (12 mL) was added DIPEA (52 mg, 401 μmol) at 25° C. The mixture was stirred at 25° C. for 10 minutes. Then, (E)-4-(dimethylamino)but-2-enoic acid (21 mg, 161 μmol) and HATU (61 mg, 161 μmol) were added. The mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated to give crude material, which was purified by preparative HPLC (Column: Boston Prime C18 150 x 30 mm x 5 μm, Conditions: water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN, Start B47, End B77, Gradient time (min) 10, Retention time 100% B (min) 2, Flow rate (mL / min) 25, Injection 3) to give (E)-5-(tert-butyl)-N-(4-(3-(4-(4-(dimethylamino)but-2-enoyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-N-methyl-1,2,4-oxadiazole-3-carboxamide as a white solid (30.2 mg, 40% yield). LCMS: m / z = M+H + :560.5. 1 H NMR:(500 MHz, methanol-d4) δ=8.32-8.24 (m, 2H), 7.66-7.56 (m, 2H), 7.42-7.29 (m, 2H), 6.82-6.72 (m, 1H), 6.63-6.60 (m, 1H), 4.89 (s, 2H), 3.61 (s, 4H), 3.16 (d, J=6.5 Hz, 2H), 3.14-3.08 (m, 3H), 3.00-2.89 (m, 4H), 2.47-2.34 (m, 3H), 2.31-2.28 (m, 6H), 1.54-1.45 (m, 9H).

[0332] Example 72: (E)-1-(tert-butyl)-5-(4-(3-(4-(4-(dimethylamino)but-2-enoyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one [ka] Synthesis of 1,5-(4-bromo-2-methylbenzyl)-1-(tert-butyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one [ka] To a solution of 1-(tert-butyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (440 mg, 2.28 mmol) in THF (20 mL) was added sodium hydride (455 mg, 11.4 mmol, 60% purity) at 0° C. The mixture was stirred at 20° C. for 30 minutes. Then, 4-bromo-1-(chloromethyl)-2-methylbenzene (500 mg, 2.28 mmol) was added, and the mixture was stirred at 20° C. for 10 hours. The mixture was quenched with MeOH (2 mL) and concentrated in vacuo to give a crude residue. The residue was purified by preparative TLC (ethyl acetate) to give 5-(4-bromo-2-methylbenzyl)-1-(tert-butyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one as a white solid (170 mg, 20% yield). LCMS: m / z=M+H + :375.9, 377.9.

[0333] 2. Synthesis of 1-(tert-butyl)-5-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one [ka] To a solution of 5-(4-bromo-2-methylbenzyl)-1-(tert-butyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (170 mg, 452 μmol) in dioxane (10 mL) was added B2Pin2 (229 mg, 904 μmol), KOAc (89 mg, 904 μmol), and Pd(dppf)Cl (33 mg, 45 μmol) at 20° C. The mixture was stirred at 90° C. under N for 16 h. The mixture was concentrated in vacuo to give the crude material, which was purified by silica gel chromatography (petroleum ether to ethyl acetate gradient) to give 1-(tert-butyl)-5-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one as a colorless oil (140 mg, 73% yield). LCMS: m / z=M+H + :424.3.

[0334] 3. Synthesis of tert-butyl 4-(4-(4-((1-(tert-butyl)-4-oxo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)methyl)-3-methylphenyl)pyridin-3-yl)piperazine-1-carboxylate [ka] To a solution of 1-(tert-butyl)-5-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (140 mg, 331 μmol) in dioxane (5 mL) and water (1 mL) was added KCO (91 mg, 661 μmol), tert-butyl 4-(4-chloropyridin-3-yl)piperazine-1-carboxylate (98 mg, 331 μmol), and Pd(dtbpf)Cl (22 mg, 33 μmol) at 20° C. The mixture was stirred at 90° C. under N for 2 hours. The mixture was concentrated in vacuo to give a crude residue. The residue was purified by silica gel chromatography (petroleum ether to ethyl acetate gradient) to give tert-butyl 4-(4-(4-((1-(tert-butyl)-4-oxo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)methyl)-3-methylphenyl)pyridin-3-yl)piperazine-1-carboxylate as a yellow oil (100 mg, 54% yield). LCMS: m / zM+H + :559.5. 4. Synthesis of 1-(tert-butyl)-5-(2-methyl-4-(3-(piperazin-1-yl)pyridin-4-yl)benzyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one hydrochloride [ka] To a solution of tert-butyl 4-(4-(4-((1-(tert-butyl)-4-oxo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)methyl)-3-methylphenyl)pyridin-3-yl)piperazine-1-carboxylate (100 mg, 179 μmol) in DCM (10 mL) was added a solution of HCl in ethyl acetate (8 mL, 4 M) at 20° C. The mixture was stirred at 20° C. for 1 h. The mixture was concentrated in vacuo to give 1-(tert-butyl)-5-(2-methyl-4-(3-(piperazin-1-yl)pyridin-4-yl)benzyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one hydrochloride as a yellow solid (80 mg, crude), which was carried forward without further purification. LCMS: m / z = M + H + :459.3.

[0335] 5. Synthesis of (E)-1-(tert-butyl)-5-(4-(3-(4-(4-(dimethylamino)but-2-enoyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one [ka] To a solution of 1-(tert-butyl)-5-(2-methyl-4-(3-(piperazin-1-yl)pyridin-4-yl)benzyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one hydrochloride (80 mg, 162 μmol) in DCM (50 mL) was added DIPEA (42 mg, 323 μmol), (E)-4-(dimethylamino)but-2-enoic acid (21 mg, 162 μmol), and HATU (62 mg, 162 μmol) at 20° C. The mixture was stirred at 20° C. for 30 minutes. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150 x 25 mm x 5 μm, conditions: water (10 mM NH4HCO3)-ACN, start B23, end B53, gradient time (min): 10, retention time 100% B (min): 2, flow rate (mL / min): 25) to give (E)-1-(tert-butyl)-5-(4-(3-(4-(4-(dimethylamino)but-2-enoyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one as a yellow solid (30 mg, 32% yield). LCMS: m / z = M+H + :570.3. 1 H NMR:(500 MHz, DMSO-d6) δ=8.30-8.27 (m, 2H), 7.71 (s, 1H), 7.58-7.55 (m, 2H), 7.26-7.22 (m, 2H), 6.59-6.55 (m, 2H), 4.65 (s, 2H), 3.51-3.47 (m, 6H), 3.21 (t, J=6.5 Hz, 2H), 2.99 (d, J=4.5 Hz, 2H), 2.85-2.81 (m, 4H), 2.33 (s, 3H), 2.12 (s, 6H), 1.57 (s, 9H).

[0336] Example 73: (E)-N-(4-(3-(4-(4-(dimethylamino)but-2-enoyl)piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide [ka] 1. Synthesis of N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide [ka] To a suspension of (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine hydrochloride (3.12 g, 12.6 mmol) and potassium 3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxylate (2 g, 9.70 mmol) in EtOAc (30 mL) was added T3P (12.3 g, 19.4 mmol, 50% purity). DIPEA (6.27 g, 48.5 mmol, 8.5 mL) was then added at 25° C. The mixture was stirred at 25° C. for 16 h. The mixture was poured into water (100 mL) and extracted with EtOAc (2×80 mL). The organic layer was washed with brine (130 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude material was purified by silica gel column chromatography (petroleum ether / ethyl acetate=10 / 1) to give N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide as a colorless oil (3.2 g, 83% yield). LCMS: m / z=M+H + :398.3. 1 H NMR:(400 MHz, MeOH-d4) δ: 7.52-7.57 (m, 2H), 7.27 (d, J=7.6 Hz, 1H), 4.58 (s, 2H), 2.37 (s, 3H), 1.52 (s, 3H), 1.34 (s, 12H), 1.27-1.30 (m, 2H), 0.93-0.96 (m, 2H).

[0337] 2. Synthesis of tert-butyl 4-(4-(3-methyl-4-((3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamido)methyl)phenyl)pyridin-3-yl)piperazine-1-carboxylate [ka] 3. The synthesis of tert-butyl 4-(4-(3-methyl-4-((3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamido)methyl)phenyl)pyridin-3-yl)piperazine-1-carboxylate was similar to the synthesis of tert-butyl 4-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyridin-3-yl)piperazine-1-carboxylate in Step 1 of Example 57. The crude material was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give tert-butyl 4-(4-(3-methyl-4-((3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamido)methyl)phenyl)pyridin-3-yl)piperazine-1-carboxylate as a brown solid (330 mg, 62% yield). LCMS: m / z = M+H + :533.3.

[0338] 4. Synthesis of N-(2-methyl-4-(3-(piperazin-1-yl)pyridin-4-yl)benzyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride [ka] 5. The synthesis of N-(2-methyl-4-(3-(piperazin-1-yl)pyridin-4-yl)benzyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride was similar to the synthesis of 5-(tert-butyl)-N-(4-(3-cyano-5-(piperazin-1-yl)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-...

Claims

1. Formula (IIA) or Formula (IIB) 【Chemistry 1】 A compound represented by or a pharmaceutically acceptable salt thereof, Ring A is a 4-8 membered monocyclic saturated aza ring optionally substituted with one or two R 11 ; n is 0 or 1; m is 0 or 1; R １ is a 5-6 membered heteroaryl optionally substituted with one or two R 12 ; R １２ is independently at each occurrence optionally substituted with 1 to 3 halogens, C １－６ alkyl, and C 3-6 cycloalkyl optionally substituted with one or two C 1-3 alkyl; R ２ is H or C1-3 alkyl; Or, R １ and R ２ are taken together with their intervening atoms to form Ring B selected from a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, N, and S, a 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from O, N, and S, a 7-10 membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from O, N, and S, and an 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from O, N, and S, and Ring B optionally contains one or two R １００ is replaced by R １００ is independently expressed as C １－６ alkyl, C 3-6 cycloalkyl, halogen, —CN, and —OR 100a, wherein said C 1-6 alkyl and C 3-6 cycloalkyl are each optionally substituted with 1 to 3 substituents independently selected from halogen and C 1-3 alkyl; R 100a is independently selected at each occurrence from H, C 1-6 alkyl, C 3-6 cycloalkyl, and 4- to 6-membered monocyclic heterocyclyl; R ３ is H, R ４ is H, halogen, -CN, -OR ４ａ , C １－６ alkyl, and C 3-6 cycloalkyl, and １－６ alkyl, and C 3-6 cycloalkyl are each optionally substituted with 1 to 3 halogens; R ４ａ is C1-4 alkyl optionally substituted with 1 to 3 halogens; Or, R ３ and R ４ together with the intervening atoms to form a ring C, wherein ring C is selected from a 5- to 7-membered monocyclic carbocycle and a 5- to 7-membered monocyclic heterocycle, and ring C is optionally selected from R ３００ is replaced by R ３００ is independently expressed as C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 3- to 7-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halogen, —C(O)R ３００ａ , -OR ３００ａ , and -S(O) ２ R ３００ａ and R ３００ The C represented by １－６ alkyl, the C ２－６ alkenyl, the C ２－６ The alkynyl, the 3- to 7-membered monocyclic carbocyclyl, and the 4- to 6-membered monocyclic heterocyclyl each optionally include one or more R ３５０ is replaced by R ３００ａ is H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R ３００ａ The C represented by １－６ alkyl, the C ２－６ alkenyl, the C ２－６ The alkynyl, the 3- to 7-membered monocyclic carbocyclyl, and the 4- to 6-membered monocyclic heterocyclyl each optionally include one or more R ３５０ is replaced by R ３５０ is independently expressed as C １－６ Alkyl, halogen, —CN, C(O)R ３５０ａ , -C(O)N(R ３５０ａ ) ２ , -C(R ３５０ａ ) ２ N (R ３５０ａ ) ２ , and -OR ３５０ａ is selected from R ３５０ａ is independently at each occurrence H or C optionally substituted with 1 to 3 halogens １－６ is alkyl, R ５ is H, and -NHR ５ｓ is selected from R ５ａ is H or C1-3 alkyl, R ６ is H or a halogen, R 6A is H, halogen, or CN; R ７ and R ８ are each independently H or halogen and C １－６ C optionally substituted with one or more substituents independently selected from alkoxy １－６ is alkyl, R ９ is H, C １－６ Alkyl or C ３－６ cycloalkyl, １－６ The alkyl group may be selected from halogen and C １－６ Optionally substituted with one or more substituents independently selected from alkoxy, ３－６ Cycloalkyl is C １－６ Alkyl, halogen, C １－６ Haloalkyl and C １－６ optionally substituted with one or more substituents independently selected from alkoxy; or when m is 1, R ９ and R of ring A １１ together with the intervening atoms, optionally halogen, —CN, —OH, C １－６ Alkyl and C １－６ forming a 4- to 7-membered monocyclic saturated or partially saturated heterocyclyl substituted with one or more substituents independently selected from alkoxy; R １０ is C ２－６ Alkenyl, C ２－６ Alkynyl, C ２－６ Alkylene oxide, or C ４－７ cycloalkenyl, and R １０ The C represented by ２－６ Alkenyl is halo, C １－６ Alkyl, C １－６ Alkoxy and -NR １０ａ R １０ｂ and R １０ The C represented by ２－６ Alkynyl is C １－６ Alkyl and C １－６ optionally substituted with one or more substituents independently selected from alkoxy; １０ The C represented by ２－６ The alkylenyl oxide may be one or more C １－６ optionally substituted with alkyl; R １０ａ and R １０ｂ are each independently H or C １－３ alkyl, or R １０ａ and R １０ｂ together with the nitrogen atom to which they are attached, represent halo and C １－６ forming a 4- to 7-membered monocyclic saturated heterocyclyl optionally substituted with one or more substituents independently selected from alkyl; R １１ is independently at each occurrence H, halogen, —CN, —OH, C １－６ Alkyl, C １－６ Haloalkyl and C １－６ alkoxy, or two R １１ taken together with the same carbon atom to which they are attached to form a -C(=O)- group, or a pharmaceutically acceptable salt thereof.

2. R １０ is C ２－６ Alkenyl, C ２－６ Alkynyl, or C ２－６ alkylenyl oxide, and R １０ The C represented by ２－６ Alkenyl is C １－６ Alkyl, C １－６ Alkoxy and -NR １０ａ R １０ｂ and R １０ The C represented by ２－６ Alkynyl is C １－６ Alkyl and C １－６ optionally substituted with one or more substituents independently selected from alkoxy; １０ The C represented by ２－６ The alkylenyl oxide may be one or more C １－６ optionally substituted with alkyl; R １０ａ and R １０ｂ are each independently H or C １－３ is alkyl, R １１ is independently at each occurrence H, halogen, —CN, —OH, C １－６ Alkyl and C １－６ alkoxy, or two R １１ together with the same carbon atom to which they are attached to form a -C(=O)- group, or a pharmaceutically acceptable salt thereof.

3. R １ is a 5-membered heteroaryl selected from pyridinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and tetrazolyl, each of which is selected from one or two R １２ optionally replaced by 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof.

4. R 1 is represented by the following formula: 【Chemistry 2】 is expressed as 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof.

5. Ring B has the following formula: 【Transformation 3】 is represented by one of The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, wherein R 5 is H.

7. The compound has the formula: 【Chemistry 4】 is expressed as X is O or CHR １１Ｂ and R １１Ａ is H or R １１Ａ and R ９ together with the intervening atoms form a 4- to 6-membered saturated monocyclic azacycle; R １１Ｂ is H or R １１Ｂ and R ９ together with the intervening atoms form a 4- to 6-membered saturated monocyclic azacycle; Y is CH or N; p is 0, 1, or 2; p1 is 0, 1, or 2; p2 is 0, 1, or 2; q1 is 0, 1, or 2, and when Y is N, q1 is not 0; q2 is 0, 1, or 2, provided that q1 and q2 are not both 0; 7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein s is 0, 1 or 2.

8. The compound has the formula: 【Transformation 5】 【Transformation 6】 【Transformation 7】 is expressed as p1 is 1 or 2; s is 1 or 2; r1 is 1 or 2, X is O or CH ２ and optionally, p is 2 and two R １１ and together with the same carbon atom to which they are attached form a -C(=O)- group, or a pharmaceutically acceptable salt thereof.

9. R ９ is C １‐３ Alkyl or C ３‐６ is cycloalkyl, and R １０ is one or more halo, C １－６ Alkyl, C １－６ Alkoxy, or —NR １０ａ R １０ｂ C optionally substituted with ２－６ alkenyl or C ４－７ cycloalkenyl, and R １０ａ and R １０ｂ are each independently H or C １－３ alkyl or R １０ａ and R １０ｂ together with the nitrogen atom to which they are attached, represent halo and C １－６ 9. The compound of any one of claims 1 and 3 to 8, or a pharmaceutically acceptable salt thereof, which forms a 4-7 membered monocyclic saturated heterocyclyl optionally substituted with one or more substituents independently selected from alkyl.

10. R １ is expressed as follows: 【Transformation 8】 is expressed as R １２ is independently at each occurrence a C optionally substituted with 1 to 3 halogens １－４ alkyl or optionally one or two C １－３ C substituted with alkyl ３‐６ is cycloalkyl, R ２ is H or C １－３ is alkyl, R ３ is H, R ４ is C １－３ is alkyl, R ５ is H, R ６ is H or a halogen, R ６Ａ The compound according to any one of claims 7 to 9, or a pharmaceutically acceptable salt thereof, wherein is H, halogen, or CN.

11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

12. 12. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 11, for use in a method for treating a disorder responsive to Bruton's tyrosine kinase inhibition in a subject, wherein the disorder is an autoimmune disorder, rheumatoid arthritis, lupus erythematosus, atopic dermatitis, leukemia, or lymphoma.

13. The compound or pharmaceutically acceptable salt thereof or pharmaceutical composition according to claim 12, wherein the disorder is multiple sclerosis.

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