Bruton's tyrosine kinase inhibitors

Abstract

Provided are compounds of formula (I), or pharmaceutically acceptable salts thereof, and methods of use and preparation thereof. TIFF2022532235000183.tif6168

Description

Related Applications

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. § 119(e) of the filing date of U.S. Provisional Application No. 62 / 847,985, filed May 15, 2019, the entire contents of which are incorporated herein by reference. [Technical Field]

[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 numerous human diseases related to 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 expression has been detected in endothelial cells and hepatocytes. Tec kinases (Itk, Rlk, and Tec) are expressed in T cells and are all activated downstream of the T cell receptor (TCR). Btk is a downstream mediator of B cell receptor (BCR) signaling, involved in regulating B cell activation, proliferation, and differentiation. More specifically, Btk contains a PH domain that binds phosphatidylinositol (3,4,5)-triphosphate (PIP3). PIP3 binding induces Btk to phosphorylate phospholipase C (PLCy), which then hydrolyzes PIP2, generating two second messengers, inositol triphosphate (IP3) and diacylglycerol (DAG), which activate the protein kinase PKC and induce further B cell signaling. Mutations that abolish Btk enzymatic activity result in the primary immunodeficiency disorder XLA syndrome (X-linked agammaglobulinemia). Given the important role Tec kinases play in both B cell and T cell signaling, they are attractive targets for autoimmune diseases.

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

[0005] A first embodiment of the present invention is a compound of formula (I): [ka] [In formula: Ring A is selected from aryl and 5- to 6-membered heteroaryl, and the aryl and 5- to 6-membered heteroaryl are each selected from one or more R 1 is optionally replaced by; m is an integer selected from 0, 1, 2, and 3; q is an integer selected from 0, 1, and 2; Q 1 , Q 2 , and Q 3 are CR 4 and N, Q 1 , Q 2 , and Q 3 at most one of is N; R 1 is independently generated for each occurrence of C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 4-6 membered monocyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, halo, -CN, -C(O)R 1a , -C(O)2R 1a , -C(O)N(R 1a )2, -N(R 1a )2, -N(R 1a )C(O)R 1a , -N(R 1a )C(O)2R 1a , -N(R 1a )C(O)N(R 1a )2, -N(R 1a )S(O)2R 1a , -OR 1a , -OC(O)R 1a , -OC(O)N(R 1a )2, -SR 1a , -S(O)R 1a , -S(O)2R 1a , -S(O)N(R 1a )2, and -S(O)2N(R 1a )2, and the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each may have one or more R 10optionally independently substituted by; R 1a For each occurrence, independently, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each may have one or more R 10 optionally independently substituted by; R 2 is H and C 1-6 alkyl; R 3 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl, halo, -CN, -C(O)R 3a , -C(O)2R 3a , -C(O)N(R 3a )2, -N(R 3a )2, -N(R 3a )C(O)R 3a , -N(R 3a )C(O)2R 3a , -N(R 3a )C(O)N(R 3a )2, -N(R 3a )S(O)2R 3a , -OR 3a , -OC(O)R 3a , -OC(O)N(R 3a )2, -SR 3a , -S(O)R 3a , -S(O)2R 3a , -S(O)N(R 3a )2, and -S(O)2N(R 3a )2, and the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl are each independently selected from the group consisting of one or more R30 is optionally replaced by; R 3a For each occurrence, independently, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each may have one or more R 30 or optionally independently replaced by; Or R 2 and R 3 together with the intervening atoms form a 7-membered carbocyclic or heterocyclic ring, and the 7-membered carbocyclic or heterocyclic ring is 20 is optionally replaced by; R 4 For each occurrence, independently, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 4-6 membered monocyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, halo, -CN, -C(O)R 4a , -C(O)2R 4a , -C(O)N(R 4a )2, -N(R 4a )2, -N(R 4a )C(O)R 4a , -N(R 4a )C(O)2R 4a , -N(R 4a )C(O)N(R 4a )2, -N(R 4a )S(O)2R 4a , -OR 4a , -OC(O)R 4a , -OC(O)N(R 4a )2, -SR 4a , -S(O)R 4a , -S(O)2R 4a , -S(O)N(R 4a )2, and -S(O)2N(R 4a )2, and the C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each may have one or more R 40 optionally independently substituted by; R 4a For each occurrence, independently, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each may have one or more R 40 or optionally independently replaced by; R 5 is independently generated for each occurrence of C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 4-6 membered monocyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, halo, -CN, -C(O)R 5a , -C(O)2R 5a , -C(O)N(R 5a )2, -N(R 5a )2, -N(R 5a )C(O)R 5a , -N(R 5a )C(O)2R 5a , -N(R 5a )C(O)N(R 5a )2, -N(R 5a )S(O)2R 5a , -OR 5a , -OC(O)R 5a , -OC(O)N(R 5a )2, -SR 5a , -S(O)R 5a , -S(O)2R 5a , -S(O)N(R 5a )2, and -S(O)2N(R 5a )2, and the C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each may have one or more R 50 optionally independently substituted by; R 5a For each occurrence, independently, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each may have one or more R 50 or optionally independently replaced by; R 6 is independently generated for each occurrence of C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 4-6 membered monocyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, halo, -CN, -C(O)R 6a , -C(O)2R 6a , -C(O)N(R 6a )2, -N(R 6a )2, -N(R 6a )C(O)R 6a , -N(R 6a )C(O)2R 6a , -N(R 6a )C(O)N(R 6a )2, -N(R 6a )S(O)2R 6a , -OR 6a , -OC(O)R 6a , -OC(O)N(R 6a )2, -SR 6a , -S(O)R 6a , -S(O)2R 6a , -S(O)N(R 6a )2, and -S(O)2N(R 6a )2, and the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each may have one or more R 60 or optionally independently replaced by; Or two R's 6 The substituents, together with the intervening atoms, form a 3- to 5-membered carbocyclic ring or a 3- to 5-membered heterocyclic ring, and the 3- to 5-membered carbocyclic ring and the 3- to 5-membered heterocyclic ring are each independently selected from the group consisting of one or more R 60 is optionally replaced by; R 6a For each occurrence, independently, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each may have one or more R 60 optionally independently substituted by; R 10 is independently generated for each occurrence of C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 4-6 membered monocyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, halo, -CN, -C(O)R 10a , -C(O)2R 10a , -C(O)N(R 10a )2, -N(R 10a )2, -N(R 10a )C(O)R 10a , -N(R 10a )C(O)2R 10a , -N(R 10a )C(O)N(R 10a )2, -N(R 10a )S(O)2R 10a , -OR 10a , -OC(O)R 10a , -OC(O)N(R 10a )2, -SR 10a , -S(O)R 10a , -S(O)2R 10a , -S(O)N(R10a )2, and -S(O)2N(R 10a )2 is selected; R 10a For each occurrence, independently, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 selected from alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 20 is independently generated for each occurrence of C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 4-6 membered monocyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, halo, -CN, -C(O)R 20a , -C(O)2R 20a , -C(O)N(R 20a )2, -N(R 20a )2, -N(R 20a )C(O)R 20a , -N(R 20a )C(O)2R 20a , -N(R 20a )C(O)N(R 20a )2, -N(R 20a )S(O)2R 20a , -OR 20a , -OC(O)R 20a , -OC(O)N(R 20a )2, -SR 20a , -S(O)R 20a , -S(O)2R 20a , -S(O)N(R 20a )2, and -S(O)2N(R 20a )2, and the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each may have one or more R 25 is optionally replaced by; R 20a For each occurrence, independently, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each may have one or more R 25 optionally independently substituted by; R 25 is independently generated for each occurrence of C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 4-6 membered monocyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, halo, -CN, -C(O)R 25a , -C(O)2R 25a , -C(O)N(R 25a )2, -N(R 25a )2, -N(R 25a )C(O)R 25a , -N(R 25a )C(O)2R 25a , -N(R 25a )C(O)N(R 25a )2, -N(R 25a )S(O)2R 25a , -OR 25a , -OC(O)R 25a , -OC(O)N(R 25a )2, -SR 25a , -S(O)R 25a , -S(O)2R 25a , -S(O)N(R 25a )2, and -S(O)2N(R 25a )2 is selected; R 25a For each occurrence, independently, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 selected from alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 30 is independently generated for each occurrence of C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, 4-6 membered monocyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, halo, -CN, -C(O)R 30a , -C(O)2R 30a , -C(O)N(R 30a )2, -N(R 30a )2, -N(R 30a )C(O)R 30a , -N(R 30a )C(O)2R 30a , -N(R 30a )C(O)N(R 30a )2, -N(R 30a )S(O)2R 30a , -OR 30a , -OC(O)R 30a , -OC(O)N(R 30a )2, -SR 30a , -S(O)R 30a , -S(O)2R 30a , -S(O)N(R 30a )2, and -S(O)2N(R 30a )2 is selected; R 30a For each occurrence, independently, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 selected from alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 40 is independently generated for each occurrence of C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 4-6 membered monocyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, halo, -CN, -C(O)R 40a , -C(O)2R 40a , -C(O)N(R 40a )2, -N(R 40a )2, -N(R 40a )C(O)R 40a , -N(R 40a )C(O)2R 40a , -N(R 40a )C(O)N(R 40a )2, -N(R 40a )S(O)2R 40a , -OR 40a, -OC(O)R 40a , -OC(O)N(R 40a )2, -SR 40a , -S(O)R 40a , -S(O)2R 40a , -S(O)N(R 40a )2, and -S(O)2N(R 40a )2 is selected; R 40a For each occurrence, independently, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 selected from alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 50 is independently generated for each occurrence of C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 4-6 membered monocyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, halo, -CN, -C(O)R 50a , -C(O)2R 50a , -C(O)N(R 50a )2, -N(R 50a )2, -N(R 50a )C(O)R 50a , -N(R 50a )C(O)2R 50a , -N(R 50a )C(O)N(R 50a )2, -N(R 50a )S(O)2R 50a , -OR 50a , -OC(O)R 50a , -OC(O)N(R 50a )2, -SR 50a , -S(O)R 50a , -S(O)2R 50a , -S(O)N(R 50a )2, and -S(O)2N(R 50a )2 is selected; R 50a For each occurrence, independently, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 selected from alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 60 is independently generated for each occurrence of C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 4-6 membered monocyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, halo, -CN, -C(O)R 60a , -C(O)2R 60a , -C(O)N(R 60a )2, -N(R 60a )2, -N(R 60a )C(O)R 60a , -N(R 60a )C(O)2R 60a , -N(R 60a )C(O)N(R 60a )2, -N(R 60a )S(O)2R 60a , -OR 60a , -OC(O)R 60a , -OC(O)N(R 60a )2, -SR 60a , -S(O)R 60a , -S(O)2R 60a , -S(O)N(R 60a )2, and -S(O)2N(R 60a )2 is selected; R 60a For each occurrence, independently, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl. or a pharmaceutically acceptable salt thereof.

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

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

[0009] Other features and 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 of the present invention, the compound is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , and Q 3 are each independently CR 4 and the definitions of the other variables are as defined in the first embodiment.

[0012] In a third embodiment of the present invention, the compound is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein Q 1 is CH; the definitions of the variables are as defined in the first or second embodiment.

[0013] In a fourth embodiment of the present invention, the compound has formula (II) or (III): [ka] or a pharmaceutically acceptable salt thereof, wherein the definitions of the variables are as defined in the first, second, or third embodiment.

[0014] In a fifth embodiment of the present invention, the compound is represented by Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1, and the other variables are as defined in the first, second, third, or fourth embodiment.

[0015] In a sixth embodiment of the present invention, the compound has formula (IV) or (V): [ka] or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1, and the other variables are as defined in the first embodiment.

[0016] In a seventh embodiment of the present invention, the compound is represented by formula (I), (II), (III), (IV), or (V), or a pharmaceutically acceptable salt thereof, wherein: R 3 is C 1-6 Alkyl, C 3-5 Cycloalkyl, halo, or -OR 3a and the C 1-6 Alkyl or C 3-5 Cycloalkyl is C 1-3 1 to 3 R independently selected from alkyl and halo 30 is optionally replaced by; R 3a is C optionally substituted with 1 to 3 halo 1-6 and alkyl; and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, or sixth embodiment. In specific embodiments, R 3 is C 1-4 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, -F, -Cl, or -OR 3a and the C 1-4alkyl is optionally substituted with 1 to 3 fluoro; R 3a is C optionally substituted with 1 to 3 fluoro 1-4 In another specific embodiment, R 3 is -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CHF2, -CF3, cyclopropyl, cyclobutyl, -F, -Cl, -OCF3, or -OCH3.

[0017] In an eighth embodiment of the present invention, the compound is represented by formula (I), (II), (III), (IV), or (V), or a pharmaceutically acceptable salt thereof, wherein R 2 is H or methyl; the definitions of the variables are as defined in the first, second, third, fourth, fifth, sixth, or seventh embodiment. In more specific embodiments, R 2 is H.

[0018] In a ninth embodiment of the present invention, the compound is represented by formula (I), (II), (III), (IV), or (V), or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 together with their intervening atoms form a seven-membered carbocyclic or heterocyclic ring, the seven-membered heterocyclic ring having one heteroatom selected from N and O; the seven-membered carbocyclic or heterocyclic ring having one or two R 20 and optionally replaced by; the definitions of the other variables are as defined in the first, second, third, fourth, fifth, or sixth embodiment.

[0019] In a tenth embodiment of the present invention, the compound has formula (VIa), (VIa'), (VIb), (VIb'), (VIIa), (VIIa'), (VIIb), (VIIb'), (VIIIa), (VIIIa'), (VIIIb), (VIIIb'), (IXa), (IXa'), (IXb), or (IXb'): [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein the definitions of the variables are as defined in the first, second, third, fourth, fifth, or sixth embodiment.

[0020] In an eleventh embodiment of the present invention, the compound is represented by formula (VIa), (VIa'), (VIb), or (VIb'), or a pharmaceutically acceptable salt thereof, wherein: R 20 is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered saturated monocyclic heterocyclyl, halo, -OR 20a , -OC(O)R 20a , -OC(O)N(R 20a )2, and -SR 20a C is selected from 1-6 Alkyl, C 3-6 Cycloalkyl and 4- to 6-membered saturated monocyclic heterocyclyl are each substituted with 1 to 3 R 25 is optionally replaced by; R 20a is independently H or C for each occurrence 1-6 alkyl, and the C 1-6 Each occurrence of alkyl is one R 25 optionally independently substituted by; R 25 is independently generated for each occurrence of C 1-6 alkyl or halo; the definitions of the other variables are as defined in the first, second, third, fourth, fifth, or sixth embodiment. In specific embodiments, R 20 is H.

[0021] In a twelfth embodiment of the present invention, the compound is represented by formula (VIIIa), (VIIIa'), (VIIIb), (VIIIb'), (IXa), (IXa'), (IXb)), or (IXb'), or a pharmaceutically acceptable salt thereof, wherein: R 20 is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered saturated monocyclic heterocyclyl, -C(O)R 20a , -C(O)2R 20a , and -S(O)R 20a C is selected from 1-6 Alkyl, C 3-6 Cycloalkyl and 4- to 6-membered saturated monocyclic heterocyclyl are each substituted with 1 to 3 R 25 is optionally replaced by; R 20a For each occurrence, independently, H, C 1-6 Alkyl, C 4-6 cycloalkyl, and 4- to 6-membered saturated monocyclic heterocyclyl, 1-6 Alkyl, C 4-6 Cycloalkyl and 4- to 6-membered saturated monocyclic heterocyclyl each have one or more R 25 optionally independently substituted by; R 25 is independently generated for each occurrence of C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered saturated monocyclic heterocyclyl, halo, -CN, -N(R 25a )2, and -OR 25a Selected from; R 25a is independently H or C for each occurrence 1-6 and alkyl; and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, or sixth embodiment. In specific embodiments, R 20 is C optionally substituted with 1 to 3 fluoro 1-6 In another specific embodiment, R 20 is -CH2CF3.

[0022] In a thirteenth embodiment of the present invention, the compound is represented by formula (I), (II), (III), (IV), (V), (VIa), (VIa'), (VIb), (VIb'), (VIIa), (VIIa'), (VIIb), (VIIb'), (VIIIa), (VIIIa'), (VIIIb), (VIIIb'), (IXa), (IXa'), (IXb), or (IXb'), or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered N-containing heteroaryl having one or two additional heteroatoms independently selected from O, N, and S, and ring A is a 5-membered N-containing heteroaryl having one or two independently selected R 1 and optionally replaced by; the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment, or any specific embodiment described therein.

[0023] In a fourteenth embodiment of the present invention, the compound is represented by formula (I), (II), (III), (IV), (V), (VIa), (VIa'), (VIb), (VIb'), (VIIa), (VIIa'), (VIIb), (VIIb'), (VIIIa), (VIIIa'), (VIIIb), (VIIIb'), (IXa), (IXa'), (IXb), or (IXb'), or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of pyrazole, imidazole, oxazole, isoxazole, thiadiazole, isothiazole, 1,2,3-oxadiazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,2,4-thiadiazole, 1,2,3-triazole, and 1,2,4-triazole, each of which is selected from the group consisting of one or two independently selected R 1 and optionally replaced by; the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment, or any specific embodiment described therein.

[0024] In a fifteenth embodiment of the present invention, the compound is represented by formula (I), (II), (III), (IV), (V), (VIa), (VIa'), (VIb), (VIb'), (VIIa), (VIIa'), (VIIb), (VIIb'), (VIIIa), (VIIIa'), (VIIIb), (VIIIb'), (IXa), (IXa'), (IXb), or (IXb'), or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of: [ka] and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment, or any specific embodiment described therein.

[0025] In a sixteenth embodiment, the compound is represented by formula (I), (II), (III), (IV), (V), (VIa), (VIa'), (VIb), (VIb'), (VIIa), (VIIa'), (VIIb), (VIIb'), (VIIIa), (VIIIa'), (VIIIb), (VIIIb'), (IXa), (IXa'), (IXb), or (IXb'), or a pharmaceutically acceptable salt thereof, wherein: R 1 For each occurrence, independently, halo, C 1-6 Alkyl, or C 3-5 is cycloalkyl, and the C 1-6 Alkyl and C 3-5 Cycloalkyl is one to three independently selected R 10 is optionally replaced by; R 10 are, for each occurrence, independently, halo, -OH, and C 1-6 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, or fifteenth embodiment, or any specific embodiment described therein.

[0026] In a seventeenth embodiment of the present invention, the compound is represented by formula (I), (II), (III), (IV), (V), (VIa), (VIa'), (VIb), (VIb'), (VIIa), (VIIa'), (VIIb), (VIIb'), (VIIIa), (VIIIa'), (VIIIb), (VIIIb'), (IXa), (IXa'), (IXb), or (IXb'), or a pharmaceutically acceptable salt thereof, wherein R 1 For each occurrence, independently, halo, C 1-4 alkyl, cyclopropyl, cyclobutyl, or cyclopentyl, 1-4 Alkyl, cyclopropyl, cyclobutyl, or cyclopentyl is selected from 1 to 3 R independently selected from methyl, fluoro, and —OH. 10 and the definitions of the other variables are as defined in the sixteenth embodiment. In a specific embodiment, R 1 is, at each occurrence, independently: -F, -C(CH3)3, -C(CH2OH)(CH3)2, -C(CH2F)(CH3)2, or [ka] is.

[0027] In an eighteenth embodiment of the present invention, the compound is represented by formula (I), (II), (III), (IV), (V), (VIa), (VIa'), (VIb), (VIb'), (VIIa), (VIIa'), (VIIb), (VIIb'), (VIIIa), (VIIIa'), (VIIIb), (VIIIb'), (IXa), (IXa'), (IXb), or (IXb'), or a pharmaceutically acceptable salt thereof, wherein R 4 is H, halo, or C 1-3 and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenth embodiment, or any specific embodiment described therein. In specific embodiments, R 4 is H, -F, -Cl, or -CH3.

[0028] In a nineteenth embodiment of the present invention, the compound is represented by formula (I), (II), (III), (IV), (V), (VIa), (VIa'), (VIb), (VIb'), (VIIa), (VIIa'), (VIIb), (VIIb'), (VIIIa), (VIIIa'), (VIIIb), (VIIIb'), (IXa), (IXa'), (IXb), or (IXb'), or a pharmaceutically acceptable salt thereof, wherein m 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, or eighteenth embodiment, or any specific embodiment described therein.

[0029] In a twentieth embodiment of the present invention, the compound is represented by formula (I), (II), (III), (IV), (V), (VIa), (VIa'), (VIb), (VIb'), (VIIa), (VIIa'), (VIIb), (VIIb'), (VIIIa), (VIIIa'), (VIIIb), (VIIIb'), (IXa), (IXa'), (IXb), or (IXb'), or a pharmaceutically acceptable salt thereof, wherein m is 1; R 5 is C optionally substituted with halo or 1 to 3 fluoro 1-3 and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, or eighteenth embodiment, or any specific embodiment described therein. In specific embodiments, R 5 is -F, -Cl, or -CF3.

[0030] In a twenty-first embodiment of the present invention, the compound is represented by formula (I), (II), (III), (IV), (V), (VIa), (VIa'), (VIb), (VIb'), (VIIa), (VIIa'), (VIIb), (VIIb'), (VIIIa), (VIIIa'), (VIIIb), (VIIIb'), (IXa), (IXa'), (IXb), or (IXb'), or a pharmaceutically acceptable salt thereof, wherein q 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, or twentieth embodiment, or any specific embodiment described therein.

[0031] In a twenty-second embodiment of the present invention, the compound is represented by formula (I), (II), (III), (IV), (V), (VIa), (VIa'), (VIb), (VIb'), (VIIa), (VIIa'), (VIIb), (VIIb'), (VIIIa), (VIIIa'), (VIIIb), (VIIIb'), (IXa), (IXa'), (IXb), or (IXb'), or a pharmaceutically acceptable salt thereof; 6 each occurrence independently represents halo, —CN, and C optionally substituted with 1 to 3 halo 1-6 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, or twentieth embodiment, or any specific embodiment described therein. In specific embodiments, R 6 is, at each occurrence, independently -CH3, -CF3, -F, or -CN.

[0032] In a twenty-third embodiment of the present invention, the compound is represented by formula (I), (II), (III), (IV), (V), (VIa), (VIa'), (VIb), (VIb'), (VIIa), (VIIa'), (VIIb), (VIIb'), (VIIIa), (VIIIa'), (VIIIb), (VIIIb'), (IXa), (IXa'), (IXb), or (IXb'), or a pharmaceutically acceptable salt thereof, wherein q is 2; and two R 6 the substituents, together with their intervening atoms, form a 3- to 5-membered cycloalkyl or a 4- to 5-membered saturated heterocycle; 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, or twentieth embodiment, or any specific embodiment described therein. In a specific embodiment, two R 6 The substituents, together with their intervening atoms, form cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, or oxathiolanyl. 6 The substituents, together with their intervening atoms, form a cyclopropyl, cyclobutyl, cyclopentyl, or tetrahydrofuranyl.

[0033] In a twenty-fourth embodiment of the present invention, the compound has formula (IV) or (V): [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from one or two independently selected R 1 is an oxadiazole optionally substituted by R 1 Each occurrence is independently a halo or C 1-6 is alkyl; R2 is H or C 1-3 is alkyl; R 3 is a halo or C 1-3 Is it alkyl; Alternatively, R 2 and R 3 together with their intervening atoms form a 7-membered carbocyclic or heterocyclic ring, the 7-membered heterocyclic ring having one heteroatom selected from N and O, the 7-membered carbocyclic or heterocyclic ring containing one R 20 is optionally replaced by; R 20 is C optionally substituted with 1 to 3 fluoro 1-6 is alkyl; R 4 is H or halo; R 5 is a halo; R 6 is a halo or C 1-3 is alkyl; m is 0 or 1; q is 0 or 1.

[0034] In a twenty-fifth embodiment, the compound is represented by formula (IV) or (V), or a pharmaceutically acceptable salt thereof, wherein ring A is of the following formula: [ka] the definitions of the other variables are as defined in the twenty-fourth embodiment.

[0035] In a 26th embodiment, the compound is represented by formula (IV) or (V), or a pharmaceutically acceptable salt thereof, wherein R 1 is —C(CH 3 ) 3 ; the definitions of the other variables are as defined in the twenty-fourth or twenty-fifth embodiment.

[0036] In a 27th embodiment, the compound is represented by formula (IV) or (V), or a pharmaceutically acceptable salt thereof, wherein q is 0; or q is 1 and R6 is -F or -CH3; the definitions of the other variables are as defined in the twenty-fourth, twenty-fifth, or twenty-sixth embodiment.

[0037] In a twenty-eighth embodiment, the compound is represented by formula (IV) or (V), or a pharmaceutically acceptable salt thereof, wherein m is 0; or m is 1 and R 5 is -F or -Cl; the definitions of the other variables are as defined in the twenty-fourth, twenty-fifth, twenty-sixth, or twenty-seventh embodiment.

[0038] In a 29th embodiment, the compound is represented by formula (IV) or (V), or a pharmaceutically acceptable salt thereof, wherein R 2 is H or -CH3; R 3 is -Cl, -CH3, or -CF3; the definitions of the other variables are as defined in the twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, or twenty-eighth embodiment.

[0039] In a thirtieth embodiment, the compound is represented by formula (IV) or (V), or a pharmaceutically acceptable salt thereof, wherein R 4 is H or -F; the definitions of the other variables are as defined in the twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, or twenty-ninth embodiment.

[0040] In a thirty-first embodiment, the compound has formula (VIC), (VIc'), (VIIIc), or (VIIIc'): [ka] or a pharmaceutically acceptable salt thereof, wherein the definitions of the variables are as defined in the twenty-fourth, twenty-fifth, twenty-sixth, or twenty-seventh embodiment. 20 is C 1-6 alkyl or 4- to 6-membered saturated monocyclic heterocyclyl, 1-6 Alkyl and 4- to 6-membered saturated monocyclic heterocyclyl are each substituted by 1 to 3 R 25Optionally replaced by R 25 is a halo for each occurrence independently; R 20 is selected from azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, and dioxinyl; 1-6 alkyl or 4- to 6-membered saturated monocyclic heterocyclyl, 1-6 The alkyl is optionally substituted with 1 to 3 halo. In another specific embodiment, R 20 is -CH2CF3.

[0041] In a thirty-second embodiment, the compound of the present invention is 3-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride; 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride; 5-(tert-butyl)-N-(4-(2-(2-fluorocyclopropane-1-carboxamido)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamide)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(4-(2-((1R,2R)-2-fluorocyclopropane-1-carboxamide)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(4-(2-((1S,2R)-2-fluorocyclopropane-1-carboxamide)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(4-(2-((1R,2S)-2-fluorocyclopropane-1-carboxamide)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(2-methyl-4-(2-(2-methylcyclopropane-1-carboxamido)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(2-methyl-4-(2-((1S,2S)-2-methylcyclopropane-1-carboxamide)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(2-methyl-4-(2-((1S,2R)-2-methylcyclopropane-1-carboxamide)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(2-methyl-4-(2-((1R,2S)-2-methylcyclopropane-1-carboxamide)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(2-methyl-4-(2-((1R,2R)-2-methylcyclopropane-1-carboxamide)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(4-(5-chloro-2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide; 3-(tert-butyl)-N-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide; 5-(tert-butyl)-N-(8-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide; (R)-5-(tert-butyl)-N-(8-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide; (S)-5-(tert-butyl)-N-(8-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 3-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-5-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide; 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-5-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluorobenzyl)-1,2,4-oxadiazole-3-carboxamide; 3-(tert-butyl)-N-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide; 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxamide; 3-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-(2-(2-(cyclopropanecarboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; (R)-3-(tert-butyl)-N-(2-(2-(cyclopropanecarboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; (S)-3-(tert-butyl)-N-(2-(2-(cyclopropanecarboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 5-(tert-butyl)-N-(1-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide; (R)-5-(tert-butyl)-N-(1-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide; (S)-5-(tert-butyl)-N-(1-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)-5-fluoropyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide; (R)-5-(tert-butyl)-N-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide; (S)-5-(tert-butyl)-N-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)-5-fluoropyridin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide; (R)-5-(tert-butyl)-N-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)-5-fluoropyridin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide; (S)-5-(tert-butyl)-N-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)-5-fluoropyridin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide; N-(4-(2-(3-oxabicyclo[3.1.0]hexane-6-carboxamido)pyridin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(2-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide; (R)-5-(tert-butyl)-N-(2-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide; (S)-5-(tert-butyl)-N-(2-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(2-methyl-4-(2-(2-(trifluoromethyl)cyclopropane-1-carboxamide)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(2-methyl-4-(2-((1R,2R)-2-(trifluoromethyl)cyclopropane-1-carboxamide)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(2-methyl-4-(2-((1R,2S)-2-(trifluoromethyl)cyclopropane-1-carboxamide)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(2-methyl-4-(2-((1S,2R)-2-(trifluoromethyl)cyclopropane-1-carboxamide)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(2-methyl-4-(2-((1S,2S)-2-(trifluoromethyl)cyclopropane-1-carboxamide)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)-5-(trifluoromethyl)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 3-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(difluoromethyl)-3-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide; 1-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)-4-fluoro-1H-pyrazole-3-carboxamide; 1-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-cyclopropyl-3-fluorobenzyl)-4-fluoro-1H-pyrazole-3-carboxamide; 2-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-cyclopropyl-3-fluorobenzyl)oxazole-5-carboxamide; 1-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluoro-2-methylbenzyl)-4-fluoro-1H-pyrazole-3-carboxamide; 2-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluoro-2-methylbenzyl)oxazole-5-carboxamide; 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-cyclopropyl-3-fluorobenzyl)-1,2,4-oxadiazole-3-carboxamide; 3-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-cyclopropyl-3-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide; N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)-5-(1-hydroxy-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(2-methyl-4-(2-(spiro[2.3]hexane-1-carboxamido)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(4-(2-((1R,2S)-2-fluorocyclopropane-1-carboxamide)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(4-(2-((1S,2R)-2-fluorocyclopropane-1-carboxamide)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)-3-(1-fluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-5-carboxamide; 5-(tert-butyl)-N-(2-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide; (R)-5-(tert-butyl)-N-(2-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide; (S)-5-(tert-butyl)-N-(2-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide; N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)-5-(1-fluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxamide; 3-(tert-butyl)-N-(2-(2-(spiro[2.3]hexane-1-carboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((R)-2-(2-((R)-spiro[2.3]hexane-1-carboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((R)-2-(2-((S)-spiro[2.3]hexane-1-carboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((S)-2-(2-((R)-spiro[2.3]hexane-1-carboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((S)-2-(2-((S)-spiro[2.3]hexane-1-carboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-(2-(2-(spiro[2.2]pentane-1-carboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((R)-2-(2-((R)-spiro[2.2]pentane-1-carboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((R)-2-(2-((S)-spiro[2.2]pentane-1-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((S)-2-(2-((R)-spiro[2.2]pentane-1-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((S)-2-(2-((S)-spiro[2.2]pentane-1-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)-3-fluoropyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 3-(tert-butyl)-N-((R)-2-(2-((R)-2,2-dimethylcyclopropane-1-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; N-(2-(2-(3-oxabicyclo[3.1.0]hexane-6-carboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide; N-((R)-2-(2-((1R,5S,6s)-3-oxabicyclo[3.1.0]hexane-6-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide; N-((R)-2-(2-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexane-6-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide; N-((R)-2-(2-((1R,5R)-3-oxabicyclo[3.1.0]hexane-6-carboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide; N-((R)-2-(2-((1S,5S)-3-oxabicyclo[3.1.0]hexane-6-carboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide; N-((R)-2-(2-((1S,5R,6r)-3-oxabicyclo[3.1.0]hexane-6-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide; N-((R)-2-(2-((1S,5R,6s)-3-oxabicyclo[3.1.0]hexane-6-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide; N-((S)-2-(2-((1R,5S,6s)-3-oxabicyclo[3.1.0]hexane-6-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide; N-((S)-2-(2-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexane-6-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide; N-((S)-2-(2-((1R,5R)-3-oxabicyclo[3.1.0]hexane-6-carboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide; N-((S)-2-(2-((1S,5S)-3-oxabicyclo[3.1.0]hexane-6-carboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide; N-((S)-2-(2-((1S,5R,6r)-3-oxabicyclo[3.1.0]hexane-6-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide; N-((S)-2-(2-((1S,5R,6s)-3-oxabicyclo[3.1.0]hexane-6-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide; N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(4-(2-(2,2-dimethylcyclopropane-1-carboxamido)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(4-(2-(2,2-difluorocyclopropane-1-carboxamido)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 3-(tert-butyl)-N-(2-(2-(2-cyanocyclopropane-1-carboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((R)-2-(2-((1R,2S)-2-cyanocyclopropane-1-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((R)-2-(2-((1S,2S)-2-cyanocyclopropane-1-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((R)-2-(2-((1S,2R)-2-cyanocyclopropane-1-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((R)-2-(2-((1R,2R)-2-cyanocyclopropane-1-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((S)-2-(2-((1R,2S)-2-cyanocyclopropane-1-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((S)-2-(2-((1S,2S)-2-cyanocyclopropane-1-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((S)-2-(2-((1S,2R)-2-cyanocyclopropane-1-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((S)-2-(2-((1R,2R)-2-cyanocyclopropane-1-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-(2-(2-(2-cyanocyclopropane-1-carboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((R)-2-(2-((1R,2R)-2-cyanocyclopropane-1-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((R)-2-(2-((1R,2S)-2-cyanocyclopropane-1-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((R)-2-(2-((1S,2R)-2-cyanocyclopropane-1-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((R)-2-(2-((1S,2S)-2-cyanocyclopropane-1-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((S)-2-(2-((1R,2R)-2-cyanocyclopropane-1-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((S)-2-(2-((1R,2S)-2-cyanocyclopropane-1-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((S)-2-(2-((1S,2R)-2-cyanocyclopropane-1-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((S)-2-(2-((1S,2S)-2-cyanocyclopropane-1-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-(2-(2-(2-(trifluoromethyl)cyclopropane-1-carboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((R)-2-(2-((1R,2R)-2-(trifluoromethyl)cyclopropane-1-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((R)-2-(2-((1R,2S)-2-(trifluoromethyl)cyclopropane-1-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((R)-2-(2-((1S,2R)-2-(trifluoromethyl)cyclopropane-1-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((R)-2-(2-((1S,2S)-2-(trifluoromethyl)cyclopropane-1-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((S)-2-(2-((1R,2R)-2-(trifluoromethyl)cyclopropane-1-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((S)-2-(2-((1R,2S)-2-(trifluoromethyl)cyclopropane-1-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((S)-2-(2-((1S,2R)-2-(trifluoromethyl)cyclopropane-1-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((S)-2-(2-((1S,2S)-2-(trifluoromethyl)cyclopropane-1-carboxamide)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 5-(tert-butyl)-N-(8-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,2,4-oxadiazole-3-carboxamide; (S)-5-(tert-butyl)-N-(8-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,2,4-oxadiazole-3-carboxamide; (R)-5-(tert-butyl)-N-(8-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,2,4-oxadiazole-3-carboxamide; 3-(tert-butyl)-N-(8-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-(8-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,2,4-oxadiazole-5-carboxamide; (R)-3-(tert-butyl)-N-(8-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,2,4-oxadiazole-5-carboxamide; (S)-3-(tert-butyl)-N-(8-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,2,4-oxadiazole-5-carboxamide; 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-isopropylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)-5-fluoropyridin-4-yl)-3-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 3-(tert-butyl)-N-(2-(2-(2,2-difluorocyclopropane-1-carboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((5R)-2-(2-(2,2-difluorocyclopropane-1-carboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-((5S)-2-(2-(2,2-difluorocyclopropane-1-carboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; N-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluorobenzyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide; N-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)benzyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3,5-difluoro-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-5-fluoro-2-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxamide; 2-(tert-butyl)-N-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)benzyl)oxazole-4-carboxamide; 2-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)oxazole-4-carboxamide; 5-(tert-butyl)-N-(8-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,2,4-oxadiazole-3-carboxamide; (R)-5-(tert-butyl)-N-(8-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,2,4-oxadiazole-3-carboxamide; (S)-5-(tert-butyl)-N-(8-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,2,4-oxadiazole-3-carboxamide; 3-(tert-butyl)-N-(1-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide; (R)-3-(tert-butyl)-N-(1-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide; (S)-3-(tert-butyl)-N-(1-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide; 5-(tert-butyl)-N-(2-(2-(cyclopropanecarboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide; (R)-5-(tert-butyl)-N-(2-(2-(cyclopropanecarboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide; (S)-5-(tert-butyl)-N-(2-(2-(cyclopropanecarboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide; 2-(tert-butyl)-N-(2-(2-(cyclopropanecarboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)oxazole-4-carboxamide; (R)-2-(tert-butyl)-N-(2-(2-(cyclopropanecarboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)oxazole-4-carboxamide; (S)-2-(tert-butyl)-N-(2-(2-(cyclopropanecarboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)oxazole-4-carboxamide; 3-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluoro-2-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-5-fluorophenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide; (R)-3-(tert-butyl)-N-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-5-fluorophenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide; (S)-3-(tert-butyl)-N-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-5-fluorophenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide; 5-(tert-butyl)-N-(1-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide; (R)-5-(tert-butyl)-N-(1-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide; (S)-5-(tert-butyl)-N-(1-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(2-(tert-butyl)-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-ethylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluorophenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide; (R)-5-(tert-butyl)-N-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluorophenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide; (S)-5-(tert-butyl)-N-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluorophenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide; 3-(tert-butyl)-N-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluorophenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide; (R)-3-(tert-butyl)-N-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluorophenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide; (S)-3-(tert-butyl)-N-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluorophenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide; 5-(tert-butyl)-N-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-5-fluorophenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide; (R)-5-(tert-butyl)-N-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-5-fluorophenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide; (S)-5-(tert-butyl)-N-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-5-fluorophenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-cyclopropylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(1-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(trifluoromethyl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide; (R)-5-(tert-butyl)-N-(1-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(trifluoromethyl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide; (S)-5-(tert-butyl)-N-(1-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(trifluoromethyl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide; 3-(tert-butyl)-N-(1-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(trifluoromethyl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide; (R)-3-(tert-butyl)-N-(1-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(trifluoromethyl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide; (S)-3-(tert-butyl)-N-(1-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(trifluoromethyl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(trifluoromethoxy)benzyl)-1,2,4-oxadiazole-5-carboxamide; 2-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide; 5-(tert-butyl)-N-(4-(2-(1-fluorocyclopropane-1-carboxamido)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(1-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(trifluoromethoxy)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide; (R)-5-(tert-butyl)-N-(1-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(trifluoromethoxy)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide; (S)-5-(tert-butyl)-N-(1-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(trifluoromethoxy)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(3-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(1-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-5-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide; (R)-5-(tert-butyl)-N-(1-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-5-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide; (S)-5-(tert-butyl)-N-(1-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-5-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluoro-2-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methoxybenzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(2-cyclobutyl-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide; 1-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)-1H-1,2,3-triazole-4-carboxamide; 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)-1,3,4-oxadiazole-2-carboxamide; 3-(tert-butyl)-N-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide; (R)-3-(tert-butyl)-N-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide; (S)-3-(tert-butyl)-N-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-(8-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-5-carboxamide; (R)-3-(tert-butyl)-N-(8-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-5-carboxamide; (S)-3-(tert-butyl)-N-(8-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-(1-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide; (R)-3-(tert-butyl)-N-(1-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide; (S)-3-(tert-butyl)-N-(1-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide; 3-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide; 1-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)-1H-imidazole-4-carboxamide; 1-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)-1H-pyrazole-4-carboxamide; 4-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)oxazole-2-carboxamide; 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)oxazole-2-carboxamide; 1-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)-1H-pyrazole-3-carboxamide; 3-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-fluoro-3-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide; 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-fluoro-3-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-fluoro-5-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)-5-fluoropyridin-4-yl)-5-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-5-fluorobenzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)isoxazole-3-carboxamide; 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)-5-fluoropyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; and 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(trifluoromethoxy)benzyl)-1,2,4-oxadiazole-3-carboxamide; or a pharmaceutically acceptable salt thereof.

[0042] In a specific embodiment, the compound of the invention is 3-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride; 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride; 5-(tert-butyl)-N-(4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamide)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(4-(2-((1R,2R)-2-fluorocyclopropane-1-carboxamide)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(2-methyl-4-(2-((1S,2S)-2-methylcyclopropane-1-carboxamide)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(2-methyl-4-(2-((1R,2R)-2-methylcyclopropane-1-carboxamide)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(4-(5-chloro-2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide; 3-(tert-butyl)-N-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide; (R)-5-(tert-butyl)-N-(8-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 3-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-5-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide; 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-5-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluorobenzyl)-1,2,4-oxadiazole-3-carboxamide; 3-(tert-butyl)-N-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide; 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxamide; 3-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide; (R)-3-(tert-butyl)-N-(2-(2-(cyclopropanecarboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide; (R)-5-(tert-butyl)-N-(1-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)-5-fluoropyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; (R)-5-(tert-butyl)-N-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide; and (R)-5-(tert-butyl)-N-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)-5-fluoropyridin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide; or a pharmaceutically acceptable salt thereof.

[0043] As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety. Preferably, alkyl contains 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In some embodiments, alkyl contains 6 to 20 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl.

[0044] "Alkenyl" refers to an unsaturated hydrocarbon group that may be straight-chained or branched and has at least one carbon-carbon double bond. Alkenyl groups having 2 to 6 carbon atoms may be preferred. Alkenyl groups may contain 1, 2, or 3 carbon-carbon double bonds, or more. Examples of alkenyl groups include ethenyl, n-propenyl, isopropenyl, n-but-2-enyl, n-hex-3-enyl, and the like.

[0045] "Alkynyl" refers to an unsaturated hydrocarbon group that may be straight-chained or branched and has at least one carbon-carbon triple bond. Alkynyl groups having 2 to 6 carbon atoms may be preferred. Alkynyl groups may contain 1, 2, or 3 carbon-carbon triple bonds, or more. Examples of alkynyl groups include ethynyl, n-propynyl, n-but-2-ynyl, n-hex-3-ynyl, and the like.

[0046] 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 4 carbon atoms.

[0047] "Halogen" or "halo" can be fluoro, chloro, bromo, or iodo.

[0048] As used herein, the term "heterocyclyl" refers to a saturated or unsaturated monocyclic or bicyclic ring system (e.g., a fused, bridged, or spiro ring system) having 3 to 11 ring members, or particularly 3 to 8, 3 to 7, 3 to 6, 4 to 6, 5 to 7, or 4 to 7 ring members, at least one of which is a heteroatom and up to four (e.g., 1, 2, 3, or 4) of which may be heteroatoms, independently selected from O, S, and N, where C can be oxidized (e.g., C(O)), N can be oxidized (e.g., N(O)) or quaternized, and S can optionally be oxidized to sulfoxide and sulfone. Unsaturated heterocycles include heteroaryl rings.

[0049] As used herein, the term "heteroaryl" refers to a 5- or 6-membered monocyclic aromatic ring system having 1 to 4 heteroatoms independently selected from O, S, and N, where N can be oxidized (e.g., N(O)) or quaternized, and S can be optionally oxidized to sulfoxide and sulfone. Examples of heteroaryl include, but are not limited to, pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, oxathianyl, triazinyl, and tetrazinyl. In one embodiment, heteroaryl is a 5-membered monocyclic aromatic ring system. Examples of 5-membered heteroaryls include, but are not limited to, pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, and tetrazolyl. As used herein, a "5-membered N-containing heteroaryl" is a 5-membered heteroaryl having at least one nitrogen ring atom.

[0050] In one embodiment, the heterocyclyl is a 3- to 7-membered saturated monocyclic ring, or a 3- to 6-membered saturated monocyclic ring, or a 5- to 7-membered saturated monocyclic ring, or a 4- to 6-membered saturated monocyclic ring. In one embodiment, the heterocyclyl is a 4- to 6-membered monocyclic ring. In another embodiment, the heterocyclyl is an 11-membered bicyclic ring. In yet another embodiment, the heterocyclyl is a 4- to 7-membered monocyclic non-aromatic ring. In another embodiment, the heterocyclyl is a 6- to 8-membered spiro or bridged bicyclic ring. The heterocyclyl group may be attached to a heteroatom or a carbon atom. Examples of heterocyclyl include aziridinyl, oxiranyl, thiiranyl, oxaziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, trithianyl, azepanyl, oxepanyl, thiepanyl, dihydrofuranyl, imidazolinyl, dihydropyranyl. and heteroaryl rings, such as, but not limited to, azetyl, thiethyl, pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, oxathianyl, triazinyl, tetrazinyl, azepinyl, oxepinyl, thiepinyl, diazepinyl, and thiazepinyl.

[0051] As used herein, the term "fused ring system" refers to a ring system having two rings, each independently selected from carbocyclyl or heterocyclyl, where the two ring structures share two adjacent ring atoms. The fused ring system may have 9 to 12 ring members.

[0052] As used herein, the term "bridged ring system" refers to a ring system having a carbocyclyl or heterocyclyl ring in which two non-adjacent atoms of the ring are joined (bridged) by one or more (preferably 1 to 3) atoms selected from C, N, O, or S. The bridged ring system can have 6 to 8 ring members.

[0053] As used herein, the term "spiro ring system" refers to a ring system having two rings, each independently selected from carbocyclyl or heterocyclyl, with one ring atom in common between the two ring structures. Spiro ring systems can have 5 to 8 ring members.

[0054] In one embodiment, the heterocyclyl is a 4-6 membered monocyclic heterocyclyl. Examples of 4-6 membered monocyclic heterocyclic ring systems include azetidinyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, dihydrofuranyl, imidazolinyl, dihydropyranyl, pyrrolidinyl, and the like. 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.

[0055] In another embodiment, the heterocyclyl is a 4-6 membered saturated monocyclic heterocyclyl. Examples of 4-6 membered saturated monocyclic heterocyclic ring systems include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, and dithiinyl. In another embodiment, the 4-6 membered saturated monocyclic heterocyclyl is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.

[0056] In another embodiment, the heterocyclyl is a 4-5 membered saturated monocyclic heterocyclyl. Examples of 4-5 membered saturated monocyclic heterocyclic ring systems include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, and oxathiolanyl.

[0057] As used herein, the term "carbocyclyl" refers to a saturated or unsaturated monocyclic or bicyclic hydrocarbon group having 3 to 12, 3 to 7, 3 to 5, 3 to 6, 4 to 6, or 5 to 7 carbon atoms. The term "carbocyclyl" encompasses cycloalkyl and aromatic groups. The term "cycloalkyl" refers to a fully saturated monocyclic, bicyclic, or spiro hydrocarbon group having 3 to 7 carbon atoms, 3 to 6 carbon atoms, or 5 to 7 carbon atoms. Exemplary monocyclic carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopentyl, cyclohexenyl, cycloheptenyl, cyclobutadienyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl, phenyl, and cycloheptatrienyl. Exemplary bicyclic carbocyclyl groups include bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, tricyclo[2.2.1.0]heptenyl, and tricyclo[2.2.1.0]heptenyl. 2,6 ]heptanyl, 6,6-dimethylbicyclo[3.1.1]heptyl, or 2,6,6-trimethylbicyclo[3.1.1]heptyl, spiro[2.2]pentanyl, and spiro[3.3]heptanyl. In one embodiment, the carbocyclyl is a 4- to 6-membered monocyclic carbocyclyl. In another embodiment, the carbocyclyl is a C 1 -substituted cycloalkyl, such as cyclopropyl, cyclobutyl, or cyclopentyl. 3-5 In one embodiment, carbocyclyl is a C cycloalkyl, such as cyclobutyl, cyclopentyl, or cyclohexyl. 4-6 It is cycloalkyl.

[0058] 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 suitable. 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 salts.

[0059] Pharmaceutically acceptable salts can be obtained by reacting a sufficiently basic compound, such as an amine, with a suitable acid that provides 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 made.

[0060] Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases may include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, or magnesium salts. Salts derived from organic bases include salts of primary, secondary, or tertiary amines, such as alkylamines, dialkylamines, trialkylamines, substituted alkylamines, di(substituted alkyl)amines, tri(substituted alkyl)amines, alkenylamines, dialkenylamines, trialkenylamines, substituted alkenylamines, di(substituted alkenyl)amines, tri(substituted alkenyl)amines, cycloalkylamines, di(cycloalkyl)amines, tri(cycloalkyl)amines, substituted cycloalkylamines, disubstituted cycloalkylamines, trisubstituted cycloalkylamines, cycloalkenylamines, di(cycloalkenyl)amines, tri(cycloalkenyl)amines, substituted cycloalkanes, ... The amines may include, but are not limited to, arylamines, disubstituted cycloalkenylamines, trisubstituted cycloalkenylamines, arylamines, diarylamines, triarylamines, heteroarylamines, diheteroarylamines, triheteroarylamines, heterocycloalkylamines, diheterocycloalkylamines, triheterocycloalkylamines, or mixed diamines and triamines in which 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. Also included are amines in which two or three of the substituents together with the amino nitrogen form a heterocycloalkyl or heteroaryl group. Non-limiting examples of amines may include isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, trimethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purine, piperazine, piperidine, morpholine, or N-ethylpiperidine, and the like.Other carboxylic acid derivatives may be useful, such as carboxylic acid amides, including carboxamides, lower alkyl carboxamides, or dialkyl carboxamides.

[0061] The compounds described herein or their pharmaceutically acceptable salts may contain one or more asymmetric centers in the molecule. According to the present disclosure, any structure in which the 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, as well as mixtures thereof (racemic mixtures or enantiomerically enriched mixtures). Methods for preparing such optically active forms are well known in the art (e.g., resolution of racemic forms by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using chiral stationary phases).

[0062] When a specific stereoisomer of a compound is described 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 relative to the combined weight of all stereoisomers.

[0063] When a specific enantiomer of a compound is described by name or structure, the stereochemical purity of the compound is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%. "Stereochemical purity" means the percent by weight of the desired enantiomer relative to the combined weight of all stereoisomers.

[0064] When the stereochemistry of a disclosed compound is named or described by structure, and the named or described structure encompasses multiple stereoisomers (e.g., as a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. Furthermore, the stereochemical purity of the named or described stereoisomer is to be understood to be at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%. Stereochemical purity is the weight percent of the desired stereoisomer encompassed by the name or structure relative to the total weight of all stereoisomers.

[0065] Where a disclosed compound is named or described by structure without indicating stereochemistry, and the compound has one chiral center, the name or structure should be understood to encompass one enantiomer of the compound in pure or substantially pure form, as well as mixtures thereof, including racemic mixtures of the compound and mixtures enriched in one enantiomer as compared to the corresponding optical isomer.

[0066] Where a disclosed compound is named or described by structure without indicating stereochemistry, for example, where the compound has at least two chiral centers, the name or structure should be understood to encompass one stereoisomer of the compound in pure or substantially pure form, as well as mixtures thereof, including mixtures of stereoisomers and mixtures of stereoisomers that are enriched in one or more stereoisomers relative to the other stereoisomer(s).

[0067] The disclosed compounds may exist in tautomeric forms and mixtures, and separate individual tautomers are contemplated. Additionally, some compounds may exhibit polymorphism.

[0068] In one embodiment, the compound of the invention or a pharmaceutically acceptable salt thereof includes deuterium.

[0069] 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.

[0070] The compounds described herein, or pharmaceutically acceptable salts thereof, can be used to decrease the activity of Btk or otherwise affect the properties and / or behavior of Btk, such as its stability, phosphorylation, kinase activity, interactions with other proteins, etc.

[0071] In some embodiments, the present invention provides methods for reducing Btk enzymatic activity. In some embodiments, such methods comprise 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.

[0072] One embodiment of the present invention includes a method of treating a disorder responsive to inhibition of Btk in a subject, comprising administering to the subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof.

[0073] In one embodiment, the present invention provides a method of treating autoimmune disorders, inflammatory disorders, and cancer in a subject in need thereof, comprising administering to the subject an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof.

[0074] The term "autoimmune disease" 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, type 1 diabetes, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, lupus erythematosus, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polymyositis, primary biliary cirrhosis, Sjogren's syndrome, temporal arteritis, and Wegener's granulomatosis. The term "inflammatory disorder" includes diseases or disorders involving acute or chronic inflammation, such as allergies, asthma, prostatitis, glomerulonephritis, pelvic inflammatory disease (PID), inflammatory bowel disease (IBD, e.g., Crohn's disease, ulcerative colitis), reperfusion injury, rheumatoid arthritis, transplant rejection, and vasculitis. In some embodiments, the present invention provides methods of treating rheumatoid arthritis or lupus. In some embodiments, the present invention provides methods of treating multiple sclerosis.

[0075] The term "cancer" includes diseases or disorders involving abnormal cell growth and / or proliferation, such as glioma, thyroid cancer, breast cancer, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer), gastric cancer, gastrointestinal stromal tumor, pancreatic cancer, bile duct cancer, ovarian cancer, endometrial cancer, prostate cancer, renal cell carcinoma, lymphoma (e.g., anaplastic large cell lymphoma), leukemia (e.g., acute myeloid leukemia, T-cell leukemia, chronic lymphocytic leukemia), multiple myeloma, malignant mesothelioma, malignant melanoma, and colon cancer (e.g., microsatellite-high instability colorectal carcinoma). In some embodiments, the present invention provides methods of treating leukemia or lymphoma.

[0076] 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.

[0077] 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; alleviating or ameliorating clinical symptoms or indicators associated with a disorder; or delaying, inhibiting, or reducing the likelihood of progression of a disease, disorder, or syndrome.

[0078] The effective dose of a compound provided herein, or a pharmaceutically acceptable salt thereof, administered to a subject can be from 10 μg to 500 mg.

[0079] Administering a compound described herein or a pharmaceutically acceptable salt thereof to a mammal includes any suitable delivery method. Administering a compound described herein or a pharmaceutically acceptable salt thereof to a mammal includes topical, enteral, parenteral, transdermal, transmucosal, inhalation, intracisternal, epidural, intravaginal, intravenous, intramuscular, subcutaneous, intradermal, or intravitreal administration of the compound described herein or a pharmaceutically acceptable salt thereof to a mammal. Administering a compound described herein or a pharmaceutically acceptable salt thereof to a mammal also includes topical, enteral, parenteral, transdermal, transmucosal, inhalation, intracisternal, epidural, intravaginal, intravenous, intramuscular, subcutaneous, intradermal, or intravitreal administration of a compound that is metabolized to a compound described herein or a pharmaceutically acceptable salt thereof on or within the body of the mammal to a mammal.

[0080] Thus, the compounds described herein or their pharmaceutically acceptable salts can be administered systemically, e.g., orally, in combination with a pharmaceutically acceptable vehicle, such as an inert diluent or an assimilable edible carrier. They can be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or ingested directly with the patient's diet. For oral therapeutic administration, the compounds described herein or their pharmaceutically acceptable salts can be mixed with one or more excipients and used in the form of orally ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and 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 can be such that an effective dosage level will be obtained.

[0081] The tablets, troches, pills, capsules, etc. may contain the following: a binder such as tragacanth, acacia, cornstarch, or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as cornstarch, potato starch, or alginic acid; a lubricant such as magnesium stearate; or a sweetening or flavoring agent such as sucrose, fructose, lactose, or aspartame.

[0082] The active compound can 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.

[0083] Exemplary pharmaceutical dosage forms for injection or infusion may 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 must be sterile, fluid, and stable under the conditions of manufacture and storage.

[0084] Sterile injectable solutions can be prepared by blending the required amount of active compound in a suitable solvent with various other ingredients as listed above, as needed, followed by filtration sterilization. In the case of sterile powders for preparing sterile injectable solutions, the preferred preparation method can be vacuum drying and freeze-drying techniques, which can yield a powder of the active ingredient and any additional desired ingredients present in a previously sterile-filtered solution.

[0085] Exemplary solid carriers may include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, etc. Useful liquid carriers include water, alcohols, or glycols, or water-alcohol / glycol mixtures, in which a compound described herein or a pharmaceutically acceptable salt thereof can be dissolved or dispersed at effective levels, optionally with the use of a non-toxic surfactant.

[0086] 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).

[0087] The amount of a compound described herein or a pharmaceutically acceptable salt thereof required for therapeutic use may vary depending on the particular salt selected, as well as the route of administration, the nature of the condition being treated, and the age and condition of the patient, and is ultimately at the discretion of the attending physician or clinician. Generally, however, dosages may be in the range of about 0.1 to about 10 mg / kg body weight per day.

[0088] 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, a dose of 5 mg / kg or less may be suitable.

[0089] For convenience, the desired dose may be presented in a single dose or in divided doses administered at appropriate intervals.

[0090] The disclosed methods may include a kit comprising a compound described herein or a pharmaceutically acceptable salt thereof and instructions that can describe the administration of the compound described herein or a pharmaceutically acceptable salt thereof, or a composition comprising the compound described herein or a pharmaceutically acceptable salt thereof, to a cell or a subject. This should be construed to include other embodiments of the kit known to those skilled in the art, such as a kit that includes a solvent (e.g., sterile) for dissolving or suspending the compound described herein or a pharmaceutically acceptable salt thereof or composition before administering the compound described herein or a pharmaceutically acceptable salt thereof or composition to a cell or a subject. In some embodiments, the subject may be a human.

[0091] Example LCMS Method: Samples were analyzed on a Waters Acquity UPLC BEH C18 1.7 μM 2.1 x 50 mm column, part number 186002350, MS mode: ESI + scan range 100–1000 daltons, PDA detection 210–400 nm. The method used was a linear gradient from 95% H2O / 5% CH3CN (initial conditions) to 5% H2O / 95% CH3CN in 0.1% trifluoroacetic acid (0.1% v / v) at 0.7 mL / min, with a 1-minute hold at 5% H2O / 95% CH3CN. The injection volume was 0.5 μL.

[0092] Example 1: 3-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride (Compound 1) [ka] 1. Synthesis of (4-bromo-2-methylphenyl)methanamine [ka] To a solution of 4-bromo-2-methylbenzonitrile (3 g, 15 mmol) in THF (20 mL) was added BH3·THF (1 M, 45 mL, 45 mmol) at 0 °C. The solution was stirred for 1 h and heated to 80 °C for 2 h. The mixture was quenched with HO (50 mL) and extracted with EtOAc (50 mL × 3). The organic layer was concentrated in vacuo to give a residue, which was suspended in saturated HCl / EtOAc solution and filtered. The filter cake was washed with diethyl ether (20 mL × 3) and dried under vacuum to give (4-bromo-2-methylphenyl)methanamine hydrochloride as a white solid (2.1 g, yield: 69%). ESI-MS (M+H) + : 200.1.

[0093] Synthesis of tert-butyl 2,4-bromo-2-methylbenzylcarbamate [ka] To a solution of (4-bromo-2-methylphenyl)methanamine (1.2 g, 6 mmol) in DCM (30 mL) was added EtN (1.82 g, 18 mmol) and BocO (1.43 g, 6.6 mmol). The mixture was stirred at room temperature for 1 h, diluted with water (50 mL), and extracted with DCM (50 mL x 2). The organic phase was washed with brine (50 mL), dried (NaSO), filtered, and concentrated in vacuo to give tert-butyl (4-bromo-2-methylbenzyl)carbamate as a white solid (1.7 g, 95% yield), which was carried forward without further purification. ESI-MS (M+H) + : 300.1.

[0094] 3. Synthesis of tert-butyl 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate [ka] To a solution of tert-butyl (4-bromo-2-methylbenzyl)carbamate (1.5 g, 5.0 mmol) in DMF (6 mL) was added bis(pinacolato)diboron (1.52 g, 6.0 mmol), KOAc (1.75 g, 18 mmol), and Pd(dppf)Cl₂·DCM (407 mg, 0.5 mmol) under nitrogen. The mixture was stirred at 100 °C for 2 h, cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried (NaSO), concentrated in vacuo, and purified by silica gel column chromatography (petroleum ether / EtOAc, 10:1) to give tert-butyl (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate as a white solid (1.2 g, yield: 69%). ESI-MS (M+H) + : 348.2. 1 H NMR (400 MHz, CDCl3) δ: 7.61-7.59 (m, 2H), 7.26 (s, 1H), 4.68 (br s, 1H), 4.33 (d, J= 5.6 Hz, 2H), 2.32 (s, 3H), 1.45 (s, 9H), 1.34 (s, 12H).

[0095] 4. Synthesis of N-(4-bromo-2-pyridyl)cyclopropanecarboxamide [ka] Pyridine (914 mg, 12 mmol, 933 μL) was added to a solution of 4-bromopyridin-2-amine (1.00 g, 6 mmol) in DCM (19 mL), and the reaction mixture was stirred at room temperature for 5 minutes. Cyclopropanecarbonyl chloride (725 mg, 7 mmol, 631 μL) was added, and the solution was stirred for 2 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (EtOAc / heptane, gradient from 0% to 50%) to give N-(4-bromo-2-pyridyl)cyclopropane-carboxamide as a white solid (1.39 g, yield: 100%). ESI-MS (M+H) + : 243.0.

[0096] 5. Synthesis of tert-butyl N-[[4-[2-(cyclopropanecarbonylamino)-4-pyridyl]-2-methyl-phenyl]methyl]carbamate [ka] To a solution of tert-butyl N-[[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]carbamate (3.00 g, 8.6 mmol) in 1,4-dioxane / HO (v / v = 20 / 1, 210 mL) was added N-(4-bromo-2-pyridyl)cyclopropanecarboxamide (2.1 g, 8.6 mmol), Pd(dppf)Cl·DCM (353 mg, 432 μmol), and KCO (2.4 g, 17.3 mmol). The mixture was heated to 85 °C and stirred at that temperature for 17 h. The mixture was concentrated to give a crude material, which was purified by silica gel column chromatography (petroleum ether / EtOAc, gradient from 10:1 to 2:1) to give tert-butyl N-[[4-[2-(cyclopropanecarbonylamino)-4-pyridyl]-2-methyl-phenyl]methyl]carbamate as a white solid (3.1 g, yield: 94%). ESI-MS (M+H) + : 382.4.

[0097] 6. Synthesis of N-[4-[4-(aminomethyl)-3-methyl-phenyl]-2-pyridyl]cyclopropanecarboxamide hydrochloride [ka] To a solution of tert-butyl N-[[4-[2-(cyclopropanecarbonylamino)-4-pyridyl]-2-methyl-phenyl]methyl]carbamate (3.1 g, 8.1 mmol) in DCM (150 mL) was added a solution of HCl in EtOAc (4.0 M, 60 mL). The mixture was stirred at 15 °C for 4 h. The reaction mixture was concentrated to give crude N-[4-[4-(aminomethyl)-3-methyl-phenyl]-2-pyridyl]cyclopropane-carboxamide hydrochloride (2.5 g, yield: 97%), which was carried forward without further purification. ESI-MS (M+H) + : 282.0.

[0098] 7. Synthesis of 3-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride (Compound 1) [ka] To a solution of N-(4-(4-(aminomethyl)-3-methylphenyl)pyridin-2-yl)cyclopropanecarboxamide hydrochloride (120 mg, 377 μmol) in a DCM / DMF (v / v = 25 / 1, 52 mL) mixture was added 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylic acid (77 mg, 453 μmol), HATU (172 mg, 453 μmol), and DIPEA (244 mg, 1.89 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was poured into HO (100 mL) and extracted with DCM (50 mL × 2). The combined organic layers were concentrated to give the crude material, which was purified by preparative HPLC (0.05% HCl / HO in CHCN / HO as mobile phase) to give 3-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride as a white solid (59 mg, yield: 36%). ESI-MS (M+H) + : 434.2. 1 H NMR (400 MHz, CD3OD) δ: 8.31 (d, J = 6.4 Hz, 1H), 7.79 (s, 1H), 7.77-7.74 (m, 1H), 7.70-7.64 (m, 2H), 7.52 (d, J = 8.0 Hz, 1H), 4.65 (s, 2H), 2.50 (s, 3H), 1.97-1.91 (m, 1H), 1.41 (s, 9H), 1.16-1.12 (m, 2H), 1.10-1.05 (m, 2H).

[0099] Example 2: 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride (Compound 2) [ka] To a solution of N-[4-[4-(aminomethyl)-3-methyl-phenyl]-2-pyridyl]cyclopropane-carboxamide hydrochloride (1.30 g, 4.09 mmol) in a DCM / DMF (v / v = 30 / 1, 310 mL) mixture, 5-tert-butyl-1,2,4-oxadiazole-3-carboxylic acid (766 mg, 4.50 mmol), HATU (1.72 g, 4.50 mmol), and DIPEA (2.64 g, 20.5 mmol, 3.57 mL) were added. The reaction mixture was stirred at 15 °C for 2 h. The reaction mixture was poured into HO (400 mL) and extracted with DCM (150 mL × 3). The combined organic layers were concentrated to give the crude material, which was purified by silica gel column chromatography (petroleum ether / EtOAc, gradient from 4:1 to 1:1) to give the crude product (3.1 g, crude). The material was then purified by preparative HPLC (0.05% HCl / HO in CHCN / HO as mobile phase) to give 5-tert-butyl-N-[[4-[2-(cyclopropanecarbonyl-amino)-4-pyridyl]-2-methyl-phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide hydrochloride as a white solid (1.30 g, yield: 67%). ESI-MS (M+H) + : 434.1. 1 H NMR (400 MHz, CD3OD-d4) δ: 8.32 (d, J = 6.4 Hz, 1H), 7.87 (dd, J1= 6.8 Hz, J2= 1.6 Hz, 1H), 7.74-7.63 (m, 2H), 7.66 (d, J = 1.2 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 4.66 (s, 2H), 2.51 (s, 3H), 1.98-1.91 (m, 1H), 1.48 (s, 9H), 1.20-1.16 (m, 2H), 1.14-1.10 (m, 2H).

[0100] Examples 3 and 4: 5-(tert-butyl)-N-(4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamide)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide (Compound 3) and 5-(tert-butyl)-N-(4-(2-((1R,2R)-2-fluorocyclopropane-1-carboxamide)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide (Compound 4) [ka] 1. Synthesis of cis-2-fluorocyclopropane-1-carbonyl chloride [ka] Cis-2-fluorocyclopropane-1-carboxylic acid (200 mg, 1.92 mmol) was added to SOCl (3 mL) pre-cooled to 8 °C. The reaction mixture was then heated to 65 °C and stirred at that temperature for 3 h. The reaction mixture was cooled to room temperature and concentrated to give crude cis-2-fluorocyclopropane-1-carbonyl chloride as a colorless oil (220 mg, crude) which was carried forward without further purification.

[0101] 2. Synthesis of cis-N-(4-bromopyridin-2-yl)-2-fluorocyclopropane-1-carboxamide [ka] To a solution of 4-bromopyridin-2-amine (430 mg, 2.5 mol) and pyridine (395 mg, 5 mmol) in a mixture of DMF (1 mL) and DCM (20 mL) in an ice-water bath at 8 °C was added crude cis-2-fluorocyclopropane-1-carbonyl chloride (220 mg, crude). The reaction mixture was then heated to 40 °C and stirred at that temperature for 3 h. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by preparative HPLC (CHCN / HO containing 0.05% NHOH / HO as the mobile phase) to give cis-N-(4-bromopyridin-2-yl)-2-fluorocyclopropane-1-carboxamide as a white solid (145 mg, yield: 29% for two steps). 1 H NMR: (400 MHz, CDCl3) δ: 8.50 (s, 1H), 8.21 (br s, 1H), 8.08 (d, J = 6.0 Hz, 1H), 7.21 (d, J = 4.0 Hz, 1H), 1.97-1.89 (m, 1H), 1.83-1.79 (m, 1H), 1.28-1.23 (m, 2H).

[0102] 3. Synthesis of tert-butyl (4-(2-((cis-2-fluorocyclopropane-1-carboxamido)pyridin-4-yl)-2-methylbenzyl)carbamate [ka] The synthesis of tert-butyl (4-(2-((cis-2-fluorocyclopropane-1-carboxamido)pyridin-4-yl)-2-methylbenzyl)carbamate was carried out similarly to the synthesis of tert-butyl N-[[4-[2-(cyclopropanecarbonylamino)-4-pyridyl]-2-methyl-phenyl]methyl]carbamate in Example 1, Step 5. The crude material was purified by silica gel column chromatography (petroleum ether / EtOAc, gradient from 4:1 to 1:3) to afford tert-butyl (4-(2-((cis-2-fluorocyclopropane-1-carboxamido)pyridin-4-yl)-2-methylbenzyl)carbamate as a pale gray solid (145 mg, yield: 65%). 1H NMR (400 MHz, CDCl3) δ: 8.51 (s, 1H), 8.33-8.27 (m, 2H), 7.49 (s, 2H), 7.33 (s, 1H), 7.31 (s, 1H), 4.75 (br s, 1H), 4.35 (d, J = 5.2 Hz, 2H), 2.38 (s, 3H), 1.93-1.85 (m, 2H), 1.25-1.23 (m, 10H).

[0103] 4. Synthesis of cis-N-(4-(4-(aminomethyl)-3-methylphenyl)pyridin-2-yl)-2-fluorocyclopropane-1-carboxamide hydrochloride [ka] tert-Butyl (4-(2-((cis-2-fluorocyclopropane-1-carboxamide)pyridin-4-yl)-2-methylbenzyl)carbamate (145 mg, 0.36 mmol) was added to a solution of HCl in EtOAc (2 M, 8 mL) at 8° C. The reaction mixture was stirred at 8° C. for 2 h. The reaction mixture was concentrated in vacuo to give cis-N-(4-(4-(aminomethyl)-3-methylphenyl)pyridin-2-yl)-2-fluorocyclopropane-1-carboxamide hydrochloride as a grey solid (110 mg, yield: 91%). ESI-MS (M+H) + : 300.0.

[0104] 5. Synthesis of 5-(tert-butyl)-N-(4-(cis-2-fluorocyclopropane-1-carboxamido)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide [ka] To a solution of 5-tert-butyl-1,2,4-oxadiazole-3-carboxylic acid (200 mg, 0.85 mmol) in a mixture of DCM (35 mL) and DMF (500 μL) was added SOCl (450 mg, 3.78 mmol, 276 μL) at 20° C. The reaction mixture was stirred at 20° C. for 30 min and then concentrated in vacuo to give crude 5-tert-butyl-1,2,4-oxadiazole-3-carbonyl chloride. The crude material was dissolved in DCM (20 mL) and added to a solution of cis-N-(4-(4-(aminomethyl)-3-methylphenyl)pyridin-2-yl)-2-fluorocyclopropane-1-carboxamide hydrochloride (110 mg, 0.33 mmol) and DIPEA (169 mg, 1.308 mmol) in a mixture of DCM (30 mL) and DMF (2 mL) at 10° C. The reaction mixture was stirred at 10° C. for 2 h. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (10 mM NHOH / HO in CHCN / HO as mobile phase) to give 5-(tert-butyl)-N-(4-(cis-2-fluorocyclopropane-1-carboxamide)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid (40 mg, yield: 27%). 1 H NMR (400 MHz, CD3OD) δ: 8.37 (s, 1H), 8.30 (d, J = 5.2 Hz, 1H), 7.57-7.51 (m, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.36 (dd, J1= 5.2 Hz, J1= 1.6 Hz, 1H), 4.97-4.77 (m, 1H), 4.63 (s, 2H), 2.45 (s, 3H), 2.12-2.10 (m, 1H), 1.84-1.76 (m, 1H), 1.47 (s, 9H), 1.23-1.19 (m, 1H).

[0105] 6. Chiral separation of 5-(tert-butyl)-N-(4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamide)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide (3) and 5-(tert-butyl)-N-(4-(2-((1R,2R)-2-fluorocyclopropane-1-carboxamide)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide (4) [ka] 5-(tert-butyl)-N-(4-(cis-2-fluorocyclopropane-1-carboxamide)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide (40.3 mg, 0.089 mmol, 1 equiv.) was purified by SFC (mobile phase: supercritical CO2 / EtOH (0.05% Et2NH); column: Chiralcel OD-3 150 × 4.6 mm ID, 3 μm; detection wavelength: 220 nm) to give (arbitrarily assigned) 5-(tert-butyl)-N-(4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamide)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid (R t = 0.691 min, 15 mg, yield: 37%) and 5-(tert-butyl)-N-(4-(2-((1R,2R)-2-fluorocyclopropane-1-carboxamide)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid (R t = 1.109 min, 13 mg, yield: 32%). (1S,2S): ESI-MS (M+Na) + : 474.1. 1H NMR (400 MHz, CD3OD) δ: 8.38 (s, 1H), 8.30 (d, J = 5.2 Hz, 1H), 7.57-7.53 (m, 2H), 7.42 (d, J = 7.6 Hz, 1H), 7.37 (dd, J1= 5.2 Hz, J1= 1.6 Hz, 1H), 4.97-4.77 (m, 1H), 4.64 (s, 2H), 2.46 (s, 3H), 2.14-2.12 (m, 1H), 1.83-1.76 (m, 1H), 1.48 (s, 9H), 1.23-1.19 (m, 1H). (1R,2R): ESI-MS (M+Na) + : 474.1. 1 H NMR (400 MHz, CD3OD) δ: 8.38 (s, 1H), 8.30 (d, J = 5.2 Hz, 1H), 7.57-7.53 (m, 2H), 7.42 (d, J = 7.6 Hz, 1H), 7.37 (dd, J1= 5.2 Hz, J1= 1.6 Hz, 1H), 4.97-4.77 (m, 1H), 4.64 (s, 2H), 2.46 (s, 3H), 2.14-2.12 (m, 1H), 1.83-1.76 (m, 1H), 1.48 (s, 9H), 1.23-1.19 (m, 1H).

[0106] Example 5: 5-(tert-butyl)-N-(2-methyl-4-(2-((1S,2S)-2-methylcyclopropane-1-carboxamide)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (Compound 5) [ka] 1. Synthesis of (1S,2S)-N-(4-bromo-2-pyridyl)-2-methyl-cyclopropanecarboxamide [ka] Oxalyl chloride (1.01 g, 7.98 mmol, 675 μL) was slowly added to a suspension of (1S,2S)-2-methylcyclopropanecarboxylic acid (799 mg, 7.98 mmol, 799 μL) in DCE (13 mL) at 0 °C, followed by the addition of two drops of DMF. The mixture was stirred for 2 h while warming to room temperature. Next, 4-bromopyridin-2-amine (1.15 g, 6.65 mmol) and EtN (2.02 g, 20 mmol, 2.77 mL) were added. The reaction mixture was heated to 80 °C and stirred at that temperature for 18 h. The reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with DCM (50 mL × 2). The combined organic extracts were washed with brine (75 mL), dried (NaSO), filtered, and concentrated. The crude material was purified by silica gel column chromatography (EtOAc / heptane, gradient from 0% to 50%) to give (1S,2S)-N-(4-bromo-2-pyridyl)-2-methyl-cyclopropanecarboxamide as a pale yellow oil (645 mg, yield: 38%). ESI-MS (M+H) + : 257.0.

[0107] 2. Synthesis of tert-butyl N-[[2-methyl-4-[2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4-pyridyl]phenyl]methyl]carbamate [ka] The synthesis of tert-butyl N-[[2-methyl-4-[2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4-pyridyl]phenyl]methyl]carbamate was carried out similarly to the synthesis of tert-butyl N-[[4-[2-(cyclopropanecarbonylamino)-4-pyridyl]-2-methyl-phenyl]methyl]carbamate in Example 1, Step 5. The crude material was purified by silica gel column chromatography ([3:1 EtOAc:EtOH] / heptane, gradient from 0% to 75%) to afford tert-butyl N-[[2-methyl-4-[2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4-pyridyl]phenyl]methyl]carbamate as a pale yellow solid (198 mg, yield: 87%). ESI-MS (M+H) + : 396.3.

[0108] 3. Synthesis of (1S,2S)-N-[4-[4-(aminomethyl)-3-methyl-phenyl]-2-pyridyl]-2-methyl-cyclopropanecarboxamide hydrochloride [ka] tert-Butyl N-[[2-methyl-4-[2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4-pyridyl]phenyl]methyl]carbamate (198 mg, 501 μmol) was dissolved in MeOH (1.74 mL) and placed in an ice-water bath. HCl solution (1.25 M in MeOH, 4.01 mL) was added dropwise over 2 minutes. After stirring at 0°C for 5 minutes, the ice-water bath was removed, and the reaction mixture was allowed to warm to room temperature and stirred at that temperature for 48 hours. The reaction was concentrated in vacuo to give (1S,2S)-N-[4-[4-(aminomethyl)-3-methyl-phenyl]-2-pyridyl]-2-methyl-cyclopropanecarboxamide hydrochloride as a yellow solid (168 mg, 91% yield), which was carried forward without further purification. ESI-MS (M+H) + : 296.2.

[0109] 4. Synthesis of 5-(tert-butyl)-N-(2-methyl-4-(2-((1S,2S)-2-methylcyclopropane-1-carboxamide)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (Compound 5) [ka] To a solution of (1S,2S)-N-[4-[4-(aminomethyl)-3-methyl-phenyl]-2-pyridyl]-2-methyl-cyclopropanecarboxamide hydrochloride (75 mg, 254 μmol) and sodium 5-tert-butyl-1,2,4-oxadiazole-3-carboxylate (51 mg, 267 μmol) in DMF (1.69 mL) was added DIPEA (164 mg, 1.27 mmol, 222 μL). The reaction mixture was cooled to 0 °C, and HATU (116 mg, 305 μmol) was added in one portion. The reaction mixture was allowed to warm to room temperature and continued stirring at that temperature for 18 h. The reaction mixture was diluted with EtOAc (20 mL) and washed sequentially with HO (20 mL × 2) and brine (50 mL). The organic phase was then dried (NaSO), filtered, and concentrated. The crude material was purified by silica gel column chromatography ([3:1 EtOAc:EtOH] / heptane, gradient 0% to 100%) to give 5-(tert-butyl)-N-(2-methyl-4-(2-((1S,2S)-2-methylcyclopropane-1-carboxamide)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide as an off-white solid (25 mg, yield: 22%). ESI-MS (M+H) + : 448.3. 1H NMR (500 MHz, DMSO-d6) δ: 10.78 (s, 1H), 9.45 (t, J = 5.80 Hz, 1H), 8.41-8.28 (m, 2H), 7.56-7.46 (m, 2H), 7.42-7.31 (m, 2H), 4.49 (d, J = 5.5 Hz, 2H), 2.40 (s, 3H), 1.79 (dt, J1= 8.1 Hz, J2= 4.2 Hz, 1H), 1.43 (s, 9H), 1.32-1.21 (m, 2H), 1.09 (d, J = 6.1 Hz, 3H), 1.06-1.00 (m, 1H), 0.70-0.64 (m, 1H).

[0110] Example 6: 5-(tert-butyl)-N-(2-methyl-4-(2-((1R,2R)-2-methylcyclopropane-1-carboxamido)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (Compound 6) [ka] 1. Synthesis of (1R,2R)-N-(4-bromo-2-pyridyl)-2-methyl-cyclopropanecarboxamide [ka] The synthesis of (1R,2R)-N-(4-bromo-2-pyridyl)-2-methyl-cyclopropanecarboxamide was carried out similarly to the synthesis of (1S,2S)-N-(4-bromo-2-pyridyl)-2-methyl-cyclopropanecarboxamide in Example 5, Step 1. The crude material was purified by silica gel column chromatography (EtOAc / heptane, gradient from 0% to 50%) to give (1R,2R)-N-(4-bromo-2-pyridyl)-2-methyl-cyclopropanecarboxamide as a pale yellow oil (73 mg, yield: 34%). ESI-MS (M+H) + : 257.0.

[0111] 2. Synthesis of tert-butyl N-[[2-methyl-4-[2-[[(1R,2R)-2-methylcyclopropanecarbonyl]amino]-4-pyridyl]phenyl]methyl]carbamate [ka] The synthesis of tert-butyl N-[[2-methyl-4-[2-[[(1R,2R)-2-methylcyclopropanecarbonyl]amino]-4-pyridyl]phenyl]methyl]carbamate was carried out similarly to the synthesis of tert-butyl N-[[2-methyl-4-[2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4-pyridyl]phenyl]methyl]carbamate in Example 5, Step 2. The crude material was purified by silica gel column chromatography (EtOAc / heptane, gradient from 0% to 50%) to afford tert-butyl N-[[2-methyl-4-[2-[[(1R,2R)-2-methylcyclopropanecarbonyl]amino]-4-pyridyl]phenyl]methyl]carbamate as a pale yellow solid (100 mg, yield: 88%). ESI-MS (M+H) + : 396.2.

[0112] 3. Synthesis of (1R,2R)-N-[4-[4-(aminomethyl)-3-methyl-phenyl]-2-pyridyl]-2-methyl-cyclopropanecarboxamide hydrochloride [ka] The synthesis of (1R,2R)-N-[4-[4-(aminomethyl)-3-methyl-phenyl]-2-pyridyl]-2-methyl-cyclopropanecarboxamide hydrochloride was carried out similarly to the synthesis of (1S,2S)-N-[4-[4-(aminomethyl)-3-methyl-phenyl]-2-pyridyl]-2-methyl-cyclopropanecarboxamide hydrochloride in Example 5, Step 3. The reaction mixture was concentrated in vacuo to give (1R,2R)-N-[4-[4-(aminomethyl)-3-methyl-phenyl]-2-pyridyl]-2-methyl-cyclopropanecarboxamide hydrochloride as a white solid (80 mg, yield: 95%), which was carried forward without further purification. ESI-MS (M+H)+ : 296.1.

[0113] 4. Synthesis of 5-(tert-butyl)-N-(2-methyl-4-(2-((1R,2R)-2-methylcyclopropane-1-carboxamido)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (Compound 6) [ka] To a solution of (1R,2R)-N-[4-[4-(aminomethyl)-3-methyl-phenyl]-2-pyridyl]-2-methyl-cyclopropanecarboxamide hydrochloride (40 mg, 121 μmol) and sodium 5-tert-butyl-1,2,4-oxadiazole-3-carboxylate (23 mg, 121 μmol) in DMF (1.21 mL) was added DIPEA (47 mg, 362 μmol, 63 μL). After cooling the reaction mixture to 0 °C, T3P (153 mg, 241 μmol, 163 μL, 50% purity) was added in one portion. The reaction mixture was warmed to room temperature and stirred at that temperature for 18 h. The reaction mixture was diluted with EtOAc (20 mL) and washed sequentially with HO (20 mL × 2) and brine (50 mL). The organic phase was then dried (Na2SO4), filtered, and concentrated. The crude material was purified by silica gel column chromatography ([3:1 EtOAc:EtOH] / heptane, gradient 0% to 100%) to give 5-(tert-butyl)-N-(2-methyl-4-(2-((1R,2R)-2-methylcyclopropane-1-carboxamide)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide as an off-white solid (32 mg, yield: 59%). ESI-MS (M+H) + : 448.2. 1H NMR (500 MHz, DMSO-d6) δ: 10.78 (s, 1H), 9.45 (t, J = 5.8 Hz, 1H), 8.38-8.31 (m, 2H), 7.55-7.47 (m, 2H), 7.41-7.32 (m, 2H), 4.49 (d, J = 6.1 Hz, 2H), 2.40 (s, 3H), 1.79 (dt, J1= 8.1 Hz, J2= 4.2 Hz, 1H), 1.43 (s, 9H), 1.31-1.22 (m, 1H), 1.09 (d, J = 5.5 Hz, 3H), 1.06-1.01 (m, 1H), 0.71-0.62 (m, 1H).

[0114] Example 7: 5-(tert-butyl)-N-(4-(5-chloro-2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide (Compound 7) [ka] 1. Synthesis of tert-butyl (4-(2,5-dichloropyridin-4-yl)-2-methylbenzyl)carbamate [ka] A solution of tert-butyl (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (400 mg, 1.15 mmol), 2,5-dichloro-4-iodopyridine (316 mg, 1.15 mmol), KOAc (226 mg, 2.30 mmol), and Pd(dppf)Cl·DCM (50 mg, 0.12 mmol) in 1,4-dioxane / HO (5:1, 12 mL) was stirred at 90 °C for 12 h under N. The reaction mixture was cooled to room temperature and filtered. The filtrate was dissolved in EtOAc (50 mL) and washed with water (10 mL × 3). The organic phase was dried (NaSO), filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc, 10:1) to give tert-butyl (4-(2,5-dichloropyridin-4-yl)-2-methylbenzyl)carbamate as a colorless oil (350 mg, yield: 83%). ESI-MS (M+H) + : 367.0.

[0115] 2. Synthesis of tert-butyl (4-(5-chloro-2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)carbamate [ka] A solution of tert-butyl (4-(2,5-dichloropyridin-4-yl)-2-methylbenzyl)carbamate (350 mg, 953 μmol), cyclopropanecarboxamide (162 mg, 1.91 mmol), Pd(dba) (50 mg, catalytic), Xantphos (30 mg, catalytic), and CsCO (621 mg, 1.91 mmol) in 1,4-dioxane (10 mL) was stirred at 90 °C for 12 h under N. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (petroleum ether / EtOAc, gradient from 10:1 to 5:1) to give tert-butyl (4-(5-chloro-2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)carbamate as a colorless oil (300 mg, yield: 76%). ESI-MS (M+H)+ : 416.1.

[0116] 3. Synthesis of N-(4-(4-(aminomethyl)-3-methylphenyl)-5-chloropyridin-2-yl)cyclopropanecarboxamide hydrochloride [ka] A solution of tert-butyl (4-(5-chloro-2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)carbamate (300 mg, 721 μmol) in HCl / EtOAc (4 M, 10 mL) was stirred at 15° C. for 2 hours. The reaction mixture was concentrated in vacuo to give crude N-(4-(4-(aminomethyl)-3-methylphenyl)-5-chloropyridin-2-yl)cyclopropanecarboxamide hydrochloride as a white solid (254 mg, 100% yield), which was carried forward without further purification. ESI-MS (M+H) + : 315.9.

[0117] 4. Synthesis of 5-(tert-butyl)-N-(4-(5-chloro-2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide (Compound 7) [ka] A mixture of N-(4-(4-(aminomethyl)-3-methylphenyl)-5-chloropyridin-2-yl)cyclopropanecarboxamide hydrochloride (250 mg, 0.71 mmol), 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylic acid (242 mg, 1.42 mmol), HATU (424 mg, 1.42 mmol), and DIPEA (183 mg, 1.42 mmol) in DCM (10 mL) was stirred at 15 °C for 2 h. The reaction mixture was diluted with additional DCM (50 mL) and washed with HO (10 mL × 3). The combined organic extracts were dried (NaSO), filtered, and concentrated in vacuo. The crude material was purified by preparative HPLC (10 mM NHOH / HO in CHCN / HO as mobile phase) to give 5-(tert-butyl)-N-(4-(5-chloro-2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid (100 mg, yield: 30%). ESI-MS (M+Na) + : 490.1. 1 H NMR (400 MHz, CDCl3) δ: 8.36 (s, 1H), 8.15 (s, 1H), 7.44-7.42 (m, 1H), 7.35-7.29 (m, 2H), 4.67 (s, 2H), 2.46 (s, 3H), 1.92-1.89 (m, 1H), 1.51 (s, 9H), 1.00-0.98 (m, 2H), 0.93-0.91(m, 2H).

[0118] Example 8: 5-(tert-butyl)-N-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (Compound 8) [ka] 1. Synthesis of (4-bromo-2-chlorophenyl)methanamine [ka] To a solution of 4-bromo-2-chlorobenzonitrile (3.2 g, 15 mmol) in THF (20 mL) was added BH3·THF (45 mL, 45 mmol) at 0 °C. The solution was stirred at 0 °C for 1 h and heated to 80 °C for 2 h. The mixture was quenched with HO and extracted with EtOAc (50 mL × 3). The organic layer was collected and concentrated in vacuo. The residue was stirred with saturated HCl / EtOAc solution and filtered. The filter cake was rinsed with ether (20 mL) and dried under vacuum to give (4-bromo-2-chlorophenyl)methanamine as a white solid (2.3 g, yield: 70%). ESI-MS (M+H) + : 220.1.

[0119] 2. Synthesis of tert-butyl (4-bromo-2-chlorobenzyl)carbamate [ka] To a solution of (4-bromo-2-chlorophenyl)methanamine (1.3 g, 6 mmol) in DCM (30 mL) were added EtN (1.82 g, 18 mmol) and BocO (1.43 g, 6.6 mmol). The mixture was stirred at room temperature for 1 h. After dilution with water (50 mL), the mixture was extracted with DCM (50 mL × 2). The combined organic extracts were washed with brine (50 mL), dried (NaSO), filtered, and concentrated to give crude tert-butyl (4-bromo-2-chlorobenzyl)carbamate as a white solid (1.5 g, yield: 80%), which was used directly in the next step without further purification. ESI-MS (M+H): 320.1.

[0120] 3. Synthesis of tert-butyl (2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate [ka] To a solution of tert-butyl (4-bromo-2-chlorobenzyl)carbamate (1.6 g, 5.0 mmol) in dry DMF (6 mL), bis(pinacolato)diboron (1.52 g, 6.0 mmol), KOAc (1.75 g, 18 mmol), and Pd(dppf)Cl₂·DCM (407 mg, 0.5 mmol) were added under N₂. The mixture was stirred at 100 °C for 2 h. After cooling to room temperature, the mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL × 3). The combined organic extracts were washed with brine (200 mL), dried, concentrated, and purified by silica gel column chromatography (petroleum ether / EtOAc, 10:1) to give tert-butyl (2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate as a white solid (1.1 g, 60% yield). ESI-MS (2M+Na) + : 757.2. 1 H NMR (400 MHz, CDCl3) δ: 7.78 (s, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 5.01 (br s, 1H), 4.41 (d, J = 6.4 Hz, 2H), 1.44 (s, 9H), 1.35 (s, 12H).

[0121] 4. Synthesis of tert-butyl (2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)benzyl)carbamate [ka] The synthesis of tert-butyl (2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)benzyl)carbamate was carried out similarly to the synthesis of tert-butyl N-[[4-[2-(cyclopropanecarbonylamino)-4-pyridyl]-2-methyl-phenyl]methyl]carbamate in Example 1, Step 5. The crude material was purified by silica gel column chromatography (petroleum ether / EtOAc, gradient from 3:1 to 1:1) to give tert-butyl (2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)benzyl)carbamate as a yellow oil (300 mg, yield: 91%). ESI-MS (M+H) + : 402.1. 1 H NMR (400 MHz, CD3OD) δ: 8.37-8.35 (m, 2H), 7.75 (d, J = 1.6 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.37 (dd, J1= 5.2, Hz, J2= 1.2 Hz, 1H), 4.39 (d, J = 4.4 Hz, 2H), 1.96-1.87 (m, 1H), 1.49 (s, 9H), 1.06-0.99 (m, 2H), 0.97-0.91 (m, 2H).

[0122] 5. Synthesis of N-(4-(4-(aminomethyl)-3-chlorophenyl)pyridin-2-yl)cyclopropanecarboxamide hydrochloride [ka] To a solution of tert-butyl (2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)benzyl)carbamate (300 mg, 0.75 mmol) in EtOAc (1 mL) was added HCl / EtOAc solution (1 M, 10 mL) at 20° C. The reaction mixture was kept stirring at that temperature for 17 h. The reaction mixture was filtered and the filter cake was dried to give N-(4-(4-(aminomethyl)-3-chlorophenyl)pyridin-2-yl)cyclopropanecarboxamide hydrochloride as a yellow solid (200 mg, yield: 79%), which was carried forward without further purification. ESI-MS (M+H) + : 301.9.

[0123] 6. Synthesis of 5-(tert-butyl)-N-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (Compound 8) [ka] To a solution of N-(4-(4-(aminomethyl)-3-chlorophenyl)pyridin-2-yl)cyclopropanecarboxamide hydrochloride (150 mg, 0.44 mmol) in DMF (5 mL) at 15° C., DIPEA (115 mg, 0.89 mmol), 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylic acid (151 mg, 0.89 mmol), and HATU (338 mg, 0.89 mmol) were added. The reaction mixture was stirred at that temperature for 1 hour. The mixture was filtered, and the filtrate was concentrated. The crude material was purified by preparative HPLC (10 mM NHOH / HO in CHCN / HO as mobile phase) to give 5-(tert-butyl)-N-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid (125 mg, yield: 63%). ESI-MS (M+H) + : 454.0. 1H NMR (400 MHz, DMSO-d6) δ: 10.92 (s, 1H), 9.54 (t, J = 5.6 Hz, 1H), 8.37-8.36 (m, 2H), 7.76 (d, J = 1.6 Hz, 1H), 7.66 (dd, J1= 8.0 Hz, J2= 1.6 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.41 (dd, J1= 4.8 Hz, J2= 1.2 Hz, 1H), 4.56 (d, J = 6.0 Hz, 2H), 2.05-1.99 (m, 1H), 1.42 (s, 9H), 0.82-0.78 (m, 4H).

[0124] Example 9: 3-(tert-butyl)-N-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (Compound 9) [ka] To a solution of N-(4-(4-(aminomethyl)-3-chlorophenyl)pyridin-2-yl)cyclopropanecarboxamide hydrochloride (80 mg, 0.24 mmol) in DMF (1 mL) and DCM (20 mL) was added EtN (49 mg, 0.48 mmol), 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylic acid (40 mg, 0.24 mmol), and HATU (90 mg, 0.24 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was washed with HO (15 mL), and the organic phase was dried (NaSO), filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (0.05% HCl / HO in CHCN / HO as mobile phase) to give 3-(tert-butyl)-N-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide as an off-white solid (44 mg, yield: 41%). ESI-MS (M+Na) + : 476.1. 1H NMR: (400 MHz, CD3OD) δ: 8.35 (s, 1H), 7.99 (s, 1H), 7.88 (s, 1H), 7.74-7.71 (m, 1H), 7.61-7.59 (s, 2H), 4.73 (s, 2H), 1.92 (br s, 1H), 1.41 (s, 9H), 1.10-1.01 (m, 4H).

[0125] Example 10: (R)-5-(tert-butyl)-N-(8-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide (Compound 10) [ka] 1. Synthesis of 3-(3-bromo-benzylamino)-propionic acid ethyl ester [ka] To a solution of ethyl 3-aminopropanoate (46.0 g, 0.3 mol) and 3-bromobenzaldehyde (55.5 g, 0.3 mol) in MeOH (1.2 L), EtN (60.7 g, 0.6 mol) and NaCNBH (56.5 g, 0.9 mol) were added portionwise. The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo, and the residue was diluted with water (600 mL). The mixture was extracted with EtOAc (500 mL × 3). The combined organic layers were washed with brine (100 mL), dried (NaSO), filtered, and concentrated in vacuo to give 3-(3-bromo-benzylamino)-propionic acid ethyl ester as a pale yellow oil (46.5 g, 54% yield). 1H NMR (300 MHz, DMSO-d6,): δ 7.52 (s, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.31-7.25 (m, 2H), 4.04 (q, J = 7.2 Hz, 2H), 3.67 (s, 2H), 2.69 (t, J = 7.2 Hz, 2H), 2.42 (t, J = 6.9 Hz, 2H), 1.17 (t, J = 6.9 Hz, 3H).

[0126] 2. Synthesis of 3-[(3-bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionic acid ethyl ester [ka] To a solution of 3-(3-bromo-benzylamino)-propionic acid ethyl ester (45.6 g, 0.16 mol) in pyridine (500 mL) was added TosCl (61.0 g, 0.32 mol) at room temperature. The reaction mixture was stirred at 120° C. for 16 hours. The solvent was removed in vacuo to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc, gradient from 10:1 to 5:1) to give 3-[(3-bromo-benzyl)-(toluene-4-sulfonyl)-amino]propionic acid ethyl ester as a pale yellow oil (61 g, yield: 88%). 1 H NMR (300 MHz, DMSO-d6): δ 7.74 (d, J = 8.4 Hz, 2H), 7.49-7.41 (m, 4H), 7.31 (d, J = 5.1 Hz, 2H), 4.33 (s, 2H), 3.93 (q, J = 7.2 Hz, 2H), 3.32 (t, J = 7.2 Hz, 2H), 2.41 (s, 3H), 2.36 (t, J = 6.9 Hz, 2H), 1.10 (t, J = 6.9 Hz, 3H).

[0127] 3. Synthesis of 3-[(3-bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionic acid [ka] To a solution of 3-[(3-bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionic acid ethyl ester (60.0 g, 0.14 mol) in a mixed solvent of EtOH (600 mL) and HO (60 mL), NaOH (11.2 g, 0.28 mol) was added portionwise. The reaction solution was then heated to 60 °C and stirred at that temperature for 4 h. The reaction solution was cooled to 0 °C and acidified to pH = 5 with concentrated HCl. The solvent was concentrated in vacuo to give a residue, which was extracted with EtOAc (150 mL × 3). The combined organic extracts were dried (NaSO), filtered, and concentrated in vacuo to give 3-[(3-bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionic acid as a white solid (45.2 g, yield: 79%). 1 H NMR (300 MHz, DMSO-d6): δ 12.28 (br, 1H), 7.74 (d, J = 8.1 Hz, 2H), 7.49-7.41 (m, 4H), 7.32 (d, J = 5.1 Hz, 2H), 4.33 (s, 2H), 3.29 (t, J = 6.9 Hz, 2H), 2.41 (s, 3H), 2.27 (t, J = 7.5 Hz, 2H).

[0128] 4. Synthesis of 3-[(3-bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionyl chloride [ka] To a solution of 3-[(3-bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionic acid (45.2 g, 0.11 mol) in DCM (1000 mL) was added DMF (1 mL) dropwise and oxalyl chloride (27.9 g, 0.22 mol) was added portionwise. The reaction solution was heated to 55° C. and stirred at that temperature for 2 hours. The mixture was concentrated in vacuo to give crude 3-[(3-bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionyl chloride as a black oil (47.2 g, 99% yield), which was used in the next step without further purification.

[0129] 5. Synthesis of 8-bromo-2-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-benzo[c]azepin-5-one [ka] To a solution of 3-[(3-bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionyl chloride (47.0 g, 0.11 mol) in anhydrous DCM (1200 mL) was added AlCl (29.3 g, 0.22 mol) portionwise at room temperature. The reaction mixture was heated to 55 °C and stirred at that temperature for 2 hours. The reaction mixture was poured into ice water (1.2 L) and extracted with DCM (500 mL). The organic layer was concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc, gradient from 5:1 to 2:1) to give 8-bromo-2-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-benzo[c]azepin-5-one as a white solid (35 g, yield: 81%). 1 H NMR (300 MHz, DMSO-d6): δ 7.65 (d, J = 8.4 Hz, 3H), 7.60-7.51 (m, 2H), 7.36 (d, J = 8.1 Hz, 2H), 4.68 (s, 2H), 3.42 (t, J = 9.2 Hz, 2H), 2.96 (t, J = 6.3 Hz, 2H), 2.37 (s, 3H).

[0130] 6. Synthesis of [8-bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl]-carbamic acid tert-butyl ester [ka] To a solution of 8-bromo-2-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-benzo[c]azepin-5-one (32.0 g, 0.08 mol) in EtOH (600 mL), NHOAc (18.5 g, 0.24 mol) and NaCNBH (14.9 g, 0.24 mol) were added portionwise at room temperature. The reaction mixture was then heated to 95 °C and stirred at that temperature for 16 h. The mixture was poured into ice water (500 mL), and the EtOH was removed in vacuo. The residue was extracted with DCM (500 mL × 3). The combined extracts were concentrated. The residue was redissolved in DCM (300 mL), and EtN (12.2 g, 0.12 mol) and BocO (34.6 g, 0.12 mol) were added at room temperature. The mixture was stirred at room temperature for 4 h and then concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc, gradient from 8:1 to 2:1) to give [8-bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl]-carbamic acid tert-butyl ester as a white solid (16.7 g, yield: 42%). 1 H NMR (300 MHz, DMSO-d6): δ 7.62-7.51 (m, 2H), 7.47 (d, J = 9.9 Hz, 1H), 7.41-7.34 (m, 3H), 7.10 (d, J = 8.4 Hz, 1H), 4.81-4.74 (m, 1H), 4.53 (d, J = 15.0 Hz, 1H), 4.28 (d, J = 15.3 Hz, 1H), 3.64-3.57 (m, 1H), 3.41-3.30 (m, 1H), 2.35 (s, 3H), 1.85-1.77 (m, 1H), 1.69-1.63 (m, 1H), 1.36 (s, 9H).

[0131] 7. Synthesis of 8-bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-ylamine [ka] A solution of [8-bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl]-carbamic acid tert-butyl ester (14.8 g, 0.03 mol) in HCl / EtOAc (150 mL) was stirred at 25 °C for 4 h. The resulting solid was filtered and washed with MeOH and EtO to give the product, 8-bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-ylamine, as a white solid (10.5 g, 89% yield). ESI-MS (M+H) + : 395.0 / 397.0. 1 H NMR (300 MHz, DMSO-d6): δ 8.79 (br s, 3H), 7.64-7.58 (m, 3H), 7.53 (s, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 1H), 4.71-4.61 (m, 2H), 4.31 (d, J = 15.3 Hz, 1H), 3.82 (d, J = 18.3 Hz, 1H), 2.38 (s, 3H), 2.14-2.07 (m, 1H), 1.77-1.71 (m, 1H).

[0132] 8. Synthesis of 8-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-amine [ka] A solution of 8-bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-ylamine (2.00 g, 5.06 mmol) in HBr (33% in acetic acid, 20 mL) was heated to 50° C. and stirred at that temperature for 12 hours. After cooling to room temperature, the mixture was diluted with EtOAc (50 mL). The white solid was collected by filtration and dried under vacuum to give the crude product 8-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-amine (1.66 g, 82% yield), which was used directly in the next step. ESI-MS (M+H) + : 241.1. 1H NMR (400 MHz, CD3OD) δ: 7.72-7.55 (m, 2H), 7.18 (d, J = 8.4 Hz, 1H), 4.99-4.98 (m, 1H), 4.51 (d, J = 14.4 Hz, 1H), 4.39 (d, J = 14.4 Hz, 1H), 3.62-3.49 (m, 2H), 2.38-2.24 (m, 1H), 2.16-2.00 (m, 1H).

[0133] 9. Synthesis of tert-butyl 5-amino-8-bromo-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate [ka] To a solution of 8-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-amine (640 mg, 1.6 mmol) and EtN (490 mg, 4.8 mmol) in DCM (20 mL) was added BocO (314 mg, 1.4 mmol). The mixture was stirred at room temperature for 1 hour. After dilution with DCM (100 mL), the mixture was washed with brine (20 mL x 2). The organic phase was concentrated in vacuo, and the residue was purified by preparative HPLC (CHCN / H2O containing 0.05% NH4OH / H2O as the mobile phase) to give tert-butyl 5-amino-8-bromo-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate as a colorless oil (364 mg, 67% yield). ESI-MS (M+H) analysis. + : 341.1.

[0134] 10. Synthesis of tert-butyl (5R)-8-bromo-5-(((4-oxidodinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin-4-yl)oxy)amino)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate [ka] To tert-butyl 5-amino-8-bromo-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate (23.5 g, 69.1 mmol) was added MeOH (141 mL, 6 volumes) and (S)-(-)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (24.0 g, 69.1 mmol). The mixture was stirred at 25 °C for 30 minutes, forming a yellow paste-like slurry. The slurry was then heated to reflux (approximately 70 °C) and stirred at that temperature until the solids dissolved and a yellow solution was obtained. The mixture was then concentrated to dryness on a rotary evaporator to give the racemic product (50.4 g). IPAc (100 mL, 2 volumes) was added, and the mixture was heated at 70 °C for 3 hours before being cooled to room temperature. Additional IPAc (100 mL, 2 volumes) was added, and the mixture was continued to stir at 25 °C for 16 hours. The slurry was filtered using a centrifuge, and the cake was washed three times with seven volumes of IPAc. The wet cake was dried briefly to give the product as a white solid with 91.3% ee. IPAc (350 mL, 7 volumes) was added, and the mixture was heated at 70°C for 3 hours, then cooled to 25°C and stirred for an additional 16 hours. The thick slurry was filtered using a centrifuge, and the cake was washed three times with 10 volumes (500 mL) of IPAc. The cake was then dried under vacuum at 80°C for 36 hours to give tert-butyl (5R)-8-bromo-5-(((4-oxidodinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin-4-yl)oxy)amino)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate as a white solid (40.5g, 97.2% ee, 85% yield). ESI-MS (M+H) + : 340.9.

[0135] 11. Synthesis of tert-butyl (5R)-5-amino-8-bromo-1,3,4,5-tetrahydro-2-benzazepine-2-carboxylate [ka] tert-Butyl (5R)-8-bromo-5-(((4-oxidodinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin-4-yl)oxy)amino)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate (40.5 g, 58.7 mmol) was suspended in 500 mL of EtOAc, and aqueous NaOH (2 N, 500 mL) was added. The biphasic suspension / mixture was transferred to a 2 L separatory funnel and vigorously shaken. As the previous insoluble salt dissolved in the biphasic mixture, another white solid began to elute from solution. The entire biphasic mixture was filtered to remove the white solid. The insoluble solid was rinsed with additional EtOAc and 2 M NaOH solution. After this initial filtration, the phases were separated, and the aqueous phase was extracted with two additional portions of EtOAc (500 mL each). The organic phases were combined and concentrated. The residue was dissolved in dichloromethane (500 mL) and transferred to a 2 L separatory funnel. Aqueous NaOH (1 M, 500 mL) was added and the layers were vigorously shaken. The entire biphasic suspension was filtered through a Celite® pad. After filtration, the layers were separated and the aqueous phase was extracted with two additional portions of DCM (500 mL × 2). The organic layers were combined, washed with brine (1000 mL), dried (NaSO), filtered, and concentrated in vacuo to give tert-butyl (5R)-8-bromo-5-[(5-tert-butyl-1,2,4-oxadiazole-3-carbonyl)amino]-1,3,4,5-tetrahydro-2-benzazepine-2-carboxylate as a yellow oil (20.0 g, 100% yield). ESI-MS (M+H) + : 340.9. 1 H NMR (400 MHz, CD3OD) δ: 7.44-7.31 (m, 3H), 4.33-4.23 (m, 2H), 4.01 (br dd, J1= 9.3 Hz, J2= 3.3 Hz, 1H), 3.96-3.86 (m, 1H), 3.62-3.40 (m, 1H), 2.00-1.86 (m, 1H), 1.75-1.60 (m, 1H), 1.41-1.36 (m, 9H).

[0136] 12. Synthesis of tert-butyl (5R)-8-bromo-5-[(5-tert-butyl-1,2,4-oxadiazole-3-carbonyl)amino]-1,3,4,5-tetrahydro-2-benzazepine-2-carboxylate [ka] To a solution of 5-tert-butyl-1,2,4-oxadiazole-3-carboxylic acid (2.99 g, 17.6 mmol) in THF (60 mL) in an ice-water bath, EtN (4.45 g, 44.0 mmol, 6.09 mL) and HATU (8.64 g, 22.0 mmol) were added. The reaction mixture was stirred at 0 °C for 10 minutes, and then tert-butyl (5R)-5-amino-8-bromo-1,3,4,5-tetrahydro-2-benzazepine-2-carboxylate (5.00 g, 14.7 mmol) was added. The reaction mixture was warmed to 23 °C and stirred at room temperature for 2 hours. Water (100 mL) was added to quench the reaction. EtOAc (100 mL) was added, and the layers were separated. The aqueous phase was extracted with EtOAc (100 mL × 2). The organic phases were combined, washed with brine (150 mL), dried (NaSO), filtered, and concentrated. The crude material was purified by silica gel column chromatography (EtOAc / heptane, 5% to 100% gradient) to give tert-butyl (5R)-8-bromo-5-[(5-tert-butyl-1,2,4-oxadiazole-3-carbonyl)amino]-1,3,4,5-tetrahydro-2-benzazepine-2-carboxylate as a white foam (6.84 g, 95% yield). ESI-MS (Mt-Bu) + : 439.1.

[0137] 13. Synthesis of N-[(5R)-8-bromo-2,3,4,5-tetrahydro-1H-2-benzazepin-5-yl]-5-tert-butyl-1,2,4-oxadiazole-3-carboxamide hydrochloride [ka] To a solution of tert-butyl (5R)-8-bromo-5-[(5-tert-butyl-1,2,4-oxadiazole-3-carbonyl)amino]-1,3,4,5-tetrahydro-2-benzazepine-2-carboxylate (1.50 g, 3.04 mmol) in MeOH (12 mL) was added HCl (1.25 M in MeOH, 12 mL). The reaction mixture was stirred at ambient temperature for 5 days. The reaction mixture was concentrated in vacuo to give crude N-[(5R)-8-bromo-2,3,4,5-tetrahydro-1H-2-benzazepin-5-yl]-5-tert-butyl-1,2,4-oxadiazole-3-carboxamide hydrochloride as a white solid (1.29 g, 99% yield), which was carried forward without further purification. ESI-MS (M+H) + : 395.1.

[0138] 14. Synthesis of N-[(5R)-8-bromo-2-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2-benzazepin-5-yl]-5-tert-butyl-1,2,4-oxadiazole-3-carboxamide [ka] To a mixture of N-[(5R)-8-bromo-2,3,4,5-tetrahydro-1H-2-benzazepin-5-yl]-5-tert-butyl-1,2,4-oxadiazole-3-carboxamide hydrochloride (602 mg, 1.4 mmol) in acetonitrile (7 mL) was added KCO (580 mg, 4.2 mmol), followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (650 mg, 2.8 mmol, 404 μL) and EtN (213 mg, 2.1 mmol, 291 μL). The mixture was heated to 70 °C and stirred at that temperature for 4 h. The mixture was diluted with DCM (20 mL) and filtered. The filter residue was washed with DCM (50 mL), and the combined filtrates were concentrated in vacuo. The crude material was purified by silica gel column chromatography (EtOAc / heptane, gradient 0% to 100%) to give N-[(5R)-8-bromo-2-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2-benzazepin-5-yl]-5-tert-butyl-1,2,4-oxadiazole-3-carboxamide as an off-white solid (571 mg, yield: 86%). ESI-MS (M+H) + : 477.0.

[0139] 15. Synthesis of 5-tert-butyl-N-[(5R)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2-benzazepin-5-yl]-1,2,4-oxadiazole-3-carboxamide [ka] A solution of N-[(5R)-8-bromo-2-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2-benzazepin-5-yl]-5-tert-butyl-1,2,4-oxadiazole-3-carboxamide (570 mg, 1.2 mmol), KOAc (353 mg, 3.6 mmol), Pd(dppf)Cl·DCM (98 mg, 0.12 mmol), and bis(pinacolato)diboron (339 mg, 1.32 mmol) in 1,4-dioxane (12 mL) was heated to 100 °C and stirred at that temperature for 4 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL), and filtered through a pad of Celite®. The solid was washed with EtOAc (100 mL), and the combined filtrates were concentrated in vacuo. The crude material was purified by silica gel column chromatography (EtOAc / heptane, 0% to 100%) to give 5-tert-butyl-N-[(5R)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2-benzazepin-5-yl]-1,2,4-oxadiazole-3-carboxamide as an off-white solid (381 mg, yield: 61%). ESI-MS (M+H) + : 523.3.

[0140] 16. Synthesis of N-(4-iodopyridin-2-yl)cyclopropanecarboxamide [ka] A mixture of 4-iodopyridin-2-amine (2.21 g, 10 mmol, 1.21 mL), DMAP (123 mg, 1 mmol), and DIPEA (1.95 g, 15 mmol, 2.63 mL) in DCM (40 mL) was cooled to -20 °C. Cyclopropanecarbonyl chloride (2.10 g, 20 mmol, 1.83 mL) was added dropwise with stirring. The mixture was allowed to warm to room temperature and continued stirring at room temperature for 18 h. The reaction was quenched with HO (40 mL), and the layers were separated. The aqueous phase was back-extracted with DCM (50 mL), and the combined DCM phases were dried (MgSO) and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (EtOAc / heptane, gradient from 0% to 50%) to give N-(4-iodopyridin-2-yl)cyclopropanecarboxamide as a white solid (2.2 g, yield: 95%). ESI-MS (M+H) + : 289.0. 1 H NMR (400 MHz, CD3OD) δ: 8.57-8.54 (m, 1H), 7.97 (d, J = 5.3 Hz, 1H), 7.46 (dd, J1= 5.3 Hz, J2= 1.5 Hz, 1H), 1.90-1.82 (m, 1H), 1.01-0.94 (m, 2H), 0.92-0.86 (m, 2H).

[0141] 17. Synthesis of (R)-5-(tert-butyl)-N-(8-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1,2,4-oxadiazole-3-carboxamide (Compound 10) [ka] A mixture of 5-tert-butyl-N-[(5R)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2-benzazepin-5-yl]-1,2,4-oxadiazole-3-carboxamide (114 mg, 218 μmol), N-(4-iodo-2-pyridyl)cyclopropanecarboxamide (75 mg, 262 μmol), KCO (90 mg, 655 μmol), and Pd(dppf)Cl·DCM (8.9 mg, 11 μmol) was dissolved in 1,4-dioxane (1.75 mL) and HO (438 μL). The reaction mixture was heated to 100 °C and stirred at that temperature for 18 h. The reaction was diluted with HO (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic extracts were washed with brine (20 mL), dried (NaSO), filtered, and concentrated. The crude material was purified by silica gel column chromatography ([3:1 EtOAc:EtOH] / heptane, gradient 0% to 100%) to afford 5-tert-butyl-N-[(5R)-8-[2-(cyclopropanecarbonylamino)-4-pyridyl]-2-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2-benzazepin-5-yl]-1,2,4-oxadiazole-3-carboxamide as a white solid (64 mg, yield: 53%). ESI-MS (M+H) + : 557.2. 1H NMR (500 MHz, DMSO-d6) δ: 10.89 (s, 1H), 9.56 (br d, J = 7.9 Hz, 1H), 8.39 (s, 1H), 8.37 (d, J = 5.5 Hz, 1H), 7.61 (dd, J1= 7.9 Hz, J2= 1.8 Hz, 1H), 7.54 (d, J = 1.8 Hz, 1H), 7.41 (dd, J1= 5.5 Hz, J2= 1.8 Hz, 1H), 7.35 (d, J = 7.9 Hz, 1H), 5.42 (br t, J = 9.5 Hz, 1H), 4.26 (br d, J = 15.3 Hz, 1H), 4.03-3.96 (m, 1H), 3.34-3.26 (m, 1H), 3.22-3.04 (m, 3H), 2.12-2.00 (m, 2H), 1.79 (br d, J = 14.7 Hz, 1H), 1.45 (s, 9H), 0.87-0.78 (m, 4H).

[0142] Example 11: 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide (Compound 11) [ka] Synthesis of 1,4-bromo-2-fluoro-3-methylaniline [ka] To a solution of 2-fluoro-3-methylaniline (25.0 g, 200 mmol) in MeCN (200 mL) was added dropwise a solution of NBS (39.1 g, 220 mmol) in MeCN (100 mL) at 25° C. The reaction mixture was stirred at 25° C. for 4 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether / EtOAc, 50:1) to give 4-bromo-2-fluoro-3-methylaniline as a brown oil (30 g, yield: 74%). 1H NMR: (400 MHz, DMSO-d6) δ: 7.02 (dd, J1= 8.8 Hz, J2= 1.6 Hz, 1H), 6.55 (t, J = 8.8 Hz, 1H), 5.21 (s, 2H), 2.16 (d, J = 2.4 Hz, 3H).

[0143] 2. Synthesis of N-(4-bromo-2-fluoro-3-methylphenyl)acetamide [ka] To a solution of 4-bromo-2-fluoro-3-methylaniline (30 g, 147 mmol) and EtN (29.8 g, 294 mmol) in DCM (300 mL) was added AcCl (23.1 g, 294 mmol) dropwise at 0 °C. The mixture was then stirred at 25 °C for 1 h. The reaction mixture was poured into HO (300 mL) and extracted with DCM (200 mL × 2). The combined organic layers were washed with brine (400 mL), dried (NaSO), filtered, and concentrated to give N-(4-bromo-2-fluoro-3-methylphenyl)acetamide as a brown solid (34.0 g, yield: 94%). 1 H NMR: (400 MHz, DMSO-d6) δ: 9.74 (s, 1H), 7.71 (t, J = 8.4 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 2.25 (d, J = 2.4 Hz, 3H), 2.06 (s, 3H).

[0144] 3. Synthesis of N-(4-cyano-2-fluoro-3-methylphenyl)acetamide [ka] A mixture of N-(4-bromo-2-fluoro-3-methylphenyl)acetamide (32 g, 0.13 mol) and Cu(I)CN (23.3 g, 0.26 mol) in DMF (300 mL) was prepared under N and heated at 140 °C for 17 h. The reaction mixture was poured into HO (500 mL) and extracted with EtOAc (300 mL × 3). The combined organic extracts were washed with brine (500 mL), dried (NaSO), filtered, and concentrated to give the crude material. The crude material was triturated with petroleum ether / EtOAc (50:1, 300 mL), filtered, and concentrated to give N-(4-cyano-2-fluoro-3-methylphenyl)acetamide as a yellow solid (25.0 g, 94% yield). 1 H NMR: (400 MHz, DMSO-d6) δ: 10.04 (s, 1H), 8.08 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 2.36 (s, 3H), 2.11 (s, 3H).

[0145] 4. Synthesis of 4-amino-3-fluoro-2-methylbenzonitrile [ka] To a solution of N-(4-cyano-2-fluoro-3-methylphenyl)acetamide (25.0 g, 130 mmol) in EtOH (200 mL) was added concentrated HCl solution (12 N, 100 mL). The mixture was heated at 90 °C for 17 h. The mixture was concentrated in vacuo. The resulting white solid was dissolved in EtOAc (200 mL), and the pH of the solution was adjusted to pH = 7 with saturated aqueous NaCO (100 mL). The layers were separated, and the organic phase was dried (NaSO), filtered, and concentrated in vacuo to give 4-amino-3-fluoro-2-methylbenzonitrile as a brown solid (19.0 g, 97% yield). 1 H NMR: (400 MHz, DMSO-d6) δ: 7.20 (d, J = 8.4 Hz, 1H), 6.61 (t, J = 8.4 Hz, 1H), 6.13 (s, 2H), 2.24 (d, J = 2.4 Hz, 3H).

[0146] 5. Synthesis of 4-bromo-3-fluoro-2-methylbenzonitrile [ka] To a suspension of Cu(I)Br (32.5 g, 226 mmol) in MeCN (300 mL) was added tert-butyl nitrite (23.4 g, 226 mmol) at room temperature. Next, a solution of 4-amino-3-fluoro-2-methylbenzonitrile (17 g, 113 mmol) in MeCN (50 mL) was added dropwise at 65° C. over 1 hour. The mixture was stirred at 65° C. for 17 hours, cooled to room temperature, and concentrated to give a crude material. The crude material was purified by silica gel column chromatography (petroleum ether / EtOAc, 15:1) to give 4-bromo-3-fluoro-2-methylbenzonitrile as a yellow oil (14.5 g, yield: 60%). 1 H NMR: (400 MHz, DMSO-d6) δ: 7.74 (t, J = 7.6 Hz, 1H), 7.59 (dd, J1= 8.4 Hz, J2= 0.8 Hz, 1H), 2.41 (d, J = 2.4 Hz, 3H).

[0147] 6. 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 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.

[0148] 7. 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) were added EtN (13 g, 128 mmol) and BocO (16.8 g, 77 mmol) at 25° C. The mixture was stirred at 25° C. for 2 h. The mixture was concentrated in vacuo and purified by silica gel column chromatography (petroleum ether / EtOAc, 50:1) to give tert-butyl (4-bromo-3-fluoro-2-methylbenzyl)carbamate as a white solid (12.0 g, yield: 59%). 1 H NMR: (400 MHz, DMSO-d6) δ: 7.47 (t, J = 7.6 Hz, 1H), 7.37 (t, J = 5.2 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 4.07 (d, J = 6.0 Hz, 2H), 2.19 (d, J = 2.0 Hz, 3H), 1.37 (s, 9H).

[0149] 8. 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, 31.4 mmol) in 1,4-dioxane (150 mL) was added bis(pinacolato)diboron (9.6 g, 37.7 mmol) and KOAc (6.2 g, 62.9 mmol). Next, Pd(dppf)Cl·DCM (2.1 g, 2.5 mmol) was added under a N atmosphere. The reaction mixture was stirred at 80 °C under N for 17 h. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (petroleum ether / EtOAc, 20:1) to give 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, impure), which was used without further purification. ESI-MS (Mt-Bu) + : 310.1.

[0150] 9. Synthesis of tert-butyl (4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluoro-2-methylbenzyl)carbamate [ka] To a solution of tert-butyl (3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (400 mg, 1.10 mmol) in a 1,4-dioxane / HO (v / v = 3 / 1, 8 mL) mixture, N-(4-bromopyridin-2-yl)cyclopropanecarboxamide (264 mg, 1.10 mmol) and KCO (303 mg, 2.20 mmol) were added. Then, Pd(dppf)Cl·DCM (90 mg, 0.11 mmol) was added under a N atmosphere. The mixture was heated to 85 °C and stirred at that temperature for 4 h under N. The mixture was concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (petroleum ether / EtOAc, gradient from 3:1 to 1:1) to give tert-butyl (4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluoro-2-methylbenzyl)carbamate as a yellow oil (350 mg, yield: 80%). ESI-MS (M+H) + : 400.2. 1 H NMR: (400 MHz, CD3OD) δ: 8.33 (d, J = 4.8 Hz, 1H), 8.29 (s, 1H), 7.36 (t, J = 8.4 Hz, 1H), 7.29 (d, J = 4.8 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 4.31 (d, J = 4.0 Hz, 2H), 2.30 (d, J = 2.0 Hz, 3H), 1.96-1.88 (m, 1H), 1.49 (s, 9H), 1.03-0.99 (m, 2H), 0.94-0.90 (m, 2H).

[0151] 10. Synthesis of N-(4-(4-(aminomethyl)-2-fluoro-3-methylphenyl)pyridin-2-yl)cyclopropanecarboxamide hydrochloride [ka] To a solution of tert-butyl (4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluoro-2-methylbenzyl)carbamate (350 mg, 0.88 mmol) in EtOAc (1 mL) was added HCl / EtOAc solution (4 M, 10 mL). The reaction mixture was stirred at 20° C. for 2 h. The reaction mixture was filtered and the filter cake was dried to give N-(4-(4-(aminomethyl)-2-fluoro-3-methylphenyl)pyridin-2-yl)cyclopropanecarboxamide hydrochloride as a yellow solid (200 mg, yield: 68%), which was carried forward without further purification. ESI-MS (M+H) + : 300.1.

[0152] 11. Synthesis of 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide (Compound 11) [ka] To a solution of N-(4-(4-(aminomethyl)-2-fluoro-3-methylphenyl)pyridin-2-yl)cyclopropanecarboxamide hydrochloride (150 mg, 0.45 mmol) in DMF (5 mL) was added DIPEA (116 mg, 0.90 mmol), 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylic acid (152 mg, 0.90 mmol), and HATU (342 mg, 0.90 mmol). The reaction mixture was stirred at 15° C. for 1 hour. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (CHCN / HO containing 0.05% NHOH / HO as mobile phase) to give an impure product (130 mg), which was repurified by preparative HPLC (CHCN / HO containing 0.05% HCl / HO as mobile phase) to give 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid (117 mg, yield: 58%). ESI-MS (M+H) + : 452.1.1 H NMR: (400 MHz, CD3OD) δ: 8.38 (d, J = 4.8 Hz, 1H), 7.80 (d, J = 6.0 Hz, 1H), 7.72 (s, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 4.70 (s, 2H), 2.42 (d, J = 2.0 Hz, 3H), 1.98 (m, 1H), 1.51 (s, 9H), 1.22-1.14 (m, 4H).

[0153] Example 12: 3-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-5-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide (Compound 12) [ka] 1. Synthesis of tert-butyl (4-bromo-5-fluoro-2-methylbenzyl)carbamate [ka] To a solution of 4-bromo-5-fluoro-2-methylbenzonitrile (15.4 g, 72.0 mmol) in THF (185 mL) was added BH3·THF (1.0 M in THF, 223 mL, 223 mmol), and the mixture was heated under reflux for 2 h. The reaction was cooled to room temperature, and HCl solution (1 M, 45 mL) was added dropwise to the solution (WARNING: The reaction is extremely exothermic), and the mixture was again heated to reflux for 1 h. It was then cooled to room temperature, and the solvent was removed under reduced pressure. The residue was dissolved in DCM (690 mL), and Et3N (57 mL, 409 mmol) and Boc2O (35 mL, 152 mmol) were added. The mixture was left stirring at room temperature for 2 h. HO (500 mL) was then added, and the layers were separated. The aqueous layer was extracted with DCM (500 mL x 2), and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The solvent was removed under reduced pressure. The crude material was purified by silica gel column chromatography (EtOAc / heptane, gradient from 0% to 20%) to give tert-butyl (4-bromo-5-fluoro-2-methylbenzyl)carbamate as a white solid (17.2 g, yield: 75%). ESI-MS (Mt-Bu) + : 262.0.

[0154] 2. Synthesis of tert-butyl (5-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate [ka] A solution of tert-butyl (4-bromo-5-fluoro-2-methylbenzyl)carbamate (2.45 g, 6.73 mmol) and bis(pinacolato)diboron (1.88 g, 7.40 mmol) in dry 1,4-dioxane (58 mL) was degassed with N for 10 minutes. KOAc (1.98 g, 20.2 mmol) and Pd(dppf)Cl·DCM (0.49 g, 0.67 mmol) were added, and the solution was degassed with N for 10 minutes. The reaction mixture was heated to 100 °C and stirred at that temperature for 20 hours. The reaction mixture was cooled to room temperature and filtered through a pad of Celite®. The solvent was removed under reduced pressure, and the residue was diluted with EtOAc (100 mL). Water (100 mL) was added, and the layers were separated. The aqueous layer was extracted with EtOAc (100 mL × 2). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (EtOAc / heptane, 0% to 10% gradient) to give the impure product as a pale yellow oil. This impure oil was triturated with pentane to give tert-butyl (5-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate as a white solid (1.89 g, yield: 77%). ESI-MS (Mt-Bu) + : 310.2.

[0155] 3. Synthesis of tert-butyl (4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-5-fluoro-2-methylbenzyl)carbamate [ka] To a solution of tert-butyl (5-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (150 mg, 0.41 mmol) in a 1,4-dioxane / HO (v / v = 15 / 1, 6 mL) mixture, N-(4-iodopyridin-2-yl)cyclopropanecarboxamide (142 mg, 0.49 mmol) and KCO (85 mg, 0.61 mmol) were added. The reaction mixture was degassed with N for 5 min, and then Pd(dppf)Cl·DCM (17 mg, 0.02 mmol) was added under a N atmosphere. The mixture was heated to 100 °C and stirred at that temperature for 1 h under N. The reaction mixture was cooled to room temperature, and EtOAc (50 mL) was added. The organic phase was washed with HO (50 mL × 2), dried (NaSO), filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography ([3:1 EtOAc:EtOH] / heptane, gradient from 5% to 100%) to give tert-butyl (4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-5-fluoro-2-methylbenzyl)carbamate as an off-white solid (140 mg, yield: 85%). ESI-MS (M+H) + : 400.3.

[0156] 4. Synthesis of N-(4-(4-(aminomethyl)-2-fluoro-5-methylphenyl)pyridin-2-yl)cyclopropanecarboxamide hydrochloride [ka] To a solution of tert-butyl (4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-5-fluoro-2-methylbenzyl)carbamate (140 mg, 0.35 mmol) in EtOAc (3 mL) was added a solution of HCl / EtOAc (1.25 M, 1.54 mL). The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo to give N-(4-(4-(aminomethyl)-2-fluoro-5-methylphenyl)pyridin-2-yl)cyclopropanecarboxamide hydrochloride as a yellow solid (105 mg, crude), which was carried forward without further purification. ESI-MS (M+H)+ : 300.1.

[0157] 5. Synthesis of 3-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-5-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide (Compound 12) [ka] To a solution of potassium 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylate (40 mg, 0.19 mmol) in THF (1.7 mL) in an ice-water bath was added EtN (53 mg, 0.53 mmol, 73 μL) and HATU (103 mg, 0.26 mmol). The reaction mixture was stirred at 0° C. for 10 minutes, and then N-(4-(4-(aminomethyl)-2-fluoro-5-methylphenyl)pyridin-2-yl)cyclopropanecarboxamide hydrochloride (52 mg, 0.17 mmol) was added. The reaction mixture was warmed to room temperature and continued stirring at that temperature for 24 hours. Water (5 mL) was added, followed by EtOAc (5 mL), and the layers were separated. The aqueous phase was extracted with EtOAc (5 mL × 2). The combined organic extracts were washed with brine (10 mL), dried (NaSO), filtered, and concentrated in vacuo. The crude material was purified by preparative HPLC (0.05% TFA / HO in CHCN / HO as mobile phase) to give the TFA salt of 3-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-5-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide as a white solid (31 mg, yield: 32%). ESI-MS (M+H) + : 452.2. 1H NMR (400 MHz, CD3OD) δ: 8.34 (d, J = 6.0 Hz, 1H), 7.94-7.89 (m, 1H), 7.59 (d, J = 6.0 Hz, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.26 (d, J = 12.0 Hz, 1H), 4.62 (s, 2H), 2.44 (s, 3H), 1.91 (s, 1H), 1.46-1.39 (m, 9H), 1.14-1.08 (m, 2H), 1.04 (dt, J1= 8.0 Hz, J2= 3.2 Hz, 2H).

[0158] Example 13: 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-5-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide (Compound 13) [ka] The synthesis of 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-5-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide was carried out similarly to the synthesis of 3-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-5-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide in Example 12, Step 5. The crude material was purified by preparative HPLC (0.05% TFA / HO in CHCN / HO as mobile phase) to give the TFA salt of 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-5-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid (47 mg, yield: 47%). ESI-MS (M+H) + : 452.2. 1H NMR (400 MHz, CD3OD) δ: 8.34 (d, J = 5.8 Hz, 1H), 7.86 (s, 1H), 7.63 (dt, J1= 6.2 Hz, J2= 1.4 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 12.0 Hz, 1H), 4.63 (s, 2H), 2.45 (s, 3H), 2.02-1.82 (m, 1H), 1.49 (s, 9H), 1.17-1.10 (m, 2H), 1.08-1.01 (m, 2H).

[0159] Example 14: 5-(tert-butyl)-N-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluorobenzyl)-1,2,4-oxadiazole-3-carboxamide (Compound 14) [ka] Synthesis of 1,4-bromo-3-chloro-2-fluoroaniline [ka] To a mixture of 3-chloro-2-fluoroaniline (18.0 g, 124 mmol) in MeCN (100 mL) was added dropwise a solution of NBS (26.4 g, 148 mmol) in MeCN (100 mL) at 25° C. The mixture was stirred at 25° C. for 4 hours. The reaction mixture was concentrated to give the crude product. The crude material was purified by silica gel column chromatography (petroleum ether / EtOAc, 50:1) to give 4-bromo-3-chloro-2-fluoroaniline as a brown oil (18.0 g, yield: 65%). 1 H NMR: (400 MHz, CD3OD) δ: 7.13 (dd, J1= 8.8 Hz, J2= 2.0 Hz, 1H), 6.66 (t, J = 8.4 Hz, 1H).

[0160] 2. Synthesis of N-(4-bromo-3-chloro-2-fluorophenyl)acetamide [ka] To a solution of 4-bromo-3-chloro-2-fluoroaniline (18.0 g, 80 mmol) in DCM (150 mL) placed in an ice-water bath at 0 °C, AcCl (12.6 g, 160 mmol) was added dropwise, followed by EtN (16.2 g, 160 mmol). The mixture was then stirred at 30 °C for 1 h. The reaction mixture was poured into HO (200 mL) and extracted with DCM (100 mL × 2). The combined organic extracts were washed with brine (400 mL), dried (NaSO), filtered, and concentrated to give crude N-(4-bromo-3-chloro-2-fluorophenyl)acetamide (20.0 g, unpurified). The crude material was carried forward without further purification. 1 H NMR: (400 MHz, CD3OD) δ: 7.85 (t, J = 8.8 Hz, 1H), 7.44 (d, J = 10.0 Hz, 1H), 2.17 (s, 3H).

[0161] 3. Synthesis of N-(3-chloro-4-cyano-2-fluorophenyl)acetamide [ka] A solution of N-(4-bromo-3-chloro-2-fluorophenyl)acetamide (20.0 g, 75 mmol) and Cu(I)CN (13.4 g, 150 mmol) in DMF (200 mL) was heated to 140 °C and stirred at that temperature for 17 h under N. The reaction mixture was poured into HO (500 mL) and extracted with EtOAc (200 mL × 3). The combined organic extracts were washed with brine (500 mL), dried (NaSO), filtered, and concentrated to give crude N-(3-chloro-4-cyano-2-fluorophenyl)acetamide as a brown solid (14.0 g, 88% yield). The crude material was carried forward without further purification. 1 H NMR: (400 MHz, CD3OD) δ: 8.30 (t, J = 7.2 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 2.19 (s, 3H).

[0162] 4. Synthesis of 4-amino-2-chloro-3-fluorobenzonitrile [ka] To a solution of N-(3-chloro-4-cyano-2-fluorophenyl)acetamide (8.0 g, 38 mmol) in EtOH (100 mL) was added concentrated HCl solution (12 N, 50 mL). The mixture was heated at 90 °C for 2 h. The reaction mixture was concentrated in vacuo, and the resulting white solid was dissolved in EtOAc (100 mL). The pH of the solution was adjusted to pH = 7 with saturated aqueous NaCO (100 mL), and the layers were separated. The organic phase was dried (NaSO), filtered, and concentrated. The crude material was purified by silica gel column chromatography (petroleum ether / EtOAc, 2:1) to give 4-amino-2-chloro-3-fluorobenzonitrile as a yellow solid (5.0 g, yield: 78%). 1 H NMR: (400 MHz, CDCl3) δ: 7.23 (dd, J1= 8.8 Hz, J2= 1.6 Hz, 1H), 6.66 (t, J = 8.4 Hz, 1H), 4.36 (s, 2H).

[0163] 5. Synthesis of 2-chloro-3-fluoro-4-iodobenzonitrile [ka] To a suspension of Cu(I)I (11.2 g, 59 mmol) in MeCN (50 mL) was added tert-butyl nitrite (6.0 g, 59 mmol) at room temperature. The reaction mixture was heated to 65° C., and a solution of 4-amino-2-chloro-3-fluorobenzonitrile (5.0 g, 29 mmol) in MeCN (50 mL) was added dropwise at 65° C. over 1 hour. The mixture was stirred at 65° C. for 17 hours and then concentrated. The crude material was purified by silica gel column chromatography (petroleum ether / EtOAc, 2:1) to give 2-chloro-3-fluoro-4-iodobenzonitrile as a yellow solid (6.0 g, yield: 73%). 1H NMR: (400 MHz, CDCl3) δ: 7.78 (s, 1H), 7.20 (d, J = 7.2 Hz, 1H).

[0164] 6. Synthesis of (2-chloro-3-fluoro-4-iodophenyl)methanamine [ka] To a solution of 2-chloro-3-fluoro-4-iodobenzonitrile (6.0 g, 21 mmol) in THF (50 mL) was added BH3·Me2S (3.2 mL, 32 mmol, 10 M) at 30 °C. The mixture was heated to 65 °C and stirred at that temperature for 2 h. MeOH (5 mL) was added, and the reaction mixture was concentrated in vacuo. The crude material was purified by silica gel column chromatography (petroleum ether / EtOAc, gradient from 5:1 to 2:1) to give (2-chloro-3-fluoro-4-iodophenyl)methanamine as a yellow solid (3.5 g, yield: 58%). 1 H NMR: (400 MHz, DMSO-d6) δ: 7.79 (dd, J1= 8.4 Hz, J2= 6.4 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 3.77 (s, 2H).

[0165] 7. Synthesis of tert-butyl (2-chloro-3-fluoro-4-iodobenzyl)carbamate [ka] To a solution of (2-chloro-3-fluoro-4-iodophenyl)methanamine (3.5 g, 12 mmol) in DCM (50 mL) were added DIPEA (2.4 g, 18 mmol) and BocO (3.2 g, 15 mmol). The mixture was heated at 30° C. for 2 hours. The mixture was concentrated in vacuo, and the crude material was purified by silica gel column chromatography (petroleum ether / EtOAc, 10:1) to give tert-butyl (2-chloro-3-fluoro-4-iodobenzyl)carbamate as a yellow oil (4.5 g, yield: 95%). 1H NMR: (400 MHz, DMSO-d6) δ: 7.77 (dd, J1= 8.0 Hz, J2= 6.4 Hz, 1H), 7.48 (t, J = 4.8 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 4.14 (d, J = 6.0 Hz, 2H), 1.36 (s, 9H).

[0166] 8. Synthesis of tert-butyl (2-chloro-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate [ka] To a solution of tert-butyl (2-chloro-3-fluoro-4-iodobenzyl)carbamate (3.5 g, 9.1 mmol) in 1,4-dioxane (50 mL) under a N atmosphere, bis(pinacolato)diboron (2.8 g, 10.9 mmol), KOAc (1.8 g, 18.2 mmol), and Pd(dppf)Cl·DCM (734 mg, 0.9 mmol) were added sequentially. The mixture was heated to 80 °C and stirred at that temperature for 17 h under N. The mixture was poured into H2O (100 mL) and extracted with DCM (50 mL × 3). The combined organic extracts were washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude material, tert-butyl (2-chloro-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate, was used in the next step without further purification. ESI-MS (Mt-Bu) + : 329.9.

[0167] 9. Synthesis of tert-butyl (2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluorobenzyl)carbamate [ka] To a solution of tert-butyl (2-chloro-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (300 mg, 0.78 mmol) in a mixture of 1,4-dioxane / HO (v / v = 10 / 1, 22 mL) was added N-(4-bromopyridin-2-yl)cyclopropanecarboxamide (187 mg, 0.78 mmol) and KCO (215 mg, 1.56 mmol). Next, Pd(dppf)Cl·DCM (32 mg, 0.04 mmol) was added under a N atmosphere. The mixture was heated to 90 °C and stirred at that temperature for 16 h under N. The mixture was concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (petroleum ether / EtOAc, gradient from 10:1 to 1:1) to give tert-butyl (2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluorobenzyl)carbamate as a yellow solid (280 mg, yield: 86%). ESI-MS (M+H) + : 420.1.

[0168] 10. Synthesis of N-(4-(4-(aminomethyl)-3-chloro-2-fluorophenyl)pyridin-2-yl)cyclopropanecarboxamide hydrochloride [ka] To a solution of tert-butyl (2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluorobenzyl)carbamate (280 mg, 0.67 mmol) in DCM (10 mL) was added HCl / EtOAc solution (1 M, 10 mL). The reaction mixture was stirred at 15° C. for 3 h. The reaction mixture was concentrated in vacuo to give N-(4-(4-(aminomethyl)-3-chloro-2-fluorophenyl)pyridin-2-yl)cyclopropanecarboxamide hydrochloride as a yellow solid (200 mg, crude), which was carried forward without further purification. ESI-MS (M+H) + : 320.1.

[0169] 11. Synthesis of 5-(tert-butyl)-N-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluorobenzyl)-1,2,4-oxadiazole-3-carboxamide (Compound 14) [ka] To a solution of N-(4-(4-(aminomethyl)-3-chloro-2-fluorophenyl)pyridin-2-yl)cyclopropanecarboxamide hydrochloride (180 mg, 0.56 mmol) in a DCM / DMF (v / v=50 / 1, 102 mL) mixture, 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylic acid (115 mg, 0.67 mmol), HATU (257 mg, 0.67 mmol), and DIPEA (364 mg, 2.8 mmol) were added. The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was poured into HO (100 mL) and extracted with DCM (100 mL × 2). The combined organic extracts were concentrated in vacuo. The crude material was purified by preparative HPLC (0.05% HCl / HO in CHCN / HO as mobile phase) to give 5-(tert-butyl)-N-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluorobenzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid (153 mg, yield: 58%). ESI-MS (M+H) + : 472.1. 1 H NMR: (400 MHz, CD3OD) δ: 8.39 (d, J = 6.4 Hz, 1H), 7.77-7.70 (m, 2H), 7.68-7.63 (m, 1H), 7.48-7.44 (m, 1H), 4.76 (s, 2H), 1.98-1.90 (m, 1H), 1.49 (s, 9H), 1.19-1.14 (m, 2H), 1.12-1.07 (m, 2H).

[0170] Example 15: 3-(tert-butyl)-N-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide (Compound 15) [ka] The synthesis of 3-(tert-butyl)-N-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide was carried out similarly to the synthesis of 5-(tert-butyl)-N-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluorobenzyl)-1,2,4-oxadiazole-3-carboxamide in Example 14, Step 11. The crude material was purified by preparative HPLC (0.05% HCl / HO in CHCN / HO as mobile phase) to give 3-(tert-butyl)-N-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide as a white solid (86 mg, yield: 44%). ESI-MS (M+H) + : 472.1. 1 H NMR: (400 MHz, DMSO-d6) δ: 11.00 (s, 1H), 9.94 (t, J = 6.0 Hz, 1H), 8.40 (d, J = 5.2 Hz, 1H), 8.27 (s, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.30-7.26 (m, 1H), 4.59 (d, J = 6.0 Hz, 2H), 2.04-1.98 (m, 1H), 1.35 (s, 9H), 0.83-0.80 (m, 4H).

[0171] Example 16: 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxamide (Compound 16) [ka] 1. Synthesis of tert-butyl (4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(trifluoromethyl)benzyl)carbamate [ka] The synthesis of tert-butyl (4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(trifluoromethyl)benzyl)carbamate was carried out similarly to the synthesis of tert-butyl (4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluoro-2-methylbenzyl)carbamate in Example 11, Step 9. tert-Butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)benzyl)carbamate was prepared as described in WO2015 / 089337. The crude material was purified by silica gel column chromatography (petroleum ether / EtOAc, 2:1) to give tert-butyl (4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(trifluoromethyl)benzyl)carbamate as a white solid (380 mg, yield: 80%). ESI-MS (M+H) + : 436.1

[0172] 2. Synthesis of N-(4-(4-(aminomethyl)-3-(trifluoromethyl)phenyl)pyridin-2-yl)cyclopropanecarboxamide hydrochloride [ka] The synthesis of N-(4-(4-(aminomethyl)-3-(trifluoromethyl)phenyl)pyridin-2-yl)cyclopropanecarboxamide hydrochloride was carried out similarly to the synthesis of N-(4-(4-(aminomethyl)-2-fluoro-3-methylphenyl)pyridin-2-yl)cyclopropanecarboxamide hydrochloride in Example 11, Step 10. The reaction mixture was concentrated in vacuo to give N-(4-(4-(aminomethyl)-3-(trifluoromethyl)phenyl)pyridin-2-yl)cyclopropanecarboxamide hydrochloride as a white solid (280 mg, crude) which was carried forward without further purification. ESI-MS (M+H) + : 336.0.

[0173] Synthesis of 3.5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxamide (16) [ka] The synthesis of 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxamide was carried out similarly to the synthesis of 5-(tert-butyl)-N-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluorobenzyl)-1,2,4-oxadiazole-3-carboxamide in Example 14, Step 11. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative HPLC (0.05% HCl / HO in CHCN / HO as mobile phase) to give 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid (104 mg, yield: 51%). ESI-MS (M+H) + : 488.1. 1H NMR: (400 MHz, CD3OD) δ: 8.39-8.37 (m, 1H), 8.14 (s, 1H), 8.08-8.05 (m, 1H), 7.92 (s, 1H), 7.79-7.74 (m, 2H), 4.88 (s ,2H), 1.95-1.92 (m, 1H), 1.50 (s, 9H), 1.14-1.06 (m,4H).

[0174] Example 17: 3-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide (Compound 17) [ka] The synthesis of 3-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide was carried out in a similar manner to the synthesis of 3-(tert-butyl)-N-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide in Example 15. The reaction mixture was concentrated in vacuo and the crude material was purified by preparative HPLC (0.05% HCl / HO in CHCN / HO as mobile phase) to give 3-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide as a white solid (88 mg, yield: 43%). ESI-MS (M+H) + : 488.1. 1H NMR: (400 MHz, CD3OD) δ: 8.39-8.37 (m, 1H), 8.13 (s, 1H), 8.07-8.05 (m, 1H), 7.98 (s, 1H), 7.80-7.78 (m, 1H), 7.72-7.70 (m, 1H), 4.86 (s, 2H), 1.95-1.92 (m, 1H), 1.43 (s, 9H), 1.13-1.04 (m, 4H).

[0175] Example 18: (R)-3-(tert-butyl)-N-(2-(2-(cyclopropanecarboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide (Compound 18) [ka] 1. Synthesis of tert-butyl (R)-(2-(2-(cyclopropanecarboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate [ka] To a solution of (R)-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate (prepared as described in WO 2015 / 089327, 300 mg, 0.77 mmol) in 1,4-dioxane / HO (v / v = 3 / 1, 12 mL) was added N-(4-bromopyridin-2-yl)cyclopropanecarboxamide (187 mg, 0.77 mmol) and KCO (214 mg, 1.55 mmol). Next, Pd(dppf)Cl·DCM (63 mg, 0.08 mmol) was added under a N atmosphere. The mixture was heated to 85 °C and stirred at that temperature for 16 h under N. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude material was purified by silica gel column chromatography (petroleum ether / EtOAc, 5:1) to give tert-butyl (R)-(2-(2-(cyclopropanecarboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate as a white solid (250 mg, yield: 77%). ESI-MS (M+H) + : 422.2. 1 H NMR (400 MHz, DMSO-d6) δ: 10.85 (s, 1H), 8.36 (s, 1H), 8.31 (d, J = 5.2 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.43 (s, 1H), 7.36 (dd, J1= 5.2 Hz, J2= 1.2 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 4.72 (t, J = 8.8 Hz, 1H), 2.87-2.79 (m, 2H), 2.04-2.00 (m, 1H), 1.84-1.73 (m, 4H), 1.49-1.47 (m, 1H), 1.39 (s, 9H), 1.25-1.23 (m, 1H), 0.81-0.79 (m, 4H).

[0176] 2. Synthesis of (R)-N-(4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)pyridin-2-yl)cyclopropanecarboxamide hydrochloride [ka] To a solution of tert-butyl (R)-(2-(2-(cyclopropanecarboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate (250 mg, 0.59 mmol) in EtOAc (2 mL) at 15° C., HCl / EtOAc solution (4 M, 6 mL) was added, and the resulting mixture was stirred at 15° C. for 2 h. The reaction mixture was filtered, and the filter cake was dried to give (R)-N-(4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)pyridin-2-yl)cyclopropanecarboxamide hydrochloride as a white solid (180 mg, yield: 95%), which was carried forward without further purification. ESI-MS (M+H) + : 322.2.

[0177] 3. Synthesis of (R)-3-(tert-butyl)-N-(2-(2-(cyclopropanecarboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide (compound 18) [ka] To a solution of (R)—N-(4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)pyridin-2-yl)cyclopropanecarboxamide hydrochloride (130 mg, 0.36 mmol) in DCM / DMF (v / v=25 / 1, 52 mL) was added 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylic acid (74 mg, 0.44 mmol), HATU (166 mg, 0.44 mmol), and DIPEA (235 mg, 1.82 mmol). The reaction mixture was stirred at 25 °C for 1 h, poured into HO (100 mL), and extracted with DCM (50 mL × 2). The combined organic extracts were concentrated in vacuo. The crude material was purified by preparative HPLC (0.05% HCl / HO in CHCN / HO as mobile phase) to give (R)-3-(tert-butyl)-N-(2-(2-(cyclopropanecarboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide as a white solid (84 mg, yield: 49%, ee=100%). ESI-MS (M+H) + : 474.0. 1 H NMR: (400 MHz, CD3OD) δ: 8.31 (d, J = 6.4 Hz, 1H), 7.81-7.74 (m, 2H), 7.69-7.65 (m, 2H), 7.46-7.44 (m, 1H), 5.40 (d, J = 9.6 Hz, 1H), 3.11-3.00 (m, 2H), 2.13-1.82 (m, 6H), 1.45 (s, 9H), 1.41-1.37 (m, 1H), 1.16-1.12 (m, 2H), 1.10-1.05 (m, 2H).

[0178] Example 19: (R)-5-(tert-butyl)-N-(1-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide (Compound 19) [ka] 1. Synthesis of 1-(4-bromo-2-methylphenyl)ethan-1-one [ka] To a solution of 4-bromo-2-methyl-benzonitrile (4.0 g, 20.4 mmol) in THF (20 mL) was added iodine(methyl)magnesium (3 M, 10.2 mL) dropwise at room temperature. The reaction mixture was heated to reflux (approximately 70 °C) for 2 h, then cooled to room temperature and stirred for 72 h. The reaction mixture was placed in an ice-water cooling bath, and saturated aqueous NH4Cl (100 mL) was added, followed by EtOAc (100 mL). The layers were separated, and the aqueous phase was extracted with EtOAc (100 mL). The combined organic extracts were concentrated in vacuo, and the resulting residue was treated with HCl solution (4 N, 20 mL) at 0 °C. The mixture was then stirred at room temperature for 18 h. The reaction mixture was extracted with EtOAc (50 mL), and the organic layer was washed with HO (50 mL), dried (Na2SO4), and filtered. The filtrate was concentrated in vacuo to give 1-(4-bromo-2-methylphenyl)ethan-1-one as a pale orange oil (3.04 g, yield: 70%). ESI-MS (M+H) + : 213.0. 1 H NMR (500 MHz, CDCl3) δ: 7.57 (d, J = 7.9 Hz, 1H), 7.43-7.40 (m, 2H), 2.56 (s, 3H), 2.52 (s, 3H).

[0179] 2. Synthesis of (R,E)-N-(1-(4-bromo-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide [ka] To a solution of 1-(4-bromo-2-methylphenyl)ethan-1-one (3.04 g, 14.3 mmol) in THF (48 mL) was added (R)-(+)-2-methyl-2-propanesulfinamide (1.73 g, 14.3 mmol) and Ti(IV)(OEt) (6.51 g, 28.5 mmol, 5.97 mL). The reaction mixture was heated to 70 °C for 20 h. After cooling to room temperature, the mixture was quenched with brine (100 mL) and EtOAc (100 mL) was added to give a biphasic solution with a thick white precipitate. The solution was filtered and the solid was washed with EtOAc (100 mL). The filtrate layers were separated, and the organic layer was dried (NaSO), filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (EtOAc / heptane, gradient from 0% to 50%) to give (R,E)-N-(1-(4-bromo-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide as a yellow oil (2.96 g, yield: 66%). ESI-MS (M+H) + : 318.0.

[0180] 3. Synthesis of (R)-N-((R)-1-(4-bromo-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide [ka] To a solution of (R,E)-N-(1-(4-bromo-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (2.96 g, 9.4 mmol) in a THF / HO mixture (98 / 2, 62.4 mL) cooled to −50 °C in a dry ice / acetonitrile cold bath was added NaBH (1.06 g, 28.1 mmol) slowly in portions. The mixture was stirred at −50 °C for 7 h, then stirred for 18 h until the internal temperature warmed to 10 °C. The reaction was quenched with HO (20 mL) and diluted with EtOAc (100 mL). The layers were separated, and the organic phase was dried (NaSO), filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (EtOAc / heptane, gradient from 20% to 100%) to give (R)-N-((R)-1-(4-bromo-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide as a colorless oil (1.6 g, yield: 55%). ESI-MS (M+H) + : 320.1. 1 H NMR (400 MHz, CDCl3) δ: ppm 7.37-7.33 (m, 1H), 7.33-7.31 (m, 1H), 7.29-7.25 (m, 1H), 4.78-4.68 (m, 1H), 3.31 (br s, 1H), 2.36 (s, 3H), 1.47 (d, J = 6.5 Hz, 3H), 1.24 (s, 9H).

[0181] 4. Synthesis of (R)-1-(4-bromo-2-methylphenyl)ethan-1-amine hydrochloride [ka] To a solution of (R)-N-((R)-1-(4-bromo-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (4.5 g, 14.1 mmol) in EtOAc (5 mL) at 15 °C was added HCl / EtOAc solution (4 M, 30 mL). The reaction mixture was stirred for 2 h and filtered. The filter cake was dried under vacuum to give (R)-1-(4-bromo-2-methylphenyl)ethan-1-amine hydrochloride as a white solid (3.3 g, 93% yield), which was carried forward without further purification. ESI-MS (M-NH2) + : 198.9. 1 H NMR (400 MHz, DMSO-d6) δ: 8.54 (s, 1H), 7.53-7.50 (m, 2H), 7.47 (s, 1H), 4.47 (t, J = 6.0 Hz, 1H), 2.33 (s, 3H), 1.43 (d, J = 6.4 Hz, 3H).

[0182] 5. Synthesis of tert-butyl (R)-(1-(4-bromo-2-methylphenyl)ethyl)carbamate [ka] To a mixture of (R)-1-(4-bromo-2-methylphenyl)ethan-1-amine hydrochloride (3.3 g, 13.2 mmol) in DCM (40 mL) at 15 °C, EtN (2.67 g, 26.3 mmol) and BocO (3.7 g, 17.1 mmol) were added. The mixture was stirred at 15 °C for 17 h, concentrated in vacuo, and purified by silica gel column chromatography (petroleum ether / EtOAc, 20:1) to give (R)-(1-(4-bromo-2-methylphenyl)ethyl)tert-butylcarbamate as a white solid (3.8 g, yield: 92%). ESI-MS (M-Boc-NH) + : 198.8.

[0183] 6. Synthesis of tert-butyl (R)-(1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate [ka] To a solution of (R)-(1-(4-bromo-2-methylphenyl)ethyl)tert-butylcarbamate (3.8 g, 12.1 mmol) in 1,4-dioxane (30 mL) under N was added bis(pinacolato)diboron (3.69 g, 14.5 mmol), Pd(dppf)Cl·DCM (987 mg, 1.2 mmol), and KOAc (2.37 g, 24.2 mmol). The mixture was heated to 85 °C under N and stirred at that temperature for 17 h, cooled to room temperature, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (petroleum ether / EtOAc, 20:1) to give tert-butyl (R)-(1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate as a yellow oil (4.0 g, yield: 87%). 1 H NMR: (400 MHz, CD3OD) δ: 7.53 (d, J = 7.6 Hz, 1H), 7.50 (s, 1H), 7.30 (d, J = 7.6 Hz, 1H), 3.65 (s, 1H), 2.37 (s, 3H), 1.41 (s, 9H), 1.33 (s, 12H), 1.25-1.22 (m, 3H).

[0184] 7. Synthesis of tert-butyl (R)-(1-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylphenyl)ethyl)carbamate [ka] To a solution of tert-butyl (R)-(1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate (300 mg, 0.83 mmol) in 1,4-dioxane (6 mL) and HO (2 mL) was added N-(4-bromopyridin-2-yl)cyclopropanecarboxamide (240 mg, 1.0 mmol), Pd(dppf)Cl·DCM (68 mg, 0.08 mmol), and KCO (230 mg, 1.66 mmol). The mixture was heated to 85 °C under N and stirred at that temperature for 17 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude material was purified by silica gel column chromatography (petroleum ether / EtOAc, 1:1) to give tert-butyl (R)-(1-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylphenyl)ethyl)carbamate as a yellow amorphous solid (250 mg, yield: 76%). ESI-MS (M+H) + : 396.2.

[0185] 8. Synthesis of (R)-N-(4-(4-(1-aminoethyl)-3-methylphenyl)pyridin-2-yl)cyclopropanecarboxamide hydrochloride [ka] To a mixture of (R)-(1-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylphenyl)ethyl)tert-butylcarbamate (250 mg, 0.63 mmol) in EtOAc (2 mL) at 15° C. was added HCl / EtOAc solution (4 M, 6 mL). The mixture was stirred at 15° C. for 1 h and filtered. The filter cake was dried in vacuo to give (R)-N-(4-(4-(1-aminoethyl)-3-methylphenyl)pyridin-2-yl)cyclopropanecarboxamide hydrochloride as a yellow solid (200 mg, yield: 96%), which was carried forward without further purification. ESI-MS (M+H) + : 296.0.

[0186] 9. Synthesis of (R)-5-(tert-butyl)-N-(1-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide (Compound 19) [ka] To a mixture of (R)—N-(4-(4-(1-aminoethyl)-3-methylphenyl)pyridin-2-yl)cyclopropanecarboxamide hydrochloride (100 mg, 0.30 mmol) in DMF (5 mL) at 15° C. was added 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylic acid (102 mg, 0.60 mmol), DIPEA (78 mg, 0.60 mmol), and HATU (172 mg, 0.45 mmol). The mixture was stirred at 15° C. for 1 h, filtered, and concentrated in vacuo. The crude material was purified by preparative HPLC (0.05% HCl / HO in CHCN / HO as mobile phase) to give (R)-5-(tert-butyl)-N-(1-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide as a white solid (108 mg, yield: 80%). ESI-MS (M+H) + : 448.2. 1 H NMR (400 MHz, CD3OD) δ: 8.31 (d, J = 6.8 Hz, 1H), 7.83 (dd, J1= 6.4 Hz, J2= 1.6 Hz, 1H), 7.72-7.70 (m, 3H), 7.64 (d, J = 8.0 Hz, 1H), 5.47 (dd, J1= 14.0 Hz, J2= 6.8 Hz, 1H), 2.57 (s, 3H), 1.98-1.92 (m, 1H), 1.58 (d, J = 6.8 Hz, 3H), 1.47 (s, 9H), 1.19-1.15 (m, 2H), 1.13-1.09 (m, 2H).

[0187] Example 20: 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)-5-fluoropyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide (Compound 20) [ka] 1. Synthesis of tert-butyl (R)-(1-(4-(2-chloro-5-fluoropyridin-4-yl)-2-methylphenyl)ethyl)carbamate [ka] To a solution of (R)-(1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)tert-butylcarbamate (500 mg, 1.38 mmol) in 1,4-dioxane / HO (v / v = 3 / 1, 12 mL) were added 2-chloro-5-fluoro-4-iodopyridine (427 mg, 1.66 mmol) and KOAc (272 mg, 2.77 mmol). Next, Pd(dppf)Cl·DCM (113 mg, 0.14 mmol) was added under a N atmosphere, and the reaction mixture was heated to 85 °C. The mixture was stirred at this temperature under N for 17 h and then concentrated in vacuo. The crude material was purified by silica gel column chromatography (petroleum ether / EtOAc, 5:1) to give (R)-(1-(4-(2-chloro-5-fluoropyridin-4-yl)-2-methylphenyl)ethyl) tert-butylcarbamate as a yellow amorphous solid (400 mg, yield: 80%). ESI-MS (M+H) + : 365.0. 1 H NMR (400 MHz, CD3OD) δ: 8.31 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 6.0 Hz, 1H), 7.47 (s, 2H), 7.43 (s, 1H), 4.95-4.93 (m, 1H), 2.45 (s, 3H), 1.42 (s, 9H), 1.36 (d, J = 6.8 Hz, 3H).

[0188] 2. Synthesis of tert-butyl (R)-(1-(4-(2-(cyclopropanecarboxamido)-5-fluoropyridin-4-yl)-2-methylphenyl)ethyl)carbamate [ka] To a solution of (R)-(1-(4-(2-chloro-5-fluoropyridin-4-yl)-2-methylphenyl)ethyl)tert-butylcarbamate (400 mg, 1.1 mmol) in 1,4-dioxane (10 mL) was added cyclopropanecarboxamide (121 mg, 1.4 mmol) and CsCO (714 mg, 2.2 mmol). Next, Pd(dba) (101 mg, 0.11 mmol) and Xantphos (191 mg, 0.33 mmol) were added under a N atmosphere. The reaction mixture was heated to 85 °C and stirred at that temperature for 17 h under N. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude material was purified by silica gel column chromatography (petroleum ether / EtOAc, gradient from 10:1 to 3:1) to give tert-butyl (R)-(1-(4-(2-(cyclopropanecarboxamido)-5-fluoropyridin-4-yl)-2-methylphenyl)ethyl)carbamate as a yellow amorphous solid (220 mg, yield: 48%). ESI-MS (M+H) + : 414.1.

[0189] 3. Synthesis of (R)-N-(4-(4-(1-aminoethyl)-3-methylphenyl)-5-fluoropyridin-2-yl)cyclopropanecarboxamide hydrochloride [ka] To a solution of tert-butyl (R)-(1-(4-(2-(cyclopropanecarboxamido)-5-fluoropyridin-4-yl)-2-methylphenyl)ethyl)carbamate (220 mg, 0.53 mmol) in EtOAc (2 mL) at 15° C., HCl / EtOAc solution (1.25 M, 8 mL) was added, and the resulting mixture was stirred at 15° C. for 1 h. The mixture was filtered, and the filter cake was dried in vacuo to give (R)-N-(4-(4-(1-aminoethyl)-3-methylphenyl)-5-fluoropyridin-2-yl)cyclopropanecarboxamide hydrochloride as a yellow solid (150 mg, yield: 81%), which was carried forward without further purification. ESI-MS (M+H) + : 314.0.

[0190] 4. Synthesis of (R)-5-(tert-butyl)-N-(1-(4-(2-(cyclopropanecarboxamido)-5-fluoropyridin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide (Compound 20) [ka] To a solution of (R)—N-(4-(4-(1-aminoethyl)-3-methylphenyl)-5-fluoropyridin-2-yl)cyclopropanecarboxamide hydrochloride (100 mg, 0.29 mmol) in DMF (5 mL) at 15° C. was added DIPEA (75 mg, 0.58 mmol), 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylic acid (97 mg, 0.57 mmol), and HATU (165 mg, 0.43 mmol). The mixture was stirred at 15° C. for 1 h, filtered, and the filtrate was purified by preparative HPLC (0.05% HCl / HO in CHCN / HO as mobile phase) to give (R)-5-(tert-butyl)-N-(1-(4-(2-(cyclopropanecarboxamido)-5-fluoropyridin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide as a white solid (75 mg, yield: 56%). ESI-MS (M+Na) + : 488.2. 1H NMR (400 MHz, CD3OD) δ: 8.25 (s, 1H), 8.12 (d, J = 5.6 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.50-7.47 (m, 2H), 5.47 (dd, J1= 13.6 Hz, J2= 6.8 Hz, 1H), 2.51 (s, 3H), 1.88-1.87 (m, 1H), 1.58 (d, J = 6.8 Hz, 3H), 1.47 (s, 9H), 1.02-0.99 (m, 2H), 0.95-0.90 (m, 2H).

[0191] Example 21: (R)-5-(tert-butyl)-N-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide (Compound 21) [ka] Synthesis of 1,4-bromo-2-chloro-N-methoxy-N-methylbenzamide [ka] To a solution of 4-bromo-2-chlorobenzoic acid (8 g, 34 mmol) and N,O-dimethylhydroxylamine hydrochloride (4 g, 41 mmol) in DCM (200 mL) at 9 °C, HATU (15.5 g, 41 mmol) and DIPEA (17.6 g, 136 mmol) were added. The reaction mixture was stirred at 9 °C for 4 h and then concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc, gradient from 7:1 to 2:1) to give 4-bromo-2-chloro-N-methoxy-N-methylbenzamide as a light brown oil (5.6 g, yield: 60%). 1 H NMR: (400 MHz, CDCl3) δ: 7.59 (d, J = 2.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 3.46 (s, 3H), 3.37 (s, 3H).

[0192] 2. Synthesis of 1-(4-bromo-2-chlorophenyl)ethan-1-one [ka] To a solution of 4-bromo-2-chloro-N-methoxy-N-methylbenzamide (5.6 g, 20 mmol, 1 equiv) in THF (80 mL) was added MeMgBr (3 M, 10 mL, 30 mmol, 1.5 equiv) at 8 °C. The reaction mixture was stirred at 8 °C for 6 h and then concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and poured into saturated aqueous NH4Cl (200 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (100 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to give 1-(4-bromo-2-chlorophenyl)ethan-1-one as a light brown solid (4 g, 86% yield), which was carried forward without further purification. 1 H NMR: (400 MHz, CDCl3) δ: 7.60 (s, 1H), 7.48-7.43 (m, 2H), 2.63 (s, 3H).

[0193] 3. Synthesis of (S,E)-N-(1-(4-bromo-2-chlorophenyl)ethylidene)-2-methylpropane-2-sulfinamide [ka] To a solution of 1-(4-bromo-2-chlorophenyl)ethan-1-one (4 g, 17.1 mmol) and (S)-2-methylpropane-2-sulfinamide (10.3 g, 85.5 mmol) in THF (100 mL) was added Ti(IV)(OEt) (19.5 g, 85.5 mmol) at 9 °C. The reaction mixture was heated to 80 °C and stirred at that temperature for 16 h. The reaction mixture was concentrated in vacuo, and the residue was dissolved in EtOAc (120 mL). The organic phase was poured into saturated aqueous NH Cl (250 mL), the layers were separated, and the aqueous phase was extracted with EtOAc (120 mL). The combined organic extracts were dried (Na SO ), filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (petroleum ether / EtOAc, gradient from 8:1 to 3:1) to give (S,E)-N-(1-(4-bromo-2-chlorophenyl)ethylidene)-2-methylpropane-2-sulfinamide as an orange oil (3.7 g, yield: 65%). 1 H NMR (400 MHz, CDCl3) δ: 7.58-7.55 (m, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 2.70 (s, 3H), 1.29 (s, 9H).

[0194] 4. Synthesis of (S)-N-((R)-1-(4-bromo-2-chlorophenyl)ethyl)-2-methylpropane-2-sulfinamide [ka] To a solution of (S,E)-N-(1-(4-bromo-2-chlorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (2 g, 6 mmol) in THF (100 mL) at 10 °C under N was added a solution of L-selectride (1 M, 18 mL, 18 mmol) dropwise. The reaction mixture was stirred at 10 °C under N for 3 h and then concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and poured into saturated aqueous NH4Cl (300 mL). The layers were separated, and the aqueous phase was extracted with EtOAc (100 mL × 2). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (petroleum ether / EtOAc, gradient from 6:1 to 1:2) to give (S)—N-((R)-1-(4-bromo-2-chlorophenyl)ethyl)-2-methylpropane-2-sulfinamide as a light brown solid (1.3 g, yield: 64%). 1 H NMR (400 MHz, CDCl3) δ: 7.52-7.38 (m, 2H), 7.32-7.30 (m, 1H), 4.99 (q, J = 6.4 Hz, 1H), 3.34 (s, 1H), 1.52 (d, J = 6.4 Hz, 3H), 1.20 (s, 9H).

[0195] 5. Synthesis of (R)-1-(4-bromo-2-chlorophenyl)ethan-1-amine hydrochloride [ka] To a solution of (S)—N—((R)-1-(4-bromo-2-chlorophenyl)ethyl)-2-methylpropane-2-sulfinamide (2.02 g, 5.98 mmol) in EtOAc (5 mL) at 9° C. was added HCl / EtOAc solution (2 M, 50 mL). The reaction mixture was stirred at 9° C. for 2 h. The resulting suspension was filtered, and the filter cake was dried under vacuum to give (R)-1-(4-bromo-2-chlorophenyl)ethan-1-amine hydrochloride as a pale gray solid (1.6 g, yield: 99%), which was carried forward without further purification. 1H NMR (400 MHz, DMSO-d6) δ: 8.83 (br s, 3H), 7.81 (d, J = 2.0 Hz, 1H), 7.75-7.70 (m, 2H), 4.60 (q, J = 6.4 Hz, 1H), 1.47 (d, J = 6.4 Hz, 3H).

[0196] 6. Synthesis of tert-butyl (R)-(1-(4-bromo-2-chlorophenyl)ethyl)carbamate [ka] To a solution of (R)-1-(4-bromo-2-chlorophenyl)ethan-1-amine hydrochloride (1.6 g, 5.92 mmol) and DIPEA (2.3 g, 17.8 mmol) in DCM (80 mL) at 5° C. was added BocO (1.7 g, 7.70 mmol). The reaction mixture was stirred at 5° C. for 2 h. The reaction mixture was concentrated in vacuo, and the crude material was purified by silica gel column chromatography (petroleum ether / EtOAc, gradient from 15:1 to 5:1) to give tert-butyl (R)-(1-(4-bromo-2-chlorophenyl)ethyl)carbamate as a pale gray solid (1.8 g, yield: 91%). 1 H NMR: (400 MHz, CDCl3) δ: 7.50 (d, J = 2.0 Hz, 1H), 7.39-7.36 (m, 1H), 7.21 (d, J = 8.0 Hz, 1H), 5.05-4.94 (m, 2H), 1.45-1.36 (m, 12H).

[0197] 7. Synthesis of tert-butyl (R)-(1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate [ka] To a solution of tert-butyl (R)-(1-(4-bromo-2-chlorophenyl)ethyl)carbamate (1.8 g, 5.38 mmol) in 1,4-dioxane (80 mL) under N was added bis(pinacolato)diboron (1.77 g, 6.99 mmol), Pd(dppf)Cl·DCM (351 mg, 0.43 mmol), and KOAc (1.06 g, 10.8 mmol). The mixture was heated to 80 °C under N and stirred at that temperature for 16 h, cooled to room temperature, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (petroleum ether / EtOAc, gradient from 12:1 to 3:1) to give tert-butyl (R)-(1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate as a pale white solid (1.5 g, yield: 73%). ESI-MS (Mt-Bu) + : 326.0.

[0198] 8. Synthesis of tert-butyl (R)-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)phenyl)ethyl)carbamate [ka] To a solution of tert-butyl (R)-(1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate (200 mg, 0.52 mmol) in 1,4-dioxane (15 mL) and HO (3 mL) was added N-(4-bromopyridin-2-yl)cyclopropanecarboxamide (152 mg, 0.63 mmol), Pd(dppf)Cl·DCM (21 mg, 0.03 mmol), and KCO (145 mg, 1.05 mmol). The mixture was heated to 85 °C under N and stirred at that temperature for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude material was purified by silica gel column chromatography (petroleum ether / EtOAc, gradient from 10:1 to 1:1) to give tert-butyl (R)-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)phenyl)ethyl)carbamate as a white solid (180 mg, yield: 83%). ESI-MS (M+H) + : 416.1.

[0199] 9. Synthesis of (R)-N-(4-(4-(1-aminoethyl)-3-chlorophenyl)pyridin-2-yl)cyclopropanecarboxamide hydrochloride [ka] To a solution of tert-butyl (R)-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)phenyl)ethyl)carbamate (180 mg, 0.43 mmol) in DCM (10 mL) at 20° C. was added HCl / EtOAc solution (4 M, 10 mL). The mixture was stirred at 20° C. for 2 h and concentrated in vacuo to give crude (R)-N-(4-(4-(1-aminoethyl)-3-chlorophenyl)pyridin-2-yl)cyclopropanecarboxamide hydrochloride as a yellow solid (130 mg, crude), which was carried forward without further purification. ESI-MS (M+H) + : 316.1.

[0200] 10. Synthesis of (R)-5-(tert-butyl)-N-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide (Compound 21) [ka] To a solution of (R)—N-(4-(4-(1-aminoethyl)-3-chlorophenyl)pyridin-2-yl)cyclopropanecarboxamide hydrochloride (130 mg, 0.41 mmol) in a DCM / DMF mixture (v / v=25 / 1, 52 mL) at 20° C., 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylic acid (84 mg, 0.49 mmol), HATU (187 mg, 0.49 mmol), and DIPEA (266 mg, 2.1 mmol) were added. The reaction mixture was stirred at 20° C. for 2 h, poured into HO (100 mL), and extracted with DCM (50 mL × 2). The combined organic extracts were concentrated in vacuo to give the crude material. The crude material was purified by preparative HPLC (0.05% HCl / HO in CHCN / HO as mobile phase) to give (R)-5-(tert-butyl)-N-(1-(2-chloro-4-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide as a white solid (87 mg, yield: 45%, ee: 99.5%). ESI-MS (M+Na) + : 490.1. 1 H NMR (400 mHz, CD3OD) δ: 8.35 (d, J = 6.4 Hz, 1H), 7.90 (d, J = 1.6 Hz, 1H), 7.85 (s, 1H), 7.79-7.75 (m, 1H), 7.73-7.67 (m, 2H), 5.61 (q, J = 7.2 Hz, 1H), 1.96-1.89 (m, 1H), 1.60 (d, J = 7.2 Hz, 3H), 1.48 (s, 9H), 1.16-1.10 (m, 2H), 1.08-1.03 (m, 2H).

[0201] Example 22: (R)-5-(tert-butyl)-N-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)-5-fluoropyridin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide (Compound 22) [ka] 1. Synthesis of tert-butyl (R)-(1-(2-chloro-4-(2-chloro-5-fluoropyridin-4-yl)phenyl)ethyl)carbamate [ka] To a solution of (R)-(1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)tert-butylcarbamate (400 mg, 1.05 mmol) in 1,4-dioxane / HO (v / v = 10 / 1, 22 mL) was added 2-chloro-5-fluoro-4-iodopyridine (324 mg, 1.26 mmol) and KOAc (206 mg, 2.10 mmol). Next, Pd(dppf)Cl·DCM (43 mg, 0.05 mmol) was added under a N atmosphere, and the reaction mixture was heated to 85 °C. The mixture was stirred at this temperature under N for 5 h and then concentrated in vacuo. The crude material was purified by silica gel column chromatography (petroleum ether / EtOAc, gradient from 20:1 to 10:1) to give tert-butyl (R)-(1-(2-chloro-4-(2-chloro-5-fluoropyridin-4-yl)phenyl)ethyl)carbamate as a colorless oil (250 mg, yield: 62%). ESI-MS (M+H) + : 385.0.

[0202] 2. Synthesis of tert-butyl (R)-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)-5-fluoropyridin-4-yl)phenyl)ethyl)carbamate [ka] To a solution of (R)-(1-(2-chloro-4-(2-chloro-5-fluoropyridin-4-yl)phenyl)ethyl)tert-butylcarbamate (250 mg, 0.65 mmol) in 1,4-dioxane (20 mL) was added cyclopropanecarboxamide (66 mg, 0.78 mmol) and CsCO (423 mg, 1.3 mmol). Next, Pd(dba) (60 mg, 0.07 mmol) and Xantphos (75 mg, 0.13 mmol) were added under a N atmosphere. The reaction mixture was heated to 90 °C and stirred at that temperature for 17 h under N. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude material was purified by silica gel column chromatography (petroleum ether / EtOAc, gradient from 10:1 to 1:1) to give tert-butyl (R)-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)-5-fluoropyridin-4-yl)phenyl)ethyl)carbamate as a yellow solid (130 mg, yield: 46%). ESI-MS (M+H) + : 434.0.

[0203] 3. Synthesis of (R)-N-(4-(4-(1-aminoethyl)-3-chlorophenyl)-5-fluoropyridin-2-yl)cyclopropanecarboxamide hydrochloride [ka] To a solution of tert-butyl (R)-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)-5-fluoropyridin-4-yl)phenyl)ethyl)carbamate (130 mg, 0.30 mmol) in DCM (10 mL) at 20° C. was added HCl / EtOAc solution (1.25 M, 10 mL), and the resulting mixture was stirred at 20° C. for 3 h. The reaction mixture was concentrated in vacuo to give crude (R)-N-(4-(4-(1-aminoethyl)-3-chlorophenyl)-5-fluoropyridin-2-yl)cyclopropanecarboxamide hydrochloride as a yellow solid (100 mg, crude), which was carried forward without further purification. ESI-MS (M+H) + : 333.9.

[0204] 4. Synthesis of (R)-5-(tert-butyl)-N-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)-5-fluoropyridin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide (Compound 22) [ka] To a solution of (R)-N-(4-(4-(1-aminoethyl)-3-chlorophenyl)-5-fluoropyridin-2-yl)cyclopropanecarboxamide hydrochloride (100 mg, 0.30 mmol) in a DCM / DMF mixture (v / v=25 / 1, 52 mL) at 20° C., DIPEA (194 mg, 1.5 mmol), 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylic acid (62 mg, 0.36 mmol), and HATU (137 mg, 0.36 mmol) were added. The mixture was stirred at 20° C. for 2 h, poured into HO (100 mL), and extracted with DCM (50 mL × 2). The combined organic extracts were concentrated in vacuo and the crude material was purified by preparative HPLC (0.05% HCl / HO in CHCN / HO as mobile phase) to give (R)-5-(tert-butyl)-N-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)-5-fluoropyridin-4-yl)phenyl)ethyl-1,2,4-oxadiazole-3-carboxamide as a white solid (48 mg, yield: 33%, ee: 98.9%). ESI-MS (M+H) + : 486.1. 1 H NMR: (400 MHz, CD3OD) δ: 8.33 (d, J = 2.8 Hz, 1H), 8.01 (d, J = 6.0 Hz, 1H), 7.75 (s, 1H), 7.69-7.61 (m, 2H), 5.61 (q, J = 7.2 Hz, 1H), 1.93-1.84 (m, 1H), 1.61 (d, J = 7.2 Hz, 3H), 1.48 (s, 9H), 1.07-1.03 (m, 2H), 1.00-0.95 (m, 2H).

[0205] Examples 23 to 107 The following compounds were prepared according to procedures similar to those described in Examples 1-22. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18] [Table 1-19] [Table 1-20] [Table 1-21] [Table 1-22]

[0206] Example 108. In vitro BTK kinase assay: BTK-POLYGAT-LS assay The purpose of the BTK in vitro assay is to detect IC 50The purpose of this assay is to determine the potency of compounds against BTK by measuring the phosphorylation of fluorescein-labeled polyGAT peptide (Invitrogen PV3611) in the presence of active BTK enzyme (Upstate 14-552), ATP, and inhibitors, followed by compound inhibition. BTK kinase reactions were performed in black 96-well plates (Costar 3694). In a typical assay, a 24 pL aliquot of ATP / peptide master mix (final concentrations: ATP 10 μM, polyGAT 100 nM) in kinase buffer (10 mM Tris-HCl pH 7.5, 10 mM MgCl2, 200 μM Na3PO4, 5 mM DTT, 0.01% Triton X-100, and 0.2 mg / ml casein) was added to each well. Next, 1 pL of 4X, 40X compound titration in 100% DMSO solvent was added, followed by 15 μL of BTK enzyme mix (final concentration 0.25 nM) in 1X kinase buffer. The assay was incubated for 30 minutes and then stopped with 28 μL of 50 mM EDTA solution. An aliquot (5 μL) of the kinase reaction was transferred to a low-volume white 384-well plate (Come 3674) and 5 μL of 2X detection buffer (Invitrogen PV3574, containing 4 nM Tb-PY20 antibody, Invitrogen PV3552) was added. The plate was covered and incubated for 45 minutes at room temperature. Time-resolved fluorescence (TRF) was measured using a Molecular Devices M5 (excitation 332 nm; emission 488 nm; fluorescein emission 518 nm). IC was calculated using a four-parameter fit with 100% enzyme activity determined from the DMSO control and 0% activity from the EDTA control. 50 Calculate the value.

[0207] Table 1 shows the activity of selected compounds of the present invention in the in vitro Btk kinase assay, where each compound number corresponds to the compound number shown in Examples 1-107 herein. "†" indicates IC 50 indicates that the IC is 1000nM or less or more than 10nM. 50 indicates that the IC is 10 nM or less or more than 1 nM. 50is 1 nM or less. [Table 2]

[0208] Example 109. In vitro PD assay in human whole blood Heparinized human venous blood was purchased from Bioreclamation, Inc. or SeraCare Life Sciences and arrived the next day. Whole blood was dispensed into a 96-well plate and "spiked" with serial DMSO dilutions of test compounds or drug-free DMSO. The final DMSO concentration in all wells was 0.1%. The plate was incubated at 37°C for 30 minutes. Lysis buffer containing protease and phosphatase inhibitors was added to the drug-containing sample and one of the DMSO-only samples (+PPi, high control), and lysis buffer containing protease inhibitors was added to the other DMSO-only sample (-PPi, low control). All lysed whole blood samples were subjected to the BTK capture and phosphotyrosine detection method described in US20160311802, incorporated herein by reference. ECL values ​​were graphed in Prism, and the test compound concentration resulting in 50% inhibition of the ECL signal by interpolation was estimated using a best fit curve constrained by the maximum and minimum values ​​defined by the +PPi high and −PPi low controls.

[0209] Table 2 shows the activity of selected compounds of the present invention in the pBTK assay, where each compound number corresponds to the compound number shown in Examples 1-107 described herein. "†" indicates IC 50 indicates that the IC is less than 10,000 nM but greater than 500 nM, and "††" indicates that the IC is 50 indicates that the IC is less than 500 nM but greater than 100 nM, and "†††" indicates that the IC is less than 500 nM but greater than 100 nM. 50 * indicates that the IC 50 A value greater than 10,000 nM is indicated. [Table 3]

Claims

1. The following formula: 【Chemical 1】 [In the formula: Ring A is a 5-membered N-containing heteroaryl having one or two additional heteroatoms independently selected from O, N, and S, and Ring A is a 5-membered N-containing heteroaryl having one or two independently selected R １ optionally replaced by m is 0 or 1; q is an integer selected from 0, 1, and 2; Q １ , Q ２ , and Q ３ are each independently C-R ４ and R １ For each occurrence, independently, halo, C １－６ Alkyl, or C ３－５ is cycloalkyl, １－６ Alkyl and C ３－５ Cycloalkyl is one to three independently selected R １０ optionally replaced by R ２ is selected from H and methyl; R ３ is C １－６ Alkyl, C ３－５ cycloalkyl, halo, or -OR ３ａ and the C １－６ Alkyl or C ３－５ Cycloalkyl is C １－３ 1 to 3 R independently selected from alkyl and halo ３０ optionally replaced by R ３ａ is C optionally substituted with 1 to 3 halo １－６ Is alkyl; Or, R ２ and R ３ together with their intervening atoms form a 7-membered carbocyclic or heterocyclic ring, said 7-membered heterocyclic ring having one heteroatom selected from N and O, and said 7-membered carbocyclic or heterocyclic ring containing one or two R ２０ optionally replaced by R ４ is, at each occurrence, independently H, halo, or C １－３ alkyl; R ５ is C optionally substituted with halo or 1 to 3 fluoro １－３ is alkyl; R ６ is independently selected at each occurrence from halo, —CN, and C optionally substituted with 1 to 3 halo. １－６ selected from alkyl; Or, two R's ６ the substituents, together with their intervening atoms, form a 3- to 5-membered cycloalkyl or a 4- to 5-membered saturated heterocyclic ring; R １０ is independently selected from halo, —OH, and C １－６ alkyl; R ２０ For each occurrence, independently, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 4- to 6-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halo, —CN, —C(O)R ２０ａ , —C(O) ２ R ２０ａ , -C(O)N(R ２０ａ ) ２ , -N(R ２０ａ ) ２ , -N(R ２０ａ ) C(O)R ２０ａ , -N(R ２０ａ ) C(O) ２ R ２０ａ , -N(R ２０ａ )C(O)N(R ２０ａ ) ２ , -N(R ２０ａ ) S (O) ２ R ２０ａ , -OR ２０ａ , -OC(O)R ２０ａ , -OC(O)N(R ２０ａ ) ２ , -SR ２０ａ , -S(O)R ２０ａ , -S(O) ２ R ２０ａ , -S(O)N(R ２０ａ ) ２ , and -S(O) ２ N (R ２０ａ ) ２ and C is selected from １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl may each occur with one or more R ２５ optionally replaced by R ２０ａ For each occurrence, independently, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl may each occur with one or more R ２５ optionally independently substituted by; R ２５ For each occurrence, independently, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 4- to 6-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halo, —CN, —C(O)R ２５ａ , —C(O) ２ R ２５ａ , -C(O)N(R ２５ａ ) ２ , -N(R ２５ａ ) ２ , -N(R ２５ａ ) C(O)R ２５ａ , -N(R ２５ａ ) C(O) ２ R ２５ａ , -N(R ２５ａ )C(O)N(R ２５ａ ) ２ , -N(R ２５ａ ) S (O) ２ R ２５ａ , -OR ２５ａ , -OC(O)R ２５ａ , -OC(O)N(R ２５ａ ) ２ , -SR ２５ａ , -S(O)R ２５ａ , -S(O) ２ R ２５ａ , -S(O)N(R ２５ａ ) ２ , and -S(O) ２ N (R ２５ａ ) ２ Selected from: R ２５ａ For each occurrence, independently, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl. or a pharmaceutically acceptable salt thereof.

2. The compound has the following formula: 【Chemistry 2】 or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1.

3. R ３ But -CH ３ , -CH ２ CH ３ , -CH(CH ３ ) ２ , -C(CH ３ ) ３ , -CHF ２ , -CF ３ , cyclopropyl, cyclobutyl, -F, -Cl, -OCF ３ , or -OCH ３ 3. The compound of claim 1 or 2, wherein

4. The compound has the following formula: 【Chemistry 3-1】 【Chemistry 3-2】 【Chemistry 3-3】 【Chemistry 3-4】 or a pharmaceutically acceptable salt thereof, R ２０ is C １－６ Alkyl, monocyclic C ４－６ Cycloalkyl, 4-6 membered saturated monocyclic heterocyclyl, —C(O)R ２０ａ , —C(O) ２ R ２０ａ , and -S(O) ２ R ２０ａ and C is selected from １－６ Alkyl, monocyclic C ４－６ Cycloalkyl and 4- to 6-membered saturated monocyclic heterocyclyl are each a group consisting of 1 to 3 R ２５ optionally replaced by R ２０ａ For each occurrence, independently, H, C １－６ Alkyl, monocyclic C ４－６ cycloalkyl, and 4- to 6-membered saturated monocyclic heterocyclyl, １－６ Alkyl, monocyclic C ４－６ Cycloalkyl and 4- to 6-membered saturated monocyclic heterocyclyl each have one or more R ２５ optionally independently substituted by; R ２５ For each occurrence, independently, C １－６ Alkyl, C ３－６ Cycloalkyl, 4-6 membered saturated monocyclic heterocyclyl, halo, —CN, —N(R ２５ａ ) ２ , and -OR ２５ａ Selected from: R ２５ａ is, for each occurrence, independently H or C １－６ 3. The compound of claim 1 or 2, wherein the compound is alkyl.

5. Ring A is selected from the group consisting of pyrazole, imidazole, oxazole, isoxazole, thiadiazole, isothiazole, 1,2,3-oxadiazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,2,4-thiadiazole, 1,2,3-triazole, and 1,2,4-triazole, each of which is selected from the group consisting of one or two independently selected R １ The compound of any one of claims 1 to 4, optionally substituted by:

6. Ring A is of the following formula: 【Chemistry 4】 The compound according to any one of claims 1 to 4, represented by:

7. R １ Each occurrence of is independently -F, -C(CH ３ ) ３ , -C(CH ２ OH)(CH ３ ) ２ , -C(CH ２ F) (CH ３ ) ２ ,or 【Chemistry 5】 The compound according to any one of claims 1 to 6,

8. R ４ is H, —F, —Cl, or —CH ３ The compound according to any one of claims 1 to 7,

9. m is 0 or m is 1, and R ５ is —F, —Cl, or —CF ３ The compound according to any one of claims 1 to 8,

10. The compound according to any one of claims 1 to 9, wherein q is 0.

11. R ６ Each occurrence of is independently -CH ３ , -CF ３ 10. The compound of any one of claims 1 to 9, wherein the group is selected from -F and -CN.

12. q is 2; and two R ６ 10. The compound of any one of claims 1 to 9, wherein the substituents, together with their intervening atoms, form cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, or oxathiolanyl.

13. The compound has the following formula: 【Chemistry 6】 [In the formula: Ring A is one or two independently selected R １ is an oxadiazole optionally substituted by R １ is, at each occurrence, independently, a halo or C １－６ is alkyl; R ３ is halo or C １－３ Is alkyl; Or, R ２ and R ３ together with their intervening atoms form a 7-membered carbocyclic or heterocyclic ring, said 7-membered heterocyclic ring having one heteroatom selected from N and O, said 7-membered carbocyclic or heterocyclic ring containing one R ２０ optionally replaced by R ２０ is C optionally substituted with 1 to 3 fluoro １－６ is alkyl; R ４ is H or halo; R ５ is a halo; R ６ is halo or C １－３ is alkyl; m is 0 or 1; q is 0 or 1. or a pharmaceutically acceptable salt thereof, and optionally wherein ring A is represented by the following formula: 【Chemistry 7】 where R １ But -C(CH ３ ) ３ and q is 0; or q is 1, and R ６ is -F or -CH ３ and m is 0; or m is 1; R ５ is —F or —Cl; R ２ is H or -CH ３ and R ３ is -Cl, -CH ３ , or -CF ３ and R ４ The compound of claim 1, wherein is H or —F.

14. The compound has the following formula: 【Chemistry 8】 or a pharmaceutically acceptable salt thereof, optionally with R ２０ But -CH ２ CF ３ 14. The compound of claim 13, wherein:

15. A pharmaceutical composition comprising the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

16. 15. A pharmaceutical composition comprising a compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, for treating a disorder responsive to inhibition of Bruton's tyrosine kinase in a subject, optionally wherein the disorder is an autoimmune disorder or multiple sclerosis.

Images