Inhibiting agents for bruton's tyrosine kinase

Abstract

To provide agents for inhibiting Bruton's tyrosine kinase (Btk), and methods for use and production of such agents.SOLUTION: Provided are compounds of formula (I), or pharmaceutically acceptable salts thereof, and methods for their use and production.SELECTED DRAWING: None

Description

Related Applications

[0001] Cross - References to Related Applications This application claims the benefit of the filing date of U.S. Provisional Application No. 62 / 847,985, filed on May 15, 2019, under 35 U.S.C. § 119(e), the entire content of which is incorporated herein by reference.

Technical Field

[0002] Provided are certain agents that inhibit Bruton's tyrosine kinase (Btk), as well as methods for manufacturing and using such agents.

Background Art

[0003] Protein kinases are a large multigene family consisting 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 (tyrosine kinase expressed in hepatocellular carcinoma), Btk (Bruton's tyrosine kinase), Itk (interleukin-2 (IL-2)-inducible T cell kinase; also known as Emt or Tsk), Rlk (resting lymphocyte kinase; also known as Txk), and Bmx (bone marrow tyrosine kinase gene on chromosome X; also known as Etk)), which are mainly expressed in hematopoietic cells, although the expression of Bmx and Tec 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 the regulation of B cell activation, proliferation, and differentiation. More specifically, Btk contains a PH domain that binds to phosphatidylinositol (3,4,5)-trisphosphate (PIP3). Binding of PIP3 induces phosphorylation of phospholipase C (PLCy) by Btk, thereby hydrolyzing PIP2 to generate two second messengers, inositol trisphosphate (IP3) and diacylglycerol (DAG), which activate protein kinase PKC and induce further B cell signaling. As a result of mutations that inactivate Btk enzyme activity, XLA syndrome (X-linked agammaglobulinemia), a primary immunodeficiency disorder, occurs. Considering the important role that Tec kinases play in signaling in both B cells and T cells, Tec kinases are targets for autoimmune diseases.

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

Summary of the Invention

[0005] The first embodiment of the present invention is of formula (I):

Chemical formula

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

[0007] In one embodiment, the present 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 the compounds described herein or pharmaceutically acceptable salts thereof for use as a medicament. In another embodiment, the present invention provides the compounds described herein or pharmaceutically acceptable salts thereof for use in treating a disorder responsive to inhibition of Btk.

[0009] Other features or advantages will be apparent from the detailed description of the following embodiments and from the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

[0010] The compounds described herein or pharmaceutically acceptable salts thereof may have activity as Btk modulators. In particular, the compounds described herein or pharmaceutically acceptable salts thereof may 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 C-R 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; and the definitions of the variables are as defined in the first or second embodiment.

[0013] In the fourth embodiment of the present invention, the compound is of formula (II) or (III):

Chemical formula

[0014] In the 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 definitions of the other variables are as defined in the first, second, third, or fourth embodiment.

[0015] In the sixth embodiment of the present invention, the compound is of formula (IV) or (V):

Chemical formula

[0016] In the 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 optionally substituted by 1 to 3 R 1-3 independently selected from C 30 alkyl and halo; R 3a is C 1-6 alkyl optionally substituted by 1 to 3 halo; and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, or sixth embodiment. In a specific embodiment, R 3is C 1-4 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, -F, -Cl, or -OR 3a wherein said C 1-4 alkyl is optionally substituted by 1 to 3 fluoros; R 3a is C 1-4 alkyl optionally substituted by 1 to 3 fluoros. 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 a more specific embodiment, 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 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 is optionally substituted by one or two R 20 ; the definitions of the other variables are as defined in the first, second, third, fourth, fifth, or sixth embodiment.

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

[0020] In the 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 selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered saturated monocyclic heterocyclyl, halo, -OR 20a , -OC(O)R 20a , -OC(O)N(R 20a )2, and -SR 20a , and the C 1-6 alkyl, C 3-6 cycloalkyl, and 4- to 6-membered saturated monocyclic heterocyclyl are optionally substituted by 1 to 3 R 25 ; R 20a is, each occurrence, independently, H or C 1-6 alkyl, and the C 1-6 alkyl is, each occurrence, independently optionally substituted by one R 25 ; R 25 is, each occurrence, independently, C 1-6Selected from alkyl or halo; the definitions of the other variables are as defined in the first, second, third, fourth, fifth, or sixth embodiments. In a specific embodiment, R 20 is H.

[0021] In a twelfth embodiment of the 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- to 6-membered saturated monocyclic heterocyclyl, -C(O)R 20a , -C(O)2R 20a , and -S(O)2R 20a selected from, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, and 4- to 6-membered saturated monocyclic heterocyclyl are optionally substituted by 1 to 3 R 25 ; R 20a is, each occurrence, independently selected from H, C 1-6 alkyl, C 4-6 cycloalkyl, and 4- to 6-membered saturated monocyclic heterocyclyl, wherein the C 1-6 alkyl, C 4-6 cycloalkyl, and 4- to 6-membered saturated monocyclic heterocyclyl are each occurrence independently optionally substituted by one or more R 25 ; R 25 is, each occurrence, independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered saturated monocyclic heterocyclyl, halo, -CN, -N(R 25a )2, and -OR 25a ; R 25a is, each occurrence, independently H or C 1-6is alkyl; the definitions of the other variables are as defined in the first, second, third, fourth, fifth, or sixth embodiments. In a specific embodiment, R 20 is C 1-6 alkyl optionally substituted by 1 to 3 fluoro. In another specific embodiment, R 20 is -CH2CF3.

[0022] In the 13th 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 optionally substituted by one or two independently selected R 1 ; 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 as defined in any specific embodiment described therein.

[0023] In the 14th 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 optionally substituted by one or two independently selected R 1 ; and the definitions of the other variables are as defined in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, or 12th embodiment, or any specific embodiment described therein.

[0024] In the 15th 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 represented by the following formula:

Chemical formula

[0025] In the 16th 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 is, each occurrence, independently, halo, C 1-6 alkyl, or C 3-5 cycloalkyl, and the C 1-6 alkyl and C 3-5 cycloalkyl are optionally substituted by 1 to 3 independently selected R 10 ; R 10 is, each occurrence, independently, selected from halo, -OH, and C 1-6 alkyl; the definitions of the other variables are as defined in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, or 15th embodiment, or as defined in any specific embodiment described therein.

[0026] In the 17th 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 is, each occurrence, independently, halo, C 1-4 alkyl, cyclopropyl, cyclobutyl, or cyclopentyl, and the C 1-4 alkyl, cyclopropyl, cyclobutyl, or cyclopentyl is optionally substituted by 1 to 3 R 10 independently selected from methyl, fluoro, and -OH; the definitions of the other variables are as defined in the 16th embodiment. In a specific embodiment, R1 For each occurrence, independently, -F, -C(CH3)3, -C(CH2OH)(CH3)2, -C(CH2F)(CH3)2, or

Chemical formula

[0027] In the 18th embodiment of the present invention, the compound is of 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 alkyl; the definitions of the other variables are as defined in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, or 17th embodiment, or any specific embodiment described therein. In a specific embodiment, R 4 is H, -F, -Cl, or -CH3.

[0028] In the 19th embodiment of the present invention, the compound is of 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; the definitions of the other variables are as defined in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, or 18th embodiment, or any specific embodiment described therein.

[0029] In the 20th 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 halo, or C 1-3 alkyl optionally substituted by 1 to 3 fluoros; the definitions of the other variables are as defined in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, or 18th embodiment, or any specific embodiment described therein. In a specific embodiment, R 5 is -F, -Cl, or -CF3.

[0030] In the 21st 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; the definitions of the other variables are as defined in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, or 20th embodiment, or any specific embodiment described therein.

[0031] In the 22nd 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, where R 6 is, independently for each occurrence, selected from halo, -CN, and C 1-6 alkyl optionally substituted with one to three halo; the definitions of the other variables are as defined in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, or 20th embodiment, or any specific embodiment described therein. In a specific embodiment, R 6 is, independently for each occurrence, -CH3, -CF3, -F, or -CN.

[0032] In the 23rd 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; two R 6 substituents, together with their intervening atoms, form a 3- to 5-membered cycloalkyl or a 4- to 5-membered saturated heterocycle; the definitions of the other variables are as defined in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, or 20th embodiment, or any specific embodiment described therein. In a specific embodiment, two R 6The substituents, together with their intervening atoms, form cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, or oxathiolanyl. In another specific embodiment, two R 6 The substituents, together with their intervening atoms, form cyclopropyl, cyclobutyl, cyclopentyl, or tetrahydrofuranyl.

[0033] In a twenty-fourth embodiment of the invention, the compound is of formula (IV) or (V):

Chemical formula

[0034] In the 25th embodiment, the compound is represented by formula (IV) or (V), or a pharmaceutically acceptable salt thereof, wherein ring A is of the following formula:

Chemical formula

[0035] In the 26th embodiment, the compound is represented by formula (IV) or (V), or a pharmaceutically acceptable salt thereof, wherein R 1 is -C(CH3)3; the definitions of the other variables are as defined in the 24th or 25th embodiment.

[0036] In the 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 R 6 is -F or -CH3; the definitions of the other variables are as defined in the 24th, 25th, or 26th embodiment.

[0037] In the 28th 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 24th, 25th, 26th, or 27th embodiment.

[0038] In the 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 3is -Cl, -CH3, or -CF3; the definitions of the other variables are as defined in Embodiment 24, 25, 26, 27, or 28.

[0039] In Embodiment 30, 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 Embodiment 24, 25, 26, 27, 28, or 29.

[0040] In Embodiment 31, the compound is of formula (VIC), (VIc’), (VIIIc), or (VIIIc’):

Chemical formula

[0041] In the 32nd 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-carboxamido)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-Butyl)-N-(4-(2-((1R,2R)-2-fluorocyclopropane-1-carboxamido)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-Butyl)-N-(4-(2-((1S,2R)-2-fluorocyclopropane-1-carboxamido)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-Butyl)-N-(4-(2-((1R,2S)-2-fluorocyclopropane-1-carboxamido)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-carboxamido)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-Butyl)-N-(2-methyl-4-(2-((1S,2R)-2-methylcyclopropane-1-carboxamido)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-Butyl)-N-(2-methyl-4-(2-((1R,2S)-2-methylcyclopropane-1-carboxamido)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-Butyl)-N-(2-methyl-4-(2-((1R,2R)-2-methylcyclopropane-1-carboxamido)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)pentafluoropyridin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-Butyl)-N-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)pentafluoropyridin-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-carboxamido)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-Butyl)-N-(2-methyl-4-(2-((1R,2R)-2-(trifluoromethyl)cyclopropane-1-carboxamido)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-Butyl)-N-(2-methyl-4-(2-((1R,2S)-2-(trifluoromethyl)cyclopropane-1-carboxamido)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-Butyl)-N-(2-methyl-4-(2-((1S,2R)-2-(trifluoromethyl)cyclopropane-1-carboxamido)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-Butyl)-N-(2-methyl-4-(2-((1S,2S)-2-(trifluoromethyl)cyclopropane-1-carboxamido)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; 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-carboxamido)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-Butyl)-N-(4-(2-((1S,2R)-2-fluorocyclopropane-1-carboxamido)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-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[2.2]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-((S)-2-(2-((S)-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; 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-carboxamido)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-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,6r)-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,5R)-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,5S)-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,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-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,6s)-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-(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-cyanocyclopropan-1-car Boxamide)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-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-((1R,2R)-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-(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-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-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-((1S,2R)-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-((1S,2S)-2-Cyano 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-((S)-2-(2-((1R,2R)-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-((S)-2-(2-((1R,2S)-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-((S)-2-(2-((1S,2R)-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-((S)-2-(2-((1S,2S)-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-(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-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-(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-((1S,2R)-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-((1S,2S)-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-((S)-2-(2-((1R,2R)-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-((S)-2-(2-((1R,2S)-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-((S)-2-(2-((1S,2R)-2-(Trifluoromethyl)cyclopropane-1-carboxamido)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxa diazole-5-carboxamide; 3-(tert-Butyl)-N-((S)-2-(2-((1S,2S)-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; 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-(cyclopropanecarbox oxamido)pyridin-4-yl)-5-fluorophenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide; (R)-3-(tert-Butyl)-N-(1-(2-chloro-4-(2-(cyclopropanecarboxamide)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, selected from or a pharmaceutically acceptable salt thereof.

[0042] In a specific 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-((1S,2S)-2-fluorocyclopropane-1-carboxamido)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-Butyl)-N-(4-(2-((1R,2R)-2-fluorocyclopropane-1-carboxamido)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-Butyl)-N-(2-methyl-4-(2-((1S,2S)-2-methylcyclopropane-1-carboxamido)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide; 5-(tert-Butyl)-N-(2-methyl-4-(2-((1R,2R)-2- methylcyclopropane-1-carboxamido)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 from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms. In some embodiments, alkyl contains from 6 to 20 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl.

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

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

[0046] The number of carbon atoms therein is specified herein by the prefix "C x-xx "(wherein x and xx are integers). For example, "C 1-4 alkyl" is an alkyl group having 1 to 4 carbon atoms.

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

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

[0050] In one embodiment, the heterocycle 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 heterocycle is a 4- to 6-membered monocyclic ring. In another embodiment, the heterocycle is an 11-membered bicyclic ring. In yet another embodiment, the heterocycle is a 4- to 7-membered monocyclic non-aromatic ring. In another embodiment, the heterocycle is a 6- to 8-membered spiro or bridged bicyclic ring. The heterocyclic group may be bonded to a heteroatom or a carbon atom. Examples of the heterocycle include aziridinyl, oxiranyl, thiaranyl, 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 azetyl, thienyl, 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, but are not limited thereto.

[0051] As used herein, the term "fused ring system" is a ring system having two rings each independently selected from a carbocyclic or heterocyclic ring, and 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 carbocyclic ring or a heterocyclic ring in which two non-adjacent atoms of the ring are linked (bridged) by one or more (preferably 1 to 3) atoms selected from C, N, O, or S. The bridged ring system may 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 carbocyclic or heterocyclic, and having one ring atom common to the two ring structures. The spiro ring system may have 5 to 8 ring members.

[0054] In one embodiment, the heterocyclyl is a 4- to 6-membered monocyclic heterocyclyl. Examples of 4- to 6-membered monocyclic heterocyclic systems include azetidinyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, dihydrofuranyl, imidazolinyl, dihydropyranyl, pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, o xazinyl, thiazinyl, dioxinyl, dithiinyl, oxathianyl, triazinyl, and tetrazinyl, but are not limited thereto.

[0055] In another embodiment, the heterocyclic ring is a 4- to 6-membered saturated monocyclic heterocyclic ring. Examples of 4- to 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- to 6-membered saturated monocyclic heterocyclic ring is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.

[0056] In another embodiment, the heterocyclic ring is a 4- to 5-membered saturated monocyclic heterocyclic ring. Examples of 4- to 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 "carbocyclic" 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 "carbocyclic" encompasses cycloalkyl groups and aromatic groups. The term "cycloalkyl" refers to a fully saturated monocyclic, bicyclic or spiro hydrocarbon group having 3 to 7, 3 to 6, or 5 to 7 carbon atoms. Exemplary monocyclic carbocyclic 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 carbocyclic groups include bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, tricyclo[2.2.1.0 2,6 heptanyl, 6,6-dimethylbicyclo[3.1.1]heptyl, or 2,6,6-trimethylbicyclo[3.1.1]heptyl, spiro[2.2]pentanyl, and spiro[3.3]heptanyl. In one embodiment, the carbocyclic is a 4- to 6-membered monocyclic carbocyclic. In another embodiment, the carbocyclic is a C 3-5 cycloalkyl such as cyclopropyl, cyclobutyl, or cyclopentyl. In one embodiment, the carbocyclic is a C 4-6 cycloalkyl such as cyclobutyl, cyclopentyl, or cyclohexyl.

[0058] If the compounds provided herein are sufficiently basic or acidic to form stable, non-toxic acidic or basic salts, the preparation and administration of the compounds as pharmaceutically acceptable salts may be appropriate. Examples of pharmaceutically acceptable salts include organic acid addition salts formed with acids that form physiologically acceptable anions, such as tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate, or α-glycerophosphate. Inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate.

[0059] Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example, by reacting a sufficiently basic compound, such as an amine, with an appropriate acid that provides a physiologically acceptable anion. Alkali metal (e.g., sodium, potassium, or lithium) salts or alkaline earth metal (e.g., calcium) salts of carboxylic acids can also be prepared.

[0060] Pharmaceutically acceptable base addition salts can be prepared from inorganic bases and organic bases. Salts derived from inorganic bases can include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, or magnesium. 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 cycloalkenylamines, disubstituted cycloalkenylamines, trisubstituted cycloalkenylamines, arylamines, diarylamines, triarylamines, heteroarylamines, diheteroarylamines, triheteroarylamines, heterocycloalkylamines, diheterocycloalkylamines, triheterocycloalkylamines, or mixed diamines and triamines where at least two of the substituents on the amine may be different and may be, for example, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, or heterocycloalkyl. Also included are amines where two or three substituents together with the amino nitrogen form a heterocycloalkyl group or a heteroaryl group. Non-limiting examples of amines can include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, trimethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucosamine, theobromine, purine, piperazine, piperidine, morpholine, or N-ethylpiperidine, etc.Other carboxylic acid derivatives, such as carboxamides, lower alkyl carboxamides, or dialkyl carboxamides, etc., may be useful carboxylic acid amides.

[0061] The compounds described herein or their pharmaceutically acceptable salts may contain one or more chiral centers in the molecule. According to the present disclosure, any structure in which the stereochemistry is not specified should be understood to include 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 the racemic form by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase).

[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 weight percentage of the target stereoisomer relative to the total 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 weight percentage of the target enantiomer relative to the total weight of all stereoisomers.

[0064] The stereochemistry of the disclosed compounds is named or described by the structure, and when the named or described structure encompasses multiple stereoisomers (such as a pair of diastereomers), it should be understood that one of the included stereoisomers or any mixture of the included stereoisomers is included. Further, the stereochemical purity of the named or described stereoisomer should 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 percentage of the intended stereoisomer whose name or structure is included relative to the total weight of all stereoisomers.

[0065] When the disclosed compound is named or described by the structure without showing stereochemistry and the compound has one chiral center, the name or structure should be understood to include one enantiomer of the compound in pure or substantially pure form, as well as mixtures thereof (such as a racemic mixture of the compound and mixtures enriched in one enantiomer compared to the corresponding optical isomers).

[0066] When the disclosed compound is named or described by the structure without showing stereochemistry and, for example, the compound has at least two chiral centers, the name or structure should be understood to include one stereoisomer of the compound in pure or substantially pure form, as well as mixtures thereof (such as a mixture of stereoisomers and mixtures enriched in one or more stereoisomers compared to other stereoisomer(s)).

[0067] The disclosed compounds may exist in tautomeric forms and mixtures, and the isolated individual tautomers are contemplated. In addition, some compounds may exhibit polymorphs.

[0068] In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof contain 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] Use of the compounds described herein or pharmaceutically acceptable salts thereof can reduce the activity of Btk or otherwise affect the properties and / or behavior of Btk, such as stability, phosphorylation, kinase activity, interaction with other proteins, etc.

[0071] In some embodiments, the present invention provides a method of reducing Btk enzyme activity. In some embodiments, such a method comprises contacting Btk with an effective amount of a Btk inhibitor. Accordingly, the present invention further provides a method of inhibiting Btk enzyme activity by contacting Btk with the 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" refers to a disease or Comprising disorders, for example, this includes acute disseminated encephalomyelitis (ADEM), Addison's disease, alopecia areata, antiphospholipid antibody syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, bullous pemphigoid (BP), celiac disease, dermatomyositis, type 1 diabetes, Goodpasture syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, lupus erythematosus, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polymyositis, primary biliary cirrhosis, Sjögren's syndrome, temporal arteritis, and Wegener's granulomatosis. The term "inflammatory disorder" includes diseases or disorders associated with acute or chronic inflammation, for example, this includes allergies, asthma, prostatitis, glomerulonephritis, pelvic inflammatory disease (PID), inflammatory bowel disease (IBD, e.g., Crohn's disease, ulcerative colitis), reperfusion injury, rheumatoid arthritis, graft rejection, and vasculitis. In some embodiments, the present invention provides a method for treating rheumatoid arthritis or lupus. In some embodiments, the present invention provides a method for treating multiple sclerosis.

[0075] The term "cancer" includes diseases or disorders associated with abnormal cell growth and / or proliferation, for example, this includes 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, cholangiocarcinoma, ovarian cancer, endometrial cancer, prostate cancer, renal cell carcinoma, lymphoma (e.g., anaplastic large cell lymphoma), leukemia (e.g., acute myeloid leukemia, T-cell leukemia, chronic lymphocytic leukemia), multiple myeloma, malignant mesothelioma, malignant melanoma, and colon cancer (e.g., microsatellite instability-high colorectal cancer). In some embodiments, the present invention provides a method for treating leukemia or lymphoma.

[0076] As used herein, the terms "subject" and "patient" may be used interchangeably and mean a mammal in need of treatment, for example, a companion animal (e.g., dog, cat, etc.), a livestock animal (e.g., cow, pig, horse, sheep, goat, etc.), and a laboratory animal (e.g., rat, mouse, guinea pig, etc.). Usually, 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 can be therapeutic and includes, for example, partially or completely reducing the degree of a disease, disorder, or syndrome; alleviating or improving clinical symptoms or markers associated with the disorder; or partially or substantially achieving one or more of delaying, inhibiting, or reducing the likelihood of progression of a disease, disorder, or syndrome.

[0078] The effective dosage of the compounds or pharmaceutically acceptable salts thereof provided herein, when administered to a subject, can be from 10 μg to 500 mg.

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

[0080] Accordingly, the compounds or pharmaceutically acceptable salts thereof described herein are, for example , in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an absorbable edible carrier, can be administered systemically, for example, orally. These can be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or taken directly with food for patients. In the case of oral therapeutic administration, the compounds described herein or their pharmaceutically acceptable salts are mixed with one or more excipients and used in the form of tablets for oral ingestion, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, or cachets. Such compositions and preparations need to contain at least about 0.1% of the active compound. The ratios of the compositions and preparations may of course vary and can be, for convenience, about 2% to about 60% of the weight of a given unit dosage form. The amount of the active compound in such therapeutically useful compositions can be such that an effective dosage level is obtained.

[0081] Tablets, lozenges, pills, capsules, etc. may contain the following: binders such as tragacanth gum, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, alginic acid; lubricants such as magnesium stearate; or sweetening or flavoring agents 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 with water and optionally mixed with a non-toxic 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 immediate preparation of sterile solutions or dispersions for injection or infusion. In any case, the final dosage form needs to be sterile, fluid, and stable under the manufacturing and storage conditions.

[0084] The sterile injectable solutions can be prepared by incorporating the required amount of the active compound, optionally with various other ingredients enumerated above, into a suitable solvent and then filtering and sterilizing. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation can be vacuum drying and lyophilization 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 can include micronized solids such as talc, clay, microcrystalline cellulose, silica, alumina, etc. Useful liquid carriers include water, alcohols, or glycols, or mixtures of water-alcohol / glycol, into which the compounds described herein or their pharmaceutically acceptable salts can be dissolved or dispersed at effective levels, optionally using non-toxic surfactants.

[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 extrapolating effective dosages in humans from effective dosages in mice and other animals are known in the art; see, for example, U.S. Patent No. 4,938,949, which is incorporated herein by reference in its entirety.

[0087] The amount of the compounds described herein or their pharmaceutically acceptable salts required for therapeutic use can vary depending not only on the particular salt selected, but also on the route of administration, the nature of the condition being treated, and the age and condition of the patient, and can ultimately be at the discretion of the attending physician or clinician. However, generally, the dosage can be in the range of about 0.1 to about 10 mg / kg body weight per day.

[0088] The compounds described herein or their pharmaceutically acceptable salts can, for convenience, be administered in unit dosage form, for example, containing from 0.01 to 10 mg, or from 0.05 to 1 mg of the active ingredient per unit dosage form. In some embodiments, dosages of 5 mg / kg or less may be suitable.

[0089] For convenience, there may be a desired dosage for a single dosage amount, or divided dosage amounts administered at appropriate intervals.

[0090] The disclosed method may include a kit that includes 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 containing the compound described herein or a pharmaceutically acceptable salt thereof, to cells or a subject. This should be construed to include other embodiments of kits known to those skilled in the art. For example, this may be a kit that includes a solvent (e.g., sterile) for dissolving or suspending the compound described herein or a pharmaceutically acceptable salt thereof or a composition before administering the compound described herein or a pharmaceutically acceptable salt thereof or a composition to cells or a subject. In some embodiments, the subject can be a human.

[0091] Illustration LCMS method: Samples were analyzed on a Waters Acquity UPLC BEH C18 1.7 μM 2.1×50 mm, part number 186002350 machine, MS mode: MS: 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 at 0.7 ml / min in 0.1% trifluoroacetic acid (0.1% v / v) for 1 minute, holding at 5% H2O / 95% CH3CN for 1.3 minutes, and 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)

Chemical formula

Chemical formula

[0093] Synthesis of tert-butyl 4-bromo-2-methylbenzylcarbamate

Chemical formula

[0094] Synthesis of tert-butyl 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate

Chemical formula

[0095] 4. Synthesis of N-(4-bromo-2-pyridyl)cyclopropanecarboxamide

Chemical Structure

[0096] 5. Synthesis of tert-butyl N-[[4-[2-(cyclopropanecarbonylamino)-4-pyridyl]-2-methyl-phenyl]methyl]carbamate

Chemical Structure

[0097] Synthesis of 6-N-[4-[4-(aminomethyl)-3-methyl-phenyl]-2-pyridyl]cyclopropanecarboxamide hydrochloride

Chem.

[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)

Chem.

[0099] Example 2: 5-(tert-Butyl)-N-(4-(2-(cyclopropanecarbox amide)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride (Compound 2)

Chem.

[0100] Examples 3 and 4: 5-(tert-Butyl)-N-(4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamido)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-carboxamido)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide (Compound 4)

Chem.

Chem.

[0101] 2. Synthesis of cis-N-(4-bromopyridin-2-yl)-2-fluorocyclopropane-1-carboxamide

Chem.

[0102] 3. Synthesis of tert-butyl (4-(2-((cis-2-fluorocyclopropane-1-carboxamido)pyridin-4-yl)-2-methylbenzyl)carbamate

Chemical Structure

[0103] 4. Synthesis of cis-N-(4-(4-(aminomethyl)-3-methylphenyl)pyridin-2-yl)-2-fluorocyclopropane-1-carboxamide hydrochloride

Chemical formula

[0104] Synthesis of 5.5-(tert-butyl)-N-(4-(cis-2-fluorocyclopropane-1-carboxamido)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide

Chemical formula

[0105] Chiral separation of 6.5-(tert-butyl)-N-(4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamido)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide (3) and 5-(tert-butyl)-N-(4-(2-((1R,2R)-2-fluorocyclopropane-1-carboxamido)pyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide (4)

Chemical formula

[0106] Example 5: 5-(tert-Butyl)-N-(2-methyl-4-(2-((1S,2S)-2-methylcyclopropane-1-carboxamido)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (Compound 5)

Chemical Structure

Chemical Structure

[0107] 2. Synthesis of tert-butyl N-[[2-methyl-4-[2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4-pyridyl]phenyl]methyl]carbamate

Chemical Structure

[0108] 3. Synthesis of (1S,2S)-N-[4-[4-(aminomethyl)-3-methylphenyl]-2-pyridyl]-2-methylcyclopropanecarboxamide hydrochloride

Chemical Structure

[0109] Synthesis of 4.5-(tert-butyl)-N-(2-methyl-4-(2-((1S,2S)-2-methylcyclopropane-1-carboxamido)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (Compound 5) [Chemical formula] (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) solution, DIPEA (164 mg, 1.27 mmol, 222 μL) was added. The reaction mixture was cooled to 0 °C, and HATU (116 mg, 305 μmol) was added all at once. The reaction mixture was warmed to room temperature and stirred at that temperature for 18 hours. The reaction mixture was diluted with EtOAc (20 mL) and washed successively with H2O (20 mL × 2) and brine (50 mL). Then, the organic phase was dehydrated (Na2SO4), filtered, and concentrated. The crude material was purified by silica gel column chromatography ([3:1 EtOAc:EtOH] / heptane, gradient from 0% to 100%) to give 5-(tert-butyl)-N-(2-methyl-4-(2-((1S,2S)-2-methylcyclopropane-1-carboxamido)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. 1 H 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)

Chemical formula

Chemical formula

[0111] 2. Synthesis of tert-butyl N-[[2-methyl-4-[2-[[(1R,2R)-2-methylcyclopropanecarbonyl]amino]-4-pyridyl]phenyl]methyl]carbamate

Chemical formula

[0112] 3. Synthesis of (1R,2R)-N-[4-[4-(aminomethyl)-3-methylphenyl]-2-pyridyl]-2-methylcyclopropanecarboxamide hydrochloride

Chemical Structure

[0113] Synthesis of 4.5-(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) [Chemical formula] (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) solution, DIPEA (47 mg, 362 μmol, 63 μL) was added. After cooling the reaction mixture to 0 °C, T3P (153 mg, 241 μmol, 163 μL, purity 50%) was added all at once. 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 successively with H2O (20 mL×2) and brine (50 mL). Next, the organic phase was dehydrated (Na2SO4), filtered, and concentrated. The crude material was purified by silica gel column chromatography ([3:1 EtOAc:EtOH] / heptane, gradient from 0% to 100%) to give 5-(tert-butyl)-N-(2-methyl-4-(2-((1R,2R)-2-methylcyclopropane-1-carboxamido)pyridin-4-yl)ben zil)-1,2,4-oxadiazole-3-carboxamide as an off-white solid (32 mg, yield: 59%). ESI-MS (M+H) + : 448.2. 11H 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)

Chemical formula

Chemical formula

[0115] 2. Synthesis of tert-butyl (4-(5-chloro-2-(cyclopropanecarboxamido)pyridin-4-yl)-2-methylbenzyl)carbamate

Chemical Structure

[0116] 3. Synthesis of N-(4-(4-(aminomethyl)-3-methylphenyl)-5-chloropyridin-2-yl)cyclopropanecarboxamide hydrochloride

Chem.

[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)

Chem.

[0118] Example 8: 5-(tert-Butyl)-N-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (Compound 8)

Chemical Structure

Chemical Structure

[0119] 2. Synthesis of tert-butyl (4-bromo-2-chlorobenzyl)carbamate

Chemical formula

[0120] 3. Synthesis of tert-butyl (2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate

Chemical formula

[0121] 4. Synthesis of tert-butyl (2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)benzyl)carbamate

Chemical Structure

[0122] 5. Synthesis of N-(4-(4-(aminomethyl)-3-chlorophenyl)pyridin-2-yl)cyclopropanecarboxamide hydrochloride

Chemical formula

[0123] Synthesis of 6.5-(tert-butyl)-N-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (Compound 8)

Chemical Structure

[0124] Example 9: 3-(tert-Butyl)-N-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (Compound 9) [Chemical Structure] 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) were added Et3N (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 hour. The reaction mixture was washed with H2O (15 mL), the organic phase was dehydrated (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (CH3CN / H2O containing 0.05% HCl / H2O as the 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. 1 H 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, 1 H), 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)

Chemical Structure

Chemical Structure

[0126] Synthesis of Ethyl 2-[(3-bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionate

Chemical Structure

[0127] Synthesis of 2-[(3-bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionic acid

Chemical Structure

[0128] Synthesis of 3-[(3-bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionyl chloride

Chemical formula

[0129] Synthesis of 8-bromo-2-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-benzo[c]azepin-5-one [Chemical formula] 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), AlCl3 (29.3 g, 0.22 mol) was added portionwise at room temperature. The reaction mixture was heated to 55 °C and stirred at that temperature for 2 h. 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 (gradient from petroleum ether / EtOAc, 5:1 to 2:1) to give 8-bromo-2-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-benzo[c]azepin-5-one 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 tert-Butyl [8-bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl]carbamate [Chemical formula] A solution of 8-bromo-2-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-benzo[c]azepin-5-one (32.0 g, 0.08 mol) in EtOH (600 mL) was added with NH4OAc (18.5 g, 0.24 mol) and NaCNBH3 (14.9 g, 0.24 mol) little by little at room temperature. Next, the reaction mixture was heated to 95 °C and stirred at that temperature for 16 h. The mixture was poured into ice water (500 mL), and then EtOH was removed under vacuum. The residue was extracted with DCM (500 mL×3). The combined extracts were concentrated. The residue was redissolved in DCM (300 mL), and Et3N (12.2 g, 0.12 mol) and Boc2O (34.6 g, 0.12 mol) were added at room temperature. The mixture was stirred at room temperature for 4 h and then concentrated under vacuum to obtain a crude product. The crude product was purified by silica gel column chromatography (gradient from petroleum ether / EtOAc, 8:1 to 2:1) to obtain tert-butyl [8-bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl]-carbamate 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] Synthesis of 7.8-bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-ylamine

Chemical formula

[0132] Synthesis of 8-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-amine

Chemical Structure

[0133] Synthesis of tert - butyl 9.5 - amino - 8 - bromo - 4,5 - dihydro - 1H - benzo[c]azepine - 2(3H) - carboxylate

Chemical Structure

[0134] Synthesis of tert - butyl (5R) - 8 - bromo - 5 - (((4 - oxido - dinaphtho[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

Chemical Structure

[0135] 11. Synthesis of tert-butyl (5R)-5-amino-8-bromo-1,3,4,5-tetrahydro-2-benzoazepine-2-carboxylate

Chemical Structure

[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

Chem.

[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

Chem.

[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

Chemical Structure

[0139] Synthesis of 15.5-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 [Chemical formula] 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)Cl2·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 hours. 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), the filtrates were combined, and 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

Chemical Structure

[0141] 17. Synthesis of (R)-5-(tert-butyl)-N-(8-(2-(cyclopropanecar boxamido)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)

Chemical Structure

[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)

Chem.

Chem.

[0143] 2. Synthesis of N-(4-bromo-2-fluoro-3-methylphenyl)acetamide

Chem.

[0144] 3. Synthesis of N-(4-cyano-2-fluoro-3-methylphenyl)acetamide

Chemical formula

[0145] Synthesis of 4-Amino-3-fluoro-2-methylbenzonitrile

Chemical Structure

[0146] Synthesis of 5-Bromo-3-fluoro-2-methylbenzonitrile

Chemical Structure

[0147] 6. Synthesis of (4-bromo-3-fluoro-2-methylphenyl)methanamine

Chemical formula

[0148] 7. Synthesis of tert-butyl (4-bromo-3-fluoro-2-methylbenzyl)carbamate

Chemical formula

[0149] 8. Synthesis of tert-butyl (3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate

Chemical Structure

[0150] 9. Synthesis of (4-(2-(Cyclopropanecarboxamido)pyridin-4-yl)-3-fluoro-2-methylbenzyl)carbamic acid tert-butyl [Chemical formula] 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 / H2O (v / v = 3 / 1, 8 mL) mixture was added with N-(4-bromopyridin-2-yl)cyclopropanecarboxamide (264 mg, 1.10 mmol) and K2CO3 (303 mg, 2.20 mmol). Next, Pd(dppf)Cl2·DCM (90 mg, 0.11 mmol) was added under a N2 atmosphere. The mixture was heated to 85 °C and stirred at that temperature for 4 h under N2. The mixture was concentrated under vacuum to obtain a crude material. The crude material was purified by silica gel column chromatography (gradient from petroleum ether / EtOAc, 3:1 to 1:1) to obtain 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, CD 3OD) 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, 2 H), 0.94-0.90 (m, 2H).

[0151] 10. Synthesis of N-(4-(4-(aminomethyl)-2-fluoro-3-methylphenyl)pyridin-2-yl)cyclopropanecarboxamide hydrochloride

Chemical Structure

[0152] Synthesis of 5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide (Compound 11) [Chemical formula] 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) were 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 h. The reaction mixture was filtered and the filtrate was purified by preparative HPLC (CH3CN / H2O containing 0.05% NH4OH / H2O as the mobile phase) to give an impure product (130 mg), which was further purified by preparative HPLC (CH3CN / H2O containing 0.05% HCl / H2O as the 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 1H 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)

Chemical Structure

Chemical Structure

[0154] 2. Synthesis of tert-butyl (5-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate

Chemical formula

[0155] 3. Synthesis of tert-butyl (4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-5-fluoro-2-methylbenzyl)carbamate [Chemical formula] 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 / H2O (v / v = 15 / 1, 6 mL) mixture was added with N-(4-iodopyridin-2-yl)cyclopropanecarboxamide (142 mg, 0.49 mmol) and K2CO3 (85 mg, 0.61 mmol). After the reaction mixture was degassed with N2 for 5 minutes, Pd(dppf)Cl2·DCM (17 mg, 0.02 mmol) was added under an N2 atmosphere. The mixture was heated to 100 °C and stirred at that temperature for 1 hour under N2. The reaction mixture was cooled to room temperature and EtOAc (50 mL) was added. The organic phase was washed with H2O (50 mL × 2), dehydrated (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography ([3:1 EtOAc:Et OH] / 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

Chemical Structure

[0157] Synthesis of 5.3-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-5-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide (Compound 12)

Chemical Structure

[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)

Chemical Structure

[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)

Chemical formula

Chemical formula

[0160] 2. Synthesis of N-(4-bromo-3-chloro-2-fluorophenyl)acetamide

Chemical formula

[0161] 3. Synthesis of N-(3-chloro-4-cyano-2-fluorophenyl)acetamide

Chem.

[0162] 4. Synthesis of 4-amino-2-chloro-3-fluorobenzonitrile

Chem.

[0163] 5. Synthesis of 2-chloro-3-fluoro-4-iodobenzonitrile [ka] A suspension of Cu(I)I (11.2 g, 59 mmol) in MeCN (50 mL) was added to nitrite. tert-Butyl (6.0 g, 59 mmol) was added 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 h. The mixture was stirred at 65° C. for 17 h 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%). 1 H NMR: (400 MHz, CDCl3) δ: 7.78 (s, 1H), 7.20 (d, J = 7.2Hz, 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 hours. MeOH (5 mL) was added and the reaction mixture was concentrated under vacuum. The crude material was purified by silica gel column chromatography (gradient from petroleum ether / EtOAc, 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

Chemical formula

[0166] 8. Synthesis of tert-Butyl (2-Chloro-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)benzyl)carbamate

Chemical Structure

[0167] 9. Synthesis of tert-Butyl (2-Chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluorobenzyl)carbamate

Chemical Structure

[0168] 10. Synthesis of N-(4-(4-(Aminomethyl)-3-chloro-2-fluorophenyl)pyridin-2-yl)cyclopropanecarboxamide hydrochloride [Chemical formula] 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 an 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 obtain N-(4-(4-(aminomethyl)-3-chloro-2-fluorophenyl)pyridin-2-yl)cyclopropanecarboxamide hydrochloride as a yellow solid (200 mg, unpurified), which was carried forward without further purification. ESI-MS (M+H) + : 320.1.

[0169] Synthesis of 11.5-(tert-Butyl)-N-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-fluorobenzyl)-1,2,4-oxadiazole-3-carboxamide (Compound 14)

Chemical Structure

[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) [Chemical formula] 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 in the same manner as 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 product was purified by preparative HPLC (CH3CN / H2O containing 0.05% HCl / H2O as the mobile phase) to obtain 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 1H 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)

Chemical formula

Chemical formula

[0172] 2. Synthesis of N-(4-(4-(Aminomethyl)-3-(trifluoromethyl)phenyl)pyridin-2-yl)cyclopropanecarboxamide Hydrochloride

Chemical formula

[0173] Synthesis of 3.5-(tert-butyl)-N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxamide (16)

Chemical formula

[0174] Example 17: 3-(tert-Butyl)-N-(4-(2-(Cyclopropanecarboxamido)pyridin-4-yl)-2-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide (Compound 17) [Chemical Structure Diagram] 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 the same manner as 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 (CH3CN / H2O containing 0.05% H Cl / H2O) 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. 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, 1 H), 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)

Chemical Structure

Chemical Structure

[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

Chemical Structure

[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)

Chemical Structure

[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)

Chemical Structure

Chemical formula

[0179] Synthesis of (R,E)-N-(1-(4-bromo-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide

Chemical formula

[0180] 3. Synthesis of (R)-N-((R)-1-(4-bromo-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide

Chemical formula

[0181] 4. Synthesis of (R)-1-(4-bromo-2-methylphenyl)ethan-1-amine hydrochloride

Chemical formula

[0182] 5. Synthesis of tert-butyl (R)-(1-(4-bromo-2-methylphenyl)ethyl)carbamate [Chemical formula] 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 were added Et3N (2.67 g, 26.3 mmol) and Boc2O (3.7 g, 17.1 mmol). 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 tert-butyl (R)-(1-(4-bromo-2-methylphenyl)ethyl)carbamate as a white solid (3.8 g, yield: 92%). ESI-MS (M-Boc-NH2) + : 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

Chem.

[0184] 7. Synthesis of tert-Butyl (R)-(1-(4-(2-(Cyclopropanecarboxamido)pyridin-4-yl)-2-methylphenyl)ethyl)carbamate

Chem.

[0185] 8. Synthesis of (R)-N-(4-(4-(1-Aminoethyl)-3-methylphenyl)pyridin-2-yl)cyclopropanecarboxamide hydrochloride [Chemical formula] To a mixture of (R)-(1-(4-(2-(Cyclopropanecarboxamido)pyridin-4-yl)-2-methylphenyl)ethyl)carbamic acid tert-butyl (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%) and 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)

Chemical Structure

[0187] Example 20: 5-(tert-Butyl)-N-(4-(2-(Cyclopropanecarboxamido)-5-fluoropyridin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide (Compound 20) [Chemical formula] 1. Synthesis of tert-Butyl (R)-(1-(4-(2-chloro-5-fluoropyridin-4-yl)-2-methylphenyl)ethyl)carbamate [Chemical formula] 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 (500 mg, 1.38 mmol) in 1,4-dioxane / H2O (v / v = 3 / 1, 12 mL), 2-Chloro-5-fluoropyridin-4-iodide (427 mg, 1.66 mmol) and KOAc (272 mg, 2.77 mmol) were added. Next, Pd(dppf)Cl2·DCM (113 mg, 0.14 mmol) was added under an N2 atmosphere, and the reaction mixture was heated to 85 °C. The mixture was stirred at that temperature for 17 h under N2 and then concentrated in vacuo. The crude material was purified by silica gel column chromatography (petroleum ether / EtOAc, 5:1) to give tert-Butyl (R)-(1-(4-(2-chloro-5-fluoropyridin-4-yl)-2-methylphenyl)ethyl)carbamate 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 H z, 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

Chemical formula

[0189] 3. Synthesis of (R)-N-(4-(4-(1-Aminoethyl)-3-methylphenyl)-5-fluoropyridin-2-yl)cyclopropanecarboxamide Hydrochloride

Chemical formula

[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) [Chemical formula] 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 were 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 hour, filtered, and the filtrate was purified by preparative HPLC (CH3CN / H2O containing 0.05% HCl / H2O as the 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. 11H 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)

Chemical Structure

Chemical Structure

[0192] Synthesis of 2.1-(4-Bromo-2-chlorophenyl)ethan-1-one

Chemical Structure

[0193] 3. Synthesis of (S,E)-N-(1-(4-Bromo-2-chlorophenyl)ethylidene)-2-methylpropane-2-sulfinamide

Chemical Structure

[0194] 4. Synthesis of (S)-N-((R)-1-(4-bromo-2-chlorophenyl)ethyl)-2-methylpropane-2-sulfinamide

Chemical formula

[0195] 5. Synthesis of (R)-1-(4-bromo-2-chlorophenyl)ethane-1-amine hydrochloride

Chemical formula

[0196] 6. (R)-(1-(4-Bromo-2-chlorophenyl)ethyl)carbamic acid ter t-butyl synthesis

Chemical Structure

[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

Chemical Structure

[0198] 8. Synthesis of tert-butyl (R)-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)phenyl)ethyl)carbamate [Chemical formula] (R)-(1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamic acid tert-butyl (200 mg, 0.52 mmol) in a solution of 1,4-dioxane (15 mL) and H2O (3 mL) was added N-(4-bromopyridin-2-yl)cyclopropanecarboxamide (152 mg, 0.63 mmol), Pd(dppf)Cl2·DCM (21 mg, 0.03 mmol), and K2CO3 (145 mg, 1.05 mmol). The mixture was heated to 85 °C under N2 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 (gradient from petroleum ether / EtOAc, 10:1 to 1:1) to give (R)-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)phenyl)ethyl)carbamic acid tert-butyl 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

Chemical formula

[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)

Chemical Structure

[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)

Chemical formula

Chemical formula

[0202] 2. Synthesis of tert-Butyl (R)-(1-(2-chloro-4-(2-(cyclopropanecarboxamido)-5-fluoropyridin-4-yl)phenyl)ethyl)carbamate

Chemical formula

[0203] 3. Synthesis of (R)-N-(4-(4-(1-aminoethyl)-3-chlorophenyl)-5-fluoropyridin-2-yl)cyclopropanecarboxamide hydrochloride

Chemical Structure

[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)

Chemical Structure

[0205] Examples 23 to 107 The following compounds were prepared according to the same procedures as those described in Examples 1 to 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 IC 50To determine the efficacy of a compound against BTK by measurement. After monitoring the phosphorylation amount of fluorescein-labeled polyGAT peptide (Invitrogen PV3611) in the presence of active BTK enzyme (Upstate 14-552), ATP, and inhibitor, the inhibition of the compound is measured. The BTK kinase reaction was carried out in black 96-well plates (costar 3694). In a normal assay, 24 pL aliquots of ATP / peptide master mix (final concentration; 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) are added to each well. Next, 1 pL of a 4-fold, 40X compound titrant in 100% DMSO solvent is added, followed by 15 μL of BTK enzyme mix (final concentration 0.25 nM) in 1-fold kinase buffer. After incubating the assay solution for 30 minutes, it is stopped with 28 pL of 50 mM EDTA solution. An aliquot (5 μL) of the kinase reaction is transferred to a low-volume white 384-well plate (Coming 3674), and 5 pL of 2X detection buffer (Invitrogen PV3574, containing 4 nM Tb-PY20 antibody, Invitrogen PV3552) is added. The plate is covered and incubated at room temperature for 45 minutes. Time-resolved fluorescence (TRF) is measured with a Molecular Devices M5 (excitation 332 nm; emission 488 nm; fluorescein emission 518 nm). Using four-parameter fitting based on 100% enzyme activity determined from the DMSO control and 0% activity from the EDTA control, the IC 50 value is calculated.

[0207] Table 1 shows the activities of selected compounds of the present invention in an in vitro Btk kinase assay, where each compound number here corresponds to the compound numbers shown in Examples 1 to 107 of this specification. "†" indicates that the IC 50 is 1000 nM or less and more than 10 nM, and "††" indicates that the IC 50 is 10 nM or less and more than 1 nM, and "†††" indicates that the IC 50It represents being 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. The whole blood was dispensed into 96-well plates and "spiked" with DMSO serial dilutions of the test compound or drug-free DMSO. The final DMSO concentration in all wells was 0.1%. The plates were incubated at 37 °C for 30 minutes. Lysis buffer containing protease inhibitors and phosphatase inhibitors was added to one of the drug-containing samples and the DMSO-only samples (+PPi, high control), and lysis buffer containing protease inhibitors was added to the other DMSO-only samples (-PPi, low control). The total BTK capture and phosphotyrosine detection method described in US20160311802, which is incorporated herein by reference, was applied to all lysed whole blood samples. The ECL values were graphed in Prism, and the test compound concentration at which the ECL signal was 50% inhibited by interpolation was estimated using the optimal curve constrained by the maximum and minimum values defined by the +PPi high control and -PPi low control. The test compound concentration at which the ECL signal was 50% inhibited by interpolation was estimated.

[0209] Table 2 shows the activities of selected compounds of the present invention in the pBTK assay, where each compound number here corresponds to the compound numbers shown in Examples 1 to 107 described herein. "†" represents that the IC 50 is 10,000 nM or less but more than 500 nM, "††" represents that the IC 50 is 500 nM or less but more than 100 nM, "†††" represents that the IC 50 is 100 nM or less. * represents that the IC 50 value is more than 10,000 nM.

Table 3

Claims

[Claim 1] The formula: 【Chemistry 1】 [In the formula: Ring A is selected from aryl and 5- to 6-membered heteroaryl, wherein the aryl and 5- to 6-membered heteroaryl are selected from one or more R １ 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 C-R ４ and N; Q １ , Q ２ , and Q ３ is N; R １ For each occurrence, independently, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 4-6 membered monocyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, halo, -CN, -C(O)R １ａ , -C(O) ２ R １ａ , -C(O)N(R １ａ ) ２ , -N(R １ａ ) ２ , -N(R １ａ ) C(O)R １ａ , -N(R １ａ ) C(O) ２ R １ａ , -N(R １ａ ) C(O)N(R １ａ ) ２ , -N(R １ａ ) S (O) ２ R １ａ , -OR １ａ , -OC(O)R １ａ , -OC(O)N(R １ａ ) ２ , -SR １ａ , -S(O)R １ａ , -S(O) ２ R １ａ , -S(O)N(R １ａ ) ２ , and -S(O) ２ N (R １ａ ) ２ and C is selected from １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Each occurrence of alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl may be represented by one or more R １０ optionally independently substituted by; R １ａ For each occurrence, 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 Each occurrence of alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl may be represented by 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) ２ R ３ａ , -C(O)N(R ３ａ ) ２ , -N(R ３ａ ) ２ , -N(R ３ａ ) C(O)R ３ａ , -N(R ３ａ ) C(O) ２ R ３ａ , -N(R ３ａ ) C(O)N(R ３ａ ) ２ , -N(R ３ａ ) S (O) ２ R ３ａ , -OR ３ａ , -OC(O)R ３ａ , -OC(O)N(R ３ａ ) ２ , -SR ３ａ , -S(O)R ３ａ , -S(O) ２ R ３ａ , -S(O)N(R ３ａ ) ２ , and -S(O) ２ N (R ３ａ ) ２ and C is selected from １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl are each independently selected from the group consisting of one or more R ３０ optionally replaced by; R ３ａ For each occurrence, 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 Each occurrence of alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl may be represented by one or more R ３０ or Or, R ２ and R ３ together with their intervening atoms form a 7-membered carbocyclic or heterocyclic ring, said 7-membered carbocyclic or heterocyclic ring being selected from one or more of R ２０ optionally replaced by; R ４ For each occurrence, 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) ２ R ４ａ , -C(O)N(R ４ａ ) ２ , -N(R ４ａ ) ２ , -N(R ４ａ ) C(O)R ４ａ , -N(R ４ａ ) C(O) ２ R ４ａ , -N(R ４ａ ) C(O)N(R ４ａ ) ２ , -N(R ４ａ ) S (O) ２ R ４ａ , -OR ４ａ , -OC(O)R ４ａ , -OC(O)N(R ４ａ ) ２ , -SR ４ａ , -S(O)R ４ａ , -S(O) ２ R ４ａ , -S(O)N(R ４ａ ) ２ , and -S(O) ２ N (R ４ａ ) ２ and C is selected from １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Each occurrence of alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl may be represented by one or more R ４０ optionally independently substituted by; R ４ａ For each occurrence, 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 Each occurrence of alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl may be represented by one or more R ４０ optionally independently substituted by; R ５ For each occurrence, independently, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 4-6 membered monocyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, halo, -CN, -C(O)R ５ａ , -C(O) ２ R ５ａ , -C(O)N(R ５ａ ) ２ , -N(R ５ａ ) ２ , -N(R ５ａ ) C(O)R ５ａ , -N(R ５ａ ) C(O) ２ R ５ａ , -N(R ５ａ ) C(O)N(R ５ａ ) ２ , -N(R ５ａ ) S (O) ２ R ５ａ , -OR ５ａ , -OC(O)R ５ａ , -OC(O)N(R ５ａ ) ２ , -SR ５ａ , -S(O)R ５ａ , -S(O) ２ R ５ａ , -S(O)N(R ５ａ ) ２ , and -S(O) ２ N (R ５ａ ) ２ and C is selected from １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Each occurrence of alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl may be represented by one or more R ５０ optionally independently substituted by; R ５ａ For each occurrence, 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 Each occurrence of alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl may be represented by one or more R ５０ optionally independently substituted by; R ６ For each occurrence, independently, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 4-6 membered monocyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, halo, -CN, -C(O)R ６ａ , -C(O) ２ R ６ａ , -C(O)N(R ６ａ ) ２ , -N(R ６ａ ) ２ , -N(R ６ａ ) C(O)R ６ａ , -N(R ６ａ ) C(O) ２ R ６ａ , -N(R ６ａ ) C(O)N(R ６ａ ) ２ , -N(R ６ａ ) S (O) ２ R ６ａ , -OR ６ａ , -OC(O)R ６ａ , -OC(O)N(R ６ａ ) ２ , -SR ６ａ , -S(O)R ６ａ , -S(O) ２ R ６ａ , -S(O)N(R ６ａ ) ２ , and -S(O) ２ N (R ６ａ ) ２ and C is selected from １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Each occurrence of alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl may be represented by one or more R ６０ or Or, two R's ６ The substituents together with their intervening atoms form a 3- to 5-membered carbocyclic or 3- to 5-membered heterocyclic ring, and the 3- to 5-membered carbocyclic or 3- to 5-membered heterocyclic ring is selected from the group consisting of one or more R ６０ optionally replaced by; R ６ａ For each occurrence, 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 Each occurrence of alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl may be represented by one or more R ６０ optionally independently substituted by; R １０ For each occurrence, independently, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 4-6 membered monocyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, halo, -CN, -C(O)R １０ａ , -C(O) ２ R １０ａ , -C(O)N(R １０ａ ) ２ , -N(R １０ａ ) ２ , -N(R １０ａ ) C(O)R １０ａ , -N(R １０ａ ) C(O) ２ R １０ａ , -N(R １０ａ ) C(O)N(R １０ａ ) ２ , -N(R １０ａ ) S (O) ２ R １０ａ , -OR １０ａ , -OC(O)R １０ａ , -OC(O)N(R １０ａ ) ２ , -SR １０ａ , -S(O)R １０ａ , -S(O) ２ R １０ａ , -S(O)N(R １０ａ ) ２ , and -S(O) ２ N (R １０ａ ) ２ Selected from: R １０ａ For each occurrence, 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 For each occurrence, independently, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 4-6 membered monocyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, halo, -CN, -C(O)R ２０ａ , -C(O) ２ R ２０ａ , -C(O)N(R ２０ａ ) ２ , -N(R ２０ａ ) ２ , -N(R ２０ａ ) C(O)R ２０ａ , -N(R ２０ａ ) C(O) ２ R ２０ａ , -N(R ２０ａ ) C(O)N(R ２０ａ ) ２ , -N(R ２０ａ ) S (O) ２ R ２０ａ , -OR ２０ａ , -OC(O)R ２０ａ , -OC(O)N(R ２０ａ ) ２ , -SR ２０ａ , -S(O)R ２０ａ , -S(O) ２ 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 Each occurrence of alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl may be represented by one or more R ２５ optionally replaced by; R ２０ａ For each occurrence, 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 Each occurrence of alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl may be represented by 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, 4-6 membered monocyclic carbocyclyl, 4-6 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, 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 For each occurrence, independently, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 4-6 membered monocyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, halo, -CN, -C(O)R ３０ａ , -C(O) ２ R ３０ａ , -C(O)N(R ３０ａ ) ２ , -N(R ３０ａ ) ２ , -N(R ３０ａ ) C(O)R ３０ａ , -N(R ３０ａ ) C(O) ２ R ３０ａ , -N(R ３０ａ ) C(O)N(R ３０ａ ) ２ , -N(R ３０ａ ) S (O) ２ R ３０ａ , -OR ３０ａ , -OC(O)R ３０ａ , -OC(O)N(R ３０ａ ) ２ , -SR ３０ａ , -S(O)R ３０ａ , -S(O) ２ R ３０ａ , -S(O)N(R ３０ａ ) ２ , and -S(O) ２ N (R ３０ａ ) ２ Selected from: R ３０ａ For each occurrence, 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 For each occurrence, independently, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 4-6 membered monocyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, halo, -CN, -C(O)R ４０ａ , -C(O) ２ R ４０ａ , -C(O)N(R ４０ａ ) ２ , -N(R ４０ａ ) ２ , -N(R ４０ａ ) C(O)R ４０ａ , -N(R ４０ａ ) C(O) ２ R ４０ａ , -N(R ４０ａ ) C(O)N(R ４０ａ ) ２ , -N(R ４０ａ ) S (O) ２ R ４０ａ , -OR ４０ａ , -OC(O)R ４０ａ , -OC(O)N(R ４０ａ ) ２ , -SR ４０ａ , -S(O)R ４０ａ , -S(O) ２ R ４０ａ , -S(O)N(R ４０ａ ) ２ , and -S(O) ２ N (R ４０ａ ) ２ Selected from: R ４０ａ For each occurrence, 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 For each occurrence, independently, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 4-6 membered monocyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, halo, -CN, -C(O)R ５０ａ , -C(O) ２ R ５０ａ , -C(O)N(R ５０ａ ) ２ , -N(R ５０ａ ) ２ , -N(R ５０ａ ) C(O)R ５０ａ , -N(R ５０ａ ) C(O) ２ R ５０ａ , -N(R ５０ａ ) C(O)N(R ５０ａ ) ２ , -N(R ５０ａ ) S (O) ２ R ５０ａ , -OR ５０ａ , -OC(O)R ５０ａ , -OC(O)N(R ５０ａ ) ２ , -SR ５０ａ , -S(O)R ５０ａ , -S(O) ２ R ５０ａ , -S(O)N(R ５０ａ ) ２ , and -S(O) ２ N (R ５０ａ ) ２ Selected from: R ５０ａ For each occurrence, 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 For each occurrence, independently, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 4-6 membered monocyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, halo, -CN, -C(O)R ６０ａ , -C(O) ２ R ６０ａ , -C(O)N(R ６０ａ ) ２ , -N(R ６０ａ ) ２ , -N(R ６０ａ ) C(O)R ６０ａ , -N(R ６０ａ ) C(O) ２ R ６０ａ , -N(R ６０ａ ) C(O)N(R ６０ａ ) ２ , -N(R ６０ａ ) S (O) ２ R ６０ａ , -OR ６０ａ , -OC(O)R ６０ａ , -OC(O)N(R ６０ａ ) ２ , -SR ６０ａ , -S(O)R ６０ａ , -S(O) ２ R ６０ａ , -S(O)N(R ６０ａ ) ２ , and -S(O) ２ N (R ６０ａ ) ２ Selected from: R ６０ａ For each occurrence, 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 pharma- ceutically acceptable salt thereof.

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