1-(([1,1',-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(3-(methylsulfonyl)allyl)piperidine-4-carboxamide derivative as a RAS-PI3K modulator for the treatment of EG cancer

Abstract

The present invention relates to a compound represented by formula (I) as a RAS-PI3K modulator used in methods for treating cancer, immunological disorders, and wound healing. Preferred compounds are, for example, 1-(([1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(3-(methylsulfonyl)allyl)piperidine-4-carboxamide derivatives. [Formula 1] TIFF2026509001000290.tif42140

Description

[Technical Field]

[0001] References to related applications This application claims the benefit of the prior filing date of U.S. Provisional Patent Application No. 63 / 487,431, filed on 28 February 2023 pursuant to 35 U.S.C. § 119(e). The entire contents of that application are incorporated herein by reference. This disclosure relates to compounds and methods that modulate RAS-PI3K. [Background technology]

[0002] Improved cancer drugs and treatment methods are needed. [Overview of the Initiative] [Problems that the invention aims to solve]

[0003] In some embodiments, RAS-PI3K modulators are disclosed herein. Some such embodiments relate to RAS-PI3K agonists. Some embodiments relate to RAS-PI3K inhibitors. The RAS-PI3K modulator may encompass the compounds described herein. The RAS-PI3K modulator may be useful in the methods described herein. [Means for solving the problem]

[0004] In one embodiment, the following is described herein: Formula (I): [ka]

[0005] [During the ceremony, Z is either C(=O) or S(=O)²; Ring A is phenyl, a 5-10 membered heteroaryl, a C3-C8 cycloalkyl, a C8-C9 spirocyclyl, or a 5-8 membered heterocycloalkyl; Y is N, CH, or CR1 and; each R 1 is independently halogen, -CN, -OH, -OR a , -SH, -SR a , -NO2, -N(R b )2, -C(=O)R a , -C(=O)OR a , -C(=O)NR a R b [[ID=1**]]is independently halogen, -CN, -OH, -OR each R 2 is independently halogen, -CN, -OH, -OR a , -SH, -SR a , -NO2, -N(R b )2, -S(=O)2R a , -C(=O)R a , -C(=O)OR a , -C(=O)NR a R b is independently oxo(=O), optionally substituted C1-C6 alkyl, optionally substituted C1-C6 deuterated alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl or optionally substituted C3-C6 cycloalkyl; or, two Rs 2 combine together with the atom(s) to which they are attached to form a C3-C5 cycloalkyl, 4-5 membered heterocycloalkyl or 5 membered heteroaryl ring; each R 3 is independently halogen, -CN, -OH, -OR a, C1-C6 alkyl, C1-C6 deuterated alkyl, or C1-C6 haloalkyl; R 4 H, halogen, -OH, -OR a or C1-C6 alkyl; R A teeth, [ka]

[0006] And here, R 5 is H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, or optionally substituted C1-C3 hydroxyalkyl; R 6a and R 6b These are H, -CN, and -C(=O)OR, respectively, independently. 7 -C(=O)N(R 7 )2, -S(=O)R 7 -S(=O)2R 7 Or -S(=O)(=NH)R 7 And here, Each R 7 These are independently a substituted C1-C6 alkyl, a substituted C3-C6 cycloalkyl, or a substituted 4-6 member heterocycloalkyl ring; Or, Two R's 7 They combine with the nitrogen atom to which they are bonded to form a substituted or otherwise substituted 4- to 5-membered heterocycloalkyl ring; Or, R 5 and R 7 They combine with the atoms to which they are bonded to form a five-membered heterocycloalkyl ring; R 6c is H or -CN; Or, R 6c and R 7 They combine with the atoms to which they are bonded to form a four-membered heterocycloalkyl ring; R 5a is H; or R 5a and R 6c They combine with the nitrogen atom to which they are bonded to form a four-membered heterocycloalkyl ring; or, R 5a It does not exist, and R 6c R A It directly bonds to the nitrogen atom to which it is bonded, forming a four-membered heterocyclic ring; Or, R 5a and R 5 Together with the nitrogen and carbon atoms to which they are bonded, they form a four-membered heterocyclic ring; R 5b is H or C1-C3 alkyl; Each R a Each of these is independently H, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C5-C8 aryl, C5-C8 heteroaryl, -C1-C6 alkyl(aryl), -C1-C6 alkyl(heteroaryl), -C1-C6 alkyl(cycloalkyl), or -C1-C6 alkyl(heterocycloalkyl); where each alkyl, deuterated alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), and alkyl(heterocycloalkyl) may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy; Each R b These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, or C1-C6 haloalkyl; Or, Two R's on a nitrogen atom b The groups, together with the nitrogen atoms to which they are bonded, form a heterocycloalkyl (which may be substituted with 1, 2, or 3 C1-C6 alkyl or C1-C6 haloalkyl); n1 and n2 are independently 0, 1, 2, or 3; p is 0, 1, 2, or 3; q is 0, 1, or 2; and, t is 0, 1, 2, or 3. A compound having the structure represented by , or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt of atropisomer thereof.

[0007] In some embodiments of formula (I), R 4 is a halogen. In some embodiments of formula (I), R 5a and R 5b These are H, respectively. In some embodiments of equation (I), R 5 is a C1-C3 alkyl group. In some embodiments of formula (I), R 5 is -CH3 or -CH2CH3. In some embodiments of formula (I), R 5a and R 6c These combine with the nitrogen atom to which they are bonded to form a four-membered heterocycloalkyl ring.

[0008] In some embodiments, the compound represented by formula (I) has the structure represented by formula (Ia), or is a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof: [ka]

[0009] In the above formula, Z is either C(=O) or S(=O)²; Ring A is phenyl, a 5-10 membered heteroaryl, a C3-C8 cycloalkyl, a C8-C9 spirocyclyl, or a 5-8 membered heterocycloalkyl; Y is CH or CR 1 and; Each R 1 These are, independently, halogen, -CN, -OH, and -OR a -SH, -SR a -NO2, -N(R b )2, -C(=O)R a , -C(=O)OR a -C(=O)NR a R b , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 deuterated alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, or optionally substituted C3-C6 cycloalkyl; Each R 2 These are, independently, halogen, -CN, -OH, and -OR a -SH, -SR a -NO2, -N(R b )2, -S(=O)2R a -C(=O)R a , -C(=O)OR a -C(=O)NR a R b , oxo (=O), optionally substituted C1-C6 alkyl, optionally substituted C1-C6 deuterated alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkylamino, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted arylalkyl, or optionally substituted 4-6 member heterocycloalkyl; Or, Two R's 2combine with the atom(s) to which they are attached to form a C3-C5 cycloalkyl, 4- to 5-membered heterocycloalkyl or 5-membered heteroaryl ring; Each R 3 is independently halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 deuterated alkyl or C1-C6 haloalkyl; R 6a and R 6b are each independently H, -CN, -C(=O)OR 7 , -C(=O)N(R 7 )2, -S(=O)R 7 , -S(=O)2R 7 or -S(=O)(=NH)R 7 ; where each R 7 is independently optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl or optionally substituted 4- to 6-membered heterocycloalkyl ring; or two Rs 7 combine with the nitrogen atom to which they are attached to form an optionally substituted 4- to 5-membered heterocycloalkyl ring; or R 5 and R 7 combine with the atom to which they are attached to form a 5-membered heterocycloalkyl ring; R 6c is H or -CN; or R 6c and R 7 combine with the atom to which they are attached to form a 4-membered heterocycloalkyl ring; Each R aHere, each alkyl, deuterated alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2C6 alkenyl, C2C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C5-C8 aryl, C5-C8 heteroaryl, -C1-C6 alkyl(aryl), -C1-C6 alkyl(heteroaryl), -C1-C6 alkyl(cycloalkyl), or -C1-C6 alkyl(heterocycloalkyl); where each alkyl, deuterated alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), and alkyl(heterocycloalkyl) may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy; Each R b These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, or C1-C6 haloalkyl; Or, Two R's on a nitrogen atom b The groups, together with the nitrogen atoms to which they are bonded, form a heterocycloalkyl (which may be substituted with 1, 2, or 3 C1-C6 alkyl or C1-C6 haloalkyl); n1 and n2 are independently 0, 1, 2, or 3; p is 0, 1, 2, or 3; q is 0, 1, or 2; and, t is 0, 1, 2, or 3.

[0010] In some embodiments of formula (I) or formula (Ia), ring A is a C5-C7 cycloalkyl or a 5-7 membered heterocycloalkyl.

[0011] In some embodiments, the compound represented by formula (I) has the structure represented by formula (II), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof:

Chemical formula

[0012] In the above formulae, X 1 and X 2 are each independently CH2, CHR 2 CR 2 R 2 O or NR 2a wherein at least one of X 1 or X 2 is CH2, CHR 2 or CR 2 R 2 ; X 3 is CR 8 or N, provided that when X 3 is N, R 8 is absent; Y is N, CH or CR 1 ; Z is C(=O) or S(=O)2; Each R 1 is independently halogen, -CN, -OH, -OR a , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 deuterated alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 haloalkyl or optionally substituted C1-C6 hydroxyalkyl or optionally substituted C3-C6 cycloalkyl; Each R 2 is independently halogen, -CN, -OH, -OR a , -N(R b)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 deuterated alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted arylalkyl, or optionally substituted 4-6 member heterocycloalkyl; Or, Two R's 2 They combine with the atom(s) to which they are bonded to form a C3-C5 cycloalkyl group; R 2a H, -S(=O)2R a -C(=O)R a , -C(=O)OR a -C(=O)NR a R b , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, C3-C6 cycloalkyl, or phenyl; Each R 3 These are, independently, halogen, -CN, -OH, and -OR a , C1-C6 alkyl, C1-C6 deuterated alkyl, or C1-C6 haloalkyl; R 4 H, halogen, -OH, -OR a or C1-C6 alkyl; R 5 is H, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 hydroxyalkyl; R 5b is H or C1-C3 alkyl; R 6a and R 6b These are H, -CN, and -C(=O)OR, respectively, independently. 7 -C(=O)N(R 7 )2, -S(=O)R 7 -S(=O)2R 7 Or -S(=O)(=NH)R 7 And here, Each R 7These are independently a substituted C1-C6 alkyl, a substituted C3-C6 cycloalkyl, or a substituted 4-6 member heterocycloalkyl ring; Or, Two R's 7 They combine with the nitrogen atom to which they are bonded to form a substituted or otherwise substituted 4- to 5-membered heterocycloalkyl ring; Or, R 5 and R 7 They combine with the atoms to which they are bonded to form a five-membered heterocycloalkyl ring; R 6c is H or -CN; Or, R 6c and R 7 They combine with the atoms to which they are bonded to form a four-membered heterocycloalkyl ring; R 8 It does not exist, or it is H, halogen, -OCH3, or -CH3; Each R a Each of these is independently H, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C5C8 aryl, C5C8 heteroaryl, -C1-C6 alkyl(aryl), -C1-C6 alkyl(heteroaryl), -C1-C6 alkyl(cycloalkyl), or -C1-C6 alkyl(heterocycloalkyl); where each alkyl, deuterated alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), and alkyl(heterocycloalkyl) may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy; Each R bThese are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, or C1-C6 haloalkyl; Or, Two R's on a nitrogen atom b The groups, together with the nitrogen atoms to which they are bonded, form a heterocycloalkyl (which may be substituted with 1, 2, or 3 C1-C6 alkyl or C1-C6 haloalkyl); m is either 0 or 1; n1 and n2 are independently 0, 1, 2, or 3; p is 0, 1, 2, or 3; q is 0, 1, or 2; and, t is 1, 2, or 3.

[0013] In some embodiments of equation (II), Z is -C(=O)-. In some embodiments of equation (II), X 3 CR 8 And; and, R 8 is H. In some embodiments of equation (II), m is 0. In some embodiments of equation (II), X 1 , NR 2a X 2 This is CH2.

[0014] In some embodiments, the compound represented by formula (II) has the structure represented by (IIb), or is a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof: [ka]

[0015] In the above formula, Y is CH or CR 1 and; Each R 1 These are, independently, halogen, -CN, -OH, and -OR a , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 deuterated alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 haloalkyl or C1-C6 hydroxyalkyl; Each R 2 These are independently a substituted C1-C6 alkyl, a substituted C1-C6 deuterated alkyl, a substituted C1-C6 haloalkyl, or a substituted C3-C6 cycloalkyl; R 2a H, -C(=O)OR a -C(=O)NR a R b , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted arylalkyl, or optionally substituted C3-C6 cycloalkyl; Each R 3 These are independently C1-C3 alkyl or C1-C3 deuterated alkyl; R 5 is H, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 hydroxyalkyl; R 5b is H or C1-C3 alkyl; R 6a and R 6b These are H, -CN, and -C(=O)OR, respectively, independently. 7 -C(=O)N(R 7 )2, -S(=O)R 7 -S(=O)2R 7 Or -S(=O)(=NH)R 7 And here, Each R 7 These are independently a substituted C1-C6 alkyl, a substituted C3-C6 cycloalkyl, or a substituted 4-6 member heterocycloalkyl ring; Or, Two R's 7 They combine with the nitrogen atom to which they are bonded to form a substituted or otherwise substituted 4- to 5-membered heterocycloalkyl ring; Or, R 5 and R 7 They combine with the atoms to which they are bonded to form a five-membered heterocycloalkyl ring; R 6c is H or -CN; Or, R 6c and R 7 They combine with the atoms to which they are bonded to form a four-membered heterocycloalkyl ring; Each R a Each of these is independently H, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C5-C8 aryl, C5-C8 heteroaryl, -C1-C6 alkyl(aryl), -C1-C6 alkyl(heteroaryl), -C1-C6 alkyl(cycloalkyl), or -C1-C6 alkyl(heterocycloalkyl); where each alkyl, deuterated alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), and alkyl(heterocycloalkyl) may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy; Each R b These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, or C1-C6 haloalkyl; Or, Two R's on a nitrogen atom b The groups, together with the nitrogen atoms to which they are bonded, form a heterocycloalkyl (which may be substituted with 1, 2, or 3 C1-C6 alkyl or C1-C6 haloalkyl); n1 and n2 are independently 0, 1, 2, or 3; p is 0, 1, 2, or 3; q is 0, 1, or 2; and, t is 1, 2, or 3.

[0016] In some embodiments of formula (IIb), R 2a is -C(=O)R a , -C(=O)OR a , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C3-C6 cycloalkyl; where each R a These are independently C1-C6 alkyl groups. In some embodiments of formula (IIb), p is 0. In some embodiments of formula (IIb), Y is CH or CR 1 And each R 1 It is a halogen, and R 2a It is a C1-C6 haloalkyl, and R 5 It is a C1-C3 alkyl group, and R 5b H is R 6a and R 6b These are, independently, H or -S(=O)(=NH)R 7 And here, each R 7 These are independently C1-C6 alkyl, or R 5 and R 7 They combine with the atoms to which they are bonded to form a 5-membered heterocycloalkyl ring, R 6c H is H, n1 and n2 are independently 1 or 2, p is 0 or 1, q is 0 or 1, and t is 1 or 2.

[0017] In some embodiments of formula (I) or formula (Ia), ring A is phenyl or a 5- to 10-membered heteroaryl. In some embodiments of formula (I) or formula (Ia), ring A is phenyl or pyridinyl.

[0018] In some embodiments, the compound represented by formula (I) has the structure represented by formula (III), or is a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof: [ka]

[0019] In the above formula, Y is N, CH, or CR 1 and; Z is either C(=O) or S(=O)²; X 4 CH, CR 2 or N; X 5 CH, CR 2 or N; Each R 1 These are, independently, halogen, -CN, -OH, and -OR a , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 deuterated alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, or optionally substituted C3-C6 cycloalkyl; Each R 2 These are, independently, halogen, -CN, -OH, and -OR a , -N(R b)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 deuterated alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted arylalkyl, or optionally substituted 4-6 member heterocycloalkyl; Or, Two R's 2 They combine with the atom(s) to which they are bonded to form a C3-C5 cycloalkyl, a 4-5 membered heterocycloalkyl, or a 5-membered heteroaryl ring; Each R 3 These are, independently, halogen, -CN, -OH, and -OR a , C1-C6 alkyl, C1-C6 deuterated alkyl, or C1-C6 haloalkyl; R 4 H, halogen, -OH, -OR a or C1-C6 alkyl; R 5 is H, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 hydroxyalkyl; R 5b is H or C1-C3 alkyl; R 6a and R 6b These are H, -CN, and -C(=O)OR, respectively, independently. 7 -C(=O)N(R 7 )2, -S(=O)R 7 -S(=O)2R 7 Or -S(=O)(=NH)R 7 And here, Each R 7 These are independently a substituted C1-C6 alkyl, a substituted C3-C6 cycloalkyl, or a substituted 4-6 member heterocycloalkyl ring; Or, Two R's 7They combine with the nitrogen atom to which they are bonded to form a substituted or otherwise substituted 4- to 5-membered heterocycloalkyl ring; Or, R 5 and R 7 They combine with the atoms to which they are bonded to form a five-membered heterocycloalkyl ring; R 6c is H or -CN; Or, R 6c and R 7 They combine with the atoms to which they are bonded to form a four-membered heterocycloalkyl ring; Each R a Each of these is independently H, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C5-C8 aryl, C5-C8 heteroaryl, -C1-C6 alkyl(aryl), -C1-C6 alkyl(heteroaryl), -C1-C6 alkyl(cycloalkyl), or -C1-C6 alkyl(heterocycloalkyl); where each alkyl, deuterated alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), and alkyl(heterocycloalkyl) may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy; Each R b These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, or C1-C6 haloalkyl; Or, Two R's on a nitrogen atom bThe groups, together with the nitrogen atoms to which they are bonded, form a heterocycloalkyl (which may be substituted with 1, 2, or 3 C1-C6 alkyl or C1-C6 haloalkyl); n1 and n2 are independently 0, 1, or 2; p is 0, 1, 2, or 3; q is 0, 1, or 2; and, t is 0, 1, 2, or 3.

[0020] In some embodiments of equation (III), Z is -S(=O)²-. In some embodiments of equation (III), R 4 It is a halogen.

[0021] In some embodiments, the compound represented by formula (III) has the structure represented by formula (IIIa), or is a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof: [ka]

[0022] In the above formula, Y is CH or CR 1 and; X 4 CH, CR 2 or N; X 5 CH, CR 2 or N; Each R 1 These are, independently, halogen, -CN, -OH, and -OR a , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 deuterated alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or optionally substituted C3-C6 cycloalkyl; Each R 2 These are, independently, halogen, -CN, -OH, and -ORa , -N(R b )2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 deuterated alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 4-6 member heterocycloalkyl, or optionally substituted arylalkyl; Each R 3 These are independently C1-C3 alkyl or C1-C3 deuterated alkyl; R 5 is H, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 hydroxyalkyl; R 5b is H or C1-C3 alkyl; R 6a and R 6b These are H, -CN, and -C(=O)N(R) independently of each other. 7 )2, -S(=O)2R 7 Or -S(=O)(=NH)R 7 And here, Each R 7 This is independently a C1-C3 alkyl or a four-membered heterocycloalkyl ring which may be substituted with up to two fluorine atoms; Or, Two R's 7 They combine with the nitrogen atom to which they are bonded to form a four-membered heterocycloalkyl ring which may be substituted with up to two fluorine atoms; Or, R 5 and R 7 They combine with the atoms to which they are bonded to form a five-membered heterocycloalkyl ring; R 6c is H or -CN; Or, R 6c and R 7 They combine with the atoms to which they are bonded to form a four-membered heterocycloalkyl ring; Each R a Each of these is independently H, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C5-C8 aryl, C5-C8 heteroaryl, -C1-C6 alkyl(aryl), -C1-C6 alkyl(heteroaryl), -C1-C6 alkyl(cycloalkyl), or -C1-C6 alkyl(heterocycloalkyl); where each alkyl, deuterated alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), and alkyl(heterocycloalkyl) may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy; Each R b These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, or C1-C6 haloalkyl; Or, Two R's on a nitrogen atom b The groups, together with the nitrogen atoms to which they are bonded, form a heterocycloalkyl (which may be substituted with 1, 2, or 3 C1-C6 alkyl or C1-C6 haloalkyl); n1 and n2 are independently 0, 1, or 2; p is 0, 1, 2, or 3; q is 0, 1, or 2; and, t is 0, 1, 2, or 3.

[0023] In some embodiments of formula (III) or formula (IIIa), X 4 CH or CR2 X 5 CH or CR 2 In some embodiments of formula (III) or formula (IIIa), X 4 is N; and X 5 CH or CR 2 In some embodiments of formula (III) or formula (IIIa), X 4 CH or CR 2 X 5 is N. In some embodiments of formula (III) or formula (IIIa), p is 1.

[0024] In some embodiments, the compound represented by formula (III) has the structure represented by formula (IIIb), or is a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof: [ka]

[0025] In the above formula, X 4 is either CH or N; Y is CR 1 or CH; Each R 1 These are, independently, halogen, -CN, and -OR. a , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 deuterated alkyl, C2-C4 alkynyl, or C1-C3 fluoroalkyl; R 2 These are halogen, -CN, -OH, -OR a , -N(R b )2, -C(=O)R a, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 deuterated alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 fluoroalkyl, optionally substituted C1-C3 hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 4-6 member heterocycloalkyl; Each R 3 These are independently -CH3 or -CD3; R 5 is H, -CH3, or -CH2CH3; R 5b is H or C1-C3 alkyl; R 6a and R 6b These are H, -CN, and -C(=O)N(R) independently of each other. 7 )2, -S(=O)2R 7 Or -S(=O)(=NH)R 7 And here, Each R 7 This is independently a C1-C3 alkyl or a four-membered heterocycloalkyl ring which may be substituted with up to two fluorine atoms; Or, Two R's 7 They combine with the nitrogen atom to which they are bonded to form a four-membered heterocycloalkyl ring which may be substituted with up to two fluorine atoms; Or, R 5 and R 7 They combine with the atoms to which they are bonded to form a five-membered heterocycloalkyl ring; R 6c is H or -CN; Each R a These are independently C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C3 fluoroalkyl; Each R b These are independently H or C1-C3 alkyl; q is 0, 1, or 2; and, t is 0, 1, or 2.

[0026] In some embodiments of formula (III), formula (IIIa), or formula (IIIb), each R 2 These are, independently, halogen, -CN, -OH, and -OR a , -N(R b )2, -C(=O)R a , optionally substituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 fluoroalkyl, optionally substituted C1-C3 hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 4-6 member heterocycloalkyl. In some embodiments of formula (III), formula (IIIa), or formula (IIIb), each R 2 Independently, are Cl, Br, F, -CN, -CH3, -CH2CH3, -CH(CH3)2, -CF3, -CH2CF3, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCF3, -N(CH3)2, azetidine, oxetane, pyrrolidine, piperazine, or morpholine. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), R 1 These are, independently, halogen, -CN, -OH, and -OR a , -C(=O)OR a -C(=O)NR a R b , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 haloalkyl. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), each R 1 These are, independently, halogen, -OR a Alternatively, it may be a C1-C6 alkyl group that is substituted.

[0027] In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), each R 1t is independently Cl, Br, F, -OCH3, or -CH3. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), t is 1. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), t is 2. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), each R 3 is CH3. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), q is 1. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), q is 0. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), n1 is 1; and n2 is 1. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), R 6a S(=O2)R 7 And; and, R 6b and R 6c These are H, respectively. In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), R 6b S(=O2)R 7 And; and, R 6a and R 6c These are H, respectively. In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), each R 7 R is independently a C1-C6 alkyl which may be substituted. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), R 5 and R 7These combine with the atoms to which they are bonded to form a five-membered heterocycloalkyl ring. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), R 6c and R 7 These combine with the atoms to which they are bonded to form a four-membered heterocycloalkyl ring. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), R 6a is -C(=O)N(R 7 )2, and R 6b and R 6c These are H and R respectively; 6b is -C(=O)N(R 7 )2, and R 6a and R 6c These are H, and here, two R 7 These combine with the nitrogen atom to which they are bonded to form a 4-5 membered ring, which may be substituted.

[0028] In another embodiment, provided herein are pharmaceutical compositions comprising a compound represented by formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a pharmaceutically acceptable salt of a stereoisomer thereof or an atropisomer thereof or a pharmaceutically acceptable salt of an atropisomer thereof; and at least one pharmaceutically acceptable excipient.

[0029] In another embodiment, provided herein are methods for modulating RAS-PI3K, the methods comprising administering to a subject in need of modulating RAS-PI3K a therapeutically effective dose of a compound represented by formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a pharmaceutically acceptable salt thereof or an atropisomer thereof or a pharmaceutically acceptable salt thereof. In some embodiments, the methods include inhibiting RAS-PI3K. In some embodiments, the methods include activating RAS-PI3K.

[0030] In another embodiment, provided herein are methods for treating a disease or condition, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound represented by formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a pharmaceutically acceptable salt thereof or an atropisomer thereof or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or condition is mediated by modulation of RAS-PI3K. In some embodiments, the disease is cancer. In some embodiments, the cancer is selected from the group consisting of bladder cancer, uterine cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, cervical cancer, lung cancer, colorectal cancer, bile duct cancer, gastric cancer, kidney cancer, and pancreatic cancer. In some embodiments, the disease or condition is an immunological disease or condition. In some embodiments, the immunological state is wound healing.

[0031] Further aspects and advantages of the Disclosure will be readily apparent to those skilled in the art from the following detailed description, but herein only exemplary embodiments of the Disclosure are shown and described. As will be understood, the Disclosure enables other different embodiments, and several of its details can all be modified in various obvious ways without departing from the scope of the Disclosure. Accordingly, the drawings and description should be considered factually exemplary and not restrictive.

[0032] Built-in by reference All publications, patents, and patent applications referenced herein are incorporated by reference to the same extent as each individual publication, patent, and patent application is specifically and individually incorporated by reference. Where any publications, patents, or patent applications incorporated by reference conflict with any disclosures contained herein, this specification is intended to supersede and / or take precedence over all such conflicts. [Modes for carrying out the invention]

[0033] RAS proteins are small GTPase molecules known to be involved in tumorigenesis. RAS operates within a complex signaling network with multiple activators and effectors, enabling them to regulate cellular functions such as cell proliferation, differentiation, apoptosis, and senescence. Phosphatidylinositol 3-kinase (PI3K) is one of the major effector pathways of RAS, regulating cell proliferation, cell cycle initiation, cell survival, cytoskeletal rearrangement, and metabolism. Its involvement in human tumors is of particular interest. PI3K has been shown to be essential for RAS-induced transformation in vitro. Mice with mutations in the PI3K catalytic subunit p110α, which inhibits its ability to interact with RAS, exhibit high resistance to endogenous oncogenic KRAS-induced lung tumorigenesis and HRAS-induced skin malignancy. These animals also show delayed development of lymphatic and vascular structures.

[0034] Disclosed herein are compounds and methods for modulating RAS-PI3K activity. Some embodiments relate to compounds or methods for inhibiting RAS-PI3K activity. Some embodiments relate to compounds or methods for activating RAS-PI3K activity. Modulation of RAS-PI3K activity may be in vitro or in vivo. Compounds that modulate RAS-PI3K activity can be formulated for administration to subjects. Modulation of RAS-PI3K may be performed in the body of a subject.

[0035] The compounds disclosed herein may be useful in treating diseases in which RAS-PI3K activity may be involved. In some embodiments, the compounds are used in wound healing. In some embodiments, the compounds are used in the treatment of cancer.

[0036] Compounds of the Disclosure Disclosed in some embodiments herein is a modulator for RAS-PI3K.

[0037] In one embodiment, the formula (I) is provided herein: [ka]

[0038] [During the ceremony, Z is either C(=O) or S(=O)²; Ring A is phenyl, a 5-10 membered heteroaryl, a C3-C8 cycloalkyl, a C8-C9 spirocyclyl, or a 5-8 membered heterocycloalkyl; Y is N, CH, or CR 1 and; Each R 1 These are, independently, halogen, -CN, -OH, and -OR a -SH, -SR a -NO2, -N(R b )2, -C(=O)R a , -C(=O)OR a -C(=O)NR a R b , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 deuterated alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, or optionally substituted C3-C6 cycloalkyl; Each R 2 These are, independently, halogen, -CN, -OH, and -OR a -SH, -SR a -NO2, -N(R b )2, -S(=O)2R a -C(=O)R a , -C(=O)OR a -C(=O)NR a R b, oxo (=O), optionally substituted C1-C6 alkyl, optionally substituted C1-C6 deuterated alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkylamino, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted arylalkyl, or optionally substituted 4-6 member heterocycloalkyl; Or, Two R's 2 They combine with the atom(s) to which they are bonded to form a C3-C5 cycloalkyl, a 4-5 membered heterocycloalkyl, or a 5-membered heteroaryl ring; Each R 3 These are, independently, halogen, -CN, -OH, and -OR a , C1-C6 alkyl, C1-C6 deuterated alkyl, or C1-C6 haloalkyl; R 4 H, halogen, -OH, -OR a or C1-C6 alkyl; R A teeth, [ka]

[0039] And here, R 5 is H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, or optionally substituted C1-C3 hydroxyalkyl; R 6a and R 6b These are H, -CN, and -C(=O)OR, respectively, independently. 7 -C(=O)N(R 7 )2, -S(=O)R 7 -S(=O)2R 7 Or -S(=O)(=NH)R 7 And here, Each R 7These are independently a substituted C1-C6 alkyl, a substituted C3-C6 cycloalkyl, or a substituted 4-6 member heterocycloalkyl ring; Or, Two R's 7 They combine with the nitrogen atom to which they are bonded to form a substituted or otherwise substituted 4- to 5-membered heterocycloalkyl ring; Or, R 5 and R 7 They combine with the atoms to which they are bonded to form a five-membered heterocycloalkyl ring; R 6c is H or -CN; Or, R 6c and R 7 They combine with the atoms to which they are bonded to form a four-membered heterocycloalkyl ring; R 5a is H; or R 5a and R 6c They combine with the nitrogen atom to which they are bonded to form a four-membered heterocycloalkyl ring; or, R 5a It does not exist, and R 6c R A It directly bonds to the nitrogen atom to which it is bonded, forming a four-membered heterocyclic ring; Or, R 5a and R 5 Together with the nitrogen and carbon atoms to which they are bonded, they form a four-membered heterocyclic ring; R 5b is H or C1-C3 alkyl; Each R aEach of these is independently H, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C5-C8 aryl, C5-C8 heteroaryl, -C1-C6 alkyl(aryl), -C1-C6 alkyl(heteroaryl), -C1-C6 alkyl(cycloalkyl), or -C1-C6 alkyl(heterocycloalkyl); where each alkyl, deuterated alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), and alkyl(heterocycloalkyl) may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl or C1-C6 haloalkyl or C1-C6 alkoxy; Each R b These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, or C1-C6 haloalkyl; Or, Two R's on a nitrogen atom b The groups, together with the nitrogen atoms to which they are bonded, form a heterocycloalkyl (which may be substituted with 1, 2, or 3 C1-C6 alkyl or C1-C6 haloalkyl); n1 and n2 are independently 0, 1, 2, or 3; p is 0, 1, 2, or 3; q is 0, 1, or 2; and, t is 0, 1, 2, or 3. A compound having the structure represented by , or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt of atropisomer thereof.

[0040] In some embodiments, provided herein are compounds having the structure represented by formula (I), or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or atropisomers thereof, or pharmaceutically acceptable salts thereof: [ka]

[0041] In the above formula, Z is either C(=O) or S(=O)²; Ring A is phenyl, pyridinyl, or a 5-6 member heterocycloalkyl group; Y is CH or CR 1 and; Each R 1 These are, independently, halogen, -CN, -OH, and -OR a These are C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl; Each R 2 These are, independently, halogen, -CN, -OH, and -OR a , -N(R b )2, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, or substituted 4-6 member heterocycloalkyl; Each R 3 These are independently C1-C3 alkyl or C1-C3 deuterated alkyl; R 4 is F; R A teeth, [ka]

[0042] And here, R 5is H, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 hydroxyalkyl; R 6a and R 6b These are H, -CN, and -C(=O)OR, respectively, independently. 7 -C(=O)N(R 7 )2 or -S(=O)2R 7 And here, Each R 7 These are independently a substituted or substituted C1-C3 alkyl or a substituted or substituted 4-6 membered heterocycloalkyl ring; Or, Two R's 7 They combine with the nitrogen atom to which they are bonded to form a substituted or otherwise substituted 4- to 5-membered heterocycloalkyl ring; Or, R 5 and R 7 They combine with the atoms to which they are bonded to form a five-membered heterocycloalkyl ring; R 6c H is; Or, R 6c and R 7 They combine with the atoms to which they are bonded to form a four-membered heterocycloalkyl ring; R 5a is H; or R 5a and R 6c They combine with the nitrogen atom to which they are bonded to form a four-membered heterocycloalkyl ring; R 5b is H or C1-C3 alkyl; n1 and n2 are independently 0, 1, or 2; Each R a These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, or aryl; where each alkyl, cycloalkyl, heterocycloalkyl, or aryl may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, or C1-C6 haloalkyl; Each R bThese are independently H or C1-C6 alkyl; Or, Two R's on a nitrogen atom b The groups, together with the nitrogen atoms to which they are bonded, form a heterocycloalkyl (which may be substituted with 1, 2, or 3 C1-C6 alkyl or C1-C6 haloalkyl); p is 0, 1, 2, or 3; q is 0, 1, or 2; and, t is 1, 2, or 3.

[0043] In some embodiments, provided herein are compounds having the structure represented by formula (I), or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or atropisomers thereof, or pharmaceutically acceptable salts thereof: [ka]

[0044] In the above formula, Z is either C(=O) or S(=O)²; Ring A is phenyl, pyridinyl, or a five-membered heterocycloalkyl; Y is CH or CR 1 and; Each R 1 These are independently Cl, Br, F, -OCH3, CH3, or -CD3; Each R 2 These are, independently, halogen, -CN, -OH, and -OR a , -N(R b )2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, or 4-6 member heterocycloalkyl; Each R 3 These are independently -CH3 or -CD3; R 4 is F; R A teeth, [ka]

[0045] And here, R 5 is H, -CH3, or -CH2CH3; R 6a and R 6b These are H, -CN, and -C(=O)OR, respectively, independently. 7 -C(=O)N(R 7 )2 or -S(=O)2R 7 And here, Each R 7 These are independently a substituted or substituted C1-C3 alkyl or a substituted or substituted 4-6 membered heterocycloalkyl ring; Or, Two R's 7 They combine with the nitrogen atom to which they are bonded to form a substituted or otherwise substituted 4- to 5-membered heterocycloalkyl ring; Or, R 5 and R 7 They combine with the atoms to which they are bonded to form a five-membered heterocycloalkyl ring; R 6c H is; Or, R 6c and R 7 They combine with the atoms to which they are bonded to form a four-membered heterocycloalkyl ring; R 5a is H; or R 5a and R 6c They combine with the nitrogen atom to which they are bonded to form a four-membered heterocycloalkyl ring; R 5b is H or C1-C3 alkyl; n1 and n2 are independently 0, 1, or 2; Each R a These are independently H, C1-C6 alkyl, or C1-C6 haloalkyl; Each R bThese are independently H or C1-C6 alkyl; p is 0, 1, 2, or 3; q is 0, 1, or 2; and, t is 1, 2, or 3.

[0046] In some embodiments, the compound represented by formula (I) has the structure represented by formula (Ia), or is a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof: [ka]

[0047] In the above formula, Z is either C(=O) or S(=O)²; Ring A is phenyl, a 5-10 membered heteroaryl, a C3-C8 cycloalkyl, a C8-C9 spirocyclyl, or a 5-8 membered heterocycloalkyl; Y is CH or CR 1 and; Each R 1 These are, independently, halogen, -CN, -OH, and -OR a -SH, -SR a -NO2, -N(R b )2, -C(=O)R a , -C(=O)OR a -C(=O)NR a R b , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 deuterated alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, or optionally substituted C3-C6 cycloalkyl; Each R 2 These are, independently, halogen, -CN, -OH, and -OR a -SH, -SR a -NO2, -N(R b)2, -S(=O)2R a -C(=O)R a , -C(=O)OR a -C(=O)NR a R b , oxo (=O), optionally substituted C1-C6 alkyl, optionally substituted C1-C6 deuterated alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkylamino, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted arylalkyl, or optionally substituted 4-6 member heterocycloalkyl; Or, Two R's 2 They combine with the atom(s) to which they are bonded to form a C3-C5 cycloalkyl, a 4-5 membered heterocycloalkyl, or a 5-membered heteroaryl ring; Each R 3 These are, independently, halogen, -CN, -OH, and -OR a , C1-C6 alkyl, C1-C6 deuterated alkyl, or C1-C6 haloalkyl; R 6a and R 6b These are H, -CN, and -C(=O)OR, respectively, independently. 7 -C(=O)N(R 7 )2, -S(=O)R 7 -S(=O)2R 7 Or -S(=O)(=NH)R 7 And here, Each R 7 These are independently a substituted C1-C6 alkyl, a substituted C3-C6 cycloalkyl, or a substituted 4-6 member heterocycloalkyl ring; Or, Two R's 7 They combine with the nitrogen atom to which they are bonded to form a substituted or otherwise substituted 4- to 5-membered heterocycloalkyl ring; Or, R5 and R 7 They combine with the atoms to which they are bonded to form a five-membered heterocycloalkyl ring; R 6c is H or -CN; Or, R 6c and R 7 They combine with the atoms to which they are bonded to form a four-membered heterocycloalkyl ring; Each R a Each of these is independently H, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C5-C8 aryl, C5-C8 heteroaryl, -C1-C6 alkyl(aryl), -C1-C6 alkyl(heteroaryl), -C1-C6 alkyl(cycloalkyl), or -C1-C6 alkyl(heterocycloalkyl); where each alkyl, deuterated alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), and alkyl(heterocycloalkyl) may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy; Each R b These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, or C1-C6 haloalkyl; Or, Two R's on a nitrogen atom b The groups, together with the nitrogen atoms to which they are bonded, form a heterocycloalkyl (which may be substituted with 1, 2, or 3 C1-C6 alkyl or C1-C6 haloalkyl); n1 and n2 are independently 0, 1, 2, or 3; p is 0, 1, 2, or 3; q is 0, 1, or 2; and, t is 0, 1, 2, or 3.

[0048] In some embodiments of formula (I) or formula (Ia), Y is N. In some embodiments of formula (I) or formula (Ia), Y is CH or CR. 1 In some embodiments of formula (I) or formula (Ia), Y is CH. In some embodiments of formula (I) or formula (Ia), Y is CR. 1 That is the case.

[0049] In some embodiments of formula (I) or formula (Ia), ring A is a C5-C7 cycloalkyl or a 5-7 membered heterocycloalkyl. In some embodiments of formula (I) or formula (Ia), ring A is a C3-C8 cycloalkyl. In some embodiments of formula (I) or formula (Ia), ring A is a C5-C7 cycloalkyl. In some embodiments of formula (I) or formula (Ia), ring A is cyclopentyl. In some embodiments of formula (I) or formula (Ia), ring A is cyclohexyl. In some embodiments, ring A is cyclohexene.

[0050] In some embodiments of formula (I) or formula (Ia), ring A is a 5- to 8-membered heterocycloalkyl. In some embodiments of formula (I) or formula (Ia), ring A is a heterocycloalkyl. In some embodiments of formula (I) or formula (Ia), the heterocycloalkyl is monocyclic, bicyclic, or polycyclic. In some embodiments of formula (I) or formula (Ia), ring A is a 5- to 7-membered heterocycloalkyl. In some embodiments of formula (I) or formula (Ia), ring A is a 5- to 6-membered heterocycloalkyl. In some embodiments of formula (I) or formula (Ia), ring A is a 5-membered heterocycloalkyl containing one or two heteroatoms selected from O or N. In some embodiments of formula (I) or formula (Ia), ring A is a 5-membered heterocycloalkyl containing one heteroatom selected from O or N. In some embodiments, ring A is a 6-membered heterocycloalkyl. In some embodiments of formula (I) or formula (Ia), ring A is a six-membered heterocycloalkyl group containing one or two heteroatoms selected from O or N. In some embodiments of formula (I) or formula (Ia), ring A is a six-membered heterocycloalkyl group containing one heteroatom selected from O or N. In some embodiments of formula (I) or formula (Ia), the heterocycloalkyl group is piperazine, piperidine, morpholine, tetrahydropyran, pyrrolidine, or tetrahydrofuran. In some embodiments of formula (I) or formula (Ia), the heterocycloalkyl group is piperazine. In some embodiments of formula (I) or formula (Ia), the heterocycloalkyl group is piperidine or morpholine. In some embodiments of formula (I) or formula (Ia), the heterocycloalkyl group is tetrahydropyran. In some embodiments of formula (I) or formula (Ia), the heterocycloalkyl group is pyrrolidine. In some embodiments of formula (I) or formula (Ia), the heterocycloalkyl is tetrahydrofuran.

[0051] In another embodiment, provided herein are compounds having the structure represented by formula (II), or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or pharmaceutically acceptable salts of stereoisomers thereof, or atropisomers thereof, or pharmaceutically acceptable salts of atropisomers thereof: [ka]

[0052] In the above formula, X 1 and X 2 These are CH2 and CHR, which operate independently. 2 CR 2 R 2 , O or NR 2a And; here, X 1 or X 2 At least one of them is CH2, CHR 2 or CR 2 R 2 and; X 3 CR 8 or N, however X 3 If R is N, 8 It does not exist; Y is N, CH, or CR 1 and; Z is either C(=O) or S(=O)²; Each R 1 These are, independently, halogen, -CN, -OH, and -OR a , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 deuterated alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 haloalkyl or optionally substituted C1-C6 hydroxyalkyl or optionally substituted C3-C6 cycloalkyl; Each R 2 These are, independently, halogen, -CN, -OH, and -OR a , -N(R b)2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 deuterated alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted arylalkyl, or optionally substituted 4-6 member heterocycloalkyl; Or, Two R's 2 They combine with the atom(s) to which they are bonded to form a C3-C5 cycloalkyl group; R 2a H, -S(=O)2R a -C(=O)R a , -C(=O)OR a -C(=O)NR a R b , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, C3-C6 cycloalkyl, or phenyl; Each R 3 These are, independently, halogen, -CN, -OH, and -OR a , C1-C6 alkyl, C1-C6 deuterated alkyl, or C1-C6 haloalkyl; R 4 H, halogen, -OH, -OR a or C1-C6 alkyl; R 5 is H, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 hydroxyalkyl; R 5b is H or C1-C3 alkyl; R 6a and R 6b These are H, -CN, and -C(=O)OR, respectively, independently. 7 -C(=O)N(R 7 )2, -S(=O)R 7 -S(=O)2R 7 Or -S(=O)(=NH)R 7 And here, Each R 7These are independently a substituted C1-C6 alkyl, a substituted C3-C6 cycloalkyl, or a substituted 4-6 member heterocycloalkyl ring; Or, Two R's 7 They combine with the nitrogen atom to which they are bonded to form a substituted or otherwise substituted 4- to 5-membered heterocycloalkyl ring; Or, R 5 and R 7 They combine with the atoms to which they are bonded to form a five-membered heterocycloalkyl ring; R 6c is H or -CN; Or, R 6c and R 7 They combine with the atoms to which they are bonded to form a four-membered heterocycloalkyl ring; R 8 It does not exist, or it is H, halogen, -OCH3, or -CH3; Each R a Each of these is independently H, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C5-C8 aryl, C5-C8 heteroaryl, -C1-C6 alkyl(aryl), -C1-C6 alkyl(heteroaryl), -C1-C6 alkyl(cycloalkyl), or -C1-C6 alkyl(heterocycloalkyl); where each alkyl, deuterated alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), and alkyl(heterocycloalkyl) may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy; Each R bThese are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, or C1-C6 haloalkyl; Or, Two R's on a nitrogen atom b The groups, together with the nitrogen atoms to which they are bonded, form a heterocycloalkyl (which may be substituted with 1, 2, or 3 C1-C6 alkyl or C1-C6 haloalkyl); m is either 0 or 1; n1 and n2 are independently 0, 1, 2, or 3; p is 0, 1, 2, or 3; q is 0, 1, or 2; and, t is 1, 2, or 3.

[0053] In another embodiment, provided herein are compounds having the structure represented by formula (II), or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or pharmaceutically acceptable salts of stereoisomers thereof, or atropisomers thereof, or pharmaceutically acceptable salts of atropisomers thereof: [ka]

[0054] In the above formula, X 1 and X 2 These are CH2 and CHR, which operate independently. 2 CR 2 R 2 , O or NR 2a And; here, X 1 or X 2 At least one of them is CH2, CHR 2 or CR 2 R 2 and; X3 CR 8 or N, however X 3 If R is N, 8 It does not exist; Y is CH or CR 1 and; Z is either C(=O) or S(=O)²; Each R 1 These are, independently, halogen, -CN, -OH, and -OR a , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 deuterated alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 haloalkyl or C1-C6 hydroxyalkyl; Each R 2 These are, independently, halogen, -CN, -OH, and -OR a , -N(R b )2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 deuterated alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 4-6 member heterocycloalkyl; Or, Two R's 2 They combine with the atom(s) to which they are bonded to form a C3-C5 cycloalkyl group; R 2a H, -C(=O)OR a -C(=O)NR a R b , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C3-C6 cycloalkyl; Each R 3 These are independently C1-C3 alkyl or C1-C3 deuterated alkyl; R 4 is H or halogen; R 5is H, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 hydroxyalkyl; R 6a and R 6b These are H, -CN, and -C(=O)OR, respectively, independently. 7 -C(=O)N(R 7 )2, -S(=O)R 7 -S(=O)2R 7 Or -S(=O)(=NH)R 7 And here, Each R 7 These are independently a substituted C1-C6 alkyl, a substituted C3-C6 cycloalkyl, or a substituted 4-6 member heterocycloalkyl ring; Or, Two R's 7 They combine with the nitrogen atom to which they are bonded to form a substituted or otherwise substituted 4- to 5-membered heterocycloalkyl ring; Or, R 5 and R 7 They combine with the atoms to which they are bonded to form a five-membered heterocycloalkyl ring; R 6c is H or -CN; Or, R 6c and R 7 They combine with the atoms to which they are bonded to form a four-membered heterocycloalkyl ring; R 8 It does not exist, or it is H, halogen, -OCH3, or -CH3; Each R aThese are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C1-C6 alkyl(aryl), -C1-C6 alkyl(heteroaryl), -C1-C6 alkyl(cycloalkyl), or -C1-C6 alkyl(heterocycloalkyl); where each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, or C1-C6 haloalkyl; Each R b These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, or C1-C6 haloalkyl; Or, Two R's on a nitrogen atom b The groups, together with the nitrogen atoms to which they are bonded, form a heterocycloalkyl (which may be substituted with 1, 2, or 3 C1-C6 alkyl or C1-C6 haloalkyl); m is either 0 or 1; n1 and n2 are independently 0, 1, or; p is 0, 1, 2, or 3; q is 0, 1, or 2; and, t is 1, 2, or 3.

[0055] In some embodiments, provided herein are compounds having the structure represented by formula (II), or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or atropisomers thereof, or pharmaceutically acceptable salts thereof: [ka]

[0056] In the above formula, X 1 and X 2 These are CH2 and CHR, which operate independently. 2 CR 2 R 2 , O or NR 2a And; here, X 1 or X 2 At least one of them is CH2, CHR 2 or CR 2 R 2 and; X 3 CR 8 and; Y is CH or CR 1 and; Z is C (=O); Each R 1 These are independently Cl, Br, F, -OCH3, CH3, or -CD3; Each R 2 These are, independently, halogen, -CN, -OH, and -OR a , -N(R b )2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4-6 member heterocycloalkyl; R 2a is -C(=O)R a , -C(=O)OR a , C1-C6 haloalkyl or C3-C6 cycloalkyl; Each R 3 These are independently -CH3 or -CD3; R 4 is F; R 5 is H, -CH3, or -CH2CH3; R 6a and R 6b These are H, -CN, and -C(=O)OR, respectively, independently. 7 -C(=O)N(R 7 )2 or -S(=O)2R 7 And here, Each R 7These are independently a substituted or substituted C1-C3 alkyl or a substituted or substituted 4-6 membered heterocycloalkyl ring; Or, Two R's 7 They combine with the nitrogen atom to which they are bonded to form a substituted or otherwise substituted 4- to 5-membered heterocycloalkyl ring; Or, R 5 and R 7 They combine with the atoms to which they are bonded to form a five-membered heterocycloalkyl ring; R 6c H is; Or, R 6c and R 7 They combine with the atoms to which they are bonded to form a four-membered heterocycloalkyl ring; R 5a is H; or R 5a and R 6c They combine with the nitrogen atom to which they are bonded to form a four-membered heterocycloalkyl ring; R 8 H is; Each R a These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, or aryl; where each alkyl, cycloalkyl, heterocycloalkyl, or aryl may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, or C1-C6 haloalkyl; Each R b These are independently H or C1-C6 alkyl; Or, Two R's on a nitrogen atom b The groups, together with the nitrogen atoms to which they are bonded, form a heterocycloalkyl (which may be substituted with 1, 2, or 3 C1-C6 alkyl or C1-C6 haloalkyl); n1 and n2 are independently 0, 1, or 2; m is either 0 or 1; p is 0, 1, 2, or 3; q is 0, 1, or 2; and, t is 1, 2, or 3.

[0057] In some embodiments of formula (II), X 3 CR 8 In some embodiments of equation (II), X 3 It is N.

[0058] In some embodiments of formula (II), R 8 is H, halogen, OCH3, or CH3. In some embodiments of formula (II), R 8 is a halogen. In some embodiments of formula (II), R 8 is F, Cl, or Br. In some embodiments of formula (II), R 8 is OCH3 or CH3. In some embodiments of formula (II), R 8 H is H.

[0059] In some embodiments, the compound represented by formula (II) has the structure represented by (IIa), or is a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof: [ka]

[0060] In the above formula, X 1 and X 2 These are CH2 and CHR, which operate independently. 2 CR 2 R 2 , O or NR 2a And; here, X 1 or X 2 At least one of them is CH2, CHR 2 or CR 2 R 2 and; X 3 CR 8 and; Y is CH or CR 1 and; Each R 1 These are, independently, halogen, -CN, -OH, and -OR a , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 deuterated alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 haloalkyl or C1-C6 hydroxyalkyl; Each R 2 These are independently a substituted C1-C6 alkyl, a substituted C1-C6 deuterated alkyl, a substituted C1-C6 haloalkyl, or a substituted C3-C6 cycloalkyl; R 2a H, -C(=O)OR a -C(=O)NR a R b , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted arylalkyl, or optionally substituted C3-C6 cycloalkyl; Each R 3 These are independently C1-C3 alkyl or C1-C3 deuterated alkyl; R 5 is H, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 hydroxyalkyl; R 5b is H or C1-C3 alkyl; R 6a and R 6b These are H, -CN, and -C(=O)OR, respectively, independently. 7 -C(=O)N(R 7 )2, -S(=O)R 7 -S(=O)2R 7 Or -S(=O)(=NH)R 7 And here, Each R 7 These are independently a substituted C1-C6 alkyl, a substituted C3-C6 cycloalkyl, or a substituted 4-6 member heterocycloalkyl ring; Or, Two R's 7 They combine with the nitrogen atom to which they are bonded to form a substituted or otherwise substituted 4- to 5-membered heterocycloalkyl ring; Or, R 5 and R 7 They combine with the atoms to which they are bonded to form a five-membered heterocycloalkyl ring; R 6c is H or -CN; Or, R 6c and R 7 They combine with the atoms to which they are bonded to form a four-membered heterocycloalkyl ring; R 8 is H, halogen, -OCH3, or -CH3; Each R a Each of these is independently H, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C5-C8 aryl, C5-C8 heteroaryl, -C1-C6 alkyl(aryl), -C1-C6 alkyl(heteroaryl), -C1-C6 alkyl(cycloalkyl), or -C1-C6 alkyl(heterocycloalkyl); where each alkyl, deuterated alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), and alkyl(heterocycloalkyl) may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy; Each R bThese are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, or C1-C6 haloalkyl; Or, Two R's on a nitrogen atom b The groups, together with the nitrogen atoms to which they are bonded, form a heterocycloalkyl (which may be substituted with 1, 2, or 3 C1-C6 alkyl or C1-C6 haloalkyl); n1 and n2 are independently 0, 1, 2, or 3; p is 0, 1, 2, or 3; q is 0, 1, or 2; and, t is 1, 2, or 3.

[0061] In some embodiments of formula (II) or formula (IIa), X 1 CH2, CHR 2 or CR 2 R 2 X 2 CH2, CHR 2 or CR 2 R 2 In some embodiments of formula (II) or formula (IIa), X 1 CH2, CHR 2 or CR 2 R 2 X 2 is O or NR 2a In some embodiments of formula (II) or formula (IIa), X 1 CH2, CHR 2 or CR 2 R 2 X 2 is O. In some embodiments of formula (II) or formula (IIa), X 1 CH2, CHR 2 or CR 2 R2 X 2 , NR 2a In some embodiments of formula (II) or formula (IIa), X 2 CH2, CHR 2 or CR 2 R 2 X 1 is O or NR 2a In some embodiments of formula (II) or formula (IIa), X 2 CH2, CHR 2 or CR 2 R 2 X 1 is O. In some embodiments of formula (II) or formula (IIa), X 2 CH2, CHR 2 or CR 2 R 2 X 1 , NR 2a That is the case.

[0062] In some embodiments, the compound represented by formula (II) has the structure represented by (IIb), or is a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof: [ka]

[0063] In the above formula, Y is CH or CR 1 and; Each R 1 These are, independently, halogen, -CN, -OH, and -OR a , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 deuterated alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 haloalkyl or C1-C6 hydroxyalkyl; Each R 2These are independently substituted C1-C6 haloalkyl or substituted C3-C6 cycloalkyl; R 2a H, -C(=O)OR a -C(=O)NR a R b , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted arylalkyl, or optionally substituted C3-C6 cycloalkyl; Each R 3 These are independently C1-C3 alkyl or C1-C3 deuterated alkyl; R 5 is H, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 hydroxyalkyl; R 5b is H or C1-C3 alkyl; R 6a and R 6b These are H, -CN, and -C(=O)OR, respectively, independently. 7 -C(=O)N(R 7 )2, -S(=O)R 7 -S(=O)2R 7 Or -S(=O)(=NH)R 7 And here, Each R 7 These are independently a substituted C1-C6 alkyl, a substituted C3-C6 cycloalkyl, or a substituted 4-6 member heterocycloalkyl ring; Or, Two R's 7 They combine with the nitrogen atom to which they are bonded to form a substituted or otherwise substituted 4- to 5-membered heterocycloalkyl ring; Or, R 5 and R 7 They combine with the atoms to which they are bonded to form a five-membered heterocycloalkyl ring; R 6c is H or -CN; Or, R 6c and R7 They combine with the atoms to which they are bonded to form a four-membered heterocycloalkyl ring; Each R a Each of these is independently H, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2C6 alkenyl, C2C6 alkynyl, C3C6 cycloalkyl, C3C6 heterocycloalkyl, C5C8 aryl, C5C8 heteroaryl, -C1-C6 alkyl(aryl), -C1-C6 alkyl(heteroaryl), -C1-C6 alkyl(cycloalkyl), or -C1-C6 alkyl(heterocycloalkyl); where each alkyl, deuterated alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), and alkyl(heterocycloalkyl) may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy; Each R b These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, or C1-C6 haloalkyl; Or, Two R's on a nitrogen atom b The groups, together with the nitrogen atoms to which they are bonded, form a heterocycloalkyl (which may be substituted with 1, 2, or 3 C1-C6 alkyl or C1-C6 haloalkyl); n1 and n2 are independently 0, 1, 2, or 3; p is 0, 1, 2, or 3; q is 0, 1, or 2; and, t is 1, 2, or 3.

[0064] In some embodiments, provided herein are compounds represented by formula (IIb) or pharmaceutically acceptable salts thereof or stereoisomers thereof or pharmaceutically acceptable salts of stereoisomers thereof or atropisomers thereof or pharmaceutically acceptable salts of atropisomers thereof: [ka]

[0065] In the above formula, Y is CH or CR 1 and; Each R 1 These are independently Cl, Br, F, -OCH3, CH3, or CD3; Each R 2 These are, independently, halogen, -CN, -OH, and -OR a , -N(R b )2, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4-6 member heterocycloalkyl; R 2a is H, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl; Each R 3 These are independently -CH3 or -CD3; R 5 is H, -CH3, or -CH2CH3; R 6a and R 6b These are H, -CN, and -C(=O)OR, respectively, independently. 7 -C(=O)N(R 7 )2 or -S(=O)2R 7 And here, Each R 7 These are independently a substituted or substituted C1-C3 alkyl or a substituted or substituted 4-6 membered heterocycloalkyl ring; Or, Two R's 7 They combine with the nitrogen atom to which they are bonded to form a substituted or otherwise substituted 4- to 5-membered heterocycloalkyl ring; Or, R 5 and R 7 They combine with the atoms to which they are bonded to form a five-membered heterocycloalkyl ring; R 6c H is; Or, R 6c and R 7 They combine with the atoms to which they are bonded to form a four-membered heterocycloalkyl ring; R 5b is H or C1-C3 alkyl; Each R a These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, or aryl; where each alkyl, cycloalkyl, heterocycloalkyl, or aryl may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, or C1-C6 haloalkyl; Each R b These are independently H or C1-C6 alkyl; n1 and n2 are independently 0, 1, or 2; p is 0, 1, 2, or 3; q is 0, 1, or 2; and, t is 1, 2, or 3.

[0066] In some embodiments of formula (II), formula (IIa), or formula (IIb), R 2a H, -S(=O)2R a -C(=O)R a , -C(=O)OR a -C(=O)NR a R b , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C3-C6 cycloalkyl or phenyl. In some embodiments of formula (II), formula (IIa) or formula (IIb), R 2a is -C(=O)R a , -C(=O)OR a, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, or an optionally substituted C3-C6 cycloalkyl. In some embodiments of formula (II), formula (IIa), or formula (IIb), R 2a is -C(=O)R a OR -C(=O)OR a In some embodiments of formula (II), formula (IIa), or formula (IIb), R 2a R is an optionally substituted C1-C6 alkyl or optionally substituted C1-C6 haloalkyl. In some embodiments of formula (II), formula (IIa), or formula (IIb), R 2a is -CF3, -CHF2, -CH2CF3, -CH2CHF2, -CH2CClCF2, -CH3, or -CH2CH3. In some embodiments of formula (II), formula (IIa), or formula (IIb), R 2a is -CH2CF3, -CH2CHF2, or -CH2CClCF2. In some embodiments of formula (II), formula (IIa), or formula (IIb), R 2a is a C3-C6 cycloalkyl which may be substituted. In some embodiments of formula (II), formula (IIa), or formula (IIb), R 2a This is cyclopropyl, cyclobutyl, or cyclopropyl.

[0067] In some embodiments of formula (II), formula (IIa), or formula (IIb), R 2a These are -CF3, -CHF2, -CH2CF3, -CH2CHF2, -CH2CClCF2, -CH2CF(cyclopropyl), -CH2phenyl, -CH2CH2CF3, -CH2CF2CH3, -CH2CF2CHF2, -CH2CF2-(phenyl), -CH2CF2CH2CH3, -C(=O)OCH3, -C(=O)OC(CH3)3, -C(=O)C(CH3)3, -C(=O)CH3, -C(=O)phenyl, or cyclopropyl.

[0068] In some embodiments of formula (II), formula (IIa), or formula (IIb), R 2a teeth, [ka]

[0069] That is the case.

[0070] In some embodiments of formula (II), formula (IIa), or formula (IIb), R 2a teeth, [ka]

[0071] In some embodiments of formula (II), formula (IIa), or formula (IIb), R 2a teeth, [ka]

[0072] In some embodiments of formula (II), formula (IIa), or formula (IIb), R 2a teeth, [ka]

[0073] In some embodiments of formula (II), formula (IIa), or formula (IIb), R 2a teeth, [ka]

[0074] In some embodiments of formula (II), formula (IIa), or formula (IIb), R 2a teeth, [ka]

[0075] That is the case.

[0076] In some embodiments of formula (I) or formula (Ia), ring A is phenyl or a 5- to 10-membered heteroaryl. In some embodiments of formula (I) or formula (Ia), ring A is a 5- to 8-membered heteroaryl containing one, two, three, or four heteroatoms selected from N, O, and S. In some embodiments of formula (I) or formula (Ia), ring A is a 5-membered heteroaryl containing one, two, or three heteroatoms selected from N or O. In some embodiments of formula (I) or formula (Ia), ring A is a 6-membered heteroaryl containing one, two, or three heteroatoms selected from N or O. In some embodiments of formula (I) or formula (Ia), ring A is phenyl, pyridinyl, pyrimidinyl, pyridine-2-one, furanyl, isoxazolyl, or pyrrolyl. In some embodiments of formula (I) or formula (Ia), ring A is phenyl or pyridinyl. In some embodiments of formula (I) or formula (Ia), ring A is phenyl. In some embodiments of formula (I) or formula (Ia), ring A is pyridinyl.

[0077] In another embodiment, provided herein are compounds having the structure represented by formula (III), or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or pharmaceutically acceptable salts of stereoisomers thereof, or atropisomers thereof, or pharmaceutically acceptable salts of atropisomers thereof: [ka]

[0078] In the above formula, Y is N, CH, or CR 1 and; Z is either C(=O) or S(=O)²; X 4 CH, CR 2 or N; X 5 CH, CR 2 or N; Each R 1 These are, independently, halogen, -CN, -OH, and -OR a, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 deuterated alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 haloalkyl or optionally substituted C1-C6 hydroxyalkyl or optionally substituted C3-C6 cycloalkyl; Each R 2 These are, independently, halogen, -CN, -OH, and -OR a , -N(R b )2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 deuterated alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted arylalkyl, or optionally substituted 4-6 member heterocycloalkyl; Or, Two R's 2 They combine with the atom(s) to which they are bonded to form a C3-C5 cycloalkyl, a 4-5 membered heterocycloalkyl, or a 5-membered heteroaryl ring; Each R 3 These are, independently, halogen, -CN, -OH, and -OR a , C1-C6 alkyl, C1-C6 deuterated alkyl, or C1-C6 haloalkyl; R 4 H, halogen, -OH, -OR a or C1-C6 alkyl; R 5 is H, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 hydroxyalkyl; R 5b is H or C1-C3 alkyl; R 6a and R 6b These are H, -CN, and -C(=O)OR, respectively, independently. 7 -C(=O)N(R 7 )2, -S(=O)R 7 -S(=O)2R 7Or -S(=O)(=NH)R 7 And here, Each R 7 These are independently a substituted C1-C6 alkyl, a substituted C3-C6 cycloalkyl, or a substituted 4-6 member heterocycloalkyl ring; Or, Two R's 7 They combine with the nitrogen atom to which they are bonded to form a substituted or otherwise substituted 4- to 5-membered heterocycloalkyl ring; Or, R 5 and R 7 They combine with the atoms to which they are bonded to form a five-membered heterocycloalkyl ring; R 6c is H or -CN; Or, R 6c and R 7 They combine with the atoms to which they are bonded to form a four-membered heterocycloalkyl ring; Each R a Each of these is independently H, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C5-C8 aryl, C5-C8 heteroaryl, -C1-C6 alkyl(aryl), -C1-C6 alkyl(heteroaryl), -C1-C6 alkyl(cycloalkyl), or -C1-C6 alkyl(heterocycloalkyl); where each alkyl, deuterated alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), and alkyl(heterocycloalkyl) may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy; Each R bThese are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, or C1-C6 haloalkyl; Or, Two R's on a nitrogen atom b The groups, together with the nitrogen atoms to which they are bonded, form a heterocycloalkyl (which may be substituted with 1, 2, or 3 C1-C6 alkyl or C1-C6 haloalkyl); n1 and n2 are independently 0, 1, or 2; p is 0, 1, 2, or 3; q is 0, 1, or 2; and, t is 0, 1, 2, or 3.

[0079] In another embodiment, provided herein are compounds having the structure represented by formula (III), or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or pharmaceutically acceptable salts of stereoisomers thereof, or atropisomers thereof, or pharmaceutically acceptable salts of atropisomers thereof: [ka]

[0080] In the above formula, Y is CH or CR 1 and; Z is either C(=O) or S(=O)²; X 4 CH, CR 2 or N; X 5 CH, CR 2 or N; Each R 1 These are, independently, halogen, -CN, -OH, and -OR a, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 deuterated alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 haloalkyl or C1-C6 hydroxyalkyl; Each R 2 These are, independently, halogen, -CN, -OH, and -OR a , -N(R b )2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 deuterated alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 4-6 member heterocycloalkyl; Or, Two R's 2 They combine with the atom(s) to which they are bonded to form a C3-C5 cycloalkyl, a 4-5 membered heterocycloalkyl, or a 5-membered heteroaryl ring; Each R 3 These are independently C1-C3 alkyl or C1-C3 deuterated alkyl; R 4 It is a halogen; R 5 is H, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 hydroxyalkyl; R 5b is H or C1-C3 alkyl; R 6a and R 6b These are H, -CN, and -C(=O)OR, respectively, independently. 7 -C(=O)N(R 7 )2 or -S(=O)2R 7 And here, Each R 7 These are independently a substituted or substituted C1-C3 alkyl or a substituted or substituted 4-6 membered heterocycloalkyl ring; Or, Two R's 7They combine with the nitrogen atom to which they are bonded to form a substituted or otherwise substituted 4- to 5-membered heterocycloalkyl ring; Or, R 5 and R 7 They combine with the atoms to which they are bonded to form a five-membered heterocycloalkyl ring; R 6c is H or -CN; Or, R 6c and R 7 They combine with the atoms to which they are bonded to form a four-membered heterocycloalkyl ring; Each R a These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C1-C6 alkyl(aryl), -C1-C6 alkyl(heteroaryl), -C1-C6 alkyl(cycloalkyl), or -C1-C6 alkyl(heterocycloalkyl); where each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, or C1-C6 haloalkyl; Each R b These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, or C1-C6 haloalkyl; Or, Two R's on a nitrogen atom b The groups, together with the nitrogen atoms to which they are bonded, form a heterocycloalkyl (which may be substituted with 1, 2, or 3 C1-C6 alkyl or C1-C6 haloalkyl); n1 and n2 are independently 0, 1, or 2; p is 0, 1, 2, or 3; q is 0, 1, or 2; and, t is 0, 1, 2, or 3.

[0081] In some embodiments of equation (III), Z is -S(=O)²-.

[0082] In another embodiment, provided herein are compounds having the structure represented by formula (III), or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or pharmaceutically acceptable salts of stereoisomers thereof, or atropisomers thereof, or pharmaceutically acceptable salts of atropisomers thereof: [ka]

[0083] In the above formula, Z is S(=O)²; X 4 CH, CR 2 or N; X 5 CH or CR 2 and; Y is CH or CR 1 and; Each R 1 These are, independently, halogen, -OR a These are C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl; Each R 2 These are, independently, halogen, -OH, and -OR a , -N(R b )2, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4-6 member heterocycloalkyl; Or, Two R's 2 They combine with the atom(s) they are bonded to to form a five-membered heteroaryl ring; Each R3 These are independently -CH3 or CD3; R 4 is F; R 5 is H, -CH3, or -CH2CH3; R 6a and R 6b These are H, -CN, and -C(=O)OR, respectively, independently. 7 -C(=O)N(R 7 )2 or -S(=O)2R 7 And here, Each R 7 These are independently a substituted or substituted C1-C3 alkyl or a substituted or substituted 4-6 membered heterocycloalkyl ring; Or, Two R's 7 They combine with the nitrogen atom to which they are bonded to form a substituted or otherwise substituted 4- to 5-membered heterocycloalkyl ring; Or, R 5 and R 7 They combine with the atoms to which they are bonded to form a five-membered heterocycloalkyl ring; R 6c H is; Or, R 6c and R 7 They combine with the atoms to which they are bonded to form a four-membered heterocycloalkyl ring; R 5a is H; or R 5a and R 6c They combine with the nitrogen atom to which they are bonded to form a four-membered heterocycloalkyl ring; Each R a These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, or aryl; where each alkyl, cycloalkyl, heterocycloalkyl, or aryl may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, or C1-C6 haloalkyl; Each R bThese are independently H or C1-C6 alkyl; n1 and n2 are independently 1 or 2; p is 1; q is 0, 1, or 2; and, t is 1, 2, or 3.

[0084] In some embodiments, the compound represented by formula (III) has the structure represented by formula (IIIa), or is a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof: [ka]

[0085] In the above formula, Y is CH or CR 1 and; X 4 CH, CR 2 or N; X 5 CH, CR 2 or N; Each R 1 These are, independently, halogen, -CN, -OH, and -OR a , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 deuterated alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or optionally substituted C3-C6 cycloalkyl; Each R 2 These are, independently, halogen, -CN, -OH, and -OR a , -N(R b)2) C1-C6 alkyl which may be substituted, C1-C6 deuterated alkyl which may be substituted, C2-C6 alkenyl which may be substituted, C2-C6 alkynyl which may be substituted, C1-C6 haloalkyl which may be substituted, C1-C6 hydroxyalkyl which may be substituted, C3-C6 cycloalkyl which may be substituted, arylalkyl which may be substituted or 4-6 membered heterocycloalkyl which may be substituted; Each R 3 is independently C1-C3 alkyl or C1-C3 deuterated alkyl; R 5 is H, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 hydroxyalkyl; R 5b is H or C1-C3 alkyl; R 6a and R 6b are each independently H, -CN, -C(=O)N(R 7 )2, -S(=O)2R 7 or -S(=O)(=NH)R 7 ; where each R 7 is independently C1-C3 alkyl or a 4-membered heterocycloalkyl ring which may be substituted with up to 2 fluorine atoms; or two Rs 7 combine with the nitrogen atom to which they are attached to form a 4-membered heterocycloalkyl ring which may be substituted with up to 2 fluorine atoms; or R 5 and R 7 combine with the atom to which they are attached to form a 5-membered heterocycloalkyl ring; R 6c is H or -CN; or R 6c and R 7 combine with the atom to which they are attached to form a 4-membered heterocycloalkyl ring; Each R aEach of these is independently H, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C5-C8 aryl, C5-C8 heteroaryl, -C1-C6 alkyl(aryl), -C1-C6 alkyl(heteroaryl), -C1-C6 alkyl(cycloalkyl), or -C1-C6 alkyl(heterocycloalkyl); where each alkyl, deuterated alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), and alkyl(heterocycloalkyl) may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy; Each R b These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, or C1-C6 haloalkyl; Or, Two R's on a nitrogen atom b The groups, together with the nitrogen atoms to which they are bonded, form a heterocycloalkyl (which may be substituted with 1, 2, or 3 C1-C6 alkyl or C1-C6 haloalkyl); n1 and n2 are independently 0, 1, or 2; p is 0, 1, 2, or 3; q is 0, 1, or 2; and, t is 0, 1, 2, or 3.

[0086] In some embodiments, the compound represented by formula (III) has the structure represented by formula (IIIb), or is a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof: [ka]

[0087] In the above formula, X 4 is either CH or N; Y is CR 1 or CH; Each R 1 These are, independently, halogen, -CN, and -OR. a , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 deuterated alkyl, C2-C4 alkynyl, or C1-C3 fluoroalkyl; R 2 These are halogen, -CN, -OH, -OR a , -N(R b )2, -C(=O)R a , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 deuterated alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 fluoroalkyl, optionally substituted C1-C3 hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 4-6 member heterocycloalkyl; Each R 3 These are independently -CH3 or -CD3; R 5 is H, -CH3, or -CH2CH3; R 5b is H or C1-C3 alkyl; R 6a and R 6b These are H, -CN, and -C(=O)N(R) independently of each other. 7 )2, -S(=O)2R 7 Or -S(=O)(=NH)R 7 And here, Each R 7 This is independently a C1-C3 alkyl or a four-membered heterocycloalkyl ring which may be substituted with up to two fluorine atoms; Or, Two R's 7 They combine with the nitrogen atom to which they are bonded to form a four-membered heterocycloalkyl ring which may be substituted with up to two fluorine atoms; Or, R 5 and R 7 They combine with the atoms to which they are bonded to form a five-membered heterocycloalkyl ring; R 6c is H or -CN; Each R a These are independently C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C3 fluoroalkyl; Each R b These are independently H or C1-C3 alkyl; q is 0, 1, or 2; and, t is 0, 1, or 2.

[0088] In some embodiments of formula (III) or formula (IIIa), X 4 CH or CR 2 X 5 CH or CR 2 In some embodiments of formula (III) or formula (IIIa), X 4 is N; and X 5 It is N.

[0089] In some embodiments of formula (III) or formula (IIIa), X 4 CH or CR 2 In some embodiments of formula (III), formula (IIIa), or formula (IIIb), X 4 is CH. In some embodiments of formula (III), formula (IIIa), or formula (IIIb), X 4 It is N.

[0090] In some embodiments of formula (III) or formula (IIIa), X 5 CH or CR 2 In some embodiments of formula (III) or formula (IIIa), X 5 is CH. In some embodiments of formula (III) or formula (IIIa), X 5 It is N.

[0091] In some embodiments of formula (I), R A teeth, [ka]

[0092] And here, R 5 is H, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 hydroxyalkyl; R 6a and R 6b These are H, -CN, and -C(=O)OR, respectively, independently. 7 -C(=O)N(R 7 )2, -S(=O)R 7 -S(=O)2R 7 Or -S(=O)(=NH)R 7 And here, Each R 7 These are independently a substituted C1-C6 alkyl, a substituted C3-C6 cycloalkyl, or a substituted 4-6 member heterocycloalkyl ring; Or, Two R's 7 They combine with the nitrogen atom to which they are bonded to form a substituted or otherwise substituted 4- to 5-membered heterocycloalkyl ring; Or, R 5 and R 7 They combine with the atoms to which they are bonded to form a five-membered heterocycloalkyl ring; R 6c is H or -CN; Or, R 6c and R7 They combine with the atoms to which they are attached to form a 4-membered heterocycloalkyl ring.

[0093] In some embodiments of formula (I), R A is

Chemical formula

[0094] where; R 5 is H, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 hydroxyalkyl; R 6a and R 6b are each independently H, -CN, -C(=O)OR 7 , -C(=O)N(R 7 )2 or -S(=O)2R 7 where; each R 7 is independently optionally substituted C1-C3 alkyl or optionally substituted 4-6 membered heterocycloalkyl ring; or, two Rs 7 combine with the nitrogen atom to which they are attached to form an optionally substituted 4-5 membered heterocycloalkyl ring; or, R 5 and R 7 combine with the atoms to which they are attached to form a 5-membered heterocycloalkyl ring; R 6c is H; or, R 6c and R 7 combine with the atoms to which they are attached to form a 4-membered heterocycloalkyl ring.

[0095] In some embodiments of formula (I), R A is

Chemical formula

[0096] And here, R 5 It is a C1-C3 alkyl group; R 6a and R 6b These are H and -C(=O)N(R) independently of each other. 7 )2 or -S(=O)2R 7 And here, Each R 7 These are independently a substituted or substituted C1-C3 alkyl or a substituted or substituted 4-6 membered heterocycloalkyl ring; Or, Two R's 7 They combine with the nitrogen atom to which they are bonded to form a substituted or otherwise substituted 4- to 5-membered heterocycloalkyl ring; Or, R 5 and R 7 They combine with the atoms to which they are bonded to form a five-membered heterocycloalkyl ring; R 6c H is; Or, R 6c and R 7 These combine with the atoms to which they are bonded to form a four-membered heterocycloalkyl ring.

[0097] In some embodiments of formula (I), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), R 5 is a C1-C3 alkyl, a C1-C3 haloalkyl, or a C1-C3 hydroxyalkyl. In some embodiments of formula (I), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), R 5 R is a C1-C3 haloalkyl. In some embodiments of formula (I), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), R 5is -CF3 or -CH2CF3. In some embodiments of formula (I), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), R 5 R is a C1-C3 alkyl group. In some embodiments of formula (I), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), R 5 is -CH3 or -CH2CH3. In some embodiments of formulas (I), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), R 5 is -CH2CH3. In some embodiments of formula (I), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), R 5 R is a C1-C3 hydroxyalkyl group. In some embodiments of formula (I), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), R 5 is -CH2OCH3 or -CH2OCH2CH3. In some embodiments of formula (I), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), R 5 is H, -CH3, -CH2CH3, -CH2OCF3, or -CH2OCH3. In some embodiments of formula (I), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), R 5 H is H.

[0098] In some embodiments of formula (I) or formula (Ia), R 5a H is H.

[0099] In some embodiments of formula (I) or formula (Ia), R 5a and R 6c These combine with the nitrogen atom to which they are bonded to form a four-membered heterocycloalkyl ring.

[0100] In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), R6a -CN, -C(=O)OR 7 -C(=O)N(R 7 )2 or -S(=O)2R 7 And; and, R 6b and R 6c These are H, respectively. In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), R 6a is -C(=O)N(R 7 )2 or -S(=O)2R 7 And; and, R 6b and R 6c These are H, respectively. In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), R 6a S(=O2)R 7 And; and, R 6b and R 6c These are H, respectively.

[0101] In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), R 6b -CN, -C(=O)OR 7 -C(=O)N(R 7 )2 or -S(=O)2R 7 And; and, R 6a and R 6c These are H, respectively. In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), R 6b is -C(=O)N(R 7 )2 or -S(=O)2R 7 ; and, R 6a and R 6c These are H, respectively. In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), R 6b S(=O2)R 7 And; and, R 6aand R 6c These are H, respectively.

[0102] In some embodiments of formula (I), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), R 5 and R 7 These combine with the atoms to which they are bonded to form a five-membered heterocycloalkyl ring.

[0103] In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), R 6c and R 7 These combine with the atoms to which they are bonded to form a four-membered heterocycloalkyl ring.

[0104] In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), each R 7 R is independently a substituted or substituted C1-C3 alkyl or a substituted or substituted 4-6 member heterocycloalkyl ring. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), each R 7 R is independently a C1-C3 alkyl group. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), each R 7 These are independently 4- to 6-membered heterocycloalkyl rings.

[0105] In some embodiments of formula (I), R A teeth, [ka] TIFF2026509001000038.tif37147

[0106] That is the case.

[0107] In some embodiments of formula (I), R A teeth, [ka]

[0108] In some embodiments of equation (I), R A teeth, [ka]

[0109] That is the case.

[0110] In some embodiments of formula (I), R A teeth, [ka]

[0111] In some embodiments of equation (I), R A teeth, [ka]

[0112] In some embodiments of equation (I), R A teeth, [ka]

[0113] In some embodiments of equation (I), R A teeth, [ka]

[0114] In some embodiments of equation (I), R A teeth, [ka]

[0115] In some embodiments of equation (I), R A teeth, [ka]

[0116] In some embodiments of equation (I), R A teeth, [ka]

[0117] That is the case.

[0118] In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), R 6a is -C(=O)N(R 7 )2, and R 6b and R 6c These are H and R respectively; 6b is -C(=O)N(R 7 )2, and R 6a and R 6c These are H, and here, two R 7 These combine with the nitrogen atoms to which they are bonded to form a substituted 4-5 membered ring. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), R 6a is -C(=O)N(R 7 )2, and R 6b and R 6c These are H, respectively. In some embodiments, R 6b is -C(=O)N(R 7 )2, and R 6a and R 6c These are H, respectively.

[0119] In some embodiments of formula (I), R A teeth, [ka]

[0120] That is the case.

[0121] In some embodiments of formula (I), R A teeth, [ka]

[0122] That is the case.

[0123] In some embodiments of formula (I), R A teeth, [ka]

[0124] That is the case.

[0125] In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), each R 1 These are, independently, halogen, -CN, -OH, and -OR a -SH, -SR a -NO2, -N(R b )2, -C(=O)R a , -C(=O)OR a -C(=O)NR a R b , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 haloalkyl or C1-C6 hydroxyalkyl. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa) or formula (IIIb), each R 1 These are, independently, halogen, -CN, -OH, and -OR a, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 haloalkyl or C1-C6 hydroxyalkyl. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa) or formula (IIIb), each R 1 These are, independently, halogen, -OR a , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 haloalkyl or C1-C6 hydroxyalkyl. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa) or formula (IIIb), each R 1 R is independently a halogen. In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), each R 1 R is independently Br, Cl, or F. In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), each R 1 R is independently a C1-C6 alkyl which may be substituted. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), each R 1 R is independently -CH3 or -CH2CH3. In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), each R 1 These are, independently, -OR a In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), each R 1 R is independently -O(alkyl), -O(haloalkyl), or -O(cycloalkyl). In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), each R1 These are independently -OCH3, -OCH2CH3, -OCF3, -O(cyclopropyl), or -O(cyclobutyl).

[0126] In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), each R 1 R is independently Cl, F, -CF3, -CH3, -CH2CH3, -OCH3, -O(cyclopropyl), or -O(cyclobutyl). In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), each R 1 R is independently Cl, F, -CH3, -CH2CH3, or -OCH3. In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), each R 1 R is independently Cl, F, or -CH3. In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), each R 1 R is independently Cl or F. In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), each R 1 Independently, is Cl. In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), each R 1 These are F independently.

[0127] In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), each R 2 These are, independently, halogen, -CN, -OH, and -OR a -SH, -SR a -NO2, -N(R b )2, -S(=O)2R a -C(=O)R a , -C(=O)ORa -C(=O)NR a R b , oxo (=O), optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkylamino, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 4-6 member heterocycloalkyl. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), each R 2 These are, independently, halogen, -CN, -OH, and -OR a , -N(R b )2, an optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 21-C6 alkynyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 4-6 member heterocycloalkyl.

[0128] In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), each R 2 R is independently a halogen. In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), each R 2 R is independently Cl, Br, or F. In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), each R 2 These are, independently, -OR a or -N(R b )2. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), each R 2These are independently -OCH3, -OCF3, -OCH2CH3, -OCHF2, -OCH(CH3)2, -O(cyclopropyl) or -N(CH3)2. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa) or formula (IIIb), each R 2 R is independently a C1-C6 alkyl which may be substituted. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), each R 2 These are independently -CH3, -CH2CH3, -CHCH2, or -CH(CH3)2. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), each R 2 R is independently a substituted or substituted C1-C6 haloalkyl or a substituted or substituted C1-C6 hydroxyalkyl. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), each R 2 These are independently -CH2OH, -CH2CH2OH, -CHOHCH3, -CF3, -CHF2, -CH2CF3, or -CH2CHF2. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), each R 2 R is independently a substituted or optionally substituted C3-C6 cycloalkyl or a substituted or optionally substituted 4-6 member heterocycloalkyl. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), each R 2 These are independently azetidine, oxetane, pyrrolidine, piperazine, or morpholine.

[0129] In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), each R 2These are independently Cl, F, Br, -CN, -OH, -OCH3, -OCF3, -OCH2CH3, -OCHF2, -OCH(CH3)2, -O(cyclopropyl), -N(CH3)2, -CH3, -CH2CH3, -CHCH2, -CH(CH3)2, -CH2OH, -CH2CH2OH, -CHOHCH3, -CF3, -CHF2, -CH2CF3, -CH2CHF2, azetidine, oxetane, pyrrolidine, piperazine or morpholine or pyrrolidine-2-one. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa) or formula (IIIb), each R 2 These are independently Cl, F, Br, -OCH3, -OCF3, -OCH2CH3, -OCHF2, -OCH(CH3)2, -O(cyclopropyl), -N(CH3)2, -CH3, -CH2CH3, -CHCH2, -CH(CH3)2, -CH2OH, -CH2CH2OH, -CHOHCH3, -CF3, -CHF2, -CH2CF3, or -CH2CHF2.

[0130] In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), each R 2 Independently, [ka]

[0131] That is the case.

[0132] In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), or formula (IIIa), two R 2 These combine with the atom(s) to which they are bonded to form a C3-C5 cycloalkyl, a 4-5 membered heterocycloalkyl, or a 5 membered heteroaryl ring. In some embodiments, the two R 2 The group is located on the same carbon atom or on an adjacent atom. In some embodiments, the two R groups 2The group is located on the same carbon. In some embodiments, the two R groups 2 The group is located on an adjacent atom. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), or formula (IIIa), there are two R 2 These combine with the atom(s) to which they are bonded to form a C3-C5 cycloalkyl ring. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), or formula (IIb), two R 2 These combine with the carbon atoms to which they are bonded to form cyclopropyl or cyclobutyl. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), or formula (IIIa), two R 2 These combine with the atom(s) to which they are bonded to form a 4-5 membered heterocycloalkyl ring. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), or formula (IIb), two R 2 These atoms, together with the carbon atoms to which they are bonded, form oxetanes.

[0133] In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), each R 3 These are, independently, halogen, -CN, -OH, and -OR a , C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), each R 3 These are, independently, halogen, -OH, and -OR a or C1-C6 alkyl. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), each R 3 These are independently C1-C6 alkyl groups. In some embodiments, each R 3R is independently a C1-C3 alkyl group. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), each R 3 R is independently -CH3 or -CH2CH3. In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), each R 3 Independently, is -CH3. In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), each R 3 Independently, is -CH2CH3. In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), each R 3 R is independently a halogen. In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), each R 3 R is independently F, Cl, or Br. In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), each R 3 Independently, F. In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), each R 3 Independently, is Cl. In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), each R 3 It is independently Br.

[0134] In some embodiments of formula (I), formula (Ia), formula (II), or formula (III), two R 3 These combine with the atom(s) to which they are bonded to form a C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl ring. In some embodiments of formula (I), formula (Ia), formula (II), or formula (III), two R 3These combine with the atom(s) to which they are bonded to form a C3-C8 cycloalkyl group.

[0135] In some embodiments of formula (I), formula (II), or formula (III), R 4 These are halogen, -OH, and -OR a or C1-C6 alkyl. In some embodiments of formula (I), formula (II), or formula (III), R 4 is H or a halogen. In some embodiments of formula (I), formula (II), or formula (III), R 4 is a halogen. In some embodiments of formula (I), formula (II), or formula (III), R 4 is Cl, Br, or F. In some embodiments of formula (I), formula (II), or formula (III), R 4 is F. In some embodiments of formula (I), formula (II), or formula (III), R 4 is -OR a or C1-C6 alkyl. In some embodiments of formula (I), formula (II), or formula (III), R 4 is -OCH3 or -CH3. In some embodiments of formula (I), formula (II), or formula (III), R 4 H is H.

[0136] In some embodiments of equation (II), m is 1. In some embodiments of equation (II), m is 0.

[0137] In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), or formula (IIIa), n1 and n2 are independently 0, 1, 2, or 3. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), or formula (IIIa), n1 and n2 are independently 0, 1, or 2. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), or formula (IIIa), n1 and n2 are independently 1 or 2. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), or formula (IIIa), n1 and n2 are independently 1. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), or formula (IIIa), n1 is 1 or 2; and n2 is 1. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), or formula (IIIa), n1 is 2; and n2 is 1. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), or formula (IIIa), n1 is 1; and n2 is 1.

[0138] In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), or formula (IIIa), p is an integer between 0 and 8. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), or formula (IIIa), p is an integer between 0 and 4. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), or formula (IIIa), p is an integer between 0 and 3. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), or formula (IIIa), p is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), or formula (IIIa), p is 0, 1, 2, 3, or 4. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), or formula (IIIa), p is 0, 1, 2, or 3. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), or formula (IIIa), p is 0, 1, or 2. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), or formula (IIIa), p is 1 or 2. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), or formula (IIIa), p is 3. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), or formula (IIIa), p is 2. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), or formula (IIIa), p is 1. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), or formula (IIIa), p is 0.

[0139] In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), q is an integer between 0 and 12. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), q is an integer between 0 and 8. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), q is an integer between 0 and 2. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), q is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), q is 0, 1, 2, 3, or 4. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), q is 0, 1, 2, or 3. In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), q is 0, 1, or 2. In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), q is 0 or 1. In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), q is 3. In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), q is 2. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), q is 1. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), q is 0.

[0140] In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), t is 0, 1, 2, or 3. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), t is 0, 1, or 2. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), t is 0 or 1. In some embodiments of formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), t is 3. In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), t is 2. In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), t is 1. In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), t is 0.

[0141] In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), each R a R is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C1-C6 alkyl(aryl), -C1-C6 alkyl(heteroaryl), -C1-C6 alkyl(cycloalkyl), or -C1-C6 alkyl(heterocycloalkyl); where each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, each R aR is independently a C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, each R a is independently a C1-C6 alkyl or C1-C6 heteroalkyl; where the alkyl or heteroalkyl may independently be substituted with 1, 2 or 3 halogens, -OH, C1-C6 alkyl, or C1-C6 haloalkyl.

[0142] In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), each R b R is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, each R b R is independently H, C1-C6 alkyl, or C1-C6 heteroalkyl; where the alkyl or heteroalkyl may independently be substituted with 1, 2, or 3 halogens, -OH, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, each R b It is hydrogen.

[0143] In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), or (IIIa), two R atoms on the nitrogen atom b The groups, together with the nitrogen atom to which they are bonded, form a heterocycloalkyl (which may be substituted with 1, 2, or 3 C1-C6 alkyl or C1-C6 haloalkyl). In some embodiments, two R groups on the nitrogen atom b The groups, together with the nitrogen atom to which they are bonded, form a 3- to 7-membered heterocycloalkyl (which may be substituted with 1, 2, or 3 C1-C6 alkyl or C1-C6 haloalkyl). In some embodiments, two R groups on the nitrogen atom b The groups, together with the nitrogen atom to which they are bonded, form a 5-membered or 6-membered heterocycloalkyl (which may be substituted with 1, 2, or 3 C1-C6 alkyl or C1-C6 haloalkyl). In some embodiments, two R groups on the nitrogen atom b The groups, together with the nitrogen atom to which they are bonded, form pyrrolidine, piperidine, or morpholine (which may be substituted with 1, 2, or 3 C1-C6 alkyl or C1-C6 haloalkyl groups). In some embodiments, two R groups on the nitrogen atom b The groups, together with the nitrogen atoms to which they are bonded, form pyrrolidine, piperidine, or morpholine.

[0144] The compounds represented by formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), and (IIIb) may exist in chiral or achiral form. This form may be a racemate or in an R or S configuration. The compounds represented by formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), and (IIIb) may be stereoisomers. These compounds may be atropisomers or pharmaceutically acceptable salts of atropisomers.

[0145] The compounds of this disclosure include, but are not limited to, the compounds in Table 1 or their pharmaceutically acceptable salts or their stereoisomers or pharmaceutically acceptable salts of their stereoisomers or their atropisomers or pharmaceutically acceptable salts of their atropisomers.

[0146] All stereocenters labeled (S) or (R) are known absolute stereochemistrys. If the stereochemistry is pure but unknown, the stereocenter is drawn and defined as (*S) or (*R). Stereochemistrys that are drawn but not labeled are the correct cis or trans configurations but are racemates and are denoted as "rac" or RS. [Table 1] TIFF2026509001000053.tif220166TIFF2026509001000054.tif222166TIFF2026509001000055.tif223166TIFF2026509001000056.tif220166 TIFF2026509001000057.tif220166 TIFF2026509001000058.tif221166 TIFF2026509001000059.tif222166 TIFF2026509001000060.tif222166 TIFF2026509001000061.tif221166 TIFF2026509001000062.tif219166 TIFF2026509001000063.tif221166 TIFF2026509001000064.tif222166 TIFF2026509001000065.tif221166 TIFF2026509001000066.tif223166 TIFF2026509001000067.tif221166 TIFF2026509001000068.tif222166 TIFF2026509001000069.tif220166 TIFF2026509001000070.tif221165 TIFF2026509001000071.tif222166 TIFF2026509001000072.tif221166 TIFF2026509001000073.tif222166 TIFF2026509001000074.tif222166 TIFF2026509001000075.tif221166 TIFF2026509001000076.tif222166 TIFF2026509001000077.tif220166 TIFF2026509001000078.tif220166 TIFF2026509001000079.tif220166 TIFF2026509001000080.tif219166 TIFF2026509001000081.tif221166 TIFF2026509001000082.tif220166 TIFF2026509001000083.tif220166 TIFF2026509001000084.tif202166 TIFF2026509001000085.tif232166 TIFF2026509001000086.tif221166 TIFF2026509001000087.tif232166 TIFF2026509001000088.tif227166 TIFF2026509001000089.tif212166 TIFF2026509001000090.tif232166 TIFF2026509001000091.tif225166 TIFF2026509001000092.tif209166 TIFF2026509001000093.tif225166 TIFF2026509001000094.tif227166 TIFF2026509001000095.tif220166 TIFF2026509001000096.tif219166 TIFF2026509001000097.tif236166 TIFF2026509001000098.tif222166 TIFF2026509001000099.tif221166 TIFF2026509001000100.tif219166 TIFF2026509001000101.tif204166 TIFF2026509001000102.tif227166 TIFF2026509001000103.tif200166 TIFF2026509001000104.tif215166 TIFF2026509001000105.tif117166

[0147] Further forms of compounds In some embodiments, the compounds disclosed herein have one or more stereocenters, each stereocenter existing independently in either an R or S configuration. The compounds presented herein encompass all diastereomer, enantiomer, and epimer forms, as well as suitable mixtures thereof. Furthermore, the compounds may also exist as atrop isomers. The compounds and methods provided herein encompass all cis isomers, trans isomers, syn isomers, anti isomers, entgegen(E) isomers, and zusammen(Z) isomers, as well as suitable mixtures thereof. In certain embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form diastereomer compound / salt pairs, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, the resolving of the enantiomers is carried out using covalent diastereomer derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation / resolution techniques based on differences in solubility. In yet another embodiment, the separation of stereoisomers is performed by chromatography, or by forming diastereomer salts and separating them by recrystallization, chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley and Sons, Inc., 1981. In one embodiment, stereoisomers are obtained by stereoselective synthesis.

[0148] In some embodiments, the compounds described herein are prepared as prodrugs. “Prodrug” refers to a substance that is converted to a parent drug in vivo. Prodrugs are often useful because they may be easier to administer than the parent drug. For example, while the parent drug has no bioavailability when administered orally, the prodrug is bioavailable when administered orally. Prodrugs may exhibit improved solubility in pharmaceutical compositions than the parent drug. In some embodiments, the design of the prodrug improves its effective water solubility. A non-limiting example of a prodrug is a compound described herein, which is administered as an ester (prodrug) to facilitate permeability across cell membranes where water solubility is unfavorable for mobility, and then, upon entering the cell where water solubility is favorable, is metabolically hydrolyzed to the active component, a carboxylic acid. Further examples of prodrugs include short-chain peptides (polyamino acids) bound to an acid group, which are metabolized to expose the active group. In certain embodiments, when administered in vivo, the prodrug is chemically converted to a biologically, pharmacologically, or therapeutically active form of the compound. In certain embodiments, the prodrug is enzymatically metabolized by one or more steps or processes to obtain a biological, pharmacological, or therapeutically active form of the compound.

[0149] In one embodiment, prodrugs are designed to alter the metabolic stability or transport properties of a drug, to mask side effects or toxicity, to improve the flavor of a drug, or to alter other properties or characteristics of a drug. If a pharmaceutically active compound is known through knowledge of pharmacokinetic, pharmacodynamic processes and drug metabolism in vivo, it becomes possible to design a prodrug of that compound. (For example, see the following: Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pages 352-401, Rooseboom et al., Pharmacological Reviews, 56:53-102, 2004; Aesop Cho, “Recent Advances in Oral Prodrug Discovery”, Annual Reports in Medicinal Chemistry, Vol. 41, 395-407, 2006; T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series).

[0150] In some embodiments, some of the compounds described herein may be prodrugs for other derivatives or active compounds.

[0151] In some embodiments, the aromatic ring portion of the compounds described herein is sensitive to various metabolic reactions. Therefore, by introducing appropriate substituents on the aromatic ring structure, these metabolic pathways can be reduced, minimized, or eliminated. In certain embodiments, suitable substituents for reducing or eliminating the sensitivity of the aromatic ring to metabolic reactions are, for example, halogens or alkyl groups.

[0152] In another embodiment, the compounds described herein are isotope-labeled (e.g., using radioactive isotopes) or labeled by other means (e.g., chromophores or fluorescent moieties, bioluminescent labeling, or chemiluminescent labeling, but not limited to these).

[0153] The compounds disclosed herein, in some embodiments, are in various isotope enrichment forms (e.g., 2 H, 3 H, 11 C, 13 C and / or 14 It is used in a form enriched with C content. In certain embodiments, the compound is deuterated at at least one position. Such deuterated forms can be produced by the procedures described in U.S. Patents 5,846,514 and 6,334,997. As described in U.S. Patents 5,846,514 and 6,334,997, deuteration improves metabolic stability and / or efficacy, thereby extending the duration of action of the drug.

[0154] Unless otherwise indicated, the compounds described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present invention except that hydrogen is replaced with deuterium or tritium, or carbon 13 C or 14 Compounds having the structure of the present invention, except that C is replaced with enriched carbon, are included within the scope of this disclosure.

[0155] The compounds of this disclosure may optionally contain unnatural proportions of atomic isotopes in one or more atoms constituting such compounds. For example, the compound may contain deuterium ( 2 H), tritium ( 3 H), Iodine-125( 125 I) or carbon-14 ( 14 It can be labeled with isotopes such as C). 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br and 125 All isotopic substitutions by I are expected. All isotopic variants of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0156] In some embodiments of the compounds disclosed herein, R 1 Group, R 2 Group, R 3 Group, R 4 Group, R 5 Group, R 5a Group, R 6a Group, R 6b Group, R 6c Group, R 7 Base and R 8 One or more of the groups contain deuterium in a proportion exceeding the natural abundance of deuterium.

[0157] In some embodiments of the compounds disclosed herein, the following group R 1 , R 2 , R3 , R 4 , R 5 , R 5a , R 6a , R 6b , R 6c , R 7 and R 8 In one or more of these, one or more hydrogen atoms are replaced by one or more deuterium atoms.

[0158] In some embodiments of the compounds disclosed herein, R 1 , R 2 , R 3 , R 4 , R 5 , R 5a , R 6a , R 6b , R 6c , R 7 and R 8 The deuterium content in each of them is, independently, at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of the total amount of hydrogen and deuterium.

[0159] In certain embodiments, the compounds disclosed herein include: 1 Some or all of the H atoms 2 It is replaced by a hydrogen atom. Methods for synthesizing deuterium-containing compounds are known in the art and include, as non-limiting examples, the following synthesis methods.

[0160] Deuterium-substituted compounds are synthesized using various methods, for example, those described below: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0161] Deuterated starting materials are readily available, and deuterium-containing compounds are synthesized by subjecting such deuterated starting materials to the synthesis methods described herein. Many types of deuterium-containing reagents and building blocks are commercially available from chemical suppliers (e.g., Aldrich Chemical Co.).

[0162] In further embodiments, the compounds described herein are metabolized upon administration to an organism that requires the production of metabolites, and are subsequently used to produce a desired effect (including a desired therapeutic effect).

[0163] When used herein, "pharmaceutically acceptable" refers to a substance (e.g., a carrier or diluent) that does not inhibit the biological activity or properties of the compound and is relatively non-toxic (i.e., the substance can be administered to an individual without causing undesirable biological effects or harmful interactions with any of the components of a composition containing the compound).

[0164] The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not inhibit the biological activity and properties of the compound without causing significant irritation to the administered organism. In some embodiments, pharmaceutically acceptable salts are obtained by reacting the compounds disclosed herein with an acid. Pharmaceutically acceptable salts can also be obtained by reacting the compounds disclosed herein with a base to form a salt.

[0165] The compounds described herein may be formed and / or used as pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include, but are not limited to, (1) acid addition salts: these are salts in which the free base form of the compound is formed with a pharmaceutically acceptable inorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, etc.) or a pharmaceutically acceptable organic acid (e.g., acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo[2.2.2]o (1) Formed by reacting with 2-en-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, etc.; (2) Salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion (e.g., lithium, sodium, potassium), an alkaline earth ion (e.g., magnesium or calcium), or an aluminum ion. In some examples, the compounds described herein may coordinate with organic bases (e.g., ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine, etc.). In other cases, the compounds described herein may form salts with amino acids (e.g., arginine, lysine, etc., but not limited to these).Acceptable inorganic bases used to form salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide.

[0166] It should be understood that the reference to “pharmaceutically acceptable salts” includes solvated forms (in particular, solvates). Solvates can be formed during crystallization processes using pharmaceutically acceptable solvents such as water and ethanol, containing stoichiometric or nonstoichiometric amounts of solvent. When the solvent is water, a hydrate is formed; when the solvent is alcohol, an alcoholate is formed. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. Furthermore, the compounds provided herein can exist in solvate and non-solvate forms. In general, with respect to the purpose of the compounds and methods provided herein, the solvate form is considered equivalent to the non-solvate form.

[0167] Pharmaceutical composition In another embodiment, provided herein are compounds represented by formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb) or pharmaceutically acceptable salts thereof or stereoisomers thereof or pharmaceutically acceptable salts thereof or atropisomers thereof or pharmaceutically acceptable salts thereof, for use in the manufacture of pharmaceuticals.

[0168] In one embodiment, the compounds described herein (e.g., compounds represented by formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or atropisomers thereof, or pharmaceutically acceptable salts thereof) are formulated into pharmaceutical compositions. The pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inert components that facilitate the processing of the active compounds into pharmaceutically usable preparations. The appropriate formulation depends on the selected route of administration. Outlines of the pharmaceutical compositions described herein can be found, for example, in: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999): These disclosures are incorporated herein by reference.

[0169] When used herein, "pharmaceutical composition" refers to a mixture of the compounds disclosed herein with other chemical components (i.e., pharmaceutically acceptable), such as carriers, excipients, binders, fillers, suspending agents, fragrances, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, antifoaming agents, antioxidants, preservatives, or a combination of one or more thereof. The pharmaceutical composition facilitates the administration of the compounds to a living organism.

[0170] The pharmaceutical formulations described herein can be administered to subjects in various ways by a variety of routes of administration (this includes, but is not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, intrathecal, intrathecal, direct intraventricular, intraperitoneal, intralymphatic, intranasal), nasal, oral, local, or transdermal routes). The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposome dispersions, aerosols, solid dosage forms, powders, immediate-release formulations, controlled-release formulations, rapidly dissolving formulations, tablets, capsules, pills, delayed-release formulations, sustained-release formulations, pulsating-release formulations, multi-particle formulations, and mixed immediate and controlled-release formulations.

[0171] In some embodiments, the compounds disclosed herein are administered orally.

[0172] In some embodiments, the compounds disclosed herein are administered topically. In such embodiments, the compounds disclosed herein are formulated into a variety of topically administered compositions, such as solutions, suspensions, lotions, gels, pastes, shampoos, scrubs, rubs, smears, medicated sticks, medicated bandages, balms, creams, or ointments. In one embodiment, the compounds disclosed herein are administered topically to the skin.

[0173] In another embodiment, the compounds disclosed herein are administered by inhalation.

[0174] In another embodiment, the compounds disclosed herein are formulated for intranasal administration. Such formulations include nasal sprays and nasal mists.

[0175] In another embodiment, the compounds disclosed herein are formulated as eye drops.

[0176] In further embodiments included in any of the above embodiments, an effective amount of the compound disclosed herein is administered (a) systemically to a mammal; and / or (b) orally to a mammal; and / or (c) intravenously to a mammal; and / or (d) by inhalation to a mammal; and / or (e) intranasally to a mammal; and / or (f) by injection to a mammal; and / or (g) topically to a mammal; and / or (h) by intraocular administration; and / or (i) rectally to a mammal; and / or (j) non-systemically or topically to a mammal.

[0177] Further embodiments included in any of the above embodiments include administering a single dose of an effective amount of the compound disclosed herein, which further includes (i) embodiments in which the compound is administered once; (ii) embodiments in which the compound is administered to a mammal multiple times over a day; (iii) embodiments in which the compound is administered continuously; or (iv) embodiments in which the compound is administered sequentially.

[0178] Further embodiments included in any of the above embodiments include administering multiple doses of an effective amount of the compound disclosed herein, which further include (i) embodiments in which the compound is administered continuously or intermittently (as a single dose); (ii) embodiments in which the time interval between doses is every 6 hours; (iii) embodiments in which the compound is administered to a mammal every 8 hours; (iv) embodiments in which the compound is administered to a mammal every 12 hours; and (v) embodiments in which the compound is administered to a mammal every 24 hours. In further or alternative embodiments, the method includes a “drug-free period” during which the administration of the compound disclosed herein is temporarily discontinued or the dose of the compound administered is temporarily reduced; after the end of the drug-free period, the administration of the compound is resumed. In one embodiment, the length of the drug-free period varies from 2 days to 1 year.

[0179] In certain embodiments, the compounds disclosed herein are administered topically rather than systemically.

[0180] In some embodiments, the compounds disclosed herein are administered topically. In some embodiments, the compounds disclosed herein are administered systemically.

[0181] In some embodiments, the pharmaceutical formulation is in the form of a tablet. In other embodiments, the pharmaceutical formulation of the compound disclosed herein is in the form of a capsule.

[0182] In one embodiment, the dosage form of a liquid formulation for oral administration is an aqueous suspension or solution (which is selected from the group including, but is not limited to, aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups).

[0183] When administered by inhalation, the compounds disclosed herein are formulated for use as aerosols, mists, or powders.

[0184] For oral or sublingual administration, the composition may be in the form of tablets, lozenges, or gels prepared in a conventional manner.

[0185] In some embodiments, the compounds disclosed herein are prepared in a transdermal administration form.

[0186] In one embodiment, the compounds disclosed herein are formulated into pharmaceutical compositions suitable for intramuscular, subcutaneous, or intravenous injection.

[0187] In some embodiments, the compounds disclosed herein are administered topically and can be formulated into a variety of topically administered compositions, such as solutions, suspensions, lotions, gels, pastes, medicinal sticks, balms, creams, or ointments.

[0188] In some embodiments, the compounds disclosed herein are formulated into crude rectal products such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, gel suppositories, or retaining enemas.

[0189] Treatment method In another embodiment, provided herein are compounds represented by formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb) for use in methods of modulating RAS-PI3K, or pharmaceutically acceptable salts thereof or stereoisomers thereof or pharmaceutically acceptable salts thereof or atropisomers thereof or pharmaceutically acceptable salts thereof. In some embodiments, the method includes inhibiting RAS-PI3K. In some embodiments, the method includes activating RAS-PI3K.

[0190] In another embodiment, provided herein are compounds represented by formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb) or pharmaceutically acceptable salts thereof or stereoisomers thereof or pharmaceutically acceptable salts thereof or atropisomers thereof or pharmaceutically acceptable salts thereof, for use in methods of treating a disease or condition. In some embodiments, provided herein are methods of treating a disease or condition, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound represented by formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), or a pharmaceutically acceptable salt thereof or stereoisomers thereof or pharmaceutically acceptable salts thereof or atropisomers thereof or pharmaceutically acceptable salts thereof, for use in methods of treating a disease or condition. In some embodiments, the disease or condition is mediated by RAS-PI3K. In some embodiments, the disease is cancer.

[0191] In another embodiment, provided herein are compounds represented by formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb) or pharmaceutically acceptable salts thereof or stereoisomers thereof or pharmaceutically acceptable salts thereof or atropisomers thereof or pharmaceutically acceptable salts thereof, for use in the manufacture of pharmaceuticals for modulating RAS-PI3K.

[0192] In another embodiment, provided herein are compounds represented by formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb) or pharmaceutically acceptable salts thereof or stereoisomers thereof or pharmaceutically acceptable salts thereof or atropisomers thereof or pharmaceutically acceptable salts thereof, for use in the treatment of cancer in subjects requiring treatment for cancer.

[0193] In another embodiment, provided herein are compounds represented by formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb) or pharmaceutically acceptable salts thereof or stereoisomers thereof or pharmaceutically acceptable salts thereof or atropisomers thereof or pharmaceutically acceptable salts thereof, for use in the manufacture of pharmaceuticals for treating cancer in persons who require treatment for cancer.

[0194] In some embodiments, the disease mediated by RAS-PI3K is cancer. In some embodiments, the cancer is selected from the group consisting of bladder cancer, uterine cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, lung cancer, colorectal cancer, cervical cancer, bile duct cancer, gastric cancer, kidney cancer, and pancreatic cancer.

[0195] In another embodiment, provided herein are compounds represented by formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb) or pharmaceutically acceptable salts thereof or stereoisomers thereof or pharmaceutically acceptable salts thereof or atropisomers thereof or pharmaceutically acceptable salts thereof, for use in methods of treating immunological diseases or conditions.

[0196] In another embodiment, provided herein are compounds represented by formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb) or pharmaceutically acceptable salts thereof or stereoisomers thereof or pharmaceutically acceptable salts thereof or atropisomers thereof or pharmaceutically acceptable salts thereof, for use in the manufacture of pharmaceuticals for treating immunological diseases or conditions in persons requiring treatment of immunological diseases or conditions.

[0197] In some embodiments, the immunological disease or condition is selected from psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, lupus (which includes systemic lupus erythematosus, cutaneous lupus, and lupus nephritis), rheumatoid arthritis, juvenile idiopathic arthritis, Still's disease, spondyloarthritis and scleroderma, acute cytokine release syndrome associated with viral infection (e.g., COVID), acute cytokine release syndrome associated with cell therapy such as CAR-T therapy, or acute cytokine release syndrome associated with gene therapy.

[0198] In another embodiment, provided herein are compounds represented by formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb) or pharmaceutically acceptable salts thereof or stereoisomers thereof or pharmaceutically acceptable salts thereof stereoisomers or pharmaceutically acceptable salts thereof atropisomers or pharmaceutically acceptable salts thereof atropisomers, for use in methods of treating a disease or condition.

[0199] In some embodiments, administration of a compound represented by formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, promotes wound healing.

[0200] In another embodiment, provided herein are the use of compounds represented by formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), or formula (IIIb) or pharmaceutically acceptable salts thereof or stereoisomers thereof or pharmaceutically acceptable salts thereof or atropisomers thereof or pharmaceutically acceptable salts thereof for the treatment of immunological diseases or conditions or cancer.

[0201] Administration and treatment plan In one embodiment, the compounds disclosed herein are used in the preparation of pharmaceuticals for the treatment of diseases or conditions described herein. Furthermore, a method for treating any of the diseases or conditions described herein in a subject requiring treatment of said disease or condition comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compounds disclosed herein or a pharmaceutically acceptable salt thereof, active metabolite, prodrug, or solvate thereof.

[0202] In some embodiments, compositions containing the compounds disclosed herein are administered for prophylactic and / or therapeutic purposes. In specific therapeutic uses, the composition is administered to a patient or subject already suffering from a disease or condition in an amount sufficient to treat or at least partially suppress at least one symptom of the disease or condition. The effective amount for this use depends on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, response to the drug, and the judgment of the treating physician. The therapeutically effective dose may be determined by specific methods (including, but not limited to, dose-escalation clinical trials).

[0203] For preventative use, compositions containing the compounds disclosed herein are administered to patients who are susceptible to or at risk of certain diseases, disorders, or conditions.

[0204] In some embodiments, the dose of the administered drug may be temporarily reduced or temporarily discontinued for a specific period (i.e., a “drug-free period”). Doses used for the treatment of adult humans are typically in the range of 0.01 mg to 5000 mg per day, or in the range of about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently provided as a single dose or in divided doses.

[0205] Combination therapy In some cases, it may be appropriate to administer at least one of the compounds disclosed herein in combination with other therapeutic agents.

[0206] In a particular embodiment, the compound disclosed herein is co-administered with a second therapeutic agent, where the compound disclosed herein and the second therapeutic agent modulate different aspects of the disease, disorder, or condition under treatment, thereby providing a greater overall benefit than if either therapeutic agent were administered alone.

[0207] With respect to the combination therapies described herein, the dose of the co-administered compound will vary depending on the type of co-administered drug used, the specific drug used, the disease or condition being treated, etc. In additional embodiments, when co-administered with one or more other therapeutic agents, the compounds provided herein may be administered simultaneously with or sequentially with the other one or more therapeutic agents.

[0208] When administered simultaneously, the multiple therapeutic agents may be provided, for example, in a single integrated form or in multiple forms.

[0209] definition Where used herein and in the appended claims, the singular forms "a," "an," and "the" encompass the plural form unless the context clearly indicates otherwise. Furthermore, the term "or" is used to include "and / or" unless the context clearly indicates otherwise. In addition, the headings provided herein are for convenience only and do not constitute an interpretation of the scope or meaning of the claimed invention.

[0210] The following terms, when used in this specification, have the meanings set forth below unless otherwise indicated.

[0211] "Oxo" indicates an O substituent.

[0212] "Alkyl" refers to a linear or branched hydrocarbon chain radical having 1 to 20 carbon atoms, with the remainder of the molecule bonded by single bonds. Alkyls containing 10 or fewer carbon atoms are C1-C10 Alkyls are referred to as alkyls, and similarly, alkyls containing, for example, six or fewer carbon atoms are referred to as C1-C6 alkyls. Alkyls containing other numbers of carbon atoms (and other substructures as defined herein) are similarly represented. Alkyls include, but are not limited to, C1-C6 alkyls. 10 Examples of alkyl groups include C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C2-C8 alkyl, C3-C8 alkyl, and C4-C8 alkyl. Representative alkyl groups, though not limited to these, include methyl, ethyl, n-propyl, 1-methylethyl (i-propyl), n-butyl, i-butyl, s-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and 1-ethylpropyl. In some embodiments, the alkyl group is methyl or ethyl. Unless otherwise specifically indicated herein, the alkyl group may be substituted as described below.

[0213] "Alkylene" refers to a straight or branched divalent hydrocarbon chain that links the remainder of the molecule to a radical group. In some embodiments, the alkenylene is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments, the alkenylene is -CH2-. In some embodiments, the alkenylene is -CH2CH2-. In some embodiments, the alkenylene is -CH2CH2CH2-.

[0214] "Alkoxy" refers to a radical represented by the formula -OR [where R is a defined alkyl group]. Unless otherwise specifically indicated herein, the alkoxy group may be substituted as described below. Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and pentoxy. In some embodiments, the alkoxy is methoxy. In some embodiments, the alkoxy is ethoxy.

[0215] "Heteroalkyl" refers to an alkyl radical as described above in which one or more carbon atoms of the alkyl group are replaced with oxygen atoms, nitrogen atoms (i.e., NH, N-alkyl), or sulfur atoms. "Heteroalkylene" refers to a linear or branched divalent heteroalkyl chain that links the remainder of the molecule to the radical group. Unless otherwise specifically indicated herein, the heteroalkyl or heteroalkylene group may be substituted as described below. Representative heteroalkyl groups include, but are not limited to, -OCH2OMe, -OCH2CH2OMe, or -OCH2CH2OCH2CH2NH2. Representative heteroalkylene groups include, but are not limited to, -OCH2CH2O-, -OCH2CH2OCH2CH2O-, or -OCH2CH2OCH2CH2OCH2CH2O-.

[0216] "Alkylamino" refers to a radical represented by the formula -NHR or -NRR [wherein each R is independently an alkyl radical as defined above]. Unless otherwise specifically indicated herein, the alkylamino group may be substituted as described below.

[0217] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2π (where n is an integer) electrons. Aromatic compounds may be substituted. The term "aromatic" includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[0218] "Aryl" refers to an aromatic ring in which each atom constituting the ring is a carbon atom. The aryl group may be substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. In some embodiments, the aryl is phenyl. Depending on its structure, the aryl group may be a monoradical or a diradical (i.e., an arylene group). Unless otherwise specifically indicated herein, the term "aryl" or the prefix "ar-" (e.g., "aralkyl (aralkyl)") is intended to include optionally substituted aryl radicals.

[0219] "Carboxylate" refers to -CO2H. In some embodiments, the carboxyl portion may be replaced with a "carboxylic acid bioequivalent" [this refers to a functional group or portion that exhibits physical and / or chemical properties similar to those of the carboxylic acid portion]. The carboxylic acid bioequivalent has biological properties similar to those of the carboxylic acid group. A compound having a carboxylic acid group may have a carboxylic acid portion replaced with a carboxylic acid bioequivalent and exhibit similar physical and / or biological properties compared to a carboxylic acid-containing compound. For example, in one embodiment, the carboxylic acid bioequivalent ionizes to approximately the same extent as the carboxylic acid group at physiological pH. Examples of carboxylic acid bioequivalents include, but are not limited to, [ka]

[0220] These are some examples.

[0221] "Cycloalkyl" refers to a monocyclic or polycyclic non-aromatic radical in which all atoms forming the ring (i.e., the skeletal atoms) are carbon atoms. Cycloalkyls can be saturated or partially unsaturated. Cycloalkyls can condense with aromatic rings (in this case, the cycloalkyl is bonded via non-aromatic ring carbon atoms). Cycloalkyls include groups having 3 to 10 ring atoms. Typical cycloalkyls, though not limited to these, include cycloalkyls with 3 to 10 carbon atoms, cycloalkyls with 3 to 8 carbon atoms, cycloalkyls with 3 to 6 carbon atoms, or cycloalkyls with 3 to 5 carbon atoms. In some embodiments, the cycloalkyl is a C3-C6 cycloalkyl. In some examples, the cycloalkyl is monocyclic, bicyclic, or polycyclic. In some embodiments, the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.2]decane, norbornyl, dekalinyl, and adamantyl. In some embodiments, the cycloalkyl group is monocyclic. Examples of monocyclic cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the cycloalkyl group is bicyclic. Bicyclic cycloalkyl groups include condensed bicyclic cycloalkyl groups, spiro-bicyclic cycloalkyl groups, and bridged bicyclic cycloalkyl groups.In some embodiments, the cycloalkyl group is selected from spiro[2.2]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.2]decane, norbornyl, 3,4-dihydronaphthalene-1(2H)-one, and dekalinyl. In some embodiments, the cycloalkyl group is polycyclic. Examples of polycyclic radicals include adamantyl. In some embodiments, the polycyclic cycloalkyl group is adamantyl. Unless otherwise specifically indicated herein, the cycloalkyl group may be substituted.

[0222] "Condensation" refers to a ring structure described herein that is condensed with an existing ring structure. If the condensed ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure that becomes part of the condensed heterocyclyl ring or condensed heteroaryl ring may be replaced by a nitrogen atom.

[0223] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodine.

[0224] "Haloalkyl" refers to an alkyl radical as defined above, which is substituted with one or more halo radicals as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless otherwise specifically indicated herein, haloalkyls may be substituted.

[0225] "Haloalkoxy" refers to an alkoxy radical as defined above, which is substituted with one or more halo radicals as defined above, such as trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 1,2-difluoroethoxy, 3-bromo-2-fluoropropoxy, 1,2-dibromoethoxy, etc. Unless otherwise specifically indicated herein, the haloalkoxy group may be substituted.

[0226] "Heterocycloalkyl" or "heterocyclyl" or "heterocyclic ring" refers to a stable 3- to 14-membered non-aromatic ring group containing 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless otherwise specifically indicated herein, the heterocycloalkyl radical may be a monocyclic ring, a bicyclic ring (which includes fused bicyclic heterocycloalkyls (where the heterocycloalkyl is bonded via non-aromatic ring atoms when fused with an aryl ring or heteroaryl ring)), a bridging heterocycloalkyl, or a spiroheterocycloalkyl) or a polycyclic ring. In some embodiments, the heterocycloalkyl is monocyclic or bicyclic. In some embodiments, the heterocycloalkyl is monocyclic. In some embodiments, the heterocycloalkyl is bicyclic. The nitrogen, carbon, or sulfur atoms in the heterocyclyl radical may be oxidized. The nitrogen atom may optionally be quaternized. The heterocycloalkyl radical is partially or completely saturated. Examples of such heterocycloalkyl radicals, though not limited to them, include dioxolanil, thienyl[1,3]dithianil, decahydroisoquinolyl, imidazolinil, imidazolidinil, isothiazolidinil, isoxazolidinil, morpholinil, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinil, 2-oxopiperidinil, 2-oxopyrrolidinil, oxazolidinil, piperidinil, piperazinil, 4-piperidonil, pyrrolidinil, pyrazolidinil, quinuclidinil, thiazolidinil, tetrahydrofluryl, trithianil, tetrahydropyranil, thiomorpholinil, thiamorpholinil, 1-oxo-thiomorpholinil, and 1,1-dioxo-thiomorpholinil. The term "heterocycloalkyl" encompasses all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise indicated, heterocycloalkyls have 2 to 10 carbon atoms in the ring. In some embodiments, heterocycloalkyls have 2 to 8 carbon atoms in the ring.In some embodiments, the heterocycloalkyl group has approximately 8 carbon atoms and 1 or 2 nitrogen atoms in the ring. In some embodiments, the heterocycloalkyl group has 2 to 10 carbon atoms, 0 to 2 nitrogen atoms, 0 to 2 oxygen atoms, and 0 to 1 sulfur atom in the ring. In some embodiments, the heterocycloalkyl group has 2 to 10 carbon atoms, 1 to 2 nitrogen atoms, 0 to 1 oxygen atom, and 0 to 1 sulfur atom in the ring. When referring to the number of carbon atoms in a heterocycloalkyl group, it should be understood that the number of carbon atoms in the heterocycloalkyl group is not the same as the total number of atoms constituting the heterocycloalkyl group (i.e., the skeletal atoms of the heterocycloalkyl ring) (including heteroatoms). Unless otherwise specifically indicated herein, heterocycloalkyl groups may be substituted.

[0227] "Heteroaryl" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryls can be monocyclic or bicyclic. Exemplary examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, flazanyl, indidine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolidine, quinoline, isoquinoline, cinnoline, phthalazine, quinoazoline, quinoxaline, 1,8-naphthyridine, and pteridine. Examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and flazanil. Examples of bicyclic heteroaryls include indidine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolidine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, the heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl, or furyl. In some embodiments, the heteroaryl contains 0 to 4 nitrogen atoms in the ring. In some embodiments, the heteroaryl ring contains 1 to 4 N atoms. In some embodiments, the heteroaryl ring contains 0 to 4 N atoms, 0 to 1 O atom, and 0 to 1 S atom. In some embodiments, the heteroaryl ring contains 1 to 4 N atoms, 0 to 1 O atom, and 0 to 1 S atom. In some embodiments, the heteroaryl ring is a C1-C9 heteroaryl ring. In some embodiments, the monocyclic heteroaryl ring is a C1-C5 heteroaryl ring.In some embodiments, the monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, the bicyclic heteroaryl is a C6-C9 heteroaryl.

[0228] The terms "optionally substituted" or "substituted" mean that the referenced group may be substituted with one or more additional groups individually and independently selected from alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkyne, C1-C6 alkylalkyne, halogen, acyl, acyloxy, -CO2H, -CO2alkyl, nitro, and amino (which includes monosubstituted amino groups and disubstituted amino groups (e.g., -NH2, -NHR, -NR2)) and their protected derivatives. In some embodiments, the optional substituent is independently selected from alkyl, alkoxy, haloalkyl, cycloalkyl, halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, and -CO2alkyl. In some embodiments, the optional substituents are independently selected from fluoro, chloro, bromo, iodo, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, the substituents are replaced with one or two of the aforementioned groups. In some embodiments, the optional substituents on aliphatic carbon atoms (cyclic or acyclic) include oxo (=O).

[0229] A "tautomer" is a compound that exhibits a proton shift from one atom in a molecule to another atom in the same molecule. The compounds provided herein may exist as tautomers. Tautomers are compounds that can be interconverted by the movement of hydrogen atoms, involving the switching of single bonds and adjacent double bonds. A chemical equilibrium of tautomers exists in bond configurations that allow for tautomerization. All tautomer forms of the compounds disclosed herein are intended. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Some examples of tautomer interconversion include: [ka]

[0230] The term “co-administration” or similar terms, as used herein, are intended to encompass the administration of selected therapeutic agents to a single patient and to encompass treatment regimens in which multiple drugs are administered via the same or different routes of administration or at the same or different times.

[0231] The terms “effective dose” or “therapeutic effective dose,” as used herein, refer to a sufficient amount of an administered drug or compound to alleviate, to some extent, one or more symptoms of a disease or condition being treated. The result may be a reduction and / or mitigation of the symptoms, signs, or causes of the disease, or other desirable changes in the biological system. For example, “effective dose” in therapeutic use is the amount of a composition containing the compound disclosed herein required to produce a clinically significant reduction in the symptoms of the disease. An appropriate “effective” dose in individual cases may be determined using techniques such as dose-escalation studies. “Effective dose” is a sufficient amount of the compound to achieve a given objective (e.g., to achieve the intended effect of administration, to treat a disease, to reduce enzyme activity, to increase enzyme activity, to reduce a signaling pathway, or to reduce one or more symptoms of a disease or condition) compared to the absence of the compound. An example of an “effective dose” is a sufficient amount to contribute to the treatment, prevention, or alleviation of one or more symptoms of a disease, which may also be referred to as a “therapeutic effective dose.” "Reduction" of one or more symptoms (and grammatically equivalent expressions in this phrase) means a reduction in the severity or frequency of the symptoms, or the disappearance of the symptoms. The "prophylactic effective dose" of a drug is the amount of drug administered to a subject that produces the intended preventive effect (e.g., preventing or delaying the onset (or recurrence) of an injury, disease, pathology, or condition, or reducing the likelihood of the onset (or recurrence) of an injury, disease, pathology, or condition or its symptoms). Complete preventive effect is not necessarily achieved with a single dose, but may only occur after a series of doses. Therefore, a prophylactic effective dose may be administered in one or more doses. "Activity-reducing dose," as used herein, refers to the amount of antagonist required to reduce the activity of an enzyme compared to the absence of the antagonist. "Functional impairment dose," as used herein, refers to the amount of antagonist required to impair the function of an enzyme or protein compared to the absence of the antagonist.The exact amount depends on the therapeutic purpose and can be determined by those skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0232] The term "pharmaceutical combination," as used herein, means a product obtained as a result of mixing or combining two or more active ingredients, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients (e.g., the compound represented by formula (I) and a co-agent) are administered to the patient simultaneously as a single entity or dosage form. The term "non-fixed combination" means that the active ingredients (e.g., the compound represented by formula (I) and a co-agent) are administered to the patient simultaneously, in parallel or sequentially as separate entities without any specific time interval restrictions, where such administration results in effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy (e.g., administration of three or more active ingredients).

[0233] The terms "subject" or "patient" encompass mammals. Examples of mammals include, but are not limited to, humans. In one embodiment, the mammal is a human.

[0234] The terms “treat,” “treating,” or “treatment,” as used herein, include alleviating, reducing, or improving at least one symptom of a disease or condition; preventing additional symptoms; suppressing a disease or condition (e.g., preventing the onset of a disease or condition); mitigating a disease or condition; causing regression of a disease or condition; alleviating a condition caused by a disease or condition; or preventing and / or therapeutically cessating the symptoms of a disease or condition. [Table 2] TIFF2026509001000109.tif88165 [Examples]

[0235] Example 1. Synthesis of the compound of the present disclosure Scheme 1. Synthesis of the intermediate (R,Z)-4-(methylsulfonyl)buta-3-en-2-amine [ka]

[0236] Stage 1 Sodium 4-methylbenzene sulfonothioate (30 g, 143 mmol, 1.0 eq) was dissolved in DMF (100 mL, 1.4 M), and iodomethane (8.9 mL, 143 mmol, 1.0 eq) was added to the solution. The reaction mixture was stirred under N2 at 25°C for 24 hours. The reaction mixture was quenched with water (300 mL) and extracted with SiO2 (300 mL x 2). The organic layers were combined, washed with brine (300 mL x 3), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified on silica using FCC (PE:SiO2 = 50:1) to obtain S-methyl 4-methylbenzene sulfonothioate (27 g, 133 mmol, 94% yield) as a white solid.

[0237] 1H NMR (400 MHz, CDCl3) δ ppm 7.81 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 2.50 (s, 3H), 2.46 (s, 3H). Stage 2 8.0 g, 47.3 mmol, 1.0 eq of tert-butyl(R)-buta-3-in-2-ylcarbamate and 5.5 g, 47.3 mmol, 1.0 eq of N,N,N,N-tetramethylethylenediamine were dissolved in 30 mL, 0.24 M anhydrous THF. While stirring the solution, n-butyllithium (39.7 mL, 99.3 mmol, 2.1 eq) was added dropwise at 0°C under an N2 atmosphere. After 30 minutes, 10 g, 49.6 mmol, 1.1 eq of S-methyl 4-methylbenzene sulfonothioate in 80 mL, 0.60 M THF was added. The reaction mixture was stirred at 0°C for 2 hours, then quenched with 200 mL of saturated aqueous solution NH4Cl at 0°C, and extracted with ethyl acetate (200 mL x 3). The organic layers were combined, washed with brine (200 mL), dehydrated with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified on silica using FCC (PE:siRNA=5:1) to obtain tert-butyl (R)-(4-(methylthio)buta-3-in-2-yl)carbamate (9.0 g, 41.8 mmol, 88% yield) as a white solid.

[0238] 1 H NMR (400 MHz, CDCl3) δ ppm 4.65 - 4.76 (m, 1H), 4.50 - 4.63 (m, 1H), 2.37 (s, 3H), 1.46 (s, 9H), 1.39 (d, J = 6.88 Hz, 3H). Stage 33.0 g, 13.9 mmol, 1.0 eq of tert-butyl (R), 4-(methylthio)buta-3-en-2-yl)carbamate, 900 mg of Lindler catalyst, and 6 mL of hexene were added to 30 mL, 0.46 M methanol. The reaction mixture was stirred at 25°C for 3 hours under H2 (30 psi). The mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by FCC (PE:HCl=3:1) to obtain tert-butyl (R,Z)-(4-(methylthio)buta-3-en-2-yl)carbamate (2.6 g, 12.0 mmol, 86% yield) as a white solid.

[0239] 1 H NMR (400 MHz, DMSO-d6) δ ppm 5.96 (d, J = 9.6 Hz, 1H), 5.43 (dd, J = 8.0, 9.5 Hz, 1H), 4.63 - 4.34 (m, 2H), 2.28 (s, 3H), 1.45 (s, 9H), 1.22 (d, J = 6.4 Hz, 3H). Stage 4 To a solution of tert-butyl (R,Z)-(4-(methylthio)buta-3-en-2-yl)carbamate (2.6 g, 12.0 mmol, 1.0 eq) dissolved in DCM (10 mL, 1.2 M), 3-chloroperbenzoic acid (6.2 g, 35.9 mmol, 3.0 eq) was added in small amounts over 5 minutes. The reaction mixture was stirred at 25°C for 2 hours, then diluted with saturated aqueous solution Na2SO3 (100 mL x 2), and extracted with DCM (200 mL). The extract was washed with saturated aqueous solution NaHCO3 (100 mL x 2), then washed with brine (200 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue was purified using FCC (PE:siRNA=1:1) on silica to obtain tert-butyl (R,Z)-(4-(methylsulfonyl)buta-3-en-2-yl)carbamate (2.4 g, 9.47 mmol, 79% yield) as a white solid.

[0240] 1H NMR (400 MHz, CDCl3) δ ppm 6.31 - 6.22 (m, 1H), 6.21 - 6.11 (m, 1H), 4.63 (s, 1H), 3.19 (s, 3H), 1.42 (s, 9H), 1.31 (d, J = 6.8 Hz, 3H). Stage 5 tert-butyl (R,Z)-(4-(methylsulfonyl)buta-3-en-2-yl)carbamate (2.4 g, 9.47 mmol, 1.0 eq) and p-toluenesulfonic acid monohydrate (1.8 g, 9.47 mmol, 1.0 eq) were added to MeCN (30 mL, 0.32 M). The reaction mixture was stirred at 40°C for 16 hours. The mixture was concentrated under reduced pressure to obtain (R,Z)-4-(methylsulfonyl)buta-3-en-2-amine (TsOH salt, 3.0 g, 9.33 mmol, 99% yield) as a white solid. This was used directly in the next step.

[0241] 1 H NMR (400 MHz, CDCl3) δ ppm 8.13 (br s, 1H), 7.51 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 6.75 (d, J = 11.2 Hz, 1H), 6.37 (dd, J = 9.6, 11.2 Hz, 1H), 5.09 (br s, 2H), 4.95 - 4.75 (m, 1H), 3.12 (s, 3H), 2.29 (s, 3H), 1.31 (d, J = 6.8 Hz, 3H). Intermediate: (S,Z)-4-(methylsulfonyl)buta-3-en-2-amine, 4-methylbenzenesulfonate It was synthesized starting from tert-butyl (S)-buta-3-in-2-ylcarbamate by the same method as (R,Z)-4-(methylsulfonyl)buta-3-en-2-amine.

[0242] Scheme 2. Synthesis of the intermediate ethyl 4-fluoropiperidine-4-carboxylate [ka]

[0243] Stage 11-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (54 g, 209.9 mmol, 1 eq) was dissolved in THF (500 mL) and 2 M LDA (157 mL, 315 mmol, 1.5 eq) was added dropwise at -45°C. The mixture was stirred at -45°C for 0.5 hours. Next, NFSI (82.7 g, 262 mmol, 1.3 eq) in THF (500 mL) was added dropwise to the mixture. The resulting solution was stirred at -45°C for 1 hour and then at -45 to 15°C for 1 hour. The reaction product was quenched with saturated aqueous solution NH4Cl (1 L) and extracted with SiO2 (1 L x 2). The organic phases were combined, washed with brine (1 L x 2), dehydrated with Na2SO4, filtered, concentrated, and purified by FCC (PE:SiO=9:1) to obtain 1-tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate as a pale yellow oily substance (47.3 g, 172 mmol, 82% yield).

[0244] 1 H NMR (400 MHz, CDCl3) δ ppm 4.26 (q, J = 7.2 Hz, 2H), 4.09 - 3.94 (m, 2H), 3.11 (br s, 2H), 2.05 (s, 1H), 1.99 - 1.88 (m, 3H), 1.48 (s, 9H), 1.32 (t, J = 7.2 Hz, 3H). Stage 2 A mixture of 1-tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate (30 g, 109 mmol, 1 eq) in HCl / siRNA (4 M, 350 mL) was stirred at 25°C for a specified time. The reaction product was concentrated to obtain a crude product as a pink solid. The crude product was washed with a mixed solvent MTBE / PE (1:1,100 mL × 3) to obtain ethyl 4-fluoropiperidine-4-carboxylate as a pale pink solid (22.3 g, 106 mmol, 97%).

[0245] 1H NMR (400 MHz, methanol-d4) δ ppm 4.28 (q, J = 7.1 Hz, 2H), 3.48 - 3.39 (m, 2H), 3.30 - 3.20 (m, 2H), 2.42 - 2.18 (m, 4H), 1.32 (t, J = 7.2 Hz, 3H). Intermediate: Methyl 4-fluoropiperidine-4-carboxylate It was prepared from 1-tert-butyl 4-methyl 4-fluoropiperidine-1,4-dicarboxylate in the same manner as in step 2 of the synthesis of ethyl 4-fluoropiperidine-4-carboxylate.

[0246] Scheme 3. Synthesis of (S,Z)-1-((5-chloro-3'-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide (Compound 1) [ka]

[0247] Stage 1In a beaker equipped with a mechanical stirrer, 2-bromo-4-chloroaniline (1.5 g, 7.26 mmol, 1.0 eq) was added all at once to a mixture of concentrated hydrochloric acid (3 mL) and glacial acetic acid (1 mL). The resulting concentrated pink hydrochloride salt was cooled to 0°C in an ice bath. A solution of sodium nitrite (553 mg, 8.0 mmol, 1.1 eq) dissolved in water (1.5 mL) was added dropwise at a rate that did not exceed 0°C. This mixture was stirred at 0°C for 45 minutes. In a separate beaker, sulfur dioxide gas was passed through 5 mL of glacial acetic acid for 30 minutes with vigorous stirring. Copper(I) chloride (274 mg) was added to this solution, and the passage of sulfur dioxide gas was continued until the yellow-green suspension turned blue-green and most of the solids dissolved (approximately 30 minutes). The mixture was cooled to 0°C while stirring in an ice bath, and the diazotization mixture was added in small amounts over 30 minutes. Then the ice bath was removed, and the mixture was heated to room temperature. The mixture was stirred for another 30 minutes. The reaction product was poured into ice water (10 mL), and the precipitated rubbery solid was extracted with MTBE (20 mL x 3). The extracts were combined and washed with saturated aqueous sodium bicarbonate (30 mL) until neutral, washed with water (30 mL x 2), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-bromo-4-chlorobenzenesulfonyl chloride as a dark green solid (1.4 g, 4.72 mmol, 65%).

[0248] 1 H NMR (400 MHz, CDCl3) δ ppm 8.14 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.54 (dd, J = 8.6, 2.0 Hz, 1H). Stage 2To a solution of methyl 4-fluoropiperidine-4-carboxylate (300 mg, 1.52 mmol, 1 eq) dissolved in DCM (5 mL, 0.3 M), TEA (307 mg, 3.04 mmol, 2 eqs) and 2-bromo-4-chlorobenzenesulfonyl chloride (572 mg, 1.97 mmol, 1.3 eq) were added at 0°C. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into water (10 mL) and extracted with DCM (10 mL x 3). The organic layers were combined, washed with brine (10 mL x 2), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified using FCC (PE:Â=8:2) on silica to obtain methyl 1-(2-bromo-4-chlorophenyl)sulfonyl-4-fluoropiperidine-4-carboxylate (600 mg, 1.45 mmol, 95% yield) as a yellow oil.

[0249] C 13 H 14 The calculated [M+H] value for BrClFNO4S is 415; the measured value is 416. Stage 3Methyl 1-(2-bromo-4-chlorophenyl)sulfonyl-4-fluoropiperidine-4-carboxylate (200 mg, 0.48 mmol, 1.0 eq) and 3-methoxyphenylboronic acid (80.6 mg, 0.53 mmol, 1.1 eq) were dissolved in toluene (9 mL, 0.04 M) and water (3 mL, 0.04 M). To this solution, Na2CO3 (153 mg, 1.45 mmol, 3.0 eq) and Pd(PPh3)4 (55.7 mg, 0.05 mmol, 0.1 eq) were added under N2 conditions at 25°C. The mixture was stirred at 80°C for 18 hours. After cooling to room temperature, the reaction mixture was poured into water (15 mL) and extracted with RINKAN (15 mL x 3). The organic layers were combined, washed with brine (10 mL x 2), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (PE:siRNA=80:20) to obtain methyl 1-[4-chloro-2-(3-methoxyphenyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (160 mg, 0.36 mmol, 75% yield) as a yellow oil.

[0250] 1 H NMR (400 MHz, CDCl3) δ ppm 8.02 (d, J = 8.7 Hz, 1H), 7.40 (dd, J = 8.6, 2.2 Hz, 1H), 7.23 - 7.31 (m, 2H), 6.84 - 6.95(m, 3H), 3.77 (s, 3H), 3.70 (s, 3H), 3.12 (br d, J = 13.1 Hz, 2H), 2.50 - 2.60 (m, 2H), 1.65 - 1.81 (m, 4H). C 20 H 21 [M+H] Calculated value for ClFNO5S: 441; Measured value: 442. Stage 4A solution of methyl 1-[4-chloro-2-(3-methoxyphenyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (160 mg, 0.36 mmol, 1.0 eq) was dissolved in THF (6 mL, 0.05 M) and water (2 mL, 0.05 M). LiOH (43.4 mg, 1.81 mmol, 5.0 eq) was added to this solution. The mixture was stirred at 50°C for 3 hours. After cooling to room temperature, the mixture was acidified with 1N HCl to pH 4-5, poured into water (10 mL), and extracted with RINKAN (10 mL x 3). The organic layers were combined, washed with brine (10 mL x 2), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The compound 1-[4-chloro-2-(3-methoxyphenyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylic acid was obtained as a yellow oily substance (140 mg, 0.33 mmol, 90%).

[0251] Stage 5 1-[4-chloro-2-(3-methoxyphenyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylic acid (50 mg, 0.12 mmol, 1 eq) was dissolved in DCM (3 mL, 0.04 M). To this solution, (S,Z)-4-(methylsulfonyl)buta-3-en-2-amine (TsOH salt, 41 mg, 0.13 mmol, 1.1 eq), HATU (67 mg, 0.18 mmol, 1.5 eq), and DIPEA (38 mg, 0.29 mmol, 2.5 eq) were added at 0°C. The mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into water (10 mL) and extracted with ELISA (10 mL x 3). The organic layers were combined, washed with brine (10 mL x 2), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM:MeOH=20:1) to obtain (S,Z)-1-((5-chloro-3'-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide ( compound 1 (35 mg, 0.06 mmol, 53%) was obtained.

[0252] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.36 (br d, J = 7.9 Hz, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.70 (dd, J = 8.6, 2.2 Hz, 1H), 7.47 (d, J = 2.3 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 6.93 - 7.03 (m, 3H), 6.45 (d, J = 11.2 Hz, 1H), 6.26 (dd, J = 11.1, 9.6 Hz, 1H), 5.25 - 5.41 (m, 1H), 3.78 (s, 3H), 3.12 (s, 5H), 2.52 - 2.56 (m, 2H), 1.58 - 1.84 (m, 4H), 1.20 (d, J = 6.78 Hz, 3H). C 24 H 28 For ClFN2O6S2, the calculated [M+H] value is 558.1; the measured value is 559.1. Compound 2-Compound 18 , Compound 219-Compound 220 and Compound 267-Compound 268 In step 1, starting with the appropriate aniline, and in step 3, starting with the appropriate boronic acid, compound 1 It was synthesized using a similar method. In step 2, either methyl 4-fluoropiperidine-4-carboxylate or ethyl 4-fluoropiperidine-4-carboxylate was used.

[0253] compound 19 and compound 200 teeth, compound 1 It was synthesized from a suitable sulfonyl chloride using the same method as in steps 2-5.

[0254] Intermediate: 4-Fluoro-1-((3'-Methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)piperidine-4-carboxylic acid and Intermediate 1-((2'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxylic acid teeth, compound 1 It was synthesized from appropriate sulfonyl chlorides and boronic acids using the same method as in steps 2-4.

[0255] Compound 201 In step 2, ethyl 4-methyl-4-piperidine carboxylate hydrochloride is used. compound 1 It was synthesized using the same method as before.

[0256] compound 203 In step 5, (R,Z)-4-(methylsulfonyl)buta-3-en-2-amine, TsOH salt was used. Compound 201 It was synthesized using the same method as before.

[0257] Intermediate: Ethyl 1-((5-chloro-3'-hydroxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxylate In step 3, 3-hydroxyphenylboronic acid is used, compound 1 It was prepared using the same method as in steps 1-3.

[0258] Scheme 4. Synthesis of the intermediate 1-[ethoxy(methylsulfonylmethyl)phosphoryl]oxyethane [ka]

[0259] To a mixture of diethyl (methylthiomethyl)phosphonate (20 g, 101 mmol, 1 eq) in MeCN (160 mL, 0.42 M) and water (80 mL, 0.42 M), Oxon (185 g, 303 mmol, 3 eq) was added in small amounts at 0-5°C. The mixture was stirred at 25°C for 2 hours. The reaction mixture was filtered, and the filtrate was quenched with saturated aqueous solution Na2SO3 (200 mL) at 0-5°C. The mixture was then concentrated under reduced pressure to remove MeCN. The residue was extracted with DCM (100 mL x 2). The organic layers were combined, washed with brine (100 mL x 1), dehydrated with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 1-[ethoxy(methylsulfonylmethyl)phosphoryl]oxyethane (21 g, 91.2 mmol, 90%) as a white solid.

[0260] 1 H NMR (400 MHz, CDCl3) δ ppm 4.20 - 4.32 (m, 4H), 3.59 (d, J = 16.4 Hz, 2H), 3.21 (s, 3H), 1.38 (t, J = 7.1 Hz, 6H). Scheme 5. Synthesis of the intermediate (E)-3-(methylsulfonyl)propa-2-ene-1-amine [ka]

[0261] Stage 1 A suspension of tert-butyl N-(2,3-dihydroxypropyl)carbamate (2.5 g, 13.1 mmol, 1 eq) in water (20 mL, 0.65 M) was to be mixed with NaIO4 (3.1 g, 14.4 mmol, 1.1 eq) at 0°C. The flask was covered with aluminum foil to protect the NaIO4 from light. The mixture was stirred under N2 at 0°C for 4 hours. The mixture was extracted with DCM (10 mL x 5). The organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain tert-butyl N-(2-oxoethyl)carbamate (1.6 g, 9.80 mmol, 75%) as a colorless oil.

[0262] 1 H NMR (400 MHz, CDCl3) δ ppm 9.65 (s, 1H), 5.21 (br s, 1H), 4.07 (br d, J = 4.5 Hz, 2H), 1.45 (s, 9H) Stage 2 To a suspension of 1-[ethoxy(methylsulfonylmethyl)phosphoryl]oxyethane (13.6 g, 59.07 mmol, 1 eq) and potassium carbonate (24.5 g, 177 mmol, 3 eq) in THF (140 mL, 0.42 M), tert-butyl N-(2-oxoethyl)carbamate (8.5 g, 53.2 mmol, 0.9 eq) was added at 25°C under N2. The mixture was stirred at 50°C for 8 hours. After cooling to room temperature, the mixture was diluted with water (150 mL) and extracted with SiO2 (100 mL x 3). The organic layers were combined, dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC (PE:Â=4:1→1:1) to obtain tert-butyl N-[(E)-3 methylsulfonylallyl]carbamate (8.5g, 36.1 mmol, 61%) as a yellow oily substance.

[0263] 1H NMR (400 MHz, CDCl3) δ ppm 6.89 - 6.96 (m, 1H), 6.46 - 6.55 (m, 1H), 4.77 - 4.91 (m, 1H), 3.93 - 4.05 (m, 2H), 1.46 (s, 9H), 2.95 (s, 3H) Stage 3 To a solution of tert-butyl N-[(E)-3-methylsulfonylallyl]carbamate (8.5 g, 36.3 mmol, 1 eq) dissolved in MeCN (85 mL, 0.43 M), p-toluenesulfonic acid monohydrate (8.3 g, 43.5 mmol, 1.2 eq) was added. The mixture was stirred at 60°C for 12 hours. The reaction product was then filtered and concentrated under reduced pressure to obtain 4-methylbenzenesulfonate; (E)-3-methylsulfonylpropa-2-en-1-amine (6.7 g, 21.9 mmol, 60%) as a white solid.

[0264] 1 HNMR (400 MHz, DMSO-d6) δ ppm 8.04 (br s, 3H), 7.45 - 7.52 (m, 2H), 7.11 (d, J = 7.8 Hz, 2H), 6.97 (dt, J = 15.48, 1.6 Hz, 1H), 6.73 (dt, J = 15.42, 5.6 Hz, 1H), 3.74 (dd, J = 5.57, 1.6 Hz, 2H), 3.05 (s, 3H), 2.28 (s, 3H). Compound 36-Compound 45 In step 1, starting with a suitable aniline; in step 3, starting with a suitable boronic acid; and in step 5, using (E)-3-methylsulfonylpropa-2-ene-1-amine. compound 1 It was synthesized using the same method as described above. In step 2, either methyl 4-fluoropiperidine-4-carboxylate or ethyl 4-fluoropiperidine-4-carboxylate was used.

[0265] Intermediate: 3-((methylsulfonyl)methylene)azetidineIt was synthesized in the same manner as in steps 2-3 of (E)-3-(methylsulfonyl)propa-2-ene-1-amine, starting from tert-butyl 3-oxoazetidine-1-carboxylate in step 2.

[0266] Scheme 6. Synthesis of 1-[4-bromo-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoro-N-[(Z,1R)-1-methyl-3-methylsulfonyl-allyl]piperidine-4-carboxamide (compound 47) [ka]

[0267] Stage 1 4-Bromo-2-iodoaniline (1 g, 3.36 mmol, 1 eq) was dissolved in concentrated HCl (15 mL) / acetic acid (5 mL, 0.09 M), and NaNO2 (254 mg, 3.70 mmol, 1.1 eq) was added at 0°C. This mixture 1 was stirred at 0°C for 1 hour. In a separate flask, acetic acid (33 mL, 0.09 M) was aerated with SO2 at 0°C for about 10 minutes, and then CuCl (99 mg, 1.01 mmol, 0.3 eq) was added. Mixture 2 was aerated with SO2 for about 10 minutes. mixture 2 at 0℃ mixture 1 The mixture was then stirred at 0°C to 20°C for 1 hour. The reaction mixture was quenched with water (30 mL) and extracted with MTBE (30 mL x 2). The organic layers were combined and washed with saturated aqueous sodium bicarbonate (30 mL x 2) and 30 mL of brine. The organic layers were then separated, dehydrated (Na2SO4), and evaporated under reduced pressure. The crude product was purified by FCC (PE: siRNA 50:1) to obtain 4-bromo-2-iodobenzenesulfonyl chloride (4 g, 10.5 mmol, 62% yield) as a yellow oil.

[0268] 1 H NMR (400 MHz, CDCl3) δ ppm 7.72 (dd, J = 8.6, 1.9 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 8.37 (d, J = 1.9 Hz, 1H). Stage 24-Bromo-2-iodobenzenesulfonyl chloride (3.6 g, 9.44 mmol, 1 eq) and ethyl 4-fluoropiperidine-4-carboxylate hydrochloride (2.0 g, 9.44 mmol, 1 eq) were dissolved in DCM (10 mL, 0.9 M), to which triethylamine (2.9 g, 28.3 mmol, 3 eq) was added dropwise at 0°C. The resulting mixture was stirred at 20°C for 1 hour. The reaction mixture was quenched with water (15 mL) and extracted with DCM (15 mL x 2). The organic layers were combined and washed with 20 mL of brine. The organic layers were then separated, dehydrated (Na2SO4), and evaporated under reduced pressure. Next, the crude substance was purified by FCC to obtain ethyl 1-(4-bromo-2-iodophenyl)sulfonyl-4-fluoropiperidine-4-carboxylate (4.3 g, 8.3 mmol, 87% yield) as a yellow solid.

[0269] 1 H NMR (400 MHz, CDCl3) δ ppm 8.28 (d, J = 1.88 Hz, 1H), 7.99 (d, J = 8.50 Hz, 1H), 7.64 (dd, J = 8.44, 1.94 Hz, 1H), 4.27 (q, J = 7.13 Hz, 2H), 3.75 (dt, J = 13.01, 2.56 Hz, 2H), 3.18 (td, J = 12.76, 2.75 Hz, 2H), 2.12 - 2.31 (m, 2H), 1.99 - 2.08 (m, 2H), 1.32 (t, J = 7.13 Hz, 3H). Stage 3Ethyl 1-(4-bromo-2-iodophenyl)sulfonyl-4-fluoropiperidine-4-carboxylate (878 mg, 1.69 mmol, 1 eq) was dissolved in 1,4-dioxane (9 mL, 0.2 M) and 1 M aqueous K3PO4 (2.7 mL). To this solution, 2-chlorophenylboronic acid (290 mg, 1.86 mmol, 1.1 eq) and tetrakis(triphenylphosphine)palladium (0) (195 mg, 0.169 mmol, 0.1 eq) were added. The mixture was stirred under nitrogen at 80°C for 16 hours. The mixture was diluted with water (100 mL) and extracted with siRNA (150 mL x 3). The organic layers were combined, washed with brine (100 mL x 2), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (PE: siRNA 3:1) to obtain ethyl 1-[4-bromo-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (400 mg, 0.79 mmol, 47% yield) as a yellow oil.

[0270] 1 H NMR (400 MHz, CDCl3) δ ppm 8.01 (d, J = 8.5 Hz, 1H), 7.67 (dd, J = 1.9, 8.5 Hz, 1H), 7.55 - 7.44 (m, 2H), 7.43 - 7.27 (m, 3H), 4.22 (q, J = 7.0 Hz, 2H), 3.24 (br d, J = 13.4 Hz, 1H), 3.07 (br d, J = 13.3 Hz, 1H), 2.98 - 2.85 (m, 1H), 2.72 - 2.58 (m, 1H), 2.04 - 1.79 (m, 4H), 1.34 - 1.27 (m, 3H). C 20 H 20 [M+H] for BrClFNO4S: Calculated value 505; Measured value 506 Stage 4Ethyl 1-[4-bromo-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (460 mg, 0.911 mmol, 1 eq) and lithium hydroxide monohydrate (115 mg, 2.73 mmol, 3 eq) were placed in THF (6 mL, 0.11 M) and water (2 mL, 0.11 M). The mixture was stirred at 25°C for 2 hours. The mixture was concentrated to remove the organic solvent, and then acidified with 6 M HCl to adjust the pH to 2-4. The precipitate was filtered to obtain 1-[4-bromo-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylic acid (400 mg, 0.84 mmol, 92% yield) as a white solid.

[0271] Stage 5 1-[4-bromo-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylic acid (500 mg, 1.05 mmol, 1 eq), (R,Z)-4-(methylsulfonyl)buta-3-en-2-amine (TsOH salt, 438 mg, 1.36 mmol, 1.3 eq), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphospholinane-2,4,6-trioxide (1.7 g, 2.62 mmol, 2.5 eq), and DIPEA (407 mg, 3.15 mmol, 3 eq) were combined in DCM (5 mL, 0.21 M). The mixture was stirred at 25°C for 2 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL). The extract was washed with brine (20 mL), dehydrated with Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (PE: siRNA 10:1~1:1) to obtain 1-[4-bromo-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoro-N-[(Z,1R)-1-methyl-3-methylsulfonyl-allyl]piperidine-4-carboxamide ( compound 47 The solution was obtained as a white solid (428 mg, 0.70 mmol, 66.5% yield).

[0272] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.37 (br d, J = 6.0 Hz, 1H), 7.99 - 7.92 (m, 1H), 7.92 - 7.86 (m, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.58 - 7.51 (m, 1H), 7.49 - 7.41 (m, 1H), 7.39 (d, J = 4.1 Hz, 2H), 6.45 (d, J = 11.3 Hz, 1H), 6.28 (dd, J = 9.5, 11.1 Hz, 1H), 5.44 - 5.27 (m, 1H), 3.21 - 3.05 (m, 5H), 2.79 - 2.69 (m, 1H), 2.65 - 2.56 (m, 1H), 2.02 - 1.61 (m, 4H), 1.20 (d, J = 6.9 Hz, 3H). C 23 H 25 The calculated [M+H] value for BrClFN2O5S2 is 606; the measured value is 607. Compound 20-Compound 35 This involves using appropriate aniline in step 1 and appropriate boronic acid in step 3. compound 47 It was synthesized using the same method as described above. In step 2, either methyl 4-fluoropiperidine-4-carboxylate or ethyl 4-fluoropiperidine-4-carboxylate was used.

[0273] Compound 48-Compound 58 In step 3, using the appropriate boronic acid, compound 47 It was synthesized using the same method as described above. In step 2, either methyl 4-fluoropiperidine-4-carboxylate or ethyl 4-fluoropiperidine-4-carboxylate was used.

[0274] Compound 59-Compound 60 In step 3, instead of boronic acid, use appropriate pinacol boronic acid ester. compound 47 It was synthesized using the same method as described above. In step 2, either methyl 4-fluoropiperidine-4-carboxylate or ethyl 4-fluoropiperidine-4-carboxylate was used.

[0275] Compound 61-Compound 62 In step 3, an appropriate boronic acid is used, and in step 5, (S,Z)-4-(methylsulfonyl)buta-3-en-2-amine, TsOH salt is used. compound 47 It was synthesized using the same method as described above. In step 2, either methyl 4-fluoropiperidine-4-carboxylate or ethyl 4-fluoropiperidine-4-carboxylate was used.

[0276] Compound 63-Compound 64 In step 3, an appropriate boronic acid is used, and in step 5, (E)-3-(methylsulfonyl)propa-2-en-1-amine, TsOH salt is used. compound 47 It was synthesized using the same method as described above. In step 2, either methyl 4-fluoropiperidine-4-carboxylate or ethyl 4-fluoropiperidine-4-carboxylate was used.

[0277] compound 65 In step 5, 3-amino-2,3-dihydrothiophene 1,1-dioxide is used. compound 47 It was synthesized using the same method as before.

[0278] compound 66 In step 5, (R)-3-amino-2,3-dihydrothiophene 1,1-dioxide is used. compound 47 It was synthesized using the same method as before.

[0279] compound 67 In step 5, (S)-3-amino-2,3-dihydrothiophene 1,1-dioxide is used. compound 47 It was synthesized using the same method as before.

[0280] Compound 202 In step 2, starting from 2-bromo-4,5-dimethoxybenzenesulfonyl chloride, compound 47 It was synthesized using the same method as before.

[0281] compound 204In step 3, 3-chloro-2-(tributylstannyl)pyridine is used, and the reaction is carried out at 140°C for 1 hour under microwave irradiation. compound 47 It was synthesized using the same method as before.

[0282] compound 273 In step 5, 3-((methylsulfonyl)methylene)azetidine is used. compound 47 It was synthesized using the same method as before.

[0283] Scheme 7. Synthesis of the intermediate (E)-4-aminobuta-2-ennitrile [ka]

[0284] Stage 1 N-boc-2-aminoacetaldehyde (11 g, 69.1 mmol, 1.0 eq) was dissolved in THF (130 mL, 0.53 M), and diethyl cyanomethylphosphonate (12.2 g, 69.1 mmol, 1 eq) and K2CO3 (19.1 g, 138 mmol, 2 eq) were added at 0°C. The mixture was stirred at 25°C for 12 hours. The reaction mixture was poured into water (100 mL) and extracted with ELISA (100 mL x 3). The organic phases were combined, washed with brine (80 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain tert-butyl (3-cyanoallyl)carbamate (8 g, 43.9 mmol, 63%) as a yellow oil.

[0285] Stage 2 Crude tert-butyl N-(3-cyanoallyl)carbamate (4 g, 22 mmol, 1 eq) was purified by prep-HPLC to obtain tert-butyl N-[(E)-3-cyanoallyl]carbamate (1 g, 5.5 mmol, 25%) and tert-butyl N-[(Z)-3-cyanoallyl]carbamate (300 mg, 1.64 mmol, 7.5%).

[0286] Stage 3100 mg, 0.55 mmol, 1 eq of tert-butyl N-[(E)-3-cyanoallyl]carbamate was dissolved in 3 mL, 0.15 M DCM, and 0.5 mL of TFA was added under N2 conditions. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain (E)-4-aminobuta-2-ennitrile; 2,2,2-trifluoroacetic acid (80 mg, 0.408 mmol, 74%) as a yellow oily substance.

[0287] 1 H NMR (400 MHz, methanol-d4) δ ppm 6.77 (dt, J = 16.4, 6.2 Hz, 1H), 5.92 (d, J = 16.4 Hz, 1H), 3.77 (d, J = 6.1 Hz, 2H). Intermediate (Z)-4-aminobuta-2-ennitrile It was synthesized using tert-butyl N-[(Z)-3-cyanoallyl]carbamate in the same manner as in step 3 of (E)-4-aminobuta-2-ennitrile.

[0288] compound 68 In step 5, (E)-4-aminobuta-2-ennitrile is used. compound 47 It was synthesized using the same method as before.

[0289] compound 69 In step 1, starting with the appropriate aniline, compound 68 It was synthesized using the same method as before.

[0290] compound 70 In step 5, (Z)-4-aminobuta-2-ennitrile is used. compound 47 It was synthesized using the same method as before.

[0291] compound 71 In step 5, (Z)-4-aminobuta-2-ennitrile is used. compound 1 It was synthesized using the same method as before.

[0292] Intermediate (R,E)-4-aminopenta-2-ennitrileIt was synthesized in the same manner as (E)-4-aminobuta-2-ennitrile, starting from 1,1-dimethylethyl N-[(1R)-1-methyl-2-oxoethyl]carbamate in step 1.

[0293] compound 229 In step 5, (R,E)-4-aminopenta-2-ennitrile and 1-((2'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxylic acid are used. compound 1 It was synthesized using the same method as in step 5.

[0294] Scheme 8. Synthesis of the intermediate 2-(aminomethyl)acrylonitrile [ka]

[0295] Stage 1 Hexamethylenetetramine (7 g, 49.9 mmol, 1 eq) was dissolved in chloroform (50 mL, 1.0 M), and 2,3-dibromopropene (10.2 g, 50.9 mmol, 1.02 eq) was added at 70°C. The mixture was stirred at 70°C for 3 hours. The mixture was cooled in an ice bath (ice batch), and the salt was collected by filtration to obtain a crude solid. This solid was dissolved in a warm solution consisting of 40 mL of water, 200 mL of EtOH, and 45 mL of concentrated HCl. A white precipitate of NH4Cl was formed, and the reaction mixture was left at 25°C for 16 hours. The white solid was removed again by filtration, the mother liquor was concentrated, and dehydrated to obtain 2-bromopropa-2-en-1-amine hydrochloride (13.5 g, 78.3 mmol) as a white solid.

[0296] Stage 22-bromopropa-2-en-1-amine hydrochloride (1 g, 5.80 mmol, 1 eq) and di-tert-butyl dicarbonate (1.5 g, 6.95 mmol, 1.2 eq) were placed in DCM (20 mL, 0.29 M). The mixture was stirred at 20°C for 10 hours. The mixture was diluted with H2O (15 mL) and extracted with DCM (80 mL). The extract was washed with brine (30 mL), dehydrated with Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain tert-butyl N-(2-bromoallyl)carbamate (600 mg, 2.54 mmol, 44% yield) as a white solid.

[0297] Stage 3 A mixture of tert-butyl N-(2-bromoaryl)carbamate (200 mg, 0.85 mmol, 1 eq) in DMF (2 mL, 0.42 M) was mixed with Zn(CN)2 (149 mg, 1.27 mmol, 1.5 eq) and Pd(PPh3)4 (98 mg, 0.085 mmol, 0.1 eq). The mixture was stirred at 110°C for 12 hours. After cooling to room temperature, the reaction mixture was poured into water (5 mL) and extracted with RINKAN (20 mL x 3). The organic layers were combined, washed with brine (10 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain tert-butyl N-(2-cyanoallyl)carbamate (80 mg, 0.44 mmol, 52% yield) as a white solid.

[0298] Stage 4 80 mg, 0.44 mmol, 1 eq of tert-butyl N-(2-cyanoallyl)carbamate was dissolved in 0.3 mL, 1.5 M DCM, and TFA (0.1 mL) was added to the solution. The mixture was stirred at 20°C for 2 hours. The solvent was removed under reduced pressure to obtain 2-(aminomethyl)propa-2-ennitrile (23 mg, 0.28 mmol, 64% yield) as a yellow oily substance. This was used directly in the next step.

[0299] 1H NMR (400 MHz, MeOD-d4) δ ppm 6.37 (s, 1H), 6.28 (s, 1H), 3.82 (s, 2H). compound 72 In step 5, 2-(aminomethyl)propa-2-ennitrile is used. compound 47 It was synthesized using the same method as before.

[0300] Scheme 9. Synthesis of 1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-((2R,Z)-4-(S-methylsulfonimidoyl)buta-3-en-2-yl)piperidine-4-carboxamide (compound 73) [ka]

[0301] Stage 1 0.8 g, 3.68 mmol, 1 eq of tert-butyl (R,Z)-(4-(methylthio)buta-3-en-2-yl)carbamate was dissolved in 10 mL, 0.37 M butyl, to which m-CPBA (667 mg, 3.68 mmol, 1 eq) was added at 0°C, and the reaction mixture was stirred at 20°C for 4 hours. The solution was diluted with aqueous Na2SO3 (20 mL) and extracted with butyl (20 mL x 3). The organic layers were combined and washed with brine (10 mL x 3), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:HCl = 0:1) to obtain tert-butyl ((2R,Z)-4-(methylsulfinyl)buta-3-en-2-yl)carbamate (0.65 g, 2.8 mmol, 76%).

[0302] Stage 2 300 mg, 1.29 mmol, 1 eq of tert-butyl ((2R,Z)-4-(methylsulfinyl)buta-3-en-2-yl)carbamate was dissolved in MeCN (3 mL, 0.43 M). 4-methylbenzenesulfonic acid (332 mg, 1.93 mmol, 1.5 eq) was added to this solution at 15°C, and the reaction mixture was stirred at 50°C for 18 hours. The solution was evaporated to obtain crude (2R,Z)-4-(methylsulfinyl)buta-3-en-2-amine (350 mg, 1.1 mmol, 89%).

[0303] Stage 3 1-[4-bromo-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylic acid (100 mg, 0.21 mmol, 1 eq) and (2R,Z)-4-(methylsulfinyl)buta-3-en-2-amine (28 mg, 0.21 mmol, 1 eq) were dissolved in DCM (3 mL, 0.07 M). DIPEA (81.3 mg, 0.63 mmol, 3 eq) and T3P (0.2 mL, 1.5 eq, 60%) were added to the solution at 15°C. The reaction mixture was stirred at 15°C for 1 hour. The solution was diluted with H2O (10 mL) and extracted with DCM (10 mL x 3). The organic layers were combined, washed with brine (20 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM:MeOH = 10:1). The product 1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-((2R,Z)-4-(methylsulfinyl)buta-3-en-2-yl)piperidine-4-carboxamide (60 mg, 0.11 mmol, 48%) was obtained as a yellow oil.

[0304] Stage 4 1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-((2R,Z)-4-(methylsulfinyl)buta-3-en-2-yl)piperidine-4-carboxamide (60 mg, 0.10 mmol, 1 eq) was dissolved in methanol (3 mL, 0.03 M), to which PhI(OAc)2 (163 mg, 0.30 mmol, 3 eq) and NH4COONH2 (131 mg, 1.00 mmol, 10 eq) were added. The reaction mixture was stirred at 15°C for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to obtain 1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-((2R,Z)-4-(S-methylsulfonimidoyl)buta-3-en-2-yl)piperidine-4-carboxamide( compound 73 (32.6 mg, 0.05 mmol, 53%) was obtained as a yellow oily substance.

[0305] 1 H NMR (400 MHz, CDCl3) δ ppm 8.56 (br t, J = 6.7 Hz, 1H), 8.01 - 7.92 (m, 1H), 7.92 - 7.86 (m, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.49 - 7.42 (m, 1H), 7.39 (d, J = 4.4 Hz, 2H), 6.85 - 6.62 (m, 2H), 5.39 - 5.20 (m, 1H), 3.79 - 3.61 (m, 3H), 3.15 (br s, 2H), 2.76 - 2.56 (m, 4H), 2.01 - 1.63 (m, 4H), 1.25 (d, J = 6.8 Hz, 3H). C 23 H 26 The calculated [M+H] value for BrClFN3O4S2 is 605; the measured value is 606. compound 74 In step 3, starting from a chiral sulfoxide, compound 73 It was synthesized using the same method as before.

[0306] Scheme 10. Synthesis of the intermediate 2-trimethylsilylethyl 3-[(E,3S)-3-aminobuta-1-enyl]sulfonylazetidine-1-carboxylate [ka]

[0307] Stage 1To a solution of tert-butyl 3-sulfanyl azetidine-1-carboxylate (6 g, 31.7 mmol, 1 eq) dissolved in THF (60 mL), NaH (1.4 g, 34.87 mmol, 1.1 eq) was added at 0°C. The mixture was stirred at 0°C for 1 hour. Diethyl iodomethyl phosphonate (9.7 g, 34.9 mmol, 1.1 eq) was added, and the reaction product was stirred at 25°C for 1 hour. The reaction mixture was poured into saturated aqueous NH4Cl (50 mL) and extracted with SiO2 (30 mL x 3). The organic layers were combined, washed with brine (10 mL x 2), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. Crude tert-butyl 3-(diethoxyphosphorylmethylsulfanyl)azetidine-1-carboxylate (11.1 g, 32.7 mmol) was obtained as a yellow oily substance. This was used in the next step without further purification.

[0308] Stage 2 To tert-butyl 3-(diethoxyphosphorylmethylsulfanyl)azetidine-1-carboxylate (11.1 g, 32.7 mmol, 1 eq) in DCM (30 mL, 0.55 M), TFA (30 mL, 0.55 M) was added. The mixture was stirred at 20°C for 8 hours. The mixture was concentrated under reduced pressure to obtain 3-(diethoxyphosphorylmethylsulfanyl)azetidine-1-ium;2,2,2-trifluoroacetate (11.6 g, 34.0 mmol, 100%) as a yellow oily substance. This was used in the next step without further purification.

[0309] Stage 33-(diethoxyphosphorylmethylsulfanyl)azetidine-1-ium;2,2-trifluoroacetate (11.6 g, 34.0 mmol, 1.0 eq) was dissolved in methanol (50 mL) and DCM (50 mL). To this solution, (2,5-dioxopyrrolidine-1-yl)2-trimethylsilylethyl carbonate (9.7 g, 37.5 mmol, 1.1 eq) and triethylamine (10.3 g, 102 mmol, 3 eq) were added. The mixture was stirred at 30°C for 5 hours. The reaction mixture was poured into water (45 mL) and extracted with RINKAN (45 mL x 3). The organic layers were combined, washed with brine (50 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. Crude 2-trimethylsilylethyl 3-(diethoxyphosphorylmethylsulfanyl)azetidine-1-carboxylate (12.7 g, 33.11 mmol, 97%) was obtained as a yellow oily substance. This was used in the next step without further purification.

[0310] Stage 4 2-trimethylsilylethyl 3-(diethoxyphosphorylmethylsulfanyl)azetidine-1-carboxylate (16.7 g, 43.5 mmol, 1 eq) was dissolved in DCM (100 mL, 0.44 M), and 3-chloroperbenzoic acid (19.4 g, 95.8 mmol, 2.2 eq) was added at 0°C. The mixture was stirred at 20°C for 12 hours. The reaction mixture was poured into saturated aqueous solution Na2SO3 (100 mL) and extracted with DCM (50 mL x 3). The organic layers were combined, washed with brine (100 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 2-trimethylsilylethyl 3-(diethoxyphosphorylmethylsulfonyl)azetidine-1-carboxylate (7.7 g, 18.5 mmol, 43%).

[0311] Stage 5A solution of 2-trimethylsilylethyl 3-(diethoxyphosphorylmethylsulfonyl)azetidine-1-carboxylate (1 g, 2.41 mmol, 1 eq) dissolved in THF (20 mL, 0.12 M) was cooled to -78°C. Then, lithium bis(trimethylsilyl)amide (2.6 mL, 2.64 mmol, 1.1 eq) was added. The mixture was stirred at -78°C for 1 hour. Tert-butyl (S)-(1-oxopropan-2-yl)carbamate (458 mg, 2.65 mmol, 1.1 eq) was added. After 10 minutes, the mixture was heated to 20°C and stirred for 1 hour. The reaction mixture was poured into saturated aqueous solution NH4Cl (100 mL) and extracted with RINKAN (30 mL x 3). The organic layers were combined, washed with brine (10 mL x 2), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The crude substance was purified by column chromatography to obtain 2-trimethylsilylethyl 3-[(E,3S)-3-(tert-butoxycarbonylamino)buta-1-enyl]sulfonylazetidine-1-carboxylate (0.8 g, 1.84 mmol, 76%) as a yellow oily substance.

[0312] Stage 6 2-trimethylsilylethyl 3-[(E,3S)-3-(tert-butoxycarbonylamino)buta-1-enyl]sulfonylazetidine-1-carboxylate (0.8 g, 1.84 mmol, 1 eq) was added to MeCN (5 mL, 0.37 M), and p-toluenesulfonic acid monohydrate (350 mg, 1.84 mmol, 1 eq) was added. The mixture was stirred at 20°C for 2 hours. The mixture was filtered to obtain 4-methylbenzenesulfonate; 2-trimethylsilylethyl 3-[(E,3S)-3-aminobuta-1-enyl]sulfonylazetidine-1-carboxylate (500 mg, 0.99 mmol, 54%) as a white solid.

[0313] Intermediate: 2-trimethylsilylethyl 3-[(E,3R)-3-aminobuta-1-enyl]sulfonylazetidine-1-carboxylate , 2-(trimethylsilyl)ethyl(S,E)-3-((3-aminopenta-1-en-1-yl)sulfonyl)azetidine-1-carboxylate and 2-(trimethylsilyl)ethyl (R,E)-3-((3-aminopenta-1-en-1-yl)sulfonyl)azetidine-1-carboxylateIt was synthesized in a similar manner to 2-trimethylsilylethyl 3-[(E,3S)-3-aminobuta-1-enyl]sulfonylazetidine-1-carboxylate, starting from a suitable aldehyde in step 5.

[0314] Scheme 11. Synthesis of (S,E)-N-(4-(azetidine-3-ylsulfonyl)buta-3-en-2-yl)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxamide (compound 75) [ka]

[0315] Stage 1 1-[4-bromo-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylic acid (150 mg, 0.315 mmol, 1 eq) and 4-methylbenzenesulfonate; 2-trimethylsilylethyl 3-[(E,3S)-3-aminobuta-1-enyl]sulfonylazetidine-1-carboxylate (239 mg, 0.472 mmol, 1.5 eq) were dissolved in MeCN (1 mL, 0.31 M). To this solution, 1-methylimidazole (77.5 mg, 0.94 mmol, 3 eq) and N-[chloro(dimethylamino)methylidene]-N-methylmethaneaminium hexafluorophosphate (132 mg, 0.472 mmol, 1.5 eq) were added. The mixture was stirred at 25°C for 1 hour. The mixture was purified by column chromatography to obtain 2-(trimethylsilyl)ethyl (S,E)-3-((3-(1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxamide)buta-1-en-1-yl)sulfonyl)azetidine-1-carboxylate (200 mg, 0.25 mmol, 80%).

[0316] Stage 22-(trimethylsilyl)ethyl (S,E)-3-((3-(1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxamide)buta-1-en-1-yl)sulfonyl)azetidine-1-carboxylate (200 mg, 0.252 mmol, 1 eq) in DCM (1 mL) was mixed with TFA (0.3 mL). The mixture was stirred at 20 °C for 1 hour. The mixture was concentrated under reduced pressure and purified by prep-HPLC to obtain (S,E)-N-(4-(azetidine-3-ylsulfonyl)buta-3-en-2-yl)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxamide ( compound 75 (117.9 mg, 0.18 mmol, 72%) was obtained.

[0317] 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.18 - 8.98 (m, 2H), 8.52 - 8.42 (m, 1H), 7.97 - 7.85 (m, 2H), 7.59 (d, J = 2.0 Hz, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.48 - 7.35 (m, 3H), 6.85 (dd, J = 5.0, 15.2 Hz, 1H), 6.65 (dd, J = 1.2, 15.3 Hz, 1H), 4.65 - 4.54 (m, 1H), 4.49 - 4.37 (m, 1H), 4.29 - 4.18 (m, 2H), 4.12 - 4.00 (m, 2H), 3.19 - 3.09 (m, 2H), 2.78 - 2.67 (m, 1H), 2.63 - 2.52 (m, 1H), 1.97 - 1.67 (m, 4H), 1.22 (d, J = 7.0 Hz, 3H). C 25 H 28 The calculated [M+H] value for BrClFN3O5S2 is 647; the measured value is 648. Compound 76-Compound 78 From a suitable intermediate, compound 75 It was synthesized using the same method as before.

[0318] Scheme 12. Synthesis of the intermediate (R,E)-4-methylsulfonylbuta-3-en-2-amine [ka]

[0319] Stage 1 Diethyl ((methylsulfonyl)methyl)phosphonate (2.7 g, 11.5 mmol, 1.0 eq) was dissolved in THF (60 mL) and NaH (462 mg, 1 eq, 11.5 mmol, 60%) was added at 0°C. The mixture was stirred at 0°C for 0.5 hours, and then (R)-tert-butyl (1-oxopropan-2-yl)carbamate (2 g, 11.5 mmol, 1.0 eq) in THF (10 mL) was added to the mixture. The reaction product was stirred at 0°C for 1 hour. The reaction product was quenched with water (50 mL) and extracted with SiO2 (30 mL x 3). The organic layers were combined, dehydrated with Na2SO4, filtered, and concentrated to obtain a crude mixture. The residue was purified by prep-HPLC to obtain tert-butyl (R,E)-(4-(methylsulfonyl)buta-3-en-2-yl)carbamate (950 mg, 3.81 mmol, 33%) as a white solid, and tert-butyl (R,Z)-(4-(methylsulfonyl)buta-3-en-2-yl)carbamate (160 mg, 0.64 mmol, 5.6%) as a white solid.

[0320] Stage 2 200 mg, 0.8 mmol, 1 eq of tert-butyl (R,E)-(4-(methylsulfonyl)buta-3-en-2-yl)carbamate was dissolved in 3 mL of MeCN, to which 138 mg, 0.8 mmol, 1 eq of 4-methylbenzenesulfonic acid was added. The mixture was stirred at 60°C for 12 hours. The reaction product was concentrated to obtain 4-methylbenzenesulfonic acid;(R,E)-4-methylsulfonylbuta-3-en-2-amine (200 mg, 0.62 mmol, 78%) as a white solid.

[0321] 1H NMR (400 MHz, methanol-d4) δ ppm 7.71 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8 Hz, 2H), 6.92 - 7.01 (m, 1H), 6.81 - 6.89 (m, 1H), 4.18 (q, J = 6.5 Hz, 1H), 3.02 (s, 3H), 2.37 (s, 3H), 1.47 (d, J = 6.8 Hz, 3H) Intermediate (S,E)-4-methylsulfonylbuta-3-en-2-amine It was synthesized by the same method as (R,E)-4-methylsulfonylbuta-3-en-2-amine.

[0322] compound 79 In step 5, (R,E)-4-methylsulfonylbuta-3-ene-2-amine is used. compound 47 It was synthesized using the same method as before.

[0323] compound 80 In step 5, (R,E)-4-methylsulfonylbuta-3-ene-2-amine is used. compound 1 It was synthesized using the same method as before.

[0324] compound 81 In step 5, (S,E)-4-methylsulfonylbuta-3-ene-2-amine is used. compound 47 It was synthesized using the same method as before.

[0325] Scheme 13. Synthesis of the intermediate bis(2,2,2-trifluoroethyl)((methylsulfonyl)methyl)phosphonate [ka]

[0326] Stage 1A mixture of chloromethyl methyl sulfide (1.5 mg, 15.2 mmol, 1 eq) and tris(2,2,2-trifluoroethyl) phosphite (5 g, 15.2 mmol, 1 eq) was heated at 160°C for 7 hours, and then heated at 140°C for 16 hours. The reaction product was directly concentrated to obtain 1,1,1-trifluoro-2-[methylsulfanylmethyl(2,2,2-trifluoroethoxy)phosphoryl]oxyethane (4 g, 13.1 mmol, 86%) as a colorless oil. This was used directly in the next step.

[0327] Stage 2 1,1,1-Trifluoro-2-[methylsulfanylmethyl(2,2,2-trifluoroethoxy)phosphoryl]oxyethane (4 g, 13.1 mmol, 1 eq) was dissolved in DCM (100 mL, 0.13 M). To this solution, m-CPBA (6.6 g, 32.7 mmol, 2.2 eq) was added in small amounts at 0°C, and the mixture was stirred at 20°C for 15 hours. The reaction product was quenched with 10% aqueous Na2S2O3 (100 mL) and saturated aqueous NaHCO3 (100 mL). The mixture was then extracted with DCM (100 mL x 2). The organic layers were combined, dehydrated with Na2SO4, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain bis(2,2,2-trifluoroethyl)((methylsulfonyl)methyl)phosphonate (3.5 g, 10.3 mmol, 79%) as a white solid.

[0328] Scheme 14. Synthesis of the intermediate (S,Z)-1-(methylsulfonyl)penta-1-ene-3-amine [ka]

[0329] Stage 10.5 g, 2.64 mmol, 1 eq of tert-butyl N-[(1S)-1-(hydroxymethyl)propyl]carbamate was dissolved in 10 mL, 0.26 M DCM, and dess-martin periodinane (1.2 g, 2.77 mmol, 1.1 eq) was added at 0°C. The mixture was stirred for 10 minutes. The mixture was then heated to 20°C and stirred for 16 hours. The reaction mixture was quenched with 10% aqueous Na2S2O4 (20 mL). The organic layer was washed with saturated aqueous NaHCO3 (20 mL), dehydrated with Na2SO4, filtered, and concentrated to dryness. The crude product was then purified by column chromatography to obtain the product tert-butyl N-[(1S)-1-formylpropyl]carbamate (360 mg, 1.92 mmol, 73%) as a colorless oil.

[0330] Stage 2 To a solution of bis(2,2,2-trifluoroethyl)((methylsulfonyl)methyl)phosphonate (650 mg, 1.92 mmol, 1 eq) dissolved in THF (8 mL, 0.16 M), NaH (76.9 mg, 1.92 mmol, 1 eq) was added in small amounts at 0°C, and the mixture was stirred for 0.5 hours. Then, tert-butyl N-[(1S)-1-formylpropyl]carbamate (360 mg, 1.92 mmol, 1 eq) in THF (4 mL, 0.16 M) was added dropwise at 0°C, and the mixture was stirred for 2 hours. The reaction mixture was quenched by adding aqueous saturated NH4Cl (10 mL) at 0°C, and then extracted with siRNA (10 mL x 2). The organic layers were combined, washed with brine (10 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain tert-butyl N-[(Z,1S)-1-ethyl-3-methylsulfonyl-allyl]carbamate (210 mg, 0.80 mmol, 41%) as a yellow oily substance, and tert-butyl N-[(E,1S)-1-ethyl-3-methylsulfonyl-allyl]carbamate (190 mg, 0.72 mmol, 37%) as a yellow oily substance.

[0331] Stage 3To a solution of tert-butyl N-[(Z,1S)-1-ethyl-3-methylsulfonyl-allyl]carbamate (210 mg, 0.80 mmol, 1 eq) dissolved in MeCN (6 mL, 0.13 M), p-toluenesulfonic acid monohydrate (152 mg, 0.80 mmol, 1 eq) was added. The mixture was stirred at 65°C for 16 hours. The reaction mixture was concentrated to obtain the product 4-methylbenzenesulfonic acid; (S,Z)-1-(methylsulfonyl)penta-1-en-3-amine (267 mg, 0.80 mmol, 100%) as a yellow solid.

[0332] Intermediate (R,Z)-1-(methylsulfonyl)penta-1-ene-3-amine It was synthesized by the same method as (S,Z)-1-(methylsulfonyl)penta-1-en-3-amine.

[0333] compound 82 In step 5, (S,Z)-1-(methylsulfonyl)penta-1-en-3-amine is used. compound 47 It was synthesized using the same method as before.

[0334] compound 83 In step 5, (S,Z)-1-(methylsulfonyl)penta-1-en-3-amine is used. compound 1 It was synthesized using the same method as before.

[0335] compound 84 In step 3, using the appropriate boronic acid, compound 83 It was synthesized using the same method as before.

[0336] Intermediate (Z)-3-(2-(methylsulfonyl)vinyl)azetidine It was synthesized in step 2 starting from tert-butyl 3-formylazetidine-1-carboxylate, in the same manner as (S,Z)-1-(methylsulfonyl)penta-1-en-3-amine.

[0337] compound 230 In step 5, (Z)-3-(2-(methylsulfonyl)vinyl)azetidine and 1-((2'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxylic acid are used. compound 1 It was synthesized using the same method as in step 5.

[0338] Scheme 15. Synthesis of 1-[4-(dimethylamino)-2-(3-methoxyphenyl)phenyl]sulfonyl-4-fluoro-N-[rac-(Z,1S)-1-methyl-3-methylsulfonyl-allyl]piperidine-4-carboxamide (compound 86) [ka]

[0339] Stage 1 To a mixture of HCl (2.4 mL) and acetic acid (0.7 mL, 0.47 M), 2-bromo-4-nitroaniline (1 g, 4.61 mmol, 1.0 eq) was added. After a white solid precipitated, the beaker was placed in an ice-ethanol bath. At -10°C, a solution of NaNO2 (350 mg, 5.07 mmol, 1.1 eq) dissolved in water (1 mL, 0.47 M) was added. This mixture was stirred at -10°C for a further 1 hour. Simultaneously, acetic acid (8 mL, 0.47 M) was ablated with SO2 separately, and CuCl (150 mg, 1.52 mmol, 0.3 eq) was added. The ablation of SO2 was continued until the color of the suspension changed from yellow-green to blue-green. The entire procedure was completed in approximately 30 minutes. Once the temperature reached 10°C, the above diazotization reaction mixture was carefully added over 30 minutes. The mixture was poured into ice water. Extraction was performed using ethyl acetate (50 mL). The organic layer was washed with NaHCO3 (60 mL), dehydrated with Na2SO4, filtered, and concentrated. 2-bromo-4-nitrobenzenesulfonyl chloride was obtained as a yellow oil (1 g, 3.32 mmol, 72% yield).

[0340] 1 H NMR (400 MHz, CDCl3) δ ppm 8.71 (d, J = 1.5 Hz, 1H), 8.42 - 8.38 (m, 2H). Stage 2At 0°C, 2-bromo-4-nitrobenzenesulfonyl chloride (772 mg, 2.57 mmol, 1.7 eq) was added to a mixture of ethyl 4-fluoropiperidine-4-carboxylate hydrochloride (320 mg, 1.51 mmol, 1 eq) and TEA (306 mg, 3.02 mmol, 2 eq) in DCM (5 mL, 0.30 M). The resulting mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into water (15 mL) and extracted with DCM (15 mL x 3). The organic layers were combined, washed with brine (10 mL x 2), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:Â=10:0-8:2). Ethyl 1-(2-bromo-4-nitrophenyl)sulfonyl-4-fluoropiperidine-4-carboxylate was obtained as a yellow oil (450 mg, 1.02 mmol, 68% yield).

[0341] 1 H NMR (400 MHz, CDCl3) δ ppm 8.60 (d, J = 1.6 Hz, 1H), 8.35 - 8.25 (m, 2H), 4.27 (q, J = 7.1 Hz, 2H), 3.91 - 3.79 (m, 2H), 3.23 (dt, J = 2.7, 12.8 Hz, 2H), 2.31 - 2.01 (m, 4H), 1.33 (t, J = 7.1 Hz, 3H). Stage 3A solution of ethyl 1-(2-bromo-4-nitrophenyl)sulfonyl-4-fluoropiperidine-4-carboxylate (400 mg, 0.91 mmol, 1.0 eq), 3-methoxyphenylboronic acid (415 mg, 2.73 mmol, 3.0 eq), and K2CO3 (483 mg, 4.55 mmol, 5 eq) dissolved in toluene (9 mL, 0.08 M) and water (3 mL, 0.08 M) was placed under N2. Pd(PPh3)4 (105 mg, 0.09 mmol, 0.1 eq) was added, and the mixture was stirred at 80°C for 16 hours. The reaction product was quenched with water (30 mL) and extracted with RINKAN (30 mL x 3). The organic layers were combined and washed with brine (50 mL). The organic layers were dehydrated with Na2SO4, filtered, and the filtrate was concentrated to obtain the crude product. The residue was purified by column chromatography (PE:siRNA = 10:0-7:3). Ethyl 4-fluoro-1-[2-(3-methoxyphenyl)-4-nitrophenyl]sulfonyl-piperidine-4-carboxylate was obtained as a colorless oil (320 mg, 0.69 mmol, 75%).

[0342] 1 H NMR (400 MHz, CDCl3) δ ppm 8.39 - 8.28 (m, 2H), 8.20 (d, J = 2.1 Hz, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.04 - 6.97 (m, 3H), 4.23 (q, J = 7.2 Hz, 2H), 3.86 (s, 3H), 3.22 (br d, J = 13.1 Hz, 2H), 2.70 - 2.57 (m, 2H), 1.98 - 1.75 (m, 4H), 1.30 (t, J = 7.1 Hz, 3H). C 21 H 23 For FN2O7S, the calculated [M+H] value was 466; the measured value was 467. Stage 4A mixture of ethyl 4-fluoro-1-[2-(3-methoxyphenyl)-4-nitro-phenyl]sulfonyl-piperidine-4-carboxylate (400 mg, 0.86 mmol, 1 eq) and NH4Cl (229 mg, 4.29 mmol, 5 eq) in ethanol (10 mL, 0.07 M) and water (2 mL, 0.07 M) was mixed with Fe (240 mg, 4.29 mmol, 5 eq). The resulting mixture was stirred at 80°C for 3 hours. After filtration, the filtrate was concentrated. The residue was purified by column chromatography (PE:siRNA = 10:0-7:3). Ethyl 1-[4-amino-2-(3-methoxyphenyl)phenyl]sulfonyl-4-fluoro-piperidine-4-carboxylate was obtained as a yellow oil (320 mg, 0.73 mmol, 85%).

[0343] 1 H NMR (400 MHz, CDCl3) δ ppm 7.92 (d, J = 8.7 Hz, 1H), 7.33 - 7.28 (m, 1H), 7.05 - 7.00 (m, 1H), 6.98 (d, J = 7.6 Hz, 1H), 6.91 (dd, J = 1.9, 8.2 Hz,1H), 6.67 (dd, J = 2.5, 8.6 Hz, 1H), 6.55 (d, J = 2.4 Hz, 1H), 4.21 (q, J = 7.2 Hz, 2H), 4.14 (s, 2H), 3.84 (s, 3H), 3.19 (br d, J = 12.6 Hz, 2H), 2.65 - 2.53 (m, 2H), 1.89 - 1.70 (m, 4H), 1.29 (t, J = 7.2 Hz, 3H). C 21 H 25 For FN2O5S, the calculated [M+H] value is 436; the measured value is 437. Stage 5A mixture of ethyl 1-[4-amino-2-(3-methoxyphenyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (200 mg, 0.46 mmol, 1 eq) and paraformaldehyde (27.5 mg, 0.92 mmol, 2 eq) in acetic acid (1.8 mL, 0.25 M) was mixed with NaBH3CN (63 mg, 1.01 mmol, 2.2 eq). The resulting mixture was stirred at 25°C for 0.5 hours, then heated to 65°C and stirred for 2 hours. The pH was adjusted to approximately 10 with aqueous NaOH (5 M), and then diluted with siRNA (80 mL). The layers were separated, and the aqueous layer was extracted with siRNA (50 mL x 2). The organic layers were combined, washed with brine (50 mL x 2), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE: siRNA = 100:0-85:15). Ethyl 1-[4-(dimethylamino)-2-(3-methoxyphenyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate was obtained as a yellow solid (170 mg, 0.37 mmol, 79%).

[0344] 1 H NMR (400 MHz, CDCl3) δ ppm 7.97 (d, J = 9.0 Hz, 1H), 7.33 - 7.28 (m, 1H), 7.05 (d, J = 2.2 Hz, 1H), 7.01 (d, J = 7.5 Hz, 1H), 6.92 (dd, J = 1.8, 8.3Hz, 1H), 6.66 (dd, J = 2.8, 9.0 Hz, 1H), 6.52 (d, J = 2.8 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.85 (s, 3H), 3.20 (br d, J = 13.0 Hz, 2H), 3.06 (s, 6H), 2.67 - 2.53 (m,2H), 1.91 - 1.69 (m, 4H), 1.29 (t, J = 7.2 Hz, 3H). Stage 6Ethyl 1-[4-(dimethylamino)-2-(3-methoxyphenyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (170 mg, 0.37 mmol, 1.0 eq) was dissolved in THF (6 mL, 0.05 M) and water (2 mL, 0.05 M), to which LiOH.H2O (123 mg, 2.93 mmol, 8 eq) was added. The mixture was stirred at 50°C for 3 hours. The mixture was acidified with 1N HCl to pH=4, poured into water (10 mL), and extracted with RINKAN (10 mL x 3). The organic layers were combined, washed with brine (10 mL x 2), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain 1-[4-(dimethylamino)-2-(3-methoxyphenyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylic acid as a yellow oil (160 mg, 0.37 mmol, 100%).

[0345] 1 H NMR (400 MHz, CDCl3) δ ppm 7.97 (d, J = 9.0 Hz, 1H), 7.31 (t, J = 7.9 Hz, 1H), 7.07 - 7.00 (m, 2H), 6.92 (dd, J = 2.1, 8.3 Hz, 1H), 6.67 (dd, J = 2.6, 9.0 Hz, 1H), 6.53 (d, J = 2.6 Hz, 1H), 3.84 (s, 3H), 3.22 (br d, J = 12.9 Hz, 2H), 3.06 (s, 6H), 2.69 - 2.58 (m, 2H), 1.90 - 1.72 (m, 4H). Stage 7A mixture of 1-[4-(dimethylamino)-2-(3-methoxyphenyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylic acid (60 mg, 0.14 mmol, 1 eq), (S,Z)-4-(methylsulfonyl)buta-3-en-2-amine (44 mg, 0.14 mmol, 1 eq), and DIPEA (44 mg, 0.34 mmol, 2.5 eq) in DCM (3 mL, 0.05 M) was mixed with HATU (78 mg, 0.21 mmol, 1.5 eq). The resulting mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (10 mL x 3). The organic layers were combined, washed with brine (10 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC. 1-[4-(dimethylamino)-2-(3-methoxyphenyl)phenyl]sulfonyl-4-fluoro-N-[rac-(Z,1S)-1-methyl-3-methylsulfonyl-allyl]piperidine-4-carboxamide ( compound 86 ) was obtained as a white solid (21.6 mg, 0.04 mmol, 27% yield).

[0346] 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.32 (br d, J = 7.7 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.31 - 7.24 (m, 1H), 6.96 - 6.89 (m, 3H), 6.78 (dd, J = 2.8, 9.2 Hz, 1H), 6.50 - 6.41 (m, 2H), 6.26 (dd, J = 9.6, 11.1 Hz, 1H), 5.40 - 5.26 (m, 1H), 3.77 (s, 3H), 3.12 (s, 3H), 3.06 (br d, J = 12.7 Hz, 2H), 3.01 (s, 6H), 2.43 (br d, J = 12.7Hz, 2H), 1.75 - 1.56 (m, 4H), 1.19 (d, J = 6.9 Hz, 3H). C 26 H 34 For FN3O6S2, the calculated [M+H] value is 567; the measured value is 568. Compound 87-Compound 90 In step 3, using the appropriate boronic acid, compound 86 It was synthesized using the same method as described above. In step 2, either methyl 4-fluoropiperidine-4-carboxylate or ethyl 4-fluoropiperidine-4-carboxylate was used.

[0347] compound 85 In step 3, an appropriate boronic acid is used, and in step 7, (R,Z)-1-(methylsulfonyl)penta-1-ene-3-amine is used. compound 86 It was synthesized using the same method as before.

[0348] Compound 91-Compound 93 In step 3, an appropriate boronic acid is used, and in step 7, (R,Z)-4-(methylsulfonyl)buta-3-ene-2-amine is used. compound 86 It was synthesized using the same method as described above. In step 2, either methyl 4-fluoropiperidine-4-carboxylate or ethyl 4-fluoropiperidine-4-carboxylate was used.

[0349] Compound 94-Compound 96 In step 3, an appropriate boronic acid is used, and in step 7, (E)-3-methylsulfonylpropa-2-ene-1-amine is used. compound 86 It was synthesized using the same method as described above. In step 2, either methyl 4-fluoropiperidine-4-carboxylate or ethyl 4-fluoropiperidine-4-carboxylate was used.

[0350] compound 97 In step 3, an appropriate boronic acid is used, and in step 7, (E)-4-aminobuta-2-ennitrile is used. compound 86 It was synthesized using the same method as before.

[0351] Scheme 16. Synthesis of the intermediate ethyl 1-[2-(2-chlorophenyl)-4-cyclobutylphenyl]sulfonyl-4-fluoropiperidine-4-carboxylate [ka]

[0352] Stage 1 Magnesium (88 mg, 3.33 mmol, 1.5 eq) was dissolved in THF (10 mL, 0.22 M), and bromocyclobutane (300 mg, 2.22 mmol, 1 eq) was added to the solution. The reaction mixture was stirred at 25°C for 1 hour. Dichlorozinc (909 mg, 6.67 mmol, 3 eq) was added to the reaction mixture, and it was stirred for another hour. The zinc reagent was used directly in the next step without purification.

[0353] Stage 2 Bromo(cyclobutyl)zinc (300 mg, 1.5 mmol, 1 eq) was dissolved in THF (10 mL) and ethyl 1-[4-bromo-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (100 mg, 0.20 mmol, 0.13 eq), CuI (100 mg), and Pd(dppf)Cl2 (100 mg) were added under N2 conditions. The reaction mixture was stirred at 25°C for 16 hours. The reaction product was quenched with 20 mL of saturated aqueous solution NH4Cl and extracted with  (20 mL). The crude product was purified by prep-TLC (PE:siRNA=3:1) to obtain ethyl 1-[2-(2-chlorophenyl)-4-cyclobutylphenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (40 mg, 0.08 mmol, 40% yield) as a yellow solid.

[0354] 1H NMR (400 MHz, CDCl3) δ ppm 8.05 (d, J = 8.3 Hz, 1H), 7.40 - 7.53 (m, 2H), 7.28 - 7.36 (m, 3H), 7.13 (s, 1H), 4.14 - 4.29 (m, 2H), 3.62 (q, J = 8.8 Hz, 1H), 3.26 (br d, J = 13.2 Hz, 1H), 3.12 (br d, J = 15.8 Hz, 1H), 2.84 - 2.96 (m, 1H), 2.58 - 2.70 (m, 1H), 2.31 - 2.44 (m, 3H), 1.95 - 2.24 (m, 7H), 1.76 - 1.91 (m, 4H), 1.24 - 1.31 (m, 4H). Ethyl 1-[4-bromo-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate is compound 47 In the same manner as in stages 4 and 5, compound 98 They converted it to that.

[0355] Scheme 17. Synthesis of the intermediate ethyl 1-[4-(1-tert-butoxycarbonylazetidine-3-yl)-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate [ka]

[0356] Stage 1 To a solution of Zn (289 mg, 6.62 mmol, 2.5 eq) dissolved in DMA (8 mL, 0.33 M), 1,2-dibromoethane (299 mg, 1.59 mmol, 0.6 eq) and TMSCl (0.14 mL, 1.06 mmol, 0.4 eq) were added at 50°C, and the reaction mixture was stirred at 50°C for 30 minutes. Then, 1-boc-3-iodoazetidine (750 mg, 2.65 mmol, 1 eq) was added at 50°C, and the mixture was stirred at 50°C for 30 minutes. The reaction mixture of (1-tert-butoxycarbonylazetidine-3-yl)-iodo-zinc (923 mg, 2.65 mmol, 100%) was used directly in the next step.

[0357] Stage 2Ethyl 1-[4-bromo-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (400 mg, 0.79 mmol, 1 eq) was dissolved in DMA (5 mL, 0.16 M). CuI (15 mg, 0.047 mmol, 0.06 eq), Pd(dppf)Cl2 (78 mg, 0.039 mmol, 0.05 eq), and (1-tert-butoxycarbonylazetidine-3-yl)-iodo-zinc (828 mg, 2.38 mmol, 3 eq, in DMA) were added at 15°C. The mixture was stirred under N2 at 80°C for 2 hours. The solution was diluted with water (15 mL) and extracted with RINKAN (10 mL x 3). The organic layers were combined, washed with brine (30 mL x 2), dehydrated with Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (PE:siRNA = 1:0 → 10:1) to obtain ethyl 1-[4-(1-tert-butoxycarbonylazetidine-3-yl)-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (500 mg, 0.8 mmol, 100%) as a brown solid.

[0358] 1 HNMR (400 MHz, CDCl3) δ ppm 8.13 (d, J = 8.3 Hz, 1H), 7.52 - 7.42 (m, 3H), 7.39 - 7.32 (m, 2H), 7.26 (d, J = 1.8 Hz, 1H), 4.37 (dt, J = 2.4, 8.7 Hz, 2H), 4.18 - 4.09 (m, 1H), 4.04 - 3.95 (m, 2H), 3.87 - 3.70 (m, 1H), 3.32 - 3.07 (m, 2H), 2.94 - 2.86 (m, 1H), 2.66 (dt, J = 2.7, 12.9 Hz, 1H), 2.04 - 1.76 (m, 4H), 1.46 (s, 9H), 1.33 - 1.28 (m, 3H). Ethyl 1-[4-(1-tert-butoxycarbonylazetidine-3-yl)-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate is compound 47 In the same manner as in stages 4 and 5, compound 99 They converted it to that.

[0359] Scheme 18. Synthesis of the intermediate (3-propa-1-inylphenyl)boronic acid. [ka]

[0360] Stage 1 To a solution of 1-bromo-3-iodobenzene (3 g, 10.6 mmol, 1 eq) dissolved in toluene (30 mL, 0.35 M), CuI (604 mg, 3.18 mmol, 0.3 eq) and Pd(PPh3)4 (300 mg) were added. This mixture was stirred for 5 minutes. Next, 1-(trimethylsilyl)-1-propyne (1.2 g, 10.6 mmol, 1 eq), TEA (3.5 g, 35.0 mmol, 3.3 eq), and TBAF (1 M, 10.6 mL, 1.0 eq) were added to the mixture at room temperature. The resulting mixture was stirred at 20 °C for 5 hours. The reaction mixture was quenched with water (50 mL), extracted with MTBE (20 mL x 3), and the organic layers were combined. The organic phase was washed with brine (50 mL), dehydrated with Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (PE=100%) to obtain 1-bromo-3-propa-1-inylbenzene (2 g, 10.2 mmol, 96%) as a colorless oil.

[0361] 1 H NMR (400 MHz, CDCl3) δ ppm 7.54 (t, J = 1.6 Hz, 1H), 7.40 (dt, J = 8.0, 1.3 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.08 - 7.19 (m, 1H), 2.05 (s, 3H). Stage 21-Bromo-3-(propa-1-in-1-yl)benzene (500 mg, 2.56 mmol, 1 eq) and triisopropyl borate (530 mg, 2.82 mmol, 1.1 eq) were dissolved in THF (3 mL, 0.85 M) and toluene (9 mL). To this solution, n-BuLi (1.1 mL, 1.1 eq, 1 M) was added at -78°C. The reaction mixture was stirred at -78°C for 30 minutes. The mixture was raised to 15°C and stirred at 15°C for 1 hour. The reaction mixture was cooled to -78°C, 3 M HCl was added to adjust the pH to 2, and the mixture was stirred at 15°C for 15 minutes. Potassium hydroxide was added to adjust the pH to 8. 2-Methyltetrahydrofuran was added, and the solution was filtered. The product (3-propa-1-inylphenyl)boronic acid (350 mg, 2.18 mmol, 85%) was obtained as a white solid.

[0362] 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.55 - 7.82 (m, 2H), 6.95 - 7.23 (m, 2H), 2.01 (s, 3H). compound 100 In step 3, (3-propa-1-inylphenyl)boronic acid is used. compound 1 It was synthesized using the same method as before.

[0363] compound 46 In step 5, (E)-3-(methylsulfonyl)propa-2-ene-1-amine is used. compound 100 It was synthesized using the same method as before.

[0364] Scheme 19. Synthesis of the intermediate 1-((2'-chloro-5-cyclopropoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxylic acid [ka]

[0365] Stage 1 2-Bromo-4-fluoroaniline (15 g, 78.9 mmol, 1 eq) was dissolved in HCl / acetic acid (v / v 3:1, 44 mL, 1.3 M), and NaNO2 (6 g, 86.8 mmol, 1.1 eq) was added at 0°C. mixture 1The mixture was stirred at 0°C for 1 hour. In a separate flask, SO2 was passed through acetic acid (50 mL, 1.3 M) at 0°C for 10 minutes, and then CuCl (2.3 g, 23.7 mmol, 0.3 eq) was added. SO2 was passed through mixture 2 for about 10 minutes. Mixture 1 was added to mixture 2 at 0°C. The resulting mixture was stirred at 0-20°C for 1 hour. The reaction mixture was quenched with water (300 mL) and extracted with MTBE (300 mL x 2). The organic layer was washed with saturated aqueous sodium bicarbonate (300 mL x 2) and 300 mL of brine. The organic layer was then separated, dehydrated with Na2SO4, filtered, and concentrated to dryness. Next, the crude substance was purified by column chromatography (PE:siRNA=50:1) to obtain 2-bromo-4-fluorobenzenesulfonyl chloride (10 g, 36.6 mmol, 46%) as a yellow oily substance.

[0366] 1 H NMR (400 MHz, CDCl3) δ ppm 8.24 (dd, J = 9.1, 5.4 Hz, 1H), 7.61 (dd, J = 7.8, 2.6 Hz, 1H), 7.27 (s, 1H). Stage 2 2-Bromo-4-fluorobenzenesulfonyl chloride (5 g, 18.3 mmol, 1 eq) and ethyl 4-fluoropiperidine-4-carboxylate hydrochloride (3.9 g, 18.3 mmol, 1 eq) were dissolved in DCM (100 mL, 0.18 M), to which TEA (5.5 g, 54.8 mmol, 3 eq) was added dropwise at 0°C. The resulting mixture was stirred at 0°C for 1 hour. The mixture was quenched with H2O (80 mL) and extracted with DCM (100 mL x 2). The organic layer was washed with 120 mL of brine. The organic layer was then separated, dehydrated with Na2SO4, filtered, and concentrated to dryness. Next, the crude product was purified by column chromatography (PE:HCl=3:1) to obtain the product ethyl 1-(2-bromo-4-fluorophenyl)sulfonyl-4-fluoropiperidine-4-carboxylate as a yellow solid.

[0367] 1H NMR (400 MHz, CDCl3) δ ppm 8.14 (dd, J = 8.9, 5.8 Hz, 1H), 7.51 (dd, J = 8.0, 2.5 Hz, 1H), 7.17 (ddd, J = 8.9, 7.4, 2.6 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 3.80 (dt, J = 12.9, 2.6 Hz, 2H), 3.16 (td, J = 12.7, 2.8 Hz, 2H), 2.10 - 2.29 (m, 2H), 2.06 (br s, 1H), 1.99 - 2.05 (m, 1H), 1.32 (t, J = 7.1 Hz, 3H). Stage 3 Ethyl 1-(2-bromo-4-fluorophenyl)sulfonyl-4-fluoropiperidine-4-carboxylate (1.5 g, 3.64 mmol, 1 eq) was dissolved in 1,4-dioxane / water (v / v 10:1, 22 mL, 0.18 M), to which 2-chlorophenylboronic acid (1.1 g, 7.28 mmol, 2 eq) and K2CO3 (1 g, 7.28 mmol, 2.0 eq) were added. The mixture was placed under N2 and Pd(dppf)Cl2 (500 mg) was added. The resulting mixture was stirred at 90°C for 12 hours. After cooling to room temperature, the reaction mixture was quenched with H2O (30 mL) and extracted with siRNA (20 mL x 2). The organic layer was washed with 30 mL of brine. The organic matter was then separated, dehydrated with Na2SO4, filtered, and concentrated to dryness. Next, the crude substance was purified by column chromatography to obtain the product ethyl 1-[2-(2-chlorophenyl)-4-fluorophenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (1 g, 2.25 mmol, 62%) as a yellow oil.

[0368] 1H NMR (400 MHz, CDCl3) δ ppm 8.18 (dd, J = 5.6, 8.8 Hz, 1H), 7.52 - 7.47 (m, 1H), 7.46 - 7.41 (m, 1H), 7.40 - 7.31 (m, 2H), 7.25 - 7.19 (m, 1H), 7.04 (dd, J = 2.6, 8.8 Hz, 1H), 4.28 - 4.16 (m, 2H), 3.25 (br dd, J = 2.1, 13.4 Hz, 1H), 3.08 (td, J = 2.3, 13.3 Hz, 1H), 2.98 - 2.87 (m, 1H), 2.73 - 2.58 (m, 1H), 2.16 - 1.76 (m, 5H), 1.31 - 1.27 (m, 3H). Stage 4 Ethyl 1-[2-(2-chlorophenyl)-4-fluorophenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (150 mg, 0.34 mmol, 1 eq) was dissolved in DMF (2 mL, 0.17 M), and NaH (27 mg, 0.68 mmol, 2.0 eq, 60%) was added at 0°C. The reaction mixture was stirred for 30 minutes, and then cyclopropanol (196 mg, 3.38 mmol, 10 eq) was added dropwise at 0°C. The resulting mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with H2O (10 mL) and extracted with MTBE (10 mL). The aqueous phase was adjusted to pH=4 with aqueous HCl and extracted with ELISA (5 mL × 2). The organic layers were combined and washed with 10 mL of brine, dehydrated with Na2SO4, and filtered. The filtrate was concentrated to obtain 1-((2'-chloro-5-cyclopropoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxylic acid (100 mg, 0.22 mmol, 65% yield) as a yellow oil.

[0369] Compound 101 teeth, compound 47 It was synthesized from 1-((2'-chloro-5-cyclopropoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxylic acid using the same method as in step 5.

[0370] Compound 102-Compound 103 In step 3, an appropriate boronic acid is used, and in step 4, an appropriate alcohol is used. Compound 101 It was synthesized using the same method as before.

[0371] Compound 104-Compound 105 In stage 4, using appropriate alcohol, Compound 101 It was synthesized using the same method as before.

[0372] compound 106 In step 3, using the appropriate boronic acid, Compound 101 It was synthesized using the same method as before.

[0373] Scheme 20. Synthesis of the intermediate methyl 1-[2-(2-chlorophenyl)-4-vinylphenyl]sulfonyl-4-fluoropiperidine-4-carboxylate. [ka]

[0374] Stage 1 1-[4-bromo-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylic acid (200 mg, 0.42 mmol, 1 eq) was dissolved in methanol (6 mL, 0.07 M), and SOCl2 (0.1 mL, 0.84 mmol, 2 eq) was added at 0°C. The mixture was stirred at 60°C for 3 hours. After cooling to room temperature, the reaction mixture was poured into ice water (15 mL) and extracted with ELISA (15 mL x 3). The organic layers were combined, washed with brine (10 mL x 2), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (PE:siRNA = 1:0 → 10:1) to obtain methyl 1-[4-bromo-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (140 mg, 0.29 mmol, 68%) as a yellow solid.

[0375] 1H NMR (400 MHz, CDCl3) δ ppm 7.98 - 8.04 (m, 1H), 7.62 - 7.70 (m, 1H), 7.47 - 7.51 (m, 2H), 7.40 - 7.43 (m, 1H), 7.31 - 7.39 (m, 2H), 3.79 (s, 3H), 3.26 (dt, J = 13.5, 2.4 Hz, 1H), 3.04 - 3.12 (m, 1H), 2.93 (td, J = 12.8, 3.1 Hz, 1H), 2.59 - 2.69 (m, 1H), 1.75 - 2.10 (m, 4H). Stage 2 A solution of methyl 1-[4-bromo-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (100 mg, 0.21 mmol, 1 eq) was dissolved in ethanol (5 mL, 0.04 M), to which potassium vinyltrifluoroborate (33 mg, 0.25 mmol, 1.2 eq) and TEA (41 mg, 0.41 mmol, 2 eq) were added. The mixture was stirred at 20°C for 10 minutes. Next, Pd(dppf)Cl2.CH2Cl2 (50 mg, 0.021 mmol, 0.1 eq) was added to the mixture. The mixture was stirred at 85°C for 12 hours. After cooling to room temperature, the mixture was diluted with water (5 mL) and extracted with RINKAN (5 mL x 3). The organic layers were combined, washed with brine (5 mL x 2), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue prep-TLC(PE:Â=3:1, R f The product was purified using (product) = 0.6. Methyl 1-[2-(2-chlorophenyl)-4-vinylphenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (75 mg, 0.17 mmol, 84%) was obtained as a colorless oil.

[0376] 1H NMR (400 MHz, CDCl3) δ ppm 8.10 (d, J = 8.3 Hz, 1H), 7.52 - 7.63 (m, 1H), 7.41 - 7.51 (m, 2H), 7.30 - 7.38 (m, 3H), 6.76 (dd, J = 17.5, 10.9 Hz, 1H), 5.86 - 5.95 (m, 1H), 5.86 - 5.95 (m, 1H), 5.42 - 5.50 (m, 1H), 3.64 - 3.83 (m, 3H), 3.28 (br d, J = 14.9 Hz, 1H), 3.12 (br d, J = 10.8 Hz, 1H), 2.83 - 2.98 (m, 2H), 2.60 - 2.73 (m, 1H), 2.60 - 2.73 (m, 1H), 1.91 - 2.04 (m, 2H), 1.75 - 1.90 (m, 2H). C 21 H 21 For ClFNO4S, the calculated [M+H] value was 437, and the measured value was 438. compound 107 This uses methyl 1-[2-(2-chlorophenyl)-4-vinylphenyl]sulfonyl-4-fluoropiperidine-4-carboxylate, compound 47 It was synthesized using the same method as in steps 4-5.

[0377] Intermediate: Methyl 4-fluoro-1-((2'-methyl-5-vinyl-[1,1'-biphenyl]-2-yl)sulfonyl)piperidine-4-carboxylate It was prepared starting from 1-((5-bromo-2'-methyl-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxylic acid by the same method as methyl 1-[2-(2-chlorophenyl)-4-vinylphenyl]sulfonyl-4-fluoropiperidine-4-carboxylate.

[0378] compound 108 This uses methyl 4-fluoro-1-((2'-methyl-5-vinyl-[1,1'-biphenyl]-2-yl)sulfonyl)piperidine-4-carboxylate, compound 47 It was synthesized using the same method as in steps 4-5.

[0379] Compound 109-Compound 110 In step 1, an appropriate carboxylic acid is used, and in step 2, potassium trifluoro(isopropenyl)borate is used. compound 107 It was synthesized using the same method as before.

[0380] Scheme 21. Synthesis of the intermediate ethyl 1-[2-(2-chlorophenyl)-4-ethylphenyl]sulfonyl-4-fluoropiperidine-4-carboxylate [ka]

[0381] Stage 1 Ethyl 1-[4-bromo-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (100 mg, 0.19 mmol, 1 eq) was dissolved in ethanol (5 mL, 0.04 M), to which potassium vinyltrifluoroborate (32 mg, 0.24 mmol, 1.2 eq) and TEA (40 mg, 0.40 mmol, 2 eq) were added. The mixture was stirred at 20°C for 10 minutes. Then, Pd(dppf)Cl2.CH2Cl2 (50 mg, 0.019 mol, 0.1 eq) was added to the mixture. The mixture was stirred at 85°C for 12 hours. After cooling to room temperature, the mixture was diluted with water (5 mL) and extracted with RINKAN (5 mL x 3). The organic layers were combined, washed with brine (5 mL x 2), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (PE:Â=3:1). Ethyl 1-[2-(2-chlorophenyl)-4-vinylphenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (70 mg, 0.15 mmol, 79%) was obtained as a colorless oil.

[0382] 1H NMR (400MHz, CDCl3) δ ppm 8.09 (d, J = 8.3 Hz, 1H), 7.54 (dd, J = 1.8, 8.3 Hz, 1H), 7.50 - 7.46 (m, 1H), 7.45 - 7.42 (m, 1H), 7.38 - 7.30 (m, 3H), 6.75 (dd, J = 10.9, 17.6 Hz, 1H), 5.89 (d, J = 17.6 Hz, 1H), 5.47 - 5.42 (m, 1H), 4.26 - 4.17 (m, 2H), 3.27 (td, J = 2.2, 13.3 Hz, 1H), 3.12 (td, J = 2.2, 13.3 Hz, 1H), 2.91 (dt, J = 2.9, 12.7 Hz, 1H), 2.66 (dt, J = 2.8, 12.8 Hz, 1H), 2.14 - 1.77 (m, 4H), 1.29 (t, J = 7.2 Hz, 3H). Stage 2 Ethyl 1-[2-(2-chlorophenyl)-4-vinylphenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (60 mg, 0.13 mmol, 1 eq) was dissolved in methanol (5 mL, 0.03 M), and Pd / C (100 mg, 5%, moistened with approximately 55% water) was added. The mixture was stirred under H2 at 20°C for 30 minutes. The mixture was filtered and concentrated under reduced pressure to obtain ethyl 1-[2-(2-chlorophenyl)-4-ethylphenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (50 mg, 0.11 mmol, 83%) as a colorless oil.

[0383] Compound 111 This uses ethyl 1-[2-(2-chlorophenyl)-4-ethylphenyl]sulfonyl-4-fluoropiperidine-4-carboxylate, compound 47 It was synthesized using the same method as in steps 4-5.

[0384] Intermediate: Ethyl 1-((5-ethyl-2'-methyl-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxylate and Ethyl 1-((5-ethyl-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxylateIt was prepared by a similar method to that used for ethyl 1-[2-(2-chlorophenyl)-4-ethyl-phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate, starting from appropriately substituted biphenylsulfonamide.

[0385] Compound 112-Compound 113 In step 1, using an appropriate intermediate, Compound 111 It was synthesized using the same method as before.

[0386] Intermediate: Ethyl 1-((2'-chloro-5-isopropyl-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxylate This was prepared in step 1 using potassium trifluoro(isopropenyl)borate in a manner similar to that of ethyl 1-[2-(2-chlorophenyl)-4-ethyl-phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate.

[0387] compound 114 This uses ethyl 1-((2'-chloro-5-isopropyl-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxylate, compound 47 It was synthesized using the same method as in steps 4-5.

[0388] Intermediate: Ethyl 4-fluoro-1-((5-isopropyl-2'-methyl-[1,1'-biphenyl]-2-yl)sulfonyl)piperidine-4-carboxylate It was prepared using appropriately substituted biphenylsulfonamides in a similar manner to ethyl 1-((2'-chloro-5-isopropyl-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxylate.

[0389] compound 115 This uses ethyl 4-fluoro-1-((5-isopropyl-2'-methyl-[1,1'-biphenyl]-2-yl)sulfonyl)piperidine-4-carboxylate, compound 47 It was synthesized using the same method as in steps 4-5.

[0390] Scheme 22. Synthesis of the intermediate 1-[4-(azetidine-1-yl)-2-(o-tolyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylic acid [ka]

[0391] Stage 1 To a solution of ethyl 1-(4-bromo-2-iodophenyl)sulfonyl-4-fluoropiperidine-4-carboxylate (200 mg, 0.38 mmol, 1 eq) dissolved in 1,4-dioxane (3 mL, 0.12 M), o-trilboronic acid (78 mg, 0.58 mmol, 1.5 eq), Na2CO3 (140 mg, 0.96 mmol, 2.5 eq) and Pd(dppf)Cl2 (0.15 eq, 0.058 mmol, 59 mg) in water (0.38 mL, 0.17 M) were added. The reaction mixture was heated to 90°C and stirred for 16 hours. After cooling to room temperature, the reaction mixture was quenched with water (10 mL) and extracted with siRNA (10 mL x 2). The organic phase was dehydrated with Na2SO4, filtered, and evaporated under reduced pressure. The crude product was purified by prep-TLC (PE:Â=3:1) to obtain ethyl 1-[4-bromo-2-(o-tolyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (154 mg, 0.32 mmol, 83%) as a colorless oil.

[0392] 1 H NMR (400 MHz, CDCl3) δ ppm 8.00 (d, J = 8.6 Hz, 1H), 7.64 (dd, J = 8.6, 2.2 Hz, 1H), 7.40 - 7.50 (m, 1H), 7.28 (br d, J = 3.1 Hz, 2H), 7.19 - 7.25 (m, 2H), 4.19 - 4.25 (m, 2H), 3.16 (br d, J = 12.5 Hz, 2H), 2.61 - 2.75 (m, 2H), 2.07 - 2.12 (m, 3H), 1.82 - 2.05 (m, 4H), 1.25 - 1.30 (m, 3H). Stage 2Ethyl 1-[4-bromo-2-(o-tolyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (154 mg, 0.32 mmol, 1 eq) was dissolved in 1,4-dioxane (3 mL, 0.1 M). To this solution, azetidine (22 mg, 0.38 mmol, 1.2 eq), t-BuONa (91 mg, 0.95 mmol, 3 eq), Pd2(dba)3 (14 mg, 0.016 mmol, 0.05 eq), and XantPhos (18 mg, 0.03 mmol, 0.1 eq) were added. The reaction mixture was heated to 100°C and stirred for 16 hours. After cooling to room temperature, the mixture was quenched with water (10 mL) and the pH was adjusted to 3 with 1N HCl. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The organic layers were combined, washed with brine (20 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain 1-[4-(azetidine-1-yl)-2-(o-tolyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylic acid (120 mg, 0.27 mmol, 87%) as a yellow solid.

[0393] 1 H NMR (400 MHz, CDCl3) δ ppm 7.84 (d, J = 8.7 Hz, 1H), 7.31 - 7.58 (m, 4H), 7.06 - 7.13 (m, 2H), 3.90 (br t, J = 7.3 Hz, 4H), 3.06 - 3.23 (m, 4H), 2.46 - 2.74 (m, 4H), 2.31 - 2.41 (m, 2H), 2.05 (s, 3H). C 22 H 25 For FN2O4S, the calculated [M+H] value is 432, and the measured value is 433. compound 116 This uses 1-[4-(azetidine-1-yl)-2-(o-tolyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylic acid, compound 47 It was synthesized using the same method as in step 5.

[0394] compound 117It starts with methyl 1-(4-bromo-2-phenylphenyl)sulfonyl-4-fluoropiperidine-4-carboxylate, and uses pyrrolidine and BINAP instead of XantPhos as reagents. compound 116 It was synthesized using the same method as before.

[0395] Intermediate: Ethyl 1-((2'-chloro-5-(2-oxopyrrolidine-1-yl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxylate This compound was synthesized in the same manner as 1-[4-(azetidine-1-yl)-2-(o-tolyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylic acid, using 2-chlorophenylboronic acid in step 1 and 2-pyrrolidone in step 2.

[0396] compound 205 It is derived from ethyl 1-((2'-chloro-5-(2-oxopyrrolidine-1-yl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxylate, compound 47 It was synthesized using the same method as in steps 4-5.

[0397] Scheme 23. Synthesis of the intermediate tert-butyl 4-[3-(2-chlorophenyl)-4-[(4-ethoxycarbonyl-4-fluoro-1-piperidyl)sulfonyl]phenyl]piperazine-1-carboxylate [ka]

[0398] Stage 1Ethyl 1-[2-(2-chlorophenyl)-4-fluorophenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (100 mg, 0.23 mmol, 1 eq) was dissolved in MeCN (2 mL, 0.11 M), to which tert-butylpiperazine-4-ium-1-carboxylate (50 mg, 0.27 mmol, 1.2 eq) and DIPEA (58 mg, 0.46 mmol, 2 eq) were added at room temperature. The reaction mixture was slowly heated to 100°C and stirred for 36 hours. Then, the mixture was heated at 130°C for 16 hours. When the reaction was complete, it was cooled to room temperature, the reaction mixture was quenched with water (10 mL), and the aqueous solution was extracted with ELISA (10 mL x 3). The organic layers were combined, dehydrated with Na₂SO₄, filtered, and evaporated under reduced pressure. The crude product was purified by prep-TLC to obtain tert-butyl 4-[3-(2-chlorophenyl)-4-[(4-ethoxycarbonyl-4-fluoro-1-piperidyl)sulfonyl]phenyl]piperazine-1-carboxylate (50 mg, 0.08 mmol, 36%) as a white solid.

[0399] 1 H NMR (400 MHz, CDCl3) δ ppm 7.99 (d, J = 8.9 Hz, 1H), 7.40 - 7.51 (m, 2H), 7.30 - 7.35 (m, 2H), 6.90 (dd, J = 9.0, 2.6 Hz, 1H), 6.70 (d, J = 2.5 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.58 (br d, J = 5.3 Hz, 4H), 3.34 (br d, J = 5.1 Hz, 4H), 3.25 (br d, J = 13.0 Hz, 1H), 3.13 (br d, J = 11.5 Hz, 1H), 2.82 - 2.94 (m, 1H), 2.62 - 2.71 (m, 1H), 1.76 - 2.03 (m, 4H), 1.56 - 1.58 (m, 9H), 1.29 - 1.32 (m, 3H). compound 118This uses tert-butyl 4-[3-(2-chlorophenyl)-4-[(4-ethoxycarbonyl-4-fluoro-1-piperidyl)sulfonyl]phenyl]piperazine-1-carboxylate, compound 47 It was synthesized using the same method as in steps 4-5.

[0400] Compound 119 and compound 121 In step 4, using an appropriate amine, compound 118 It was synthesized using the same method as before.

[0401] compound 120 , compound 122 and compound 123 In step 3, an appropriate boronic acid is used, and in step 4, an amine is used. compound 118 It was synthesized using the same method as before.

[0402] compound 124 It was synthesized by combining ethyl 1-(2-bromo-4-fluorophenyl)sulfonyl-4-fluoro-piperidine-4-carboxylate and azetidine in the same manner as in step 4 of tert-butyl 4-[3-(2-chlorophenyl)-4-[(4-ethoxycarbonyl-4-fluoro-1-piperidyl)sulfonyl]phenyl]piperazine-1-carboxylate, followed by coupling with 2-chlorophenylboronic acid in the same manner as in step 3 of tert-butyl 4-[3-(2-chlorophenyl)-4-[(4-ethoxycarbonyl-4-fluoro-1-piperidyl)sulfonyl]phenyl]piperazine-1-carboxylate, followed by hydrolysis and coupling with (R,Z)-4-(methylsulfonyl)buta-3-en-2-amine.

[0403] Scheme 24. Synthesis of the intermediate 1-[4-chloro-2-[3-(2-methoxyethyl)phenyl]phenyl]sulfonyl-4-fluoropiperidine-4-carboxylic acid [ka]

[0404] Stage 1To a solution of ethyl 1-(2-bromo-4-chlorophenyl)sulfonyl-4-fluoropiperidine-4-carboxylate (150 mg, 0.35 mmol, 1 eq) dissolved in 1,4-dioxane (2 mL, 0.16 M), [3-(2-hydroxyethyl)phenyl]boronic acid (70 mg, 0.420 mmol, 1.2 eq), K2CO3 (96 mg, 0.70 mmol, 2 eq) and Pd(dppf)Cl2 (45 mg, 0.035 mmol, 0.1 eq) in water (0.2 mL, 0.16 M) were added. The reaction mixture was heated to 90°C and stirred for 2 hours. After cooling to room temperature, the mixture was quenched with water (5 mL) and extracted with siRNA (5 mL x 3). The organic phase was dehydrated with Na2SO4, filtered, and evaporated under reduced pressure. The crude product was purified by prep-TLC to obtain ethyl 1-[4-chloro-2-[3-(2-hydroxyethyl)phenyl]phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (100 mg, 0.21 mmol, 61%) as a yellow oil.

[0405] 1 H NMR (400 MHz, CDCl3) δ ppm 8.08 (d, J = 8.6 Hz, 1H), 7.48 (dd, J = 8.6, 2.2 Hz, 1H), 7.37 - 7.42 (m, 1H), 7.35 - 7.37 (m, 1H), 7.33 (s, 1H), 7.29 (s, 2H), 4.22 (q, J = 7.1 Hz, 2H), 3.15 (br d, J = 12.9 Hz, 2H), 2.93 (t, J = 6.2 Hz, 2H), 2.52 - 2.63 (m, 2H), 1.74 - 1.94 (m, 4H), 1.29 (t, J = 7.2 Hz, 3H). Stage 2Ethyl 1-[4-chloro-2-[3-(2-hydroxyethyl)phenyl]phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (100 mg, 0.21 mmol, 1 eq) was placed in THF (2 mL, 1.2 M) and placed under N2. NaH (10 mg, 0.43 mmol, 2.0 eq) was added in small amounts at 0°C. After 5 minutes, CH3I (90 mg, 0.64 mmol, 3 eq) was added, and the resulting solution was stirred at 0°C for 1 hour. The reaction mixture was then heated to room temperature. The reaction product was then quenched by adding water (5 mL) and acidified with 1N HCl until the pH was 3. The aqueous phase was extracted with ethyl acetate (5 mL x 3). The separated organic phase was dehydrated with Na2SO4, filtered, and evaporated to dryness to obtain 1-[4-chloro-2-[3-(2-methoxyethyl)phenyl]phenyl]sulfonyl-4-fluoropiperidine-4-carboxylic acid (100 mg, 0.22 mmol, 100%) as a yellow oily substance.

[0406] 1 H NMR (400 MHz, CDCl3) δ ppm 8.11 (d, J = 8.6 Hz, 1H), 7.47 (dd, J = 8.6, 2.2 Hz, 1H), 7.33 - 7.40 (m, 2H), 7.29 (s, 3H), 3.69 (t, J = 6.7 Hz, 2H), 3.38 (s, 3H), 3.10 (br d, J = 12.9 Hz, 2H), 2.95 (t, J = 6.7 Hz, 2H), 2.54 - 2.66 (m, 2H), 1.73 - 1.93 (m, 5H). C 21 H 23 For ClFNO5S, the calculated [M+H] value is 455, and the measured value is 456. compound 125 This is derived from 1-[4-chloro-2-[3-(2-methoxyethyl)phenyl]phenyl]sulfonyl-4-fluoropiperidine-4-carboxylic acid. compound 1 It was synthesized using the same method as in step 5.

[0407] compound 126It starts from [3-(hydroxymethyl)phenyl]boronic acid, compound 125 It was synthesized using the same method as before.

[0408] Scheme 25. Synthesis of the intermediate ethyl 1-[4-chloro-2-[3-[(E)-methoxyiminomethyl]phenyl]phenyl]phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate [ka]

[0409] Stage 1 Ethyl 1-(2-bromo-4-chlorophenyl)sulfonyl-4-fluoropiperidine-4-carboxylate (0.1 g, 0.23 mmol, 1 eq) was dissolved in 1,4-dioxane / water (v / v 3:1, 2.0 mL, 0.15 M). To this solution, 3-formylphenylboronic acid (0.04 g, 0.30 mmol, 1.3 eq), K2CO3 (1.9 g, 0.69 mmol, 3 eq), and Pd(dppf)Cl2 (500 mg, 0.023 mmol, 0.1 eq) were added. The reaction mixture was stirred under N2 at 90°C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water (30 mL) and extracted with RINKAN (30 mL x 3). The aqueous layers were combined and acidified with 1N HCl until pH=5, and then concentrated. Ethyl 1-[4-chloro-2-(3-formylphenyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (0.1 g, 0.26 mmol) was obtained as a yellow solid.

[0410] 1H NMR (400 MHz, CDCl3) δ ppm 10.08 (s, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.89 - 7.99 (m, 2H), 7.73 (d, J = 7.6 Hz, 1H), 7.59 - 7.65 (m, 1H), 7.54 (dd, J = 8.5, 2.1 Hz, 1H), 7.37 (d, J = 2.1 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.18 (br d, J = 13.3 Hz, 2H), 2.59 - 2.73 (m, 2H), 1.70 - 1.91 (m, 4H), 1.28 - 1.31 (m, 2H). Stage 2 Ethyl 1-[4-chloro-2-(3-formylphenyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (50 mg, 0.11 mmol, 1 eq) and O-methylhydroxylamine hydrochloride (11 mg, 0.13 mmol, 1.2 eq) were dissolved in methanol / DCM (v / v 1:1, 2 mL, 0.05 M). Na2CO3 (11 mg, 0.11 mmol, 1 eq) was added to the solution until the pH reached 7-8. AcOH (1 drop) was added to the solution, and the mixture was stirred at 20°C for 15 minutes. The reaction mixture was quenched with water (5 mL) and extracted with DCM (5 mL x 3). The organic layers were combined, washed with brine (12 mL), dehydrated with Na2SO4, filtered, concentrated, and purified by prep-TLC (PE:siRNA=3:1) to obtain ethyl 1-[4-chloro-2-[3-[(E)-methoxyiminomethyl]phenyl]phenyl]phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (36 mg, 0.07 mmol, 68%) as a colorless oil.

[0411] 1H NMR (400 MHz, CDCl3) δ ppm 8.07 - 8.11 (m, 2H), 7.60 - 7.65 (m, 2H), 7.49 (dd, J = 8.5, 2.0 Hz, 1H), 7.42 - 7.45 (m, 2H), 7.36 (d, J = 2.1 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.98 (s, 3H), 3.18 (br d, J = 12.9 Hz, 2H), 2.59 - 2.70 (m, 2H), 1.74 - 1.93 (m, 4H), 1.29 (t, J = 7.2Hz, 3H). compound 127 From ethyl 1-[4-chloro-2-[3-[(E)-methoxyiminomethyl]phenyl]phenyl]phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate, compound 1 It was synthesized using the same method as in steps 4 and 5.

[0412] Scheme 26. Synthesis of intermediates 1-[2-(2-chlorophenyl)-4-(2-hydroxyethyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylic acid and 1-[2-(2-chlorophenyl)-4-(1-hydroxyethyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylic acid [ka]

[0413] Stage 1A solution of ethyl 1-[2-(2-chlorophenyl)-4-vinylphenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (280 mg, 0.62 mmol, 1.0 eq) dissolved in THF (5 mL, 0.12 M) was added dropwise at 0°C to a solution of BH3.THF (0.93 mL, 0.93 mmol, 1 M, 1.5 eq). The mixture was stirred at 25°C for 1 hour. A solution of NaOH (1 M, 4 mL) was added to the mixture at 0°C, followed by the addition of H2O2 (0.53 mL, 6.2 mmol, 10 eq). The mixture was stirred at 0°C for 30 minutes, and then stirred at 25°C for 30 minutes. The mixture was diluted with aqueous Na2SO3 (40 mL) and extracted with DCM (20 mL). The organic phase was washed with saturated aqueous solution NaHCO3 (20 mL x 2), then washed with brine (20 mL), dehydrated with Na2SO4, filtered, and concentrated. Purification by prep-HPLC yielded 1-[2-(2-chlorophenyl)-4-(2-hydroxyethyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylic acid (50 mg, 0.12 mmol, 18%) as a white solid, and 1-[2-(2-chlorophenyl)-4-(1-hydroxyethyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylic acid (25 mg, 0.06 mmol, 9%) as a white solid.

[0414] compound 128 This is derived from 1-[2-(2-chlorophenyl)-4-(2-hydroxyethyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylic acid. compound 47 It was synthesized using the same method as in step 5.

[0415] compound 129 This is derived from 1-[2-(2-chlorophenyl)-4-(1-hydroxyethyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylic acid. compound 47 It was synthesized using the same method as in step 5.

[0416] Scheme 27. Synthesis of the intermediate ethyl 1-[2-(2-chlorophenyl)-4-(hydroxymethyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate [ka]

[0417] Stage 1 Ethyl 1-[4-bromo-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (50 mg, 0.099 mmol, 1 eq) was dissolved in DMF (5 mL, 0.12 M), to which Pd(PPh3)4 (69 mg, 0.059 mmol, 0.1 eq) and tributylstannyl methanol (191 mg, 0.59 mmol, 1 eq) were added. The solution was purged with N2 and stirred at 100°C for 12 hours. After cooling to room temperature, the reaction mixture was quenched with water (10 mL) and extracted with ELISA (20 mL x 2). The organic layers were combined, washed with brine (10 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by prep-TLC (PE:siRNA=3:1) to obtain ethyl 1-[2-(2-chlorophenyl)-4-(hydroxymethyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (70 mg, 0.15 mmol, 26%) as a colorless oil.

[0418] compound 130 It is derived from ethyl 1-[2-(2-chlorophenyl)-4-(hydroxymethyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate, compound 47 It was synthesized using the same method as in steps 4 and 5.

[0419] Scheme 28. Synthesis of the intermediate ethyl 1-((2'-chloro-5-(propa-1-in-1-yl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxylate [ka]

[0420] Stage 1Ethyl 1-[4-bromo-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (150 mg, 0.30 mmol, 1 eq) and propargyltrimethylsilane (67 mg, 0.59 mmol, 2 eqs) were dissolved in TEA (1 mL), and Pd(PPh3)2Cl2 (21 mg, 0.03 mmol, 0.1 eq) was added to the solution. The mixture was stirred at 70°C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated. The residue was quenched with NH4Cl (10 mL) and extracted with ELISA (3 mL × 2). The organic layers were combined and washed with 10 mL of brine, dehydrated with Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by prep-HPLC (neutral conditions) to obtain ethyl 1-((2'-chloro-5-(propa-1-in-1-yl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxylate (60 mg, 0.11 mmol, 95% yield) as a white solid.

[0421] Compound 131 It is derived from ethyl 1-((2'-chloro-5-(propa-1-in-1-yl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxylate, compound 47 It was synthesized using the same method as in steps 4 and 5.

[0422] Scheme 29. Synthesis of the intermediate ethyl 1-((2'-chloro-5-(oxetan-3-yl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxylate [ka]

[0423] Stage 1Ethyl 1-[4-bromo-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (200 mg, 0.39 mmol, 1 eq), 3-iodooxetane (146 mg, 0.79 mmol, 2 eq), and (4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl]phenyl]iridium(III) in dimethoxyethane (10 mL, 0.04 M) A mixture of hexafluorophosphate (4.4 mg, 0.004 mmol, 0.01 eq), dichloro(dimethoxyethane)nickel (0.4 mg, 0.002 mmol, 0.005 eq), sodium carbonate (84 mg, 0.79 mmol, 2 eq), tris(trimethylsilyl)silane (98 mg, 0.39 mmol, 1 eq), and 4,4-di-tert-butyl-2,2-dipyridyl (0.5 mg, 0.002 mmol, 0.005 eq) was stirred at 25°C for 16 hours under 34-watt blue LED irradiation. The reaction product was quenched with water (30 mL) and extracted with siRNA (20 mL x 2). The organic phase was combined, washed with brine (40 mL), dehydrated with Na2SO4, filtered, concentrated, and purified by column chromatography (PE:siRNA = 5:1 → 3:1) to obtain ethyl 1-((2'-chloro-5-(oxetan-3-yl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxylate (125 mg, 0.42 mmol, 52% yield) as a colorless oil.

[0424] 1H NMR (400MHz, CDCl3) δ ppm 8.07 (d, J = 8.2 Hz, 1H), 7.48 (dd, J = 1.8, 8.2 Hz, 1H), 7.44 - 7.40 (m, 1H), 7.39 - 7.35 (m, 1H), 7.29 - 7.27 (m, 2H), 7.19 (s, 1H), 5.05 (ddd, J = 2.3, 6.1, 8.3 Hz, 2H), 4.70 (dt, J = 1.9, 6.3 Hz, 2H), 4.26 - 4.12 (m, 3H), 3.20 (td, J = 2.2, 13.2 Hz, 1H), 3.04 (td, J = 2.3, 13.3 Hz, 1H), 2.85 (s, 1H), 2.59 (dt, J = 2.8, 12.8 Hz, 1H), 1.96 - 1.67 (m, 4H), 1.22 (t, J = 7.1 Hz, 3H). compound 132 It is derived from ethyl 1-((2'-chloro-5-(oxetan-3-yl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxylate, compound 47 It was synthesized using the same method as in steps 4 and 5.

[0425] Scheme 30. Synthesis of the intermediate methyl 4-methoxypiperidine-4-carboxylate. [ka]

[0426] Stage 1 To a solution of 1-tert-butoxycarbonyl-4-methoxypiperidine-4-carboxylic acid (500 mg, 1.93 mmol, 1 eq), HCl / 1,4-dioxane (4 M, 5 mL) was added, and the reaction mixture was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain 4-methoxypiperidine-4-carboxylic acid (300 mg, 98% yield) as a white solid.

[0427] 1¹H NMR (400 MHz, methanol-d4): δ ppm 2.96 (s, 3H), 2.95 (br s, 4H), 1.70 - 1.94 (m, 4H). Stage 2 4-methoxypiperidine-4-carboxylic acid (300 mg, 1.88 mmol, 1 eq) was dissolved in methanol (3 mL, 0.6 M), and thionyl chloride (404 mg, 3.39 mmol) was added to the solution. The reaction mixture was stirred at 25°C for 2 hours. After evaporating the solvent, methyl 4-methoxypiperidine-4-carboxylate (310 mg, 1.79 mmol, 95%) was obtained as a yellow solid.

[0428] 1 ¹H NMR (400 MHz, methanol-d4): δ ppm 2.05 - 2.25 (m, 4H), 3.09 - 3.28 (m, 4H), 3.28 (s, 3H), 3.79 (s, 3H). compound 133 In step 2, methyl 4-methoxypiperidine-4-carboxylate is used instead of ethyl 4-fluoropiperidine-4-carboxylate. compound 47 It was synthesized using the same method as before.

[0429] Scheme 31. Synthesis of the intermediate (E,4R)-4-amino-1-(3,3-difluoroazetidine-1-yl)penta-2-en-1-one [ka]

[0430] Stage 1Trimethyl phosphonoacetate (18.9 g, 104 mmol, 1.2 eq) was dissolved in THF (40 mL, 2.2 M), and LiHMDS (40 mL, 1.4 eq, 1 M) was added at -70°C and the mixture was stirred at -70°C for 1 hour. To this mixture, tert-butyl (R)-(1-oxopropan-2-yl)carbamate (15 g, 86.6 mmol, 1.0 eq) in THF (20 mL) was added, and the reaction product was stirred at -70°C for 1 hour. The reaction mixture was quenched with saturated aqueous solution NH4Cl (80 mL) and extracted with SiO2 (50 mL x 3). The organic layers were then combined, dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by FCC (PE:siRNA = 1:0-5:1) on silica, and then by prep-HPLC to obtain methyl (E,4R)-4-(tert-butoxycarbonylamino)penta-2-enoate (2.5 g, 10.9 mmol, 13%).

[0431] 1 H NMR (400 MHz, CDCl3) δ ppm 6.88 (dd, J = 5.0, 15.7 Hz, 1H), 5.91 (dd, J = 1.6, 15.7 Hz, 1H), 4.61 - 4.33 (m, 2H), 3.74 (s, 3H), 1.44 (s, 9H), 1.27 (d, J = 7.0 Hz, 3H). Stage 2Methyl(E,4R)-4-(tert-butoxycarbonylamino)penta-2-enoate (200 mg, 0.87 mmol, 1.0 eq) was dissolved in THF (3 mL, 0.22 M) and water (1 mL, 0.22 M), to which lithium hydroxide hydrate (110 mg, 2.62 mmol, 3.0 eq) was added. The reaction solution was stirred at 25°C for 12 hours. The reaction solution was extracted with ELISA (10 mL x 3) to adjust the pH to 4. The organic layers were combined and washed with brine (20 mL), dehydrated with Na2SO4, and filtered. The filtrate was concentrated to obtain (E,4R)-4-(tert-butoxycarbonylamino)penta-2-enoic acid (190 mg, 0.88 mmol, quantitative yield) as a colorless oil. This was used directly in the next step without purification.

[0432] 1 H NMR (400 MHz, CDCl3) δ ppm 6.98 (br dd, J = 4.4, 15.8 Hz, 1H), 5.92 (dd, J = 1.4, 15.7 Hz, 1H), 4.64 - 4.37 (m, 1H), 1.46 (s, 9H), 1.29 (d, J = 6.9 Hz, 3H). Stage 3 (E,4R)-4-(tert-butoxycarbonylamino)penta-2-enoic acid (1.5 g, 6.97 mmol, 1 eq), 3,3-difluoroazetidine HCl (1.1 g, 8.36 mmol, 1.2 eq), and T3P (3.3 g, 10.4 mmol, 1.5 eq) were dissolved in DCM (5 mL, 1.4 M), to which DIPEA (2.3 g, 17.4 mmol, 2.5 eq) was added. The reaction solution was stirred at 25°C for 2 hours. The reaction mixture was purified by column chromatography (PE:SiO=5:1) to obtain tert-butyl N-[(E,1R)-4-(3,3-difluoroazetidine-1-yl)-1-methyl-4-oxobuta-2-enyl]carbamate (1.4 g, 4.82 mmol, 69%) as a white solid.

[0433] 1H NMR (400 MHz, CDCl3) δ ppm 6.82 (br dd, J = 5.4, 15.1 Hz, 1H), 5.93 (dd, J = 1.2, 15.3 Hz, 1H), 4.59 - 4.30 (m, 6H), 1.45 (s, 9H), 1.28 (d, J = 6.9 Hz, 3H). C 13 H 20 For F2N2O3, the calculated [M+H] value is 290, and the measured value is 291. Stage 4 300 mg, 1.03 mmol, 1 eq of tert-butyl N-[(E,1R)-4-(3,3-difluoroazetidine-1-yl)-1-methyl-4-oxobuta-2-enyl]carbamate was dissolved in MeCN (5 mL, 0.21 M), and 4-methylbenzenesulfonic acid (890 mg, 5.17 mmol, 5.0 eq) was added to the solution. The reaction solution was stirred at 65°C for 12 hours. The reaction solution was concentrated to obtain 4-methylbenzenesulfonate (300 mg, 0.83 mmol, 80%) of (E,4R)-4-amino-1-(3,3-difluoroazetidine-1-yl)penta-2-en-1-one.

[0434] Intermediate (R,E)-4-amino-1-(3-fluoroazetidine-1-yl)penta-2-en-1-one It was synthesized in the same manner as (E,4R)-4-amino-1-(3,3-difluoroazetidine-1-yl)penta-2-en-1-one, using 3-fluoroazetidine HCl in step 3.

[0435] Intermediate (E)-4-amino-1-(3,3-difluoroazetidine-1-yl)-4-methylpenta-2-en-1-one It was synthesized in the same manner as (E,4R)-4-amino-1-(3,3-difluoroazetidine-1-yl)penta-2-en-1-one, using 1,1-dimethylethyl N-(1,1-dimethyl-2-oxoethyl)carbamate in step 1.

[0436] Intermediate (E)-4-amino-1-(3,3-difluoroazetidine-1-yl)buta-2-en-1-oneIt was synthesized in the same manner as (E,4R)-4-amino-1-(3,3-difluoroazetidine-1-yl)penta-2-en-1-one, using tert-butyl (2-oxoethyl)carbamate in step 1.

[0437] compound 282 In step 5, (E)-4-amino-1-(3,3-difluoroazetidine-1-yl)buta-2-en-1-one is used. compound 47 It was synthesized using the same method as before.

[0438] Scheme 32. Synthesis of 1-[2-(2-chlorophenyl)-4-(trifluoromethyl)phenyl]sulfonyl-4-fluoro-N-[(E,1R)-4-(3,3-difluoroazetidine-1-yl)-1-methyl-4-oxobuta-2-enyl]piperidine-4-carboxamide (compound 134) [ka]

[0439] Stage 1 2-Bromo-4-(trifluoromethyl)aniline (10 g, 41.7 mmol, 1 eq) was dissolved in HCl / acetic acid (v / v 3:1, 20 mL, 0.48 M), and sodium nitrite (3.2 g, 45.8 mmol, 1.1 eq) was added at 0°C. Mixture 1 was stirred at 0°C for 1 hour. SO2 was passed through acetic acid (60 mL, 0.69 M) at 0°C for 10 minutes, and then cuprous chloride (1.2 g, 12.5 mmol, 0.3 eq) was added. SO2 was passed through mixture 2 at 10 minutes. Then, mixture 1 was added to mixture 2 at 0°C. The resulting mixture was stirred at 0-20°C for 1 hour. The reaction mixture was quenched with H2O (100 mL) and extracted with MTBE (60 mL x 3). The organic layer was washed with NaHCO3 (50 mL x 2) and brine (30 mL). The organic layers were combined and separated, dehydrated with Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (PE) to obtain 2-bromo-4-(trifluoromethyl)benzenesulfonyl chloride (3.8 g, 11.7 mmol, 28%) as a yellow solid.

[0440] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.07 - 8.11 (m, 1H), 7.90 (s, 1H), 7.70 - 7.75 (m, 1H). Stage 2 Ethyl 4-fluoropiperidine-4-carboxylate hydrochloride (2.2 g, 10.5 mmol, 1 eq) was dissolved in DCM (40 mL, 0.26 M), to which TEA (3.2 g, 31.5 mmol, 3 eq) and 2-bromo-4-(trifluoromethyl)benzenesulfonyl chloride (3.4 g, 10.5 mmol, 1 eq) were added. The mixture was stirred at 20°C for 2 hours. The reaction mixture was poured into saturated aqueous solution NH4Cl (20 mL) and extracted with DCM (20 mL x 3). The organic layers were combined, washed with brine (20 mL x 2), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:HCl = 1:0-3:1) to obtain ethyl 1-[2-bromo-4-(trifluoromethyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (4.8 g, 10.4 mmol, 99%) as a white solid.

[0441] 1 H NMR (400 MHz, CDCl3) δ ppm 8.21 - 8.27 (m, 1H), 7.99 - 8.04 (m, 1H), 7.72 (dd, J = 8.3, 1.0 Hz, 1H), 4.24 - 4.30 (m, 2H), 3.80 - 3.87 (m, 2H), 3.21 (td, J = 12.8, 2.8 Hz, 2H), 2.12 - 2.30 (m, 2H), 2.07 - 2.10 (m, 1H), 2.02 (br s, 1H), 1.32 (t, J = 7.1 Hz, 3H). Stage 3Ethyl 1-[2-bromo-4-(trifluoromethyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (3.5 g, 7.57 mmol, 1 eq) was dissolved in 1,4-dioxane / water (v / v 10:1, 44 mL, 0.17 M). To this solution, under N2 conditions, 2-chlorophenylboronic acid (1.8 g, 11.4 mmol, 1.5 eq), sodium carbonate (2 g, 18.9 mmol, 2.5 eq), and tetrakis(triphenylphosphine)palladium (0) (0) were added. The mixture was stirred at 90°C for 16 hours. After cooling to room temperature, the reaction mixture was poured into saturated aqueous solution NH4Cl (30 mL) and extracted with SiO2 (40 mL x 3). The organic layers were combined, washed with brine (50 mL x 2), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:siRNA = 10:0-9:1) to obtain ethyl 1-[2-(2-chlorophenyl)-4-(trifluoromethyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate as a white solid.

[0442] 1 H NMR (400 MHz, CDCl3) δ ppm 8.30 (d, J = 8.3 Hz, 1H), 7.80 (dd, J = 8.3, 1.2 Hz, 1H), 7.59 (d, J = 1.3 Hz, 1H), 7.50 - 7.54 (m, 1H), 7.43 - 7.47 (m, 1H), 7.34 - 7.42 (m, 2H), 4.24 (q, J = 7.1 Hz, 2H), 3.22 3.35 (m, 1H), 3.03 - 3.15 (m, 1H), 2.96 (td, J = 12.8, 2.9 Hz, 1H), 2.59 - 2.72 (m, 1H), 1.93 - 2.13 (m, 2H), 1.78 - 1.91 (m, 2H), 1.30 (t, J = 7.2 Hz, 3H). C 21 H 20 For ClF4NO4S, the calculated [M+H] value was 493, and the measured value was 494. Stage 4 Ethyl 1-[2-(2-chlorophenyl)-4-(trifluoromethyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylate (3.5 g, 6.51 mmol, 1 eq) was dissolved in THF / water (v / v 3:1, 40 mL, 0.16 M), to which LiOH.H2O (820 mg, 19.5 mmol, 3 eq) was added. The mixture was stirred at 20°C for 3 hours. The pH was adjusted to approximately 4 with HCl. The mixture was extracted with ELISA (20 mL x 3). The organic layers were combined and washed with brine (30 mL x 2), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain 1-[2-(2-chlorophenyl)-4-(trifluoromethyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylic acid (3 g, 6.44 mmol, 99%) as a yellow solid.

[0443] 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.26 (d, J = 8.4 Hz, 1H), 8.06 (dd, J = 8.4, 1.4 Hz, 1H), 7.74 (d, J = 1.1 Hz, 1H), 7.54 - 7.61 (m, 1H), 7.38 - 7.51 (m, 3H), 3.16 (br dd, J = 12.2, 1.8 Hz, 2H), 2.59 - 2.83 (m, 2H), 1.75 - 1.97 (m, 4H). Stage 5To a solution of 1-[2-(2-chlorophenyl)-4-(trifluoromethyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylic acid (100 mg, 0.21 mmol, 1 eq) dissolved in DCM (2 mL, 0.11 M), (E,4R)-4-amino-1-(3,3-difluoroazetidine-1-yl)penta-2-en-1-one 4-methylbenzene sulfonate (156 mg, 0.43 mmol, 2 eq), T3P (205 mg, 0.32 mmol, 1.5 eq), and DIPEA (69 mg, 0.54 mmol, 2.5 eq) were added. The mixture was stirred at 25°C for 1 hour. The reaction product is purified by prep-TLC (PE:HCl=1:2) to obtain 1-[2-(2-chlorophenyl)-4-(trifluoromethyl)phenyl]sulfonyl-4-fluoro-N-[(E,1R)-4-(3,3-difluoroazetidine-1-yl)-1-methyl-4-oxobuta-2-enyl]piperidine-4-carboxamide ( compound 134 (27 mg, 0.04 mmol, 19%) was obtained as a white solid.

[0444] 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.34 (dd, J = 1.7, 8.2 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 8.06 (dd, J = 1.4, 8.4 Hz, 1H), 7.74 (s, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.52 - 7.39 (m, 3H), 6.66 (dd, J = 5.9, 15.5 Hz, 1H), 5.93 (dd, J = 1.2, 15.4 Hz, 1H), 4.62 (br t, J = 10.9 Hz, 2H), 4.56 - 4.48 (m, 1H), 4.31 (br t, J = 11.4 Hz, 2H), 3.24 - 3.18 (m, 2H), 2.78 (dt, J = 2.6, 12.6 Hz, 1H), 2.69 - 2.58 (m, 1H), 2.06 - 1.75 (m, 4H), 1.19 (d, J = 7.0Hz, 3H). C 27 H26 For ClF6N3O4S, the calculated [M+H] value is 637; the measured value is 638. Compound 135-Compound 138 Using the appropriate starting aniline, compound 134 It was synthesized using the same method as before.

[0445] compound 139 In step 2, methyl 4-methoxypiperidine-4-carboxylate is used instead of ethyl 4-fluoropiperidine-4-carboxylate, and in step 5, (R,Z)-4-(methylsulfonyl)buta-3-en-2-amine is used. compound 134 It was synthesized using the same method as before.

[0446] compound 216 In step 5, (R,E)-4-amino-1-(3-fluoroazetidine-1-yl)penta-2-en-1-one is used. compound 134 It was synthesized using the same method as before.

[0447] compound 249 In step 5, (E)-4-amino-1-(3,3-difluoroazetidine-1-yl)-4-methylpenta-2-en-1-one is used. compound 134 It was synthesized using the same method as before.

[0448] compound 283 In step 5, (E)-4-amino-1-(3,3-difluoroazetidine-1-yl)buta-2-en-1-one is used. compound 134 It was synthesized using the same method as before.

[0449] Intermediate: 1-[4-acetyl-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylic acid It was synthesized by the same method as 1-[2-(2-chlorophenyl)-4-(trifluoromethyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylic acid.

[0450] Scheme 33. Synthesis of the intermediate 1-[2-(2-chlorophenyl)-4-(1-hydroxyethyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylic acid [ka]

[0451] Stage 1 1-[4-acetyl-2-(2-chlorophenyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylic acid (120 mg, 0.27 mmol, 1 eq) was dissolved in methanol (2 mL, 0.14 M), and sodium borohydride (50 mg, 1.32 mmol, 4.8 eq) was added to the solution. The mixture was stirred at 25°C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. This residue was purified by prep-HPLC to obtain 1-[2-(2-chlorophenyl)-4-(1-hydroxyethyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylic acid (70 mg, 0.16 mmol, 58%) as a white solid.

[0452] 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.94 (d, J = 8.3 Hz, 1H), 7.61 (dd, J = 8.2, 1.3 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.31 - 7.46 (m, 3H), 7.26 (d, J = 1.5 Hz, 1H), 5.33 - 5.53 (m, 1H), 4.76 - 4.89 (m, 1H), 3.99 - 4.22 (m, 1H), 3.03 - 3.13 (m, 2H), 2.61 - 2.72 (m, 1H), 2.53 - 2.59 (m, 1H), 1.59 - 1.99 (m, 4H), 1.35 (dd, J = 6.5, 2.1 Hz, 3H). compound 140 This uses 1-[2-(2-chlorophenyl)-4-(1-hydroxyethyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylic acid, compound 134 It was synthesized using the same method as in step 5.

[0453] Intermediate (2R,4S)-1-((2'-chloro-5-(1-hydroxyethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-2-methylpiperidine-4-carboxylic acidIt was synthesized using (2R,4S)-1-((5-acetyl-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-2-methylpiperidine-4-carboxylic acid in the same manner as 1-[2-(2-chlorophenyl)-4-(1-hydroxyethyl)phenyl]sulfonyl-4-fluoropiperidine-4-carboxylic acid.

[0454] compound 25 2 uses (2R,4S)-1-((2'-chloro-5-(1-hydroxyethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-2-methylpiperidine-4-carboxylic acid, compound 134 It was synthesized using the same method as in step 5.

[0455] Scheme 34. Synthesis of the intermediate 2'-chloro-5-methoxy-[1,1'-biphenyl]-2-sulfonyl chloride [ka]

[0456] Stage 1 To a mixture of 1-bromo-2-iodo-4-methoxybenzene (45 g, 144 mmol, 1 eq) in 1,4-dioxane / water (v / v 10:1, 550 mL, 0.26 M), 2-chlorophenylboronic acid (2.7 g, 173 mmol, 1.2 eq), K2CO3 (50 g, 364 mmol, 2.5 eq), and Pd(dppf)Cl2 (3.6 g, 12.2 mmol, 0.08 eq) were added. The mixture was stirred under N2 at 90°C for 12 hours. After cooling to room temperature, the reaction mixture was diluted with water (300 mL) and extracted with siRNA (300 mL x 2). The organic layers were combined, washed with brine (300 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:SiO=1:0-10:1) to obtain 1-bromo-2-(2-chlorophenyl)-4-methoxybenzene (40g, 269 mmol, 94%) as a yellow oil.

[0457] Stage 21-Bromo-2-(2-chlorophenyl)-4-methoxybenzene (40 g, 134 mmol, 1.0 eq) was dissolved in THF (400 mL, 0.34 M), and n-BuLi (100 mL, 252 mmol, 1.9 eq) was added at -78°C and the mixture was stirred for 30 minutes. To this solution, a solution of SO2 dissolved in THF (saturated 400 mL) was added. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated and the solvent was removed. n-Hexane was added to the residue and the mixture was stirred for 10 minutes. The mixture was filtered, and the filtered cake was dissolved in AcOH (150 mL), after which NCS (20 g, 151 mmol, 1.2 eq) was added. The resulting reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was poured into water (600 mL) and extracted with ELISA (600 mL x 3). The organic layers were combined, washed with brine (200 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:Â=1:0-95:5). 2'-Chloro-5-methoxy-[1,1'-biphenyl]-2-sulfonyl chloride (35 g, 110.34 mmol, 41% yield) was obtained as a yellow oil.

[0458] Scheme 35. Synthesis of the intermediate 2-(2-chlorophenyl)-4-(trifluoromethyl)benzenesulfonyl chloride [ka]

[0459] Stage 12-Bromo-4-(trifluoromethyl)aniline (1.0 g, 4.17 mmol, 1.0 eq) was dissolved in dimethoxyethane / water (v / v 1:1, 20 mL, 0.21 M). To this solution, 2-chlorophenylboronic acid (0.80 g, 4.99 mmol, 1.2 eq), sodium carbonate (1.3 g, 12.5 mmol, 3.0 eq), and Pd(PPh3)4 (481 mg, 0.417 mmol, 0.1 eq) were added. The reaction mixture was placed under N2 and stirred at 80°C for 16 hours. After cooling to room temperature, the reaction mixture was quenched with water (20 mL) and extracted with SiO2 (30 mL x 3). The organic phases were combined, washed with brine (20 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (PE:siRNA = 1:0 → 10:1) on silica to obtain 2-(2-chlorophenyl)-4-(trifluoromethyl)aniline (670 mg, 2.47 mmol, 59% yield) as a yellow oily substance.

[0460] 1 H NMR (400 MHz, CDCl3) δ ppm 7.56 - 7.50 (m, 1H), 7.44 (dd, J = 8.5, 1.7 Hz, 1H), 7.40 - 7.30 (m, 4H), 6.81 (d, J = 8.4 Hz, 1H). Stage 2A solution of 2-(2-chlorophenyl)-4-(trifluoromethyl)aniline (300 mg, 1.10 mmol, 1.0 eq) dissolved in HCl / acetic acid (v / v 3:1, 1.3 mL, 2.8 M) was added dropwise at 0°C to a solution of sodium nitrite (84 mg, 1.21 mmol, 1.1 eq) dissolved in water (0.10 mL, 2.8 M). This mixture 1 was stirred at 0°C for 1 hour. In a separate beaker, glacial acetic acid (3.0 mL) was vigorously stirred while sulfur dioxide gas was passed through it for 20 minutes. Cuprous chloride (32.8 mg, 0.331 mmol, 0.3 eq) was added, and the sulfur dioxide gas was continued until the yellowish-green suspension turned almost black and most of the solid was dissolved (approximately 30 minutes). Mixture 1 was added to this solution, and the reaction product was heated to 20°C. The reaction mixture was stirred for 2 hours, then poured into water (20 mL) and extracted with MTBE (10 mL x 2). The organic phases were combined and washed with saturated aqueous solution NaHCO3 (50 mL), dehydrated with Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain 2-(2-chlorophenyl)-4-(trifluoromethyl)benzenesulfonyl chloride (200 mg, 0.563 mmol, 51% yield) as a yellow oil.

[0461] 1 H NMR (400 MHz, CDCl3) δ ppm 8.39 (d, J = 8.4 Hz, 1H), 7.93 (dd, J = 1.4, 8.5 Hz, 1H), 7.76 - 7.66 (m, 2H), 7.61 - 7.50 (m, 3H). The intermediates 2-(2-chlorophenyl)-4-cyanobenzenesulfonyl chloride, 5-bromo-2'-chloro-[1,1'-biphenyl]-2-sulfonyl chloride, and 5-bromo-3'-chloro-[1,1'-biphenyl]-2-sulfonyl chloride were synthesized in the same manner as 2-(2-chlorophenyl)-4-(trifluoromethyl)benzenesulfonyl chloride, using appropriate aniline and boronic acids in step 1.

[0462] Scheme 36. Synthesis of the intermediate rac-(2R,4S)-1-tert-butoxycarbonyl-4-fluoro-2-methylpiperidine-4-carboxylic acid [ka]

[0463] Step 1. 2-methylpyridine-4-carboxylic acid (50 g, 365 mmol, 1.0 eq) was dissolved in methanol (500 mL, 0.73 M), and SOCl2 (50 mL) was added at 0°C. The reaction solution was stirred at 60°C for 6 hours. The reaction solution was concentrated to obtain methyl 2-methylpyridine-4-carboxylate (55 g, 364 mmol, 100%) as a white solid. The crude product was used directly in the next step.

[0464] Stage 2 Methyl 2-methylpyridine-4-carboxylate (50 g, 331 mmol, 1 eq) was dissolved in methanol (400 mL, 0.83 M). Ditert-butyl dicarbonate (145 g, 663 mmol, 2.0 eq) and PtO2 (3.5 g) were added under Ar. The reaction solution was stirred at 25°C for 12 hours under H2 (45 psi). The reaction solution was filtered, and the filtrate was concentrated to obtain methyl 2-methylpiperidine-4-carboxylate (50 g, 318 mmol, 96%) as a white solid.

[0465] Stage 3 Methyl 2-methylpiperidine-4-carboxylate (50 g, 318 mmol, 1 eq) was dissolved in THF (300 mL, 1.1 M), and di-tert-butyl dicarbonate (69 g, 318 mmol, 1.0 eq) and TEA (133 mL, 954 mmol, 3 eq) were added at 0°C. The reaction solution was stirred at 0-25°C for 12 hours. The reaction solution was concentrated. The crude product was purified by column chromatography (PE:siRNA = 1:0-5:1) to obtain 1-(tert-butyl)4-methyl 2-methylpiperidine-1,4-dicarboxylate (52 g, 202 mmol, 64%) as a colorless oil.

[0466] 1H NMR (400 MHz, CDCl3, 298 K) δ ppm 4.21 - 4.15 (m, 1H), 3.87 - 3.79 (m, 1H), 3.71 (s, 3H), 3.10 (ddd, J = 4.1, 12.0, 13.9 Hz, 1H), 2.59 (t, J = 5.7 Hz, 1H), 2.03 - 1.87 (m, 3H), 1.81 - 1.69 (m, 1H), 1.46 (s, 9H), 1.08 (d, J = 6.9 Hz, 3H). Stage 4 1-tert-butyl 4-methyl 2-methylpiperidine-1,4-dicarboxylate (10 g, 38.9 mmol, 1 eq) was dissolved in THF (300 mL), and LDA (39 mL, 77.7 mmol, 2 eq) was added dropwise at -30°C. The mixture was stirred at -30°C for 1.5 hours. N-fluorobenzenesulfonimide (18.4 g, 58.3 mmol, 1.5 eq) in THF (10 mL) was added dropwise at -30°C. The resulting solution was stirred at -30-15°C for 2 hours. The reaction product was quenched with aqueous saturated NH4Cl (200 mL) and extracted with ELISA (200 mL x 2). The organic phases were combined, washed with brine (40 mL x 2), dehydrated with Na2SO4, filtered, concentrated, purified by column chromatography (PE:siRNA = 1:0-3:1), and then purified by prep-HPLC to obtain 1-tert-butyl 4-methyl 4-fluoro-2-methylpiperidine-1,4-dicarboxylate (8 g, 29.10 mmol, 75% yield) as a white solid.

[0467] Stage 51-tert-butyl 4-methyl 4-fluoro-2-methylpiperidine-1,4-dicarboxylate (20 g, 72.6 mmol, 1.0 eq) and LiOH.H2O (9.1 g, 218 mmol, 3.0 eq) were dissolved in THF (200 mL, 0.27 M) and water (70 mL, 0.27 M). The solution was stirred at 25°C for 2 hours, and the mixture was extracted with ELISA (20 mL). The aqueous phase was adjusted to pH 2 with 1 M HCl, diluted with water (50 mL), and extracted with ELISA (70 mL x 4). The organic phases were combined and concentrated to obtain rac-(2R,4S)-1-tert-butoxycarbonyl-4-fluoro-2-methylpiperidine-4-carboxylic acid (19 g, 72.7 mmol, 100%) as a colorless oil. This was used directly in the next step.

[0468] 1 H NMR (400 MHz, CDCl3, 298 K) δ ppm 4.26 - 4.17 (m, 1H), 4.01 - 3.91 (m, 1H), 3.24 - 3.14 (m, 1H), 2.33 - 2.21 (m, 1H), 2.16 - 2.13 (m, 1H), 2.04 -1.88 (m, 2H), 1.47 (s, 9H), 1.20 (d, J = 6.8 Hz, 3H). Scheme 37. Synthesis of the intermediate (2R,4S)-4-fluoro-2-methyl-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide [ka]

[0469] Stage 1rac-(2R,4S)-1-tert-butoxycarbonyl-4-fluoro-2-methylpiperidine-4-carboxylic acid (42 g, 161 mmol, 1.0 eq) and (R,Z)-4-(methylsulfonyl)buta-3-en-2-amine, TsOH salt (56.8 g, 177 mmol, 1.1 eq) were dissolved in DMF (420 mL, 0.38 M). HATU (73.3 g, 193 mmol, 1.2 eq) and DIPEA (62.3 g, 482 mmol, 3 eq) were added dropwise at 25°C. The reaction solution was stirred at 25°C for 0.5 hours. The reaction solution was quenched with water (500 mL) and extracted with ELISA (100 mL x 4). The organic phases were combined, washed with brine (300 mL), dehydrated with Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography to obtain tert-butyl (rac-2R,4S)-4-fluoro-2-methyl-4-(((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)carbamoyl)piperidine-1-carboxylate (75 g).

[0470] Stage 2 tert-butyl (rac-2R,4S)-4-fluoro-2-methyl-4-(((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)carbamoyl)piperidine-1-carboxylate was separated by SFC (stationary phase: IC (25 × 5 cm); mobile phase: 35% iPrOH / CO2 (containing 0.1% NH4OH)) to obtain tert-butyl (2S,4R)-4-fluoro-2-methyl-4-[[(Z,1R)-1-methyl-3-methylsulfonyl-allyl]carbamoyl]piperidine-1-carboxylate (R t =8.85 min, 33 g, 84.1 mmol) was obtained as a colorless oily substance, and tert-butyl (2R,4S)-4-fluoro-2-methyl-4-[[(Z,1R)-1-methyl-3-methylsulfonyl-allyl]carbamoyl]piperidine-1-carboxylate (R t (9.95 min, 33 g, 84.1 mmol) was obtained as a colorless oily substance.

[0471] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.43 (dd, J = 1.9, 7.7 Hz, 1H), 6.47 (d, J = 11.1 Hz, 1H), 6.30 (dd, J = 9.6, 11.1 Hz, 1H), 5.45 - 5.30 (m, 1H), 3.97 (td, J = 6.5, 9.2 Hz, 1H), 3.80 - 3.66 (m, 1H), 3.16 - 3.05 (m, 4H), 2.21 - 2.05 (m, 1H), 2.02 - 1.94 (m, 1H), 1.89 - 1.69 (m, 2H), 1.23 (d, J = 6.9 Hz, 3H), 1.11 (d, J = 6.5 Hz, 3H). Stage 3 tert-butyl (2R,4S)-4-fluoro-2-methyl-4-[[(Z,1R)-1-methyl-3-methylsulfonyl-allyl]carbamoyl]piperidine-1-carboxylate (33 g, 84.1 mmol, 1 eq) was dissolved in MeCN (330 mL, 0.25 M), to which p-toluenesulfonic acid monohydrate (17.6 g, 92.5 mmol, 1.1 eq) was added, and the mixture was stirred at 60°C for 12 hours. The mixture was concentrated to obtain crude (2R,4S)-4-fluoro-2-methyl-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide 4-methylbenzenesulfonic acid (35.5 g, 76.4 mmol, 91% yield) as a colorless oil. This was used directly in the next step.

[0472] Intermediate (2R,4S)-N-((R,E)-5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoro-2-methylpiperidine-4-carboxamideThe compound was synthesized by separating rac-(2R,4S)-1-tert-butoxycarbonyl-4-fluoro-2-methylpiperidine-4-carboxylic acid by chiral SFC to obtain (2R,4S)-1-tert-butoxycarbonyl-4-fluoro-2-methylpiperidine-4-carboxylic acid and (2S,4R)-1-tert-butoxycarbonyl-4-fluoro-2-methylpiperidine-4-carboxylic acid, using the same method as for (2R,4S)-4-fluoro-2-methyl-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide. The title compound was obtained by coupling with (E,4R)-4-amino-1-(3,3-difluoroazetidine-1-yl)penta-2-en-1-one and removing tert-butyl carbamate.

[0473] Scheme 38. Synthesis of (2R,4S)-1-((2'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-2-methyl-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide (compound 141) [ka]

[0474] Stage 1A solution of 4-methylbenzenesulfonate (35.5 g, 76.4 mmol, 1 eq) of (2R,4S)-4-fluoro-2-methyl-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide was dissolved in DCM (500 mL, 0.15 M), to which DIPEA (29.6 g, 229 mmol, 3 eq) was added. A solution of 2-(2-chlorophenyl)-4-methoxybenzenesulfonyl chloride (29 g, 91.7 mmol, 1.2 eq) dissolved in DCM (15 mL) was added dropwise at 0°C. The mixture was stirred at 30°C for 12 hours. The reaction mixture was poured into water (300 mL) and extracted with DCM (100 mL x 3). The organic layers were combined and washed with brine (100 mL x 2), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:HCl = 10:0-3:7), then suspended in MTBE (60 mL) to obtain (2R,4S)-1-[2-(2-chlorophenyl)-4-methoxyphenyl]sulfonyl-4-fluoro-2-methyl-N-[(Z,1R)-1-methyl-3-methylsulfonyl-allyl]piperidine-4-carboxamide ( compound 141 (20.9 g, 36.1 mmol, 47%) was obtained as a white solid.

[0475] 1H NMR (400 MHz, DMSO-d6, 298 K) δ ppm 8.41 - 8.30 (m, 1H), 7.98 (dd, J = 2.2, 8.9 Hz, 1H), 7.61 - 7.51 (m, 1H), 7.45 - 7.30 (m, 3H), 7.16 (td, J = 3.2, 8.9 Hz, 1H), 6.88 - 6.80 (m, 1H), 6.44 (d, J = 11.1 Hz, 1H), 6.26 (dd, J = 9.6, 11.0 Hz, 1H), 5.34 (td, J = 7.8, 15.7 Hz, 1H), 3.85 (s, 3H), 3.43 - 3.33 (m, 1H), 3.12 (d, J = 2.5 Hz, 3H), 2.96 - 2.74 (m, 1H), 2.66 - 2.58 (m, 1H), 2.36 - 2.23 (m, 1H), 2.13 - 1.52 (m, 4H), 1.20 (d, J = 6.9 Hz, 3H), 1.09 - 0.99 (m, 3H). C 25 H 30 For ClFN2O6S2, the calculated [M+H] value is 572; the measured value is 573. Compound 142-Compound 145 Starting with a suitable sulfonyl chloride, compound 141 It was synthesized using the same method as before.

[0476] Compound 151-Compound 155 From (2R,4S)-N-((R,E)-5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoro-2-methylpiperidine-4-carboxamide and a suitable sulfonyl chloride, compound 141 It was synthesized using the same method as before.

[0477] Scheme 39. Synthesis of 1-[2-(2-chlorophenyl)-4-methoxyphenyl]sulfonyl-4-methoxy-N-[(Z,1R)-1-methyl-3-methylsulfonylallyl]piperidine-4-carboxamide (compound 146) [ka]

[0478] Stage 11-tert-butoxycarbonyl-4-methoxypiperidine-4-carboxylic acid (400 mg, 1.54 mmol, 1 eq) and (R,Z)-4-(methylsulfonyl)buta-3-en-2-amine, TsOH salt (545 mg, 1.7 mmol, 1.1 eq) were dissolved in DCM (2 mL, 0.77 M). To this solution, DIPEA (598 mg, 4.6 mmol, 3 eq) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphospholinane-2,4,6-trioxide (1.5 g, 2.3 mmol, 1.5 eq) were added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with water (5 mL), extracted with DCM (5 mL x 2), dehydrated with Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:SiO=1:0-1:1) to obtain tert-butyl 4-methoxy-4-[[(Z,1R)-1-methyl-3-methylsulfonyl-allyl]carbamoyl]piperidine-1-carboxylate (420 mg, 1.1 mmol, 70% yield) as a colorless oil.

[0479] 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.16 (d, J = 8.0 Hz, 1H), 6.44 (d, J = 11.4 Hz, 1H), 6.29 (dd, J = 9.5, 11.1 Hz, 1H), 5.42 - 5.30 (m, 1H), 3.69 (br d, J = 9.3 Hz, 2H), 3.11 (d, J = 6.0 Hz, 3H), 3.04 - 2.90 (m, 2H), 1.99 (s, 3H), 1.75 - 1.62 (m, 4H), 1.39 (s, 9H), 1.22 - 1.19 (m, 3H). Stage 2420 mg, 1.1 mmol, 1 eq of tert-butyl 4-methoxy-4-[[(Z,1R)-1-methyl-3-methylsulfonyl-allyl]carbamoyl]piperidine-1-carboxylate (420 mg, 1.1 mmol, 1 eq) was dissolved in MeCN (5 mL, 0.22 M), and p-toluenesulfonic acid monohydrate (225 mg, 1.2 mmol, 1.1 eq) was added to the solution. The mixture was stirred at 65°C for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain 4-methoxy-N-[(Z,1R)-1-methyl-3-methylsulfonyl-allyl]piperidine-4-carboxamide 4-methylbenzenesulfonate (180 mg, 1.04 mmol, 96% yield) as a yellow solid.

[0480] Stage 3 4-Methoxy-N-[(Z,1R)-1-methyl-3-methylsulfonyl-allyl]piperidine-4-carboxamide and 4-methylbenzenesulfonic acid (200 mg, 0.43 mmol, 1 eq) were dissolved in DCM (1 mL, 0.43 M). To this solution, 2-(2-chlorophenyl)-4-methoxybenzenesulfonyl chloride (205 mg, 0.65 mmol, 1.5 eq) and DIPEA (167 mg, 1.3 mmol, 3 eq) were added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. This residue was purified by prep-HPLC to obtain 1-[2-(2-chlorophenyl)-4-methoxyphenyl]sulfonyl-4-methoxy-N-[(Z,1R)-1-methyl-3-methylsulfonyl-allyl]piperidine-4-carboxamide ( compound 146 (47 mg, 0.08 mmol, 19% yield) was obtained as a white solid.

[0481] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.11 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.9 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.44 - 7.31 (m, 3H), 7.18 (dd, J = 2.7, 9.0 Hz, 1H), 6.83 (d, J = 2.6 Hz, 1H), 6.43 (d, J = 11.2 Hz, 1H), 6.30 - 6.23 (m, 1H), 5.40 - 5.28 (m, 1H), 3.85 (s, 3H), 3.11 (s, 3H), 3.02 (s, 3H), 3.00 - 2.92 (m, 2H), 2.65 - 2.52 (m, 2H), 1.74 - 1.56 (m, 4H), 1.19 (d, J = 6.9 Hz, 3H). C 25 H 31 For ClN2O7S2, the calculated [M+H] value is 570; the measured value is 571. Intermediate 4-fluoro-N-[(Z,1R)-1-methyl-3-methylsulfonyl-allyl]piperidine-4-carboxamide, 4-methylbenzenesulfonate It was synthesized by the same method as 4-methoxy-N-[(Z,1R)-1-methyl-3-methylsulfonyl-allyl]piperidine-4-carboxamide and 4-methylbenzenesulfonate.

[0482] Scheme 40. Synthesis of the intermediates (2*R,4*R)-4-fluoro-1-[(4-methoxyphenyl)methyl]-2-methyl-N-[(Z,1R)-1-methyl-3-methylsulfonyl-allyl]piperidine-4-carboxamide and (2*S,4*S)-4-fluoro-1-[(4-methoxyphenyl)methyl]-2-methyl-N-[(Z,1R)-1-methyl-3-methylsulfonyl-allyl]piperidine-4-carboxamide [ka]

[0483] Stage 1Methyl 2-methylpiperidine-4-carboxylate (2.6 g, 13.4 mmol, 1 eq) was dissolved in DMF (260 mL, 0.06 M), to which K2CO3 (5.6 g, 40.3 mmol, 3 eq) and 4-methoxybenzyl chloride (2.5 g, 16.1 mmol, 1.2 eq) were added. The reaction mixture was stirred at 25...

Claims

1. Equation (I): 【Chemistry 1】 [During the ceremony, Z is C (=O) or S (=O) ２ And; Ring A consists of phenyl, a 5-10 membered heteroaryl, and C ３ -C ８ Cycloalkyl, C ８ -C ９ It is a spirocyclyl or a 5- to 8-membered heterocycloalkyl; Y is N, CH, or CR １ And; Each R １ is, independently, halogen, -CN, -OH, -OR ａ , -SH, -SR ａ , -NO ２ , -N(R ｂ ) ２ , -C(=O)R ａ , -C(=O)OR ａ , -C(=O)NR ａ R[[ID=​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ Each R ２ These are, independently, halogen, -CN, -OH, -OR ａ -SH, -SR ａ , -NO ２ , -N(R ｂ ) ２ , -S (=O) ２ R ａ , -C(=O)R ａ , -C (=O) OR ａ , -C(=O)NR ａ R ｂ , oxo (=O), C may be substituted. １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkyl deuterated, optionally substituted C ２ -C ６ Alkenyl, C may be substituted. ２ -C ６ Alkynyl, C may be substituted. １ -C ６ Alkylamino, optionally substituted C １ -C ６ Haloalkyl, optionally substituted C １ -C ６ Hydroxyalkyl, optionally substituted C ３ -C ６ A cycloalkyl, an optionally substituted arylalkyl, or an optionally substituted 4- to 6-membered heterocycloalkyl; Or, Two R's ２ They combine with the atom(s) they are bonded to, C ３ -C ５ Forming a cycloalkyl, 4- to 5-membered heterocycloalkyl, or 5-membered heteroaryl ring; Each R ３ These are, independently, halogen, -CN, -OH, -OR ａ , C １ -C ６ Alkyl, C １ -C ６ Alkyl deuterated or C １ -C ６ It is a haloalkyl; R ４ H, halogen, -OH, -OR ａ or C １ -C ６ It is alkyl; R Ａ teeth, 【Chemistry 2】 And here, R ５ H, and C which may be substituted. １ -C ３ Alkyl, optionally substituted C １ -C ３ Haloalkyl or optionally substituted C １ -C ３ It is a hydroxyalkyl group; R ６ａ and R ６ｂ are each independently H, -CN, -C(=O)OR ７ , -C(=O)N(R ７ ), ２ , -S(=O)R ７ , -S(=O) ２ R ７ or -S(=O)(=NH)R ７ where; Each R ７ C may be substituted independently. １ -C ６ Alkyl, optionally substituted C ３ -C ６ A cycloalkyl or optionally substituted 4- to 6-membered heterocycloalkyl ring; Or, Two R's ７ They combine with the nitrogen atom to which they are bonded to form a substituted or otherwise substituted 4- to 5-membered heterocycloalkyl ring; Or, R ５ and R ７ combine together with the atoms to which they are attached to form a 5-membered heterocycloalkyl ring; R ６ｃ is H or -CN; Or, R ６ｃ and R ７ They combine with the atoms to which they are bonded to form a four-membered heterocycloalkyl ring; R ５ａ is H; or R ５ａ and R ６ｃ They combine with the nitrogen atom to which they are bonded to form a four-membered heterocycloalkyl ring; or R ５ａ It does not exist, and R ６ｃ R Ａ It directly bonds to the nitrogen atom to which it is bonded, forming a four-membered heterocyclic ring; Or, R ５ａ and R ５ Together with the nitrogen and carbon atoms to which they are bonded, they form a four-membered heterocyclic ring; R ５ｂ is H or C １ -C ３ It is alkyl; Each R ａ These are H and C, independently. １ -C ６ Alkyl, C １ -C ６ Alkyl deuterated, C １ -C ６ Haloalkyl, C １ -C ６ Heteroalkyl, C ２ C ６ Alkenil, C ２ C ６ Alkinyl, C ３ C ６ Cycloalkyl, C ３ C ６ Heterocycloalkyl, C ５ C ８ Ariel, C ５ C ８ Heteroaryl, -C １ -C ６ Alkyl (aryl), -C １ -C ６ Alkyl (heteroaryl), -C １ -C ６ Alkyl (cycloalkyl) or -C １ -C ６ Alkyl (heterocycloalkyl); where each alkyl, deuterated alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), and alkyl(heterocycloalkyl) independently comprises 1, 2, or 3 halogens, -OH, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl or C １ -C ６ It is also acceptable if it is substituted with an alkoxy; Each R ｂ These are H and C, independently. １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ The alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently one, two, or three halogens, -OH, C １ -C ６ Alkyl or C １ -C ６ It may also be substituted with a haloalkyl; Or, Two R's on the nitrogen atom ｂ The groups, together with the nitrogen atoms to which they are bonded, form heterocycloalkyl (which is 1, 2, or 3 C atoms). １ -C ６ Alkyl or C １ -C ６ Forms a haloalkyl group (which may be substituted); n1 and n2 are independently 0, 1, 2, or 3; p is 0, 1, 2, or 3; q is 0, 1, or 2; and, t is 0, 1, 2, or 3. A compound represented by or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof.

2. R ４ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a halogen.

3. R ５ａ and R ５ｂ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein each of these is H.

4. R ５ However, C １ -C ３ A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is alkyl.

5. R ５ However, CH ３ or CH ２ CH ３ The compound according to claim 4 or a pharmaceutically acceptable salt thereof.

6. R ５ａ and R ６ｃ The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein they combine with the nitrogen atom to which they are bonded to form a four-membered heterocycloalkyl ring.

7. The aforementioned compound is of formula (Ia): 【Transformation 3】 [During the ceremony, Z is C (=O) or S (=O) ２ And; Ring A consists of phenyl, a 5-10 membered heteroaryl, and C ３ -C ８ Cycloalkyl, C ８ -C ９ It is a spirocyclyl or a 5- to 8-membered heterocycloalkyl; Y is CH or CR １ And; Each R １ These are, independently, halogen, -CN, -OH, -OR ａ -SH, -SR ａ , -NO ２ , -N(R ｂ ) ２ , -C(=O)R ａ , -C (=O) OR ａ , -C(=O)NR ａ R ｂ C may be substituted. １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, C may be substituted. ２ -C ６ Alkynyl, C may be substituted. １ -C ６ Haloalkyl, optionally substituted C １ -C ６ Hydroxyalkyl or optionally substituted C ３ -C ６ It is cycloalkyl; Each R ２ These are, independently, halogen, -CN, -OH, -OR ａ -SH, -SR ａ , -NO ２ , -N(R ｂ ) ２ , -S (=O) ２ R ａ , -C(=O)R ａ , -C (=O) OR ａ , -C(=O)NR ａ R ｂ , oxo (=O), C may be substituted. １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, C may be substituted. ２ -C ６ Alkynyl, C may be substituted. １ -C ６ Alkylamino, optionally substituted C １ -C ６ Haloalkyl, optionally substituted C １ -C ６ Hydroxyalkyl, optionally substituted C ３ -C ６ A cycloalkyl, an optionally substituted arylalkyl, or an optionally substituted 4- to 6-membered heterocycloalkyl; Or, Two R's ２ They combine with the atom(s) they are bonded to, C ３ -C ５ Forming a cycloalkyl, 4- to 5-membered heterocycloalkyl, or 5-membered heteroaryl ring; Each R ３ These are, independently, halogen, -CN, -OH, -OR ａ , C １ -C ６ Alkyl or C １ -C ６ It is a haloalkyl; R ６ａ and R ６ｂ These are H, -CN, -C(=O)OR, each independently. ７ , -C(=O)N(R ７ ) ２ , -S(=O)R ７ , -S (=O) ２ R ７ or -S(=O)(=NH)R ７ And here, Each R ７ C may be substituted independently. １ -C ６ Alkyl, optionally substituted C ３ -C ６ A cycloalkyl or optionally substituted 4- to 6-membered heterocycloalkyl ring; Or, Two R's ７ They combine with the nitrogen atom to which they are bonded to form a substituted or otherwise substituted 4- to 5-membered heterocycloalkyl ring; Or, R ５ and R ７ They combine with the atoms to which they are bonded to form a five-membered heterocycloalkyl ring; R ６ｃ is H or -CN; Or, R ６ｃ and R ７ They combine with the atoms to which they are bonded to form a four-membered heterocycloalkyl ring; Each R ａ These are H and C, independently. １ -C ６ Alkyl, C １ -C ６ Alkyl deuterated, C １ -C ６ Haloalkyl, C １ -C ６ Heteroalkyl, C ２ C ６ Alkenil, C ２ C ６ Alkinyl, C ３ C ６ Cycloalkyl, C ３ C ６ Heterocycloalkyl, C ５ C ８ Ariel, C ５ C ８ Heteroaryl, -C １ -C ６ Alkyl (aryl), -C １ -C ６ Alkyl (heteroaryl), -C １ -C ６ Alkyl (cycloalkyl) or -C １ -C ６ Alkyl (heterocycloalkyl); where each alkyl, deuterated alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), and alkyl(heterocycloalkyl) independently comprises 1, 2, or 3 halogens, -OH, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl or C １ -C ６ It is also acceptable if it is substituted with an alkoxy; Each R ｂ These are H and C, independently. １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ The alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently one, two, or three halogens, -OH, C １ -C ６ Alkyl or C １ -C ６ It may also be substituted with a haloalkyl; Or, Two R's on the nitrogen atom ｂ The groups, together with the nitrogen atoms to which they are bonded, form heterocycloalkyl (which is 1, 2, or 3 C atoms). １ -C ６ Alkyl or C １ -C ６ Forms a haloalkyl group (which may be substituted); n1 and n2 are independently 0, 1, 2, or 3; p is 0, 1, 2, or 3; q is 0, 1, or 2; and, t is 0, 1, 2, or 3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof, having a structure represented by the above.

8. Ring A is C ５ -C ７ A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, which is a cycloalkyl or a 5- to 7-membered heterocycloalkyl.

9. The aforementioned compound is of formula (II): 【Chemistry 4】 [During the ceremony, X １ and X ２ Each is independent of CH ２ _CHR ２ CR ２ R ２ , O or NR ２ａ And here, X １ or X ２ At least one of them is CH ２ _CHR ２ or CR ２ R ２ And; X ３ CR ８ or N, however X ３ If R is N, ８ It does not exist; Y is N, CH, or CR １ And; Z is C (=O) or S (=O) ２ And; Each R １ These are, independently, halogen, -CN, -OH, -OR ａ C may be substituted. １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkyl deuterated, optionally substituted C ２ -C ６ Alkynyl, C may be substituted. １ -C ６ Haloalkyl or optionally substituted C １ -C ６ Hydroxyalkyl or optionally substituted C ３ -C ６ It is cycloalkyl; Each R ２ These are, independently, halogen, -CN, -OH, -OR ａ , -N(R ｂ ) ２ C may be substituted. １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkyl deuterated, optionally substituted C ２ -C ６ Alkenyl, C may be substituted. ２ -C ６ Alkynyl, C may be substituted. １ -C ６ Haloalkyl, optionally substituted C １ -C ６ Hydroxyalkyl, optionally substituted C ３ -C ６ A cycloalkyl, an optionally substituted arylalkyl, or an optionally substituted 4- to 6-membered heterocycloalkyl; Or, Two R's ２ They combine with the atom(s) they are bonded to, C ３ -C ５ Forms a cycloalkyl group; R ２ａ H, -S (=O) ２ R ａ , -C(=O)R ａ , -C (=O) OR ａ , -C(=O)NR ａ R ｂ C may be substituted. １ -C ６ Alkyl, optionally substituted C １ -C ６ Haloalkyl, C ３ -C ６ It is cycloalkyl or phenyl; Each R ３ These are, independently, halogen, -CN, -OH, -OR ａ , C １ -C ６ Alkyl, C １ -C ６ Alkyl deuterated or C １ -C ６ It is a haloalkyl; R ４ H, halogen, -OH, -OR ａ or C １ -C ６ It is alkyl; R ５ H, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl or C １ -C ３ It is a hydroxyalkyl group; R ５ｂ is H or C １ -C ３ It is alkyl; R ６ａ and R ６ｂ These are H, -CN, -C(=O)OR, each independently. ７ , -C(=O)N(R ７ ) ２ , -S(=O)R ７ , -S (=O) ２ R ７ or -S(=O)(=NH)R ７ And here, Each R ７ C may be substituted independently. １ -C ６ Alkyl, optionally substituted C ３ -C ６ A cycloalkyl or optionally substituted 4- to 6-membered heterocycloalkyl ring; Or, Two R's ７ They combine with the nitrogen atom to which they are bonded to form a substituted or otherwise substituted 4- to 5-membered heterocycloalkyl ring; Or, R ５ and R ７ They combine with the atoms to which they are bonded to form a five-membered heterocycloalkyl ring; R ６ｃ is H or -CN; Or, R ６ｃ and R ７ They combine with the atoms to which they are bonded to form a four-membered heterocycloalkyl ring; R ８ It does not exist, or H, halogen, -OCH ３ or -CH ３ And; Each R ａ These are H and C, independently. １ -C ６ Alkyl, C １ -C ６ Alkyl deuterated, C １ -C ６ Haloalkyl, C １ -C ６ Heteroalkyl, C ２ C ６ Alkenil, C ２ C ６ Alkinyl, C ３ C ６ Cycloalkyl, C ３ C ６ Heterocycloalkyl, C ５ C ８ Ariel, C ５ C ８ Heteroaryl, -C １ -C ６ Alkyl (aryl), -C １ -C ６ Alkyl (heteroaryl), -C １ -C ６ Alkyl (cycloalkyl) or -C １ -C ６ Alkyl (heterocycloalkyl); where each alkyl, deuterated alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), and alkyl(heterocycloalkyl) independently comprises 1, 2, or 3 halogens, -OH, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl or C １ -C ６ It is also acceptable if substituted with an alkoxyl; Each R ｂ These are H and C, independently. １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ The alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently one, two, or three halogens, -OH, C １ -C ６ Alkyl or C １ -C ６ It may also be substituted with a haloalkyl; Or, Two R's on the nitrogen atom ｂ The groups, together with the nitrogen atoms to which they are bonded, form heterocycloalkyl (which is 1, 2, or 3 C atoms). １ -C ６ Alkyl or C １ -C ６ Forms a haloalkyl group (which may be substituted); m is either 0 or 1; n1 and n2 are independently 0, 1, 2, or 3; p is 0, 1, 2, or 3; q is 0, 1, or 2; and, t is 1, 2, or 3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof, having a structure represented by the above.

10. X ３ However, CR ８ And, R ８ The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein H is present.

11. X １ However, NR ２ａ X ２ However, CH ２ The compound according to claim 9 or 10, or a pharmaceutically acceptable salt thereof.

12. R ４ A compound according to any one of claims 9-11 or a pharmaceutically acceptable salt thereof, wherein the compound is a halogen.

13. A compound according to any one of claims 9-12 or a pharmaceutically acceptable salt thereof, wherein Z is -C(=O)-.

14. A compound according to any one of claims 9-13 or a pharmaceutically acceptable salt thereof, wherein m is 0.

15. The aforementioned compound is of formula (IIb): 【Transformation 5】 [During the ceremony, Y is CH or CR １ And; Each R １ These are, independently, halogen, -CN, -OH, -OR ａ C may be substituted. １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkyl deuterated, optionally substituted C ２ -C ６ Alkynyl, C may be substituted. １ -C ６ Haloalkyl or C １ -C ６ It is a hydroxyalkyl group; Each R ２ C may be substituted independently. １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkyl deuterated, optionally substituted C １ -C ６ Haloalkyl or optionally substituted C ３ -C ６ It is cycloalkyl; R ２ａ is H, -C(=O)OR ａ , -C(=O)NR ａ R ｂ C may be substituted. １ -C ６ Alkyl, optionally substituted C １ -C ６ Haloalkyl, optionally substituted arylalkyl, or optionally substituted C ３ -C ６ It is cycloalkyl; Each R ３ Independently, C １ -C ３ Alkyl or C １ -C ３ It is an alkyl deuterated; R ５ H, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl or C １ -C ３ It is a hydroxyalkyl group; R ５ｂ is H or C １ -C ３ It is alkyl; R ６ａ and R ６ｂ These are H, -CN, -C(=O)OR, each independently. ７ , -C(=O)N(R ７ ) ２ , -S(=O)R ７ , -S (=O) ２ R ７ or -S(=O)(=NH)R ７ And here, Each R ７ C may be substituted independently. １ -C ６ Alkyl, optionally substituted C ３ -C ６ A cycloalkyl or optionally substituted 4- to 6-membered heterocycloalkyl ring; Or, Two R's ７ They combine with the nitrogen atom to which they are bonded to form a substituted or otherwise substituted 4- to 5-membered heterocycloalkyl ring; Or, R ５ and R ７ They combine with the atoms to which they are bonded to form a five-membered heterocycloalkyl ring; R ６ｃ is H or -CN; Or, R ６ｃ and R ７ They combine with the atoms to which they are bonded to form a four-membered heterocycloalkyl ring; Each R ａ These are H and C, independently. １ -C ６ Alkyl, C １ -C ６ Alkyl deuterated, C １ -C ６ Haloalkyl, C １ -C ６ Heteroalkyl, C ２ C ６ Alkenil, C ２ C ６ Alkinyl, C ３ C ６ Cycloalkyl, C ３ C ６ Heterocycloalkyl, C ５ C ８ Ariel, C ５ C ８ Heteroaryl, -C １ -C ６ Alkyl (aryl), -C １ -C ６ Alkyl (heteroaryl), -C １ -C ６ Alkyl (cycloalkyl) or -C １ -C ６ Alkyl (heterocycloalkyl); where each alkyl, deuterated alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), and alkyl(heterocycloalkyl) independently comprises 1, 2, or 3 halogens, -OH, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl or C １ -C ６ It is also acceptable if substituted with an alkoxyl; Each R ｂ These are H and C, independently. １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ The alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently one, two, or three halogens, -OH, C １ -C ６ Alkyl or C １ -C ６ It may also be substituted with a haloalkyl; Or, Two R's on the nitrogen atom ｂ The groups, together with the nitrogen atoms to which they are bonded, form heterocycloalkyl (which is 1, 2, or 3 C atoms). １ -C ６ Alkyl or C １ -C ６ Forms a haloalkyl group (which may be substituted); n1 and n2 are independently 0, 1, 2, or 3; p is 0, 1, 2, or 3; q is 0, 1, or 2; and, t is 1, 2, or 3. The compound according to claim 9, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof, having a structure represented by the above.

16. Y is CH or R １ And; R １ However, it is a halogen; R ２ａ However, C １ -C ６ It is a haloalkyl; R ５ However, C １ -C ３ It is alkyl; R ５ｂ However, it is H; R ６ａ and R ６ｂ However, each is independent of H or -S (=O) (=NH)R ７ And here, each R ７ Independently, C １ -C ６ Alkyl, or R ５ and R ７ However, they combine with the atoms to which they are bonded to form a five-membered heterocycloalkyl ring; R ６ｃ However, it is H; n1 and n2 are independently 1 or 2; p is 0 or 1; q is 0 or 1; and, t is 1 or 2; The compound according to claim 15 or a pharmaceutically acceptable salt thereof.

17. R ２ａ However, -C(=O)R ａ , -C (=O) OR ａ C may be substituted. １ -C ６ Alkyl, optionally substituted C １ -C ６ Haloalkyl or optionally substituted C ３ -C ６ It is a cycloalkyl group; where each R ａ Independently, C １ -C ６ The compound according to claim 15, or a pharmaceutically acceptable salt thereof, which is alkyl or aryl.

18. R ２ａ but, 【Transformation 6】 The compound according to claim 15 or a pharmaceutically acceptable salt thereof.

19. R ２ａ but, 【Transformation 7】 A compound according to claim 18, selected from the group consisting of the following.

20. A compound according to any one of claims 15-19 or a pharmaceutically acceptable salt thereof, wherein p is 0.

21. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl or a 5- to 10-membered heteroaryl.

22. The compound according to claim 21 or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl or pyridinyl.

23. The aforementioned compound is of formula (III): 【Transformation 8】 [During the ceremony, Y is N, CH, or CR １ And; Z is C (=O) or S (=O) ２ And; X ４ CH, CR ２ or N; X ５ CH, CR ２ or N; Each R １ These are, independently, halogen, -CN, -OH, -OR ａ C may be substituted. １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkyl deuterated, optionally substituted C ２ -C ６ Alkynyl, C may be substituted. １ -C ６ Haloalkyl, optionally substituted C １ -C ６ Hydroxyalkyl or optionally substituted C ３ -C ６ It is cycloalkyl; Each R ２ These are, independently, halogen, -CN, -OH, -OR ａ , -N(R ｂ ) ２ C may be substituted. １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkyl deuterated, optionally substituted C ２ -C ６ Alkenyl, C may be substituted. ２ -C ６ Alkynyl, C may be substituted. １ -C ６ Haloalkyl, optionally substituted C １ -C ６ Hydroxyalkyl, optionally substituted C ３ -C ６ A cycloalkyl, an optionally substituted arylalkyl, or an optionally substituted 4- to 6-membered heterocycloalkyl; Or, Two R's ２ They combine with the atom(s) they are bonded to, C ３ -C ５ Forming a cycloalkyl, 4- to 5-membered heterocycloalkyl, or 5-membered heteroaryl ring; Each R ３ These are, independently, halogen, -CN, -OH, -OR ａ , C １ -C ６ Alkyl, C １ -C ６ Alkyl deuterated or C １ -C ６ It is a haloalkyl; R ４ H, halogen, -OH, -OR ａ or C １ -C ６ It is alkyl; R ５ H, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl or C １ -C ３ It is a hydroxyalkyl group; R ５ｂ is H or C １ -C ３ It is alkyl; R ６ａ and R ６ｂ These are H, -CN, -C(=O)OR, each independently. ７ , -C(=O)N(R ７ ) ２ , -S(=O)R ７ , -S (=O) ２ R ７ or -S(=O)(=NH)R ７ And here, Each R ７ C may be substituted independently. １ -C ６ Alkyl, optionally substituted C ３ -C ６ A cycloalkyl or optionally substituted 4- to 6-membered heterocycloalkyl ring; Or, Two R's ７ They combine with the nitrogen atom to which they are bonded to form a substituted or otherwise substituted 4- to 5-membered heterocycloalkyl ring; Or, R ５ and R ７ They combine with the atoms to which they are bonded to form a five-membered heterocycloalkyl ring; R ６ｃ is H or -CN; Or, R ６ｃ and R ７ They combine with the atoms to which they are bonded to form a four-membered heterocycloalkyl ring; Each R ａ These are H and C, independently. １ -C ６ Alkyl, C １ -C ６ Alkyl deuterated, C １ -C ６ Haloalkyl, C １ -C ６ Heteroalkyl, C ２ C ６ Alkenil, C ２ C ６ Alkinyl, C ３ C ６ Cycloalkyl, C ３ C ６ Heterocycloalkyl, C ５ C ８ Ariel, C ５ C ８ Heteroaryl, -C １ -C ６ Alkyl (aryl), -C １ -C ６ Alkyl (heteroaryl), -C １ -C ６ Alkyl (cycloalkyl) or -C １ -C ６ Alkyl (heterocycloalkyl); where each alkyl, deuterated alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), and alkyl(heterocycloalkyl) independently comprises 1, 2, or 3 halogens, -OH, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl or C １ -C ６ It is also acceptable if substituted with an alkoxyl; Each R ｂ These are H and C, independently. １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ The alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently one, two, or three halogens, -OH, C １ -C ６ Alkyl or C １ -C ６ It may also be substituted with a haloalkyl; Or, Two R's on the nitrogen atom ｂ The groups, together with the nitrogen atoms to which they are bonded, form heterocycloalkyl (which is 1, 2, or 3 C atoms). １ -C ６ Alkyl or C １ -C ６ Forms a haloalkyl group (which may be substituted); n1 and n2 are independently 0, 1, or 2; p is 0, 1, 2, or 3; q is 0, 1, or 2; and, t is 0, 1, 2, or 3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof, having a structure represented by the above.

24. Z is -S (=O) ２ - The compound according to claim 23 or a pharmaceutically acceptable salt thereof.

25. R ４ The compound according to claim 23 or 24, or a pharmaceutically acceptable salt thereof, which is a halogen.

26. The aforementioned compound is of formula (IIIa): 【Chemistry 9】 [During the ceremony, Y is CH or CR １ And; X ４ CH, CR ２ or N; X ５ CH, CR ２ or N; Each R １ These are, independently, halogen, -CN, -OH, -OR ａ C may be substituted. １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkyl deuterated, optionally substituted C ２ -C ６ Alkynyl, C may be substituted. １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl or optionally substituted C ３ -C ６ It is cycloalkyl; Each R ２ These are, independently, halogen, -CN, -OH, -OR ａ , -N(R ｂ ) ２ C may be substituted. １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkyl deuterated, optionally substituted C ２ -C ６ Alkenyl, C may be substituted. ２ -C ６ Alkynyl, C may be substituted. １ -C ６ Haloalkyl, optionally substituted C １ -C ６ Hydroxyalkyl, optionally substituted C ３ -C ６ A cycloalkyl, an optionally substituted arylalkyl, or an optionally substituted 4- to 6-membered heterocycloalkyl; Each R ３ Independently, C １ -C ３ Alkyl or C １ -C ３ It is an alkyl deuterated; R ５ H, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl or C １ -C ３ It is a hydroxyalkyl group; R ５ｂ is H or C １ -C ３ It is alkyl; R ６ａ and R ６ｂ These are H, -CN, and -CN(=O)(R) independently of each other. ７ ) ２ , -S (=O) ２ R ７ or -S(=O)(=NH)R ７ And here, Each R ７ Independently, C １ -C ３ A four-membered heterocycloalkyl ring that is alkyl or may be substituted with up to two fluorine atoms; Or, Two R's ７ They combine with the nitrogen atom to which they are bonded to form a four-membered heterocycloalkyl ring which may be substituted with up to two fluorine atoms; Or, R ５ and R ７ They combine with the atoms to which they are bonded to form a five-membered heterocycloalkyl ring; R ６ｃ is H or -CN; Or, R ６ｃ and R ７ They combine with the atoms to which they are bonded to form a four-membered heterocycloalkyl ring; Each R ａ These are H and C, independently. １ -C ６ Alkyl, C １ -C ６ Alkyl deuterated, C １ -C ６ Haloalkyl, C １ -C ６ Heteroalkyl, C ２ C ６ Alkenil, C ２ C ６ Alkinyl, C ３ C ６ Cycloalkyl, C ３ C ６ Heterocycloalkyl, C ５ C ８ Ariel, C ５ C ８ Heteroaryl, -C １ -C ６ Alkyl (aryl), -C １ -C ６ Alkyl (heteroaryl), -C １ -C ６ Alkyl (cycloalkyl) or -C １ -C ６ Alkyl (heterocycloalkyl); where each alkyl, deuterated alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), and alkyl(heterocycloalkyl) independently comprises 1, 2, or 3 halogens, -OH, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl or C １ -C ６ It is also acceptable if substituted with an alkoxyl; Each R ｂ These are H and C, independently. １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ The alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently one, two, or three halogens, -OH, C １ -C ６ Alkyl or C １ -C ６ It may also be substituted with a haloalkyl; Or, Two R's on the nitrogen atom ｂ The groups, together with the nitrogen atoms to which they are bonded, form heterocycloalkyl (which is 1, 2, or 3 C atoms). １ -C ６ Alkyl or C １ -C ６ Forms a haloalkyl group (which may be substituted); n1 and n2 are independently 0, 1, or 2; p is 0, 1, 2, or 3; q is 0, 1, or 2; and, t is 0, 1, 2, or 3. The compound according to claim 23, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof, having a structure represented by the above.

27. X ４ However, CH or CR ２ X ５ However, CH or CR ２ The compound according to any one of claims 23-26 or a pharmaceutically acceptable salt thereof.

28. X ４ However, N is; and X ５ However, CH or CR ２ The compound according to any one of claims 23-26 or a pharmaceutically acceptable salt thereof.

29. X ４ However, CH or CR ２ X ５ The compound according to any one of claims 23-26 or a pharmaceutically acceptable salt thereof, wherein N is present.

30. A compound according to any one of claims 23-29 or a pharmaceutically acceptable salt thereof, wherein p is 1.

31. The aforementioned compound is of formula (IIIb): 【Chemistry 10】 [During the ceremony, X ４ is CH or N; Y is CR １ or CH; Each R １ is, independently, halogen, -CN, -OR ａ , optionally substituted C １ -C ４ alkyl, C １ -C ４ deuterated alkyl, C ２ -C ４ alkynyl or C １ -C ３ fluoroalkyl; R ２ These are halogen, -CN, -OH, -OR ａ , -N(R ｂ ) ２ , -C(=O)R ａ C may be substituted. １ -C ４ Alkyl, C １ -C ４ Alkyl deuterated, C ２ -C ４ Alkenil, C ２ -C ４ Alkinyl, C １ -C ３ Fluoroalkyl, optionally substituted C １ -C ３ Hydroxyalkyl, optionally substituted C ３ -C ６ A cycloalkyl or optionally substituted 4-6 member heterocycloalkyl; Each R ３ It is independently, -CH ３ or -CD ３ And; R ５ H, -CH ３ or -CH ２ CH ３ And; R ５ｂ is H or C １ -C ３ It is alkyl; R ６ａ and R ６ｂ These are H, -CN, and -CN(=O)(R) independently of each other. ７ ) ２ , -S (=O) ２ R ７ or -S(=O)(=NH)R ７ And here, Each R ７ Independently, C １ -C ３ A four-membered heterocycloalkyl ring that is alkyl or may be substituted with up to two fluorine atoms; Or, Two R's ７ They combine with the nitrogen atom to which they are bonded to form a four-membered heterocycloalkyl ring which may be substituted with up to two fluorine atoms; Or, R ５ and R ７ They combine with the atoms to which they are bonded to form a five-membered heterocycloalkyl ring; R ６ｃ is H or -CN; Each R ａ Independently, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl or C １ -C ３ It is a fluoroalkyl; Each R ｂ H or C １ -C ３ It is alkyl; q is 0, 1, or 2; and, t is 0, 1, or 2. The compound according to claim 26 or a pharmaceutically acceptable salt thereof having the structure represented by .

32. Each R ２ is independently halogen, -CN, -OH, -OR ａ , -N(R ｂ ), -C(=O)R ２ , optionally substituted C ａ -C １ -C ４ alkyl, C ２ -C ４ alkenyl, C ２ -C ４ alkynyl, C １ -C ３ fluoroalkyl, optionally substituted C １ -C ３ hydroxyalkyl, optionally substituted C ３ -C ６ cycloalkyl or optionally substituted 4- to 6-membered heterocycloalkyl, the compound according to any one of claims 23-31 or a pharmaceutically acceptable salt thereof.

33. Each R ２ However, independently, halogen, -CN, -OH, -OR ａ , -N(R ｂ ) ２ , C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ The compound according to claim 32, or a pharmaceutically acceptable salt thereof, which is a hydroxyalkyl or a 4- to 6-membered heterocycloalkyl.

34. Each R ２ However, independently, Cl, Br, F, -CN, -CH ３ ien-CH ２ CH ３ , -CH(CH ３ ) ２ , -CF ３ ien-CH ２ CF ３ , -OCH ３ , -OCH ２ CH ３ , -OCH(CH ３ ) ２ , -OCF ３ , -N(CH ３ ) ２ The compound according to claim 32, or a pharmaceutically acceptable salt thereof, which is azetidine, oxetane, pyrrolidine, piperazine, or morpholine.

35. Each R ２ However, they became independent, 【Chemistry 11】 The compound according to any one of claims 23-31 or a pharmaceutically acceptable salt thereof.

36. Each R １ However, independently, halogen, -CN, -OH, -OR ａ , -C (=O) OR ａ , -C(=O)NR ａ R ｂ C may be substituted. １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, C may be substituted. ２ -C ６ Alkynyl or possibly substituted C １ -C ６ A compound according to any one of claims 1-35, or a pharmaceutically acceptable salt thereof, which is a haloalkyl compound.

37. Each R １ However, independently, halogen, -OR ａ C may be replaced １ -C ６ A compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, which is alkyl.

38. Each R １ However, independently, Cl, Br, F, -OCH ３ or CH ３ The compound according to claim 36 or a pharmaceutically acceptable salt thereof.

39. A compound according to any one of claims 1-38 or a pharmaceutically acceptable salt thereof, wherein t is 1 or 2.

40. The compound according to claim 39 or a pharmaceutically acceptable salt thereof, wherein t is 1.

41. The compound according to claim 39 or a pharmaceutically acceptable salt thereof, wherein t is 2.

42. Each R ３ However, independently, C １ -C ３ A compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, which is alkyl.

43. Each R ３ However, -CH ３ The compound according to claim 42 or a pharmaceutically acceptable salt thereof.

44. A compound according to any one of claims 1-43 or a pharmaceutically acceptable salt thereof, wherein q is 1.

45. A compound according to any one of claims 1-44 or a pharmaceutically acceptable salt thereof, wherein q is 0.

46. A compound according to any one of claims 1-45 or a pharmaceutically acceptable salt thereof, wherein n1 is 1 and n2 is 1.

47. R ６ａ However, S (= O ２ ) R ７ And, R ６ｂ and R ６ｃ The compound according to any one of claims 1-46 or a pharmaceutically acceptable salt thereof, wherein each of these is H.

48. R ６ｂ However, S (= O ２ ) R ７ And, R ６ａ and R ６ｃ The compound according to any one of claims 1-47 or a pharmaceutically acceptable salt thereof, wherein each of the atoms is H.

49. R ７ However, C may be substituted independently. １ -C ３ A compound according to claim 47 or 48, or a pharmaceutically acceptable salt thereof, which is alkyl.

50. R ５ and R ７ The compound according to any one of claims 1-46 or a pharmaceutically acceptable salt thereof, wherein they combine with the atoms to which they are bonded to form a five-membered heterocycloalkyl ring.

51. R ６ｃ and R ７ The compound according to any one of claims 1 to 46 or a pharmaceutically acceptable salt thereof, wherein they combine with the atoms to which they are bonded to form a four-membered heterocycloalkyl ring.

52. R Ａ but, 【Chemistry 12】 The compound according to any one of claims 1 to 46 or a pharmaceutically acceptable salt thereof.

53. R Ａ but, 【Chemistry 13】 The compound according to claim 52 or a pharmaceutically acceptable salt thereof.

54. R ６ａ However, -C(=O)N(R ７ ) ２ And, R ６ｂ and R ６ｃ However, each of them is H; Or, R ６ｂ However, -C(=O)N(R ７ ) ２ And, R ６ａ and R ６ｃ However, each of them is H; Here, two R ７ They combine with the nitrogen atom to which they are bonded to form a substituted, or possibly substituted, 4- to 5-membered ring; A compound according to any one of claims 1 to 46 or a pharmaceutically acceptable salt thereof.

55. R Ａ but, 【Chemistry 14】 The compound according to any one of claims 1 to 46 or a pharmaceutically acceptable salt thereof.

56. The aforementioned compound, (S,Z)-1-((5-chloro-3'-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((5-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((3',5-dichloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-4-fluoro-1-((5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((3',5-dimethoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((2',5-dichloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((3'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((5-chloro-3'-cyano-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-4-fluoro-1-((5-fluoro-3'-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((5-chloro-3'-ethoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((2'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-4-fluoro-1-((5-methoxy-2'-methyl-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((5-chloro-3'-propoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((5-chloro-3'-cyclopropoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((2',5-dichloro-5'-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((5-chloro-3'-(ethoxymethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((2'-chloro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-4-fluoro-1-((3'-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((5-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-4-fluoro-1-((5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((3'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((2',5-dichloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-4-fluoro-1-((5-methoxy-2'-methyl-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((2'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((2'-chloro-3'-fluoro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((2'-chloro-4'-fluoro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((2'-chloro-5'-fluoro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((2',4-dichloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; 1-((2'-chloro-6'-fluoro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((2'-chloro-5-fluoro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; 1-((2',6-dichloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((2'-chloro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((2'-chloro-5-(trifluoromethoxy)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((2'-chloro-5-cyano-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (E)-1-((5-chloro-3'-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(3-(methylsulfonyl)allyl)piperidine-4-carboxamide; (E)-1-((5-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(3-(methylsulfonyl)allyl)piperidine-4-carboxamide; (E)-4-fluoro-1-((5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(3-(methylsulfonyl)allyl)piperidine-4-carboxamide; (E)-1-((3',5-dimethoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(3-(methylsulfonyl)allyl)piperidine-4-carboxamide; (E)-1-((2',5-dichloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(3-(methylsulfonyl)allyl)piperidine-4-carboxamide; (E)-1-((3'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(3-(methylsulfonyl)allyl)piperidine-4-carboxamide; (E)-4-fluoro-1-((3'-methoxy-5-methyl-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(3-(methylsulfonyl)allyl)piperidine-4-carboxamide; (E)-1-((2'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(3-(methylsulfonyl)allyl)piperidine-4-carboxamide; (E)-4-fluoro-1-((5-methoxy-2'-methyl-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(3-(methylsulfonyl)allyl)piperidine-4-carboxamide; (E)-1-((3',5-dichloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(3-(methylsulfonyl)allyl)piperidine-4-carboxamide; (E)-1-((5-chloro-3'-(propa-1-in-1-yl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(3-(methylsulfonyl)allyl)piperidine-4-carboxamide; (R,Z)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((5-bromo-2'-chloro-5'-fluoro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((5-bromo-2'-methyl-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((5-bromo-2'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((5-bromo-2'-ethyl-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((5-bromo-2'-chloro-3'-fluoro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((5-bromo-2'-chloro-4'-methyl-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((5-bromo-2'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((5-bromo-3'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((5-bromo-3'-fluoro-2'-methyl-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((5-bromo-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((3',5-dibromo-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((5-bromo-2'-chloro-3'-methyl-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; 1-((5-bromo-2'-chloro-6'-methyl-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((5-bromo-3'-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (E)-1-((5-bromo-3'-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(3-(methylsulfonyl)allyl)piperidine-4-carboxamide; (E)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(3-(methylsulfonyl)allyl)piperidine-4-carboxamide; 1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(1,1-dioxide-2,3-dihydrothiophen-3-yl)-4-fluoropiperidine-4-carboxamide; (R)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(1,1-dioxide-2,3-dihydrothiophen-3-yl)-4-fluoropiperidine-4-carboxamide; (S)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(1,1-dioxide-2,3-dihydrothiophen-3-yl)-4-fluoropiperidine-4-carboxamide; (E)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(3-cyanoallyl)-4-fluoropiperidine-4-carboxamide; (E)-N-(3-cyanoallyl)-1-((2',5-dichloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxamide; (Z)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(3-cyanoallyl)-4-fluoropiperidine-4-carboxamide; (Z)-1-((2'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(3-cyanoallyl)-4-fluoropiperidine-4-carboxamide; 1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(2-cyanoallyl)-4-fluoropiperidine-4-carboxamide; 1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-((2R,Z)-4-(S-methylsulfonimidoyl)buta-3-en-2-yl)piperidine-4-carboxamide; 1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-((R,Z)-4-((R)-S-methylsulfonimidoyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,E)-N-(4-(azetidine-3-ylsulfonyl)buta-3-en-2-yl)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxamide; (R,E)-N-(4-(azetidine-3-ylsulfonyl)buta-3-en-2-yl)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxamide; (R,E)-N-(1-(azetidine-3-ylsulfonyl)penta-1-en-3-yl)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxamide; (S,E)-N-(1-(azetidine-3-ylsulfonyl)penta-1-en-3-yl)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxamide; (R,E)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,E)-1-((5-chloro-3'-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,E)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(1-(methylsulfonyl)penta-1-en-3-yl)piperidine-4-carboxamide; (S,Z)-1-((5-chloro-3'-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(1-(methylsulfonyl)penta-1-en-3-yl)piperidine-4-carboxamide; (S,Z)-1-((5-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(1-(methylsulfonyl)penta-1-en-3-yl)piperidine-4-carboxamide; (R,Z)-1-((2'-chloro-5-(dimethylamino)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(1-(methylsulfonyl)penta-1-en-3-yl)piperidine-4-carboxamide; (S,Z)-1-((5-(dimethylamino)-3'-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((2'-chloro-5-(dimethylamino)-5'-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((5-(dimethylamino)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((2'-chloro-5-(dimethylamino)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((2'-chloro-5-(dimethylamino)-3'-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((5-(dimethylamino)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((2'-chloro-5-(dimethylamino)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((5-(dimethylamino)-2'-methyl-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (E)-1-((5-(dimethylamino)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(3-(methylsulfonyl)allyl)piperidine-4-carboxamide; (E)-1-((2'-chloro-5-(dimethylamino)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(3-(methylsulfonyl)allyl)piperidine-4-carboxamide; (E)-1-((5-(dimethylamino)-3'-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(3-(methylsulfonyl)allyl)piperidine-4-carboxamide; (E)-1-((2'-chloro-5-(dimethylamino)-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(3-cyanoallyl)-4-fluoropiperidine-4-carboxamide; (R,Z)-1-((2'-chloro-5-cyclobutyl-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; tert-butyl (R,Z)-3-(2'-chloro-6-((4-fluoro-4-((4-(methylsulfonyl)buta-3-en-2-yl)carbamoyl)piperidine-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)azetidine-1-carboxylate; (S,Z)-1-((5-chloro-3'-(propa-1-in-1-yl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((2'-chloro-5-cyclopropoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((5-ethoxy-2'-methyl-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-4-fluoro-1-((5-isopropoxy-2'-methyl-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((2'-chloro-5-hydroxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((2'-chloro-5-isopropoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((5-cyclopropoxy-2'-methyl-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((2'-chloro-5-vinyl-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-4-fluoro-1-((2'-methyl-5-vinyl-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((2'-chloro-5-(propa-1-en-2-yl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-4-fluoro-1-((2'-methyl-5-(prop-1-en-2-yl)-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((2'-chloro-5-ethyl-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((5-ethyl-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((5-ethyl-2'-methyl-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((2'-chloro-5-isopropyl-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-4-fluoro-1-((5-isopropyl-2'-methyl-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((5-(azetidine-1-yl)-2'-methyl-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)-1-((5-(pyrroridine-1-yl)-[1,1'-biphenyl]-2-yl)sulfonyl)piperidine-4-carboxamide; tert-butyl (R,Z)-4-(2'-chloro-6-((4-fluoro-4-((4-(methylsulfonyl)buta-3-en-2-yl)carbamoyl)piperidine-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)piperazine-1-carboxylate; (R,Z)-1-((2'-chloro-5-(pyrrolidine-1-yl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-4-fluoro-1-((2'-methyl-5-(pyrrolidine-1-yl)-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((2'-chloro-5-morpholino-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-4-fluoro-1-((2'-methyl-5-morpholino-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((2'-chloro-4'-fluoro-5-(pyrrolidine-1-yl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((5-(azetidine-1-yl)-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((5-chloro-3'-(2-methoxyethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((5-chloro-3'-(methoxymethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; 1-((5-chloro-3'-((E)-(methoxyimino)methyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-((S,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((2'-chloro-5-(2-hydroxyethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; 1-((2'-chloro-5-(1-hydroxyethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((2'-chloro-5-(hydroxymethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((2'-chloro-5-(propa-1-in-1-yl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((2'-chloro-5-(oxetan-3-yl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-methoxy-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,E)-1-((2'-chloro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoropiperidine-4-carboxamide; (R,E)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoropiperidine-4-carboxamide; (R,E)-1-((2'-chloro-5-cyano-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoropiperidine-4-carboxamide; (R,E)-1-((2'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoropiperidine-4-carboxamide; (R,E)-1-((5-acetyl-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoropiperidine-4-carboxamide; (R,Z)-1-((2'-chloro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-methoxy-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; 1-((2'-chloro-5-(1-hydroxyethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-N-((R,E)-5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoropiperidine-4-carboxamide; (2R,4S)-1-((2'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-2-methyl-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (2R,4S)-1-((2'-chloro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-2-methyl-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (2R,4S)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-2-methyl-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (2R,4S)-1-((2'-chloro-5-cyano-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-2-methyl-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (2R,4S)-1-((5-bromo-3'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-2-methyl-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((2'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-methoxy-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (2R,4R)-1-((2'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-2-methyl-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (2S,4S)-1-((2'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-2-methyl-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (2R,4S)-1-((2'-chloro-5-(methoxymethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-2-methyl-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R)-1-((2'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-2,2-dimethyl-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (2R,4S)-1-((2'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-N-((R,E)-5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (2R,4S)-1-((2'-chloro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-N-((R,E)-5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (2R,4S)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-N-((R,E)-5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (2R,4S)-1-((2'-chloro-5-cyano-[1,1'-biphenyl]-2-yl)sulfonyl)-N-((R,E)-5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (2R,4S)-1-((5-bromo-3'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-N-((R,E)-5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (2R,4S)-1-((2'-chloro-5-(methoxymethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-N-((R,E)-5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (R,Z)-1-((5-(2-chlorophenyl)benzo[b]thiophen-6-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; tert-butyl cis-(3RS,4RS)-3-(2-chlorophenyl)-4-(4-fluoro-4-(((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)carbamoyl)piperidine-1-carbonyl)pyrrolidine-1-carboxylate; Isopropyl (3R,4R)-3-(2-chlorophenyl)-4-(4-fluoro-4-(((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)carbamoyl)piperidine-1-carbonyl)pyrrolidine-1-carboxylate; Ethyl (3R,4R)-3-(2-chlorophenyl)-4-(4-fluoro-4-(((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)carbamoyl)piperidine-1-carbonyl)pyrrolidine-1-carboxylate; 1-((3R,4R)-4-(2-chlorophenyl)-1-pivaloylpyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; 1-((3R,4R)-1-benzoyl-4-(2-chlorophenyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; 1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; 1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-N-((R)-1,1-dioxide-2,3-dihydrothiophen-3-yl)-4-fluoropiperidine-4-carboxamide; (R)-1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3 ＊ R,4 ＊ R)-4-(2-chloro-5-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3 ＊ R,4 ＊ R)-4-(2-chloro-4-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3 ＊ R,4 ＊ R)-4-(2-chloro-3-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3 ＊ R,4 ＊ R)-4-(2-chloro-4-methylphenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3 ＊ R,4 ＊ R)-4-(2-chloro-5-methylphenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3R,4R)-4-(2-chloro-6-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3 ＊ R,4 ＊ R)-4-(2-chloro-3-methylphenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3 ＊ R,4 ＊ R)-4-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (2 ＊ S, 4 ＊ S)-1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-N-((R)-1,1-dioxide-2,3-dihydrothiophen-3-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (2 ＊ S, 4 ＊ S)-1-((3 ＊ R,4 ＊ R)-4-(2-chloro-3-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-N-((R)-1,1-dioxide-2,3-dihydrothiophen-3-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (R)-1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-N-((R)-1,1-dioxide-2,3-dihydrothiophen-3-yl)-4-fluoroazepan-4-carboxamide; (R)-1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,E)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; 1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2-difluorobutyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; 1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2-difluoropropyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R)-1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2-difluoropropyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; 1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2-difluoro-2-phenylethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; 1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2,3,3,3-pentafluoropropyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R)-1-((3R,4R)-4-(2-chloro-6-fluorophenyl)-1-(2,2-difluoropropyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3 ＊ R,4 ＊ R)-4-(2-chloro-6-fluorophenyl)-1-((1-fluorocyclopropyl)methyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3R,4R)-4-(2-chlorophenyl)-1-((1-fluorocyclopropyl)methyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R,Z)-1-((4-(2-chlorophenyl)-6-methoxypyridine-3-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((4-(2-chlorophenyl)-6-methoxypyridine-3-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (E)-1-((4-(2-chlorophenyl)-6-methoxypyridine-3-yl)sulfonyl)-4-fluoro-N-(3-(methylsulfonyl)allyl)piperidine-4-carboxamide; (E)-4-fluoro-1-((6-methoxy-4-(o-tolyl)pyridine-3-yl)sulfonyl)-N-(3-(methylsulfonyl)allyl)piperidine-4-carboxamide; (S,Z)-4-fluoro-1-((6-methoxy-4-(o-tolyl)pyridine-3-yl)sulfonyl)-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (E)-4-fluoro-1-((6-methoxy-4-phenylpyridine-3-yl)sulfonyl)-N-(3-(methylsulfonyl)allyl)piperidine-4-carboxamide; (S,Z)-4-fluoro-1-((6-methoxy-4-phenylpyridine-3-yl)sulfonyl)-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-4-fluoro-1-((6-methoxy-4-(o-tolyl)pyridine-3-yl)sulfonyl)-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (Z)-1-((4-(2-chlorophenyl)-6-methoxypyridine-3-yl)sulfonyl)-N-(3-cyanoallyl)-4-fluoropiperidine-4-carboxamide; (R)-1-((3R,4R)-1-(2-chloro-2,2-difluoroethyl)-4-(2-chlorophenyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3R,4R)-4-(2-chlorophenyl)-1-(3,3,3-trifluoropropyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2-difluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-1-(methylsulfonyl)penta-1-en-3-yl)azepan-4-carboxamide; Isopropyl (3S,4S)-3-(2-chlorophenyl)-4-(4-fluoro-4-(((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)carbamoyl)piperidine-1-carbonyl)pyrrolidine-1-carboxylate; (S,Z)-1-((5-chloro-3-(3-methoxyphenyl)pyridine-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((5-chloro-3'-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-methyl-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((2'-chloro-4,5-dimethoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((5-chloro-3'-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-methyl-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((4-bromo-2-(3-chloropyridine-2-yl)phenyl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((2'-chloro-5-(2-oxopyrrolidine-1-yl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; 1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2-difluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((4-(2-chlorophenyl)-6-(trifluoromethyl)pyridine-3-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((4-(2-chlorophenyl)-6-(trifluoromethyl)pyridine-3-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((4-(2-chloro-3-fluorophenyl)-6-(trifluoromethyl)pyridine-3-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((4-(2-chloro-3-fluorophenyl)-6-(trifluoromethyl)pyridine-3-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((4-(2-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyridine-3-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((4-(2-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyridine-3-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,E)-1-((4-(2-chlorophenyl)-6-(trifluoromethyl)pyridine-3-yl)sulfonyl)-N-(5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoropiperidine-4-carboxamide; (2R,4S)-1-((4-(2-chlorophenyl)-6-(trifluoromethyl)pyridine-3-yl)sulfonyl)-4-fluoro-2-methyl-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (2R,4S)-1-((4-(2-chlorophenyl)-6-(trifluoromethyl)pyridine-3-yl)sulfonyl)-N-((R,E)-5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (R,E)-1-((2'-chloro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(5-(3-fluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((6-chloro-4-(2-chloro-5-methoxyphenyl)pyridine-3-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((5-bromo-3-(2-chlorophenyl)pyridine-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((2',5-dimethoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((5-chloro-3'-(2-hydroxyethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (2 ＊ S, 4 ＊ S)-1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2-difluoropropyl)pyrrolidine-3-carbonyl)-N-((R)-1,1-dioxide-2,3-dihydrothiophen-3-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (R)-1-((3 ＊ S, 4 ＊ S)-4-(2-chloro-3-fluorophenyl)-1-(2,2-difluoropropyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-4-fluoro-1-((3 ＊ R,4 ＊ R)-4-(2-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)-1-((3 ＊ R,4 ＊ R)-4-(o-tolyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)azepan-4-carboxamide; (2 ＊ S, 4 ＊ S)-1-((3 ＊ S, 4 ＊ S)-4-(2-chloro-3-fluorophenyl)-1-(2,2-difluoropropyl)pyrrolidine-3-carbonyl)-N-((R)-1,1-dioxide-2,3-dihydrothiophen-3-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (R)-1-((3 ＊ S, 4 ＊ S)-4-(2-chloro-3,6-difluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3 ＊ S, 4 ＊ S)-4-(2-chloro-4,6-difluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (E)-4-fluoro-1-((3'-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(3-((1-methylpiperidine-4-yl)sulfonyl)allyl)piperidine-4-carboxamide; (R,E)-1-((2'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(4-cyanobuta-3-en-2-yl)-4-fluoropiperidine-4-carboxamide; (Z)-(1-((2'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-yl)(3-(2-(methylsulfonyl)vinyl)azetidine-1-yl)methanone; (R,Z)-1-((6-chloro-4-(2-chlorophenyl)pyridine-3-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (E)-1-((6-chloro-4-(2-chlorophenyl)pyridine-3-yl)sulfonyl)-N-(3-cyanoallyl)-4-fluoropiperidine-4-carboxamide; 1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-N-((1,1-dioxide-2H-thieta-3-yl)methyl)-4-fluoropiperidine-4-carboxamide; ( ＊ R)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(1-(1,1-dioxide-2H-thieta-3-yl)ethyl)-4-fluoropiperidine-4-carboxamide; (R)-1-((2'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(1-(1,1-dioxide-2H-thieta-3-yl)ethyl)-4-fluoropiperidine-4-carboxamide; (R)-1-((2'-chloro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(1-(1,1-dioxide-2H-thieta-3-yl)ethyl)-4-fluoropiperidine-4-carboxamide; 1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-((R,Z)-4-((( ＊ R)-1-methylpyrrolidine-3-yl)sulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; 1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-((R,Z)-4-((( ＊ S)-1-methylpyrrolidine-3-yl)sulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; ( ＊ S,Z)-1-((2'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(5,5,5-trifluoro-1-(methylsulfonyl)penta-1-en-3-yl)piperidine-4-carboxamide; ( ＊ S,Z)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(5,5,5-trifluoro-1-(methylsulfonyl)penta-1-en-3-yl)piperidine-4-carboxamide; (R)-1-(5-bromo-2'-chloro-[1,1'-biphenyl]-2-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-(2'-chloro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-(5-bromo-2'-chloro-[1,1'-biphenyl]-2-carbonyl)-N-((R,E)-5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoroazepan-4-carboxamide; (R)-1-(2'-chloro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-carbonyl)-N-((R,E)-5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoroazepan-4-carboxamide; (4R)-1-(2'-chloro-6'-fluoro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-carbonyl)-N-((R,E)-5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoroazepan-4-carboxamide; (R,Z)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(1-methoxy-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(1-methoxy-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((2'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(1-methoxy-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (E)-1-((2'-chloro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(5-(3,3-difluoroazetidine-1-yl)-2-methyl-5-oxopenta-3-en-2-yl)-4-fluoropiperidine-4-carboxamide; (2R,4S)-1-((2'-chloro-5-(trifluoromethoxy)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-2-methyl-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (2R,4S)-1-((2'-chloro-5-(difluoromethoxy)-[1,1'-biphenyl]-2-yl)sulfonyl)-N-((R,E)-5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (2R,4S)-1-((2'-chloro-5-((RS)-1-hydroxyethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-N-((R,E)-5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (2R,4S)-1-((2'-chloro-5-(difluoromethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-N-((R,E)-5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (R)-1-((3R,4R)-4-(2-chlorophenyl)-3-methyl-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; 1 - ((1 ＊ S, 2 ＊ S)-2-(2-chlorophenyl)-4,4-dimethylcyclohexane-1-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; 1-((3 ＊ R,4 ＊ S)-4-(2-chlorophenyl)-6,6-dimethyltetrahydro-2H-pyran-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; 1-((6 ＊ R, 7 ＊ R)-6-(2-chlorophenyl)spiro[3.5]nonane-7-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; tert-butyl 5-(2-chlorophenyl)-4-(4-fluoro-4-(((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)carbamoyl)piperidine-1-carbonyl)-3,4-dihydropyridine-1(2H)-carboxylate; tert-butyl (3 ＊ R,4 ＊ S)-3-(2-chlorophenyl)-4-(4-fluoro-4-(((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)carbamoyl)piperidine-1-carbonyl)piperidine-1-carboxylate; (S,Z)-1-((5-chloro-3'-(pyridine-3-ylmethoxy)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((5-chloro-3'-((3-methoxybenzyl)oxy)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((5-chloro-3'-(pentyloxy)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((5-chloro-3'-cyclobutoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((3'-(buta-2-in-1-yloxy)-5-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((5-chloro-3'-((2-chlorobenzyl)oxy)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((5-chloro-3'-((3-chlorobenzyl)oxy)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((5-chloro-3'-phenoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((3'-(benzyloxy)-5-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((5-chloro-3'-(pyridine-2-ylmethoxy)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((6-chloro-4-(3-methoxyphenyl)pyridine-3-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((6-chloro-4-(2-chloro-5-methoxyphenyl)pyridine-3-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; ( ＊ R)-1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azocan-4-carboxamide; (1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-yl)(3-((methylsulfonyl)methylene)azetidine-1-yl)methanone; (R,Z)-1-((4-(2-chlorophenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((5-(2-chlorophenyl)-1-methyl-2-oxo-1,2-dihydropyridine-4-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((4-(2-chlorophenyl)-6-hydroxypyridine-3-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((6-bromo-4-(2-chlorophenyl)pyridine-3-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (E)-1-((6-bromo-4-(2-chlorophenyl)pyridine-3-yl)sulfonyl)-N-(3-cyanoallyl)-4-fluoropiperidine-4-carboxamide; (S,Z)-1-((5-chloro-3'-(propylcarbamoyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(5-(dimethylamino)-5-oxopenta-3-in-2-yl)-4-fluoropiperidine-4-carboxamide; (S)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(5-(dimethylamino)-5-oxopenta-3-in-2-yl)-4-fluoropiperidine-4-carboxamide; (E)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(4-(3,3-difluoroazetidine-1-yl)-4-oxobuta-2-en-1-yl)-4-fluoropiperidine-4-carboxamide; (E)-1-((2'-chloro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(4-(3,3-difluoroazetidine-1-yl)-4-oxobuta-2-en-1-yl)-4-fluoropiperidine-4-carboxamide; (Z)-1-((2'-chloro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(4-(3,3-difluoroazetidine-1-yl)-4-oxobuta-2-en-1-yl)-4-fluoropiperidine-4-carboxamide; (Z)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(4-(3,3-difluoroazetidine-1-yl)-4-oxobuta-2-en-1-yl)-4-fluoropiperidine-4-carboxamide; (Z)-N-(4-(azetidine-1-yl)-4-oxobuta-2-en-1-yl)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxamide; (S,Z)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoropiperidine-4-carboxamide; (2R,4S)-1-((2'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-N-((Z)-4-(3,3-difluoroazetidine-1-yl)-4-oxobuta-2-en-1-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (2R,4S)-1-((4-(2-chlorophenyl)-6-(trifluoromethyl)pyridine-3-yl)sulfonyl)-N-((Z)-4-(3,3-difluoroazetidine-1-yl)-4-oxobuta-2-en-1-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (2R,4S)-1-((2'-chloro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-N-((Z)-4-(3,3-difluoroazetidine-1-yl)-4-oxobuta-2-en-1-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (2R,4S)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-N-((Z)-4-(3,3-difluoroazetidine-1-yl)-4-oxobuta-2-en-1-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (2R,4S)-1-((2'-chloro-5-cyano-[1,1'-biphenyl]-2-yl)sulfonyl)-N-((Z)-4-(3,3-difluoroazetidine-1-yl)-4-oxobuta-2-en-1-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (2 ＊ R,4 ＊ S)-1-((3 ＊ R,4 ＊ S)-4-(2-chlorophenyl)-6,6-dimethyltetrahydro-2H-pyran-3-carbonyl)-N-((Z)-4-(3,3-difluoroazetidine-1-yl)-4-oxobuta-2-en-1-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (R)-1-(2'-chloro-5-methoxy-[1,1'-biphenyl]-2-carbonyl)-N-((R)-1,1-dioxide-2,3-dihydrothiophen-3-yl)-4-fluoroazepan-4-carboxamide; (R)-1-(2'-chloro-5-methoxy-[1,1'-biphenyl]-2-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3R,4R)-4-(2-chloro-6-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,E)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3R,4R)-4-(2-chloro-6-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((S,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (2R,4S)-1-((2'-chloro-5-ethoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-N-((R,E)-5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (2R,4S)-1-((2'-chloro-5-ethoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-2-methyl-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (2R,4S)-1-((2'-chloro-5-(methoxy-d3)-[1,1'-biphenyl]-2-yl)sulfonyl)-N-((R,E)-5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (2R,4S)-1-((2'-chloro-5-(methoxy-d3)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-2-methyl-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (2 ＊ S, 4 ＊ S)-1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-2-methyl-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R)-1-((3R,4R)-4-(2-chlorophenyl)-1-cyclopropylpyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; 1-((3R,4R)-4-(2-chlorophenyl)-1-cyclopropylpyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R)-1-((3 ＊ R,4 ＊ R)-1-benzyl-4-(2-chlorophenyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3 ＊ R,4 ＊ R)-3-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)piperidine-4-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; 1-((3 ＊ S, 4 ＊ S)-3-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)piperidine-4-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R)-1-((3 ＊ R,4 ＊ S)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)piperidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-(( ＊ R)-2-(2-chlorophenyl)-4-(2,2,2-trifluoroethyl)piperazine-1-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((2'-chloro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (S)-1-((2'-chloro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((2'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (S)-1-((2'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; 1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-3-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)pyrrolidine-3-carboxamide; Or, The compound or pharmaceutically acceptable salt thereof according to claim 1, which is a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a pharmaceutically acceptable salt of a stereoisomer thereof or an atropisomer thereof or a pharmaceutically acceptable salt of atropisomer thereof.

57. The aforementioned compound, (R,Z)-1-((4-(2-chlorophenyl)-6-methoxypyridine-3-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((4-(2-chlorophenyl)-6-methoxypyridine-3-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (E)-1-((4-(2-chlorophenyl)-6-methoxypyridine-3-yl)sulfonyl)-4-fluoro-N-(3-(methylsulfonyl)allyl)piperidine-4-carboxamide; (E)-4-fluoro-1-((6-methoxy-4-(o-tolyl)pyridine-3-yl)sulfonyl)-N-(3-(methylsulfonyl)allyl)piperidine-4-carboxamide; (S,Z)-4-fluoro-1-((6-methoxy-4-(o-tolyl)pyridine-3-yl)sulfonyl)-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (E)-4-fluoro-1-((6-methoxy-4-phenylpyridine-3-yl)sulfonyl)-N-(3-(methylsulfonyl)allyl)piperidine-4-carboxamide; (S,Z)-4-fluoro-1-((6-methoxy-4-phenylpyridine-3-yl)sulfonyl)-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-4-fluoro-1-((6-methoxy-4-(o-tolyl)pyridine-3-yl)sulfonyl)-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (Z)-1-((4-(2-chlorophenyl)-6-methoxypyridine-3-yl)sulfonyl)-N-(3-cyanoallyl)-4-fluoropiperidine-4-carboxamide; Or, The compound or pharmaceutically acceptable salt thereof according to claim 1, which is a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a pharmaceutically acceptable salt of a stereoisomer thereof or an atropisomer thereof or a pharmaceutically acceptable salt of atropisomer thereof.

58. The aforementioned compound, tert-butyl (3RS,4RS)-3-(2-chlorophenyl)-4-(4-fluoro-4-(((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)carbamoyl)piperidine-1-carbonyl)pyrrolidine-1-carboxylate; Isopropyl (3R,4R)-3-(2-chlorophenyl)-4-(4-fluoro-4-(((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)carbamoyl)piperidine-1-carbonyl)pyrrolidine-1-carboxylate; Ethyl (3R,4R)-3-(2-chlorophenyl)-4-(4-fluoro-4-(((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)carbamoyl)piperidine-1-carbonyl)pyrrolidine-1-carboxylate; 1-((3R,4R)-4-(2-chlorophenyl)-1-pivaloylpyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; 1-((3R,4R)-1-benzoyl-4-(2-chlorophenyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; 1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; 1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-N-((R)-1,1-dioxide-2,3-dihydrothiophen-3-yl)-4-fluoropiperidine-4-carboxamide; (R)-1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3R,4R)-4-(2-chloro-5-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3R,4R)-4-(2-chloro-4-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3R,4R)-4-(2-chloro-3-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3R,4R)-4-(2-chloro-4-methylphenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3R,4R)-4-(2-chloro-5-methylphenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3R,4R)-4-(2-chloro-6-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3R,4R)-4-(2-chloro-3-methylphenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3R,4R)-4-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (2S,4S)-1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-N-((R)-1,1-dioxide-2,3-dihydrothiophen-3-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (2S,4S)-1-((3R,4R)-4-(2-chloro-3-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-N-((R)-1,1-dioxide-2,3-dihydrothiophen-3-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (R)-1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-N-((R)-1,1-dioxide-2,3-dihydrothiophen-3-yl)-4-fluoroazepan-4-carboxamide; (R)-1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,E)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; 1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2-difluorobutyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; 1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2-difluoropropyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R)-1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2-difluoropropyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; 1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2-difluoro-2-phenylethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; 1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2,3,3,3-pentafluoropropyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R)-1-((3R,4R)-4-(2-chloro-6-fluorophenyl)-1-(2,2-difluoropropyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3R,4R)-4-(2-chloro-6-fluorophenyl)-1-((1-fluorocyclopropyl)methyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3R,4R)-4-(2-chlorophenyl)-1-((1-fluorocyclopropyl)methyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R,Z)-1-((4-(2-chlorophenyl)-6-methoxypyridine-3-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((4-(2-chlorophenyl)-6-methoxypyridine-3-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (E)-1-((4-(2-chlorophenyl)-6-methoxypyridine-3-yl)sulfonyl)-4-fluoro-N-(3-(methylsulfonyl)allyl)piperidine-4-carboxamide; (E)-4-fluoro-1-((6-methoxy-4-(o-tolyl)pyridine-3-yl)sulfonyl)-N-(3-(methylsulfonyl)allyl)piperidine-4-carboxamide; (S,Z)-4-fluoro-1-((6-methoxy-4-(o-tolyl)pyridine-3-yl)sulfonyl)-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (E)-4-fluoro-1-((6-methoxy-4-phenylpyridine-3-yl)sulfonyl)-N-(3-(methylsulfonyl)allyl)piperidine-4-carboxamide; (S,Z)-4-fluoro-1-((6-methoxy-4-phenylpyridine-3-yl)sulfonyl)-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-4-fluoro-1-((6-methoxy-4-(o-tolyl)pyridine-3-yl)sulfonyl)-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (Z)-1-((4-(2-chlorophenyl)-6-methoxypyridine-3-yl)sulfonyl)-N-(3-cyanoallyl)-4-fluoropiperidine-4-carboxamide; (R)-1-((3R,4R)-1-(2-chloro-2,2-difluoroethyl)-4-(2-chlorophenyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3R,4R)-4-(2-chlorophenyl)-1-(3,3,3-trifluoropropyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2-difluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-1-(methylsulfonyl)penta-1-en-3-yl)azepan-4-carboxamide; Isopropyl (3S,4S)-3-(2-chlorophenyl)-4-(4-fluoro-4-(((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)carbamoyl)piperidine-1-carbonyl)pyrrolidine-1-carboxylate; (S,Z)-1-((5-chloro-3-(3-methoxyphenyl)pyridine-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((5-chloro-3'-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-methyl-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((2'-chloro-4,5-dimethoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((5-chloro-3'-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-methyl-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((4-bromo-2-(3-chloropyridine-2-yl)phenyl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((2'-chloro-5-(2-oxopyrrolidine-1-yl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; 1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2-difluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((4-(2-chlorophenyl)-6-(trifluoromethyl)pyridine-3-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((4-(2-chlorophenyl)-6-(trifluoromethyl)pyridine-3-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((4-(2-chloro-3-fluorophenyl)-6-(trifluoromethyl)pyridine-3-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((4-(2-chloro-3-fluorophenyl)-6-(trifluoromethyl)pyridine-3-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((4-(2-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyridine-3-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((4-(2-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyridine-3-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,E)-1-((4-(2-chlorophenyl)-6-(trifluoromethyl)pyridine-3-yl)sulfonyl)-N-(5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoropiperidine-4-carboxamide; (2R,4S)-1-((4-(2-chlorophenyl)-6-(trifluoromethyl)pyridine-3-yl)sulfonyl)-4-fluoro-2-methyl-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (2R,4S)-1-((4-(2-chlorophenyl)-6-(trifluoromethyl)pyridine-3-yl)sulfonyl)-N-((R,E)-5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (R,E)-1-((2'-chloro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(5-(3-fluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((6-chloro-4-(2-chloro-5-methoxyphenyl)pyridine-3-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((5-bromo-3-(2-chlorophenyl)pyridine-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((2',5-dimethoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((5-chloro-3'-(2-hydroxyethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (2 ＊ S, 4 ＊ S)-1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2-difluoropropyl)pyrrolidine-3-carbonyl)-N-((R)-1,1-dioxide-2,3-dihydrothiophen-3-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (R)-1-((3 ＊ S, 4 ＊ S)-4-(2-chloro-3-fluorophenyl)-1-(2,2-difluoropropyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-4-fluoro-1-((3 ＊ R,4 ＊ R)-4-(2-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)-1-((3 ＊ R,4 ＊ R)-4-(o-tolyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)azepan-4-carboxamide; (2 ＊ S, 4 ＊ S)-1-((3 ＊ S, 4 ＊ S)-4-(2-chloro-3-fluorophenyl)-1-(2,2-difluoropropyl)pyrrolidine-3-carbonyl)-N-((R)-1,1-dioxide-2,3-dihydrothiophen-3-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (R)-1-((3 ＊ S, 4 ＊ S)-4-(2-chloro-3,6-difluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3 ＊ S, 4 ＊ S)-4-(2-chloro-4,6-difluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (E)-4-fluoro-1-((3'-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(3-((1-methylpiperidine-4-yl)sulfonyl)allyl)piperidine-4-carboxamide; (R,E)-1-((2'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(4-cyanobuta-3-en-2-yl)-4-fluoropiperidine-4-carboxamide; (Z)-(1-((2'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-yl)(3-(2-(methylsulfonyl)vinyl)azetidine-1-yl)methanone; (R,Z)-1-((6-chloro-4-(2-chlorophenyl)pyridine-3-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (E)-1-((6-chloro-4-(2-chlorophenyl)pyridine-3-yl)sulfonyl)-N-(3-cyanoallyl)-4-fluoropiperidine-4-carboxamide; 1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-N-((1,1-dioxide-2H-thieta-3-yl)methyl)-4-fluoropiperidine-4-carboxamide; ( ＊ R)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(1-(1,1-dioxide-2H-thieta-3-yl)ethyl)-4-fluoropiperidine-4-carboxamide; (R)-1-((2'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(1-(1,1-dioxide-2H-thieta-3-yl)ethyl)-4-fluoropiperidine-4-carboxamide; (R)-1-((2'-chloro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(1-(1,1-dioxide-2H-thieta-3-yl)ethyl)-4-fluoropiperidine-4-carboxamide; 1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-((R,Z)-4-((( ＊ R)-1-methylpyrrolidine-3-yl)sulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; 1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-((R,Z)-4-((( ＊ S)-1-methylpyrrolidine-3-yl)sulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; ( ＊ S,Z)-1-((2'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(5,5,5-trifluoro-1-(methylsulfonyl)penta-1-en-3-yl)piperidine-4-carboxamide; ( ＊ S,Z)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(5,5,5-trifluoro-1-(methylsulfonyl)penta-1-en-3-yl)piperidine-4-carboxamide; (R)-1-(5-bromo-2'-chloro-[1,1'-biphenyl]-2-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-(2'-chloro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-(5-bromo-2'-chloro-[1,1'-biphenyl]-2-carbonyl)-N-((R,E)-5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoroazepan-4-carboxamide; (R)-1-(2'-chloro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-carbonyl)-N-((R,E)-5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoroazepan-4-carboxamide; (4R)-1-(2'-chloro-6'-fluoro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-carbonyl)-N-((R,E)-5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoroazepan-4-carboxamide; (R,Z)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(1-methoxy-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(1-methoxy-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((2'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(1-methoxy-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (E)-1-((2'-chloro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(5-(3,3-difluoroazetidine-1-yl)-2-methyl-5-oxopenta-3-en-2-yl)-4-fluoropiperidine-4-carboxamide; (2R,4S)-1-((2'-chloro-5-(trifluoromethoxy)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-2-methyl-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (2R,4S)-1-((2'-chloro-5-(difluoromethoxy)-[1,1'-biphenyl]-2-yl)sulfonyl)-N-((R,E)-5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (2R,4S)-1-((2'-chloro-5-((RS)-1-hydroxyethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-N-((R,E)-5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (2R,4S)-1-((2'-chloro-5-(difluoromethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-N-((R,E)-5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (R)-1-((3R,4R)-4-(2-chlorophenyl)-3-methyl-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; 1 - ((1 ＊ S, 2 ＊ S)-2-(2-chlorophenyl)-4,4-dimethylcyclohexane-1-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; 1 - ((1 ＊ S, 2 ＊ S)-2-(2-chlorophenyl)-4,4-dimethylcyclohexane-1-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; 1-((6 ＊ R, 7 ＊ R)-6-(2-chlorophenyl)spiro[3.5]nonane-7-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; tert-butyl 5-(2-chlorophenyl)-4-(4-fluoro-4-(((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)carbamoyl)piperidine-1-carbonyl)-3,4-dihydropyridine-1(2H)-carboxylate; tert-butyl (3 ＊ R,4 ＊ S)-3-(2-chlorophenyl)-4-(4-fluoro-4-(((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)carbamoyl)piperidine-1-carbonyl)piperidine-1-carboxylate; (S,Z)-1-((5-chloro-3'-(pyridine-3-ylmethoxy)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((5-chloro-3'-((3-methoxybenzyl)oxy)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((5-chloro-3'-(pentyloxy)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((5-chloro-3'-cyclobutoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((3'-(buta-2-in-1-yloxy)-5-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((5-chloro-3'-((2-chlorobenzyl)oxy)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((5-chloro-3'-((3-chlorobenzyl)oxy)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((5-chloro-3'-phenoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((3'-(benzyloxy)-5-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((5-chloro-3'-(pyridine-2-ylmethoxy)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((6-chloro-4-(3-methoxyphenyl)pyridine-3-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (S,Z)-1-((6-chloro-4-(2-chloro-5-methoxyphenyl)pyridine-3-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; ( ＊ R)-1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azocan-4-carboxamide; (1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-yl)(3-((methylsulfonyl)methylene)azetidine-1-yl)methanone; (R,Z)-1-((4-(2-chlorophenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((5-(2-chlorophenyl)-1-methyl-2-oxo-1,2-dihydropyridine-4-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((4-(2-chlorophenyl)-6-hydroxypyridine-3-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R,Z)-1-((6-bromo-4-(2-chlorophenyl)pyridine-3-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (E)-1-((6-bromo-4-(2-chlorophenyl)pyridine-3-yl)sulfonyl)-N-(3-cyanoallyl)-4-fluoropiperidine-4-carboxamide; (S,Z)-1-((5-chloro-3'-(propylcarbamoyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(5-(dimethylamino)-5-oxopenta-3-in-2-yl)-4-fluoropiperidine-4-carboxamide; (S)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(5-(dimethylamino)-5-oxopenta-3-in-2-yl)-4-fluoropiperidine-4-carboxamide; (E)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(4-(3,3-difluoroazetidine-1-yl)-4-oxobuta-2-en-1-yl)-4-fluoropiperidine-4-carboxamide; (E)-1-((2'-chloro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(4-(3,3-difluoroazetidine-1-yl)-4-oxobuta-2-en-1-yl)-4-fluoropiperidine-4-carboxamide; (Z)-1-((2'-chloro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(4-(3,3-difluoroazetidine-1-yl)-4-oxobuta-2-en-1-yl)-4-fluoropiperidine-4-carboxamide; (Z)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(4-(3,3-difluoroazetidine-1-yl)-4-oxobuta-2-en-1-yl)-4-fluoropiperidine-4-carboxamide; (Z)-N-(4-(azetidine-1-yl)-4-oxobuta-2-en-1-yl)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoropiperidine-4-carboxamide; (S,Z)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoropiperidine-4-carboxamide; (2R,4S)-1-((2'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-N-((Z)-4-(3,3-difluoroazetidine-1-yl)-4-oxobuta-2-en-1-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (2R,4S)-1-((4-(2-chlorophenyl)-6-(trifluoromethyl)pyridine-3-yl)sulfonyl)-N-((Z)-4-(3,3-difluoroazetidine-1-yl)-4-oxobuta-2-en-1-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (2R,4S)-1-((2'-chloro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-N-((Z)-4-(3,3-difluoroazetidine-1-yl)-4-oxobuta-2-en-1-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (2R,4S)-1-((5-bromo-2'-chloro-[1,1'-biphenyl]-2-yl)sulfonyl)-N-((Z)-4-(3,3-difluoroazetidine-1-yl)-4-oxobuta-2-en-1-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (2R,4S)-1-((2'-chloro-5-cyano-[1,1'-biphenyl]-2-yl)sulfonyl)-N-((Z)-4-(3,3-difluoroazetidine-1-yl)-4-oxobuta-2-en-1-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (2 ＊ R,4 ＊ S)-1-((3 ＊ R,4 ＊ S)-4-(2-chlorophenyl)-6,6-dimethyltetrahydro-2H-pyran-3-carbonyl)-N-((Z)-4-(3,3-difluoroazetidine-1-yl)-4-oxobuta-2-en-1-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (R)-1-(2'-chloro-5-methoxy-[1,1'-biphenyl]-2-carbonyl)-N-((R)-1,1-dioxide-2,3-dihydrothiophen-3-yl)-4-fluoroazepan-4-carboxamide; (R)-1-(2'-chloro-5-methoxy-[1,1'-biphenyl]-2-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3R,4R)-4-(2-chloro-6-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,E)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3R,4R)-4-(2-chloro-6-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((S,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (2R,4S)-1-((2'-chloro-5-ethoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-N-((R,E)-5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (2R,4S)-1-((2'-chloro-5-ethoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-2-methyl-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (2R,4S)-1-((2'-chloro-5-(methoxy-d3)-[1,1'-biphenyl]-2-yl)sulfonyl)-N-((R,E)-5-(3,3-difluoroazetidine-1-yl)-5-oxopenta-3-en-2-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (2R,4S)-1-((2'-chloro-5-(methoxy-d3)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-2-methyl-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (2 ＊ S, 4 ＊ S)-1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-2-methyl-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R)-1-((3R,4R)-4-(2-chlorophenyl)-1-cyclopropylpyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; 1-((3R,4R)-4-(2-chlorophenyl)-1-cyclopropylpyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R)-1-((3 ＊ R,4 ＊ R)-1-benzyl-4-(2-chlorophenyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3 ＊ R,4 ＊ R)-3-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)piperidine-4-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; 1-((3 ＊ S, 4 ＊ S)-3-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)piperidine-4-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R)-1-((3 ＊ R,4 ＊ S)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)piperidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-(( ＊ R)-2-(2-chlorophenyl)-4-(2,2,2-trifluoroethyl)piperazine-1-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((2'-chloro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (S)-1-((2'-chloro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((2'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (S)-1-((2'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; Or, The compound or pharmaceutically acceptable salt thereof according to claim 1, which is a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof.

59. The aforementioned compound, 1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; 1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-N-((R)-1,1-dioxide-2,3-dihydrothiophen-3-yl)-4-fluoropiperidine-4-carboxamide; (R)-1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3 ＊ R,4 ＊ R)-4-(2-chloro-5-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3 ＊ R,4 ＊ R)-4-(2-chloro-4-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3 ＊ R,4 ＊ R)-4-(2-chloro-3-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3 ＊ R,4 ＊ R)-4-(2-chloro-4-methylphenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3 ＊ R,4 ＊ R)-4-(2-chloro-5-methylphenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3R,4R)-4-(2-chloro-6-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3 ＊ R,4 ＊ R)-4-(2-chloro-3-methylphenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3 ＊ R,4 ＊ R)-4-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (2 ＊ S, 4 ＊ S)-1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-N-((R)-1,1-dioxide-2,3-dihydrothiophen-3-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (2 ＊ S, 4 ＊ S)-1-((3 ＊ R,4 ＊ R)-4-(2-chloro-3-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-N-((R)-1,1-dioxide-2,3-dihydrothiophen-3-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (R)-1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-N-((R)-1,1-dioxide-2,3-dihydrothiophen-3-yl)-4-fluoroazepan-4-carboxamide; (R)-1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,E)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; 1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2-difluorobutyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; 1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2-difluoropropyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R)-1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2-difluoropropyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; 1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2,3,3,3-pentafluoropropyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R)-1-((3R,4R)-4-(2-chloro-6-fluorophenyl)-1-(2,2-difluoropropyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3R,4R)-1-(2-chloro-2,2-difluoroethyl)-4-(2-chlorophenyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3R,4R)-4-(2-chlorophenyl)-1-(3,3,3-trifluoropropyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2-difluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-1-(methylsulfonyl)penta-1-en-3-yl)azepan-4-carboxamide; 1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2-difluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (2 ＊ S, 4 ＊ S)-1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2-difluoropropyl)pyrrolidine-3-carbonyl)-N-((R)-1,1-dioxide-2,3-dihydrothiophen-3-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (R)-1-((3 ＊ S, 4 ＊ S)-4-(2-chloro-3-fluorophenyl)-1-(2,2-difluoropropyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-4-fluoro-1-((3 ＊ R,4 ＊ R)-4-(2-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)-1-((3 ＊ R,4 ＊ R)-4-(o-tolyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)azepan-4-carboxamide; (2 ＊ S, 4 ＊ S)-1-((3 ＊ S, 4 ＊ S)-4-(2-chloro-3-fluorophenyl)-1-(2,2-difluoropropyl)pyrrolidine-3-carbonyl)-N-((R)-1,1-dioxide-2,3-dihydrothiophen-3-yl)-4-fluoro-2-methylpiperidine-4-carboxamide; (R)-1-((3 ＊ S, 4 ＊ S)-4-(2-chloro-3,6-difluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3 ＊ S, 4 ＊ S)-4-(2-chloro-4,6-difluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3R,4R)-4-(2-chlorophenyl)-3-methyl-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; ( ＊ R)-1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azocan-4-carboxamide; (R)-1-((3R,4R)-4-(2-chloro-6-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((R,E)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (R)-1-((3R,4R)-4-(2-chloro-6-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-N-((S,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; (2 ＊ S, 4 ＊ S)-1-((3R,4R)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carbonyl)-4-fluoro-2-methyl-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R)-1-((3 ＊ R,4 ＊ R)-3-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)piperidine-4-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; 1-((3 ＊ S, 4 ＊ S)-3-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)piperidine-4-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)piperidine-4-carboxamide; (R)-1-((3 ＊ R,4 ＊ S)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)piperidine-3-carbonyl)-4-fluoro-N-((R,Z)-4-(methylsulfonyl)buta-3-en-2-yl)azepan-4-carboxamide; Or, The compound or pharmaceutically acceptable salt thereof according to claim 1, which is a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a pharmaceutically acceptable salt of a stereoisomer thereof or an atropisomer thereof or a pharmaceutically acceptable salt of atropisomer thereof.

60. A pharmaceutical composition comprising: a compound according to any one of claims 1 to 59 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a pharmaceutically acceptable salt of a stereoisomer thereof or an atropisomer thereof or a pharmaceutically acceptable salt of atropisomer thereof; and a pharmaceutically acceptable excipient or carrier; the pharmaceutical composition.

61. A method for modulating RAS-PI3K, comprising administering a therapeutically effective amount of the compound described in any one of claims 1-59 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a pharmaceutically acceptable salt of a stereoisomer thereof or an atropisomer thereof or a pharmaceutically acceptable salt of atropisomer thereof to a subject for whom modulation of RAS-PI3K is required.

62. The method according to claim 61, comprising inhibiting RAS-PI3K.

63. The method according to claim 61, comprising activating RAS-PI3K.

64. A method for treating a disease or condition, comprising administering to a person in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1-59 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a pharmaceutically acceptable salt thereof or an atropisomer thereof or a pharmaceutically acceptable salt thereof.

65. The method according to claim 64, wherein the disease or condition is mediated by the modulation of RAS-PI3K.

66. The method according to claim 64 or 65, wherein the disease is cancer.

67. The method according to claim 66, wherein the cancer is selected from the group consisting of bladder cancer, uterine cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, lung cancer, colorectal cancer, cervical cancer, bile duct cancer, stomach cancer, kidney cancer, and pancreatic cancer.

68. The method according to claim 64 or 65, wherein the disease or condition is an immunological disorder.

69. The method according to claim 68, wherein the immunological disease or condition is the promotion of wound healing.

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