EP2 antagonist compounds

Abstract

Described herein are compounds that are EP2 antagonists, methods for making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds in the treatment of diseases or conditions associated with EP2 activity.

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 214,635, filed June 24, 2021, which is incorporated by reference in its entirety herein.

[0002] FIELD OF THEINVENTION Described herein are compounds that are inhibitors of prostaglandin E2 receptor 2, also known as EP2, methods for making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds in the treatment of diseases or conditions associated with EP2 activity. [Background technology]

[0003] 2. Background of the Invention EP2 is, for example, a prostaglandin receptor that functions as a mediator of inflammation. EP2 signaling is involved in, for example, inflammatory conditions, allergic diseases, eye diseases, nervous system diseases, bone diseases, fibrotic conditions, cardiovascular diseases, and certain forms of cancer. Summary of the Invention [Means for solving the problem]

[0004] Summary of the Invention The compounds described herein are antagonists of EP2. In some embodiments, the compounds described herein are used to treat or prevent diseases and conditions in which EP2 activity contributes to the symptoms or progression of the disease and condition, such as, for example, inflammatory diseases and conditions.

[0005] In one embodiment, a compound having the structure of Formula (I): [ka] or a pharma- ceutically acceptable salt or solvate thereof, wherein: R 1 teeth [ka] , -C(O)NR d R e , -N(R f ) 2 , a substituted or unsubstituted monocyclic heterocycle, or a substituted or unsubstituted monocyclic carbocycle, where R 1 When R is a substituted monocyclic heterocycle, it may occur one or more instances of R 9 is replaced by; R a is hydrogen, deuterium, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, or C 1 ~C 6 is a fluoroalkyl; R b are hydrogen, deuterium, and C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C 6 is heterocycloalkyl; or R a and R b are substituted or unsubstituted C together with the carbon atom to which they are attached. 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C 6 heterocycloalkyl, where ring C is substituted with one or more R 11 and R c is hydrogen, C 1 ~C 6 Alkyl or R g Is it; or R a and R btogether with the carbon atom to which they are attached form a carbonyl (C=O); and R c is C 3 ~C 6 Alkyl or R g and; R d -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, C 1~6 Alkoxy, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, -OH, OR 1d , -SOR 1d , or -SO 2 R 1d where R 1d is a substituted or unsubstituted C 1 ~C 6 Alkyl, substituted or unsubstituted C 3 ~C 6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl; 1d If is substituted, it is one or more R 14 is replaced by; R e is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, C 1 ~ 6 Alkoxy, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C 6 is heterocycloalkyl; or R d and R eare substituted or unsubstituted C together with the N atom to which they are attached. 2 ~C 6 Forming a heterocycloalkyl; Each R f are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C 6 is heterocycloalkyl; Or both R f are substituted or unsubstituted C together with the N atom to which they are attached. 2 ~C 6 Forming a heterocycloalkyl; R g is C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 1 ~C 6 Heteroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C 3 ~C 6 Cycloalkyl), -alkyl-(substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl), -C(=O)R 16 , -C(=O)-OR 16 , -C(=O)N(R 16 ) 2 , -(C(R 17 ) 2 O) p -R15 , -(CH 2 CH 2 O) q -R 15 , or -(C(R 17 ) 2 ) p -OR 15 and; p is 1, 2, 3, 4, or 5; q is 1, 2, 3, 4, or 5; Each R 17 are independently hydrogen or C 1 ~C 6 is alkyl; R 15 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted C 2 ~C 10 Heterocycloalkyl, -C(=O)R 16 , -C(=O)-OR 16 , or -C(=O)N(R 16 ) 2 and; R 2 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, or C 1 ~C 6 is a fluoroalkyl; R 3 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C 6 is heterocycloalkyl; or R 2 and R 3 together with the carbon atom to which they are attached form a carbonyl (C=O) or a thiocarbonyl (C=S); or R 2 and R3 are substituted or unsubstituted C together with the carbon atom to which they are attached. 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C 6 heterocycloalkyl, where if ring B is substituted, it is substituted with one or more R 12 is replaced by; Z is N or CR 8 and; L is absent or -NH-; R 4 , R 5 , R 7 , and R 8 are each independently hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 and; R 6 is hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , -NR 16 C(=O)R 16 , substituted or unsubstituted C 3 ~C6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl; 6 If is substituted, it is one or more R 13 is replaced by; Ring A is substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl; Each R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are independently hydrogen, deuterium, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, -CN, -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 and; Each R 16 are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C 3 ~C 6 cycloalkyl), or -alkyl-(substituted or unsubstituted C 2 ~C 6 heterocycloalkyl); Or both R 16 are substituted or unsubstituted C together with the N atom to which they are attached. 2 ~C 6 Forming a heterocycloalkyl; R 18 and R 19 are independently hydrogen, deuterium, and C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, or C 1 ~C 6 Is it fluoroalkyl; or R 18 and R 19 along with the carbon atom to which they are attached, C 3 ~C 6 Cycloalkane, or C 2 ~C 6 forming a ring E which is heterocycloalkyl; m is 1 or 2; and where n is 0, 1, 2, 3, or 4.

[0006] In another embodiment, a compound having the structure of formula (II): [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0007] In another embodiment, a compound having the structure of formula (III): [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0008] In another embodiment, a compound having the structure of formula (IV): [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0009] In another embodiment, a compound having the structure of formula (VI): [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0010] In another embodiment, a compound having the structure of formula (VI-A): [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0011] In another embodiment, a compound having the structure of formula (X): [ka] (wherein: R 1a -CO 2 H, -CO 2 -R 1b , -C(O)N(R 1c ) 2 or -CN; R 1b is C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 1 ~C 6 Heteroalkyl, substituted or unsubstituted C 3 ~C6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C 3 ~C 6 Cycloalkyl), -alkyl-(substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl), -C(=O)R 16 , -C(=O)-OR 16 , -C(=O)N(R 16 ) 2 , -(C(R 17 ) 2 O) p -R 15 , -(CH 2 CH 2 O) q -R 15 , or -(C(R 17 ) 2 ) p -OR 15 and; p is 1, 2, 3, 4, or 5; q is 1, 2, 3, 4, or 5; Each R 17 are independently hydrogen or C 1 ~C 6 is alkyl; R 15 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted C 2 ~C 10 Heterocycloalkyl, -C(=O)R 16 , -C(=O)-OR 16 , or -C(=O)N(R 16 ) 2 and; Each R 1c are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, -OH, -SOR 1d , or -SO 2 R 1d where R 1d is substituted or unsubstituted C 1 ~C 6 is alkyl; Or both R 1c are substituted or unsubstituted C together with the N atom to which they are attached. 2 ~C 6 Forming a heterocycloalkyl; R 2 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, or C 1 ~C 6 is a fluoroalkyl; R 3 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C 6 is heterocycloalkyl; or R 2 and R 3 form thiocarbonyls (C=S) together with the carbon atoms to which they are attached; or R 2 and R 3 are substituted or unsubstituted C together with the carbon atom to which they are attached. 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C 6heterocycloalkyl, where if ring B is substituted, it is substituted with one or more R 12 is replaced by; Z is N or CR 8 and; L is absent or -NH-; R 4 , R 5 , R 7 , and R 8 are each independently hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 and; R 6 is hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , -NR 16 C(=O)R 16 , substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl;6 If is substituted, it is one or more R 13 is replaced by; or R 5 and R 6 together with the intervening atoms to which they are attached form a fused ring D which is a substituted or unsubstituted 5- or 6-membered carbocyclic ring or a substituted or unsubstituted 5- or 6-membered heterocyclic ring, where when ring D is substituted it is joined to one or more R 14 is replaced by; Ring A is substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl; Each R 10 , R 12 , R 13 , and R 14 are independently hydrogen, deuterium, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, -CN, -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 and; Each R 16 are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C 3 ~C 6 Cycloalkyl), -alkyl-(substituted or unsubstituted C 2 ~C 6 heterocycloalkyl); Or both R 16 are substituted or unsubstituted C together with the N atom to which they are attached. 2 ~C 6 Forming a heterocycloalkyl; R 18 and R 19 are independently hydrogen, deuterium, and C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, or C 1 ~C 6 Is it fluoroalkyl; or R 18 and R 19 along with the carbon atom to which they are attached, C 3 ~C 6 Cycloalkane or C 2 ~C 6 forming a ring E which is heterocycloalkyl; m is 1 or 2; and where n is 0, 1, 2, 3, or 4.

[0012] In another embodiment, the compound has the structure of formula (XX): [ka] or a pharma- ceutically acceptable salt or solvate thereof, wherein: R 1 teeth [ka] , -C(O)NR d R e , -N(Rf ) 2 , a substituted or unsubstituted monocyclic heterocycle, or a substituted or unsubstituted monocyclic carbocycle, where R 1 When R is a substituted monocyclic heterocycle, it may occur one or more times. 9 is replaced by; R a are hydrogen, deuterium, and C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 is a fluoroalkyl; R b are hydrogen, deuterium, and C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C 6 is heterocycloalkyl; or R a and R b are substituted or unsubstituted C together with the carbon atom to which they are attached. 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C 6 heterocycloalkyl, where ring C is substituted with one or more R 11 and R c is hydrogen, C 1 ~C 6 Alkyl or R g Is it; or R a and R b together with the carbon atom to which they are attached form a carbonyl (C=O); and R c is C 3 ~C 6 Alkyl or R g and; Rd -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, C 1 ~ 6 Alkoxy, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, -OH, -OR 1d , -SOR 1d , or -SO 2 R 1d where R 1d is a substituted or unsubstituted C 1 ~C 6 Alkyl, substituted or unsubstituted C 3 ~C 6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl; 1d If is substituted, it is one or more R 14 is replaced by; R e is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, C 1 ~ 6 Alkoxy, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C 6 is heterocycloalkyl; or R d and R e are substituted or unsubstituted C together with the N atom to which they are attached. 2 ~C 6 Forming a heterocycloalkyl; Each R fare independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C 6 is heterocycloalkyl; Or both R f are substituted or unsubstituted C together with the N atom to which they are attached. 2 ~C 6 Forming a heterocycloalkyl; R g is C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 1 ~C 6 Heteroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C 3 ~C 6 Cycloalkyl), -alkyl-(substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl), -C(=O)R 16 , -C(=O)-OR 16 , -C(=O)N(R 16 ) 2 , -(C(R 17 ) 2 O) p -R 15 , -(CH 2 CH 2 O) q -R 15 , or -(C(R 17 ) 2) p -OR 15 and; Z is N or CR 8 and; R 4 , R 5 , R 7 , and R 8 are each independently hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 and; R 6 is hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , -NR 16 C(=O)R 16 , substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl; 6 If is substituted, it is one or more R 13 is replaced by; Each R9 , R 10 , R 11 , R 13 , and R 14 are independently hydrogen, deuterium, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, -CN, -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 and; R 15 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted C 2 ~C 10 Heterocycloalkyl, -C(=O)R 16 , -C(=O)-OR 16 , or -C(=O)N(R 16 ) 2 and; Each R 16 are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C 3 ~C 6 Cycloalkyl), -alkyl-(substituted or unsubstituted C 2 ~C 6 heterocycloalkyl); Or both R 16 are substituted or unsubstituted C together with the N atom to which they are attached. 2 ~C 6 Forming a heterocycloalkyl; Each R 17 are independently hydrogen or C 1 ~C 6 is alkyl; m is 1 or 2; n is 0, 1, 2, 3, or 4; p is 1, 2, 3, 4, or 5; and and q is 1, 2, 3, 4, or 5.

[0013] In another embodiment, the compound has the structure of formula (XXI): [ka] or a pharma- ceutically acceptable salt thereof, R 1 is -C(O)OR c or -C(O)NR d R e and; R c is C 3 ~C 6 Alkyl or R g and; R d -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Fluoroalkyl, -OH, -OR 1d , or -SO 2 R 1d and; R 1d is a substituted or unsubstituted C 1 ~C 6 Alkyl, substituted or unsubstituted C 3 ~C 6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, or substituted or unsubstituted phenyl; 1d If is substituted, it is one or more R 14 is replaced by; R e is hydrogen or -CH 3 and; R g is C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 1 ~C 6 Heteroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl; R 10 is hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Fluoroalkyl or OR 16 and; R 13 are hydrogen, deuterium, halogens, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, -CN, -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 and; R 14 is hydrogen, halogen, C 1 ~C 6 Alkyl, -CN, or -OR 16 and; Each R 16 are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, or substituted or unsubstituted C 3 ~C 6 is cycloalkyl; m is 1 or 2; and where n is 0, 1, 2, 3, or 4.

[0014] In another embodiment, a compound of Table 1, Table 2, Table 3, or Table 4, or a pharma- ceutically acceptable salt or solvate or tautomer thereof, is disclosed herein.

[0015] In another embodiment, there is a compound of Formula I, Formula I', Formula II, Formula III, Formula IV, Formula V, Formula V', Formula VI, Formula VI', Formula VI-A, Formula VI-A', Formula VI-A'', Formula VI-A''', Formula VI-B, or Formula VI-C, or a pharma- ceutically acceptable salt or solvate or tautomer thereof.

[0016] In another embodiment, there is a compound of formula X, formula XI, formula XII, formula XIII, formula XIII-A, formula XIII-B, formula XIII-C, formula XIV, formula XV, or formula XVI, or a pharma- ceutically acceptable salt or solvate or tautomer thereof.

[0017] In another embodiment is a compound of formula XX, formula XXI, formula XXI', formula XXI'', formula XXI''', formula XXII, or a pharma- ceutically acceptable salt or solvate or tautomer thereof.

[0018] In another embodiment, there is a pharmaceutical composition comprising a compound disclosed herein, or a pharma- ceutically acceptable salt or solvate thereof, and at least one pharma- ceutically acceptable excipient.

[0019] In another embodiment, there is a method of modulating the activity of prostaglandin E2 receptor 2 (EP2) in a mammal, comprising administering to the mammal a compound disclosed herein or a pharma- ceutically acceptable salt or solvate thereof.

[0020] In another embodiment, there is a method for treating a disease or condition that would benefit from modulation of prostaglandin E2 receptor 2 (EP2) activity, comprising administering to a mammal a compound disclosed herein or a pharma- ceutically acceptable salt or solvate thereof.

[0021] Any combination of the above groups for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof will be chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0022] In another aspect, described herein are pharmaceutical compositions comprising a compound decribed herein or a pharma- ceutically acceptable salt or solvate thereof, and at least one pharma- ceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous, subcutaneous, oral, inhalation, or intranasal administration. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, capsule, liquid, suspension, dispersion, solution, or emulsion.

[0023] In another aspect, described herein is a method of modulating the activity of prostaglandin E2 receptor 2 (EP2) in a mammal, comprising administering to the mammal a compound described herein, or a pharma- ceutically acceptable salt or solvate thereof.

[0024] In yet another aspect, described herein is a method for treating a disease or condition that would benefit from modulation of prostaglandin E2 receptor 2 (EP2) activity, comprising administering to a mammal a compound described herein, or a pharma- ceutically acceptable salt or solvate thereof.

[0025] Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] Detailed Description of the Invention Prostaglandins act on prostaglandin receptors such as the prostaglandin DP1 receptor (DP1), prostaglandin DP2 receptor (DP2), prostaglandin EP1 receptor (EP1), prostaglandin EP2 receptor (EP2), prostaglandin EP3 receptor (EP3), prostaglandin EP4 receptor (EP4), prostaglandin F2α receptor (FP1), prostacyclin I2 receptor (IP), and thromboxane A2 receptor (TP), or combinations thereof.

[0027] Prostaglandin E2 (PGE2) is a metabolite of arachidonic acid that is synthesized by the action of cyclooxygenase and prostaglandin E synthase. PGE2 is produced in almost all organs and tissues and has a variety of physiological effects, including mucosal protection, induction of gastric acid secretion in the stomach, fever, hyperalgesia, inflammation, and immunity. PGE2 The action of PGE2 is mediated by four receptors, EP1, EP2, EP3 and EP4. PGE2 has affinity for all four EP receptor subtypes as well as other prostanoid receptors, such as the PGE2 DP1 receptor.

[0028] PGE2 is a downstream product of the cyclooxygenase-2 (COX-2) pathway and a key regulator of inflammation.

[0029] When EP2 binds to PGE2, it s It is a G protein-coupled receptor that recruits proteins and initiates a signaling cascade involving adenylyl cyclase (thereby elevating cAMP) and protein kinase A (PKA). Coupling of EP2 to Gs proteins stimulates adenylyl cyclase, the activation of which increases intracellular cAMP levels. This signaling pathway has close implications for inflammation, pain, immune regulation, mitogenesis, plasticity, and cell injury. EP2 interacts with the β-arrestin / JNK pathway, which may affect proliferation and metastasis.

[0030] Expression of the EP2 receptor has been demonstrated in a wide range of cell types and tissues, including lung, gastrointestinal tract, kidney, uterus, myleoid and thymus, and has been associated with PGE2-mediated vasodilation and smooth muscle relaxation in the lung, gastrointestinal and reproductive tracts.

[0031] In some embodiments, the compounds described herein modulate the activity of EP2. In some embodiments, the compounds described herein inhibit or reduce the magnitude of inflammatory PGE2 signaling through the EP2 receptor. In some embodiments, the compounds described herein reduce or eliminate one or more symptoms associated with an EP2-mediated disease or disorder (e.g., an EP2-mediated inflammatory disease or disorder).

[0032] Abnormal EP2 expression is observed in several forms of cancer, including colon, prostate, liver, and breast cancer. EP2 activity (e.g., overactivity) has also been linked to cancer risk factors, including chronic inflammation, immune control, angiogenesis, metastasis, and multidrug resistance. In some embodiments, disclosed herein are methods of treating cancer with the compounds disclosed herein. As used herein, the term "cancer" refers to the abnormal growth of cells that tend to proliferate uncontrollably and, in some cases, metastasize (spread).

[0033] In some embodiments, the compounds described herein reduce one or more symptoms of EP2-mediated cancer. In some embodiments, the compounds described herein reduce or reverse the progression of EP2-mediated cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is colon cancer.

[0034] In some embodiments, EP2 signaling (i.e., PGE 2 EP2 activation (by EP2 activation) contributes to inflammation by increasing vascular permeability, increasing edema and leukocyte infiltration, thereby allowing more blood flow to the inflamed body part. In some embodiments, modulation of EP2 function has an effect on B lymphocyte, T lymphocyte, cytotoxic T cell function, or a combination thereof.

[0035] In some embodiments, disclosed herein are methods of treating inflammation with the compounds disclosed herein. In some embodiments, the compounds disclosed herein are used to reduce or inhibit inflammation in a mammal. In some embodiments, the compounds disclosed herein are used in the treatment or prevention of inflammation-related conditions (e.g., allergies, pain, etc.).

[0036] In some embodiments, disclosed herein are methods of reducing inflammation in a tissue, comprising contacting an inflamed cell or tissue with a compound disclosed herein in an amount sufficient to reduce or inhibit inflammation. In some embodiments, inflammation includes inflammatory or allergic conditions.

[0037] In some embodiments, the compounds disclosed herein are disclosed to reduce one or more symptoms of a neuroinflammatory disease or disorder, including reducing the activity of EP2 (e.g., by contacting an inflamed tissue with an EP2 antagonist disclosed herein). In some embodiments, methods are disclosed herein for reducing or halting the progression of a neuroinflammatory disease or disorder, including administering a compound disclosed herein to an individual (e.g., a mammal, a human, etc.) in need thereof.

[0038] In some embodiments, reducing inflammation or treating an inflammatory condition comprises reducing or inhibiting the activity of EP2. In some embodiments, reducing inflammation or treating an inflammatory condition comprises administering an antagonist of EP2 (e.g., an EP2 antagonist disclosed herein).

[0039] In some embodiments, the inflammatory condition is an allergic condition. In some embodiments, the inflammatory condition is asthma. In some embodiments, the inflammatory condition is anaphylaxis. In some embodiments, the inflammatory condition is chronic inflammation. In some embodiments, disclosed herein is a method for treating chronic inflammation, comprising administering an EP2 antagonist (e.g., a compound disclosed herein) to an individual in need thereof.

[0040] compound The compounds described herein, including pharma- ceutically acceptable salts, prodrugs, active metabolites, and pharma- ceutically acceptable solvates thereof, are EP2 antagonists.

[0041] In one aspect, a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof is described herein: [ka] (In the formula, R 1 teeth [ka] , -C(O)NR d R e , -N(R f ) 2 , a substituted or unsubstituted monocyclic heterocycle, or a substituted or unsubstituted monocyclic carbocycle, where R 1 When R is a substituted monocyclic heterocycle, it may occur one or more times. 9 is replaced by; R a are hydrogen, deuterium, and C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 is a fluoroalkyl; R b are hydrogen, deuterium, and C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C 6 is heterocycloalkyl; or R a and R b are substituted or unsubstituted C together with the carbon atom to which they are attached. 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C 6 heterocycloalkyl, where ring C is substituted with one or more R11 and R c is hydrogen, C 1 ~C 6 Alkyl or R g Is it; or R a and R b together with the carbon atom to which they are attached form a carbonyl (C=O); and R c is C 3 ~C 6 Alkyl or R g and; R d -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, C 1 ~ 6 Alkoxy, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, OH, OR 1d , -SOR 1d , or -SO 2 R 1d where R 1d is a substituted or unsubstituted C 1 ~C 6 Alkyl, substituted or unsubstituted C 3 ~C 6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl; 1d If is substituted, it is one or more R 14 is replaced by; R e is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, C 1 ~6 Alkoxy, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C 6 is heterocycloalkyl; or R d and R e are substituted or unsubstituted C together with the N atom to which they are attached. 2 ~C 6 Forming a heterocycloalkyl; Each R f are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C 6 is heterocycloalkyl; Or both R f are substituted or unsubstituted C together with the N atom to which they are attached. 2 ~C 6 Forming a heterocycloalkyl; R g is C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 1 ~C 6 Heteroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C 3 ~C 6 Cycloalkyl), -alkyl-(substituted or unsubstituted C 2 ~C6 Heterocycloalkyl), -C(=O)R 16 , -C(=O)-OR 16 , -C(=O)N(R 16 ) 2 , -(C(R 17 ) 2 O) p -R 15 , -(CH 2 CH 2 O) q -R 15 , or -(C(R 17 ) 2 ) p -OR 15 and; p is 1, 2, 3, 4, or 5; q is 1, 2, 3, 4, or 5; Each R 17 are independently hydrogen or C 1 ~C 6 is alkyl; R 15 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted C 2 ~C 10 Heterocycloalkyl, -C(=O)R 16 , -C(=O)-OR 16 , or -C(=O)N(R 16 ) 2 and; R 2 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, or C 1 ~C 6 is a fluoroalkyl; R 3 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C6 is heterocycloalkyl; or R 2 and R 3 together with the carbon atom to which they are attached form a carbonyl (C=O) or a thiocarbonyl (C=S); or R 2 and R 3 are substituted or unsubstituted C together with the carbon atom to which they are attached. 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C 6 heterocycloalkyl, where if ring B is substituted, it is substituted with one or more R 12 is replaced by; Z is N or CR 8 and; L is absent or -NH-; R 4 , R 5 , R 7 , and R 8 are each independently hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 and; R 6 is hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, -OR 16 , -C(=O)R 16 , -CO2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , -NR 16 C(=O)R 16 , substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl; 6 If is substituted, it is one or more R 13 is replaced by; Ring A is substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl; Each R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are independently hydrogen, deuterium, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, -CN, -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 and; Each R 16 are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C 3 ~C 6 Cycloalkyl), -alkyl-(substituted or unsubstituted C 2 ~C 6 heterocycloalkyl); Or both R 16 are substituted or unsubstituted C together with the N atom to which they are attached. 2 ~C 6 Forming a heterocycloalkyl; R 18 and R 19 are independently hydrogen, deuterium, and C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, or C 1 ~C 6 Is it fluoroalkyl; or R 18 and R 19 along with the carbon atom to which they are attached, C 3 ~C 6 Cycloalkane or C 2 ~C 6 forming a ring E which is heterocycloalkyl; m is 1 or 2; and where n is 0, 1, 2, 3, or 4.

[0042] In another embodiment, a compound of formula (I') or a pharma- ceutically acceptable salt or solvate thereof is described herein: [ka] (In the formula, R1 is [ka] , -C(O)NR d R e , -N(R f ) 2 , a substituted or unsubstituted monocyclic heterocycle, or a substituted or unsubstituted monocyclic carbocycle, where R 1 When R is a substituted monocyclic heterocycle, it may occur one or more times. 9 is replaced by; R a are hydrogen, deuterium, and C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, or C 1 ~C 6 is a fluoroalkyl; R b are hydrogen, deuterium, and C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C 6 is heterocycloalkyl; or R a and R b are substituted or unsubstituted C together with the carbon atom to which they are attached. 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C 6 heterocycloalkyl, where ring C is substituted with one or more R 11 and R c is hydrogen, C 1 ~C 6 Alkyl or R g Is it; or R a and R btogether with the carbon atom to which they are attached form a carbonyl (C=O); and R c is C 3 ~C 6 Alkyl or R g and; R d is C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, C 1 ~ 6 Alkoxy, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C 6 is heterocycloalkyl; R e is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, C 1 ~ 6 Alkoxy, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C 6 is heterocycloalkyl; or R d and R e are substituted or unsubstituted C together with the N atom to which they are attached. 2 ~C 6 Forming a heterocycloalkyl; Each R f are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C6 is heterocycloalkyl; Or both R f are substituted or unsubstituted C together with the N atom to which they are attached. 2 ~C 6 Forming a heterocycloalkyl; R g is C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 1 ~C 6 Heteroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C 3 ~C 6 Cycloalkyl), -alkyl-(substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl), -C(=O)R 16 , -C(=O)-OR 16 , -C(=O)N(R 16 ) 2 , -(C(R 17 ) 2 O) p -R 15 , -(CH 2 CH 2 O) q -R 15 , or -(C(R 17 ) 2 ) p -OR 15 and; p is 1, 2, 3, 4, or 5; q is 1, 2, 3, 4, or 5; Each R 17 are independently hydrogen or C 1 ~C 6 is alkyl; R 15is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted C 2 ~C 10 Heterocycloalkyl, -C(=O)R 16 , -C(=O)-OR 16 , or -C(=O)N(R 16 ) 2 and; R 2 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, or C 1 ~C 6 is a fluoroalkyl; R 3 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C 6 is heterocycloalkyl; or R 2 and R 3 together with the carbon atom to which they are attached form a carbonyl (C=O) or a thiocarbonyl (C=S); or R 2 and R 3 are substituted or unsubstituted C together with the carbon atom to which they are attached. 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C 6 heterocycloalkyl, where if ring B is substituted, it is substituted with one or more R 12 is replaced by; Z is N or CR 8 and; L is absent or -NH-; R 4 , R 5 , R7 , and R 8 are each independently hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 and; R 6 is hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , -NR 16 C(=O)R 16 , substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl; 6 If is substituted, it is one or more R 13 is replaced by; or R 5 and R 6together with the intervening atoms to which they are attached form a fused ring D which is a substituted or unsubstituted 5- or 6-membered carbocyclic ring or a substituted or unsubstituted 5- or 6-membered heterocyclic ring, where when ring D is substituted it is joined to one or more R 14 is replaced by; Ring A is substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl; Each R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are independently hydrogen, deuterium, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, -CN, -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 and; Each R 16 are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C 3 ~C 6 Cycloalkyl), -alkyl-(substituted or unsubstituted C 2 ~C 6 heterocycloalkyl); Or both R 16 are substituted or unsubstituted C together with the N atom to which they are attached. 2 ~C 6 Forming a heterocycloalkyl; R 18 and R 19 are independently hydrogen, deuterium, and C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, or C 1 ~C 6 Is it fluoroalkyl; or R 18 and R 19 along with the carbon atom to which they are attached, C 3 ~C 6 Cycloalkane or C 2 ~C 6 forming a ring E which is heterocycloalkyl; m is 1 or 2; and where n is 0, 1, 2, 3, or 4.

[0043] For each and every embodiment, the substituents are selected from a subset of the listed options. For example, in some embodiments, ring A is unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, unsubstituted or substituted pyridazinyl, or unsubstituted or substituted triazinyl. In some embodiments, ring A is unsubstituted or substituted phenyl. In some embodiments, ring A is unsubstituted or substituted pyridinyl. In some embodiments, ring A is unsubstituted or substituted pyrimidinyl. In some embodiments, ring A is unsubstituted or substituted pyrazinyl. In some embodiments, ring A is unsubstituted or substituted pyridazinyl. In some embodiments, ring A is unsubstituted or substituted triazinyl.

[0044] In some embodiments, ring A is unsubstituted or substituted phenyl, or unsubstituted or substituted pyridinyl. In some embodiments, ring A is unsubstituted phenyl. In some embodiments, ring A is substituted pyridinyl. In some embodiments, ring A is unsubstituted phenyl. In some embodiments, ring A is substituted pyridinyl. In some embodiments, ring A is substituted phenyl or substituted pyridinyl. In some embodiments, ring A is substituted phenyl or substituted pyridinyl, where substituted phenyl or substituted pyridinyl is n occurrences of R 10 In some embodiments, Ring A is substituted with phenyl or pyridinyl, wherein the substituted phenyl or pyridinyl is substituted with one R 10 has been replaced by

[0045] In some embodiments, Ring A is a substituted phenyl or substituted pyridinyl, wherein the substituted phenyl or substituted pyridinyl is selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, F, Cl, Br, -CN, -CH 3 , -CH 2 CH 3 , -(CH 2 )2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CH 2 D, -CHD 2 , -CD 3 , -OH, -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -CO 2 H, -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -NH 2 , -NHCH 3 , or -N(CH 3 ) 2 In some embodiments, ring A is a substituted phenyl or substituted pyridinyl, wherein the substituted phenyl or substituted pyridinyl is substituted with halogen, C 1 ~ 6 Alkyl, C 1 ~ 6 In some embodiments, Ring A is substituted with fluoroalkyl, or CN. In some embodiments, Ring A is substituted phenyl or substituted pyridinyl, where the substituted phenyl or substitute pyridinyl is -F, -Cl, -Br, -I, -CH 3 , -CF 3 In some embodiments, Ring A is substituted with -F, -Cl, -CF 3, or -CN. In some embodiments, ring A is a phenyl ring substituted with -F or -Cl. In some embodiments, ring A is a phenyl ring substituted with -F. In some embodiments, ring A is a phenyl ring substituted with -Cl. In some embodiments, ring A is -CF 3 In some embodiments, ring A is a phenyl ring substituted with -CN. In some embodiments, ring A is a pyridinyl ring substituted with -F or -Cl. In some embodiments, ring A is a pyridinyl ring substituted with -F. In some embodiments, ring A is a pyridinyl ring substituted with -Cl. In some embodiments, ring A is a -CF 3 In some embodiments, Ring A is a pyridinyl ring substituted with -CN.

[0046] In some embodiments, [ka] teeth [ka] In some embodiments, [ka] teeth [ka] In some embodiments, [ka] teeth [ka] In some embodiments, [ka] teeth [ka] In some embodiments, [ka] teeth [ka] In some embodiments, [ka] teeth [ka] In some embodiments, [ka] teeth [ka] It is.

[0047] In some embodiments, L is absent or -NH-. In some embodiments, L is -NH-. In some embodiments, L is absent.

[0048] In some embodiments, R 18 and R 19 are independently hydrogen, deuterium, and C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, or C 1 ~C 6 or R 18 and R 19 along with the carbon atom to which they are attached, C 3 ~C6 Cycloalkane or C 2 ~C 6 In some embodiments, R forms a ring E which is a heterocycloalkyl. 18 and R 19 are each independently hydrogen, deuterium, or -CH 3 In some embodiments, R 18 and R 19 Each is hydrogen. In some embodiments, R 18 and R 19 Each is deuterium. In some embodiments, R 18 and R 19 are -CH 3 In some embodiments, R 18 and R 19 is hydrogen and the other is deuterium or -CH 3 In some embodiments, R 18 and R 19 One of R is hydrogen and the other is deuterium. 18 and R 19 One of the groups is hydrogen and the other is -CH 3 In some embodiments, R 18 and R 19 along with the carbon atom to which they are attached, C 3 ~C 6 Cycloalkane or C 2 ~C 6 In some embodiments, R forms a ring E which is a heterocycloalkyl. 18 and R 19 together with the carbon atom to which they are attached form a ring E which is cyclopropyl, cyclobutyl, azirane, azetidine, oxirane, or oxetane. 18 and R 19 together with the carbon atom to which they are attached form a ring E which is cyclopropyl, azetidine, or oxetane. 18 and R 19together with the carbon atom to which they are attached form a ring E which is cyclopropyl. 18 and R 19 together with the carbon atom to which they are attached form a ring E which is azetidine. 18 and R 19 together with the carbon atom to which they are attached form ring E which is an oxetane.

[0049] In some embodiments, L is -NH-, and each R 18 and R 19 is hydrogen. In some embodiments, L is absent and each R 18 and R 19 In some embodiments, L is -NH-, and each R 18 and R 19 is deuterium. In some embodiments, L is absent and each R 18 and R 19 In some embodiments, L is -NH- and R 18 and R 19 together with the carbon atom to which they are attached form a ring E which is cyclopropyl, azetidine, or oxetane. In some embodiments, L is absent and R 18 and R 19 together with the carbon atom to which they are attached form a ring E which is cyclopropyl, azetidine, or oxetane.

[0050] In some embodiments, the compound of formula (I) has the structure of formula (II): [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0051] In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, the compound of Formula (I) has the structure of Formula (III): [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0052] In some embodiments, m is 2. In some embodiments, the compound of formula (I) has the structure of formula (IV): [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0053] In some embodiments, each R 10 are independently hydrogen, deuterium, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, F, Cl, Br, -CN, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CH 2 D, -CHD 2 , -CD 3 , -OH, -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -CO 2 H, -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 )2 , -NH 2 , -NHCH 3 , or -N(CH 3 ) 2 In some embodiments, ring A is hydrogen, deuterium, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, F, Cl, Br, -CN, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CH 2 D, -CHD 2 , -CD 3 , -OH, -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -CO 2 H, -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -NH 2 , -NHCH 3 , or -N(CH 3 ) 2 In some embodiments, each R 10 are independently hydrogen, F, Cl, Br, -CN, -CH 3 , -CH 2 CH 3 , -CH 2 CN, -CH 2 F, -CHF2 , -CF 3 , -OH, -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -CO 2 H, -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -NH 2 , -NHCH 3 , or -N(CH 3 ) 2 In some embodiments, each R 10 are independently hydrogen, -F, -Cl, -Br, -CN, -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -OCF 3 , -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -NH 2 , -NHCH 3 , or -N(CH 3 ) 2 In some embodiments, each R 10 are independently -F, -Cl, -Br, -CN, -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -OCF 3 , -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -NH 2 , -NHCH 3 , or -N(CH 3 ) 2 In some embodiments, each R 10are independently -F, -Cl, -Br, -CN, -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , or -OCF 3 In some embodiments, each R 10 are independently -F, -Cl, -CN, -CH 3 , or -CF 3 In some embodiments, each R 10 is independently -F, -Cl, or -CN. In some embodiments, each R 10 is independently -F or -Cl. In some embodiments, R 10 is -F. In some embodiments, R 10 In some embodiments, R 10 In some embodiments, R 10 -CF 3 In some embodiments, R 10 Ha-CH 3 In some embodiments, R 10 -OCF 3 It is.

[0054] In some embodiments, R 1 is a substituted or unsubstituted monocyclic heterocycle or a substituted or unsubstituted monocyclic carbocycle, where R 1 When R is a substituted monocyclic heterocycle, it may occur one or more times. 9 In some embodiments, R 1 is a substituted or unsubstituted monocyclic heterocycle. In some embodiments, R 1 is an unsubstituted monocyclic heterocycle. In some embodiments, R 1 R appears one or more times 9 In some embodiments, R is a monocyclic heterocycle substituted with 1 R appears one or more times 9 In some embodiments, R is a monocyclic heteroaryl substituted with 1 R appears one or more times9 In some embodiments, R is a monocyclic heterocycloalkyl substituted with 1 R appears one or more times 9 In some embodiments, R is a 5- or 6-membered monocyclic heteroaryl substituted with 1 R appears one or more times 9 In some embodiments, R is a 5- or 6-membered monocyclic heterocycloalkyl substituted with 1 is an unsubstituted 5- or 6-membered monocyclic heterocycle. In some embodiments, R 1 is an unsubstituted 5- or 6-membered monocyclic heteroaryl. In some embodiments, R 1 is an unsubstituted 5- or 6-membered monocyclic heterocycloalkyl.

[0055] In some embodiments, R 1 teeth [ka] It is.

[0056] In some embodiments, R 1 R appears one or more times 9 In some embodiments, R is a 5-membered monocyclic heteroaryl substituted with 1 R appears one or more times 9 In some embodiments, R is a 5-membered monocyclic heterocycloalkyl substituted with 1 is an unsubstituted 5-membered monocyclic heterocycle. In some embodiments, R 1 is an unsubstituted 5-membered monocyclic heteroaryl. In some embodiments, R 1 is an unsubstituted 5-membered monocyclic heterocycloalkyl.

[0057] In some embodiments, R 1 teeth [ka] In some embodiments, R1 teeth [ka] In some embodiments, R 1 teeth [ka] It is.

[0058] In some embodiments, each R 9 are independently hydrogen, deuterium, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, -CN, -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 In some embodiments, each R 9 are independently hydrogen, deuterium, or C 1 ~C 6 In some embodiments, each R 9 are independently hydrogen or C 1 ~C 6 In some embodiments, each R 9 is C 1 ~C 6 In some embodiments, each R 9 are independently hydrogen, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , or -C(CH 3 ) 3 In some embodiments, each R 9 are independently hydrogen or -CH 3 In some embodiments, each R 9 Ha-CH 3 In some embodiments, each R 9 is hydrogen.

[0059] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] It is.

[0060] In some embodiments, R 1 teeth [ka] In some embodiments, R a are hydrogen, deuterium, and C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, or C 1 ~C 6 In some embodiments, R a is hydrogen, -CH 3 , -CH 2 CH 3 , -CD3 , -CH 2 CD 3 , -CF 3 , or -CH 2 CF 3 In some embodiments, R b are hydrogen, deuterium, and C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, or C 1 ~C 6 In some embodiments, R b is hydrogen, -CH 3 , -CH 2 CH 3 , -CD 3 , -CH 2 CD 3 , -CF 3 , or -CH 2 CF 3 In some embodiments, R a is hydrogen or deuterium. b is hydrogen or deuterium. a and R b together with the carbon atom to which they are attached form a ring C which is a substituted or unsubstituted oxetane, a substituted or unsubstituted thietane 1,1-dioxide, or a substituted or unsubstituted azetidine. a and R b together with the carbon atom to which they are attached form a ring C which is an unsubstituted oxetane, an unsubstituted thietane 1,1-dioxide, or an unsubstituted azetidine. a and R b together with the carbon atom to which they are attached form a ring C which is a substituted oxetane, a substituted thietane 1,1-dioxide, or a substituted azetidine. a and R b together with the carbon atom to which they are attached form a ring C which is a substituted or unsubstituted oxetane. In some embodiments, R a and R btogether with the carbon atoms to which they are attached form a ring C which is a substituted or unsubstituted thietane 1,1-dioxide. a and R b together with the carbon atom to which they are attached form a ring C which is a substituted or unsubstituted azetidine.

[0061] In some embodiments, R c is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 1 ~C 6 Heteroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C 3 ~C 6 Cycloalkyl), -alkyl-(substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl), -C(=O)R 16 , -C(=O)-OR 16 , -C(=O)N(R 16 ) 2 , -(CH 2 O) p -R 15 , or -(CH(CH 3 )O) p -R 15 In some embodiments, R c is hydrogen or C 1 ~C 6 In some embodiments, R c is hydrogen. In some embodiments, R c is C 1 ~C 6In some embodiments, R c is -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , or -C(CH 3 ) 3 In some embodiments, R c Ha-CH 3 In some embodiments, R c Ha-CH 2 CH 3 In some embodiments, R c is C 3 ~C 6 In some embodiments, R c is -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , or -C(CH 3 ) 3 In some embodiments, R c is R g It is.

[0062] In some embodiments, R a and R b together with the carbon atom to which they are attached form a carbonyl (C=O); and R c is C 3 ~C 6 Alkyl or R g In some embodiments, R a and R b together with the carbon atom to which they are attached form a carbonyl (C=O); and R c is -(CH 2 ) 2 CH3 , -(CH 2 ) 3 CH 3 , -(CH 2 ) 4 CH 3 , -(CH 2 ) 5 CH 3 , -CH(CH 3 ) 2 , or -C(CH 3 ) 3 It is.

[0063] In some embodiments, R a and R b together with the carbon atom to which they are attached form a carbonyl (C=O); R c is R g and R g is C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 1 ~C 6 Heteroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C 3 ~C 6 Cycloalkyl), -alkyl-(substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl), -C(=O)R 16 , -C(=O)-OR 16 , -C(=O)N(R 16 ) 2 , -(C(R 17 ) 2 O) p -R 15 , -(CH 2 CH 2 O) q -R15 , or -(C(R 17 ) 2 ) p -OR 15 It is.

[0064] In some embodiments, R a and R b together with the carbon atom to which they are attached form a carbonyl (C=O); R c is R g and R g is C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, or substituted or unsubstituted C 1 ~C 6 In some embodiments, R a and R b together with the carbon atom to which they are attached form a carbonyl (C=O); R c is R g and R g is -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , or -CF 2 CF 3 In some embodiments, R a and R b together with the carbon atom to which they are attached form a carbonyl (C=O); R c is R g and R g-CD 3 , -CD 2 CD 3 , -CF 3 , or -CF 2 CF 3 In some embodiments, R a and R b together with the carbon atom to which they are attached form a carbonyl (C=O); R c is R g and R g -CD 3 or -CD 2 CD 3 It is.

[0065] In some embodiments, R a and R b together with the carbon atom to which they are attached form a carbonyl (C=O); R c is R g and R g is -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C 3 ~C 6 Cycloalkyl), -alkyl-(substituted or unsubstituted C 2 ~C 6 heterocycloalkyl).

[0066] In some embodiments, R a and R b together with the carbon atom to which they are attached form a carbonyl (C=O); R c is R g and R g is -C(=O)R 16 , -C(=O)-OR 16 , -C(=O)N(R 16 ) 2 , -(C(R 17 ) 2 O) p -R 15 , -(CH 2 CH 2 O) q -R 15 , or -(C(R 17) 2 ) p -OR 15 In some embodiments, R a and R b together with the carbon atom to which they are attached form a carbonyl (C=O); R c is R g and R g is -C(=O)R 16 Or -C(=O)-OR 16 In some embodiments, R a and R b together with the carbon atom to which they are attached form a carbonyl (C=O); R c is R g ;R g is -(C(R 17 ) 2 O) p -R 15 , -(CH 2 CH 2 O) q -R 15 , or -(C(R 17 ) 2 ) p -OR 15 and R 15 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted C 2 ~C 10 Heterocycloalkyl, -C(=O)R 16 , -C(=O)-OR 16 , or -C(=O)N(R 16 ) 2 In some embodiments, R a and R b together with the carbon atom to which they are attached form a carbonyl (C=O); R c is R g and R g is -(CH 2 O) p -R 15 , -(CH 2 CH 2 O) q -R 15 , or -(CH 2 )p -OR 15 In some embodiments, R a and R b together with the carbon atom to which they are attached form a carbonyl (C=O); R c is R g and R g is -CH 2 OR 15 , -CH 2 CH 2 OR 15 , -(CH 2 CH 2 O) 2 -R 15 , -(CH 2 CH 2 O) 3 -R 15 , -(CH 2 CH 2 O) 4 -R 15 , -(CH 2 CH 2 O) 5 -R 15 , -(CH 2 ) 3 -OR 15 , -(CH 2 ) 4 -OR 15 , or -(CH 2 ) 5 -OR 15 In some embodiments, R a and R b together with the carbon atom to which they are attached form a carbonyl (C=O); R c is R g and R g is -CH 2 OR 15 or -CH 2 CH 2 OR 15 In some embodiments, R a and R b together with the carbon atom to which they are attached form a carbonyl (C=O); R c is R g and R g Ha-CH 2 OR15 It is.

[0067] In some embodiments, R a and R b together with the carbon atom to which they are attached form a carbonyl (C=O); R c is R g ;R g Ha-CH 2 OR 15 and R 15 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted C 2 ~C 10 Heterocycloalkyl, -C(=O)R 16 , -C(=O)-OR 16 , or -C(=O)N(R 16 ) 2 In some embodiments, R a and R b together with the carbon atom to which they are attached form a carbonyl (C=O); R c is R g ;R g Ha-CH 2 OR 15 and R 15 is a substituted or unsubstituted C 2 ~C 10 Heterocycloalkyl, -C(=O)R 16 , -C(=O)-OR 16 , or -C(=O)N(R 16 ) 2 In some embodiments, R a and R b together with the carbon atom to which they are attached form a carbonyl (C=O); R c is R g ;R g Ha-CH 2 OR 15 and R 15 is -C(=O)R 16 , -C(=O)-OR 16 , or -C(=O)N(R 16 ) 2 It is.

[0068] In some embodiments, R a and R b together with the carbon atom to which they are attached form a carbonyl (C=O); R c is R g ;R g Ha-CH 2 OR 15 ;R 15 is -C(=O)R 16 and each R 16 are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C 3 ~C 6 cycloalkyl), or -alkyl-(substituted or unsubstituted C 2 ~C 6 heterocycloalkyl).

[0069] In some embodiments, [ka] teeth [ka] In some embodiments, [ka] teeth [ka] In some embodiments, [ka] teeth [ka] In some embodiments, [ka] teeth [ka] In some embodiments, [ka] teeth [ka] and R 16 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C 3 ~C 6 cycloalkyl), or -alkyl-(substituted or unsubstituted C 2 ~C 6 heterocycloalkyl).

[0070] In some embodiments, [ka] teeth [ka] and R 16 is a substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted heteroaryl), or -alkyl-(substituted or unsubstituted C 2 ~C 6 In some embodiments, [ka] teeth [ka] and R 16 is a substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, substituted or unsubstituted heteroaryl, -CH 2 -(substituted or unsubstituted heterocycloalkyl), -(CH 2 ) 2 -(substituted or unsubstituted heterocycloalkyl), -(CH 2 ) 3 -(substituted or unsubstituted heterocycloalkyl), -CH 2 -(substituted or unsubstituted heteroaryl), -(CH 2 ) 2 -(substituted or unsubstituted heteroaryl), or -(CH 2 ) 3 -(substituted or unsubstituted heteroaryl). In some embodiments, [ka] teeth [ka] and R 16 is a substituted or unsubstituted C 2 ~C 6It is a heterocycloalkyl, or a substituted or unsubstituted heteroaryl.

[0071] In some embodiments, [ka] teeth [ka] and R 16 is a substitution C 2 ~C 6 Heterocycloalkyl or substituted heteroaryl. In some embodiments, [ka] teeth [ka] and R 16 is unsubstituted C 2 ~C 6 Heterocycloalkyl or unsubstituted heteroaryl. In some embodiments, [ka] teeth [ka] and R 16 is a substitution C 2 ~C 6 In some embodiments, [ka] teeth [ka] and R 16 is substituted heteroaryl. In some embodiments, [ka] teeth [ka] and R 16 is unsubstituted C 2 ~C 6 In some embodiments, [ka] teeth [ka] and R 16 is unsubstituted heteroaryl.

[0072] In some embodiments, [ka] teeth [ka] It is.

[0073] In some embodiments, R 1 teeth [ka] ;R a is hydrogen, -CH 3 , -CH 2 CH 3 , -CD 3 , -CH 2 CD 3 , -CF 3 , or -CH 2 CF 3 ;R b is hydrogen, -CH 3 , -CH 2 CH 3 , -CD 3 , -CH 2 CD 3 , -CF 3 , or -CH2 CF 3 or R a and R b together with the carbon atoms to which they are attached form a ring C which is a substituted or unsubstituted oxetane, a substituted or unsubstituted thietane 1,1-dioxide, or a substituted or unsubstituted azetidine; and R c is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 1 ~C 6 Heteroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C 3 ~C 6 Cycloalkyl), -alkyl-(substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl), -C(=O)R 16 , -C(=O)-OR 16 , -C(=O)N(R 16 ) 2 , -(CH 2 O) p -R 15 , or -(CH(CH 3 )O) p -R 15 p is 1, 2, 3, 4, or 5; and R 15 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted C 2 ~C 10 Heterocycloalkyl, -C(=O)R 16 , -C(=O)-OR 16 , or -C(=O)N(R 16 ) 2 It is.

[0074] In some embodiments, R 1 teeth [ka] ;R a and R b together with the carbon atom to which they are attached form a ring C which is a substituted or unsubstituted oxetane, a substituted or unsubstituted thietane 1,1-dioxide, or a substituted or unsubstituted azetidine. 1 teeth [ka] ;R a and R b together with the carbon atoms to which they are attached form a ring C which is a substituted or unsubstituted oxetane, a substituted or unsubstituted thietane 1,1-dioxide, or a substituted or unsubstituted azetidine; and R c is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, or C 1 ~C 6 In some embodiments, R 1 teeth [ka] ;R a and R b together with the carbon atoms to which they are attached form a ring C which is a substituted or unsubstituted oxetane, a substituted or unsubstituted thietane 1,1-dioxide, or a substituted or unsubstituted azetidine; and R c is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D.2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , or -CF 2 CF 3 In some embodiments, R 1 teeth [ka] ;R a and R b together with the carbon atoms to which they are attached form a ring C which is a substituted or unsubstituted oxetane, a substituted or unsubstituted thietane 1,1-dioxide, or a substituted or unsubstituted azetidine; and R c is hydrogen, -CH 3 , or -CH 2 CH 3 In some embodiments, R 1 teeth [ka] ;R a and R b together with the carbon atoms to which they are attached form a ring C which is a substituted or unsubstituted oxetane, a substituted or unsubstituted thietane 1,1-dioxide, or a substituted or unsubstituted azetidine; and R c is hydrogen.

[0075] In some embodiments, R 1 teeth [ka] ;R a and R btogether with the carbon atom to which they are attached form a ring C which is a substituted or unsubstituted oxetane. In some embodiments, R 1 teeth [ka] ;R a and R b together with the carbon atom to which they are attached form a ring C which is a substituted or unsubstituted oxetane; and R c is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , or -CF 2 CF 3 In some embodiments, R 1 teeth [ka] ;R a and R b together with the carbon atom to which they are attached form a ring C which is a substituted or unsubstituted oxetane; and R c is hydrogen.

[0076] In some embodiments, R 1 teeth [ka] ;Ra and R b together with the carbon atoms to which they are attached form a ring C which is a substituted or unsubstituted thietane 1,1-dioxide. 1 teeth [ka] ;R a and R b together with the carbon atoms to which they are attached form a ring C which is a substituted or unsubstituted thietane 1,1-dioxide; and R c is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , or -CF 2 CF 3 In some embodiments, R 1 teeth [ka] ;R a and R b together with the carbon atoms to which they are attached form a ring C which is a substituted or unsubstituted thietane 1,1-dioxide; and R c is hydrogen.

[0077] In some embodiments, R 1 teeth [ka] ;R a and R b together with the carbon atom to which they are attached form a ring C which is a substituted or unsubstituted azetidine. 1 teeth [ka] ;R a and R b together with the carbon atom to which they are attached form a ring C which is a substituted or unsubstituted azetidine; and R c is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , or -CF 2 CF 3 In some embodiments, R 1 teeth [ka] ;R a and R b together with the carbon atom to which they are attached form a ring C which is a substituted or unsubstituted azetidine; and R c is hydrogen.

[0078] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] and R c is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , or -CF 2 CF 3 In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] It is.

[0079] In some embodiments, R 1 -C(O)NR d R e In some embodiments, R 1 -C(O)NR d R e and R e is hydrogen or -CH 3 In some embodiments, R 1 -C(O)NR d R e and R e is hydrogen. In some embodiments, R 1 -C(O)NR d R e and R e Ha-CH 3 In some embodiments, R 1 -C(O)NHR d In some embodiments, R d -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Fluoroalkyl, -OH, -OR 1d , or -SO 2 R 1d In some embodiments, R d In some embodiments, R 1is -C(O)NHCN. In some embodiments, R d -OH or -OR 1d In some embodiments, R 1 is -C(O)NHOH or -C(O)NHOR 1d In some embodiments, R 1d Ha-CH 3 In some embodiments, R 1 is -C(O)NHOH or -C(O)NHOCH 3 In some embodiments, R 1 is -C(O)NH(C 1 ~C 6 In some embodiments, R 1 is -C(O)NHCH 3 , -C(O)NHCH 2 CH 3 , -C(O)NHCH(CH 3 ) 2 , -C(O)NC(CH 3 ) 3 or -C(O)NHCH 2 CH 2 CH 3 In some embodiments, R 1 -C(O)NHCH 3 In some embodiments, R 1 is -C(O)N(CH 3 ) 2 In some embodiments, R 1 is -C(O)NH(C 1 ~C 6 haloalkyl). In some embodiments, R 1 -C(O)NHCH 2 CF 3 It is.

[0080] In some embodiments, R 1 -C(O)NHSO 2 R 1d In some embodiments, R 1d is a substituted or unsubstituted C 1 ~C 6Alkyl, substituted or unsubstituted C 3 ~C 6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl; 1d If is substituted, it is one or more R 14 In some embodiments, R 1d is substituted or unsubstituted C 1 ~C 6 In some embodiments, R 1d is substituted or unsubstituted methyl, where R 1d If is substituted, it can have one, two, or three R 14 In some embodiments, R 14 is fluorine. In some embodiments, R 14 -C 1 ~C 6 In some embodiments, R 14 HA-OCH 3 In some embodiments, R 1d is -CH 3 , -CH 2 CH 3 , -CH 2 CF 3 , -CH 2 OCH 3 , -CH 2 F, -CH(CH 3 ) 2 , -CHF 2 , -C(CH 3 ) 3 , or -CF 3 In some embodiments, R 1 is -C(O)NHSO 2 CH 3 , -C(O)NHSO 2 CH 2 CH 3 , -C(O)NHSO 2 CH 2 CF 3 , -C(O)NHSO 2 CH 2 OCH3 , -C(O)NHSO 2 CH 2 F, -C(O)NHSO 2 CH(CH 3 ) 2 , -C(O)NHSO 2 CHF 2 , -C(O)NHSO 2 C(CH 3 ) 3 or -C(O)NHSO 2 CF 3 In some embodiments, R 1 -C(O)NHSO 2 (C 1 ~C 6 In some embodiments, R 1 -C(O)NHSO 2 (substituted or unsubstituted methyl).

[0081] In some embodiments, R 1d is substituted or unsubstituted C 3 ~C 6 In some embodiments, R 1d is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, or substituted or unsubstituted cyclohexyl. 1d is substituted or unsubstituted cyclopropyl. In some embodiments, R 1 -C(O)NHSO 2 (C 3 ~C 6 In some embodiments, R 1 -C(O)NHSO 2 (3- to 6-membered heterocycloalkyl). In some embodiments, R 1d is oxetanyl, azetidinyl, tetrahydrofuranyl, or pyrrolidinyl. 1 -C(O)NHSO 2 (oxetanyl). In some embodiments, R 1dis substituted or unsubstituted phenyl. In some embodiments, R 1 -C(O)NHSO 2 (phenyl). In some embodiments, R 1d is a substituted or unsubstituted 5- or 6-membered heteroaryl. In some embodiments, R 1d is substituted or unsubstituted piperidinyl, or substituted or unsubstituted pyrimidinyl. In some embodiments, R 1 -C(O)NHSO 2 (phenyl).

[0082] In some embodiments, R 2 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, or C 1 ~C 6 In some embodiments, R 2 is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , or -CF 2 CF 3 In some embodiments, R 2 is hydrogen, -CH 3 , -CH 2 CH 3 , -CD 3 , -CH2 CD 3 , -CF 3 , or -CH 2 CF 3 In some embodiments, R 2 is hydrogen, -CH 3 , -CD 3 , or -CF 3 In some embodiments, R 2 is -CH 3 , -CD 3 , or -CF 3 In some embodiments, R 2 Ha-CH 3 In some embodiments, R 2 Ha-CD 3 In some embodiments, R 2 -CF 3 In some embodiments, R 2 is hydrogen.

[0083] In some embodiments, R 3 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, or C 1 ~C 6 In some embodiments, R 3 is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF2 , -CH 2 CF 3 , or -CF 2 CF 3 In some embodiments, R 3 is hydrogen, -CH 3 , -CH 2 CH 3 , -CD 3 , -CH 2 CD 3 , -CF 3 , or -CH 2 CF 3 In some embodiments, R 3 is hydrogen, -CH 3 , -CD 3 , or -CF 3 In some embodiments, R 3 is -CH 3 , -CD 3 , or -CF 3 In some embodiments, R 3 Ha-CH 3 In some embodiments, R 3 Ha-CD 3 In some embodiments, R 3 -CF 3 In some embodiments, R 3 is hydrogen.

[0084] In some embodiments, R 2 is hydrogen, -CH 3 , -CH 2 CH 3 , -CD 3 , -CH 2 CD 3 , -CF 3 , or -CH 2 CF 3 ;R 3 is hydrogen, -CH 3 , -CH 2 CH 3 , -CD 3 , -CH 2 CD 3 , -CF 3 , or -CH 2CF 3 or R 2 and R 3 together with the carbon atom to which they are attached form a carbonyl (C=O); or R 2 and R 3 together with the carbon atoms to which they are attached form ring B which is a substituted or unsubstituted oxetane, a substituted or unsubstituted thietane 1,1-dioxide, or a substituted or unsubstituted azetidine.

[0085] In some embodiments, R 2 is hydrogen, -CH 3 , -CD 3 , or -CF 3 ;R 3 is hydrogen, -CH 3 , -CD 3 , or -CF 3 or R 2 and R 3 together with the carbon atom to which they are attached form a carbonyl (C=O); or R 2 and R 3 together with the carbon atoms to which they are attached form ring B which is a substituted or unsubstituted oxetane, a substituted or unsubstituted thietane 1,1-dioxide, or a substituted or unsubstituted azetidine.

[0086] In some embodiments, the compound of formula (I) has the structure of formula (V) or (VI): [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0087] In some embodiments, the compound of formula (I') has the structure of formula (V') or (VI'): [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0088] In some embodiments, the compound of formula (I) has the structure of formula (V): [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0089] In some embodiments, the compound of formula (I) has the structure of formula (VI): [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0090] In some embodiments, the compound of formula (I) has the structure of formula (VI-A): [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0091] In some embodiments, the compound of formula (I') has the structure of formula (VI-A'): [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0092] In some embodiments, the compound of formula (I) has the structure of formula (VI-A″): [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0093] In some embodiments, the compound of formula (I) has the structure of formula (VI-A'''): [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0094] In some embodiments, R 1 -C(O)NHSO 2 R 1d In some embodiments, R 1d is substituted or unsubstituted C 1 ~C 6 alkyl; where R 1d If is substituted, it is one or more R 14 In some embodiments, R 1d is substituted or unsubstituted methyl, where R 1d If is substituted, it can have one, two, or three R 14 In some embodiments, R 14 is fluorine. In some embodiments, R 14 -C 1 ~C 6 In some embodiments, R 14 HA-OCH 3 In some embodiments, R 1d is -CH 3 , -CH 2 CH 3 , -CH 2 CF 3 , -CH 2 OCH 3 , -CH 2 F, -CH(CH 3 ) 2 , -CHF 2 , -C(CH 3 ) 3 , or -CF 3 In some embodiments, R 1 is -C(O)NHSO 2 CH 3 , -C(O)NHSO 2 CH 2 CH 3 , -C(O)NHSO 2 CH 2 CF 3 , -C(O)NHSO 2 CH 2 OCH 3, -C(O)NHSO 2 CH 2 F, -C(O)NHSO 2 CH(CH 3 ) 2 , -C(O)NHSO 2 CHF 2 , -C(O)NHSO 2 C(CH 3 ) 3 or -C(O)NHSO 2 CF 3 In some embodiments, R 1 -C(O)NHSO 2 (C 1 ~C 6 alkyl).

[0095] In some embodiments, the compound of formula (I) has the structure of formula (VI-B) or (VI-C): [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0096] In some embodiments, the compound of formula (I) has the structure of formula (VII): [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0097] In some embodiments, the compound of formula (I) has the structure of formula (VIII) or formula (IX): [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0098] In another embodiment, described herein is a compound of formula (X), or a pharma- ceutically acceptable salt or solvate thereof: [ka] (In the formula, R 1a -CO 2 H, -CO 2 -R 1b , -C(O)N(R 1c ) 2 or -CN; R 1b is C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 1 ~C 6 Heteroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C 3 ~C 6 Cycloalkyl), -alkyl-(substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl), -C(=O)R 16 , -C(=O)-OR 16 , -C(=O)N(R 16 ) 2 , -(C(R 17 ) 2 O) p -R 15 , -(CH 2 CH 2 O) q -R 15 , or -(C(R 17 ) 2 ) p -OR 15 and; p is 1, 2, 3, 4, or 5; q is 1, 2, 3, 4, or 5; Each R 17 are independently hydrogen or C 1 ~C6 is alkyl; R 15 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted C 2 ~C 10 Heterocycloalkyl, -C(=O)R 16 , -C(=O)-OR 16 , or -C(=O)N(R 16 ) 2 and; Each R 1c are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C 6 is heterocycloalkyl; Or both R 1c are substituted or unsubstituted C together with the N atom to which they are attached. 2 ~C 6 Forming a heterocycloalkyl; R 2 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, or C 1 ~C 6 is a fluoroalkyl; R 3 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C 6 is heterocycloalkyl; or R 2 and R3 form thiocarbonyls (C=S) together with the carbon atoms to which they are attached; or R 2 and R 3 are substituted or unsubstituted C together with the carbon atom to which they are attached. 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C 6 heterocycloalkyl, where if ring B is substituted, it is substituted with one or more R 12 is replaced by; Z is N or CR 8 and; L is absent or -NH-; R 4 , R 5 , R 7 , and R 8 are each independently hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 and; R 6 is hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R16 ) 2 , -NR 16 C(=O)R 16 , substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl; 6 If is substituted, it is one or more R 13 is replaced by; or R 5 and R 6 together with the intervening atoms to which they are attached form a fused ring D which is a substituted or unsubstituted 5- or 6-membered carbocyclic ring or a substituted or unsubstituted 5- or 6-membered heterocyclic ring, where when ring D is substituted it is joined to one or more R 14 is replaced by; Ring A is substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl; Each R 10 , R 12 , R 13 , and R 14 are independently hydrogen, deuterium, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, -CN, -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 and; Each R 16are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C 3 ~C 6 Cycloalkyl), -alkyl-(substituted or unsubstituted C 2 ~C 6 heterocycloalkyl); Or both R 16 are substituted or unsubstituted C together with the N atom to which they are attached. 2 ~C 6 Forming a heterocycloalkyl; R 18 and R 19 are independently hydrogen, deuterium, and C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, or C 1 ~C 6 Is it fluoroalkyl; or R 18 and R 19 along with the carbon atom to which they are attached, C 3 ~C 6 Cycloalkane or C 2 ~C 6 forming a ring E which is heterocycloalkyl; m is 1 or 2; and where n is 0, 1, 2, 3, or 4.

[0099] In some embodiments, the compound of formula (X) has the structure of formula (XI): [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0100] In some embodiments, m is 1. In some embodiments, the compound of formula (X) has the structure of formula (XII): [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0101] In some embodiments, m is 2. In some embodiments, the compound of formula (X) has the structure of formula (XIII): [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0102] In some embodiments, R 1a -CO 2 H, -CO 2 -R 1b , -C(O)N(R 1c ) 2 or -CN. In some embodiments, R 1a -CO 2 H, -CO 2 -R 1b or -CN. In some embodiments, R 1a -CO 2 H or -CN. In some embodiments, R 1a HA-CO 2 H. In some embodiments, R 1a is -CN.

[0103] In some embodiments, R 1a -CO 2 H or -CO 2 -R 1b In some embodiments, R 1aHA-CO 2 -R 1b In some embodiments, R 1a HA-CO 2 -R 1b and R 1b is C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 1 ~C 6 Heteroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C 3 ~C 6 Cycloalkyl), -alkyl-(substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl), -C(=O)R 16 , -C(=O)-OR 16 , -C(=O)N(R 16 ) 2 , -(C(R 17 ) 2 O) p -R 15 , -(CH 2 CH 2 O) q -R 15 , or -(C(R 17 ) 2 ) p -OR 15 It is.

[0104] In some embodiments, R 1a -CO 2 H, -CO 2 -R 1b , -C(=O)N(R 1c ) 2 , -C(=O)NH2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 or -CN; R 1b is C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 1 ~C 6 Heteroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C 3 ~C 6 Cycloalkyl), -alkyl-(substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl), -C(=O)R 16 , -C(=O)-OR 16 , -C(=O)N(R 16 ) 2 , -(CH 2 O) p -R 15 , or -(CH(CH 3 )O) p -R 15 p is 1, 2, 3, 4, or 5; and R 15 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted C 2 ~C 10 Heterocycloalkyl, -C(=O)R 16 , -C(=O)-OR 16 , or -C(=O)N(R 16 ) 2 It is.

[0105] In some embodiments, R 1b is C1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 1 ~C 6 Heteroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C 3 ~C 6 Cycloalkyl), -alkyl-(substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl), -C(=O)R 16 , -C(=O)-OR 16 , -C(=O)N(R 16 ) 2 , -(CH 2 O) p -R 15 , or -(CH(CH 3 )O) p -R 15 In some embodiments, R 1b is -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , or -C(CH 3 ) 3 In some embodiments, R 1b Ha-CH 3 In some embodiments, R 1b Ha-CH 2 CH 3 In some embodiments, R1b is -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , or -C(CH 3 ) 3 It is.

[0106] In some embodiments, R 1b is C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 1 ~C 6 Heteroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C 3 ~C 6 Cycloalkyl), -alkyl-(substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl), -C(=O)R 16 , -C(=O)-OR 16 , -C(=O)N(R 16 ) 2 , -(C(R 17 ) 2 O) p -R 15 , -(CH 2 CH 2 O) q -R 15 , or -(C(R 17 ) 2 ) p -OR 15 It is.

[0107] In some embodiments, R 1b is C1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, or substituted or unsubstituted C 1 ~C 6 In some embodiments, R 1b is -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , or -CF 2 CF 3 In some embodiments, R 1b -CD 3 , -CD 2 CD 3 , -CF 3 , or -CF 2 CF 3 It is.

[0108] In some embodiments, R 1b is -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C 3 ~C 6 Cycloalkyl), -alkyl-(substituted or unsubstituted C 2 ~C 6 heterocycloalkyl).

[0109] In some embodiments, R 1b is -C(=O)R 16 , -C(=O)-OR 16, or -C(=O)N(R 16 ) 2 In some embodiments, R 1b is -C(=O)R 16 Or -C(=O)-OR 16 In some embodiments, R 1b is -(CH 2 O) p -R 15 or -(CH(CH 3 )O) p -OR 15 and R 15 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted C 2 ~C 10 Heterocycloalkyl, -C(=O)R 16 , -C(=O)-OR 16 , or -C(=O)N(R 16 ) 2 In some embodiments, R 1b is -CH 2 OR 15 , -CH(CH 3 ) OR 15 , -(CH(CH 3 )O) 2 -R 15 , -(CH(CH 3 )O) 3 -R 15 , -(CH(CH 3 )O) 4 -R 15 , or -(CH(CH 3 )O) 5 -R 15 In some embodiments, R 1b Ha-CH 2 OR 15 It is.

[0110] In some embodiments, R 1b Ha-CH 2 OR 15 and R 15 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted C 2 ~C10 Heterocycloalkyl, -C(=O)R 16 , -C(=O)-OR 16 , or -C(=O)N(R 16 ) 2 In some embodiments, R 1b Ha-CH 2 OR 15 and R 15 is a substituted or unsubstituted C 2 ~C 10 Heterocycloalkyl, -C(=O)R 16 , -C(=O)-OR 16 , or -C(=O)N(R 16 ) 2 In some embodiments, R 1b Ha-CH 2 OR 15 and R 15 is -C(=O)R 16 , -C(=O)-OR 16 , or -C(=O)N(R 16 ) 2 It is.

[0111] In some embodiments, R 1b Ha-CH 2 OR 15 ;R 15 is -C(=O)R 16 and each R 16 are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C 3 ~C 6cycloalkyl), or -alkyl-(substituted or unsubstituted C 2 ~C 6 heterocycloalkyl).

[0112] In some embodiments, R 1b Ha-CH 2 OR 15 In some embodiments, -CO 2 -R 1b teeth [ka] It is.

[0113] In some embodiments, R 15 is -C(=O)R 16 In some embodiments, -CO 2 -R 1b teeth [ka] It is.

[0114] In some embodiments, -CO 2 -R 1b teeth [ka] and R 16 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C 3 ~C6 cycloalkyl), or -alkyl-(substituted or unsubstituted C 2 ~C 6 heterocycloalkyl).

[0115] In some embodiments, -CO 2 -R 1b teeth [ka] and R 16 is a substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted heteroaryl), or -alkyl-(substituted or unsubstituted C 2 ~C 6 In some embodiments, -CO 2 -R 1b teeth [ka] and R 16 is a substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, substituted or unsubstituted heteroaryl, -CH 2 -(substituted or unsubstituted heterocycloalkyl), -(CH 2 ) 2 -(substituted or unsubstituted heterocycloalkyl), -(CH 2 ) 3 -(substituted or unsubstituted heterocycloalkyl), -CH 2 -(substituted or unsubstituted heteroaryl), -(CH 2 ) 2 -(substituted or unsubstituted heteroaryl), or -(CH 2 ) 3 -(substituted or unsubstituted heteroaryl). In some embodiments, -CO 2 -R 1b teeth [ka] and R 16 is a substituted or unsubstituted C 2 ~C 6 It is a heterocycloalkyl, or a substituted or unsubstituted heteroaryl.

[0116] In some embodiments, -CO 2 -R 1b teeth [ka] and R 16 is a substitution C 2 ~C 6 In some embodiments, -CO is a heterocycloalkyl or a substituted heteroaryl. 2 -R 1b teeth [ka] and R 16 is unsubstituted C 2 ~C 6 In some embodiments, -CO is a heterocycloalkyl or an unsubstituted heteroaryl. 2 -R 1b teeth [ka] and R 16 is a substitution C 2 ~C 6 In some embodiments, -CO is a heterocycloalkyl. 2 -R 1b teeth [ka] and R 16 is substituted heteroaryl. In some embodiments, -CO 2 -R 1b teeth [ka] and R 16 is unsubstituted C2 ~C 6 In some embodiments, -CO is a heterocycloalkyl. 2 -R 1b teeth [ka] and R 16 is unsubstituted heteroaryl. In some embodiments, -CO 2 -R 1b teeth [ka] and R 16 is a benzyl-substituted heteroaryl.

[0117] In some embodiments, -CO 2 -R 1b teeth [ka] In some embodiments, -CO 2 -R 1b teeth [ka] It is.

[0118] In some embodiments, R 1a -CO 2 H, -CO 2 -R 1b , or -C(O)N(R 1c ) 2 In some embodiments, R 1a -CO 2 H or -C(O)N(R 1c ) 2 In some embodiments, R 1a -C(O)N(R 1c ) 2 In some embodiments, R 1a -C(O)N(R 1c ) 2and each R 1c are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C 6 In some embodiments, R 1a -C(O)N(R 1c ) 2 and each R 1c are independently hydrogen, C 1 ~C 6 Alkyl or C 1 ~C 6 In some embodiments, each R 1c are independently hydrogen or C 1 ~C 6 In some embodiments, each R 1c are independently hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , or -CD 2 CD 3 In some embodiments, each R 1c are independently hydrogen, -CH 3 , -CH 2 CH 3 , -CD 3 , or -CD 2 CD 3 In some embodiments, each R 1c are independently hydrogen, -CH 3 , or -CD 3 In some embodiments, each R1c are independently hydrogen or -CH 3 In some embodiments, each R 1c are independently hydrogen or -CD 3 In some embodiments, each R 1c is hydrogen. In some embodiments, each R 1c Ha-CH 3 In some embodiments, each R 1c Ha-CD 3 It is.

[0119] In some embodiments, R 2 is hydrogen, -CH 3 , -CH 2 CH 3 , -CD 3 , -CH 2 CD 3 , -CF 3 , or -CH 2 CF 3 ;R 3 is hydrogen, -CH 3 , -CH 2 CH 3 , -CD 3 , -CH 2 CD 3 , -CF 3 , or -CH 2 CF 3 or R 2 and R 3 together with the carbon atoms to which they are attached form ring B which is a substituted or unsubstituted oxetane, a substituted or unsubstituted thietane 1,1-dioxide, or a substituted or unsubstituted azetidine.

[0120] In some embodiments, R 2 is hydrogen, -CH 3 , -CD 3 , or -CF 3 ;R 3 is hydrogen, -CH 3 , -CD 3 , or -CF 3 or R 2 and R 3together with the carbon atoms to which they are attached form ring B which is a substituted or unsubstituted oxetane, a substituted or unsubstituted thietane 1,1-dioxide, or a substituted or unsubstituted azetidine.

[0121] In some embodiments, R 6 is hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , -NR 16 C(=O)R 16 , substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl; 6 If is substituted, it is one or more R 13 or R 5 and R 6 together with the intervening atoms to which they are attached form a fused ring D which is a substituted or unsubstituted 5- or 6-membered carbocyclic ring or a substituted or unsubstituted 5- or 6-membered heterocyclic ring, where when ring D is substituted it is joined to one or more R 14 has been replaced by

[0122] In some embodiments, R 6 is hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6Fluoroalkyl, -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 In some embodiments, R 6 is hydrogen, -F, -Cl, -Br, -CN, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CF 3 , -OH, -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -CO 2 H, -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -C(=O)NH 2, -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -NH 2 , -NHCH 3 , or -N(CH 3 ) 2 It is.

[0123] In some embodiments, R 6 is hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 In some embodiments, R 6 is hydrogen, -F, -Cl, -Br, -CN, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , or -CF 2 CF 3 It is.

[0124] In some embodiments, R 6 is hydrogen, halogen, or -CN. In some embodiments, R 6 is hydrogen, -F, -Cl, -Br, or -CN. In some embodiments, R 6 is hydrogen, -F, -Cl, or -CN. In some embodiments, R 6 is -F or -Cl. In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is -F. In some embodiments, R 6 In some embodiments, R 6 is -CN.

[0125] In some embodiments, R 6 is C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 In some embodiments, R 6 is -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , or -CF 2 CF 3 In some embodiments, R 6 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CD 3 , -CH 2 F, -CHF 2 , or -CF 3 In some embodiments, R 6 is -CH 3 , -CD 3 , -CH 2 F, -CHF 2 , or -CF 3 It is.

[0126] In some embodiments, R 6 -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 In some embodiments, R 6 -OH, -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -CO 2 H, -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -NH 2 , -NHCH3 , or -N(CH 3 ) 2 It is.

[0127] In some embodiments, R 6 is a substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl, where R 6 If is substituted, it is one or more R 13 has been replaced by

[0128] In some embodiments, R 6 is unsubstituted C 3 ~C 6 Cycloalkyl, unsubstituted C 2 ~C 6 In some embodiments, R is heterocycloalkyl, unsubstituted phenyl, or unsubstituted heteroaryl. 6 is a substitution C 3 ~C 6 Cycloalkyl, substituted C 2 ~C 6 heterocycloalkyl, substituted phenyl, or substituted heteroaryl, each of which is one or more R 13 has been replaced by

[0129] In some embodiments, R 6 is a substituted or unsubstituted C 3 ~C 6 In some embodiments, R 6 is substituted or unsubstituted C 3 ~C 6 It is cycloalkyl.

[0130] In some embodiments, R 6 is substituted or unsubstituted cyclopropyl. In some embodiments, R 6is unsubstituted cyclopropyl. In some embodiments, [ka] teeth [ka] In some embodiments, R 6 is one or more R 13 In some embodiments, [ka] teeth [ka] It is.

[0131] In some embodiments, R 6 is substituted or unsubstituted phenyl or substituted or unsubstituted 6-membered heteroaryl. In some embodiments, R 6 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted triazinyl, or substituted or unsubstituted tetrazinyl, or a tautomer thereof. 6 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridinyl, or substituted or unsubstituted pyrimidinyl. 6 is substituted or unsubstituted phenyl. In some embodiments, R 6 is substituted or unsubstituted pyridinyl. In some embodiments, R 6 is substituted or unsubstituted pyrimidinyl.

[0132] In some embodiments, [ka] teeth [ka] It is.

[0133] In some embodiments, R 6 is one or more R 13 In some embodiments, [ka] teeth [ka] In some embodiments, [ka] teeth [ka] In some embodiments, R 6 is unsubstituted phenyl. In some embodiments, [ka] teeth [ka] In some embodiments, R 13 is -CN. In some embodiments, [ka] teeth [ka] It is.

[0134] In some embodiments, the compound of formula (I) has the structure of formula (XIII-A): [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0135] In some embodiments of the compound of Formula (XIII-A), R 2 and R 3 are substituted or unsubstituted C together with the carbon atom to which they are attached. 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C 6 heterocycloalkyl, where if ring B is substituted, it is substituted with one or more R 12 In some embodiments of the compound of formula (XIII-A), R 2 and R 3 together with the carbon atoms to which they are attached form ring B which is an oxetane, azetidine, thietane 1-oxide, or thietane 1,1-dioxide.

[0136] In some embodiments, the compound of formula (I) has the structure of formula (XIII-B) or (XIII-C): [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0137] In some embodiments, the compound of formula (X) has the structure of formula (XIV): [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0138] In some embodiments, the compound of formula (X) has the structure of formula (XV) or formula (XVI): [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0139] In some embodiments, R 6 is a substituted or unsubstituted C 2 ~C 6 In some embodiments, R is heterocycloalkyl or unsubstituted heteroaryl. 6 is substituted or unsubstituted C 2 ~C 6 In some embodiments, R 6 is a substituted or unsubstituted oxetane, azetidine, or thietane 1,1-dioxide.

[0140] In some embodiments, R 6 is a substituted oxetane, azetidine, or thietane 1,1-dioxide, where each R 6 is one or more R 13 In some embodiments, [ka] teeth [ka] It is.

[0141] In some embodiments, [ka] teeth [ka] It is.

[0142] In some embodiments, R 6 is substituted or unsubstituted heteroaryl. In some embodiments, R 6 is a substituted or unsubstituted pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl.

[0143] In some embodiments, R 5 and R6 together with the intervening atoms to which they are attached form a fused ring D which is a substituted or unsubstituted 5- or 6-membered carbocyclic ring or a substituted or unsubstituted 5- or 6-membered heterocyclic ring, where when ring D is substituted it is joined to one or more R 14 has been replaced by

[0144] In some embodiments, R 5 and R 6 together with the intervening atoms to which they are attached form a fused substituted or unsubstituted ring D which is a fused substituted or unsubstituted phenyl, a fused substituted or unsubstituted pyridinyl, or a fused substituted or unsubstituted cyclohexyl, where when ring D is substituted it is joined to one or more R 14 has been replaced by

[0145] In some embodiments, R 5 and R 6 together with the intervening atoms to which they are attached form a fused substituted or unsubstituted phenyl, in which ring D, if substituted, is substituted by one or more R 14 In some embodiments, R 5 and R 6 together with the intervening atoms to which they are attached form a fused unsubstituted phenyl. [ka] teeth [ka] It is.

[0146] In some embodiments, R 5 and R 6 are one or more R 14 In some embodiments, [ka] teeth [ka] In some embodiments, [ka] teeth [ka] It is.

[0147] In some embodiments, R 5 and R 6 together with the intervening atoms to which they are attached form a fused substituted or unsubstituted pyridinyl, in which ring D, if substituted, is substituted by one or more R 14 In some embodiments, R 5 and R 6 together with the intervening atom to which they are attached form a fused unsubstituted pyridinyl. [ka] teeth [ka] It is.

[0148] In some embodiments, R 5 and R 6 are one or more R 14 In some embodiments, a fused pyridinyl is formed which is substituted with [ka] teeth [ka] In some embodiments, [ka] teeth [ka] It is.

[0149] In some embodiments, R 5 and R 6 together with the intervening atoms to which they are attached form a fused substituted or unsubstituted cyclohexyl, in which ring D, if substituted, is substituted by one or more R 14 In some embodiments, R 5 and R 6 together with the intervening atoms to which they are attached form a fused unsubstituted cyclohexyl. In some embodiments, [ka] teeth [ka] It is.

[0150] In some embodiments, R 5 and R 6 are one or more R 14 In some embodiments, [ka] teeth [ka] In some embodiments, [ka] teeth [ka] In some embodiments, [ka] teeth [ka] In some embodiments, [ka] teeth [ka] It is.

[0151] In some embodiments, R 4 is hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 In some embodiments, R 4 is hydrogen, -F, -Cl, -Br, -CN, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CF 3 , -OH, -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -CO 2 H, -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -NH 2 , -NHCH 3 , or -N(CH 3 ) 2 It is.

[0152] In some embodiments, R 4 is hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 In some embodiments, R 4 is hydrogen, -F, -Cl, -Br, -CN, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 )3 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , or -CF 2 CF 3 It is.

[0153] In some embodiments, R 4 is hydrogen, halogen, or -CN. In some embodiments, R 4 is hydrogen, -F, -Cl, -Br, or -CN. In some embodiments, R 4 is hydrogen, -F, -Cl, or -CN. In some embodiments, R 4 is -F or -Cl. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -F. In some embodiments, R 4 In some embodiments, R 4 is -CN.

[0154] In some embodiments, R 4 is C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C6 In some embodiments, R 4 is -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , or -CF 2 CF 3 In some embodiments, R 4 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CD 3 , -CH 2 F, -CHF 2 , or -CF 3 In some embodiments, R 4 is -CH 3 , -CD 3 , -CH 2 F, -CHF 2 , or -CF 3 It is.

[0155] In some embodiments, R4 -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 In some embodiments, R 4 -OH, -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -CO 2 H, -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -NH 2 , -NHCH 3 , or -N(CH 3 ) 2 It is.

[0156] In some embodiments, R 5 is hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 In some embodiments, R 5 is hydrogen, -F, -Cl, -Br, -CN, -CH 3 , -CH 2CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CF 3 , -OH, -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -CO 2 H, -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -NH 2 , -NHCH 3 , or -N(CH 3 ) 2 It is.

[0157] In some embodiments, R 5 is hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, C 1~C 6 Deuteroalkyl, C 1 ~C 6 In some embodiments, R 5 is hydrogen, -F, -Cl, -Br, -CN, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , or -CF 2 CF 3 It is.

[0158] In some embodiments, R 5 is hydrogen, halogen, or -CN. In some embodiments, R 5 is hydrogen, -F, -Cl, -Br, or -CN. In some embodiments, R 5 is hydrogen, -F, -Cl, or -CN. In some embodiments, R 5 is -F or -Cl. In some embodiments, R 5 is hydrogen. In some embodiments, R 5is -F. In some embodiments, R 5 In some embodiments, R 5 is -CN.

[0159] In some embodiments, R 5 is C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 In some embodiments, R 5 is -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , or -CF 2 CF 3 In some embodiments, R 5 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CD 3, -CH 2 F, -CHF 2 , or -CF 3 In some embodiments, R 5 is -CH 3 , -CD 3 , -CH 2 F, -CHF 2 , or -CF 3 It is.

[0160] In some embodiments, R 5 -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 In some embodiments, R 5 -OH, -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -CO 2 H, -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -NH 2 , -NHCH 3 , or -N(CH 3 ) 2 It is.

[0161] In some embodiments, R 7 is hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, -OR 16, -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 In some embodiments, R 7 is hydrogen, -F, -Cl, -Br, -CN, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CF 3 , -OH, -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -CO 2 H, -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -C(=O)NH 2 , -C(=O)NHCH 3, -C(=O)N(CH 3 ) 2 , -NH 2 , -NHCH 3 , or -N(CH 3 ) 2 It is.

[0162] In some embodiments, R 7 is hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 In some embodiments, R 7 is hydrogen, -F, -Cl, -Br, -CN, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , or -CF 2 CF 3 It is.

[0163] In some embodiments, R7 is hydrogen, halogen, or -CN. In some embodiments, R 7 is hydrogen, -F, -Cl, -Br, or -CN. In some embodiments, R 7 is hydrogen, -F, -Cl, or -CN. In some embodiments, R 7 is -F or -Cl. In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is -F. In some embodiments, R 7 In some embodiments, R 7 is -CN.

[0164] In some embodiments, R 7 is C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 In some embodiments, R 7 is -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH2 F, -CH 2 CHF 2 , -CH 2 CF 3 , or -CF 2 CF 3 In some embodiments, R 7 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CD 3 , -CH 2 F, -CHF 2 , or -CF 3 In some embodiments, R 7 is -CH 3 , -CD 3 , -CH 2 F, -CHF 2 , or -CF 3 It is.

[0165] In some embodiments, R 7 -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 In some embodiments, R 7 -OH, -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -CO 2 H, -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -NH 2 , -NHCH 3 , or -N(CH3 ) 2 It is.

[0166] In some embodiments, R 8 is hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 In some embodiments, R 8 is hydrogen, -F, -Cl, -Br, -CN, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CF2 CF 3 , -OH, -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -CO 2 H, -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -NH 2 , -NHCH 3 , or -N(CH 3 ) 2 It is.

[0167] In some embodiments, R 8 is hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 In some embodiments, R 8 is hydrogen, -F, -Cl, -Br, -CN, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , or -CF 2 CF 3 It is.

[0168] In some embodiments, R 8 is hydrogen, halogen, or -CN. In some embodiments, R 8 is hydrogen, -F, -Cl, -Br, or -CN. In some embodiments, R 8 is hydrogen, -F, -Cl, or -CN. In some embodiments, R 8 is -F or -Cl. In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is -F. In some embodiments, R 8 In some embodiments, R 8 is -CN.

[0169] In some embodiments, R 8 is C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 In some embodiments, R 8 is -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 D, -CHD2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , or -CF 2 CF 3 In some embodiments, R 8 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CD 3 , -CH 2 F, -CHF 2 , or -CF 3 In some embodiments, R 8 is -CH 3 , -CD 3 , -CH 2 F, -CHF 2 , or -CF 3 It is.

[0170] In some embodiments, R 8 -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 In some embodiments, R 8 -OH, -OCH 3 , -OCH 2 CH 3 , -OCF3 , -CO 2 H, -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -NH 2 , -NHCH 3 , or -N(CH 3 ) 2 It is.

[0171] In some embodiments, R 4 , R 5 , R 7 , and R 8 are each independently hydrogen; R 6 is hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , -NR 16 C(=O)R 16 , substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl, where R 6 If is substituted, it is one or more R 13 or R 5 and R 6together with the intervening atoms to which they are attached form a fused substituted or unsubstituted ring D which is a fused substituted or unsubstituted phenyl, a fused substituted or unsubstituted pyridinyl, or a fused substituted or unsubstituted cyclohexyl, where when ring D is substituted it is substituted with one or more R 14 has been replaced by

[0172] In some embodiments, R 4 , R 5 , R 7 , and R 8 are each independently hydrogen; R 6 is hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 In some embodiments, R is heterocycloalkyl, or substituted or unsubstituted phenyl. 4 , R 5 , R 7 , and R 8 are each independently hydrogen; and R 6 is hydrogen, -F, -Cl, -CN, -CH 3 , substituted or unsubstituted cyclopropyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted azetinyl, substituted or unsubstituted thietane 1,1-dioxide, or substituted or unsubstituted phenyl. 4 , R 5 , R 7 , and R 8 are each independently hydrogen; and R 6 is hydrogen, -CN, substituted or unsubstituted oxetanyl, or substituted or unsubstituted phenyl. In some embodiments, R 4 , R 5 , R 6 , R 7 , and R 8 are each independently hydrogen. 4 , R 5 , R7 , and R 8 are each independently hydrogen; and R 6 In some embodiments, R 4 , R 5 , R 7 , and R 8 are each independently hydrogen; and R 6 is hydrogen, -CN, substituted or unsubstituted oxetanyl, or substituted or unsubstituted phenyl. In some embodiments, R 4 , R 5 , R 7 , and R 8 are each independently hydrogen; and R 6 is substituted or unsubstituted oxetanyl. In some embodiments, R 4 , R 5 , R 7 , and R 8 are each independently hydrogen; and R 6 is substituted or unsubstituted phenyl.

[0173] In some embodiments, R 10 is hydrogen, deuterium, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 In some embodiments, R 10 are hydrogen, deuterium, -F, -Cl, -Br, -CN, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2) 3 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CF 3 , -OH, -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -CO 2 H, -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -NH 2 , -NHCH 3 , or -N(CH 3 ) 2 It is.

[0174] In some embodiments, R 10 is hydrogen, deuterium, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6In some embodiments, R 10 is hydrogen, -F, -Cl, -Br, -CN, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , or -CF 2 CF 3 It is.

[0175] In some embodiments, R 10 is hydrogen, halogen, or -CN. In some embodiments, R 10 is hydrogen, -F, -Cl, -Br, or -CN. In some embodiments, R 10 is -F, -Cl, or -CN. In some embodiments, R 10 is -F or -Cl. In some embodiments, R 10 is hydrogen. In some embodiments, R 10 is deuterium. In some embodiments, R 10 is -F. In some embodiments, R 10In some embodiments, R 10 is -CN.

[0176] In some embodiments, R 10 is C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 In some embodiments, R 10 is -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , or -CF 2 CF 3 In some embodiments, R 10 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CD 3 , -CH 2 F, -CHF 2, or -CF 3 In some embodiments, R 10 is -CH 3 , -CD 3 , -CH 2 F, -CHF 2 , or -CF 3 It is.

[0177] In some embodiments, R 10 -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 In some embodiments, R 10 -OH, -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -CO 2 H, -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -NH 2 , -NHCH 3 , or -N(CH 3 ) 2 It is.

[0178] In some embodiments, R 12 is hydrogen, deuterium, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, -OR 16 , -C(=O)R 16 , -CO 2R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 In some embodiments, R 12 are hydrogen, deuterium, -F, -Cl, -Br, -CN, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CF 3 , -OH, -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -CO 2 H, -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 )2 , -NH 2 , -NHCH 3 , or -N(CH 3 ) 2 It is.

[0179] In some embodiments, R 12 is hydrogen, deuterium, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 In some embodiments, R 12 is hydrogen, -F, -Cl, -Br, -CN, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , or -CF 2 CF 3 It is.

[0180] In some embodiments, R 12is hydrogen, halogen, or -CN. In some embodiments, R 12 is hydrogen, -F, -Cl, -Br, or -CN. In some embodiments, R 12 is -F, -Cl, or -CN. In some embodiments, R 12 is -F or -Cl. In some embodiments, R 12 is hydrogen. In some embodiments, R 12 is deuterium. In some embodiments, R 12 is -F. In some embodiments, R 12 In some embodiments, R 12 is -CN.

[0181] In some embodiments, R 12 is C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 In some embodiments, R 12 is -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , or -CF 2 CF 3 In some embodiments, R 12 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CD 3 , -CH 2 F, -CHF 2 , or -CF 3 In some embodiments, R 12 is -CH 3 , -CD 3 , -CH 2 F, -CHF 2 , or -CF 3 It is.

[0182] In some embodiments, R 12 -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 In some embodiments, R 12 -OH, -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -CO 2 H, -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -NH 2 , -NHCH3 , or -N(CH 3 ) 2 It is.

[0183] In some embodiments, R 13 is hydrogen, deuterium, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 In some embodiments, R 13 are hydrogen, deuterium, -F, -Cl, -Br, -CN, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH2 CF 3 , -CF 2 CF 3 , -OH, -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -CO 2 H, -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -NH 2 , -NHCH 3 , or -N(CH 3 ) 2 It is.

[0184] In some embodiments, R 13 is hydrogen, deuterium, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 In some embodiments, R 13 is hydrogen, -F, -Cl, -Br, -CN, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , or -CF 2 CF 3 It is.

[0185] In some embodiments, R 13 is hydrogen, halogen, or -CN. In some embodiments, R 13 is hydrogen, -F, -Cl, -Br, or -CN. In some embodiments, R 13 is -F, -Cl, or -CN. In some embodiments, R 13 is -F or -Cl. In some embodiments, R 13 is hydrogen. In some embodiments, R 13 is deuterium. In some embodiments, R 13 is -F. In some embodiments, R 13 In some embodiments, R 13 is -CN.

[0186] In some embodiments, R 13 is C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 In some embodiments, R 13 is -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 )2 , -C(CH 3 ) 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , or -CF 2 CF 3 In some embodiments, R 13 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CD 3 , -CH 2 F, -CHF 2 , or -CF 3 In some embodiments, R 13 is -CH 3 , -CD 3 , -CH 2 F, -CHF 2 , or -CF 3 It is.

[0187] In some embodiments, R 13 -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 In some embodiments, R 13-OH, -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -CO 2 H, -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -NH 2 , -NHCH 3 , or -N(CH 3 ) 2 It is.

[0188] In some embodiments, R 14 is hydrogen, deuterium, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 In some embodiments, R 14 are hydrogen, deuterium, -F, -Cl, -Br, -CN, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 D, -CHD 2, -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CF 3 , -OH, -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -CO 2 H, -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -NH 2 , -NHCH 3 , or -N(CH 3 ) 2 It is.

[0189] In some embodiments, R 14 is hydrogen, deuterium, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 In some embodiments, R 14 is hydrogen, -F, -Cl, -Br, -CN, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3, -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , or -CF 2 CF 3 It is.

[0190] In some embodiments, R 14 is hydrogen, halogen, or -CN. In some embodiments, R 14 is hydrogen, -F, -Cl, -Br, or -CN. In some embodiments, R 14 is -F, -Cl, or -CN. In some embodiments, R 14 is -F or -Cl. In some embodiments, R 14 is hydrogen. In some embodiments, R 14 is deuterium. In some embodiments, R 14 is -F. In some embodiments, R 14 In some embodiments, R 14 is -CN.

[0191] In some embodiments, R 14 is C 1 ~C 6 Alkyl, C1 ~C 6 Deuteroalkyl, C 1 ~C 6 In some embodiments, R 14 is -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CH 2 D, -CH 2 C.H.D. 2 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , or -CF 2 CF 3 In some embodiments, R 14 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CD 3 , -CH 2 F, -CHF 2 , or -CF 3 In some embodiments, R 14 is -CH 3 , -CD 3 , -CH 2 F, -CHF 2 , or -CF 3 It is.

[0192] In some embodiments, R 14 -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 In some embodiments, R 14 -OH, -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -O-cyclopropyl, -O-cyclobutyl, -O-oxetanyl, -O-azetidinyl, -CO 2 H, -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -NH 2 , -NHCH 3 , or -N(CH 3 ) 2 It is.

[0193] In another embodiment, a compound having the structure of formula (XX): [ka] or a pharma- ceutically acceptable salt or solvate thereof, R 1 teeth [ka] , -C(O)NR d R e , -N(R f ) 2, a substituted or unsubstituted monocyclic heterocycle, or a substituted or unsubstituted monocyclic carbocycle, where R 1 When R is a substituted monocyclic heterocycle, it may occur one or more times. 9 is replaced by; R a are hydrogen, deuterium, and C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 is a fluoroalkyl; R b are hydrogen, deuterium, and C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C 6 is heterocycloalkyl; or R a and R b are substituted or unsubstituted C together with the carbon atom to which they are attached. 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C 6 heterocycloalkyl, where ring C is substituted with one or more R 11 and R c is hydrogen, C 1 ~C 6 Alkyl or R g Is it; or R a and R b together with the carbon atom to which they are attached form a carbonyl (C=O); and R c is C 3 ~C 6 Alkyl or R g and; R d -CN, C 1~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, C 1 ~ 6 Alkoxy, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, -OH, -OR 1d , -SOR 1d , or -SO 2 R 1d where R 1d is a substituted or unsubstituted C 1 ~C 6 Alkyl, substituted or unsubstituted C 3 ~C 6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl; 1d If is substituted, it is one or more R 14 is replaced by; R e is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, C 1 ~ 6 Alkoxy, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C 6 is heterocycloalkyl; or R d and R e are substituted or unsubstituted C together with the N atom to which they are attached. 2 ~C 6 Forming a heterocycloalkyl; Each R f are independently hydrogen, C 1 ~C 6Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, or substituted or unsubstituted C 2 ~C 6 is heterocycloalkyl; Or both R f are substituted or unsubstituted C together with the N atom to which they are attached. 2 ~C 6 Forming a heterocycloalkyl; R g is C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 1 ~C 6 Heteroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C 3 ~C 6 Cycloalkyl), -alkyl-(substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl), -C(=O)R 16 , -C(=O)-OR 16 , -C(=O)N(R 16 ) 2 , -(C(R 17 ) 2 O) p -R 15 , -(CH 2 CH 2 O) q -R 15 , or -(C(R 17 ) 2 ) p -OR 15 and; Z is N or CR 8 and; R 4 , R 5 , R 7 , and R 8 are each independently hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 and; R 6 is hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , -NR 16 C(=O)R 16 , substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl; 6 If is substituted, it is one or more R 13 is replaced by; Each R 9 , R 10 , R 11 , R13 , and R 14 are independently hydrogen, deuterium, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, -CN, -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 and; R 15 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted C 2 ~C 10 Heterocycloalkyl, -C(=O)R 16 , -C(=O)-OR 16 , or -C(=O)N(R 16 ) 2 and; Each R 16 are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C 3 ~C 6Cycloalkyl), -alkyl-(substituted or unsubstituted C 2 ~C 6 heterocycloalkyl); Or both R 16 are substituted or unsubstituted C together with the N atom to which they are attached. 2 ~C 6 Forming a heterocycloalkyl; Each R 17 are independently hydrogen or C 1 ~C 6 is alkyl; m is 1 or 2; n is 0, 1, 2, 3, or 4; p is 1, 2, 3, 4, or 5; and and q is 1, 2, 3, 4, or 5.

[0194] In some embodiments, R 1 teeth [ka] , -C(O)NR d R e or a substituted or unsubstituted monocyclic heterocycle; 1 When R is a substituted monocyclic heterocycle, it may occur one or more times. 9 is replaced by; R a and R b together with the carbon atom to which they are attached form a carbonyl (C=O); and R c is C 3 ~C 6 Alkyl or R g and; R d -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Fluoroalkyl, -OH, -OR 1d , or -SO 2 R 1d and R e is hydrogen or -CH 3It is.

[0195] In some embodiments, R 6 is substituted or unsubstituted heteroarylphenyl. In some embodiments, R 6 is substituted or unsubstituted heteroaryl. In some embodiments, R 6 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, or substituted or unsubstituted pyrimidinyl. 6 is a substituted or unsubstituted pyridone or a substituted or unsubstituted pyrimidone. In some embodiments, R 6 is unsubstituted. In some embodiments, R 6 is one or more R 13 has been replaced by

[0196] In some embodiments, R 6 is a substituted or unsubstituted phenyl, or a substituted or unsubstituted heteroaryl, where R 6 If is substituted, it is one or more R 13 has been replaced by

[0197] In some embodiments, R 6 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl; 6 If is substituted, it is one or more R 13 is replaced by; Z is N or CR 8 and; R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , and R 13 are each independently hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6Fluoroalkyl or OR 16 It is.

[0198] In some embodiments, Z is CR 8 and; R 4 , R 5 , R 7 , and R 8 is hydrogen; R 6 is a substituted phenyl; and R 13 is halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Fluoroalkyl or OCH 3 It is.

[0199] In some embodiments, R 1 is -C(O)OR c or -C(O)NR d R e In some embodiments, R 1 -N(R f ) 2 In some embodiments, R 1 is a substituted or unsubstituted monocyclic heterocycle. In some embodiments, R 1 is —C(O)OH. In some embodiments, R 1 is -C(O)OCH 3 or -C(O)OCH 2 CH 3 In some embodiments, R 1 -C(O)OR c In some embodiments, R 1 is -C(O)O(C 1 ~C 6 haloalkyl), -C(O)O(C 3 ~C 6 alkyl), -C(O)O(C 3 ~C 6 cycloalkyl), or -C(O)O(C 6aryl). In some embodiments, R 1 is -C(O)O(4-6 membered heterocycloalkyl) or -C(O)O(5-6 membered heteroaryl).

[0200] In some embodiments, R 1 -C(O)NH 2 In some embodiments, R 1 -C(O)NR d R e In some embodiments, R 1 In some embodiments, R 1 is -C(O)NHCN. In some embodiments, R 1 -C(O)NHCH 3 In some embodiments, R 1 is -C(O)N(CH 3 ) 2 In some embodiments, R 1 -C(O)NHOH, -C(O)NHOCH 3 , -C(O)N(CH 3 )OH, or -C(O)N(CH 3 )OCH 3 In some embodiments, R 1 is -C(O)NHOH or -C(O)NHOCH 3 In some embodiments, R 1 is -C(O)NHOH or -C(O)N(CH 3 )OH.

[0201] In some embodiments, R 1 -C(O)NHSO 2 R 1d In some embodiments, R 1d is a substituted or unsubstituted C 1 ~C 6 Alkyl, substituted or unsubstituted C 3 ~C 6cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl; 1d If is substituted, it is one or more R 14 In some embodiments, R 1d is substituted or unsubstituted C 1 ~C 6 In some embodiments, R 1d is substituted or unsubstituted methyl, where R 1d If is substituted, it can have one, two, or three R 14 In some embodiments, R 14 is fluorine. In some embodiments, R 14 -C 1 ~C 6 In some embodiments, R 14 HA-OCH 3 In some embodiments, R 1d is -CH 3 , -CH 2 CH 3 , -CH 2 CF 3 , -CH 2 OCH 3 , -CH 2 F, -CH(CH 3 ) 2 , -CHF 2 , -C(CH 3 ) 3 , or -CF 3 In some embodiments, R 1 is -C(O)NHSO 2 CH 3 , -C(O)NHSO 2 CH 2 CH 3 , -C(O)NHSO 2 CH 2 CF 3 , -C(O)NHSO 2 CH 2 OCH 3 , -C(O)NHSO 2 CH 2F, -C(O)NHSO 2 CH(CH 3 ) 2 , -C(O)NHSO 2 CHF 2 , -C(O)NHSO 2 C(CH 3 ) 3 or -C(O)NHSO 2 CF 3 In some embodiments, R 1 -C(O)NHSO 2 (C 1 ~C 6 In some embodiments, R 1 -C(O)NHSO 2 (substituted or unsubstituted methyl).

[0202] In some embodiments, R 1d is substituted or unsubstituted C 3 ~C 6 In some embodiments, R 1d is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, or substituted or unsubstituted cyclohexyl. 1d is substituted or unsubstituted cyclopropyl. In some embodiments, R 1 -C(O)NHSO 2 (C 3 ~C 6 In some embodiments, R 1 -C(O)NHSO 2 (3- to 6-membered heterocycloalkyl). In some embodiments, R 1d is oxetanyl, azetidinyl, tetrahydrofuranyl, or pyrrolidinyl. 1 -C(O)NHSO 2 (oxetanyl). In some embodiments, R 1d is substituted or unsubstituted phenyl. In some embodiments, R 1 -C(O)NHSO 2(phenyl). In some embodiments, R 1d is a substituted or unsubstituted 5- or 6-membered heteroaryl. In some embodiments, R 1d is substituted or unsubstituted piperidinyl, or substituted or unsubstituted pyrimidinyl. In some embodiments, R 1 -C(O)NHSO 2 (phenyl).

[0203] In some embodiments, the compound has the structure of formula XXI: [ka] or a pharma- ceutically acceptable salt thereof, R 1 is -C(O)OR c or -C(O)NR d R e and; R c is C 3 ~C 6 Alkyl or R g and; R d -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Fluoroalkyl, -OH, -OR 1d , or -SO 2 R 1d and; R 1d is a substituted or unsubstituted C 1 ~C 6 Alkyl, substituted or unsubstituted C 3 ~C 6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, or substituted or unsubstituted phenyl; 1d If is substituted, it is one or more R 14 is replaced by; R e is hydrogen or -CH 3 and; R g is C 1 ~C6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 1 ~C 6 Heteroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl; R 10 is hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Fluoroalkyl or OR 16 and; R 13 are hydrogen, deuterium, halogens, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 Heterocycloalkyl, -CN, -OR 16 , -C(=O)R 16 , -CO 2 R 16 , -C(=O)N(R 16 ) 2 , -N(R 16 ) 2 , or -NR 16 C(=O)R 16 and; R 14 is hydrogen, halogen, C 1 ~C 6 Alkyl, -CN, or -OR 16 and; Each R 16 are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C1 ~C 6 Fluoroalkyl, or substituted or unsubstituted C 3 ~C 6 is cycloalkyl; m is 1 or 2; and where n is 0, 1, 2, 3, or 4.

[0204] In some embodiments, the compound of formula (XX) has the structure of formula (XXI'): [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0205] In some embodiments, the compound of formula (XX) has the structure of formula (XXI″): [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0206] In some embodiments, the compound of formula (XX) has the structure of formula (XXI'''): [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0207] In some embodiments, the compound has the structure of formula XXII: [ka] or a pharma- ceutically acceptable salt thereof (wherein X 1 and X 2 are each independently 13 or N).

[0208] In some embodiments, R 10 , R 13 , and R 14are each independently hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Fluoroalkyl or OR 16 and R 16 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Fluoroalkyl, substituted or unsubstituted C 3 ~C 6 It is cycloalkyl.

[0209] In some embodiments, R 1 -CN, -C(O)NHCH 3 , -C(O)NHCH 2 CF 3 , -C(O)NHCN, -C(O)NHOH, -C(O)N(CH 3 )OH, -C(O)NHOCH 3 , -C(O)NHS(O) 2 CH 3 , -C(O)NHS(O) 2 CF 3 , -C(O)NHS(O) 2 CH 2 CH 3 , -C(O)NHS(O) 2 CH 2 CF 3 , -C(O)NHS(O) 2 CH 2 OCH 3 , -C(O)NHS(O) 2 -CH(CH 3 ) 2 , -C(O)NHS(O) 2 C(CH 3 ) 2 , -C(O)NHS(O) 2 Cyclopropyl, or -C(O)NHS(O) 2 It is phenyl.

[0210] In some embodiments, R10 is -CN, -F, or -OCH 3 ;R 13 is -CN, -F, or -OCH 3 and n is 1.

[0211] In some embodiments, the compound has the following structure: [ka] It has one of the following.

[0212] In some embodiments, the compound has the following structure: [ka] It has one of the following.

[0213] In some embodiments, R 5 is hydrogen; R 6 is a substituted or unsubstituted C 3 ~C 6 Cycloalkyl, substituted or unsubstituted C 2 ~C 6 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl, where R 6 If is substituted, it is one or more R 13 or R 5 and R 6 together with the intervening atoms to which they are attached form a fused substituted or unsubstituted ring D which is a fused substituted or unsubstituted phenyl, a fused substituted or unsubstituted pyridinyl, or a fused substituted or unsubstituted cyclohexyl, where when ring D is substituted it is substituted with one or more R 14 In some embodiments, R 5 is hydrogen; R 6 is a substituted or unsubstituted phenyl or a substituted or unsubstituted 6-membered heteroaryl containing 1 or 2 N atoms, where R 6 If is substituted, it is one or more R13 or R 5 and R 6 together with the intervening atoms to which they are attached form a fused substituted or unsubstituted ring D which is a fused substituted or unsubstituted phenyl, or a fused substituted or unsubstituted pyridinyl, where when ring D is substituted it is joined to one or more R 14 has been replaced by

[0214] All combinations of the groups described above with respect to the various variables are contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one of ordinary skill in the art to produce stable moieties and compounds.

[0215] Exemplary compounds include the following compounds in Tables 1, 2, 3, and 4:

[0216] [Table 1]

[0217] In some embodiments, provided herein are pharma- ceutically acceptable salts of the compounds set forth in Table 1.

[0218] [Table 2]

[0219] In some embodiments, provided herein are pharma- ceutically acceptable salts of the compounds set forth in Table 2.

[0220] [Table 3]

[0221] [Table 4]

[0222] [Table 5]

[0223] [Table 6]

[0224] In some embodiments, provided herein are pharma- ceutically acceptable salts of the compounds set forth in Table 3.

[0225] [Table 7]

[0226] [Table 8]

[0227] [Table 9]

[0228] [Table 10]

[0229] [Table 11]

[0230] [Table 12]

[0231] In some embodiments, provided herein are pharma- ceutically acceptable salts of the compounds set forth in Table 4.

[0232] In one embodiment, the compounds described herein are in the form of pharmaceutically acceptable salts.It should be noted that the active metabolites of these compounds with the same type of activity are included in the scope of the present disclosure.In addition, the compounds described herein can exist in unsolvated form as well as in solvated form with pharmaceutically acceptable solvents such as water, ethanol, etc.The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0233] As used herein, "pharmacologically acceptable" refers to a material, such as a carrier or diluent, that does not interfere with the biological activity or properties of the compound and is relatively non-toxic, i.e., a material that may be administered to an individual without causing undesirable biological effects or detrimentally interfering with any of the components of the composition in which it is contained.

[0234] The term "pharmaceutical acceptable salt" refers to a therapeutically active agent in cationic form combined with a suitable anion or, in an alternative embodiment, in a form consisting of a therapeutically active agent in anionic form combined with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. SM Berge, LD Bighley, DC Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. PH Stahl and CG Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zuerich:Wiley-VCH / VHCA, 2002. Drug salts are typically more soluble in gastrointestinal fluids and dissolve more rapidly than non-ionic species, making them useful in solid dosage forms. Furthermore, their solubility is often a function of pH, allowing selective dissolution in one part or another of the gastrointestinal tract, which can be manipulated as an aspect of delayed and sustained release behavior. Also, molecules that form salts can be in equilibrium with neutral forms, allowing for tailored transport across biological membranes.

[0235] In some embodiments, pharma- ceutically acceptable salts are obtained by reacting the compounds described herein with an acid. In some embodiments, the compounds described herein (i.e., in free base form) are basic and are reacted with an organic or inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; gi acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (-L); malonic acid; mandelic acid (DL); methanesulfonic acid; monomethyl fumarate, naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (-L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid.

[0236] In some embodiments, the compounds described herein are prepared as a chloride, sulfate, bromide, mesylate, maleate, citrate, or phosphate salt. In some embodiments, the compounds described herein are prepared as a hydrochloride salt.

[0237] In some embodiments, pharma- ceutically acceptable salts are obtained by reacting a compound described herein with a base. In some embodiments, a compound described herein is acidic and is reacted with a base. In such cases, the acidic proton of a compound described herein is replaced with a metal ion, for example, lithium, sodium, potassium, magnesium, calcium, or aluminum ion. In some cases, a compound described herein is coordinated with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, a compound described herein forms a salt with an amino acid, such as, but not limited to, arginine, lysine. 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, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds provided herein are formulated as a sodium salt, a calcium salt, a potassium salt, a magnesium salt, a meglumine salt, an N-methylglucamine salt, or an ammonium salt. In some embodiments, the compounds provided herein are formulated as a sodium salt.

[0238] It should be understood that reference to pharma-ceutically acceptable salts includes solvent addition forms. In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of a solvent and are formed during the process of crystallization with a pharma-ceutically acceptable solvent, such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. Furthermore, the compounds provided herein optionally exist in unsolvated as well as solvated forms.

[0239] The methods and formulations described herein include the use of N-oxides (where appropriate), crystalline forms (also known as polymorphs), or pharma- ceutically acceptable salts of the compounds described herein, as well as active metabolites of these compounds that have the same type of activity.

[0240] In some embodiments, sites on the organic radicals (e.g., alkyl groups, aromatic rings) of the compounds described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize, or eliminate this metabolic pathway. In specific embodiments, suitable substituents for reducing or eliminating the susceptibility of aromatic rings to metabolic reactions are, by way of example only, halogens, deuterium, alkyl groups, haloalkyl groups, or deuteroalkyl groups.

[0241] In another embodiment, the compounds described herein are labeled with an isotope (e.g., with a radioisotope) or by other means, including but not limited to the use of a chromophore or fluorescent moiety, a bioluminescent label, or a chemiluminescent label.

[0242] The compounds described herein include isotopically labeled compounds that are identical to those listed in the various formulas and structures presented herein except for the fact that one or more atoms have been replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds include, for example, 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, 36 and isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as Cl. In one embodiment, the isotopically labeled compounds described herein, e.g. 3 H and 14Incorporation of radioactive isotopes such as C are useful in drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium confers certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.

[0243] In some embodiments, the compounds described herein have one or more stereocenters, and each stereocenter is independently present in either the R or S configuration. The compounds provided herein include all diastereomeric, enantiomeric, atropisomeric, and epimeric forms, and the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, and the appropriate mixtures thereof.

[0244] Individual stereoisomers can be obtained, if desired, by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatographic columns. 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 a pair of diastereoisomeric compounds / salts, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation / resolution techniques based on differences in solubility. In other embodiments, separation of steroisomers is carried out by chromatography, or by formation of diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0245] In some embodiments, the compounds described herein are prepared as prodrugs. "Prodrug" refers to an agent that is converted to the parent drug in vivo. Prodrugs are often useful because in some situations they are easier to administer than the parent drug. They are, for example, bioavailable by oral administration, whereas the parent is not. In some situations, the prodrug may cross a membrane (e.g., cell membrane, intestinal lumen, blood-brain barrier, etc.), whereas the active agent is not. In some situations, a charged or highly polar moiety is masked with a more permeable group that can be cleaved in vivo. The prodrug may be a substrate for a transporter. Additionally or alternatively, the prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of the prodrug increases the effective water solubility. Without limitation, one example of a prodrug is a compound described herein, which is administered as an ester ("prodrug"), but is then metabolically hydrolyzed to provide the active form. In certain embodiments, upon in vivo administration, the prodrug is chemically converted to the biologically, pharma- ceutical or therapeutically active form of the compound. In certain embodiments, the prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharma- ceutical or therapeutically active form of the compound. In some embodiments, the prodrug is enzymatically metabolized in vivo to the active form by esterases, proteases, peptidases, hydrolases, etc. In some embodiments, the prodrug is converted to the active form of the compound independently of metabolic enzymes (e.g., by hydrolysis or pH-dependent degradation).

[0246] Prodrugs of the compounds described herein include, but are not limited to, esters, ethers (e.g., oxymethyl ethers), carbonates, thiocarbonates, carbamates, anhydrides, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See, for example, Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. "Design and Application of Prodrugs" in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, each of which is incorporated herein by reference. In some embodiments, hydroxyl groups in the compounds disclosed herein are used to form prodrugs, but the hydroxyl groups are incorporated into acyloxyalkyl esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphate esters, sugar esters, ethers, and the like. In some embodiments, the carboxyl group is used to provide an ester or amide (i.e., a prodrug) that is then metabolized in vivo to provide the carboxylic acid group. In some embodiments, the compounds described herein are prepared as alkyl ester prodrugs. In some embodiments, the compounds described herein are prepared as oxymethyl ether or polyoxymethylene dimethyl ether prodrugs.

[0247] Within the scope of the claims are compounds described herein in prodrug form, where the prodrug is metabolized in vivo to yield the compounds described herein. In some cases, some of the compounds described herein are prodrugs of another derivative or active compound.

[0248] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need thereof to produce metabolites which are then used to produce a desired effect, including a desired therapeutic effect.

[0249] A "metabolite" of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound that is formed when the compound is metabolized. As used herein, the term "metabolized" refers to the sum of processes by which a particular substance is altered by an organism, including but not limited to hydrolysis reactions and reactions catalyzed by enzymes. Thus, enzymes can produce particular structural changes in a compound. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while uridine diphosphate glucuronyltransferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Metabolites of a compound disclosed herein are optionally identified either by administration of the compound to a host and analysis of tissue samples from the host, or by incubation of the compound with hepatocytes in vitro and analysis of the resulting compounds.

[0250] In some embodiments, the compounds of the present disclosure provide enhanced pharmacokinetic or pharmacodynamic profiles compared to other known EP2 antagonists.For example, the compounds described herein may increase bioavailability, volume of distribution, absorption, half-life, duration of action, receptor occupancy, cell permeability, blood-brain barrier permeability, plasma stability, metabolic stability, excretion, or toxicity profile compared to currently available EP2 antagonists.In some embodiments, the compounds are formulated as prodrugs, in which case the active metabolites are cleaved in vivo after reaching target cells or tissues.In other embodiments, the compounds are not cleaved in vivo.

[0251] Specific Terms Unless otherwise stated, the following terms used in this application have the definitions given below. The terms "including" and other forms such as "include," "includes," and "included" are open-ended. The section headings used are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0252] As used herein, C 1 ~C x is C 1 ~C 2 , C 1 ~C 3 ...C 1 ~C x As just one example, "C 1 ~C 4 " indicates that there are 1 to 4 carbon atoms in the moiety, i.e., a group containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. 1 ~C 4 "Alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl group, ie, the alkyl group is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

[0253] An "alkyl" group refers to an aliphatic hydrocarbon group. An alkyl group can be branched or straight chain. In some embodiments, an "alkyl" group has 1 to 10 carbon atoms, i.e., C 1 ~C 10 Whenever it appears herein, a numerical range such as "1 to 10" refers to each integer within the given range; for example, "1 to 10 carbon atoms" means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although this definition also includes occurrences of the term "alkyl" where no numerical range is given. In some embodiments, alkyl is C 1 ~C 6 In one embodiment, the alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. Exemplary alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

[0254] "Deuteroalkyl" refers to an alkyl group in which one or more of the alkyl's hydrogen atoms has been replaced with deuterium.

[0255] The term "alkenyl" refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula -C(R)=CR 2 where R refers to the remainder of the alkenyl group, which may be the same or different. In some embodiments, R is H or alkyl. Non-limiting examples of alkenyl groups include -CH=CH 2 , -C(CH 3 )=CH 2 , -CH=CHCH 3 , -C(CH 3 )=CHCH 3 , and -CH 2 CH=CH 2 There is.

[0256] The term "alkynyl" refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkenyl group has the formula -C≡CR, where R refers to the remainder of the alkynyl group. In some embodiments, R is H or alkyl. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH 3 -C≡CCH 2 CH 3 , -CH 2 There is C≡CH.

[0257] An "alkoxy" group refers to an (alkyl)O- group, where alkyl is as defined herein.

[0258] The term "alkylamine" refers to an -N(alkyl) x H y

[0046] This refers to the group where x is 0 and y is 2, or x is 1 and y is 1, or x is 2 and y is 0.

[0259] The term "carbocyclic" or "carbocycle" refers to a ring or ring system in which the atoms forming the backbone of the ring are all carbon atoms. This term therefore distinguishes carbocyclic from "heterocyclic" rings or "heterocycles" in which the ring backbone contains at least one atom different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic.

[0260] As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. In one aspect, an aryl is phenyl or naphthyl. In some embodiments, an aryl is phenyl. In some embodiments, an aryl is C 6 ~C 13 Depending on the structure, an aryl group can be a monovalent group or a divalent group (i.e., an arylene group).

[0261] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic, non-aromatic radical in which each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. In some embodiments, the cycloalkyl is a spirocyclic or bridged compound. In some embodiments, the cycloalkyl is optionally fused to an aromatic ring, and the point of attachment is a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having 3 to 10 ring atoms. In some embodiments, the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl, and bicyclic[1.1.1]pentyl. In some embodiments, the cycloalkyl group is selected from C 3 ~C 6 It is cycloalkyl.

[0262] The term "halo" or, alternatively, "halogen" or "halide" means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0263] The term "fluoroalkyl" refers to an alkyl in which one or more hydrogen atoms have been replaced with a fluorine atom. In one embodiment, fluoroalkyl is C 1 ~C 6 It is a fluoroalkyl.

[0264] The term "heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, sulfur, or combinations thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one embodiment, a heteroalkyl is a C 1 ~C 6 It is heteroalkyl.

[0265] The term "heterocycle" or "heterocyclic" refers to heteroaromatic rings (also known as heteroaryl) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing 1 to 4 heteroatoms in the ring, where each heteroatom in the ring is selected from O, S, and N, and where each heterocyclic group has 3 to 10 atoms in its ring system, provided that no ring contains two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyl) include rings having 3 to 10 atoms in their ring system, and aromatic heterocyclic groups include rings having 5 to 10 atoms in their ring system. Heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithio ranyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindolin-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindolin-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl.Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The above groups are either C-attached (or C-linked) or N-attached where possible. For example, groups derived from pyrrole include both pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked). Furthermore, groups derived from imidazole include imidazol-1-yl or imidazol-3-yl (both N-linked) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-linked). Heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of the bicyclic heterocycle is aromatic. In some embodiments, both rings of the bicyclic heterocycle are aromatic.

[0266] The term "heteroaryl" or, alternatively, "heteroaromatic" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryl and bicyclic heteroaryl. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Monocyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, a heteroaryl contains 0-4 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains C 1 ~C 9 In some embodiments, the monocyclic heteroaryl is C 1 ~C 5 In some embodiments, the monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, the bicyclic heteroaryl is a C 6 ~C 9 It is heteroaryl.

[0267] A "heterocycloalkyl" or "heteroalicyclic" group refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl is fused to an aryl or heteroaryl. In some embodiments, a heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. The term heteroalicyclic also includes carbohydrates of all ring forms, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. In one embodiment, a heterocycloalkyl is C 2 ~C 10 In another embodiment, heterocycloalkyl is C 2 ~C 6 Heterocycloalkyl. In some embodiments, a heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring.

[0268] The term "bond" or "single bond" refers to a chemical bond between two atoms, or between two moieties when the atoms connected by the bond are considered to be part of a larger substructure. In one embodiment, when a group described herein is a bond, the recited group is not present, thereby allowing a bond to be formed between the remaining specified groups.

[0269] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often recognized as a chemical entity that is embedded in or appended to a molecule.

[0270] The term "optionally substituted" or "substituted" means that the referenced group is selected from the group consisting of halogen, -CN, -NH2 , -NH(alkyl), -N(alkyl) 2 , -OH, -CO 2 H, -CO 2 Alkyl, -C(=O)NH 2 , -C(=O)NH(alkyl), -C(=O)N(alkyl) 2 , -S(=O) 2 NH 2 , -S(=O) 2 NH(alkyl), -S(=O) 2 N(alkyl) 2 , alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, the optional substituents are halogen, -CN, -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -OH, -CO 2 H, -CO 2 (C 1 ~C 4 alkyl), -C(=O)NH 2 , -C(=O)NH(C 1 ~C 4 alkyl), -C(=O)N(C 1 ~C 4 Alkyl) 2 , -S(=O) 2 NH 2 , -S(=O) 2 NH(C 1 ~C 4 Alkyl), -S(=O) 2 N(C 1 ~C 4 Alkyl) 2 , C 1 ~C 4 Alkyl, C 3 ~C 6 Cycloalkyl, C 1 ~C 4Fluoroalkyl, C 1 ~C 4 Heteroalkyl, C 1 ~C 4 Alkoxy, C 1 ~C 4 Fluoroalkoxy, -SC 1 ~C 4 Alkyl, -S(=O)C 1 ~C 4 Alkyl, and -S(=O) 2 C 1 ~C 4 In some embodiments, the optional substituents are independently selected from halogen, -CN, -NH 2 , -OH, -NH(CH 3 ), -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CF 3 , -OCH 3 , and -OCF 3 In some embodiments, a substituted group is substituted with one or two of the foregoing groups. In some embodiments, optional substituents on an aliphatic carbon atom (acyclic or cyclic) include oxo (=O).

[0271] The term "acceptable" as used herein with respect to a formulation, composition or ingredient means having no lasting deleterious effects on the general health of the subject being treated.

[0272] The term "modulate," as used herein, means to interact with a target, either directly or indirectly, to alter the activity of the target, including, by way of example only, to increase the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to prolong the activity of the target.

[0273] The term "modulator" as used herein refers to a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, those of an agonist, partial agonist, inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, the modulator is an antagonist.

[0274] As used herein, the terms "administer", "administering", "administration" and the like refer to methods that can be used to enable delivery of a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those skilled in the art are familiar with administration techniques that can be utilized with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0275] As used herein, the term "co-administration" and the like is meant to encompass the administration of selected therapeutic agents to a single patient and is intended to include therapeutic regimens in which the agents are administered by the same or different routes of administration or at the same or different times.

[0276] The term "effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount of an administered drug or compound to relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound disclosed herein required to give a clinically significant reduction in disease symptoms. The appropriate "effective" amount in any individual case is optionally determined using techniques such as dose escalation studies.

[0277] The terms "enhance" or "enhancing," as used herein, means to increase or prolong, either in potency or duration, a desired effect. Thus, in terms of enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An "enhancing effective amount," as used herein, refers to an amount sufficient to enhance the effect of another therapeutic agent in a desired system.

[0278] The term "pharmaceutical combination" as used herein means a product resulting from the mixing or combination of two or more active ingredients, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that both active ingredients, e.g., a compound described herein or a pharmaceutically acceptable salt thereof, and a co-agent, are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g., a compound described herein or a pharmaceutically acceptable salt thereof, and a co-agent, are administered to a patient simultaneously, in parallel, or sequentially without any specific time restriction between them, as separate entities, such that such administration provides an effective level of the two compounds in the patient's body. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0279] The terms "kit" and "article of manufacture" are used synonymously.

[0280] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates such as chimpanzees, and other ape and monkey species; farm animals such as cows, horses, sheep, goats, pigs, and the like; domestic animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. In one embodiment, the mammal is a human.

[0281] As used herein, the terms "treat," "treating," or "treatment" include alleviating, attenuating, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, e.g., preventing the onset of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating conditions caused by a disease or condition, or prophylactically and / or therapeutically arresting a symptom of a disease or condition.

[0282] Pharmaceutical Compositions In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharma- ceutical acceptable inactive ingredients that facilitate the processing of active compounds into pharmaceutical preparations. Appropriate formulations depend on the route of administration selected. Overviews of 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 & Wilkins1999), which are incorporated herein by reference for such disclosures.

[0283] In some embodiments, the compounds described herein are administered alone or in combination with a pharma- ceutically acceptable carrier, excipient, or diluent in a pharmaceutical composition. Administration of the compounds and compositions described herein can be performed by any method that allows delivery of the compound to the site of action. These methods include, but are not limited to, delivery by enteral routes (including oral, gastric or duodenal feeding tubes, rectal suppositories, and rectal enemas), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural, and subcutaneous), inhalation, transdermal, transmucosal, sublingual, buccal, and topical (including transdermal, dermal, enema, eye drops, ear drops, intranasal, and intravaginal) administration, although the optimal route may depend, for example, on the condition and disorder of the recipient.

[0284] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.

[0285] Pharmaceutical compositions that can be used orally include tablets, push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, an inert diluent, or a lubricant, surfactant, or dispersing agent. Molded tablets can be produced by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and are formulated to provide a slow or controlled release of the active ingredient therein. All formulations for oral administration should be in a dosage suitable for such administration. Push-fit capsules can contain the active ingredient in admixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0286] In some embodiments, the pharmaceutical compositions are formulated for parenteral administration, e.g., by bolus injection or continuous infusion. Preparations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with added preservatives. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory agents, such as suspending, stabilizing and / or dispersing agents. The compositions may be presented in unit-dose or multi-dose containers, e.g., sealed ampoules and vials, and may be stored in powder form or freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, e.g., saline or sterile pyrogen-free water, immediately prior to use. Injectable solutions and suspensions according to the prescription may be prepared from sterile powders, granules and tablets of the kind previously described.

[0287] Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound, which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound, allowing for the preparation of highly concentrated solutions.

[0288] Pharmaceutical compositions can also be formulated as depot preparations. Such long-acting preparations can be administered by implantation (e.g., subcutaneously or intramuscularly) or intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as sparingly soluble salts.

[0289] Compound synthesis The compounds described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with the methods described herein.

[0290] The compounds are described, for example, in March's Advanced Organic Chemistry, 6 th The starting materials are prepared using standard organic chemistry techniques, such as those described in The American Chemical Society, Vol. 13, No. 1, 1999, 1999 Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be utilized, such as variations in solvents, reaction temperatures, reaction times, as well as different chemical reagents and other reaction conditions. The starting materials are available from commercial sources or are readily prepared.

[0291] In some embodiments, the preparation of the EP2 inhibitors described herein begins with the sequence of steps depicted in general Scheme A. [ka]

[0292] In some embodiments, an intermediate of formula Int-A is treated with a base and a suitable acid chloride or activated ester to become an amide of formula Compound A upon treatment with a suitable nucleophile. [ka]

[0293] In some embodiments, an intermediate of formula Int-A is treated with base and a suitable azide reagent to generate an acyl azide intermediate Int-B, which upon treatment with heat and a second azide undergoes a rearrangement reaction to generate a compound of formula Compound B. [ka]

[0294] In some embodiments, an intermediate of formula Compound A is treated with pyridine and a suitable anhydride to produce a compound of formula Compound C. d and R e are each H. An exemplary anhydride for use in Scheme C includes, but is not limited to, trifluoroacetic anhydride.

[0295] In some embodiments, the compounds described herein are synthesized as outlined in the Examples.

[0296] Methods of Dosing and Treatment Regimens In one embodiment, the compounds of formula (I) are used in the preparation of a medicament for the treatment or prevention of diseases and conditions that would benefit from or decrease or inhibit EP2 activity. Furthermore, a method of treating any of the diseases and conditions described herein in a mammal in need of such treatment comprises administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (I) or formula (X), or a pharma- ceutically acceptable salt, active metabolite, prodrug, or solvate thereof.

[0297] In certain embodiments, compositions comprising the compounds described herein are administered for prophylactic and / or therapeutic treatment. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially prevent at least one symptom of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation clinical trials.

[0298] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition.

[0299] In certain embodiments, the dosage of an administered drug may be temporarily reduced or even stopped for a particular period of time (ie, a "drug holiday").

[0300] Dosages utilized for adult human treatment typically range from 0.01 mg to 5000 mg per day, or from about 1 mg to about 1000 mg per day, in one embodiment, the desired dosage is conveniently presented as a single dose or divided doses.

[0301] In certain cases, it is appropriate to administer at least one compound of formula (I) or formula (X) in combination with another therapeutic agent. In a specific embodiment, a compound of formula (I) or formula (X) is co-administered with a second therapeutic agent, where the compound of formula (I) or formula (X) and the second therapeutic agent modulate different aspects of the disease or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.

[0302] For the combination therapies described herein, the dosage of the co-administered compounds will vary depending on the type of co-agent utilized, the specific agent utilized, the disease or condition being treated, etc. In additional embodiments, when co-administered with one or more other therapeutic agents, the compounds provided herein are administered simultaneously with or sequentially to the one or more other therapeutic agents.

[0303] When administration is simultaneous, the multiple therapeutic agents may be given in a single combined form or in multiple forms, by way of example only. EXAMPLES

[0304] Working Example The following examples are offered for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0305] Example 1: Preparation of 1-(4-fluorobenzoyl)-3-(((6-methoxynaphthalen-2-yl)oxy)methyl)-N-methylazetidine-3-carboxamide (compound 1-1): [ka] 1-(4-Fluorobenzoyl)-3-(((6-methoxynaphthalen-2-yl)oxy)methyl)-N-methylazetidine-3-carboxamide (compound 1-1): To a mixture of intermediate 1 (350 mg, 0.86 mmol) in anhydrous THF (1.0 mL) at about -15 °C, add Et 3 N (104 mg, 1.0 mmol) and ethyl chloroformate (187 mg, 0.86 mmol) were added. To the stirred solution was added 2M MeNH in THF. 2 (0.86 mL, 1.7 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 12 h, then H 2 O (10 mL) was added and the mixture was extracted with DCM (10 mL×4). The combined organic layers were extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (n-heptane / ethyl acetate, 20 / 1 to 0 / 1) to give compound 1-1 (28 mg, 8%) as a solid. LCMS (ESI): m / z [M+H] C 24 H 23 FN 2 O 4 Calculated value 422.2; measured value 423.1; 1 H NMR (400MHz, DMSO-d 6 )δ 8.10(d,J=4.4Hz,1H),7.70-7.76(m,4H),7.29(t,J=9.2Hz,4H),7.08-7.14(m,2H),4.59(d,J=8.8H z,1H),4.40(s,2H),4.24-4.30(m,2H),4.10(d,J=10.0Hz,1H),3.83(s,3H),2.66(d,J=4.4Hz,3H); 19 F NMR (377MHz, DMSO-d 6 ) δ -109.2; 13 C NMR (100 MHz, DMSO-d 6)δ 171.4,168.3,164.9(d,J=247Hz),155.9,154.7,130.6,129.7(d,J=41Hz), 128.2,118.8,115.6(d),107.7,106.2,70.5,58.0,55.2,53.9,43.6,26.2.

[0306] Example 2: Preparation of 1-(1-(4-fluorobenzoyl)-3-(((6-methoxynaphthalen-2-yl)oxy)methyl)azetidin-3-yl)-1,4-dihydro-5H-tetrazol-5-one (compound 1-2): [ka] Step 1: Synthesis of 1-(4-fluorobenzoyl)-3-(((6-methoxynaphthalen-2-yl)oxy)methyl)azetidine-3-carbonyl azide (Intermediate 2): 1-(4-Fluorobenzoyl)-3-(((6-methoxynaphthalen-2-yl)oxy)methyl)azetidine-3-carbonyl azide (Intermediate 2): N 2 To a mixture of intermediate 1 (300 mg, 0.73 mmol) in THF (1 mL) at 0-5 °C under 3 N (459 mL, 3.30 mmol) and DPPA (429 mL, 1.98 mmol) were added. The mixture was allowed to warm to room temperature and stirred for 16 h, then H 2 O (5 mL) was added and the mixture was extracted with DCM (4 mL x 3). The combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and the filtrate was concentrated under reduced pressure to give intermediate 2 (300 mg, 94%) as an oil, which was used directly in the step without further purification. LCMS (ESI): m / z [M+H]C 23 H 19 FN 4 O 4 Calculated value 434.1; measured value 435.1.

[0307] Step 2: Synthesis of 1-(1-(4-fluorobenzoyl)-3-(((6-methoxynaphthalen-2-yl)oxy)methyl)azetidin-3-yl)-1,4-dihydro-5H-tetrazol-5-one (compound 1-2): 1-(1-(4-Fluorobenzoyl)-3-(((6-methoxynaphthalen-2-yl)oxy)methyl)azetidin-3-yl)-1,4-dihydro-5H-tetrazol-5-one (compound 1-2): intermediate 2 (150 mg, 0.35 mmol) and TMSN 3 (273 mL, 2.1 mmol) was heated to 95-100 °C and stirred for 12 h. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give compound 1-2 (20 mg, 7%) as a solid. LCMS (ESI): m / z [MH]C 23 H 20 FN 5 O 4 Calculated value 449.2; measured value 448.2; 1 H NMR (400MHz, DMSO-d 6 )δ 7.70-7.79(m,4H),7.26-7.33(m,4H),7.08-7.14(m,2H),4.96-5.00(m,1 H),4.68(d,J=10.0Hz,2H),4.45(s,2H),4.43-4.46(m,1H),3.83(s,3H); 19 F NMR (377MHz, DMSO-d 6 )δ -108.9.

[0308] Example 3. Preparation of 1-(4-fluorobenzoyl)-3-(((6-methoxynaphthalen-2-yl)oxy)methyl)azetidine-3-carbonitrile (Compound 1-3) [ka] Step 1. Synthesis of 1-(4-fluorobenzoyl)-3-(((6-methoxynaphthalen-2-yl)oxy)methyl)azetidine-3-carboxamide (Intermediate 3) 1-(4-Fluorobenzoyl)-3-(((6-methoxynaphthalen-2-yl)oxy)methyl)azetidine-3-carboxamide (Intermediate 3): To a mixture of Intermediate 1 (150 mg, 0.37 mmol) in DMF (1 mL) at -10 to 0 °C, add Et 3 N (128 mL, 0.92 mmol) and a 50% solution of T3P (436 mL, 0.73 mmol) were added. The mixture was warmed to room temperature and stirred for 30 min, then NH 4 Cl (39 mg, 0.73 mmol) was added. The mixture was stirred at room temperature for 12 h and then H 2 O (2 mL) was added and the mixture was extracted with EtOAc (2 mL x 3). The combined organic layers were washed with brine solution (2 mL x 3) and anhydrous Na 2 SO 4 The mixture was dried over 1000 mg, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 3 (100 mg, 67%) as a solid, which was used directly in the next step without further purification. LCMS (ESI): m / z [M+H] C 23 H 21 FN 2 O 4 Calculated value: 408.2; measured value: 409.0.

[0309] Step 2. Synthesis of 1-(4-fluorobenzoyl)-3-(((6-methoxynaphthalen-2-yl)oxy)methyl)azetidine-3-carbonitrile (compound 1-3) 1-(4-Fluorobenzoyl)-3-(((6-methoxynaphthalen-2-yl)oxy)methyl)azetidine-3-carbonitrile (compound 1-3): To a mixture of intermediate 3 (100 mg, 0.25 mmol) in THF (1 mL) at room temperature was added pyridine (51 mL, 0.64 mmol) and trifluoroacetic anhydride (TFAA) (87 mL, 0.64 mmol). The mixture was stirred at room temperature for 12 h and then subjected to H 2 O (5 mL) was added and the mixture was extracted with EtOAc (4 mL×3). The combined organic layers were extracted with Na 2 SO 4The mixture was dried over 1000 ml and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give compound 1-3 (26 mg, 27%) as a solid. LCMS (ESI): m / z [M+H]C 23 H 19 FN 2 O 3 Calculated value 390.1; measured value 391.1; 1 H NMR (400MHz, DMSO-d 6 )δ 7.78-7.71(m,4H),7.27-7.34(m,4H),7.11-7.16(m,2H),4.83(d,J=8.4Hz ,1H),4.55(s,2H),4.42-4.50(m,2H),4.27(d,J=8.4Hz,1H),3.84(s,3H); 19 F NMR (377MHz, DMSO-d 6 )δ -107.8.

[0310] Example 4. Preparation of racemic 3-(((4'-cyano-[1,1'-biphenyl]-4-yl)oxy)methyl)-1-(4-methoxybenzoyl)-N-methylpyrrolidine-3-carboxamide (compound 2-1) [ka] Racemic 3-(((4'-cyano-[1,1'-biphenyl]-4-yl)oxy)methyl)-1-(4-methoxybenzoyl)-N-methylpyrrolidine-3-carboxamide (compound 2-1): To a mixture of (±)3-(((4'-cyano-[1,1'-biphenyl]-4-yl)oxy)methyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxylic acid intermediate 4 (600 mg, 1.3 mmol) in anhydrous THF (3.6 mL) at about -15 °C, was added Et 3 N (398 mg, 3.9 mmol) and ethyl chloroformate (569 mg, 5.2 mmol) were added. The mixture was stirred at -15°C for 3 h, then 2M methylamine (5.24 mL, 10.5 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 12 h, then H 2 O (10 mL) was added and extracted with DCM (10 mL x 4). The combined organic layers were washed with Na 2 SO4 After drying at 40° C., filtration, and concentration under reduced pressure, the residue was purified by preparative HPLC to give compound 2-1 (15 mg, 3%) as a solid. LCMS (ESI): m / z [M+H]C 28 H 27 N 3 O 4 Calculated value 469.2; measured value 470.1.

[0311] Example 5. Preparation of racemic 4'-((1-(4-methoxybenzoyl)-3-(5-oxo-4,5-dihydro-1H-tetrazol-1-yl)pyrrolidin-3-yl)methoxy)-[1,1'-biphenyl]-4-carbonitrile (Compound 2-2) [ka] Step 1. Synthesis of (±)3-(((4'-cyano-[1,1'-biphenyl]-4-yl)oxy)methyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carbonyl azide (Intermediate 5) N 2 To a mixture of (±)3-(((4'-cyano-[1,1'-biphenyl]-4-yl)oxy)methyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxylic acid intermediate 4 (0.6 g, 1.3 mmol) in THF (6 mL) at 0-5 °C under an atmosphere of 3 N (598 mg, 5.9 mmol) and DPPA (977 mg, 3.6 mmol) were added. The mixture was allowed to warm to room temperature and stirred for 16 h, then H 2 O (20 mL) was added and the mixture was extracted with DCM (20 mL x 3). The combined organic layers were extracted with Na 2 SO 4 The mixture was dried over 1000 rpm, filtered, and the filtrate was concentrated under reduced pressure to give (±)3-(((4'-cyano-[1,1'-biphenyl]-4-yl)oxy)methyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carbonyl azide (600 mg, 95%) as an oil, which was used directly in the next step without further purification. LCMS (ESI): m / z [M+H]C 27 H 23 N 5 O 4Calculated value 481.2; measured value 482.0.

[0312] Step 2. Synthesis of (±)4'-((1-(4-methoxybenzoyl)-3-(5-oxo-4,5-dihydro-1H-tetrazol-1-yl)pyrrolidin-3-yl)methoxy)-[1,1'-biphenyl]-4-carbonitrile (Compound 2-2) (±) 4'-((1-(4-methoxybenzoyl)-3-(5-oxo-4,5-dihydro-1H-tetrazol-1-yl)pyrrolidin-3-yl)methoxy)-[1,1'-biphenyl]-4-carbonitrile (compound 2-2): (±) 3-(((4'-cyano-[1,1'-biphenyl]-4-yl)oxy)methyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carbonyl azide intermediate 5 (0.6 g, 1.3 mmol) and TMSN 3 (983 mL, 7.5 mmol) was heated to 95° C. and stirred for 16 h. The mixture was directly purified by preparative HPLC to give compound 2-2 (40 mg, 6%) as a solid. LCMS (ESI): m / z [M+H]C 27 H 24 N 6 O 4 Calculated value 496.2; measured value 497.1; 1 H NMR (400 MHz, CDCl 3 )δ 8.59-8.98(m,1H),7.68(d,J=8.0Hz,2H),7.59(d,J=8.0Hz,2H),7.53(d,J=8.4Hz,2H),7.48(d,J=8.0Hz,2H),6.90-6.92 (m,4H),4.67-4.70(m,1H),4.27-4.26(m,2H),4.02-4.08(m,1H),3.78-3.90(m,5H),3.09(br.s,1H),2.49-2.57(m,1H).

[0313] Example 6. Preparation of racemic 3-(((4'-cyano-[1,1'-biphenyl]-4-yl)oxy)methyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carbonitrile (compound 2-3) [ka] Step 1. Synthesis of 3-(((4'-cyano-[1,1'-biphenyl]-4-yl)oxy)methyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxamide (Intermediate 6) 3-(((4'-cyano-[1,1'-biphenyl]-4-yl)oxy)methyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxamide (Intermediate 6): To a mixture of (±)3-(((4'-cyano-[1,1'-biphenyl]-4-yl)oxy)methyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxylic acid Intermediate 4 (0.6 g, 1.3 mmol) in DMF (6 mL) at -10 °C, was added Et 3 N (332 mg, 3.3 mmol) and a 50% T3P solution (1.56 mL, 2.6 mmol) were added. The mixture was warmed to room temperature and stirred for 0.5 h, then NH 4 Cl (141 mg, 2.6 mmol) was added and the mixture was warmed to 40° C. and stirred for 12 h. 2 O (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (10 mL×2) and anhydrous Na 2 SO 4 The mixture was dried over 1000 mg, filtered, and the filtrate was concentrated under reduced pressure to give 3-(((4'-cyano-[1,1'-biphenyl]-4-yl)oxy)methyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxamide (500 mg, 84%) as an oil, which was used directly in the next step without further purification. LCMS (ESI): m / z [M+H] C 27 H 25 N 3 O 4 Calculated value 455.2; measured value 456.0.

[0314] Step 2. Synthesis of (±)3-(((4'-cyano-[1,1'-biphenyl]-4-yl)oxy)methyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carbonitrile (compound 2-2) (±) 3-(((4'-cyano-[1,1'-biphenyl]-4-yl)oxy)methyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carbonitrile (compound 2-2): To a mixture of (±) 3-(((4'-cyano-[1,1'-biphenyl]-4-yl)oxy)methyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxamide intermediate 6 (500 mg, 1.1 mmol) in THF (3 mL) at room temperature was added pyridine (226 mg, 2.9 mmol) and TFAA (599 mg, 2.9 mmol). The mixture was stirred at room temperature for 12 h and then H 2 O (5 mL) was added and the mixture was extracted with EtOAc (4 mL×3). The combined organic layers were extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give (±)3-(((4′-cyano-[1,1′-biphenyl]-4-yl)oxy)methyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carbonitrile compound 2-3 (40 mg, 8%) as a solid; 1 H NMR (400 MHz, CDCl 3 )δ 7.72(d,J=8.4Hz,2H),7.66(d,J=8.4Hz,2H),7.56(m,4H),7.03(d,J=7.2Hz,2H),6.94(d,J=8.8H z,2H),4.13-4.19(m,3H),3.86-3.94(m,3H),3.86(s,3H),2.50-2.55(m,1H),2.33-2.34(m,1H).

[0315] Example 7: Preparation of 3-[({4'-cyano-[1,1'-biphenyl]-4-yl}oxy)methyl]-N-(ethanesulfonyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxamide (compound 4-25) [ka] To a mixture of 3-[({4'-cyano-[1,1'-biphenyl]-4-yl}oxy)methyl]-1-(4-methoxybenzoyl)pyrrolidine-3-carboxylic acid (80 mg, 0.18 mmol) in DCM (2 mL) was added CDI (113 mg, 0.70 mmol). The mixture was stirred at 50° C. for 4 h. To the mixture was added ethanesulfonamide (95 mg, 0.88 mmol) and DBU (106 mg, 0.70 mmol). The mixture was stirred at 50° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC with the following conditions (Column: XBridge Shield RP18 OBD column, 30×150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 21% B to 41% B in 7 min, 41% B; Wavelength: 254 nm; RT1 (min): 5.55; Runs: 0), affording 3-[({4'-cyano-[1,1'-biphenyl]-4-yl}oxy)methyl]-N-(ethanesulfonyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxamide (29.5 mg, 31%) as a solid. LC / MS: Mass. C 29 H 29 N 3 O 6 Calculated value of S: 547.1, Measured value: 548.1 [M+H] + ; 1 H NMR (300MHz, CD 3 OD) δ 7.77-7.80(m, 4H), 7.50-7.69(m, 4H), 6.99-7.14(m, 4H), 4.09-4.45(m, 3H), 3.85(d, J=3.0 Hz, 3H), 3.60-3.79(m, 3H), 3.20(br, 2H), 2.40-2.52(m, 1H), 2.02-2.17(m, 1H), 1.10-1.28(m, 3H). [Note: HNMR was affected by rotamers which can be widely observed in this series of targets].

[0316] Example 8: Preparation of N-cyano-3-(((4'-cyano-[1,1'-biphenyl]-4-yl)oxy)methyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxamide (compound 4-21) [ka] To a mixture of 3-[({4'-cyano-[1,1'-biphenyl]-4-yl}oxy)methyl]-1-(4-methoxybenzoyl)pyrrolidine-3-carboxylic acid (50 mg, 0.11 mmol) in DMF (1 mL) was added cyanamide (5 mg, 0.11 mmol), PyBOP (86 mg, 0.17 mmol) and DIPEA (28 mg, 0.22 mmol). The mixture was stirred at room temperature for 12 h and then filtered. The filtrate was directly purified by preparative HPLC using the following conditions: (Column: Xselect CSH C18 OBD column 30×150 mm 5 μm, n; Mobile phase A: water (0.05% HCl), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 49% B to 69% B in 7 min, 69% B; Wavelength: 254 nm; RT1 (min): 5.45; Runs: 0) to give N-cyano-3-[({4′-cyano-[1,1′-biphenyl]-4-yl}oxy)methyl]-1-(4-methoxybenzoyl)pyrrolidine-3-carboxamide (8.2 mg, 15%) as a solid. LC / MS: Mass. C 28 H 24 N 4 O 4 Calculated value: 480.1, Measured value: 481.1 [M+H] + ; 1 H NMR (300MHz, CD 3 OD)δ 7.79(s,4H),7.64-7.70(m,2H),7.54 (d,J=7.8Hz,2H),6.96-7.18(m,4H),4.15-4.37(m,3H),3.85(s,3H),3.61-3.82(m,3H),2.40-2.55(m,1H),2.26(br,1H).

[0317] Example 9: Preparation of 3-[({4'-cyano-[1,1'-biphenyl]-4-yl}oxy)methyl]-1-(4-methoxybenzoyl)-N-(2,2,2-trifluoroethanesulfonyl)pyrrolidine-3-carboxamide (compound 4-26) [ka] To a mixture of 3-[({4'-cyano-[1,1'-biphenyl]-4-yl}oxy)methyl]-1-(4-methoxybenzoyl)pyrrolidine-3-carboxylic acid (100 mg, 0.22 mmol) and 2,2,2-trifluoroethanesulfonamide (70 mg, 0.44 mmol) in DMF (2 mL) was added EDCI (63 mg, 0.33 mmol) and DMAP (13 mg, 0.11 mmol). The mixture was stirred at room temperature for 2 h and then directly purified by preparative HPLC with the following conditions (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH 4 HCO 3 +0.1%NH 3 .H 2 0), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 26% B to 56% B in 7 min, 56% B; Wavelength: 254 nm; RT1 (min): 6; Runs: 0), affording 3-[({4'-cyano-[1,1'-biphenyl]-4-yl}oxy)methyl]-1-(4-methoxybenzoyl)-N-(2,2,2-trifluoroethanesulfonyl)pyrrolidine-3-carboxamide (26.6 mg, 20%) as a solid. LC / MS: Mass. C 29 H 26 F 3 N 3 O 6 Calculated value of S: 601.1, Measured value: 602.0 [M+H] + ; 1 H NMR (300MHz, CD 3 OD)δ 7.70-7.80(m,4H),7.50-7.70(m,4H),6.94-7.15(m,4H),4.00-4.45(m,5H),3 .85(d,J=6.0Hz,3H),3.62-3.80(m,3H),2.48-2.60(m,1H),2.01-2.16(m,1H) 19 F NMR (282MHz, methanol-d 4 )δ -63.4.

[0318] The compounds in Table 5 can be prepared according to the preceding examples ("Example No.") described herein.

[0319] [Table 13]

[0320] [Table 14]

[0321] Example 9: Preparation of methoxymethanesulfonamide [ka] To a stirred mixture of chloromethanesulfonamide (500 mg, 3.86 mmol) in MeOH (5 mL) was added Ag 2 CO 3 (5.32 g, 19.3 mmol) was added. The resulting mixture was heated to 100° C. and stirred overnight, then filtered and the filter cake was washed with MeOH (3×5 mL). The filtrate was concentrated under reduced pressure to give methoxymethanesulfonamide (30 mg, 6%) as an oil. The crude product was used in the next step in the synthesis of compound 4-27 without further purification.

[0322] Example 10: Preparation of 4'-{[1-(4-methoxybenzoyl)-3-(2-methoxypyridin-4-yl)pyrrolidin-3-yl]methoxy}-[1,1'-biphenyl]-4-carbonitrile (Compound 4-32) [ka] Step 1: Synthesis of methyl 3-(2-bromopyridin-4-yl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxylate N 2 To a mixture of methyl 1-(4-methoxybenzoyl)pyrrolidine-3-carboxylate (500 mg, 1.9 mmol) and 2-bromopyridine-4-carbonitrile (420 mg, 2.28 mmol) in THF (10 mL) at −78° C. under an atmosphere of 0.1% was added 1M KHMDS in THF (2.8 mL, 2.8 mmol) slowly. The mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was diluted with NH4 It was quenched with aqueous Cl (15 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (30 mL) and MgSO 4 After filtration, the filtrate was concentrated under reduced pressure to give methyl 3-(2-bromopyridin-4-yl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxylate (500 mg, crude) as a solid. The crude product was used in the next step without further purification.

[0323] Step 2: Synthesis of [3-(2-bromopyridin-4-yl)-1-(4-methoxybenzoyl)pyrrolidin-3-yl]methanol A mixture of methyl 3-(2-bromopyridin-4-yl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxylate (500 mg, 1.19 mmol) in MeOH (10 mL) was treated with NaBH 4 (135 mg, 3.58 mmol) was added. The mixture was stirred at room temperature for 1 h and then purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.05% TFA), 20% to 70% gradient in 30 min; detector, UV 254 nm to give [3-(2-bromopyridin-4-yl)-1-(4-methoxybenzoyl)pyrrolidin-3-yl]methanol (400 mg, 86%) as a solid.

[0324] Step 3: Synthesis of 2-bromo-4-[3-(4-bromophenoxymethyl)-1-(4-methoxybenzoyl)pyrrolidin-3-yl]pyridine N 2 [3-(2-bromopyridin-4-yl)-1-(4-methoxybenzoyl)pyrrolidin-3-yl]methanol (200 mg, 0.51 mmol), 4-bromophenol (97 mg, 0.56 mmol) and PPh in toluene (3 mL) under 3(335 mg, 1.28 mmol) was added with DIAD (258 mg, 1.28 mmol). The mixture was heated to 80° C. and stirred for 2 h, then concentrated under reduced pressure and the residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.05% TFA), 20% to 80% gradient in 30 min; detector, UV 254 nm to give 2-bromo-4-[3-(4-bromophenoxymethyl)-1-(4-methoxybenzoyl)pyrrolidin-3-yl]pyridine (100 mg, 36%) as a solid.

[0325] Step 4: Synthesis of 4-[3-(4-bromophenoxymethyl)-1-(4-methoxybenzoyl)pyrrolidin-3-yl]-2-methoxypyridine Na (85 mg, 3.7 mmol) was added to dry MeOH (2 mL) and stirred at room temperature for 10 min. To the solution was added 2-bromo-4-[3-(4-bromophenoxymethyl)-1-(4-methoxybenzoyl)pyrrolidin-3-yl]pyridine (100 mg, 0.18 mmol). The mixture was heated to 80° C. and stirred for 4 h, then concentrated under reduced pressure and the residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.05% TFA), 20% to 70% gradient in 30 min; detector, UV 254 nm to give 4-[3-(4-bromophenoxymethyl)-1-(4-methoxybenzoyl)pyrrolidin-3-yl]-2-methoxypyridine (40 mg, 44%) as an oil.

[0326] Step 5: Synthesis of 4'-{[1-(4-methoxybenzoyl)-3-(2-methoxypyridin-4-yl)pyrrolidin-3-yl]methoxy}-[1,1'-biphenyl]-4-carbonitrile (compound 4-32) N 2 In an atmosphere of DMF (2 mL) and H 2To a mixture of 4-[3-(4-bromophenoxymethyl)-1-(4-methoxybenzoyl)pyrrolidin-3-yl]-2-methoxypyridine (40 mg, 0.08 mmol) and 4-cyanophenylboronic acid (11 mg, 0.08 mmol) in 0 (0.4 mL) was added Cs 2 CO 3 (52 mg, 0.160 mmol) and Pd(dppf)Cl 2 (5 mg, 0.008 mmol) was added. The mixture was heated to 80° C. and stirred for 3 h, then filtered and the filtrate purified by preparative HPLC under the following conditions (Column: XBridge Prep Phenyl OBD column, 19×150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH 4 HCO 3 +0.1%NH 3 .H 2 0), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 52% B to 82% B in 7 min, 82% B; Wavelength: 254 nm; RT1 (min): 5; Runs: 0) to give 4'-{[1-(4-methoxybenzoyl)-3-(2-methoxypyridin-4-yl)pyrrolidin-3-yl]methoxy}-[1,1'-biphenyl]-4-carbonitrile (6.8 mg, 16%) as a solid. LC / MS: Mass. C 32 H 29 N 3 O 4 Calculated value: 519.2, Measured value: 520.2 [M+H] + ; 1 H NMR (300MHz, CD 3 OD)δ 8.05-8.12(m,1H),7.76(s,4H),7.50-7.67(m,4H),6.75-7.14(m,6H),4.08-4.38(m,3H),3. 95-4.00(m,1H),3.83-3.95(m,7H),3.68-3.71(m,1H),2.51-2.60(m,1H),2.34-2.51(m,1H).

[0327] Example 11: Preparation of 4'-{[1-(4-methoxybenzoyl)-3-(2-oxo-1H-pyridin-4-yl)pyrrolidin-3-yl]methoxy}-[1,1'-biphenyl]-4-carbonitrile (compound 4-16) [ka] To a mixture of 4'-{[1-(4-methoxybenzoyl)-3-(2-methoxypyridin-4-yl)pyrrolidin-3-yl]methoxy}-[1,1'-biphenyl]-4-carbonitrile (30 mg, 0.06 mmol) in DMF (1 mL) was added pyridine hydrobromide (55 mg, 0.35 mmol). The mixture was heated to 100 °C and stirred for 2 h, then purified by preparative HPLC with the following conditions (Column: XBridge Prep Phenyl OBD column, 19 × 250 mm, 5 μm; Mobile phase A: water (10 mmol / L NH 4 HCO 3 +0.1%NH 3 .H 2 0), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 40% B to 70% B in 7 min, 70% B; Wavelength: 254 nm; RT1 (min): 6; Runs: 0), affording 4'-{[1-(4-methoxybenzoyl)-3-(2-oxo-1H-pyridin-4-yl)pyrrolidin-3-yl]methoxy}-[1,1'-biphenyl]-4-carbonitrile (13.6 mg, 47%) as a solid. LC / MS: Mass. C 31 H 27 N 3 O 4 Calculated value: 505.2, Measured value: 506.2 [M+H] + ; 1 H NMR (300MHz, CD 3 OD)δ 7.77(s,4H),7.59-7.69(m,4H),7.38-7.44(m,1H),6.93-7.12(m,4H),6.50-6.60(m,1H),6.42-6.52(m,1H),4.24-4.3 9(m,1H),4.03-4.18(m,2H),3.90-3.98(m,1H),3.86(s,4H),3.62-3.71(m,1H),2.49-3.59(m,1H),2.21-2.37(m,1H).

[0328] Example 12: Preparation of 1-[1-(4-bromophenyl)-2,2,2-trifluoroethyl]-3-[({4'-cyano-[1,1'-biphenyl]-4-yl}oxy)methyl]pyrrolidine-3-carboxylic acid (compound 4-34) [ka] Step 1: Synthesis of 1-tert-butyl 3-methyl 3-(iodomethyl)pyrrolidine-1,3-dicarboxylate N 2 To a mixture of 1-tert-butyl 3-methylpyrrolidine-1,3-dicarboxylate (2.0 g, 8.7 mmol) in THF (100 mL) at −78° C. under an atmosphere of 0.1% was added dropwise 2M LDA in THF (6.5 mL, 13.0 mmol). The mixture was stirred at −78° C. for 1 h and then diluted with CH 2 I 2 (3.04 g, 11.3 mmol) was added at -78 °C. The mixture was warmed to room temperature and stirred for 1 h, then H 2 O (100 mL) was added and the mixture was extracted with EtOAc (80 mL×3). The combined organic layers were washed with brine and Na 2 SO 4 Drying at 40° C., filtering and concentrating gave 1-tert-butyl 3-methyl 3-(iodomethyl)pyrrolidine-1,3-dicarboxylate (2 g, 62%) as an oil.

[0329] Step 2: Synthesis of 1-tert-butyl 3-methyl 3-[({4'-cyano-[1,1'-biphenyl]-4-yl}oxy)methyl]pyrrolidine-1,3-dicarboxylate A mixture of 1-tert-butyl 3-methyl 3-(iodomethyl)pyrrolidine-1,3-dicarboxylate (2.0 g, 5.4 mmol) and 4'-hydroxy-[1,1'-biphenyl]-4-carbonitrile (1.59 g, 8.125 mmol) in DMF (50 mL) was diluted with K 2 CO 3 (1.5 g, 10.86 mmol) was added. The mixture was heated to 80° C. and stirred for 16 h. The mixture was filtered and the filter cake was washed with EtOAc (50 mL). The filtrate was diluted with H 2The combined organic layers were washed with brine (150 mL) and the aqueous layer was extracted with EtOAc (80 mL×3). 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give 1-tert-butyl 3-methyl 3-[({4'-cyano-[1,1'-biphenyl]-4-yl}oxy)methyl]pyrrolidine-1,3-dicarboxylate (2.0 g, 85%) as an oil.

[0330] Step 3: Synthesis of methyl 3-[({4'-cyano-[1,1'-biphenyl]-4-yl}oxy)methyl]pyrrolidine-3-carboxylate To a mixture of 1-tert-butyl 3-methyl 3-[({4'-cyano-[1,1'-biphenyl]-4-yl}oxy)methyl]pyrrolidine-1,3-dicarboxylate (3.0 g, 6.9 mmol) in DCM (50 mL) was added TFA (10 mL). The mixture was stirred at room temperature for 1 h, then concentrated under reduced pressure and the residue was purified by reverse column chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.05% TFA), 30% to 80% gradient in 30 min; detector, UV 254 nm to give methyl 3-[({4'-cyano-[1,1'-biphenyl]-4-yl}oxy)methyl]pyrrolidine-3-carboxylate (1.2 g, 52%) as an oil.

[0331] Step 4: Synthesis of 1-(4-bromophenyl)-2,2,2-trifluoroethanol A mixture of 1-(4-bromophenyl)-2,2,2-trifluoroethanone (500 mg, 2.0 mmol) in i-PrOH (10 mL) was treated with NaBH 4 (150 mg, 3.95 mmol) was added. The mixture was quenched with 1M HCl (15 mL) and extracted with MTBE (10 mL x 3). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at rt, filtered and concentrated to give 1-(4-bromophenyl)-2,2,2-trifluoroethanol (200 mg, 40%) as an oil.

[0332] Step 5: Synthesis of 1-(4-bromophenyl)-2,2,2-trifluoroethyl trifluoromethanesulfonate A mixture of 1-(4-bromophenyl)-2,2,2-trifluoroethanol (30 mg, 0.12 mmol) and 2,6-lutidine (18 mg, 0.18 mmol) in DCE (1 mL) at -15 °C was diluted with Tf 2 2H2O (50 mg, 0.18 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 1 h, then diluted with DCM (5 mL) and 2 The organic layer was washed with 5 mL of 1M HCl (5 mL) and brine (5 mL). 2 SO 4 The mixture was dried at rt, filtered and concentrated under reduced pressure to give 1-(4-bromophenyl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (30 mg, 66%) as an oil.

[0333] Step 6: Synthesis of methyl 1-[1-(4-bromophenyl)-2,2,2-trifluoroethyl]-3-[({4'-cyano-[1,1'-biphenyl]-4-yl}oxy)methyl]pyrrolidine-3-carboxylate A mixture of methyl 3-[({4'-cyano-[1,1'-biphenyl]-4-yl}oxy)methyl]pyrrolidine-3-carboxylate (200 mg, 0.6 mmol) and 1-(4-bromophenyl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (690 mg, 1.79 mmol) in cyclohexane (5 mL) was treated with DMAP (72 mg, 0.6 mmol) and K 2 CO 3 (164 mg, 1.19 mmol) was added. The mixture was warmed to 75° C. and stirred for 16 h, then diluted with DCM (10 mL) and washed with brine (10 mL) and added Na 2 SO 4The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.05% TFA), 50% to 100% gradient in 20 min; detector, UV 254 nm to give methyl 1-[1-(4-bromophenyl)-2,2,2-trifluoroethyl]-3-[({4'-cyano-[1,1'-biphenyl]-4-yl}oxy)methyl]pyrrolidine-3-carboxylate (40 mg, 12%) as an oil.

[0334] Step 7: Synthesis of 1-[1-(4-bromophenyl)-2,2,2-trifluoroethyl]-3-[({4'-cyano-[1,1'-biphenyl]-4-yl}oxy)methyl]pyrrolidine-3-carboxylic acid (compound 4-34) To a mixture of methyl 1-[1-(4-bromophenyl)-2,2,2-trifluoroethyl]-3-[({4'-cyano-[1,1'-biphenyl]-4-yl}oxy)methyl]pyrrolidine-3-carboxylate (30 mg, 0.05 mmol) in MeOH (1 mL) was added 2M aqueous LiOH (0.5 mL). The mixture was stirred at room temperature for 16 h, then concentrated under reduced pressure and the residue was purified by preparative HPLC in the following conditions (Column: Xselect CSH C18 OBD column 30×150 mm 5 μm, n; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 70% B to 90% B, 90% B in 7 min; Wavelength: 254 nm; RT1 (min): 5.87; Runs: 0) to give 1-[1-(4-bromophenyl)-2,2,2-trifluoroethyl]-3-[({4′-cyano-[1,1′-biphenyl]-4-yl}oxy)methyl]pyrrolidine-3-carboxylic acid (1.2 mg, 4%) as a solid. LC / MS: Mass. C 27 H 22 BrF 3 N 2 O 3 Calculated value: 558.0, Measured value: 559.0 [M+H] + ; 1 H NMR (300MHz, CD 3OD)δ 7.79(d,J=3.0Hz,4H),7.54-7.67(m,4H),7.44 -7.50(m,2H),6.99-7.10(m,2H),4.36-4.45(m,1H),4.20-4.26(m,2H),3.18-3.33( m,1H),3.01-3.12(m,1H),2.78-3.00(m,2H),2.30-2.38(m,1H),1.95-2.05(m,1H); 19 F NMR (282MHz, CD 3 O.D.)δ -69.8.

[0335] Example 13: Preparation of 3-[({4'-cyano-[1,1'-biphenyl]-4-yl}oxy)methyl]-1-[2,2,2-trifluoro-1-(4-methoxyphenyl)ethyl]pyrrolidine-3-carboxylic acid; trifluoroacetic acid (Compound 4-1) [ka] N 2To a mixture of methyl 1-[1-(4-bromophenyl)-2,2,2-trifluoroethyl]-3-[({4'-cyano-[1,1'-biphenyl]-4-yl}oxy)methyl]pyrrolidine-3-carboxylate (25 mg, 0.044 mmol) in MeOH (1 mL) under an atmosphere of Tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane; {2'-amino-[1,1'-biphenyl]-2-yl}paradiomethanesulfonate (4 mg, 0.004 mmol) and di-tert-butyl[2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane (2 mg, 0.004 mmol) were added. The mixture was heated to 100° C. and stirred for 16 h, then filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 19×250 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 50% B to 80% B, 80% B in 7 min; Wavelength: 254 nm; RT1 (min): 6; Runs: 0) to give 3-[({4′-cyano-[1,1′-biphenyl]-4-yl}oxy)methyl]-1-[2,2,2-trifluoro-1-(4-methoxyphenyl)ethyl]pyrrolidine-3-carboxylic acid; trifluoroacetic acid (2.6 mg, 10%) as a solid. LC / MS: Mass. C 30 H 26 F 6 N 2 O 6 Calculated value: 510.1, Measured value: 511.2 [M+H] + ; 1 H NMR (300MHz, DMSO-d 6 )δ 7.80-7.93(m,4H),7.65-7.75(m,2H),7.25-7.40(m,2H),7.01-7.13(m,2H),6.90-7.00(m,2H),4.22-4. 37(m,1H),4.12(s,2H),3.77(d,J=3.0Hz,3H),2.56-3.05(m,4H),2.12-2.25(m,1H),1.77-1.93(m,1H); 19F NMR (282MHz, DMSO-d 6 )δ -68.1,-74.0.

[0336] Biological Examples Example B1: EP2 Potency Assay Compounds of the present disclosure have a median inhibitory concentration (IC) of less than 25 μM. 50 Compound potency was measured using a cAMP TR-FRET assay.

[0337] CHO-K1 cells (ATCC) were cultured at 9.75 × 10 5 The cells were seeded in 6 cm plates at a density of 1000 cells / well, and then the next day the cell medium was changed to Opti-Mem I reduced serum medium (Gibco) and transfected with plasmids for expression of the EP2 receptor (target receptor of interest) using FuGENE 6 transfection reagent (Promega). After 6 h of incubation, the cell medium was changed to F12 medium supplemented with 10% FBS and 100 U / ml Pen-Strep. 24 h after transfection, the cells were harvested and seeded in 384-well plates at a density of 3000 cells / well to perform cAMP assays using the LANCE Ultra cAMP Assay Kit (PerkinElmer).

[0338] For each test compound of interest, 10 nl / well of serially diluted test compound was added to each well to obtain 10 serially diluted compound concentrations ranging from 10000 nM to 0.038 nM, with duplicate wells at each concentration. The plate was then centrifuged at 1000 rpm for 1 minute, agitated at 600 rpm for 2 minutes at room temperature, and incubated at 25°C for 5 minutes. The reference agonist, prostaglandin E2 (MCE), was added to each well at the appropriate concentration to reach its EC80 value. The plate was then centrifuged at 1000 rpm for 1 minute, agitated at 600 rpm for 2 minutes at room temperature, and incubated at 25°C for 30 minutes.

[0339] To measure the levels of cAMP, 5 μl / well of Eu-cAMP working solution and 5 μl / well of Ulight-anti-cAMP working solution were added to each well, and the plate was centrifuged at 1000 rpm for 1 min, agitated at 600 rpm for 2 min at room temperature, and agitated at 25° C. for 15 min. The level of TR-FRET fluorescence was measured in each well using an EnVision microplate reader (excitation wavelength=337 nm and emission wavelength=615 and 665 nm). Dose-response curves were generated by plotting the percent inhibition of each compound concentration, and IC50 was then calculated by fitting a curve to the plotted values ​​and extrapolating the IC50 concentration.

[0340] The potency of the compounds disclosed herein is shown in Table B1. The potency data are summarized as follows: AA (IC 50 <100nM); A(IC 50 = 100-500 nM); B(IC 50 = 500 nM to 1 μM); C(IC 50 = 1 μM to 5 μM); and D(IC 50 >5μM).

[0341] [Table 15]

[0342] Example B2: Stability Assay (a) Human liver microsome stability Compounds to be tested were incubated in duplicate with human liver microsomes (0.5 mg / mL) at 37°C. These incubations were performed at a final test article concentration of 2 μM for a total incubation period of 60 min. Samples were taken at 0, 15, 30, 45 and 60 min and the reaction was stopped by the addition of 4 volumes of acetonitrile containing internal standards (100 nM alprazolam, 200 nM imipramine, 200 nM labetalol and 2 μM ketoprofen). Diclofenac was used as a positive control in this study. Samples were analyzed by UPLC-MS / MS to determine the concentration of the test compound and to measure the percent remaining, intrinsic clearance (in vitro CLint ) and half-life (t 1 / 2 ) values ​​were calculated.

[0343] Chromatographic analysis was performed on a Shimadzu UPLC system (Kyoto, Japan) consisting of a gradient pump (LC-30AD model), an autoinjector (HTC PAL System model) and an online degasser (DGU-20A5R model). Detection was a triple quadrupole tandem mass spectrometer (API 4000 / Triple Quad 4500 / Triple Quad 5500 / Triple Quad 6500) equipped with a turbo ion spray interface. Data acquisition and integration were performed by LC-MS software (Analyst 1.6) directly coupled to the LC-MS / MS system. Chromatographic separation was achieved on an XSelect Hss T3 2.5μ (2.1×30 mm) column. The mobile phases were 0.1% formic acid in water (A) and 0.1% formic acid in acetonitrile (B). The flow rate was 1.0 mL / min and the column was kept at 40°C.

[0344] (b) Human hepatocyte stability The compounds to be tested were cultured in human hepatocytes (0.5 × 10 6 The cells were incubated in duplicate with incubation medium (Williams Medium E with 1x GlutaMAX) containing 1000 mM glycerol / mL. These incubations were performed at a final test concentration of 1 μM for a total incubation period of 120 min. Samples were taken at 0, 15, 30, 60, 90 and 120 min and the reaction was stopped by the addition of acetonitrile containing internal standards (100 nM alprazolam, 200 nM labetalol, 200 nM caffeine and 200 nM diclofenac). Verapamil was used as a positive control in this study. Samples were analyzed by UPLC-MS / MS to determine the concentration of the tested compounds and to analyze the percentage remaining, intrinsic clearance (in vitro CL int ) and half-life (t1 / 2) values ​​were calculated.

[0345] Chromatographic analysis was performed on a Shimadzu UPLC system (Kyoto, Japan) consisting of a gradient pump (LC-30AD model), an autoinjector (HTC PAL System model) and an online degasser (DGU-20A5R model). Detection was a triple quadrupole tandem mass spectrometer (API 4000 / Triple Quad 4500 / Triple Quad 5500 / Triple Quad 6500) equipped with a turbo ion spray interface. Data acquisition and integration were performed by LC-MS software (Analyst 1.6) directly coupled to the LC-MS / MS system. Chromatographic separation was achieved on an XSelect Hss T3 2.5μ (2.1×30 mm) column. The mobile phases were 0.1% formic acid in water (A) and 0.1% formic acid in acetonitrile (B). The flow rate was 1.0 mL / min and the column was kept at 40°C.

[0346] The stability data for the compounds disclosed herein are shown in Table B2.

[0347] Half-life (T 1 / 2 ) Data are measured in minutes and in Table B2, the data are categorized into the following categories for both the microsomal and liver assays: AT 1 / 2 =1000+ BT 1 / 2 =500~1000 CT 1 / 2 =100~500 DT 1 / 2 <100

[0348] In vitro clearance (CL int ) Data is measured in μL / min / mg protein and in Table B2, for both the microsomal and liver assays, the data is categorized into the following categories: A CL int <1 BCL int =1~10 CCL int =10~20 DCL int =20+

[0349] [Table 16]

[0350] The reference compound ("Ref") in Table 2 has the following structure: [ka] and PF-04852946, which has the following structure:

[0351] Composition Examples Example C1: Parenteral pharmaceutical composition To prepare a parenteral pharmaceutical composition suitable for administration by injection (subcutaneous, intravenous, etc.), 100 mg of a water-soluble salt of a compound described herein or a pharma- ceutically acceptable salt or solvate thereof is dissolved in sterile water and then mixed with 10 mL of 0.9% sterile saline. The mixture is incorporated into a dosage unit form suitable for administration by injection.

[0352] Example C2: Oral pharmaceutical composition To prepare the pharmaceutical composition for oral delivery, 100 mg of the compound described herein or its pharma- ceutically acceptable salt or solvate is mixed with 750 mg of starch.The mixture is incorporated into an oral dosage unit, such as a hard gelatin capsule, suitable for oral administration.

[0353] Example C3: Pharmaceutical gel composition for external use To prepare a topical gel composition, 100 mg of the compound described herein or a pharma- ceutically acceptable salt or solvate thereof is mixed with 1.75 g of hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate, and 100 mL of purified alcohol USP. The resulting gel mixture is then incorporated into a container, such as a tube, suitable for topical administration.

[0354] Example C4: Ophthalmic solution To prepare pharmaceutical opthalmic solution composition, 100mg of the compound described herein or its pharma- ceutically acceptable salt or solvate is mixed with 0.9g NaCl in 100mL of purified water and filtered using a 0.2 micron filter.The resulting isotonic solution is then incorporated into an ophthalmic delivery unit, such as an eye dropper, suitable for ophthalmic administration.

[0355] The examples and embodiments described herein are for illustrative purposes only, and various modifications or alterations that occur to those skilled in the art are intended to be included within the spirit and scope of this application and the scope of the appended claims.

Claims

1. A compound having the structure of formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt or solvate thereof (wherein, R １ is 【Chemical Formula 2】 , -C(O)NR ｄ R ｅ , -N(R ｆ ), ２ is a substituted or unsubstituted monocyclic heterocyclic ring or a substituted or unsubstituted monocyclic carbocyclic ring, where when R １ is a substituted monocyclic heterocyclic ring, it is substituted by R ９ which appears one or more times; R ａ is hydrogen, deuterium, C １ to C ６ alkyl, C １ to C ６ duteroalkyl, or C １ to C ６ fluoroalkyl; R ｂ is hydrogen, deuterium, C １ to C ６ alkyl, C １ to C ６ duteroalkyl, C １ to C ６ fluoroalkyl, substituted or unsubstituted C ３ to C ６ cycloalkyl, or substituted or unsubstituted C ２ to C ６ heterocycloalkyl; or or R ａ and R ｂ together with the carbon atom to which they are attached, form a substituted or unsubstituted C ３ -C ６ cycloalkyl, or a substituted or unsubstituted C ２ -C ６ heterocycloalkyl ring C, where when ring C is substituted, it is substituted by one or more R １１ ; and R ｃ is hydrogen, C １ -C ６ alkyl, or R ｇ ; or or R ａ and R ｂ together with the carbon atom to which they are attached form a carbonyl (C=O); and R ｃ is C ３ to C ６ alkyl or R ｇ is; R ｄ is -CN, C １ ~C ６ alkyl, C １ ~C ６ duteroalkyl, C １ ~C ６ fluoroalkyl, C １ ~ ６ alkoxy, substituted or unsubstituted C ３ ~C ６ cycloalkyl, substituted or unsubstituted C ２ ~C ６ heterocycloalkyl, -OH, OR １ｄ , -SOR １ｄ , or -SO ２ R １ｄ ; wherein, R １ｄ is substituted or unsubstituted C １ ~C ６ alkyl, substituted or unsubstituted C ３ ~C ６ cycloalkyl, substituted or unsubstituted 3 - 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 - 6 membered heteroaryl; wherein, when R １ｄ is substituted, it is substituted by one or more R １４ ; R ｅ is hydrogen, C １ to C ６ alkyl, C １ to C ６ deuterioalkyl, C １ to C ６ fluoroalkyl, C １ to ６ alkoxy, substituted or unsubstituted C ３ to C ６ cycloalkyl, or substituted or unsubstituted C ２ to C ６ heterocycloalkyl; or R ｄ and R ｅ together with the N atom to which they are attached form a substituted or unsubstituted C ２ -C ６ heterocycloalkyl; Each R ｆ is, independently, hydrogen, C １ to C ６ alkyl, C １ to C ６ deuterated alkyl, C １ to C ６ fluoroalkyl, substituted or unsubstituted C ３ to C ６ cycloalkyl, or substituted or unsubstituted C ２ to C ６ heterocycloalkyl; or or both Rs ｆ together with the N atom to which they are attached form a substituted or unsubstituted C ２ -C ６ -heterocycloalkyl; R ｇ is C １ to C ６ duterialkyl, C １ to C ６ fluoroalkyl, substituted or unsubstituted C １ to C ６ heteroalkyl, substituted or unsubstituted C ３ to C ６ cycloalkyl, substituted or unsubstituted C ２ to C ６ heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C ３ to C ６ cycloalkyl), -alkyl-(substituted or unsubstituted C ２ to C ６ heterocycloalkyl), -C(=O)R １６ ,-C(=O)-OR １６ ,-C(=O)N(R １６ ) ２ ,-(C(R １７ ) ２ O) ｐ -R １５ ,-(CH ２ CH ２ O) ｑ -R １５ ,or-(C(R １７ ) ２ ) ｐ -OR １５ ; p is 1, 2, 3, 4, or 5; q is 1, 2, 3, 4, or 5; Each R １７ is, independently, hydrogen or C １ to C ６ alkyl; R １５ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted C ２ -C １０ -C hetero cycloalkyl, -C(=O)R １６ , -C(=O)-OR １６ , or -C(=O)N(R １６ ) ２ and; R ２ is hydrogen, C １ to C ６ alkyl, C １ to C ６ deuterioalkyl, or C １ to C ６ fluoroalkyl; R ３ is hydrogen, C １ -C ６ -alkyl, C １ -C ６ -duteroalkyl, C １ -C ６ -fluoroalkyl, substituted or unsubstituted C ３ -C ６ -cycloalkyl, or substituted or unsubstituted C ２ -C ６ -heterocycloalkyl; or R ２ and R ３ together with the carbon atom to which they are attached form a carbonyl (C=O) or thiocarbonyl (C=S); or R ２ and R ３ together with the carbon atom to which they are attached, form a substituted or unsubstituted C ３ to C ６ cycloalkyl, or a substituted or unsubstituted C ２ to C ６ heterocycloalkyl ring B, where when ring B is substituted, it is substituted by one or more R １２ ; Z is N or CR ８ wherein; L is absent or -NH-; R ４ 、 R ５ 、 R ７ 、 and R ８ are each independently hydrogen, halogen, -CN, C １ ~C ６ alkyl, C １ ~C ６ deuterated alkyl, C １ ~C ６ fluoroalkyl, -OR １６ 、 -C(=O)R １６ 、 -CO ２ R １６ 、 -C(=O)N(R １６ ) ２ 、 -N(R １６ ) ２ 、 or -NR １６ C(=O)R １６ ; R ６ is hydrogen, halogen, -CN, C １ ~C ６ alkyl, C １ ~C ６ deuterioalkyl, C １ ~C ６ fluoroalkyl, -OR １６ ,-C(=O)R １６ ,-CO ２ R １６ ,-C(=O)N(R １６ ) ２ ,-N(R １６ ) ２ ,-NR １６ C(=O)R １６ , substituted or unsubstituted C ３ ~C ６ cycloalkyl, substituted or unsubstituted C ２ ~C ６ heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl; where, when R ６ is substituted, it is substituted by one or more R １３ ; Ring A is substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl; Each R ９ 、R １０ 、R １１ 、R １２ 、R １３ 、and R １４ is independently hydrogen, deuterium, halogen, C １ - C ６ - C alkyl, C １ - C ６ - deuteroalkyl, C １ - C ６ - fluoroalkyl, substituted or unsubstituted C ３ - C ６ - cycloalkyl, substituted or unsubstituted C ２ - C ６ - heterocycloalkyl, - CN, - OR １６ 、 - C(=O)R １６ 、 - CO ２ R １６ 、 - C(=O)N(R １６ ) ２ 、 - N(R １６ ) ２ 、or - NR １６ C(=O)R １６ ; Each R １６ is, independently, hydrogen, C １ to C ６ alkyl, C １ to C ６ duteroalkyl, C １ to C ６ fluoroalkyl, substituted or unsubstituted C ３ to C ６ cycloalkyl, substituted or unsubstituted C ２ to C ６ heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C ３ to C ６ cycloalkyl), -alkyl-(substituted or unsubstituted C ２ to C ６ heterocycloalkyl); or both Rs １６ together with the N atom to which they are attached form a substituted or unsubstituted C ２ to C ６ heterocycloalkyl; R １８ and R １９ are each independently hydrogen, deuterium, C １ to C ６ alkyl, C １ to C ６ duteroalkyl, or C １ to C ６ fluoroalkyl; or R １８ and R １９ together with the carbon atom to which they are attached form a ring E which is C ３ -C ６ -cycloalkyl, or C ２ -C ６ -heterocycloalkyl; m is 1 or 2; and n is 0, 1, 2, 3, or 4).

2. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, unsubstituted or substituted pyridazinyl, or unsubstituted or substituted triazinyl.

3. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is unsubstituted or substituted phenyl, or unsubstituted or substituted pyridinyl.

4. 【Fig. 3】 is [Chemical Formula 4] The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, which is

5. The structure of formula (II): 【Chemical Formula 5】 The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (II) or a pharmaceutically acceptable salt or solvate thereof.

6. The structure of formula (III): 【Chemical Formula 6】 The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (III) or a pharmaceutically acceptable salt or solvate thereof.

7. The structure of formula (IV): 【Chemical Formula 7】 The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (IV) or a pharmaceutically acceptable salt or solvate thereof.

8. Each R １０ is, independently, hydrogen, deuterium, a substituted or unsubstituted C ３ to C ６ cycloalkyl, F, Cl, Br, -CN, -CH ３ , -CH ２ CH ３ , -(CH ２ ) ２ CH ３ , -(CH ２ ) ３ CH ３ , -CH(CH ３ ) ２ , -C(CH ３ ) ３ , -CH ２ F, -CHF ２ , -CF ３ , -CH ２ CF ３ , -CH ２ D, -CHD ２ , -CD ３ , -OH, -OCH ３ , -OCH ２ CH ３ , -OCF ３ , -CO ２ H, -CO ２ CH ３ , -CO ２ CH ２ CH ３ , -C(=O)NH ２ , -C(=O)NHCH ３ , -C(=O)N(CH ３ ) ２ , -NH ２ , -NHCH ３ , or -N(CH ３ ) ２ is the compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

9. R １ is - C(O)NR ｄ R ｅ and; R ｄ is -CN, C １ ~C ６ alkyl, C １ ~C ６ fluoroalkyl, -OH, or -SO ２ R １ｄ and; and R ｅ is hydrogen or -CH ３ The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

10. R １ is -C(O)NHSO ２ R １ｄ and; and R １ｄ is substituted or unsubstituted C １ -C ６ -C alkyl, substituted or unsubstituted C ３ -C ６ -C cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl; wherein, when R １ｄ is substituted, it is substituted by one or more R １４ The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

11. R １ｄ is a substituted or unsubstituted C １ -C ６ alkyl, the compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

12. R １ｄ is a substituted or unsubstituted C １ -C ６ alkyl, substituted or unsubstituted cyclopropyl, or substituted or unsubstituted phenyl, the compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

13. R １ｄ The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R is a substituted or unsubstituted methyl.

14. R １ｄ The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R is cyclopropyl or phenyl.

15. Structure: [Chemical Formula 8] The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, having

16. R １ is -C(O)NR ｄ R ｅ and; R ｄ is -CN, -CH ３ , -OH, or -OCH ３ ; and R ｅ is hydrogen or -CH ３ The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

17. R １ is 【Chemical Formula 9】 The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, which is

18. R ２ is hydrogen, -CH ３ , -CH ２ CH ３ , -CD ３ , -CH ２ CD ３ , -CF ３ , or -CH ２ CF ３ ; R ３ is hydrogen, -CH ３ , -CH ２ CH ３ , -CD ３ , -CH ２ CD ３ , -CF ３ , or -CH ２ CF ３ ; or or R ２ and R ３ form a carbonyl (C=O) together with the carbon atom to which they are attached, the compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

19. R ２ is hydrogen, -CH ３ , -CD ３ , or -CF ３ ; R ３ is hydrogen, -CH ３ , -CD ３ , or -CF ３ ; or or R ２ and R ３ form a carbonyl (C=O) together with the carbon atom to which they are attached, the compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

20. Z is CH; R ４ 、R ５ 、and R ７ each is hydrogen; R ６ is a halogen or a substituted phenyl; and R １３ is halogen, -CN, -OH, or -OCH ３ The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

21. R ２ is hydrogen; R ３ is -CF ３ and; R ６ is halogen or substituted phenyl; and R １３ The compound according to claim 20, or a pharmaceutically acceptable salt or solvate thereof, wherein R is -CN.

22. The structure of formula (VI): 【Chemical 10】 The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (VI) or a pharmaceutically acceptable salt or solvate thereof.

23. The compound, wherein the compound has the structure of formula (VI-A): 【Chemical 11】 The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, having or being a pharmaceutically acceptable salt or solvate thereof.

24. Z is CH; R ４ 、R ５ 、and R ７ each is hydrogen; Each R １０ is independently selected from -F, -Cl, -CN, -CH ３ , -CF ３ , and -OCF ３ ; R １３ is hydrogen, halogen, or -CN; and n is 1, the compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

25. R １３ The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R is -CN.

26. R １０ The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R is -F.

27. A compound of formula (X), or a pharmaceutically acceptable salt or solvate thereof: 【Chemical Formula 12】 (wherein, R １ａ is -CO ２ H, -CO ２ -R １ｂ -, -C(O)N(R １ｃ ), ２ or -CN; R １ｂ is C １ to C ６ alkyl, C １ to C ６ duteroalkyl, C １ to C ６ fluoroalkyl, substituted or unsubstituted C １ to C ６ heteroalkyl, substituted or unsubstituted C ３ to C ６ cycloalkyl, substituted or unsubstituted C ２ to C ６ heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C ３ to C ６ cycloalkyl), -alkyl-(substituted or unsubstituted C ２ to C ６ heterocycloalkyl), -C(=O)R １６ , -C(=O)-OR １６ , -C(=O)N(R １６ ) ２ , -(C(R １７ ) ２ O) ｐ -R １５ , -(CH ２ CH ２ O) ｑ -R １５ , or -(C(R １７ ) ２ ) ｐ -OR １５ ; p is 1, 2, 3, 4, or 5; q is 1, 2, 3, 4, or 5; Each R １７ is, independently, hydrogen or C １ to C ６ alkyl; R １５ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted C ２ -C １０ -C heterocycloalkyl, -C(=O)R １６ , -C(=O)-OR １６ , or -C(=O)N(R １６ ) ２ and; Each R １ｃ is, independently, hydrogen, C １ to C ６ alkyl, C １ to C ６ deuterioalkyl, C １ to C ６ fluoroalkyl, substituted or unsubstituted C ３ to C ６ cycloalkyl, substituted or unsubstituted C ２ to C ６ heterocycloalkyl, -OH, -SOR １ｄ , or -SO ２ R １ｄ ; where R １ｄ is substituted or unsubstituted C １ to C ６ alkyl; or both Rs １ｃ together with the N atom to which they are attached form a substituted or unsubstituted C ２ -C ６ -heterocycloalkyl; R ２ is hydrogen, C １ ~C ６ alkyl, C １ ~C ６ deuterated alkyl, or C １ ~C ６ fluoroalkyl; R ３ is hydrogen, C １ ~C ６ alkyl, C １ ~C ６ deuterioalkyl, C １ ~C ６ fluoroalkyl, substituted or unsubstituted C ３ ~C ６ cycloalkyl, or substituted or unsubstituted C ２ ~C ６ heterocycloalkyl; or or R ２ and R ３ together with the carbon atom to which they are attached, form a thiocarbonyl (C=S); or R ２ and R ３ together with the carbon atom to which they are attached, form a substituted or unsubstituted C ３ -C ６ cycloalkyl, or a substituted or unsubstituted C ２ -C ６ heterocycloalkyl ring B, where when ring B is substituted, it is substituted by one or more R １２ ; Z is N or CR ８ wherein; L is absent or is -NH-; R ４ 、 R ５ 、 R ７ 、 and R ８ are each independently hydrogen, halogen, -CN, C １ ~C ６ alkyl, C １ ~C ６ deuterated alkyl, C １ ~C ６ fluoroalkyl, -OR １６ , -C(=O)R １６ , -CO ２ R １６ , -C(=O)N(R １６ ) ２ , -N(R １６ ) ２ , or -NR １６ C(=O)R １６ ; R ６ is hydrogen, halogen, -CN, C １ ~C ６ alkyl, C １ ~C ６ duteroalkyl, C １ ~C ６ fluoroalkyl, -OR １６ , -C(=O)R １６ , -CO ２ R １６ , -C(=O)N(R １６ ) ２ , -N(R １６ ) ２ , -NR １６ C(=O)R １６ , substituted or unsubstituted C ３ ~C ６ cycloalkyl, substituted or unsubstituted C ２ ~C ６ heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl; wherein, when R ６ is substituted, it is substituted by one or more R １３ ; or R ５ and R ６ together with the intervening atoms to which they are attached form a fused ring D which is a substituted or unsubstituted 5- or 6-membered carbocyclic ring or a substituted or unsubstituted 5- or 6-membered heterocyclic ring, where when the ring D is substituted it is substituted by one or more R １４ ; ring A is substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl; Each R １０ 、R １２ 、R １３ 、and R １４ is, independently, hydrogen, deuterium, halogen, C １ ~C ６ alkyl, C １ ~C ６ duteroalkyl, C １ ~C ６ fluoroalkyl, substituted or unsubstituted C ３ ~C ６ cycloalkyl, substituted or unsubstituted C ２ ~C ６ heterocycloalkyl, -CN, -OR １６ , -C(=O)R １６ , -CO ２ R １６ , -C(=O)N(R １６ ) ２ , -N(R １６ ) ２ , or -NR １６ C(=O)R １６ ; Each R １６ is, independently, hydrogen, C １ to C ６ alkyl, C １ to C ６ duteroalkyl, C １ to C ６ fluoroalkyl, substituted or unsubstituted C ３ to C ６ cycloalkyl, substituted or unsubstituted C ２ to C ６ heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C ３ to C ６ cycloalkyl), or -alkyl-(substituted or unsubstituted C ２ to C ６ heterocycloalkyl); or both Rs １６ together with the N atom to which they are attached form a substituted or unsubstituted C ２ -C ６ heterocycloalkyl; R １８ and R １９ are each independently hydrogen, deuterium, C １ to C ６ alkyl, C １ to C ６ duteroalkyl, or C １ to C ６ fluoroalkyl; or R １８ and R １９ together with the carbon atom to which they are attached form a ring E which is C ３ -C ６ cycloalkyl, or C ２ -C ６ heterocycloalkyl; m is 1 or 2; and n is 0, 1, 2, 3, or 4).

28. 【Fig. 13】 being 【Chemical Formula 14】 the compound according to claim 27, or a pharmaceutically acceptable salt or solvate thereof.

29. The structure of formula (XIII): 【Chemical Formula 15】 having the compound according to claim 27, or a pharmaceutically acceptable salt or solvate thereof.

30. R １ａ is -CO ２ H or -CN; R ２ is hydrogen, -CH ３ , -CH ２ CH ３ , -CD ３ , -CH ２ CD ３ , -CF ３ , or -CH ２ CF ３ ; and R ３ is hydrogen, -CH ３ , -CH ２ CH ３ , -CD ３ , -CH ２ CD ３ , -CF ３ , or -CH ２ CF ３ The compound according to claim 27, or a pharmaceutically acceptable salt or solvate thereof.

31. Structure: 【Chemical 16】 or the compound according to claim 27 having a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate thereof.

32. A compound having the structure of formula (XX): 【Chemical 17】 or a pharmaceutically acceptable salt or solvate thereof (wherein, R １ is 【Chemical 18】 , -C(O)NR ｄ R ｅ , -N(R ｆ ), ２ , is a substituted or unsubstituted monocyclic heterocyclic ring or a substituted or unsubstituted monocyclic carbocyclic ring, wherein when R １ is a substituted monocyclic heterocyclic ring, it is substituted by R ９ which appears one or more times; R ａ is hydrogen, deuterium, C １ to C ６ alkyl, C １ to C ６ duteroalkyl, or C １ to C ６ fluoroalkyl; R ｂ is hydrogen, deuterium, C １ to C ６ alkyl, C １ to C ６ dueteroalkyl, C １ to C ６ fluoroalkyl, substituted or unsubstituted C ３ to C ６ cycloalkyl, or substituted or unsubstituted C ２ to C ６ heterocycloalkyl; or or R ａ and R ｂ together with the carbon atom to which they are attached, form a substituted or unsubstituted C ３ to C ６ cycloalkyl, or a substituted or unsubstituted C ２ to C ６ heterocycloalkyl ring C, where when ring C is substituted, it is substituted by one or more R １１ ; and R ｃ is hydrogen, C １ to C ６ alkyl, or R ｇ ; or or R ａ and R ｂ together with the carbon atom to which they are attached forms a carbonyl (C=O); and R ｃ is C ３ to C ６ alkyl or R ｇ is; R ｄ is -CN, C １ ~C ６ alkyl, C １ ~C ６ duteroalkyl, C １ ~C ６ fluoroalkyl, C １ ~ ６ alkoxy, substituted or unsubstituted C ３ ~C ６ cycloalkyl, substituted or unsubstituted C ２ ~C ６ heterocycloalkyl, -OH, -OR １ｄ , -SOR １ｄ , or -SO ２ R １ｄ ; where R １ｄ is substituted or unsubstituted C １ ~C ６ alkyl, substituted or unsubstituted C ３ ~C ６ cycloalkyl, substituted or unsubstituted 3 - 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 - 6 membered heteroaryl; where when R １ｄ is substituted, it is substituted by one or more R １４ ; R ｅ is hydrogen, C １ -C ６ alkyl, C １ -C ６ duteroalkyl, C １ -C ６ fluoroalkyl, C １ - ６ alkoxy, substituted or unsubstituted C ３ -C ６ cycloalkyl, or substituted or unsubstituted C ２ -C ６ heterocycloalkyl; or or R ｄ and R ｅ together with the N atom to which they are attached form a substituted or unsubstituted C ２ -C ６ heterocycloalkyl; Each R ｆ is, independently, hydrogen, C １ to C ６ alkyl, C １ to C ６ duteroalkyl, C １ to C ６ fluoroalkyl, substituted or unsubstituted C ３ to C ６ cycloalkyl, or substituted or unsubstituted C ２ to C ６ heterocycloalkyl; or or both Rs ｆ together with the N atom to which they are attached form a substituted or unsubstituted C ２ -C ６ -heterocycloalkyl; R ｇ is C １ to C ６ dueteroalkyl, C １ to C ６ fluoroalkyl, substituted or unsubstituted C １ to C ６ heteroalkyl, substituted or unsubstituted C ３ to C ６ cycloalkyl, substituted or unsubstituted C ２ to C ６ heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C ３ to C ６ cycloalkyl), -alkyl-(substituted or unsubstituted C ２ to C ６ heterocycloalkyl), -C(=O)R １６ 、 -C(=O)-OR １６ 、 -C(=O)N(R １６ ) ２ 、 -(C(R １７ )) ２ O) ｐ -R １５ 、 -(CH ２ CH ２ O) ｑ -R １５ 、 or -(C(R １７ )) ２ ) ｐ -OR １５ ; Z is N or CR ８ and; R ４ 、R ５ 、R ７ 、and R ８ are each independently hydrogen, halogen, -CN, C １ ~C ６ alkyl, C １ ~C ６ duteroalkyl, C １ ~C ６ fluoroalkyl, -OR １６ 、-C(=O)R １６ 、-CO ２ R １６ 、-C(=O)N(R １６ ) ２ 、-N(R １６ ) ２ 、or -NR １６ C(=O)R １６ ; R ６ is hydrogen, halogen, -CN, C １ ~C ６ alkyl, C １ ~C ６ duteroalkyl, C １ ~C ６ fluoroalkyl, -OR １６ , -C(=O)R １６ , -CO ２ R １６ , -C(=O)N(R １６ ) ２ , -N(R １６ ) ２ , -NR １６ C(=O)R １６ , substituted or unsubstituted C ３ ~C ６ cycloalkyl, substituted or unsubstituted C ２ ~C ６ heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl; where, when R ６ is substituted, it is substituted by one or more R １３ ; Each R ９ 、R １０ 、R １１ 、R １３ 、and R １４ is, independently, hydrogen, deuterium, halogen, C １ -C ６ alkyl, C １ -C ６ duteroalkyl, C １ -C ６ fluoroalkyl, substituted or unsubstituted C ３ -C ６ cycloalkyl, substituted or unsubstituted C ２ -C ６ heterocycloalkyl, -CN, -OR １６ 、-C(=O)R １６ 、-CO ２ R １６ 、-C(=O)N(R １６ ) ２ 、-N(R １６ ) ２ 、or -NR １６ C(=O)R １６ ; R １５ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted C ２ -C １０ -C heteroalkyl, -C(=O)R １６ -C(=O)-OR １６ -C(=O)N(R １６ ) ２ and; Each R １６ is, independently, hydrogen, C １ to C ６ alkyl, C １ to C ６ duteroalkyl, C １ to C ６ fluoroalkyl, substituted or unsubstituted C ３ to C ６ cycloalkyl, substituted or unsubstituted C ２ to C ６ heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted C ３ to C ６ cycloalkyl), -alkyl-(substituted or unsubstituted C ２ to C ６ heterocycloalkyl); or both Rs １６ together with the N atom to which they are attached form a substituted or unsubstituted C ２ -C ６ heterocycloalkyl; Each R １７ is, independently, hydrogen or C １ to C ６ alkyl; m is 1 or 2; n is 0, 1, 2, 3, or 4; p is 1, 2, 3, 4, or 5; and q is 1, 2, 3, 4, or 5).

33. R １ is 【Chemical 19】 , -C(O)NR ｄ R ｅ , or a substituted or unsubstituted monocyclic heterocyclic ring; wherein, when R １ is a substituted monocyclic heterocyclic ring, it is substituted by R ９ which appears one or more times; R ａ and R ｂ together with the carbon atom to which they are attached form a carbonyl (C=O); and R ｃ is C ３ to C ６ alkyl or R ｇ is; R ｄ is -CN, C １ ~C ６ alkyl, C １ ~C ６ fluoroalkyl, -OH, -OR １ｄ , or -SO ２ R １ｄ and; and R ｅ is hydrogen or -CH ３ and is the compound according to claim 32, or a pharmaceutically acceptable salt or solvate thereof.

34. R ６ is substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl, wherein R ６ when substituted, is substituted by one or more R １３ The compound according to claim 32, or a pharmaceutically acceptable salt or solvate thereof.

35. R ６ is a substituted or unsubstituted phenyl, a substituted or unsubstituted pyridinyl, or a substituted or unsubstituted pyrimidinyl; wherein, when R ６ is substituted, it is substituted by one or more R １３ ; Z is N or CR ８ wherein; R ４ 、 R ５ 、 R ７ 、 R ８ 、 R ９ 、 R １０ 、 and R １３ are each independently hydrogen, halogen, -CN, C １ ~C ６ alkyl, C １ ~C ６ fluoroalkyl, or OR １６ The compound according to claim 32, or a pharmaceutically acceptable salt or solvate thereof.

36. Z is CR ８ and; R ４ 、R ５ 、R ７ 、and R ８ is hydrogen; R ６ is a substituted phenyl; and R １３ is halogen, -CN, C １ ~C ６ alkyl, C １ ~C ６ fluoroalkyl, or OCH ３ The compound according to claim 32, or a pharmaceutically acceptable salt or solvate thereof.

37. The structure of formula XXII: 【Chemical 20】 or a pharmaceutically acceptable salt thereof, the compound according to claim 32, or a pharmaceutically acceptable salt or solvate thereof (wherein, R １ is -C(O)OR ｃ or -C(O)NR ｄ R ｅ and; R ｃ is C ３ to C ６ alkyl or R ｇ and; R ｄ is -CN, C １ ~C ６ alkyl, C １ ~C ６ fluoroalkyl, -OH, -OR １ｄ or -SO ２ R １ｄ and is; R １ｄ is a substituted or unsubstituted C １ -C ６ alkyl, substituted or unsubstituted C ３ -C ６ cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, or substituted or unsubstituted phenyl; wherein, when R １ｄ is substituted, it is substituted by one or more R １４ ; R ｅ is hydrogen or -CH ３ ; R ｇ is C １ to C ６ dueteroalkyl, C １ to C ６ fluoroalkyl, substituted or unsubstituted C １ to C ６ heteroalkyl, substituted or unsubstituted C ３ to C ６ cycloalkyl, substituted or unsubstituted C ２ to C ６ heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl; R １０ is hydrogen, halogen, -CN, C １ ~C ６ alkyl, C １ ~C ６ fluoroalkyl, or OR １６ ; R １３ is hydrogen, deuterium, halogen, C １ ~C ６ alkyl, C １ ~C ６ deuterated alkyl, C １ ~C ６ fluoroalkyl, substituted or unsubstituted C ３ ~C ６ cycloalkyl, substituted or unsubstituted C ２ ~C ６ heterocycloalkyl, -CN, -OR １６ ,-C(=O)R １６ ,-CO ２ R １６ ,-C(=O)N(R １６ ) ２ ,-N(R １６ ) ２ ,or -NR １６ C(=O)R １６ ; R １４ is hydrogen, halogen, C １ to C ６ alkyl, -CN, or -OR １６ ; Each R １６ is, independently, hydrogen, C １ to C ６ alkyl, C １ to C ６ duteroalkyl, C １ to C ６ fluoroalkyl, or substituted or unsubstituted C ３ to C ６ cycloalkyl; m is 1 or 2; and n is 0, 1, 2, 3, or 4).

38. R １０ 、 R １３ 、 and R １４ are each independently hydrogen, halogen, -CN, C １ ~C ６ alkyl, C １ ~C ６ fluoroalkyl, or OR １６ ; and R １６ is hydrogen, C １ -C ６ alkyl, C １ -C ６ deuterioalkyl, C １ -C ６ fluoroalkyl, or substituted or unsubstituted C ３ -C ６ cycloalkyl, the compound according to claim 37, or a pharmaceutically acceptable salt or solvate thereof.

39. R １ is -CN, -C(O)NHCH ３ -, -C(O)NHCH ２ CF ３ -, -C(O)NHCN, -C(O)NHOH, -C(O)N(CH ３ ),OH, -C(O)NH(OCH ３ -, -C(O)NH(S(O) ２ CH ３ -, -C(O)NH(S(O) ２ CF ３ -, -C(O)NH(S(O) ２ CH ２ CH ３ -, -C(O)NH(S(O) ２ CH ２ CF ３ -, -C(O)NH(S(O) ２ CH ２ OCH ３ -, -C(O)NH(S(O) ２ CH(CH ３ )) ２ -, -C(O)NH(S(O) ２ C(CH ３ )) ２ -, -C(O)NH(S(O) ２ cyclopropyl, or -C(O)NH(S(O) ２ phenyl, the compound according to claim 37, or a pharmaceutically acceptable salt or solvate thereof.

40. R １０ is -CN, -F, or -OCH ３ and; R １３ is -CN, -F, or -OCH ３ and; and n is 1, the compound according to claim 37, or a pharmaceutically acceptable salt or solvate thereof.

41. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable excipient.

42. The pharmaceutical composition according to claim 41, formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, or intranasal administration.

43. The pharmaceutical composition according to claim 41, in the form of tablets, pills, capsules, solutions, suspensions, dispersions, liquids, or emulsions. Claim 44 A composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof for use in modulating the activity of prostaglandin E2 receptor 2 (EP2) in mammals. Claim 45 A composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of diseases or conditions that would benefit from modulation of prostaglandin E2 receptor 2 (EP2) activity.

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