Amide prodrugs and their uses

Abstract

This article describes amide prodrugs, methods for preparing such compounds, pharmaceutical compositions and medicines comprising such compounds, and methods for using such compounds in the treatment of CNS diseases or conditions.

Description

[0001] Cross-references This application claims the benefit of U.S. Provisional Patent Application No. 63 / 536,004, filed August 31, 2023, which is incorporated herein by reference in its entirety. Background Technology

[0002] The blood-brain barrier, composed of tightly connected endothelial cells, restricts the entry of pathogens and certain types of small and large molecules from the blood into the brain. This crucial protective function also limits the spread of therapeutic drugs to the brain, posing a significant challenge to the development of new drugs for CNS diseases. Summary of the Invention

[0003] In one respect, this article describes compounds having the structure of formula (I), or pharmaceutically acceptable salts or solvates thereof: ; in: X is selected from -C(R) 7 (R) 8 )C(R 7 (R) 8 )-、-C(R 7 (R) 8 )C(O)-、-C(O)C(R 7 (R) 8 )-、-C(R 7 (R) 8 )S-、-SC(R 7 (R) 8 )-、-C(R 7 (R) 8 )O-、-OC(R 7 (R) 8 )-、-C(R 7 (R) 8 )N(R 9 )-、-N(R 9 )C(R 7 (R) 8 )-、-C(R 7 (R) 8 -, -C(O)-, -N(R) 9 )-, -O-, -S-, -S(O)- and -S(O)2-; R 1 Selected from hydrogen, -OR 7 -N(R) 7 (R) 8 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocyclic alkyl, C 1-9Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Halogenated alkyl, C3-C6 cycloalkyl, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups may be substituted; R 2 Selected from -OR 7 -N(R) 7 (R) 8 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocyclic alkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Halogenated alkyl, C3-C6 cycloalkyl, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups are substituted; or R 1 With R 2 The combination forms elements optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 C2-C9 heterocyclic alkyl groups substituted with 1, 2, or 3 groups; R 3 For R 3a R 3b R 3c R 3d and R 3e Substituted phenyl; R 3a Selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、S(=O)(=NH)N(R 10 (R) 11 -CH2C(O)N(R) 10 (R) 11 ), -CH2N(R 12 )C(O)R 13 -CH2S(O)2R 13 and -CH2S(O)2N(R 10 (R) 11 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10 One, two, or three groups are substituted; R3b R 3c R 3d and R 3e Independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、S(=O)(=NH)N(R 10 (R) 11 -CH2C(O)N(R) 10 (R) 11 ), -CH2N(R 12 )C(O)R 13 -CH2S(O)2R 13 and -CH2S(O)2N(R 10 (R) 11 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10 Substitution with one, two, or three groups; or R 3a With R 3b The combination forms elements optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 C2-C9 heterocyclic alkyl groups substituted with 1, 2, or 3 groups; Each R 4 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11)-、S(=O)(=NH)N(R 10 (R) 11 -CH2C(O)N(R) 10 (R) 11 ), -CH2N(R 12 )C(O)R 13 -CH2S(O)2R 13 and -CH2S(O)2N(R 10 (R) 11 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10 One, two, or three groups are substituted; R 5 and R 6 Independently selected from hydrogen and C1-C6 alkyl groups; Each R 7 and each R 8 Independently selected from hydrogen and C1-C6 alkyl groups; R 9 Selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 12 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 13 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is substituted with one, two, or three groups; and p can be 0, 1, 2, 3, or 4.

[0004] In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a Selected from -OR 10 C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl groups, wherein C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10One, two, or three groups are substituted. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a Selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a It is a halogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3b R 3c R 3d and R 3e Independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3b Selected from hydrogen, halogens, -CN and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3b It is a halogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3c R 3d and R 3e For example, it is hydrogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is selected from -C(R) 7 (R) 8 )C(R 7 (R) 8 )- and -C(R 7 (R) 8 In some embodiments, X is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(R) 7 (R) 8 In some embodiments, X is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(R) 7 (R) 8 )C(R 7 (R) 8 In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 7 and each R 8 It is hydrogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R6 It is hydrogen.

[0005] In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (Ia): .

[0006] In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (Ib): .

[0007] In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (Ic): .

[0008] In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (Id): .

[0009] In some embodiments, it is a compound of formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 Independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvation thereof, wherein each R 4 Independently selected from halogens. In some embodiments, it is a compound of formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 Selected independently from C 1-6 Alkyl group. In some embodiments, it is a compound of formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvation thereof, wherein p is 2. In some embodiments, it is a compound of formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvation thereof, wherein p is 1. In some embodiments, it is a compound of formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvation thereof, wherein p is 0.

[0010] On the other hand, this article describes compounds having the structure of formula (II), or pharmaceutically acceptable salts or solvates thereof: ; in: Ring A and ring B are each independently selected from a 6-membered heteroaryl group and a phenyl group, wherein at least one of ring A and ring B is a 6-membered heteroaryl group; X is selected from -C(R) 7 (R) 8 )C(R 7 (R) 8 )-、-C(R 7 (R) 8 )C(O)-、-C(O)C(R 7 (R) 8 )-、-C(R 7 (R) 8 )S-、-SC(R 7 (R) 8 )-、-C(R 7 (R) 8 )O-、-OC(R 7 (R) 8 )-、-C(R 7 (R) 8 )N(R 9 )-、-N(R 9 )C(R 7 (R) 8 )-、-C(R 7 (R) 8 -, -C(O)-, -N(R) 9 )-, -O-, -S-, -S(O)- and -S(O)2-; R 1 Selected from hydrogen, -OR 7 -N(R) 7 (R) 8 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocyclic alkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Halogenated alkyl, C3-C6 cycloalkyl, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups may be substituted; R 2 Selected from -OR7 -N(R) 7 (R) 8 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocyclic alkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Halogenated alkyl, C3-C6 cycloalkyl, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups are substituted; or R 1 With R 2 The combination forms elements optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 C2-C9 heterocyclic alkyl groups substituted with 1, 2, or 3 groups; Each R 3 and each R 4 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、S(=O)(=NH)N(R 10 (R) 11 -CH2C(O)N(R) 10 (R) 11 ), -CH2N(R 12 )C(O)R 13 -CH2S(O)2R 13 and -CH2S(O)2N(R 10 (R) 11 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10 One, two, or three groups are substituted; R 5 and R 6 Independently selected from hydrogen and C1-C6 alkyl groups; Each R 7 and each R 8 Independently selected from hydrogen and C1-C6 alkyl groups; R 9 Selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 12 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 13 Choose C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; n is 1, 2, 3, 4, or 5; and p can be 0, 1, 2, 3, or 4.

[0011] In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein ring A is pyridyl and ring B is phenyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein ring A is phenyl and ring B is pyridyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein ring A is pyridyl and ring B is pyridyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein each R... 3 Selected from halogen, -CN, -OR 10 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl groups, wherein C 1-6 Alkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10 One, two, or three groups are substituted. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 Independently selected from halogen, -CN, -OR 10 C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and unsubstituted C 3-6 cycloalkyl and each R 10 Selected independently from C 1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein n is 2. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein n is 1. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein each R 4 Independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 Selected independently from C 1-6Alkyl group. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein p is 1. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein p is 0. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein X is selected from -C(R 7 (R) 8 )C(R 7 (R) 8 )- and -C(R 7 (R) 8 In some embodiments, X is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(R) 7 (R) 8 In some embodiments, X is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(R) 7 (R) 8 )C(R 7 (R) 8 In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 7 and each R 8 It is hydrogen. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 It is hydrogen.

[0012] On the other hand, this article describes compounds having the structure of formula (III), or pharmaceutically acceptable salts or solvates thereof: ; in: Ring A is a C2-C6 heterocyclic alkyl ring; Z is -N(R) 1 (R) 2 ) or -OH; R 1 Selected from hydrogen, -OR 7 -N(R) 7 (R) 8 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocyclic alkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Halogenated alkyl, C3-C6 cycloalkyl, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups may be substituted; R 2 Selected from -OR 7 -N(R) 7 (R) 8 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocyclic alkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Halogenated alkyl, C3-C6 cycloalkyl, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups are substituted; or R 1 With R 2 The combination forms elements optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 C2-C9 heterocyclic alkyl groups substituted with 1, 2, or 3 groups; Each R 3 and each R 4 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10(R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、S(=O)(=NH)N(R 10 (R) 11 -CH2C(O)N(R) 10 (R) 11 ), -CH2N(R 12 )C(O)R 13 -CH2S(O)2R 13 and -CH2S(O)2N(R 10 (R) 11 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10 One, two, or three groups are substituted; R 5 and R 6 Independently selected from hydrogen and C1-C6 alkyl groups; Each R 7 and each R 8 Independently selected from hydrogen and C1-C6 alkyl groups; Each R 10 Independently selected from hydrogen and C1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 12 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 13 Choose C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; n is 1, 2, 3, 4, or 5; and p can be 0, 1, 2, or 3.

[0013] In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (IIIa): .

[0014] On the other hand, this article describes compounds having the structure of formula (IV), or pharmaceutically acceptable salts or solvates thereof: ; in: Ring A is a C2-C6 heterocyclic alkyl ring; Z is -N(R) 1 (R) 2 ) or -OH; R 1 Selected from hydrogen, -OR 7 -N(R) 7 (R) 8 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocyclic alkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Halogenated alkyl, C3-C6 cycloalkyl, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups may be substituted; R 2 Selected from -OR 7 -N(R) 7 (R) 8 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocyclic alkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Halogenated alkyl, C3-C6 cycloalkyl, -CN, -OR10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups are substituted; or R 1 With R 2 The combination forms elements optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 C2-C9 heterocyclic alkyl groups substituted with 1, 2, or 3 groups; Each R 3 and each R 4 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、S(=O)(=NH)N(R 10 (R) 11-CH2C(O)N(R) 10 (R) 11 ), -CH2N(R 12 )C(O)R 13 -CH2S(O)2R 13 and -CH2S(O)2N(R 10 (R) 11 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10 One, two, or three groups are substituted; R 5 and R 6 Independently selected from hydrogen and C1-C6 alkyl groups; Each R 7 and each R 8 Independently selected from hydrogen and C1-C6 alkyl groups; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; Each R11 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 12 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 13 Choose C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; n is 0, 1, 2, 3, or 4; and p can be 0, 1, 2, 3, or 4.

[0015] In some embodiments, it is a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (IVa): .

[0016] In some embodiments, it is a compound of formula (III), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 Selected from halogen, -CN, -OR 10 C 1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (III), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein each R 3Selected from halogens. In some embodiments, it is a compound of formula (III), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 Selected from C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (III), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein each R 3 Selected from -OR 10 And each R 3 C 1-6 Alkyl group. In some embodiments, it is a compound of formula (III), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein n is 2. In some embodiments, it is a compound of formula (III), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein n is 1. In some embodiments, it is a compound of formula (III), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein n is 0. In some embodiments, it is a compound of formula (III), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein each R 4 Independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (III), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein each R 4 Selected independently from C 1-6 Alkyl group. In some embodiments, it is a compound of formula (III), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein p is 1. In some embodiments, it is a compound of formula (III), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein p is 0. In some embodiments, it is a compound of formula (III), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein R 5 and R 6 Z is hydrogen. In some embodiments, it is a compound of formula (III), (IIIa), (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -N(R 1 (R) 2 In some embodiments, it is a compound of formula (III), (IIIa), (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -OH.

[0017] On the other hand, this article describes compounds having the structure of formula (V), or pharmaceutically acceptable salts or solvates thereof: ; in: Y is selected from -O-, -N(R) 9 )-, -S-, -S(O)-, -S(O)2-, -C(R 7 (R) 8 - and -C(O)-; R 1 Selected from hydrogen, -OR 7 -N(R) 7 (R) 8 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocyclic alkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Halogenated alkyl, C3-C6 cycloalkyl, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups may be substituted; R 2 Selected from -OR 7 -N(R) 7 (R) 8 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocyclic alkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Halogenated alkyl, C3-C6 cycloalkyl, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups are substituted; or R 1 With R 2 The combination forms elements optionally selected from halogens, C 1-6Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 C2-C9 heterocyclic alkyl groups substituted with 1, 2, or 3 groups; R 3 Selected from C3-C8 alkyl, C3-C8 alkenyl, and C3-C8 alkynyl, wherein the C3-C8 alkyl, C3-C8 alkenyl, and C3-C8 alkynyl are optionally selected from halogens, C... 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 -C(O)R 13 and -S(O)2R 13 One, two, or three groups may be substituted; Each R 4 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R)11 )-、S(=O)(=NH)N(R 10 (R) 11 -CH2C(O)N(R) 10 (R) 11 ), -CH2N(R 12 )C(O)R 13 -CH2S(O)2R 13 and -CH2S(O)2N(R 10 (R) 11 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10 One, two, or three groups are substituted; R 5 and R 6 Independently selected from hydrogen and C1-C6 alkyl groups; Each R 7 and each R 8 Independently selected from hydrogen and C1-C6 alkyl groups; R 9 Selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 12 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 13 Choose C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is substituted with one, two, or three groups; and m can be 0, 1, 2, 3, or 4.

[0018] In some embodiments, Y is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is selected from -O-, -N(R) 9 -, -S- and -C(R) 7 (R) 8 In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvation thereof, wherein Y is -O-. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvation thereof, wherein R is -O-. 3 For being optionally selected from halogen, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R)11 -C(O)R 13 and -S(O)2R 13 One, two, or three groups substituted with C3-C8 alkyl groups. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 For being optionally selected from halogen, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 The alkyl group substituted with one, two, or three groups is a C3-C8 alkyl group. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 It is an unsubstituted C3-C8 alkyl group. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 It is hydrogen. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0.

[0019] In some embodiments, it is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is hydrogen. In some embodiments, it is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvation thereof, wherein R 1 It is a C1-C6 alkyl group. In some embodiments, it is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 Optionally selected from halogens, C1-C6 alkyl groups, C 1-6 Halogenated alkyl groups, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups substituted in a C1-C6 alkyl group. In some embodiments, it is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvation thereof, wherein R 2For being selected from halogens, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 A C1-C6 alkyl group substituted with one, two, or three groups. In some embodiments, it is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 It is a C1-C6 alkyl group substituted with 1, 2, or 3 -OH groups. In some embodiments, it is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 It is a C1-C6 alkyl group substituted with 1, 2, or 3 halogens. In some embodiments, it is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 It is an unsubstituted C1-C6 alkyl group. In some embodiments, it is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 -CH3. In some embodiments, it is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Optionally selected from halogens, C1-C6 alkyl groups, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 A C3-C6 cycloalkyl group substituted with one, two, or three groups. In some embodiments, it is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2It is an unsubstituted C3-C6 cycloalkyl group. In some embodiments, it is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 Optionally selected from halogens, C1-C6 alkyl groups, C 1-6 Halogenated alkyl groups, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 C with 1, 2 or 3 substituents 1-9 Heteroaryl. In some embodiments, it is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, R 2 Optionally selected from halogens, C1-C6 alkyl groups, C 1-6 Halogenated alkyl groups, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 C with 1, 2 or 3 substituents 1-9 heteroaryl, of which C 1-9 The heteroaryl group is selected from pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl. In some embodiments, it is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Selected from unsubstituted pyridinyl, unsubstituted pyridazinyl, unsubstituted pyrimidinyl, and unsubstituted pyrazinyl. In some embodiments, it is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvation thereof, wherein R 1 With R 2 The combination forms elements optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13One, two, or three groups substituted in a C2-C9 heterocyclic alkyl group. In some embodiments, it is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 With R 2 They combine to form unsubstituted C2-C9 heterocyclic alkyl groups.

[0020] In another aspect, this document describes a pharmaceutical composition comprising a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, a pharmaceutical composition comprising a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient, further comprising a peripherally limiting fatty acid amide hydrolase (FAAH) inhibitor. In some embodiments, a pharmaceutical composition comprises a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient, and further comprises a peripherally limiting fatty acid amide hydrolase (FAAH) inhibitor, wherein the peripherally limiting FAAH inhibitor is ASP-3652.

[0021] On the other hand, this document describes a method for treating a CNS disease or condition in a patient in need, comprising administering to the patient a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, this document describes a method for treating a CNS disease or condition in a patient in need, comprising administering to the patient a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvation thereof, further comprising administering a peripherally limiting fatty acid amide hydrolase (FAAH) inhibitor. In some embodiments, this document describes a method for treating a CNS disease or condition in a patient in need, comprising administering to the patient a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, and further comprising administering a peripherally limiting fatty acid amide hydrolase (FAAH) inhibitor, wherein the peripherally limiting FAAH inhibitor is ASP-3652. In some implementations, a method of treating a patient with a CNS disease or condition includes administering to the patient a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, wherein the CNS disease or condition is selected from neurodegenerative diseases, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), substance abuse including alcohol abuse, bipolar disorder, mild cognitive impairment, age-related memory impairment (AAMI), Alzheimer's disease, epilepsy, AIDS-related dementia, Pick's disease, Lewy body-related dementia, Down syndrome-related dementia, schizophrenia, schizoaffective disorder, smoking cessation, multiple sclerosis, CNS dysfunction associated with traumatic brain injury, infertility, poor circulation, wound healing-related angiogenesis requirements, ischemia, sepsis, neurodegeneration, and neuropathic pain.

[0022] This document considers any combination of the groups described above for various variables. Throughout the specification, those skilled in the art select groups and their substituents to provide stable moieties and compounds.

[0023] Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. However, it should be understood that while the detailed description and specific examples indicate particular embodiments, they are given by way of illustration only, as various changes and modifications within the spirit and scope of this disclosure will be apparent to those skilled in the art from this detailed description. Detailed Implementation

[0024] Spingosine-1-phosphate (S1P) is a pleiotropic signaling molecule that mediates a variety of biological responses through interactions with members of the endothelial cell differentiation gene family (EDG receptors) of G protein-coupled receptors located on the plasma membrane. Five members of this family have been identified in various cell types: S1P1 (EDG-1), S1P2 (EDG-5), S1P3 (EDG-3), S1P4 (EDG-6), and S1P5 (EDG-8). The receptor subtypes S1P1, S1P2, and S1P3 are widely expressed in peripheral tissues and the central nervous system (CNS) and play crucial roles in cardiovascular regulation, lymphocyte transport, and neurogenesis. The S1P4 receptor is primarily expressed in the immune and hematopoietic systems and typically mediates immune cell proliferation and cytokine production in the presence of high concentrations of S1P. S1P5 receptor expression is significantly more restricted, primarily expressed in oligodendrocytes of the central nervous system (CNS), and is considered to play a key role in myelin biology, as well as mediating cellular transport in natural killer cells and other lymphocytes in the spleen. S1P5 is also thought to be important in regulating blood-brain barrier permeability and integrity. Oligodendrocyte precursor cells (OPCs), pre-oligodendrocytes, and fully differentiated mature oligodendrocytes all express S1P5 receptors at high levels. Activation of the S1P5 receptor can promote OPC survival and induce pre-oligodendrocytes to mature into myelin-forming oligodendrocytes. In fact, preclinical models in mice and Xenopus tadpoles have shown evidence of S1P5-mediated myelin regeneration. Furthermore, in several animal models of neurodegenerative diseases, administration of selective S1P5 agonists has been reported to normalize protein disorders and improve clinical scores. These data support the use of S1P5 agonists to treat a variety of neurological disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Niemann-Pick disease type C.

[0025] In some implementations, selectively and simultaneously modulating S1P1 and S1P5 receptors in the brain tissue of patients with neurological disorders should provide neuroprotective and myelin regeneration benefits. S1P1 / 5 receptors are expressed on astrocytes, microglia, neurons, and oligodendrocytes and have been shown to regulate processes associated with demyelinating neuropathology, including astrocyte activation, microglia activation, oligodendrocyte precursor cell migration and maturation, and oligodendrocyte survival. Studies in EAE mouse models of MS have shown that gene deletion or pharmacological antagonism of S1P1 reduces demyelination, axonal loss, and astrocyte proliferation. S1P5 is highly expressed on myelin-forming oligodendrocytes, and S1P5 stimulation / modulation has been shown to promote the survival of mature oligodendrocytes. In a conditionally demyelinated Xenopus tadpole model, use of dual S1P1 / S1P5 agonists or a selective S1P5 agonist resulted in increased intersegmental myelination compared to controls, while the use of a selective S1P1 agonist did not produce the same phenotype. On the other hand, S1P1 expression was higher than S1P5 expression on astrocytes, microglia, and endothelial cells, and was associated with reduced cytokine release and inflammatory signaling, as well as improved BBB integrity. These data collectively suggest that simultaneous regulation of these two receptor subtypes can lead to improved treatment of various neurological disorders, including epilepsy, multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Niemann-Pick disease type C.

[0026] Fatty acid amide hydrolases (FAAHs) are integrase-bound serine hydrolases that degrade the fatty acid amide family of signaling lipids and hydrolyze selected amide prodrugs. FAAHs are highly conserved across species and expressed to varying degrees in many tissues, including the central nervous system (CNS). Selected carboxylic acids can be converted into more permeable amide prodrugs, which are then able to cross the blood-brain barrier, where they can be converted into the active molecule by the action of FAAHs. This results in the delivery of a larger amount of parent carboxylic acid to the CNS compared to administration of the parent compound alone. However, peripherally expressed FAAHs also hydrolyze the prodrug, leading to significant nonproductive prodrug conversion. Co-administration of peripherally restricted FAAH inhibitors with CNS-permeable FAAH-convertible prodrugs improves the selectivity of prodrug delivery to the CNS. It also results in lower exposure of the parent molecule in plasma and peripheral tissues compared to prodrug administration alone.

[0027] certain terms Unless otherwise stated, the following terms as used in this application have the definitions given below. The use of the term "including" and other forms such as "include," "includes," and "included" is not restrictive. Section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter.

[0028] The C1-C used in this article x Including C1-C2, C1-C3...C1-C x For example only, a group designated as "C1-C4" indicates that the moiety contains 1 to 4 carbon atoms, that is, a group containing 1, 2, 3, or 4 carbon atoms. Therefore, for example only, "C1-C4 alkyl" indicates that the alkyl group contains 1 to 4 carbon atoms, meaning the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0029] An alkyl group refers to an aliphatic hydrocarbon group. Alkyl groups can be branched or straight-chain. In some embodiments, the alkyl group has 1 to 10 carbon atoms, i.e., C1-C1. 10 Alkyl. Whenever it appears herein, numerical ranges such as “1 to 10” refer to each integer within a given range; for example, “1 to 10 carbon atoms” means that an alkyl group consists of 1, 2, 3, 4, 5, 6, etc., up to and including 10 carbon atoms, but this definition also covers the occurrence of the term “alkyl” where no numerical range is specified. In some embodiments, the alkyl group is a C1-C6 alkyl group. In one aspect, the alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, or hexyl.

[0030] An "alkylene group" refers to a divalent alkyl group. Any of the aforementioned monovalent alkyl groups can become an alkylene group by removing a second hydrogen atom from an alkyl group. In some embodiments, the alkylene group is C1-C6 alkylene. In other embodiments, the alkylene group is C1-C4 alkylene. In some embodiments, the alkylene group contains 1 to 4 carbon atoms (e.g., C1-C4 alkylene). In other embodiments, the alkylene group contains 1 to 3 carbon atoms (e.g., C1-C3 alkylene). In other embodiments, the alkylene group contains 1 to 2 carbon atoms (e.g., C1-C2 alkylene). In other embodiments, the alkylene group contains 1 carbon atom (e.g., C1 alkylene). In other embodiments, the alkylene group contains 2 carbon atoms (e.g., C2 alkylene). In other embodiments, the alkylene group contains 2 to 4 carbon atoms (e.g., C2-C4 alkylene). Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2, etc.

[0031] "Deuteryl" refers to an alkyl group in which one or more hydrogen atoms in an alkyl group are replaced by deuterium.

[0032] The term "alkenyl" refers to a class of alkyl groups containing at least one carbon-carbon double bond. In one embodiment, the alkenyl group has the formula -C(R)=CR2, where R refers to the remaining portion of the alkenyl group, which may be the same or different. In some embodiments, R is H or an alkyl group. In some embodiments, the alkenyl group is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, etc. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0033] The term "alkynyl" refers to a class of alkyl groups containing at least one carbon-carbon triple bond. In one embodiment, the alkenyl group has the formula -C≡CR, where R represents the remainder of the alkynyl group. In some embodiments, R is H or an alkyl group. In some embodiments, the alkynyl group is selected from ethynyl, propynyl, butynyl, pentyynyl, hexynyl, etc. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3, -C≡CCH2CH3, and -CH2C≡CH.

[0034] The "alkoxy" group refers to the (alkyl) O- group, where the alkyl group is as defined herein.

[0035] The term "alkylamine" refers to -N (alkyl) x H y A group, wherein x is 0 and y is 2, or wherein x is 1 and y is 1, or wherein x is 2 and y is 0.

[0036] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π electrons, where n is an integer. The term "aromatic" includes carbocyclic aryl ("aryl", e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings sharing adjacent carbon or nitrogen atom pairs) groups.

[0037] The term "carbocyclic" or "carbocycle" refers to a ring or ring system whose ring skeleton is composed entirely of carbon atoms. Therefore, this term distinguishes a carbocyclic ring from a "heterocyclic" ring or "heterocycle" whose ring skeleton contains at least one atom other than carbon. In some embodiments, at least one of the two rings of a bicyclic carbocyclic ring is aromatic. In some embodiments, both rings of a bicyclic carbocyclic ring are aromatic. Carbocyclic rings include cycloalkyl and aryl groups.

[0038] As used herein, the term "aryl" refers to an aromatic ring in which each atom forming the ring is a carbon atom. In one aspect, the aryl group is phenyl or naphthyl. In some embodiments, the aryl group is phenyl. In some embodiments, the aryl group is C6-C. 10 Aryl group. Based on its structure, the aryl group can be monomethyl or dimethyl (i.e., arylene group).

[0039] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic nonaromatic group in which each atom forming the ring (i.e., the skeletal atom) is a carbon atom. In some embodiments, the cycloalkyl is a spirocyclic or bridging compound. In some embodiments, the cycloalkyl is optionally fused to an aromatic ring, and the bonding point is located on a carbon atom of a nonaromatic ring. 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 bicyclo[1.1.1]pentyl. In some embodiments, the cycloalkyl is a C3-C6 cycloalkyl. In some embodiments, the cycloalkyl is a monocyclic cycloalkyl. Monocyclic cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.2]octyl and bicyclo[2.2.1]heptyl), norbornyl, decahydronaphthyl, 7,7-dimethylbicyclo[2.2.1]heptyl, etc.

[0040] The term "halo," or alternatively "halogen" or "halide," refers to fluorine, chlorine, bromine, or iodine. In some embodiments, the halogen is fluorine, chlorine, or bromine.

[0041] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen atoms. In one respect, fluoroalkyl groups are C1-C6 fluoroalkyl groups.

[0042] The term "fluoroalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by fluorine atoms. In one aspect, the fluoroalkyl group is a C1-C6 fluoroalkyl group. In some embodiments, the fluoroalkyl group is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc.

[0043] The term "heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl group are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. The heteroalkyl group is attached to the rest of the molecule at a carbon atom. In one aspect, the heteroalkyl group is a C1-C6 heteroalkyl group.

[0044] The term "heteroalkylene" refers to a divalent heteroalkyl group.

[0045] The term "heterocycle" or "heterocyclic" refers to a heteroaromatic ring (also called a heteroaryl ring) and a heterocyclic alkyl ring (also called a heteroalicyclic group) containing 1 to 4 heteroatoms, wherein each heteroatom in the ring is selected from O, S, and N, and each heterocyclic group has 3 to 10 atoms in its ring system, provided that no ring contains two adjacent O or S atoms. In some embodiments, the heterocycle is a monocyclic, bicyclic, polycyclic, spirocyclic, or bridging compound. Non-aromatic heterocyclic groups (also called heterocyclic alkyl groups) 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[a]-fused ring systems. Examples of non-aromatic heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, oxazolidinyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thiaxyl, piperazine, aziridinyl, aziridine, aziridine, oxacyclobutane, oxacyclobutane, thiohepane, homopiperidinyl, oxacycloheptane, thiohepane, oxazolidinyl, and diazazyl. , thiazazyl, 1,2,3,6-tetrahydropyridyl, pyrrololin-2-yl, pyrrololin-3-yl, indololinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxapentanyl, pyrazolinyl, dithiaalkyl, dithiacyclopentanyl, dihydropyranyl, dihydrothiophenyl, dihydrofuranyl, pyrazolyl, imidazolinyl, imidazolinyl, 3-azabicyclo[3.1.0]hexane 3-azabicyclo[4.1.0]heptyl, 2-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, 5-azabicyclo[2.1.1]hexyl, 6-azabicyclo[3.1.1]heptyl, 7-azabicyclo[2.2.1]heptyl, 8-azabicyclo[3.2.1]octyl, 3H-indolyl, indololin-2-one, isoindolyl Lin-1-keto, isoindoline-1,3-diketo, 3,4-dihydroisoquinoline-1(2H)-keto, 3,4-dihydroquinoline-2(1H)-keto, isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-keto, 1H-benzo[d]imidazol-2(3H)-keto, benzo[d]thiazol-2(3H)-keto, and quinazinyl. Examples of aromatic heterocyclic groups include pyridinyl, imidazole, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thiophene, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrroleyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinolinyl, indazole, inazinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purine, oxadiazolyl, thiazolyl, furazonyl, benzofuranyl, benzothiophene, benzothiazolyl, benzooxazolyl, quinazolinyl, quinoxolinyl, naphridinyl, and furanpyridinyl.The aforementioned groups can be C-linked (or C-coupled) or N-linked (if possible). For example, groups derived from pyrrole include pyrrolo-1-yl (N-linked) or pyrrolo-3-yl (C-linked). Furthermore, groups derived from imidazole include imidazole-1-yl or imidazole-3-yl (both N-linked) or imidazole-2-yl, imidazole-4-yl, or imidazole-5-yl (both C-linked). Heterocyclic groups include benzo[a]-fused-ring systems. Non-aromatic heterocycles are optionally substituted with one or both oxo (=O) moieties, such as pyrrolidine-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.

[0046] The term "heteroaryl" or alternatively "heteroarylene" refers to an aryl group comprising one or more cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. Exemplary examples of heteroaryl groups include monocyclic and bicyclic heteroaryl groups. Monocyclic heteroaryl groups include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thiophene, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrroleyl, pyridazinyl, triazinyl, oxadiazolyl, thiazolyl, and furanyl. Bicyclic heteroaryl groups include indazine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinazine, quinoline, isoquinoline, cinnamoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthidine, and pteridine. In some embodiments, the heteroaryl group contains 0-4 nitrogen atoms in the ring. In some embodiments, the heteroaryl group contains 1-4 nitrogen atoms in the ring. In some embodiments, the heteroaryl group contains 0-4 nitrogen atoms, 0-1 oxygen atoms, and 0-1 sulfur atoms in the ring. In some embodiments, the heteroaryl group contains 1-4 nitrogen atoms, 0-1 oxygen atoms, and 0-1 sulfur atoms in the ring. In some embodiments, the heteroaryl group is a C1-C9 heteroaryl group. In some embodiments, the monocyclic heteroaryl group is a C1-C5 heteroaryl group. In some embodiments, the monocyclic heteroaryl group is a 5- or 6-membered heteroaryl group. In some embodiments, the bicyclic heteroaryl group is a C6-C9 heteroaryl group.

[0047] The term "heterocyclic alkyl" or "heterocyclic aliphatic" group refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic alkyl group is fused with an aryl or heteroaryl group. In some embodiments, the heterocyclic alkyl group is oxazolidinone, pyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, piperidin-2-one, pyrrolidine-2,5-dithioyl, pyrrolidine-2,5-diketone, pyrrolidine-ketone, imidazoalkyl, imidazoalkyl-2-one, or thiazoalkyl-2-one. The term heterocyclic also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. On one hand, the heterocyclic alkyl group is C2-C 10Heterocyclic alkyl groups. On the other hand, heterocyclic alkyl groups are C4-C. 10 Heterocyclic alkyl groups. In some embodiments, the heterocyclic alkyl group contains 0-2 nitrogen atoms in the ring. In some embodiments, the heterocyclic alkyl group contains 0-2 nitrogen atoms, 0-2 oxygen atoms, and 0-1 sulfur atoms in the ring.

[0048] The term "oxo" refers to the =O group.

[0049] The term "bond" or "single bond" refers to a chemical bond between two atoms or two parts when the atoms connected by the bond are considered part of a larger substructure. In one aspect, when the group described herein is a bond, the cited group is absent, thus allowing bonds to form between the remaining identified groups.

[0050] The term "part" refers to a specific segment or functional group of a molecule. A chemical part is generally a recognized chemical entity that is embedded in or attached to a molecule.

[0051] The terms “optionally substituted” or “substituted” mean that the referenced group is optionally substituted by one or more other groups, which are individually and independently selected from D, halogen, -CN, -NH2, -NH (alkyl), -N (alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH (alkyl), -C(=O)N (alkyl)2, -S(=O)2NH2, -S(=O)2NH (alkyl), -S(=O)2N (alkyl)2, alkyl, alkenyl, alkynyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, and aryl sulfone. In some other embodiments, the optional substituents are independently selected from D, halogens, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4 alkyl), -S(=O)2N(C1-C4 alkyl)2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, -SC1-C4 alkyl, -S(=O)C1-C4 alkyl and -S(=O)2C1-C4 alkyl. In some embodiments, the optional substituents are independently selected from D, halogens, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, the substituent group is replaced by one or both of the aforementioned groups. In some embodiments, the optional substituents on the aliphatic carbon atom (acyclic or cyclic) include oxo (=O).

[0052] As used in this article, the term "acceptable" in relation to formulations, compositions, or ingredients means that it does not have a lasting harmful effect on the overall health of the person receiving treatment.

[0053] As used in this article, the term "modulation" refers to interacting with a target directly or indirectly to alter the target's activity, including (by way of example only) enhancing, inhibiting, limiting, or prolonging the target's activity.

[0054] As used herein, the term "modulator" refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, interactions between agonists, partial agonists, inverse agonists, antagonists, degraders, or combinations thereof. In some embodiments, the modulator is an agonist.

[0055] As used herein, the terms “administer,” “administering,” and “administration” refer to methods that can be used to deliver a compound or composition to a desired biological site of action. These methods include, but are not limited to, oral administration, duodenal administration, parenteral administration (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), local administration, and rectal administration. Those skilled in the art are familiar with administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0056] The term “co-administration” or similar terms used in this article are intended to cover the administration of selected therapeutic agents to a single patient and are intended to include treatment regimens in which agents are administered via the same or different routes of administration or at the same or different times.

[0057] As used herein, the term "effective amount" or "therapeutic effective amount" refers to an adequate quantity of an applied agent or compound that will, to a certain extent, alleviate one or more symptoms of the disease or condition being treated. Results include a reduction and / or relief of the signs, symptoms, or cause of the disease, or any other desired biological systemic changes. For example, an "effective amount" for therapeutic use is an amount in which a composition comprising a compound disclosed herein provides a clinically significant reduction in the symptoms of a disease. In any single case, the appropriate "effective" amount may optionally be determined using techniques such as dose escalation studies.

[0058] As used herein, the terms "enhance" or "enhancing" refer to increasing or prolonging the potency or duration of a desired effect. Therefore, regarding the enhancement of a therapeutic agent's effect, the term "enhancement" refers to the ability to increase or prolong the potency or duration of the effect of another therapeutic agent on the system. As used herein, "enhancing effective amount" refers to an amount sufficient to enhance the effect of another therapeutic agent in the desired system.

[0059] As used herein, the term "drug combination" refers to a product resulting from a mixture or combination of more than one active ingredient, including fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to an active ingredient, such as a compound described herein or a pharmaceutically acceptable salt thereof, and an excipient, administered simultaneously to a patient as a single entity or dose. The term "non-fixed combination" refers to an active ingredient, such as a compound described herein or a pharmaceutically acceptable salt thereof, and an excipient, administered simultaneously, in parallel, or sequentially to a patient as a single entity without a specific intermediate time limit, wherein such administration provides effective levels of both compounds in the patient. The latter also applies to cocktail therapies, such as the administration of three or more active ingredients.

[0060] The terms “kit” and “product” are used as synonyms.

[0061] The term "object" or "patient" encompasses mammals. Examples of mammals include, but are not limited to, any member of the mammal class: humans; non-human primates such as chimpanzees and other apes and monkeys; farm animals such as cattle, horses, sheep, goats, and pigs; livestock such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. In one respect, the mammal is the human being.

[0062] As used herein, the terms “treat,” “treating,” or “treatment” include relieving, reducing, or improving at least one symptom of a disease or condition, preventing other symptoms, inhibiting a disease or condition, such as preventing the development of a disease or condition, alleviating a disease or condition, causing a disease or condition to subside, relieving a condition caused by a disease or condition, or preventing and / or therapeutically stopping the symptoms of a disease or condition.

[0063] compound In some embodiments, the compounds described herein (including their pharmaceutically acceptable salts, active metabolites, and pharmaceutically acceptable solvates) are selective S1P5 receptor agonists. In some embodiments, the compounds described herein (including their pharmaceutically acceptable salts, active metabolites, and pharmaceutically acceptable solvates) are amide prodrugs of selective S1P5 receptor agonists.

[0064] In some embodiments, the compounds described herein (including their pharmaceutically acceptable salts, active metabolites, and pharmaceutically acceptable solvates) are dual S1P1 and S1P5 receptor agonists. In some embodiments, the compounds described herein (including their pharmaceutically acceptable salts, active metabolites, and pharmaceutically acceptable solvates) are amide prodrugs of dual S1P1 and S1P5 receptor agonists.

[0065] In some embodiments, this document describes compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof: ; in, X is selected from -C(R) 7 (R) 8 )C(R 7 (R) 8 )-、-C(R 7 (R) 8 )C(O)-、-C(O)C(R 7 (R) 8 )-、-C(R 7 (R) 8 )S-、-SC(R 7 (R) 8 )-、-C(R 7 (R) 8 )O-、-OC(R 7 (R) 8 )-、-C(R 7 (R) 8 )N(R 9 )-、-N(R 9 )C(R 7 (R) 8 )-、-C(R 7 (R) 8 -, -C(O)-, -N(R) 9 )-, -O-, -S-, -S(O)- and -S(O)2-; R 1 Selected from hydrogen, -OR 7 -N(R) 7 (R) 8 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocyclic alkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Halogenated alkyl, C3-C6 cycloalkyl, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups may be substituted; R 2 Selected from -OR 7-N(R) 7 (R) 8 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocyclic alkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Halogenated alkyl, C3-C6 cycloalkyl, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups are substituted; or R 1 With R 2 The combination forms elements optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 C2-C9 heterocyclic alkyl groups substituted with 1, 2, or 3 groups; R 3 For R 3a R 3b R 3c R 3d and R 3e Substituted phenyl; R 3a Selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12)S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、S(=O)(=NH)N(R 10 (R) 11 -CH2C(O)N(R) 10 (R) 11 ), -CH2N(R 12 )C(O)R 13 -CH2S(O)2R 13 and -CH2S(O)2N(R 10 (R) 11 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10 One, two, or three groups are substituted; R 3b R 3c R 3d and R 3e Independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 -SR 10 -N(R) 10 (R)11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、S(=O)(=NH)N(R 10 (R) 11 -CH2C(O)N(R) 10 (R) 11 ), -CH2N(R 12 )C(O)R 13 -CH2S(O)2R 13 and -CH2S(O)2N(R 10 (R) 11 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10 Substitution with one, two, or three groups; or R 3a With R 3b The combination forms elements optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R)10 (R) 11 C2-C9 heterocyclic alkyl groups substituted with 1, 2, or 3 groups; Each R 4 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、S(=O)(=NH)N(R 10 (R) 11 -CH2C(O)N(R) 10 (R) 11 ), -CH2N(R 12 )C(O)R 13 -CH2S(O)2R 13 and -CH2S(O)2N(R 10 (R) 11 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10 One, two, or three groups are substituted; R 5 and R 6 Independently selected from hydrogen and C1-C6 alkyl groups; Each R 7 and each R 8 Independently selected from hydrogen and C1-C6 alkyl groups; R 9 Selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 12 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 13Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is substituted with one, two, or three groups; and p can be 0, 1, 2, 3, or 4.

[0066] For any and all embodiments, the substituent is selected from a subset of the listed substitutes. For example, in some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is selected from -C(R 7 (R) 8 )C(R 7 (R) 8 )-、-C(R 7 (R) 8 )C(O)-、-C(O)C(R 7 (R) 8 )-、-C(R 7 (R) 8 )S-、-SC(R 7 (R) 8 )-、-C(R 7 (R) 8 )O-、-OC(R 7 (R) 8 )-、-C(R 7 (R) 8 )N(R 9 - and -N(R) 9 )C(R 7 (R) 8 In some embodiments, X is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is selected from -C(R) 7 (R)8 )C(R 7 (R) 8 )-、-C(R 7 (R) 8 )O-and-OC(R 7 (R) 8 In some embodiments, X is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is selected from -C(R) 7 (R) 8 )C(R 7 (R) 8 )- and -C(R 7 (R) 8 In some embodiments, X is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(R) 7 (R) 8 In some embodiments, X is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -OC(R) 7 (R) 8 In some embodiments, X is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(R) 7 (R) 8 )C(R 7 (R) 8 In some embodiments, X is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(R) 7 (R) 8 -, -C(O)-, -N(R) 9 -, -O-, -S-, -S(O)-, and -S(O)2-. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein X is -O-. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein X is -C(R)-. 7 (R) 8 )-.

[0067] In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 7 and each R 8The substance is hydrogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein X is -CH2O-. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein X is -OCH2-. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein X is -CH2CH2-. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein X is -CH2-.

[0068] In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a Selected from -OR 10 C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl groups, wherein C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10 One, two, or three groups are substituted. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a Selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a It is a halogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a -Cl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a C 1-6 Alkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R 3a -CH3. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a It is -CF3.

[0069] In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3b R 3c R 3d and R 3e Independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3b Selected from hydrogen, halogens, -CN and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3b It is hydrogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3b It is a halogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3b -Cl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3b -CN. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3b C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3b For -CF3. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3c R 3d and R 3e It is hydrogen.

[0070] In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 Independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 Independently selected from halogens. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -Cl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 Selected independently from C 1-6Alkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -CH3. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 Selected independently from C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 It is -CF3.

[0071] In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein p is 1. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein p is 2. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein p is 3. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein p is 4.

[0072] In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.

[0073] In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 It is hydrogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 It is hydrogen and R 6 It is a C1-C6 alkyl group. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 It is hydrogen and R 6 -CH3. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 Independently selected from C1-C6 alkyl groups. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R 5 and R 6 It is -CH3.

[0074] In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is hydrogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1It is a C1-C6 alkyl group. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -CH3.

[0075] In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Optionally selected from halogens, C1-C6 alkyl groups, C 1-6 Halogenated alkyl groups, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups substituted with C1-C6 alkyl groups. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 For being selected from halogens, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 The compound is a C1-C6 alkyl group substituted with one, two, or three groups. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R... 2 It is a C1-C6 alkyl group substituted with 1, 2, or 3 -OH groups. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is a C1-C6 alkyl group substituted with 1, 2, or 3 halogens. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is an unsubstituted C1-C6 alkyl group. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is -CH3.

[0076] In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Optionally selected from halogens, C1-C6 alkyl groups, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 The compound is a C3-C6 cycloalkyl group substituted with one, two, or three groups. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R... 2 It is an unsubstituted C3-C6 cycloalkyl group. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 It is the unsubstituted cyclopropyl group.

[0077] In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Optionally selected from halogens, C1-C6 alkyl groups, C 1-6 Halogenated alkyl groups, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 C with 1, 2 or 3 substituents 1-9 Heteroaryl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, R 2 Optionally selected from halogens, C1-C6 alkyl groups, C 1-6 Halogenated alkyl groups, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 C with 1, 2 or 3 substituents 1-9 heteroaryl, of which C 1-9 The heteroaryl group is selected from pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 Selected from unsubstituted pyridinyl, unsubstituted pyridazinyl, unsubstituted pyrimidinyl, and unsubstituted pyrazinyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 It is an unsubstituted pyridinyl group. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is an unsubstituted pyridazinyl group. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is an unsubstituted pyrimidine group. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is an unsubstituted pyrazinyl group.

[0078] In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 With R 2 The combination forms elements optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11) and -S(O)2R 13 One, two, or three groups substituted with C2-C9 heterocyclic alkyl groups. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 With R 2 Combinations can be optionally selected from C 1-6 A C2-C9 heterocyclic alkyl group substituted with one, two, or three alkyl groups. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 With R 2 The combination forms an unsubstituted C2-C9 heterocyclic alkyl group. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 With R 2 They combine to form unsubstituted nitrogen-containing heterocyclic butyl groups.

[0079] In some embodiments, compounds of formula (Ia), (Ib), (Ic), or (Id), or pharmaceutically acceptable salts or solvates thereof, are described herein: ; ; ; ; in, R 1 Selected from hydrogen, -OR 7 -N(R) 7 (R) 8 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocyclic alkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Halogenated alkyl, C3-C6 cycloalkyl, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups may be substituted; R 2 Selected from -OR 7 -N(R) 7 (R) 8C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocyclic alkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Halogenated alkyl, C3-C6 cycloalkyl, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups are substituted; or R 1 With R 2 The combination forms elements optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 C2-C9 heterocyclic alkyl groups substituted with 1, 2, or 3 groups; R 3a Selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R)10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、S(=O)(=NH)N(R 10 (R) 11 -CH2C(O)N(R) 10 (R) 11 ), -CH2N(R 12 )C(O)R 13 -CH2S(O)2R 13 and -CH2S(O)2N(R 10 (R) 11 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10 One, two, or three groups are substituted; R 3b Selected from hydrogen, halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12)S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、S(=O)(=NH)N(R 10 (R) 11 -CH2C(O)N(R) 10 (R) 11 ), -CH2N(R 12 )C(O)R 13 -CH2S(O)2R 13 and -CH2S(O)2N(R 10 (R) 11 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10 Substitution with one, two, or three groups; or R 3a With R 3b The combination forms elements optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 C2-C9 heterocyclic alkyl groups substituted with 1, 2, or 3 groups; Each R 4 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、S(=O)(=NH)N(R 10 (R) 11 -CH2C(O)N(R) 10 (R) 11 ), -CH2N(R 12 )C(O)R 13 -CH2S(O)2R 13 and -CH2S(O)2N(R 10 (R) 11 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10 One, two, or three groups are substituted; Each R 7 and each R 8 Independently selected from hydrogen and C1-C6 alkyl groups; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 12 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 13 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is substituted with one, two, or three groups; and p can be 0, 1, 2, 3, or 4.

[0080] In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a Selected from -OR 10 C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl groups, wherein C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10 One, two, or three groups are substituted. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a Selected from halogens, C 1-6 Alkyl and C 1-6 Haloalkyl. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a It is a halogen. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a -Cl. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a C 1-6 Alkyl group. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvation thereof, wherein R 3a -CH3. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a C 1-6 Haloalkyl. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R3a It is -CF3.

[0081] In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3b Selected from hydrogen, halogens, -CN and C 1-6 Haloalkyl. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3b It is hydrogen. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3b It is a halogen. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3b -Cl. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3b -CN. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3b C 1-6 Haloalkyl. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3b It is -CF3.

[0082] In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 Independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 Independently selected from halogens. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -Cl. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 Selected independently from C 1-6Alkyl group. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvation thereof, wherein each R... 4 -CH3. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 Selected independently from C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 It is -CF3.

[0083] In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvation thereof, wherein p is 1. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvation thereof, wherein p is 2. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvation thereof, wherein p is 3. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvation thereof, wherein p is 4.

[0084] In some embodiments, it is a compound of formula (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.

[0085] In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is hydrogen. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is a C1-C6 alkyl group. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -CH3.

[0086] In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Optionally selected from halogens, C1-C6 alkyl groups, C 1-6 Halogenated alkyl groups, -CN, -OR 10 -N(R)10 (R) 11 ) and -S(O)2R 13 One, two, or three groups substituted for a C1-C6 alkyl group. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 For being selected from halogens, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 A C1-C6 alkyl group substituted with 1, 2, or 3 groups. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is a C1-C6 alkyl group substituted with 1, 2, or 3 -OH groups. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 It is a C1-C6 alkyl group substituted with 1, 2, or 3 halogens. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is an unsubstituted C1-C6 alkyl group. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is -CH3.

[0087] In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 -CH3. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Optionally selected from halogens, C1-C6 alkyl groups, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 A C3-C6 cycloalkyl group substituted with 1, 2, or 3 groups. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is an unsubstituted C3-C6 cycloalkyl group. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2It is the unsubstituted cyclopropyl group.

[0088] In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Optionally selected from halogens, C1-C6 alkyl groups, C 1-6 Halogenated alkyl groups, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 C with 1, 2 or 3 substituents 1-9 Heteroaryl. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, R 2 Optionally selected from halogens, C1-C6 alkyl groups, C 1-6 Halogenated alkyl groups, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 C with 1, 2 or 3 substituents 1-9 heteroaryl, of which C 1-9 The heteroaryl group is selected from pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 Selected from unsubstituted pyridinyl, unsubstituted pyridazinyl, unsubstituted pyrimidinyl, and unsubstituted pyrazinyl. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 It is an unsubstituted pyridinyl group. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 It is an unsubstituted pyridazinyl group. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is an unsubstituted pyrimidine group. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 It is an unsubstituted pyrazinyl group.

[0089] In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 and R 2 The combination forms elements optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups substituted in a C2-C9 heterocyclic alkyl group. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 Combinations can be optionally selected from C 1-6 A C2-C9 heterocyclic alkyl group substituted with one, two, or three alkyl groups. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 The combination forms an unsubstituted C2-C9 heterocyclic alkyl group. In some embodiments, it is a compound of formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 They combine to form unsubstituted nitrogen-containing heterocyclic butyl groups.

[0090] In some embodiments, this document describes compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof: ; in: Ring A and ring B are each independently selected from a 6-membered heteroaryl group and a phenyl group, wherein at least one of ring A and ring B is a 6-membered heteroaryl group; X is selected from -C(R) 7 (R) 8 )C(R 7 (R) 8 )-、-C(R 7 (R) 8 )C(O)-、-C(O)C(R 7 (R) 8 )-、-C(R 7 (R) 8 )S-、-SC(R 7 (R) 8 )-、-C(R 7 (R) 8 )O-、-OC(R 7 (R) 8 )-、-C(R 7 (R)8 )N(R 9 )-、-N(R 9 )C(R 7 (R) 8 )-、-C(R 7 (R) 8 -, -C(O)-, -N(R) 9 )-, -O-, -S-, -S(O)- and -S(O)2-; R 1 Selected from hydrogen, -OR 7 -N(R) 7 (R) 8 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocyclic alkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Halogenated alkyl, C3-C6 cycloalkyl, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups may be substituted; R 2 Selected from -OR 7 -N(R) 7 (R) 8 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocyclic alkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Halogenated alkyl, C3-C6 cycloalkyl, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups are substituted; or R 1 With R 2 The combination forms elements optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10-N(R) 10 (R) 11 ) and -S(O)2R 13 C2-C9 heterocyclic alkyl groups substituted with 1, 2, or 3 groups; Each R 3 and each R 4 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、S(=O)(=NH)N(R 10 (R) 11 -CH2C(O)N(R) 10 (R) 11 ), -CH2N(R 12 )C(O)R 13 -CH2S(O)2R 13 and -CH2S(O)2N(R 10 (R) 11 ), where C 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10 One, two, or three groups are substituted; R 5 and R 6 Independently selected from hydrogen and C1-C6 alkyl groups; Each R 7 and each R 8 Independently selected from hydrogen and C1-C6 alkyl groups; R 9 Selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 12 Independently selected from hydrogen and C 1-6 Alkyl and C1-6 Halogenated alkyl groups; Each R 13 Choose C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; n is 1, 2, 3, 4, or 5; and p can be 0, 1, 2, 3, or 4.

[0091] In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein ring A is pyridyl and ring B is phenyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein ring A is phenyl and ring B is pyridyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein ring A is pyridyl and ring B is pyridyl.

[0092] In some embodiments, X is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is selected from -C(R 7 (R) 8 )C(R 7 (R) 8 )-、-C(R 7 (R) 8 )C(O)-、-C(O)C(R 7 (R) 8 )-、-C(R 7 (R) 8 )S-、-SC(R 7 (R) 8 )-、-C(R 7 (R)8 )O-、-OC(R 7 (R) 8 )-、-C(R 7 (R) 8 )N(R 9 - and -N(R) 9 )C(R 7 (R) 8 In some embodiments, X is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is selected from -C(R 7 (R) 8 )C(R 7 (R) 8 )-、-C(R 7 (R) 8 )O-and-OC(R 7 (R) 8 In some embodiments, X is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is selected from -C(R 7 (R) 8 )C(R 7 (R) 8 )- and -C(R 7 (R) 8 In some embodiments, X is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(R) 7 (R) 8 In some embodiments, X is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -OC(R) 7 (R) 8 In some embodiments, X is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(R) 7 (R) 8 )C(R 7 (R) 8 In some embodiments, X is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(R) 7 (R) 8 -, -C(O)-, -N(R) 9 -, -O-, -S-, -S(O)-, and -S(O)2-. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein X is -O-. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein X is -C(R)-. 7 (R) 8)-.

[0093] In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 7 and each R 8 The substance is hydrogen. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein X is -CH2O-. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein X is -OCH2-. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein X is -CH2CH2-. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein X is -CH2-.

[0094] In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 Selected from halogen, -CN, -OR 10 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl groups, wherein C 1-6 Alkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10 One, two, or three groups are substituted. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 Independently selected from halogen, -CN, -OR 10 C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and unsubstituted C 3-6 cycloalkyl and each R 10 Selected independently from C 1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 Independently selected from halogens, -CN, C 1-6 Alkyl and C 1-6Halogenated alkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 Independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 Selected independently from C 1-6 Halogenated alkyl groups and unsubstituted C 3-6 Cycloalkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 Independently selected from -CN and -OR 10 And each R 10 Selected independently from C 1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 Independently selected from -CN and -OR 10 And each R 10 Selected independently from C 1-6 Alkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 Independently selected from halogens. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -Cl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -CN. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 Selected independently from C 1-6 Alkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -CH3. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 Selected independently from C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 For -CF3. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 For -OR 10And each R 10 Selected independently from C 1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 For -OR 10 And each R 10 Selected independently from C 1-6 alkyl.

[0095] In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein n is 2. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein n is 1.

[0096] In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 Independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 Independently selected from halogens. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -Cl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 Selected independently from C 1-6 Alkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -CH3. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 Selected independently from C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 It is -CF3.

[0097] In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein p is 0. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein p is 1. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein p is 2.

[0098] In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 It is hydrogen. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 It is hydrogen and R 6 It is a C1-C6 alkyl group. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 It is hydrogen and R 6 -CH3. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 Independently selected from C1-C6 alkyl groups. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein R 5 and R 6 It is -CH3.

[0099] In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is hydrogen. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is a C1-C6 alkyl group. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -CH3.

[0100] In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Optionally selected from halogens, C1-C6 alkyl groups, C 1-6 Halogenated alkyl groups, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups substituted with C1-C6 alkyl groups. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 For being selected from halogens, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 A C1-C6 alkyl group substituted with 1, 2, or 3 groups. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2It is a C1-C6 alkyl group substituted with 1, 2, or 3 -OH groups. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is a C1-C6 alkyl group substituted with 1, 2, or 3 halogens. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is an unsubstituted C1-C6 alkyl group. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is -CH3.

[0101] In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Optionally selected from halogens, C1-C6 alkyl groups, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 The compound is a C3-C6 cycloalkyl group substituted with one, two, or three groups. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R... 2 It is an unsubstituted C3-C6 cycloalkyl group. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is the unsubstituted cyclopropyl group.

[0102] In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Optionally selected from halogens, C1-C6 alkyl groups, C 1-6 Halogenated alkyl groups, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 C with 1, 2 or 3 substituents 1-9 Heteroaryl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, R 2 Optionally selected from halogens, C1-C6 alkyl groups, C 1-6 Halogenated alkyl groups, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 C with 1, 2 or 3 substituents 1-9 heteroaryl, of which C 1-9The heteroaryl group is selected from pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Selected from unsubstituted pyridinyl, unsubstituted pyridazinyl, unsubstituted pyrimidinyl, and unsubstituted pyrazinyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 It is an unsubstituted pyridinyl group. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is an unsubstituted pyridazinyl group. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is an unsubstituted pyrimidine group. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 It is an unsubstituted pyrazinyl group.

[0103] In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 With R 2 The combination forms elements optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups substituted with C2-C9 heterocyclic alkyl groups. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 With R 2 Combinations can be optionally selected from C 1-6 A C2-C9 heterocyclic alkyl group substituted with one, two, or three alkyl groups. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 With R 2 The combination forms an unsubstituted C2-C9 heterocyclic alkyl group. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 With R 2 They combine to form unsubstituted nitrogen-containing heterocyclic butyl groups.

[0104] In some embodiments, this document describes compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof: ; in: Ring A is a C2-C6 heterocyclic alkyl ring; Z is -N(R) 1 (R) 2 ) or -OH; R 1 Selected from hydrogen, -OR 7 -N(R) 7 (R) 8 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocyclic alkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Halogenated alkyl, C3-C6 cycloalkyl, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups may be substituted; R 2 Selected from -OR 7 -N(R) 7 (R) 8 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocyclic alkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Halogenated alkyl, C3-C6 cycloalkyl, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups are substituted; or R 1 With R 2 The combination forms elements optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 C2-C9 heterocyclic alkyl groups substituted with 1, 2, or 3 groups; Each R 3 and each R 4 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、S(=O)(=NH)N(R 10 (R) 11 -CH2C(O)N(R) 10 (R) 11 ), -CH2N(R 12 )C(O)R 13 -CH2S(O)2R 13 and -CH2S(O)2N(R 10 (R) 11 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10 One, two, or three groups are substituted; R 5 and R 6 Independently selected from hydrogen and C1-C6 alkyl groups; Each R 7 and each R 8 Independently selected from hydrogen and C1-C6 alkyl groups; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 12 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 13 Choose C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; n is 1, 2, 3, 4, or 5; and p can be 0, 1, 2, or 3.

[0105] In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (IIIa): .

[0106] In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 Selected from halogen, -CN, -OR 10 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl groups, wherein C 1-6 Alkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10 One, two, or three groups are substituted. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 Independently selected from halogen, -CN, -OR 10 C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and unsubstituted C 3-6 cycloalkyl and each R 10 Selected independently from C1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein each R 3 Independently selected from halogens, -CN, C 1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein each R 3 Independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein each R 3 Selected independently from C 1-6 Halogenated alkyl groups and unsubstituted C 3-6 Cycloalkyl. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 Independently selected from -CN and -OR 10 And each R 10 Selected independently from C 1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein each R 3 Independently selected from -CN and -OR 10 And each R 10 Selected independently from C 1-6 Alkyl. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein each R 3 Independently selected from halogens. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -Cl. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -CN. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 Selected independently from C 1-6 Alkyl. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein each R 3-CH3. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 Selected independently from C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein each R 3 For -CF3. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 For -OR 10 And each R 10 Selected independently from C 1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein each R 3 For -OR 10 And each R 10 Selected independently from C 1-6 alkyl.

[0107] In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein n is 2. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein n is 1.

[0108] In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 Independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein each R 4 Independently selected from halogens. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -Cl. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 Selected independently from C 1-6 Alkyl. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein each R 4-CH3. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 Selected independently from C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein each R 4 It is -CF3.

[0109] In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein p is 0. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein p is 1. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein p is 2.

[0110] In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 It is hydrogen. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 It is hydrogen and R 6 It is a C1-C6 alkyl group. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R 5 It is hydrogen and R 6 -CH3. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 Independently selected from C1-C6 alkyl groups. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R 5 and R 6 It is -CH3.

[0111] In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -OH.

[0112] In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -N(R 1 (R) 2 ).

[0113] In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is hydrogen. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is a C1-C6 alkyl group. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R 1 It is -CH3.

[0114] In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Optionally selected from halogens, C1-C6 alkyl groups, C 1-6 Halogenated alkyl groups, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups substituted for C1-C6 alkyl groups. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 For being selected from halogens, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 A C1-C6 alkyl group substituted with 1, 2, or 3 groups. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 It is a C1-C6 alkyl group substituted with 1, 2, or 3 -OH groups. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is a C1-C6 alkyl group substituted with 1, 2, or 3 halogens. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 It is an unsubstituted C1-C6 alkyl group. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is -CH3.

[0115] In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2Optionally selected from halogens, C1-C6 alkyl groups, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 A C3-C6 cycloalkyl group substituted with 1, 2, or 3 groups. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 It is an unsubstituted C3-C6 cycloalkyl group. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is the unsubstituted cyclopropyl group.

[0116] In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Optionally selected from halogens, C1-C6 alkyl groups, C 1-6 Halogenated alkyl groups, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 C with 1, 2 or 3 substituents 1-9 Heteroaryl. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, R 2 Optionally selected from halogens, C1-C6 alkyl groups, C 1-6 Halogenated alkyl groups, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 C with 1, 2 or 3 substituents 1-9 heteroaryl, of which C 1-9 The heteroaryl group is selected from pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 Selected from unsubstituted pyridinyl, unsubstituted pyridazinyl, unsubstituted pyrimidinyl, and unsubstituted pyrazinyl. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 It is an unsubstituted pyridinyl group. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R 2It is an unsubstituted pyridazinyl group. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is an unsubstituted pyrimidinyl group. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 It is an unsubstituted pyrazinyl group.

[0117] In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 With R 2 The combination forms elements optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups substituted in a C2-C9 heterocyclic alkyl group. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 With R 2 Combinations can be optionally selected from C 1-6 A C2-C9 heterocyclic alkyl group substituted with one, two, or three alkyl groups. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R 1 With R 2 The combination forms an unsubstituted C2-C9 heterocyclic alkyl group. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 With R 2 They combine to form unsubstituted nitrogen-containing heterocyclic butyl groups.

[0118] In some embodiments, this document describes compounds of formula (IV), or pharmaceutically acceptable salts or solvates thereof: ; in: Ring A is a C2-C6 heterocyclic alkyl ring; Z is -N(R) 1 (R) 2 ) or -OH; R 1 Selected from hydrogen, -OR 7 -N(R) 7 (R) 8C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocyclic alkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Halogenated alkyl, C3-C6 cycloalkyl, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups may be substituted; R 2 Selected from -OR 7 -N(R) 7 (R) 8 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocyclic alkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Halogenated alkyl, C3-C6 cycloalkyl, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups are substituted; or R 1 With R 2 The combination forms elements optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 C2-C9 heterocyclic alkyl groups substituted with 1, 2, or 3 groups; Each R 3 and each R 4 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、S(=O)(=NH)N(R 10 (R) 11 -CH2C(O)N(R) 10 (R) 11 ), -CH2N(R 12 )C(O)R 13 -CH2S(O)2R 13 and -CH2S(O)2N(R 10 (R) 11 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10 One, two, or three groups are substituted; R5 and R 6 Independently selected from hydrogen and C1-C6 alkyl groups; Each R 7 and each R 8 Independently selected from hydrogen and C1-C6 alkyl groups; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 12 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 13 Choose C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, hydroxyl, C1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; n is 0, 1, 2, 3, or 4; and p can be 0, 1, 2, 3, or 4.

[0119] In some embodiments, it is a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (IVa): .

[0120] In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 Selected from halogen, -CN, -OR 10 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl groups, wherein C 1-6 Alkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10 One, two, or three groups are substituted. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 Independently selected from halogen, -CN, -OR 10 C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and unsubstituted C 3-6 cycloalkyl and each R 10 Selected independently from C 1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein each R 3 Independently selected from halogens, -CN, C 1-6 Alkyl and C 1-6Halogenated alkyl. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein each R 3 Independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein each R 3 Selected independently from C 1-6 Halogenated alkyl groups and unsubstituted C 3-6 Cycloalkyl. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 Independently selected from -CN and -OR 10 And each R 10 Selected independently from C 1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein each R 3 Independently selected from -CN and -OR 10 And each R 10 Selected independently from C 1-6 Alkyl group. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein each R... 3 Independently selected from halogens. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein each R 3 -Cl. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 -CN. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 Selected independently from C 1-6 Alkyl group. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein each R... 3 -CH3. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 Selected independently from C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein each R 3For -CF3. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 For -OR 10 And each R 10 Selected independently from C 1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein each R 3 For -OR 10 And each R 10 Selected independently from C 1-6 alkyl.

[0121] In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein n is 2. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein n is 1.

[0122] In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 Independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein each R 4 Independently selected from halogens. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein each R 4 -Cl. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 Selected independently from C 1-6 Alkyl group. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein each R... 4 -CH3. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 Selected independently from C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein each R 4 It is -CF3.

[0123] In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein p is 0. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein p is 1. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein p is 2.

[0124] In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 It is hydrogen. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 It is hydrogen and R 6 It is a C1-C6 alkyl group. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein R 5 It is hydrogen and R 6 -CH3. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 Independently selected from C1-C6 alkyl groups. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein R 5 and R 6 It is -CH3.

[0125] In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -OH.

[0126] In some embodiments, Z is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -N(R 1 (R) 2 ).

[0127] In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is hydrogen. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is a C1-C6 alkyl group. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein R 1 It is -CH3.

[0128] In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Optionally selected from halogens, C1-C6 alkyl groups, C 1-6 Halogenated alkyl groups, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups substituted for C1-C6 alkyl groups. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 For being selected from halogens, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 A C1-C6 alkyl group substituted with 1, 2, or 3 groups. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 It is a C1-C6 alkyl group substituted with 1, 2, or 3 -OH groups. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 It is a C1-C6 alkyl group substituted with 1, 2, or 3 halogens. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is an unsubstituted C1-C6 alkyl group. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 It is -CH3.

[0129] In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Optionally selected from halogens, C1-C6 alkyl groups, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 The compound is a C3-C6 cycloalkyl group substituted with one, two, or three groups. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R... 2 It is an unsubstituted C3-C6 cycloalkyl group. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2It is the unsubstituted cyclopropyl group.

[0130] In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Optionally selected from halogens, C1-C6 alkyl groups, C 1-6 Halogenated alkyl groups, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 C with 1, 2 or 3 substituents 1-9 Heteroaryl. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, R 2 Optionally selected from halogens, C1-C6 alkyl groups, C 1-6 Halogenated alkyl groups, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 C with 1, 2 or 3 substituents 1-9 heteroaryl, of which C 1-9 The heteroaryl group is selected from pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 Selected from unsubstituted pyridinyl, unsubstituted pyridazinyl, unsubstituted pyrimidinyl, and unsubstituted pyrazinyl. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 It is an unsubstituted pyridinyl group. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 It is an unsubstituted pyridazinyl group. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is an unsubstituted pyrimidine group. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 It is an unsubstituted pyrazinyl group.

[0131] In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 With R 2 The combination forms elements optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups substituted in a C2-C9 heterocyclic alkyl group. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 With R 2 Combinations can be optionally selected from C 1-6 A C2-C9 heterocyclic alkyl group substituted with one, two, or three alkyl groups. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvation thereof, wherein R 1 With R 2 The combination forms an unsubstituted C2-C9 heterocyclic alkyl group. In some embodiments, it is a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 With R 2 They combine to form unsubstituted nitrogen-containing heterocyclic butyl groups.

[0132] In some embodiments, this document describes compounds of formula (V), or pharmaceutically acceptable salts or solvates thereof: ; in, Y is selected from -O-, -N(R) 9 )-, -S-, -S(O)-, -S(O)2-, -C(R 7 (R) 8 - and -C(O)-; R 1 Selected from hydrogen, -OR 7 -N(R) 7 (R) 8 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocyclic alkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Halogenated alkyl, C3-C6 cycloalkyl, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups may be substituted; R 2Selected from -OR 7 -N(R) 7 (R) 8 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocyclic alkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Halogenated alkyl, C3-C6 cycloalkyl, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups are substituted; or R 1 With R 2 The combination forms elements optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 C2-C9 heterocyclic alkyl groups substituted with 1, 2, or 3 groups; R 3 Selected from C3-C8 alkyl, C3-C8 alkenyl, and C3-C8 alkynyl, wherein the C3-C8 alkyl, C3-C8 alkenyl, and C3-C8 alkynyl are optionally selected from halogens, C... 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 -C(O)R 13 and -S(O)2R 13 One, two, or three groups may be substituted; Each R 4 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10-OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、S(=O)(=NH)N(R 10 (R) 11 -CH2C(O)N(R) 10 (R) 11 ), -CH2N(R 12 )C(O)R 13 -CH2S(O)2R 13 and -CH2S(O)2N(R 10 (R) 11 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10 One, two, or three groups are substituted; R 5 and R 6 Independently selected from hydrogen and C1-C6 alkyl groups; Each R 7 and each R 8 Independently selected from hydrogen and C1-C6 alkyl groups; R9 Selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 12 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 13 Choose C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is substituted with one, two, or three groups; and m can be 0, 1, 2, 3, or 4.

[0133] In some embodiments, Y is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is selected from -O-, -N(R) 9 -, -S- and -C(R) 7 (R) 8 In some embodiments, Y is a compound of formula (V), or a pharmaceutically acceptable salt or solvation thereof, wherein Y is -O-. In some embodiments, Y is a compound of formula (V), or a pharmaceutically acceptable salt or solvation thereof, wherein Y is -N(R)-. 9 In some embodiments, Y is a compound of formula (V), or a pharmaceutically acceptable salt or solvation thereof, wherein Y is -N(H)-. In some embodiments, Y is a compound of formula (V), or a pharmaceutically acceptable salt or solvation thereof, wherein Y is -S-. In some embodiments, Y is a compound of formula (V), or a pharmaceutically acceptable salt or solvation thereof, wherein Y is -C(R)-. 7 (R) 8 In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvation thereof, wherein Y is -CH2-.

[0134] In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 For being optionally selected from halogen, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 -C(O)R 13 and -S(O)2R 13 One, two, or three groups substituted with C3-C8 alkyl groups. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 For being optionally selected from halogen, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 The alkyl group substituted with one, two, or three groups is a C3-C8 alkyl group. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3It is an unsubstituted C3-C8 alkyl group. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 It is -(CH2)2CH3. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 The form is -(CH2)2CH(CH3)2. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 It is -(CH2)3CH3. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 The form is -(CH2)3CH(CH3)2. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 It is -(CH2)4CH3. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 The form is -(CH2)4CH(CH3)2. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 It is -(CH2)5CH3. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 It is -(CH2)5CH(CH3)2. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 It is -(CH2)6CH3. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 It is -(CH2)7CH3.

[0135] In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 Independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 Independently selected from halogens. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 -Cl. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 Selected independently from C 1-6Alkyl. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvation thereof, wherein each R... 4 -CH3. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 Selected independently from C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 It is -CF3.

[0136] In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvation thereof, wherein m is 1. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvation thereof, wherein m is 2. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvation thereof, wherein m is 3. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvation thereof, wherein m is 4.

[0137] In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0.

[0138] In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 It is hydrogen. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 It is hydrogen and R 6 It is a C1-C6 alkyl group. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 It is hydrogen and R 6 -CH3. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 Independently selected from C1-C6 alkyl groups. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 It is -CH3.

[0139] In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is hydrogen. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1It is a C1-C6 alkyl group. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -CH3.

[0140] In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Optionally selected from halogens, C1-C6 alkyl groups, C 1-6 Halogenated alkyl groups, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups substituted with C1-C6 alkyl groups. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 For being selected from halogens, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 A C1-C6 alkyl group substituted with 1, 2, or 3 groups. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is a C1-C6 alkyl group substituted with 1, 2, or 3 -OH groups. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is a C1-C6 alkyl group substituted with 1, 2, or 3 halogens. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is an unsubstituted C1-C6 alkyl group. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is -CH3.

[0141] In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 -CH3. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Optionally selected from halogens, C1-C6 alkyl groups, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 The compound is a C3-C6 cycloalkyl group substituted with one, two, or three groups. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R... 2It is an unsubstituted C3-C6 cycloalkyl group. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is the unsubstituted cyclopropyl group.

[0142] In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Optionally selected from halogens, C1-C6 alkyl groups, C 1-6 Halogenated alkyl groups, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 C with 1, 2 or 3 substituents 1-9 Heteroaryl. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, R 2 Optionally selected from halogens, C1-C6 alkyl groups, C 1-6 Halogenated alkyl groups, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 C with 1, 2 or 3 substituents 1-9 heteroaryl, of which C 1-9 The heteroaryl group is selected from pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Selected from unsubstituted pyridinyl, unsubstituted pyridazinyl, unsubstituted pyrimidinyl, and unsubstituted pyrazinyl. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 It is an unsubstituted pyridinyl group. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is an unsubstituted pyridazinyl group. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is an unsubstituted pyrimidinyl group. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvation thereof, wherein R 2 It is an unsubstituted pyrazinyl group.

[0143] In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 With R 2 The combination forms elements optionally selected from halogens, C 1-6 Alkyl, C 1-6Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups substituted with C2-C9 heterocyclic alkyl groups. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 With R 2 Combinations can be optionally selected from C 1-6 A C2-C9 heterocyclic alkyl group substituted with one, two, or three alkyl groups. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 With R 2 The combination forms an unsubstituted C2-C9 heterocyclic alkyl group. In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 With R 2 They combine to form unsubstituted nitrogen-containing heterocyclic butyl groups.

[0144] This document considers any combination of the groups described above for various variables. Throughout the specification, the groups and their substituents are selected by those skilled in the art to provide stable moieties and compounds.

[0145] In some embodiments, it is a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from: .

[0146] In some embodiments, it is a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from: .

[0147] In some embodiments, it is a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from: .

[0148] In some embodiments, it is a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from: .

[0149] In some embodiments, the compounds described herein are in the form of pharmaceutically acceptable salts. Similarly, active metabolites of these compounds having the same type of activity are also included within the scope of this disclosure. Furthermore, the compounds described herein may exist in unsolvable forms as well as in solvable forms with pharmaceutically acceptable solvents (such as water, ethanol, etc.). The solvable forms of the compounds provided herein are also considered part of this disclosure.

[0150] As used herein, “pharmaceutically acceptable” means a material, such as a carrier or diluent, that does not eliminate the biological activity or properties of a compound and is relatively non-toxic, i.e., that the material, when applied to an individual, does not cause adverse biological effects or interact in a harmful manner with any component of a composition containing the material.

[0151] The term "pharmaceutically acceptable salt" refers to a therapeutically active agent in which a cationic therapeutic agent is combined with a suitable anionic form, or, in an alternative embodiment, a therapeutically active agent in which an anionic therapeutic agent is combined with a suitable cationic form. (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. Edited by PH Stahl and CG Wermuth.) Handbook of Pharmaceutical Salts: Properties, Selection and Use Weinheim / Zürich: Wiley-VCH / VHCA, 2002. Pharmaceutical salts are generally more soluble and dissolve faster in gastric and intestinal fluids than nonionic salts, thus making them suitable for solid dosage forms. Furthermore, since their solubility is generally a function of pH, they can selectively dissolve in one or more parts of the digestive tract, a capability that can be controlled as an aspect of delayed and sustained release behavior. Additionally, because salt-forming molecules can maintain equilibrium with neutral forms, channels across biological membranes can be modulated.

[0152] In some embodiments, a pharmaceutically acceptable salt is obtained by reacting the compound described herein with an acid to provide a "pharmaceutically acceptable acid addition salt". In some embodiments, the compound described herein (i.e., in its free base form) is basic and reacts 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, but are not limited to, 1-hydroxy-2-naphthylcarboxylic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetaminobenzoic 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; caproic acid; caprylic acid; octanoic acid. acid); carbonic acid; cinnamic acid; citric acid; cyclohexylsulfamic acid; dodecyl sulfate; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactosidic acid; gentic acid; glucoheponic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutamate; glycerophosphate; 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; dihydroxynaphthalic acid; phosphoric acid; propionic acid; pyroglutamic acid (-L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L); thiocyanate; toluenesulfonic acid (p); and undecanoic acid.

[0153] In some embodiments, the compounds described herein are prepared as chloride salts, sulfates, bromide salts, methanesulfonates, maleates, citrates, or phosphates.

[0154] In some implementations, a pharmaceutically acceptable salt is obtained by reacting the compound described herein with a base to provide a "pharmaceutically acceptable base addition salt".

[0155] In some embodiments, the compounds described herein are acidic and react with bases. In this case, the acidic proton of the compounds described herein is replaced by a metal ion (e.g., lithium, sodium, potassium, magnesium, calcium, or aluminum ions). In some cases, the compounds described herein coordinate with an organic base such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucosamine, dicyclohexylamine, and tris(hydroxymethyl)methylamine. In other cases, the compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, etc. Acceptable inorganic bases for forming 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, etc. In some embodiments, the compounds provided herein are prepared as sodium salts, calcium salts, potassium salts, magnesium salts, meglumine salts, N-methylglucosamine salts, or ammonium salts.

[0156] It should be understood that references to pharmaceutically acceptable salts include solvation forms. In some embodiments, the solvate contains stoichiometric or non-stoichiometric amounts of solvent and is formed during the separation or purification of the compound using a pharmaceutically acceptable solvent (such as water, ethanol, etc.). A hydrate is formed when the solvent is water, or an alcohol is formed when the solvent is an alcohol. The solvates of the compounds described herein are conveniently prepared or formed in the processes described herein. Furthermore, the compounds provided herein are optionally present in both non-solvated and solvated forms.

[0157] The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of the compounds described herein, as well as active metabolites of these compounds having the same type of activity.

[0158] In some embodiments, sites on the organic groups (e.g., alkyl groups, aromatic rings) of the compounds described herein are susceptible to various metabolic reactions. Introducing appropriate substituents onto the organic groups will reduce, minimize, or eliminate this metabolic pathway. In specific embodiments, appropriate substituents that reduce or eliminate the sensitivity of the aromatic ring to metabolic reactions are, by way of example only, halogens, deuterium, alkyl groups, haloalkyl groups, or deuterated alkyl groups.

[0159] In another embodiment, the compounds described herein are labeled with isotopes (e.g., with radioactive isotopes) or by other means, including but not limited to the use of chromophores or fluorescent portions, bioluminescent labeling, or chemiluminescent labeling.

[0160] The compounds described herein include isotopically labeled compounds that are identical to those described in the various formulas and structures provided herein, but in fact, one or more atoms are replaced by atoms having a different atomic mass or mass number than those commonly found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as, by way of example. 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 35 S, 18 F, 36 Cl. In one aspect, the isotope-labeled compounds described herein, for example those doped with radioactive isotopes (such as... 3 H and 14 Compounds of type C) can be used in drug and / or substrate tissue distribution assays. In one aspect, substitution with an isotope such as deuterium provides certain therapeutic advantages resulting from increased metabolic stability, such as, for example, increased in vivo half-life or reduced dose requirement. In some embodiments, one or more hydrogen atoms of the compounds described herein are substituted with deuterium.

[0161] In some embodiments, the compounds described herein have one or more stereocenters, each of which exists independently in an R or S configuration. The compounds provided herein include all diastereomers, enantiomers, trans-isomers, and epimers, as well as suitable mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, E (E), and Z (Z) isomers, as well as suitable mixtures thereof.

[0162] If desired, a single stereoisomer is obtained by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatography. In some embodiments, the compound is prepared into a single stereoisomer by reacting a racemic mixture of the compounds described herein with an optically active resolving agent to form a pair of diastereomeric compounds / salts, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, enantiomer separation is performed using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by a separation / resolution technique based on solubility differences. In other embodiments, the separation of stereoisomers is carried out by chromatography or by forming diastereomeric salts and separating 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, the stereoisomer is obtained by stereoselective synthesis.

[0163] Compound Synthesis The compounds described herein were synthesized using standard synthetic techniques or by combining methods known in the art with those described herein.

[0164] Unless otherwise specified, standard methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology are used.

[0165] The compounds were prepared using standard organic chemistry techniques, such as those described in March's Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions to the synthetic transformations described herein may be employed, such as variations in solvent, reaction temperature, reaction time, and different chemical reagents and other reaction conditions. Starting materials are commercially available or readily prepared.

[0166] Suitable references and papers that provide detailed descriptions of the synthesis of the reactants used to prepare the compounds described herein, or that provide reference to articles describing such preparations, include, for example, "Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York; SR Sandler et al., "Organic Functional Group Preparations," 2nd ed., Academic Press, New York, 1983; HO House, "Modern Synthetic Reactions," 2nd ed., WA Benjamin, Inc., Menlo Park, Calif. 1972; TL Gilchrist, "Heterocyclic Chemistry," 2nd ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th ed., Wiley-Interscience, New York, 1992. Other suitable references and papers that describe in detail the synthesis of the reactants used to prepare the compounds described herein or provide reference to articles describing such preparations include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", 2nd ed., Revised and Expanded (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd ed. (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J."Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry ofFunctional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, TWG "Organic Chemistry" 7th edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, JC, "Intermediate Organic Chemistry" 2nd edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: StartingMaterials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley &Sons, ISBN: 3-527-29645-X, 8 volumes; "Organic Reactions" (1942-2000) John Wiley &Sons, over 55 Volume; and "Chemistry of Functional Groups" John Wiley & Sons, Volume 73. .

[0167] In some implementations, the compound is prepared as described in the examples.

[0168] Treatment In some implementations, this document describes a method for treating a CNS disease or condition in a patient in need, including administering to the patient a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof. In some implementations, a method of treating a patient with a CNS disease or condition includes administering to the patient a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvation thereof, wherein the CNS disease or condition is selected from neurodegenerative diseases, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), substance abuse including alcohol abuse, bipolar disorder, mild cognitive impairment, age-related memory impairment (AAMI), Alzheimer's disease, epilepsy, AIDS-related dementia, Pick's disease, Lewy body-related dementia, Down syndrome-related dementia, schizophrenia, schizoaffective disorder, smoking cessation, multiple sclerosis, CNS dysfunction associated with traumatic brain injury, infertility, poor circulation, wound healing-related angiogenesis requirements, ischemia, sepsis, neurodegeneration, and neuropathic pain. In some embodiments, a method of treating a CNS disease or condition in a patient in need includes administering to the patient a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvation thereof, wherein the CNS disease or condition is selected from multiple sclerosis. In some embodiments, a method of treating a CNS disease or condition in a patient in need includes administering to the patient a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvation thereof, wherein the CNS disease or condition is X-linked adrenoleukodystrophy.

[0169] In some implementations, this document describes a method for treating a CNS disease or condition in a patient in need, including administering to the patient a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, and also includes administering to the patient a peripherally limiting fatty acid amide hydrolase (FAAH) inhibitor. In some implementations, a method of treating a patient with a CNS disease or condition includes administering to the patient a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, wherein the CNS disease or condition is selected from neurodegenerative diseases, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), substance abuse including alcohol abuse, bipolar disorder, mild cognitive impairment, age-related memory impairment (AAMI), Alzheimer's disease, epilepsy, AIDS-related dementia, Pick's disease, Lewy body-related dementia, Down syndrome-related dementia, schizophrenia, schizoaffective disorder, smoking cessation, multiple sclerosis, CNS dysfunction associated with traumatic brain injury, infertility, poor circulation, wound healing-related angiogenesis requirements, ischemia, sepsis, neurodegeneration, and neuropathic pain, and also includes administering to the patient a peripherally limiting fatty acid amide hydrolase (FAAH) inhibitor.

[0170] In some embodiments of the method described herein, the peripherally restricted FAAH inhibitor is ASP-3652.

[0171] Pharmaceutical Composition In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. The pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate the processing of the active compound into a pharmaceutical formulation. Appropriate formulations depend on the chosen route of administration. Abstracts of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, 19th edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., editors, Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for this disclosure.

[0172] In some embodiments, the compounds described herein are administered alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents as a pharmaceutical composition. In some embodiments disclosed herein, the pharmaceutical composition further comprises a peripherally limiting fatty acid amide hydrolase (FAAH) inhibitor. In some embodiments, the pharmaceutical composition further comprises a peripherally limiting FAAH inhibitor, wherein the peripherally limiting FAAH inhibitor is ASP-3652.

[0173] Any method capable of delivering a compound to the site of action can be used to administer the compounds and compositions described herein. These methods include, but are not limited to, delivery via the enteral route (including oral, gastric or duodenal feeding tubes, rectal suppositories, and rectal enemas), the parenteral route (injection or infusion, including intra-arterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural, and subcutaneous), inhalation, transdermal, transmucosal, sublingual, buccal, and topical (including epidermal, dermal, enema, eye drops, ear drops, intranasal, and vaginal) administration, but the most suitable route may depend, for example, on the recipient's condition and illness.

[0174] In some embodiments, the pharmaceutical composition suitable for oral administration is present in discrete unit form such as capsules, pouches, or tablets, each unit containing a predetermined amount of the active ingredient; in powder or granule form; in solution or suspension in an aqueous or non-aqueous liquid; or in oil-in-water or water-in-oil emulsions. In some embodiments, the active ingredient is present in pills, ointments, or pastes.

[0175] Orally administered pharmaceutical compositions include tablets, push-in capsules made of gelatin, and soft-sealable capsules made of gelatin and plasticizers such as glycerin or sorbitol. Tablets can be prepared by compression or molding, optionally with one or more excipients. Compressed tablets can be prepared by compressing an active ingredient in a free-flowing form (such as powder or granules) in a suitable machine, said active ingredient optionally mixed with a binder, an inert diluent or lubricant, a surfactant, or a dispersant. Molded tablets can be prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine. In some embodiments, the tablets are coated or scored and formulated to provide a slow or controlled release of the active ingredient therein. All formulations intended for oral administration should have a dosage suitable for such administration. Push-in capsules may contain an active ingredient mixed with a filler (such as lactose), a binder (such as starch), and / or a lubricant (such as talc or magnesium stearate), and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, a stabilizer is added. The sugar-coated core is fitted with a suitable coating. For this purpose, a concentrated sugar solution may be used, which optionally contains gum arabic, talc, polyvinylpyrrolidone, carbomer gel, polyethylene glycol and / or titanium dioxide, lacquer solution, and a suitable organic solvent or solvent mixture. Dyes or pigments may be added to the tablet or sugar-coated core coating to identify or characterize different combinations of active compound dosages.

[0176] In some embodiments, the pharmaceutical composition is formulated for parenteral administration by injection, such as by bolus or continuous infusion. The injectable formulation may be present in a single dosage form, such as in ampoules or multi-dose containers, with added preservatives. The composition may be in the form of a suspension, solution, or emulsion in an oily or aqueous medium and may contain formulations such as suspending agents, stabilizers, and / or dispersants. The composition may be present in single-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in powder form or under lyophilized (freeze-dried) conditions, requiring only the addition of a sterile liquid carrier, such as saline or sterile pyrogen-free water, immediately before use. Ready-to-use injectable solutions and suspensions may be prepared from sterile powders, granules, and tablets of the types described above.

[0177] Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oil-based) sterile injectable solutions of the active compound, which may contain antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickeners. Suitable lipophilic solvents or mediators include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injectable suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or reagents that increase the solubility of the compound to allow for the preparation of high-concentration solutions.

[0178] The pharmaceutical composition can also be formulated into a reservoir formulation. Such a long-acting formulation can be administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Thus, for example, the compound can be formulated with a suitable polymer or hydrophobic material (e.g., as an emulsion in an acceptable oil) or ion exchange resin, or as a slightly soluble derivative, for example, as a slightly soluble salt.

[0179] For buccal or sublingual application, the composition can be in the form of tablets, lozenges, lozenges, or gels formulated in a conventional manner. The active ingredient may be contained in a flavoring matrix such as sucrose and gum arabic or tragacanth.

[0180] The pharmaceutical composition can also be formulated into rectal compositions, such as suppositories or retention enemas, for example containing a conventional suppository base, such as cocoa butter, polyethylene glycol or other glycerides.

[0181] The pharmaceutical composition can be administered topically, i.e., not systemically. This includes applying the compound of the invention externally to the epidermis or mouth, and instilling the compound into the ear, eye, and nose, such that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0182] Pharmaceutical compositions suitable for topical application include liquid or semi-liquid formulations suitable for penetration through the skin to the site of inflammation, such as gels, liniments, lotions, creams, ointments, or pastes, as well as drops suitable for application to the eyes, ears, or nose. For topical application, the active ingredient may be 0.001% to 10% w / w, for example, 1% to 2% by weight of the formulation.

[0183] Pharmaceutical compositions intended for inhalation administration are conveniently delivered from an inhaler, nebulizer pressurized package, or other convenient aerosol spray delivery device. The pressurized package may contain a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of pressurized aerosols, the dosage unit can be determined by providing a valve to deliver a measured amount. Alternatively, for inhalation or inhalation administration, the pharmaceutical formulation may be in the form of a dry powder composition, such as a mixture of a compound and a suitable powder matrix (such as lactose or starch). The powder composition may be present in unit dosage forms, such as capsules, cartridges, gelatin, or blister packs, from which the powder can be administered using an inhaler or inhaler.

[0184] In some embodiments, the compounds disclosed herein are formulated to achieve delivery of the compounds to a specific region of the gastrointestinal tract. For example, the compounds disclosed herein are formulated for oral delivery together with bioadhesive polymers, pH-sensitive coatings, time-dependent biodegradable polymers, microbiome activation systems, etc., to achieve delivery of the compounds to a specific region of the gastrointestinal tract.

[0185] In some embodiments, the compounds disclosed herein are formulated to provide controlled release of the compound. Controlled release refers to the release of the compound described herein from its incorporated dosage form over an extended period of time according to a desired profile. Controlled release profiles include, for example, sustained release, extended release, pulsatile release, and delayed release profiles. Compared to immediately released compositions, controlled release compositions allow for the delivery of the agent to the subject over an extended period of time according to a predetermined profile. Compared to conventional rapid-release dosage forms, this release rate can provide a therapeutically effective level of the agent over an extended period of time, thereby providing a longer-lasting pharmacological response while minimizing side effects. This longer-lasting response provides numerous inherent benefits that are not achieved by corresponding short-acting immediately released formulations.

[0186] Methods for delivering an intact therapeutic compound to a specific area of ​​the gastrointestinal tract (e.g., the colon) include: (i) Polymer coating: By coating drug molecules with suitable polymers, the intact molecules can be delivered to the colon without being absorbed in the upper part of the intestine, where the polymers degrade only in the colon.

[0187] (ii) Coating with pH-sensitive polymers: Most enteric and colon-targeted delivery systems are based on the coating of tablets or pills that are filled into conventional hard gelatin capsules. The most commonly used pH-dependent coating polymers are methacrylic acid copolymers, commonly known as Eudragit® S, and more specifically Eudragit® L and Eudragit® S. Eudragit® L100 and S100 are copolymers of methacrylic acid and methyl methacrylate.

[0188] (iii) Coating with a biodegradable polymer; (iv) Embedded in the matrix; (v) Embedded in biodegradable matrices and hydrogels; (vi) Embedded in a pH-sensitive matrix; (vii) Timed release system; (viii) Redox-sensitive polymers; (ix) Bioadhesion systems; (x) Coating with microparticles; (xi) Osmosis-controlled drug delivery; Another approach to colon-targeted drug delivery or controlled-release systems involves embedding a drug package within a polymer matrix to capture and release the drug into the colon. These matrices can be pH-sensitive or biodegradable. Matrix-based systems, such as multi-matrix (MMX) based sustained-release tablets, ensure drug release in the colon.

[0189] Other pharmaceutical approaches that target the delivery of therapeutic agents to specific regions of the gastrointestinal tract are known. Chourasia MK, Jain SK, Pharmaceutical approaches to colon targeted drug delivery systems., J Pharm Pharm Sci. 2003 Jan-Apr;6(1):33-66. Patel M, Shah T, Amin A. Therapeutic opportunities in colon-specific drug-delivery systems Crit RevTher Drug Carrier Syst. 2007;24(2):147-202. Kumar P, Mishra B. targeteddrug delivery systems--an overview. Curr Drug Deliv. 2008 Jul;5(3):186-98. Van den Mooter G. Colon drug delivery. Expert Opin Drug Deliv. 2006 Jan;3(1):111-25. Seth Amidon, Jack E. Brown, and Vivek S. Dave, Colon-Targeted OralDrug Delivery Systems: Design Trends and Approaches, AAPS PharmSciTech. August 2015; 16(4): 731-741.

[0190] It should be understood that, in addition to the ingredients specifically mentioned above, the compounds and compositions described herein may also include other conventional pharmaceutical agents in the art relevant to the types of formulations discussed, such as flavoring agents, those suitable for oral administration.

[0191] Administration method and treatment regimen In one embodiment, the compounds described herein or pharmaceutically acceptable salts thereof are used to prepare a medicament for treating a disease or condition in a mammal that will benefit from the administration of a selective S1P5 receptor agonist or a dual S1P1 and S1P5 receptor agonist. A method of treating any of the diseases or conditions described herein in a mammal with such a therapeutic need comprises administering to the mammal a therapeutically effective amount of a pharmaceutical composition comprising at least one compound described herein or a pharmaceutically acceptable salt thereof, an active metabolite, a prodrug, or a pharmaceutically acceptable solvate.

[0192] Some embodiments disclosed herein involve the combined administration of dual S1P1 and S1P5 receptor agonists with an additional therapeutic agent. Some embodiments involve the combined administration of dual S1P1 and S1P5 receptor agonists with a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor. Some embodiments involve the combined administration of dual S1P1 and S1P5 receptor agonists with a peripherally restricted FAAH inhibitor, wherein the peripherally restricted FAAH inhibitor is ASP-3652.

[0193] Some embodiments disclosed herein involve the combined administration of an S1P5 receptor agonist with another therapeutic agent. In some embodiments, a method is provided for the combined administration of an S1P5 receptor agonist with a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor. In some embodiments, a method is provided for the combined administration of an S1P5 receptor agonist with a peripherally restricted FAAH inhibitor, wherein the peripherally restricted FAAH inhibitor is ASP-3652.

[0194] In some embodiments, compositions containing one or more compounds described herein are administered for preventative and / or therapeutic treatment. In some therapeutic applications, the composition is administered to a patient who already has a disease or condition in an amount sufficient to cure or at least partially suppress at least one symptom of the disease or condition. The effective amount for this purpose depends on the severity and duration of the disease or condition, prior treatment, the patient's health status, weight, and response to the drug, as well as the judgment of the treating physician. The therapeutically effective amount may optionally be determined by methods including, but not limited to, dose escalation and / or dose range clinical trials.

[0195] In prophylactic applications, a composition containing the compounds described herein is administered to a patient who is susceptible to or at risk of developing a specific disease, condition, or illness. This amount is defined as the “preventative effective amount or dose.” In this use, the precise amount also depends on the patient’s health condition, weight, etc. When used on a patient, the effective amount for this purpose will depend on the severity and course of the disease, condition, or illness, prior treatment, the patient’s health condition and response to the drug, and the judgment of the treating physician. In one aspect, prophylactic treatment comprises administering a pharmaceutical composition containing the compounds described herein or pharmaceutically acceptable salts thereof to a mammal who has previously experienced at least one symptom of a treated disease and is currently in remission to prevent recurrence of the symptoms of the disease or illness.

[0196] In some implementation schemes in which the patient’s condition does not improve, the compound is administered long-term, i.e., for an extended period of time, including throughout the patient’s life, in accordance with the physician’s judgment, to improve or otherwise control or limit the symptoms of the patient’s disease or condition.

[0197] In some implementation schemes where the patient's condition does indeed improve, the dosage of the administered medication is temporarily reduced or suspended for a period of time (i.e., a "medication holiday"). In specific implementation schemes, the length of the medication holiday ranges from 2 days to 1 year, including (for example only) 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dosage reduction during the medication holiday is (for example only) 10%-100%, including (for example only) 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0198] Once the patient's condition improves, a maintenance dose is administered if necessary. Subsequently, in specific implementation plans, the dose or frequency, or both, are reduced to a level that maintains the improvement of the disease, symptoms, or condition, depending on the symptoms. However, in some implementation plans, the patient requires long-term intermittent treatment should any recurrence of symptoms occur.

[0199] The amount of a given drug corresponding to such quantities varies depending on a variety of factors, such as the specific compound, the disease condition and its severity, and the identity of the person or host requiring treatment (e.g., weight, sex). However, the amount can still be determined based on the specific circumstances surrounding the case, including, for example, the specific drug administered, the route of administration, the condition being treated, and the person or host being treated.

[0200] However, generally, the dosage for adult treatment is typically in the range of 0.01 mg to 5000 mg per day. In one aspect, the dosage for adult treatment is about 1 mg to about 1000 mg per day. In one embodiment, the desired dosage is conveniently provided as a single dose or in fractions, which are administered simultaneously or at appropriate intervals, such as two, three, four or more sub-dose administrations per day.

[0201] In one embodiment, the daily dose of the compound described herein or a pharmaceutically acceptable salt thereof is from about 0.01 to about 50 mg / kg / body weight. In some embodiments, the daily dose or amount of the active substance in the dosage form may be lower or higher than the range shown herein, based on several variables relating to an individual treatment regimen. In various embodiments, the daily dose and unit dose vary according to several variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the method of administration, the individual's requirements, the severity of the disease or condition being treated, and the physician's judgment.

[0202] The toxicity and efficacy of such treatment regimens are determined using standard pharmaceutical procedures in cell culture or laboratory animals, including but not limited to LD50. 50 and ED 50 The determination of toxicity and therapeutic effect. The dose ratio between toxicity and therapeutic effect is the therapeutic index, expressed as LD50. 50 and ED 50 The ratio between. In some embodiments, data obtained from cell culture assays and animal studies are used to determine the therapeutically effective daily dose range and / or therapeutically effective unit dose for mammals (including humans). In some embodiments, the daily dose of the compounds described herein is within the range of ED. 50 Within the range of cyclic concentrations with minimal toxicity. In some embodiments, the daily dose range and / or unit dose vary within this range, depending on the dosage form and route of administration.

[0203] In any of the foregoing aspects, further embodiments are provided, wherein an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof is: (a) administered systemically to a mammal; and / or (b) administered orally to a mammal; and / or (c) administered intravenously to a mammal; and / or (d) administered by injection to a mammal; and / or (e) administered locally to a mammal; and / or (f) administered neither systemically nor locally to a mammal.

[0204] In any of the foregoing aspects, further embodiments are provided, including single-application of an effective amount of the compound, including further embodiments in which (i) the compound is applied once daily; or (ii) the compound is applied multiple times to a mammal over a day.

[0205] In any of the foregoing embodiments, further embodiments are provided, including multiple administrations of an effective amount of the compound, further including embodiments wherein (i) the compound is administered continuously or intermittently in the form of a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to a mammal every 8 hours; (iv) the compound is administered to a mammal every 12 hours; (v) the compound is administered to a mammal every 24 hours. In a further or alternative embodiment, the method includes a drug holiday, wherein administration of the compound is temporarily stopped or the dose of the administered compound is temporarily reduced; at the end of the drug holiday, administration of the compound is resumed. In one embodiment, the length of the drug holiday ranges from 2 days to 1 year.

[0206] In certain circumstances, it is appropriate to administer at least one of the compounds described herein or a pharmaceutically acceptable salt thereof in combination with one or more other therapeutic agents.

[0207] In one embodiment, the therapeutic effect of one of the compounds described herein is enhanced by administering an adjuvant (i.e., the adjuvant itself has minimal therapeutic benefit, but when used in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Alternatively, in some embodiments, the benefit experienced by the patient is increased by administering one of the compounds described herein together with another agent (including treatment regimens) that also has therapeutic benefits.

[0208] In one specific implementation, the compound described herein or a pharmaceutically acceptable salt thereof is administered in combination with a second therapeutic agent, wherein the compound described herein or a pharmaceutically acceptable salt thereof and the second therapeutic agent modulate different aspects of the disease, symptom, or condition being treated, thereby providing a greater overall benefit than either therapeutic agent alone.

[0209] In any case, regardless of the disease, condition, or illness being treated, the overall benefit experienced by the patient may be the sum of the two treatments, or the patient may experience synergistic benefits.

[0210] In some embodiments, when the compounds disclosed herein are administered in combination with one or more other agents (such as other therapeutically effective drugs, adjuvants, etc.), different therapeutically effective doses of the compounds disclosed herein will be used to formulate the pharmaceutical composition and / or for the treatment regimen. Optionally, the therapeutically effective doses of the drugs and other agents used in the combination treatment regimen are determined in a manner similar to that described above for the active substance itself. Furthermore, the preventative / treatment methods described herein include the use of metronome dosing, i.e., providing more frequent, lower doses to minimize toxic side effects. In some embodiments, the combination treatment regimen includes treatment in which the compounds described herein or pharmaceutically acceptable salts thereof are initiated before, during, or after treatment with the second agent described herein, and continue at any time during treatment with the second agent or after the termination of treatment with the second agent. It also includes treatment with the compounds described herein or pharmaceutically acceptable salts thereof, along with the second agent used in combination, administered simultaneously or at different times and / or at reduced or increased intervals during treatment. Combination treatment also includes periodic treatment that is started and stopped at different times to assist in the clinical management of patients.

[0211] It should be understood that dosage regimens for treating, preventing, or improving the condition for which remission is sought are modified based on a variety of factors, such as the subject's disease, condition, or illness; the subject's age, weight, sex, diet, and medical history. Therefore, in some cases, the actual dosage regimen used may differ, and in some implementations, may deviate from the dosage regimens described herein.

[0212] For the combination therapies described herein, the dosage of the co-administered compounds varies depending on the type of combined medications used, the specific medications used, and the disease or condition being treated. In another embodiment, when co-administered with one or more other therapeutic agents, the compounds provided herein are administered simultaneously or sequentially with one or more other therapeutic agents.

[0213] In combination therapy, multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administered simultaneously, by way of example only, the multiple therapeutic agents are provided in a single, uniform form or in multiple forms (e.g., as a single tablet or as two separate tablets).

[0214] The compounds described herein, or pharmaceutically acceptable salts thereof, and combination therapies are administered before, during, or after the onset of a disease or condition, and the timing of administration of compositions containing the compounds varies. Thus, in one embodiment, the compounds described herein are used as a preventative agent and are administered continuously to a subject with a predisposition to develop a condition or disease to prevent its occurrence. In another embodiment, the compounds and compositions are administered to the subject as soon as possible during or after the onset of symptoms. In a specific embodiment, the compounds described herein are administered as soon as possible after the onset of a disease or condition is detected or suspected, and for the duration required to treat the disease. In some embodiments, the duration of treatment varies, and the duration of treatment is adjusted according to the specific needs of each subject. For example, in a specific embodiment, the compounds described herein or formulations containing the compounds are administered for at least 2 weeks, about 1 month, to about 5 years.

[0215] Example The following embodiments are provided for illustrative purposes only and do not limit the scope of the claims provided herein.

[0216] As used above, and throughout the description of this invention, unless otherwise stated, the following abbreviations should be understood to have the following meanings: Example 1: Synthesis of 1-(2-cyclopropyl-4-((3,4-dichlorobenzyl)oxy)benzyl)azacyclobutane-3-carboxylic acid Step 1: Under a nitrogen atmosphere, at 0 °C, a borane-tetrahydrofuran complex (1 M, 23 mL) was added to a solution of 2-bromo-4-hydroxybenzoic acid (2.50 g, 11.5 mmol) in THF (10 mL). The mixture was stirred at room temperature for 16 h, quenched with water (50 mL * 2), and extracted with DCM (50 mL * 2). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated under vacuum to give 3-bromo-4-(hydroxymethyl)phenol (1.80 g, 77.0% yield) as a colorless oil.

[0217] Step 2: Manganese dioxide (7.71 g, 88.7 mmol) was added to a solution of 3-bromo-4-(hydroxymethyl)phenol (1.80 g, 8.87 mmol) in THF (18 mL). The resulting mixture was stirred at room temperature for 16 h and then filtered. The filtrate was concentrated under vacuum and purified by silica gel chromatography to give 2-bromo-4-hydroxybenzaldehyde (1.00 g, 56.1% yield) as a yellow solid.

[0218] Step 3: To a solution of 2-bromo-4-hydroxybenzaldehyde (1.00 g, 4.97 mmol) in DMF (10 mL), 1,2-dichloro-4-(chloromethyl)benzene (972 mg, 4.97 mmol) and potassium carbonate (2.06 g, 14.9 mmol) were added. The mixture was stirred at 60 °C for 4 h, diluted with water (50 mL), and extracted with EtOAc (50 mL x 2). The combined organic extracts were washed with brine (50 mL x 2), dried over Na2SO4, and concentrated under vacuum to give 2-bromo-4-((3,4-dichlorobenzyl)oxy)benzaldehyde (1.70 g, 94.9% yield) as a yellow solid.

[0219] Step 4: Potassium carbonate (1.96 g, 14.2 mmol) and Pd(dppf)Cl2 (383 mg, 472 µmol) were added to a solution of 2-bromo-4-((3,4-dichlorobenzyl)oxy)benzaldehyde (1.70 g, 4.72 mmol) and cyclopropylboronic acid (1.22 g, 14.2 mmol) in toluene (10 mL) and water (2 mL). The resulting mixture was stirred at 80 °C for 6 h, filtered, diluted with water (50 mL), and extracted with DCM (50 mL x 3). The combined organic extracts were washed with brine (50 mL x 2), dried over Na2SO4, concentrated under vacuum, and purified by preparative TLC to give 2-cyclopropyl-4-((3,4-dichlorobenzyl)oxy)benzaldehyde (400 mg, 26.4% yield) as a colorless oil.

[0220] Step 5: Acetic acid (0.2 mL) and aziridine-3-carboxylic acid (94.4 mg, 934 µmol) were added to a solution of 2-cyclopropyl-4-((3,4-dichlorobenzyl)oxy)benzaldehyde (300 mg, 934 µmol) in MeOH (2 mL). The mixture was stirred at room temperature for 0.5 h, and then sodium cyanoborohydride (23.5 mg, 374 µmol) was added. The reaction mixture was stirred at room temperature for 16 h, diluted with water (50 mL), and extracted with EtOAc (50 mL x 2). The combined organic extracts were washed with brine (20 mL x 2), dried over Na2SO4, concentrated under vacuum, and purified by reversed-phase chromatography to give 1-(2-cyclopropyl-4-((3,4-dichlorobenzyl)oxy)benzyl)aziridine-3-carboxylic acid (40.0 mg, 10.5% yield) as a white solid. LCMS: 406.0 [M+1] + .

[0221] Example 2: Synthesis of 1-(4-((3,4-dichlorobenzyl)(methyl)amino)-2-ethylbenzyl)azacyclobutane-3-carboxylic acid Step 1: Methyl 4-amino-2-ethylbenzoate (625 mg, 3.49 mmol) and acetic acid (20 µL, 349 µmol) were added to a solution of 3,4-dichlorobenzaldehyde (732 mg, 4.18 mmol) in MeOH (6 mL). The resulting mixture was stirred at room temperature for 4 h. Sodium cyanoborohydride (131 mg, 2.09 mmol) was added, and the reaction mixture was stirred at room temperature for 4 h, quenched with water (10 mL), and extracted with EtOAc (10 mL x 3). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, concentrated under vacuum, and purified by preparative TLC followed by preparative HPLC to give methyl 4-((3,4-dichlorobenzyl)amino)-2-ethylbenzoate (800 mg, 67.8% yield) as a white solid.

[0222] Step 2: Formaldehyde (3 mL, 29.6 mmol) and acetic acid (16.9 µL, 296 µmol) were added to a solution of 4-((3,4-dichlorobenzyl)amino)-2-ethylbenzoate (1.00 g, 2.96 mmol) in MeOH (10 mL). The resulting mixture was stirred at 30 °C for 16 h. Sodium cyanoborohydride (111 mg, 1.77 mmol) was added, and the reaction mixture was stirred at room temperature for 4 h, quenched with water (10 mL), and extracted with EtOAc (10 mL x 3). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, concentrated under vacuum, and purified by preparative TLC to give methyl 4-((3,4-dichlorobenzyl)(methyl)amino)-2-ethylbenzoate (900 mg, 86.4% yield) as a yellow solid.

[0223] Step 3: Lithium aluminum hydride (145 mg, 3.83 mmol) was added to a solution of methyl 4-((3,4-dichlorobenzyl)(methyl)amino)-2-ethylbenzoate (900 mg, 2.55 mmol) in THF (10 mL) at 0 °C. The resulting mixture was stirred at room temperature for 2 h, quenched with an aqueous solution of potassium sodium tartrate (10 mL), and extracted with EtOAc (10 mL x 3). The combined organic extracts were washed with water (10 mL x 2) and brine (10 mL), dried over Na2SO4, and concentrated under vacuum to give (4-((3,4-dichlorobenzyl)(methyl)amino)-2-ethylphenyl)methanol (400 mg, 43.5% yield) as a colorless oil.

[0224] Step 4: Add Desmond-Martin periodane (706 mg, 1.67 mmol) to a solution of (360 mg, 1.11 mmol, 4-dichlorobenzyl(methyl)amino)-2-ethylphenyl)methanol in DCM (6 mL). The mixture was stirred at room temperature for 16 h, quenched with water (20 mL), and extracted with EtOAc (10 mL x 2). The combined organic extracts were washed with water (20 mL x 2) and brine (20 mL), dried over Na2SO4, concentrated under vacuum, and purified by silica gel chromatography to give 4-((3,4-dichlorobenzyl(methyl)amino)-2-ethylbenzaldehyde (200 mg, 55.9% yield) as a colorless oil.

[0225] Step 5: Acetic acid (2.13 µL, 37.2 µmol) was added to a solution of 4-((3,4-dichlorobenzyl)(methyl)amino)-2-ethylbenzaldehyde (120 mg, 372 µmol) and aziridine-3-carboxylic acid (45.2 mg, 447 µmol) in MeOH (5 mL). The mixture was stirred at room temperature for 3 h and then sodium cyanoborohydride (14.0 mg, 223 µmol) was added. After stirring for 16 h, the reaction mixture was purified by reversed-phase chromatography to give 1-(4-((3,4-dichlorobenzyl)(methyl)amino)-2-ethylbenzyl)aziridine-3-carboxylic acid (50.0 mg, 32.8% yield) as a white solid. LCMS: 405.05 [M-1].

[0226] Examples 3 and 4 in the table below were prepared using the above procedure, but the specified reagents were used alternatively. Example 5: Synthesis of 1-(4-(((4-(trifluoromethyl)pyridin-2-yl)methyl)amino)benzyl)azacyclobutane-3-carboxylic acid Step 1: A solution of 4-(trifluoromethyl)pyridin-2-carboxaldehyde (280 mg, 1.60 mmol) and methyl 4-aminobenzoate (242 mg, 1.60 mmol) in MeOH (10 mL) and acetic acid (1 mL) was stirred at room temperature for 16 h. Sodium cyanoborohydride (121 mg, 1.92 mmol) was added, and the mixture was stirred at room temperature for 3 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with brine (50 mL x 3), dried over Na2SO4, concentrated under vacuum, and purified by reversed-phase chromatography to give methyl 4-(((4-(trifluoromethyl)pyridin-2-yl)methyl)amino)benzoate (260 mg, 52.4% yield) as a white solid.

[0227] Step 2: Diisobutylaluminum hydride (1.13 mL, 1.13 mmol in 1.0 N hexane solution) was added to a solution of methyl 4-({[4-(trifluoromethyl)pyridin-2-yl]methyl}amino)benzoate (100 mg, 322 µmol) in THF (5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 h, quenched with water (50 mL), and extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with brine (50 mL x 3), dried over Na2SO4, concentrated under vacuum, and purified by preparative TLC to give [4-({[4-(trifluoromethyl)pyridin-2-yl]methyl}amino)phenyl]methanol (50.0 mg, 55.0% yield) as a white solid.

[0228] Step 3: At 0 °C, Dysmartin periodane (316 mg, 744 µmol) was added to a solution of [4-({[4-(trifluoromethyl)pyridin-2-yl]methyl}amino)phenyl]methanol (140 mg, 496 µmol) in THF (3 mL). The resulting mixture was stirred at 0 °C for 3 h, diluted with water (50 mL), and extracted with EtOAc (20 mL*3). The combined organic extracts were washed with brine (50 mL*3), dried over Na2SO4, concentrated under vacuum, and purified by preparative TLC to give 4-({[4-(trifluoromethyl)pyridin-2-yl]methyl}amino)benzaldehyde (80.0 mg, 57.6% yield) as a yellow solid.

[0229] Step 4: A solution of 4-({[4-(trifluoromethyl)pyridin-2-yl]methyl}amino)benzaldehyde (70.0 mg, 250 µmol) and aziridine-3-carboxylic acid (25.3 mg, 250 µmol) in MeOH (3 mL) and acetic acid (0.2 mL) was stirred at room temperature for 16 h. Sodium cyanoborohydride (25.6 mg, 408 µmol) was added and the mixture was stirred at room temperature for 3 h, diluted with water (50 mL), neutralized with 1 N HCl to pH = 5-6, and extracted with EtOAc (20 mL * 3). The combined organic extracts were washed with brine (50 mL x 3), dried over Na2SO4, concentrated under vacuum, and purified by reversed-phase chromatography to give 1-{[4-({[4-(trifluoromethyl)pyridin-2-yl]methyl}amino)phenyl]methyl}azacyclobutane-3-carboxylic acid (20.0 mg, 21.6% yield), as a yellow oil. LCMS: 364.0 [M-1].

[0230] Example 6: Synthesis of 1-(4-((methyl(6-(trifluoromethyl)pyridin-2-yl)amino)methyl)benzyl)azacyclobutane-3-carboxylic acid Step 1: A mixture of 6-(trifluoromethyl)pyridin-2-amine (1.00 g, 6.17 mmol), methyl 4-formylbenzoate (1.22 g, 7.40 mmol), and acetic acid (37.0 mg, 617 µmol) in MeOH (10 mL) was stirred at 35 °C for 16 h. Sodium cyanoborohydride (1.16 g, 18.5 mmol) was added, and the mixture was stirred at 35 °C for 4 h. The mixture was then poured into water and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with water (20 mL x 3) and brine (20 mL) and concentrated under vacuum. The crude material was purified by silica gel chromatography to give methyl 4-({[6-(trifluoromethyl)pyridin-2-yl]amino}methyl)benzoate (1.50 g, 78.2% yield) as a white solid.

[0231] Step 2: Sodium hydride (60% mineral oil solution, 370 mg, 9.67 mmol) was added to a mixture of methyl 4-({[6-(trifluoromethyl)pyridin-2-yl]amino}methyl)benzoate (1.50 g, 4.83 mmol) in DMF (10 mL) at 0 °C, and the mixture was stirred at 0 °C for 1 h. Iodimethane (1.37 g, 9.67 mmol) was added, and the mixture was stirred at room temperature for 4 h. The mixture was then poured into water and extracted with EtOAc (30 mL x 3). The combined organic extracts were washed with water (30 mL x 3) and brine (40 mL) and concentrated under vacuum. The crude substance was purified by silica gel chromatography to give methyl 4-({methyl[6-(trifluoromethyl)pyridin-2-yl]amino}methyl)benzoate (740 mg, 47.2% yield) as a white solid.

[0232] Step 3: Lithium aluminum hydride (173 mg, 4.56 mmol) was added to a mixture of methyl 4-({methyl[6-(trifluoromethyl)pyridin-2-yl]amino}methyl)benzoate (740 mg, 2.28 mmol) in THF (10 mL) at 0 °C. The resulting mixture was stirred at room temperature for 4 h, quenched with water, and filtered. The filtrate was extracted with EtOAc (20 mL*3), and the combined organic extracts were washed with water (20 mL*3) and brine (20 mL), dried over Na2SO4, and concentrated under vacuum. The crude substance was purified by silica gel chromatography to give [4-({methyl[6-(trifluoromethyl)pyridin-2-yl]amino}methyl)phenyl]methanol (650 mg, 96.1% yield) as a white solid.

[0233] Step 4: Manganese dioxide (1.91 g, 21.9 mmol) was added to a solution of [4-({methyl[6-(trifluoromethyl)pyridin-2-yl]amino}methyl)phenyl]methanol (650 mg, 2.19 mmol) in chloroform (10 mL). The resulting mixture was stirred at 80 °C for 16 h, filtered, and concentrated under vacuum. The crude substance was purified by silica gel chromatography to give 4-({methyl[6-(trifluoromethyl)pyridin-2-yl]amino}methyl)benzaldehyde (440 mg, 1.50 mmol) as a white solid.

[0234] Step 5: A mixture of 4-({methyl[6-(trifluoromethyl)pyridin-2-yl]amino}methyl)benzaldehyde (100 mg, 340 µmol), azacyclobutane-3-carboxylic acid (51.5 mg, 510 µmol), and acetic acid (2.04 mg, 34 µmol) in MeOH (10 mL) was stirred at 35 °C for 16 h. Sodium cyanoborohydride (64.1 mg, 1.02 mmol) was added, and the mixture was stirred at 35 °C for 4 h. The mixture was then poured into water and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with water (20 mL x 3) and brine (20 mL) and concentrated under vacuum. The crude substance was purified by reversed-phase chromatography to give 1-{[4-({methyl[6-(trifluoromethyl)pyridin-2-yl]amino}methyl)phenyl]methyl}azacyclobutane-3-carboxylic acid (40.0 mg, 105 µmol), as a white solid. LCMS: 380.1 [M+1] + .

[0235] Example 7 in the table below was prepared using the above procedure, but the specified reagents were used alternatively. Example 8: Synthesis of 1-(4-(((6-(trifluoromethyl)pyridin-2-yl)amino)methyl)benzyl)azacyclobutane-3-carboxylic acid Step 1: A mixture of 6-(trifluoromethyl)pyridin-2-amine (1.00 g, 6.17 mmol), 4-(methoxymethyl)benzaldehyde (1.22 g, 7.40 mmol), and acetic acid (37.0 mg, 617 µmol) in MeOH (10 mL) was stirred at 35 °C for 16 h. Sodium cyanoborohydride (1.16 g, 18.5 mmol) was added, and the reaction mixture was stirred at 35 °C for 4 h. The mixture was then poured into water and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with water (20 mL x 3) and brine (20 mL) and concentrated under vacuum. The crude material was purified by silica gel chromatography to give methyl 4-(((6-(trifluoromethyl)pyridin-2-yl)amino)methyl)benzoate (1.60 g, 83.6% yield) as a white solid.

[0236] Step 2: Lithium aluminum hydride (245 mg, 6.45 mmol) was added to a mixture of methyl 4-(((6-(trifluoromethyl)pyridin-2-yl)amino)methyl)benzoate (1.00 g, 3.22 mmol) in THF (10 mL) at 0 °C. The resulting mixture was stirred at room temperature for 4 h, then poured into water and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with water (20 mL x 3) and brine (20 mL), dried over Na2SO4, and concentrated under vacuum. The crude substance was purified by silica gel chromatography to give (4-(((6-(trifluoromethyl)pyridin-2-yl)amino)methyl)phenyl)methanol (750 mg, 82.4% yield) as a white solid.

[0237] Step 3: Manganese dioxide (2.31 g, 26.6 mmol) was added to a solution of (750 mg, 2.66 mmol) in chloroform (20 mL). The resulting mixture was stirred at 80 °C for 16 h, filtered, and concentrated under vacuum. The crude substance was purified by silica gel chromatography to give 4-(((6-(trifluoromethyl)pyridin-2-yl)amino)methyl)benzaldehyde (650 mg, 82.3%) as a white solid.

[0238] Step 4: A mixture of 4-(((6-(trifluoromethyl)pyridin-2-yl)amino)methyl)benzaldehyde (100 mg, 357 µmol), azacyclobutane-3-carboxylic acid (54.1 mg, 535 µmol), and acetic acid (0.1 mL) in MeOH (10 mL) was stirred at 35 °C for 16 h. Sodium cyanoborohydride (67.3 mg, 1.07 mmol) was added, and the reaction mixture was stirred at 35 °C for 4 h. The mixture was then poured into water, neutralized to pH 5-6 with 2 N HCl, and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with water (20 mL x 3) and brine (20 mL) and concentrated under vacuum. The crude substance was purified by reversed-phase chromatography to give 1-(4-(((6-(trifluoromethyl)pyridin-2-yl)amino)methyl)benzyl)azacyclobutane-3-carboxylic acid (50.0 mg, 38.4% yield) as a white solid. LCMS: 366.0 [M-1].

[0239] Example 9 in the table below was prepared using the above procedure, but the specified reagents were used alternatively. Example 10: Synthesis of 1-(2,6-dimethyl-4-(7-(trifluoromethyl)-3,4-dihydroisoquinoline-2(1H)-yl)benzyl)azacyclobutane-3-carboxylic acid Step 1: Potassium carbonate (888 mg, 6.42 mmol) was added to a solution of 5-bromo-2-(chloromethyl)-1,3-dimethylbenzene (500 mg, 2.14 mmol) and methyl aziridine-3-carboxylate hydrochloride (389 mg, 2.57 mmol) in DMF (5 mL). The mixture was stirred at 60 °C for 16 h, diluted with water (40 mL), and extracted with EtOAc (30 mL x 3). The combined organic extracts were washed with water (30 mL x 2) and brine (30 mL), dried over Na2SO4, and concentrated under vacuum to give methyl 1-(4-bromo-2,6-dimethylbenzyl)aziridine-3-carboxylate (600 mg, 89.8% yield) as a colorless oil.

[0240] Step 2: To a solution of methyl 1-(4-bromo-2,6-dimethylbenzyl)azacyclobutane-3-carboxylate (500 mg, 2.49 mmol) and 7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline (853 mg, 2.73 mmol) in 1,4-dioxane (10 mL), Pd2(dba)3 (228 mg, 249 µmol), RuPhos (116 mg, 249 µmol), and cesium carbonate (2.43 g, 7.46 mmol) were added. The mixture was stirred at 110 °C for 16 h under N2 and then filtered. The filtrate was diluted with water (50 mL) and extracted with EtOAc (80 mL x 3). The combined organic extracts were washed with brine (100 mL x 2), dried over Na2SO4, and concentrated under vacuum. The crude substance was purified by silica gel chromatography to obtain methyl 1-(2,6-dimethyl-4-(7-(trifluoromethyl)-3,4-dihydroisoquinoline-2(1H)-yl)benzyl)azacyclobutane-3-carboxylate (400 mg, 37.2% yield), as a yellow solid.

[0241] Step 3: LiOH·H₂O (77.6 mg, 1.85 mmol) and water (1 mL) were added to a solution of methyl 1-(2,6-dimethyl-4-(7-(trifluoromethyl)-3,4-dihydroisoquinoline-2(1H)-yl)benzyl)azacyclobutane-3-carboxylate (400 mg, 925 µmol) in THF (5 mL). The resulting mixture was stirred at room temperature for 3 h, acidified to pH 5-6 with 0.5 N HCl, diluted with water (10 mL), and extracted with EtOAc (30 mL x 3). The combined organic extracts were washed with brine (20 mL x 2), dried over Na₂SO₄, and concentrated under vacuum. The crude substance was purified by reversed-phase chromatography to give 1-(2,6-dimethyl-4-(7-(trifluoromethyl)-3,4-dihydroisoquinoline-2(1H)-yl)benzyl)azacyclobutane-3-carboxylic acid (120 mg, 30.7% yield), as a yellow oil. LCMS: 417.05 [M-1].

[0242] Example 11: Synthesis of 1-(4-(7-(trifluoromethyl)-3,4-dihydroisoquinoline-2(1H)-yl)benzyl)azacyclobutane-3-carboxylic acid Step 1: 4-fluorobenzaldehyde (272 µL, 2.53 mmol) and potassium carbonate (954 mg, 6.91 mmol) were added to a solution of 7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (547 mg, 2.30 mmol) in DMF (5 mL). The resulting mixture was stirred at 100 °C for 16 h, diluted with water (50 mL), and extracted with EtOAc (20 mL x 2). The combined organic extracts were washed with water (50 mL x 2) and brine (50 mL), dried over Na2SO4, concentrated under vacuum, and purified by silica gel chromatography to give 4-(7-(trifluoromethyl)-3,4-dihydroisoquinoline-2(1H)-yl)benzaldehyde (220 mg, 26.5% yield) as a colorless oil.

[0243] Step 2: A solution of 4-(7-(trifluoromethyl)-3,4-dihydroisoquinoline-2(1H)-yl)benzaldehyde (100 mg, 328 µmol) and aziridine-3-carboxylic acid (49.7 mg, 491 µmol) in MeOH (2 mL) was stirred at room temperature for 2 h. Sodium cyanoborohydride (22.6 mg, 360 µmol) and AcOH (1.88 µL, 32.8 µmol) were added, and the reaction mixture was stirred at room temperature for 3 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL x 2). The combined organic extracts were washed with brine (50 mL x 2), dried over Na₂SO₄, concentrated under vacuum, and purified by reversed-phase chromatography to give 1-(4-(7-(trifluoromethyl)-3,4-dihydroisoquinoline-2(1H)-yl)benzyl)azacyclobutane-3-carboxylic acid (70.0 mg, 54.7% yield) as a yellow solid. LCMS: 389.2 [M⁻¹].

[0244] Examples 12-15 in the table below were prepared using the above procedure, but the specified reagents were used alternatively: Example 16: Synthesis of 1-(4-((4-cyano-5-isopropoxypyridin-2-yl)ethynyl)benzyl)azacyclobutane-3-carboxylic acid Step 1: Cesium carbonate (12.7 g, 39.2 mmol) was added to a solution of 2-iodopropane (2.90 mL, 29.4 mmol) and 6-chloro-4-iodopyridin-3-ol (5.00 g, 19.6 mmol) in DMF (30 mL). The resulting mixture was stirred at room temperature for 16 h, diluted with water (300 mL), and extracted with EtOAc (150 mL x 3). The combined organic extracts were washed with water (300 mL x 3) and brine (300 mL), dried over Na2SO4, and concentrated under vacuum to give 2-chloro-4-iodo-5-isopropoxypyridine L (5.10 g, 87.5% yield) as a yellow oil.

[0245] Step 2: Cuprous cyanide (2.30 g, 25.7 mmol) was added to a solution of 2-chloro-4-iodo-5-(propane-2-yloxy)pyridine (5.10 g, 17.1 mmol) in DMF (30 mL). The reaction mixture was microwaved at 140 °C for 6 h, filtered, and washed with EtOAc. The filtrate was diluted with water (300 mL) and extracted with EtOAc (150 mL x 3). The combined organic extracts were washed with water (300 mL x 3) and brine (300 mL), dried over Na2SO4, and concentrated under vacuum. The crude substance was purified by silica gel chromatography to give 2-chloro-5-isopropoxyisonicotinonitrile (1.80 g, 53.4% ​​yield) as a white solid.

[0246] Step 3: Add bromotrimethylsilane (2.34 g, 15.3 mmol) to a solution of 2-chloro-5-isopropoxyisonicotinonitrile (1.50 g, 7.63 mmol) in MeCN (20 mL). The resulting mixture was stirred at 80 °C for 16 h, diluted with water (50 mL), and extracted with EtOAc (30 mL x 2). The combined organic extracts were washed with water (100 mL x 3) and brine (60 mL), dried over Na2SO4, and concentrated under vacuum to give 2-bromo-5-isopropoxyisonicotinonitrile (1.50 g, 81.6% yield) as a brown solid.

[0247] Step 4: To a solution of 2-bromo-5-isopropoxyisonicotinonitrile (1.00 g, 4.15 mmol) in THF (10 mL), 4-ethynylbenzaldehyde (1.08 g, 8.29 mmol), cuprous iodide (126 mg, 665 µmol), tetrakis(triphenylphosphine)palladium (384 mg, 332 µmol), and triethylamine (841 mg, 8.29 mmol) were added. The resulting mixture was stirred at room temperature under N2 for 16 h, diluted with water (30 mL), filtered, and extracted with EtOAc (20 mL x 2). The combined organic extracts were washed with brine (40 mL), dried over Na2SO4, and concentrated under vacuum. The crude substance was purified by silica gel chromatography to give 2-((4-formylphenyl)ethynyl)-5-isopropoxyisonicotinonitrile (430 mg, 35.7% yield) as a yellow solid.

[0248] Step 5: To a solution of 2-((4-formylphenyl)ethynyl)-5-isopropoxyisonicotinonitrile (280 mg, 964 µmol) in MeOH (5 mL), aziridine-3-carboxylic acid (117 mg, 1.16 mmol) and acetic acid (0.1 mL) were added. The resulting mixture was stirred at room temperature for 4 h, and then sodium cyanoborohydride (121 mg, 1.93 mmol) was added. After stirring at room temperature for 16 h, the reaction mixture was concentrated under vacuum and purified by reversed-phase chromatography followed by preparative HPLC to give 1-(4-((4-cyano-5-isopropoxypyridin-2-yl)ethynyl)benzyl)aziridine-3-carboxylic acid (200 mg, 55.3% yield) as a yellow solid. LCMS: 374.2 [M-1].

[0249] Example 17 in the table below was prepared using the above procedure, but the specified reagents were used alternatively: Example 18: Synthesis of 1-(4-(2-(4-cyano-5-isopropoxypyridin-2-yl)ethyl)benzyl)azacyclobutane-3-carboxylic acid Step 1: 10% Pd / C (30 mg) was added to a solution of 1-(4-((4-cyano-5-isopropoxypyridin-2-yl)ethynyl)benzyl)azacyclobutane-3-carboxylic acid (150 mg, 0.400 mmol) in THF (6 mL). The resulting mixture was stirred at 50 °C for 16 h under H2 atmosphere, filtered, and washed with MeOH. The filtrate was concentrated under vacuum and purified by preparative HPLC to give 1-(4-(2-(4-cyano-5-isopropoxypyridin-2-yl)ethyl)benzyl)azacyclobutane-3-carboxylic acid (50.0 mg, 33.0% yield) as a yellow oil. LCMS: 378.2 [M-1].

[0250] Examples 19-21 in the table below were prepared using the above procedure, but the specified reagents were used alternatively: Example 22: Synthesis of 1-(4-(2-(pyridin-3-yl)ethyl)benzyl)azacyclobutane-3-carboxylic acid Step 1: Cuprous iodide (39.0 mg, 205 µmol), triethylamine (1.14 mL, 8.19 mmol), and bis(triphenylphosphine)palladium(II) chloride (287 mg, 409 µmol) were added to a solution of 3-ethynylpyridine (507 mg, 4.91 mmol) and 4-iodobenzaldehyde (950 mg, 4.09 mmol) in toluene (5 mL). After stirring at 70 °C for 1 h, water (30 mL) was added, and the resulting mixture was extracted with EtOAc (10 mL * 2). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na₂SO₄, concentrated under vacuum, and purified by preparative TLC to give 4-[2-(pyridin-3-yl)ethynyl]benzaldehyde (750 mg, 88.4% yield) as a yellow solid.

[0251] Step 2: Acetic acid (19.3 µL, 338 µmol) was added to a solution of 4-[2-(pyridin-3-yl)ethynyl]benzaldehyde (700 mg, 3.38 mmol) and aziridine-3-carboxylic acid (342 mg, 3.38 mmol) in MeOH (7 mL). The mixture was stirred at room temperature for 3 h, and sodium cyanoborohydride (127 mg, 2.03 mmol) was added. After stirring at room temperature for 16 h, water (10 mL) was added, and the resulting mixture was extracted with EtOAc (10 mL). The aqueous phase was concentrated under vacuum, dissolved in DCM / MeOH = 10 / 1 (10 mL), filtered, concentrated under vacuum, and purified by reversed-phase chromatography to give 1-({4-[2-(pyridin-3-yl)ethynyl]phenyl}methyl)aziridine-3-carboxylic acid (650 mg, 65.8% yield) as a yellow solid.

[0252] Step 3: 10% Pd / C (140 mg) was added to a solution of 1-({4-[2-(pyridin-3-yl)ethynyl]phenyl}methyl)azacyclobutane-3-carboxylic acid (710 mg, 2.43 mmol) in THF (9.59 mL, 118 mmol). The resulting mixture was stirred at 60 °C in H2 for 16 h, filtered, and purified by preparative HPLC to give 1-({4-[2-(pyridin-3-yl)ethyl]phenyl}methyl)azacyclobutane-3-carboxylic acid (100 mg, 13.9% yield) as a yellow solid. LCMS: 297.2 [M+1] + .

[0253] Example 23: Synthesis of 1-(4-(bicyclo[2.2.2]octane-2-ylmethoxy)-2-methylbenzyl)azacyclobutane-3-carboxylic acid Step 1: Triethylamine (1.01 mL, 7.24 mmol) was added to a solution of bicyclo[2.2.2]oct-5-en-2-ylmethanol (500 mg, 3.62 mmol) in DCM (8 mL) at 0 °C, followed by dropwise addition of methanesulfonyl chloride (280 µL, 3.62 mmol). The resulting mixture was stirred at room temperature for 1 h, quenched with water (10 mL), and extracted with DCM (10 mL x 2). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and concentrated under vacuum to give bicyclo[2.2.2]oct-5-en-2-ylmethylmethanesulfonate (500 mg, 63.9% yield) as a yellow oil.

[0254] Step 2: 4-hydroxy-2-methylbenzaldehyde (296 mg, 2.17 mmol) and cesium carbonate (1.42 g, 4.35 mmol) were added to a solution of bicyclo[2.2.2]oct-5-en-2-ylmethylmethanesulfonate (235 mg, 1.09 mmol) in DMF (5 mL). The resulting mixture was stirred at 80 °C for 16 h, diluted with water (20 mL), and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with water (20 mL x 2) and brine (20 mL), dried over Na2SO4, concentrated under vacuum, and purified by preparative TLC to give 4-(bicyclo[2.2.2]oct-5-en-2-ylmethoxy)-2-methylbenzaldehyde (160 mg, 57.5% yield) as a colorless oil.

[0255] Step 3: Acetic acid (2.68 µL, 46.8 µmol) was added to a solution of 4-(bicyclo[2.2.2]oct-5-en-2-ylmethoxy)-2-methylbenzaldehyde (120 mg, 468 µmol) and aziridine-3-carboxylic acid (56.8 mg, 562 µmol) in MeOH (4 mL). The mixture was stirred at room temperature for 3 h, and then sodium cyanoborohydride (17.6 mg, 281 µmol) was added. After stirring at room temperature for 16 h, the mixture was filtered to give 1-(4-(bicyclo[2.2.2]oct-5-en-2-ylmethoxy)-2-methylbenzyl)aziridine-3-carboxylic acid (80.0 mg, 50.1% yield) as a white solid.

[0256] Step 4: 10% Pd / C (20 mg) was added to a solution of 1-(4-(bicyclo[2.2.2]octane-5-en-2-ylmethoxy)-2-methylbenzyl)azacyclobutane-3-carboxylic acid (80.0 mg, 234 µmol) in MeOH (5 mL). The resulting mixture was stirred at 30 °C under H2 atmosphere for 16 h, filtered, and purified by preparative HPLC to give 1-(4-(bicyclo[2.2.2]octane-2-ylmethoxy)-2-methylbenzyl)azacyclobutane-3-carboxylic acid (10.0 mg, 12.2% yield) as a white solid. LCMS: 344.2 [M+1] + .

[0257] Examples 24-27 in the table below were prepared using the above procedure, but the specified reagents were used alternatively: Example 28: Synthesis of 1-(4-((3-cyano-4-isopropoxybenzyl)oxy)-2-ethylbenzyl)azacyclobutane-3-carboxylic acid Step 1: 5-(hydroxymethyl)-2-(propane-2-yloxy)benzonitrile (200 mg, 1.05 mmol) and diisopropyl azodicarboxylate (309 µL, 1.57 mmol) were added to a solution of 2-ethyl-4-hydroxybenzaldehyde (157 mg, 1.05 mmol) and triphenylphosphine (411 mg, 1.57 mmol) in THF (5 mL) at 0 °C. The resulting mixture was stirred at room temperature for 10 h, diluted with water (30 mL), and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with water (100 mL x 3) and brine (100 mL), dried over Na2SO4, and concentrated under vacuum. The crude substance was purified by reversed-phase chromatography to obtain 5-[(3-ethyl-4-formylphenoxy)methyl]-2-(propane-2-yloxy)benzonitrile (200 mg, 59.1% yield), which was a yellow oil.

[0258] Step 2: Add aziridine-3-carboxylic acid (70.3 mg, 696 µmol) to a solution of 5-[(3-ethyl-4-formylphenoxy)methyl]-2-(propane-2-yloxy)benzonitrile (150 mg, 464 µmol) and aziridine-3-carboxylic acid (70.3 mg, 696 µmol) in MeOH (2 mL). Stir the resulting mixture for 2 h and add AcOH (27.9 mg, 464 µmol) and sodium cyanoborohydride (43.7 mg, 696 µmol). After stirring at room temperature for 16 h, dilute the reaction mixture with water (20 mL) and extract with EtOAc (20 mL x 3). The combined organic extracts were dried over Na₂SO₄ and purified by reversed-phase chromatography followed by preparative HPLC to give 1-(4-((3-cyano-4-isopropoxybenzyl)oxy)-2-ethylbenzyl)azacyclobutane-3-carboxylic acid (40.0 mg, 21.1% yield) as a white solid. LCMS: 409.15 [M+1] + .

[0259] Examples 29-68 in the table below were prepared using the above procedure, but the specified reagents were used alternatively: Example 69: Synthesis of 1-(4-((3-(trifluoromethyl)phenoxy)methyl)benzyl)azacyclobutane-3-carboxylic acid Step 1: Diisopropyl azodicarboxylate (936 mg, 4.63 mmol) was added to a solution of 3-(trifluoromethyl)phenol (1.21 g, 4.63 mmol) in THF (15 mL) at 0 °C, and the resulting mixture was stirred at 0 °C for 30 min. 4-(hydroxymethyl)benzaldehyde (462 mg, 3.39 mmol) and triphenylphosphine (500 mg, 3.08 mmol) were added, and the mixture was stirred at room temperature for 16 h. The mixture was diluted with water (100 mL) and extracted with DCM (100 mL x 3). The combined organic extracts were washed with water (100 mL x 3) and brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to give 4-((3-(trifluoromethyl)phenoxy)methyl)benzaldehyde (380 mg, 44.0% yield) as a colorless oil.

[0260] Step 2: To a solution of 4-((3-(trifluoromethyl)phenoxy)methyl)benzaldehyde (380 mg, 1.36 mmol) in MeOH (4 mL), aziridine-3-carboxylic acid (206 mg, 2.03 mmol) and AcOH (catalyst) were added. The reaction mixture was stirred at room temperature for 3 h, followed by the addition of sodium cyanoborohydride (256 mg, 4.07 mmol). After stirring at room temperature for 3 h, the reaction mixture was purified by reversed-phase chromatography to give 1-(4-((3-(trifluoromethyl)phenoxy)methyl)benzyl)aziridine-3-carboxylic acid (200 mg, 40.4% yield) as a white solid. LCMS: 366.0 [M+1] + .

[0261] Example 70: Synthesis of 1-(4-(2-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)ethyl)-3,5-dimethylbenzyl)azacyclobutane-3-carboxylic acid Step 1: A solution of 2,5-dichloro-4-(trifluoromethyl)pyridine (2.00 g, 9.26 mmol), potassium vinyltrifluoroborate (1.49 g, 11.1 mmol), triethylamine (1.56 mL, 11.1 mmol), and Pd(dppf)Cl2•CH2Cl2 (375 mg, 463 µmol) in EtOH (15.1 mL, 258 mmol) was microwave-heated at 120 °C for 2 h. The resulting mixture was filtered, quenched with water (35 mL), and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with water (15 mL x 3) and brine (5 mL), dried over Na2SO4, and concentrated under vacuum to give 5-chloro-4-(trifluoromethyl)-2-vinylpyridine (1.80 g, 93.6% yield) as a brown oil.

[0262] Step 2: A mixture of 5-chloro-4-(trifluoromethyl)-2-vinylpyridine (2.00 g, 9.63 mmol), 5-bromo-2-iodo-m-xylene (3.60 g, 11.6 mmol), tris(o-tolyl)phosphine (293 mg, 963 µmol), and triethylamine (1.95 g, 19.3 mmol) in DMF (25 mL) was microwaved at 130 °C for 2 h, quenched with water (100 mL), and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with water (50 mL x 3) and brine (50 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel chromatography to give 2-[(E)-2-(4-bromo-2,6-dimethyl)vinyl]-5-chloro-4-(trifluoromethyl)pyridine (2.00 g, 53.1% yield) as a white solid.

[0263] Step 3: A mixture of 2-[(E)-2-(4-bromo-2,6-dimethyl)vinyl]-5-chloro-4-(trifluoromethyl)pyridine (5.00 g, 12.8 mmol), bis(acetic acid)palladium (144 mg, 640 µmol), bis[1-(diphenylphosphino)-2,4-cyclopentadien-1-oxide]iron (355 mg, 640 µmol) and triethylamine (3.89 g, 38.4 mmol) in DMF (30 mL) and MeOH (30 mL) was stirred at 100 °C under CO2 at 3 atm for 7 h, then diluted with water (100 mL) and extracted with EtOAc (20 mL x 2). The combined organic extracts were washed with water (100 mL x 3) and brine (50 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel chromatography to give methyl 4-{(E)-2-[5-chloro-4-(trifluoromethyl)-2-pyridyl]vinyl}-3,5-dimethylcarboxylate (2.00 g, 42.3% yield) as a yellow solid.

[0264] Step 4: Platinum dioxide (290 mg, 1.28 mmol) was added to a mixture of methyl 4-{(E)-2-[5-chloro-4-(trifluoromethyl)-2-pyridyl]ethenyl}-3,5-dimethylcarboxylate (2.90 g, 7.84 mmol) in THF (30 mL). The mixture was stirred at room temperature for 18 h, then filtered, concentrated under vacuum, and purified by reversed-phase chromatography to give methyl 4-{2-[5-chloro-4-(trifluoromethyl)-2-pyridyl]ethyl}-3,5-dimethylcarboxylate (2.30 g, 78.9% yield) as a white solid.

[0265] Step 5: Lithium aluminum hydride (147 mg, 3.87 mmol) was added to a solution of methyl 4-{2-[5-chloro-4-(trifluoromethyl)-2-pyridyl]ethyl}-3,5-dimethylbenzenecarboxylate (1.20 g, 3.23 mmol) in THF (24 mL) at 0 °C. The mixture was stirred at 0 °C for 10 min, then quenched with water (50 mL) and extracted with EtOAc (20 mL). The combined organic extracts were washed with water (25 mL x 3) and brine (25 mL), dried over Na2SO4, and concentrated under vacuum to give (4-{2-[5-chloro-4-(trifluoromethyl)-2-pyridyl]ethyl}-3,5-dimethylbenzene)methanol (700 mg, 63.1% yield) as a white solid.

[0266] Step 6: A mixture of (4-{2-[5-chloro-4-(trifluoromethyl)-2-pyridyl]ethyl}-3,5-dimethylyl)methanol (600 mg, 1.75 mmol) and Desmartin periodane (1.11 g, 2.62 mmol) in DCM (6 mL) was stirred at room temperature for 18 h, then filtered, concentrated under vacuum, and purified by silica gel chromatography to give 4-{2-[5-chloro-4-(trifluoromethyl)-2-pyridyl]ethyl}-3,5-dimethylformaldehyde (300 mg, 50.3% yield) as a white solid.

[0267] Step 7: A solution of 4-{2-[5-chloro-4-(trifluoromethyl)-2-pyridyl]ethyl}-3,5-dimethylbenzaldehyde (60.0 mg, 176 µmol) and 3-azacyclobutanecarboxylic acid (35.5 mg, 351 µmol) in MeOH (2 mL) was stirred at 40 °C for 2 h. Sodium cyanoborohydride (21.0 mg, 351 µmol) was added, and the resulting mixture was stirred at 40 °C for 2 h. The reaction mixture was purified by reversed-phase chromatography to give 1-[(4-{2-[5-chloro-4-(trifluoromethyl)-2-pyridyl]ethyl}-3,5-dimethyl)methyl]-3-azacyclobutanecarboxylic acid (45.0 mg, 59.7% yield) as a white solid. LCMS: 427.10.

[0268] Example 71: Synthesis of 1-((2-(3,4-dichlorophenyl)-8-methyl-1,2,3,4-tetrahydroisoquinoline-6-yl)methyl)azacyclobutane-3-carboxylic acid Step 1: To a solution of 6-bromo-8-methyl-1,2,3,4-tetrahydroisoquinoline (700 mg, 3.10 mmol) in DMF (20 mL), (3,4-dichlorophenyl)boric acid (1.77 g, 9.29 mmol), copper(II) acetate (927 mg, 4.64 mmol), and pyridine (735 mg, 9.29 mmol) were added. The resulting mixture was stirred at 60 °C under O2 for 16 h, diluted with an aqueous solution of Na2CO3 (20 mL), and extracted with EtOAc (20 mL x 2). The combined organic extracts were washed with water (20 mL x 2) and brine (20 mL), dried over Na2SO4, concentrated under vacuum, and purified by silica gel chromatography to give 6-bromo-2-(3,4-dichlorophenyl)-8-methyl-1,2,3,4-tetrahydroisoquinoline (350 mg, 30.5% yield) as a yellow solid.

[0269] Step 2: Palladium acetate (21.2 mg, 94.3 µmol), triethylamine (286 mg, 2.83 mmol), and 1,3-bis(diphenylphosphine)propane (77.8 mg, 189 µmol) were added to a solution of 6-bromo-2-(3,4-dichlorophenyl)-8-methyl-1,2,3,4-tetrahydroisoquinoline (350 mg, 943 µmol) in DMSO (2 mL) and MeOH (2 mL). The resulting mixture was stirred at 80 °C under CO (1 atm) for 16 h, diluted with water (5 mL), and extracted with EtOAc (5 mL x 2). The combined organic extracts were washed with water (5 mL*3) and brine (5 mL), dried over Na2SO4, concentrated under vacuum, and purified by preparative TLC to give methyl 2-(3,4-dichlorophenyl)-8-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (195 mg, 59.0% yield) as a yellow solid.

[0270] Step 3: Lithium aluminum hydride (42.3 mg, 1.11 mmol) was added to a solution of methyl 2-(3,4-dichlorophenyl)-8-methyl-1,2,3,4-tetrahydro-6-isoquinoline-6-carboxylate (195 mg, 557 µmol) in THF (4 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h, quenched with water (5 mL), and extracted with EtOAc (5 mL x 2). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried over Na2SO4, and concentrated under vacuum to give [2-(3,4-dichlorophenyl)-8-methyl-1,2,3,4-tetrahydro-6-isoquinoline]methanol (170 mg, 94.8% yield) as a yellow solid.

[0271] Step 4: At 0 °C, add Dysmartin periodane (269 mg, 633 µmol) to a solution of [2-(3,4-dichlorophenyl)-8-methyl-1,2,3,4-tetrahydro-6-isoquinolinyl]methanol (170 mg, 528 µmol) in DCM (4 mL). The resulting mixture was stirred at room temperature for 1 h, quenched with an aqueous solution of NaHCO3 (5 mL), and extracted with DCM (5 mL x 2). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried over Na2SO4, concentrated under vacuum, and purified by preparative TLC to give 2-(3,4-dichlorophenyl)-8-methyl-1,2,3,4-tetrahydroisoquinolinyl-6-carboxaldehyde (35.0 mg, 20.7% yield) as a red solid.

[0272] Step 5: To a solution of 2-(3,4-dichlorophenyl)-8-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxaldehyde (20.0 mg, 62.5 µmol) in MeOH (2 mL), aziridine-3-carboxylic acid (9.47 mg, 93.7 µmol) and acetic acid (20 µL) were added. The resulting mixture was stirred at 40 °C for 16 h. Sodium cyanoborohydride (2.24 mg, 37.5 µmol) was added, and the mixture was stirred for 1 h. The mixture was then concentrated under vacuum and purified by reversed-phase chromatography to give 1-((2-(3,4-dichlorophenyl)-8-methyl-1,2,3,4-tetrahydroisoquinoline-6-yl)methyl)aziridine-3-carboxylic acid (10.0 mg, 39.5% yield) as a white solid. LCMS: 405.1 [M+1] + .

[0273] Example 72 in the table below was prepared using the above procedure, but the specified reagents were used alternatively: Example 73: Synthesis of 1-(4-(3-(difluoromethoxy)phenethyl)benzyl)azacyclobutane-3-carboxylic acid Step 1: Pd(PPh3)2Cl2 (266 mg, 387 μmol) and cesium carbonate (4.93 g, 15.1 mmol) were added to a solution of 4-vinylbenzaldehyde (1.00 g, 7.57 mmol) and 1-iodo-3-(trifluoromethoxy)benzene (1.75 mL, 11.3 mmol) in DMF (10 mL). The resulting mixture was stirred at 120 °C under N2 atmosphere for 16 h, diluted with water (50 mL), and extracted with EtOAc (50 mL x 2). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, and concentrated under vacuum. The crude residue was purified by silica gel chromatography to give (E)-4-(3-(trifluoromethoxy)styryl)benzaldehyde (600 mg, 24.4% yield) as a yellow solid.

[0274] Step 2: N-methylazacyclobutane-3-carboxamide (684 mg, 5.99 mmol) and AcOH (catalyst) were added to a solution of (E)-4-(3-(trifluoromethoxy)styryl)benzaldehyde (350 mg, 1.20 mmol) in MeOH (5 mL). The mixture was stirred at room temperature for 16 h, and then sodium cyanoborohydride (45.2 mg, 719 µmol) was added. After stirring at room temperature for 2 h, the reactants were diluted with water (30 mL) and extracted with EtOAc (30 mL * 2). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, and concentrated under vacuum. The crude residue was purified by preparative HPLC to give methyl (E)-1-(4-(3-(trifluoromethoxy)styryl)benzyl)azacyclobutane-3-carboxylate (180 mg, 30.8% yield) as a yellow oil.

[0275] Step 3: 10% Pd / C (450 mg, 4.23 mmol) was added to a solution of (E)-1-(4-(3-(trifluoromethoxy)styryl)benzyl)azacyclobutane-3-carboxylate (2.30 g, 5.88 mmol) in MeOH (10 mL). The resulting mixture was stirred at 40 °C under H2 atmosphere for 16 h, filtered, and purified by reversed-phase chromatography to give methyl 1-(4-(3-(trifluoromethoxy)phenethyl)benzyl)azacyclobutane-3-carboxylate (1.00 g, 43.3% yield) as a yellow oil.

[0276] Step 4: LiOH (256 mg, 6.10 mmol) was added to a solution of methyl 1-(4-(3-(trifluoromethoxy)phenethyl)benzyl)azacyclobutane-3-carboxylic acid (1.50 g, 3.05 mmol) in THF (6 mL) and water (10 mL). The mixture was stirred at room temperature for 2 h, neutralized to pH = 6 with 2 M HCl, and extracted with EtOAc (20 mL * 2). The combined organic extracts were washed with brine (50 mL), dried over Na₂SO₄, and concentrated under vacuum. The crude residue was purified by preparative HPLC to give 1-(4-(3-(trifluoromethoxy)phenethyl)benzyl)azacyclobutane-3-carboxylic acid (450 mg, 38.8% yield) as a white solid. LCMS: 380.2 [M+1] + .

[0277] Example 74 in the table below was prepared using the above procedure, but the specified reagents were used alternatively: Example 75: Synthesis of 1-(4-(cyclohexylmethoxy)-3-methylbenzyl)azacyclobutane-3-carboxylic acid Step 1: 4-hydroxy-3-methylbenzaldehyde (500 mg, 3.67 mmol) was added to a solution of cyclohexylmethanol (840 mg, 7.34 mmol) and triphenylphosphine (1.44 g, 5.51 mmol) in THF (10 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min, and diisopropyl azodicarboxylate (1.08 mL, 5.51 mmol) was added. The mixture was stirred at room temperature for 16 h, quenched with water (50 mL), and extracted with EtOAc (60 mL*2). The combined organic extracts were washed with brine (150 mL), dried over Na2SO4, concentrated under vacuum, and purified by silica gel chromatography to give 4-(cyclohexylmethoxy)-3-methylbenzaldehyde (500 mg, 29.3% yield) as a colorless oil.

[0278] Step 2: A mixture of 4-(cyclohexylmethoxy)-3-methylbenzaldehyde (500 mg, 2.15 mmol), methyl aziridine-3-carboxylate hydrochloride (248 mg, 2.15 mmol), diisopropylethylamine (278 mg, 2.15 mmol), and acetic acid (12.9 mg, 215 µmol) in a DCE (10 mL) was stirred at 35 °C for 16 h. Sodium triacetoxyborohydride (1.37 g, 6.46 mmol) was added, and the mixture was stirred at 35 °C for 4 h. The mixture was then diluted with water (50 mL) and extracted with DCM (50 mL x 2). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, concentrated under vacuum, and purified by reversed-phase chromatography to give methyl 1-(4-(cyclohexylmethoxy)-3-methylbenzyl)azacyclobutane-3-carboxylate (500 mg, 70.1% yield) as a yellow solid.

[0279] Step 3: LiOH (190 mg, 4.53 mmol) was added to a solution of methyl 1-(4-(cyclohexylmethoxy)-3-methylbenzyl)azacyclobutane-3-carboxylate (500 mg, 1.51 mmol) in THF (5 mL) and H₂O (1 mL). The resulting mixture was stirred at room temperature for 2 h, acidified to pH 6-7 with 2 N HCl, and concentrated under vacuum. The crude substance was purified by reversed-phase chromatography to give 1-{[4-(cyclohexylmethoxy)-3-methylphenyl]methyl}azacyclobutane-3-carboxylic acid (300 mg, 62.7% yield) as a white solid. LCMS: 318.2 [M+1] +.

[0280] Examples 76-87 in the table below were prepared using the above procedure, but the specified reagents were used alternatively: Example 88: Synthesis of 1-(4-((3,4-dichlorophenoxy)methyl)-3,5-dimethylbenzyl)azacyclobutane-3-carboxylic acid Step 1: Sulfonyl chloride (506 µL, 6.97 mmol) was added to a solution of (4-bromo-2,6-dimethylphenyl)methanol (1.00 g, 4.65 mmol) in DCM (10 mL) at 0 °C. The mixture was stirred at room temperature for 2 h, and then concentrated under vacuum to give 5-bromo-2-(chloromethyl)-1,3-dimethylbenzene (1.08 g, 99.9% yield) as a yellow solid.

[0281] Step 2: 5-Bromo-2-(chloromethyl)-1,3-dimethylbenzene (1.04 g, 4.45 mmol) was added to a mixture of 3,4-dichlorophenol (762 mg, 4.68 mmol) and potassium carbonate (1.85 g, 13.4 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature for 16 h, diluted with water (100 mL), and extracted with EtOAc (100 mL x 2). The combined organic extracts were washed with water (100 mL x 3) and brine (200 mL), dried over Na2SO4, and concentrated under vacuum to give 5-bromo-2-((3,4-dichlorophenoxy)methyl)-1,3-dimethylbenzene (1.48 g, 92.5% yield) as a yellow solid.

[0282] Step 3: BINAP (86.5 mg, 139 µmol), diisopropylethylamine (359 mg, 2.78 mmol), and Pd(dppf)Cl2 (56.7 mg, 69.4 µmol) were added to a solution of 5-bromo-2-((3,4-dichlorophenoxy)methyl)-1,3-dimethylbenzene (500 mg, 1.39 mmol) in MeOH (10 mL). The resulting mixture was stirred at 60 °C for 16 h under a CO atmosphere (1 atm), diluted with water (50 mL), and extracted with EtOAc (50 mL * 2). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, concentrated under vacuum, and purified by preparative TLC to give methyl 4-((3,4-dichlorophenoxy)methyl)-3,5-dimethylbenzoate (417 mg, 88.5% yield) as a white solid.

[0283] Step 4: Lithium aluminum hydride (54.6 mg, 1.44 mmol) was added to a solution of methyl 4-((3,4-dichlorophenoxy)methyl)-3,5-dimethylbenzoate (407 mg, 1.20 mmol) in THF (4 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h, quenched with water (50 mL), filtered, and the filtrate was extracted with EtOAc (30 mL * 2). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated under vacuum to give (4-((3,4-dichlorophenoxy)methyl)-3,5-dimethylphenyl)methanol (250 mg, 66.9% yield) as a colorless oil.

[0284] Step 5: Add Desmond-Martin periodane (654 mg, 1.54 mmol) to a solution of (4-((3,4-dichlorophenoxy)methyl)-3,5-dimethylphenyl)methanol (400 mg, 1.29 mmol) in DCM (8 mL) at 0 °C. The mixture was stirred at room temperature under N2 for 3 h, quenched with saturated Na2S2O3 aqueous solution (50 mL), and extracted with EtOAc (50 mL*2). The combined organic extracts were washed with water (50 mL*2) and brine (50 mL*2), dried over Na2SO4, concentrated under vacuum, and purified by preparative TLC to give 4-((3,4-dichlorophenoxy)methyl)-3,5-dimethylbenzaldehyde (260 mg, 65.4% yield) as a white solid.

[0285] Step 6: To a solution of 4-((3,4-dichlorophenoxy)methyl)-3,5-dimethylbenzaldehyde (260 mg, 841 µmol) in MeOH (5 mL), aziridine-3-carboxylic acid (85.0 mg, 841 µmol) and acetic acid (0.2 mL) were added. The mixture was stirred at room temperature for 1 h, and then sodium cyanoborohydride (79.3 mg, 1.26 mmol) was added. The mixture was stirred at room temperature for 16 h, and then purified by reversed-phase chromatography to give 1-(4-((3,4-dichlorophenoxy)methyl)-3,5-dimethylbenzyl)aziridine-3-carboxylic acid (150 mg, 45.2% yield) as a white solid. LCMS: 394.1 [M+1] + .

[0286] Example 89: Synthesis of 1-((2-(3,4-dichlorophenyl)chroman-6-yl)methyl)azacyclobutane-3-carboxylic acid Step 1: 3,4-Dichlorobenzaldehyde (5.00 g, 28.6 mmol) was added dropwise to a solution of vinyl magnesium bromide (4.50 g, 34.3 mmol) in THF (50 mL) at -78 °C. The reaction mixture was stirred at room temperature under N2 for 3 h, quenched with water (200 mL), and extracted with EtOAc (500 mL x 2). The combined organic extracts were washed with brine (200 mL), dried over Na2SO4, and concentrated under vacuum to give 1-(3,4-dichlorophenyl)prop-2-en-1-ol (5.00 g, 86.2% yield) as a colorless oil.

[0287] Step 2: XPhos Pd G2 (283 mg, 360 µmol) was added to a solution of 1-(3,4-dichlorophenyl)prop-2-en-1-ol (1.46 g, 7.19 mmol), methyl 4-hydroxy-3-iodobenzoate (1.00 g, 3.60 mmol), and N-cyclohexyl-N-methylcyclohexylamine (2.31 mL, 10.8 mmol) in toluene (25 mL). The reaction mixture was stirred at 100 °C under N2 for 16 h, diluted with water (200 mL), and extracted with EtOAc (200 mL x 2). The combined organic extracts were washed with brine (200 mL), dried over Na2SO4, and concentrated under vacuum to give methyl (E)-3-(3-(3,4-dichlorophenyl)-3-hydroxypropyl-1-en-1-yl)-4-hydroxybenzoate (1.20 g, 94.5% yield), as a yellow oil.

[0288] Step 3: Sodium borohydride (193 mg, 5.10 mmol) was added to a solution of methyl (E)-3-(3-(3,4-dichlorophenyl)-3-hydroxypropyl-1-en-1-yl)-4-hydroxybenzoate (1.50 g, 4.25 mmol) in THF (15 mL) at 0 °C. The mixture was stirred at room temperature for 16 h, diluted with water (20 mL), and extracted with EtOAc (20 mL x 2). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, and concentrated under vacuum. The crude substance was purified by reversed-phase chromatography to give methyl 3-(3-(3,4-dichlorophenyl)-3-hydroxypropyl)-4-hydroxybenzoate (1.00 g, 74.6% yield) as a yellow oil.

[0289] Step 4: Cesium carbonate (2.09 g, 6.42 mmol) was added to a solution of methyl 3-(3-(3,4-dichlorophenyl)-3-hydroxypropyl)-4-hydroxybenzoate (800 mg, 2.14 mmol) in DMF (5 mL). The mixture was stirred at room temperature for 3 h, diluted with water (40 mL), and extracted with EtOAc (80 mL x 2). The combined organic extracts were washed with water (40 mL x 3) and brine (100 mL), dried over Na2SO4, and concentrated under vacuum. The crude substance was purified by reversed-phase chromatography to give methyl 2-(3,4-dichlorophenyl)chroman-6-carboxylate (500 mg, 69.3% yield) as a yellow oil.

[0290] Step 5: Lithium aluminum hydride (432 mg, 11.4 mmol) was added to a solution of methyl 2-(3,4-dichlorophenyl)chroman-6-carboxylate (3.20 g, 9.49 mmol) in THF (30 mL) at 0 °C. The mixture was stirred at room temperature for 5 h, quenched with water (100 mL), acidified with 3 N HCl to pH = 5–6, and extracted with EtOAc (100 mL * 2). The combined organic extracts were washed with brine (50 mL), dried over Na₂SO₄, and concentrated under vacuum. The crude substance was purified by reversed-phase chromatography to give methyl(2-(3,4-dichlorophenyl)chroman-6-yl)methanol (1.50 g, 51.1% yield) as a yellow oil.

[0291] Step 6: Sulfonyl chloride (56.3 µL, 776 µmol) was added to a solution of methyl(2-(3,4-dichlorophenyl)chroman-6-yl)methanol (200 mg, 647 µmol) in DCM (3 mL) at 0 °C. The resulting mixture was stirred at room temperature for 3 h, and then concentrated under vacuum to give 6-(chloromethyl)-2-(3,4-dichlorophenyl)chroman (200 mg, 94.4% yield) as a yellow solid.

[0292] Step 7: Cesium carbonate (597 mg, 1.83 mmol) was added to a solution of 6-(chloromethyl)-2-(3,4-dichlorophenyl)chromanol (200 mg, 610 µmol) and methyl aziridine-3-carboxylate (141 mg, 1.22 mmol) in DMF (3 mL). The mixture was stirred at room temperature for 16 h, diluted with water (50 mL), and extracted with EtOAc (30 mL x 3). The combined organic extracts were washed with brine (20 mL x 2), dried over Na2SO4, and concentrated under vacuum. The crude substance was purified by reversed-phase chromatography to give methyl 1-((2-(3,4-dichlorophenyl)chromanol-6-yl)methyl)aziridine-3-carboxylate (60.0 mg, 19.4% yield) as a yellow oil.

[0293] Step 8: A solution of lithium hydroxide (310 mg, 7.38 mmol) in water (5 mL) was added to a solution of methyl 1-((2-(3,4-dichlorophenyl)chroman-6-yl)methyl)azacyclobutane-3-carboxylic acid (600 mg, 1.48 mmol) in THF (20 mL). The mixture was stirred at room temperature for 16 h, acidified to pH 5-6 with 2 N HCl, diluted with water (50 mL), and extracted with EtOAc (100 mL x 3). The combined organic extracts were washed with water (40 mL x 3) and brine (100 mL x 2), dried over Na2SO4, and concentrated under vacuum. The crude material was purified by preparative HPLC to give 1-((2-(3,4-dichlorophenyl)chroman-6-yl)methyl)azacyclobutane-3-carboxylic acid (30.0 mg, 5.17% yield) as a white solid. LCMS: 392.10 [M+1] + .

[0294] Example 90 in the table below was prepared using the above procedure, but the specified reagents were used alternatively: Example 91: Synthesis of (R)-1-(4-((3-(trifluoromethyl)benzyl)oxy)benzyl)pyrrolidine-3-carboxylic acid Step 1: Potassium carbonate (4.26 g, 30.8 mmol) was added to a solution of 1-(chloromethyl)-3-(trifluoromethyl)benzene (2.00 g, 10.3 mmol) and 4-hydroxybenzaldehyde (1.26 g, 10.3 mmol) in ACN (20 mL). The mixture was stirred at 80 °C for 16 h, diluted with water (100 mL), and extracted with EtOAc (100 mL x 2). The combined organic extracts were washed with water (200 mL x 2) and brine (200 mL), dried over Na2SO4, and concentrated under vacuum to give 4-((3-(trifluoromethyl)benzyl)oxy)benzaldehyde (2.50 g, 86.8% yield) as a white solid.

[0295] Step 2: DIEA (231 mg, 1.78 mmol) and acetic acid (10.7 mg, 178 µmol) were added to a solution of 4-{[3-(trifluoromethyl)phenyl]methoxy}benzaldehyde (500 mg, 1.78 mmol) and (3R)-pyrrolidine-3-carboxylate hydrochloride (295 mg, 1.78 mmol) in DCE (10 mL). The mixture was stirred at 35 °C for 16 h. Sodium triacetoxyborohydride (1.13 g, 5.35 mmol) was added, and the mixture was stirred at 35 °C for 4 h, diluted with water (50 mL), and extracted with DCM (50 mL x 2). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, concentrated under vacuum, and purified by silica gel chromatography to give (R)-1-(4-((3-(trifluoromethyl)benzyl)oxy)benzyl)pyrrolidine-3-carboxylic acid methyl ester (440 mg, 62.7% yield), as a yellow oil.

[0296] Step 3: LiOH (53.6 mg, 2.24 mmol) was added to a mixture of (R)-1-(4-((3-(trifluoromethyl)benzyl)oxy)benzyl)pyrrolidine-3-carboxylic acid methyl ester (440 mg, 1.12 mmol) in THF (3 mL) and H₂O (1 mL). The resulting mixture was stirred at room temperature for 4 h, acidified to pH 6-7 with 2 N HCl, and filtered. The separated solid was washed with DCM and dried under vacuum to give (R)-1-(4-((3-(trifluoromethyl)benzyl)oxy)benzyl)pyrrolidine-3-carboxylic acid (350 mg, 82.5% yield) as a white solid. LCMS: 380.1 [M+1] + .

[0297] Examples 92-115 in the table below were prepared using the above procedure, but the specified reagents were used alternatively: Example 116: Synthesis of 1-(4-((3,4-dichlorobenzyl)oxy)-3,5-dimethylbenzyl)azacyclobutane-3-carboxylic acid Step 1: To a solution of 4-hydroxy-3,5-dimethylbenzaldehyde (80.0 g, 533 mmol) in DMF (250 mL), 1,2-dichloro-4-(chloromethyl)benzene (81.2 mL, 586 mmol) and potassium carbonate (110 g, 799 mmol) were added, and the mixture was stirred at 60 °C for 3 h. The reaction mixture was poured into ice water (300 mL) and stirred for 30 min. The resulting precipitate was filtered and washed with water followed by petroleum ether / EtOAc (20 / 1, v / v) to give 4-[(3,4-dichlorophenyl)methoxy]-3,5-dimethylbenzaldehyde (161 g, 97.8% yield) as a white solid.

[0298] Step 2: To a solution of 4-[(3,4-dichlorophenyl)methoxy]-3,5-dimethylbenzaldehyde (9.00 g, 29.1 mmol) in DCE (25 mL), aziridine-3-carboxylic acid (4.41 g, 43.7 mmol) and acetic acid (833 µL, 14.6 mmol) were added, and the mixture was heated to 50 °C and stirred for 16 h. The mixture was cooled to room temperature and sodium triacetoxyborohydride (9.25 g, 43.7 mmol) was added in portions. The mixture was stirred for 2 h and then concentrated under vacuum. The crude residue was purified by reversed-phase chromatography and washed with DCM / n-hexane (10 / 1, v / v) to give 1-(4-((3,4-dichlorobenzyl)oxy)-3,5-dimethylbenzyl)aziridine-3-carboxylic acid (8.20 g, 71.5% yield) as a white solid. LCMS: 394.1 [M+1] + .

[0299] Examples 117-368 in the table below were prepared using the above procedure, but the specified reagents were used alternatively: Example 369: Synthesis of 1-((5-((3-cyano-4-isopropoxybenzyl)oxy)-3-methylpyridin-2-yl)methyl)azacyclobutane-3-carboxylic acid Step 1: 5-(chloromethyl)-2-isopropoxybenzonitrile (4.10 g, 19.6 mmol) and potassium carbonate (3.60 g, 26.1 mmol) were added to a solution of methyl 5-hydroxy-3-methylpyridinecarboxylate (2.18 g, 13.0 mmol) in DMF (15 mL). The mixture was stirred at 60 °C for 16 h, diluted with H2O (150 mL), and extracted with EtOAc (50 mL x 2). The combined organic extracts were washed with H2O (150 mL) and brine (150 mL x 2), dried over Na2SO4, concentrated under vacuum, and purified by silica gel chromatography to give methyl 5-((3-cyano-4-isopropoxybenzyl)oxy)-3-methylpyridinecarboxylate (3.20 g, 72.0% yield) as a white solid.

[0300] Step 2: Lithium borohydride (1 N THF solution, 2.20 mL, 2.20 mmol) was added to a solution of methyl 5-((3-cyano-4-isopropoxybenzyl)oxy)-3-methylpyridinecarboxylate (500 mg, 1.47 mmol) in THF (3 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 h, diluted with H2O (50 mL), and extracted with EtOAc (30 mL x 2). The combined organic extracts were washed with brine (50 mL x 2), dried over Na2SO4, concentrated under vacuum, and purified by reversed-phase chromatography to give 5-(((6-(hydroxymethyl)-5-methylpyridin-3-yl)oxy)methyl)-2-isopropoxybenzonitrile (239 mg, 52.0% yield) as a yellow solid.

[0301] Step 3: At 0 °C, Dysmartin periodane (226 mg, 534 µmol) was added to a solution of 5-(((6-(hydroxymethyl)-5-methylpyridin-3-yl)oxy)methyl)-2-isopropoxybenzonitrile (139 mg, 445 µmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 3 h, quenched with saturated Na2S2O3 aqueous solution, diluted with H2O (50 mL), and extracted with DCM (30 mL*2). The combined organic extracts were washed with brine (50 mL*2), dried over Na2SO4, and concentrated under vacuum to give 5-(((6-formyl-5-methylpyridin-3-yl)oxy)methyl)-2-isopropoxybenzonitrile (120 mg, 86.8% yield) as a yellow solid.

[0302] Step 4: A solution of 5-(((6-formyl-5-methylpyridin-3-yl)oxy)methyl)-2-isopropoxybenzonitrile (150 mg, 429 µmol) and aziridine-3-carboxylic acid (65.1 mg, 644 µmol) in MeOH (3 mL) was stirred at room temperature for 2 h. Sodium cyanoborohydride (32.4 mg, 515 µmol) was added and the mixture was stirred at room temperature for 16 h. The pH was adjusted to 5–6 with 2 N HCl, and the mixture was diluted with H₂O (50 mL) and extracted with EtOAc (30 mL x 2). The combined organic extracts were washed with brine (50 mL x 2), dried over Na₂SO₄, concentrated under vacuum, and purified by reversed-phase chromatography to give 1-((5-(((3-cyano-4-isopropoxybenzyl)oxy)-3-methylpyridin-2-yl)methyl)azacyclobutane-3-carboxylic acid (130 mg, 54.9% yield) as a white solid. LCMS: 396.1 [M+1] + .

[0303] Examples 370-372 in the table below were prepared using the above procedure, but the specified reagents were used alternatively: Example 373: Synthesis of 1-((5-((3-(trifluoromethyl)benzyl)oxy)pyrazin-2-yl)methyl)azacyclobutane-3-carboxylic acid Step 1: Potassium carbonate (1.85 g, 5.68 mmol) was added to a solution of methyl 5-chloropyrazine-2-carboxylate (386 µL, 2.84 mmol) and (3-(trifluoromethyl)phenyl)methanol (490 mg, 2.84 mmol) in DMF (5 mL). The resulting mixture was stirred at room temperature for 16 h, diluted with water (50 mL), and extracted with EtOAc (30 mL x 3). The combined organic extracts were washed with water (50 mL x 3) and brine (50 mL), dried over Na2SO4, and concentrated under vacuum to give methyl 5-((3-(trifluoromethyl)benzyl)oxy)pyrazine-2-carboxylate (650 mg, 74.8% yield) as a yellow solid.

[0304] Step 2: Sodium borohydride (1.27 g, 33.6 mmol) was added to a solution of methyl 5-((3-(trifluoromethyl)benzyl)oxy)pyrazine-2-carboxylate (700 mg, 2.24 mmol) in MeOH (30 mL) at 0 °C. The mixture was stirred at room temperature for 1 h, quenched with saturated NH4Cl aqueous solution (20 mL), and extracted with DCM (20 mL x 2). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, and concentrated under vacuum to give (5-((3-(trifluoromethyl)benzyl)oxy)pyrazine-2-yl)methanol (500 mg, 80% purity, 62.8% yield) as a white solid.

[0305] Step 3: At 0 °C, Dysmartin periodane (716 mg, 1.69 mmol) was added to a solution of (5-{[3-(trifluoromethyl)phenyl]methoxy}pyrazin-2-yl)methanol (500 mg, 1.41 mmol) in DCM (5 mL). The mixture was stirred at room temperature for 0.5 h, quenched with saturated NaHCO3 aqueous solution (10 mL), and extracted with EtOAc (10 mL * 2). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel chromatography to give 5-{[3-(trifluoromethyl)phenyl]methoxy}pyrazin-2-carboxaldehyde (400 mg, 95.7% yield) as a white solid.

[0306] Step 4: To a solution of 5-{[3-(trifluoromethyl)phenyl]methoxy}pyrazin-2-carboxaldehyde (200 mg, 709 µmol) in MeOH (5 mL), aziridine-3-carboxylic acid (243 mg, 2.13 mmol) and AcOH (catalyst) were added. The mixture was stirred at room temperature for 16 h, and sodium cyanoborohydride (26.7 mg, 425 µmol) was added. After stirring at room temperature for 1 h, the reactants were quenched with water (20 mL) and extracted with EtOAc (20 mL * 2). The combined organic extracts were washed with brine (50 mL), dried over Na₂SO₄, and concentrated under vacuum. The crude residue was purified by preparative HPLC to give 1-((5-((3-(trifluoromethyl)benzyl)oxy)pyrazin-2-yl)methyl)aziridine-3-carboxylic acid (70.0 mg, 26.9% yield) as a white solid. LCMS: 366.1 [M+1] + .

[0307] Examples 374-377 in the table below were prepared using the above procedure, but the specified reagents were used alternatively: Example 378: Synthesis of 1-({4-[(3,4-dichlorophenyl)methoxy]-3-methoxy-5-methylphenyl}methyl)azacyclobutane-3-carboxylic acid Step 1: 2-Methoxy-6-methylphenol (3.00 g, 21.7 mmol) and formaldehyde (1.30 g, 43.4 mmol) were added to a solution of sodium hydroxide (1.74 g, 43.4 mmol) in water (30 mL). The mixture was stirred at 60 °C for 7 h. The reactants were neutralized to pH 7–8 with 2 N HCl, diluted with water (100 mL), and extracted with EtOAc (200 mL x 2). The combined organic extracts were washed with brine (300 mL), dried over Na₂SO₄, and concentrated under vacuum to give 4-(hydroxymethyl)-2-methoxy-6-methylphenol (1.70 g, 46.6% yield) as a white solid.

[0308] Step 2: 1,2-Dichloro-4-(chloromethyl)benzene (930 mg, 4.76 mmol) and cesium carbonate (3.10 g, 9.51 mmol) were added to a solution of 4-(hydroxymethyl)-2-methoxy-6-methylphenol (800 mg, 4.76 mmol) in DMF (20 mL). The reaction mixture was stirred at room temperature for 16 h, filtered, and washed with EtOAc. The filtrate was diluted with water (200 mL) and extracted with EtOAc (150 mL x 3). The combined organic extracts were washed with brine (150 mL), dried over Na2SO4, and concentrated under vacuum. The crude substance was purified by silica gel chromatography to give (4-((3,4-dichlorobenzyl)oxy)-3-methoxy-5-methylphenyl)methanol (1.50 g, 96.3% yield) as a yellow oil.

[0309] Step 3: At 0 °C, add Dysmartin periodane (2.33 g, 5.5 mmol) to a solution of (4-((3,4-dichlorobenzyl)oxy)-3-methoxy-5-methylphenyl)methanol (1.50 g, 4.58 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 2 h, filtered, and washed with DCM. The filtrate was diluted with water (100 mL) and extracted with DCM (50 mL x 2). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, concentrated under vacuum, and purified by silica gel chromatography to give 4-((3,4-dichlorobenzyl)oxy)-3-methoxy-5-methylbenzaldehyde (1.40 g, 93.9% yield) as a white solid.

[0310] Step 4: Acetic acid (0.1 mL) was added to a solution of 4-[(3,4-dichlorophenyl)methoxy]-3-methoxy-5-methylbenzaldehyde (500 mg, 1.54 mmol) and aziridine-3-carboxylic acid (155 mg, 1.54 mmol) in MeOH (5 mL). The reaction mixture was stirred at room temperature for 16 h, and sodium cyanoborohydride (145 mg, 2.31 mmol) was added. After stirring at room temperature for 5 h, the pH was adjusted to 5 with 2 N HCl. The mixture was purified by reversed-phase chromatography to give 1-({4-[(3,4-dichlorophenyl)methoxy]-3-methoxy-5-methylphenyl}methyl)aziridine-3-carboxylic acid (180 mg, 28.5% yield) as a white solid. LCMS: 410.0 [M+1] + .

[0311] Example 379: Synthesis of 1-(4-((3,4-dichlorobenzyl)thio)benzyl)azacyclobutane-3-carboxylic acid Step 1: Methyl 4-mercaptobenzoate (500 mg, 2.97 mmol) and cesium carbonate (822 mg, 5.94 mmol) were added to a solution of 1,2-dichloro-4-(chloromethyl)benzene (581 mg, 2.97 mmol) in DMF (10 mL). The mixture was stirred at room temperature for 10 h, diluted with water (80 mL), and extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with water (80 mL) and brine (80 mL), dried over Na2SO4, and concentrated under vacuum to give methyl 4-((3,4-dichlorobenzyl)thio)benzoate (800 mg, 82.3% yield) as a white solid.

[0312] Step 2: Diisobutylaluminum hydride (1.5 M in THF, 4.60 mL, 6.88 mmol) was added dropwise to a solution of methyl 4-((3,4-dichlorobenzyl)thio)benzoate (750 mg, 2.29 mmol) in THF (5 mL) at -75 °C. The mixture was stirred at -75 °C for 1 h, quenched with water (20 mL), and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with water (80 mL) and brine (80 mL), dried over Na2SO4, concentrated under vacuum, and purified by silica gel chromatography to give 4-((3,4-dichlorobenzyl)thio)benzaldehyde (500 mg, 73.4% yield) as a white solid.

[0313] Step 3: Add aziridine-3-carboxylic acid (102 mg, 1.01 mmol) to a solution of 4-((3,4-dichlorobenzyl)thio)benzaldehyde (150 mg, 505 µmol) in MeOH (2 mL). Stir the mixture at room temperature for 5 h. Add sodium cyanoborohydride (47.6 mg, 757 µmol) and stir the resulting mixture for 2 h. Adjust the pH to 5 with 1 N HCl. Purify the resulting solution by reversed-phase chromatography to give 1-(4-((3,4-dichlorobenzyl)thio)benzyl)aziridine-3-carboxylic acid (50.0 mg, 25.9% yield) as a yellow oil. LCMS: 381.9 [M+1] + .

[0314] Example 380: Synthesis of 1-[(4-{[(3,4-dichlorophenyl)methyl]thioalkyl}-3,5-dimethylphenyl)methyl]azacyclobutane-3-carboxylic acid Step 1: Sodium nitrite (2.89 g, 41.8 mmol) was slowly added to a solution of methyl 4-amino-3,5-dimethylbenzoate (5.00 g, 27.9 mmol) and hydrogen chloride (13.9 g, 139 mmol) in water (2 mL) and acetonitrile (10 mL) at -5 °C. The resulting mixture was stirred at -5 °C for 1 h. O-ethyl dithiocarbonate (17.9 g, 112 mmol) was carefully added, and the reaction mixture was stirred at 75 °C for 2 h, quenched with water (250 mL), and extracted with EtOAc (100 mL * 3). The combined organic extracts were washed with brine, dried over Na2SO4, concentrated under vacuum, and purified by silica gel chromatography to give methyl 4-[(ethoxythioformyl)thioalkyl]-3,5-dimethylbenzoate (4.00 g, 50.5% yield) as a yellow oil.

[0315] Step 2: Potassium hydroxide (1.48 g, 26.4 mmol) was added to a solution of methyl 4-[(ethoxythiocarbamoyl)thioalkyl]-3,5-dimethylbenzoate (3.00 g, 10.5 mmol) in EtOH (50 mL). The resulting mixture was stirred at 80 °C for 3 h, and then partitioned between EtOAc (500 mL) and water (500 mL). The organic layer was concentrated under vacuum to give 3,5-dimethyl-4-thioalkylbenzoic acid (1.20 g, 23.6% yield) as a yellow solid, and 4,4'-dithionidinediylbis(3,5-dimethylbenzoic acid) (1.10 g, 10.8% yield).

[0316] Step 3: Borane-dimethyl sulfide (2.10 g, 27.6 mmol) was added to a solution of 4-[(4-carboxy-2,6-dimethylphenyl)dithioalkyl]-3,5-dimethylbenzoic acid (1.00 g, 2.76 mmol) in THF at -40 °C. The resulting mixture was stirred at room temperature for 3 h, then quenched with NaHCO3 (10 mL), diluted with water (500 mL), and extracted with EtOAc (500 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to give (3,5-dimethyl-4-thioalkylphenyl)methanol (232 mg, 50.5% yield) as a yellow solid.

[0317] Step 4: 1,2-Dichloro-4-(chloromethyl)benzene (978 mg, 5.00 mmol) and cesium carbonate (3.26 g, 10.0 mmol) were added to a solution of (3,5-dimethyl-4-thioalkylphenyl)methanol (842 mg, 5.00 mmol) in DMF (10 mL). The resulting mixture was stirred at room temperature for 16 h, then diluted with water (250 mL) and extracted with EtOAc (100 mL x 3). The combined organic extracts were washed with brine, concentrated under vacuum, and purified by silica gel chromatography to give (4-{[(3,4-dichlorophenyl)methyl]thioalkyl}-3,5-dimethylphenyl)methanol (465 mg, 28.4% yield) as a white solid.

[0318] Step 5: Sulfonyl chloride (43.6 mg, 367 µmol) was added to a solution of (4-{[(3,4-dichlorophenyl)methyl]thioalkyl}-3,5-dimethylphenyl)methanol (260 mg, 794 µmol) in DCM (5 mL, 78.1 mmol). The mixture was stirred at room temperature for 3 h and then concentrated under vacuum to give 5-(chloromethyl)-2-{[(3,4-dichlorophenyl)methyl]thioalkyl}-1,3-dimethylbenzene (260 mg, 94.7% yield) as a brown oil.

[0319] Step 6: A mixture of 5-(chloromethyl)-2-{[(3,4-dichlorophenyl)methyl]thioalkyl}-1,3-dimethylbenzene (270 mg, 781 µmol), methyl aziridine-3-carboxylate (89.9 mg, 781 µmol), and potassium carbonate (432 mg, 3.13 mmol) in DMF (10 mL) was stirred at room temperature for 16 h, and then concentrated under vacuum. The crude material was purified by preparative HPLC to give methyl 1-[(4-{[(3,4-dichlorophenyl)methyl]thioalkyl}-3,5-dimethylphenyl)methyl]aziridine-3-carboxylate (300 mg, 90.5% yield) as a white solid.

[0320] Step 7: Lithium hydroxide hydrate (56.4 mg, 1.34 mmol) was added to a mixture of methyl 1-[(4-{[(3,4-dichlorophenyl)methyl]thioalkyl}-3,5-dimethylphenyl)methyl]azacyclobutane-3-carboxylic acid (190 mg, 448 µmol) in THF (4 mL) and water (1 mL). The resulting mixture was stirred at room temperature for 4 h, then concentrated under vacuum and purified by preparative HPLC to give 1-[(4-{[(3,4-dichlorophenyl)methyl]thioalkyl}-3,5-dimethylphenyl)methyl]azacyclobutane-3-carboxylic acid (80.0 mg, 43.5% yield) as a white solid. LCMS: 410.2 [M+1].

[0321] Example 381: Synthesis of 1-((5-((3-(trifluoromethyl)phenoxy)methyl)pyridin-2-yl)methyl)azacyclobutane-3-carboxylic acid Step 1: Thionyl chloride (2.13 mL, 29.4 mmol) was added to a solution of 5-(hydroxymethyl)pyridine-2-carboxylic acid (1.50 g, 9.8 mmol) in MeOH (15 mL) at 0 °C. The mixture was stirred at room temperature for 2 h, and then concentrated under vacuum to give methyl 5-(hydroxymethyl)pyridine-2-carboxylate (1.50 g, 91.5% yield) as a brown oil.

[0322] Step 2: Thionyl chloride (3.20 g, 26.9 mmol) was added to a solution of methyl 5-(hydroxymethyl)pyridine-2-carboxylate (1.5 g, 8.97 mmol) in DCM (18 mL) at 0 °C. The mixture was stirred at room temperature for 2 h, and then concentrated under vacuum to give methyl 5-(chloromethyl)pyridine-2-carboxylate (1.20 g, 72.1% yield) as a brown solid.

[0323] Step 3: Cesium carbonate (704 mg, 2.16 mmol) was added to a solution of methyl 5-(chloromethyl)pyridine-2-carboxylate (200 mg, 1.08 mmol) and 3-(trifluoromethyl)phenol (175 mg, 1.08 mmol) in DMF (3 mL). The resulting mixture was stirred at room temperature for 16 h, diluted with water (10 mL), and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with brine (20 mL x 3), concentrated under vacuum, and purified by preparative TLC to give methyl 5-{[3-(trifluoromethyl)phenoxy]methyl}pyridine-2-carboxylate (180 mg, 53.5% yield) as a white solid.

[0324] Step 4: Sodium borohydride (413 mg, 10.9 mmol) was added fractionally to a solution of methyl 5-{[3-(trifluoromethyl)phenoxy]methyl}pyridin-2-carboxylate (680 mg, 2.18 mmol) in MeOH (5 mL) at 0 °C. The mixture was stirred at room temperature for 16 h, diluted with water (20 mL), and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with brine (20 mL), concentrated under vacuum, and purified by preparative TLC to give (5-{[3-(trifluoromethyl)phenoxy]methyl}pyridin-2-yl)methanol (230 mg, 37.2% yield) as a white solid.

[0325] Step 5: At 0 °C, add Dysmartin periodane (413 mg, 974 µmol) to a solution of (230 mg, 812 µmol) of methanol in DCM (5 mL). The mixture was stirred at room temperature for 1 h, diluted with water (10 mL), and extracted with DCM (20 mL x 3). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, concentrated under vacuum, and purified by silica gel chromatography to give 5-{[3-(trifluoromethyl)phenoxy]methyl}pyridine-2-carboxaldehyde (200 mg, 87.6% yield) as a white solid.

[0326] Step 6: A solution of 5-{[3-(trifluoromethyl)phenoxy]methyl}pyridin-2-carboxaldehyde (200 mg, 711 µmol) and aziridine-3-carboxylic acid (71.9 mg, 711 µmol) in MeOH (3 mL) was stirred at room temperature for 16 h, and sodium cyanoborohydride (89.4 mg, 1.42 mmol) was added. After stirring at room temperature for 1 h, the mixture was filtered and purified by reversed-phase chromatography to give 1-[(5-{[3-(trifluoromethyl)phenoxy]methyl}pyridin-2-yl)methyl]aziridine-3-carboxylic acid (100 mg, 38.4% yield) as a white solid. LCMS: 367.0 [M+1] + .

[0327] Example 382: Synthesis of 1-(4-((4-cyclohexyl-3-(trifluoromethyl)phenoxy)methyl)-2-methylbenzyl)azacyclobutane-3-carboxylic acid Step 1: To a solution of 4-bromo-3-(trifluoromethyl)phenol (1.00 g, 4.15 mmol) in 1,4-dioxane (18 mL) and water (6 mL), cyclohexyl-1-en-1-ylboronic acid (575 mg, 4.56 mmol), Pd(dppf)Cl2 (151 mg, 207 µmol), and potassium carbonate (1.15 g, 8.30 mmol) were added. The mixture was stirred at 100 °C under N2 for 18 h, then diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, concentrated under vacuum, and purified by silica gel chromatography to give 2-(trifluoromethyl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-ol (1.00 g, 99.0% yield), as a yellow oil.

[0328] Step 2: 20% Pd / C (200 mg) and HOAc (10 µL) were added to a solution of 2-(trifluoromethyl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-ol (1.00 g, 4.13 mmol) in MeOH (15 mL). The resulting mixture was stirred at room temperature under H2 for 18 h, then filtered and concentrated under vacuum to give 4-cyclohexyl-3-(trifluoromethyl)phenol (1.00 g, 99.0% yield) as a brown oil.

[0329] Step 3: Thionyl chloride (1.45 mL, 20.0 mmol) was added to a solution of methyl 4-(hydroxymethyl)-2-methylbenzoate (1.20 g, 6.66 mmol) in DCM (20 mL) at 0 °C. The reaction mixture was stirred at room temperature for 20 min and then concentrated under vacuum to give methyl 4-(chloromethyl)-2-methylbenzoate (1.20 g, 90.9% yield) as a colorless oil.

[0330] Step 4: Methyl 4-(chloromethyl)-2-methylbenzoate (488 mg, 2.46 mmol) and potassium carbonate (1.20 g, 2.91 mmol) were added to a solution of 4-cyclohexyl-3-(trifluoromethyl)phenol (600 mg, 2.46 mmol) in DMF (10 mL). The reaction mixture was stirred at 60 °C for 18 h, then diluted with water (50 mL) and extracted with EtOAc (80 mL x 2). The combined organic extracts were washed with water (100 mL x 2) and brine (50 mL x 2), dried over Na2SO4 and concentrated under vacuum to give methyl 4-((4-cyclohexyl-3-(trifluoromethyl)phenoxy)methyl)-2-methylbenzoate (300 mg, 30.4% yield) as a colorless oil.

[0331] Step 5: Lithium aluminum hydride (41.0 mg, 1.08 mmol) was added to a solution of methyl 4-((4-cyclohexyl-3-(trifluoromethyl)phenoxy)methyl)-2-methylbenzoate (220 mg, 541 µmol)) in THF (8 mL) at 0 °C. The resulting mixture was stirred at room temperature for 2 h, then quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with water (30 mL x 3) and brine (15 mL), dried over Na2SO4, and concentrated under vacuum to give (4-((4-cyclohexyl-3-(trifluoromethyl)phenoxy)methyl)-2-methylphenyl)methanol (200 mg, 97.6% yield) as a white solid.

[0332] Step 6: Manganese dioxide (459 mg, 5.29 mmol) was added to a solution of (4-((4-cyclohexyl-3-(trifluoromethyl)phenoxy)methyl)-2-methylphenyl)methanol (200 mg, 529 µmol) in THF (8 mL). The resulting mixture was stirred at room temperature for 18 h, then filtered, concentrated under vacuum, and purified by preparative TLC to give 4-((4-cyclohexyl-3-(trifluoromethyl)phenoxy)methyl)-2-methylbenzaldehyde (120 mg, 60.3% yield) as a yellow solid.

[0333] Step 7: A solution of 4-((4-cyclohexyl-3-(trifluoromethyl)phenoxy)methyl)-2-methylbenzaldehyde (120 mg, 319 µmol) and aziridine-3-carboxylic acid (32.2 mg, 319 µmol) in MeOH (8 mL) and acetic acid (0.1 mL) was stirred at room temperature for 18 h, and then sodium cyanoborohydride (22.9 mg, 383 µmol) was added. After stirring for 5 h, the mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL * 3). The combined organic extracts were washed with water (15 mL * 3) and brine (15 mL), dried over Na2SO4, and concentrated under vacuum. The crude residue was purified by preparative HPLC and washed with EtOAc:hexane (1:2) to give 1-(4-((4-cyclohexyl-3-(trifluoromethyl)phenoxy)methyl)-2-methylbenzyl)azacyclobutane-3-carboxylic acid (20.0 mg, 13.6% yield) as a white solid. LCMS: 462.2 [M+1] + .

[0334] Example 383: Synthesis of 1-(4-((4-cyclohexyl-3-(trifluoromethyl)phenoxy)methyl)-3-methylbenzyl)azacyclobutane-3-carboxylic acid Step 1: To a solution of 4-bromo-3-(trifluoromethyl)phenol (5.00 g, 20.7 mmol) in 1,4-dioxane (60 mL), (cyclohexyl-1-en-1-yl)boronic acid (2.87 g, 22.8 mmol), Pd(dppf)Cl2 (753 mg, 1.04 mmol), potassium carbonate (5.73 g, 41.5 mmol), and H2O (20 mL) were added. The mixture was stirred at 100 °C under N2 for 16 h, diluted with water (50 mL), and extracted with EtOAc (50 mL x 2). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, concentrated under vacuum, and purified by silica gel chromatography to give 2-(trifluoromethyl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-ol (5.00 g, 99.5% yield), as a yellow oil.

[0335] Step 2: 10% Pd / C (500 mg, 4.70 mmol) and HOAc (10 µL) were added to a solution of 2-(trifluoromethyl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-ol (5.00 g, 20.6 mmol) in MeOH (50 mL). The resulting mixture was stirred at 40 °C for 16 h under H2 (1 atm), filtered, and concentrated under vacuum to give 4-cyclohexyl-3-(trifluoromethyl)phenol (4.92 g, 97.6% yield) as a brown oil.

[0336] Step 3: Thionyl chloride (2.42 mL, 33.3 mmol) was added dropwise to a solution of methyl 4-(hydroxymethyl)-3-methylbenzoate (4.00 g, 22.2 mmol) in DCM (20 mL) at 0 °C. The mixture was stirred at room temperature for 20 min and then concentrated under vacuum to give methyl 4-(chloromethyl)-3-methylbenzoate (4.00 g, 90.7% yield) as a colorless oil.

[0337] Step 4: Methyl 4-(chloromethyl)-3-methylbenzoate (4.07 g, 20.5 mmol) and potassium carbonate (5.66 g, 40.9 mmol) were added to a solution of 4-cyclohexyl-3-(trifluoromethyl)phenol (5.00 g, 20.5 mmol) in DMF (30 mL). The resulting mixture was stirred at 60 °C for 16 h, diluted with water, and extracted with EtOAc (100 mL*2). The combined organic extracts were washed with water (100 mL*2) and brine (100 mL*2), dried over Na2SO4, and concentrated under vacuum to give methyl 4-((4-cyclohexyl-3-(trifluoromethyl)phenoxy)methyl)-3-methylbenzoate (4.59 g, 55.2% yield) as a white solid.

[0338] Step 5: Lithium aluminum hydride (224 mg, 5.90 mmol) w...

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof: ； in: X is selected from -C(R 7 )(R 8 )C(R 7 )(R 8 )-, -C(R 7 )(R 8 )C(O)-, -C(O)C(R 7 )(R 8 )-, -C(R 7 )(R 8 )S-, -SC(R 7 )(R 8 )-, -C(R 7 )(R 8 )O-, -OC(R 7 )(R 8 )-, -C(R 7 )(R 8 )N(R 9 )-, -N(R 9 )C(R 7 )(R 8 )-, -C(R 7 )(R 8 )-, -C(O)-, -N(R 9 )-, -O-, -S-, -S(O)- and -S(O)2-; R 1 Selected from hydrogen, -OR 7 -N(R) 7 (R) 8 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocyclic alkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Halogenated alkyl, C3-C6 cycloalkyl, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups may be substituted; R 2 Selected from -OR 7 -N(R) 7 (R) 8 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocyclic alkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Halogenated alkyl, C3-C6 cycloalkyl, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups are substituted; or R 1 With R 2 The combination forms elements optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 C2-C9 heterocyclic alkyl groups substituted with 1, 2, or 3 groups; R 3 For R 3a R 3b R 3c R 3d and R 3e Substituted phenyl; R 3a Selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、S(=O)(=NH)N(R 10 (R) 11 -CH2C(O)N(R) 10 (R) 11 ), -CH2N(R 12 )C(O)R 13 -CH2S(O)2R 13 and -CH2S(O)2N(R 10 (R) 11 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10 One, two, or three groups are substituted; R 3b R 3c R 3d and R 3e Independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、S(=O)(=NH)N(R 10 (R) 11 -CH2C(O)N(R) 10 (R) 11 ), -CH2N(R 12 )C(O)R 13 -CH2S(O)2R 13 and -CH2S(O)2N(R 10 (R) 11 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10 Substitution with one, two, or three groups; or R 3a With R 3b The combination forms elements optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 C2-C9 heterocyclic alkyl groups substituted with 1, 2, or 3 groups; Each R 4 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、S(=O)(=NH)N(R 10 (R) 11 -CH2C(O)N(R) 10 (R) 11 ), -CH2N(R 12 )C(O)R 13 -CH2S(O)2R 13 and -CH2S(O)2N(R 10 (R) 11 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10 One, two, or three groups are substituted; R 5 and R 6 Independently selected from hydrogen and C1-C6 alkyl groups; Each R 7 and each R 8 Independently selected from hydrogen and C1-C6 alkyl groups; R 9 Selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 10 Independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; Each R 11 Independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 12 Independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 13 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is substituted with one, two, or three groups; and p can be 0, 1, 2, 3, or 4.

2. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a Selected from -OR 10 C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl, wherein C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10 One, two, or three groups are substituted.

3. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a Selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

4. The compound according to claim 3, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a It is a halogen.

5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3b R 3c R 3d and R 3e Independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3b Selected from hydrogen, halogens, -CN and C 1-6 Halogenated alkyl groups.

7. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3b It is a halogen.

8. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3c R 3d and R 3e It is hydrogen.

9. The compound according to any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein X is selected from -C(R 7 (R) 8 )C(R 7 (R) 8 )- and -C(R 7 (R) 8 )O-.

10. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(R) 7 (R) 8 )O-.

11. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(R) 7 (R) 8 )C(R 7 (R) 8 )-.

12. The compound according to any one of claims 1-11, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 7 and each R 8 It is hydrogen.

13. The compound according to any one of claims 1-12, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 It is hydrogen.

14. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (Ia): 。 15. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (Ib): 。 16. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (Ic): 。 17. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (Id): 。 18. The compound according to any one of claims 1-17, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 Independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

19. The compound according to any one of claims 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 It is independently selected from halogens.

20. The compound according to any one of claims 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 Selected independently from C 1-6 alkyl.

21. The compound according to any one of claims 1-20, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.

22. The compound according to any one of claims 1-20, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1.

23. The compound according to any one of claims 1-17, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.

24. A compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof: ； in: Ring A and ring B are each independently selected from a 6-membered heteroaryl group and a phenyl group, wherein at least one of ring A and ring B is a 6-membered heteroaryl group; X is selected from -C(R 7 )(R 8 )C(R 7 )(R 8 )-, -C(R 7 )(R 8 )C(O)-, -C(O)C(R 7 )(R 8 )-, -C(R 7 )(R 8 )S-, -SC(R 7 )(R 8 )-, -C(R 7 )(R 8 )O-, -OC(R 7 )(R 8 )-, -C(R 7 )(R 8 )N(R 9 )-, -N(R 9 )C(R 7 )(R 8 )-, -C(R 7 )(R 8 )(-, -C(O)-, -N(R 9 )-, -O-, -S-, -S(O)- and -S(O)2-; R 1 Selected from hydrogen, -OR 7 -N(R) 7 (R) 8 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocyclic alkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Halogenated alkyl, C3-C6 cycloalkyl, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups may be substituted; R 2 Selected from -OR 7 -N(R) 7 (R) 8 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocyclic alkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Halogenated alkyl, C3-C6 cycloalkyl, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups are substituted; or R 1 With R 2 The combination forms elements optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 C2-C9 heterocyclic alkyl groups substituted with 1, 2, or 3 groups; Each R 3 and each R 4 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、S(=O)(=NH)N(R 10 (R) 11 -CH2C(O)N(R) 10 (R) 11 ), -CH2N(R 12 )C(O)R 13 -CH2S(O)2R 13 and -CH2S(O)2N(R 10 (R) 11 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10 One, two, or three groups are substituted; R 5 and R 6 Independently selected from hydrogen and C1-C6 alkyl groups; Each R 7 and each R 8 Independently selected from hydrogen and C1-C6 alkyl groups; R 9 Selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 10 Independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; Each R 11 Independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 12 Independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 13 Choose C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; n is 1, 2, 3, 4, or 5; and p can be 0, 1, 2, 3, or 4.

25. The compound of claim 24, or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is pyridyl and ring B is phenyl.

26. The compound of claim 24, or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is phenyl and ring B is pyridyl.

27. The compound of claim 24, or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is pyridyl and ring B is pyridyl.

28. The compound according to any one of claims 24-27, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 Selected from halogen, -CN, -OR 10 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl, wherein C 1-6 Alkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10 One, two, or three groups are substituted.

29. The compound according to any one of claims 24-28, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 Independently selected from halogen, -CN, -OR 10 C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and unsubstituted C 3-6 cycloalkyl and each R 10 Selected independently from C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

30. The compound according to any one of claims 24-29, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.

31. The compound according to any one of claims 24-29, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.

32. The compound according to any one of claims 24-31, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 Independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

33. The compound according to any one of claims 24-32, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 Selected independently from C 1-6 alkyl.

34. The compound according to any one of claims 24-33, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1.

35. The compound according to any one of claims 24-31, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.

36. The compound according to any one of claims 24-35, or a pharmaceutically acceptable salt or solvate thereof, wherein X is selected from -C(R 7 (R) 8 )C(R 7 (R) 8 )- and -C(R 7 (R) 8 )O-.

37. The compound according to any one of claims 24-36, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(R) 7 (R) 8 )O-.

38. The compound according to any one of claims 24-36, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(R) 7 (R) 8 )C(R 7 (R) 8 )-.

39. The compound according to any one of claims 24-38, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 7 and each R 8 It is hydrogen.

40. The compound according to any one of claims 24-39, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 It is hydrogen.

41. A compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof: ； in: Ring A is a C2-C6 heterocyclic alkyl ring; Z is -N(R) 1 (R) 2 ) or -OH; R 1 Selected from hydrogen, -OR 7 -N(R) 7 (R) 8 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocyclic alkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Halogenated alkyl, C3-C6 cycloalkyl, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups may be substituted; R 2 Selected from -OR 7 -N(R) 7 (R) 8 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocyclic alkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Halogenated alkyl, C3-C6 cycloalkyl, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups are substituted; or R 1 With R 2 The combination forms elements optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 C2-C9 heterocyclic alkyl groups substituted with 1, 2, or 3 groups; Each R 3 and each R 4 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、S(=O)(=NH)N(R 10 (R) 11 -CH2C(O)N(R) 10 (R) 11 ), -CH2N(R 12 )C(O)R 13 -CH2S(O)2R 13 and -CH2S(O)2N(R 10 (R) 11 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10 One, two, or three groups are substituted; R 5 and R 6 Independently selected from hydrogen and C1-C6 alkyl groups; Each R 7 and each R 8 Independently selected from hydrogen and C1-C6 alkyl groups; Each R 10 Independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; Each R 11 Independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 12 Independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 13 Choose C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; n is 1, 2, 3, 4, or 5; and p can be 0, 1, 2, or 3.

42. The compound according to claim 41, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (IIIa): 。 43. A compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof: ； in: Ring A is a C2-C6 heterocyclic alkyl ring; Z is -N(R) 1 (R) 2 ) or -OH; R 1 Selected from hydrogen, -OR 7 -N(R) 7 (R) 8 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocyclic alkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Halogenated alkyl, C3-C6 cycloalkyl, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups may be substituted; R 2 Selected from -OR 7 -N(R) 7 (R) 8 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocyclic alkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Halogenated alkyl, C3-C6 cycloalkyl, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups are substituted; or R 1 With R 2 The combination forms elements optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 C2-C9 heterocyclic alkyl groups substituted with 1, 2, or 3 groups; Each R 3 and each R 4 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、S(=O)(=NH)N(R 10 (R) 11 -CH2C(O)N(R) 10 (R) 11 ), -CH2N(R 12 )C(O)R 13 -CH2S(O)2R 13 and -CH2S(O)2N(R 10 (R) 11 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10 One, two, or three groups are substituted; R 5 and R 6 Independently selected from hydrogen and C1-C6 alkyl groups; Each R 7 and each R 8 Independently selected from hydrogen and C1-C6 alkyl groups; Each R 10 Independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; Each R 11 Independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 12 Independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 13 Choose C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; n is 0, 1, 2, 3, or 4; and p can be 0, 1, 2, 3, or 4.

44. The compound according to claim 43, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (IVa): 。 45. The compound according to any one of claims 41-44, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 Selected from halogen, -CN, -OR 10 C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

46. ​​The compound according to any one of claims 41-45, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 Selected from halogens.

47. The compound according to any one of claims 41-45, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 Selected from C 1-6 Halogenated alkyl groups.

48. The compound according to any one of claims 41-45, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 Selected from -OR 10 And each R 3 C 1-6 alkyl.

49. The compound according to any one of claims 41-48, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.

50. The compound according to any one of claims 41-48, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.

51. The compound according to any one of claims 41-44, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

52. The compound according to any one of claims 41-51, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 Independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

53. The compound according to any one of claims 41-52, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 Selected independently from C 1-6 alkyl.

54. The compound according to any one of claims 41-53, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1.

55. The compound according to any one of claims 41-51, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.

56. The compound according to any one of claims 41-55, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 It is hydrogen.

57. The compound according to any one of claims 41-56, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -N(R 1 (R) 2 ).

58. A compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof: ； in: Y is selected from -O-, -N(R) 9 )-, -S-, -S(O)-, -S(O)2-, -C(R 7 (R) 8 - and -C(O)-; R 1 Selected from hydrogen, -OR 7 -N(R) 7 (R) 8 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocyclic alkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Halogenated alkyl, C3-C6 cycloalkyl, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups may be substituted; R 2 Selected from -OR 7 -N(R) 7 (R) 8 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocyclic alkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Halogenated alkyl, C3-C6 cycloalkyl, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 One, two, or three groups are substituted; or R 1 With R 2 The combination forms elements optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 C2-C9 heterocyclic alkyl groups substituted with 1, 2, or 3 groups; R 3 Selected from C3-C8 alkyl, C3-C8 alkenyl, and C3-C8 alkynyl, wherein the C3-C8 alkyl, C3-C8 alkenyl, and C3-C8 alkynyl are optionally selected from halogens, C... 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 -C(O)R 13 and -S(O)2R 13 One, two, or three groups may be substituted; Each R 4 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、S(=O)(=NH)N(R 10 (R) 11 -CH2C(O)N(R) 10 (R) 11 ), -CH2N(R 12 )C(O)R 13 -CH2S(O)2R 13 and -CH2S(O)2N(R 10 (R) 11 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -C(O)OR 10 One, two, or three groups are substituted; R 5 and R 6 Independently selected from hydrogen and C1-C6 alkyl groups; Each R 7 and each R 8 Independently selected from hydrogen and C1-C6 alkyl groups; R 9 Selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 10 Independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; Each R 11 Independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 12 Independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 13 Choose C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is substituted with one, two, or three groups; and m can be 0, 1, 2, 3, or 4.

59. The compound of claim 58, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is selected from -O-, -N(R) 9 -, -S- and -C(R) 7 (R) 8 )-.

60. The compound of claim 58 or claim 59, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -O-.

61. The compound according to any one of claims 58-60, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 For optional selection of halogen, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 -C(O)R 13 and -S(O)2R 13 C3-C8 alkyl groups substituted with 1, 2 or 3 groups.

62. The compound according to any one of claims 58-61, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 For optional selection of halogen, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 C3-C8 alkyl groups substituted with 1, 2 or 3 groups.

63. The compound according to any one of claims 58-62, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 It is an unsubstituted C3-C8 alkyl group.

64. The compound according to any one of claims 58-63, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 It is hydrogen.

65. The compound according to any one of claims 58-64, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0.

66. The compound according to any one of claims 1-65, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is hydrogen.

67. The compound according to any one of claims 1-65, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is a C1-C6 alkyl group.

68. The compound according to any one of claims 1-67, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Optionally selected from halogens, C1-C6 alkyl groups, C 1-6 Halogenated alkyl groups, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 C1-C6 alkyl groups substituted with 1, 2 or 3 groups.

69. The compound according to any one of claims 1-68, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 For being selected from halogens, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 C1-C6 alkyl groups substituted with 1, 2 or 3 groups.

70. The compound according to any one of claims 1-69, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is a C1-C6 alkyl group substituted with 1, 2 or 3 -OH groups.

71. The compound according to any one of claims 1-69, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is a C1-C6 alkyl group that is substituted with 1, 2 or 3 halogens.

72. The compound according to any one of claims 1-68, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is an unsubstituted C1-C6 alkyl group.

73. The compound of claim 72, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is -CH3.

74. The compound according to any one of claims 1-67, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Optionally selected from halogens, C1-C6 alkyl groups, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 C3-C6 cycloalkyl groups substituted with 1, 2 or 3 groups.

75. The compound of claim 74, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is an unsubstituted C3-C6 cycloalkyl group.

76. The compound according to any one of claims 1-67, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Optionally selected from halogens, C1-C6 alkyl groups, C 1-6 Halogenated alkyl groups, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 C with 1, 2 or 3 substituents 1-9 Mixed aromatic compounds.

77. The compound of claim 76, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Optionally selected from halogens, C1-C6 alkyl groups, C 1-6 Halogenated alkyl groups, -CN, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 C with 1, 2 or 3 substituents 1-9 heteroaryl, of which C 1-9 The heteroaryl group is selected from pyridinyl, pyridinyl, pyrimidinyl and pyrazinyl.

78. The compound of claim 77, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is selected from unsubstituted pyridinyl, unsubstituted pyridazinyl, unsubstituted pyrimidinyl and unsubstituted pyrazinyl.

79. The compound according to any one of claims 1-67, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 With R 2 The combination forms elements optionally selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 ) and -S(O)2R 13 C2-C9 heterocyclic alkyl groups substituted with 1, 2 or 3 groups.

80. The compound of claim 79, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 With R 2 They combine to form unsubstituted C2-C9 heterocyclic alkyl groups.

81. The compound according to any one of claims 41-56, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -OH.

82. A compound, or a pharmaceutically acceptable salt or solvate thereof, selected from: 。 83. A compound, or a pharmaceutically acceptable salt or solvate thereof, selected from: 。 84. A pharmaceutical composition comprising a compound according to any one of claims 1-83, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

85. The pharmaceutical composition of claim 84 further comprises a peripheral limiting fatty acid amide hydrolase (FAAH) inhibitor.

86. The pharmaceutical composition of claim 85, wherein the peripherally restricted FAAH inhibitor is ASP-3652.

87. A method of treating a CNS disease or condition in a patient in need, comprising administering to the patient a therapeutically effective amount of the compound according to any one of claims 1-83, or a pharmaceutically acceptable salt or solvate thereof.

88. The method of claim 87 further comprises administering a peripheral limiting fatty acid amide hydrolase (FAAH) inhibitor.

89. The method of claim 88, wherein the peripherally restricted FAAH inhibitor is ASP-3652.

90. A method of treating a CNS disease or condition in a patient in need, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition according to any one of claims 84-86, or a pharmaceutically acceptable salt or solvate thereof.

91. The method according to any one of claims 87-90, wherein the CNS disease or condition is selected from neurodegenerative diseases, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), substance abuse including alcohol abuse, bipolar disorder, mild cognitive impairment, age-related memory impairment (AAMI), Alzheimer's disease, epilepsy, AIDS-related dementia, Pick's disease, Lewy body-related dementia, Down syndrome-related dementia, schizophrenia, schizoaffective disorder, smoking cessation, multiple sclerosis, CNS dysfunction related to traumatic brain injury, infertility, poor circulation, wound healing-related angiogenesis requirements, ischemia, sepsis, neurodegeneration, and neuropathic pain.

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