Small molecule inhibitors of ubiquitin-specific protease 1 (USP1) and uses thereof

Abstract

Small molecule inhibitory compounds of ubiquitin-specific protease 1 (USP1) and compositions comprising the same are provided. Also provided are methods for targeting ubiquitin-specific protease 1 (USP1) and methods of treating diseases or disorders associated with USP1, such as cancer.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This patent application claims the benefit of International Application No. PCT / CN2021 / 130284, filed on November 12, 2021, and International Application No. PCT / CN2022 / 123821, filed on October 8, 2022, each of which is incorporated herein by reference in its entirety. Background Art

[0003] Ubiquitin-specific protease 1 (USP1) is a gene that plays a role in DNA damage repair. Compounds and pharmaceutical compositions targeting USP1, as well as treatments for USP1-associated diseases and conditions, such as certain cancers, have not been widely developed. Therefore, there remains a need for methods to treat USP1-associated diseases. Summary of the Invention

[0004] The present disclosure addresses the above needs and provides additional advantages as well.

[0005] In one aspect, described herein is a compound having the structure of Formula (I), or a salt or solvate thereof,

[0006]

[0007] in,

[0008] X 1 N or CR 1 ;

[0009] X 3 N or CR 3 ;

[0010] X 7 N or CR 7 ;

[0011] R 1 、R 3 and R 7 Each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl;

[0012] R 8 and R 9 are each independently selected from hydrogen, halo, -CN, optionally substituted C 1-6Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl;

[0013] Ring A is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl;

[0014] R A are each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 );

[0015] R 11 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4 Alkylene-C 3-8 Cycloalkyl, optionally substituted -C 1-4 Alkylene-C 2-7 Heterocycloalkyl, optionally substituted -C 1-4 Alkylene-phenyl or optionally substituted-C 1-4 alkylene-heteroaryl;

[0016] R 12 Each independently selected from hydrogen, -NO2, -CN, C 1-6 Alkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl;

[0017] B is a 6-membered heteroaryl group, a phenyl group or a phenyl isostere;

[0018] R B1 is halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl;

[0019] Each R B are independently halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl; or

[0020] R B1 and an R on an adjacent atom B Together with the atoms to which it is attached, it forms an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted monocyclic heteroaryl, an optionally substituted bicyclic heteroaryl, an optionally substituted C 3-8 Cycloalkyl or optionally substituted C 2-9 heterocycloalkyl; or

[0021] R B1 and an R on the same atom B Together with the atoms to which it is attached, it forms an optionally substituted C 3-8 Cycloalkyl or optionally substituted C 2-9 heterocycloalkyl; or

[0022] Two R on the same atom B Together with the atoms to which it is attached, it forms an optionally substituted C 3-8 Cycloalkyl or optionally substituted C 2-9 heterocycloalkyl;

[0023] m is 1, 2, 3 or 4;

[0024] n is 0, 1, 2, 3 or 4; and

[0025] p is 0 or 1.

[0026] In one aspect, provided herein is a compound having the structure of Formula (I) or a salt thereof,

[0027]

[0028] in,

[0029] X 1 N or CR 1 ;

[0030] X 3 N or CR 3 ;

[0031] X 7 N or CR 7 ;

[0032] R 1 、R 3 and R 7 Each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl;

[0033] R 8 and R 9 are each independently selected from hydrogen, halo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl;

[0034] Ring A is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl;

[0035] R A are each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12)2S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 );

[0036] R 11 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4 Alkylene-C 3-8 Cycloalkyl, optionally substituted -C 1-4 Alkylene-C 2-7 Heterocycloalkyl, optionally substituted -C 1-4 Alkylene-phenyl or optionally substituted-C 1-4 alkylene-heteroaryl;

[0037] R 12 Each independently selected from hydrogen, -NO2, -CN, C 1-6 Alkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl;

[0038] B is a 6-membered heteroaryl group, a phenyl group or a phenyl isostere;

[0039] R B1 is optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl;

[0040] Each R Bare independently halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl; or

[0041] Two R on the same atom B Together with the atoms to which it is attached, it forms an optionally substituted C 3-8 Cycloalkyl or optionally substituted C 2-9 heterocycloalkyl;

[0042] m is 1, 2, 3 or 4;

[0043] n is 0, 1, 2, 3 or 4; and

[0044] p is 0 or 1.

[0045] In some embodiments, the compound has the structure of Formula (Ia),

[0046]

[0047] in,

[0048] X 1 N or CR 1 ;

[0049] X 3 N or CR 3 ;

[0050] X 7 N or CR 7 ;

[0051] R 1 、R 3 and R 7 Each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl;

[0052] Y 1 N or CR Y1 ;

[0053] Y 2 N or CR Y2 ;

[0054] Y 3 N or CR Y3 ;

[0055] Y 4 N or CR Y4 ;

[0056] R Y1 、R Y2 、R Y3 and R Y4 Each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl;

[0057] R 8 and R 9 are each independently selected from hydrogen, halo, -CN, optionally substituted C1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl;

[0058] Ring A is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl;

[0059] R A are each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 );

[0060] R 11 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4 Alkylene-C 3-8 Cycloalkyl, optionally substituted -C 1-4 Alkylene-C 2-7 Heterocycloalkyl, optionally substituted -C 1-4 Alkylene-phenyl or optionally substituted-C 1-4 alkylene-heteroaryl;

[0061] R 12 Each independently selected from hydrogen, -NO2, -CN, C 1-6 Alkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl;

[0062] R B1 is optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl;

[0063] m is 1, 2, 3 or 4;

[0064] And p is 0 or 1.

[0065] In some embodiments, the compound has the structure of Formula (Ib),

[0066]

[0067] In one aspect, described herein is a structure of formula (II'), or a salt or solvate thereof,

[0068]

[0069] in,

[0070] X 1 N or CR 1 ;

[0071] X 2 N or CR 2 ;

[0072] X 3 N or CR 3 ;

[0073] X 5 is N;

[0074] X 6 N, NR 6 , CR 6 、C(R 6 )2, S(═O)2, C(═O) or C(═S);

[0075] X 7 N, NR 7 , O, S, CR 7 , S(=O)2, C(=O) or C(=S);

[0076] The conditions are: (i) when X 2 、X 3 and X 5 is N, and X 6 When it is C(=O), then X 7 O, S, CR 7 , C(=O) or C(=S), and (ii) when X 2 、X 3 and X 5 When N, then X 6 and X 7 At least one of is selected from O, S, S(═O) 2 , C(═O) or C(═S);

[0077] is a single bond or a double bond;

[0078] R 1 、R 2 、R 3 、R 6 and R 7 Each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl;

[0079] R 8 and R 9 are each independently selected from hydrogen, halo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl;

[0080] Ring A is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl;

[0081] R A are each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 );

[0082] R 11 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4 Alkylene-C 3-8 Cycloalkyl, optionally substituted -C 1-4 Alkylene-C 2-7 Heterocycloalkyl, optionally substituted -C 1-4 Alkylene-phenyl or optionally substituted-C 1-4 alkylene-heteroaryl;

[0083] R 12 Each independently selected from hydrogen, -NO2, -CN, C 1-6 Alkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl and C 3-6 Carbocyclic ring, 3-membered to 6-membered heterocyclic ring, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl;

[0084] B is a 6-membered heteroaryl group, a phenyl group or a phenyl isostere;

[0085] R B1 is halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl;

[0086] Each R B are independently halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl; or

[0087] R B1 and an R on an adjacent atom B Together with the atoms to which it is attached, it forms an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted monocyclic heteroaryl, an optionally substituted bicyclic heteroaryl, an optionally substituted C 3-8 Cycloalkyl or optionally substituted C 2-9 heterocycloalkyl; or

[0088] R B1 and an R on the same atom B Together with the atoms to which it is attached, it forms an optionally substituted C 3-8 Cycloalkyl or optionally substituted C 2-9 heterocycloalkyl; or

[0089] Two R on the same atom B Together with the atoms to which it is attached, it forms an optionally substituted C 3-8 Cycloalkyl or optionally substituted C 2-9 heterocycloalkyl;

[0090] m is 1, 2, 3 or 4;

[0091] n is 0, 1, 2, 3 or 4; and

[0092] p is 0 or 1.

[0093] In some embodiments, X 2 is N.

[0094] In some embodiments, R B1 is optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl;

[0095] Each R B are independently halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl; or two R on the same atom B Together with the atoms to which it is attached, it forms an optionally substituted C 3-8 Cycloalkyl or optionally substituted C 2-9 heterocycloalkyl;

[0096] In some embodiments, the compound has the structure of Formula (IIa),

[0097]

[0098] In some embodiments, the compound has the structure of Formula (IIa-1),

[0099]

[0100] in,

[0101] X 1 N or CR 1 ;

[0102] X 2 N or CR 2 ;

[0103] X 3 N or CR3 ;

[0104] X 7 NR 7 , O, S, S(═O) 2 , C(═O) or C(═S);

[0105] R 1 、R 2 、R 3 and R 7 Each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl;

[0106] Y 1 N or CR Y1 ;

[0107] Y 2 N or CR Y2 ;

[0108] Y 3 N or CR Y3 ;

[0109] Y 4 N or CR Y4 ;

[0110] R Y1 、R Y2 、R Y3 and R Y4 Each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl;

[0111] R 8 and R 9 are each independently selected from hydrogen, halo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl;

[0112] Ring A is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl;

[0113] R A are each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 );

[0114] R 11 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4 Alkylene-C 3-8 Cycloalkyl, optionally substituted -C 1-4 Alkylene-C 2-7 Heterocycloalkyl, optionally substituted -C 1-4 Alkylene-phenyl or optionally substituted-C 1-4 alkylene-heteroaryl;

[0115] R 12 Each independently selected from hydrogen, -NO2, -CN, C 1-6 Alkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl and C 3-6 Carbocyclic ring, 3-membered to 6-membered heterocyclic ring, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl;

[0116] R B1 is optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl;

[0117] m is 1, 2, 3 or 4; and

[0118] p is 0 or 1.

[0119] In some embodiments, the compound of formula (IIa-1) has the structure of formula (IIa-1a),

[0120]

[0121] In some embodiments, the compound has the structure of Formula (IIb),

[0122]

[0123] In some embodiments, the compound has the structure of Formula (IIb-1),

[0124]

[0125] in,

[0126] X 1 N or CR 1 ;

[0127] X 2 N or CR 2 ;

[0128] X 3 N or CR 3 ;

[0129] The condition is X 1 、X 2 、X 3 At least one of is N;

[0130] R 1 、R 2 and R 3 Each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl;

[0131] Y 1 N or CR Y1 ;

[0132] Y 2 N or CR Y2 ;

[0133] Y 3 N or CR Y3 ;

[0134] Y 4 N or CR Y4 ;

[0135] R Y1 、R Y2 、R Y3 and R Y4 Each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl;

[0136] R8 and R 9 are each independently selected from hydrogen, halo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl;

[0137] Ring A is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl;

[0138] R A are each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 );

[0139] R 11is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4 Alkylene-C 3-8 Cycloalkyl, optionally substituted -C 1-4 Alkylene-C 2-7 Heterocycloalkyl, optionally substituted -C 1-4 Alkylene-phenyl or optionally substituted-C 1-4 alkylene-heteroaryl;

[0140] R 12 Each independently selected from hydrogen, -NO2, -CN, C 1-6 Alkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl and C 3-6 Carbocyclic ring, 3-membered to 6-membered heterocyclic ring, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl;

[0141] R B1 is halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl;

[0142] m is 1, 2, 3 or 4; and

[0143] p is 0 or 1.

[0144] In some embodiments, the compound of formula (IIb-1) has the structure of formula (IIb-1a),

[0145]

[0146] In some embodiments, the compound has the structure of Formula (IIc),

[0147]

[0148]

[0149] In some embodiments, the compound has the structure of Formula (IIc-1),

[0150]

[0151] in,

[0152] R 1 、R 3 and R 7 Each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl;

[0153] Y1 N or CR Y1 ;

[0154] Y 2 N or CR Y2 ;

[0155] Y 3 N or CR Y3 ;

[0156] Y 4 N or CR Y4 ;

[0157] R Y1 、R Y2 、R Y3 and R Y4 Each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl;

[0158] R 8 and R 9 are each independently selected from hydrogen, halo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl;

[0159] Ring A is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl;

[0160] R A are each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 );

[0161] R 11 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4 Alkylene-C 3-8 Cycloalkyl, optionally substituted -C 1-4 Alkylene-C 2-7 Heterocycloalkyl, optionally substituted -C 1-4 Alkylene-phenyl or optionally substituted-C 1-4 alkylene-heteroaryl;

[0162] R 12 Each independently selected from hydrogen, -NO2, -CN, C 1-6 Alkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl and C 3-6 Carbocyclic ring, 3-membered to 6-membered heterocyclic ring, wherein the C 3-6The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl;

[0163] R B1 is optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl;

[0164] m is 1, 2, 3 or 4; and

[0165] p is 0 or 1.

[0166] In some embodiments, the compound has the structure of Formula (IId),

[0167]

[0168] In some embodiments, the compound has the structure of Formula (IId-1),

[0169]

[0170] In some embodiments, the compound has the structure of Formula (IIe),

[0171]

[0172] In some embodiments, the compound has the structure of Formula (IIg),

[0173]

[0174]

[0175] In one aspect, described herein is a compound having the structure of Formula (VI), or a salt or solvate thereof,

[0176]

[0177] in,

[0178] Ring C is phenyl or 6-membered heteroaryl, wherein said phenyl or heteroaryl are each optionally substituted;

[0179] Ring D is an aromatic, saturated or partially saturated 5-membered carbocyclic or heterocyclic ring, wherein each of the carbocyclic or heterocyclic ring is optionally substituted;

[0180] R8 and R 9 are each independently selected from hydrogen, halo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl;

[0181] Ring A is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl;

[0182] R A are each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 );

[0183] R 11is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4 Alkylene-C 3-8 Cycloalkyl, optionally substituted -C 1-4 Alkylene-C 2-7 Heterocycloalkyl, optionally substituted -C 1-4 Alkylene-phenyl or optionally substituted-C 1-4 alkylene-heteroaryl;

[0184] R 12 Each independently selected from hydrogen, -NO2, -CN, C 1-6 Alkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl and C 3-6 Carbocyclic ring, 3-membered to 6-membered heterocyclic ring, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl;

[0185] R B is hydrogen, halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl;

[0186] m is 1, 2, 3 or 4; and

[0187] p is 0 or 1

[0188] In one aspect, described herein is a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

[0189] In one aspect, described herein is a method of modulating ubiquitin-specific protease 1 (USP1) in a subject, comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of a compound described herein.

[0190] In one aspect, described herein is a method of inhibiting ubiquitin-specific protease 1 (USP1) in a subject, comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of a compound described herein.

[0191] In one aspect, described herein is a method of inhibiting or reducing DNA repair activity regulated by ubiquitin-specific protease 1 (USP1) in a subject, comprising administering to a subject in need thereof an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of a compound described herein.

[0192] In one aspect, described herein is a method of treating a disease or condition associated with ubiquitin-specific protease 1 (USP1) in a subject, comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of a compound described herein.

[0193] In one aspect, described herein is a method of treating a disease or condition associated with regulation of ubiquitin-specific protease 1 (USP1) in a subject, comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of a compound described herein. In some embodiments, the disease or condition is cancer.

[0194] In one aspect, described herein is a method of treating cancer in a subject, comprising administering to a subject in need thereof an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of a compound described herein. In some embodiments, the cancer is selected from the group consisting of lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, and breast cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is ovarian cancer or breast cancer.

[0195] In some embodiments, the cancer comprises cancer cells with elevated levels of RAD 18. In some embodiments, the cancer is a cancer deficient in a DNA damage repair pathway. In some embodiments, the cancer is a PARP inhibitor resistant or refractory cancer. In some embodiments, the cancer is a BRCA1 mutant cancer and / or a BRCA2 mutant cancer. In some embodiments, the cancer is a BRAC1 deficient cancer.

[0196] Incorporated by Reference

[0197] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent that publications, patents, or patent applications incorporated by reference conflict with the disclosure contained in this specification, this specification is intended to supersede and / or take precedence over any such conflicting material. DETAILED DESCRIPTION

[0198] Although various embodiments of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Many variations, changes, and substitutions may occur to those skilled in the art without departing from the present disclosure. It should be understood that a variety of alternatives to the embodiments of the present disclosure described herein may be used.

[0199] A. Definition

[0200] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications mentioned herein are incorporated by reference.

[0201] "Alkyl" refers to an optionally substituted straight-chain or optionally substituted branched saturated monovalent hydrocarbon group, and preferably has from one to fifteen carbon atoms (i.e., C1-C 15 In certain embodiments, the alkyl group contains from one to thirteen carbon atoms (i.e., C1-C 13 In certain embodiments, the alkyl group comprises one to eight carbon atoms (i.e., C1-C8 alkyl). In other embodiments, the alkyl group comprises one to five carbon atoms (i.e., C1-C5 alkyl). In other embodiments, the alkyl group comprises one to four carbon atoms (i.e., C1-C4 alkyl). In other embodiments, the alkyl group comprises one to three carbon atoms (i.e., C1-C3 alkyl). In other embodiments, the alkyl group comprises one to two carbon atoms (i.e., C1-C2 alkyl). Whenever a numerical range such as "C1-C3 alkyl" appears in this document, it means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, or 3 carbon atoms. In other embodiments, the alkyl group comprises one carbon atom (i.e., C1 alkyl). In other embodiments, the alkyl group comprises five to fifteen carbon atoms (i.e., C5-C 15In certain embodiments, the alkyl group is selected from the group consisting of methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). In other embodiments, examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, etc. The alkyl group is attached to the rest of the molecule by a single bond. Unless otherwise specifically stated in this specification, alkyl is optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkyl is optionally substituted by oxo, halogen, -CN, -CF , -OH, -OMe, -NH , -NO , or -C≡CH. In some embodiments, alkyl is optionally substituted by oxo, halogen, -CN, -CF , -OH, or -OMe. In some embodiments, alkyl is optionally substituted by halogen such as F.

[0202] As used herein, C1-C x (or C 1-x ) including C1-C2, C1-C3...C1-C x By way of example only, a group designated "C1-C4" indicates that there are from one to four carbon atoms in the moiety, i.e., a group containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, by way of example only, "C1-C4 alkyl" indicates that there are from one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Furthermore, by way of example, C0-C2 alkylene includes direct bonds, -CH2-, and -CH2CH2- linkages.

[0203] "Alkoxy" refers to a group bonded via an oxygen atom with the formula -O-alkyl, wherein alkyl is an alkyl chain as defined above. Unless otherwise specifically stated in this specification, alkoxy may be optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkoxy is optionally substituted by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, alkoxy is optionally substituted by oxo, halogen, -CN, -CF3, -OH or -OMe. In some embodiments, alkoxy is optionally substituted by halogen.

[0204] "Alkenyl" refers to an optionally substituted straight or branched hydrocarbon chain radical containing at least one carbon-carbon double bond and preferably having from two to twelve carbon atoms (i.e., C2-C 12In some embodiments, the alkenyl group comprises two to eight carbon atoms (i.e., C2-C8 alkenyl). In some embodiments, the alkenyl group comprises two to six carbon atoms (i.e., C2-C6 alkenyl). In other embodiments, the alkenyl group comprises two to four carbon atoms (i.e., C2-C4 alkenyl). The group may be in a cis or trans configuration around the double bond and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, etc. Whenever a numerical range such as "C2-C6 alkenyl" appears herein, it means that the alkenyl group may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. Unless otherwise specifically stated in this specification, alkenyl is optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl etc. In some embodiments, alkenyl is optionally substituted by oxo, halogen, -CN, -CF , -OH, -OMe, -NH or -NO . In some embodiments, alkenyl is optionally substituted by oxo, halogen, -CN, -CF , -OH or -OMe. In some embodiments, alkenyl is optionally substituted by halogen. Alkenyl is connected to the rest of the molecule by a single bond, such as ethenyl (i.e., vinyl (vinyl)), prop-1-enyl (i.e., allyl), but-1-enyl, penta-1-enyl, penta-1,4-dienyl etc. Unless otherwise specifically stated in this specification, alkenyl is optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkenyl is optionally substituted by oxo, halogen, -CN, -CF , -OH, -OMe, -NH or -NO . In some embodiments, alkenyl is optionally substituted by oxo, halogen, -CN, -CF , -OH or -OMe. In some embodiments, alkenyl is optionally substituted by halogen.

[0205] "Alkynyl" refers to an optionally substituted straight or branched hydrocarbon chain radical containing at least one carbon-carbon triple bond and preferably having from two to twelve carbon atoms (i.e., C2-C 12In some embodiments, the alkynyl group comprises two to eight carbon atoms (i.e., C2-C8 alkynyl). In other embodiments, the alkynyl group comprises two to six carbon atoms (i.e., C2-C6 alkynyl). In other embodiments, the alkynyl group comprises two to four carbon atoms (i.e., C2-C4 alkynyl). Whenever it appears in this article, the numerical range of "C2-C6 alkynyl" means that the alkynyl group can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. The alkynyl group is connected to the rest of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. Unless otherwise specifically stated in this specification, the alkynyl group is optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkynyl is optionally substituted with oxo, halogen, -CN, -CF , -OH, -OMe, -NH , or -NO . In some embodiments, alkynyl is optionally substituted with oxo, halogen, -CN, -CF , -OH, or -OMe. In some embodiments, alkynyl is optionally substituted with halogen.

[0206] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain that is optionally substituted and does not contain unsaturation and preferably has one to twelve carbon atoms, such as methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is connected to the rest of the molecule via a single bond and is connected to the group via a single bond. The connection point of the alkylene chain to the rest of the molecule and to the group can be realized via any two carbons in the chain. In certain embodiments, the alkylene group comprises one to ten carbon atoms (i.e., C1-C8 alkylene). In certain embodiments, the alkylene group comprises one to eight carbon atoms (i.e., C1-C8 alkylene). In other embodiments, the alkylene group comprises one to five carbon atoms (i.e., C1-C5 alkylene). In other embodiments, the alkylene group comprises one to four carbon atoms (i.e., C1-C4 alkylene). In other embodiments, the alkylene group comprises one to three carbon atoms (i.e., C1-C3 alkylene). In other embodiments, the alkylene group comprises one to two carbon atoms (i.e., C1-C2 alkylene). In other embodiments, alkylene comprises one carbon atom (i.e., C1 alkylene). In other embodiments, alkylene comprises five to eight carbon atoms (i.e., C5-C8 alkylene). In other embodiments, alkylene comprises two to five carbon atoms (i.e., C2-C5 alkylene). In other embodiments, alkylene comprises three to five carbon atoms (i.e., C3-C5 alkylene). Unless otherwise specifically stated in this specification, alkylene may be optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkylene is optionally substituted by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, alkylene is optionally substituted by oxo, halogen, -CN, -CF3, -OH or -OMe. In some embodiments, alkylene is optionally substituted by halogen. In some embodiments, alkylene is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments, alkylene is -CH2-. In some embodiments, alkylene is -CH2CH2-. In some embodiments, alkylene is -CH2CH2-. In some embodiments, alkylene is -CH2CH2CH2-.

[0207] "Aryl" refers to a group derived from a hydrocarbon ring system containing at least one aromatic ring. In some embodiments, the aryl group comprises hydrogen and 6 to 30 carbon atoms. The aryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl group is bonded through an aromatic ring atom) or a bridged ring system. In some embodiments, the aryl group is a 6- to 10-membered aryl group. In some embodiments, the aryl group is a 6-membered aryl group. Aryl groups include, but are not limited to, aryl groups derived from the following hydrocarbon ring systems: anthracene, naphthylene, phenanthrenyl, anthracene, azulene, benzene, , fluoranthene, fluorene, indane, indene, naphthalene, phenanthene, phenanthrene, pleiadene, pyrene and triphenylene. In some embodiments, aryl is phenyl. Unless otherwise specifically stated in this specification, aryl can be optionally substituted by, for example, halogen, amino, alkylamino, aminoalkyl, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -S(O)2NH-C1-C6 alkyl, etc. In some embodiments, aryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, -NO2, -S(O)2NH2, -S(O)2NHCH3, -S(O)2NHCH2CH3, -S(O)2NHCH ( In some embodiments, the aryl group is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl group is optionally substituted with halogen. In some embodiments, the aryl group is optionally substituted with alkyl, alkenyl, alkynyl, haloalkyl, or heteroalkyl, wherein each alkyl, alkenyl, alkynyl, haloalkyl, or heteroalkyl group is independently unsubstituted or substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2.

[0208] "Aralkyl" refers to a group having the formula -R c -aryl groups, where R c is an alkylene chain as defined above, for example methylene, ethylene, and the like.

[0209] "Aralkenyl" refers to a group having the formula -R d -aryl groups, where R d is an alkenylene chain as defined above. "Aralkynyl" refers to an alkylene group having the formula -R e -aryl groups, where R e is an alkynylene chain as defined above.

[0210] "Carbocycle" refers to a saturated ring, an unsaturated ring or an aromatic ring, wherein each atom of the ring is carbon.Carbocycle can include 3 to 10 yuan monocycles and 6 to 12 yuan bicyclic rings (e.g., spiro, fused or bridged rings). Each ring of a bicyclic carbocycle can be selected from a saturated ring, an unsaturated ring and an aromatic ring. Aromatic rings (e.g., phenyl) can be fused to a saturated ring or an unsaturated ring, such as cyclohexane, cyclopentane or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings is included in the definition of carbocycle when the valence number allows. In an exemplary embodiment, aromatic rings (e.g., phenyl) can be fused to a saturated ring or an unsaturated ring, such as cyclohexane, cyclopentane or cyclohexene. When the valence number allows, bicyclic carbocycle includes any combination of saturated bicyclic rings, unsaturated bicyclic rings and aromatic bicyclic rings. Bicyclic carbocycles include any combination of ring sizes, such as a 4-5 fused ring system, a 5-5 fused ring system, a 5-6 fused ring system, a 6-6 fused ring system, a 5-7 fused ring system, a 6-5 fused ring system, a 6-7 fused ring system, a 5-8 fused ring system, and a 6-8 fused ring system. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. The term "unsaturated carbocycle" refers to a carbocycle having at least one degree of unsaturation and excluding aromatic carbocycles. Examples of unsaturated carbocycles include cyclohexadiene, cyclohexene, and cyclopentene. As used herein, the term "saturated cycloalkyl" refers to a saturated carbocycle. Exemplary carbocycles include cyclopropyl, cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, norborane, and naphthyl. The carbocycle may optionally be substituted with one or more substituents, such as those described herein.

[0211] "Cycloalkyl" refers to a stable, partially or fully saturated monocyclic or polycyclic carbocyclic ring that may include fused (when fused to an aryl or heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), bridged, or spiro ring systems. Representative cycloalkyl groups include, but are not limited to, groups having three to fifteen carbon atoms (C3-C 15 cycloalkyl), three to ten carbon atoms (C3-C 10In some embodiments, the cycloalkyl group is a 3- to 6-membered cycloalkyl group. In some embodiments, the cycloalkyl group is a 5- to 6-membered cycloalkyl group. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl or carbocyclic rings include, for example, adamantyl, norbornyl, decahydronaphthalene, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decahydronaphthalene, trans-decahydronaphthalene, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane and bicyclo[3.3.2]decane and 7,7-dimethyl-bicyclo[2.2.1]heptyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Unless otherwise specifically stated in this specification, cycloalkyl is optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF , -OH, -OMe, -NH or -NO . In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF , -OH or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen.

[0212] "Cycloalkylalkyl" refers to a group having the formula -R c -cycloalkyl group, where R c is an alkylene chain as described above.

[0213] "Cycloalkylalkoxy" refers to a cycloalkylalkoxy group having the formula -OR c - a cycloalkyl group bonded via an oxygen atom, wherein R c is an alkylene chain as described above.

[0214] "Halo" or "halogen" refers to a halogen substituent such as bromo, chloro, fluoro, and iodo substituents.

[0215] As used herein, the term "haloalkyl" or "haloalkane" refers to an alkyl group as defined above that is substituted with one or more halogen groups, such as trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl group is optionally further substituted. Examples of alkanes substituted with halogens ("haloalkanes") include methyl halides (e.g., methyl chloride, methyl bromide, methyl fluoride, methyl iodide), dihalomethanes and trihalomethanes (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2-haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combination of an alkane (or substituted alkane) and a halogen (e.g., Cl, Br, F, I, etc.). When an alkyl group is substituted with more than one halogen group, each halogen can be selected independently, for example, 1-chloro, 2-fluoroethane.

[0216] "Fluoroalkyl" refers to an alkyl group as defined above substituted with one or more fluoro groups, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0217] "Hydroxyalkyl" refers to an alkyl group as defined above that is substituted with one or more hydroxyl groups. In some embodiments, the alkyl group is substituted with one hydroxyl group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

[0218] "Aminoalkyl" refers to an alkyl group as defined above that is substituted with one or more amines. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with one, two, or three amines. Aminoalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl group is aminomethyl.

[0219] The term "heteroalkyl" refers to an alkyl group in which one or more backbone atoms of the alkyl group are selected from atoms other than carbon (e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl)-), sulphur or a combination thereof). Heteroalkyl is connected to the remainder of the molecule at the carbon atom of the heteroalkyl group. In one aspect, heteroalkyl is a C1-C6 heteroalkyl group, wherein the heteroalkyl group comprises 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N (alkyl)-), sulphur or a combination thereof, wherein the heteroalkyl group is connected to the remainder of the molecule at the carbon atom of the heteroalkyl group. Examples of such heteroalkyl groups are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3 or -CH(CH3)OCH3. Unless otherwise specifically stated in this specification, heteroalkyl is optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl etc. In some embodiments, heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF , -OH, -OMe, -NH , or -NO . In some embodiments, heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF , -OH, or -OMe. In some embodiments, heteroalkyl is optionally substituted with halogen.

[0220] "Heterocycloalkyl" refers to a stable 3- to 24-membered partially or fully saturated cyclic radical containing 2 to 23 carbon atoms and at least one ring heteroatom. In some embodiments, the heterocycloalkyl contains 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. Unless otherwise specifically stated in this specification, the heterocycloalkyl may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is bonded via a non-aromatic ring atom) or bridged ring system; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl may be optionally oxidized; the nitrogen atom may be optionally quaternized.

[0221] Representative heterocycloalkyl groups include, but are not limited to, groups having two to fifteen carbon atoms (C2-C 15 Heterocycloalkyl), two to ten carbon atoms (C2-C 10In some embodiments, the heterocycloalkyl group is a 3- to 6-membered heterocycloalkyl group. In some embodiments, the heterocycloalkyl group is a 5- to 6-membered heterocycloalkyl group. Examples of such heterocycloalkyl groups include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrrolidinyl, pyridin ... The term heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. It should be understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (i.e., the backbone atoms of the heterocycloalkyl ring) that constitute the heterocycloalkyl. Unless otherwise specifically stated in this specification, heterocycloalkyl is optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heterocycloalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF , -OH, -OMe, -NH or -NO . In some embodiments, heterocycloalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF , -OH or -OMe. In some embodiments, heterocycloalkyl is optionally substituted by halogen.

[0222] "Heterocycle" or "heterocyclyl" refers to a saturated, unsaturated, or aromatic ring containing one or more ring heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include, for example, 3- to 10-membered monocycles and 6- to 12-membered bicyclic rings (e.g., spiro, fused, or bridged rings). Unless otherwise specifically stated in this specification, a heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, optionally including a fused, bridged, or spiro ring system. The heteroatoms in the heterocyclyl are optionally oxidized. If one or more nitrogen atoms are present, they are optionally quaternized. The heterocyclyl may be partially or fully saturated. A heterocyclyl is connected to the rest of the molecule via any atom of the ring. Examples of such heterocyclic groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specifically stated in the specification, the term "heterocyclic group" is intended to include heterocyclic groups as defined above that are optionally substituted with one or more substituents. For example, the heterocyclyl group may be optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioketo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2. -R b -CN, -R b -OR e -C(O)N(Ra )2. -R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R a R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain, and R e is a straight or branched alkylene or alkenylene chain, and wherein each of the above substituents is unsubstituted unless otherwise indicated.

[0223] "Heteroaryl" or "aromatic heterocycle" refers to a ring system radical comprising carbon atoms and one or more ring heteroatoms (e.g., selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur) and at least one aromatic ring. In some embodiments, the heteroaryl group is a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. The heteroaryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl group is bonded through an aromatic ring atom) or a bridged ring system; and the nitrogen, carbon, or sulfur atoms in the heteroaryl group may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5- to 6-membered heteroaryl group. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanone, isothiophene, Thiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolyl, isoquinolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxopyridinyl, 1-oxopyrimidinyl, 1-oxopyrazinyl, 1-oxopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specifically stated in this specification, heteroaryl is optionally substituted by, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroaryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF , -OH, -OMe, -NH or -NO . In some embodiments, heteroaryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF , -OH or -OMe. In some embodiments, heteroaryl is optionally substituted by halogen.

[0224] The term "substituted" refers to a portion of a substituent having one or more carbon atoms of a replacement structure or a substituent having a hydrogen atom (e.g., NH). It should be understood that "substituted" or "substituted by..." includes implicit restrictions: such substitutions are consistent with the permitted valences of the substituted atom and the substituent, and the substitution produces a stable compound, i.e., a compound that does not spontaneously undergo a transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to a portion of a substituent having two hydrogen atoms on the same carbon atom, such as replacing two hydrogen atoms on a single carbon with an oxo group, an imino group, or a thioketone group. As used herein, the term "substituted" encompasses all permissible substituents including organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For appropriate organic compounds, permissible substituents may be one or more and the same or different. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.

[0225] In some embodiments, the substituents may include any of the substituents described herein, for example, halogen, hydroxy, oxo (=O), thioketo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2. -R b -OR c -C(O)N(R a )2. -R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a)S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (wherein t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl and heterocycle, any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioketo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), SF5, -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2. -R b -OR c -C(O)N(R a )2. -R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a(where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2); where each R a is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, and heterocycle, wherein each R a It may be optionally substituted by: alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioketo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2. -R b -OR c -C(O)N(R a )2. -R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2); and wherein each R b are independently selected from a direct bond or a straight or branched alkylene, alkenylene or alkynylene chain, and each Rc is a straight or branched alkylene, alkenylene or alkynylene chain.

[0226] As used in this specification and the claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0227] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, particularly isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0228] As used herein, the phrases "parenteral administration" and "parenteral administration" mean modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0229] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0230] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of substances that can serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, Safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; and (21) other non-toxic compatible substances used in pharmaceutical preparations.

[0231] In certain embodiments, the terms "prevent" or "preventing" as used in connection with a disease or condition may mean that in a statistical sample, a compound reduces the occurrence of the condition or disorder in a treated sample relative to an untreated control sample, or delays the onset of one or more symptoms of the condition or disorder or reduces the severity of one or more symptoms relative to an untreated control sample.

[0232] As used herein, the terms "treat," "treating," and "treatment" can include alleviating, alleviating, or ameliorating the symptoms of a disease or disorder; preventing additional symptoms; ameliorating or preventing the underlying cause of the symptoms; inhibiting the disease or disorder, such as arresting the development of the disease or disorder, relieving the disease or disorder, causing regression of the disease or disorder, alleviating the condition caused by the disease or disorder, or preventing the symptoms of the disease or disorder prophylactically and / or therapeutically.

[0233] As used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of a compound disclosed herein that will be administered to alleviate to some extent one or more symptoms of the disease or disorder being treated (e.g., cancer or inflammatory disease). In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein that is necessary to achieve a clinically significant reduction in the symptoms of the disease. In some embodiments, techniques such as dose escalation studies are used to determine the appropriate "effective" amount in any individual case.

[0234] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where said event or circumstance does not occur. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl" as defined above. Additionally, optionally substituted groups may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between fully substituted and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.).

[0235] As used herein, the term "subject" can be a vertebrate, such as a mammal, fish, bird, reptile, or amphibian. Thus, the subject of the methods disclosed herein can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent. The term does not indicate a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, regardless of male or female, are intended to be encompassed. In one aspect, the subject is a mammal.

[0236] 45, 46, 47, 48, 49, or 50, and all intermediate decimal values ​​between the aforementioned integers, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to sub-ranges, "nested sub-ranges" extending from either end of the range are specifically contemplated. For example, nested sub-ranges of the exemplary range 1 to 50 may include 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.

[0237] B. Compounds of the Disclosure

[0238] In one aspect, the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof:

[0239]

[0240] in,

[0241] X 1 N or CR 1 ;

[0242] X 3 N or CR 3 ;

[0243] X 7 N or CR 7 ;

[0244] R 1 、R 3 and R 7 Each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl;

[0245] R8 and R 9 are each independently selected from hydrogen, halo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl;

[0246] Ring A is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl;

[0247] R A are each independently selected from halogen, -NO2, oxo, CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 );

[0248] R 11is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4 Alkylene-C 3-8 Cycloalkyl, optionally substituted -C 1-4 Alkylene-C 2-7 Heterocycloalkyl, optionally substituted -C 1-4 Alkylene-phenyl or optionally substituted-C 1-4 alkylene-heteroaryl;

[0249] R 12 Each independently selected from hydrogen, halogen, -OH, -NO2, CN, C 1-6 Alkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl;

[0250] B is a 6-membered heteroaryl group, a phenyl group or a phenyl isostere;

[0251] R B1 is halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl;

[0252] Each R B are independently halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl; or

[0253] R B1 and an R on an adjacent atom B Together with the atoms to which it is attached, it forms an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted monocyclic heteroaryl, an optionally substituted bicyclic heteroaryl, an optionally substituted C 3-8 Cycloalkyl or optionally substituted C 2-9 heterocycloalkyl; or

[0254] R B1 and an R on the same atom B Together with the atoms to which it is attached, it forms an optionally substituted C 3-8 Cycloalkyl or optionally substituted C 2-9 heterocycloalkyl; or

[0255] Two R on the same atom B Together with the atoms to which it is attached, it forms an optionally substituted C 3-8 Cycloalkyl or optionally substituted C 2-9 heterocycloalkyl;

[0256] m is 0, 1, 2, 3 or 4;

[0257] n is 0, 1, 2, 3 or 4; and

[0258] p is 0 or 1.

[0259] In some embodiments, the compound of formula (I),

[0260] X 1 N or CR 1 ;

[0261] X 3 N or CR 3 ;

[0262] X 7 N or CR 7 ;

[0263] R 1 、R 3 and R 7 Each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl,

[0264] wherein the alkyl, heteroalkyl, alkenyl or alkynyl group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, amino, oxo, -OH, -NO2, -CN and C 1-3 alkoxy;

[0265] R 8 and R 9 are each independently selected from hydrogen, halo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 together with the carbon to which it is attached, form an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl,

[0266] wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, amino, -OH, -NO2, oxo, -CN, C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 Haloalkyl;

[0267] Ring A is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl;

[0268] R A are each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ),

[0269] wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, oxo, amino, -CN, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, amino, -NO2, oxo, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl;

[0270] R 11 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4 Alkylene-C 3-8 Cycloalkyl, optionally substituted -C 1-4 Alkylene-C 2-7 Heterocycloalkyl, optionally substituted -C 1-4 Alkylene-phenyl or optionally substituted-C 1-4 Alkylene-heteroaryl,

[0271] wherein the alkyl, alkenyl, alkynyl, heteroalkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, amino, -NO2, oxo, C 1-6 Alkoxy, -CN, C 1-6 Alkyl and C 1-6 Haloalkyl;

[0272] R 12 Each independently selected from hydrogen, halogen, -OH, -NO2, -CN, C 1-6 Alkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl;

[0273] B is a 6-membered heteroaryl group, a phenyl group or a phenyl isostere;

[0274] R B1 is halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R12 )S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl or optionally substituted bicyclic heteroaryl,

[0275] wherein said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, naphthyl, phenyl or heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ), wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, amino, -NH(C1-6 Alkyl), -N(C 1-6 alkyl)2, oxo, -CN, C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 Haloalkyl;

[0276] Each R B are independently halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl or optionally substituted bicyclic heteroaryl,

[0277] wherein said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, naphthyl, phenyl or heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, amino, oxo, -CN, C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 haloalkyl; or

[0278] R B1 and an R on an adjacent atom B Together with the atoms to which it is attached, it forms an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted monocyclic heteroaryl, an optionally substituted bicyclic heteroaryl, an optionally substituted C 3-8 Cycloalkyl or optionally substituted C 2-9 Heterocycloalkyl,

[0279] wherein the phenyl, naphthyl, heteroaryl, cycloalkyl or heterocycloalkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, amino, -NO2, oxo, C 1-6 Alkoxy, -CN, C 1-6 Alkyl, C 1-6 haloalkyl; or

[0280] R B1 and an R on the same atom B Together with the atoms to which it is attached, it forms an optionally substituted C 3-8 Cycloalkyl or optionally substituted C 2-9 Heterocycloalkyl,

[0281] wherein the cycloalkyl or heterocycloalkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, amino, -NO2, oxo, C 1-6 Alkoxy, -CN, C 1-6 Alkyl, C 1-6 haloalkyl; or

[0282] Two R on the same atom B Together with the atoms to which it is attached, it forms an optionally substituted C 3-8 Cycloalkyl or optionally substituted C 2-9 Heterocycloalkyl,

[0283] wherein the cycloalkyl or heterocycloalkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, amino, -NO2, oxo, C 1-6 Alkoxy, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl;

[0284] m is 0, 1, 2, 3 or 4;

[0285] n is 0, 1, 2, 3 or 4; and

[0286] p is 0 or 1.

[0287] In some embodiments of the compound of formula (I), wherein

[0288] X 1N or CR 1 ;

[0289] X 3 N or CR 3 ;

[0290] X 7 N or CR 7 ;

[0291] R 1 、R 3 and R 7 Each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl,

[0292] wherein the alkyl, heteroalkyl, alkenyl or alkynyl group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, amino, oxo, -OH, -NO2, -CN and C 1-3 alkoxy;

[0293] R 8 and R 9 are each independently selected from hydrogen, halo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 together with the carbon to which it is attached, form an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl,

[0294] wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, amino, -OH, -NO2, oxo, -CN, C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 Haloalkyl;

[0295] Ring A is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl;

[0296] R Aare each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ),

[0297] wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, oxo, amino, -CN, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, amino, -NO2, oxo, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl;

[0298] R 11 is hydrogen, optionally substituted C 1-6Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4 Alkylene-C 3-8 Cycloalkyl, optionally substituted -C 1-4 Alkylene-C 2-7 Heterocycloalkyl, optionally substituted -C 1-4 Alkylene-phenyl or optionally substituted-C 1-4 Alkylene-heteroaryl,

[0299] wherein the alkyl, alkenyl, alkynyl, heteroalkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, amino, -NO2, oxo, C 1-6 Alkoxy, -CN, C 1-6 Alkyl and C 1-6 Haloalkyl;

[0300] R 12 Each independently selected from hydrogen, -NO2, -CN, C 1-6 Alkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl;

[0301] B is a 6-membered heteroaryl group, a phenyl group or a phenyl isostere;

[0302] R B1 is optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl or optionally substituted bicyclic heteroaryl,

[0303] wherein the cycloalkyl, heterocycloalkyl, naphthyl, phenyl or heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ), wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, amino, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2, oxo, -CN, C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 Haloalkyl;

[0304] Each R B are independently halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl or optionally substituted bicyclic heteroaryl,

[0305] wherein said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, naphthyl, phenyl or heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, amino, oxo, -CN, C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 haloalkyl; or

[0306] Two R on the same atom B Together with the atoms to which it is attached, it forms an optionally substituted C 3-8 Cycloalkyl or optionally substituted C 2-9 Heterocycloalkyl,

[0307] wherein the cycloalkyl or heterocycloalkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, amino, -NO2, oxo, C 1-6 Alkoxy, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl;

[0308] m is 1, 2, 3 or 4;

[0309] n is 0, 1, 2, 3 or 4; and

[0310] p is 0 or 1.

[0311] In some embodiments, the compound of formula (I) is represented by formula (Ia):

[0312]

[0313] in,

[0314] X 1 N or CR 1 ;

[0315] X 3 N or CR 3 ;

[0316] X 7 N or CR 7 ;

[0317] R 1 、R 3 and R 7 Each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl;

[0318] Y 1 N or CR Y1 ;

[0319] Y 2 N or CR Y2 ;

[0320] Y 3 N or CR Y3 ;

[0321] Y 4 N or CR Y4 ;

[0322] R Y1 、R Y2 、R Y3 and R Y4 Each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl;

[0323] R 8 and R 9 are each independently selected from hydrogen, halo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl;

[0324] Ring A is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl;

[0325] R A are each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 ),-S(O)R12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 );

[0326] R 11 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4 Alkylene-C 3-8 Cycloalkyl, optionally substituted -C 1-4 Alkylene-C 2-7 Heterocycloalkyl, optionally substituted -C 1-4 Alkylene-phenyl or optionally substituted-C 1-4 alkylene-heteroaryl;

[0327] R 12 Each independently selected from hydrogen, halogen, -OH, -NO2, -CN, C 1-6 Alkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl;

[0328] R B1 is optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl;

[0329] m is 1, 2, 3 or 4; and

[0330] p is 0 or 1.

[0331] In some embodiments, the compound of Formula (I) is represented by Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof:

[0332]

[0333] In some embodiments of compounds of Formula (I), (Ia), and (Ib), R 12 Each independently selected from hydrogen, -NO2, CN, C 1-6 Alkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 In some embodiments of compounds of Formula (I), (Ia), and (Ib), R 12 Each independently selected from hydrogen, halogen, -OH, -NO2, CN, C 1-6 Alkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl.

[0334] In some embodiments of compounds of Formula (I), (Ia), and (Ib), R 8 and R 9 are each independently selected from hydrogen, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl.

[0335] In some embodiments of compounds of Formula (I), (Ia), and (Ib), X 1 is N. In some embodiments, X 1 CR 1 In some embodiments, X 3 is N. In some embodiments, X 3 CR 3 In some embodiments, X 7 is N. In some embodiments, X 7 CR 7 .

[0336] In some embodiments of compounds of Formula (I), (Ia), and (Ib), R 1 、R 3 and R 7 are each independently selected from hydrogen, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 In some embodiments of compounds of Formula (I), (Ia), and (Ib), R 1 、R 3 and R 7 are each independently selected from hydrogen and C1-C6 alkyl.

[0337] In one aspect, the present disclosure provides a compound represented by formula (II) or a pharmaceutically acceptable salt or solvate thereof:

[0338]

[0339] in,

[0340] X 1 N or CR 1 ;

[0341] X 2 N or CR 2 ;

[0342] X 3 N or CR 3 ;

[0343] X 5 N or C;

[0344] X 6 N, NR 6 , CR 6 、C(R 6)2, S(═O)2, C(═O) or C(═S);

[0345] X 7 N, NR 7 , O, S, CR 7 , S(=O)2, C(=O) or C(=S);

[0346] The conditions are: (i) when X 2 、X 3 and X 5 is N, and X 6 When it is C(=O), then X 7 O, S, CR 7 , C(=O) or C(=S), and (ii) when X 2 、X 3 and X 5 When N, then X 6 and X 7 At least one of is selected from O, S, S(═O) 2 , C(═O) or C(═S);

[0347] is a single bond or a double bond;

[0348] R 1 、R 2 、R 3 、R 6 and R 7 Each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl;

[0349] R 8 and R 9 are each independently selected from hydrogen, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl;

[0350] Ring A is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl;

[0351] R A are each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 );

[0352] R 11 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4 Alkylene-C 3-8 Cycloalkyl, optionally substituted -C 1-4 Alkylene-C 2-7Heterocycloalkyl, optionally substituted -C 1-4 Alkylene-phenyl or optionally substituted-C 1-4 alkylene-heteroaryl;

[0353] R 12 Each independently selected from hydrogen, -NO2, -CN, C 1-6 Alkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl and C 3-6 Carbocyclic ring, 3-membered to 6-membered heterocyclic ring, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl;

[0354] B is a 6-membered heteroaryl group, a phenyl group or a phenyl isostere;

[0355] R B1 is halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl;

[0356] Each R B are independently halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl; or

[0357] R B1 and an R on an adjacent atom B Together with the atoms to which it is attached, it forms an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted monocyclic heteroaryl, an optionally substituted bicyclic heteroaryl, an optionally substituted C 3-8 Cycloalkyl or optionally substituted C 2-9 heterocycloalkyl; or

[0358] R B1 and an R on the same atom B Together with the atoms to which it is attached, it forms an optionally substituted C 3-8 Cycloalkyl or optionally substituted C 2-9 heterocycloalkyl; or

[0359] Two R on the same atom B Together with the atoms to which it is attached, it forms an optionally substituted C 3-8 Cycloalkyl or optionally substituted C 2-9 heterocycloalkyl;

[0360] m is 0, 1, 2, 3 or 4;

[0361] n is 0, 1, 2, 3 or 4; and

[0362] p is 0 or 1.

[0363] In some embodiments of the compound of Formula (II) or (II'), R 1 、R 2 、R 3 、R 6 and R 7 are each independently selected from hydrogen, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 In some embodiments of formula (II) or (II'), R 1 、R 3 、R 6 and R 7 are each independently selected from hydrogen and C 1-6 In some embodiments of formula (II) or (II'), R 1 、R 3 、R 6 and R 7 Each is hydrogen. In some embodiments of Formula (II) or (II'), (NR 6 R 6 is hydrogen, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl or optionally substituted C 2-6 In some embodiments of Formula (II) or (II'), X 6 N, NR N6 , CR 6 、C(R 6)2, S(=O)2, C(=O) or C(=S), wherein R N6 is hydrogen, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl or optionally substituted C 2-6 In some embodiments of Formula (II) or (II'), X 6 NR N6 And R N6 is hydrogen, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl or optionally substituted C 2-6 Alkynyl.

[0364] In some embodiments of Formula (II) or (II'), (NR 7 R 7 is hydrogen, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl or optionally substituted C 2-6 In some embodiments of Formula (II) or (II'), X 7 N, NR N7 , O, S, CR 7 , S(=O)2, C(=O) or C(=S), wherein R N7 is hydrogen, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl or optionally substituted C 2-6 In some embodiments of Formula (II) or (II'), X 7 NR N7 And R N7 is hydrogen, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl or optionally substituted C 2-6 Alkynyl.

[0365] In some embodiments of the compound of Formula (II) or (II'), R 12 Each independently selected from hydrogen, -NO2, CN, C 1-6 Alkyl, C 1-6 aminoalkyl, C1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 In some embodiments of the compound of formula (II) or (II'), R 12 Each independently selected from hydrogen, halogen, -OH, -NO2, CN, C 1-6 Alkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl.

[0366] In some embodiments of the compound of Formula (II) or (II'), R 8 and R 9 are each independently selected from hydrogen, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl.

[0367] In some embodiments of the compound of Formula (II) or (II'), X 2 is N.

[0368] In some embodiments, the compound of formula (II) has the structure of formula (II'),

[0369]

[0370] In some embodiments of Formula (II'), X5 is N.

[0371] In one aspect, the present disclosure provides a compound represented by formula (II') or a pharmaceutically acceptable salt or solvate thereof:

[0372]

[0373]

[0374] in,

[0375] X 1 N or CR 1 ;

[0376] X 2 N or CR 2 ;

[0377] X 3 N or CR 3 ;

[0378] X 5 is N;

[0379] X 6 N, NR N6 , CR 6 、C(R 6 )2, S(═O)2, C(═O) or C(═S);

[0380] X 7 N, NR N7 , O, S, CR 7 , S(=O)2, C(=O) or C(=S);

[0381] The conditions are: (i) when X 2 、X 3 and X 5 is N, and X 6 When it is C(=O), then X 7 O, S, CR 7 , C(=O) or C(=S), and (ii) when X 2 、X 3 and X 5 When N, then X 6 and X 7 At least one of is selected from O, S, S(═O) 2 , C(═O) or C(═S);

[0382] is a single bond or a double bond;

[0383] R 1 、R 2 、R 3、R 6 and R 7 Each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl;

[0384] R N6 and R N7 are each independently selected from hydrogen, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl;

[0385] R 8 and R 9 are each independently selected from hydrogen, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl;

[0386] Ring A is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl;

[0387] R A are each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 );

[0388] R 11 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4 Alkylene-C 3-8 Cycloalkyl, optionally substituted -C 1-4 Alkylene-C 2-7 Heterocycloalkyl, optionally substituted -C 1-4 Alkylene-phenyl or optionally substituted-C 1-4 alkylene-heteroaryl;

[0389] R 12 Each independently selected from -NO2, -CN, C 1-6 Alkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl and C 3-6 Carbocyclic ring, 3-membered to 6-membered heterocyclic ring, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl;

[0390] B is a 6-membered heteroaryl group, a phenyl group or a phenyl isostere;

[0391] R B1 is halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl;

[0392] Each R B are independently halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl; or

[0393] R B1 and an R on an adjacent atom B Together with the atoms to which it is attached, it forms an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted monocyclic heteroaryl, an optionally substituted bicyclic heteroaryl, an optionally substituted C 3-8 Cycloalkyl or optionally substituted C 2-9 heterocycloalkyl; or

[0394] R B1 and an R on the same atom B Together with the atoms to which it is attached, it forms an optionally substituted C 3-8 Cycloalkyl or optionally substituted C 2-9 heterocycloalkyl; or

[0395] Two R on the same atom B Together with the atoms to which it is attached, it forms an optionally substituted C 3-8 Cycloalkyl or optionally substituted C 2-9 heterocycloalkyl;

[0396] m is 1, 2, 3 or 4;

[0397] n is 0, 1, 2, 3 or 4; and

[0398] p is 0 or 1.

[0399] In some embodiments of Formula (II) and Formula (II'),

[0400] X 1 N or CR 1 ;

[0401] X 2 N or CR 2 ;

[0402] X 3 N or CR 3 ;

[0403] X 5 is N;

[0404] X 6 N, NR 6 , CR 6 , S(=O)2, C(=O) or C(=S);

[0405] X 7 N, NR 7 , O, S, CR 7 , S(=O)2, C(=O) or C(=S);

[0406] The conditions are: (i) when X 2 、X 3 and X 5 is N, and X 6 When it is C(=O), then X 7 O, S, CR 7 , C(=O) or C(=S), and (ii) when X 2 、X 3 and X 5 When N, then X 6 and X 7 At least one of is selected from O, S, S(═O) 2 , C(═O) or C(═S);

[0407] is a single bond or a double bond;

[0408] R 1 、R 2 、R 3 、R 6 and R 7 Each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C2-6 Alkynyl,

[0409] wherein the alkyl, heteroalkyl, alkenyl or alkynyl group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, amino, oxo, -OH, -NO2, -CN and C 1-3 alkoxy;

[0410] R 8 and R 9 are each independently selected from hydrogen, halo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 together with the carbon to which it is attached, form an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl,

[0411] wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, amino, -OH, -NO2, oxo, -CN, C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 Haloalkyl;

[0412] Ring A is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl;

[0413] R A are each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11)、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ),

[0414] wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, oxo, amino, -CN, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, amino, -NO2, oxo, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl;

[0415] R 11 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4 Alkylene-C 3-8 Cycloalkyl, optionally substituted -C 1-4 Alkylene-C 2-7 Heterocycloalkyl, optionally substituted -C 1-4 Alkylene-phenyl or optionally substituted-C 1-4 Alkylene-heteroaryl,

[0416] wherein the alkyl, alkenyl, alkynyl, heteroalkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl or 5-membered or 6-membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, amino, -NO2, oxo, C 1-6 Alkoxy, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl;

[0417] R 12 Each independently selected from hydrogen, -NO2, -CN, C 1-6 Alkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl and C 3-6 Carbocyclic ring, 3-membered to 6-membered heterocyclic ring, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl;

[0418] B is a 6-membered heteroaryl group, a phenyl group or a phenyl isostere;

[0419] R B1 is halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12),-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl or optionally substituted bicyclic heteroaryl,

[0420] wherein said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, naphthyl, phenyl or heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ), wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, amino, oxo, -CN, C 1-3 Alkoxy, C 1-3 Alkyl and C1-3 Haloalkyl;

[0421] Each R B are independently halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl or optionally substituted bicyclic heteroaryl,

[0422] wherein said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, naphthyl, phenyl or heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, amino, oxo, -CN, C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 haloalkyl; or

[0423] R B1 and an R on an adjacent atom BTogether with the atoms to which it is attached, it forms an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted monocyclic heteroaryl, an optionally substituted bicyclic heteroaryl, an optionally substituted C 3-8 Cycloalkyl or optionally substituted C 2-9 Heterocycloalkyl,

[0424] wherein the phenyl, naphthyl, heteroaryl, cycloalkyl or heterocycloalkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, amino, -NO2, oxo, C 1-6 Alkoxy, -CN, C 1-6 Alkyl, C 1-6 haloalkyl; or

[0425] R B1 and an R on the same atom B Together with the atoms to which it is attached, it forms an optionally substituted C 3-8 Cycloalkyl or optionally substituted C 2-9 Heterocycloalkyl,

[0426] wherein the cycloalkyl or heterocycloalkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, amino, -NO2, oxo, C 1-6 Alkoxy, -CN, C 1-6 Alkyl, C 1-6 haloalkyl; or

[0427] Two R on the same atom B Together with the atoms to which it is attached, it forms an optionally substituted C 3-8 Cycloalkyl or optionally substituted C 2-9 Heterocycloalkyl,

[0428] wherein the cycloalkyl or heterocycloalkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, amino, -NO2, oxo, C 1-6 Alkoxy, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl;

[0429] m is 0, 1, 2, 3 or 4;

[0430] n is 0, 1, 2, 3 or 4; and

[0431] p is 0 or 1.

[0432] In some embodiments of Formula (II) and (II'), X 6 NR N6 And R N6 is hydrogen, -CN, optionally substituted C 1-6Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl or optionally substituted C 2-6 In some embodiments of formula (II) and (II'), X 7 NR N7 And R N7 is hydrogen, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl or optionally substituted C 2-6 Alkynyl.

[0433] In some embodiments of Formula (II) and (II'), R 12 Each independently selected from hydrogen, halogen, OH, -NO2, -CN, C 1-6 Alkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl and C 3-6 Carbocyclic ring, 3-membered to 6-membered heterocyclic ring, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl.

[0434] In some embodiments, X 1 、X 2 、X 3 At least two of are N. In some embodiments, X 6 or X 7 At least one of them is N.

[0435] In some embodiments, when X 2 N and X 5 When N, R 1 、R 3 、R 6 and R 7 Each is independently hydrogen or C1-C6 alkyl.

[0436] In some embodiments of Formula (I), (Ia), (Ib), (II), or (II'), for

[0437] Y 1 N or CR Y1 ;

[0438] Y 2 N or CR Y2 ;

[0439] Y 3 N or CR Y3 ;

[0440] Y 4 N or CR Y4 ;and

[0441] R Y1 、R Y2 、R Y3 and R Y4 are each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl.

[0442] In some embodiments of Formula (I), (Ia), (Ib), (II), or (II'), X 1 is N. In some embodiments, X 2 is N. In some embodiments, X 3 is N. In some embodiments, X 5 is N. In some embodiments, X 6 is N. In some embodiments, X 7 is N.

[0443] In some embodiments, the compound of formula (II) or (II') has the structure of formula (IIa):

[0444]

[0445] In some embodiments, the compound of formula (II) or (II') has the structure of formula (IIa-1):

[0446]

[0447] in,

[0448] X 1 N or CR 1 ;

[0449] X 2 N or CR 2 ;

[0450] X3 N or CR 3 ;

[0451] X 7 NR 7 , O, S, S(═O) 2 , C(═O) or C(═S);

[0452] R 1 、R 2 、R 3 and R 7 Each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl;

[0453] Y 1 N or CR Y1 ;

[0454] Y 2 N or CR Y2 ;

[0455] Y 3 N or CR Y3 ;

[0456] Y 4 N or CR Y4 ;

[0457] R Y1 、R Y2 、R Y3 and R Y4 Each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl;

[0458] R 8 and R 9 are each independently selected from hydrogen, halo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl;

[0459] Ring A is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl;

[0460] R A are each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 );

[0461] R 11 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C3-8 Cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4 Alkylene-C 3-8 Cycloalkyl, optionally substituted -C 1-4 Alkylene-C 2-7 Heterocycloalkyl, optionally substituted -C 1-4 Alkylene-phenyl or optionally substituted-C 1-4 alkylene-heteroaryl;

[0462] R 12 Each independently selected from hydrogen, -NO2, -CN, C 1-6 Alkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl and C 3-6 Carbocyclic ring, 3-membered to 6-membered heterocyclic ring, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl;

[0463] R B1 is optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl;

[0464] m is 1, 2, 3 or 4; and

[0465] p is 0 or 1.

[0466] In some embodiments of Formula (IIa-1) and (II'), X 7 NR N7 And R N7 is hydrogen, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl or optionally substituted C 2-6 Alkynyl.

[0467] In some embodiments, the compound of formula (II) or (II') has the structure of formula (IIa-1a):

[0468]

[0469] In some embodiments, the compound of formula (II) or (II') has the structure of formula (IIb):

[0470]

[0471] In some embodiments, the compound of formula (II) or (II') has the structure of formula (IIb-1):

[0472]

[0473] in,

[0474] X 1 N or CR 1 ;

[0475] X 2 N or CR 2 ;

[0476] X 3 N or CR 3 ;

[0477] The condition is X 1 、X 2 、X 3 At least one of is N;

[0478] R 1 、R 2 and R 3 Each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl;

[0479] Y 1 N or CR Y1 ;

[0480] Y 2 N or CR Y2 ;

[0481] Y 3 N or CR Y3 ;

[0482] Y 4 N or CR Y4 ;

[0483] R Y1、R Y2 、R Y3 and R Y4 Each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl;

[0484] R 8 and R 9 are each independently selected from hydrogen, halo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl;

[0485] Ring A is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl;

[0486] R A are each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12)C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 );

[0487] R 11 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4 Alkylene-C 3-8 Cycloalkyl, optionally substituted -C 1-4 Alkylene-C 2-7 Heterocycloalkyl, optionally substituted -C 1-4 Alkylene-phenyl or optionally substituted-C 1-4 alkylene-heteroaryl;

[0488] R 12 Each independently selected from hydrogen, -NO2, -CN, C 1-6 Alkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl and C 3-6 Carbocyclic ring, 3-membered to 6-membered heterocyclic ring, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl;

[0489] R B1 is halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl;

[0490] m is 1, 2, 3 or 4; and

[0491] p is 0 or 1.

[0492] In some embodiments, the compound of formula (II) or (II') has the structure of formula (IIb-1a)

[0493]

[0494] In some embodiments, the compound of formula (II) has the structure of formula (IIc):

[0495]

[0496] In some embodiments, the compound of formula (II) or (II') has the structure of formula (IIc'):

[0497]

[0498] In some embodiments, the compound of formula (II) or (II') has the structure of formula (IIc-1):

[0499]

[0500] in,

[0501] R 1 、R 3 and R 7 Each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl;

[0502] Y 1 N or CR Y1 ;

[0503] Y 2 N or CR Y2 ;

[0504] Y 3 N or CR Y3 ;

[0505] Y 4 N or CR Y4 ;

[0506] R Y1 、R Y2 、R Y3 and R Y4 Each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl;

[0507] R 8 and R 9 are each independently selected from hydrogen, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl;

[0508] Ring A is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl;

[0509] R A are each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 );

[0510] R 11 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4Alkylene-C 3-8 Cycloalkyl, optionally substituted -C 1-4 Alkylene-C 2-7 Heterocycloalkyl, optionally substituted -C 1-4 Alkylene-phenyl or optionally substituted-C 1-4 alkylene-heteroaryl;

[0511] R 12 Each independently selected from hydrogen, -NO2, -CN, C 1-6 Alkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl and C 3-6 Carbocyclic ring, 3-membered to 6-membered heterocyclic ring, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl;

[0512] R B1 is optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl;

[0513] m is 1, 2, 3 or 4; and

[0514] p is 0 or 1.

[0515] In some embodiments, the compound of formula (II) has the structure of formula (IId):

[0516]

[0517] In some embodiments, the compound of formula (II) or (II') has the structure of formula (IId'):

[0518]

[0519] In some embodiments, the compound of formula (II) or (II') has the structure of formula (IId-1):

[0520]

[0521] In some embodiments, the compound of formula (II) or (II') has the structure of formula (IIe):

[0522]

[0523] In some embodiments, the compound of formula (II) has the structure of formula (IIf):

[0524]

[0525] In some embodiments, the compound of formula (II) or (II') has the structure of formula (IIg):

[0526]

[0527] =

[0528] In some embodiments of Formula (I), (Ia), (Ib), (II), (II'), (IIc'), (IId'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), (IIb-1a), (IIc), (IIc-1), (IId), (IId-1), (IIe), (IIf), or (IIg), Ring A is phenyl. In some embodiments, for In some embodiments, Ring A is naphthyl. In some embodiments, Ring A is a 5-membered or 6-membered monocyclic heteroaryl. In some embodiments, Ring A is pyridine, pyrimidine, pyrazine, pyridazine, triazine, imidazole, pyrazole, triazole, oxazole, isoxazole, or thiophene. In some embodiments, Ring A is a 6-membered monocyclic heteroaryl containing 1-3 heteroatoms. In some embodiments, Ring A is pyridine. In some embodiments, Ring A is pyrimidine. In some embodiments, for In some embodiments, Ring A is a bicyclic heteroaryl. In some embodiments, Ring A is a fused 5-6, 6-6, or 6-5 bicyclic heteroaryl.

[0530] In some embodiments of Formula (I), (Ia), (Ib), (II), (II'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), (IIb-1a), (IIc), (IIc-1), (IId), (IIc'), (IId'), (IId-1), (IIe), (IIf), or (IIg), R A independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ). In some embodiments, R A independently selected from -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R11 )、-N(R 12 )2S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ).

[0531] In some embodiments of Formula (I), (Ia), (Ib), (II), (II'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), (IIb-1a), (IIc), (IIc-1), (IId), (IIc'), (IId'), (IId-1), (IIe), (IIf), or (IIg), R A is independently substituted by one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, amino, -CN, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, wherein C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, amino, -NO2, oxo, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 In some embodiments, R A independently selected from -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ).

[0532] In some embodiments of Formula (I), (Ia), (Ib), (II), (II'), (IIc'), (IId'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), (IIb-1a), (IIc), (IIc-1), (IId), (IId-1), (IIe), (IIf), or (IIg, Selected from:

[0533]

[0534] In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for

[0535] In some embodiments of Formula (I), (Ia), (Ib), (II), (II'), (IIc'), (IId'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), (IIb-1a), (IIc), (IIc-1), (IId), (IId-1), (IIe), (IIf), or (IIg), p is 1. In some embodiments, p is 0.

[0536] In some embodiments of Formula (I), (Ia), (Ib), (II), (II'), (IIc'), (IId'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), (IIb-1a), (IIc), (IIc-1), (IId), (IId-1), (IIe), (IIf), or (IIg), R 8 and R 9 are each independently selected from hydrogen, halogen, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 In some embodiments, R 8 and R 9 In some embodiments, R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl. 8 and R 9 are each independently selected from hydrogen, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl.

[0537] In some embodiments of Formula (I), (Ia), (Ib), (II), (II'), (IIc'), (IId'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), (IIb-1a), (IIc), (IIc-1), (IId), (IId-1), (IIe), (IIf), or (IIg), B is a ring. In some embodiments of Formula (I), (Ia), (Ib), (II), (II'), (IIc'), (IId'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), (IIb-1a), (IIc), (IIc-1), (IId), (IId-1), (IIe), (IIf), or (IIg), Ring B is phenyl or a 6-membered heteroaryl. In some embodiments, Ring B is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, or triazine.

[0538] In some embodiments of Formula (I), (Ia), (Ib), (II), (II'), (IIc'), (IId'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), (IIb-1a), (IIc), (IIc-1), (IId), (IId-1), (IIe), (IIf), or (IIg), B is a phenyl isostere. In some embodiments, B is cubane. In some embodiments, B is and n is 0. In some embodiments, for

[0539] In some embodiments of Formula (I), (Ia), (Ib), (II), (II'), (IIc'), (IId'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), (IIb-1a), (IIc), (IIc-1), (IId), (IId-1), (IIe), (IIf), or (IIg), R B1 is halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 In some embodiments, R B1 is -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12)(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 In some embodiments, R B1 is optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 In some embodiments, R B1 is an optionally substituted monocyclic 5-6 membered heterocycloalkyl or heteroaryl. B1 is optionally substituted C 3-8 In some embodiments, R B1 In some embodiments, R B1 In some embodiments, R B1 In some embodiments, R B1 is an optionally substituted phenyl. B1 is optionally substituted C 2-9 In some embodiments, R B1 In some embodiments, R B1 In some embodiments, R B1 In some embodiments, R B1 is an optionally substituted monocyclic heteroaryl. B1 is an optionally substituted bicyclic heteroaryl group.

[0540] In some embodiments of Formula (I), (Ia), (Ib), (II), (II'), (IIc'), (IId'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), (IIb-1a), (IIc), (IIc-1), (IId), (IId-1), (IIe), (IIf), or (IIg), R B1 is optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 In some embodiments, R B1 is an optionally substituted 5-membered monocyclic heteroaryl group having 1 to 4 heteroatoms selected from N, O, S and P. In some embodiments, RB1 is imidazole, pyrazole, triazole or tetrazole, each of which is optionally substituted. B1 is an optionally substituted fused 5-6, 6-6, or 6-5 heteroaryl. B1 Optionally substituted with one or more substituents independently selected from the group consisting of halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ), wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, amino, oxo, -CN, C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 In some embodiments, R B1 Optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 11 , -NO2, oxo, -CN, optionally substituted C 1-6 Haloalkyl, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 aminoalkyl, optionally substituted C1-6 Hydroxyalkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl and optionally substituted C 2-7 Heterocycloalkyl. In some embodiments, R B1 is optionally substituted with one or more substituents independently selected from: halogen, -OR 11 , -NO2, oxo group, -CN, C 1-3 haloalkyl, C 1-3 alkyl, C 1-3 aminoalkyl, C 1-3 hydroxyalkyl, optionally substituted C 1-4 heteroalkyl (e.g., -CH2C(=O)N(CH3)2), optionally substituted C 3-6 cycloalkyl and optionally substituted C 2-5 heterocycloalkyl. In some embodiments, R B1 is optionally substituted with one or more substituents independently selected from: halogen, oxo group, -CN, C 1-3 haloalkyl, C 1-3 alkyl, C 1-3 aminoalkyl, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl and C 2-5 heterocycloalkyl. In some embodiments, R B1 is optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from C 1-3 haloalkyl and C 1-3 alkyl. In some embodiments, R B1 is substituted with halogen. In some embodiments, R B1 is substituted with -OR 11 . In some embodiments, R B1 is substituted with -NO2. In some embodiments, R B1 is substituted with an oxo group. In some embodiments, R B1 is substituted with -CN. In some embodiments, R B1 is substituted with optionally substituted C 1-6 haloalkyl. In some embodiments, R B1 is substituted with optionally substituted C 1-6 alkyl. In some embodiments, R B1 is substituted with optionally substituted C 1-6 aminoalkyl.

[0541] In some embodiments of Formula (I), (Ia), (Ib), (II), (II'), (IIc'), (IId'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), (IIb-1a), (IIc), (IIc-1), (IId), (IId-1), (IIe), (IIf), or (IIg), R B1 Selected from: In some embodiments, R B1 for In some embodiments, R B1 for In some embodiments, R B1 for In some embodiments, R B1 for In some embodiments, R B1 for In some embodiments, R B1 for

[0542] In some embodiments of Formula (I), (Ia), (Ib), (II), (II'), (IIc'), (IId'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), (IIb-1a), (IIc), (IIc-1), (IId), (IId-1), (IIe), (IIf), or (IIg), R B1 for In some embodiments of Formula (I), (Ia), (Ib), (II), (II'), (IIc'), (IId'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), (IIb-1a), (IIc), (IIc-1), (IId), (IId-1), (IIe), (IIf), or (IIg), R B1 and an R on the same atom B Together with the atoms to which it is attached, it forms an optionally substituted C 3-8 Cycloalkyl or optionally substituted C 2-9 In some embodiments, R B1 and an R on an adjacent atom B Together with the atoms to which it is attached, it forms an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted monocyclic heteroaryl, an optionally substituted bicyclic heteroaryl, an optionally substituted C 3-8 Cycloalkyl or optionally substituted C2-9 In some embodiments, R B1 and an R on an adjacent atom B Together with the atoms to which it is attached, it forms an optionally substituted 5- or 6-membered monocyclic heterocycloalkyl.

[0543] In some embodiments of Formula (I), (Ia), (Ib), (II), (II'), (IIc'), (IId'), (IIa), (IIb), (IIc), (IId), (IId-1), (IIe), (IIf), or (IIg), R B is halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 In some embodiments, two R on the same atom are optionally substituted, substituted or unsubstituted. B Together with the atoms to which it is attached, it forms an optionally substituted C 3-6 Cycloalkyl or optionally substituted C 2-5 Heterocycloalkyl.

[0544] In some embodiments of Formula (I), (Ia), (Ib), (II), (II'), (IIc'), (IId'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), (IIb-1a), (IIc), (IIc-1), (IId), (IId-1), (IIe), (IIf), or (IIg), n is 0.

[0545] In some embodiments of the compound of Formula (I), (Ia), (Ib), (II), (II'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), X 1 N or CR 1 In some embodiments, X 1 is N. In some embodiments, X 1 CR 1 .

[0546] In some embodiments of the compound of Formula (I), (Ia), (Ib), (II), (II'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), (IIb-1a), X 3 N or CR 3 In some embodiments, X3 is N. In some embodiments, X 3 CR 3 .

[0547] In some embodiments of the compound of Formula (I), (Ia), (Ib), (II), (II'), (IIc'), (IId'), (IIa), (IIa-1), (IIa-1a), (IIc), (IIc-1), (IId), (IId-1), or (IIg), X 7 N or CR 7 In some embodiments, X 7 is N. In some embodiments, X 7 CR 7 .

[0548] In some embodiments of the compound of Formula (II), (II'), (IIc'), (IId'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), (IIb-1a), (IIc), (IIc-1), (IId), (IId-1), (IIe), (IIf), or (IIg), is a single bond or a double bond. In some embodiments, Is a single bond. In some embodiments, For double bonds.

[0549] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (II'), (IIc'), (IId'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), (IIb-1a), (IIc), (IIc-1), (IId), (IId-1), (IIe), (IIf), or (IIg), R 1 、R 2 and R 7 independently selected from hydrogen, halo, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1For-OR 11 In some embodiments, R 1 For-SR 11 In some embodiments, R 1 -N(R 12 )2. In some embodiments, R 1 is optionally substituted C 1-6 In some embodiments, R 1 is optionally substituted C 1-6 In some embodiments, R 1 is optionally substituted C 2-6 In some embodiments, R 1 is optionally substituted C 2-6 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 For-OR 11 In some embodiments, R 2 For-SR 11 In some embodiments, R 2 -N(R 12 )2. In some embodiments, R 2 is optionally substituted C 1-6 In some embodiments, R 2 is optionally substituted C 1-6 In some embodiments, R 2 is optionally substituted C 2-6 In some embodiments, R 2 is optionally substituted C 2-6 In some embodiments, R 7 In some embodiments, R 7 In some embodiments, R 7 In some embodiments, R 7 For-OR 11 In some embodiments, R 7 For-SR 11 In some embodiments, R 7 -N(R 12 )2. In some embodiments, R 7 is optionally substituted C 1-6 In some embodiments, R 7 is optionally substituted C 1-6In some embodiments, R 7 is optionally substituted C 2-6 In some embodiments, R 7 is optionally substituted C 2-6 Alkynyl.

[0550] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (II'), (IIc'), (IId'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), (IIb-1a), (IIc), (IIc-1), (IId), (IId-1), (IIe), (IIf), or (IIg), R 8 and R 9 are each independently selected from hydrogen, halogen, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 In some embodiments, R 8 and R 9 are each independently selected from hydrogen, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl. 8 In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 is optionally substituted C 1-6 In some embodiments, R 8 is optionally substituted C 1-6 In some embodiments, R 8 is optionally substituted C 2-6 In some embodiments, R 8 is optionally substituted C 2-6 In some embodiments, R 9 In some embodiments, R 9 In some embodiments, R9 In some embodiments, R 9 is optionally substituted C 1-6 In some embodiments, R 9 is optionally substituted C 1-6 In some embodiments, R 9 is optionally substituted C 2-6 In some embodiments, R 9 is optionally substituted C 2-6 In some embodiments, R 8 and R 9 In some embodiments, R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl.

[0551] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (II'), (IIc'), (IId'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), (IIb-1a), (IIc), (IIc-1), (IId), (IId-1), (IIe), (IIf), or (IIg), Ring A is phenyl, naphthyl, a monocyclic heteroaryl, or a bicyclic heteroaryl. In some embodiments, Ring A is phenyl. In some embodiments, Ring A is naphthyl. In some embodiments, Ring A is a monocyclic heteroaryl. In some embodiments, Ring A is a bicyclic heteroaryl.

[0552] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (II'), (IIc'), (IId'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), (IIb-1a), (IIc), (IIc-1), (IId), (IId-1), (IIe), (IIf), or (IIg), R A are each independently selected from -NO2, oxo, CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11),-C(O)R 12 、C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ). In some embodiments, R A independently selected from -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 ),-S(O)R 12 、-S(O)2R12 and -S(O)2N(R 12 )(R 11 ). In some embodiments, each R A independently selected from halogen, OH, -NO2, oxo, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Heteroalkyl and C 3-6 In some embodiments, each R A independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 3-6 In some embodiments, each R A Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Haloalkyl and C 3-6 In some embodiments, each R A independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 Cycloalkyl, wherein the alkyl, alkoxy and cycloalkyl are optionally substituted with one or more halogens (e.g., 1-3 fluorines). A is independently selected from methyl, ethyl, propyl, butyl, -O-methyl, -O-ethyl, -O-propyl, -O-butyl, cyclopropyl, CN, OH, -O-CHF2, -O-CH2F, CHF2, CH2F and CF3. In some embodiments, R A In some embodiments, R A In some embodiments, R A In some embodiments, R A In some embodiments, R A is optionally substituted C 1-6 In some embodiments, R A is optionally substituted C 1-3 In some embodiments, R A is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CF3, -CH2CF3 or -CH2CH2F. In some embodiments, R A is optionally substituted C 2-6 In some embodiments, R Ais optionally substituted C 2-6 In some embodiments, R A is optionally substituted C 1-6 In some embodiments, R A is optionally substituted C 3-8 In some embodiments, R A is optionally substituted C 3-6 In some embodiments, R A for In some embodiments, R A is optionally substituted C 2-7 In some embodiments, R A is optionally substituted C 2-5 In some embodiments, R A For-OR 11 In some embodiments, R A For-OC 1-3 In some embodiments, R A In some embodiments, R A In some embodiments, R A for In some embodiments, R A For-SR 11 In some embodiments, R A -N(R 12 )(R 11 ). In some embodiments, R A -C(O)R 12 In some embodiments, R A C(O)OR 12 In some embodiments, R A -OC(O)R 12 In some embodiments, R A -OC(O)N(R 12 )(R 11 ). In some embodiments, R A -C(O)N(R 12 )(R 11 ). In some embodiments, R A -N(R 12 )C(O)R 12 In some embodiments, R A -N(R12 )C(O)OR 12 In some embodiments, R A -N(R 12 )C(O)N(R 12 )(R 11 ). In some embodiments, R A -N(R 12 )2S(O)2(R 12 ). In some embodiments, R A -S(O)R 12 In some embodiments, R A is -S(O)2R 12 In some embodiments, R A -S(O)2N(R 12 )(R 11 ).

[0553] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (II'), (IIc'), (IId'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), (IIb-1a), (IIc), (IIc-1), (IId), (IId-1), (IIe), (IIf), or (IIg), R 11 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4 Alkylene-C 3-8 Cycloalkyl, optionally substituted -C 1-4 Alkylene-C 2-7 Heterocycloalkyl, optionally substituted -C 1-4 Alkylene-phenyl or optionally substituted-C 1-4 In some embodiments, R 11 In some embodiments, R 11 is optionally substituted C 1-6 In some embodiments, R 11 is optionally substituted C 1-3 In some embodiments, R 11is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CF3, -CH2CF3 or -CH2CH2F. In some embodiments, R 11 is optionally substituted C 2-6 In some embodiments, R 11 is optionally substituted C 2-6 In some embodiments, R 11 is optionally substituted C 1-6 In some embodiments, R 11 is optionally substituted C 3-8 In some embodiments, R 11 is optionally substituted C 2-7 In some embodiments, R 11 is an optionally substituted phenyl. 11 In some embodiments, R 11 is optionally substituted -C 1-4 Alkylene-C 3-8 In some embodiments, R 11 is optionally substituted -C 1-4 Alkylene-C 2-7 In some embodiments, R 11 is optionally substituted -C 1-4 In some embodiments, R 11 is optionally substituted -C 1-4 Alkylene-heteroaryl.

[0554] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (II'), (IIc'), (IId'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), (IIb-1a), (IIc), (IIc-1), (IId), (IId-1), (IIe), (IIf), or (IIg), R 12 Each independently selected from hydrogen, halogen, -OH, -NO2, CN, C 1-6 Alkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, wherein the C 3-6The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 In some embodiments of the compound of Formula (I), (Ia), (Ib), (II), (II'), (IIc'), (IId'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), (IIb-1a), (IIc), (IIc-1), (IId), (IId-1), (IIe), (IIf), or (IIg), R 12 Each independently selected from hydrogen, -NO2, CN, C 1-6 Alkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 In some embodiments, R 12 In some embodiments, R 12 In some embodiments, R 12 In some embodiments, R 12 In some embodiments, R 12 In some embodiments, R 12 C 1-6 In some embodiments, R 12 C 1-6 In some embodiments, R 12 C 1-6 In some embodiments, R 12 C 1-6 In some embodiments, R 12 C 1-6 In some embodiments, R 12 C 3-6 In some embodiments, R 12 is a 3- to 6-membered heterocyclic ring, wherein C 3-6The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 In some embodiments, one or more substituents are halogen. In some embodiments, one or more substituents are -OH. In some embodiments, one or more substituents are oxo. In some embodiments, one or more substituents are amino. In some embodiments, one or more substituents are -NO2. In some embodiments, one or more substituents are CN. In some embodiments, one or more substituents are C 1-6 In some embodiments, one or more substituents are C 1-6 In some embodiments, one or more substituents are C 1-6 Haloalkyl.

[0555] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (II'), (IIc'), (IId'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), (IIb-1a), (IIc), (IIc-1), (IId), (IId-1), (IIe), (IIf), or (IIg), B is a 6-membered heteroaryl, phenyl, or a phenyl isostere. In some embodiments, Ring B is a 6-membered heteroaryl. In some embodiments, Ring B is a phenyl. In some embodiments, Ring B is a phenyl isostere. In some embodiments, B is a cubane. In some embodiments, B is and n is 0. In some embodiments, for

[0556] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (II'), (IIc'), (IId'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), (IIb-1a), (IIc), (IIc-1), (IId), (IId-1), (IIe), (IIf), or (IIg), R B1 is halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R12 )(R 11 ),-C(O)R 12 、C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 In some embodiments, R B1 is -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R12 )S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 In some embodiments, R B1 is optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 In some embodiments, R B1 In some embodiments, R B1 In some embodiments, R B1 In some embodiments, R B1 is optionally substituted C 1-6 In some embodiments, R B1 is optionally substituted C 1-3 In some embodiments, R B1 is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CF3, -CH2CF3 or -CH2CH2F. In some embodiments, R B1 is optionally substituted C 2-6 In some embodiments, R B1 is optionally substituted C 2-6 In some embodiments, R B1 is optionally substituted C 1-6 In some embodiments, R B1 For-OR 11 In some embodiments, R B1 For-SR 11 In some embodiments, R B1 -N(R 12 )(R 11 ). In some embodiments, R B1 -C(O)R 12 In some embodiments, R B1 C(O)OR 12 In some embodiments, R B1 -OC(O)R 12 In some embodiments, RB1 -OC(O)N(R 12 )(R 11 ). In some embodiments, R B1 -C(O)N(R 12 )(R 11 ). In some embodiments, R B1 -N(R 12 )C(O)R 12 In some embodiments, R B1 -N(R 12 )C(O)OR 12 In some embodiments, R B1 -N(R 12 )C(O)N(R 12 )(R 11 ). In some embodiments, R B1 -N(R 12 )S(O)2(R 12 ). In some embodiments, R B1 -S(O)R 12 In some embodiments, R B1 is -S(O)2R 12 In some embodiments, R B1 -S(O)2N(R 12 )(R 11 ). In some embodiments, R B1 is optionally substituted C 3-8 In some embodiments, R B1 is optionally substituted C 2-9 In some embodiments, R B1 In some embodiments, R B1 is an optionally substituted phenyl. B1 In some embodiments, the optionally substituted monocyclic heteroaryl is substituted by: -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl or -OR 11 In some embodiments, R B1 In some embodiments, the optionally substituted bicyclic heteroaryl is substituted with: -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl or -OR 11 .

[0557] In some embodiments of the compound of Formula (I), (Ia), (Ib), (II), (II'), (IIc'), (IId'), (IIa), (IIb), (IIc), (IId), (IId-1), (IIe), (IIf), or (IIg), R B is halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 In some embodiments, R B In some embodiments, R B In some embodiments, R B In some embodiments, R B is optionally substituted C1-6 In some embodiments, R B is optionally substituted C 2-6 In some embodiments, R B is optionally substituted C 2-6 In some embodiments, R B is optionally substituted C 1-6 In some embodiments, R B For-OR 11 In some embodiments, R B For-SR 11 In some embodiments, R B -N(R 12 )(R 11 ). In some embodiments, R B -C(O)R 12 In some embodiments, R B C(O)OR 12 In some embodiments, R B -OC(O)R 12 In some embodiments, R B -OC(O)N(R 12 )(R 11 ). In some embodiments, R B -C(O)N(R 12 )(R 11 ). In some embodiments, R B -N(R 12 )C(O)R 12 In some embodiments, R B -N(R 12 )C(O)OR 12 In some embodiments, R B -N(R 12 )C(O)N(R 12 )(R 11 ). In some embodiments, R B -N(R 12 )S(O)2(R 12 ). In some embodiments, R B -S(O)R 12 In some embodiments, R B is -S(O)2R 12 In some embodiments, R B -S(O)2N(R 12 )(R 11 ). In some embodiments, R Bis optionally substituted C 3-8 In some embodiments, R B is optionally substituted C 2-9 In some embodiments, R B In some embodiments, R B is an optionally substituted phenyl. B is an optionally substituted monocyclic heteroaryl. B In some embodiments, the substituted bicyclic heteroaryl is replaced by halogen, -OH, -NO2, amino, oxo, -CN, C 1-3 Alkoxy, C 1-3 Alkyl or C 1-3 In some embodiments, the substituted bicyclic heteroaryl is substituted with a haloalkyl radical. In some embodiments, the substituted bicyclic heteroaryl is substituted with a halogen radical. In some embodiments, the substituted bicyclic heteroaryl is substituted with -OH. In some embodiments, the substituted bicyclic heteroaryl is substituted with -NO2. In some embodiments, the substituted bicyclic heteroaryl is substituted with amino. In some embodiments, the substituted bicyclic heteroaryl is substituted with oxo. In some embodiments, the substituted bicyclic heteroaryl is substituted with -CN. In some embodiments, the substituted bicyclic heteroaryl is substituted with C 1-3 In some embodiments, the substituted bicyclic heteroaryl is replaced by C 1-3 In some embodiments, the substituted bicyclic heteroaryl is or C 1-3 Haloalkyl substitution.

[0558] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (II'), (IIc'), (IId'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), (IIb-1a), (IIc), (IIc-1), (IId), (IId-1), (IIe), (IIf), or (IIg), R B1 and an R on an adjacent atom B Together with the atoms to which it is attached, it forms an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted monocyclic heteroaryl, an optionally substituted bicyclic heteroaryl, an optionally substituted C 3-8 Cycloalkyl or optionally substituted C 2-9 In some embodiments, R B1 and an R on an adjacent atom B Together with the atoms to which they are attached, they form an optionally substituted phenyl group. B1 and an R on an adjacent atom Band the atoms to which they are attached form an optionally substituted naphthyl. B1 and an R on an adjacent atom B and the atoms to which they are attached form an optionally substituted monocyclic heteroaryl. B1 and an R on an adjacent atom B and the atoms to which they are attached form an optionally substituted bicyclic heteroaryl. B1 and an R on an adjacent atom B Together with the atoms to which it is attached, it forms an optionally substituted C 3-8 In some embodiments, R B1 and an R on an adjacent atom B Together with the atoms to which it is attached, it forms an optionally substituted C 2-9 Heterocycloalkyl.

[0559] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (II'), (IIc'), (IId'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), (IIb-1a), (IIc), (IIc-1), (IId), (IId-1), (IIe), (IIf), or (IIg), R B1 and an R on the same atom B Together with the atoms to which it is attached, it forms an optionally substituted C 3-8 Cycloalkyl or optionally substituted C 2-9 In some embodiments, R B1 and an R on the same atom B Together with the atoms to which it is attached, it forms an optionally substituted C 3-8 In some embodiments, R B1 and an R on the same atom B Together with the atoms to which it is attached, it forms an optionally substituted C 2-9 Heterocycloalkyl.

[0560] In some embodiments of Formula (I), (Ia), (Ib), (II), (II'), (IIc'), (IId'), (IIa), (IIb), (IIc), (IId), (IId-1), (IIe), (IIf), or (IIg), two R B Together with the atoms to which it is attached, it forms an optionally substituted C 3-8 Cycloalkyl or optionally substituted C 2-9 In some embodiments, two R on the same atomB Together with the atoms to which it is attached, it forms an optionally substituted C 3-8 In some embodiments, two R on the same atom B Together with the atoms to which it is attached, it forms an optionally substituted C 2-9 Heterocycloalkyl.

[0561] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (II'), (IIc'), (IId'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), (IIb-1a), (IIc), (IIc-1), (IId), (IId-1), (IIe), (IIf), or (IIg), m is 1, 2, 3, or 4. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0562] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (II'), (IIc'), (IId'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIc), (IIc-1), (IId), (IId-1), (IIe), (IIf), or (IIg), n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0563] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (II'), (IIc'), (IId'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), (IIb-1a), (IIc), (IIc-1), (IId), (IId-1), (IIe), (IIf), or (IIg), p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1.

[0564] In some embodiments of the compound of Formula (Ib), X 1 CR 1 ;X 3 N or CR 3 ;X 7 CR 7 ; R 1 and R 3 Each is hydrogen; R 8 and R 9 Each is hydrogen; for And each R A R is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C3-C6 cycloalkyl; B1 is optionally one or more selected from C 1-3 Haloalkyl and C 1-3 5-membered heteroaryl substituted with an alkyl substituent (e.g., ); and p is 1. In some embodiments, each R A are independently OH, C 1-3 Alkyl, -OCH3, C 1-3 In some embodiments, each R A are independently OH, -OCH3, C 1-3 Alkyl, C 1-3 In some embodiments, each R A Independently C 1-3 Alkyl, C 1-3 In some embodiments, -OCH3 is -OCD3. In some embodiments, R B1 Optionally 1 or 2 selected from C 1-3 Haloalkyl and C 1-3 The alkyl group is substituted with a substituent.

[0565] In one aspect, described herein is a compound having the structure of Formula (VI) or a salt or solvate thereof:

[0566]

[0567]

[0568] in,

[0569] Ring C is phenyl or 6-membered heteroaryl, wherein said phenyl or heteroaryl are each optionally substituted;

[0570] Ring D is an aromatic, saturated or partially saturated 5-membered carbocyclic or heterocyclic ring, wherein each of the carbocyclic or heterocyclic ring is optionally substituted;

[0571] R 8 and R 9 are each independently selected from hydrogen, halo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9together to form an oxo group; or R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl;

[0572] Ring A is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl;

[0573] R A are each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 );

[0574] R 11 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4 Alkylene-C 3-8 Cycloalkyl, optionally substituted -C 1-4 Alkylene-C 2-7 Heterocycloalkyl, optionally substituted -C 1-4 Alkylene-phenyl or optionally substituted-C 1-4 alkylene-heteroaryl;

[0575] R 12 Each independently selected from hydrogen, halogen, -OH, -NO2, -CN, C 1-6 Alkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl and C 3-6 Carbocyclic ring, 3-membered to 6-membered heterocyclic ring, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl;

[0576] R B is hydrogen, halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 ),-S(O)R12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl; or

[0577] m is 0, 1, 2, 3 or 4; and

[0578] p is 0 or 1

[0579] In some embodiments of Formula (VI), Ring C is phenyl or a 6-membered heteroaryl, wherein

[0580] Phenyl or heteroaryl are each optionally substituted by 1, 2, 3 or 4 R 1C Replace, and each R 1C are independently halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-SH、-SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C2-C6 alkynyl, C 3-8 Cycloalkyl, C2-7 wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally and independently replaced by one or more R 1Ca replace;

[0581] Ring D is an aromatic, saturated or partially saturated 5-membered carbocyclic or heterocyclic ring, wherein each of the carbocyclic or heterocyclic rings is optionally substituted by 1, 2, 3, 4, 5 or 6 R 1D Replace, and

[0582] Each R 1D are independently halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-SH、-SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C2-C6 alkynyl, C 3-8 Cycloalkyl, C 2-7 wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally and independently replaced by one or more R 1Da replace;

[0583] R 8 and R 9 are each independently selected from hydrogen, halo, -CN, optionally substituted C1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, amino, -OH, -NO2, oxo, -CN, C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 Haloalkyl; R A are each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11), wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, oxo, amino, -CN, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, amino, -NO2, oxo, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl;

[0584] Ring A is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl;

[0585] R A are each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ),

[0586] wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, oxo, amino, -CN, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, amino, -NO2, oxo, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl;

[0587] R 11 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4 Alkylene-C 3-8 Cycloalkyl, optionally substituted -C 1-4 Alkylene-C 2-7 Heterocycloalkyl, optionally substituted -C 1-4 Alkylene-phenyl or optionally substituted-C 1-4 Alkylene-heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, amino, -NO2, oxo, C 1-6 Alkoxy, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl;

[0588] R 12 Each independently selected from hydrogen, -NO2, -CN, C 1-6 Alkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl and C 3-6 Carbocyclic ring, 3-membered to 6-membered heterocyclic ring, wherein the C 3-6The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl;

[0589] R B is hydrogen, halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl or optionally substituted bicyclic heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, naphthyl, phenyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ), wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, amino, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2, oxo, -CN, C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 Haloalkyl;

[0590] Each R aC1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C1-C6 alkylene-cycloalkyl, -C1-C6 alkylene-heterocycloalkyl, -C1-C6 alkylene-aryl or -C1-C6 alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OC1-C6 alkyl, -S(=O)C1-C6 alkyl, -S(=O)2C -C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC1-C6 alkyl-C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0591] Each R b C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C1-C6 alkylene-cycloalkyl, -C1-C6 alkylene-heterocycloalkyl, -C1-C6 alkylene-aryl or -C1-C6 alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OC1-C6 alkyl, -S(=O)C1-C6 alkyl, -S(=O) C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC1-C6 alkyl-C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl is substituted;

[0592] Each R c and Rd C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C1-C6 alkylene-cycloalkyl, -C1-C6 alkylene-heterocycloalkyl, -C1-C6 alkylene-aryl or -C1-C6 alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OC1-C6 alkyl, -S(=O)C1-C6 alkyl, -S(=O) C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl is substituted;

[0593] or R c and R d and the atoms to which they are attached form a heterocycloalkyl group optionally substituted with one or more oxo groups, halogen, -CN, -OH, -OC1-C6 alkyl, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C -C1-C6 alkyl)2, -NHC(═O)OC1-C6 alkyl, -C(═O)C1-C6 alkyl, -C(═O)C1-C6 alkyl, -C(═O)OH, -C(═O)OC1-C6 alkyl, -C(═O)NH2, -C(═O)N(C1-C6 alkyl)2, -C(═O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0594] Each R 1Ca and R 1Da are independently halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d、-SH、-SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0595] m is 1, 2, 3 or 4; and

[0596] p is 0 or 1.

[0597] In some embodiments of Formula (VI), Ring C is a 6-membered heteroaryl and Ring D is a 5-membered heteroaryl. In some embodiments, Ring C is a 6-membered heteroaryl and Ring D is a 5-membered heterocycloalkyl.

[0598] In some embodiments of Formula (VI), R 12 Each independently selected from hydrogen, -NO2, -CN, C 1-6 Alkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl and C 3-6 Carbocyclic ring, 3-membered to 6-membered heterocyclic ring, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl.

[0599] In some embodiments of Formula (VI), Ring C and Ring D are each independently optionally substituted with one or more substituents selected from the group consisting of halo, -CN, -OR a、-SH、-SR a 、-NR c R d , optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl, and wherein the alkyl, heteroalkyl, alkenyl or alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, amino, oxo, -OH, -NO2, -CN and C 1-3 Alkoxy.

[0600] In some embodiments of Formula (VI), for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for

[0614] In some embodiments of Formula (VI), Ring A is phenyl. In some embodiments, Ring A is naphthyl. In some embodiments, Ring A is a 5- or 6-membered monocyclic heteroaryl. In some embodiments, Ring A is a 6-membered monocyclic heteroaryl containing 1-3 heteroatoms.

[0615] In some embodiments of Formula (VI), for

[0616] In some embodiments of Formula (VI), Ring A is pyridine, pyrimidine, pyrazine, pyridazine, triazine, imidazole, pyrazole, triazole, oxazole, isoxazole, or thiophene. In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for

[0617] In some embodiments of Formula (VI), Ring A is a bicyclic heteroaryl. In some embodiments, Ring A is a fused 5-6, 6-6, or 6-5 bicyclic heteroaryl.

[0618] In some embodiments of Formula (VI), R A are each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ). In some embodiments, each R A is independently substituted by one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, amino, -CN, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, amino, -NO2, oxo, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 In some embodiments, R A independently selected from -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ).

[0619] In some embodiments of Formula (VI), Selected from: In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for

[0620] In some embodiments of Formula (VI), p is 0. In some embodiments, p is 1.

[0621] In some embodiments of Formula (VI), R 8 and R 9 are each independently selected from hydrogen, halo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 In some embodiments, R 8 and R 9 are each independently selected from hydrogen, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl.

[0622] In some embodiments of Formula (VI), R 8 and R 9 Together they form an oxo group.

[0623] In some embodiments of Formula (VI), R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl.

[0624] In some embodiments of Formula (VI), R B is halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 In some embodiments, R B is an optionally substituted 5-membered monocyclic heteroaryl group having 1 to 4 heteroatoms selected from N, O, S and P. In some embodiments, R B is imidazole, pyrazole, triazole or tetrazole, each of which is optionally substituted. B is an optionally substituted fused 5-6, 6-6 or 6-5 heteroaryl.

[0625] In some embodiments of Formula (VI), R B Optionally substituted with one or more substituents independently selected from the group consisting of halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12)S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ), wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, amino, oxo, -CN, C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 In some embodiments, R B Optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 11 , -NO2, oxo, -CN, optionally substituted C 1-6 Haloalkyl, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 aminoalkyl, optionally substituted C 1-6 Hydroxyalkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl and optionally substituted C 2-7 In some embodiments, R B Optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 11 、-NO2、oxo、-CN、C 1-3 Haloalkyl, C 1-3 Alkyl, C 1-3 aminoalkyl, C 1-3 Hydroxyalkyl, optionally substituted C 1-4 Heteroalkyl (eg, -CH2C(=O)N(CH3)2), optionally substituted C 3-6 Cycloalkyl and optionally substituted C 2-5 In some embodiments, R B is optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 In some embodiments, R B is an optionally substituted monocyclic 5-6 membered heterocycloalkyl or heteroaryl. B is optionally substituted C 3-8 In some embodiments, R B In some embodiments, R BIn some embodiments, R B In some embodiments, R B is an optionally substituted phenyl. B is optionally substituted C 2-9 In some embodiments, R B In some embodiments, R B In some embodiments, R B In some embodiments, R B is an optionally substituted monocyclic heteroaryl. B is an optionally substituted bicyclic heteroaryl. B is imidazole, pyrazole, triazole or tetrazole, each of which is optionally substituted. B In some embodiments, R B In some embodiments, R B In some embodiments, R B For tetrazole.

[0626] In some embodiments of Formula (VI), R B Selected from:

[0627] In some embodiments of Formula (VI), R B for In some embodiments, R B for In some embodiments, R B for In some embodiments, R B for In some embodiments, R B for In some embodiments, R B for In some embodiments, R B for

[0628] In some embodiments of Formula (VI), Ring C is phenyl or 6-membered heteroaryl, wherein each of the phenyl or heteroaryl is optionally substituted. In some embodiments, Ring C is optionally substituted phenyl. In some embodiments, Ring C is optionally substituted 6-membered heteroaryl.

[0629] In some embodiments of Formula (VI), Ring D is an aromatic, saturated or partially saturated 5-membered carbocyclic ring or heterocyclic ring, wherein each of the carbocyclic ring or heterocyclic ring is optionally substituted. In some embodiments, Ring D is an optionally substituted aromatic 5-membered carbocyclic ring. In some embodiments, Ring D is an optionally substituted aromatic 5-membered heterocyclic ring. In some embodiments, Ring D is an optionally substituted saturated 5-membered carbocyclic ring. In some embodiments, Ring D is an optionally substituted saturated 5-membered heterocyclic ring. In some embodiments, Ring D is an optionally substituted partially saturated 5-membered carbocyclic ring. In some embodiments, Ring D is an optionally substituted partially saturated 5-membered heterocyclic ring.

[0630] In some embodiments of Formula (VI), R 8 and R 9 are each independently selected from hydrogen, halo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 In some embodiments, R 8 and R 9 are each independently selected from hydrogen, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl. 8 In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 is optionally substituted C 1-6 In some embodiments, R 8 is optionally substituted C 1-6 In some embodiments, R 8 is optionally substituted C 2-6 In some embodiments, R 8 is optionally substituted C 2-6 In some embodiments, R 9 In some embodiments, R 9 In some embodiments, R 9In some embodiments, R 9 is optionally substituted C 1-6 In some embodiments, R 9 is optionally substituted C 1-6 In some embodiments, R 9 is optionally substituted C 2-6 In some embodiments, R 9 is optionally substituted C 2-6 In some embodiments, R 8 and R 9 In some embodiments, R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl.

[0631] In some embodiments of Formula (VI), Ring A is phenyl, naphthyl, a monocyclic heteroaryl, or a bicyclic heteroaryl. In some embodiments, Ring A is phenyl. In some embodiments, Ring A is a 6-membered monocyclic heteroaryl containing 1-3 heteroatoms. In some embodiments, Ring A is pyridine. In some embodiments, Ring A is pyrimidine. In some embodiments, Ring A is naphthyl. In some embodiments, Ring A is a monocyclic heteroaryl. In some embodiments, Ring A is or a bicyclic heteroaryl.

[0632] In some embodiments of Formula (VI), R A independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ). In some embodiments, R A independently selected from -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ). In some embodiments, R A In some embodiments, R A In some embodiments, R A In some embodiments, R A In some embodiments, R A is optionally substituted C 1-6In some embodiments, R A is optionally substituted C 1-3 In some embodiments, R A is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CF3, -CH2CF3 or -CH2CH2F. In some embodiments, R A is optionally substituted C 2-6 In some embodiments, R A is optionally substituted C 2-6 In some embodiments, R A is optionally substituted C 1-6 In some embodiments, R A is optionally substituted C 3-8 In some embodiments, R A is optionally substituted C 3-6 In some embodiments, R A for In some embodiments, R A is optionally substituted C 2-7 In some embodiments, R A is optionally substituted C 2-5 In some embodiments, R A For-OR 11 In some embodiments, R A For-OC 1-3 In some embodiments, R A In some embodiments, R A In some embodiments, R A for In some embodiments, R A For-SR 11 In some embodiments, R A -N(R 12 )(R 11 ). In some embodiments, R A -C(O)R 12 In some embodiments, R A -C(O)OR 12 In some embodiments, R A -OC(O)R 12In some embodiments, R A -OC(O)N(R 12 )(R 11 ). In some embodiments, R A -C(O)N(R 12 )(R 11 ). In some embodiments, R A -N(R 12 )C(O)R 12 In some embodiments, R A -N(R 12 )C(O)OR 12 In some embodiments, R A -N(R 12 )C(O)N(R 12 )(R 11 ). In some embodiments, R A -N(R 12 )2S(O)2(R 12 ). In some embodiments, R A -S(O)R 12 In some embodiments, R A is -S(O)2R 12 In some embodiments, R A -S(O)2N(R 12 )(R 11 ).

[0633] In some embodiments of Formula (VI), R 11 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4 Alkylene-C 3-8 Cycloalkyl, optionally substituted -C 1-4 Alkylene-C 2-7 Heterocycloalkyl, optionally substituted -C 1-4 Alkylene-phenyl or optionally substituted-C 1-4 In some embodiments, R 11 In some embodiments, R 11 is optionally substituted C 1-6In some embodiments, R 11 is optionally substituted C 1-3 In some embodiments, R A is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CF3, -CH2CF3 or -CH2CH2F. In some embodiments, R 11 is optionally substituted C 2-6 In some embodiments, R 11 is optionally substituted C 2-6 In some embodiments, R 11 is optionally substituted C 1-6 In some embodiments, R 11 is optionally substituted C 3-8 In some embodiments, R 11 is optionally substituted C 2-7 In some embodiments, R 11 is an optionally substituted phenyl. 11 In some embodiments, R 11 is optionally substituted -C 1-4 Alkylene-C 3-8 In some embodiments, R 11 is optionally substituted -C 1-4 Alkylene-C 2-7 In some embodiments, R 11 is optionally substituted -C 1-4 In some embodiments, R 11 is optionally substituted -C 1-4 Alkylene-heteroaryl.

[0634] In some embodiments of Formula (VI), R 12 Each independently selected from hydrogen, halogen, -OH, -NO2, -CN, C 1-6 Alkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl and C 3-6 Carbocyclic ring, 3-membered to 6-membered heterocyclic ring, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6In some embodiments of Formula (VI), R 12 Each independently selected from hydrogen, -NO2, -CN, C 1-6 Alkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl and C 3-6 Carbocyclic ring, 3-membered to 6-membered heterocyclic ring, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 In some embodiments, R 12 In some embodiments, R 12 In some embodiments, R 12 In some embodiments, R 12 In some embodiments, R 12 In some embodiments, R 12 C 1-6 In some embodiments, R 12 C 1-6 In some embodiments, R 12 C 1-6 In some embodiments, R 12 C 1-6 In some embodiments, R 12 For and C 3-6 In some embodiments, R 12 is a 3- to 6-membered heterocyclic ring, wherein C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 In some embodiments, one or more substituents are halogen. In some embodiments, one or more substituents are -OH. In some embodiments, one or more substituents are oxo. In some embodiments, one or more substituents are amino. In some embodiments, one or more substituents are -NO2. In some embodiments, one or more substituents are -CN. In some embodiments, one or more substituents are C 1-6 In some embodiments, one or more substituents are C 1-6 In some embodiments, one or more substituents are C1-6 Haloalkyl.

[0635] In some embodiments of Formula (VI), R B is hydrogen, halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 ),-C(O)R 12 、C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 ),-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 In some embodiments, R B In some embodiments, R B In some embodiments, R B In some embodiments, R B In some embodiments, R B is optionally substituted C 1-6 In some embodiments, R B is optionally substituted C 2-6 In some embodiments, R B is optionally substituted C 2-6In some embodiments, R B is optionally substituted C 1-6 In some embodiments, R B For-OR 11 In some embodiments, R B For-SR 11 In some embodiments, R B -N(R 12 )(R 11 ). In some embodiments, R B -C(O)R 12 In some embodiments, R B -C(O)OR 12 In some embodiments, R B -OC(O)R 12 In some embodiments, R B -OC(O)N(R 12 )(R 11 ). In some embodiments, R B -C(O)N(R 12 )(R 11 ). In some embodiments, R B -N(R 12 )C(O)R 12 In some embodiments, R B -N(R 12 )C(O)OR 12 In some embodiments, R B -N(R 12 )C(O)N(R 12 )(R 11 ). In some embodiments, R B -N(R 12 )S(O)2(R 12 ). In some embodiments, R B -S(O)R 12 In some embodiments, R B is -S(O)2R 12 In some embodiments, R B -S(O)2N(R 12 )(R 11 ). In some embodiments, R B is optionally substituted C 3-8 In some embodiments, R B is optionally substituted C 2-9 In some embodiments, R BIn some embodiments, R B is an optionally substituted phenyl. B is an optionally substituted monocyclic heteroaryl. B is an optionally substituted bicyclic heteroaryl group.

[0636] In some embodiments of Formula (VI), m is 1, 2, 3, or 4. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0637] In some embodiments of Formula (VI), p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1.

[0638] Non-limiting examples of compounds described herein are the compounds presented in Table 1 and pharmaceutically acceptable salts or solvates thereof.

[0639] Table 1. Exemplary compounds of the present disclosure

[0640]

[0641]

[0642]

[0643] Table 2 presents the USP1 IC50 (nM) and MDA-MB-436 IC50 (nM) of the compounds presented in Table 1. 50 (nM) corresponding biological data.

[0644] Table 2:

[0645]

[0646]

[0647] IC50(nM):0 <A≤50;50<B≤1,000;1,000<C≤10,000;10,000<D

[0648] The present disclosure includes salts of the compounds described herein, particularly pharmaceutically acceptable salts. Compounds of the present disclosure having sufficient acidity, sufficient basicity, or both functional groups can react with a variety of inorganic bases and any of inorganic and organic acids to form salts. Alternatively, intrinsically charged compounds, such as those having quaternary nitrogen, can form salts with appropriate counterions, such as halides such as bromide, chloride, or fluoride, particularly bromide.

[0649] Chemical entities with carbon-carbon double bonds or carbon-nitrogen double bonds can exist in Z or E form (or cis or trans form). In addition, some chemical entities can exist in various tautomeric forms. Unless otherwise stated, the compounds described herein are also intended to include all Z forms, E forms and tautomeric forms.

[0650] As used herein, "phenyl isostere" refers to a moiety or functional group that exhibits physical, biological, and / or chemical properties similar to those of a phenyl group. Exemplary phenyl isosteres include, but are not limited to, cubane, bicyclo[1.1.1]pentane (BCP), bicyclo[2.2.1]heptane, bicyclo[2.1.1]hexane, bicyclo[2.2.2]octane, adamantane, norbornene, closed-1,2-carborane, closed-1,7-carborane, closed-1,12-carborane, and ethynyl. In some embodiments, the phenyl isostere is cubane. In some embodiments, the phenyl isostere is ethynyl.

[0651] "Tautomers" refer to molecules in which a proton may shift from one atom of a molecule to another atom of the same molecule. In certain embodiments, the compounds presented herein exist as tautomers. In situations where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0652]

[0653] In some embodiments, the compounds disclosed herein are isotopically enriched (e.g., 2 H. 3 H. 11 C. 13 C and / or 14 C). In a specific embodiment, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Patents 5,846,514 and 6,334,997. As described in U.S. Patents 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or efficacy, thereby increasing the duration of drug action.

[0654] Unless otherwise stated, the compounds described herein may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched in a specific isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number found in large quantities in nature. All isotopic variants of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, the compounds described herein may be artificially enriched in one or more specific isotopes. In some embodiments, the compounds described herein may be artificially enriched in one or more isotopes that are not found in large quantities in nature. In some embodiments, the compounds described herein may be artificially enriched in one or more isotopes selected from deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 In some embodiments, the compounds described herein are artificially enriched in one or more isotopes selected from: 2 H. 11 C. 13 C. 14 C. 15 C. 12 N. 13 N. 15 N. 16 N. 16 O. 17 O. 14 F. 15 F. 16 F. 17 F. 18 F. 33 S. 34 S. 35 S. 36 S. 35 Cl, 37 Cl, 79 Br, 81 Br, 131 I and 125 I. In some embodiments, the abundance of the enriched isotopes is independently at least 1 mol%, at least 10 mol%, at least 20 mol%, at least 30 mol%, at least 40 mol%, at least 50 mol%, at least 60 mol%, at least 70 mol%, at least 80 mol%, at least 90 mol%, or 100 mol%.

[0655] In some embodiments of the compounds disclosed herein, one or more R 1 、R 2 、R 3 、R 4 、R 5 、R 6、R 7 、R 8 、R 9 、R 11 、R 12 、R Y1 、R Y2 、R Y3 、R Y4 、R A 、R B 、R B1 、R 1Ca 、R 1Da 、R a 、R b 、R c and / or R d The group contains a percentage of deuterium that is greater than the natural abundance of deuterium.

[0656] In some embodiments of the compounds disclosed herein, one or more 1 H is replaced by one or more deuteriums selected from one or more of the following groups: R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 11 、R 12 、R Y1 、R Y2 、R Y3 、R Y4 、R A 、R B 、R B1 、R 1Ca 、R 1Da 、R a 、R b 、R c and / or R d .

[0657] In some embodiments of the compounds disclosed herein, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 11 、R 12 、R Y1 、R Y2 、R Y3 、RY4 、R A 、R B 、R B1 、R 1Ca 、R 1Da 、R a 、R b 、R c and / or R d The abundance of deuterium in each of is independently at least 1 mol%, at least 10 mol%, at least 20 mol%, at least 30 mol%, at least 40 mol%, at least 50 mol%, at least 60 mol%, at least 70 mol%, at least 80 mol%, at least 90 mol%, or 100 mol%.

[0658] In some embodiments of the compounds disclosed herein, one or more of Ring A, Ring B, Ring C, and / or Ring D 1 H is replaced by one or more deuteriums.

[0659] In certain embodiments, some or all of the compounds disclosed herein 1 H atoms are 2 H atom replacement. Methods for synthesizing deuterated compounds are known in the art and include the following synthetic methods as non-limiting examples only. Deuterium-substituted compounds can be synthesized using various methods described, for example, in Dean, Dennis C.; ed. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, p. 110; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0660] Deuterated starting materials are readily available and amenable to the synthetic methods described herein to provide the synthesis of deuterium-containing compounds. A large number of deuterium-containing reagents and building blocks are commercially available from chemical suppliers, such as Aldrich Chemical Co.

[0661] The compounds of the present disclosure also include crystalline and amorphous forms of these compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, and mixtures thereof.

[0662] In some cases, the compounds described herein can exist as diastereomers, enantiomers or other stereoisomeric forms. When absolute stereochemistry is not specified, the compounds presented herein include all diastereomers, enantiomers and epimeric forms and appropriate mixtures thereof. The separation of stereoisomers can be carried out by chromatography or by forming diastereomers and by recrystallization or chromatography separation or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981, this disclosure is incorporated herein by reference). Stereoisomers can also be obtained by stereoselective synthesis.

[0663] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also referred to as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. In some embodiments, active metabolites of these compounds having the same type of activity are also included within the scope of this disclosure. In addition, the compounds described herein may exist in unsolvated and solvated forms with pharmaceutically acceptable solvents (e.g., water, ethanol, etc.). The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0664] In certain embodiments, the compound or the salt of the compound may be a prodrug, for example, wherein the hydroxyl group in the parent compound is presented as an ester or carbonate, or the carboxylic acid present in the parent compound is presented as an ester. The term "prodrug" is intended to encompass compounds that are converted into pharmaceutical agents of the present disclosure under physiological conditions. A method for preparing a prodrug is to include one or more selected portions that are hydrolyzed under physiological conditions to produce the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of a host animal (e.g., a specific target cell in a host animal). For example, an ester or carbonate (e.g., an ester of an alcohol or carboxylic acid or an ester of a carbonate and a phosphonic acid) is a preferred prodrug of the present disclosure.

[0665] Prodrug forms of the compounds described herein, wherein the prodrug is metabolized in vivo to produce the compound as described herein, are included within the scope of the claims. In some cases, some of the compounds described herein may be a prodrug of another derivative or active compound.

[0666] Prodrugs are often useful because, in some cases, they can be easier to administer than the parent drug. They can, for example, be bioavailable via oral administration, whereas the parent drug is not. Prodrugs can help enhance the cell permeability of a compound relative to the parent drug. Prodrugs can also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs can be designed as reversible drug derivatives and are useful as modulators that enhance drug transport to site-specific tissues or increase drug retention within cells.

[0667] In some embodiments, the design of the prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of the prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, ACS Symposium Series Vol. 14; and Edward B. Roche, Bioreversible Carriers in Drug Delivery Systems. Design, American Pharmaceutical Association and Pergamon Press, 1987, the disclosure of which is incorporated herein in its entirety). According to another embodiment, the present disclosure provides methods for producing the compounds defined above. The compounds can be synthesized using conventional techniques. Advantageously, these compounds are preferably synthesized from readily available starting materials.

[0668] Synthetic chemistry transformations and methods for synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and PGM Wuts, Protective Groups in Organic Synthesis, 2nd ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

[0669] C. Pharmaceutical Compositions

[0670] In certain embodiments, provided herein are compositions comprising a therapeutically effective amount of any compound or salt of any of Formula (I), (Ia), (Ib), (II), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), (IIb-1), (IIc), (IIc-1), (IId), (IId-1), (IIe), (IIf), (II'), and (VI) (also referred to herein as "pharmaceutical agents").

[0671] Pharmaceutical compositions can be formulated using one or more physiologically acceptable carriers, including excipients and adjuvants that aid in processing the pharmaceutical agent into a pharmaceutically useful formulation. Appropriate formulations depend on the chosen route of administration. For example, overviews of pharmaceutical compositions are found in Remington: The Science and Practice of Pharmacy, 19th ed. (Easton, Pa., Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed. (Lippincott Williams & Wilkins, 1999).

[0672] The compositions and methods of the present disclosure can be used to treat individuals in need. In certain embodiments, the individual is a mammal, such as a human or non-human mammal. When applied to an animal (such as a human), the composition or pharmaceutical agent is preferably applied in the form of a pharmaceutical composition comprising, for example, a pharmaceutical agent and a pharmaceutically acceptable carrier or excipient. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions (such as water or buffered saline) or other solvents or vehicles (such as glycols, glycerol, oils such as olive oil or injectable organic esters). In a preferred embodiment, when such pharmaceutical compositions are used for human administration, particularly for invasive routes of administration (such as avoiding routes of transmission or diffusion via epithelial barriers, such as injection or implantation), the aqueous solution is pyrogen-free or substantially pyrogen-free. For example, excipients can be selected to achieve delayed release or selective targeting of one or more cells, tissues or organs of the reagent. The pharmaceutical composition can be in unit dosage form, such as tablets, capsules, granules, lyophilized products for rehydration, powders, solutions, slurries, suppositories, injections, etc. The composition can also be present in a transdermal delivery system (such as a skin patch). The composition may also be presented in a solution suitable for topical administration (eg, eye drops).

[0673] Pharmaceutically acceptable excipients can contain physiologically acceptable agents, which are used for example to stabilize compounds (e.g., pharmaceutical agents), increase their solubility, or increase their absorption. Such physiologically acceptable agents include, for example, carbohydrates (e.g., glucose, sucrose, or polydextrose), antioxidants (e.g., ascorbic acid or glutathione), chelating agents, low molecular weight proteins, or other stabilizers or excipients. The selection of pharmaceutically acceptable excipients including physiologically acceptable agents depends on, for example, the route of administration of the composition. Preparations or pharmaceutical compositions can be self-emulsifying drug delivery systems or self-microemulsifying drug delivery systems. Pharmaceutical compositions (preparations) can also be liposomes or other polymer matrices, into which compounds of the present disclosure can be incorporated. For example, liposomes comprising phospholipids or other lipids are physiologically acceptable and metabolizable non-toxic carriers that can be prepared and administered relatively simply.

[0674] The pharmaceutical composition (formulation) can be administered to a subject by any of a variety of routes of administration, including, for example, oral, such as bolus solutions in the form of aqueous or non-aqueous solutions or suspensions, tablets, capsules including dispersible capsules and gelatin capsules, boluses, powders, granules, pastes applied to the tongue; absorption through the oral mucosa, such as sublingually; anally, rectally or vaginally, such as in the form of pessaries, creams or foams; parenterally, including intramuscular, intravenous, subcutaneous or intrathecal, such as in the form of sterile solutions or suspensions; nasally; intraperitoneally; subcutaneously; transdermally, such as in the form of patches applied to the skin; and topically, such as in the form of creams, ointments or sprays applied to the skin, or in the form of eye drops. The compound can also be formulated for inhalation. In certain embodiments, the compound can simply be dissolved or suspended in sterile water.

[0675] The pharmaceutical composition can be a sterile aqueous or non-aqueous solution, suspension or emulsion, such as a microemulsion. The excipients described herein are examples and are not limiting in any way. An effective amount or therapeutically effective amount refers to an amount of one or more pharmaceutical agents administered to a subject in a single dose or as part of a series of doses that is effective to produce the desired therapeutic effect.

[0676] The subject can typically monitor the effectiveness of treatment using assays and methods suitable for the illness being treated, which assays will be familiar to those of ordinary skill in the art and are described herein. The pharmacokinetics of a pharmaceutical agent or one or more metabolites thereof administered to a subject can be monitored by measuring the level of the pharmaceutical agent or metabolite in a biological fluid (e.g., blood, blood fractions (e.g., serum) and / or urine) and / or other biological samples or biological tissues from the subject. Any method implemented in the art and described herein for detecting an agent can be used to measure the level of a pharmaceutical agent or metabolite during the course of treatment.

[0677] The dosage of the pharmaceutical agents described herein for treating a disease or condition may depend on the subject's condition, i.e., the stage of the disease, the severity of the symptoms caused by the disease, overall health, and age, sex, and weight, and other factors apparent to those skilled in the art of medicine. The pharmaceutical composition may be administered in a manner determined by those skilled in the art of medicine to be suitable for the disease being treated. In addition to the factors described herein and above regarding the use of pharmaceutical agents for treating a disease or condition, the suitable duration and frequency of administration of the pharmaceutical agent may also be determined or adjusted by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. Experimental models and / or clinical trials can generally be used to determine the optimal dose of the agent. The optimal dose may depend on the subject's body mass, weight, or blood volume. It is generally preferred to use the minimum dose sufficient to provide an effective therapy. The design and execution of preclinical and clinical studies of the pharmaceutical agents described herein (including when administered for preventive benefit) are fully within the skill of those skilled in the relevant art. When two or more pharmaceutical agents are administered to treat a disease or condition, the optimal dose of each pharmaceutical agent may be different, for example, less than the dose when either agent is administered alone as a single-agent therapy. In some specific embodiments, two kinds of pharmaceutical agents are combined and can be worked synergistically or additively, and any agent can be used in an amount less than that used alone.For example, the amount of the pharmaceutical agent that can be used every day can be between about 0.01mg / kg and 100mg / kg, for example, between about 0.1 to 1mg / kg, between about 1 to 10mg / kg, between about 10-50mg / kg, between about 50-100mg / kg body weight.In other embodiments, the amount of the pharmaceutical agent that can be used every day is between about 0.01mg / kg and 1000mg / kg, between about 100-500mg / kg or between about 500-1000mg / kg body weight.For the disease or illness treated, the optimum dose every day or each treatment process can be different and also can change with route of administration and treatment regimen.

[0678] Pharmaceutical compositions comprising pharmaceutical agents can be formulated in a manner suitable for the method of delivery using techniques commonly practiced in the art. The compositions can be in solid (e.g., tablets, capsules), semisolid (e.g., gels), liquid, or gaseous (e.g., aerosol) form. In other embodiments, the pharmaceutical composition is administered as a bolus infusion.

[0679] Pharmaceutically acceptable excipients are well known in the pharmaceutical field and are described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th edition, 2006 and Remington: The Science and Practice of Pharmacy (Gennaro, 21st edition, Mack Pub. Co., Easton, PA (2005)). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate-buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, etc. may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used. In general, the type of excipient is selected based on the mode of administration and the chemical composition of the active ingredient. Alternatively, the compositions described herein may be formulated as a lyophilizate. The compositions described herein may be lyophilized or otherwise formulated as a lyophilized product using one or more appropriate excipient solutions to dissolve and / or dilute the pharmaceutical agent of the composition after administration. In other embodiments, the pharmaceutical agent may be encapsulated within liposomes using techniques known and practiced in the art. In certain specific embodiments, the pharmaceutical agent is not formulated within a liposome for application to a vascular stent, which is used to treat a high-grade but not completely blocked artery.The pharmaceutical composition can be formulated for any suitable mode of administration as described herein and in the art.

[0680] For example, pharmaceutical compositions for oral administration or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery or other methods may be in liquid form. For example, liquid pharmaceutical compositions may include one or more of the following: sterile diluents, such as water, saline solutions, preferably physiological saline, Ringer's solution, isotonic sodium chloride; fixed oils that can serve as solvents or suspension media, polyethylene glycol, glycerol, propylene glycol or other solvents; antibacterial agents; antioxidants; chelating agents; buffers and for regulating osmotic properties, such as sodium chloride or dextrose. Parenteral compositions can be packaged in ampoules, disposable syringes or multidose vials made of glass or plastic. Physiological saline is preferably used, and the injectable pharmaceutical composition is preferably sterile. In another embodiment, in order to treat ophthalmic disorders or diseases, the liquid pharmaceutical composition can be applied to the eye in the form of eye drops. The liquid pharmaceutical composition can be delivered orally.

[0681] For oral formulations, at least one of the pharmaceutical agents described herein can be used alone or in combination with suitable additives to prepare tablets, powders, granules or capsules, and, where necessary, in combination with diluents, buffers, wetting agents, preservatives, colorants and flavorings. The pharmaceutical agent can be formulated with a buffer to provide protection to the compound against the low pH of the gastric environment, and / or formulated with an enteric coating. The pharmaceutical agent included in the pharmaceutical composition can be formulated for oral delivery, for example, in the form of a liquid, solid or semisolid formulation, and / or formulated with an enteric coating.

[0682] Pharmaceutical compositions comprising any of the pharmaceutical agents described herein can be formulated for sustained or slow release, also referred to as timed release or controlled release. Such compositions can typically be prepared using well-known techniques and administered, for example, orally, rectally, intradermally or subcutaneously, or by implantation at the desired target site. Sustained-release formulations may contain compounds dispersed in a carrier matrix and / or contained in a reservoir surrounded by a rate-controlling membrane. The excipients used in such formulations are biocompatible and may also be biodegradable; preferably, the formulation provides a relatively constant level of active ingredient release. The amount of pharmaceutical agent contained in a sustained-release formulation depends on the nature of the implantation site, release rate, and expected duration, as well as the illness, disease, or condition to be treated or prevented.

[0683] In certain embodiments, the pharmaceutical composition comprising the pharmaceutical agent is formulated for transdermal, intradermal or topical administration. The composition can be applied in the form of powder / talcum or other solids, liquids, sprays, aerosols, ointments, foams, creams, gels or pastes using a syringe, bandage, transdermal patch, insert or syringe-like applicator. This is preferably applied topically or injected directly into the skin near the treated area or within the treated area, such as intradermally or subcutaneously, in the form of a controlled release formulation or a sustained release formulation. The active composition can also be delivered via iontophoresis. Preservatives can be used to prevent the growth of fungi and other microorganisms. Suitable preservatives include, but are not limited to, benzoic acid, butyl parahydroxybenzoate, ethyl parahydroxybenzoate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal and combinations thereof.

[0684] Pharmaceutical compositions comprising pharmaceutical agents can be formulated as emulsions for topical application. Emulsions contain a liquid distributed in a second liquid body. Emulsions can be oil-in-water emulsions or water-in-oil emulsions. Either or both the oil phase and the aqueous phase can contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients. The oil phase can contain other oily, pharmaceutically approved excipients. Suitable surfactants include, but are not limited to, anionic surfactants, nonionic surfactants, cationic surfactants, and amphoteric surfactants. Compositions for topical application can also include at least one suitable suspending agent, antioxidant, chelating agent, emollient, or moisturizer.

[0685] For example, ointments and creams can be prepared with aqueous or oily bases, wherein suitable thickeners and / or gelling agents are added. Lotions can be prepared with aqueous or oily bases and usually should also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners or colorants. Liquid sprays can be delivered from pressurized packaging, for example, via a specially shaped closure. Oil-in-water emulsions can also be used in compositions, patches, bandages and products. These systems are semisolid emulsions, microemulsions or foam emulsion systems.

[0686] In some embodiments, the pharmaceutical agents described herein can be formulated in the form of an inhalant. Inhalation can deliver the drug directly to the respiratory tract. The pharmaceutical agent can be formulated as an aerosol, microparticles, liposomes, or nanoparticles. The pharmaceutical agent can be formulated with a solvent, a gas, a nitrate, or any combination thereof. The compositions described herein are optionally formulated into a liquid aerosol or an inhalable dry powder for delivery. The liquid aerosol formulation is optionally atomized primarily into a particle size that can be delivered to the terminal and respiratory bronchioles. The liquid aerosol and inhalable dry powder formulations are preferably delivered within the endobronchial tree to the terminal bronchioles and ultimately to the parenchymal tissue.

[0687] The aerosolized formulations described herein are optionally delivered using an aerosol-forming device, such as an ejector, a vibrating porous plate, or an ultrasonic nebulizer, preferably selected to allow the formation of aerosol particles having an average diameter primarily between 1 and 5 μm in the presence of a mass medium. Furthermore, the formulation preferably has a balanced osmotic concentration, ionic strength, and chloride concentration, and the minimum aerosolizable volume is capable of delivering an effective dose of the pharmaceutical agent. Furthermore, the aerosolized formulation preferably does not adversely impair respiratory function and does not cause undesirable side effects.

[0688] Aerosolization devices suitable for administering the aerosol formulations described herein include, for example, jets, vibrating porous plates, ultrasonic nebulizers, and powered dry powder inhalers, which are capable of atomizing the formulation into aerosol particle sizes primarily in the 1-5 μm size range. Primarily in this application means that at least 70% but preferably more than 90% of all aerosol particles produced are within the 1-5 μm range. Jet nebulizers work by separating liquid solutions into aerosol droplets through air pressure. Vibrating porous plate nebulizers work by using the sonic vacuum created by the rapid vibration of the porous plate to squeeze solvent droplets through the porous plate. Ultrasonic nebulizers work by shearing the liquid into small aerosol droplets through piezoelectric crystals. A variety of suitable devices are available, including, for example, AeroNeb™ and AeroDose™ vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, California), Nebulizer (Medic-Aid Ltd., West Sussex, England), Pari and Pari LC Jet nebulizer (Pari Respiratory Equipment, Inc., Richmond, Virginia) and Aerosonic™ (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and (Omron Healthcare, Inc., Vernon Hills, Illinois) ultrasonic nebulizer.

[0689] In some embodiments, the pharmaceutical agent can be formulated with an oily base or ointment to form a semi-solid composition with a desired shape. In addition to the pharmaceutical agent, these semi-solid compositions may contain dissolved and / or suspended bactericides, preservatives, and / or buffer systems. The petrolatum component that may be included may be any paraffin wax with a viscosity ranging from mineral oil to paraffin wax combined with isobutylene, colloidal silica, or stearate. Absorbent matrices may be used with oily systems. Additives may include, alone or in combination, cholesterol, lanolin (lanolin derivatives, beeswax, fatty alcohols, lanolin alcohols), emulsifiers with a low hydrophilic-lipophilic balance (HLB), and various ionic and nonionic surfactants.

[0690] Transdermal or local control or sustained release formulations can be realized by adding the additive (for example obtainable polymer structure, matrix in this area) of timed release.For example, compositions can be via using hot melt extrusion products, and for example bioadhesive hot melt extrusion film is used.Preparation can comprise crosslinked polycarboxylic acid polymer preparation.Cross-linking agent can provide enough adhesion amount to exist, thereby make system keep being attached to target epithelium or endothelial cell surface and continue to be enough to allow compound to realize the time of required release.

[0691] The insert, transdermal patch, bandage, or article of manufacture may comprise a mixture or coating of polymers that provides for release of the pharmaceutical agent at a constant rate over an extended period of time. In some embodiments, the article of manufacture, transdermal patch, or insert comprises a water-soluble pore-forming agent, such as polyethylene glycol (PEG), which may be mixed with a water-insoluble polymer to increase the durability of the insert and prolong the release of the active ingredient.

[0692] Transdermal devices (inserts, patches, bandages) may also contain water-insoluble polymers. Rate-controlling polymers may be suitable for application to sites where pH changes can be used to affect release. These rate-controlling polymers may be applied using a continuous coating film during the spraying and drying process of the active compound. In one embodiment, the coating formulation is used to coat pellets containing the active ingredient, which are compressed to form a solid, biodegradable insert.

[0693] Polymer formulations can also be used to provide controlled or sustained release. Bioadhesive polymers described in the art can be used. For example, sustained release gels and compounds can be incorporated into polymer matrices, such as hydrophobic polymer matrices. Examples of polymer matrices include microparticles. Microparticles can be microspheres, and the core can have a material different from the polymer shell. Alternatively, the polymer can be cast as a thin plate or film, a powder produced by grinding or other standard techniques, or a gel such as a hydrogel. The polymer can also be in the form of a coating or be a part of a bandage, vascular stent, catheter, vascular graft or other device to promote the delivery of the pharmaceutical agent. The matrix can be formed by solvent evaporation, spray drying, solvent extraction and other methods known to those skilled in the art.

[0694] Kits are provided having unit doses of one or more agents described herein, typically in oral or injectable dosage form. Such kits may include a container containing the unit dose, an informational package insert describing the use of the drug in treating the disease and the attendant benefits, and optionally an implement or device for delivering the composition.

[0695] D. Treatment methods

[0696] Ubiquitin-specific protease 1 (USP1) is a member of the ubiquitin-specific processing protease family. USP1 is a deubiquitinating enzyme ("DUB") and deubiquitinates substrates involved in key oncogenic pathways to regulate their function. Among its actions, USP1 can exhibit DNA-mediated activation at replication forks, protecting forks and promoting survival in BRCA1-deficient cells. Because loss of both USP1 and BRCA1 causes replication fork degradation, inhibition of USP1 can selectively reduce the survival rate of tumor cells with defects in BRCA deficiency, or kill tumor cells with defects in BRCA deficiency, without affecting the survival of cells with normal BRCA function.

[0697] In the United States (US), it is estimated that inherited BRCA1 and BRCA2 mutations are present in 5% to 10% of breast cancers and 10% to 15% of ovarian cancers. Breast cancer is the most common cancer in the world and the most common malignancy in women. BRCA1 and BRCA2 can be detected in at least 5% of unselected breast cancer patients and in approximately 30% of patients with a family history of breast or ovarian cancer. Currently, treatment options including chemotherapy and immune checkpoint inhibitors are limited for breast cancer patients with germline BRCA mutations, more aggressive progression, and a higher risk of recurrence. Although PARP inhibitors have been approved by the U.S. Food and Drug Administration (FDA) as monotherapy for harmful / suspected harmful germline BRCA mutations, HER2-negative breast cancer, in some cases, resistance to PARP inhibitors can be observed in breast cancer patients. Ovarian cancer is a heterogeneous group of solid tumors. On average, one-fifth of ovarian cancers can be associated with germline mutations. Of these ovarian cancers with germline mutations, 65% to 85% can be associated with germline BRCA mutations. Similar to the breast cancer setting, while PARP inhibitors can be first-line maintenance therapy for patients with BRCA-mutated ovarian cancer, these patients can develop resistance to PARP inhibitors.

[0698] The compounds described herein can be used as inhibitors of USP1. Such compounds can exhibit antiproliferative activity that is selective for BRCA1 and / or BRCA2 mutants. The compounds described herein can be used to treat BRCA1 and / or BRCA2 mutant or homologous recombination (HRD)-positive cancers. The compounds described herein can exhibit antiproliferative activity in cancer cells with BRCA1 and / or BRCA2 mutations, particularly MDA-MB-436 cells. The compounds described herein may not exhibit similar antiproliferative activity in cancer cells with wild-type BRCA, particularly SNG-M cells. In some embodiments, the compounds described herein can exhibit selectivity for mutant BRCA1 and / or BRCA2 that is at least 50-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 550-fold, 600-fold, or more, relative to wild-type BRCA.

[0699] The compounds described herein can be used to prepare a medicament for preventing or treating a disease or condition. In some embodiments, the compounds described herein are used in a method of regulating USP1 in a subject. In some embodiments, the compounds described herein are used in a method of inhibiting USP1 in a subject. In some embodiments, the compounds described herein are used in a method of inhibiting or reducing DNA repair activity regulated by USP1 in a subject. In some embodiments, the compounds described herein are used in a method of treating a disease or condition associated with USP1 in a subject. In some embodiments, the compounds described herein are used in a method of treating a disease or condition associated with the regulation of USP in a subject. In addition, a method for regulating, inhibiting or treating any of the diseases or conditions described herein in a subject in need of such treatment involves administering to the subject a pharmaceutical composition containing at least one compound described herein or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug or pharmaceutically acceptable solvate thereof in a therapeutically effective amount.

[0700] The compositions containing the compounds described herein can be administered for prophylactic and / or therapeutic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or disorder in an amount sufficient to cure or at least partially arrest the symptoms of the disease or disorder. Amounts effective for this use will depend on the severity and course of the disease or disorder, previous therapy, the patient's health, weight, response to the drugs, and the judgment of the attending physician.

[0701] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, condition, or disorder. This amount is defined as a "prophylactically effective amount or dose." In this use, the precise amount also depends on the patient's health, weight, and the like. When used in a patient, the effective amount for this use will depend on the severity of the disease, condition, or disorder, its course, previous therapy, the patient's health status and response to the drugs, and the judgment of the attending physician.

[0702] In the event that the patient's condition does not improve, the compound may be administered chronically, i.e., for an extended period of time (including the entire duration of the patient's life), at the physician's discretion, to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.

[0703] Once the patient's condition improves, a maintenance dose is administered as necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced to a level at which the improved disease, condition, or disorder is maintained, depending on the symptoms. However, the patient may require intermittent treatment on a long-term basis, depending on any recurrence of symptoms.

[0704] The amount of a given dose that will correspond to this amount will vary depending on factors such as the specific compound, the disease or disorder and its severity, the identity of the subject or subject in need of treatment (e.g., weight), but nonetheless can be determined in a manner recognized in the art based on the specific circumstances surrounding the case (including, for example, the specific agent being administered, the route of administration, the disorder being treated, and the subject or subject being treated). However, in general, dosages for adult treatment will typically range from about 0.02 to about 5000 mg per day, and in some embodiments, from about 1 to about 1500 mg per day. The desired dosage may be suitably presented in a single dose, or in divided doses administered simultaneously (or over a short period of time) or at appropriate intervals (e.g., in two, three, four, or more sub-doses per day).

[0705] The pharmaceutical compositions described herein may be in unit dosage form suitable for single administration of precise doses. In a unit dosage form, the formulation is divided into unit doses containing appropriate amounts of one or more compounds. The unit dose may be in a packaged form containing discrete amounts of the formulation. Non-limiting examples are packaged tablets or capsules and powders in vials or ampoules. Aqueous suspension compositions may be packaged in non-reclosable single-dose containers. Alternatively, reclosable multi-dose containers may be used, in which case a preservative is typically included in the composition. By way of example only, formulations for parenteral injection may be presented in unit dosage form, including but not limited to ampoules, or in multi-dose containers with added preservatives.

[0706] Toxicity and therapeutic efficacy of such treatment regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including but not limited to, determination of the LD 50 (50% population lethal dose) and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as LD 50 With ED 50 The ratio between the two groups is 1:1. Compounds that exhibit high therapeutic indices are preferred. Data obtained from cell culture assays and animal studies can be used to formulate a dosage range for use in humans. The dosage of such compounds is preferably within the range that includes the ED with minimal toxicity. 50 The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.

[0707] In one aspect, the present disclosure provides a method for modulating USP1 in a subject, comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0708] In one aspect, the present disclosure provides a method for inhibiting USP1 in a subject, comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0709] In one aspect, the present disclosure provides a method for inhibiting or reducing DNA repair activity regulated by USP1 in a subject in need thereof, comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein.

[0710] In one aspect, the present disclosure provides a method for treating a disease or condition associated with USP1 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein. In some embodiments, the disease or condition is cancer.

[0711] In one aspect, the present disclosure provides a method for treating a disease or condition associated with modulation of USP1 in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein. In some embodiments, the disease or condition is cancer.

[0712] In one aspect, the present disclosure provides a method of treating cancer in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein.

[0713] In some embodiments, the administration of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, may also comprise a combination with other biologically active ingredients (e.g., a second therapeutic agent). Other biologically active ingredients may include a second and different anti-neoplastic agent or second agent that targets a USP1-independent DNA repair mechanism. In some embodiments, the administration of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, may also comprise a combination with a non-drug therapy. Non-drug therapy may include surgery, radiation therapy, or any other type of treatment that does not include the administration of a drug. Such combinations of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, with other biologically active ingredients or non-drug therapies may enhance the effects of the compound described herein, or a pharmaceutically acceptable salt or solvate thereof. The compounds described herein may be administered simultaneously or sequentially with other biologically active ingredients, but at least two or more compounds or biologically active ingredients may be administered during a single cycle or course of therapy. In some embodiments, the second therapeutic agent is a poly ADP ribose polymerase (PARP) inhibitor. In some embodiments, a USP1 inhibitor described herein is administered together with two PARP inhibitors. In some embodiments, the PARP inhibitor is olaparib, niraparib, talazoparib, and rucaparib.

[0714] In one aspect, the present disclosure provides a method of treating cancer in a subject, the method comprising administering to a subject in need thereof an amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein. In some embodiments, the cancer is leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), or multiple myeloma (MM).

[0715] In some embodiments, the cancer is carcinoma, squamous carcinoma, adenocarcinoma, sarcoma, endometrial cancer, breast cancer, ovarian cancer, cervical cancer, fallopian tube cancer, primary peritoneal cancer, colon cancer, colorectal cancer, anogenital squamous cell carcinoma, melanoma, renal cell carcinoma, lung cancer, non-small cell lung cancer, lung squamous cell carcinoma, stomach cancer, bladder cancer, gallbladder cancer, liver cancer, thyroid cancer, laryngeal cancer, salivary gland cancer, esophageal cancer, head and neck cancer, glioblastoma, glioma, head and neck squamous cell carcinoma, prostate cancer, pancreatic cancer, mesothelioma, sarcoma, blood cancer, leukemia, lymphoma, neuroma, and combinations thereof. In some embodiments, the cancers treated by the methods of the present disclosure include, for example, carcinomas, squamous cell carcinomas (e.g., cervical canal, eyelid, conjunctiva, vagina, lung, oral cavity, skin, bladder, tongue, larynx, and esophagus) and adenocarcinomas (e.g., prostate, small intestine, endometrium, cervical canal, large intestine, lung, pancreas, esophagus, rectum, uterus, stomach, breast, and ovary). In some embodiments, the cancers treated by the methods of the present disclosure also include sarcomas (e.g., myogenic sarcomas), leukemias, neuromas, melanomas, and lymphomas. In some embodiments, the cancer treated by the methods of the present disclosure is breast cancer. In some embodiments, the cancer treated by the methods of the present disclosure is triple-negative breast cancer (TNBC). In some embodiments, the cancer treated by the methods of the present disclosure is ovarian cancer. In some embodiments, the cancer treated by the methods of the present disclosure is colorectal cancer. In some embodiments, the cancer is a homologous recombination-deficient cancer. In some embodiments, the cancer comprises cancer cells having a mutation in the gene encoding p53.

[0716] In some embodiments, the patient or patient colony treated with the pharmaceutical composition of the present disclosure suffers from solid tumors.In some embodiments, solid tumors are melanoma, renal cell carcinoma, lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gallbladder cancer, laryngeal cancer, liver cancer, thyroid cancer, gastric cancer, salivary gland cancer, prostate cancer, pancreatic cancer or Merkel cell carcinoma (Merkelcell carcinoma).In some embodiments, the patient or patient colony treated with the pharmaceutical composition of the present disclosure suffers from blood cancer.In some embodiments, the patient suffers from blood cancer, such as diffuse large B cell lymphoma ("DLBCL"), Hodgkin lymphoma ("HL"), non-Hodgkin lymphoma ("NHL"), follicular lymphoma ("FL"), acute myeloid leukemia ("AML") or multiple myeloma ("MM").In some embodiments, the patient or patient colony treated suffers from the cancer selected from the group consisting of ovarian cancer, lung cancer and melanoma.

[0717] Specific examples of cancers that can be prevented and / or treated according to the present disclosure include, but are not limited to, the following: renal cancer, kidney cancer, glioblastoma multiforme, metastatic breast cancer; breast cancer; breast sarcoma; neurofibroma; neurofibromatosis; pediatric tumors; neuroblastoma; malignant melanoma; epidermal carcinoma; leukemias, such as, but not limited to, acute leukemias, acute lymphocytic leukemias, acute myelocytic leukemias (e.g., myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemic leukemias, and myelodysplastic syndromes), chronic leukemias (e.g., chronic myelocytic (granulocytic) leukemias, chronic lymphocytic leukemias, hairy cell leukemias, polycythemia vera; lymphomas, such as, but not limited to, Hodgkin's disease and non-Hodgkin's disease; multiple myeloma, such as, but not limited to, smoldering multiple myeloma, non-secretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma, and extramedullary plasmacytoma; Waldenstrom's macroglobulinemia; monoclonal gammaglobulinemia of undetermined significance; benign monoclonal gammaglobulinemia; heavy chain disease; bone cancer and connective tissue sarcomas, such as, but not limited to, skeletal sarcoma, myeloma bone disease, multiple myeloma, cholesteatoma-induced skeletal osteosarcoma, Paget's disease of bone of bone), osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor, skeletal fibrosarcoma, chordoma, periosteal sarcoma, soft tissue sarcoma, angiosarcoma (angiosarcoma / hemangiosarcoma), fibrosarcoma, Kaposi's sarcoma sarcoma), leiomyosarcoma, liposarcoma, lymphangiosarcoma, neurilemoma, rhabdomyosarcoma, and synovial sarcoma; brain tumors, such as, but not limited to, gliomas, astrocytomas, brain stem gliomas, ependymomas, oligodendritic gliomas, non-glial tumors, acoustic neuromas, craniopharyngiomas, medulloblastomas, meningiomas, pinealocytomas, pineoblastomas, and primary brain lymphomas; breast cancer, including, but not limited to, adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mucinous breast cancer, tubular breast cancer, papillary breast cancer, Paget's disease (including juvenile Paget's disease), and inflammatory breast cancer; adrenal cancer, such as, but not limited to, pheochromocytoma and adrenocortical carcinoma; thyroid cancer, such as, but not limited to, papillary or follicular thyroid cancer, medullary thyroid cancer, and anaplastic thyroid cancer;Pancreatic cancer, such as, but not limited to, insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor; pituitary cancer, such as, but not limited to, Cushing's disease, prolactin-secreting tumor, acromegaly, and diabetes insipidus; eye cancer, such as, but not limited to, ocular melanoma (e.g., iris melanoma, choroidal melanoma, and ciliary body melanoma) and retinoblastoma; vaginal cancer, such as, but not limited to, squamous cell carcinoma, adenocarcinoma, and melanoma; vulvar cancer, such as, but not limited to, squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget's disease; cervical cancer, such as, but not limited to, squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget's disease; ovarian cancer, such as, but not limited to, epithelial ovarian cancer, borderline tumors, germ cell tumors, and stromal tumors; cervical cancer; esophageal cancer, such as, but not limited to, squamous cell carcinoma, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma; gastric cancer, such as, but not limited to, adenocarcinoma, mycosis fungoides (polypoid) carcinoma, ulcerative carcinoma, superficial spreading carcinoma, diffuse spreading carcinoma, malignant lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; colon cancer; colorectal cancer, KRAS-mutated colorectal cancer; colon cancer; rectal cancer; liver cancer, such as, but not limited to, hepatocellular carcinoma and hepatoblastoma; gallbladder cancer, such as, but not limited to, adenocarcinoma; bile duct cancer, such as, but not limited to, papillary, nodular, and diffuse bile duct cancer; lung cancer, such as, but not limited to, KRAS-mutated non-small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large cell carcinoma, and small cell lung cancer; lung carcinoma; testicular cancer, such as, but not limited to, embryonal tumor, seminoma, anaplastic cell tumor, classic (typical) cell tumor, spermatoblastoma, non-seminoma, embryonal carcinoma, teratoma, choriocarcinoma (yolk sac tumor); prostate cancer, such as, but not limited to, androgen-independent prostate cancer, androgen-dependent prostate cancer carcinoma, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; penile cancer; oral cancer, such as, but not limited to, squamous cell carcinoma; basal carcinoma; salivary gland cancer, such as, but not limited to, adenocarcinoma, mucoepidermoid carcinoma, and adenoid cystic carcinoma; pharyngeal cancer, such as, but not limited to, squamous cell carcinoma and verrucous cell carcinoma; skin cancer, such as, but not limited to, basal cell carcinoma, squamous cell carcinoma, and melanoma (superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma, acral lentiginous melanoma); kidney cancer, such as, but not limited to, renal cell carcinoma, adenocarcinoma, adrenal tumor, fibrosarcoma, transitional cell carcinoma (renal pelvis and / or ureter); renal cancer; Wilms' tumor;Bladder cancer, such as, but not limited to, transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, and carcinosarcoma. Additionally, cancers include myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphoendotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, and papillary adenocarcinoma.

[0718] In one aspect, the present disclosure provides a method for treating cancer in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein. In some embodiments, the cancer may comprise cancer cells with elevated RAD18 mRNA expression levels. In some embodiments, elevated RAD 18 levels are elevated RAD 18 protein levels. In some embodiments, RAD 18 levels can be detected using quantitative methods such as microarrays, RNA-Seq, or reverse transcriptase polymerase chain reaction (RT-PCR). In some embodiments, RAD 18 levels in cancer cells can be detected before administering the compounds described herein. In some embodiments, RAD 18 levels can be detected in cancer samples obtained from subjects. In some embodiments, if a subject has elevated RAD 18 levels, the subject can be treated with the compounds described herein. In some embodiments, elevated RAD 18 levels in cancer cells indicate that the subject administering the compounds described herein or pharmaceutical compositions has responded to treatment with the compounds described herein or pharmaceutical compositions. In some embodiments, a compound described herein is not administered to a subject with elevated RAD18 levels.

[0719] In some embodiments, the cancer is a cancer with a defect in a DNA damage repair pathway. In some embodiments, the cancer is a BRCA1 or BRCA2 mutant cancer that is resistant or refractory to PARP inhibitors. In some embodiments, the cancer comprises cells with elevated levels of RAD 18, wherein the elevated levels of RAD 18 are at least as high as the levels of RAD 18 mRNA and / or protein in ES2 cells or HEP3B217 cells.

[0720] In some embodiments, the cancer is a BRCA1 mutant cancer and / or a BRCA2 mutant cancer. In some embodiments, the cancer is a BRCA1 or BRCA2 wild-type cancer. In some embodiments, the cancer is a BRCA1 deficient cancer. In some embodiments, the cancer is a BRCA2 deficient cancer. In some embodiments, the cancer comprises cancer cells having mutations in the genes encoding BRCA1 and / or BRCA2. In some embodiments, the cancer is a BRCA1 mutant cancer and a BRCA2 deficient cancer. In some embodiments, the cancer is a BRCA1 deficient cancer and a BRCA2 mutant cancer. In some embodiments, the cancer comprises cells having elevated levels of RAD 18, wherein the elevated levels of RAD 18 are at least as high as the levels of RAD 18 mRNA and / or protein in ES2 cells or HEP3B217 cells.

[0721] Example

[0722] The following examples are provided to illustrate, but not to limit, the claimed disclosure.The following examples further illustrate the disclosure, but of course should not be construed as limiting its scope in any way.

[0723] The following synthesis schemes are provided for the purpose of illustration and not limitation. The following examples illustrate a variety of methods for preparing the compounds described herein. It should be understood that those skilled in the art may be able to prepare these compounds by similar methods or by combining other methods known to those skilled in the art. It should also be understood that those skilled in the art will be able to prepare in a similar manner as described below by using appropriate starting materials and modifying the synthetic pathway as needed. In general, starting materials and reagents can be obtained from commercial suppliers or synthesized according to sources known to those skilled in the art or prepared as described herein.

[0724] Compounds and salts of Formula (I), (Ia), (Ib), (II), (II'), (IIa), (IIa-1), (IIa-1a), (IIb), (IIb-1), (IIb-1), (IIc), (IIc'), (IIc-1), (IId), (IId'), (IId-1), (IIe), (IIf), (IIg) and (VI) can be synthesized according to one or more illustrative schemes herein and / or techniques known in the art. The materials used herein are commercially available or prepared by synthetic methods generally known in the art. These schemes are not limited to the compounds or any specific substituents listed in the examples, which are used for illustrative purposes. Although the synthetic schemes below describe and depict various steps, the steps may, in some cases, be performed in an order different from the order shown below. The numbering or R groups in each scheme do not necessarily correspond to the claims or other schemes or tables herein.

[0725] Example A_Biological Assay

[0726] Example A1: Enzyme assay

[0727] Human recombinant USP1 / UAF1 (R&D, E-568-050) expressed in baculovirus-infected Sf21 cells was used. Test compounds and / or vehicle were incubated with 2 nM USP1 / UAF1 in modified HEPES buffer (pH 8.0) for 15 minutes at room temperature. The reaction was initiated by adding 500 nM ubiquitin rhodamine 110 (R&D, U-555-050) for kinetic readings. The slope change of fluorescence intensity was read at 485 nm / 535 nm using spectrofluorometry. The dose response of the test compound or reference compound ML-323 was analyzed by nonlinear regression using GraphPad Prism software. The results of the assay are shown in Table 2.

[0728] Example A2: MDA-MB-436 breast cancer cell culture

[0729] MDA-MB-436 cells were grown in Leibovitz's L-15 medium with 10 ug / ml insulin, 16 ug / ml glutathione, and 10% FBS. Cells were passaged at subconfluence after trypsinization and maintained in an incubator at 37°C in a humidified atmosphere with 5% CO2.

[0730] Example A3: MDA-MB-436 breast cancer cell proliferation assay

[0731] use Luminescent cell viability assay (Promega, #G7573) measures cell proliferation. MDA-MB-436 cells were seeded in 384-well plates and allowed to adhere for 24 hours. Compounds were added to 384-well plates by ECHO and incubated at 37°C in a humidified atmosphere with 5% CO2. After 7 days, CellTiter-Glo was added to the 384-well plates, the contents were mixed on a 400g orbital shaker for 2 minutes, and then the plates were centrifuged at 1000 rpm for 2 minutes. After incubation at room temperature for 30 minutes, luminescence was read on Envision. The results of the assay are shown in Table 2.

[0732] Example B_Chemical Synthesis

[0733] Example B1: LCMS method

[0734] The LCMS methods used in the following synthetic procedures are provided in Table 3.

[0735] Table 3: LCMS method codes

[0736] (Flow rate is expressed in mL / min; column temperature (T) is expressed in °C; operation time is expressed in minutes).

[0737]

[0738] Example B2: Synthesis of Intermediate A:

[0739]

[0740] 4-Cyclopropyl-6-methoxypyrimidine

[0741] To a solution of 4-chloro-6-methoxypyrimidine (150.00 g, 1.04 mol) in dioxane (1500 mL) and H2O (300 mL) was added cyclopropylboronic acid (178.27 g, 2.08 mol), K2CO3 (286.82 g, 2.08 mol) and Pd(dppf)Cl2 (75.92 g, 0.10 mol). The mixture was stirred at 100 ° C for 16 hours under an Ar atmosphere. The mixture was then diluted with water (500 mL) and extracted with EtOAc (400 mL×3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluted with PE / EtOAc=20 / 1 to give the desired product (82.10 g, 0.55 mol, 53%) as a yellow oil.

[0742] LCMS: retention time: 1.157 min, (M+H) + 151.1, Method A.

[0743] 5-Bromo-4-cyclopropyl-6-methoxypyrimidine

[0744] To a solution of 4-cyclopropyl-6-methoxypyrimidine (82.00 g, 546.01 mmol) in EtOH (900 mL) was added Br (30.85 mL, 600.61 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 16 hours. The suspension was filtered and washed with MeOH (200 mL). The solid was dried to give the desired product (99.70 g, 435.22 mmol, 80%) as a white solid.

[0745] LCMS: retention time: 1.707 min, (M+H) + =229.1, Method A.

[0746] 4-Cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine

[0747] To a solution of 5-bromo-4-cyclopropyl-6-methoxypyrimidine (50.00 g, 218.26 mmol) in DMSO (500 mL) was added 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (110.88 g, 436.53 mmol), KOAc (64.26 g, 654.79 mmol) and Pd(dppf)Cl2 (15.97 g, 21.83 mmol). The mixture was stirred at 100 ° C. under an Ar atmosphere for 16 hours. The mixture was then diluted with 600 mL of water and extracted with EtOAc (500 mL×3). The combined organic layers were washed with brine (200 mL×3), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc = 10: 1 to give the desired product (28.00 g, 101.40 mmol, 46%) as a white solid.

[0748] LCMS: retention time: 1.627 min, (M+H) + =277.2, Method A.

[0749] 1 H NMR (400MHz, DMSO-d6): δ = 8.59 (s, 1H), 3.86 (s, 3H), 2.05-2.02 (m, 1H), 1.32 (s, 12H), 1.04-1.00 (m, 4H).

[0750] Example B3: Synthesis of Intermediate B:

[0751]

[0752] Methyl 4-hydrazinobenzoate hydrochloride

[0753] To a suspension of 4-aminobenzoic acid methyl ester (3.00g, 19.85mmol) in water (65mL) and concentrated HCl (25mL) was added dropwise a solution of sodium nitrite (1.51g, 21.83mmol) in water (15mL) at 0°C. The mixture was kept at 0°C for 45 minutes and SnCl (3.76g, 19.85mmol) was added in concentrated HCl (10mL). Once the addition is completed, the temperature is slowly raised until room temperature is reached. The suspension is filtered and the solid is washed with saturated brine (50mL) and ether (50mL). Dry the solid to obtain the desired product (3.02g, 18.19mmol, 92%) as a yellow solid.

[0754] LCMS: retention time: 0.827 min, (M+H) + =167.1, Method A.

[0755] Methyl 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate

[0756] To a solution of methyl 4-hydrazinobenzoate hydrochloride (1.98 g, 11.92 mmol) and 1,1,1-trifluoropentane-2,4-dione (1.84 g, 11.92 mmol) in HFIP (20 mL) was slowly added TEA (2.41 g, 23.84 mmol) at 0 ° C. The mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was then quenched with water (40 mL) and extracted with DCM (20 mL × 3). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to give a crude product. The crude product was purified by silica gel chromatography (eluted with 15% ethyl acetate / petroleum ether) to give the desired product (2.2 g, 7.75 mmol, 65% yield) as a white solid.

[0757] LCMS: retention time: 1.887 min, (M+H) + =285.0, Method A.

[0758] (4-(5-Methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol

[0759] To a solution of 4-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzoic acid methyl ester (1.70g, 5.99mmol) in anhydrous THF (20mL) was added LiAlH4(0.45g, 11.98mmol) at 0°C. The mixture was then warmed to room temperature and stirred for 2 hours. The resulting mixture was diluted with THF (20mL) and quenched with water (0.5mL) at 0°C. After 0.5 hours, Na2SO4 was added. The suspension solution was then stirred for about 15 minutes and filtered. The filtrate was concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with 30% ethyl acetate / petroleum ether) to obtain the desired product (0.75g, 2.93mmol, 49%) as a yellow oil.

[0760] LCMS: retention time: 1.677 min, (M+H) + =257.0, Method A.

[0761] 1-(4-(Chloromethyl)phenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole

[0762] To a solution of (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol (0.75 g, 2.93 mmol) in DCE (15 mL) was added SOCl (1.04 g, 8.78 mmol) in one portion. After the reactants were stirred at 50 ° C for 0.5 hours, the mixture was cooled to 0 ° C and quenched with water (10 mL). The resulting solution was neutralized with saturated NaHCO solution and extracted with DCM (50 mL × 3). The combined organic layers were dried over anhydrous Na SO, filtered and concentrated to give the desired product (0.5 g, 1.82 mmol, 62%) as a brown oil, which was used directly in the next step.

[0763] LCMS: retention time: 1.917 min, (M+H) + =275.0, Method A.

[0764] Example B4: Synthesis of Intermediate C:

[0765]

[0766] 2-(4-Hydrazinophenyl)acetic acid

[0767] At 0 ° C under N2, a solution of NaNO2 (2.28 g, 33.08 mmol) in H2O (10 mL) was added dropwise to a solution of 2- (4-aminophenyl) acetic acid (5.00 g, 33.08 mmol) in concentrated HCl (25 mL) and H2O (65 mL). The mixture was stirred at 0 ° C for 30 minutes. Then, a solution of SnCl2 (18.75 g, 99.23 mmol) in concentrated HCl (10 mL) was added dropwise at 0 ° C. After stirring for 1.5 hours, the mixture was filtered and washed with MeCN (15 mL × 2) to give the desired product (5.00 g, 30.09 mmol, 91% yield) as a white solid.

[0768] LCMS: retention time: 0.324 min, (M+H) + =167.1, Method A.

[0769] 2-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)acetic acid

[0770] To a solution of 2-(4-hydrazinophenyl)acetic acid (5.00 g, 30.09 mmol) in HFIP (15 mL) was added 1,1,1-trifluoropentane-2,4-dione (4.64 g, 30.09 mmol) and TEA (6.09 g, 60.17 mmol) at 0 ° C. under N2 atmosphere. The mixture was stirred at 0 ° C. for 1 hour. HCl (1 mol / L, 15 mL) was then added to adjust the pH to 5-6. The mixture was extracted with EtOAc (15 mL × 3). The combined organic phases were washed with brine (15 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give the desired product (5.00 g, 17.6 mmol, 59% yield) as a yellow solid.

[0771] LCMS: retention time: 1.683 min, (M+H) + =285.0, Method A.

[0772] Example B5: Synthesis of Intermediate D:

[0773]

[0774] 4-Hydrazinobenzonitrile hydrochloride

[0775] To a cooled (-5 to 0 ° C) and stirred suspension of 4-aminobenzonitrile (10.00 g, 84.65 mmol) in concentrated HCl (100 mL) was added aqueous sodium nitrite solution (6.42 g, 93.11 mmol). To this cooled (0 ° C) solution was added stannous chloride dihydrate (42.086 g, 186.22 mmol) in concentrated hydrochloric acid while stirring and maintaining the temperature below 0 ° C. The resulting solution was stirred for another 30 minutes. The white precipitate thus formed was collected by filtration and washed with Et2O (50 mL) to give the desired product (10.00 g, 58.96 mmol, 70%) as a light yellow solid.

[0776] 1 H NMR: (400MHz, DMSO-d6) δ = 10.55 (s, 2H), 9.12 (s, 1H), 7.73 (d, J = 8.8Hz, 2H), 7.04 (d, J = 8.8Hz, 2H)

[0777] 4-(5-Methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile

[0778] A mixture of 4-hydrazinobenzonitrile hydrochloride (10.00 g, 58.96 mmol), 1,1,1-trifluoropentane-2,4-dione (15.035 g, 97.63 mmol), sodium acetate (12.32 g, 150.21 mmol) and acetic acid (100 mL) was stirred at 120° C. for 1 hour. After cooling to ambient temperature, the reaction mixture was concentrated under vacuum and purified by silica gel chromatography (PE / EtOAc 50 / 1 to 10 / 1) to give the desired product (6.90 g, 27.5 mmol, 47%) as a light yellow solid.

[0779] 1 H NMR: (400MHz, DMSO-d6)δ=8.08-8.06(m,2H),7.86-7.84(m,2H),6.84(s,1H),2.44(s,3H)

[0780] (4-(5-Methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanamine

[0781] To a mixture of 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile (500 mg, 1.99 mmol) in MeOH (15 mL) and THF (5 mL) was added ammonium hydroxide (1 mL), and then an excess of wet Raney nickel (Raney Ni) was added. Under hydrogen pressure (0.5 MPa), the mixture was stirred at room temperature for 2 hours. The mixture was then filtered and concentrated to give a crude product as a yellow oil, which was used directly in the next step.

[0782] LCMS: retention time: 0.813 min, (M+H) + =256.0, method A.

[0783] Example B6: Synthesis of Intermediate E:

[0784]

[0785] 6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine

[0786] A mixture of 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (500 mg, 3.23 mmol), pyridin-1-ium 4-methylbenzene-1-sulfonate (81 mg, 0.32 mmol) and 3,4-dihydro-2H-pyran (544 mg, 6.47 mmol) in DCM (10 mL) was stirred at 40 ° C for 6 hours. The mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EtOAc from 10 / 1 to 3 / 1) to give the desired product (720 mg, 3.02 mmol, 93%) as a yellow solid.

[0787] LCMS: retention time: 1.635 min, (M+H) + =239.0, Method A.

[0788] 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine

[0789] A mixture of 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (200 mg, 0.84 mmol), 4-cyclopropyl-6-methoxy-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (347 mg, 1.26 mmol), Pd(dppf)Cl2 (123 mg, 0.17 mmol) and K2CO3 (290 mg, 2.09 mmol) in dioxane (8 mL) / water (1 mL) was stirred at 100°C for 16 hours. The mixture was then cooled to room temperature, diluted with water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic fractions were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc 10 / 1 to 1 / 1) to give the desired product (252 mg, 0.72 mmol, 86%) as a yellow solid.

[0790] LCMS: retention time: 1.407 min, (M+H) + =353.2, Method A.

[0791] 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine

[0792] A solution of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (215 mg, 0.61 mmol) in TFA (10 mL) was stirred at room temperature for 16 hours. The mixture was then concentrated under reduced pressure and dissolved in DCM (20 mL). The solution was washed with saturated NaHCO solution (20 mL), brine (20 mL), dried over NaSO, filtered and concentrated under reduced pressure to give the crude product (200 mg) as a brown oil, which was used directly in the next step.

[0793] LCMS: retention time: 0.958 min, (M+H) + =269.1, Method A.

[0794] Example B7: Synthesis of Intermediate F:

[0795]

[0796] Methyl 4-(hydroxymethyl)cubane-1-carboxylate

[0797] To a solution of 4-(methoxycarbonyl)cubane-1-carboxylic acid (1.80 g, 8.73 mmol) in THF (20 mL) was added borane dimethyl sulfide complex (5.238 mL, 2 mol / L, 10.476 mmol) at 0°C under Ar. The mixture was stirred at room temperature for 1 hour. The mixture was then quenched with water (30 mL) at 0°C and concentrated under reduced pressure to remove THF. The mixture was extracted with DCM (30 mL × 3), and the combined organic fractions were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired product (1.60 g, 8.32 mmol, 95%) as a white solid.

[0798] 1 H NMR: (400MHz, DMSO-d6) δ = 4.53 (t, J = 5.4Hz, 1H), 4.05-4.02 (m, 3H), 3.80-3.77 (m, 3H), 3.61 (s, 3H), 3.51 (d, J = 5.6Hz, 2H)

[0799] Methyl 4-formylcubane-1-carboxylate

[0800] To a solution of methyl 4-(hydroxymethyl)cubane-1-carboxylate (1.68 g, 8.74 mmol) in DCM (30 mL) was added Dess-Martin periodinane (4.08 g, 9.61 mmol) at room temperature. The mixture was stirred at room temperature for 0.5 hours. Saturated NaHCO (15 mL) and Na2SO3 solution (15 mL) were added to the mixture. After stirring for 10 minutes, the mixture was extracted with DCM (10 mL × 6). The combined organic fractions were dried over Na2SO4, filtered and concentrated under reduced pressure to give the desired product (1.20 g, 6.31 mmol, 72%) as a white solid.

[0801] 4-(4-(Trifluoromethyl)-1H-imidazol-2-yl)cubane-1-carboxamide

[0802] A mixture of 3,3-dibromo-1,1,1-trifluoropropan-2-one (2.214 g, 8.20 mmol) and sodium acetate (1.04 g, 12.62 mmol) in water (5 mL) was stirred at 100° C. for 1 hour and then cooled to room temperature. A mixture of methyl 4-formylcubane-1-carboxylate (1.20 g, 6.31 mmol), MeOH (20 mL), and ammonium hydroxide (10 mL) was added, and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was then concentrated under reduced pressure to give the crude product (1.77 g) as a white solid.

[0803] LCMS: retention time: 0.891 min, (M+H) + =282.1, Method A.

[0804] 4-(4-(Trifluoromethyl)-1H-imidazol-2-yl)cubane-1-carboxylic acid

[0805] A solution of 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)cubane-1-carboxamide (1.77 g, 6.30 mmol) in dioxane (10 mL) was added to 3N H2SO4 (6 mL). The mixture was stirred at 100 ° C for 3 hours. The mixture was then cooled to room temperature, concentrated and dissolved in water (15 mL). The solution was basified with 2N NaOH until pH = 7. The mixture was concentrated under reduced pressure and dissolved in DCM / MeOH (10 / 1). After stirring for 0.5 hours, the suspension was filtered. The filtrate was concentrated under reduced pressure to obtain the desired product (1.50 g, 5.32 mmol, 84% yield) as a white solid.

[0806] LCMS: retention time: 1.350 min, (M+H) + =283.1, Method A.

[0807] Example B8: Synthesis of Compound 1

[0808]

[0809] 6-Chloro-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[4,3-c]pyridine

[0810] To a solution of 6-chloro-1H-pyrazolo[4,3-c]pyridine (200 mg, 1.30 mmol) and 1-[4-(chloromethyl)phenyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazole (0.36 g, 1.30 mmol) in DMF (3 mL) was added KCO (0.36 g, 2.61 mmol). The mixture was stirred at room temperature for 3 hours. Saturated ammonium chloride solution (35 mL) was then added, and the resulting solution was extracted three times with ethyl acetate (15 mL). The combined organic layers were washed with brine (25 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative TLC (PE / EA=3 / 2) to give the desired product (0.17 g, 0.43 mmol, 33%) as a colorless oil.

[0811] LCMS: retention time: 1.869 min, (M+H) + =392.0, Method A.

[0812] 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[4,3-c]pyridine

[0813] To a solution of 6-chloro-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-pyrazolo[4,3-c]pyridine (0.12 g, 0.31 mmol) and 4-cyclopropyl-6-methoxy-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.13 g, 0.47 mmol) in dioxane / water (6 mL / 1 mL) was added NaCO (0.10 g, 0.93 mmol) and Pd(PPh) (0.04 g, 0.03 mmol) under N2 atmosphere. The mixture was stirred at 100 ° C for 16 hours. The reaction mixture was then cooled to room temperature and water (20 mL) was added. The resulting mixture was extracted three times with ethyl acetate (15 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative TLC (PE / EA=3 / 2) to give the desired product (0.05 g, 0.099 mmol, 32%).

[0814] LCMS: retention time: 1.710 min, (M+H) + =506.2, Method A.

[0815] 1 H NMR: (400MHz, MeOD-d4)δ=9.17(s,1H),8.59(s,1H),8.40(s,1H),7.76(s,1H),7.51-7.44(m,4H),6.56( s,1H),5.81(s,2H),3.87(s,3H),2.31(s,3H),1.64-1.59(m,1H),1.13-1.11(m,2H),0.87-0.85(m,2H).

[0816] Example B9: Synthesis of Compound 2

[0817]

[0818] N-((5-chloropyrazin-2-yl)methyl)-2-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)acetamide

[0819] To a solution of 2-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)acetic acid (1800 mg, 6.34 mmol) in DMF (15 mL) was added (5-chloropyrazin-2-yl)methanamine (927 mg, 6.48 mmol), HATU (3684 mg, 9.69 mmol) and DIPEA (4174 mg, 32.29 mmol) under N2. The mixture was stirred at 25 ° C for 16 hours. The mixture was then diluted with water (15 mL) and extracted with EtOAc (15 mL×3). The combined organic phases were washed with br...

Claims

1. A compound having a structure of formula (I) or a salt thereof, in, X 1 N or CR 1 ; X 3 N or CR 3 ; X 7 N or CR 7 ; R 1 , R 3 and R 7 are each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; R 8 and R 9 are each independently selected from hydrogen, halo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl; Ring A is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl; R A are each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 )、-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 )、-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ); R 11 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4 Alkylene-C 3-8 Cycloalkyl, optionally substituted -C 1-4 Alkylene-C 2-7 Heterocycloalkyl, optionally substituted -C 1-4 Alkylene-phenyl or optionally substituted-C 1-4 Alkylene-heteroaryl; R 12 Each independently selected from hydrogen, -NO2, -CN, C 1-6 Alkyl, C 1-6 Aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, wherein the C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl; B is a 6-membered heteroaryl group, a phenyl group or a phenyl isostere; R B1 is optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl; Each R B are independently halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 )、-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 )、-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl; or Two R on the same atom B Together with the atoms to which it is attached, it forms an optionally substituted C 3-8 Cycloalkyl or optionally substituted C 2-9 Heterocycloalkyl; m is 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; and p is 0 or 1.

2. The compound or salt thereof according to claim 1, wherein X 1 N or CR 1 ; X 3 N or CR 3 ; X 7 N or CR 7 ; R 1 , R 3 and R 7 are each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl, wherein the alkyl, heteroalkyl, alkenyl or alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, amino, oxo, -OH, -NO2, -CN and C 1-3 Alkoxy; R 8 and R 9 are each independently selected from hydrogen, halo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 together with the carbon to which it is attached, forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted by one or more substituents independently selected from the following: halogen, amino, -OH, -NO2, oxo, -CN, C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 Haloalkyl; Ring A is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl; R A are each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 )、-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 )、-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ), wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted by one or more substituents independently selected from the following: halogen, -OH, -NO2, oxo, amino, -CN, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, amino, -NO2, oxo, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl; R 11 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4 Alkylene-C 3-8 Cycloalkyl, optionally substituted -C 1-4 Alkylene-C 2-7 Heterocycloalkyl, optionally substituted -C 1-4 Alkylene-phenyl or optionally substituted-C 1-4 Alkylene-heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, amino, -NO2, oxo, C 1-6 Alkoxy, -CN, C 1-6 Alkyl and C 1-6 Haloalkyl; R 12 Each independently selected from hydrogen, -NO2, -CN, C 1-6 Alkyl, C 1-6 Aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, wherein the C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl; B is a 6-membered heteroaryl group, a phenyl group or a phenyl isostere; R B1 is optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl or optionally substituted bicyclic heteroaryl, wherein the cycloalkyl, heterocycloalkyl, naphthyl, phenyl or heteroaryl are each optionally substituted by one or more substituents independently selected from the group consisting of halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 )、-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 )、-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ), wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, amino, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2, oxo, -CN, C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 Haloalkyl; Each R B are independently halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 )、-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 )、-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl or optionally substituted bicyclic heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, naphthyl, phenyl or heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, amino, oxo, -CN, C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 haloalkyl; or Two R on the same atom B Together with the atoms to which it is attached, it forms an optionally substituted C 3-8 Cycloalkyl or optionally substituted C 2-9 Heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, amino, -NO2, oxo, C 1-6 Alkoxy, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl; m is 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; and p is 0 or 1.

3. The compound or salt thereof according to claim 1 or 2, wherein the compound has a structure of formula (Ia), in, X 1 N or CR 1 ; X 3 N or CR 3 ; X 7 N or CR 7 ; R 1 , R 3 and R 7 are each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; Y 1 N or CR Y1 ; Y 2 N or CR Y2 ; Y 3 N or CR Y3 ; Y 4 N or CR Y4 ; R Y1 , R Y2 , R Y3 and R Y4 are each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; R 8 and R 9 are each independently selected from hydrogen, halo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl; Ring A is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl; R A are each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 )、-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 )、-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ); R 11 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4 Alkylene-C 3-8 Cycloalkyl, optionally substituted -C 1-4 Alkylene-C 2-7 Heterocycloalkyl, optionally substituted -C 1-4 Alkylene-phenyl or optionally substituted-C 1-4 Alkylene-heteroaryl; R 12 Each independently selected from hydrogen, -NO2, -CN, C 1-6 Alkyl, C 1-6 Aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, wherein the C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl; R B1 is optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl; m is 1, 2, 3 or 4; and p is 0 or 1.

4. The compound or salt thereof according to any one of claims 1 to 3, wherein the compound has a structure of formula (Ib), 5. The compound or salt thereof according to any one of claims 1 to 4, wherein X 1 is N.

6. The compound or salt thereof according to any one of claims 1 to 4, wherein X 1 CR 1 .

7. The compound or salt thereof according to any one of claims 1 to 6, wherein X 3 is N.

8. The compound or salt thereof according to any one of claims 1 to 6, wherein X 3 CR 3 .

9. The compound or salt thereof according to any one of claims 1 to 8, wherein X 7 is N.

10. The compound or salt thereof according to any one of claims 1 to 8, wherein X 7 CR 7 .

11. A compound having a structure of formula (II') or a salt thereof, in, X 1 N or CR 1 ; X 2 is N; X 3 N or CR 3 ; X 5 is N; X 6 is N, NR 6 , CR 6 , C(R 6 )2, S(=O)2, C(=O) or C(=S); X 7 is N, NR 7 , O, S, CR 7 , S(=O)2, C(=O) or C(=S); The conditions are: (i) when X 2 , X 3 and X 5 is N, and X 6 When it is C(=O), then X 7 O, S, CR 7 , C(=O) or C(=S), and (ii) when X 2 , X 3 and X 5 When N is X 6 and X 7 At least one of which is selected from O, S, S(═O)2, C(═O) or C(═S); is a single bond or a double bond; R 1 , R 3 , R 6 and R 7 are each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; R 8 and R 9 are each independently selected from hydrogen, halo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl; Ring A is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl; R A are each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 )、-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 )、-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ); R 11 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4 Alkylene-C 3-8 Cycloalkyl, optionally substituted -C 1-4 Alkylene-C 2-7 Heterocycloalkyl, optionally substituted -C 1-4 Alkylene-phenyl or optionally substituted-C 1-4 Alkylene-heteroaryl; R 12 Each independently selected from hydrogen, -NO2, -CN, C 1-6 Alkyl, C 1-6 Aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl and C 3-6 Carbocyclic ring, 3-membered to 6-membered heterocyclic ring, wherein the C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl; B is a 6-membered heteroaryl group, a phenyl group or a phenyl isostere; R B1 is optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl; Each R B are independently halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 )、-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 )、-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl; or Two R on the same atom B Together with the atoms to which it is attached, it forms an optionally substituted C 3-8 Cycloalkyl or optionally substituted C 2-9 Heterocycloalkyl; m is 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; and p is 0 or 1.

12. The compound or salt thereof according to claim 11, in, X 1 N or CR 1 ; X 2 is N; X 3 N or CR 3 ; X 5 is N; X 6 N, NR 6 , CR 6 , S(=O)2, C(=O) or C(=S); X 7 is N, NR 7 , O, S, CR 7 , S(=O)2, C(=O) or C(=S); The conditions are: (i) when X 2 , X 3 and X 5 is N, and X 6 When it is C(=O), then X 7 O, S, CR 7 , C(=O) or C(=S), and (ii) when X 2 , X 3 and X 5 When N is X 6 and X 7 At least one of which is selected from O, S, S(═O)2, C(═O) or C(═S); is a single bond or a double bond; R 1 , R 3 , R 6 and R 7 are each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl, wherein the alkyl, heteroalkyl, alkenyl or alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, amino, oxo, -OH, -NO2, -CN and C 1-3 Alkoxy; R 8 and R 9 are each independently selected from hydrogen, halo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 together with the carbon to which it is attached, forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted by one or more substituents independently selected from the following: halogen, amino, -OH, -NO2, oxo, -CN, C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 Haloalkyl; Ring A is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl; R A are each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 )、-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 )、-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ), wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted by one or more substituents independently selected from the following: halogen, -OH, -NO2, oxo, amino, -CN, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, amino, -NO2, oxo, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl; R 11 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4 Alkylene-C 3-8 Cycloalkyl, optionally substituted -C 1-4 Alkylene-C 2-7 Heterocycloalkyl, optionally substituted -C 1-4 Alkylene-phenyl or optionally substituted-C 1-4 Alkylene-heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl or 5-membered or 6-membered heteroaryl is optionally substituted with one or more substituents independently selected from the following: halogen, -OH, amino, -NO2, oxo, C 1-6 Alkoxy, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl; R 12 Each independently selected from hydrogen, -NO2, -CN, C 1-6 Alkyl, C 1-6 Aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl and C 3-6 Carbocyclic ring, 3-membered to 6-membered heterocyclic ring, wherein the C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl; B is a 6-membered heteroaryl group, a phenyl group or a phenyl isostere; R B1 is optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl or optionally substituted bicyclic heteroaryl, wherein the cycloalkyl, heterocycloalkyl, naphthyl, phenyl or heteroaryl are each optionally substituted by one or more substituents independently selected from the group consisting of halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 )、-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 )、-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ), wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, amino, oxo, -CN, C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 Haloalkyl; Each R B are independently halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 )、-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 )、-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl or optionally substituted bicyclic heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, naphthyl, phenyl or heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, amino, oxo, -CN, C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 haloalkyl; or Two R on the same atom B Together with the atoms to which it is attached, it forms an optionally substituted C 3-8 Cycloalkyl or optionally substituted C 2-9 Heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, amino, -NO2, oxo, C 1-6 Alkoxy, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl; m is 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; and p is 0 or 1.

13. The compound or salt thereof according to claim 11 or 12, wherein for Y 1 N or CR Y1 ; Y 2 N or CR Y2 ; Y 3 N or CR Y3 ; Y 4 N or CR Y4 ;and R Y1 , R Y2 , R Y3 and R Y4 are each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl.

14. The compound or salt thereof according to any one of claims 11 to 13, wherein X 1 , X 2 , X 3 At least two of them are N.

15. The compound or salt thereof according to any one of claims 11 to 14, wherein X 6 or X 7 At least one of them is N.

16. The compound or salt thereof according to any one of claims 11 to 15, wherein the compound has a structure of formula (IIa), 17. The compound or salt thereof according to claim 16, wherein the compound has a structure of formula (IIa-1), in, X 1 N or CR 1 ; X 2 is N; X 3 N or CR 3 ; X 7 NR 7 , O, S, S(═O)2, C(═O) or C(═S); R 1 , R 3 and R 7 are each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; Y 1 N or CR Y1 ; Y 2 N or CR Y2 ; Y 3 N or CR Y3 ; Y 4 N or CR Y4 ; R Y1 , R Y2 , R Y3 and R Y4 are each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; R 8 and R 9 are each independently selected from hydrogen, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl; Ring A is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl; R A are each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 )、-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 )、-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ); R 11 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4 Alkylene-C 3-8 Cycloalkyl, optionally substituted -C 1-4 Alkylene-C 2-7 Heterocycloalkyl, optionally substituted -C 1-4 Alkylene-phenyl or optionally substituted-C 1-4 Alkylene-heteroaryl; R 12 Each independently selected from hydrogen, -NO2, -CN, C 1-6 Alkyl, C 1-6 Aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl and C 3-6 Carbocyclic ring, 3-membered to 6-membered heterocyclic ring, wherein the C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl; R B1 is optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl; m is 1, 2, 3 or 4; and p is 0 or 1.

18. The compound or salt thereof according to claim 17, wherein the compound of formula (IIa-1) has a structure of formula (IIa-1a), 19. A compound or salt thereof according to any one of claims 11 to 14, wherein the compound has a structure of formula (IIb), 20. The compound or salt thereof according to claim 19, wherein the compound has a structure of formula (IIb-1), in, X 1 N or CR 1 ; X 2 is N; X 3 N or CR 3 ; R 1 and R 3 are each independently selected from hydrogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; Y 1 N or CR Y1 ; Y 2 N or CR Y2 ; Y 3 N or CR Y3 ; Y 4 N or CR Y4 ; R Y1 , R Y2 , R Y3 and R Y4 are each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; R 8 and R 9 are each independently selected from hydrogen, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl; Ring A is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl; R A are each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 )、-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 )、-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ); R 11 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4 Alkylene-C 3-8 Cycloalkyl, optionally substituted -C 1-4 Alkylene-C 2-7 Heterocycloalkyl, optionally substituted -C 1-4 Alkylene-phenyl or optionally substituted-C 1-4 Alkylene-heteroaryl; R 12 Each independently selected from hydrogen, -NO2, -CN, C 1-6 Alkyl, C 1-6 Aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl and C 3-6 Carbocyclic ring, 3-membered to 6-membered heterocyclic ring, wherein the C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl; R B1 is halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 )、-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 )、-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl; m is 1, 2, 3 or 4; and p is 0 or 1.

21. The compound or salt thereof according to claim 20, wherein the compound of formula (IIb-1) has a structure of formula (IIb-1a), 22. The compound or salt thereof according to any one of claims 11 to 13, wherein the compound has a structure of formula (IIc'), 23. The compound or salt thereof according to claim 22, wherein the compound has a structure of formula (IIc-1), in, R 1 , R 3 and R 7 are each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; Y 1 N or CR Y1 ; Y 2 N or CR Y2 ; Y 3 N or CR Y3 ; Y 4 N or CR Y4 ; R Y1 , R Y2 , R Y3 and R Y4 are each independently selected from hydrogen, halogen, -CN, -OR 11 、-SR 11 、-N(R 12 ) 2. optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; R 8 and R 9 are each independently selected from hydrogen, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl; Ring A is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl; R A are each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 )、-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 )、-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ); R 11 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4 Alkylene-C 3-8 Cycloalkyl, optionally substituted -C 1-4 Alkylene-C 2-7 Heterocycloalkyl, optionally substituted -C 1-4 Alkylene-phenyl or optionally substituted-C 1-4 Alkylene-heteroaryl; R 12 Each independently selected from hydrogen, -NO2, -CN, C 1-6 Alkyl, C 1-6 Aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl and C 3-6 Carbocyclic ring, 3-membered to 6-membered heterocyclic ring, wherein the C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl; R B1 is optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl; m is 1, 2, 3 or 4; and p is 0 or 1.

24. The compound or salt thereof according to any one of claims 11 to 13, wherein the compound has a structure of formula (IId'), 25. The compound or salt thereof according to claim 24, wherein the compound has a structure of formula (IId-1), 26. A compound or salt thereof according to any one of claims 11 to 13, wherein the compound has a structure of formula (IIe), 27. A compound or salt thereof as claimed in any one of claims 11 to 13, wherein the compound has a structure of formula (IIg), 28. The compound or salt thereof according to any one of claims 1 to 27, wherein ring A is phenyl.

29. A compound or salt thereof according to any one of claims 1 to 28, wherein for 30 . The compound or salt thereof according to any one of claims 1 to 27 , wherein ring A is naphthyl.

31. The compound or salt thereof according to any one of claims 1 to 27, wherein ring A is a 5-membered or 6-membered monocyclic heteroaryl group.

32. The compound or salt thereof according to claim 31, wherein Ring A is pyrimidine.

33. The compound or a salt thereof according to claim 31, wherein Ring A is pyridine, pyrimidine, pyrazine, pyridazine, triazine, imidazole, pyrazole, triazole, oxazole, isoxazole or thiophene.

34. The compound or salt thereof as claimed in claim 33, wherein for 35. The compound or salt thereof according to any one of claims 1 to 28, wherein ring A is a bicyclic heteroaryl group.

36. The compound or salt thereof according to claim 35, wherein Ring A is a fused 5-6, 6-6 or 6-5 bicyclic heteroaryl group.

37. A compound as described in any one of claims 1 to 36, wherein R A are each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 )、-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 )、-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ).

38. The compound of claim 37, wherein at least one R A For-OR 11 、-SR 11 、-N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl or -S(O)2R 12 .

39. A compound as described in any one of claims 1 to 36, wherein each R A is independently substituted by one or more substituents independently selected from the following: halogen, -OH, -NO2, amino, -CN, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, amino, -NO2, oxo, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl.

40. The compound of claim 39, wherein each R A is independently substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, oxo and amino.

41. A compound or salt thereof according to any one of claims 1 to 28, wherein Selected from:

42. The compound or salt thereof as claimed in any one of claims 1 to 41, wherein p is 1.

43. A compound or salt thereof as described in any one of claims 1 to 42, wherein R 8 and R 9 are each independently selected from hydrogen, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl.

44. The compound or salt thereof as claimed in claim 43, wherein R 8 and R 9 Each is hydrogen.

45. A compound or salt thereof as described in any one of claims 1 to 42, wherein R 8 and R 9 Together they form an oxo group.

46. ​​A compound or salt thereof as described in any one of claims 1 to 42, wherein R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl.

47. A compound or salt thereof as described in any one of claims 1 to 41, wherein p is 0.

48. The compound or salt thereof according to any one of claims 1 to 47, wherein ring B is phenyl or a 6-membered heteroaryl group.

49. The compound or a salt thereof according to claim 48, wherein Ring B is phenyl, pyridine, pyrimidine, pyrazine, pyridazine or triazine.

50. A compound or salt thereof as described in any one of claims 1 to 49, wherein R B1 is optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-5 heterocycloalkyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl.

51. A compound or salt thereof as described in any one of claims 1 to 50, wherein R B1 is an optionally substituted monocyclic 5-6 membered heterocycloalkyl or heteroaryl.

52. The compound or salt thereof of claim 51, wherein R B1 is an optionally substituted 5-membered monocyclic heteroaryl group having 1 to 4 heteroatoms selected from N, O, S and P.

53. The compound or salt thereof of claim 52, wherein R B1 is imidazole, pyrazole, triazole or tetrazole, each of which is optionally substituted.

54. The compound or salt thereof of claim 51, wherein R B1 is an optionally substituted fused 5-6, 6-6 or 6-5 heteroaryl.

55. A compound or salt thereof as described in any one of claims 1 to 54, wherein R B1 Optionally substituted with one or more substituents independently selected from the group consisting of halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 )、-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 )、-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ), wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, amino, oxo, -CN, C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 Haloalkyl.

56. The compound or salt thereof of claim 55, wherein R B1 Optionally substituted with one or more substituents independently selected from the group consisting of halogen, -NO2, oxo, -CN, C 1-6 Haloalkyl, C 1-6 Alkyl, C 1-6 Aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl and optionally substituted C 2-7 Heterocycloalkyl.

57. A compound or salt thereof as described in any one of claims 50 to 52, wherein R B1 Selected from 58. A compound or salt thereof as described in any one of claims 50 to 52, wherein R B1 for 59. A compound or salt thereof as claimed in any one of claims 1 to 58, wherein each R B are independently halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl.

60. A compound or salt thereof as described in any one of claims 1 to 58, wherein two R on the same atom B Together with the atoms to which it is attached, it forms an optionally substituted C 3-6 Cycloalkyl or optionally substituted C 2-5 Heterocycloalkyl.

61. A compound or salt thereof as described in any one of claims 1 to 58, wherein n is 0.

62. A compound or salt thereof as described in any one of claims 1 to 61, wherein R 1 , R 3 , R 6 and R 7 Each is independently hydrogen or C1-C6 alkyl.

63. A compound or salt thereof according to any one of claims 1 to 2 or 11 to 12, X 1 CR 1 ;X 3 N or CR 3 ;X 7 CR 7 ; R 1 and R 3 Each is hydrogen; R 8 and R 9 Each is hydrogen; for And each R A R is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C3-C6 cycloalkyl; B1 is optionally one or more selected from C 1-3 Haloalkyl and C 1-3 A 5-membered heteroaryl group substituted with an alkyl substituent (e.g. ).

64. A compound having a structure of formula (VI) or a salt thereof, in, Ring C is phenyl or 6-membered heteroaryl, wherein said phenyl or heteroaryl are each optionally substituted; Ring D is an aromatic, saturated or partially saturated 5-membered carbocyclic or heterocyclic ring, wherein the carbocyclic or heterocyclic ring is each optionally substituted; R 8 and R 9 are each independently selected from hydrogen, halo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl; Ring A is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl; R A are each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 )、-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 )、-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ); R 11 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4 Alkylene-C 3-8 Cycloalkyl, optionally substituted -C 1-4 Alkylene-C 2-7 Heterocycloalkyl, optionally substituted -C 1-4 Alkylene-phenyl or optionally substituted-C 1-4 Alkylene-heteroaryl; R 12 Each independently selected from hydrogen, -NO2, -CN, C 1-6 Alkyl, C 1-6 Aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl and C 3-6 Carbocyclic ring, 3-membered to 6-membered heterocyclic ring, wherein the C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl; R B is hydrogen, halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 )、-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 )、-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl; m is 1, 2, 3 or 4; and p is 0 or 1.

65. The compound or salt thereof of claim 63, wherein Ring C is phenyl or 6-membered heteroaryl, wherein the phenyl or heteroaryl is each optionally substituted by 1, 2, 3 or 4 R 1C Replace, and Each R 1C are independently halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C2-C6 alkynyl, C 3-8 Cycloalkyl, C 2-7 wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently replaced by one or more R 1Ca replace; Ring D is an aromatic, saturated or partially saturated 5-membered carbocyclic or heterocyclic ring, wherein each of the carbocyclic or heterocyclic rings is optionally substituted by 1, 2, 3, 4, 5 or 6 R 1D Replace, and Each R 1D are independently halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C2-C6 alkynyl, C 3-8 Cycloalkyl, C 2-7 wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently replaced by one or more R 1Da replace; R 8 and R 9 are each independently selected from hydrogen, halo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl; or R 8 and R 9 together to form an oxo group; or R 8 and R 9 together with the carbon to which it is attached, forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted by one or more substituents independently selected from the following: halogen, amino, -OH, -NO2, oxo, -CN, C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 Haloalkyl; Ring A is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl; R A are each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 )、-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 )、-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ), wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted by one or more substituents independently selected from the following: halogen, -OH, -NO2, oxo, amino, -CN, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, amino, -NO2, oxo, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl; R 11 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted -C 1-4 Alkylene-C 3-8 Cycloalkyl, optionally substituted -C 1-4 Alkylene-C 2-7 Heterocycloalkyl, optionally substituted -C 1-4 Alkylene-phenyl or optionally substituted-C 1-4 Alkylene-heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, amino, -NO2, oxo, C 1-6 Alkoxy, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl; R 12 Each independently selected from hydrogen, -NO2, -CN, C 1-6 Alkyl, C 1-6 Aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl and C 3-6 Carbocyclic ring, 3-membered to 6-membered heterocyclic ring, wherein the C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring are optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, oxo, amino, -NO2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl; R B is hydrogen, halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 )、-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 )、-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl or optionally substituted bicyclic heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, naphthyl, phenyl or heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 )、-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 )、-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ), wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, amino, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2, oxo, -CN, C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 Haloalkyl; Each R a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C1-C6 alkylene-cycloalkyl, -C1-C6 alkylene-heterocycloalkyl, -C1-C6 alkylene-aryl or -C1-C6 alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently optionally substituted by one or more oxo, halogen, -CN, -OH, -OC1-C6 alkyl, -S(=O)C1-C6 alkyl, -S(=O)2C -C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; Each R b The alkyl radicals are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C1-C6 alkylene-cycloalkyl, -C1-C6 alkylene-heterocycloalkyl, -C1-C6 alkylene-aryl or -C1-C6 alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently optionally substituted by one or more oxo, halogen, -CN, -OH, -OC1-C6 alkyl, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NH C1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl is substituted; Each R c and R d The alkyl radicals are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C1-C6 alkylene-cycloalkyl, -C1-C6 alkylene-heterocycloalkyl, -C1-C6 alkylene-aryl or -C1-C6 alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently optionally substituted with one or more oxo, halogen, -CN, -OH, -OC1-C6 alkyl, -S(=O)2 C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl is substituted; or R c and R d The heterocycloalkyl group is optionally substituted with one or more oxo groups, halogen, -CN, -OH, -OC1-C6 alkyl, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C -C1-C6 alkyl)2, -NHC(═O)OC1-C6 alkyl, -C(═O)C1-C6 alkyl, -C(═O)OH, -C(═O)OC1-C6 alkyl, -C(═O)NH2, -C(═O)N(C1-C6 alkyl)2, -C(═O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; Each R 1Ca and R 1Da are independently halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; m is 1, 2, 3 or 4; and p is 0 or 1.

66. The compound of claim 64 or 65, wherein Ring C is a 6-membered heteroaryl and Ring D is a 6-membered heteroaryl.

67. The compound of any one of claims 64 to 66, wherein ring C and ring D are each independently optionally substituted by one or more substituents selected from the group consisting of halogen, -CN, -OR a , -SH, -SR a 、-NR c R d , optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 wherein the alkyl, heteroalkyl, alkenyl or alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, amino, oxo, -OH, -NO2, -CN and C 1-3 Alkoxy.

68. A compound as described in any one of claims 64 to 66, wherein for 69. The compound or salt thereof as claimed in any one of claims 64 to 68, wherein ring A is phenyl.

70. The compound or salt thereof of claim 69, wherein for 71. The compound or salt thereof as claimed in any one of claims 64 to 68, wherein ring A is naphthyl.

72. The compound or salt thereof as claimed in any one of claims 64 to 68, wherein ring A is a 5-membered or 6-membered monocyclic heteroaryl group.

73. The compound or salt thereof according to claim 72, wherein Ring A is pyridine, pyrimidine, pyrazine, pyridazine, triazine, imidazole, pyrazole, triazole, oxazole, isoxazole or thiophene.

74. The compound or salt thereof of claim 73, wherein for 75. The compound or salt thereof as claimed in any one of claims 64 to 68, wherein Ring A is a bicyclic heteroaryl.

76. The compound or salt thereof as claimed in claim 75, wherein Ring A is a fused 5-6, 6-6 or 6-5 bicyclic heteroaryl.

77. A compound or salt thereof as described in any one of claims 64 to 76, wherein R A are each independently selected from halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 )、-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )2S(O)2(R 12 )、-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ).

78. The compound or salt thereof of claim 77, wherein at least one R A For-OR 11 、-SR 11 、-N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl or -S(O)2R 12 .

79. A compound or salt thereof as described in any one of claims 64 to 78, wherein each R A is independently substituted by one or more substituents independently selected from the following: halogen, -OH, -NO2, amino, -CN, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings, wherein the C 3-6 The carbocyclic and 3- to 6-membered heterocyclic rings are optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, amino, -NO2, oxo, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl.

80. The compound or salt thereof of claim 79, wherein each R A is independently substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, oxo and amino.

81. A compound or salt thereof as described in any one of claims 64 to 68, wherein Selected from:

82. A compound or salt thereof as described in any one of claims 64 to 81, wherein p is 1.

83. A compound or salt thereof as described in any one of claims 64 to 82, wherein R 8 and R 9 are each independently selected from hydrogen, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 2-6 Alkenyl and optionally substituted C 2-6 Alkynyl.

84. The compound or salt thereof of claim 83, wherein R 8 and R 9 Each is hydrogen.

85. A compound or salt thereof as described in any one of claims 64 to 82, wherein R 8 and R 9 Together they form an oxo group.

86. A compound or salt thereof as described in any one of claims 64 to 82, wherein R 8 and R 9 Together with the carbon to which it is attached, it forms an optionally substituted 3-6 membered cycloalkyl or heterocycloalkyl.

87. A compound or salt thereof as described in any one of claims 64 to 81, wherein p is 0.

88. A compound or salt thereof as described in any one of claims 64 to 87, wherein R B is halogen, -CN, -NO2, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 )、-C(O)R 12 、C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 )、-S(O)R 12 、-S(O)2R 12 、-S(O)2N(R 12 )(R 11 ), optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl.

89. The compound or salt thereof of claim 88, wherein R B is optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl.

90. The compound or salt thereof of claim 89, wherein R B is an optionally substituted 5-membered monocyclic heteroaryl group having 1 to 4 heteroatoms selected from N, O, S and P.

91. The compound or salt thereof of claim 90, wherein R B is imidazole, pyrazole, triazole or tetrazole, each of which is optionally substituted.

92. The compound or salt thereof of claim 89, wherein R B is an optionally substituted fused 5-6, 6-6 or 6-5 heteroaryl.

93. The compound of any one of claims 64 to 92, wherein R B Optionally substituted with one or more substituents independently selected from the group consisting of halogen, -NO2, oxo, -CN, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-7 Heterocycloalkyl, -OR 11 、-SR 11 、-N(R 12 )(R 11 )、-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)N(R 12 )(R 11 )、-C(O)N(R 12 )(R 11 )、-N(R 12 )C(O)R 12 、-N(R 12 )C(O)OR 12 、-N(R 12 )C(O)N(R 12 )(R 11 )、-N(R 12 )S(O)2(R 12 )、-S(O)R 12 、-S(O)2R 12 and -S(O)2N(R 12 )(R 11 ), wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, amino, oxo, -CN, C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 Haloalkyl.

94. The compound or salt thereof of claim 93, wherein R B Optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 11 , -NO2, oxo, -CN, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 aminoalkyl, optionally substituted C 1-6 Hydroxyalkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl and optionally substituted C 2-7 Heterocycloalkyl.

95. The compound or salt thereof of claim 91, wherein R B Selected from:

96. The compound or salt thereof of claim 91, wherein R B for 97. A compound or salt thereof as described in any one of claims 1, 11 or 64, wherein the compound is a compound of Table 1.

98. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from 99. A pharmaceutical composition comprising a compound according to any one of claims 1 to 98 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

100. A method of modulating ubiquitin-specific protease 1 (USP1) in a subject, the method comprising administering to the subject a compound of any one of claims 1 to 98 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 99.

101. A method of inhibiting ubiquitin-specific protease 1 (USP1) in a subject, the method comprising administering to the subject a compound of any one of claims 1 to 98 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 99.

102. A method of inhibiting or reducing DNA repair activity regulated by ubiquitin-specific protease 1 (USP1) in a subject, the method comprising administering to the subject in need thereof an effective amount of a compound of any one of claims 1 to 98 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 99.

103. A method of treating a disease or condition associated with ubiquitin-specific protease 1 (USP1) in a subject, the method comprising administering to the subject a compound of any one of claims 1 to 98 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 99.

104. A method of treating a disease or condition associated with modulation of ubiquitin-specific protease 1 (USP1) in a subject, the method comprising administering to the subject a compound of any one of claims 1 to 98 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 99.

105. The method of claim 103 or 104, wherein the disease or condition is cancer.

106. A method of treating cancer in a subject, the method comprising administering to the subject in need thereof an effective amount of a compound of any one of claims 1 to 98 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 99.

107. The method of claim 105 or 106, wherein the cancer is selected from the group consisting of lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, and breast cancer.

108. The method of claim 105 or 106, wherein the cancer is ovarian cancer.

109. The method of claim 105 or 106, wherein the cancer is breast cancer.

110. The method of claim 109, wherein the cancer is ovarian cancer or breast cancer.

111. The method of any one of claims 105 to 110, wherein the cancer comprises cancer cells having elevated levels of RAD 18.

112. The method of any one of claims 105 to 111, wherein the cancer is a DNA damage repair pathway defective cancer.

113. The method of any one of claims 105 to 112, wherein the cancer is a PARP inhibitor-resistant or refractory cancer.

114. The method of any one of claims 105 to 113, wherein the cancer is a BRCA1 mutant cancer and / or a BRCA2 mutant cancer.

115. The method of claim 114, wherein the cancer is a BRAC1 -deficient cancer.

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