Adhesive Degradants and Their Application Methods

Abstract

This article describes gel degradative compounds, their various targets, their preparation, pharmaceutical compositions containing them, and their use in the treatment or prevention of conditions, diseases, and disorders mediated by various target proteins.

Description

[0001] Related applications

[0002] This application claims the benefit and priority of U.S. Provisional Application No. 62 / 901,229, filed September 16, 2019, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This article describes gel degradative compounds, their various targets, their preparation, pharmaceutical compositions containing them, and their use in treating conditions, diseases, and disorders mediated by various target proteins. Background Technology

[0004] The ubiquitin-proteasome pathway (UPP) is a crucial pathway for regulating key regulatory proteins and degrading misfolded or abnormal proteins. UPP is important for a wide range of cellular processes and, if defective or imbalanced, contributes to the pathogenesis of various diseases. Covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases. These ligases comprise over 500 different proteins and are classified into several categories defined by structural elements with E3 functional activity.

[0005] The cerebellum protein (CRBN) interacts with damaged DNA-binding protein 1 and forms an E3 ubiquitin ligase complex with hysterin 4. In this complex, the cerebellum protein acts as a substrate receptor, in which proteins recognized by the CRBN may be ubiquitinated and degraded by the proteasome.

[0006] The proteasome-mediated degradation of unwanted or damaged proteins plays a crucial role in maintaining normal cellular functions, such as cell survival, proliferation, and growth. Novel roles of CRBNs have been identified; that is, the binding of immunomodulatory drugs (IMiDs) (e.g., thalidomide) to CRBNs is now associated with teratogenicity and the toxicity of IMiDs (including lenalidomide), which are widely used to treat patients with multiple myeloma. CRBNs may be key players in the binding, ubiquitination, and degradation of factors involved in maintaining myeloma cell function.

[0007] Gel-degrading compounds that bind to and alter the specificity of the cereblon complex have been shown to induce proteasome-mediated degradation of selected proteins. These molecules can be used to regulate protein expression and as biochemical or therapeutic agents for treating diseases or disorders. There is a need for gel-degrading compounds that target protein degradation. This application addresses the need for gel-degrading molecules targeting a variety of proteins. Summary of the Invention

[0008] The first aspect of this disclosure relates to compounds, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers of cerebellar protein complexes, that bind to and alter the specificity of the complex-associated proteins to induce ubiquitination and degradation of the complex-associated proteins.

[0009] In another aspect, this disclosure relates to compounds comprising: (i) a tris-tryptophan pocket-binding moiety that binds to the tris-tryptophan pocket of the cerebellum protein E3 ligase; and (ii) a target affinity moiety covalently attached to the tris-tryptophan pocket-binding moiety, the tris-tryptophan pocket-binding moiety interacting with the surface of the cerebellum protein E3 ligase to alter its surface and thereby give the ligase affinity for the target protein.

[0010] Another aspect of this disclosure relates to compounds having formula (I).

[0011]

[0012] Or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer, wherein:

[0013] Is it a single bond or a double bond?

[0014] R d1 It is H, -CH2OC(O)R 15 -CH2OP(O)OHOR 15 、or -CH2OP(O)(R 15 )2;

[0015] R d2 It is H, C 1-6 Alkyl, halogen, C 1-6 Halogenated alkyl, or C 1-6 Heteroalkyl;

[0016] R d3 yes

[0017]

[0018]

[0019] A 1 It is a 5- or 6-membered heterocyclic group that optionally contains 1-3 additional heteroatoms selected from O, N, and S, or optionally contains 1-3 heteroatoms selected from N, NR, and S. 1k The other heteroatoms of O and S are surrounded by one to three R atoms. 1d Substituted 5-membered heteroaryl groups;

[0020] A 2It is C 5-7 The carbon cyclo group or contains 1-3 radicals selected from N and NR 1k Five- to seven-membered heterocyclic groups of O and S heteroatoms, wherein the carbocyclic group and the heterocyclic group are separated by one to three R atoms. 1d replace;

[0021] X 1 It is NR 4 Or S;

[0022] X 2 and X 2a Each is CR independently 1a Or N;

[0023] Each X 3 Independently is CR 1d Or N, where no more than two X's 3 It is N;

[0024] Each X 4 Independently is CR 1d Or N, where at least one X 4 It is N, and there are no more than two X's. 4 It is N;

[0025] Each X 5 Independently is CR 1a Or N, where no more than two X's 5 It is N;

[0026] X 6 It is NR 1k , O or S;

[0027] X 7 It is NR 4 , O or S;

[0028] R 1a and R 1b H and C are independent of each other. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -CN, F or Cl;

[0029] R 1c It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3Halogenated alkoxy group, halogen, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4- A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0030] Each R 1d Independently selected from H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy group, halogen, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4- A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0031] R 1e It is C 2-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -CN, F or Cl;

[0032] R 1f It is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -CN, F or Cl;

[0033] R 1g It is C 2-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Haloalkyl, C 1-6 Alkoxy, C 1-3Haloalkoxy groups, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0- 4NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR3 C(O)O(CH2) 0-4 -C 6-10 aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0034] R 1h It is C 4-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy groups, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -C 6-10 Aryl, -(CH2) 2-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0035] R 1i It is H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy groups, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6- A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0036] R 1j It is H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy group, halogen, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0037] R on the benzoxazole ring 1d R 1i and R 1j Not all of them are H at the same time;

[0038] Each R 1k Independently selected from H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy group, halogen, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -C(O)O(CH2) 0-4 -C 6-10 Aryl, or -C(O)O(CH2) 0-4- A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0039] Each R 2 Independently, it is NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 alkyl)2、-NHC(O)R 9 -N(R) 9 )C(O)(R 9 -NHS(O)2R 9 , or -NR 9 S(O)2R 9 ;

[0040] R 3 Is it H or C? 1-6 alkyl;

[0041] R 4 Is it H or C? 1-6 alkyl;

[0042] Each R 5 C is independent 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy groups, halogens, -OH, -C(O)H, -C(O)(C 1-6 Alkyl), -C(O)(C 6-10 aryl), -C(O) (5- or 6-membered heteroaryl), -C(O) (C 3-7 Carbocyclic group), -C(O) (5- to 7-membered heterocyclic groups), -(CH2) 0-3 C(O)OC 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 alkyl)2,-NHC(O)R 9 , -N(R 9 )C(O)(R 9 ), -NH2, -NH(C 1-6 Alkyl), -N(C) 1-6 alkyl)2,-NHC(O)O(R9 ), -N(R 9 )C(O)O(R 9 ), -NHS(O)2R 9 -NR 9 S(O)2R 9 , -S(O) q NHR 9 , -S(O) q N(R 9 )2,-S(O) q R 9 C 1-6 Hydroxyalkyl, -O(CH2) 1-3 CN, CN, -O(CH2) 0-6 -C 3-7 Carbocyclic group, -O(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -O(CH2) 0-3 (C6-C 10 Aryl, adamantyl, -O(CH2) 0-3 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 -C 6-10 Aryl, and -(CH2) 0-6 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally surrounded by one to three R atoms. 6 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to four R groups. 8 Replace; or two Rs 5 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 3-7 A carbocyclic group or a 5- to 7-membered heterocyclic group comprising 1-3 heteroatoms selected from O, N, and S, wherein the carbocyclic group and the heterocyclic group are optionally separated by one to three R atoms. 6 Replace; or two Rs 5 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 aryl or a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; or two R... 5 When they are on the same atom, they together with the atoms to which they are attached form C. 3-7 A spirocarbocyclic group or a 5- to 7-membered spiroheterocyclic group comprising 1-3 heteroatoms selected from O, N, and S, wherein the spirocarbocyclic group and the spiroheterocyclic group are optionally separated by one to four R atoms.10 Replace; or two Rs 5 When on the same carbon atom, it forms =(O);

[0043] R 6 It is -NH2, -NH(C 1-6 Alkyl), -N(C) 1-6 Alkyl)2,C 6-10 aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms. 7 replace;

[0044] Each R 7 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy, halogen, or C 6-10 Aryl;

[0045] Each R 8 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, or -OH;

[0046] R 9 It is C 1-6 Alkyl, C 1-6 Haloalkyl groups, comprising 1-3 heteroatoms selected from O, N, and S, consisting of 5- to 7-membered heterocyclic groups, C 6-10 aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms. 11 replace;

[0047] Each R 10 It is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, or halogens; or

[0048] Two Rs 10 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 Aryl or 5- or 6-membered heteroaryl groups containing 1-3 heteroatoms selected from O, N, and S;

[0049] Each R 11 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C1-6 Halogenated alkoxy groups, -NHC(O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(O)(C 1-6 Alkyl groups, or halogens; or

[0050] Two Rs 11 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 The aryl group or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms. 12 replace;

[0051] Each R 12 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, or C 1-3 Halogenated alkoxy groups;

[0052] R 13 It is C independently each time it appears. 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally surrounded by one or two C atoms. 1-6 The alkoxy group is substituted, and the aryl and heteroaryl groups are optionally replaced by one to three R groups. 14 replace;

[0053] Each R 14 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy groups, halogens, C 6-10 Aryl, or a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S;

[0054] R 15 Is it H or C? 1-6 Alkyl; and

[0055] q can be 0, 1, or 2.

[0056] On the other hand, this disclosure relates to compounds having formula (I):

[0057]

[0058] Or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer, wherein:

[0059] Is it a single bond or a double bond?

[0060] R d1 It is H, -CH2OC(O)R 15 -CH2OP(O)OHOR 15 、or -CH2OP(O)(R 15 )2;

[0061] R d2 It is H, C 1-6 Alkyl, halogen, C 1-6 Halogenated alkyl, or C 1-6 Heteroalkyl;

[0062] R d3 yes

[0063]

[0064]

[0065] A 1 It is a 5- or 6-membered heterocyclic group that optionally contains 1-3 additional heteroatoms selected from O, N, and S, or optionally contains 1-3 heteroatoms selected from N, NR, and S. 1k The other heteroatoms of O and S are surrounded by one to three R atoms. 1d Substituted 5-membered heteroaryl groups;

[0066] A 2 It is C 5-7 The carbon cyclo group or contains 1-3 radicals selected from N and NR 1k Five- to seven-membered heterocyclic groups of O and S heteroatoms, wherein the carbocyclic group and the heterocyclic group are separated by one to three R atoms. 1d replace;

[0067] X 1 It is NR 4 Or S;

[0068] X 2 and X 2a Each is CR independently 1a Or N;

[0069] Each X 3 Independently is CR 1d Or N, where no more than two X's 3 It is N;

[0070] Each X 3' Independently is CR 1d CR 1c Or N, where no more than two X's 3It is N, and at least one of them is X 3' It is CR 1c ;

[0071] Each X 4 Independently is CR 1d Or N, where at least one X 4 It is N, and there are no more than two X's. 4 It is N;

[0072] Each X 5 Independently is CR 1a Or N, where no more than two X's 5 It is N;

[0073] X 6 It is NR 1k , O or S;

[0074] X 7 It is NR 4 , O or S;

[0075] R 1a and R 1b H and C are independent of each other. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -CN, F or Cl;

[0076] R 1c It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy group, halogen, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6- A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0077] R 1c' It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy groups, F, Cl, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0078] Each R 1d Independently selected from H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy group, halogen, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4- A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0079] R 1e It is C 2-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -CN, F or Cl;

[0080] R 1f It is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -CN, F or Cl;

[0081] R 1g It is C 2-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Haloalkyl, C 1-6 Alkoxy, C 1-3Haloalkoxy groups, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0- 4NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR3 C(O)O(CH2) 0-4 -C 6-10 aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0082] R 1g' It is C 2-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Haloalkyl, C 2-6 Alkoxy, C 1-3 Haloalkoxy groups, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The heterocyclic group is replaced by one to five R... 5 Substitution, and the carbocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0083] R 1h It is C 4-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy groups, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -C 6-10 Aryl, -(CH2) 2-6 C 6-10 Aryl, -(CH2)0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0084] R 1h' It is C 4-6 Alkyl, C 2-6 alkenyl, C 2-6alkynyl group, C 2-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy groups, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -C 6-10 Aryl, -(CH2) 2-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The heterocyclic group is replaced by one to five R... 5 Substitution, and the carbocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0085] R 1i It is H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy groups, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0086] R 1j It is H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy group, halogen, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6- A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0087] R on the benzoxazole ring 1d R 1i and R 1j Not all of them are H at the same time;

[0088] Each R 1k Independently selected from H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy group, halogen, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -C(O)O(CH2) 0-4 -C 6-10 Aryl, or -C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0089] Each R 2 Independently, it is NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 alkyl)2、-NHC(O)R 9 -N(R) 9)C(O)(R 9 -NHS(O)2R 9 , or -NR 9 S(O)2R 9 ;

[0090] R 3 Is it H or C? 1-6 alkyl;

[0091] R 4 Is it H or C? 1-6 alkyl;

[0092] Each R 5 C is independent 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy groups, halogens, -OH, -C(O)H, -C(O)(C 1-6 Alkyl), -C(O)(C 6-10 aryl), -C(O) (5- or 6-membered heteroaryl), -C(O) (C 3-7 Carbocyclic group), -C(O) (5- to 7-membered heterocyclic groups), -(CH2) 0-3 C(O)OC 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 alkyl)2,-NHC(O)R 9 , -N(R 9 )C(O)(R 9 ), -NH2, -NH(C 1-6 Alkyl), -N(C) 1-6 alkyl)2,-NHC(O)O(R 9 ), -N(R 9 )C(O)O(R 9 ), -NHS(O)2R 9 -NR 9 S(O)2R 9 , -S(O) q NHR 9 , -S(O) q N(R 9 )2,-S(O) q R 9 C 1-6 Hydroxyalkyl, -O(CH2) 1-3 CN, CN, -O(CH2) 0-6 -C 3-7Carbocyclic group, -O(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -O(CH2) 0-3 (C6-C 10 Aryl, adamantyl, -O(CH2) 0-3 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 -C 6-10 Aryl, and -(CH2) 0-6 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally surrounded by one to three R atoms. 6 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to four R groups. 8 Replace; or two Rs 5 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 3-7 A carbocyclic group or a 5- to 7-membered heterocyclic group comprising 1-3 heteroatoms selected from O, N, and S, wherein the carbocyclic group and the heterocyclic group are optionally separated by one to three R atoms. 6 Replace; or two Rs 5 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 aryl or a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; or two R... 5 When they are on the same atom, they together with the atoms to which they are attached form C. 3-7 A spirocarbocyclic group or a 5- to 7-membered spiroheterocyclic group comprising 1-3 heteroatoms selected from O, N, and S, wherein the spirocarbocyclic group and the spiroheterocyclic group are optionally separated by one to four R atoms. 10 Replace; or two Rs 5 When on the same carbon atom, it forms =(O);

[0093] R 6 It is -NH2, -NH(C 1-6 Alkyl), -N(C) 1-6 Alkyl)2,C 6-10 aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms. 7 replace;

[0094] Each R 7 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Alkoxy, C 1-3 Halogenated alkoxy, halogen, or C 6-10 Aryl;

[0095] Each R 8 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, or -OH;

[0096] R 9 It is C 1-6 Alkyl, C 1-6 Haloalkyl groups, comprising 1-3 heteroatoms selected from O, N, and S, consisting of 5- to 7-membered heterocyclic groups, C 6-10 aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms. 11 replace;

[0097] Each R 10 It is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, or halogens; or

[0098] Two Rs 10 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 Aryl or 5- or 6-membered heteroaryl groups containing 1-3 heteroatoms selected from O, N, and S;

[0099] Each R 11 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -NHC(O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(O)(C 1-6 Alkyl groups, or halogens; or

[0100] Two Rs 11 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 The aryl group or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms. 12 replace;

[0101] Each R 12 C is independent 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 alkoxy, or C 1-3 Halogenated alkoxy groups;

[0102] R 13 It is C independently each time it appears. 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally surrounded by one or two C atoms. 1-6 The alkoxy group is substituted, and the aryl and heteroaryl groups are optionally replaced by one to three R groups. 14 replace;

[0103] Each R 14 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy groups, halogens, C 6-10 Aryl, or a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S;

[0104] R 15 Is it H or C? 1-6 Alkyl; and

[0105] q can be 0, 1, or 2.

[0106] In one aspect of this disclosure, hydrogen in the compound having formula (I) is present at its normal isotopic abundance. In a preferred aspect of this disclosure, hydrogen isotopes are enriched for deuterium (D), and in a particularly preferred aspect of the invention, position R... x The hydrogen enrichment of D, as discussed in more detail below regarding isotopes and isotope enrichment.

[0107] Another aspect of this disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition may be used to treat or prevent cerebellar protein-mediated disorders, diseases, or conditions. The pharmaceutical composition may further comprise at least one additional pharmaceutical agent.

[0108] On the other hand, this disclosure relates to a method for modulating cerebellar proteins in a biological sample, the method comprising contacting the sample with a compound having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0109] Another aspect of this disclosure relates to a method for inhibiting cerebellar proteins in a biological sample, the method comprising contacting the sample with a compound having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0110] On the other hand, this disclosure relates to a method for modulating target proteins in a biological sample, the method comprising contacting the sample with a compound having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0111] Another aspect of this disclosure relates to a method for inhibiting target proteins in a biological sample, the method comprising contacting the sample with a compound having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0112] Another aspect of this disclosure relates to a method for binding to and altering the specificity of a cerebellar protein complex to induce ubiquitination and degradation of a complex-associated protein in a biological sample selected from the groups listed in Table 1, the method comprising contacting the sample with a compound having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0113] On the other hand, this disclosure relates to methods for treating or preventing cerebellar protein-mediated disorders, diseases, or conditions in a subject, the method comprising administering to the subject a compound having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0114] Another aspect of this disclosure relates to a method for treating or preventing respiratory disorders, proliferative disorders, autoimmune disorders, autoinflammatory disorders, inflammatory disorders, neurological disorders, and infectious diseases or disorders in subjects in need, the method comprising administering to the subject a therapeutically effective amount of a compound having formula (I) or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer.

[0115] On the other hand, this disclosure relates to the use of a compound having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in the preparation of a medicament for the treatment or prevention of respiratory disorders, proliferative disorders, autoimmune disorders, autoinflammatory disorders, inflammatory disorders, neurological disorders, and infectious diseases or disorders in subjects in need.

[0116] Another aspect of this disclosure relates to the use of compounds having formula (I) or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers for the treatment or prevention of cancer.

[0117] On the other hand, this disclosure relates to a method for degrading a target protein in a biological sample, the method comprising contacting a compound having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the target protein is selected from the group listed in Table 1.

[0118] Another aspect of this disclosure relates to methods for treating or preventing target protein-mediated disorders, diseases, or conditions in a subject, the method comprising administering to the subject a compound having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0119] On the other hand, this disclosure relates to methods for treating or preventing cancer in a subject, the method comprising administering to the subject a compound having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0120] Another aspect of this disclosure relates to the use of a compound having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in the preparation of a medicament for the treatment or prevention of cerebellar protein-mediated disorders, diseases, or conditions in subjects in need.

[0121] On the other hand, this disclosure relates to the use of compounds having formula (I) or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers in the treatment or prevention of cerebellar protein-mediated disorders, diseases, or conditions in subjects in need.

[0122] Another aspect of this disclosure relates to compounds having formula (I) or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers for use in the treatment or prevention of cancer.

[0123] On the other hand, this disclosure relates to the use of a compound having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in the preparation of a medicament for the treatment or prevention in a subject of a target protein-mediated disorder, disease, or condition.

[0124] Another aspect of this disclosure relates to compounds having formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, for use in subjects to treat or prevent target protein-mediated disorders, diseases, or conditions. Detailed Implementation

[0125] This disclosure relates to compounds and compositions that modulate or inhibit target proteins by binding to and altering the specificity of cerebellar protein complexes to induce ubiquitination and degradation of complex-associated proteins. This disclosure is characterized by methods for treating, preventing, or alleviating cerebellar protein-mediated disorders, diseases, or conditions by administering a therapeutically effective amount of a compound of formula (I) or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers to a subject in need. The methods disclosed herein can be used to treat a variety of cerebellar protein-mediated disorders, diseases, or conditions by modulating target protein levels. Modulating protein levels through degradation provides novel methods for treating, preventing, or alleviating diseases, including but not limited to respiratory disorders, proliferative disorders, autoimmune disorders, autoinflammatory disorders, inflammatory disorders, neurological disorders, infectious diseases or disorders, and other cerebellar protein-mediated disorders, diseases, or conditions.

[0126] In the first aspect of this disclosure, compounds having formula (I) are described:

[0127]

[0128] Or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers, wherein R d1 R d2 and R d3 As stated above.

[0129] The details of this disclosure are set forth in the appended specification. While similar or equivalent methods and materials may be used in the practice or testing of this disclosure, illustrative methods and materials are described hereafter. Other features, objectives, and advantages of this disclosure will be apparent from the specification and the claims. In this specification and the appended claims, the singular form also includes the plural form unless the context clearly indicates otherwise. Unless otherwise defined, 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 pertains. All patents and publications cited in this specification are incorporated herein by reference in their entirety.

[0130] Definitions of terms and conventions used

[0131] Terms not explicitly defined herein shall be understood to have the meanings that a person skilled in the art would derive from this disclosure and the context. However, unless otherwise indicated, the following terms as used in this specification and the appended claims shall have the meanings indicated and shall follow the following conventions.

[0132] A. Chemical nomenclature, terminology, and conventions

[0133] In the groups (groups, radicals) or portions defined below, the number of carbon atoms is usually indicated before the group, for example (C 1-10 Alkyl refers to an alkyl group having 1 to 10 carbon atoms. Generally, for groups containing two or more subgroups, the last mentioned group is the group junction; for example, "alkylaryl" refers to a monovalent group having the formula alkyl-aryl-, while "arylalkyl" refers to a monovalent group having the formula aryl-alkyl-. Furthermore, the use of terms indicating monovalent groups where a divalent group is appropriate should be understood to indicate the corresponding divalent group, and vice versa. Unless otherwise stated, terms are assumed to correspond to conventional definitions and the valences of conventional stable atoms, and are reflected in the entire formula and group. The article "a / an" refers to one / an or more / an (e.g., at least one / an) of the grammatical object of the article. By example, "an element" refers to one element or more than one element.

[0134] Unless otherwise indicated, the term “and / or” means “and” or “or”.

[0135] The term "optionally substituted" means that a given chemical moiety (e.g., an alkyl group) may (but is not required to) bond with other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group may be a fully saturated alkyl chain (e.g., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group may have substituents other than hydrogen. For example, it may be bonded to a halogen atom, a hydroxyl group, or any other substituent described herein at any position along the chain. Thus, the term "optionally substituted" means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any other functional groups. Suitable substituents for optional substitution of said group include, but are not limited to, halogens, oxo groups, -OH, -CN, -COOH, -CH2CN, and -OC. 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -OC 2-6 alkenyl, -OC 2-6 alkynyl group, C 2-6 alkenyl, C 2-6 Alkyne, -OH, -OP(O)(OH)2, -OC(O)C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -OC(O)OC 1-6 Alkyl, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2、-NHC(O)C 1-6Alkyl, -C(O)NH(C) 1-6 Alkyl), -S(O)2C 1-6 Alkyl group, -S(O)NH(C) 1-6 Alkyl), and S(O)N(C 1-6 Alkyl)2. The substituent itself may be optionally substituted. As used herein, "optionally substituted" refers to substituted or unsubstituted, the meaning of which is described below.

[0136] The term "substituted" means that a particular group or part has one or more suitable substituents, wherein the substituents may be attached to the particular group or part at one or more positions. For example, an aryl group substituted with a cycloalkyl group may indicate that the cycloalkyl group is attached to one atom of the aryl group by a bond or by fusion with the aryl group and sharing two or more common atoms.

[0137] The term "unsubstituted" means that a particular group does not have substituents.

[0138] Unless otherwise explicitly defined, "aryl" means a cyclic aromatic hydrocarbon group having one to three aromatic rings (including monocyclic or bicyclic groups), such as phenyl, biphenyl, or naphthyl. When containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group are optionally connected at a single point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group is optionally substituted at any attachment point by one or more substituents, such as one to five substituents. Exemplary substituents include, but are not limited to, -H, -halogen, -CN, and -OC. 1-6 Alkyl, C 1-6 Alkyl, -O-C2-C6 alkenyl, -OC 2-6 alkynyl group, C 2-6 alkenyl, C 2-6 Alkyne, -OH, -OP(O)(OH)2, -OC(O)C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -OC(O)O(C 1-6 Alkyl), NH2, NH(C) 1-6 Alkyl), N(C) 1-6 Alkyl)2、-S(O)2-C 1-6 Alkyl group, -S(O)NH(C) 1-6 Alkyl), and S(O)N(C 1-6 Alkyl group 2. The substituent itself is optionally substituted. Furthermore, when containing two fused rings, the aryl group optionally has an unsaturated or partially saturated ring fused to a fully saturated ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthraceneyl, phenatenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydrobenzoxenyl, etc.

[0139] Unless otherwise explicitly defined, “heteroaryl” means a monovalent monocyclic aromatic or polycyclic aromatic group with 5 to 24 ring atoms, containing one or more cyclic heteroatoms selected from N, O, or S, with the remaining ring atom being C. As defined herein, a heteroaryl also means a bicyclic heteroaryl group, wherein the heteroatoms are selected from N, O, or S. The aromatic group may optionally be independently substituted by one or more substituents described herein. Examples include, but are not limited to, furanyl, thiophene, pyrrole, pyridinyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophene-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1, [2-b]pyrazolyl, fluoro[2,3-c]pyridyl, imidazo[1,2-a]pyridyl, indazole, pyrrolo[2,3-c]pyridyl, pyrrolo[3,2-c]pyridyl, pyrazololo[3,4-c]pyridyl, thieno[3,2-c]pyridyl, thieno[2,3-c]pyridyl, thieno[2,3-b]pyridyl, benzothiazolyl, indole, dihydroindole Indolinonyl, dihydrobenzobenzylthio, dihydrobenzofuran, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, dihydrobenzyloxane, quinolinyl, isoquinolinyl, 1,6-naphthidyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthidyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrahydroquinolinyl, dihydrobenzo[2,3-b]pyrazinyl, quinazolinyl, tetrahydroquinolinyl, dihydrobenzo[2,3-b]pyrazinyl, dihydrobenzo[2,3-b]pyrazinyl, dihydroquinolinyl, dihydroquinolinyl, dihydroquinolinyl, dihydrobenzo[3 ... Azo[1,5-a]pyridyl, [1,2,4]triazolo[4,3-a]pyridyl, isoindolyl, pyrrolo[2,3-b]pyridyl, pyrrolo[3,4-b]pyridyl, pyrrolo[3,2-b]pyridyl, imidazo[5,4-b]pyridyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1Δ 2-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, fluoro[3,2-c]pyridyl, fluoro[2,3-c]pyridyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzoisoxazolyl, fluoro[2,3-b]pyridyl, benzobenzylthio, 1,5-naphthidyl, fluoro[3,2-b]pyridine, [1,2,4]triazolo[l,5-a]pyridyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4] Triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazo[5,4d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrroleyl, 3H-indolyl, and their derivatives. Furthermore, when containing two fused rings, the aryl group as defined herein may have an unsaturated or partially saturated ring fused to a fully saturated ring. Exemplary ring systems of these heteroaryl groups include dihydroindolyl, indolone, dihydrobenzothio, dihydrobenzofuran, chromium, thiochromium, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, dihydroindolyl, indolyl, and dihydrobenzoxyl.

[0140] Halogen, or "halogenated," refers to fluorine, chlorine, bromine, or iodine.

[0141] "Alkyl" refers to a straight-chain or branched saturated hydrocarbon containing 1-12 carbon atoms. 1-6 Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[0142] "Alkoxy" refers to a straight-chain or branched saturated hydrocarbon containing 1 to 12 carbon atoms, with a terminal "O" in the chain, such as -O (alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, or pentoxy groups.

[0143] "Alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon containing 2 to 12 carbon atoms. An alkenyl group contains at least one double bond in the chain. The double bond in an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include vinyl, propenyl, n-butenyl, isobutenyl, pentenyl, or hexenyl. Alkenyl groups can be unsubstituted or substituted, and can be straight-chain or branched.

[0144] "Alynyl" refers to a straight-chain or branched unsaturated hydrocarbon containing 2-12 carbon atoms. An alkynyl group contains at least one triple bond in the chain. Examples of alynyl groups include ethynyl, propynyl, n-butynyl, isobutynyl, pentyynyl, or hexynyl. Alynyl groups can be unsubstituted or substituted.

[0145] "alkylene" or "alkylenyl" refers to a divalent alkyl group. Any of the monovalent alkyl groups mentioned above can become an alkylene group by removing a second hydrogen atom from that alkyl group. As defined herein, an alkylene group can also be C10. 1-6 Alkylene. Alkylene can be further C10. 1-4 Alkylene groups. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH-, etc.

[0146] "Cycloalkyl" or "carbocyclic" means a monocyclic or polycyclic saturated or partially unsaturated carbon ring containing 3 to 18 carbon atoms, wherein there are no shared, non-localized n electrons (aromaticity) between the ring carbons. Examples of cycloalkyl groups include, but are not limited to, cyclopropenyl, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, norbornyl, bicyclo[2.2.2]octyl, or bicyclo[2.2.2]octenyl, and their derivatives. C 3-8 Cycloalkyl groups are cycloalkyl groups containing between 3 and 8 carbon atoms. Cycloalkyl groups can be fused (e.g., decahydronaphthalene) or bridged (e.g., norbornane).

[0147] "Heteroalkyl" refers to an alkyl group that further includes at least one heteroatom selected from oxygen, nitrogen, or sulfur (e.g., 1, 2, 3, or 4 heteroatoms) located at one or more terminal positions of the parent chain (i.e., inserted between adjacent carbon atoms) and / or at one or more terminal positions of the parent chain. In some embodiments, a heteroalkyl group refers to a saturated group ("heteroalkyl") having from 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain. 1-10 Alkyl group (“Hydroalkyl”). In some embodiments, the heteroalkyl group is a saturated group (“Hydroalkyl”) having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain. 1-9 Alkyl group (“Hydroalkyl”). In some embodiments, the heteroalkyl group is a saturated group (“Hydroalkyl”) having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain. 1-8Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group (“heteroalkyl”) having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain. 1-7 Alkyl group (“Hydroalkyl”). In some embodiments, the heteroalkyl group is a saturated group (“Hydroalkyl”) having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain. 1-6 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group (“heteroalkyl”) having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain. 1-5 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group (“heteroalkyl”) having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain. 1-4 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group (“heteroalkyl”) having 1 to 3 carbon atoms and 1 heteroatom within the parent chain. 1-3 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group (“heteroalkyl”) having 1 to 2 carbon atoms and 1 heteroatom in the parent chain. 1-2 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having one carbon atom and one heteroatom (“heteroC1 alkyl”). In some embodiments, the heteroalkyl group is a saturated group having two to six carbon atoms and one or two heteroatoms within the parent chain (“heteroC1 alkyl”). 2-6 Alkyl group”). Unless otherwise stated, each instance of a heteroalkyl group is independently unsubstituted (“unsubstituted heteroalkyl”) or substituted (“substituted heteroalkyl”) having one or more substituents. In some embodiments, the heteroalkyl group is an unsubstituted heteroalkyl group. 1-10 Alkyl group. In some embodiments, the heteroalkyl group is a substituted heteroC. 1-10 alkyl.

[0148] "Heterocyclic group" refers to a saturated or partially saturated monocyclic or polycyclic ring containing a carbon atom and at least one heteroatom selected from oxygen, nitrogen, or sulfur (O, N, or S), wherein there is no shared, non-localized n electron (aromaticity) between the ring carbons or heteroatoms. Heterocyclic alkyl ring structures can be substituted by one or more substituents. The substituents themselves can be optionally substituted. Examples of heterocyclic rings include, but are not limited to, oxacyclobutane, azacyclobutane, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolinyl, thiazolinyl, thiazolinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxolinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazine, aza... basic, oxygen basalt, diazoxide The compounds include alkyl, tropane, oxazolidinone, 1,4-dioxane, dihydrofuranyl, 1,3-dioxolanecycloyl, imidazoalkyl, imidazolinyl, dithiopentaneyl, and homotropanyl.

[0149] "Hydroxyalkyl" refers to an alkyl group that is substituted with one or more -OH groups. Examples of hydroxyalkyl groups include HO-CH2-, HO-CH2CH2-, and CH2-CH(OH)-.

[0150] "Halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens. Examples of halogenated alkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.

[0151] "Haloalkoxy" refers to an alkoxy group that has been substituted by one or more halogens. Examples of halogenated alkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, and trichloromethoxy.

[0152] "Cyano" refers to a substituent that has a carbon atom connected to a nitrogen atom by a triple bond, such as C≡N.

[0153] "Amino" refers to a substituent containing at least one nitrogen atom (e.g., NH2).

[0154] "Alkylamino" refers to an amino or NH2 group in which one of the hydrogen atoms is replaced by an alkyl group, such as -NH (alkyl). Examples of alkylamino groups include, but are not limited to, methylamino (e.g., -NH(CH3)), ethylamino, propylamino, isopropylamino, n-butylamino, sec-butylamino, tert-butylamino, etc.

[0155] "Dialkylamino" refers to an amino or NH2 group in which both hydrogen atoms are replaced by alkyl groups, such as -N(alkyl)2. The alkyl groups on the amino group may be the same or different alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino (e.g., -N(CH3)2), diethylamino, dipropylamino, diisopropylamino, di-n-butylamino, di-sec-butylamino, di-tert-butylamino, methyl(ethyl)amino, methyl(butylamino), etc.

[0156] "Spirocarbocyclic" refers to a carbocyclic bicyclic system with two rings connected by a single atom. These rings can be of different sizes and properties, or they can be of the same size and properties. Examples include spiropentane, spirohexane, spiroheptane, spiroctane, spirononane, or spirodecane. One or both rings of the spirocyclic ring can be fused with another ring—a carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. 3-12 Spirocycloalkyl groups are spirocycles containing between 3 and 12 carbon atoms.

[0157] "Spiroheteroalkyl" or "spiroheteroyl group" means a spirocarbocyclic group in which at least one ring is a heterocycle (one or more carbon atoms can be substituted by heteroatoms (e.g., one or more carbon atoms in at least one ring are substituted by heteroatoms)). One or both rings of the spiroheterocycle may be fused with another ring carbocyclic, heterocyclic, aromatic, or heteroaromatic ring.

[0158] B. Terminology and Conventions for Salts, Prodrugs, Derivatives, and Solvents

[0159] "Prodrug" or "prodrug derivative" refers to a covalently bonded derivative or carrier of a parent compound or active pharmaceutical ingredient that undergoes at least some biotransformation before exhibiting one or more pharmacological effects. Generally, such prodrugs have metabolically cleavable groups and are rapidly converted in vivo to produce the parent compound, for example, through hydrolysis in the blood, and typically include esters and amide analogs of the parent compound. Prodrugs are formulated to improve chemical stability, improve patient acceptability and compliance, improve bioavailability, prolong duration of action, improve organ selectivity, improve formulation (e.g., increased water solubility), and / or reduce side effects (e.g., toxicity). Generally, prodrugs themselves have weak or no biological activity and are stable under normal conditions.Prodrugs can be readily prepared from parent compounds using methods known in the art, such as those described in: A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Gordon & Breach, 1991, particularly Chapter 5: “Design and Applications of Prodrugs”; Design of Prodrugs, edited by H. Bundgaard, Elsevier, 1985; Prodrugs: Topical and Ocular Drug Delivery, edited by KBSloan, Marcel Dekker, 1998; Methods in Enzymology, edited by K. Widder et al., Volume 42, Academic Press, 1985, especially pp. 309-396; Burger's Medicinal Chemistry and Drug Discovery, 5th edition, edited by M. Wolff, John Wiley & Sons, 1995, especially Volume 1 and pp. 172-178 and 949-982; Pro-Drugs as Novel Delivery Systems, edited by T. Higuchi and V. Stella, Am. Chem. Soc., 1975; Bioreversible Carriers in Drug Design, edited by E.B. Roche, Elsevier, 1987, each incorporated herein by reference in its entirety.

[0160] As used herein, “pharmaceuticalally acceptable prodrug” means a prodrug of the disclosed compound that, within reasonable medical judgment, is suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., in proportion to a reasonable benefit / risk ratio, and where possible, is effective for its intended use and in its zwitterionic form.

[0161] "Salt" refers to the ionic form of a parent compound or the product of a reaction between a parent compound and a suitable acid or base to prepare an acidic or basic salt of the parent compound. Salts of the compounds disclosed herein can be synthesized from parent compounds containing a basic or acidic moiety using conventional chemical methods. Typically, salts are prepared by reacting a free basic or acidic parent compound with a stoichiometric amount or an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or different combinations of solvents.

[0162] "Pharmaceutically acceptable salt" means a salt of the compounds disclosed herein that, within reasonable medical judgment, is suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., in proportion to a reasonable benefit / risk ratio, is generally water-soluble or oil-soluble or dispersible, and is effective for its intended use. This term includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. Since the compounds disclosed herein are useful in both free base form and salt form, practically using the salt form is equivalent to using the base form. A list of suitable salts is found, for example, in SM Birge et al., J. Pharm. Sci. [Journal of Pharmaceutical Sciences], 1977, 66, pp. 1-19, which is hereby incorporated by reference in its entirety.

[0163] "Pharmaceutically acceptable acid addition salts" refer to salts that retain the biological effectiveness and properties of the free base and are not biologically or otherwise undesirable. These salts react with inorganic acids (e.g., hydrobromic acid, hydroiodic acid, sulfuric acid, aminosulfonic acid, nitric acid, phosphoric acid, etc.) and organic acids (e.g., acetic acid, trichloroacetic acid, trifluoroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 2-acetoxybenzoic acid, butyric acid, camphoric acid, camphorsulfonic acid, cinnamic acid, citric acid, digluconic acid, ethanesulfonic acid, glutaric acid, etc.). It is formed from amino acids, glycolic acid, glycerophosphate, hemisulfonic acid, heptanoic acid, hexanoic acid, formic acid, fumaric acid, 2-hydroxyethanesulfonic acid (hydroxyethylsulfonic acid), lactic acid, maleic acid, hydroxymaleic acid, malic acid, malonic acid, mandelic acid, tris(methyl)toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, dihydroxynaphthaleneic acid, pectic acid, phenylacetic acid, 3-phenylpropionic acid, picric acid, neopentanoic acid, propionic acid, pyruvic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, p-aminobenzenesulfonic acid, tartaric acid, p-toluenesulfonic acid, undecanoic acid, etc.

[0164] "Pharmaceutically acceptable base addition salts" refers to salts that retain the biological effectiveness and properties of the free acid and are not biologically or otherwise undesirable. These salts are formed with inorganic bases (e.g., ammonia or hydroxides, carbonates, or ammonium bicarbonate) or metal cations (e.g., sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc.). Ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, quaternary ammonium compounds, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, and histidine. The ingredients include caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, tetramethylammonium compounds, tetraethylammonium compounds, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, dibenzylamine, N,N-dibenzylphenethylamine, 1-diphenylhydroxymethylamine, N,N'-dibenzylethylenediamine, and polyamine resins. Particularly preferred non-toxic organic alkaloids include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0165] "Solvate" refers to a complex with variable stoichiometry formed by a solute (e.g., a compound having formula (I)) and a solvent (e.g., water, ethanol, or acetic acid). This physical association may involve varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, solvates can be separated (e.g., when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid). Generally, such solvents selected for the purposes of this disclosure do not interfere with the biological activity of the solute. Solvates encompass both solution phases and separable solvates. Representative solvates include hydrates, ethanolides, methanolides, etc.

[0166] "Hydrate" refers to a solvation of one or more solvent molecules that are water.

[0167] The compounds discussed below include their free bases or acids, their salts, solvates, and prodrugs, and may include oxidized sulfur atoms or quaternized nitrogen atoms in their structure (although not explicitly stated or shown), particularly in their pharmaceutically acceptable forms. Such forms (particularly pharmaceutically acceptable forms) are intended to be included in the appended claims.

[0168] C. Isomer terminology and conventions

[0169] "Isomers" refer to compounds that have the same number and type of atoms, and therefore the same molecular weight, but differ in the spatial arrangement or configuration of the atoms. This term includes stereoisomers and geometric isomers.

[0170] "Stereoisomer" or "optical isomer" means a stable isomer having at least one chiral atom or restricted rotation resulting in a perpendicular asymmetric plane (e.g., certain biphenyl, propadiene, and spirocyclic compounds) and capable of rotating plane-polarized light. Because the asymmetric center and other chemical structures are present in the compounds disclosed herein that can lead to stereoisomerism, this disclosure considers stereoisomers and mixtures thereof. The compounds disclosed herein and their salts include asymmetric carbon atoms and can therefore exist as single stereoisomers, racemates, and mixtures of enantiomers and diastereomers. Typically, such compounds are prepared as racemic mixtures. However, if desired, such compounds can be prepared or isolated as stereoisomers, i.e., as single enantiomers or diastereomers, or as mixtures enriched with stereoisomers. As discussed in more detail below, individual stereoisomers of the compound are prepared by synthesis from an optically active starting material containing the desired chiral center, or by preparing a mixture of enantiomeric products followed by separation or resolution (e.g., conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, using chiral resolving agents, or direct separation of enantiomers on a chiral column). The starting compound of the specific stereochemistry is commercially available or prepared by the methods described below and resolved by techniques well known in the art.

[0171] "Enantiomers" refers to a pair of stereoisomers that are non-overlapping mirror images of each other.

[0172] "Diarrhetinic" or "diarrhetinic isomer" refers to optical isomers that do not form a mirror image of each other.

[0173] "Raceous mixture" or "racemate" refers to a mixture containing equal parts of individual enantiomers.

[0174] "Non-racemic mixture" refers to a mixture containing unequal amounts of individual enantiomers.

[0175] "Geometric isomers" refers to stable isomers arising from restricted rotational freedom in double bonds (e.g., cis-2-butene and trans-2-butene) or cyclic structures (e.g., cis-1,3-dichlorocyclobutane and trans-1,3-dichlorocyclobutane). Because carbon-carbon double (alkene) bonds, C=N double bonds, cyclic structures, etc., can exist in the compounds disclosed herein, this disclosure considers each of the different stable geometric isomers and mixtures thereof arising from the arrangement of substituents around these double bonds and in these cyclic structures. Substituents and isomers are indicated using the cis / trans convention or the E or Z system, where the term "E" indicates a higher-order substituent on the opposite side of the double bond, and the term "Z" indicates a higher-order substituent on the same side of the double bond. A detailed discussion of E and Z isomerism is provided in: J. March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4th ed., John Wiley & Sons, 1992, which is hereby incorporated in its entirety by reference. The following examples represent single E isomers, single Z isomers, and mixtures of E / Z isomers. The determination of E and Z isomers can be performed using analytical methods such as X-ray crystallography. 1 H NMR, and 13 C NMR.

[0176] Some of the compounds disclosed herein can exist in more than one tautomer form. As mentioned above, the compounds disclosed herein include all such tautomers.

[0177] It is well known in the art that the biological and pharmacological activities of a compound are sensitive to its stereochemistry. Therefore, for example, enantiomers often exhibit significantly different biological activities, including differences in pharmacokinetic properties (including metabolism, protein binding, etc.) and pharmacological properties (including the type, degree, and toxicity of the activity exhibited). Therefore, those skilled in the art will understand that an enantiomer may be more active or exhibit beneficial effects when enriched relative to other enantiomers or when separated from other enantiomers. Furthermore, those skilled in the art will know how to separate, enrich, or selectively prepare enantiomers of the compounds disclosed herein from the knowledge of this disclosure and the prior art.

[0178] Therefore, although racemic forms of drugs can be used, they are generally less effective than administering an equal amount of the pure enantiomer; in fact, in some cases, an enantiomer can be pharmacologically inactive and merely act as a simple diluent. For example, although ibuprofen was previously administered in racemic form, only the S-isomer of ibuprofen has been found to be effective as an anti-inflammatory agent (however, in the case of ibuprofen, although the R-isomer is inactive, it is converted to the S-isomer in vivo, so the racemic form of the drug has a slower onset of action than the pure S-isomer). Furthermore, the pharmacological activities of enantiomers can differ significantly from their biological activities. For example, S-penicillamine is used to treat chronic arthritis, while R-penicillamine is toxic. In fact, some purified enantiomers are superior to racemic ones, as it has been reported that purified individual isomers have faster transdermal penetration rates compared to racemic mixtures. See U.S. Patent Nos. 5,114,946 and 4,818,541.

[0179] Therefore, if an enantiomer has higher pharmacological activity, lower toxicity, or better in vivo distribution than other enantiomers, then administering such an enantiomer would be more beneficial for treatment. In this way, the treated patient would be exposed to a lower total dose of the drug and a lower dose of the potentially toxic enantiomer or inhibitor of other enantiomers.

[0180] The preparation of pure enantiomers or mixtures having the desired enantiomer excess (ee) or enantiomer purity can be accomplished by one or more methods known to those skilled in the art for (a) separating or resolving enantiomers, or (b) selectively synthesizing enantiomers, or by a combination of these methods. These resolution methods typically rely on chiral recognition and include, for example, chromatography using a chiral stationary phase, enantiomer-selective host-guest complexation, resolution or synthesis using chiral auxiliaries, enantiomer-selective synthesis, enzymatic and non-enzymatic kinetic resolution, or spontaneous enantiomer-selective crystallization. Such methods are typically disclosed in: Chiral Separation Techniques: A Practical Approach (2nd ed.), G. Subramanian (ed.), Wiley-VCH, 2000; T.E. Beesley and R.R. W. Scott, Chiral Chromatography, John Wiley & Sons, 1999; and Satinder Ahuja, Chiral Separations by Chromatography, Am. Chem. Soc., 2000. In addition, there are equally well-known methods for quantifying enantiomer excess or purity (e.g., GC, HPLC, CE, or NMR) and methods for identifying absolute configurations and conformations (e.g., CDORD, X-ray crystallography, or NMR).

[0181] Generally speaking, all tautomerisms and isomerisms of a chemical structure or compound, whether individual geometric isomers or stereoisomers or racemic or non-racemic mixtures, are expected unless the specific stereochemical or isomerism is explicitly specified in the name or structure of the compound.

[0182] D. Terminology and Practices for Drug Administration and Treatment

[0183] The “patient” or “subject” is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or a non-human primate, such as a monkey, chimpanzee, baboon, or rhesus monkey. In some embodiments, the subject is a primate. In still other embodiments, the subject is a human.

[0184] When used with a compound, “effective amount” or “therapeutic effective amount” means an amount of the compound disclosed herein that (i) treats or prevents a particular disease, condition or disorder, (ii) reduces, alleviates or eliminates one or more symptoms of a particular disease, condition or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition or disorder described herein.

[0185] The terms "therapeutic effective amount" or "therapeutic effective amount" mean an amount of a compound according to this disclosure that, when administered to a patient in need, is sufficient to treat a disease state, symptom, or disorder in which the compound is effective. This amount is sufficient to elicit a biological or medical response in the tissue, system, or patient sought by the researcher or clinician. The amount of a compound according to this disclosure constituting a therapeutic effective amount will vary depending on factors such as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of treatment, the type and severity of the disease state or disorder being treated, the drugs used in combination with or in combination with the compound disclosed, and the patient's age, weight, general health, sex, and diet. This therapeutic effective amount can be determined by those skilled in the art based on their own knowledge, prior art, and the conventions of this disclosure.

[0186] As used herein, the term "pharmaceutical composition" means a compound disclosed herein, or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer, and at least one pharmaceutically acceptable carrier, in a form suitable for oral or parenteral administration.

[0187] "Carrier" encompasses carriers, excipients, and diluents, and means a material, composition, or medium relating to carrying or transporting a pharmaceutical agent from one organ or part of a subject's body to another organ or part of a subject's body, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials.

[0188] Such subjects are “in need” of the treatment (preferably, human) if they will benefit from it biologically, medically, or in terms of quality of life.

[0189] As used herein, the term “inhibit (inhibition or inhibiting)” means a reduction or inhibition of a given condition, symptom or disorder, or disease, or a significant reduction in baseline activity of a biological activity or process.

[0190] As used herein, the term “treatment” for any disease or disorder means relief or reduction of the disease or disorder (i.e., slowing or halting the development of the disease or at least one of its clinical symptoms); or relief or reduction of at least one physical parameter or biomarker associated with the disease or disorder, including those physical parameters or biomarkers that the patient may not be able to identify.

[0191] As used herein, the term “prevent, preventing, or prevention” for any disease or disorder refers to preventive treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.

[0192] "Pharmaceutical acceptable" means that a substance or composition must be chemically and / or toxicologically compatible with other ingredients containing the formulation and / or with the mammals being treated with it.

[0193] Unless otherwise indicated, “obstacle” means the terms disease, symptom, or ailment, and is used interchangeably with these terms.

[0194] "Administer (administering or administration)" means the direct administration of the disclosed compound, or a pharmaceutically acceptable salt or composition of the disclosed compound, to a subject, or the administration of a prodrug derivative or analog of the compound, or a pharmaceutically acceptable salt or composition of the compound, to a subject, which may form an equivalent amount of the active compound in the subject's body.

[0195] "Prodrug" means a compound that can be converted into the disclosed compound in vivo through metabolism (e.g., through hydrolysis).

[0196] "Compounds of the present disclosure", "compounds having formula (I)", "compounds of the disclosure", and equivalent expressions (unless otherwise expressly stated) refer to compounds having formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (Iz), (Iaa), (Iab), (Iac), (Ia Compounds of (d), (Iae), (Iaf), (Iag), (Iah), (Iai), (Iaj), (Iak), (Ial), and (Iam), including their tautomers, prodrugs, salts (particularly pharmaceutically acceptable salts), and solvates and hydrates, (where context permits) and all stereoisomers (including diastereomers and enantiomers), rotational isomers, tautomers, and isotopically labeled compounds (including deuterium-substituted compounds), as well as intrinsically formed moieties (e.g., polymorphs, solvates, and / or hydrates). For the purposes of this disclosure, solvates and hydrates are generally considered to be compositions. Generally and preferably, the compounds of this disclosure and the formulas representing the compounds of this disclosure should be understood to include only their stable compounds and exclude unstable compounds, even if unstable compounds may be considered to be actually included in the compound formula. Similarly, where context permits, references to intermediates (whether or not they are claimed in themselves) are intended to include their salts and solvates. For clarity, specific cases that are permissible in the context are sometimes indicated in the text, but these are purely illustrative and not intended to exclude other cases that are permissible in the context.

[0197] "Stable compound" or "stable structure" means a compound that is robust enough to withstand separation from the reaction mixture to a useful purity and formulation into an effective therapeutic or diagnostic agent. For example, compounds having a "dangling valence" or a carbanion are not considered in this disclosure.

[0198] The provided compounds are conjugates of CRBN and are therefore intended for the treatment of one or more disorders associated with the activity of CRBN or its mutants. Accordingly, in some embodiments, this disclosure provides a method for treating CRBN-mediated disorders, the method comprising the step of administering the disclosed compounds or pharmaceutically acceptable compositions thereof to a patient in need.

[0199] As used herein, the term "CRBN-mediated" disorder, disease, and / or condition means any disease, condition, or disorder in which a CRBN or a mutant thereof is known to play a role. Therefore, another embodiment relates to the treatment or prevention of one or more diseases in which a CRBN or a mutant thereof is known to play a role. Such CRBN-mediated disorders include, but are not limited to, respiratory disorders, proliferative disorders, autoimmune disorders, autoinflammatory disorders, inflammatory disorders, neurological disorders, or infectious diseases or disorders.

[0200] In one particular embodiment, the terms “about” or “approximately” mean within 20%, preferably within 10%, and more preferably within 5% of a given value or range.

[0201] The yields of each reaction described in this article are expressed as a percentage of the theoretical yield.

[0202] D. Specific examples and methods for testing compounds having formula (I)

[0203] This disclosure relates to compounds, or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, which can be used to treat or prevent diseases and disorders associated with the regulation of protein levels by binding to and altering the specificity of cerebellar protein complexes to induce proteasome-mediated degradation of selected proteins. This disclosure further relates to compounds, or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, which can be used to treat or prevent diseases and disorders associated with reduced or decreased protein levels by binding to and altering the specificity of cerebellar protein complexes to induce proteasome-mediated degradation of selected proteins.

[0204] In one embodiment, a compound having formula (I) has a formula selected from the following:

[0205]

[0206]

[0207]

[0208] Or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers.

[0209] In some embodiments having the above formulas (i.e., formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (Iz), (Iaa), (Iab), (Iac), (Iad), (Iae), (Iaf), (Iag), (Iah), (Iai), (Iaj), (Iak), (Ial), and / or (Iam)), It is a double bond. In another embodiment, It is a single key.

[0210] In some embodiments having the above formula, R d1 It is -CH2OC(O)R 15 -CH2OP(O)OHOR 15 、or CH2OP(O)(R 15 )2. In another embodiment, R d1 It is H, -CH2OC(O)R 15 、or -CH2OP(O)OHOR 15 In yet another embodiment, R d1 It is H, -CH2OC(O)R 15 、or -CH2OP(O)(R 15 )2. In another embodiment, R d1 It is H, -CH2OP(O)OHOR 15 、or -CH2OP(O)(R 15 )2. In yet another embodiment, R d1 It is H or -CH2OC(O)R 15 In another embodiment, R d1 It is H or -CH2OP(O)OHOR 15 In yet another embodiment, R d1 Is it H or -CH2OP(O)(R 15 )2. In another embodiment, R d1 It's H.

[0211] In some embodiments having the above formula, R d2 It is H, C 1-3 Alkyl, halogen, C 1-3 Halogenated alkyl, or C 1-3 Heteroalkyl. In another embodiment, Rd2 It is H, C 1-3 Alkyl, halogen, or C 1-3 Haloalkyl. In yet another embodiment, R d2 It is H, C 1-6 Alkyl, halogen, or C 1-6 Heteroalkyl. In another embodiment, R d2 It is H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, or C 1-6 Heteroalkyl. In yet another embodiment, R d2 It is H, halogen, C 1-6 Halogenated alkyl, or C 1-6 Heteroalkyl. In another embodiment, R d2 It is H, C 1-6 Alkyl or halogen. In yet another embodiment, R d2 It is H, C 1-6 Alkyl, or C 1-6 Halogenated alkyl group. In another embodiment, R d2 It is H, C 1-6 Alkyl, or C 1-6 Heteroalkyl. In yet another embodiment, R d2 It is H or a halogen. In yet another embodiment, R d2 Is it H or C? 1-6 Halogenated alkyl group. In another embodiment, R d2 Is it H or C? 1-6 Heteroalkyl. In yet another embodiment, R d2 Is it H or C? 1-6 Alkyl group. In another embodiment, R d2 Is it H or C? 1-3 Alkyl group. In yet another embodiment, R d2 It is H, methyl, ethyl, n-propyl, or isopropyl. In another embodiment, R d2 It is H, methyl, or ethyl. In yet another embodiment, R d2 It is H or methyl. In another embodiment, R d2 It is H, methyl, or F. In yet another embodiment, R d2 It's H.

[0212] In some embodiments having the above formula, R d3 yes

[0213] In another embodiment, R d3 yes

[0214]

[0215] In another embodiment, R d3 yes

[0216] In another embodiment, R d3 yes

[0217] In another embodiment, R d3 yes

[0218] In another embodiment, R d3 yes

[0219] In another embodiment, R d3 yes

[0220] In another embodiment, R d3 yes

[0221] In another embodiment, R d3 yes

[0222] In another embodiment, R d3 yes

[0223] In another embodiment, R d3 yes

[0224] In another embodiment, R d3 yes

[0225] In another embodiment, R d3 yes

[0226] In another embodiment, R d3 yes

[0227] In another embodiment, R d3 yes

[0228] In another embodiment, R d3 yes

[0229] In another embodiment, R d3 yes

[0230] In another embodiment, R d3 yes

[0231]

[0232]

[0233]

[0234]

[0235] In another embodiment, R d3 yes

[0236]

[0237]

[0238]

[0239]

[0240] In another embodiment, R d3 yes

[0241] In another embodiment, R d3 yes

[0242] In another embodiment, R d3 yes

[0243] In another embodiment, R d3 yes

[0244]

[0245] In another embodiment, R d3 yes

[0246] In another embodiment, R d3 yes

[0247]

[0248]

[0249]

[0250]

[0251] In another embodiment, R d3 yes

[0252]

[0253]

[0254]

[0255]

[0256] In another embodiment, R d3 yes

[0257]

[0258]

[0259]

[0260]

[0261] In another embodiment, R d3 yes

[0262]

[0263]

[0264]

[0265] In another embodiment, R d3 yes

[0266]

[0267] In another embodiment, R d3 yes

[0268]

[0269] In another embodiment, R d3 yes

[0270] In another embodiment, R d3 yes

[0271] In another embodiment, R d3 yes

[0272] In some embodiments having the above formula, A 1 It is a 5- or 6-membered heterocyclic group that optionally contains 1-3 additional heteroatoms selected from O, N, and S, or optionally contains 1-3 heteroatoms selected from N, NR, and S. 1k The other heteroatoms of O and S are also affected by one or two R atoms. 1d The substituted 5-membered heteroaryl group. In another embodiment, A 1 It is a 5- or 6-membered heterocyclic group that optionally contains 1-3 additional heteroatoms selected from O, N, and S, or optionally contains 1-3 heteroatoms selected from N, NR, and S. 1k The other heteroatoms of O and S are 5-membered heteroaryl groups. In yet another embodiment, A 1 It is a 5-membered heterocyclic group that optionally contains 1-3 additional heteroatoms selected from O, N, and S, or optionally contains 1-3 heteroatoms selected from N, NR, and S. 1k The other heteroatoms of O and S are surrounded by one to three R atoms. 1d The substituted 5-membered heteroaryl group. In another embodiment, A 1 It is a 5-membered heterocyclic group that optionally contains 1-3 additional heteroatoms selected from O, N, and S, or optionally contains 1-3 heteroatoms selected from N, NR, and S.1k The other heteroatoms of O and S are 5-membered heteroaryl groups. In yet another embodiment, A 1 It is a 6-membered heterocyclic group that optionally contains 1-3 additional heteroatoms selected from O, N, and S, or optionally contains 1-3 heteroatoms selected from N, NR, and S. 1k The other heteroatoms of O and S are surrounded by one to three R atoms. 1d The substituted 5-membered heteroaryl group. In another embodiment, A 1 It is a 6-membered heterocyclic group that optionally contains 1-3 additional heteroatoms selected from O, N, and S, or optionally contains 1-3 heteroatoms selected from N, NR, and S. 1k The other heteroatoms of O and S are 5-membered heteroaryl groups.

[0273] In another embodiment, A 1 It can optionally include 1-3 elements selected from N and NR. 1k The other heteroatoms of O and S are also affected by one or two R atoms. 1d The substituted 5- or 6-membered heterocyclic group. In another embodiment, A 1 It can optionally include 1-3 elements selected from N and NR. 1k 5- or 6-membered heterocyclic groups of O and S. In yet another embodiment, A 1 It can optionally include 1-3 elements selected from N and NR. 1k The other heteroatoms of O and S are surrounded by one to three R atoms. 1d The substituted 5-membered heterocyclic group. In another embodiment, A 1 It can optionally include 1-3 elements selected from N and NR. 1k Five-membered heterocyclic groups containing additional heteroatoms of O and S. In yet another embodiment, A 1 It can optionally include 1-3 elements selected from N and NR. 1k The other heteroatoms of O and S are surrounded by one to three R atoms. 1d The substituted 6-membered heterocyclic group. In another embodiment, A 1 It can optionally include 1-3 elements selected from N and NR. 1k 6-membered heterocyclic groups with additional heteroatoms of O and S.

[0274] In another embodiment, A 1 It can optionally include 1-3 elements selected from N and NR. 1k The other heteroatoms of O and S are surrounded by one to three R atoms. 1d The substituted 5-membered heteroaryl group. In another embodiment, A 1 It can optionally include 1-3 elements selected from N and NR. 1k The other heteroatoms of O and S are 5-membered heteroaryl groups.

[0275] In some embodiments having the above formula, A 2 It is C 5-7 The carbon cyclo group or contains 1-3 radicals selected from N and NR 1k Five- to seven-membered heterocyclic groups of O and S heteroatoms, wherein the carbocyclic group and the heterocyclic group are separated by one to three R atoms. 1d replace.

[0276] In some embodiments having the above formula, X 1 It is NR 4 In another embodiment, X 1 It is S.

[0277] In some embodiments having the above formula, X 2 It is CR 1a Or N. In another embodiment, X 2 It is CR 1a In yet another embodiment, X 2 It is N.

[0278] In some embodiments having the above formula, X 2a It is CR 1a Or N. In another embodiment, X 2a It is CR 1a In yet another embodiment, X 2a It is N.

[0279] In some embodiments having the above formula, X 2 It is CR 1a Or N, and X 2a It is CR 1a In another embodiment, X 2 It is CR 1a Or N, and X 2a It is N. In yet another embodiment, X 2a It is CR 1a Or N, and X 2 It is CR 1a In another embodiment, X 2a It is CR 1a Or N, and X 2 It is N. In yet another embodiment, X 2a It is CR 1a And X 2 It is N. In another embodiment, X 2a It is N, and X 2 It is N. In yet another embodiment, X 2a It is CR 1a And X 2 It is N.

[0280] In some embodiments having the above formula, each X 3 Independently is CR 1d Or N; where no more than two X's 3 It is N.

[0281] In some embodiments having the above formula, each X 3' Independently is CR 1d CR 1c Or N, where no more than two X's 3 It is N, and at least one of them is X 3' It is CR 1c In another embodiment, each X 3' Independently is CR 1d or CR 1c , of which at least one X 3' It is CR 1c In another embodiment, each X 3' Independently is CR 1c Or N, where no more than two X's 3 It is N.

[0282] In some embodiments having the above formula, each X 4 Independently is CR 1d Or N, where at least one X 4 It is N, and there are no more than two X's. 4 It is N.

[0283] In some embodiments having the above formula, each X 5 Independently is CR 1a Or N; where no more than two X's 5 It is N.

[0284] In some embodiments having the above formula, X 6 It is NR 1k Or O. In another embodiment, X 6 It is NR 1k Or S. In yet another embodiment, X 6 It is O or S. In another embodiment, X 6 It is NR 1k In yet another embodiment, X 6 It is O. In another embodiment, X 6 It is S.

[0285] In some embodiments having the above formula, X 7 It is NR 4 Or O. In another embodiment, X 7 It is N, NR 4 Or S. In yet another embodiment, X7 It is O or S. In another embodiment, X 7 It is NR 4 In yet another embodiment, X 7 It is O. In another embodiment, X 7 It is S.

[0286] In some embodiments having the above formula, R 1a It is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -CN, F, or Cl. In another embodiment, R 1a It is H, C 2-4 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -CN, F, or Cl. In yet another embodiment, R 1a It is H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 alkoxy, or C 1-3 Haloalkoxy group. In another embodiment, R 1a It is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 alkoxy, or C 1-3 Haloalkoxy group. In yet another embodiment, R 1a It is -NH2, -NH(C 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -CN, F, or Cl. In another embodiment, R 1a It is H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -CN, F, or Cl. In yet another embodiment, R 1a It is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy group, -CN, F, or Cl. In another embodiment, R 1a It is H, C 1-3Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, F, or Cl. In yet another embodiment, R 1a It is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, F, or Cl. In another embodiment, R 1a It is H, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -CN, F, or Cl. In yet another embodiment, R 1a It is C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -CN, F, or Cl. In another embodiment, R 1a It is H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, or -CN. In yet another embodiment, R 1a It is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2 or -CN. In another embodiment, R 1a It is H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, or F. In yet another embodiment, R 1a It is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, or F. In another embodiment, R 1a It is H, C 1-3 Alkyl, C 1-3 Halogenated alkyl group, or F. In yet another embodiment, R1a It is C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, or F.

[0287] In some embodiments having the above formula, R 1b It is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -CN, F, or Cl. In another embodiment, R 1b It is H, C 2-4 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -CN, F, or Cl. In yet another embodiment, R 1b It is H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 alkoxy, or C 1-3 Haloalkoxy group. In another embodiment, R 1b It is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 alkoxy, or C 1-3 Haloalkoxy group. In yet another embodiment, R 1b It is -NH2, -NH(C 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -CN, F, or Cl. In another embodiment, R 1b It is H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -CN, F, or Cl. In yet another embodiment, R 1b It is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy group, -CN, F, or Cl. In another embodiment, R 1b It is H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3Haloalkoxy, F, or Cl. In yet another embodiment, R 1b It is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, F, or Cl. In another embodiment, R 1b It is H, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -CN, F, or Cl. In yet another embodiment, R 1b It is C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -CN, F, or Cl. In another embodiment, R 1b It is H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, or -CN. In yet another embodiment, R 1b It is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2 or -CN. In another embodiment, R 1b It is H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, or F. In yet another embodiment, R 1b It is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, or F. In another embodiment, R 1b It is H, C 1-3 Alkyl, C 1-3 Halogenated alkyl group, or F. In yet another embodiment, R 1b It is C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, or F.

[0288] In some embodiments having the above formula, R 1c It is C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy group, halogen, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 Replacement. In another embodiment, R 1c It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy groups, halogens, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2、-(CH2) 0-4 -C(O)NH(R 13 -(CH2) 0-4 -C(O)N(R 13 )2, wherein the alkynyl group is optionally surrounded by one to three R 2 replace.

[0289] In another embodiment, R 1c It is -(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2)0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally separated by one to five R atoms. 5 replace.

[0290] In another embodiment, R 1c It is C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, halogen, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6-C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0- 4NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace.

[0291] In some embodiments having the above formula, R 1c’ It is C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy groups, F, Cl, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2)0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 Replacement. In another embodiment, R 1c’ It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy groups, F, Cl, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2、-(CH2) 0-4 -C(O)NH(R 13 -(CH2) 0-4 -C(O)N(R 13 )2, wherein the alkynyl group is optionally surrounded by one to three R 2 replace.

[0292] In another embodiment, R 1c’ It is -(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2)0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally separated by one to five R atoms. 5 replace.

[0293] In another embodiment, R 1c’ It is C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, F, Cl, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4-C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0- 4NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4- A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace.

[0294] In some embodiments having the above formula, R 1d It is H, C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy group, halogen, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2)0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 Replacement. In another embodiment, R 1d It is H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy groups, halogens, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2、-(CH2) 0-4 -C(O)NH(R 13 -(CH2) 0-4 -C(O)N(R 13 )2, wherein the alkynyl group is optionally surrounded by one to three R 2 replace.

[0295] In another embodiment, R 1d It is H, -(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally separated by one to five R atoms. 5 replace.

[0296] In another embodiment, R 1d It is H, C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, halogen, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2)0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0- 4NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace.

[0297] In some embodiments having the above formula, R 1e It is C 2-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -CN, or F. In another embodiment, R 1e It is C 2-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -CN, or Cl. In yet another embodiment, R 1e It is C 2-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, F, or Cl. In another embodiment, R 1e It is C 2-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, -CN, F, or Cl. In yet another embodiment, R 1e It is C 2-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy group, -CN, F, or Cl. In another embodiment, R 1e It is C 2-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -CN, F, or Cl. In yet another embodiment, R 1e It is C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy group, -CN, F, or Cl. In another embodiment, R 1e It is C 2-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, or -CN. In yet another embodiment, R 1e It is C 2-3 Alkyl, C 1-3Halogenated alkyl group, -CN, F, or Cl. In another embodiment, R 1e It is C 1-3 Alkoxy, C 1-3 Haloalkoxy, -CN, F, or Cl. In yet another embodiment, R 1e It is C 2-3 Alkyl, C 1-3 Halogenated alkyl, F, or Cl.

[0298] In some embodiments having the above formula, R 1f It is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -CN, or F. In another embodiment, R 1f It is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -CN, or Cl. In yet another embodiment, R 1f It is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, F, or Cl. In another embodiment, R 1f It is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, -CN, F, or Cl. In yet another embodiment, R 1f It is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy group, -CN, F, or Cl. In another embodiment, R 1f It is C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -CN, F, or Cl. In yet another embodiment, R 1f It is C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy group, -CN, F, or Cl. In another embodiment, R 1f It is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, or -CN. In yet another embodiment, R 1f It is C 1-3Alkyl, C 1-3 Halogenated alkyl group, -CN, F, or Cl. In another embodiment, R 1f It is C 1-3 Alkoxy, C 1-3 Haloalkoxy, -CN, F, or Cl. In yet another embodiment, R 1f It is C 1-3 Alkyl, C 1-3 Halogenated alkyl, F, or Cl.

[0299] In some embodiments having the above formula, R 1g It is C 2-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2、-(CH2) 0-4 -C(O)NH(R 13 -(CH2) 0-4 -C(O)N(R 13 )2, wherein the alkynyl group is optionally surrounded by one to three R 2 replace.

[0300] In another embodiment, R 1g It is -(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4- A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally separated by one to five R atoms. 5 replace.

[0301] In another embodiment, R 1g It is C 3-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy groups, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace.

[0302] In another embodiment, R 1g It is C 2-6 alkenyl, C 2-6alkynyl group, C 2-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy groups, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace.

[0303] In another embodiment, R 1g It is C 2-6 Alkyl, C 2-6 alkynyl group, C 2-6 Haloalkyl, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace.

[0304] In some embodiments having the above formula, R 1g’ It is C 2-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2、-(CH2) 0-4 -C(O)NH(R 13 ), or -(CH2) 0-4 -C(O)N(R 13 )2, wherein the alkynyl group is optionally surrounded by one to three R 2 replace.

[0305] In another embodiment, R 1g’ It is -(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6- A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 carbon cyclic group,

[0306] -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, wherein the heterocyclic group is surrounded by one to five R atoms. 5 Substitution, and the carbocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5replace.

[0307] In another embodiment, R 1g’ It is C 3-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy groups, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The heterocyclic group is replaced by one to five R... 5 Substitution, and the carbocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace.

[0308] In another embodiment, R 1g’ It is C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy groups, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The heterocyclic group is replaced by one to five R... 5 Substitution, and the carbocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace.

[0309] In another embodiment, R 1g’ It is C 2-6 Alkyl, C 2-6 alkynyl group, C 2-6 Haloalkyl, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The heterocyclic group is replaced by one to five R... 5Substitution, and the carbocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace.

[0310] In some embodiments having the above formula, R 1h It is C 4-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2、-(CH2) 0-4 -C(O)NH(R 13 -(CH2) 0-4 -C(O)N(R 13 )2, wherein the alkynyl group is optionally surrounded by one to three R 2 Replacement. In another embodiment, R 1h It is -(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -C 6-10 Aryl, -(CH2) 2-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally separated by one to five R atoms. 5 replace.

[0311] In another embodiment, R 1h It is C 4-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy groups, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -C 6-10 Aryl, -(CH2) 2-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace.

[0312] In another embodiment, R 1h It is C 4-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Haloalkyl, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4-C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -C 6-10 Aryl, -(CH2) 2-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace.

[0313] In some embodiments having the above formula, R 1h’ It is C 4-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2、-(CH2) 0-4 -C(O)NH(R 13 ), or -(CH2) 0-4 -C(O)N(R 13 )2, wherein the alkynyl group is optionally surrounded by one to three R 2 Replacement. In another embodiment, R 1h’ It is -(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -C 6-10 Aryl, -(CH2) 2-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4- A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, wherein the heterocyclic group is surrounded by one to five R atoms. 5 Substitution, and the carbocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace.

[0314] In another embodiment, R 1h’ It is C 4-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy groups, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -C 6-10Aryl, -(CH2) 2-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The heterocyclic group is replaced by one to five R... 5 Substitution, and the carbocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace.

[0315] In another embodiment, R 1h’ It is C 4-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Haloalkyl, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -C 6-10 Aryl, -(CH2) 2-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The heterocyclic group is replaced by one to five R... 5 Substitution, and the carbocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace.

[0316] In some embodiments having the above formula, R 1i It is H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2、-(CH2) 0-4 -C(O)NH(R 13 -(CH2) 0-4 -C(O)N(R 13 )2, wherein the alkynyl group is optionally surrounded by one to three R 2 Replacement. In another embodiment, R 1i It is -(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4- A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally separated by one to five R atoms. 5 replace.

[0317] In another embodiment, R 1i It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy groups, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4-C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4- A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace.

[0318] In another embodiment, R 1i It is H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0- 4NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace.

[0319] In some embodiments having the above formula, R 1j It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy group, halogen, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace.

[0320] In another embodiment, R 1j It is H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy groups, halogens, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2、-(CH2)0-4 -C(O)NH(R 13 -(CH2) 0-4 -C(O)N(R 13 )2, wherein the alkynyl group is optionally surrounded by one to three R 2 Replacement. In another embodiment, R 1j It is -(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0- 4NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally separated by one to five R atoms. 5 replace.

[0321] In another embodiment, R 1j It is H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, halogen, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0- 4NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace.

[0322] In some embodiments having the above formula, R on the benzoxazole ring 1d R 1i and R 1j Not all of them are H at the same time. In another embodiment, R 1d and R 1i It is H, and R 1j Not H. In another embodiment, R 1i and R 1j It is H, and R 1d Not H. In another embodiment, R 1d and R 1j It is H, and R 1i Not H. In another embodiment, R 1d It is H, and R 1i and R 1j Not H. In another embodiment, R 1i It is H, and R 1d and R 1j Not H. In another embodiment, R 1j It is H, and R 1d and R 1i Not H.

[0323] In some embodiments having the above formula, each R 1kIndependently selected from H and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy groups, halogens, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2、-(CH2) 0-4 -C(O)NH(R 13 ), wherein the alkynyl group is optionally surrounded by one to three R 2 Replacement. In another embodiment, each R 1k Independently selected from H,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -C(O)O(CH2) 0-4 -C 6-10 Aryl, or -C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally separated by one to five R atoms. 5 replace.

[0324] In another embodiment, each R 1k Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy groups, halogens, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2、-(CH2) 0-4 -C(O)NH(R 13 -(CH2) 0-4 -C(O)N(R 13)2, wherein the alkynyl group is optionally surrounded by one to three R 2 Replacement. In yet another embodiment, each R 1k Independently selected from -(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -C(O)O(CH2) 0-4 -C 6-10 Aryl, or -C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally separated by one to five R atoms. 5 replace.

[0325] In some embodiments having the above formula, each R 2 Independently, it is NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, -C(O)NH2, -C(O)NH(C 1-4 Alkyl), -C(O)N(C 1-4 alkyl)2、-NHC(O)R 9 -N(R) 9 )C(O)(R 9 -NHS(O)2R 9 , or -NR 9 S(O)2R 9 In another embodiment, each R 2 Independently, it is NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 alkyl)2、-NHC(O)R 9 -N(R) 9 )C(O)(R 9 ), or -NHS(O)2R 9 In yet another embodiment, each R 2Independently, it is NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 alkyl)2、-NHC(O)R 9 -N(R) 9 )C(O)(R 9 ), or -NR 9 S(O)2R 9 In another embodiment, each R 2 Independently, it is NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 alkyl)2、-NHC(O)R 9 -NHS(O)2R 9 , or -NR 9 S(O)2R 9 In yet another embodiment, each R 2 Independently, it is NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 Alkyl)2, -N(R 9 )C(O)(R 9 -NHS(O)2R 9 , or -NR 9 S(O)2R 9 In another embodiment, each R 2 Independently, it is NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -NHC(O)R 9 -N(R) 9 )C(O)(R 9 -NHS(O)2R 9 , or -NR 9 S(O)2R 9 In another embodiment, each R 2 Independently, it is NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -C(O)NH2, -C(O)N(C1-6 alkyl)2、-NHC(O)R 9 -N(R) 9 )C(O)(R 9 -NHS(O)2R 9 , or -NR 9 S(O)2R 9 .

[0326] In another embodiment, each R 2 Independently, it is NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 alkyl)2、-C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 alkyl)2、-NHC(O)R 9 -N(R) 9 )C(O)(R 9 -NHS(O)2R 9 , or -NR 9 S(O)2R 9 In yet another embodiment, each R 2 Independently, it is NH2, -NH(C) 1-6 Alkyl), -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 alkyl)2、-NHC(O)R 9 -N(R) 9 )C(O)(R 9 -NHS(O)2R 9 , or -NR 9 S(O)2R 9 In another embodiment, each R 2 Independently, it is NH2, -N(C) 1-6 Alkyl)2, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 alkyl)2、-NHC(O)R 9 -N(R) 9 )C(O)(R 9 -NHS(O)2R 9 , or -NR 9 S(O)2R 9 In yet another embodiment, each R 2 Independently is -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, -C(O)NH2, -C(O)NH(C 1-6Alkyl), -C(O)N(C 1-6 alkyl)2、-NHC(O)R 9 -N(R) 9 )C(O)(R 9 -NHS(O)2R 9 , or -NR 9 S(O)2R 9 In another embodiment, each R 2 Independently, it is NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 alkyl)2、-NHC(O)R 9 、or -N(R 9 )C(O)(R 9 In yet another embodiment, each R 2 Independently, it is NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 alkyl)2、-NHS(O)2R 9 , or -NR 9 S(O)2R 9 In another embodiment, each R 2 Independently, it is NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -C(O)NH2, -NHC(O)R 9 -N(R) 9 )C(O)(R 9 -NHS(O)2R 9 , or -NR 9 S(O)2R 9 In yet another embodiment, each R 2 Independently, they are NH2, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 alkyl)2、-NHC(O)R 9 -N(R) 9 )C(O)(R 9 -NHS(O)2R 9 , or -NR 9 S(O)2R 9 .

[0327] In some embodiments having the above formula, R 3 Is it H or C? 1-3 Alkyl group. In another embodiment, R 3 It is C 1-6 Alkyl group. In yet another embodiment, R 3 Is it H or C? 2-6 Alkyl group. In another embodiment, R 3 Is it H or C? 3-6 Alkyl group. In yet another embodiment, R 3 It is H, methyl, ethyl, n-propyl, or isopropyl. In another embodiment, R 3 It is H, ethyl, n-propyl, or isopropyl. In yet another embodiment, R 3 It is H, n-propyl, or isopropyl. In another embodiment, R 3 It is H, methyl, or ethyl. In yet another embodiment, R 3 It is H or methyl. In another embodiment, R 3 It's H.

[0328] In some embodiments having the above formula, R 4 Is it H or C? 1-3 Alkyl group. In another embodiment, R 4 It is C 1-6 Alkyl group. In yet another embodiment, R 4 Is it H or C? 2-6 Alkyl group. In another embodiment, R 4 Is it H or C? 3-6 Alkyl group. In yet another embodiment, R 4 It is H, methyl, ethyl, n-propyl, or isopropyl. In another embodiment, R 4 It is H, ethyl, n-propyl, or isopropyl. In yet another embodiment, R 4 It is H, n-propyl, or isopropyl. In another embodiment, R 4 It is H, methyl, or ethyl. In yet another embodiment, R 4 It is H or methyl. In another embodiment, R 4 It's H.

[0329] In some embodiments having the above formula, each R 5 C is independent 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy groups, halogens, -OH, -C(O)H, -C(O)(C 1-6 Alkyl), -C(O)(C6-10 aryl), -C(O) (5- or 6-membered heteroaryl), -C(O) (C 3-7 Carbocyclic group), -C(O) (5- to 7-membered heterocyclic groups), -(CH2) 0-3 C(O)OC 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 alkyl)2,-NHC(O)R 9 , -N(R 9 )C(O)(R 9 ), -NH2, -NH(C 1-6 Alkyl), -N(C) 1-6 alkyl)2,-NHC(O)O(R 9 ), -N(R 9 )C(O)O(R 9 ), -NHS(O)2R 9 -NR 9 S(O)2R 9 , -S(O) q NHR 9 , -S(O) q N(R 9 )2,-S(O) q R 9 C 1-6 Hydroxyalkyl, -O(CH2) 1-3 CN, -(CH2) 0-6 -C 3-7 Carbocyclic group, CN, -O(CH2) 0-3 (C6-C 10 Aryl, adamantyl, -O(CH2) 0-3 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 -C 6-10 Aryl, and -(CH2) 0-6 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally surrounded by one to three R atoms. 6 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to four R groups. 8 Replace; or two Rs 5 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 3-7 A carbocyclic group or a 5- to 7-membered heterocyclic group comprising 1-3 heteroatoms selected from O, N, and S, wherein the carbocyclic group and the heterocyclic group are optionally separated by one to three R atoms.6 Replace; or two Rs 5 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 aryl or a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; or two R... 5 When they are on the same atom, they together with the atoms to which they are attached form C. 3-7 A spirocarbocyclic group or a 5- to 7-membered spiroheterocyclic group comprising 1-3 heteroatoms selected from O, N, and S, wherein the spirocarbocyclic group and the spiroheterocyclic group are optionally separated by one to four R atoms. 10 Replace; or two Rs 5 When on the same carbon atom, it forms =(O);

[0330] In another embodiment, each R 5 C is independent 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy groups, halogens, -OH, -C(O)H, -C(O)(C 1-6 Alkyl), -C(O)(C 6-10 aryl), -C(O) (5- or 6-membered heteroaryl), -C(O) (C 3-7 (Carbocyclic group), -C(O) (5- to 7-membered heterocyclic group)-(CH2) 0-3 C(O)OC 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 alkyl)2,-NHC(O)R 9 , -N(R 9 )C(O)(R 9 ), -NH2, -NH(C 1-6 Alkyl), -N(C) 1-6 alkyl)2,-NHC(O)O(R 9 ), -N(R 9 )C(O)O(R 9 ), -NHS(O)2R 9 -NR 9 S(O)2R 9 , -S(O) q NHR 9 , -S(O) q N(R 9 )2,-S(O) q R 9 C 1-6Hydroxyalkyl, -O(CH2) 1-3 CN, CN, -O(CH2) 0-6 -C 3-7 Carbocyclic group, -O(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -O(CH2) 0-3 (C6-C 10 Aryl, adamantyl, -O(CH2) 0-3 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 -C 6-10 Aryl, and -(CH2) 0-6 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally surrounded by one to three R atoms. 6 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to four R groups. 8 Replace; or two Rs 5 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 3-7 A carbocyclic group or a 5- to 7-membered heterocyclic group comprising 1-3 heteroatoms selected from O, N, and S, wherein the carbocyclic group and the heterocyclic group are optionally separated by one to three R atoms. 6 Replace; or two Rs 5 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 aryl or a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; or two R... 5 When they are on the same atom, they together with the atoms to which they are attached form C. 3-7 A spirocarbocyclic group or a 5- to 7-membered spiroheterocyclic group comprising 1-3 heteroatoms selected from O, N, and S, wherein the spirocarbocyclic group and the spiroheterocyclic group are optionally separated by one to four R atoms. 10 Replace; or two Rs 5 When on the same carbon atom, it forms =(O).

[0331] In another embodiment, each R 5 C is independent 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy groups, halogens, -OH, -C(O)H, -C(O)(C1-6 Alkyl), -C(O)(C 6-10 aryl), -C(O) (5- or 6-membered heteroaryl), -C(O) (C 3-7 (Carbocyclic group), -C(O) (5- to 7-membered heterocyclic group)-(CH2) 0-3 C(O)OC 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 alkyl)2,-NHC(O)R 9 , -N(R 9 )C(O)(R 9 ), -NH2, -NH(C 1-6 Alkyl), -N(C) 1-6 alkyl)2,-NHC(O)O(R 9 ), -N(R 9 )C(O)O(R 9 ), -NHS(O)2R 9 -NR 9 S(O)2R 9 , -S(O) q NHR 9 , -S(O) q N(R 9 )2,-S(O) q R 9 C 1-6 Hydroxyalkyl, -O(CH2) 1-3 CN, CN, -O(CH2) 0-6 -C 3-7 Carbocyclic group, -O(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -O(CH2) 0-3 (C6-C 10 Aryl, adamantyl, -O(CH2) 0-3 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 -C 6-10 Aryl, and -(CH2) 0-6 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally surrounded by one to three R atoms. 6 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to four R groups. 8replace.

[0332] In another embodiment, two R 5 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 3-7 A carbocyclic group or a 5- to 7-membered heterocyclic group comprising 1-3 heteroatoms selected from O, N, and S, wherein the carbocyclic group and the heterocyclic group are optionally separated by one to three R atoms. 6 Replace; or two Rs 5 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 aryl or a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; or two R... 5 When they are on the same atom, they together with the atoms to which they are attached form C. 3-7 A spirocarbocyclic group or a 5- to 7-membered spiroheterocyclic group comprising 1-3 heteroatoms selected from O, N, and S, wherein the spirocarbocyclic group and the spiroheterocyclic group are optionally separated by one to four R atoms. 10 Replace; or two Rs 5 When on the same carbon atom, it forms =(O).

[0333] In another embodiment, two R 5 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 3-7 A carbocyclic group or a 5- to 7-membered heterocyclic group comprising 1-3 heteroatoms selected from O, N, and S, wherein the carbocyclic group and the heterocyclic group are optionally separated by one to three R atoms. 6 Replacement. In yet another embodiment, the two R... 5 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 The aryl group or a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S. In another embodiment, the two R groups... 5 When they are on the same atom, they together with the atoms to which they are attached form C. 3-7 A spirocarbocyclic group or a 5- to 7-membered spiroheterocyclic group comprising 1-3 heteroatoms selected from O, N, and S, wherein the spirocarbocyclic group and the spiroheterocyclic group are optionally separated by one to four R atoms. 10 Replacement. In yet another embodiment, the two R... 5 When on the same carbon atom, it forms =(O).

[0334] In another embodiment, each R 5 C is independent 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy groups, halogens, -OH, -C(O)H, -C(O)(C1-6 Alkyl), -C(O)(C 6-10 aryl), -C(O) (5- or 6-membered heteroaryl), -C(O) (C 3-7 (Carbocyclic group), -C(O) (5- to 7-membered heterocyclic group)-(CH2) 0-3 C(O)OC 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 alkyl)2、-NHC(O)R 9 -N(R) 9 )C(O)(R 9 -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2、-NHC(O)O(R 9 ), -N(R 9 )C(O)O(R 9 -NHS(O)2R 9 -NR 9 S(O)2R 9 -S(O) q NHR 9 -S(O) q N(R 9 )2、-S(O) q R 9 C 1-6 Hydroxyalkyl, -O(CH2) 1-3 CN, wherein the alkyl group is optionally surrounded by one to three R 6 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to four R groups. 8 Replace; or two Rs 5 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 3-7 A carbocyclic group or a 5- to 7-membered heterocyclic group comprising 1-3 heteroatoms selected from O, N, and S, wherein the carbocyclic group and the heterocyclic group are optionally separated by one to three R atoms. 6 Replace; or two Rs 5 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 aryl or a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; or two R... 5 When they are on the same atom, they together with the atoms to which they are attached form C. 3-7 A spirocarbocyclic group or a 5- to 7-membered spiroheterocyclic group comprising 1-3 heteroatoms selected from O, N, and S, wherein the spirocarbocyclic group and the spiroheterocyclic group are optionally separated by one to four R atoms. 10 Replace; or two Rs 5When on the same carbon atom, it forms =(O).

[0335] In another embodiment, each R 5 Independently, it is -O(CH2). 0-6 -C 3-7 Carbocyclic group, -O(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -O(CH2) 0-3 (C6-C 10 Aryl, adamantyl, -O(CH2) 0-3 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 -C 6-10 Aryl, and -(CH2) 0-6 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the carbocyclic group, heterocyclic group, aryl group, and heteroaryl group are optionally separated by one to four R atoms. 8 Replace; or two Rs 5 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 3-7 A carbocyclic group or a 5- to 7-membered heterocyclic group comprising 1-3 heteroatoms selected from O, N, and S, wherein the carbocyclic group and the heterocyclic group are optionally separated by one to three R atoms. 6 Replace; or two Rs 5 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 aryl or a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; or two R... 5 When they are on the same atom, they together with the atoms to which they are attached form C. 3-7 A spirocarbocyclic group or a 5- to 7-membered spiroheterocyclic group comprising 1-3 heteroatoms selected from O, N, and S, wherein the spirocarbocyclic group and the spiroheterocyclic group are optionally separated by one to four R atoms. 10 Replace; or two Rs 5 When on the same carbon atom, it forms =(O).

[0336] In some embodiments having the above formula, R 6 It is -NH2, -NH(C 1-4 Alkyl), -N(C) 1-4 Alkyl)2,C 6-10 aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms.7 Replacement. In another embodiment, R 6 It is -NH2, -NH(C 1-6 alkyl), or -N(C) 1-6 Alkyl)2. In another embodiment, R 6 It is C 6-10 The aryl group or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms. 7 Replacement. In yet another embodiment, R 6 It is -NH2, -NH(C 1-6 Alkyl), -N(C) 1-6 alkyl)2phenyl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally surrounded by one to three R atoms. 7 Replacement. In another embodiment, R 6 It is -NH2, -NH(C 1-6 Alkyl), -N(C) 1-6 Alkyl)2,C 6-10 aryl, or a 5-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are optionally separated by one to three R atoms. 7 Replacement. In yet another embodiment, R 6 It is -NH2, -NH(C 1-6 Alkyl), -N(C) 1-6 Alkyl)2,C 6-10 aryl, or a 6-membered heteroaryl comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl are optionally separated by one to three R atoms. 7 Replacement. In another embodiment, R 6 It is -NH2, -NH(C 1-6 Alkyl), -N(C) 1-6 alkyl)2phenyl, or a 5-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the phenyl and heteroaryl group are optionally surrounded by one to three R atoms. 7 replace.

[0337] In another embodiment, R 6 It is -NH2, -NH(C 1-6 Alkyl), -N(C) 1-6 alkyl)2phenyl, or a 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the phenyl and heteroaryl group are optionally separated by one to three R atoms. 7 Replacement. In yet another embodiment, R 6 It is -NH2, -NH(C 1-6 alkyl), -N(C) 1-6alkyl)2, or optionally with one to three R 7 Replacement C 6-10 Aryl. In another embodiment, R 6 It is -NH2, -NH(C 1-6 Alkyl), -N(C) 1-6 Alkyl group 2, comprising 1-3 heteroatoms selected from O, N and S and optionally surrounded by one to three R atoms. 7 The substituted 5- or 6-membered heteroaryl group. In another embodiment, R 6 It is -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 alkyl)2, or optionally with one to three R 7 Substituted phenyl. In yet another embodiment, R 6 It is -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 alkyl)2, optionally with one to three R 7 The substituted 5-membered heteroaryl group. In another embodiment, R 6 It is -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 alkyl)2, optionally with one to three R 7 Substituted 6-membered heteroaryl group.

[0338] In some embodiments having the above formula, each R 7 C is independent 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, halogen, or C 6-10 Aryl. In another embodiment, each R 7 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy, halogen, or phenyl. In yet another embodiment, each R 7 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy groups, or halogens. In another embodiment, each R 7 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy, or C 6-10 Aryl. In yet another embodiment, each R7 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogen, or C 6-10 Aryl. In another embodiment, each R 7 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-3 Halogenated alkoxy, halogen, or C 6-10 Aryl. In yet another embodiment, each R 7 C is independent 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy, halogen, or C 6-10 Aryl. In another embodiment, each R 7 C is independent 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy, halogen, or C 6-10 Aryl. In yet another embodiment, each R 7 C is independent 1-6 Alkyl, C 1-6 Halogenated alkyl, halogen, or C 6-10 Aryl. In another embodiment, each R 7 C is independent 1-6 Alkoxy, C 1-3 Halogenated alkoxy, halogen, or C 6-10 Aryl. In yet another embodiment, each R 7 C is independent 1-6 Alkyl, C 1-6 Alkoxy, halogen, or C 6-10 Aryl. In another embodiment, each R 7 C is independent 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Or C 6-10 Aryl. In yet another embodiment, each R 7 C is independent 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, halogen, or phenyl.

[0339] In some embodiments having the above formula, each R 8 C is independent 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C1-3 Haloalkoxy, halogen, or -OH. In another embodiment, each R 8 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or halogen. In yet another embodiment, each R 8 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or -OH. In another embodiment, each R 8 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, halogen, or -OH. In yet another embodiment, each R 8 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, halogen, or -OH. In another embodiment, each R 8 C is independent 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, or -OH. In yet another embodiment, each R 8 C is independent 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, or -OH. In another embodiment, each R 8 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, halogen, or -OH. In yet another embodiment, each R... 8 C is independent 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, or -OH. In another embodiment, each R 8 C is independent 1-6 Alkyl, C 1-6 Alkyl, halogen, or -OH. In yet another embodiment, each R 8 It is independently a halogen or -OH. In another embodiment, each R 8 C is independent 1-6 Alkyl, C 1-6 Halogenated alkyl groups or halogens.

[0340] In some embodiments having the above formula, R 9 It is C1-4 Alkyl, C 1-4 Haloalkyl groups, comprising 1-3 heteroatoms selected from O, N, and S, consisting of 5- to 7-membered heterocyclic groups, C 6-10 aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms. 11 Replacement. In another embodiment, R 9 It is C 1-6 Alkyl, C 1-6 A haloalkyl group, comprising a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, a phenyl group, or a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, wherein the phenyl group and the heteroaryl group are optionally surrounded by one to three R atoms. 11 Replacement. In another embodiment, R 9 It is C 1-6 Alkyl or C 1-6 Haloalkyl. In yet another embodiment, R 9 It is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, C 6-10 aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms. 11 Replacement. In another embodiment, R 9 It is C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms. 11 Replacement. In yet another embodiment, R 9 It is C 1-6 Alkyl, C 1-6 Haloalkyl groups comprising 5- to 7-membered heterocyclic groups containing 1-3 heteroatoms selected from O, N, and S, or comprising 1-3 5- or 6-membered heteroaryl groups containing 1-3 heteroatoms selected from O, N, and S, wherein the heteroaryl group is optionally surrounded by one to three R groups. 11 Replacement. In another embodiment, R 9 It is C 1-6 Alkyl, C 1-6 Haloalkyl groups comprising 1-3 heteroatoms selected from O, N, and S, consisting of 5- to 7-membered heterocyclic groups, or 5- or 6-membered heteroaryl groups, wherein the heteroaryl group is optionally surrounded by one to three R atoms. 11 replace.

[0341] In another embodiment, R 9 It is C 1-6 Alkyl, C 1-6A haloalkyl group, comprising a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, a phenyl group, or a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, wherein the phenyl group and the heteroaryl group are optionally surrounded by one to three R atoms. 11 Replacement. In yet another embodiment, R 9 It is C 1-6 Alkyl, C 1-6 A haloalkyl group, a 5- to 7-membered heterocyclic group comprising 1-3 heteroatoms selected from O, N, and S, a phenyl group, or a 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally surrounded by one to three R atoms. 11 Replacement. In another embodiment, R 9 It is C 1-6 Alkyl, C 1-6 A haloalkyl group, a 5- to 7-membered heterocyclic group comprising 1-3 heteroatoms selected from O, N, and S, a phenyl group, or a 5-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the phenyl and heteroaryl groups are optionally surrounded by one to three R atoms. 11 Replacement. In yet another embodiment, R 9 It is C 1-6 Alkyl, C 1-6 A haloalkyl group, a 5- or 6-membered heterocyclic group comprising 1-3 heteroatoms selected from O, N, and S, a phenyl group, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the phenyl group and the heteroaryl group are optionally surrounded by one to three R atoms. 11 Replacement. In another embodiment, R 9 It is C 1-6 Alkyl, C 1-6 A haloalkyl group, a 6- or 7-membered heterocyclic group comprising 1-3 heteroatoms selected from O, N, and S, a phenyl group, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the phenyl group and the heteroaryl group are optionally surrounded by one to three R atoms. 11 Replacement. In yet another embodiment, R 9 It is C 1-6 Alkyl, C 1-6 A haloalkyl group, a 5- to 7-membered heterocyclic group comprising 1-3 heteroatoms selected from O, N, and S, a phenyl group, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally surrounded by one to three R atoms. 11 Replacement. In another embodiment, R 9 It is C 1-6 Alkyl, C 1-6 Haloalkyl, or a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, R 9 It is C 1-6 Alkyl, C 1-6Halogenated alkyl, or optionally with one to three R 11 Substituted phenyl. In another embodiment, R 9 It is C 1-6 Alkyl, C 1-6 Haloalkyl, or a 5- or 6-membered heteroaryl group comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the heteroaryl group is optionally surrounded by one to three R atoms. 11 replace.

[0342] In some embodiments having the above formula, each R 10 It is C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy or halogen; or two Rs 10 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 The aryl group or a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S. In another embodiment, each R 10 It is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy or halogen. In yet another embodiment, each R 10 It is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, or C 1-6 Halogenated alkoxy groups; or two R groups 10 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 The aryl group or a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S. In another embodiment, each R 10 It is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or halogen; or two Rs 10 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 The aryl group or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, each R 10 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or halogen; or two Rs 10 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 Aryl or 5- or 6-membered heteroaryl groups containing 1-3 heteroatoms selected from O, N and S.

[0343] In another embodiment, each R 10 It is C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or halogen; or two Rs 10 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 The aryl group or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, each R 10 It is C 1-6 Alkyl, C 1-6 Halogenated alkyl groups or halogens; or two R groups 10 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 The aryl group or a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S. In another embodiment, each R 10 It is C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or halogen; or two Rs 10 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 The aryl group or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, each R 10 It is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or halogen; or two Rs 10 When on adjacent atoms, it forms a phenyl group or a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, together with the atoms to which they are attached.

[0344] In another embodiment, each R 10 It is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or halogen; or two Rs 10 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 The aryl group or a 5-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, each R 10 It is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or halogen; or two Rs 10When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 The aryl group or a six-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S. In another embodiment, each R 10 It is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or halogen; or two Rs 10 When on adjacent atoms, together with the atoms to which they are attached, they form a phenyl group or a 5-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S. In another embodiment, each R 10 It is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or halogen; or two Rs 10 When on adjacent atoms, they together with the atoms to which they are attached form a phenyl group or a 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, the two R... 10 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 The aryl group or a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S. In another embodiment, the two R groups... 10 When on adjacent atoms, they together with the atoms to which they are attached form a phenyl group or a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S. In yet another embodiment, the two R... 10 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 Aryl. In another embodiment, two R 10 When on adjacent atoms, together with the atoms to which they are attached, they form a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S.

[0345] In some embodiments having the above formula, each R 11 C is independent 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, -NHC(O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(O)(C 1-6 Alkyl groups, or halogens; or two R groups. 11 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10The aryl group or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms. 12 Replacement. In another embodiment, each R 11 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-4 Halogenated alkoxy groups, -NHC(O)(C 1-6 alkyl), or -N(C) 1-6 Alkyl)C(O)(C 1-6 Alkyl); or two R 11 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 The aryl group or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms. 12 Replacement. In yet another embodiment, each R 11 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-4 Halogenated alkoxy groups, -NHC(O)(C 1-6 Alkyl groups, or halogens; or two R groups. 11 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 The aryl group or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms. 12 Replacement. In another embodiment, each R 11 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-4 Halogenated alkoxy groups, -N(C) 1-6 Alkyl)C(O)(C 1-6 Alkyl groups, or halogens; or two R groups. 11 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 The aryl group or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms. 12 replace.

[0346] In another embodiment, each R 11 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -NHC(O)(C 1-6alkyl), -N(C) 1-6 Alkyl)C(O)(C 1-6 Alkyl groups, or halogens; or two R groups. 11 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 The aryl group or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms. 12 Replacement. In yet another embodiment, each R 11 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-4 Halogenated alkoxy groups, -NHC(O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(O)(C 1-6 Alkyl groups, or halogens; or two R groups. 11 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 The aryl group or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms. 12 Replacement. In another embodiment, each R 11 C is independent 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 Halogenated alkoxy groups, -NHC(O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(O)(C 1-6 Alkyl groups, or halogens; or two R groups. 11 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 The aryl group or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms. 12 replace.

[0347] In another embodiment, each R 11 C is independent 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-4 Halogenated alkoxy groups, -NHC(O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(O)(C 1-6 Alkyl groups, or halogens; or two R groups. 11 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10The aryl group or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms. 12 Replacement. In yet another embodiment, each R 11 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-4 Halogenated alkoxy groups, -NHC(O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(O)(C 1-6 Alkyl groups, or halogens; or two R groups. 11 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 The aryl group or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms. 12 Replacement. In another embodiment, each R 11 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-4 Halogenated alkoxy groups, -NHC(O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(O)(C 1-6 Alkyl groups, or halogens; or two R groups. 11 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 The aryl group or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms. 12 replace.

[0348] In another embodiment, each R 11 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-4 Halogenated alkoxy groups, -NHC(O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(O)(C 1-6 Alkyl groups, or halogens. In yet another embodiment, each R... 11 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-4 Halogenated alkoxy or halogen; or two Rs 11 When it is on adjacent atoms, it forms C together with the atoms to which they are attached.6-10 The aryl group or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms. 12 Replacement. In another embodiment, each R 11 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, -NHC(O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(O)(C 1-6 Alkyl groups, or halogens; or two R groups. 11 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 The aryl group or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms. 12 Replacement. In yet another embodiment, each R 11 C is independent 1-6 Alkoxy, C 1-4 Halogenated alkoxy groups, -NHC(O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(O)(C 1-6 Alkyl groups, or halogens; or two R groups. 11 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 The aryl group or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms. 12 replace.

[0349] In another embodiment, each R 11 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-4 Halogenated alkoxy groups, -NHC(O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(O)(C 1-6 Alkyl groups, or halogens; or two R groups. 11 When on adjacent atoms, together with the atoms to which they are attached, they form a phenyl group or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the phenyl group and the heteroaryl group are optionally surrounded by one to three R atoms. 12 Replacement. In yet another embodiment, each R 11 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-4Halogenated alkoxy groups, -NHC(O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(O)(C 1-6 Alkyl groups, or halogens; or two R groups. 11 When on adjacent atoms, together with the atoms to which they are attached, they form a phenyl group or a 5-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, wherein the phenyl group and the heteroaryl group are optionally surrounded by one to three R atoms. 12 Replacement. In another embodiment, each R 11 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-4 Halogenated alkoxy groups, -NHC(O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(O)(C 1-6 Alkyl groups, or halogens; or two R groups. 11 When on adjacent atoms, together with the atoms to which they are attached, they form a phenyl group or a 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, wherein the phenyl group and the heteroaryl group are optionally surrounded by one to three R atoms. 12 Replacement. In yet another embodiment, the two R... 11 When on adjacent atoms, together with the atoms to which they are attached, they form a phenyl group or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the phenyl group and the heteroaryl group are optionally surrounded by one to three R atoms. 12 Replacement. In another embodiment, the two Rs 11 When on adjacent atoms, together with the atoms to which they are attached, they form an optional structure with one to three R atoms. 12 Substituted phenyl groups. In another embodiment, two R groups... 11 When on adjacent atoms, together with the atoms to which they are attached, they form a heteroatom consisting of 1-3 atoms selected from O, N, and S, and optionally surrounded by one to three R atoms. 12 Replacement of 5- or 6-membered heteroaryl groups.

[0350] In some embodiments having the above formula, each R 12 C is independent 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 alkoxy, or C 1-3 Haloalkoxy groups. In another embodiment, each R 12 C is independent 1-6 Alkyl, C 1-6 Halogenated alkyl, or C 1-6 Alkyl groups. In yet another embodiment, each R... 12 C is independent 1-6Alkyl, C 1-6 Halogenated alkyl, or C 1-3 Haloalkoxy groups. In another embodiment, each R 12 C is independent 1-6 Alkyl, C 1-6 alkoxy, or C 1-3 Haloalkoxy groups. In yet another embodiment, each R 12 C is independent 1-6 Haloalkyl, C 1-6 alkoxy, or C 1-3 Haloalkoxy groups. In another embodiment, each R 12 C is independent 1-6 Alkyl or C 1-6 Halogenated alkyl groups. In yet another embodiment, each R 12 C is independent 1-6 Alkyl or C 1-6 Alkyl groups. In another embodiment, each R 12 C is independent 1-6 Alkyl or C 1-3 Haloalkoxy groups. In yet another embodiment, each R 12 C is independent 1-6 Halogenated alkyl or C 1-6 Alkyl groups. In another embodiment, each R 12 C is independent 1-6 Halogenated alkyl or C 1-3 Haloalkoxy groups. In yet another embodiment, each R 12 C is independent 1-6 Alkoxy or C 1-3 Haloalkoxy groups. In another embodiment, each R 12 C is independent 1-6 Alkyl group. In yet another embodiment, each R 12 C is independent 1-6 Halogenated alkyl groups. In another embodiment, each R 12 C is independent 1-3 Haloalkoxy groups. In yet another embodiment, each R 12 C is independent 1-6 Alkyl group.

[0351] In some embodiments having the above formula, R 13 It is C independently each time it appears. 1-4 Alkyl, C 1-4 Haloalkyl, C 6-10 aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally surrounded by one or two C atoms. 1-6The alkoxy group is substituted, and the aryl and heteroaryl groups are optionally replaced by one to three R groups. 14 Replacement. In another embodiment, R 13 It is C independently each time it appears. 1-6 Alkyl or C 1-6 Haloalkyl, wherein the alkyl group is optionally surrounded by one or two C2 atoms. 1-6 Alkyloxy substitution. In yet another embodiment, R... 13 It is C independently each time it appears. 6-10 The aryl group or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the heteroaryl group and the heteroaryl group are optionally separated by one to three R atoms. 14 Replacement. In another embodiment, R 13 It is C independently each time it appears. 1-6 Alkyl, C 1-6 Haloalkyl, phenyl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally surrounded by one or two C atoms. 1-6 The alkoxy group is substituted, and the phenyl and heteroaryl groups are optionally replaced by one to three R groups. 14 Replacement. In yet another embodiment, R 13 It is C independently each time it appears. 1-6 Alkyl, C 6-10 aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally surrounded by one or two C atoms. 1-6 The alkoxy group is substituted, and the aryl and heteroaryl groups are optionally replaced by one to three R groups. 14 replace.

[0352] In another embodiment, R 13 It is C independently each time it appears. 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 aryl, or a 5-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally surrounded by one or two C atoms. 1-6 The alkoxy group is substituted, and the aryl and heteroaryl groups are optionally replaced by one to three R groups. 14 Replacement. In yet another embodiment, R 13 It is C independently each time it appears. 1-6 Alkyl, C 1-6 Haloalkyl, phenyl, or a 5-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally surrounded by one or two C atoms. 1-6 The alkoxy group is substituted, and the phenyl and heteroaryl groups are optionally replaced by one to three R groups. 14 Replacement. In another embodiment, R 13 It is C independently each time it appears. 1-6Alkyl, C 1-6 Haloalkyl, C 6-10 aryl, or a 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally surrounded by one or two C atoms. 1-6 The alkoxy group is substituted, and the aryl and heteroaryl groups are optionally replaced by one to three R groups. 14 Replacement. In yet another embodiment, R 13 It is C independently each time it appears. 1-6 Alkyl, C 1-6 Haloalkyl, phenyl, or a 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally surrounded by one or two C atoms. 1-6 The alkoxy group is substituted, and the phenyl and heteroaryl groups are optionally replaced by one to three R groups. 14 replace.

[0353] In some embodiments having the above formula, each R 14 C is independent 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, halogens, C 6-10 Aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, each R 14 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy groups, or halogens. In another embodiment, each R 14 C is independent 6-10 The aryl group or a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S. In another embodiment, each R 14 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy, halogen, phenyl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, each R 14 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy, C 6-10 Aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, each R 14 C is independent 1-6 Alkyl, C 1-6Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogen, C 6-10 Aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, each R 14 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-3 Halogenated alkoxy groups, halogens, C 6-10 Aryl, or a 5- or 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from O, N and S.

[0354] In another embodiment, each R 14 C is independent 1-6 Alkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy groups, halogens, C 6-10 Aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, each R 14 C is independent 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy groups, halogens, C 6-10 Aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, each R 14 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, halogen, C 6-10 Aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, each R 14 C is independent 1-6 Alkoxy, C 1-3 Halogenated alkoxy groups, halogens, C 6-10 Aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, each R 14 C is independent 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 6-10 Aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, each R 14 C is independent 1-6 Haloalkyl, C 1-3 Halogenated alkoxy groups, halogens, C 6-10 Aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S. In another embodiment, each R 14 C is independent1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy, halogen, phenyl, or a 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S. In another embodiment, each R 14 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy, halogen, phenyl, or a 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S.

[0355] In some embodiments having the above formula, R 15 Is it H or C? 1-3 Alkyl group. In another embodiment, R 15 It is C 1-6 Alkyl group. In yet another embodiment, R 15 Is it H or C? 2-6 Alkyl group. In another embodiment, R 15 Is it H or C? 3-6 Alkyl group. In yet another embodiment, R 15 It is H, methyl, ethyl, n-propyl, or isopropyl. In another embodiment, R 15 It is H, ethyl, n-propyl, or isopropyl. In yet another embodiment, R 15 It is H, n-propyl, or isopropyl. In another embodiment, R 15 It is H, methyl, or ethyl. In yet another embodiment, R 15 It is H or methyl. In another embodiment, R 15 It's H.

[0356] In some embodiments having the above formula, q is 0 or 1. In another embodiment, q is 1 or 2. In another embodiment, q is 0 or 2. In another embodiment, q is 0. In another embodiment, q is 1. In another embodiment, q is 2.

[0357] In some embodiments having the above formula, R d1 It's H.

[0358] In some embodiments having the above formula, R d1 It is H, and R d2 It's H.

[0359] In some embodiments having the above formula, R d1 It is H, and It is a double bond.

[0360] In some embodiments having the above formula, R d1 It is H, and It is a single key.

[0361] In some embodiments having the above formula, R d2 It is H, and It is a double bond.

[0362] In some embodiments having the above formula, R d2 It is H, and It is a single key.

[0363] In some embodiments having the above formula, R d1 It is H, R d2 It is H, and It is a double bond.

[0364] In some embodiments having the above formula, R d1 It is H, R d2 It is H, and It is a single key.

[0365] In one embodiment, the compounds disclosed herein, such as those having formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (Iz), (Iaa), (Iab), (Iac), (Iad), (Iae), (Iaf), (Iag), (Iah), (Iai), (Iaj), (Iak), (Ial), or (Iam), or compounds I-1 to I-18, can be used as targeted ligase conjugates to prepare bifunctional degraders. In one embodiment, the bifunctional degrader is a compound having formula (A):

[0366]

[0367] in:

[0368] The targeting ligand is a group that can bind to a target protein (such as the target proteins in Table 1 disclosed herein);

[0369] The linker either lacks a group that covalently links the target ligand to the target ligase conjugate; and

[0370] The targeted ligase conjugate is a group capable of binding to a ligase (e.g., cerebellar protein E3 ubiquitin ligase), wherein the targeted ligase conjugate is a compound having the formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (Iz), (Iaa), (Iab), (Iac), (Iad), (Iae), (Iaf), (Iag), (Iah), (Iai), (Iaj), (Iak), (Ial), or (Iam), or compounds I-1 to I-18, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof.

[0371] Examples of the linker and target ligand and their synthesis are provided in the related U.S. Provisional Application entitled “Bifunctional Degrader and Method of Use Thereof”, filed September 16, 2019, and in designated U.S. Serial No. 62 / 901,161 (Novartis, Attorney’s File No. PAT058639-US-PSP), the entire contents of which are incorporated herein by reference.

[0372] Example 1: A compound or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer can bind to a cerebellar protein complex and alter its specificity to induce ubiquitination and degradation of the complex-associated protein.

[0373] Example 2: A compound as described in Example 1, wherein the compound comprises (i) a tris-tryptophan pocket binding moiety that binds to the tris-tryptophan pocket of the cerebellar protein E3 ligase; and (ii) a target affinity moiety covalently attached to the tris-tryptophan pocket binding moiety, the tris-tryptophan pocket binding moiety interacting with the surface of the cerebellar protein E3 ligase to alter its surface and make the ligase have affinity for the target protein.

[0374] Example 3: A compound as described in Example 1 or 2, wherein the compound has formula (I):

[0375]

[0376] Or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer, wherein:

[0377] Optionally, it is a double bond;

[0378] R d1 It is H, -CH2OC(O)R 15 -CH2OP(O)OHOR 15 、or -CH2OP(O)(R 15 )2;

[0379] R d2 It is H, C 1-6 Alkyl, halogen, C 1-6 Halogenated alkyl, or C 1-6 Heteroalkyl;

[0380] R d3 yes

[0381] A 1 It is a 5- or 6-membered heterocyclic group that optionally contains 1-3 additional heteroatoms selected from O, N, and S, or optionally contains 1-3 heteroatoms selected from NR. 1k The other heteroatoms of O and S are surrounded by one to three R atoms. 1d Substituted 5-membered heteroaryl groups;

[0382] A 2 It is C 5-7 The carbon cyclo group or contains 1-3 radicals selected from N and NR 1k Five- to seven-membered heterocyclic groups of O and S heteroatoms, wherein the carbocyclic group and the heterocyclic group are separated by one to three R atoms. 1d replace;

[0383] X 1 It is NR 4 Or S;

[0384] X 2 and X 2a Each is CR independently 1a Or N;

[0385] Each X 3 Independently is CR 1d Or N; where no more than two X's 3 It is N;

[0386] Each X 4 Independently is CR 1d Or N, where at least one X 4 It is N, and there are no more than two X's. 4 It is N;

[0387] Each X 5 Independently is CR 1a Or N; where no more than two X's 5 It is N;

[0388] X 6 It is NR 1k , O or S;

[0389] X 7 It is NR 4 , O or S;

[0390] R 1a and R 1b H and C are independent of each other. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -CN, F or Cl;

[0391] R 1c It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy group, halogen, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0392] Each R 1d Independently selected from H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy group, halogen, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5replace;

[0393] R 1e It is C 2-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -CN, F or Cl;

[0394] R 1f It is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -CN, F or Cl;

[0395] R 1g It is C 2-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy groups, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0- 4NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4- A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0396] R 1h It is C 4-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy groups, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -C 6-10Aryl, -(CH2) 2-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0397] R 1iIt is H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy groups, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0398] R 1j It is H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy group, halogen, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0399] R on the benzoxazole ring 1d R 1i and R 1j Not all of them are H at the same time;

[0400] Each R 1k Independently selected from H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy group, halogen, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -C(O)O(CH2) 0-4 -C 6-10 Aryl, or -C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0401] Each R 2 Independently, it is NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 alkyl)2、-NHC(O)R 9 -N(R) 9 )C(O)(R 9 -NHS(O)2R 9 , or -NR 9 S(O)2R 9 ;

[0402] R 3 Is it H or C? 1-6 alkyl;

[0403] R 4 Is it H or C? 1-6 alkyl;

[0404] Each R 5 C is independent 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6Alkoxy, C 1-3 Halogenated alkoxy groups, halogens, -OH, -C(O)H, -C(O)(C 1-6 Alkyl), -C(O)(C 6-10 aryl), -C(O) (5- or 6-membered heteroaryl), -C(O) (C 3-7 (Carbocyclic group), -C(O) (5- to 7-membered heterocyclic group)-(CH2) 0-3 C(O)OC 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 alkyl)2,-NHC(O)R 9 , -N(R 9 )C(O)(R 9 ), -NH2, -NH(C 1-6 Alkyl), -N(C) 1-6 alkyl)2,-NHC(O)O(R 9 ), -N(R 9 )C(O)O(R 9 ), -NHS(O)2R 9 -NR 9 S(O)2R 9 , -S(O) q NHR 9 , -S(O) q N(R 9 )2,-S(O) q R 9 C 1-6 Hydroxyalkyl, -O(CH2) 1-3 CN, CN, -O(CH2) 0-6 -C 3-7 Carbocyclic group, -O(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -O(CH2) 0-3 (C6-C 10 Aryl, adamantyl, -O(CH2) 0-3 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 -C 6-10 Aryl, and -(CH2) 0-6 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally surrounded by one to three R atoms.6 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to four R groups. 8 Replace; or two Rs 5 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 3-7 A carbocyclic group or a 5- to 7-membered heterocyclic group comprising 1-3 heteroatoms selected from O, N, and S, wherein the carbocyclic group and the heterocyclic group are optionally separated by one to three R atoms. 6 Replace; or two Rs 5 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 aryl or a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; or two R... 5 When they are on the same atom, they together with the atoms to which they are attached form C. 3-7 A spirocarbocyclic group or a 5- to 7-membered spiroheterocyclic group comprising 1-3 heteroatoms selected from O, N, and S, wherein the spirocarbocyclic group and the spiroheterocyclic group are optionally separated by one to four R atoms. 10 Replace; or two Rs 5 When on the same carbon atom, it forms =(O);

[0405] R 6 It is -NH2, -NH(C 1-6 Alkyl), -N(C) 1-6 Alkyl)2,C 6-10 aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms. 7 replace;

[0406] Each R 7 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy, halogen, or C 6-10 Aryl;

[0407] Each R 8 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, or -OH;

[0408] R 9 It is C 1-6 Alkyl, C 1-6 Haloalkyl groups, comprising 1-3 heteroatoms selected from O, N, and S, consisting of 5- to 7-membered heterocyclic groups, C 6-10aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms. 11 replace;

[0409] Each R 10 It is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, or halogens; or

[0410] Two Rs 10 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 Aryl or 5- or 6-membered heteroaryl groups containing 1-3 heteroatoms selected from O, N, and S;

[0411] Each R 11 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -NHC(O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(O)(C 1-6 Alkyl groups, or halogens; or

[0412] Two Rs 11 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 The aryl group or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms. 12 replace;

[0413] Each R 12 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, or C 1-3 Halogenated alkoxy groups;

[0414] R 13 It is C independently each time it appears. 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally surrounded by one or two C atoms. 1-6 The alkoxy group is substituted, and the aryl and heteroaryl groups are optionally replaced by one to three R groups. 14 replace;

[0415] Each R 14 C is independent1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy groups, halogens, C 6-10 Aryl, or a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S;

[0416] R 15 Is it H or C? 1-6 Alkyl; and

[0417] q can be 0, 1, or 2.

[0418] Example 4: The compound as described in Example 3, wherein R d1 It's H.

[0419] Example 5: A compound as described in Example 3, wherein R d1 It is -CH2OC(O)R 15 -CH2OP(O)OHOR 15 、or -CH2OP(O)(R 15 )2.

[0420] Example 6: A compound as described in any one of Examples 1-5, wherein R d2 It's H.

[0421] Example 7: A compound as described in any one of Examples 1-6, wherein R d1 and R d2 Each is H independently.

[0422] Example 8: A compound as described in any one of Examples 1-7, wherein R 1d It's H.

[0423] Example 9: A compound as described in any one of Examples 1-8, wherein R d3 yes

[0424]

[0425]

[0426]

[0427]

[0428]

[0429] Example 10: A compound as described in any one of Examples 1-9, wherein R d3 yes

[0430]

[0431]

[0432]

[0433] Example 11: A compound as described in any one of Examples 1-10, wherein the compound has a formula selected from the following:

[0434]

[0435]

[0436] Or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer.

[0437] Example 12: A compound as described in any one of Examples 1-11, wherein the compound is selected from:

[0438] 1-(benzofuran-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0439] 1-(6-ethynylbenzofuran-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0440] 1-(5-methylbenzofuran-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0441] 1-(5-Iodobenzofuran-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0442] 1-(6-Iodobenzofuran-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0443] Phenyl(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzofuran-5-yl)carbamate;

[0444] 1-(6-chloropyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0445] 1-(7-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0446] 1-(7-(1-(4-(tert-butyl)benzoyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; and

[0447] 1-(6-(1-benzylpiperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0448] Or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer.

[0449] Example 13: A pharmaceutical composition comprising a compound as described in any one of Examples 1-12 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.

[0450] Example 14: A pharmaceutical composition as described in Example 13, the pharmaceutical composition further comprising at least one other pharmaceutical agent.

[0451] Example 15: The pharmaceutical composition as described in Example 13 or Example 14 is used for the treatment or prevention of cerebellar protein-mediated disorders, diseases, or conditions.

[0452] Example 16: The pharmaceutical composition as described in Example 13 or Example 14 is used for the treatment or prevention of respiratory disorders, proliferative disorders, autoimmune disorders, autoinflammatory disorders, inflammatory disorders, neurological disorders, and infectious diseases or disorders.

[0453] Example 17: A method for regulating cerebellar proteins in a biological sample, the method comprising contacting the sample with a compound as described in any one of Examples 1-12 or a pharmaceutically acceptable salt thereof.

[0454] Example 18: A method for binding to and altering the specificity of a cerebellar protein complex to induce ubiquitination and degradation of a complex-associated protein selected from the groups listed in Table 1 in a biological sample, the method comprising contacting the sample with a compound as described in any one of Examples 1-12 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0455] Example 19: A method for treating or preventing cerebellar protein-mediated disorders, diseases, or conditions in a subject, the method comprising administering to the subject a compound as described in any one of Examples 1-12 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0456] Example 20: The method as described in Example 19, wherein the disorder, disease, or symptom is a respiratory disorder, a proliferative disorder, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a neurological disorder, or an infectious disease or disorder.

[0457] Example 21: The method as described in Example 20, wherein the disorder, disease, or symptom is a proliferative disorder.

[0458] Example 22: The method as described in Example 21, wherein the proliferative disorder is cancer.

[0459] Example 23: The method as described in Example 20, wherein the disorder, disease, or symptom is a neurological disorder.

[0460] Example 24: A method for treating or preventing respiratory disorders, proliferative disorders, autoimmune disorders, autoinflammatory disorders, inflammatory disorders, neurological disorders, or infectious diseases or disorders in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of Examples 1-12.

[0461] Example 25: The method as described in Example 24, wherein the disorder or disease is a proliferative disorder.

[0462] Example 26: The method as described in Example 25, wherein the proliferative disorder is cancer.

[0463] Example 27: The method as described in Example 24, wherein the disorder or disease is a neurological disorder.

[0464] Example 28: Use of any compound of any one of Examples 1-12 or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer in the preparation of a medicament for the treatment or prevention of respiratory disorders, proliferative disorders, autoimmune disorders, autoinflammatory disorders, inflammatory disorders, neurological disorders, or infectious diseases or disorders in subjects in need.

[0465] Example 29: Use of the compounds described in Examples 1-12, or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, for the treatment or prevention of cancer.

[0466] Example 30: A method for degrading a target protein in a biological sample, the method comprising contacting a compound as described in any one of Examples 1-12 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the target protein is selected from the group listed in Table 1.

[0467] Example 31: A method for treating or preventing target protein-mediated disorders, diseases, or conditions in a subject, the method comprising administering to the subject a compound as described in any one of Examples 1-12 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0468] Example 32: The method as described in Example 31, wherein the disorder, disease, or symptom is a proliferative disorder.

[0469] Example 33: The method as described in Example 32, wherein the proliferative disorder is cancer.

[0470] Example 34: The method as described in Example 31, wherein the disorder, disease, or symptom is a neurological disorder.

[0471] Example 35: A compound selected from:

[0472]

[0473]

[0474] Example 35A: A compound selected from:

[0475]

[0476]

[0477]

[0478]

[0479] Or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer.

[0480] Example 36: A pharmaceutical composition comprising a compound as described in Example 35 or Example 35A, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.

[0481] Example 37: A pharmaceutical composition as described in Example 36, the pharmaceutical composition further comprising at least one additional pharmaceutical agent.

[0482] Example 38: The pharmaceutical composition as described in Example 36 or Example 37 is used for the treatment or prevention of cerebellar protein-mediated disorders, diseases, or conditions.

[0483] Example 39: The pharmaceutical composition as described in Example 36 or Example 37 is used for the treatment or prevention of respiratory disorders, proliferative disorders, autoimmune disorders, autoinflammatory disorders, inflammatory disorders, neurological disorders, or infectious diseases or disorders.

[0484] Example 40: A method for inhibiting cerebellar proteins in a biological sample, the method comprising contacting the sample with a compound as described in Example 35 or Example 35A, or a pharmaceutically acceptable salt thereof.

[0485] Example 41: A method for binding to and altering the specificity of a cerebellar protein complex to induce ubiquitination and degradation of a complex-associated protein in a biological sample selected from the groups listed in Table 1, the method comprising contacting the sample with a compound as described in Example 35 or Example 35A, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0486] Example 42: A method for treating or preventing cerebellar protein-mediated disorders, diseases, or conditions in a subject, the method comprising administering to the subject a compound as described in Example 35 or Example 35A, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0487] Example 43: The method as described in Example 42, wherein the disorder, disease, or symptom is a respiratory disorder, a proliferative disorder, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a neurological disorder, or an infectious disease or disorder.

[0488] Example 44: The method as described in Example 43, wherein the disorder, disease, or symptom is a proliferative disorder.

[0489] Example 45: The method as described in Example 44, wherein the proliferative disorder is cancer.

[0490] Example 46: The method as described in Example 43, wherein the disorder, disease, or symptom is a neurological disorder.

[0491] Example 47: A method for treating or preventing respiratory disorders, proliferative disorders, autoimmune disorders, autoinflammatory disorders, inflammatory disorders, neurological disorders, or infectious diseases or disorders in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound as described in Example 35 or Example 35A, or a pharmaceutically acceptable salt thereof.

[0492] Example 48: The method as described in Example 47, wherein the disorder or disease is a proliferative disorder.

[0493] Example 49: The method as described in Example 48, wherein the proliferative disorder is cancer.

[0494] Example 50: The method as described in Example 47, wherein the disorder or disease is a neurological disorder.

[0495] Example 51: Use of the compound as described in Example 35 or Example 35A, or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer in the preparation of a medicament for the treatment or prevention of respiratory disorders, proliferative disorders, autoimmune disorders, autoinflammatory disorders, inflammatory disorders, neurological disorders, or infectious diseases or disorders in subjects in need.

[0496] Example 52: Use of the compound as described in Example 35 or Example 35A, or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer for the treatment or prevention of cancer.

[0497] Example 53: A method for degrading a target protein in a biological sample, the method comprising contacting a compound as described in Example 35 or Example 35A, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the target protein is selected from the group listed in Table 1.

[0498] Example 54: A method for treating or preventing target protein-mediated disorders, diseases, or conditions in a subject, the method comprising administering to the subject a compound as described in Example 35 or Example 35A, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0499] Example 55: The method as described in Example 54, wherein the disorder, disease, or symptom is a proliferative disorder.

[0500] Example 56: The method as described in Example 55, wherein the proliferative disorder is cancer.

[0501] Example 57: The method as described in Example 54, wherein the disorder, disease, or symptom is a neurological disorder.

[0502] Example 58: A method for treating or preventing cancer in a subject, the method comprising administering to the subject a compound as described in Example 35 or Example 35A, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0503] Example 59: The compound of any one of Examples 1-12, or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer, for use in treating or preventing respiratory disorders, proliferative disorders, autoimmune disorders, autoinflammatory disorders, inflammatory disorders, neurological disorders, or infectious diseases or disorders in subjects in need.

[0504] Example 60: The compound as described in Examples 1-12, or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer, is intended for use in the treatment or prevention of cancer.

[0505] Example 61: Use of the compound described in Examples 1-12 or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer in the preparation of a medicament for the treatment or prevention of a target protein-mediated disorder, disease, or condition in a subject.

[0506] Example 62: The compound as described in Examples 1-12, or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer, is used in subjects for the treatment or prevention of target protein-mediated disorders, diseases, or conditions.

[0507] Example 63: The compound as described in Example 35 or Example 35A, or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer, for use in treating or preventing respiratory disorders, proliferative disorders, autoimmune disorders, autoinflammatory disorders, inflammatory disorders, neurological disorders, or infectious diseases or disorders in subjects in need.

[0508] Example 64: A compound as described in Example 35 or Example 35A, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment or prevention of cancer.

[0509] Example 65: Use of the compound as described in Example 35 or Example 35A, or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer in the preparation of a medicament for the treatment or prevention of a target protein-mediated disorder, disease, or condition in a subject.

[0510] Example 66: The compound as described in Example 35 or Example 35A, or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer, is used in subjects for the treatment or prevention of target protein-mediated disorders, diseases, or conditions.

[0511] Example 67: A method for treating or preventing cancer in a subject, the method comprising administering to the subject a compound as described in any one of Examples 1-12 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0512] Example 68: A compound or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer can bind to a cerebellar protein complex and alter its specificity to induce ubiquitination and degradation of the complex-associated protein.

[0513] Example 69: A compound as described in Example 68, wherein the compound comprises (i) a tris-tryptophan pocket binding moiety that binds to the tris-tryptophan pocket of the cerebellum protein E3 ligase; and (ii) a target affinity moiety covalently attached to the tris-tryptophan pocket binding moiety, the tris-tryptophan pocket binding moiety interacting with the surface of the cerebellum protein E3 ligase to alter its surface and make the ligase have affinity for the target protein.

[0514] Example 70: A compound as described in Example 68 or 69, wherein the compound has the formula (I):

[0515]

[0516] Or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer, wherein:

[0517] Is it a single bond or a double bond?

[0518] R d1 It is H, -CH2OC(O)R 15 -CH2OP(O)OHOR 15 、or -CH2OP(O)(R 15 )2;

[0519] R d2 It is H, C 1-6 Alkyl, halogen, C 1-6 Halogenated alkyl, or C 1-6 Heteroalkyl;

[0520] R d3 yes

[0521]

[0522] A 1It is a 5- or 6-membered heterocyclic group that optionally contains 1-3 additional heteroatoms selected from O, N, and S, or optionally contains 1-3 heteroatoms selected from NR. 1k The other heteroatoms of O and S are surrounded by one to three R atoms. 1d Substituted 5-membered heteroaryl groups;

[0523] A 2 It is C 5-7 The carbon cyclo group or contains 1-3 radicals selected from N and NR 1k Five- to seven-membered heterocyclic groups of O and S heteroatoms, wherein the carbocyclic group and the heterocyclic group are separated by one to three R atoms. 1d replace;

[0524] X 1 It is NR 4 Or S;

[0525] X 2 and X 2a Each is CR independently 1a Or N;

[0526] Each X 3 Independently is CR 1d Or N, where no more than two X's 3 It is N;

[0527] Each X 3' Independently is CR 1d CR 1c Or N, where no more than two X's 3 It is N, and at least one of them is X 3' It is CR 1c ;

[0528] Each X 4 Independently is CR 1d Or N, where at least one X 4 It is N, and there are no more than two X's. 4 It is N;

[0529] Each X 5 Independently is CR 1a Or N, where no more than two X's 5 It is N;

[0530] X 6 It is NR 1k , O or S;

[0531] X 7 It is NR 4 , O or S;

[0532] R 1a and R 1b H and C are independent of each other.1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -CN, F or Cl;

[0533] R 1c It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy group, halogen, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0534] R 1c' It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy groups, F, Cl, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4-C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0535] Each R 1d Independently selected from H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy group, halogen, CN, -C(O)OH, -C(O)OC1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2)0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0536] R 1e It is C 2-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -CN, F or Cl;

[0537] R 1f It is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -CN, F or Cl;

[0538] R 1g It is C 2-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy groups, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0- 4NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2)0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0539] R 1g' It is C 2-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Haloalkyl, C 2-6 Alkoxy, C 1-3 Haloalkoxy groups, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4- A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The heterocyclic group is replaced by one to five R... 5 Substitution, and the carbocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0540] R 1h It is C 4-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy groups, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -C 6-10 Aryl, -(CH2) 2-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0541] R 1h' It is C 4-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy groups, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -C 6-10 Aryl, -(CH2) 2-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2)0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 Aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The heterocyclic group is replaced by one to five R... 5 Substitution, and the carbocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0542] R 1i It is H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3Haloalkoxy groups, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR3 C(O)O(CH2) 0-4 -C 6-10 aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0543] R 1j It is H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy group, halogen, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0544] R on the benzoxazole ring 1d R 1i and R 1j Not all of them are H at the same time;

[0545] Each R 1k Independently selected from H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy group, halogen, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6- A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -C(O)O(CH2) 0-4 -C 6-10 Aryl, or -C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace;

[0546] Each R 2 Independently, it is NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 alkyl)2、-NHC(O)R 9 -N(R) 9 )C(O)(R 9 -NHS(O)2R 9 , or -NR 9 S(O)2R 9 ;

[0547] R 3 Is it H or C? 1-6 alkyl;

[0548] R 4 Is it H or C? 1-6 alkyl;

[0549] Each R 5 C is independent 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy groups, halogens, -OH, -C(O)H, -C(O)(C 1-6 Alkyl), -C(O)(C 6-10aryl), -C(O) (5- or 6-membered heteroaryl), -C(O) (C 3-7 Carbocyclic group), -C(O) (5- to 7-membered heterocyclic groups), -(CH2) 0-3 C(O)OC 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 alkyl)2,-NHC(O)R 9 , -N(R 9 )C(O)(R 9 ), -NH2, -NH(C 1-6 Alkyl), -N(C) 1-6 alkyl)2,-NHC(O)O(R 9 ), -N(R 9 )C(O)O(R 9 ), -NHS(O)2R 9 -NR 9 S(O)2R 9 , -S(O) q NHR 9 , -S(O) q N(R 9 )2,-S(O) q R 9 C 1-6 Hydroxyalkyl, -O(CH2) 1-3 CN, CN, -O(CH2) 0-6 -C 3-7 Carbocyclic group, -O(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -O(CH2) 0-3 (C6-C 10 Aryl, adamantyl, -O(CH2) 0-3 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 -C 6-10 Aryl, and -(CH2) 0-6 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally surrounded by one to three R atoms. 6 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to four R groups. 8 Replace; or two Rs 5When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 3-7 A carbocyclic group or a 5- to 7-membered heterocyclic group comprising 1-3 heteroatoms selected from O, N, and S, wherein the carbocyclic group and the heterocyclic group are optionally separated by one to three R atoms. 6 Replace; or two Rs 5 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 aryl or a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; or two R... 5 When they are on the same atom, they together with the atoms to which they are attached form C. 3-7 A spirocarbocyclic group or a 5- to 7-membered spiroheterocyclic group comprising 1-3 heteroatoms selected from O, N, and S, wherein the spirocarbocyclic group and the spiroheterocyclic group are optionally separated by one to four R atoms. 10 Replace; or two Rs 5 When on the same carbon atom, it forms =(O);

[0550] R 6 It is -NH2, -NH(C 1-6 Alkyl), -N(C) 1-6 Alkyl)2,C 6-10 aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms. 7 replace;

[0551] Each R 7 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy, halogen, or C 6-10 Aryl;

[0552] Each R 8 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, or -OH;

[0553] R 9 It is C 1-6 Alkyl, C 1-6 Haloalkyl groups, comprising 1-3 heteroatoms selected from O, N, and S, consisting of 5- to 7-membered heterocyclic groups, C 6-10 aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms. 11 replace;

[0554] Each R10 It is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, or halogens; or

[0555] Two Rs 10 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 Aryl or 5- or 6-membered heteroaryl groups containing 1-3 heteroatoms selected from O, N, and S;

[0556] Each R 11 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -NHC(O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(O)(C 1-6 Alkyl groups, or halogens; or

[0557] Two Rs 11 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 The aryl group or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms. 12 replace;

[0558] Each R 12 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, or C 1-3 Halogenated alkoxy groups;

[0559] R 13 It is C independently each time it appears. 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally surrounded by one or two C atoms. 1-6 The alkoxy group is substituted, and the aryl and heteroaryl groups are optionally replaced by one to three R groups. 14 replace;

[0560] Each R 14 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy groups, halogens, C 6-10Aryl, or a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S;

[0561] R 15 Is it H or C? 1-6 Alkyl; and

[0562] q can be 0, 1, or 2.

[0563] Example 71: The compound as described in Example 70, wherein R d1 It's H.

[0564] Example 72: The compound as described in Example 70, wherein R d1 It is -CH2OC(O)R 15 -CH2OP(O)OHOR 15 、or -CH2OP(O)(R 15 )2.

[0565] Example 73: A compound as described in any one of Examples 70-72, wherein R d2 It's H.

[0566] Example 74: A compound as described in any one of Examples 70-73, wherein R d1 and R d2 Each is H independently.

[0567] Example 75: A compound as described in any one of Examples 70-74, wherein R 1d It's H.

[0568] Example 76: A compound as described in any one of Examples 70-75, wherein R d3 yes

[0569]

[0570]

[0571]

[0572]

[0573]

[0574] Example 77: A compound as described in any one of Examples 70-76, wherein R d3 yes

[0575]

[0576]

[0577]

[0578] Example 78: A compound as described in any one of Examples 70-77, wherein the compound has a formula selected from the following:

[0579]

[0580]

[0581]

[0582] Or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer.

[0583] Example 79: A compound as described in any one of Examples 68-78, wherein the compound is selected from:

[0584] 1-(benzofuran-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0585] 1-(6-ethynylbenzofuran-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0586] 1-(6-ethynylbenzofuran-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0587] 1-(5-Iodobenzofuran-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0588] 1-(6-Iodobenzofuran-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0589] Phenyl(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzofuran-5-yl)carbamate;

[0590] 1-(6-chloropyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0591] 1-(7-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0592] 1-(7-(1-(4-(tert-butyl)benzoyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0593] 1-(6-(1-benzylpiperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0594] 1-(6-(3-(dimethylamino)prop-1-yn-1-yl)benzofuran-3-yl)dihydropyrimidin-2,4(1H,3H)-dione;

[0595] N-Benzyl-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzofuran-6-carboxamide;

[0596] 1-(6-Methylbenzo[d]isoxazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0597] 1-(5-Chlorobenzo[d]isoxazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0598] 1-(6-(4-methylphenethoxy)benzo[d]isoxazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;

[0599] 1-(6-(1-benzylpiperidin-4-yl)quinolin-3-yl)pyrimidin-2,4(1H,3H)-dione;

[0600] 1-(7-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2,4(1H,3H)-dione; and

[0601] 1-(7-bromoimidazolo[1,2-a]pyridin-3-yl)pyrimidin-2,4(1H,3H)-dione;

[0602] Or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer.

[0603] Example 80: A pharmaceutical composition comprising a compound as described in any one of Examples 68-79 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.

[0604] Example 81: A pharmaceutical composition as described in Example 80, the pharmaceutical composition further comprising at least one other pharmaceutical agent.

[0605] Example 82: The pharmaceutical composition as described in Example 80 or Example 81 14 is used for the treatment or prevention of cerebellar protein-mediated disorders, diseases or conditions.

[0606] Example 83: The pharmaceutical composition as described in Example 80 or Example 81 is used for the treatment or prevention of respiratory disorders, proliferative disorders, autoimmune disorders, autoinflammatory disorders, inflammatory disorders, neurological disorders, or infectious diseases or disorders.

[0607] Example 84: A method for regulating cerebellar proteins in a biological sample, the method comprising contacting the sample with a compound as described in any one of Examples 68-79 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0608] Example 85: A method for binding to and altering the specificity of a cerebellar protein complex to induce ubiquitination and degradation of a complex-associated protein selected from the groups listed in Table 1 in a biological sample, the method comprising contacting the sample with a compound as described in any one of Examples 68-79 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0609] Example 86: A method for treating or preventing cerebellar protein-mediated disorders, diseases, or conditions in a subject, the method comprising administering to the subject a compound as described in any one of Examples 68-79 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0610] Example 87: The method as described in Example 86, wherein the disorder, disease, or symptom is a respiratory disorder, a proliferative disorder, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a neurological disorder, or an infectious disease or disorder.

[0611] Example 88: The method as described in Example 87, wherein the disorder, disease, or symptom is a proliferative disorder.

[0612] Example 89: The method as described in Example 88, wherein the proliferative disorder is cancer.

[0613] Example 90: The method as described in Example 87, wherein the disorder, disease, or symptom is a neurological disorder.

[0614] Example 91: A method for treating or preventing respiratory disorders, proliferative disorders, autoimmune disorders, autoinflammatory disorders, inflammatory disorders, neurological disorders, or infectious diseases or disorders in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound as described in any one of Examples 68-79, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0615] Example 92: The method as described in Example 91, wherein the disorder or disease is a proliferative disorder.

[0616] Example 93: The method as described in Example 92, wherein the proliferative disorder is cancer.

[0617] Example 94: The method as described in Example 91, wherein the disorder or disease is a neurological disorder.

[0618] Example 95: Use of any compound of any one of Examples 68-79, or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer, in the preparation of a medicament for the treatment or prevention of respiratory disorders, proliferative disorders, autoimmune disorders, autoinflammatory disorders, inflammatory disorders, neurological disorders, or infectious diseases or disorders in subjects in need.

[0619] Example 96: Use of any compound as described in any of Examples 68-79, or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer, in the preparation of a medicament for the treatment or prevention of cancer.

[0620] Example 97: A method for degrading a target protein in a biological sample, the method comprising contacting the target protein with a compound as described in any one of Examples 68-79 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the target protein is selected from the group listed in Table 1.

[0621] Example 98: A method for treating or preventing target protein-mediated disorders, diseases, or conditions in a subject, the method comprising administering to the subject a compound as described in any one of Examples 68-79 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0622] Example 99: The method as described in Example 98, wherein the disorder, disease, or symptom is a proliferative disorder.

[0623] Example 100: The method as described in Example 99, wherein the proliferative disorder is cancer.

[0624] Example 101: The method as described in Example 98, wherein the disorder, disease, or symptom is a neurological disorder.

[0625] Example 102: A method for treating or preventing cancer in a subject, the method comprising administering to the subject a compound as described in any one of Examples 68-79 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0626] Example 103: The compound of any one of Examples 68-79, or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer, for use in treating or preventing respiratory disorders, proliferative disorders, autoimmune disorders, autoinflammatory disorders, inflammatory disorders, neurological disorders, or infectious diseases or disorders in subjects in need.

[0627] Example 104: The compound of any one of Examples 68-79, or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer, for use in the treatment or prevention of cancer.

[0628] Example 105: Use of any compound as described in any of Examples 68-79, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the preparation of a medicament for the treatment or prevention in a subject of a target protein-mediated disorder, disease, or condition.

[0629] Example 106: The compound of any one of Examples 68-79, or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer, is used in subjects for the treatment or prevention of target protein-mediated disorders, diseases, or conditions.

[0630] In one embodiment, the target protein comprises a β-hairpin.

[0631] In one embodiment, the target protein is a protein containing a β-turn. In another embodiment, the protein containing a β-turn is a protein selected from the group listed in Table 1.

[0632] In one embodiment, the target protein is selected from the group consisting of the following Table 1:

[0633] Table 1:

[0634]

[0635]

[0636]

[0637]

[0638]

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652]

[0653]

[0654]

[0655]

[0656]

[0657]

[0658]

[0659]

[0660]

[0661]

[0662]

[0663]

[0664]

[0665]

[0666]

[0667]

[0668]

[0669]

[0670]

[0671]

[0672]

[0673]

[0674]

[0675]

[0676]

[0677]

[0678]

[0679]

[0680]

[0681]

[0682]

[0683]

[0684]

[0685]

[0686]

[0687]

[0688]

[0689]

[0690]

[0691]

[0692]

[0693]

[0694]

[0695]

[0696]

[0697]

[0698]

[0699]

[0700]

[0701]

[0702]

[0703]

[0704]

[0705]

[0706]

[0707]

[0708]

[0709]

[0710]

[0711]

[0712]

[0713]

[0714]

[0715]

[0716]

[0717]

[0718]

[0719]

[0720]

[0721]

[0722]

[0723]

[0724]

[0725]

[0726]

[0727]

[0728]

[0729]

[0730]

[0731]

[0732]

[0733]

[0734] In another embodiment of this disclosure, the compounds disclosed herein are enantiomers. In some embodiments, the compound is an (S)-enantiomer. In other embodiments, the compound is an (R)-enantiomer. In still other embodiments, the compounds disclosed herein may be (+) or (-) enantiomers.

[0735] It should be understood that all isomers are included in this disclosure, including mixtures thereof. If the compound contains a double bond, the substituents may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent may have a cis or trans configuration. All tautomers are also included.

[0736] The compounds disclosed herein, as well as their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, and prodrugs, can exist in their tautomeric forms (e.g., as amides or imine ethers). All such tautomeric forms are considered part of this disclosure herein.

[0737] The compounds disclosed herein may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds disclosed herein, and mixtures thereof (including racemic mixtures), constitute a part of this disclosure. Furthermore, this disclosure includes all geometric and positional isomers. For example, if the compounds disclosed herein contain a double bond or a fused ring, both the cis and trans forms, as well as mixtures thereof, are included within the scope of this disclosure. Each compound disclosed herein includes all enantiomers conforming to the general structure of the compound. Compounds may exist in racemic or enantiomerically pure forms, or any other form for stereochemical purposes. Measurement results may reflect data collected for the racemic form, the enantiomerically pure form, or any other form for stereochemical purposes.

[0738] A mixture of diastereomers can be separated into their individual diastereomers based on their physicochemical differences using methods well known to those skilled in the art (such as, for example, chromatography and / or stepwise crystallization). Enantiomers can be separated by reacting the enantiomer mixture with a suitable optically active compound (e.g., a chiral auxiliary agent, such as a chiral alcohol or Mosher's acid chloride) to convert the enantiomer mixture into a diastereomer mixture, separating these diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers into their corresponding pure enantiomers. Furthermore, some compounds disclosed herein can be transisomers (e.g., substituted biaryl groups) and are considered part of this disclosure. Enantiomers can also be separated using chiral HPLC columns.

[0739] The compounds disclosed herein may also exist in different tautomeric forms, and all such forms are included within the scope of this disclosure, as well as in their chemical structures and names. Furthermore, for example, all keto-enol and imine-enamine forms of the compounds are included in this disclosure.

[0740] All stereoisomers (e.g., geometric isomers, optical isomers, etc.) of the compounds disclosed herein (including salts, solvates, esters, and prodrugs of those compounds, and salts, solvates, and esters of prodrugs), such as those that may exist due to asymmetric carbons on different substituents (including enantiomers (even in the absence of asymmetric carbons), rotational isomers, trans-blocking isomers, and diastereomeric isomers), are included within the scope of this disclosure. Positional isomers (like, for example, 4-pyridyl and 3-pyridyl) are also included within the scope of this disclosure. (For example, if a compound having formula (I) contains a double bond or a fused ring, both the cis and trans forms, as well as mixtures thereof, are included within the scope of this disclosure. Furthermore, for example, all keto-enol and imine-enamine forms of the compound are included in this disclosure.) Individual stereoisomers of the compounds disclosed herein may, for example, be substantially free of other isomers, or may be, for example, as racemates or mixed with all other, or other alternative, stereoisomers.

[0741] The chiral center of the compounds disclosed herein may have an S-configuration or an R-configuration as recommended by IUPAC 1974. In some embodiments, each asymmetric atom has at least 50% enantiomer excess, at least 60% enantiomer excess, at least 70% enantiomer excess, at least 80% enantiomer excess, at least 90% enantiomer excess, at least 95% enantiomer excess, or at least 99% enantiomer excess in either the (R)- or (S)-configuration. If possible, substitutions on atoms having unsaturated double bonds may be in cis-(Z)- or trans-(E)- form.

[0742] The use of the terms “salt,” “solvent,” “ester,” “prodrug,” etc., is intended to equally apply to salts, solvates, esters, and prodrugs of enantiomers, stereoisomers, rotational isomers, tautomers, positional isomers, racemates, or prodrugs of the inventive compound.

[0743] The compounds disclosed herein can form salts, which are also within the scope of this disclosure. Unless otherwise indicated, references to compounds having the formula herein are generally understood to include references to their salts.

[0744] Compounds and intermediates can be separated and used as compounds themselves. Any formulas given herein are also intended to represent the unlabeled form of the compound as well as its isotopically labeled form. Isotopically labeled compounds have the structure represented by the formulas given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, ph...

Claims

1. A compound, or a pharmaceutically acceptable salt or tautomer thereof, capable of binding to a cerebellar protein E3 ligase and imparting an affinity of the ligase for a target protein, wherein the target protein is selected from IKZF1, GSPT1, and SALL4. The compounds mentioned therein are selected from: Or its pharmaceutically acceptable salts or tautomers, wherein: R 1a and R 1b H and C are independent of each other. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -CN, F or Cl; R 1c It is C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, halogen, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace; R 1c' It is -(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally separated by one to five R groups. 5 replace; R 1d It is H; R 1e It is C 2-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, -CN, F, or Cl; R 1i It is H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace; R 1j It is H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, halogen, CN, -C(O)OH, -C(O)OC 1-6 Alkyl group, -(CH2) 0-4 -C(O)NH2,-(CH2) 0-4 -C(O)NH(R 13 ), -(CH2) 0-4 -C(O)N(R 13 )2,-(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 C 6-10 Aryl, -(CH2) 0-6 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 3-7 Carbocyclic group, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 NR 3 (CH2) 0-4 -C 6-10 Aryl, -(CH2) 0-4 NR 3 (CH2) 0-4 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 3-7 Carbocyclic group, -(CH2) 0-4 -NR 3 C(O)- is a 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-4 -NR 3 C(O)-C 6-10 Aryl, -(CH2) 0-4 -NR 3 C(O)- is a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S; -NR 3 C(O)O(CH2) 0-4 -C 3-7 Carbocyclic group, -NR 3 C(O)O(CH2) 0-4 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S; - NR 3 C(O)O(CH2) 0-4 -C 6-10 aryl, or -NR 3 C(O)O(CH2) 0-4 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkynyl group is optionally surrounded by one to three R atoms. 2 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to five R groups. 5 replace; R on the benzoxazole ring 1d R 1i and R 1j Not all of them are H at the same time; Each R 2 Independently, it is NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 alkyl)2、-NHC(O)R 9 -N(R) 9 )C(O)(R 9 -NHS(O)2R 9 , or -NR 9 S(O)2R 9 ; R 3 Is it H or C? 1-6 alkyl; R 4 Is it H or C? 1-6 alkyl; R 5 C is independent 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy groups, halogens, -OH, -C(O)H, -C(O)(C 1-6 Alkyl), -C(O)(C 6-10 aryl), -C(O) (5- or 6-membered heteroaryl), -C(O) (C 3-7 Carbocyclic group), -C(O) (5- to 7-membered heterocyclic groups), -(CH2) 0-3 C(O)OC 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 alkyl)2,-NHC(O)R 9 , -N(R 9 )C(O)(R 9 ), -NH2, -NH(C 1-6 Alkyl), -N(C) 1-6 alkyl)2,-NHC(O)O(R 9 ), -N(R 9 )C(O)O(R 9 ), -NHS(O)2R 9 -NR 9 S(O)2R 9 , -S(O) q NHR 9 , -S(O) q N(R 9 )2,-S(O) q R 9 C 1-6 Hydroxyalkyl, -O(CH2) 1-3 CN, CN, -O(CH2) 0-6 -C 3-7 Carbocyclic group, -O(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -O(CH2) 0-3 (C6-C 10 Aryl, adamantyl, -O(CH2) 0-3 - A 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 -C 3-7 Carbocyclic group, -(CH2) 0-6 - A 5- to 7-membered heterocyclic group containing 1-3 heteroatoms selected from O, N, and S, -(CH2) 0-6 -C 6-10 Aryl, and -(CH2) 0-6 - A 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally surrounded by one to three R atoms. 6 The carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally replaced by one to four R groups. 8 replace; R 6 It is -NH2, -NH(C 1-6 Alkyl), -N(C) 1-6 Alkyl)2,C 6-10 aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms. 7 replace; Each R 7 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy, halogen, or C 6-10 Aryl; Each R 8 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, or -OH; R 9 It is C 1-6 Alkyl, C 1-6 Haloalkyl groups, comprising 1-3 heteroatoms selected from O, N, and S, consisting of 5- to 7-membered heterocyclic groups, C 6-10 aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms. 11 replace; Each R 11 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -NHC(O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(O)(C 1-6 Alkyl groups, or halogens; or Two Rs 11 When it is on adjacent atoms, it forms C together with the atoms to which they are attached. 6-10 The aryl group or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the aryl and heteroaryl groups are optionally separated by one to three R atoms. 12 replace; Each R 12 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, or C 1-3 Halogenated alkoxy groups; R 13 It is C independently each time it appears. 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 aryl, or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from O, N, and S, wherein the alkyl group is optionally separated by one or two C atoms. 1-6 The alkoxy group is substituted, and the aryl and heteroaryl groups are optionally replaced by one to three R groups. 14 replace; Each R 14 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-3 Halogenated alkoxy groups, halogens, C 6-10 Aryl, or a 5- or 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from O, N, and S.

2. A compound selected from: 1-(benzofuran-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-ethynylbenzofuran-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-methylbenzofuran-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-Iodobenzofuran-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-Iodobenzofuran-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; (3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzofuran-5-yl)carbamate phenyl ester; 1-(6-chloropyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(7-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(7-(1-(4-(tert-butyl)benzoyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-benzylpiperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(3-(dimethylamino)prop-1-yn-1-yl)benzofuran-3-yl)dihydropyrimidin-2,4(1H,3H)-dione; N-Benzyl-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzofuran-6-carboxamide; 1-(6-Methylbenzo[d]isoxazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-Chlorobenzo[d]isoxazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(4-methylphenethoxy)benzo[d]isoxazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(7-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2,4(1H,3H)-dione; and 1-(7-bromoimidazolo[1,2-a]pyridin-3-yl)pyrimidin-2,4(1H,3H)-dione; Or its pharmaceutically acceptable salt or tautomer.

3. The compound of claim 1, wherein the compound is a compound of formula (Ic): Or its pharmaceutically acceptable salt or tautomer.

4. The compound of claim 1, wherein the compound is a compound of formula (Ia): Or its pharmaceutically acceptable salt or tautomer.

5. The compound of claim 1, wherein the compound is a compound of formula (Ib): Or its pharmaceutically acceptable salt or tautomer.

6. A pharmaceutical composition comprising a compound as described in any one of claims 1-5 or a pharmaceutically acceptable salt or tautomer thereof, and a pharmaceutically acceptable carrier or excipient, optionally further comprising at least one other pharmaceutical agent.

Images