CN117479944A - Cyclin dependent kinase inhibitors - Google Patents
Cyclin dependent kinase inhibitors Download PDFInfo
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- CN117479944A CN117479944A CN202280039868.5A CN202280039868A CN117479944A CN 117479944 A CN117479944 A CN 117479944A CN 202280039868 A CN202280039868 A CN 202280039868A CN 117479944 A CN117479944 A CN 117479944A
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
A series of compounds or pharmaceutically acceptable salts thereof are provided that are potent inhibitors of Cyclin Dependent Kinases (CDKs). Corresponding compositions are also provided.
Description
Background
Members of the cyclin-dependent kinase (CDK) family that trigger passage through the cell cycle are considered attractive therapeutic targets, especially for cancers. There is a continuing need for CDK inhibitors.
Disclosure of Invention
The present disclosure provides compounds having the structure of formula (I),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R is 8 Are each independently absent or are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl;
n is not less than 0.
In some embodiments of the compounds having the structure of formula (I), wherein R 1 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
Having the structure in the compoundIn some embodiments of the structure of formula (I), wherein R 1 Is an optionally substituted methyl group.
In some embodiments of the compounds having the structure of formula (I), wherein R 1 Is/are R 9 Substituted, R 9 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of the compounds having the structure of formula (I), wherein R 9 Selected from hydrogen and optionally substituted (C) 6 -C 10 ) Aryl groups.
In some embodiments of the compounds having the structure of formula (I), wherein R 9 Is optionally substituted phenyl.
In some embodiments of the compounds having the structure of formula (I), wherein R 9 Is/are R 10 Substituted, R 10 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl groupOptionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of the compounds having the structure of formula (I), wherein R 10 Each independently selected from hydrogen, optionally substituted amino and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of the compounds having the structure of formula (I), wherein R 10 Is optionally substituted pyrazolyl.
In some embodiments of the compounds having the structure of formula (I), wherein R 10 Respectively by one or more R 11 Substituted, R 11 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of the compounds having the structure of formula (I), wherein R 11 Independently selected from hydrogen,=o and optionally substituted (C 1 -C 6 ) An alkyl group.
In some embodiments of the compounds having the structure of formula (I), wherein R 11 Is an optionally substituted methyl group.
In some embodiments of the compounds having the structure of formula (I), wherein R 2 Is hydrogen.
In some embodiments of the compounds having the structure of formula (I), wherein R 3 Is hydrogen.
In some embodiments of the compounds having the structure of formula (I), wherein R 4 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
In some embodiments of the compounds having the structure of formula (I), wherein R 4 Is an optionally substituted isopropyl group.
In some embodiments of the compounds having the structure of formula (I), wherein R 5 Selected from hydrogen, optionally substituted amino and optionally substituted (C 2 -C 9 ) A heterocycle.
In some embodiments of the compounds having the structure of formula (I), wherein R 5 Is an optionally substituted amino group.
In some embodiments of the compounds having the structure of formula (I), wherein R 5 Is optionally substituted C 4 A heterocycle.
In some embodiments of the compounds having the structure of formula (I), wherein R 5 Is an optionally substituted heterocyclic ring containing two heteroatoms.
In some embodiments of the compounds having the structure of formula (I), wherein R 5 Is an optionally substituted heterocyclic ring containing two nitrogen atoms.
In some embodiments of the compounds having the structure of formula (I), wherein R 5 Is/are R 12 Substituted, R 12 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally takenSubstituted phosphorus-containing groups, optionally substituted silicon-containing groups, optionally substituted thio groups, optionally substituted amino groups, optionally substituted carboxyl groups, optionally substituted sulfonyl groups, optionally substituted sulfinyl groups, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of the compounds having the structure of formula (I), wherein R 12 Independently selected from hydrogen, optionally substituted (C) 1 -C 6 ) Alkyl and optionally substituted (C) 2 -C 9 ) A heterocycle.
In some embodiments of the compounds having the structure of formula (I), wherein R 12 Is optionally substituted C 4 Heterocyclic or optionally substituted C 5 A heterocycle.
In some embodiments of the compounds having the structure of formula (I), wherein R 12 Is an optionally substituted heterocyclic ring containing one heteroatom.
In some embodiments of the compounds having the structure of formula (I), wherein R 12 Is an optionally substituted heterocyclic ring containing one nitrogen atom.
In some embodiments of the compounds having the structure of formula (I), wherein R 6 Is hydrogen.
In some embodiments of the compounds having the structure of formula (I), wherein R 7 Is hydrogen.
In some embodiments of the compounds having the structure of formula (I), wherein R 8 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
Chemical combinationA solvate or hydrate of any of the above, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, wherein the compound is selected from the group consisting of:
the present disclosure provides compounds having the structure of formula (II),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
Wherein,
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 and R 7 Are each independently absent or are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of the compounds having the structure of formula (II), wherein R 1 Selected from hydrogen and optionally quiltSubstituted (C) 1 -C 6 ) An alkyl group.
In some embodiments of the compounds having the structure of formula (II), wherein R 1 Is an optionally substituted methyl group.
In some embodiments of the compounds having the structure of formula (I), wherein R 1 Is/are R 8 Substituted, R 8 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of the compounds having the structure of formula (II), wherein R 8 Selected from hydrogen and optionally substituted (C) 6 -C 10 ) Aryl groups.
In some embodiments of the compounds having the structure of formula (II), wherein R 8 Is optionally substituted phenyl.
In some embodiments of the compounds having the structure of formula (II), wherein R 8 Is/are R 9 Substituted, R 9 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally taken Substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of the compounds having the structure of formula (II), wherein R 9 Selected from hydrogen and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of the compounds having the structure of formula (II), wherein R 9 Is optionally substituted pyrazolyl.
In some embodiments of the compounds having the structure of formula (II), wherein R 2 Is hydrogen.
In some embodiments of the compounds having the structure of formula (II), wherein R 3 Is hydrogen.
In some embodiments of the compounds having the structure of formula (II), wherein R 4 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
In some embodiments of the compounds having the structure of formula (II), wherein R 4 Selected from hydrogen and optionally substituted isopropyl.
In some embodiments of the compounds having the structure of formula (II), wherein R 5 Is hydrogen.
In some embodiments of the compounds having the structure of formula (II), wherein R 6 Is hydrogen.
In some embodiments of the compounds having the structure of formula (II), wherein R 7 Is hydrogen.
The present disclosure provides a compound or a pharmaceutically acceptable salt thereofA prodrug or metabolite, or a solvate or hydrate of any of the above, wherein the compound is
The present disclosure provides a compound, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is
The present disclosure provides compounds having the structure of formula (III),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
X 1 and X 2 Each independently selected from C, N and O;
a is selected from optionally substituted (C 2 -C 9 ) Heterocycles and optionally substituted (C) 1 -C 9 ) Heteroaryl;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 and R is 10 Are each independently absent or are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substitutedOf (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl;
n and m are each independently not less than 0.
In some embodiments of the compounds having the structure of formula (III), wherein X is 1 Is N.
In some embodiments of the compounds having the structure of formula (III), wherein X is 2 Is C.
In some embodiments of compounds having the structure of formula (III), wherein A is optionally substituted (C 1 -C 9 ) Heteroaryl groups.
In some embodiments of compounds having the structure of formula (III), wherein A is optionally substituted C 3 Heteroaryl groups.
In some embodiments of compounds having the structure of formula (III), wherein a is optionally substituted pyrazolyl.
In some embodiments of the compounds having the structure of formula (III), wherein R 1 Is hydrogen.
In some embodiments of the compounds having the structure of formula (III), wherein R 2 Is hydrogen.
In some embodiments of the compounds having the structure of formula (III), wherein R 3 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
In some embodiments of the compounds having the structure of formula (III), wherein R 3 Is an optionally substituted isopropyl group.
In some embodiments of the compounds having the structure of formula (III), wherein R 4 Is hydrogen.
In some embodiments of the compounds having the structure of formula (III), wherein R 5 Is hydrogen.
In some embodiments of the compounds having the structure of formula (III), wherein R 6 Is hydrogen.
In some embodiments of the compounds having the structure of formula (III), wherein R 7 Is hydrogen.
In some embodiments of the compounds having the structure of formula (III), wherein R 8 Is hydrogen.
In some embodiments of the compounds having the structure of formula (III), wherein R 9 Hydrogen, respectively.
In some embodiments of the compounds having the structure of formula (III), wherein R 10 Hydrogen, respectively.
The present disclosure provides a compound, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is
The present disclosure provides compounds having the structure of formula (IV),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
Wherein,
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R is 8 Are each independently absent or are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) A heteroaryl group, which is a group,
n and m are each independently not less than 0.
In some embodiments of compounds having the structure of formula (IV), wherein R 1 Is hydrogen.
In some embodiments of compounds having the structure of formula (IV), wherein R 2 Is hydrogen.
In some embodiments of compounds having the structure of formula (IV), wherein R 3 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
In some embodiments of compounds having the structure of formula (IV), wherein R 3 Is an optionally substituted isopropyl group.
In some embodiments of compounds having the structure of formula (IV), wherein R 4 Selected from hydrogen, optionally substituted (C) 1 -C 6 ) Acyl and optionally substituted (C) 1 -C 6 ) An alkyl group.
In some embodiments of compounds having the structure of formula (IV), wherein R 4 Is optionally substituted propionyl.
In some embodiments of compounds having the structure of formula (IV), wherein R 4 Is an optionally substituted methyl group.
In some embodiments of compounds having the structure of formula (IV), wherein R 4 Is/are R 9 Substituted, R 9 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substitutedA phosphorus-containing group, an optionally substituted silicon-containing group, an optionally substituted thio group, an optionally substituted amino group, an optionally substituted carboxy group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, an optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of compounds having the structure of formula (IV), wherein R 9 Selected from hydrogen, optionally substituted amino, optionally substituted (C 1 -C 6 ) Alkyl and optionally substituted (C) 6 -C 10 ) Aryl groups.
In some embodiments of compounds having the structure of formula (IV), wherein R 9 Is an optionally substituted methyl group.
In some embodiments of compounds having the structure of formula (IV), wherein R 9 Is optionally substituted phenyl.
In some embodiments of compounds having the structure of formula (IV), wherein R 5 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
In some embodiments of compounds having the structure of formula (IV), wherein R 5 Is an optionally substituted methyl group.
In some embodiments of compounds having the structure of formula (IV), wherein R 6 Is hydrogen.
In some embodiments of compounds having the structure of formula (IV), wherein R 7 Selected from hydrogen and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In which the compound has a structure of the formula (IV)In some embodiments, wherein the R 7 Is optionally substituted C 3 Heteroaryl groups.
In some embodiments of compounds having the structure of formula (IV), wherein R 7 Is optionally substituted pyrazolyl.
In some embodiments of compounds having the structure of formula (IV), wherein n is 1.
In some embodiments of compounds having the structure of formula (IV), wherein R 8 Is hydrogen.
The present disclosure provides a compound, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:
the present disclosure provides a compound, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:
the present disclosure provides compounds having the structure of formula (V),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 and R is 11 Are each independently absent or are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl;
n and m are each independently not less than 0.
In some embodiments of the compounds having the structure of formula (V), wherein R 1 Is hydrogen.
In some embodiments of the compounds having the structure of formula (V), wherein R 2 Is hydrogen.
In some embodiments of the compounds having the structure of formula (V), wherein R 3 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
In some embodiments of the compounds having the structure of formula (V), wherein R 3 Is an optionally substituted methyl group.
In some embodiments of the compounds having the structure of formula (V), wherein R 4 Is hydrogen.
In some embodiments of the compounds having the structure of formula (V), wherein R 5 Is hydrogen.
In some embodiments of the compounds having the structure of formula (V), wherein R 6 Is hydrogen.
In some embodiments of the compounds having the structure of formula (V), wherein R 7 Is hydrogen.
In some embodiments of the compounds having the structure of formula (V), wherein R 8 Selected from hydrogen and optionally substituted sulfonyl.
In some embodiments of the compounds having the structure of formula (V), wherein R 8 Is/are R 12 Substituted, R 12 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of the compounds having the structure of formula (V), wherein R 12 Selected from hydrogen and optionally substituted (C) 6 -C 10 ) Aryl groups.
In some embodiments of the compounds having the structure of formula (V), wherein R 12 Is optionally substituted phenyl.
In some embodiments of the compounds having the structure of formula (V), wherein R 12 Is/are R 13 Substituted, R 13 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing groupA group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of the compounds having the structure of formula (V), wherein R 13 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
In some embodiments of the compounds having the structure of formula (V), wherein R 13 Is an optionally substituted methyl group.
In some embodiments of the compounds having the structure of formula (V), wherein R 9 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
In some embodiments of the compounds having the structure of formula (V), wherein R 9 Is an optionally substituted methyl group.
In some embodiments of compounds having the structure of formula (V), wherein n may be 1.
In some embodiments of the compounds having the structure of formula (V), wherein R 9 Is/are R 14 Substituted, R 14 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of the compounds having the structure of formula (V), wherein R 14 Selected from hydrogen and optionally substituted hydroxy.
In some embodiments of the compounds having the structure of formula (V), wherein R 10 Is hydrogen.
In some embodiments of the compounds having the structure of formula (V), wherein R 11 Selected from hydrogen, halogen and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of the compounds having the structure of formula (V), wherein R 11 F.
In some embodiments of compounds having the structure of formula (V), wherein m is 2.
In some embodiments of the compounds having the structure of formula (V), wherein R 11 Is optionally substituted C 3 Heteroaryl groups.
In some embodiments of the compounds having the structure of formula (V), wherein R 11 Is optionally substituted pyrazolyl.
The present disclosure provides a compound, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:
the present disclosure provides compounds having the structure of formula (VI),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
X 1 and X 2 Each independently selected from C, N and O;
A is selected from optionally substituted (C 2 -C 9 ) Heterocycles and optionally substituted (C) 1 -C 9 ) Heteroaryl;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 and R 7 Are each independently absent or are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl;
n is not less than 0.
In some embodiments of compounds having the structure of formula (VI), wherein the X 1 Is N.
In some embodiments of compounds having the structure of formula (VI), wherein the X 2 Is C.
In some embodiments of compounds having the structure of formula (VI), wherein a is optionally substituted (C 1 -C 9 ) Heteroaryl groups.
In some embodiments of compounds having the structure of formula (VI), wherein a is optionally substituted C 3 Heteroaryl groups.
In some embodiments of compounds having the structure of formula (VI), wherein a is optionally substituted pyrazolyl.
In some embodiments of compounds having the structure of formula (VI), wherein the A is substituted with one or more R 8 Substituted, R 8 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of compounds having the structure of formula (VI), wherein R 8 Selected from hydrogen, optionally substituted amino and optionally substituted (C 1 -C 6 ) An alkyl group.
In some embodiments of compounds having the structure of formula (VI), wherein R 8 Is an optionally substituted methyl group.
In some embodiments of compounds having the structure of formula (VI), wherein R 8 Is/are R 9 Substituted, R 9 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of compounds having the structure of formula (VI), wherein R 9 Selected from hydrogen and halogen.
In some embodiments of compounds having the structure of formula (VI), wherein R 9 F.
In some embodiments of compounds having the structure of formula (VI), wherein R 1 Is hydrogen.
In some embodiments of compounds having the structure of formula (VI), wherein R 2 Is hydrogen.
In some embodiments of compounds having the structure of formula (VI), wherein R 3 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
In some embodiments of compounds having the structure of formula (VI), wherein R 3 Is an optionally substituted isopropyl group.
In some embodiments of compounds having the structure of formula (VI), wherein R 4 Selected from hydrogen and optionally substituted hydroxy.
In some embodiments of compounds having the structure of formula (VI), wherein R 5 Is hydrogen.
In some embodiments of compounds having the structure of formula (VI), wherein R 6 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
In some embodiments of compounds having the structure of formula (VI), wherein R 6 Is an optionally substituted methyl group.
In some embodiments of compounds having the structure of formula (VI), wherein R 6 Is/are R 10 Substituted, R 10 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of compounds having the structure of formula (VI), wherein R 10 Selected from hydrogen and optionally substituted (C) 6 -C 10 ) Aryl groups.
In some embodiments of compounds having the structure of formula (VI), wherein R 10 Is optionally substituted phenyl.
In some embodiments of compounds having the structure of formula (VI), wherein R 10 Is/are R 11 Substituted, R 11 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionallyA substituted phosphorus-containing group, an optionally substituted silicon-containing group, an optionally substituted thio group, an optionally substituted amino group, an optionally substituted carboxyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, an optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of compounds having the structure of formula (VI), wherein R 11 Selected from hydrogen and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of compounds having the structure of formula (VI), wherein R 11 Is optionally substituted pyrazolyl.
In some embodiments of compounds having the structure of formula (VI), wherein R 7 Is hydrogen.
The present disclosure provides a compound, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:/>
the present disclosure provides compounds having the structure of formula (VII),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
X 1 and X 2 Each independently selected from C, N and O;
a is selected from optionally substituted (C 2 -C 9 ) Heterocycles and optionally substituted (C) 1 -C 9 ) Heteroaryl;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R is 8 Are each independently absent or are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl;
n and m are each independently not less than 0.
In some embodiments of the compounds having the structure of formula (VII), wherein X is 1 Is N.
In some embodiments of the compounds having the structure of formula (VII), wherein X is 2 Is C.
In some embodiments of compounds having the structure of formula (VII), wherein A is optionally substituted (C 1 -C 9 ) Heteroaryl groups.
In some embodiments of compounds having the structure of formula (VII), wherein A is optionally substituted C 3 Heteroaryl groups.
In some embodiments of compounds having the structure of formula (VII), wherein a is optionally substituted pyrazolyl.
In some embodiments of compounds having the structure of formula (VII), wherein R 1 Is hydrogen.
In some embodiments of compounds having the structure of formula (VII), wherein R 2 Selected from hydrogen, optionally substituted (C) 1 -C 6 ) Alkyl and optionally substituted (C) 3 -C 10 ) Carbocycles.
In some embodiments of compounds having the structure of formula (VII), wherein R 2 Is an optionally substituted isopropyl group.
In some embodiments of compounds having the structure of formula (VII), wherein R 2 Is optionally substituted C 5 Carbocycles.
In some embodiments of compounds having the structure of formula (VII), wherein R 2 Is optionally substituted cyclopentyl.
In some embodiments of compounds having the structure of formula (VII), wherein R 3 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
In some embodiments of compounds having the structure of formula (VII), wherein R 3 Is methyl.
In some embodiments of compounds having the structure of formula (VII), wherein R 4 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
In some embodiments of compounds having the structure of formula (VII), wherein R 4 Is methyl.
In some embodiments of compounds having the structure of formula (VII), wherein R 5 Is hydrogen.
In some embodiments of compounds having the structure of formula (VII), wherein R 6 Selected from hydrogen and halogen.
Having general function in the compoundsIn some embodiments of the structure of formula (VII), wherein R 6 Is halogen.
In some embodiments of compounds having the structure of formula (VII), wherein R 6 F.
In some embodiments of compounds having the structure of formula (VII), wherein n is 1.
In some embodiments of compounds having the structure of formula (VII), wherein R 7 Is hydrogen.
The present disclosure provides a compound, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:
/>
the present disclosure provides compounds having the structure of formula (VIIs),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
R 1 、R 2 、R 3 、R 4 and R is 5 Are each independently absent or are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of compounds having the structure of formula (VIIS), wherein R 1 Is hydrogen.
In some embodiments of compounds having the structure of formula (VIIS), wherein R 2 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
In some embodiments of compounds having the structure of formula (VIIS), wherein R 2 Is an optionally substituted isopropyl group.
In some embodiments of compounds having the structure of formula (VIIS), wherein R 3 Selected from hydrogen, optionally substituted (C) 1 -C 6 ) Alkyl and optionally substituted (C) 2 -C 9 ) A heterocycle.
In some embodiments of compounds having the structure of formula (VIIS), wherein R 3 Is an optionally substituted methyl group.
In some embodiments of compounds having the structure of formula (VIIS), wherein R 3 Is optionally substituted C 5 A heterocycle.
In some embodiments of compounds having the structure of formula (VIIS), wherein R 3 Is an optionally substituted piperidinyl group.
In some embodiments of compounds having the structure of formula (VIIS), wherein R 3 Is/are R 6 Substituted, R 6 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionallyA substituted silicon-containing group, an optionally substituted thio group, an optionally substituted amino group, an optionally substituted carboxyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, an optionally substituted (C 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of compounds having the structure of formula (VIIS), wherein R 6 Selected from hydrogen, optionally substituted (C) 1 -C 6 ) Alkyl and optionally substituted (C) 2 -C 9 ) A heterocycle.
In some embodiments of compounds having the structure of formula (VIIS), wherein R 6 Is optionally substituted ethyl.
In some embodiments of compounds having the structure of formula (VIIS), wherein R 6 Is optionally substituted C 5 A heterocycle.
In some embodiments of compounds having the structure of formula (VIIS), wherein R 6 Is an optionally substituted piperidinyl group.
In some embodiments of compounds having the structure of formula (VIIS), wherein R 6 Is/are R 7 Substituted, R 7 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Sulfur (S)Substituted acyl, optionally substituted (C) 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of compounds having the structure of formula (VIIS), wherein R 7 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An acyl group.
In some embodiments of compounds having the structure of formula (VIIS), wherein R 7 Is an optionally substituted acetyl group.
In some embodiments of compounds having the structure of formula (VIIS), wherein R 7 Is/are R 8 Substituted, R 8 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of compounds having the structure of formula (VIIS), wherein R 8 Selected from hydrogen and optionally substituted amino.
In some cases where the compound has the structure of formula (VIIS)In embodiments, wherein the R 8 Is/are R 9 Substituted, R 9 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of compounds having the structure of formula (VIIS), wherein R 9 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
In some embodiments of compounds having the structure of formula (VIIS), wherein R 9 Is an optionally substituted methyl group.
In some embodiments of compounds having the structure of formula (VIIS), wherein R 4 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
In some embodiments of compounds having the structure of formula (VIIS), wherein R 4 Is an optionally substituted methyl group.
In some embodiments of compounds having the structure of formula (VIIS), wherein R 4 Is/are R 10 Substituted, R 10 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substitutedThio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of compounds having the structure of formula (VIIS), wherein R 10 Is optionally substituted (C) 6 -C 10 ) Aryl groups.
In some embodiments of compounds having the structure of formula (VIIS), wherein R 10 Is optionally substituted phenyl.
In some embodiments of compounds having the structure of formula (VIIS), wherein R 10 Is/are R 11 Substituted, R 11 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of compounds having the structure of formula (VIIS), wherein R 11 Selected from hydrogen, halogen and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of compounds having the structure of formula (VIIS), wherein R 11 Is optionally substituted pyrazolyl.
In some embodiments of compounds having the structure of formula (VIIS), wherein R 11 F.
In some embodiments of compounds having the structure of formula (VIIS), wherein R 5 Is hydrogen.
The present disclosure provides a compound, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:
the present disclosure provides a compound, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:
the present disclosure provides compounds having the structure of formula (VIII),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 and R 7 Are each independently absent or are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl;
n is independently not less than 0.
In some embodiments of compounds having the structure of formula (VIII), wherein R 1 Is hydrogen.
In some embodiments of compounds having the structure of formula (VIII), wherein R 2 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
In some embodiments of compounds having the structure of formula (VIII), wherein R 2 Is an optionally substituted isopropyl group.
In some embodiments of compounds having the structure of formula (VIII), wherein R 3 Is hydrogen.
In some embodiments of compounds having the structure of formula (VIII), wherein R 4 Is hydrogen.
In some embodiments of compounds having the structure of formula (VIII), wherein R 5 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
In some embodiments of compounds having the structure of formula (VIII), wherein R 5 Is optionally substitutedMethyl of (c).
In some embodiments of compounds having the structure of formula (VIII), wherein R 5 Is/are R 8 Substituted, R 8 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of compounds having the structure of formula (VIII), wherein R 8 Selected from hydrogen and optionally substituted (C) 6 -C 10 ) Aryl groups.
In some embodiments of compounds having the structure of formula (VIII), wherein R 8 Is optionally substituted phenyl.
In some embodiments of compounds having the structure of formula (VIII), wherein R 8 Is/are R 9 Substituted, R 9 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally takenSubstituted (C) 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of compounds having the structure of formula (VIII), wherein R 9 Selected from hydrogen, halogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
In some embodiments of compounds having the structure of formula (VIII), wherein R 9 F.
In some embodiments of compounds having the structure of formula (VIII), wherein R 9 Is an optionally substituted methyl group.
In some embodiments of compounds having the structure of formula (VIII), wherein R 9 Is/are R 10 Substituted, R 10 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of compounds having the structure of formula (VIII), wherein R 10 Selected from the group consisting ofHydrogen and halogen.
In some embodiments of compounds having the structure of formula (VIII), wherein R 10 F.
In some embodiments of compounds having the structure of formula (VIII), wherein R 6 Is hydrogen.
In some embodiments of compounds having the structure of formula (VIII), wherein R 7 Is hydrogen.
The present disclosure provides a compound, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:
The present disclosure provides compounds having the structure of formula (IX),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
X 1 and X 2 Each independently selected from C, N and O;
a is selected from optionally substituted (C 2 -C 9 ) Heterocycles and optionally substituted (C) 1 -C 9 ) Heteroaryl;
R 1 、R 2 、R 3 、R 4 、R 5 and R is 6 Are each independently absent or are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing groups, optionally substituted silicon-containing groups, optionally substituted thio, optionally substituted amino, optionally substituted carboxy,Optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl;
n and m are each independently not less than 0.
In some embodiments of compounds having the structure of formula (IX), wherein X is 1 Is N.
In some embodiments of compounds having the structure of formula (IX), wherein X is 2 Is C.
In some embodiments of compounds having the structure of formula (IX), wherein A is optionally substituted (C 1 -C 9 ) Heteroaryl groups.
In some embodiments of compounds having the structure of formula (IX), wherein A is optionally substituted C 3 Heteroaryl groups.
In some embodiments of compounds having the structure of formula (IX), wherein a is optionally substituted pyrazolyl.
In some embodiments of compounds having the structure of formula (IX), wherein R 1 Is hydrogen.
In some embodiments of compounds having the structure of formula (IX), wherein R 2 Selected from hydrogen, optionally substituted (C) 1 -C 6 ) Alkyl and optionally substituted (C) 3 -C 10 ) Carbocycles.
In some embodiments of compounds having the structure of formula (IX), wherein R 2 Is an optionally substituted isopropyl group.
In some embodiments of compounds having the structure of formula (IX), wherein R 2 Is optionally substituted C 5 Carbocycles.
In some embodiments of compounds having the structure of formula (IX), wherein R 2 Is optionally substituted cyclopentyl.
In some embodiments of compounds having the structure of formula (IX), wherein R 3 Is hydrogen.
In some embodiments of compounds having the structure of formula (IX), wherein R 4 Is hydrogen.
In some embodiments of compounds having the structure of formula (IX), wherein R 5 Is hydrogen.
In some embodiments of compounds having the structure of formula (IX), wherein R 6 Is hydrogen.
The present disclosure provides a compound, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:
the present disclosure provides compounds having the structure of formula (X),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
X 1 、X 2 and X 3 Each independently selected from C, N and O;
a is selected from optionally substituted (C 2 -C 9 ) Heterocycles and optionally substituted (C) 1 -C 9 ) Heteroaryl;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 and R 7 Are each independently absent or are each independently selected from hydrogen, protium, deuterium, tritium, and halogenPlain, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl;
n and m are each independently not less than 0.
In some embodiments of the compounds having the structure of formula (X), wherein X is 1 Is N.
In some embodiments of the compounds having the structure of formula (X), wherein X is 2 Is C.
In some embodiments of compounds having the structure of formula (X), wherein A is optionally substituted (C 1 -C 9 ) Heteroaryl groups.
In some embodiments of compounds having the structure of formula (X), wherein A is optionally substituted C 3 Heteroaryl groups.
In some embodiments of compounds having the structure of formula (X), wherein a is optionally substituted pyrazolyl.
In some embodiments of compounds having the structure of formula (X), wherein R 1 Is hydrogen.
In some embodiments of compounds having the structure of formula (X), wherein R 2 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
In some embodiments of the compounds having the structure of formula (X), wherein the R 2 Is an optionally substituted isopropyl group.
In some embodiments of the compounds having the structure of formula (X), wherein X is 3 Is N.
In some embodiments of the compounds having the structure of formula (X), wherein X is 3 Is O.
In some embodiments of compounds having the structure of formula (X), wherein R 3 Absent, or R is 3 Is hydrogen.
In some embodiments of compounds having the structure of formula (X), wherein R 4 Is hydrogen.
In some embodiments of compounds having the structure of formula (X), wherein R 5 Is hydrogen.
In some embodiments of compounds having the structure of formula (X), wherein R 6 Is hydrogen.
In some embodiments of compounds having the structure of formula (X), wherein R 7 Is hydrogen.
The present disclosure provides a compound, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:
the present disclosure provides compounds having the structure of formula (XI),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
R X is halogen;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 and R is 9 Are each independently absent or are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl;
n and m are each independently not less than 0.
In some embodiments of compounds having the structure of formula (XI), wherein R is X F.
In some embodiments of compounds having the structure of formula (XI), wherein n is selected from 1 to 2.
In some embodiments of compounds having the structure of formula (XI), wherein R is 1 Is hydrogen.
In some embodiments of compounds having the structure of formula (XI), wherein R is 2 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
In some embodiments of compounds having the structure of formula (XI), wherein R is 2 Is an optionally substituted methyl group.
In some embodiments of compounds having the structure of formula (XI), wherein R is 3 Is hydrogen.
In some embodiments of compounds having the structure of formula (XI), wherein R is 4 Is hydrogen.
In some embodiments where the compound has the structure of formula (XI)In the scheme, wherein the R 5 Is hydrogen.
In some embodiments of compounds having the structure of formula (XI), wherein R is 6 Is hydrogen.
In some embodiments of compounds having the structure of formula (XI), wherein R is 7 Selected from hydrogen, =o and optionally substituted (C 1 -C 6 ) An alkyl group.
In some embodiments of compounds having the structure of formula (XI), wherein R is 7 Is an optionally substituted methyl group.
In some embodiments of compounds having the structure of formula (XI), wherein R is 8 Selected from hydrogen, optionally substituted (C) 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 1 -C 6 ) Acyl and optionally substituted sulfonyl.
In some embodiments of compounds having the structure of formula (XI), wherein R is 8 Selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.
In some embodiments of compounds having the structure of formula (XI), wherein R is 8 Is propenyl.
In some embodiments of compounds having the structure of formula (XI), wherein R is 8 Is butynyl.
In some embodiments of compounds having the structure of formula (XI), wherein R is 8 Is formyl.
In some embodiments of compounds having the structure of formula (XI), wherein R is 8 Is/are R 10 Substituted, R 10 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally takenSubstituted sulfinyl, optionally substituted (C 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of compounds having the structure of formula (XI), wherein R is 10 Selected from the group consisting of hydrogen, optionally substituted hydroxy, optionally substituted amino, and optionally substituted (C 6 -C 10 ) Aryl groups.
In some embodiments of compounds having the structure of formula (XI), wherein R is 10 Is optionally substituted phenyl.
In some embodiments of compounds having the structure of formula (XI), wherein R is 10 Is/are R 11 Substituted, R 11 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In which the compounds have the structure of formula (XI)In some embodiments, wherein the R 11 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
In some embodiments of compounds having the structure of formula (XI), wherein R is 11 Is an optionally substituted methyl group.
In some embodiments of compounds having the structure of formula (XI), wherein R is 9 Selected from hydrogen and optionally substituted sulfonyl.
In some embodiments of compounds having the structure of formula (XI), wherein R is 9 Is/are R 12 Substituted, R 12 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of compounds having the structure of formula (XI), wherein R is 12 Selected from hydrogen and optionally substituted amino.
The present disclosure provides a compound, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:
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The present disclosure provides compounds having the structure of formula (XII),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
R X is halogen;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 and R 7 Are each independently absent or are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl;
n and m are each independently not less than 0.
In some embodiments of compounds having the structure of formula (XII), wherein R X F.
In some embodiments of compounds having the structure of formula (XII), wherein R 1 Is hydrogen.
In some embodiments of compounds having the structure of formula (XII), wherein R 2 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
In some embodiments of compounds having the structure of formula (XII), wherein R 2 Is an optionally substituted isopropyl group.
In some embodiments of compounds having the structure of formula (XII), wherein R 3 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
In some embodiments of compounds having the structure of formula (XII), wherein R 3 Is an optionally substituted methyl group.
In some embodiments of compounds having the structure of formula (XII), wherein n is selected from 1 to 4.
In some embodiments of compounds having the structure of formula (XII), wherein n is 4.
In some embodiments of compounds having the structure of formula (XII), wherein R 4 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An acyl group.
In some embodiments of compounds having the structure of formula (XII), wherein R 4 Is optionally substituted propionyl.
In some embodiments of compounds having the structure of formula (XII), wherein R 4 Is/are R 9 Substituted, R 9 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted sulfurSubstituted, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In some embodiments of compounds having the structure of formula (XII), wherein R 9 Selected from hydrogen, optionally substituted amino, optionally substituted (C 1 -C 6 ) Alkyl and optionally substituted (C) 6 -C 10 ) Aryl groups.
In some embodiments of compounds having the structure of formula (XII), wherein R 9 Is an optionally substituted methyl group.
In some embodiments of compounds having the structure of formula (XII), wherein R 9 Is optionally substituted phenyl.
In some embodiments of compounds having the structure of formula (XII), wherein R 5 Is hydrogen.
In some embodiments of compounds having the structure of formula (XII), wherein R 6 Is hydrogen.
In some embodiments of compounds having the structure of formula (XII), wherein R 7 Is hydrogen.
The present disclosure provides a compound, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:/>
the present disclosure provides a compound, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:
the present disclosure provides a compound, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is
The present disclosure provides a compound, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:
the present disclosure provides a compound, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is
The present disclosure provides a compound, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or any combination thereof A solvate or hydrate of the molecule, wherein the compound is selected from the group consisting of:
the present disclosure provides a compound, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:
the present disclosure provides a compound, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:/>
the present disclosure provides a compound, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:
the present disclosure provides a compound, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:/>
the present disclosure provides a compound, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:/>
the present disclosure provides a compound, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of: />
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The present disclosure provides a compound, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:/>
the present disclosure provides a compound or a pharmaceutical thereofA pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of: />
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the present disclosure provides a composition comprising a compound of the present application, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the above components, and optionally a pharmaceutically acceptable carrier.
The present disclosure provides a method for inhibiting Cyclin Dependent Kinase (CDK) activity, comprising administering to a subject in need thereof an effective amount of a compound of the present application, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing.
In some embodiments, wherein the Cyclin Dependent Kinase (CDK) is CDK 7.
In some embodiments, wherein the method is selected from the group consisting of an in vitro method, an ex vivo method, and an in vivo method.
Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in the art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments and its several details are capable of modification in various obvious respects, all without departing from the present disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.
Incorporation by reference
All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.
Detailed Description
While various embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Many changes, modifications and substitutions may be made by one of ordinary skill in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed.
As used herein, the term "alkyl", alone or in other terms, generally refers to a straight or branched chain saturated hydrocarbyl substituent containing from 1 to 20 carbon atoms (i.e., a substituent obtained from a hydrocarbon by removal of hydrogen); for example 1 to 12 carbon atoms; in another example from 1 to 10 carbon atoms; in another embodiment from 1 to 6 carbon atoms; and in another embodiment from 1 to 4 carbon atoms (e.g., 1, 2, 3, or more carbon atoms). Examples of such substituents may includeSuch as methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl, isopentyl, hexyl, and the like. In some cases, the number of carbon atoms in the hydrocarbyl substituent (i.e., alkyl, alkenyl, cycloalkyl, aryl, etc.) may be prefixed with the prefix "C a -C b "means that where a is the minimum number of carbon atoms in the substituent and b is the maximum number of carbon atoms in the substituent. Thus, for example, "C 1 -C 6 Alkyl "may refer to alkyl substituents containing from 1 to 6 carbon atoms. The "alkyl" group may be optionally substituted with one or more substitutions.
As used herein, the term "alkenyl", alone or in other terms, generally refers to a straight or branched chain carbon radical having at least one carbon-carbon double bond. The term "alkenyl" may comprise conjugated and non-conjugated carbon-carbon double bonds or combinations thereof. An alkenyl group, for example, but not limited to, may contain 2 to about 20 carbon atoms, or in particular embodiments, may contain 2 to about 12 carbon atoms. In embodiments, the alkenyl group may contain 2 to about 4 carbon atoms (e.g., 2, 3, or more carbon atoms). Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The term "alkenyl" includes groups having "cis" and "trans" orientations, or alternatively, having "E" and "Z" orientations. In some cases, the number of carbon atoms may be prefixed with the prefix "C a -C b "means that where a is the minimum number of carbon atoms in the substituent and b is the maximum number of carbon atoms in the substituent. The "alkenyl" group may be optionally substituted with one or more substitutions.
As used herein, the term "alkynyl", whether alone or in other terms, generally refers to a straight or branched chain carbon radical having at least one carbon-carbon triple bond. The term "alkynyl" may include conjugated and non-conjugated carbon-carbon triple bonds or combinations thereof. Alkynyl groups, for example and without limitation, may contain 2 to about 20 carbon atoms, or in particular embodiments, may contain 2 to about 12 carbon atoms. In embodiments, alkynyl groups may contain 2 to about 10 carbon atoms. Some examples may be alkynyl groups having 2 to about 4 carbon atoms (e.g., 2, 3, or more carbon atoms). In some cases, the number of carbon atoms may be prefixed with the prefix "C a -C b "means that where a is the minimum number of carbon atoms in the substituent and b is the maximum number of carbon atoms in the substituent. Examples of such groups include propargyl, butynyl, and the like. The "alkynyl" group may be optionally substituted with one or more substitutions.
As used herein, the term "amino", whether alone or in other terms, generally refers to the formula-NH 2 A group. The "amino" group may be optionally substituted with one or more substitutions.
As used herein, the term "carbocycle", whether alone or in other terms, generally refers to a saturated or unsaturated, non-aromatic, monocyclic, bicyclic, or polycyclic ring system having 3 to 14 ring atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), wherein all ring atoms are carbon atoms. A monocyclic carbocyclic ring may have 3 to 6 ring atoms, or 5 to 6 ring atoms. Bicyclic carbocycles may have 7 to 12 ring atoms, e.g. arranged as bicyclo [4,5 ]]、[5,5]Or [6,6 ]]Is, or is arranged as, bicyclo [ 5.6 ]]Or [6,6 ]]9 or 10 ring atoms. The term "carbocycle" may include, for example, a monocyclic carbocycle fused to an aryl ring (e.g., a monocyclic carbocycle fused to a benzene ring). Carbocycles may have 3 to 8 carbon ring atoms. In some cases, the number of carbon atoms may be prefixed with the prefix "C a -C b "means that where a is the minimum number of carbon atoms in the substituent and b is the maximum number of carbon atoms in the substituent. The "carbocyclic" group may be optionally substituted with one or more substitutions.
As used herein, the term "heterocycle", alone or in other terms, generally refers to a monocyclic, bicyclic, or polycyclic ring system having from 3 to 14 ring atoms (also referred to as ring members), wherein at least one ring atom in at least one ring may be a heteroatom selected from N, O, P or S (and all combinations and subcombinations of ranges and specific numbers of carbon atoms and heteroatoms therein). The heterocycle may have 1 to 4 ring heteroatoms independently selected from N, O, P or S. One or more N, C or S atoms in the heterocyclic ring The seed may be oxidized. The monocyclic heterocycle may have 3 to 7 ring members (e.g., 2 to 6 carbon atoms and 1 to 3 heteroatoms independently selected from N, O, P or S), and the bicyclic heterocycle may have 5 to 10 ring members (e.g., 4 to 9 carbon atoms and 1 to 3 heteroatoms independently selected from N, O, P or S). The heterocyclic ring containing a heteroatom may be non-aromatic. Unless otherwise indicated, a heterocycle is attached to its pendant group on any heteroatom or carbon atom that results in a stable structure. In some cases, the number of carbon atoms may be prefixed with the prefix "C a -C b "means that where a is the minimum number of carbon atoms in the substituent and b is the maximum number of carbon atoms in the substituent. The "heterocyclic" group may be optionally substituted with one or more substitutions.
As used herein, the term "aryl", alone or in other terms, generally refers to an aromatic substituent containing one ring or two or three fused rings. The aryl substituent may have from 6 to 18 carbon atoms. For example, an aryl substituent may have 6 to 14 carbon atoms. The term "aryl" may refer to substituents such as phenyl, naphthyl, and anthracenyl. The term "aryl" may also include fused to C 4 -C 10 Carbocycles (e.g. C 5 Or C 6 Carbocycle) or substituents fused to a four to ten membered heterocyclic ring, such as phenyl, naphthyl and anthracenyl, wherein the group having such fused aryl group as a substituent is bonded to the aromatic carbon of the aryl group. When such fused aryl groups are substituted with one or more substituents, the one or more substituents may each be bound to an aromatic carbon of the fused aryl group unless otherwise specified. Condensed C 4 -C 10 The carbocycle or quaternary to deca-membered heterocycle may be optionally substituted. Examples of aryl groups may accordingly include phenyl, naphthyl, tetrahydronaphthyl (also referred to as "tetrahydronaphthalene"), indenyl, isoindenyl, indanyl, anthracenyl, phenanthrenyl, benzonaphthylene (also referred to as "phenalenyl radical"), and fluorenyl. In some cases, the number of carbon atoms may be prefixed with the prefix "C a -C b "means that where a is the minimum number of carbon atoms in the substituent and b is the maximum number of carbon atoms in the substituent. The "aryl" group may optionally be taken by one or moreSubstituted by a substituent.
As used herein, the term "heteroaryl", whether alone or in other terms, generally refers to an aromatic ring structure comprising 5 to 14 ring atoms, at least one of which is a heteroatom (e.g., oxygen, nitrogen, or sulfur), the remaining ring atoms being independently selected from carbon, oxygen, nitrogen, or sulfur. Heteroaryl groups may be monocyclic or 2 or 3 fused rings. Examples of heteroaryl substituents may include, but are not limited to: 6-membered ring substituents such as pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl; a 5-membered ring substituent such as triazolyl, imidazolyl, furanyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2, 5-or 1,3, 4-oxadiazolyl and isothiazolyl; 6/5 membered condensed ring substituents such as benzothiofuranyl, isobenzofuranyl, benzisoxazolyl, benzoxazolyl, purinyl and anthranilic anhydride groups; and 6/6 membered fused ring substituents such as quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl and 1, 4-benzoxazinyl. In a group having a heteroaryl substituent, the ring atom of the heteroaryl substituent bound to the group may be the at least one heteroatom, or it may be a ring carbon atom, wherein the ring carbon atom may be in the same ring as the at least one heteroatom, or wherein the ring carbon atom may be in a different ring than the at least one heteroatom. Similarly, if the heteroaryl substituent is in turn substituted with a group or substituent, the group or substituent may be bound to the at least one heteroatom, or it may be bound to a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom, or where the ring carbon atom may be in a different ring than the at least one heteroatom. In some cases, the number of carbon atoms may be prefixed with the prefix "C a -C b "means that where a is the minimum number of carbon atoms in the substituent and b is the maximum number of carbon atoms in the substituent. The "heteroaryl" group may be optionally substituted with one or more substitutions.
As used herein, the term "halogen", whether alone or in other terms, generally refers to fluorine (which may be described as-F), chlorine (which may be described as-Cl), bromine (which may be described as-Br), or iodine (which may be described as-I). In one embodiment, the halogen may be chlorine. In another embodiment, the halogen may be fluorine. In another embodiment, the halogen may be bromine.
As used herein, the term "cyano", whether alone or in other terms, generally refers to a group of formula-CN.
As used herein, the term "nitro", whether alone or in other terms, generally refers to the formula-NO 2 A group.
As used herein, the term "hydroxy", whether alone or in other terms, generally refers to a group of formula-OH. The "hydroxy" group may be optionally substituted with one or more substitutions.
As used herein, the term "phosphorus-containing group", whether alone or in other terms, generally refers to a functional group containing one or more phosphorus atoms. The phosphorus-containing group may be referred to as-O-P- (OH) 2 、-O-PH-(OH)、-O-PH 2 、-P-(OH) 2 、-PH-(OH)、-PH 4 、-PH 2 ＝CH 2 、-CH＝PH 3 、-O-P(＝O) 2 、-O-P(＝O)-(OH) 2 、-O-PH(＝O)-OH、-P(＝O)-(OH) 2 、-O-PH 2 (＝O)、-PH(＝O)-OH、-PH 2 (＝O)、-O-P(＝O)(OH)-P(＝O)(OH) 2 、-O-P(＝O)(OH)-O-P(＝O)(OH) 2 、-PH-PH 2 Or-p=ph. The "phosphorus-containing group" may be optionally substituted with one or more substitutions.
As used herein, the term "silicon-containing group", whether alone or in other terms, generally refers to a functional group containing one or more silicon atoms. The silicon-containing group may be referred to as-SiH 3 . The "silicon-containing group" may be optionally substituted with one or more substitutions.
As used herein, the term "thio", whether alone or in other terms, generally refers to a group of formula-SH. The "thio" group may be optionally substituted with one or more substitutions.
As used herein, the term "carboxy", whether alone or in other terms, generally refers to an OH group of formula-C (=o). The "carboxyl" group may be optionally substituted with one or more substitutions.
As used herein, the term "sulfonyl", whether alone or in other terms, generally refers to the formula-S (=o) 2 -H groups. The "sulfonyl" group may be optionally substituted with one or more substitutions.
As used herein, the term "sulfinyl", whether alone or in other terms, generally refers to a group of formula-S (=o) -H. The "sulfinyl" group may be optionally substituted with one or more substitutions.
As used herein, the term "acyl", alone or in other terms, generally refers to a carboxylate of the formula-C (O) R, wherein the non-carbonyl portion of the ester group (i.e., R) may be selected from linear alkyl, branched alkyl, or cycloalkyl. The term acyl may include, but is not limited to, acetyl, propionyl, butyryl and pentanoyl. In some cases, the number of carbon atoms may be prefixed with the prefix "C a -C b "means that where a is the minimum number of carbon atoms in the substituent and b is the maximum number of carbon atoms in the substituent. The "acyl" group may be optionally substituted with one or more substitutions.
As used herein, the term "thioacyl", alone or in other terms, generally refers to the formula-C (S) R, wherein the portion of the ester group (i.e., R) may be selected from linear alkyl, branched alkyl, or cycloalkyl. In some cases, the number of carbon atoms may be prefixed with the prefix "C a -C b "means that where a is the minimum number of carbon atoms in the substituent and b is the maximum number of carbon atoms in the substituent. The "thioacyl" group may be optionally substituted with one or more substitutions.
As used herein, the term "ring", whether alone or in other terms, generally refers to any covalently closed structure. The ring may include, for example, carbocycles, heterocycles, aryl and heteroaryl groups. The rings may be monocyclic or polycyclic. The "ring" group may be optionally substituted with one or more substitutions.
As used herein, the term "pharmaceutically acceptable salt" generally refers to a salt that is pharmaceutically acceptable and that can possess the desired pharmacological activity of the parent compound. Such salts may include: an acid addition salt with an inorganic acid or with an organic acid or a base addition salt with a conjugate base of any inorganic acid, wherein the conjugate base comprises a cationic component.
As used herein, the term "pharmaceutically acceptable carrier" generally refers to an aqueous or non-aqueous solution, dispersion, suspension or emulsion, as well as sterile powders for reconstitution into a sterile injectable solution or dispersion prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles can include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethyl cellulose and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters such as ethyl oleate. For example, proper fluidity can be maintained by the use of a coating material such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions may also contain adjuvants such as preserving, wetting, emulsifying and dispersing agents. The prevention of the action of microorganisms can be ensured by adding various antibacterial and antifungal agents, such as nipagin, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical forms can be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin. Injectable depot forms can be prepared by forming a microcapsule matrix of the drug in biodegradable polymers such as polylactic acid-polyglycolide, poly (orthoesters) and poly (anhydrides). Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations may be sterilized, for example, by filtration through bacterial-retaining filters, or by the addition of sterilizing agents in the form of sterile solid compositions which may be dissolved or dispersed in sterile water or other sterile injection medium immediately prior to use. Suitable inert carriers may include sugars, such as lactose. Preferably, at least 95% by weight of the active ingredient particles may have an effective particle size in the range of 0.01 to 10 microns.
As used herein, the term "prodrug" generally refers to a compound that is metabolized (e.g., hydrolyzed or oxidized) in a host to form a compound of the invention. Typical examples of prodrugs may include compounds having a biostable protecting group on the functional moiety of the active compound. Prodrugs can include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrogenated, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated to produce an active compound.
As used herein, the term "cyclin dependent kinase" or "CDK" generally refers to a protein having activity in modulating the cell cycle. For example, inhibiting Cyclin Dependent Kinase (CDK) activity may include interacting with a cyclin-CDK complex to block kinase activity. For example, CDKs may include CDK7. The UniPort ID for CDK7 may be P50613.
As used herein, a substituent is "substitutable" or capable of being "substituted" if the substituent contains at least one atom bonded to one or more hydrogen atoms. If a substituent is described as "substituted," a hydrogen or non-hydrogen substituent replaces a hydrogen substituent on the atom of the substituent. Thus, for example, a substituted alkyl substituent is an alkyl substituent in which at least one hydrogen or non-hydrogen substituent replaces a hydrogen substituent on the alkyl substituent. For example, a monofluoroalkyl is an alkyl substituted with one fluoro substituent, and a bifluoroalkyl is an alkyl substituted with two fluoro substituents. It will be appreciated that if there is more than one substitution on a substituent, each substituent may be the same or different (unless otherwise indicated).
If substituents are described as "independently selected," each substituent may be selected independently of the others. Thus, each substituent may be the same as or different from the other substituents.
As used herein, the term "optionally substituted" generally means that a given moiety may consist of only hydrogen substituents through available valences (unsubstituted), or may further include one or more non-hydrogen substituents through available valences (substituted) that are not otherwise specified by the name of the given moiety. For example, "R x Optionally substituted "or" R x Quilt R y Optionally substituted "may mean R x Can be substituted with 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9R y Substitution, e.g. R x Can be substituted with 0, 1, 2, 3, 4 or 5R y Substitution, e.g. R x Can be 1, 2 or 3R y Substitution, e.g. R x Can be one R y Substitution, e.g. R x Can be 2R y Substitution, e.g. R x Can be substituted with 3R y Substitution, e.g. R x Can be substituted by 4R y Substitution, e.g. R x Can be substituted with 5R y Substitution, e.g. R x Can be substituted by 6R y Substitution, e.g. R x Can be substituted by 7R y Substitution, e.g. R x Can be substituted by 8R y Substitution, e.g. R x Can be 9R y And (3) substitution. In general, a non-hydrogen substituent may be any substituent that may be bound to a given moiety at the designated substituted atom. Examples of substituents include, but are not limited to, hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Trifluoromethyl, hydroxy, phosphorus-containing groups, silicon-containing groups, thio, amino, carboxyl, sulfonyl, sulfinyl, (C) 1 -C 6 ) Acyl group (C) 1 -C 6 ) Thioacyl, (C) 1 -C 6 ) Alkyl, (C) 2 -C 6 ) Alkenyl group (C) 2 -C 6 ) Alkynyl, (C) 3 -C 10 ) Carbocycles, (C) 2 -C 9 ) Heterocycles, (C) 6 -C 10 ) Aryl, (C) 1 -C 9 ) Heteroaryl, trifluoromethyl (C) 1 -C 6 ) Alkyl, cyano (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) Alkyl, nitro (C) 1 -C 6 ) Alkyl, hydroxy (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkoxy, (C) 1 -C 6 ) Alkylthio, thio (C) 1 -C 6 ) Alkyl, amino (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkylamino, ((C) 1 -C 6 ) Alkyl group 2 Amino, (C) 1 -C 6 ) Acyl group(C 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkylsulfonyl, (C) 1 -C 6 ) Alkylsulfinyl, hydroxysulfonyl, hydroxysulfinyl, (C) 3 -C 10 ) Carbocycle (C) 1 -C 6 ) Alkyl, (C) 2 -C 9 ) Heterocycle (C) 1 -C 6 ) Alkyl, (C) 6 -C 10 ) Aryl (C) 1 -C 6 ) Alkyl and (C) 1 -C 9 ) Heteroaryl (C) 1 -C 6 ) An alkyl group. In addition, the substituent itself is optionally substituted with another substituent. In a particular embodiment, examples of another substituent include, but are not limited to, hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Trifluoromethyl, hydroxy, phosphorus-containing groups, silicon-containing groups, thio, amino, carboxyl, sulfonyl, sulfinyl, (C) 1 -C 6 ) Acyl group (C) 1 -C 6 ) Thioacyl, (C) 1 -C 6 ) Alkyl, (C) 2 -C 6 ) Alkenyl group (C) 2 -C 6 ) Alkynyl, (C) 3 -C 10 ) Carbocycles, (C) 2 -C 9 ) Heterocycles, (C) 6 -C 10 ) Aryl, (C) 1 -C 9 ) Heteroaryl, trifluoromethyl (C) 1 -C 6 ) Alkyl, cyano (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) Alkyl, nitro (C) 1 -C 6 ) Alkyl, hydroxy (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkoxy, (C) 1 -C 6 ) Alkylthio, thio (C) 1 -C 6 ) Alkyl, amino (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkylamino, ((C) 1 -C 6 ) Alkyl group 2 Amino, (C) 1 -C 6 ) Acyl (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkylsulfonyl, (C) 1 -C 6 ) Alkylsulfinyl, hydroxysulfonyl, hydroxysulfinyl, (C) 3 -C 10 ) Carbocycle (C) 1 -C 6 ) Alkyl, (C) 2 -C 9 ) Heterocycle (C) 1 -C 6 ) Alkyl, (C) 6 -C 10 ) Aryl (C) 1 -C 6 ) Alkyl and (C) 1 -C 9 ) Heteroaryl (C) 1 -C 6 ) An alkyl group.
As used herein, the term "formula" may be referred to hereinafter as "compounds of the invention". Such terms are also defined to include all forms of the compounds of formula (la), including hydrates, solvates, isomers, crystalline and non-crystalline forms, polymorphs, and metabolites thereof. For example, the compound of formula (la) or a pharmaceutically acceptable salt thereof may be present in undissolved and dissolved form. When the solvent or water is tightly bound, the complex may have a well-defined stoichiometry independent of humidity. However, when the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content may depend on humidity and drying conditions. In this case, the non-stoichiometry would be normal.
The compounds of "formula" may have asymmetric carbon atoms. The carbon-carbon bond of the compounds of formula (la) may be depicted herein using solid, solid or dashed wedges. The use of a solid line to depict the bond of an asymmetric carbon atom may be meant to indicate that all possible stereoisomers at that carbon atom (e.g., specific enantiomers, racemic mixtures, etc.) are included. The use of solid or dashed wedges to depict the bonds of asymmetric carbon atoms may be meant to indicate that only the stereoisomers shown are included. The compounds of the present application may contain more than one asymmetric carbon atom. In these compounds, the use of solid lines to depict the bonds of asymmetric carbon atoms may be meant to indicate that all possible stereoisomers are included. For example, unless otherwise indicated, compounds of formula (la) may exist as enantiomers and diastereomers or racemates, and mixtures thereof. The use of solid lines to depict the bond of one or more asymmetric carbon atoms in a compound of formula, and solid or dashed wedges to depict the bond of other asymmetric carbon atoms in the same compound, may be meant to indicate the presence of a mixture of diastereomers.
The compounds of the present application (e.g., compounds of formula (la)) may exist in the form of inclusion complexes or other complexes. Included within the scope of the invention are complexes, such as clathrates, drug-host inclusion complexes, wherein the drug and host may be present in stoichiometric or non-stoichiometric amounts as compared to the solvates described above. Also included may be a compound of the formula containing two or more organic and/or inorganic components, which may be in stoichiometric or non-stoichiometric amounts. The resulting complex may be ionized, partially ionized, or non-ionized.
Stereoisomers of formula (la) may include cis and trans isomers, optical isomers such as R and S enantiomers, diastereomers, geometric isomers, rotamers, conformational isomers and tautomers of compounds of formula (la), including compounds exhibiting more than one isomeric type; and mixtures thereof (e.g., racemates and diastereomeric pairs). Also included may be acid addition salts or base addition salts in which the counterion is optically active, such as D-lactic acid or L-lysine, or racemic, such as DL tartaric acid or DL arginine.
When any racemate is crystallized, two different types of crystals are possible. The first type is the racemic compound (true racemate) mentioned above, in which a homogeneous form of crystals is produced, containing equimolar amounts of the two enantiomers. The second type is a racemic mixture or aggregate, where two forms of crystals are produced in equimolar amounts, each form comprising a single enantiomer.
Compounds of formula (la) may exhibit tautomerism and structural isomerism. For example, the compounds of formula (la) may exist in several tautomeric forms, including the enol and imine forms, the ketone and enamine forms, and geometric isomers and mixtures thereof. All such tautomeric forms may be included within the scope of the compounds of formula (i). Tautomers may exist as a mixture of tautomeric sets in solution. In solid form, one tautomer is usually predominant. Even though one tautomer may be described, the present invention includes all tautomers of the compounds of formula (la).
The invention also includes isotopically-labelled compounds, which are identical to those recited in the formula above, but for the fact that one or more atoms may be of an atomic mass or mass number different from those usually found in natureAtoms of atomic mass or mass number are substituted. Examples of isotopes that can be included into compounds of formula (la) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to 2 H、 3 H、 13 C、 14 C、 15 N、 18 O、 17 O、 31 P、 32 P、 35 S、 18 F and F 36 Cl. Certain isotopically-labelled compounds of formula (la), e.g. incorporating radioactive isotopes such as 3 H and 14 the compound of C can be used for medicine and/or matrix tissue distribution determination. Tritiated isotopes (i.e., due to their ease of preparation and detection 3 H) And carbon-14 (i.e 14 C) Isotopes may be particularly useful. In addition, the use of heavier isotopes such as deuterium (i.e 2 H) Substitution may provide certain therapeutic advantages resulting from higher metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and thus may be used in certain circumstances. Isotopically-labeled compounds of formula (la) can generally be prepared by carrying out the procedures disclosed in the schemes and/or in the examples below, by substituting a non-isotopically-labeled reagent with an isotopically-labeled reagent.
The compounds of the present application may be used in the form of salts derived from inorganic or organic acids. Depending on the particular compound, salts of the compound may be advantageous due to one or more physical properties of the salt, such as enhanced drug stability at different temperatures and humidities, or desired solubility in water or oil. In some cases, salts of the compounds may also be used as adjuvants for the isolation, purification and/or decomposition of the compounds.
Compounds of formula (I)
In one aspect, the present application provides compounds having the structure of formula (I),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R is 8 May be independently absent or may be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl;
n may be not less than 0.
In the compound with the structure of the general formula (I), wherein R 1 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group.
In the compound with the structure of the general formula (I), wherein R 1 May be an optionally substituted methyl group.
In the compound with the structure of the general formula (I), wherein R 1 May be one or more R 9 Substituted, R 9 Can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally takenSubstituted (C) 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In the compound with the structure of the general formula (I), wherein R 9 May be selected from hydrogen and optionally substituted (C 6 -C 10 ) Aryl groups.
In the compound with the structure of the general formula (I), wherein R 9 May be optionally substituted phenyl.
In the compound with the structure of the general formula (I), wherein R 9 May be one or more R 10 Substituted, R 10 Can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In the compound with the structure of the general formula (I), wherein R 10 Can be independently selected from hydrogen, optionally substituted amino and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
Among the compounds having the structure of the general formula (I), wherein,the R is 10 May be optionally substituted pyrazolyl.
In the compound with the structure of the general formula (I), wherein R 10 May be respectively substituted by one or more R 11 Substituted, R 11 Can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In the compound with the structure of the general formula (I), wherein R 11 Can be independently selected from hydrogen, =o and optionally substituted (C 1 -C 6 ) An alkyl group.
In the compound with the structure of the general formula (I), wherein R 11 May be an optionally substituted methyl group.
In the compound with the structure of the general formula (I), wherein R 2 May be hydrogen.
In the compound with the structure of the general formula (I), wherein R 3 May be hydrogen.
In the compound with the structure of the general formula (I), wherein R 4 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group.
In the compound with the structure of the general formula (I), wherein R 4 May be an optionally substituted isopropyl group.
Tool for putting onIn the compound with the structure of the general formula (I), wherein R 5 May be selected from hydrogen, optionally substituted amino and optionally substituted (C 2 -C 9 ) A heterocycle.
In the compound with the structure of the general formula (I), wherein R 5 May be an optionally substituted amino group.
In the compound with the structure of the general formula (I), wherein R 5 May be optionally substituted C 4 A heterocycle.
In the compound with the structure of the general formula (I), wherein R 5 May be an optionally substituted heterocyclic ring containing two heteroatoms.
In the compound with the structure of the general formula (I), wherein R 5 May be an optionally substituted heterocyclic ring containing two nitrogen atoms.
In the compound with the structure of the general formula (I), wherein R 5 May be one or more R 12 Substituted, R 12 Can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In the compound with the structure of the general formula (I), wherein R 12 Can be independently selected from hydrogen, optionally substituted (C) 1 -C 6 ) Alkyl and optionally substituted (C) 2 -C 9 ) A heterocycle.
In the compound with the structure of the general formula (I), wherein R 12 May be optionally substituted C 4 Heterocyclic or optionally substituted C 5 A heterocycle.
In the compound with the structure of the general formula (I), wherein R 12 May be an optionally substituted heterocyclic ring containing one heteroatom.
In the compound with the structure of the general formula (I), wherein R 12 May be an optionally substituted heterocyclic ring containing one nitrogen atom.
In the compound with the structure of the general formula (I), wherein R 6 May be hydrogen.
In the compound with the structure of the general formula (I), wherein R 7 May be hydrogen.
In the compound with the structure of the general formula (I), wherein R 8 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group.
In the compound with the structure of the general formula (I), wherein R 1 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group; the R is 1 May be one or more R 9 Substitution, said R 9 May be optionally substituted phenyl; the R is 9 May be one or more R 10 Substitution, said R 10 Can be independently selected from hydrogen and optionally substituted (C) 1 -C 9 ) Heteroaryl; the R is 2 May be hydrogen; the R is 3 May be hydrogen; the R is 4 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group; the R is 5 May be selected from hydrogen and optionally substituted C containing two nitrogen atoms 4 A heterocycle; the R is 5 May be one or more R 12 Substitution, said R 12 May be optionally substituted C containing a heteroatom 4 Heterocyclic or optionally substituted C containing one hetero atom 5 A heterocycle; r is R 6 May be hydrogen; r is R 7 May be hydrogen; and said R is 8 Can be selected from hydrogen and optionally beSubstituted (C) 1 -C 6 ) An alkyl group.
In some cases, the present application provides a compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound may be selected from:
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in another aspect, the present application provides compounds having the structure of formula (II),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 and R 7 May be independently absent or may be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In the compound having the structure of the general formula (II), wherein R 1 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group.
In the compound having the structure of the general formula (II), wherein R 1 May be an optionally substituted methyl group.
In the compound having the structure of the general formula (II), wherein R 1 May be one or more R 8 Substituted, R 8 Can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In the compound having the structure of the general formula (II), wherein R 8 May be selected from hydrogen and optionally substituted (C 6 -C 10 ) Aryl groups.
In the compound having the structure of the general formula (II), wherein R 8 May be optionally substituted phenyl.
In the compound having the structure of the general formula (II), wherein R 8 May be one or more R 9 Substituted, R 9 Can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano,Nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In the compound having the structure of the general formula (II), wherein R 9 May be selected from hydrogen and optionally substituted (C 1 -C 9 ) Heteroaryl groups.
In the compound having the structure of the general formula (II), wherein R 9 May be optionally substituted pyrazolyl.
In the compound having the structure of the general formula (II), wherein R 2 May be hydrogen.
In the compound having the structure of the general formula (II), wherein R 3 May be hydrogen.
In the compound having the structure of the general formula (II), wherein R 4 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group.
In the compound having the structure of the general formula (II), wherein R 4 May be selected from hydrogen and optionally substituted isopropyl.
In the compound having the structure of the general formula (II), wherein R 5 May be hydrogen.
In the compound having the structure of the general formula (II), wherein R 6 May be hydrogen.
In the compound having the structure of the general formula (II), wherein R 7 May be hydrogen.
In the compound having the structure of the general formula (II), wherein R 1 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group; the R is 1 May be one or more R 8 Substitution, said R 8 May be optionally substituted phenyl; the R is 8 May be one or more R 9 Substitution, said R 9 May be optionally substituted pyrazolyl; the R is 2 May be hydrogen; the R is 3 May be hydrogen; the R is 4 May be selected from hydrogen and optionally substituted isopropyl; the R is 5 May be hydrogen; the R is 6 May be hydrogen; and said R is 7 May be hydrogen.
In some cases, the present application provides a compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound can be:
in some cases, the present application provides a compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound can be:
in another aspect, the present application provides compounds having the structure of formula (III),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
X 1 and X 2 Can be respectively and independentlySelected from C, N and O;
a may be selected from optionally substituted (C 2 -C 9 ) Heterocycles and optionally substituted (C) 1 -C 9 ) Heteroaryl;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 and R is 10 May be independently absent or may be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl;
n and m may each independently be not less than 0.
In the compound having the structure of the general formula (III), wherein, X 1 May be N.
In the compound having the structure of the general formula (III), wherein, X 2 May be C.
In the compounds having the structure of formula (III), wherein the A may be optionally substituted (C 1 -C 9 ) Heteroaryl groups.
In the compounds having the structure of formula (III), wherein the A may be optionally substituted C 3 Heteroaryl groups.
In the compounds having the structure of formula (III), wherein a may be optionally substituted pyrazolyl.
In the compound having the structure of the general formula (III), wherein R 1 May be hydrogen.
In the compound having the structure of the general formula (III), wherein R 2 May be hydrogen.
In the compound having the structure of the general formula (III), wherein R 3 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group.
In the compound having the structure of the general formula (III), wherein R 3 May be an optionally substituted isopropyl group.
In the compound having the structure of the general formula (III), wherein R 4 May be hydrogen.
In the compound having the structure of the general formula (III), wherein R 5 May be hydrogen.
In the compound having the structure of the general formula (III), wherein R 6 May be hydrogen.
In the compound having the structure of the general formula (III), wherein R 7 May be hydrogen.
In the compound having the structure of the general formula (III), wherein R 8 May be hydrogen.
In the compound having the structure of the general formula (III), wherein R 9 May be hydrogen, respectively.
In the compound having the structure of the general formula (III), wherein R 10 May be hydrogen, respectively.
In the compound having the structure of the general formula (III), wherein, X 1 May be N; the X is 2 May be C; the A may be optionally substituted C 3 Heteroaryl; the R is 3 May be optionally substituted isopropyl; and said R is 1 And R is 4 To R 11 May be hydrogen.
In some cases, the present application provides a compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound can be:
in another aspect, the present application provides compounds having the structure of formula (IV),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R is 8 May be independently absent or may be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) A heteroaryl group, which is a group,
n and m may each independently be not less than 0.
In the compound having the structure of the general formula (IV), wherein R 1 May be hydrogen.
In the compound having the structure of the general formula (IV), wherein R 2 May be hydrogen.
In the compound having the structure of the general formula (IV), wherein R 3 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group.
In the compound having the structure of the general formula (IV), wherein R 3 May be an optionally substituted isopropyl group.
In the compound having the structure of the general formula (IV), wherein R 4 May be selected from hydrogen, optionally substituted (C) 1 -C 6 ) Acyl and optionally substituted (C) 1 -C 6 ) An alkyl group.
In the compound having the structure of the general formula (IV), wherein R 4 May be optionally substituted propionyl.
In the compound having the structure of the general formula (IV), wherein R 4 May be an optionally substituted methyl group.
In the compound having the structure of the general formula (IV), wherein R 4 May be one or more R 9 Substituted, R 9 Can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In the compound having the structure of the general formula (IV), wherein R 9 May be selected from hydrogen, optionally substituted amino, optionally substituted (C 1 -C 6 ) Alkyl groupOptionally substituted (C) 6 -C 10 ) Aryl groups.
In the compound having the structure of the general formula (IV), wherein R 9 May be an optionally substituted methyl group.
In the compound having the structure of the general formula (IV), wherein R 9 May be optionally substituted phenyl.
In the compound having the structure of the general formula (IV), wherein R 5 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group.
In the compound having the structure of the general formula (IV), wherein R 5 May be an optionally substituted methyl group.
In the compound having the structure of the general formula (IV), wherein R 6 May be hydrogen.
In the compound having the structure of the general formula (IV), wherein R 7 May be selected from hydrogen and optionally substituted (C 1 -C 9 ) Heteroaryl groups.
In the compound having the structure of the general formula (IV), wherein R 7 May be optionally substituted C 3 Heteroaryl groups.
In the compound having the structure of the general formula (IV), wherein R 7 May be optionally substituted pyrazolyl.
In the compound having the structure of the general formula (IV), wherein n may be 1.
In the compound having the structure of the general formula (IV), wherein R 8 May be hydrogen.
In the compound having the structure of the general formula (IV), wherein R 1 May be hydrogen; the R is 2 May be hydrogen; the R is 3 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group; the R is 4 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group; the R is 5 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group; the R is 6 May be hydrogen; the R is 7 May be optionally substituted C containing two nitrogen atoms 3 Heteroaryl; the n may be 1; and said R is 8 May be hydrogen.
In some cases, the present application provides a compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound may be selected from:
In some cases, the present application provides a compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound may be selected from:
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in another aspect, the present application provides compounds having the structure of formula (V),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 and R is 11 May be independently absent or may be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containingA group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl;
n and m may each independently be not less than 0.
In the compound having the structure of the general formula (V), wherein R 1 May be hydrogen.
In the compound having the structure of the general formula (V), wherein R 2 May be hydrogen.
In the compound having the structure of the general formula (V), wherein R 3 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group.
In the compound having the structure of the general formula (V), wherein R 3 May be an optionally substituted methyl group.
In the compound having the structure of the general formula (V), wherein R 4 May be hydrogen.
In the compound having the structure of the general formula (V), wherein R 5 May be hydrogen.
In the compound having the structure of the general formula (V), wherein R 6 May be hydrogen.
In the compound having the structure of the general formula (V), wherein R 7 May be hydrogen.
In the compound having the structure of the general formula (V), wherein R 8 May be selected from hydrogen and optionally substituted sulfonyl.
In the compound having the structure of the general formula (V), wherein R 8 May be one or more R 12 Substituted, R 12 Can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In the compound having the structure of the general formula (V), wherein R 12 May be selected from hydrogen and optionally substituted (C 6 -C 10 ) Aryl groups.
In the compound having the structure of the general formula (V), wherein R 12 May be optionally substituted phenyl.
In the compound having the structure of the general formula (V), wherein R 12 May be one or more R 13 Substituted, R 13 Can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl group,Optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In the compound having the structure of the general formula (V), wherein R 13 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group.
In the compound having the structure of the general formula (V), wherein R 13 May be an optionally substituted methyl group.
In the compound having the structure of the general formula (V), wherein R 9 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group.
In the compound having the structure of the general formula (V), wherein R 9 May be an optionally substituted methyl group.
In the compound having the structure of the general formula (V), wherein n may be 1.
In the compound having the structure of the general formula (V), wherein R 9 May be one or more R 14 Substituted, R 14 Can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In the compound having the structure of the general formula (V), wherein R 14 May be selected from hydrogen and optionally substituted hydroxy.
In the compound having the structure of the general formula (V), wherein R 10 May be hydrogen.
In the compound having the structure of the general formula (V), wherein R 11 May be selected from hydrogen, halogen and optionally substituted (C 1 -C 9 ) Heteroaryl groups.
In the compound having the structure of the general formula (V), wherein R 11 May be F.
In the compound having the structure of the general formula (V), wherein m may be 2.
In the compound having the structure of the general formula (V), wherein R 11 May be optionally substituted C 3 Heteroaryl groups.
In the compound having the structure of the general formula (V), wherein R 11 May be optionally substituted pyrazolyl.
In the compound having the structure of the general formula (V), wherein R 1 May be hydrogen; the R is 2 May be hydrogen; the R is 3 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group; the R is 4 To R 8 May be hydrogen; the R is 9 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group; the R is 9 May be one or more R 14 Substitution, said R 14 May be selected from hydrogen and optionally substituted hydroxy; the R is 10 May be hydrogen; the m may be 1 to 2; and said R is 11 May be selected from hydrogen, halogen and optionally substituted C containing two nitrogen atoms 3 Heteroaryl groups.
In some cases, the present application provides a compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound may be selected from:
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in another aspect, the present application provides compounds having the structure of formula (VI),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
X 1 and X 2 May be independently selected from C, N and O;
a may be selected from optionally substituted (C 2 -C 9 ) Heterocycles and optionally substituted (C) 1 -C 9 ) Heteroaryl;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 and R 7 May be independently absent or may be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl;
n may be not less than 0.
In the compound having the structure of the general formula (VI), wherein, the X 1 May be N.
In the compound having the structure of the general formula (VI), wherein, the X 2 May be C.
In the compounds having the structure of formula (VI), wherein the A may be optionally substituted (C 1 -C 9 ) Heteroaryl groups.
In the compounds having the structure of formula (VI), wherein A may be optionally substituted C 3 Heteroaryl groups.
In the compounds having the structure of formula (VI), wherein a may be optionally substituted pyrazolyl.
In the compounds having the structure of formula (VI), wherein the A may be substituted with one or more R 8 Substituted, R 8 Can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In the compound having the structure of the general formula (VI), wherein R 8 May be selected from hydrogen, optionally substituted amino and optionally substituted (C 1 -C 6 ) An alkyl group.
In the compound having the structure of the general formula (VI), wherein R 8 May be an optionally substituted methyl group.
In the compound having the structure of the general formula (VI), wherein R 8 May be one or more R 9 Substituted, R 9 Can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In the compound having the structure of the general formula (VI), wherein R 9 May be selected from hydrogen and halogen.
In the compound having the structure of the general formula (VI), wherein R 9 May be F.
In the compound having the structure of the general formula (VI), wherein R 1 May be hydrogen.
In the compound having the structure of the general formula (VI), wherein R 2 May be hydrogen.
In the compound having the structure of the general formula (VI), wherein R 3 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group.
In the compound having the structure of the general formula (VI), wherein R 3 May be an optionally substituted isopropyl group.
In the compound having the structure of the general formula (VI), wherein R 4 May be selected from hydrogen and optionally substituted hydroxy.
In the compound having the structure of the general formula (VI), wherein R 5 May be hydrogen.
In the compound having the structure of the general formula (VI), wherein R 6 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group.
In the compound having the structure of the general formula (VI), wherein R 6 May be an optionally substituted methyl group.
In the compound having the structure of the general formula (VI), wherein R 6 May be one or more R 10 Substituted, R 10 Can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In the compound having the structure of the general formula (VI), wherein R 10 May be selected from hydrogen and optionally substituted (C 6 -C 10 ) Aryl groups.
In the compound having the structure of the general formula (VI), wherein R 10 May be optionally substituted phenyl.
In the compound having the structure of the general formula (VI), wherein R 10 May be one or more R 11 Substituted, R 11 Can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, =O、N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In the compound having the structure of the general formula (VI), wherein R 11 May be selected from hydrogen and optionally substituted (C 1 -C 9 ) Heteroaryl groups.
In the compound having the structure of the general formula (VI), wherein R 11 May be optionally substituted pyrazolyl.
In the compound having the structure of the general formula (VI), wherein R 7 May be hydrogen.
In the compound having the structure of the general formula (VI), wherein, the X 1 May be N; the X is 2 May be C; the A may be optionally substituted C containing two nitrogen atoms 3 Heteroaryl; the A may be substituted with one or more R 8 Substitution, said R 8 May be selected from hydrogen, optionally substituted amino and optionally substituted (C 1 -C 6 ) An alkyl group; the R is 8 May be one or more R 9 Substitution, said R 9 May be selected from hydrogen and halogen; r is R 1 And R is 2 May be hydrogen; the R is 3 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group; the R is 4 May be selected from hydrogen and optionally substituted hydroxy; the R is 5 May be hydrogen; the R is 6 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group; the R is 6 May be one or more R 10 Substitution, said R 10 May be selected from hydrogen and optionally substituted (C 6 -C 10 ) An aryl group; the R is 10 May be one or more R 11 Substitution, said R 11 May be selected from hydrogen and optionally substituted C containing two nitrogen atoms 3 Heteroaryl; and said R is 7 May be hydrogen.
In some cases, the present application provides a compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound may be selected from:
in another aspect, the present application provides compounds having the structure of formula (VII),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
Wherein,
X 1 and X 2 May be independently selected from C, N and O;
a may be selected from optionally substituted (C 2 -C 9 ) Heterocycles and optionally substituted (C) 1 -C 9 ) Heteroaryl;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R is 8 May be independently absent or may be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, =O、N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl;
n and m may each independently be not less than 0.
In the compound having the structure of the general formula (VII), wherein, X 1 May be N.
In the compound having the structure of the general formula (VII), wherein, X 2 May be C.
In the compounds having the structure of formula (VII), wherein the A may be optionally substituted (C 1 -C 9 ) Heteroaryl groups.
In the compounds having the structure of formula (VII), wherein the A may be optionally substituted C 3 Heteroaryl groups.
In the compounds having the structure of formula (VII), wherein a may be optionally substituted pyrazolyl.
In the compound having the structure of the general formula (VII), wherein R 1 May be hydrogen.
In the compound having the structure of the general formula (VII), wherein R 2 May be selected from hydrogen, optionally substituted (C) 1 -C 6 ) Alkyl and optionally substituted (C) 3 -C 10 ) Carbocycles.
In the compound having the structure of the general formula (VII), wherein R 2 May be an optionally substituted isopropyl group.
In the compound having the structure of the general formula (VII), wherein R 2 May be optionally substituted C 5 Carbocycles.
In the compound having the structure of the general formula (VII), wherein R 2 May be optionally substituted cyclopentyl.
In the compound having the structure of the general formula (VII), wherein R 3 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group.
In the compound having the structure of the general formula (VII), wherein R 3 May be methyl.
In the compound having the structure of the general formula (VII), wherein R 4 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group.
In the compound having the structure of the general formula (VII), wherein R 4 May be methyl.
In the compound having the structure of the general formula (VII), wherein R 5 May be hydrogen.
In the compound having the structure of the general formula (VII), wherein R 6 May be independently selected from hydrogen and halogen.
In the compound having the structure of the general formula (VII), wherein R 6 May be halogen.
In the compound having the structure of the general formula (VII), wherein R 6 May be F.
In the compound having the structure of the general formula (VII), wherein n may be 1.
In the compound having the structure of the general formula (VII), wherein R 7 May be hydrogen.
In the compound having the structure of the general formula (VII), wherein, X 1 May be N; the X is 2 May be C; the A may be optionally substituted (C 1 -C 9 ) Heteroaryl; the R is 1 May be hydrogen; the R is 2 May be selected from hydrogen, optionally substituted (C) 1 -C 6 ) Alkyl and optionally substituted (C) 3 -C 10 ) A carbocycle; the R is 3 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group; the R is 4 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group; the R is 5 May be hydrogen; the R is 6 May be independently selected from hydrogen and halogen; the n may be 1; and said R is 7 May be hydrogen.
In the compound having the structure of the general formula (VII), wherein, X 1 May be N; the X is 2 May be C; the A may be optionally substituted C 3 Heteroaryl; the R is 1 May be hydrogen; the R is 2 May be selected from hydrogen, optionally substituted (C) 1 -C 3 ) Alkyl and optionally substituted (C) 3 -C 5 ) A carbocycle; the R is 3 May be selected from hydrogen and optionally substituted (C 1 -C 3 ) An alkyl group; the R is 4 May be selected from hydrogen and optionally substituted (C 1 -C 3 ) An alkyl group; the R is 5 May be hydrogen; the R is 6 May be independently selected from hydrogen and halogen; the n may be 1; and said R is 7 May be hydrogen.
In the compound having the structure of the general formula (VII), wherein, X 1 May be N; the X is 2 May be C; the A may be optionally substituted C containing two nitrogen atoms 3 Heteroaryl; the R is 1 May be hydrogen; the R is 2 May be selected from hydrogen, optionally substituted (C) 1 -C 3 ) Alkyl and optionally substituted (C) 3 -C 5 ) A carbocycle; the R is 3 May be selected from hydrogen and optionally substituted (C 1 -C 3 ) An alkyl group; the R is 4 May be selected from hydrogen and optionally substituted (C 1 -C 3 ) An alkyl group; the R is 5 May be hydrogen; the R is 6 May be independently selected from hydrogen and halogen; the n may be 1; and said R is 7 May be hydrogen.
In the compound having the structure of the general formula (VII), wherein, X 1 May be N; the X is 2 May be C; the A may be optionalSubstituted pyrazolyl; the R is 1 May be hydrogen; the R is 2 May be selected from hydrogen, optionally substituted (C) 1 -C 3 ) Alkyl and optionally substituted (C) 3 -C 5 ) A carbocycle; the R is 3 May be selected from hydrogen and optionally substituted (C 1 -C 3 ) An alkyl group; the R is 4 May be selected from hydrogen and optionally substituted (C 1 -C 3 ) An alkyl group; the R is 5 May be hydrogen; the R is 6 May be independently selected from hydrogen and halogen; the n may be 1; and said R is 7 May be hydrogen.
In the compound having the structure of the general formula (VII), wherein, X 1 May be N; the X is 2 May be C; the a may be optionally substituted pyrazolyl; the R is 1 May be hydrogen; the R is 2 May be selected from hydrogen, optionally substituted isopropyl and optionally substituted cyclopentyl; the R is 3 May be selected from hydrogen and optionally substituted methyl; the R is 4 May be selected from hydrogen and optionally substituted methyl; the R is 5 May be hydrogen; the R is 6 May be hydrogen; and said R is 7 May be hydrogen.
In the compound having the structure of the general formula (VII), wherein, X 1 May be N; the X is 2 May be C; the A can be pyrazolyl; the R is 2 May be selected from hydrogen, isopropyl and cyclopentyl; the R is 3 May be selected from hydrogen and methyl; and said R is 4 May be selected from hydrogen and methyl.
In some cases, the present application provides a compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound may be selected from:
in another aspect, the present application provides compounds having the structure of formula (VIIS),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
R 1 、R 2 、R 3 、R 4 and R is 5 May be independently absent or may be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In the compound having the structure of formula (VIIS), wherein R 1 May be hydrogen.
In the compound having the structure of formula (VIIS), wherein R 2 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group.
In the compound having the structure of formula (VIIS), wherein R 2 May be an optionally substituted isopropyl group.
In the compounds having the structure of formula (VIIS)Wherein, the R is 3 May be selected from hydrogen, optionally substituted (C) 1 -C 6 ) Alkyl and optionally substituted (C) 2 -C 9 ) A heterocycle.
In the compound having the structure of formula (VIIS), wherein R 3 May be an optionally substituted methyl group.
In the compound having the structure of formula (VIIS), wherein R 3 May be optionally substituted C 5 A heterocycle.
In the compound having the structure of formula (VIIS), wherein R 3 May be optionally substituted piperidinyl.
In the compound having the structure of formula (VIIS), wherein R 3 May be one or more R 6 Substituted, R 6 Can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In the compound having the structure of formula (VIIS), wherein R 6 May be selected from hydrogen, optionally substituted (C) 1 -C 6 ) Alkyl and optionally substituted (C) 2 -C 9 ) A heterocycle.
In the compound having the structure of formula (VIIS), wherein R 6 May be an optionally substituted ethyl group.
In the compound having the structure of formula (VIIS), wherein R 6 May be optionally substituted C 5 A heterocycle.
In the compound having the structure of formula (VIIS), wherein R 6 May be optionally substituted piperidinyl.
In the compound having the structure of formula (VIIS), wherein R 6 May be one or more R 7 Substituted, R 7 Can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In the compound having the structure of formula (VIIS), wherein R 7 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An acyl group.
In the compound having the structure of formula (VIIS), wherein R 7 May be an optionally substituted acetyl group.
In the compound having the structure of formula (VIIS), wherein R 7 May be one or more R 8 Substituted, R 8 Can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally takenSubstituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In the compound having the structure of formula (VIIS), wherein R 8 May be selected from hydrogen and optionally substituted amino groups.
In the compound having the structure of formula (VIIS), wherein R 8 May be one or more R 9 Substituted, R 9 Can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In the compound having the structure of formula (VIIS), wherein R 9 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group.
In a structure having the general formula (VIIS)Wherein R is as defined in 9 May be an optionally substituted methyl group.
In the compound having the structure of formula (VIIS), wherein R 4 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group.
In the compound having the structure of formula (VIIS), wherein R 4 May be an optionally substituted methyl group.
In the compound having the structure of formula (VIIS), wherein R 4 May be one or more R 10 Substituted, R 10 Can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In the compound having the structure of formula (VIIS), wherein R 10 May be optionally substituted (C 6 -C 10 ) Aryl groups.
In the compound having the structure of formula (VIIS), wherein R 10 May be optionally substituted phenyl.
In the compound having the structure of formula (VIIS), wherein R 10 May be one or more R 11 Substituted, R 11 Can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally is covered bySubstituted hydroxy, optionally substituted phosphorus-containing groups, optionally substituted silicon-containing groups, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In the compound having the structure of formula (VIIS), wherein R 11 May be selected from hydrogen, halogen and optionally substituted (C 1 -C 9 ) Heteroaryl groups.
In the compound having the structure of formula (VIIS), wherein R 11 May be optionally substituted pyrazolyl.
In the compound having the structure of formula (VIIS), wherein R 11 May be F.
In the compound having the structure of formula (VIIS), wherein R 5 May be hydrogen.
In the compound having the structure of formula (VIIS), wherein R 1 May be hydrogen; the R is 2 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group; the R is 3 May be selected from hydrogen, optionally substituted (C) 1 -C 6 ) Alkyl and optionally substituted C containing one nitrogen atom 5 A heterocycle; the R is 3 May be one or more R 6 Substitution, said R 6 May be selected from hydrogen, optionally substituted (C) 1 -C 6 ) Alkyl and optionally substituted C containing one nitrogen atom 5 A heterocycle; the R is 6 May be one or more R 7 Substitution, said R 7 May be selected from hydrogen and optionally substitutedOf (C) 1 -C 6 ) An acyl group; the R is 7 May be one or more R 8 Substitution, said R 8 May be selected from hydrogen and optionally substituted amino; the R is 8 May be one or more R 9 Substitution, said R 9 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group; the R is 4 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group; the R is 4 May be one or more R 10 Substitution, said R 10 May be optionally substituted phenyl; the R is 10 May be one or more R 11 Substitution, said R 11 May be optionally substituted pyrazolyl; and said R is 5 May be hydrogen.
In some cases, the present application provides a compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound may be selected from:
in some cases, the present application provides a compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound may be selected from:
in another aspect, the present application provides compounds having the structure of formula (VIII),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 and R 7 May be independently absent or may be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl;
n may independently be not less than 0.
In the compound having the structure of the general formula (VIII), wherein R 1 May be hydrogen.
In the compound having the structure of the general formula (VIII), wherein R 2 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group.
In the compound having the structure of the general formula (VIII), wherein R 2 May be an optionally substituted isopropyl group.
In the compound having the structure of the general formula (VIII), wherein R 3 May be hydrogen.
In the compound having the structure of the general formula (VIII), whereinR 4 May be hydrogen.
In the compound having the structure of the general formula (VIII), wherein R 5 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group.
In the compound having the structure of the general formula (VIII), wherein R 5 May be an optionally substituted methyl group.
In the compound having the structure of the general formula (VIII), wherein R 5 May be one or more R 8 Substituted, R 8 Can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In the compound having the structure of the general formula (VIII), wherein R 8 May be selected from hydrogen and optionally substituted (C 6 -C 10 ) Aryl groups.
In the compound having the structure of the general formula (VIII), wherein R 8 May be optionally substituted phenyl.
In the compound having the structure of the general formula (VIII), wherein R 8 May be one or more R 9 Substituted, R 9 Can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing groups,Optionally substituted silicon-containing groups, optionally substituted thio groups, optionally substituted amino groups, optionally substituted carboxyl groups, optionally substituted sulfonyl groups, optionally substituted sulfinyl groups, optionally substituted (C 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In the compound having the structure of the general formula (VIII), wherein R 9 May be selected from hydrogen, halogen and optionally substituted (C 1 -C 6 ) An alkyl group.
In the compound having the structure of the general formula (VIII), wherein R 9 May be F.
In the compound having the structure of the general formula (VIII), wherein R 9 May be an optionally substituted methyl group.
In the compound having the structure of the general formula (VIII), wherein R 9 May be one or more R 10 Substituted, R 10 Can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In the compound having the structure of the general formula (VIII), wherein R 10 May be selected from hydrogen and halogen.
In the compound having the structure of the general formula (VIII), wherein R 10 May be F.
In the compound having the structure of the general formula (VIII), wherein R 6 May be hydrogen.
In the compound having the structure of the general formula (VIII), wherein R 7 May be hydrogen.
In the compound having the structure of the general formula (VIII), wherein R 1 May be hydrogen; the R is 2 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group; r is R 3 And R is 4 May be hydrogen; r is R 5 May be selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group; the R is 5 May be one or more R 8 Substitution, said R 8 May be selected from hydrogen and optionally substituted (C 6 -C 10 ) An aryl group; the R is 8 May be one or more R 9 Substitution, said R 9 May be selected from hydrogen, halogen and optionally substituted (C 1 -C 6 ) An alkyl group; the R is 9 May be one or more R 10 Substitution, said R 10 May be selected from hydrogen and halogen; and said R is 6 And R is 7 May be hydrogen.
In some cases, the present application provides a compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound may be selected from:
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in another aspect, the present application provides compounds having the structure of formula (IX),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
X 1 and X 2 May be independently selected from C, N and O;
a may be selected from optionally substituted (C 2 -C 9 ) Heterocycles and optionally substituted (C) 1 -C 9 ) Heteroaryl;
R 1 、R 2 、R 3 、R 4 、R 5 and R is 6 May be independently absent or may be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl;
n and m may each independently be not less than 0.
In the compound having the structure of the general formula (IX), wherein, the X 1 May be N.
In the compound having the structure of the general formula (IX), wherein, the X 2 May be C.
In the compounds having the structure of formula (IX), wherein the A may be optionally substituted (C 1 -C 9 ) Heteroaryl groups.
In the compounds having the structure of formula (IX), wherein the A may be optionally substituted C 3 Heteroaryl groups.
In the compounds having the structure of formula (IX), wherein a may be optionally substituted pyrazolyl.
In the compound having the structure of the general formula (IX), wherein R 1 May be hydrogen.
In the compound having the structure of the general formula (IX), wherein R 2 May be selected from hydrogen, optionally substituted (C) 1 -C 6 ) Alkyl and optionally substituted (C) 3 -C 10 ) Carbocycles.
In the compound having the structure of the general formula (IX), wherein R 2 May be an optionally substituted isopropyl group.
In the compound having the structure of the general formula (IX), wherein R 2 May be optionally substituted C 5 Carbocycles.
In the compound having the structure of the general formula (IX), wherein R 2 May be optionally substituted cyclopentyl.
In the compound having the structure of the general formula (IX), wherein R 3 May be hydrogen.
In the compound having the structure of the general formula (IX), wherein R 4 May be hydrogen.
In the compound having the structure of the general formula (IX), wherein R 5 May be hydrogen.
In the compound having the structure of the general formula (IX), wherein R 6 May be hydrogen.
In the compound having the structure of the general formula (IX), wherein, the X 1 May be N; the X is 2 May be C; the A may be optionally substituted C containing two nitrogen atoms 3 Heteroaryl; the R is 1 May be hydrogen; the R is 2 May be selected from hydrogen, optionally substituted (C) 1 -C 6 ) Alkyl and optionally substituted C 5 A carbocycle; and said R is 3 To R 6 May be hydrogen.
In some cases, the present application provides a compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound may be selected from:
in another aspect, the present application provides compounds having the structure of formula (X),
Or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
X 1 、X 2 and X 3 May be independently selected from C, N and O;
a may be selected from optionally substituted (C 2 -C 9 ) Heterocycles and optionally substituted (C) 1 -C 9 ) Heteroaryl;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 and R 7 May be independently absent or may be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substitutedOptionally substituted carboxyl, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl;
n and m may each independently be not less than 0.
In the compound having the structure of the general formula (X), wherein the X 1 May be N.
In the compound having the structure of the general formula (X), wherein the X 2 May be C.
In the compounds having the structure of the general formula (X), wherein the A may be optionally substituted (C 1 -C 9 ) Heteroaryl groups.
In the compounds having the structure of formula (X), wherein the A may be optionally substituted C 3 Heteroaryl groups.
In the compounds having the structure of the general formula (X), wherein a may be optionally substituted pyrazolyl.
In the compound having the structure of the general formula (X), wherein R 1 May be hydrogen.
In the compound having the structure of the general formula (X), wherein R 2 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group.
In the compound having the structure of the general formula (X), wherein R 2 May be an optionally substituted isopropyl group.
In the compound having the structure of the general formula (X), wherein the X 3 May be N.
In the compound having the structure of the general formula (X), wherein the X 3 Can be used forIs O.
In the compound having the structure of the general formula (X), wherein R 3 May be absent, or the R 3 May be hydrogen.
In the compound having the structure of the general formula (X), wherein R 4 May be hydrogen.
In the compound having the structure of the general formula (X), wherein R 5 May be hydrogen.
In the compound having the structure of the general formula (X), wherein R 6 May be hydrogen.
In the compound having the structure of the general formula (X), wherein R 7 May be hydrogen.
In the compound having the structure of the general formula (X), wherein the X 1 May be N; the X is 2 May be C; the A may be optionally substituted C containing two nitrogen atoms 3 Heteroaryl; the R is 1 May be hydrogen; the R is 2 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group; the X is 3 May be N or O; wherein the R is 4 To R 7 May be hydrogen.
In some cases, the present application provides a compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound may be selected from:
in another aspect, the present application provides compounds having the structure of formula (XI),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
R X may be halogen;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 and R is 9 May be independently absent or may be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl;
n and m may each independently be not less than 0.
In the compound having the structure of the general formula (XI), wherein R X May be F.
In the compounds having the structure of formula (XI), wherein n may be selected from 1 to 2.
In the compound having the structure of the general formula (XI), wherein R 1 May be hydrogen.
In the compound having the structure of the general formula (XI), wherein R 2 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group.
In the compound having the structure of the general formula (XI), wherein R 2 May be an optionally substituted methyl group。
In the compound having the structure of the general formula (XI), wherein R 3 May be hydrogen.
In the compound having the structure of the general formula (XI), wherein R 4 May be hydrogen.
In the compound having the structure of the general formula (XI), wherein R 5 May be hydrogen.
In the compound having the structure of the general formula (XI), wherein R 6 May be hydrogen.
In the compound having the structure of the general formula (XI), wherein R 7 Can be selected from hydrogen, =o and optionally substituted (C 1 -C 6 ) An alkyl group.
In the compound having the structure of the general formula (XI), wherein R 7 May be an optionally substituted methyl group.
In the compound having the structure of the general formula (XI), wherein R 8 May be selected from hydrogen, optionally substituted (C) 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 1 -C 6 ) Acyl and optionally substituted sulfonyl.
In the compound having the structure of the general formula (XI), wherein R 8 May be selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.
In the compound having the structure of the general formula (XI), wherein R 8 May be propenyl.
In the compound having the structure of the general formula (XI), wherein R 8 But may be butynyl.
In the compound having the structure of the general formula (XI), wherein R 8 May be formyl.
In the compound having the structure of the general formula (XI), wherein R 8 May be one or more R 10 Substituted, R 10 Can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In the compound having the structure of the general formula (XI), wherein R 10 May be selected from hydrogen, optionally substituted hydroxy, optionally substituted amino and optionally substituted (C 6 -C 10 ) Aryl groups.
In the compound having the structure of the general formula (XI), wherein R 10 May be optionally substituted phenyl.
In the compound having the structure of the general formula (XI), wherein R 10 May be one or more R 11 Substituted, R 11 Can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) A heterocyclic ring,Optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In the compound having the structure of the general formula (XI), wherein R 11 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group.
In the compound having the structure of the general formula (XI), wherein R 11 May be an optionally substituted methyl group.
In the compound having the structure of the general formula (XI), wherein R 9 May be selected from hydrogen and optionally substituted sulfonyl.
In the compound having the structure of the general formula (XI), wherein R 9 May be one or more R 12 Substituted, R 12 Can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In the compound having the structure of the general formula (XI), wherein R 12 May be selected from hydrogen and optionally substituted amino groups.
In the compound having the structure of the general formula (XI), wherein R X May be F; the n may be selected from 1 to 2; the R is 1 May be hydrogen; the R is 2 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) Alkyl group；R 3 To R 6 May be hydrogen; the R is 7 Can be selected from hydrogen, =o and optionally substituted (C 1 -C 6 ) An alkyl group; the R is 8 May be selected from hydrogen, optionally substituted (C) 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 1 -C 6 ) Acyl and optionally substituted sulfonyl; the R is 8 May be one or more R 10 Substitution, said R 10 May be optionally substituted phenyl; the R is 10 May be one or more R 11 Substitution, said R 11 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group; the R is 9 May be selected from hydrogen and optionally substituted sulfonyl; and said R is 9 May be one or more R 12 Substitution, said R 12 May be selected from hydrogen and optionally substituted amino groups.
In some cases, the present application provides a compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound may be selected from:
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in another aspect, the present application provides compounds having the structure of formula (XII),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
R X may be halogen;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 and R 7 May be independently absent or may be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl;
n and m may each independently be not less than 0.
In the compound having the structure of the general formula (XII), wherein R X May be F.
In the compound having the structure of the general formula (XII), wherein R 1 May be hydrogen.
In the compounds having the structure of formula (XII)Wherein, R is as follows 2 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group.
In the compound having the structure of the general formula (XII), wherein R 2 May be an optionally substituted isopropyl group.
In the compound having the structure of the general formula (XII), wherein R 3 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group.
In the compound having the structure of the general formula (XII), wherein R 3 May be an optionally substituted methyl group.
In the compounds having the structure of the general formula (XII), wherein n may be selected from 1 to 4.
In the compound having the structure of the general formula (XII), wherein n may be 4.
In the compound having the structure of the general formula (XII), wherein R 4 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An acyl group.
In the compound having the structure of the general formula (XII), wherein R 4 May be optionally substituted propionyl.
In the compound having the structure of the general formula (XII), wherein R 4 May be one or more R 9 Substituted, R 9 Can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocycle, anyOptionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
In the compound having the structure of the general formula (XII), wherein R 9 May be selected from hydrogen, optionally substituted amino, optionally substituted (C 1 -C 6 ) Alkyl and optionally substituted (C) 6 -C 10 ) Aryl groups.
In the compound having the structure of the general formula (XII), wherein R 9 May be an optionally substituted methyl group.
In the compound having the structure of the general formula (XII), wherein R 9 May be optionally substituted phenyl.
In the compound having the structure of the general formula (XII), wherein R 5 May be hydrogen.
In the compound having the structure of the general formula (XII), wherein R 6 May be hydrogen.
In the compound having the structure of the general formula (XII), wherein R 7 May be hydrogen.
In the compound having the structure of the general formula (XII), wherein R X May be F, said R 2 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group; the R is 3 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An alkyl group; the n may be selected from 1 to 4; the R is 4 May be selected from hydrogen and optionally substituted (C 1 -C 6 ) An acyl group; the R is 4 May be one or more R 9 Substitution, said R 9 May be selected from hydrogen, optionally substituted amino, optionally substituted (C 1 -C 6 ) Alkyl and optionally substituted (C) 6 -C 10 ) An aryl group; and said R is 5 To R 7 May be hydrogen.
In some cases, the present application provides a compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound may be selected from:
in some cases, the present application provides a compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound may be selected from:
In some cases, the present application provides a compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound may be selected from:
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in one aspect, the present application provides a method for inhibiting Cyclin Dependent Kinase (CDK) activity, comprising administering to a subject in need thereof an effective amount of the present application, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing. For example, the Cyclin Dependent Kinase (CDK) may be CDK 7. For example, the method may be selected from in vitro methods, ex vivo methods, and in vivo methods.
In another embodiment, the present application provides the use of a compound of the present application, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the above components of the present application, in the manufacture of a medicament and/or kit for inhibiting Cyclin Dependent Kinase (CDK) activity. For example, the Cyclin Dependent Kinase (CDK) may be CDK 7. For example, the method of using the drug and/or the kit may be selected from an in vitro method, an ex vivo method, and an in vivo method.
In another embodiment, the present application provides a compound of the present application, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the above-mentioned components of the present application, for use in inhibiting Cyclin Dependent Kinase (CDK) activity. For example, the Cyclin Dependent Kinase (CDK) may be CDK 7. For example, the method or the use may be selected from in vitro methods, ex vivo methods and in vivo methods.
In one aspect, the present application provides a composition comprising a compound of the present application, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the above components, and optionally a pharmaceutically acceptable carrier.
The compounds of the present application may be administered orally. Oral administration may involve swallowing, whereby the compound enters the gastrointestinal tract, or may be administered orally or sublingually, whereby the compound is directly passed into the blood stream.
In some cases, the compounds of the present application may also be administered directly into the blood stream, into muscles or into the viscera. Suitable methods of parenteral administration may include intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous administration. Suitable devices for parenteral administration may include needle (including microneedle) syringes, needleless syringes and infusion techniques.
The compounds of the present application may also be administered topically to the skin or mucosa, i.e., transdermally. In some cases, the compounds of the present application may also be administered by intranasal or inhalation. In some cases, the compounds of the present application may be administered rectally or vaginally. In another embodiment, the compounds of the present application may also be administered directly to the eye or ear.
The dosing regimen of the compound and/or the composition comprising the compound is based on a variety of factors including the type, age, weight, sex and condition of the patient; severity of the condition; a route of administration; and the activity of the particular compound employed. Thus, the dosing regimen may vary widely. Dosage levels calculated on a daily basis of body weight may be useful.
Suitable subjects according to the invention include mammalian subjects. Mammals according to the present invention may include, but are not limited to, dogs, cats, cattle, goats, horses, sheep, pigs, rodents, lagomorphs, primates, etc., and include intrauterine mammals. In one embodiment, the human is a suitable subject. The human subject may be of any sex, or may be at any stage of development.
In another embodiment, the present application provides the use of one or more compounds of the present application in the manufacture of a medicament.
For example, the compounds of the present application may be administered as the compounds themselves. Alternatively, pharmaceutically acceptable salts may be suitable for medical applications because they have greater water solubility relative to the parent compound.
In another embodiment, the present application provides a composition. Such compositions may comprise a compound of the present application in combination with a pharmaceutically acceptable carrier. The carrier may be a solid product, a liquid, or both, and may be formulated with the compound as a unit dose composition, such as a tablet, which may contain the active compound. The compounds of the present application may be conjugated with suitable polymers as targetable drug carriers. Other pharmacologically active substances may also be present.
The compounds of the invention may be administered by any suitable route, and may be in the form of pharmaceutical compositions suitable for such route. The active compounds and compositions can be administered, for example, orally, rectally, parenterally or topically.
The compounds of the present application may be used alone or in combination with other therapeutic agents. The compounds of the present application and other therapeutic agents may be administered simultaneously (in the same dosage form or in different dosage forms) or sequentially.
A "combined" administration of two or more compounds may mean that the two compounds are administered in sufficiently close time that the presence of one compound alters the biological effect of the other. Two or more compounds may be administered simultaneously, concurrently or sequentially. In addition, simultaneous administration may be performed by mixing the compounds prior to administration or by administering the compounds at the same point in time but at different anatomical sites or using different routes of administration.
The phrases "concurrently administered," "co-administered," "simultaneously administered," and "administered simultaneously" may mean that the compounds are administered in combination.
1. A compound having the structure of formula (I),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R is 8 Are each independently absent or are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl;
n is not less than 0.
2. The compound of clause 1, wherein the R 1 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
3. The compound of any one of clauses 1-2, wherein the R 1 Is an optionally substituted methyl group.
4. The compound of any one of clauses 1-3, wherein the R 1 Is/are R 9 Substituted, R 9 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl groupOptionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
5. The compound of clause 4, wherein the R 9 Selected from hydrogen and optionally substituted (C) 6 -C 10 ) Aryl groups.
6. The compound of any one of clauses 4-5, wherein the R 9 Is optionally substituted phenyl.
7. The compound of any one of clauses 4-6, wherein the R 9 Is/are R 10 Substituted, R 10 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
8. The compound of clause 7, wherein the R 10 Each independently selected from hydrogen, optionally substituted amino and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
9. The compound of any of clauses 7-8, wherein the R 10 Is optionally substituted pyrazolyl.
10. The compound of any one of clauses 7-9, wherein the R 10 Respectively by one or more R 11 Substituted, R 11 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
11. The compound of clause 10, wherein the R 11 Each independently selected from hydrogen, =o and optionally substituted (C 1 -C 6 ) An alkyl group.
12. The compound of any of clauses 10-11, wherein the R 11 Is an optionally substituted methyl group.
13. The compound of any one of clauses 1-12, wherein the R 2 Is hydrogen.
14. The compound of any one of clauses 1-13, wherein the R 3 Is hydrogen.
15. The compound of any one of clauses 1-14, wherein the R 4 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
16. The compound of any one of clauses 1-15, wherein the R 4 Is an optionally substituted isopropyl group.
17. The compound of any one of clauses 1-16, whereinThe R is 5 Selected from hydrogen, optionally substituted amino and optionally substituted (C 2 -C 9 ) A heterocycle.
18. The compound of any one of clauses 1-17, wherein the R 5 Is an optionally substituted amino group.
19. The compound of any one of clauses 1-18, wherein the R 5 Is optionally substituted C 4 A heterocycle.
20. The compound of any one of clauses 1-19, wherein the R 5 Is an optionally substituted heterocyclic ring containing two heteroatoms.
21. The compound of any one of clauses 1-20, wherein the R 5 Is an optionally substituted heterocyclic ring containing two nitrogen atoms.
22. The compound of any one of clauses 1-21, wherein the R 5 Is/are R 12 Substituted, R 12 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
23. The compound of clause 22, wherein the R 12 Independently selected from hydrogen, optionally substituted (C) 1 -C 6 ) Alkyl and optionally substituted (C) 2 -C 9 ) A heterocycle.
24. The compound of any one of clauses 22-23, wherein the R 12 Is optionally substituted C 4 Heterocyclic or optionally substituted C 5 A heterocycle.
25. The compound of any one of clauses 22-24, wherein the R 12 Is an optionally substituted heterocyclic ring containing one heteroatom.
26. The compound of any of clauses 22-25, wherein the R 12 Is an optionally substituted heterocyclic ring containing one nitrogen atom.
27. The compound of any one of clauses 1-26, wherein the R 6 Is hydrogen.
28. The compound of any one of clauses 1-27, wherein the R 7 Is hydrogen.
29. The compound of any one of clauses 1-28, wherein the R 8 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
30. A compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:
31. a compound having the structure of formula (II),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 and R 7 Are respectively and independently absent orEach independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
32. The compound of clause 31, wherein the R 1 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
33. The compound of any of clauses 31-32, wherein the R 1 Is an optionally substituted methyl group.
34. The compound of any of clauses 31-33, wherein the R 1 Is/are R 8 Substituted, R 8 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
35. The compound of clause 34, wherein the R 8 Selected from hydrogen and optionally substituted (C) 6 -C 10 ) Aryl groups.
36. The compound of any one of clauses 34-35, wherein the R 8 Is optionally substituted phenyl.
37. The compound of any one of clauses 34-36, wherein the R 8 Is/are R 9 Substituted, R 9 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
38. The compound of clause 37, wherein the R 9 Selected from hydrogen and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
39. The compound of any one of clauses 37-38, wherein the R 9 Is optionally substituted pyrazolyl.
40. The compound of any of clauses 31-39, wherein the R 2 Is hydrogen.
41. The compound of any of clauses 31-40, wherein the R 3 Is hydrogen.
42. The compound of any of clauses 31-41, wherein the R 4 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
43. The compound of any of clauses 31-42, wherein the R 4 Selected from hydrogen and optionally substituted isopropyl.
44. The compound of any of clauses 31-43, wherein the R 5 Is hydrogen.
45. The compound of any of clauses 31-44, wherein the R 6 Is hydrogen.
46. The compound of any of clauses 31-45, wherein the R 7 Is hydrogen.
47. A compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is
48. A compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is
49. A compound having the structure of formula (III),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
X 1 and X 2 Each independently selected from C, N and O;
a is selected from optionally substituted (C 2 -C 9 ) Heterocyclic ring and optional quiltSubstituted (C) 1 -C 9 ) Heteroaryl;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 and R is 10 Are each independently absent or are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl;
n and m are each independently not less than 0.
50. The compound of clause 49, wherein the X 1 Is N.
51. The compound of any of clauses 49-50, wherein the X 2 Is C.
52. The compound of any of clauses 49-51, wherein the a is optionally substituted (C 1 -C 9 ) Heteroaryl groups.
53. The compound of any of clauses 49-52, wherein the a is optionally substituted C 3 Heteroaryl groups.
54. The compound of any of clauses 49-53, wherein the a is optionally substituted pyrazolyl.
55. The compound of any of clauses 49-54, wherein the R 1 Is hydrogen.
56.The compound of any of clauses 49-55, wherein the R 2 Is hydrogen.
57. The compound of any of clauses 49-56, wherein the R 3 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
58. The compound of any of clauses 49-57, wherein the R 3 Is an optionally substituted isopropyl group.
59. The compound of any of clauses 49-58, wherein the R 4 Is hydrogen.
60. The compound of any of clauses 49-59, wherein the R 5 Is hydrogen.
61. The compound of any of clauses 49-60, wherein the R 6 Is hydrogen.
62. The compound of any of clauses 49-61, wherein the R 7 Is hydrogen.
63. The compound of any of clauses 49-62, wherein the R 8 Is hydrogen.
64. The compound of any of clauses 49-63, wherein the R 9 Hydrogen, respectively.
65. The compound of any of clauses 49-64, wherein the R 10 Hydrogen, respectively.
66. A compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is
67. A compound having the structure of formula (IV),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R is 8 Are each independently absent or are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) A heteroaryl group, which is a group,
n and m are each independently not less than 0.
68. The compound of clause 67, wherein the R 1 Is hydrogen.
69. The compound of any of clauses 67-68, wherein the R 2 Is hydrogen.
70. The compound of any of clauses 67-69, wherein the R 3 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
71. The compound of any of clauses 67-70, wherein the R 3 Is an optionally substituted isopropyl group.
72. The compound of any of clauses 67-71, wherein the R 4 Selected from hydrogen, optionally substituted (C) 1 -C 6 ) Acyl and optionally substituted (C) 1 -C 6 ) An alkyl group.
73. The method of any one of clauses 67-72A compound, wherein R is 4 Is optionally substituted propionyl.
74. The compound of any of clauses 67-73, wherein the R 4 Is an optionally substituted methyl group.
75. The compound of any of clauses 67-74, wherein the R 4 Is/are R 9 Substituted, R 9 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
76. The compound of clause 75, wherein the R 9 Selected from hydrogen, optionally substituted amino, optionally substituted (C 1 -C 6 ) Alkyl and optionally substituted (C) 6 -C 10 ) Aryl groups.
77. The compound of any of clauses 75-76, wherein the R 9 Is an optionally substituted methyl group.
78. The compound of any of clauses 75-77, wherein the R 9 Is optionally substituted phenyl.
79. The compound of any of clauses 67-78, wherein the R 5 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
80. The method according to any one of clauses 67-79 The compound, wherein R is 5 Is an optionally substituted methyl group.
81. The compound of any of clauses 67-80, wherein the R 6 Is hydrogen.
82. The compound of any of clauses 67-81, wherein the R 7 Selected from hydrogen and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
83. The compound of any of clauses 67-82, wherein the R 7 Is optionally substituted C 3 Heteroaryl groups.
84. The compound of any of clauses 67-83, wherein the R 7 Is optionally substituted pyrazolyl.
85. The compound of any of clauses 67-84, wherein n is 1.
86. The compound of any of clauses 67-85, wherein the R 8 Is hydrogen.
87. A compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:
88. a compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:/>
89. a compound having the structure of formula (V),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
Wherein,
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 and R is 11 Are each independently absent or are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl;
n and m are each independently not less than 0.
90. The compound of clause 89, wherein the R 1 Is hydrogen.
91. The compound of any of clauses 89-90, wherein the R 2 Is hydrogen.
92. The compound of any of clauses 89-91, wherein the R 3 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
93. The compound of any of clauses 89-92, wherein the R 3 Is an optionally substituted methyl group.
94.The compound of any of clauses 89-93, wherein the R 4 Is hydrogen.
95. The compound of any of clauses 89-94, wherein the R 5 Is hydrogen.
96. The compound of any of clauses 89-95, wherein the R 6 Is hydrogen.
97. The compound of any of clauses 89-96, wherein the R 7 Is hydrogen.
98. The compound of any of clauses 89-97, wherein the R 8 Selected from hydrogen and optionally substituted sulfonyl.
99. The compound of any of clauses 89-98, wherein the R 8 Is/are R 12 Substituted, R 12 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
100. The compound of clause 99, wherein the R 12 Selected from hydrogen and optionally substituted (C) 6 -C 10 ) Aryl groups.
101. The compound of any of clauses 99-100, wherein the R 12 Is optionally substituted phenyl.
102. The method according to any one of clauses 99-101Wherein R is a compound of formula (I) 12 Is/are R 13 Substituted, R 13 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
103. The compound of clause 102, wherein the R 13 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
104. The compound of any of clauses 102-103, wherein the R 13 Is an optionally substituted methyl group.
105. The compound of any of clauses 89-104, wherein the R 9 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
106. The compound of any of clauses 89-105, wherein the R 9 Is an optionally substituted methyl group.
107. The compound of any of clauses 89-106, wherein n is 1.
108. The compound of any of clauses 89-107, wherein the R 9 Is/are R 14 Substituted, R 14 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substitutedA phosphorus-containing group, an optionally substituted silicon-containing group, an optionally substituted thio group, an optionally substituted amino group, an optionally substituted carboxy group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, an optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
109. The compound of clause 108, wherein the R 14 Selected from hydrogen and optionally substituted hydroxy.
110. The compound of any of clauses 89-109, wherein the R 10 Is hydrogen.
111. The compound of any of clauses 89-110, wherein the R 11 Selected from hydrogen, halogen and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
112. The compound of any of clauses 89-111, wherein the R 11 F.
113. The compound of any of clauses 89-112, wherein m is 2.
114. The compound of any of clauses 89-113, wherein the R 11 Is optionally substituted C 3 Heteroaryl groups.
115. The compound of any of clauses 89-114, wherein the R 11 Is optionally substituted pyrazolyl.
116. A compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:
117. a compound having the structure of formula (VI),
Or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
X 1 and X 2 Each independently selected from C, N and O;
a is selected from optionally substituted (C 2 -C 9 ) Heterocycles and optionally substituted (C) 1 -C 9 ) Heteroaryl;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 and R 7 Are each independently absent or are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl;
n is not less than 0.
118. The compound of clause 117, wherein the X 1 Is N.
119. The compound of any of clauses 117-118, wherein the X 2 Is C.
120. The compound of any of clauses 117-119, wherein the a is optionally substituted (C 1 -C 9 ) Heteroaryl groups.
121. The compound of any of clauses 117-120, wherein the a is optionally substituted C 3 Heteroaryl groups.
122. The compound of any of clauses 117-121, wherein a is optionally substituted pyrazolyl.
123. The compound of any of clauses 117-122, wherein the a is substituted with one or more R 8 Substituted, R 8 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
124. The compound of clause 123, wherein the R 8 Selected from hydrogen, optionally substituted amino and optionally substituted (C 1 -C 6 ) An alkyl group.
125. The compound of any of clauses 123-124, wherein the R 8 Is an optionally substituted methyl group.
126. The process of any one of clauses 123-125A compound, wherein R is 8 Is/are R 9 Substituted, R 9 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
127. The compound of clause 126, wherein the R 9 Selected from hydrogen and halogen.
128. The compound of any of clauses 126-127, wherein the R 9 F.
129. The compound of any of clauses 117-128, wherein the R 1 Is hydrogen.
130. The compound of any of clauses 117-129, wherein the R 2 Is hydrogen.
131. The compound of any of clauses 117-130, wherein the R 3 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
132. The compound of any of clauses 117-131, wherein the R 3 Is an optionally substituted isopropyl group.
133. The compound of any of clauses 117-132, wherein the R 4 Selected from hydrogen and optionally substituted hydroxy.
134. The compound of any one of clauses 117-133, whereinIn the formula, R is 5 Is hydrogen.
135. The compound of any of clauses 117-134, wherein the R 6 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
136. The compound of any of clauses 117-135, wherein the R 6 Is an optionally substituted methyl group.
137. The compound of any of clauses 117-136, wherein the R 6 Is/are R 10 Substituted, R 10 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
138. The compound of clause 137, wherein the R 10 Selected from hydrogen and optionally substituted (C) 6 -C 10 ) Aryl groups.
139. The compound of any of clauses 137-138, wherein the R 10 Is optionally substituted phenyl.
140. The compound of any of clauses 137-139, wherein the R 10 Is/are R 11 Substituted, R 11 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substitutedA phosphorus-containing group, an optionally substituted silicon-containing group, an optionally substituted thio group, an optionally substituted amino group, an optionally substituted carboxy group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, an optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
141. The compound of clause 140, wherein the R 11 Selected from hydrogen and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
142. The compound of any of clauses 140-141, wherein the R 11 Is optionally substituted pyrazolyl.
143. The compound of any of clauses 117-142, wherein the R 7 Is hydrogen.
144. A compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:
145. a compound having the structure of formula (VII),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
X 1 and X 2 Each independently selected from C, N and O;
a is selected from optionally substituted (C 2 -C 9 ) Heterocycles and optionally substituted (C) 1 -C 9 ) Heteroaryl;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R is 8 Are each independently absent or are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl;
n and m are each independently not less than 0.
146. The compound of clause 145, wherein the X 1 Is N.
147. The compound of any of clauses 145-146, wherein the X 2 Is C.
148. The compound of any of clauses 145-147, wherein the a is optionally substituted (C 1 -C 9 ) Heteroaryl groups.
149. The compound of any of clauses 145-148, wherein the a is optionally substituted C 3 Heteroaryl groups.
150. The compound of any of clauses 145-149, wherein the a is optionally substituted pyrazolyl.
151. The compound of any of clauses 145-150, wherein the R 1 Is hydrogen.
152. The compound of any of clauses 145-151, wherein the R 2 Selected from hydrogen, optionally substituted (C) 1 -C 6 ) Alkyl and optionally substituted (C) 3 -C 10 ) Carbocycles.
153. The compound of any of clauses 145-152, wherein the R 2 Is an optionally substituted isopropyl group.
154. The compound of any of clauses 145-153, wherein the R 2 Is optionally substituted C 5 Carbocycles.
155. The compound of any of clauses 145-154, wherein the R 2 Is optionally substituted cyclopentyl.
156. The compound of any of clauses 145-155, wherein the R 3 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
157. The compound of any of clauses 145-156, wherein the R 3 Is methyl.
158. The compound of any of clauses 145-157, wherein the R 4 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
159. The compound of any of clauses 145-158, wherein the R 4 Is methyl.
160. The compound of any of clauses 145-159, wherein the R 5 Is hydrogen.
161. The compound of any of clauses 145-160, wherein the R 6 Each independently selected from hydrogen and halogen.
162. The compound of any of clauses 145-161, wherein the R 6 Is halogen.
163. The compound of any one of clauses 145-162Wherein, the R is 6 F.
164. The compound of any of clauses 145-163, wherein n is 1.
165. The compound of any of clauses 145-164, wherein the R 7 Is hydrogen.
166. A compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:
167. a compound having the structure of formula (VIIS),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
R 1 、R 2 、R 3 、R 4 and R is 5 Are each independently absent or are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
168. The compound of clause 167, wherein the R 1 Is hydrogen.
169. The compound of any of clauses 167-168, wherein the R 2 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
170. The compound of any of clauses 167-169, wherein the R 2 Is an optionally substituted isopropyl group.
171. The compound of any of clauses 167-170, wherein the R 3 Selected from hydrogen, optionally substituted (C) 1 -C 6 ) Alkyl and optionally substituted (C) 2 -C 9 ) A heterocycle.
172. The compound of any of clauses 167-171, wherein the R 3 Is an optionally substituted methyl group.
173. The compound of any of clauses 167-172, wherein the R 3 Is optionally substituted C 5 A heterocycle.
174. The compound of any of clauses 167-173, wherein the R 3 Is an optionally substituted piperidinyl group.
175. The compound of any of clauses 167-174, wherein the R 3 Is/are R 6 Substituted, R 6 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally coveredSubstituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
176. The compound of clause 175, wherein the R 6 Selected from hydrogen, optionally substituted (C) 1 -C 6 ) Alkyl and optionally substituted (C) 2 -C 9 ) A heterocycle.
177. The compound of any of clauses 175-176, wherein the R 6 Is optionally substituted ethyl.
178. The compound of any of clauses 175-177, wherein the R 6 Is optionally substituted C 5 A heterocycle.
179. The compound of any of clauses 175-178, wherein the R 6 Is an optionally substituted piperidinyl group.
180. The compound of any of clauses 175-179, wherein the R 6 Is/are R 7 Substituted, R 7 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
181. The compound of clause 180, wherein the R 7 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An acyl group.
182. The compound of any of clauses 180-181, wherein the R 7 Is an optionally substituted acetyl group.
183. The compound of any of clauses 180-182, wherein the R 7 Is/are R 8 Substituted, R 8 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
184. The compound of clause 183, wherein the R 8 Selected from hydrogen and optionally substituted amino.
185. The compound of any of clauses 183-184, wherein the R 8 Is/are R 9 Substituted, R 9 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
186. The compound of clause 185, wherein the R 9 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
187. The compound of any of clauses 185-186, wherein the R 9 Is an optionally substituted methyl group.
188. The compound of any of clauses 167-187, wherein the R 4 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
189. The compound of any of clauses 167-188, wherein the R 4 Is an optionally substituted methyl group.
190. The compound of any of clauses 167-189, wherein the R 4 Is/are R 10 Substituted, R 10 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Impurity(s)Aryl groups.
191. The compound of clause 190, wherein the R 10 Is optionally substituted (C) 6 -C 10 ) Aryl groups.
192. The compound of any of clauses 190-191, wherein the R 10 Is optionally substituted phenyl.
193. The compound of any of clauses 190-192, wherein the R 10 Is/are R 11 Substituted, R 11 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
194. The compound of clause 193, wherein the R 11 Selected from hydrogen, halogen and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
195. The compound of any of clauses 193-194, wherein the R 11 Is optionally substituted pyrazolyl.
196. The compound of any of clauses 193-195, wherein the R 11 F.
197. The compound of any of clauses 193-196, wherein the R 5 Is hydrogen.
198. A compound or pharmaceutically acceptable salt, prodrug thereofA solvate or metabolite, or a solvate or hydrate of any of the above, wherein the compound is selected from the group consisting of:
199. a compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:
200. a compound having the structure of formula (VIII),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 and R 7 Are each independently absent or are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl;
n is independently not less than 0.
201. The compound of clause 200, wherein the R 1 Is hydrogen.
202. The compound of any of clauses 200-201, wherein the R 2 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
203. The compound of any of clauses 200-202, wherein the R 2 Is an optionally substituted isopropyl group.
204. The compound of any of clauses 200-203, wherein the R 3 Is hydrogen.
205. The compound of any of clauses 200-204, wherein the R 4 Is hydrogen.
206. The compound of any of clauses 200-205, wherein the R 5 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
207. The compound of any of clauses 200-206, wherein the R 5 Is an optionally substituted methyl group.
208. The compound of any of clauses 200-207, wherein the R 5 Is/are R 8 Substituted, R 8 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl group,Optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
209. The compound of clause 208, wherein the R 8 Selected from hydrogen and optionally substituted (C) 6 -C 10 ) Aryl groups.
210. The compound of any of clauses 208-209, wherein the R 8 Is optionally substituted phenyl.
211. The compound of any of clauses 208-210, wherein the R 8 Is/are R 9 Substituted, R 9 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
212. The compound of clause 211, wherein the R 9 Selected from hydrogen, halogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
213. The compound of any of clauses 211-212, wherein the R 9 F.
214. The compound of any of clauses 211-213, wherein the R 9 Is an optionally substituted methyl group.
215. The compound of any of clauses 211-214, wherein the R 9 Is/are R 10 Substituted, R 10 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
216. The compound of clause 215, wherein the R 10 Selected from hydrogen and halogen.
217. The compound of any of clauses 215-216, wherein the R 10 F.
218. The compound of any of clauses 200-217, wherein the R 6 Is hydrogen.
219. The compound of any of clauses 200-218, wherein the R 7 Is hydrogen.
220. A compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:
221. a compound having the structure of formula (IX),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
X 1 and X 2 Each independently selected from C, N and O;
a is selected from optionally substituted (C 2 -C 9 ) Heterocycles and optionally substituted (C) 1 -C 9 ) Heteroaryl;
R 1 、R 2 、R 3 、R 4 、R 5 and R is 6 Are each independently absent or are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl;
n and m are each independently not less than 0.
222. The compound of clause 221, wherein the X 1 Is N.
223. The compound of any of clauses 221-222, wherein the X 2 Is C.
224. The method according to any one of clauses 221-223The compound, wherein A is optionally substituted (C 1 -C 9 ) Heteroaryl groups.
225. The compound of any of clauses 221-224, wherein the a is optionally substituted C 3 Heteroaryl groups.
226. The compound of any of clauses 221-225, wherein the a is optionally substituted pyrazolyl.
227. The compound of any of clauses 221-226, wherein the R 1 Is hydrogen.
228. The compound of any of clauses 221-227, wherein the R 2 Selected from hydrogen, optionally substituted (C) 1 -C 6 ) Alkyl and optionally substituted (C) 3 -C 10 ) Carbocycles.
229. The compound of any of clauses 221-228, wherein the R 2 Is an optionally substituted isopropyl group.
230. The compound of any of clauses 221-229, wherein the R 2 Is optionally substituted C 5 Carbocycles.
231. The compound of any of clauses 221-230, wherein the R 2 Is optionally substituted cyclopentyl.
232. The compound of any of clauses 221-231, wherein the R 3 Is hydrogen.
233. The compound of any of clauses 221-232, wherein the R 4 Is hydrogen.
234. The compound of any of clauses 221-233, wherein the R 5 Is hydrogen.
235. The compound of any of clauses 221-234, wherein the R 6 Is hydrogen.
236. A compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:
237. a compound having the structure of formula (X),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
X 1 、X 2 and X 3 Each independently selected from C, N and O;
a is selected from optionally substituted (C 2 -C 9 ) Heterocycles and optionally substituted (C) 1 -C 9 ) Heteroaryl;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 and R 7 Are each independently absent or are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl;
n and m are each independently not less than 0.
238. The compound of clause 237, wherein the X 1 Is N.
239. The method of any one of clauses 237-238Wherein, the X 2 Is C.
240. The compound of any of clauses 237-239, wherein the a is optionally substituted (C 1 -C 9 ) Heteroaryl groups.
241. The compound of any of clauses 237-240, wherein the a is optionally substituted C 3 Heteroaryl groups.
242. The compound of any of clauses 237-241, wherein a is optionally substituted pyrazolyl.
243. The compound of any of clauses 237-242, wherein the R 1 Is hydrogen.
244. The compound of any of clauses 237-243, wherein the R 2 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
245. The compound of any of clauses 237-244, wherein the R 2 Is an optionally substituted isopropyl group.
246. The compound of any of clauses 237-245, wherein the X 3 Is N.
247. The compound of any of clauses 237-246, wherein the X 3 Is O.
248. The compound of any of clauses 237-247, wherein the R 3 Is hydrogen.
249. The compound of any of clauses 237-248, wherein the R 4 Is hydrogen.
250. The compound of any of clauses 237-249, wherein the R 5 Is hydrogen.
251. The compound of any of clauses 237-250, wherein the R 6 Is hydrogen.
252. The compound of any of clauses 237-251, wherein the R 7 Is hydrogen.
253. A compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing,wherein the compound is selected from:
254. a compound having the structure of formula (XI),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
R X is halogen;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 and R is 9 Are each independently absent or are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl;
n and m are each independently not less than 0.
255. The compound of clause 254, wherein the R X F.
256. The compound of any of clauses 254-255, wherein n is selected from 1 to 2.
257. The compound of any of clauses 254-256, wherein the R 1 Is hydrogen.
258. The compound of any of clauses 254-257, wherein the R 2 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
259. The compound of any of clauses 254-258, wherein the R 2 Is an optionally substituted methyl group.
260. The compound of any of clauses 254-259, wherein the R 3 Is hydrogen.
261. The compound of any of clauses 254-260, wherein the R 4 Is hydrogen.
262. The compound of any of clauses 254-261, wherein the R 5 Is hydrogen.
263. The compound of any of clauses 254-262, wherein the R 6 Is hydrogen.
264. The compound of any of clauses 254-263, wherein the R 7 Selected from hydrogen, =o and optionally substituted (C 1 -C 6 ) An alkyl group.
265. The compound of any of clauses 254-264, wherein the R 7 Is an optionally substituted methyl group.
266. The compound of any of clauses 254-265, wherein the R 8 Selected from hydrogen, optionally substituted (C) 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 1 -C 6 ) Acyl and optionally substituted sulfonyl.
267. The compound of any of clauses 254-266, wherein the R 8 Selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.
268. The compound of any of clauses 254-267, wherein the R 8 Is propenyl.
269. The compound of any of clauses 254-268, wherein the R 8 Is butynyl.
270. The compound of any of clauses 254-269, wherein the R 8 Is formyl.
271. The compound of any of clauses 254-270, wherein the R 8 Is/are R 10 Substituted, R 10 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
272. The compound of clause 271, wherein the R 10 Selected from the group consisting of hydrogen, optionally substituted hydroxy, optionally substituted amino, and optionally substituted (C 6 -C 10 ) Aryl groups.
273. The compound of any of clauses 271-272, wherein the R 10 Is optionally substituted phenyl.
274. The compound of any of clauses 271-273, wherein the R 10 Is/are R 11 Substituted, R 11 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing groups optionally substituted silicon-containing groups, optionallyOptionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
275. The compound of clause 274, wherein the R 11 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
276. The compound of any of clauses 274-275, wherein the R 11 Is an optionally substituted methyl group.
277. The compound of any of clauses 274-276, wherein the R 9 Selected from hydrogen and optionally substituted sulfonyl.
278. The compound of any of clauses 274-277, wherein the R 9 Is/are R 12 Substituted, R 12 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Impurity(s)Ring, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
279. The compound of clause 278, wherein the R 12 Selected from hydrogen and optionally substituted amino.
280. A compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of: />
/>
281. A compound having the structure of formula (XII),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
R X is halogen;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 and R 7 Are each independently absent or are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl;
n and m are each independently not less than 0.
282. The compound of clause 281, wherein the R X F.
283. The compound of any of clauses 281-282, wherein the R 1 Is hydrogen.
284. The compound of any of clauses 281-283, wherein the R 2 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
285. The compound of any of clauses 281-284, wherein the R 2 Is an optionally substituted isopropyl group.
286. The compound of any of clauses 281-285, wherein the R 3 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
287. The compound of any of clauses 281-286, wherein the R 3 Is an optionally substituted methyl group.
288. The compound of any of clauses 281-287, wherein n is selected from 1 to 4.
289. The compound of any of clauses 281-288, wherein n is 4.
290. The compound of any of clauses 281-289, wherein the R 4 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An acyl group.
291. The compound of any of clauses 281-290, wherein the R 4 Is optionally substituted propionyl.
292. The compound of any of clauses 281-291, wherein the R 4 Is/are R 9 Substituted, R 9 Each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl groups.
293. The compound of clause 292, wherein the R 9 Selected from hydrogen, optionally substituted amino, optionally substituted (C 1 -C 6 ) Alkyl and optionally substituted (C) 6 -C 10 ) Aryl groups.
294. The compound of any of clauses 292-293, wherein the R 9 Is an optionally substituted methyl group.
295. The compound of any of clauses 292-294, wherein the R 9 Is optionally substituted phenyl.
296. The compound of any of clauses 281-295, wherein the R 5 Is hydrogen.
297. The compound of any of clauses 281-296, wherein the R 6 Is hydrogen.
298. The compound of any of clauses 281-297, wherein the R 7 Is hydrogen.
299. A compound or pharmaceutically acceptable thereofOr a prodrug or metabolite, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:
300. A compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:
301. a compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is
302. A compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:
303. a compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is
304. A compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:/>
305. a compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:
306. a compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:
307. A compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:
308. a compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:/>
309. a compound orA pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:/>
310. a compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of: />
/>
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311. a compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:/>
312. a compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a combination thereofA solvate or hydrate of any component, wherein the compound is selected from the group consisting of: />
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313. a composition comprising a compound of any one of clauses 1-312, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the above components, and optionally a pharmaceutically acceptable carrier.
314. A method for inhibiting Cyclin Dependent Kinase (CDK) activity, comprising administering to a subject in need thereof an effective amount of a compound of any one of clauses 1-312, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing.
315. The method of clause 314, wherein the Cyclin Dependent Kinase (CDK) is CDK 7.
316. The method of any of clauses 314-315, wherein the method is selected from the group consisting of an in vitro method, an ex vivo method, and an in vivo method.
Examples
The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or only performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees celsius, and pressure is at or near atmospheric pressure. Standard abbreviations, such as bp, base pairs, may be used; kb, kilobases; pl, picoliter; s or sec, seconds; min, min; h or hr, hr; aa, amino acids; nt, nucleotide; m., intramuscular (ground); p., intraperitoneal (ground); s.c., subcutaneously (ground); etc.
Example 1 preparation of Compounds
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EXAMPLE 2 biological Activity
Material
Human CDKs, cyclin and other chaperones are expressed in insect cells, purified separately, recombined, then purified to homogeneity, and then used in kinase activity assays. The fluorescently labeled substrate peptides used in the assays are listed in table 1.
TABLE 1 list of CDK peptides for kinase assay
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Method
Kinase activity of CDKs was determined by Mobility Shift Analysis (MSA), in which the formation of phosphorylated fluorescent-labeled peptides in the reaction mixture was monitored by capillary electrophoresis in a microfluidic environment. The kinase reaction was performed in 384 well plates in a total volume of 12. Mu.l containing 20mM MES (pH 6.75), 0.01% Tween 20, 0.05mg/ml BSA, 6mM MgCl 2 2. Mu.M substrate peptide, 2mM ATP, 3nM CDK/cyclin, 2% DMSO, and 10 doses of compound, 3 serial dilutions starting at 10. Mu.M. The mixture was incubated at 27℃for 40 min, then quenched with 4. Mu.l of 80mM EDTA and then read on LabChip EZ Reader II (Caliper Life Science). IC of compounds for CDKs was calculated by Prism (GraphPad) using a four parameter nonlinear curve fit 50 。
The CDK inhibition results (IC) are summarized in Table 2 50 ). The CDK may be CDK7.
TABLE 2 CDK inhibition List
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To evaluate CDK inhibitory activity of the present application, IC was used 50 [nM]The following ranges:
A：IC50≤100nM；
B：100nM<IC50≤500nM；
C：500nM<IC50≤1000nM；
D：1000nM<IC50。
example 3 inhibition of cell proliferation
Exemplary compounds of the present invention were tested for their ability to inhibit proliferation of various cancer cell lines at various concentrations (10. Mu.M to 610pM; 4-fold serial dilutions). The known kinase inhibitor staurosporine was used as a positive control. Cells were grown in the indicator media listed below. All cell lines were supplemented with FBS (Life Technologies) and 100U-mL -1 Penicillin, 100. Mu.g.mL -1 Streptomycin (Invitrogen) and in the presence of 5% CO 2 Is incubated at 37℃in a humidified chamber of the above. Proliferation assays were performed over a 120 hour period. The antiproliferative effect of the compounds was evaluated using the CyQuant assay kit (ThermoFisher) as indicated by the manufacturer.
The following cancer cell lines can be tested using the exemplary medium conditions shown:
breast cancer cell lines
-MDA-MB231: leibovitz's L-15 Medium+10% FBS+1% Glutamax
-MCF7：RPMI 1640+10％FBS+1％Glutamax
-T47D: RPMI 1640+10% FBS+1% Glutamax+0.2 units/ml bovine insulin
-HCC70：RPMI1640+10％FBS+1％Glutamax
Ovarian cancer cell lines
-OVCAR3: RPMI 1640+0.01mg/ml bovine insulin+20% FBS+1% Glutamax
Prostate cancer cell lines
-DU145：EMEM+10％FBS+1％Glutamax
Colon cancer cell line
-HCT-116：McCoy`5A+10％FBS+1％Glutamax
Exemplary results of these assays are shown in Table 3, where "A" represents an IC of less than 0.2. Mu.M 50 A value; "B" means an IC of between 0.2. Mu.M and 1. Mu.M inclusive 50 A value; and "C" represents an IC of greater than 1. Mu.M 50 Values. "NT" means a compound not tested for assignment in a given assay.
TABLE 3 IC for inhibition of cell proliferation 50 Value of
While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. The invention is not limited by the specific embodiments provided in the specification. While the invention has been described with reference to the above specification, the descriptions and illustrations of the embodiments herein are not meant to be construed in a limiting sense. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. Furthermore, it is to be understood that all aspects of the invention are not limited to the specific depictions, configurations or relative proportions set forth herein which depend upon a variety of conditions and variables. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. Accordingly, the present invention is intended to embrace any such alternatives, modifications, variations or equivalents. The following claims define the scope of the invention and methods and structures within the scope of these claims and their equivalents are covered thereby.
SEQUENCE LISTING
<110> Taizhou Yitengjing ang pharmaceutical Co., ltd
<120> cyclin-dependent kinase inhibitor
<130> 0082-PA-022
<160> 2
<170> PatentIn version 3.5
<210> 1
<211> 26
<212> PRT
<213> Artificial Sequence
<220>
<223> CDKs peptide 1
<400> 1
Tyr Ser Pro Ser Thr Ser Pro Ser Tyr Ser Thr Pro Ser Pro Ser Tyr
1 5 10 15
Ser Pro Thr Ser Pro Ser Lys Lys Lys Lys
20 25
<210> 2
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> CDKs peptide 2
<400> 2
Gly Ser Arg Thr Pro Met Tyr
1 5
Claims (26)
1. A compound having the structure of formula (VII),
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate or hydrate of any of the above,
wherein,
X 1 and X 2 Each independently selected from C, N and O;
a is selected from optionally substituted (C 2 -C 9 ) Heterocycles and optionally substituted (C) 1 -C 9 ) Heteroaryl;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R is 8 Are each independently absent or are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =s, = O, N 3 Optionally substituted hydroxy, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxy, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C) 1 -C 6 ) Acyl, optionally substituted (C) 1 -C 6 ) Thioacyl, optionally substituted (C 1 -C 6 ) Alkyl, optionally substituted (C) 2 -C 6 ) Alkenyl, optionally substituted (C) 2 -C 6 ) Alkynyl, optionally substituted (C) 3 -C 10 ) Carbocycles, optionally substituted (C) 2 -C 9 ) Heterocyclic, optionally substituted (C) 6 -C 10 ) Aryl and optionally substituted (C) 1 -C 9 ) Heteroaryl;
n and m are each independently not less than 0.
2. The compound of claim 1, wherein said X 1 Is N.
3. The compound of any one of claims 1-2, wherein the X 2 Is C.
4. A compound according to any one of claims 1 to 3, wherein a is optionally substituted (C 1 -C 9 ) Heteroaryl groups.
5. The compound of any one of claims 1-4, wherein a is optionally substituted C 3 Heteroaryl groups.
6. The compound of any one of claims 1-5, wherein a is optionally substituted pyrazolyl.
7. The compound of any one of claims 1-6, wherein R 1 Is hydrogen.
8. The compound of any one of claims 1-7, wherein R 2 Selected from hydrogen, optionally substituted (C) 1 -C 6 ) Alkyl and optionally substituted (C) 3 -C 10 ) Carbocycles.
9. The compound of any one of claims 1-8, wherein R 2 Is an optionally substituted isopropyl group.
10. The compound of any one of claims 1-9, wherein R 2 Is optionally substituted C 5 Carbocycles.
11. The compound of any one of claims 1-10, wherein R 2 Is optionally substituted cyclopentyl.
12. The compound of any one of claims 1-11, wherein R 3 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) Alkyl group。
13. The compound of any one of claims 1-12, wherein R 3 Is methyl.
14. The compound of any one of claims 1-13, wherein R 4 Selected from hydrogen and optionally substituted (C) 1 -C 6 ) An alkyl group.
15. The compound of any one of claims 1-14, wherein R 4 Is methyl.
16. The compound of any one of claims 1-15, wherein R 5 Is hydrogen.
17. The compound of any one of claims 1-16, wherein R 6 Selected from hydrogen and halogen.
18. The compound of any one of claims 1-17, wherein R 6 Is halogen.
19. The compound of any one of claims 1-18, wherein R 6 F.
20. The compound of any one of claims 1-19, wherein n is 1.
21. The compound of any one of claims 1-20, wherein R 7 Is hydrogen.
22. A compound or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from the group consisting of:
23. A composition comprising a compound of any one of claims 1-22, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing, and optionally a pharmaceutically acceptable carrier.
24. A method for inhibiting Cyclin Dependent Kinase (CDK) activity, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-22, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing.
25. The method of claim 24, wherein the Cyclin Dependent Kinase (CDK) is CDK 7.
26. The method of any one of claims 24-25, wherein the method is selected from the group consisting of an in vitro method, an ex vivo method, and an in vivo method.
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| CN2021085188 | 2021-04-02 | ||
| CNPCT/CN2021/085188 | 2021-04-02 | ||
| PCT/CN2022/083906 WO2022206795A1 (en) | 2021-04-02 | 2022-03-30 | A cyclin-dependent kinase inhibitor |
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| CN116178374A (en) * | 2023-01-13 | 2023-05-30 | 河北医科大学 | Small-conductance calcium-activated potassium ion channel agonist, synthesis and application thereof |
| CN116396298A (en) * | 2023-06-06 | 2023-07-07 | 四川维亚本苑生物科技有限公司 | Intermediate XII of CDK bond-1 and preparation method of CDK bond-1 |
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| FR2818642B1 (en) * | 2000-12-26 | 2005-07-15 | Hoechst Marion Roussel Inc | NOVEL DERIVATIVES OF PURINE, PROCESS FOR PREPARING THEM, THEIR USE AS MEDICAMENTS, PHARMACEUTICAL COMPOSITIONS AND THEIR NEW USE |
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