EP300/CREBBP inhibitor

Patent metadata

Field	Value
Publication number	US-11274100-B2
Application number	US-201816625578-A
Country	US
Kind code	B2
Filing date	Jun 21, 2018
Priority date	Jun 21, 2017
Publication date	Mar 15, 2022
Grant date	Mar 15, 2022

Abstract

The present invention provides a compound having excellent histone acetyl transferase inhibitory activity against EP300 and/or CREBBP, or a pharmacologically acceptable salt thereof. The compound is represented by the following formula (1) or a pharmacologically acceptable salt thereof:

wherein ring Q 1 , ring Q 2 , R 1 , R 2 , R 3 and R 4 respectively have the same meanings as defined in the specification.

First claim

The invention claimed is:

1. A compound represented by formula (1) or a pharmacologically acceptable salt thereof:

wherein ring Q 1 represents a phenyl group optionally having 1 to 3 substituents independently selected from group A;
ring Q 2 represents an 8-membered to 10-membered bicyclic aromatic heterocyclic group optionally having, in a ring, 1 to 4 hetero atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom (wherein the 8-membered to 10-membered bicyclic aromatic heterocyclic group optionally has 1 to 3 substituents independently selected from group B);
R 1 and R 2 each independently represent a C 1-6 alkyl group or a C 1-6 alkoxy group, or
R 1 and R 2 form, together with a carbon atom to which R 1 and R 2 are bonded, a 3-membered to 7-membered cycloalkyl ring optionally having 1 to 3 substituents independently selected from group C, a tetrahydropyran ring optionally having 1 to 3 substituents independently selected from group C, or a dioxane ring optionally having 1 to 3 substituents independently selected from group C; and
R 3 and R 4 form, together with a nitrogen atom to which R 3 is bonded and a carbon atom to which R 4 is bonded, an azetidine ring optionally having 1 to 3 substituents independently selected from group D, a pyrrolidine ring optionally having 1 to 3 substituents independently selected from group D, a hexamethyleneimine ring optionally having 1 to 3 substituents independently selected from group D, a thiazolidine ring optionally having 1 to 3 substituents independently selected from group D, a 1-oxothiazolidine ring optionally having 1 to 3 substituents independently selected from group D, a 1,1-dioxothiazolidine ring optionally having 1 to 3 substituents independently selected from group D, or a 4-oxopyrrolidine ring optionally having 1 to 3 substituents independently selected from group D:
Group A: a halogen atom, a hydroxy group, a carboxy group, a C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a C 1-6 alkoxy group, a halo C 1-6 alkoxy group, a C 1-6 alkoxycarbonyl group, a C 2-7 alkanoyl group, a halo C 2-7 alkanoyl group, a C 2-7 alkanoylamino group, a C 1-6 alkylsulfonyl group, a C 1-6 alkylsulfonylamino group, a C 3-7 cycloalkylsulfonylamino group, a phenyl group, a phenylsulfonylamino group, a carbamoyl group, a C 1-6 alkylcarbamoyl group, a di-C 1-6 alkylcarbamoyl group, a benzyloxycarbonyl group, a C 3-7 cycloalkylsulfonylcarbamoyl group, a halo C 1-6 alkylsulfonyloxy group and a phenyl sulfonyl group,
Group B: a halogen atom, a cyano group, an amino group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a hydroxy C 1-6 alkyl group, a C 1-6 alkylamino group, a C 1-6 alkylamino C 1-6 alkyl group, a morpholinyl C 1-6 alkyloxy group, a phenyl group, a benzyloxy group, a C 1-6 alkoxy C 1-6 alkyl group, a hydroxy group, a halo C 1-6 alkyl group, a C 1-6 alkoxycarbonyl group, a C 2-7 alkanoylamino group, a halo C 1-6 alkoxy group, a C 1-6 alkoxy C 1-6 alkoxy group, a C 1-6 alkylsulfonylamino group, a morpholinyl C 1-6 alkyl group and a C 1-6 alkylsulfonyl group,
Group C: a halogen atom, a C 1-6 alkyl group and a C 1-6 alkoxy group, and
Group D: a halogen atom, a hydroxy group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkoxy C 1-6 alkoxy group, a C 2-6 alkynyl group, a C 2-7 alkanoylamino group, an amino group and a di-C 1-6 alkylamino group.

2. A compound according to claim 1 , or a pharmacologically acceptable salt thereof, wherein the ring Q 1 represents formula (2A):

wherein R 5 , R 6 and R 7 each independently represent a hydrogen atom, a halogen atom, a hydroxy group, a carboxy group, a C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a C 1-6 alkoxy group, a halo C 1-6 alkoxy group, a C 1-6 alkoxycarbonyl group, a C 2-7 alkanoyl group, a halo C 2-7 alkanoyl group, a C 2-7 alkanoylamino group, a C 1-6 alkylsulfonyl group, a C 1-6 alkylsulfonylamino group, a C 3-7 cycloalkylsulfonylamino group, a phenyl group or a phenylsulfonylamino group.

3. A compound according to claim 1 , or a pharmacologically acceptable salt thereof, wherein the ring Q 1 is a p-hydroxyphenyl group, a p-methoxyphenyl group, a p-fluoromethoxyphenyl group, a p-difluoromethoxyphenyl group, a p-acetylphenyl group, a p-trifluoroacetylphenyl group, a p-(2-hydroxypropan-2-yl)phenyl group, a 6-methoxypyridin-3-yl group, a m-fluoro-p-methoxyphenyl group or a m-fluoro-p-difluoromethoxyphenyl group.

4. A compound according to claim 1 , or a pharmacologically acceptable salt thereof, wherein the ring Q 2 represents any one of formulae (3A) to (3F):

wherein X represents a nitrogen atom or —CR 13 ;
Y represents a nitrogen atom or —CR 14 ;
Z represents —NH or —CH 2 in the formula (3B), and a nitrogen atom or —CH in the formula (3C);
W represents an oxygen atom or —CH 2 ;
R 12 represents a hydrogen atom or a C 1-6 alkyl group;
R 13 represents a hydrogen atom, a fluorine atom or a cyano group; and
R 14 represents a hydrogen atom, a C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a C 1-6 alkylamino C 1-6 alkyl group or a phenyl group.

5. A compound according to claim 1 , or a pharmacologically acceptable salt thereof, wherein the ring Q 2 represents any one of formulae (4A) to (4D):

wherein R 15 represents a hydrogen atom, a methyl group, a hydroxymethyl group or a methylaminomethyl group.

6. A compound according to claim 1 , or a pharmacologically acceptable salt thereof, wherein R 1 and R 2 each independently represent a methyl group.

7. A compound according to claim 1 , or a pharmacologically acceptable salt thereof, wherein R 1 and R 2 form, together with a carbon atom to which to R 1 and R 2 are bonded, a cyclobutane ring, a 3,3-dihalocyclobutane ring, a 3,3-di-C 1-6 alkyl cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a 4,4-dihalocyclohexane ring, a tetrahydropyran ring, a cycloheptane ring or a spiro[3.3]heptane ring.

8. A compound according to claim 1 , or a pharmacologically acceptable salt thereof, wherein R 1 and R 2 form, together with a carbon atom to which R 1 and R 2 are bonded, a 3,3-difluorocyclobutane ring, a 3,3-dimethylcyclobutane ring, a cyclopentane ring, a cyclohexane ring, a 4,4-difluorocyclohexane ring or a 4-tetrahydropyran ring.

9. A compound according to claim 1 , or a pharmacologically acceptable salt thereof, wherein R 3 and R 4 represent, together with a nitrogen atom to which R 3 is bonded and a carbon atom to which R 4 is bonded, any one of formulae (5A) to (5D):

wherein R 16 represents a hydrogen atom, a halogen atom, a hydroxy group, a C 1-6 alkoxy group or a di-C 1-6 alkylamino group;
R 17 represents a hydrogen atom or a hydroxy group; and
R 18 represents a C 1-6 alkyl group or a C 2-6 alkynyl group.

10. A compound according to claim 1 , or a pharmacologically acceptable salt thereof, wherein R 3 and R 4 represent, together with a nitrogen atom to which R 3 is bonded and a carbon atom to which R 4 is bonded, any one of formulae (6A) t

Assignees

• Daiichi Sankyo Co Ltd

Inventors

• Naito Hiroyuki
• Kagoshima Yoshiko
• Funami Hideaki
• Nakamura Akifumi
• Asano Masayoshi
• Haruta Makoto
• Suzuki Takashi
• Watanabe Jun
• Kanada Ryutaro
• Higuchi Saito
• Ito Kentaro
• Egami Akiko
• Kobayashi Katsuhiro

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D277/06

  with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms · CPC title