Tetrahydro-imidazo quinoline compositions as CBP/P300 inhibitors
The present disclosure is directed to inhibitors of the CBP/p300 family of bromodomains. The compounds can be useful in the treatment of disease or disorders associated with the inhibition of the CBP/p300 family of bromodomains. For instance, the disclosure is concerned with compounds and compositions for inhibition of the CBP/p300 family of bromodomains, methods of treating, preventing, or ameliorating diseases or disorders associated with the inhibition of CBP/p300 family of bromodomains, and methods of synthesis of these compounds.
1. A compound of Formula (I-d):
or a pharmaceutically acceptable salt thereof,
wherein:
Ring B represents —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, heterocyclyl, aryl, spirocycloalkyl, spiroheterocyclyl, or heteroaryl;
R 1 is —OR 5 or —C 1 -C 6 alkyl;
R 3 is —H, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, spirocycloalkyl, spiroheterocyclyl, heterocyclyl, heteroaryl, or aryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, spirocycloalkyl, spiroheterocyclyl, heterocyclyl, heteroaryl, or aryl is optionally substituted with one or more R 7 ;
R 4 and R 4′ are each independently —H, halogen, —OH, —CN, or —NH 2 ;
R 5 is —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R 7 is independently, at each occurrence, —H, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, heterocyclyl, aryl, spirocycloalkyl, spiroheterocyclyl, heteroaryl, —OH, halogen, oxo, —CN, —SR 8 , —OR 8 , —(CH 2 )˜—OR 8 , —NHR 8 , —NR 8 R 9 , —S(O) 2 NR 8 R 9 , —S(O) 2 R 8′ , —C(O)R 8′ , —C(O)OR 8 , —C(O)NR 8 R 9 , —NR 8 C(O)R 9′ , —NR 8 S(O) 2 R 9′ , —S(O)R 8′ , —S(O)NR 8 R 9 , or —NR 8 S(O)R 9′ , wherein each alkyl, cycloalkyl, heterocyclyl, spirocycloalkyl, spiroheterocyclyl, heteroaryl, or aryl is optionally substituted with one or more R 10 ;
wherein any two R 7 , when on non-adjacent atoms, can combine to form a bridging cycloalkyl or heterocyclyl;
wherein any two R 7 , when on adjacent atoms, can combine to form a cycloalkyl, heterocyclyl, aryl or heteroaryl;
R 8 and R 9 are each independently, at each occurrence, —H, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R 10 or R 11 ; or
R 8 and R 9 may combine with the atom to which they are both attached to form a —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, spirocycloalkyl, spiroheterocyclyl, heterocyclyl, heteroaryl, or aryl, wherein the formed —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, spirocycloalkyl, spiroheterocyclyl, heterocyclyl, heteroaryl, or aryl is optionally substituted with one or more R 10 or R 11 ;
R 8′ and R 9′ are each independently, at each occurrence, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R 10 or R 11 ; or
R 8′ and R 9′ may combine with the atom to which they are both attached to form a —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, spirocycloalkyl, spiroheterocyclyl, heterocyclyl, heteroaryl, or aryl, wherein the formed —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, spirocycloalkyl, spiroheterocyclyl, heterocyclyl, heteroaryl, or aryl is optionally substituted with one or more R 10 or R 11 ;
R 10 and R 11 are each independently, at each occurrence, —H, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, heterocyclyl, heteroaryl, aryl, —OH, halogen, oxo, —NO 2 , —CN, —NH 2 , —OC 1 -C 6 alkyl, —NHC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl) 2 , —S(O) 2 NH(C 1 -C 6 alkyl), —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 C 1 -C 6 alkyl, —C(O)C 1 -C 6 alkyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —C(O)OC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)SO 2 C 1 -C 6 alkyl, —S(O)(C 1 -C 6 alkyl), —S(O)N(C 1 -C 6 alkyl) 2 , or —N(C 1 -C 6 alkyl)S(O)(C 1 -C 6 alkyl), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, or aryl is optionally substituted with one or more —R 2 ;
wherein any two R 10 or any two R 11 , when on non-adjacent atoms, can combine to form a bridging cycloalkyl or heterocyclyl;
wherein any two R 10 or any two R 11 , when on adjacent atoms, can combine to form a cycloalkyl, heterocyclyl, aryl or heteroaryl;
R 12 is independently, at each occurrence, —H, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, heterocyclyl, heteroaryl, aryl, —OH, halogen, oxo, —NO 2 , —CN, —NH 2 , —OC 1 -C 6 alkyl, —NHC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl) 2 , —S(O) 2 NH(C 1 -C 6 alkyl), —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 C 1 -C 6 alkyl, —C(O)C 1 -C 6 alkyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —C(O)OC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)SO 2 C 1 -C 6 alkyl, —S(O)(C 1 -C 6 alkyl), —S(O)N(C 1 -C 6 alkyl) 2 , or —N(C 1 -C 6 alkyl)S(O)(C 1 -C 6 alkyl);
n is an integer from 1 to 4; and
p is an integer from 1 to 2.
2. The compound of claim 1 , wherein R 5 is —C 1 -C 6 alkyl.
3. The compound of claim 1 , wherein R 1 is —OCH 3 .
4. The compound of claim 1 , wherein R 1 is —C 1 -C 6 alkyl.
5. The compound of claim 1 , wherein R 3 is —C 1 -C 6 alkyl.
6. The compound of claim 1 , wherein R 3 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl optionally substituted with one or more —R 7 .
7. The compound of claim 1 , wherein R 3 is cyclohexyl optionally substituted with one or more —R 7 .
8. The compound of claim 1 , wherein R 3 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl optionally substituted with one or more —S(O) 2 NH 2 , —C(O)OH, —C(O)NH 2 , or —S(O)NH 2 .
9. The compound of claim 1 , wherein R 3 is cyclohexyl optionally substituted with one or more —S(O) 2 NH 2 , —C(O)OH, —C(O)NH 2 , or —S(O)NH 2 .
10. The compound of claim 1 , wherein Ring B is aryl.
11. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 1 selected from the group consisting of:
Compound No.
Structure
Name
16
(1R,3R)-3-[(7S)-2-benzyl-6-(methoxycarbonyl)-7- methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3- yl]cyclohexane-1-carboxylic acid
17
(1S,3S)-3-[(7S)-2-benzyl-6-(methoxycarbonyl)-7- methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3- yl]cyclohexane-1-carboxylic acid
18
(1R,3S)-3-[(7S)-2-benzyl-6-(methoxycarbonyl)-7- methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3- yl]cyclohexane-1-carboxylic acid
19
(1S,3R)-3-[(7S)-2-benzy1-6-(methoxycarbonyl)-7- methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3- yl]cyclohexane-1-carboxylic acid
22
cis-4-[(7S)-2-benzyl-6-(methoxycarbonyl)-7-methyl- 3H,6H,7H,8H,9H-imidazo [4,5-f]quinolin-3- yl]cyclohexane-l-carboxylic acid
23
trans-4-[(7S)-2-benzyl-6-(methoxycarbonyl)-7- methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3- yl]cyclohexane-1-carboxylic acid
27
trans-4-[(7S)-6-(methoxycarbonyl)-2-[(4- methoxyphenyl)methyl]-7-methyl- 3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3- yl]cyclohexane-1-carboxylic acid
28
trans-4-[(7S)-2-[(3-fluoro-4- methoxyphenyl)methyl]-6-(methoxycarbonyl)-7- methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3- yl]cyclohexane-1-carboxylic acid
48
(1R,4S)-4-[(7S)-2-benzyl-6-(methoxycarbonyl)-7- methyl-3H,6H,7H,8H,9H-imidazo [4,5-f]quinolin-3- yl]-2,2-dimethylcyclohexane-1-carboxylic acid
263
methyl (7S)-2-benzyl-3-cyclohexyl-7-methyl- 3H,6H,7H,8H,9H-imidazo[4,5-f]quinoline-6- carboxylate.
13. The compound of claim 1 of the chemical formula:
or a pharmaceutically acceptable salt thereof.
14. The compound of claim 1 of the chemical formula:
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 1 of the chemical formula:
or a pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
17. A compound of Formula (I-e):
or a pharmaceutically acceptable salt thereof,
wherein:
R 6 and R 7 are each independently, at each occurrence, —H, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, heterocyclyl, aryl, spirocycloalkyl, spiroheterocyclyl, heteroaryl, —OH, halogen, oxo, —CN, —SR 8 , —OR 8 , —(CH 2 ) n —OR 8 , —NHR 8 , —NR 8 R 9 , —S(O) 2 NR 8 R 9 , —S(O) 2 R 8′ , —C(O)R 8′ , —C(O)OR 8 , —C(O)NR 8 R 9 , —NR 8 C(O)R 9′ , —NR 8 S(O) 2 R 9′ , —S(O)R 8′ , —S(O)NR 8 R 9 , or —NR 8 S(O)R 9′ , wherein each alkyl, cycloalkyl, heterocyclyl, spirocycloalkyl, spiroheterocyclyl, heteroaryl, or aryl is optionally substituted with one or more R 10 ;
wherein any two R 6 or any two R 7 , when on non-adjacent atoms, can combine to form a bridging cycloalkyl or heterocyclyl;
wherein any two R 6 or any two R 7 , when on adjacent atoms, can combine to form a cycloalkyl, heterocyclyl, aryl or heteroaryl;
R 8 and R 9 are each independently, at each occurrence, —H, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R 10 or R 11 ; or
R 8 and R 9 may combine with the atom to which they are both attached to form a —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, spirocycloalkyl, spiroheterocyclyl, heterocyclyl, heteroaryl, or aryl, wherein the formed —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, spirocycloalkyl, spiroheterocyclyl, heterocyclyl, heteroaryl, or aryl is optionally substituted with one or more R 10 or R 11 ;
R 8′ and R 9′ are each independently, at each occurrence, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R 10 or R 11 ; or
R 8′ and R 9′ may combine with the atom to which they are both attached to form a —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, spirocycloalkyl, spiroheterocyclyl, heterocyclyl, heteroaryl, or aryl, wherein the formed —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, spirocycloalkyl, spiroheterocyclyl, heterocyclyl, heteroaryl, or aryl is optionally substituted with one or more R 10 or R 11 ;
R 10 and R 11 are each independently, at each occurrence, —H, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, heterocyclyl, heteroaryl, aryl, —OH, halogen, oxo, —NO 2 , —CN, —NH 2 , —OC 1 -C 6 alkyl, —NHC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl) 2 , —S(O) 2 NH(C 1 -C 6 alkyl), —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 C 1 -C 6 alkyl, —C(O)C 1 -C 6 alkyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —C(O)OC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)SO 2 C 1 -C 6 alkyl, —S(O)(C 1 -C 6 alkyl), —S(O)N(C 1 -C 6 alkyl) 2 , or —N(C 1 -C 6 alkyl)S(O)(C 1 -C 6 alkyl), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, or aryl is optionally substituted with one or more —R 12 ;
wherein any two R 10 or any two R 11 , when on non-adjacent atoms, can combine to form a bridging cycloalkyl or heterocyclyl;
wherein any two R 10 or any two R 11 , when on adjacent atoms, can combine to form a cycloalkyl, heterocyclyl, aryl or heteroaryl;
R 12 is independently, at each occurrence, —H, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, —C 4 -C 8 cycloalkenyl, heterocyclyl, heteroaryl, aryl, —OH, halogen, oxo, —NO 2 , —CN, —NH 2 , —OC 1 -C 6 alkyl, —NHC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl) 2 , —S(O) 2 NH(C 1 -C 6 alkyl), —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 C 1 -C 6 alkyl, —C(O)C 1 -C 6 alkyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —C(O)OC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)SO 2 C 1 -C 6 alkyl, —S(O)(C 1 -C 6 alkyl), —S(O)N(C 1 -C 6 alkyl) 2 , or —N(C 1 -C 6 alkyl)S(O)(C 1 -C 6 alkyl);
n is an integer from 1 to 4; and
p is 1 or 2.
18. The compound of claim 17 , wherein p is 1.
19. The compound of claim 18 , wherein R 7 is —C(O)OH.
20. The compound of claim 19 , wherein R 6 is aryl or heteroaryl, wherein each aryl or heteroaryl is optionally substituted with one or more R 10 .