Opioid receptor modulators
Provided herein are opioid receptor modulators and pharmaceutical compositions comprising said compounds.
1. A compound having the structure of Formula (I):
wherein:
R 1 is selected from C 6-10 aryl and C 1-9 heteroaryl, wherein C 6-10 aryl and C 1-9 heteroaryl are optionally substituted with one, two, three, four, or five R 7 ;
R 2 is selected from C 6-10 aryl and C 1-9 heteroaryl, wherein C 6-10 aryl and C 1-9 heteroaryl are optionally substituted with one, two, three, four, or five R 8 ;
R 3 is —X—R 3a ;
X is a bond;
R 3a is C 3-8 cycloalkyl substituted with one, two, three, four, or five R 9 ;
R 4 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R 5 and R 6 are each independently selected from hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; or R 5 and R 6 are combined to form an azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl ring;
each R 7 is independently selected from halogen, —CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, —OR 10 , —SR 10 , —C(O)OR 10 ,—OC(O)N(R 10 (R 11 ), —N(R 12 )C(O)N(R 10 )(R 11 ), —N(R 12 )C(O)R 13 , —N(R 12 )C(O)OR 13 , N(R 12 )S(O) 2 R 13 , —C(O)R 13 , —OC(O)R 13 ,—C(O)N(R 10 (R 11 )-C(O)C(O)N(R 10 )(R 11 ),—S(O)R 13 , S(O) 2 R 13 and —S(O) 2 N(R 10 )(R 11 ), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, —OR 14 , —C(O)OR 14 ,—OC(O)N(R 14 )(R 15 ), —N(R 16 )C(O)N(R 14 )(R 15 ), —N(R 16 )C(O)R 17 , —N(R 66 )C(O)OR 17 , —N(R 16 )S(O) 2 R 17 , —C(O)R 17 , —OC(O)R 17 , —C(O)N(R 14 )(R 15 ), —C(O)C(O)N(R 14 )(R 15 ), —S(O)R 17 , —S(O) 2 R 17 , and —S(O) 2 N(R 14 )(R 15 ); or two R 7 are combined to form a heterocycloalkyl ring optionally substituted with oxo; or R 7 and R 6 are combined to form a heterocycloalkyl ring;
each R 8 and each R 9 are each independently selected from halogen, —CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, —OR 10 , —C(O)OR 10 , —OC(O)N(R 10 )(R 11 ),—N(R 12 )C(O)N(R 10 (R 11 ), —N(R 12 )C(O)R 13 , —N(R 12 )C(O)OR 13 , —N(R 12 )S(O) 2 R 13 , —C(O)R 13 , —OC(O)R 13 , —C(O)N(R 10 )(R 11 ), —C(O)C(O)N(R 10 )(R 11 ), —S(O)R 13 , —S(O) 2 R 13 , and —S(O) 2 N(R 10 )(R 11 ), wherein C 1-6 alky, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, C 1-6 alkyl, C 2-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, —OR 14 , —SR 14 , —C(O)OR 14 , —OC(O)N(R 14 )(R 16 ), —N(R 16 )C(O)N(R 14 )(R 15 ), —N(R 66 )C(O)R 17 , —N(R 16 )C(O)OR 17 , —N(R 16 )S(O) 2 R 17 , —C(O)R 17 , —OC(O)R 17 , —OC(O)N(R 14 (R 15 ), —C(O)C(O)N(R 14 )(R 15 ), —S(O)R 17 , —S(O) 2 R 17 , and —S(O) 2 N(R 14 )(R 15 );
each R 10 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-6 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl;
each R 11 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;
each R 12 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;
each R 13 is independently selected C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-100 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl;
each R 14 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 ,heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl;
each R 15 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;
each R 16 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; and
each R 17 is independently selected C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl;
or a pharmaceutically acceptable salt or solvate thereof.
2. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ia):
wherein n is 0, 1, 2, 3, or 4.
3. The compound of claim 2 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 10 is independently selected from hydrogen and C 1-6 alkyl.
4. The compound of claim 3 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is hydrogen.
5. The compound of claim 4 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 is hydrogen.
6. The compound of claim 5 , or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2.
7. The compound of claim 6 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 7 is independently selected from halogen and C 1-6 alkyl.
8. The compound of claim 7 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is cyclopropyl substituted with one, two, or three R 9 .
9. The compound of claim 8 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 9 is independently selected from halogen, —CN, C 1-6 alkyl, and C 1-6 haloalkyl.
10. The compound of claim 9 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is cyclopropyl substituted with one R 9 .
11. The compound of claim 10 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is cyclopropyl substituted with —CF 3 .
12. The compound of claim 7 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is phenyl optionally substituted with one, two, or three R 8 or R 2 is pyridinyl, pyrimidinyl, or thiazolyl, wherein pyridinyl, pyrimidinyl, and thiazolyl are optionally substituted with one, two, or three R 8 .
13. The compound of claim 12 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 8 is independently selected from halogen C 1-6 alkyl, C 1-6 haloalkyl, and —OR 10 .
14. The compound of claim 7 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 are C 1 -C 6 alkyl.
15. A compound selected from:
or a pharmaceutically acceptable salt or solvate thereof.
16. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.