Sulfone compounds which modulate the CB2 receptor
Compounds which modulate the CB2 receptor are disclosed. Compounds according to the invention bind to and are agonists of the CB2 receptor, and are useful for treating inflammation. Those compounds which are agonists are additionally useful for treating pain.
1. A compound of formula I, wherein
R 1 is aryl optionally independently substituted with 1 to 3 substituents chosen from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulfonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylaminocarbonyl, C 1-6 acylamino, C 1-6 dialkylaminocarbonyl, halogen, cyano, nitro, aryl and heteroaryl; or
R 1 is C 1-10 alkyl, C 3-6 cycloalkyl, 3-10 membered saturated heterocyclic ring, each optionally independently substituted with 1-3 substituents chosen from C 1-10 alkyl, C 3-10 cycloalkyl, C 1-6 acyl, cyano, phenyl, oxo, hydroxyl and halogen; each R 1 and R 1 substituent where possible is optionally substituted with 1 to 3 halogen atoms; or
R 1 is C 1-6 alkyl substituted with 3-10 membered saturated heterocyclic ring each optionally independently substituted with 1-3 substituents chosen from C 1-10 alkyl, C 3-10 cycloalkyl, C 1-6 acyl, cyano, phenyl, oxo, hydroxyl and halogen;
R 2 is hydrogen or C 1-6 alkyl;
R 3 is heteroaryl optionally independently substituted with 1 to 3 substituents chosen from C 1-6 alkyl (which is optionally partially or fully halogenated) and halogen;
R 4 is C 1-6 alkyl, aryl or heteroaryl each optionally independently substituted with 1 to 3 substituents chosen from C 1-6 alkyl and C 1-6 alkoxy;
each R 4 or R 4 substituent where possible is optionally partially or fully halogenated;
n is 1;
or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 wherein,
R 1 is phenyl, naphthyl each optionally independently substituted with 1 to 3 substituents chosen from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulfonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylaminocarbonyl, C 1-6 acylamino, C 1-6 dialkylaminocarbonyl, halogen, cyano, nitro and phenyl; or
R 1 is C 1-10 alkyl, C 3-10 cycloalkyl, heterocyclic ring chosen from tetrahydropyranyl, tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl and pyrrolidinyl, each optionally independently substituted with 1-3 substituents chosen from C 1-10 alkyl, C 3-10 cycloalkyl, C 1-6 acyl, cyano, phenyl, oxo, hydroxyl and halogen; each R 1 and R 1 substituent where possible is optionally substituted with 1 to 3 halogen atoms; or
R 1 is C 1-3 alkyl substituted with 3-10 membered saturated heterocyclic ring each optionally independently substituted with 1-3 substituents chosen from C 1-10 alkyl, phenyl, oxo, hydroxyl and halogen;
R 2 is hydrogen or C 1-5 alkyl;
R 3 is furanyl, pyranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, pyrrolyl, imidazolyl, thienyl, thiadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, indolyl, isoindolyl, benzofuranyl or benzopyranyl each optionally independently substituted with 1 to 3 substituents chosen from C 1-6 alkyl (which is optionally substituted with 1 to 3 halogen atoms) and halogen;
R 4 is C 1-5 alkyl, phenyl or naphthyl each optionally independently substituted with 1 to 3 substituents chosen from C 1-5 alkyl and C 1-5 alkoxy;
each R 4 or R 4 substituent where possible is optionally partially or fully halogenated;
n is 1.
3. The compound according to claim 2 wherein,
R 1 is C 1-6 alkyl, C 3-6 cycloalkyl and phenyl; each optionally independently substituted with 1-3 substituents chosen from C 1-3 alkyl, C 3-6 cycloalkyl, cyano, phenyl and halogen, or
R 1 is tetrahydropyranyl or tetrahydofuranyl optionally substituted with 1-3 substituents chosen from C 1-10 alkyl, C 3-10 cycloalkyl, C 1-6 acyl, cyano, phenyl, oxo, hydroxyl and halogen; or
R 1 is methyl substituted with tetrahydropyranyl or tetrahydofuranyl optionally substituted with 1-3 substituents chosen from C 1-10 alkyl, phenyl, oxo, hydroxyl and halogen;
R 2 is hydrogen or C 1-4 alkyl;
R 3 is oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl, each optionally independently substituted with 1 to 3 substituents chosen from C 1-5 alkyl (which is optionally substituted with 1 to 3 halogen atoms) and halogen;
R 4 is C 1-5 alkyl or phenyl each optionally independently substituted with 1 to 3 substituents chosen from C 1-4 alkyl and C 1-4 alkoxy;
each R 4 or R 4 substituent where possible is optionally partially or fully halogenated.
4. The compound according to claim 3 wherein,
R 2 is hydrogen or C 1-3 alkyl;
R 3 is oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl or pyridinyl;
R 4 is C 1-4 alkyl or phenyl each optionally independently substituted with C 1-3 alkyl;
each R 4 or R 4 substituent where possible is optionally partially or fully halogenated.
5. The compound according to claim 4 wherein,
R 1 is phenyl or tetrahydropyranyl each optionally partially or fully halogenated;
R 2 is hydrogen or C 1-2 alkyl;
R 4 is C 1-4 alkyl or phenyl each optionally partially or fully halogenated.
6. The compound according to claim 5 wherein,
R 1 is phenyl optionally substituted with halogen or tetrahydropyranyl;
R 2 is hydrogen or methyl;
R 3 is thiadiazolyl, isoxazolyl, pyridinyl or triazolyl;
R 4 is C 1-4 alkyl optionally partially or fully halogenated or phenyl.
7. A compound of the formula IA:
L—R 3 —R 4 (IA)
wherein for the formula (IA)
is chosen independently from members of column A in Table I, and
is chosen independently from members of column B in Table I:
TABLE I
A
B
or a pharmaceutically acceptable salt thereof.
8. A compound chosen from
or a pharmaceutically acceptable salt thereof.
9. A compound of formula IB wherein
R 1 is aryl optionally independently substituted with 1 to 3 substituents chosen from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulfonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylaminocarbonyl, C 1-6 acylamino, C 1-6 dialkylaminocarbonyl, halogen, cyano, nitro, aryl and heteroaryl; or
R 1 is C 1-10 alkyl, C 3-6 cycloalkyl, 3-10 membered saturated heterocyclic ring, each optionally independently substituted with 1-3 substituents chosen from C 1-10 alkyl, C 3-10 cycloalkyl, C 1-6 acyl, cyano, phenyl, oxo, hydroxyl and halogen; each R 1 and
R 1 substituent where possible is optionally substituted with 1 to 3 halogen atoms; or
R 1 is C 1-6 alkyl substituted with 3-10 membered saturated heterocyclic ring each optionally independently substituted with 1-3 substituents chosen from C 1-10 alkyl, C 3-10 cycloalkyl, C 1-6 acyl, cyano, phenyl, oxo, hydroxyl and halogen;
R 2 is hydrogen or C 1-6 alkyl;
R 3 is heteroaryl optionally independently substituted with 1 to 3 substituents chosen from C 1-6 alkyl (which is optionally partially or fully halogenated) and halogen;
R 4 is C 1-6 alkyl, aryl or heteroaryl each optionally independently substituted with 1 to 3 substituents chosen from C 1-6 alkyl and C 1-6 alkoxy;
each R 4 or R 4 substituent where possible is optionally partially or fully halogenated;
R is hydrogen or C 1-6 alkyl optionally substituted with phenyl or 1-3 halogen atoms; and
n is 1;
or a pharmaceutically acceptable salt thereof.
10. The compound according to claim 9 wherein,
R 1 is phenyl, naphthyl each optionally independently substituted with 1 to 3 substituents chosen from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulfonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylaminocarbonyl, C 1-6 acylamino, C 1-6 dialkylaminocarbonyl, halogen, cyano, nitro and phenyl; or
R 1 is C 1-10 alkyl, C 3-10 cycloalkyl, heterocyclic ring chosen from tetrahydropyranyl, tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl and pyrrolidinyl, each optionally independently substituted with 1-3 substituents chosen from C 1-10 alkyl, C 3-10 cycloalkyl, C 1-6 acyl, cyano, phenyl, oxo, hydroxyl and halogen; each R 1 and R 1 substituent where possible is optionally substituted with 1 to 3 halogen atoms; or
R 1 is C 1-3 alkyl substituted with 3-10 membered saturated heterocyclic ring each optionally independently substituted with 1-3 substituents chosen from C 1-10 alkyl, phenyl, oxo, hydroxyl and halogen;
R 2 is hydrogen or C 1-5 alkyl;
R 3 is furanyl, pyranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, pyrrolyl, imidazolyl, thienyl, thiadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, indolyl, isoindolyl, benzofuranyl or benzopyranyl each optionally independently substituted with 1 to 3 substituents chosen from C 1-6 alkyl (which is optionally substituted with 1 to 3 halogen atoms) and halogen;
R 4 is C 1-5 alkyl, phenyl or naphthyl each optionally independently substituted with 1 to 3 substituents chosen from C 1-5 alkyl and C 1-5 alkoxy;
each R 4 or R 4 substituent where possible is optionally partially or fully halogenated;
R is hydrogen or C 1-5 alkyl; and
n is 1.
11. The compound according to claim 10 wherein,
R 1 is C 1-6 alkyl, C 3-6 cycloalkyl and phenyl; each optionally independently substituted with 1-3 substituents chosen from C 1-3 alkyl, C 3-6 cycloalkyl, cyano, phenyl and halogen, or
R 1 is tetrahydropyranyl or tetrahydofuranyl optionally substituted with 1-3 substituents chosen from C 1-10 alkyl, C 3-10 cycloalkyl, C 1-6 acyl, cyano, phenyl, oxo, hydroxyl and halogen; or
R 1 is methyl substituted with tetrahydropyranyl or tetrahydofuranyl optionally substituted with 1-3 substituents chosen from C 1-10 alkyl, phenyl, oxo, hydroxyl and halogen;
R 2 is hydrogen or C 1-4 alkyl;
R 3 is oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl, each optionally independently substituted with 1 to 3 substituents chosen from C 1-5 alkyl (which is optionally substituted with 1 to 3 halogen atoms) and halogen;
R 4 is C 1-5 alkyl or phenyl each optionally independently substituted with 1 to 3 substituents chosen from C 1-4 alkyl and C 1-4 alkoxy;
each R 4 or R 4 substituent where possible is optionally partially or fully halogenated;
R is hydrogen or C 1-4 alkyl.
12. The compound according to claim 11 wherein,
R 2 is hydrogen or C 1-3 alkyl;
R 3 is oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl or pyridinyl;
R 4 is C 1-4 alkyl or phenyl each optionally independently substituted with C 1-3 alkyl;
each R 4 or R 4 substituent where possible is optionally partially or fully halogenated;
R is hydrogen, benzyl or C 1-3 alkyl.
13. The compound according to claim 12 wherein,
R 1 is phenyl or tetrahydropyranyl each optionally partially or fully halogenated;
R 2 is hydrogen or C 1-2 alkyl;
R 4 is C 1-4 alkyl or phenyl each optionally partially or fully halogenated;
R is hydrogen or C 1-3 alkyl.
14. The compound according to claim 13 wherein,
R 1 is phenyl optionally substituted with halogen or tetrahydropyranyl;
R 2 is hydrogen or methyl;
R 3 is thiadiazolyl, isoxazolyl, pyridinyl or triazolyl;
R 4 is C 1-4 alkyl optionally partially or fully halogenated or phenyl;
R is hydrogen.
15. A compound of the formula IC:
L—R 3—R 4
wherein for the formula (IC)
is chosen independently from members of column A in Table IV, and
is chosen independently from members of column B in Table IV
TABLE IV
A
B
wherein R is hydrogen or halogen;
or a pharmaceutically acceptable salt thereof.
16. A compound chosen from
or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 .
18. A method of treating pain comprising administering to a patient a therapeutically effective amount of a compound according to claim 1 .
19. A method of treating a disease or condition chosen from an acute pain, visceral pain, neuropathic pain, inflammatory and nociceptive pain and cancer pain, comprising administering to a patient a therapeutically effective amount of a compound according to claim 1 .