Therapeutic uses of compounds which selectively modulate the CB2 receptor

1. A method of treating pain comprising administering a therapeutically effective amount of a compound of the formula (I)

wherein:

Het is a 5-membered heteroaryl ring;

R 1 is C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, 3-10 membered saturated heterocyclic ring, 5-10 membered mono or bicyclic heteroaryl ring or phenyl each optionally independently substituted with 1-3 substituents chosen from C 1-4 alkyl, C 1-4 alkoxy, C 3-10 cycloalkyl, C 1-4 alkylsulfonyl, acyl, oxo, cyano, phenyl, hydroxyl and halogen;

R 2 and R 3 are C 1 -C 4 alkyl or hydrogen with the proviso that both R 2 and R 3 cannot be hydrogen; or R 2 and R 3 together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl or heterocyclic ring;

R 4 is hydrogen or methyl;

R 5 is chosen from

m is 0, 1, 2 or 3

R 6 is hydrogen or C 1-4 alkyl;

wherein R 7 and R 8 are each independently hydrogen or C 1-4 alkyl with the proviso that both R 7 and R 8 cannot be hydrogen; and wherein R 7 and R 8 optionally can cyclize to form a C 3-7 cycloalkyl ring;

n is 0, 1 or 2;

wherein any carbon atom on the formula (I) or any R substituent listed above is optionally partially or fully halogenated where possible;

or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 , and wherein

Het is

R 1 is C 1-4 alkyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, piperidinyl; benzoxazolyl, benzothiazolyl, benzimidazolyl, dioxanyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, pyrrolyl, imidazolyl, thienyl, thiomorpholinyl, 1,1-Dioxo-1λ 6 -thiomorpholinyl, morpholinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolidinyl, piperazinyl, purinyl, quinolinyl, Dihydro-2H-quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, indolyl, benzofuranyl, benzopyranyl or benzodioxolyl each optionally substituted by a substituent chosen from halogen, C 1-4 alkyl, C 1-4 alkylsulfonyl and oxo;

R 2 and R 3 are independently methyl, ethyl, n-propyl, isopropyl; or hydrogen with the proviso that both R 2 and R 3 cannot be hydrogen; or R 2 and R 3 together with the carbon to which they are attached form a cyclopropyl, cyclobutyl; or cyclopentyl ring;

R 4 is hydrogen;

R 5 is chosen from

R 6 is hydrogen or C 1-3 alkyl;

wherein R 7 and R 8 are each C 1-3 alkyl

or a pharmaceutically acceptable salt thereof.

3. The method according to claim 2 , and wherein

R 1 is C 1-4 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, piperidinyl, dioxanyl, thiomorpholinyl, 1,1-Dioxo-1λ 6 -thiomorpholinyl, morpholinyl, pyrrolidinyl or piperazinyl, each optionally substituted by a substituent chosen from halogen, C 1-4 alkyl, C 1-4 alkylsulfonyl and oxo or a pharmaceutically acceptable salt thereof.

4. The method according to claim 3 , and wherein

Het is

R 1 is C 1-2 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl or piperidinyl each optionally substituted by a substituent chosen from by halogen, C 1-4 alkyl, C 1-4 alkylsulfonyl and oxo;

R 2 and R 3 are methyl, or R 2 and R 3 together with the carbon to which they are attached form a cyclopropyl or cyclobutyl ring;

R 6 is hydrogen or C 1-2 alkyl;

R 7 and R 8 are each C 1-2 alkyl

or a pharmaceutically acceptable salt thereof.

5. The method according to claim 4 , and wherein

Het is

R 1 is cyclopropyl, cyclobutyl, tetrahydropyranyl, tetrahydrofuranyl or azetidinyl each optionally substituted by a substituent chosen from by halogen, C 1-4 alkyl, C 1-4 alkylsulfonyl and oxo

or a pharmaceutically acceptable salt thereof.

6. The method according to claim 3 , and wherein

Het is

R 2 and R 3 are methyl

or a pharmaceutically acceptable salt thereof.

7. The method according to claim 6 , and wherein

Het is

and

R 5 is

or a pharmaceutically acceptable salt thereof.

8. The method according to claim 7 , and wherein

Het is

or a pharmaceutically acceptable salt thereof.

9. The method according to claim 7 , and wherein

R 5 is

or a pharmaceutically acceptable salt thereof.

10. The method according to claim 7 , and wherein

R 1 is C 1-4 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, piperidinyl or pyrrolidinyl each optionally substituted by a substituent chosen from by halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylsulfonyl and oxo or a pharmaceutically acceptable salt thereof.

11. The method according to claim 7 , and wherein

R 1 is CF 3 —CH 2 —CH 2 —CH 2 — or tetrahydropyranyl

or a pharmaceutically acceptable salt thereof.

12. The method according to claim 2 , and wherein

Het is

R 1 is phenyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, pyrrolyl, imidazolyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, purinyl, quinolinyl, Dihydro-2H-quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, indolyl, benzofuranyl, benzopyranyl or benzodioxolyl each optionally substituted by a substituent chosen from halogen, C 1-4 alkyl, C 1-4 alkylsulfonyl and oxo;

R 2 and R 3 are independently methyl, ethyl, n-propyl, isopropyl; or hydrogen with the proviso that both R 2 and R 3 cannot be hydrogen; or R 2 and R 3 together with the carbon to which they are attached form a cyclopropyl, cyclobutyl or cyclopentyl ring

or a pharmaceutically acceptable salt thereof.

13. The method according to claim 12 , and wherein

Het is

R 1 is phenyl or benzimidazoyl each optionally substituted by a substituent chosen from halogen, C 1-4 alkyl, C 1-4 alkylsulfonyl and oxo;

R 2 and R 3 are methyl; or R 2 and R 3 together with the carbon to which they are attached form a cyclopropyl or cyclobutyl ring;

R 6 is hydrogen or C 1-2 alkyl;

R 7 and R 8 are each C 1-2 alkyl

or a pharmaceutically acceptable salt thereof.

14. The method according claim 13 and wherein

Het is

R 1 is phenyl optionally substituted by a substituent chosen from by halogen, C 1-4 alkyl and C 1-4 alkylsulfonyl

or a pharmaceutically acceptable salt thereof.

15. The method according to claim 1 , and wherein

R 1 is C 1-4 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, piperidinyl, dioxanyl, thiomorpholinyl, 1,1-Dioxo-1λ 6 -thiomorpholinyl, morpholinyl, pyrrolidinyl or piperazinyl, optionally substituted by a substituent chosen from halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylsulfonyl and oxo or a pharmaceutically acceptable salt thereof.

16. The method according to claim 1 which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 and one or more pharmaceutically acceptable carriers and/or adjuvants.

17. The method according to claim 1 wherein the compound is

or a pharmaceutically acceptable salt thereof.

18. The method according to claim 1 wherein pain is chosen from acute pain, visceral pain, spasm of the gastrointestinal tract or uterus, colics, neuropathic pain, inflammatory and nociceptive pain, cancer pain and headache.

19. The method according to claim 18 wherein neuropathic pain is chosen from low back pain, non-herpetic neuralgia, post herpetic neuralgia, diabetic neuropathy, nerve injury, acquired immune deficiency syndrome (AIDS) related neuropathic pain, head trauma related neuropathic pain, painful traumatic mononeuropathy, toxin and chemotherapy induced pain, phantom limb pain, painful polyneuropathy, thalamic pain syndrome, post-stroke pain, central nervous system injury related neuropathic pain, post surgical pain, stump pain, repetitive motion pain, pain induced by post mastectomy syndrome related neuropathic pain, multiple sclerosis related neuropathic pain, root avulsions, postthoracotomy syndrome related neuropathic pain, neuropathic pain associated hyperalgesia and allodynia.

20. A method of treating pain comprising administering a therapeutically effective amount of a compound of the formula (I)

of the formula (I) is chosen from column A1-A26 in Table I, and

of the formula (I) is chosen from column B1-B20 in Table I,

TABLE I

A1 

B1 

A2 

B2 

A3 

B3 

A4 

B4 

A5 

B5 

A6 

B6 

A7 

B7 

A8 

B8 

A9 

B9 

A10

B10

A11

B11

A12

B12

A13

B13

A14

B14

A15

B15

A16

B16

A17

B17

A18

B18

A19

B19

A20

B20

A21

A22

A23

A24

A25

A26

or a pharmaceutically acceptable salt thereof.