Compounds which selectively modulate the CB2 receptor

1. A compound of the formula (I)

wherein:

Het is a 5-membered heteroaryl ring optionally substituted by C 1-5 alkyl;

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 1-8 alkyl, C 1-4 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkylC 1-5 alkyl, C 1-4 alkylsulfonyl, C 1-4 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;

each R 6 is independently hydrogen, C 1-6 alkyl, 3-10 membered saturated heterocyclic ring, aryl, benzyl or —(CH 2 ) 1-3 —O—(CH 2 ) 0-1 —X wherein X is aryl or CH 3 ; wherein each heterocyclic, benzyl or aryl ring is optionally substituted by one or more C 1-4 alkyl, C 1-4 alkoxy or halogen;

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;

R 9 is C 1-4 alkyl which replaces a methylene hydrogen on —(CH 2 ) n — or is absent;

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. A compound of the formula (I)

wherein

Het is

R 1 is C 1-6 alkyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, piperidinyl; benzoxazolyl, benzothiazolyl, benzimidazolyl, dioxalanyl, 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 1-2 substituents chosen from halogen, C 1-6 alkyl, hydroxyl, C 1-4 alkoxy, C 1-4 alkylsulfonyl, C 3-10 cycloalkylC 1-5 alkyl or 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 or methyl;

R 5 is chosen from

wherein Ar is tetrahydropyranyl or tetrahydrofuranyl each optionally substituted by C 1-3 alkyl,

wherein R 10 is hydrogen or methyl,

m is 0, 1, 2 or 3;

R 6 is hydrogen, benzyl, phenyl or C 1-4 alkyl, each benzyl or phenyl ring is optionally substituted by one or more C 1-4 alkyl, C 1-4 alkoxy or halogen;

R 7 and R 8 are each C 1-3 alkyl or C 3-6 cycloalkyl wherein R 7 and R 8 optionally can cyclize to form a C 3-6 cycloalkyl ring

R 9 is C 1-4 alkyl which replaces a methylene hydrogen on —(CH 2 ) n or is absent;

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.

3. The compound according to claim 2 wherein:

Het is

R 1 is C 1-5 alkyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuranyl, tetrahydropyranyl, dioxalanyl, dioxanyl, azetidinyl, piperidinyl, benzimidazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl or piperazinyl, each optionally substituted by 1-2 substituents chosen from halogen, C 1-6 alkyl, C 1-4 alkylsulfonyl, C 3-10 cycloalkylC 1-5 alkyl, hydroxyl, C 1-4 alkoxy 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 or methyl;

R 5 is chosen from

R 5 is chosen from

wherein Ar is tetrahydropyranyl or tetrahydrofuranyl each optionally substituted by C 1-3 alkyl,

wherein R 10 is hydrogen or methyl;

m is 0, 1, 2 or 3;

each R 6 is independently hydrogen, C 1-6 alkyl, 3-10 membered saturated heterocyclic rin56g, aryl, benzyl or —(CH 2 ) 1-3 —O—(CH 2 ) 0-1 —X wherein X is aryl or CH 3 ; wherein each heterocyclic, benzyl or aryl ring is optionally substituted by one or more C 1-4 alkyl, C 1-4 alkoxy or halogen; 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;

R 9 is C 1-4 alkyl which replaces a methylene hydrogen on —(CH 2 ) n — or is absent;

n is 0 or 1;

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.

4. The compound according to claim 2 , and wherein

Het is

R 1 is phenyl or benzimidazoyl each optionally substituted by 1-2 substituents chosen from halogen, C 1-6 alkyl, C 1-4 alkylsulfonyl, C 3-6 cycloalkylC 1-3 alkyl, or oxo; or R 1 is C 1-5 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 alkoxy, C 1-4 alkylsulfonyl or oxo;

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

R 7 and R 8 are each C 1-2 alkyl wherein R 7 and R 8 optionally can cyclize to form a C 3-6 cycloalkyl ring.

5. The compound according to claim 4 , and wherein

Het is

6. The compound according to claim 5 , and wherein

R 1 is phenyl or benzimidazoyl each optionally substituted by 1-2 substituents chosen from halogen, C 1-6 alkyl or C 3-5 cycloalkylC 1-3 alkyl;

or R 1 is C 1-5 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, tetrahydrofuranyl or piperidinyl each optionally substituted by a substituent chosen from by halogen, C 1-4 alkyl, C 1-4 alkoxy or C 1-4 alkylsulfonyl.

7. A compound of the formula (II)

wherein

of the formula (I) is chosen from column A1-A10 in Table I, and

of the formula (I) is chosen from column B1-B28 in Table I,

TABLE I

A1

A2

A3

A4

A5

A6

A7

A8

A9

A10

B1

B2

B3

B4

B5

B6

B7

B8

B9

B10

B11

B12

B13

B14

B15

B16

B17

B18

B19

B20

B21

B22

B23

B24

B25

B26

B27

B28

or a pharmaceutically acceptable salt thereof.

8. A compound chosen from

or a pharmaceutically acceptable salt thereof.

9. A compound chosen from

or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and one or more pharmaceutically acceptable carriers and/or adjuvants.

11. A method of treating pain comprising administering a therapeutically effective amount of a compound according to claim 1 .

12. The method according to claim 11 wherein pain is chosen from acute pain, visceral pain, neuropathic pain, inflammatory and nociceptive pain, cancer pain and headache comprising administering a therapeutically effective amount of a compound according to claim 1 .