Azetidine 2-carboxamide derivatives which modulate the CB2 receptor

1. A compound of the formula (I)

wherein:

Ar 1 is chosen from carbocycle, heterocyclyl and heteroaryl each optionally substituted by 1-3 C 1-5 alkyl which is optionally substituted with halogens, C 1-5 alkoxy, hydroxyl, CN, halogen, NO 2 , —S(O) m —C 1-5 alkyl, —CO 2 —C 1-5 alkyl, —NH(C 1-5 alkyl)—CO 2 —C 1-10 alkyl, —C(O)—NH(C 1-5 alkyl), —C(O)—N(C 1-5 alkyl) 2 , —NH(C 1-5 alkyl), —N(C 1-5 alkyl)-C(O)—C 1-10 alkyl, —N(C 1-5 alkyl)-S(O) m —C 1-10 alkyl, carbocycle or heterocyclyl;

Ar 2 is chosen from carbocycle, heterocyclyl and heteroaryl each optionally substituted by 1-3 C 1-10 alkyl which is optionally substituted with halogens, C 3-10 cycloalkyl, carbocycle, C 1-10 alkylcarbocycle, heteroaryl, CN or halogen, wherein the C 1-10 alkyl and carbocycle may be additionally optionally substituted by halogen, hydroxyl or C 1-5 alkoxy;

with the proviso that Ar 1 and Ar 2 cannot simultaneously be unsubstituted phenyl;

L 1 is a bond;

L 2 is a bond;

R 1 is chosen from hydrogen, oxo (═O) and OH;

m is 0, 1 or 2;

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 and wherein:

Ar 1 is chosen from phenyl, C 3-6 cycloalkyl, dioxanyl, tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl, 1,1-Dioxo-1λ 6 -thiomorpholinyl, morpholinyl and pyridinyl, each optionally substituted by 1-3 C 1-5 alkyl which is optionally substituted with halogens, C 1-5 alkoxy, hydroxyl, CN, S(O) m —C 1-3 alkyl or halogen;

Ar 2 is chosen from oxazolyl, isoxazolyl, oxadiazoyl, thiazoyl, thiadiazoyl, benzothiazoyl, triazoyl, isothiazoyl, phenyl, pyrimidinyl, pyridizinyl, pyrazinyl and pyridinyl, each optionally substituted by 1-3 C 1-6 alkyl which is optionally substituted with halogens, C 1-5 alkoxyl, or hydroxyl, phenyl optionally substituted with halogens, halogen or C 3-8 cycloalkyl;

R 1 is hydrogen;

L 1 is a bond;

L 2 is a bond.

3. The compound according to claim 2 and wherein:

Ar 1 is chosen from phenyl, C 3-6 cycloalkyl, tetrahydropyranyl and pyridinyl, each optionally substituted by 1-3 C 1-5 alkyl, trifluoromethyl, S(O) m —C 1-3 alkyl or halogen;

Ar 2 is chosen from isoxazolyl, oxazolyl, thiazolyl, phenyl, benzothiazolyl, isothiazolyl and thiadiazolyl, each optionally substituted by 1-3 C 1-5 alkyl optionally substituted with C 1-5 alkoxyl, or hydroxyl, phenyl optionally substituted with halogen, halogen, C 3-6 cycloalkyl or trifluoromethyl;

L 1 is a bond.

4. The compound according to claim 3 and wherein:

Ar 1 is chosen from phenyl, cyclopentyl, cyclohexyl, tetrahydropyranyl and pyridinyl, each optionally substituted by 1-3 C 1-3 alkyl, trifluoromethyl, methylsulfonyl or halogen.

5. The compound according to claim 4 and wherein:

Ar 2 is chosen from

6. The compound according claim 5 and wherein:

Ar 2 is chosen from

7. A compound of the formula (II)

wherein

Ar 1 is chosen from phenyl, C 3-6 cycloalkyl, dioxanyl, tetrahydrofuranyl, tetrahydropyranyl, oxazolyl, isoxazolyl, oxadiazoyl, thiazoyl, thiadiazoyl, benzothiazoyl, triazoyl, isothiazoyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl and pyrazolyl each optionally substituted by 1-3 C 1-6 alkyl which is optionally substituted with halogens, S(O) m —C 1-3 alkyl, C 1-6 alkoxy, hydroxyl or halogen;

Ar 2 is chosen from oxazolyl, isoxazolyl, oxadiazoyl, thiazoyl, thiadiazoyl, benzothiazoyl, triazoyl, isothiazoyl, phenyl, pyrimidinyl, pyridizinyl, pyrazinyl and pyridinyl, each optionally substituted by 1-3 C 1-6 alkyl which is optionally substituted with halogens, C 1-6 alkoxyl or hydroxyl, phenyl optionally substituted with halogens, halogen, C 1-6 alkoxyl, or C 3-8 cycloalkyl;

L 1 is a bond;

L 2 is a bond;

or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 7 and wherein:

Ar 1 is chosen from phenyl, C 3-6 cycloalkyl, tetrahydropyranyl and pyridinyl, each optionally substituted by 1-3 C 1-6 alkyl, trifluoromethyl, S(O) m —C 1-3 alkyl or halogen;

Ar 2 is chosen from isoxazolyl, oxazolyl, thiazolyl, phenyl, benzothiazolyl, isothiazolyl and thiadiazolyl, each optionally substituted by 1-3 C 1-6 alkyl optionally substituted with C 1-6 alkoxyl or hydroxyl, phenyl optionally substituted with halogen, halogen, C 1-6 alkoxyl, C 3-6 cycloalkyl or trifluoromethyl;

L 1 is a bond.

9. The compound according to claim 8 and wherein:

Ar 1 is chosen from phenyl, cyclopentyl, cyclohexyl, tetrahydropyranyl and pyridinyl, each optionally substituted by 1-3 C 1-3 alkyl, trifluoromethyl or halogen.

10. The compound according to claim 9 and wherein:

Ar 2 is chosen from

11. The compound according to claim 10 and wherein:

Ar 2 is chosen from

12. A compound of the formula (III)

wherein

of the formula (III) is chosen from A1-A15 of Table I, and

of the formula (III) is chosen from B1-B25 of 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

B16

B17

B18

B19

B20

B21

B22

B23

B24

B25

or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 12 wherein the stereogenic carbon in the formula (III) indicated with an arrow is in the (S) configuration.

14. A compound chosen from:

or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 , 7 or 12 and one or more pharmaceutically acceptable carriers and/or adjuvants.

16. A method of treating pain comprising administering a therapeutically effective amount of a compound according to claim 1 , 7 or 12 .

17. A method of treating pain wherein the pain is chosen from acute pain, visceral pain, comprising administering a therapeutically effective amount of a compound according to claim 1 , 7 or 12 .