TRPM8 antagonists

1. A method for the treatment of a disease associated with the activity of TRPM8, wherein the disease is selected from itch, irritable bowel diseases, cold-induced and/or exacerbated respiratory disorders, ischaemia, urological disorders, stroke, psychiatric disorders, neuropathic pain, postoperative pain, cancer pain, rheumatoid arthritic pain, neuralgia, fibromyalgia, neuropathies, fibromyalgia, algesia, nerve injury, migraine, headache, painful bladder syndrome, interstitial cystitis, detrusor overactivity, urinary incontinence, neurogenic detrusor overactivity, idiopathic detrusor overactivity, benign prostatic hyperplasia, lower urinary tract disorders and lower urinary tract symptoms, anxiety, depression and cold-induced/or exacerbated pulmonary hypertension, COPD, and asthma, the method comprising administering to a patient in need thereof a compound having formula I:

or a pharmaceutically acceptable salt thereof,

wherein:

X is selected from S or O;

R 1 is selected from the group consisting of:

—OR 5 wherein R 5 is selected from H; C 1 -C 4 alkyl, trifluoromethanesulfonyl, benzyl, (trifluoromethyl)benzyl, (halo)benzyl, (trifluoromethyl)benzoyl, N-benzylcarbamoyl, cyclohexyloxyacetoyl substituted with at least one C 1 -C 3 alkyl group, (C 1 -C 3 alkoxy)methyl, C 1 -C 3 alkanoyl and CH 2 CH 2 NHR 6 , wherein

R 6 is selected from H and (furan-2-yl)methyl;

—NHR 7 wherein R 7 is selected from H, tert-butoxycarbonyl, C 1 -C 3 alkanoyl, (4-trifluoromethyl)benzoyl, N-phenylaminoacarbonyl, CH 2 R 8 , wherein

R 8 is selected from phenyl, benzo[d][1,3] dioxole, pyridin-3-yl, (pyrrolidin-1-yl)methyl, —CH 2 NHR 9 wherein

R 9 is selected from H, C 1 -C 3 alkyl and cycloalkyl;

R 2 is selected from the group consisting of

—COOR 10 wherein

R 10 is selected from H, C 1 -C 3 alkyl and cyclohexyl, optionally substituted with at least one C 1 -C 3 alkyl group;

—OH; —CONH 2 ; CN

-tetrazol-5-yl or 1-(C 1 -C 3 alkyl)tetrazol-5-yl,

-5-(C 1 -C 3 alkyl)1,2,4 triazol-3-yl,

-5-(C 1 -C 3 alkyl) 1,2,4-oxadiazol-3yl,

-5-(C 1 -C 3 alkyl) 1,3,4-oxadiazol-2-yl;

R 3 is selected from F or H,

R 4 is selected from H, CH 3 , halogen, dimethylamino, pyridin-4-yl, phenyl, 2- or 4-(halo)phenyl, 2- or 4-(trifluoromethyl)phenyl and 2- and/or 4-halobenzyloxy.

2. The method of claim 1 , wherein

when R 3 is F, R 3 is in position ortho of the aromatic ring and R 4 is F in position para of the aromatic ring.

3. The method of claim 1 , wherein

when R 3 is H, R 4 is in position para or meta on the aromatic ring.

4. The method of claim 1 , wherein

R 5 is selected from H; C 1 -C 4 alkyl; trifluoromethanesulfonyl; benzyl; (trifluoromethyl)benzyl, (chloro)benzyl; (trifluoromethyl)benzoyl, N-benzylcarbamoyl, cyclohexyloxyacetoyl substituted with at least one C 1 -C 3 alkyl group, (methoxy)methyl, propanoyl and —CH 2 CH 2 NHR 6 ;

wherein R 6 is selected from H and (furan-2-yl)methyl.

5. The method of claim 1 , wherein

R 7 is selected from H, tert-butoxycarbonyl, acetyl, (4-trifluoromethyl)benzoyl; N-phenylaminoacarbonyl, CH 2 R 8 , wherein

R 8 is selected from phenyl, benzo[d][1,3] dioxole, pyridin-3-yl, (pyrrolidin-1-yl)methyl, —CH 2 NHR 9 wherein

R 9 is selected from H, C 1 -C 3 alkyl and cyclopentyl.

6. The method of claim 1 , wherein

R 10 is selected from H; C 1 -C 3 alkyl and 2-isopropyl-5-methyl-cyclohexyl.

7. The method of claim 1 , wherein:

R 4 is selected from H; CH 3 , F; Cl; dimethylamino; pyridin-4-yl; phenyl, 2-F-phenyl, 2-trifluoromethylphenyl; 2- or 4-halobenzyloxy.

8. The method of claim 1 , wherein R 1 is selected from:

OR 5 , wherein R 5 is selected from H, benzyl, (chloro)benzyl, (trifluoromethyl)benzoyl; and

CH 2 —CH 2 NH 2 ; and

NHCH 2 CH 2 R 9 wherein R 9 is selected from C 1 -C 3 alkyl and H.

9. The method of claim 1 , wherein R 2 is COOR 10 wherein R 10 is selected from H, C 1 -C 3 alkyl.

10. The method of claim 1 , wherein R 3 is H.

11. The method of claim 1 , wherein said compound of formula I is selected from:

2-(4-chlorophenyl)-4-hydroxy-1,3-thiazole-5-carboxylic acid (1)

4-hydroxy-2-(4-methylphenyl)-1,3-thiazole-5-carboxylic acid (2)

2-(3-fluorophenyl)-4-hydroxy-1,3-thiazole-5-carboxylic acid (3)

2-(4-fluorophenyl)-4-hydroxy-1,3-thiazole-5-carboxylic acid (4)

methyl 4-hydroxy-2-phenyl-1,3-thiazole-5-carboxylate (5)

methyl 2-(2,4-difluorophenyl)-4-hydroxy-1,3-thiazole-5-carboxylate (6)

ethyl 4-hydroxy-2-phenyl-1,3-thiazole-5-carboxylate (7)

ethyl 2-(4-chlorophenyl)-4-hydroxy-1,3-thiazole-5-carboxylate (8)

ethyl 4-hydroxy-2-(4-methylphenyl)-1,3-thiazole-5-carboxylate (9)

ethyl 2-(3-fluorophenyl)-4-hydroxy-1,3-thiazole-5-carboxylate (10)

ethyl 2-(4-fluorophenyl)-4-hydroxy-1,3-thiazole-5-carboxylate (11)

ethyl 4-hydroxy-2-(pyridin-4-yl)-1,3-thiazole-5-carboxylate (12)

ethyl 2-[4-(dimethylamino)phenyl]-4-hydroxy-1,3-thiazole-5-carboxylate (13)

ethyl 2-(3-chlorophenyl)-4-hydroxy-1,3-thiazole-5-carboxylate (14)

ethyl 4-hydroxy-2-[2′-(trifluoromethyl)biphenyl-3-yl]-1,3-thiazole-5-carboxylate (15)

ethyl 2-(2′-fluorobiphenyl-3-yl)-4-hydroxy-1,3-thiazole-5-carboxylate (16)

ethyl 4-hydroxy-2-[2′-(trifluoromethyl)biphenyl-4-yl]-1,3-thiazole-5-carboxylate (17)

ethyl 2-(2′-fluorobiphenyl-4-yl)-4-hydroxy-1,3-thiazole-5-carboxylate (18)

ethyl 2-{4-[(2-fluorobenzyl)oxy]phenyl}-4-hydroxy-1,3-thiazole-5-carboxylate (19)

ethyl 2-{4-[(4-fluorobenzyl)oxy]phenyl}-4-hydroxy-1,3-thiazole-5-carboxylate (20)

ethyl 2-(4-fluorophenyl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1,3-thiazole-5-carboxylate (21)

ethyl 4-methoxy-2-(4-methylphenyl)-1,3-thiazole-5-carboxylate (22)

ethyl 2-(4-methylphenyl)-4-(2-methylpropoxy)-1,3-thiazole-5-carboxylate (23)

ethyl 4-(benzyloxy)-2-phenyl-1,3-thiazole-5-carboxylate (24)

ethyl 4-[(3-chlorobenzyl)oxy]-2-(4-chlorophenyl)-1,3-thiazole-5-carboxylate (25)

ethyl 4-[(3-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1,3-thiazole-5-carboxylate (26)

ethyl 4-[(4-chlorobenzyl)oxy]-2-phenyl-1,3-thiazole-5-carboxylate (27)

ethyl 4-[(4-chlorobenzyl)oxy]-2-(3-chlorophenyl)-1,3-thiazole-5-carboxylate (28)

ethyl 4-[(4-chlorobenzyl)oxy]-2-(4-methylphenyl)-1,3-thiazole-5-carboxylate (29)

ethyl 4-[(4-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1,3-thiazole-5-carboxylate (30)

ethyl 4-[(2-chlorobenzyl)oxy]-2-phenyl-1,3-thiazole-5-carboxylate (31)

ethyl 4-[(2-chlorobenzyl)oxy]-2-(4-fluorophenyl)-1,3-thiazole-5-carboxylate (32)

ethyl 4-[(2-chlorobenzyl)oxy]-2-(4-chlorophenyl)-1,3-thiazole-5-carboxylate (33)

ethyl 4-[(2-chlorobenzyl)oxy]-2-(3-chlorophenyl)-1,3-thiazole-5-carboxylate (34)

ethyl 4-[(2-chlorobenzyl)oxy]-2-(4-methylphenyl)-1,3-thiazole-5-carboxylate (35)

ethyl 2-phenyl-4-{[4-(trifluoromethyl)benzoyl]oxy}-1,3-thiazole-5-carboxylate (36)

ethyl 2-(3-fluorophenyl)-4-{[4-(trifluoromethyl)benzoyl]oxy}-1,3-thiazole-5-carboxylate (37)

ethyl 2-(4-methylphenyl)-4-{[4-(trifluoromethyl)benzoyl]oxy}-1,3-thiazole-5-carboxylate (38)

ethyl4-(2-((1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy)acetoyloxy)-2-(4-methylphenyl)-1,3-thiazole-5-carboxylate (39)

ethyl 4-[(benzylcarbamoyl)oxy]-2-(4-chlorophenyl)-1,3-thiazole-5-carboxylate (40)

ethyl 4-(2-aminoethoxy)-2-(4-chlorophenyl)-1,3-thiazole-5-carboxylate (41)

ethyl 2-(4-chlorophenyl)-4-{2-[(furan-2-ylmethyl)amino]ethoxy}-1,3-thiazole-5-carboxylate (42)

4-[(4-chlorobenzyl)oxy]-2-(4-methylphenyl)-1,3-thiazole-5-carboxylic acid (43)

4-[(4-chlorobenzyl)oxy]-2-phenyl-1,3-thiazole-5-carboxylic acid (44)

4-[(4-chlorobenzyl)oxy]-2-(4-chlorophenyl)-1,3-thiazole-5-carboxylic acid (45)

4-[(4-chlorobenzyl)oxy]-2-(3-chlorophenyl)-1,3-thiazole-5-carboxylic acid (46)

4-(benzyloxy)-2-phenyl-1,3-thiazole-5-carboxylic acid (47)

4-[(3-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1,3-thiazole-5-carboxylic acid (48)

4-[(2-chlorobenzyl)oxy]-2-phenyl-1,3-thiazole-5-carboxylic acid (49)

4-[(2-chlorobenzyl)oxy]-2-(4-fluorophenyl)-1,3-thiazole-5-carboxylic acid (50)

4-[(2-chlorobenzyl)oxy]-2-(4-chlorophenyl)-1,3-thiazole-5-carboxylic acid (51)

4-[(2-chlorobenzyl)oxy]-2-(3-chlorophenyl)-1,3-thiazole-5-carboxylic acid (52)

4-[(2-chlorobenzyl)oxy]-2-(4-methylphenyl)-1,3-thiazole-5-carboxylic acid (53)

4-[(2-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1,3-thiazole-5-carboxylic acid (54)

2-phenyl-4-{[4-(trifluoromethyl)benzyl]oxy}-1,3-thiazole-5-carboxylic acid (55)

2-(3-fluorophenyl)-4-{[4-(trifluoromethyl)benzyl]oxy}-1,3-thiazole-5-carboxylic acid (56)

2-phenyl-4-{[4-(trifluoromethyl)benzoyl]oxy}-1,3-thiazole-5-carboxylic acid (57)

2-(3-fluorophenyl)-4-{[4-(trifluoromethyl)benzoyl]oxy}-1,3-thiazole-5-carboxylic acid (58)

2-(4-methylphenyl)-4-{[4-(trifluoromethyl)benzoyl]oxy}-1,3-thiazole-5-carboxylic acid (59)

4-methoxy-2-(4-methylphenyl)-1,3-thiazole-5-carboxylic acid (60)

2-(4-methylphenyl)-4-(2-methylpropoxy)-1,3-thiazole-5-carboxylic acid (61)

ethyl 4-[(tert-butoxycarbonyl)amino]-2-(4-fluorophenyl)-1,3-thiazole-5-carboxylate (62)

ethyl 4-amino-2-(4-fluorophenyl)-1,3-thiazole-5-carboxylate hydrochloride (63)

ethyl 4-(acetylamino)-2-(4-methylphenyl)-1,3-thiazole-5-carboxylate (64)

ethyl 2-(4-methylphenyl)-4-{[4-(trifluoromethyl)benzoyl]amino}-1,3-thiazole-5-carboxylate (65)

ethyl 2-(4-methylphenyl)-4-[(phenylcarbamoyl)amino]-1,3-thiazole-5-carboxylate (66)

ethyl 4-[(2-aminoethyl)amino]-2-(4-methylphenyl)-1,3-thiazole-5-carboxylate (67)

ethyl 2-(4-chlorophenyl)-4-{[2-(methylamino)ethyl]amino}-1,3-thiazole-5-carboxylate (68)

ethyl 2-(4-chlorophenyl)-4-{[2-(propylamino)ethyl]amino}-1,3-thiazole-5-carboxylate (69)

ethyl 4-[(2-aminoethyl)amino]-2-(4-chlorophenyl)-1,3-thiazole-5-carboxylate (70)

ethyl 4-{[2-(methylamino)ethyl]amino}-2-(4-methylphenyl)-1,3-thiazole-5-carboxylate (71)

ethyl 4-[(2-aminoethyl)amino]-2-[2′-(trifluoromethyl)biphenyl-4-yl]-1,3-thiazole-5-carboxylate (72)

ethyl 4-[(2-aminoethyl)amino]-2-[2′-(trifluoromethyl)biphenyl-3-yl]-1,3-thiazole-5-carboxylate (73)

ethyl 2-(4-chlorophenyl)-4-{[2-(cyclopentylamino)ethyl]amino}-1,3-thiazole-5-carboxylate (74)

ethyl 2-phenyl-4-{[2-(pyrrolidin-1-yl)ethyl]amino}-1,3-thiazole-5-carboxylate (75)

ethyl 4-(benzylamino)-2-(3-fluorophenyl)-1,3-thiazole-5-carboxylate (76)

ethyl 4-[(1,3-benzodioxol-5-ylmethyl)amino]-2-(3-fluorophenyl)-1,3-thiazole-5-carboxylate (77)

ethyl 2-(3-fluorophenyl)-4-[(pyridin-3-ylmethyl)amino]-1,3-thiazole-5-carboxylate (78)

4-[(2-aminoethyl)amino]-2-(4-methylphenyl)-1,3-thiazole-5-carboxylic acid (79)

4-{[2-(methylamino)ethyl]amino}-2-(4-methylphenyl)-1,3-thiazole-5-carboxylic acid (80)

4-[(2-aminoethyl)amino]-2-(3-fluorophenyl)-1,3-thiazole-5-carboxylic acid (81)

sodium 4-[(3-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1,3-thiazole-5-carboxylate (82)

sodium 4-[(4-chlorobenzyl)oxy]-2-(4-methylphenyl)-1,3-thiazole-5-carboxylate (83)

sodium 4-(4-chlorobenzyloxy)-2-(4-chlorophenyl)-1,3-thiazole-5-carboxylate (84)

sodium 4-(2-chlorobenzyloxy)-2-(4-chlorophenyl)-1,3-thiazole-5-carboxylate (85)

sodium 4-(2-chlorobenzyloxy)-2-(4-methylphenyl)-1,3-thiazole-5-carboxylate (86)

sodium 4-(2-chlorobenzyloxy)-2-(3-fluorophenyl)-1,3-thiazole-5-carboxylate (87)

sodium 4-(4-chlorobenzyloxy)-2-(3-fluorophenyl)-1,3-thiazole-5-carboxylate (88)

(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl-4-(benzyloxy)-2-(4-methylphenyl)-1,3-thiazole-5-carboxylate (89)

(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl-4-hydroxy-2-(4-methylphenyl)-1,3-thiazole-5-carboxylate (90)

ethyl 2-(4-chlorophenyl)-4-(methoxymethoxy)-1,3-thiazole-5-carboxylate (91)

2-(4-chlorophenyl)-4-(methoxymethoxy)-1,3-thiazole-5-carboxylic acid (92)

2-(4-chlorophenyl)-4-(methoxymethoxy)-1,3-thiazole-5-carboxamide (93)

2-(4-chlorophenyl)-4-(methoxymethoxy)-1,3-thiazole-5-carbonitrile (94)

2-(4-chlorophenyl)-5-(1H-tetrazol-5-yl)-1,3-thiazol-4-ol (95)

2-(4-chlorophenyl)-5-(1-methyl-1H-tetrazol-5-yl)-1,3-thiazol-4-ol (96)

2-(3-fluorophenyl)-5-(1-methyl-1H-tetrazol-5-yl)-1,3-thiazol-4-ol (97)

2-(4-chlorophenyl)-5-(5-methyl-4H-1,2,4-triazol-3-yl)-1,3-thiazol-4-ol (98)

2-(3-fluorophenyl)-5-(5-methyl-4H-1,2,4-triazol-3-yl)-1,3-thiazol-4-ol (99)

2-(4-chlorophenyl)-5-(5-methyl-1,2,4-oxadiazol-3-yl)-1,3-thiazol-4-ol (100)

2-(3-fluorophenyl)-5-(5-methyl-1,2,4-oxadiazol-3-yl)-1,3-thiazol-4-ol (101)

3-{4-[(4-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1,3-thiazol-5-yl}-5-methyl-1,2,4-oxadiazole (102)

2-(4-chlorophenyl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)-1,3-thiazol-4-ol (103)

2-(3-fluorophenyl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)-1,3-thiazol-4-ol (104)

ethyl 4-hydroxy-2-phenyl-1,3-oxazole-5-carboxylate (105)

ethyl 2-(3-fluorophenyl)-4-hydroxy-1,3-oxazole-5-carboxylate (106)

ethyl 4-hydroxy-2-(4-methylphenyl)-1,3-oxazole-5-carboxylate (107)

ethyl 4-[(4-chlorobenzyl)oxy]-2-phenyl-1,3-oxazole-5-carboxylate (108)

ethyl 4-[(4-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1,3-oxazole-5-carboxylate (109)

ethyl 4-[(4-chlorobenzyl)oxy]-2-(4-methylphenyl)-1,3-oxazole-5-carboxylate (110)

ethyl 2-phenyl-4-{[4-(trifluoromethyl)benzoyl]oxy}-1,3-oxazole-5-carboxylate (111)

4-[(4-chlorobenzyl)oxy]-2-phenyl-1,3-oxazole-5-carboxylic acid (112)

4-[(4-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1,3-oxazole-5-carboxylic acid (113)

4-[(4-chlorobenzyl)oxy]-2-(4-methylphenyl)-1,3-oxazole-5-carboxylic acid (114)

2-(3-fluorophenyl)-5-(5-methyl-1,2,4-oxadiazol-3-yl)-1,3-oxazol-4-ol (115)

3-{4-[(4-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1,3-oxazol-5-yl}-5-methyl-1,2,4-oxadiazole (116)

ethyl 2-(3-fluorophenyl)-5-hydroxy-1,3-thiazole-4-carboxylate (117)

2-(3-fluorophenyl)-5-(2-ethyl-2H-tetrazol-5-yl)-1,3-thiazol-4-ol (118).