Trpm8 antagonists

A method for the prevention and/or treatment of a disease associated with the activity of TRPM8, 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;
• R1 is selected from the group consisting of:
• —OR5 wherein R5 is selected from H;
• C1-C4 alkyl, trifluoromethanesulfonyl, benzyl, (trifluoromethyl)benzyl, (halo)benzyl, (trifluoromethyl)benzoyl, N-benzylcarbamoyl, cyclohexyloxyacetoyl substituted with at least one C1-C3 alkyl group, (C1-C3 alkoxy)methyl, C1-C3 alkanoyl and CH2CH2NHR6, wherein
• R6 is selected from H and (furan-2-yl)methyl;
• —NHR7 wherein R7 is selected from H, tert-butoxycarbonyl, C1-C3 alkanoyl, (4-trifluoromethyl)benzoyl, N-phenylaminoacarbonyl, CH2R8, wherein
• R8 is selected from phenyl, benzo[d][1,3]dioxole, pyridin-3-yl, (pyrrolidin-1-yl)methyl, —CH2NHR9 wherein
• R9 is selected from H, C1-C3 alkyl and cycloalkyl;
• R2 is selected from the group consisting of
• —COOR10 wherein
• R10 is selected from H, C1-C3 alkyl and cyclohexyl, optionally substituted with at least one C1-C3 alkyl group;
• —OH;
• —CONH2;
• CN
• -tetrazol-5-yl or 1-(C1-C3 alkyl)tetrazol-5-yl,
• -5-(C1-C3 alkyl)1,2,4 triazol-3-yl,
• -5-(C1-C3 alkyl)1,2,4-oxadiazol-3yl,
• -5-(C1-C3 alkyl)1,3,4-oxadiazol-2-yl;
• R3 is selected from F or H,
• R4 is selected from H, CH3, halogen, dimethylamino, pyridin-4-yl, phenyl, 2- or 4-(halo)phenyl, 2- or 4-(trifluoromethyl)phenyl and 2- and/or 4-halobenzyloxy.

A compound 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 2-(2,4-difluorophenyl)-4-hydroxy-1,3-thiazole-5-carboxylate (6)
• 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 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-(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-(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-amino ethoxy)-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).