Ask 1 inhibiting pyrrolopyrimidine derivatives

Abstract

This invention relates to pyrrolopyrimidine derivatives of formula (I): where R 1 , X, p, R 4 , R 2 and R 3 are as defined herein, and their use as pharmaceuticals.

1 - 29 . (canceled) 
     
     
         30 . A compound of formula (I) 
       
         
           
           
               
               
           
         
       
       where
 X is (CH 2 ) m  or CH 2 O, where m is 1 or 2; 
 p is 0 or 1; 
 R 1  is phenyl or a 5 or 6 membered heteroaryl group selected from the group consisting of imidazolyl, isoxazolyl, pyridinyl, pyridazinyl or pyrimidinyl, which phenyl or heteroaryl group is optionally substituted with 1 or 2 substituents selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halo, (CH 2 ) n NR 5 R 6  where R 5  and R 6  are independently H or (C 1-4 )alkyl and n is 0 or 1, pyrrolidinyl, morpholinyl, piperidinyl, pyrrolidin(C 1-4 )alkyl, morpholin(C 1-4 )alkyl, piperidin(C 1-4 )alkyl, pyrrolidin(C 1-4 )alkoxy, morpholin(C 1-4 )alkoxy, piperidin(C 1-4 )alkoxy wherein said pyrrolidinyl, morpholinyl or piperidinyl groups are optionally substituted with halo or (C 1-4 )alkyl, with the proviso that when R 1  is phenyl or a 6 membered heteroaryl group, which phenyl or 6 membered heteroaryl group has a substitutent on the atom at the para position, said substituent is selected from the group consisting of methyl, ethyl, isopropyl, methoxy, halo or (CH 2 ) n NR 5 R 6  where R 5  and R 6  are methyl; 
 R 2  is H, methoxy, ethoxy or CH 2 OCH 3 ; 
 R 3  is H, (C 1-4 )alkyl, (C 2-4 )alkenyl, halo, cyano, furanyl or pyrazolyl, which pyrazolyl is optionally substituted with 1 methyl group; 
 R 4  is H or (C 1-4 )alkyl; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         31 . A compound according to  claim 30  where p is 0, or a pharmaceutically acceptable salt thereof. 
     
     
         32 . A compound according to  claim 30  where p is 1, or a pharmaceutically acceptable salt thereof. 
     
     
         33 . A compound according to  claim 32  where X is methyl or methoxy, or a pharmaceutically acceptable salt thereof. 
     
     
         34 . A compound according to  claim 30  where R 2  is H, or a pharmaceutically acceptable salt thereof. 
     
     
         35 . A compound according to  claim 30  where R 3  is methyl, or a pharmaceutically acceptable salt thereof. 
     
     
         36 . A compound according to  claim 30  where R 4  is H, or a pharmaceutically acceptable salt thereof. 
     
     
         37 . A compound according to  claim 30  where R 1  is unsubstituted phenyl or an unsubstituted 5 or 6 membered heteroaryl group selected from the group consisting of imidazolyl, isoxazolyl, pyridinyl, pyridazinyl or pyrimidinyl, or a pharmaceutically acceptable salt thereof. 
     
     
         38 . A compound according to  claim 37  where R 1  is unsubstituted phenyl. 
     
     
         39 . A compound according to  claim 30  where R 1  is phenyl substituted with (C 1-4 )alkyl or (C 1-4 )alkoxy. 
     
     
         40 . A compound according to  claim 30  where R 1  is pyridinyl substituted with (C 1-4 )alkyl or (C 1-4 )alkoxy, or a pharmaceutically acceptable salt thereof. 
     
     
         41 . A compound according to  claim 30  where R 1  is isoxazolyl substituted with 1 or 2 (C 1-4 )alkyl groups, or a pharmaceutically acceptable salt thereof. 
     
     
         42 . A compound according to  claim 30  where R 1  is imidazolyl substituted with 1 or 2 (C 1-4 )alkyl groups, or a pharmaceutically acceptable salt thereof. 
     
     
         43 . A compound according to  claim 30  which is selected from the group consisting of:
 N-[1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide; 
 3-(Methyloxy)-N-[1-(1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide; 
 3-(Dimethylamino)-N-[1-(1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide; 
 4-(Dimethylamino)-N-[1-(1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide; 
 2-(Dimethylamino)-N-[1-(1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide; 
 3-[(Dimethylamino)methyl]-N-[1-(1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide; 
 3-(1-Pyrrolidinyl)-N-[1-(1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide; 
 3-(4-Morpholinyl)-N-[1-(1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide; 
 N-[1-(1H-Pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-2-pyridinecarboxamide; 
 N-[1-(1H-Pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-3-pyridinecarboxamide; 
 N-[1-(1H-Pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-4-pyridinecarboxamide; 
 2-Methyl-N-[1-(1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-4-pyridinecarboxamide; 
 N-[1-(1H-Pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-4-pyridazinecarboxamide; 
 N-[1-(1H-Pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-5-pyrimidinecarboxamide; 
 2-(Methyloxy)-N-[1-(1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-4-pyridinecarboxamide; 
 5-Methyl-N-[1-(1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-3-isoxazolecarboxamide; 
 N-[1-(5-Methyl-1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide; 
 N-[1-(5-Ethyl-1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide; 
 N-{1-[5-(1-Methylethenyl)-1H-pyrrolo[2,3-d]pyrimidin-4-yl]-4-piperidinyl}benzamide; 
 N-{1-[5-(1-Methylethyl)-1H-pyrrolo[2,3-d]pyrimidin-4-yl]-4-piperidinyl}benzamide; 
 N-[1-(5-Methyl-1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-2-pyridinecarboxamide; 
 6-Methyl-N-[1-(5-methyl-1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-3-pyridinecarboxamide; 
 2-(Methyloxy)-N-[1-(5-methyl-1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-4-pyridinecarboxamide; 
 3-(Methyloxy)-N-[1-(5-methyl-1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide; 
 2-Methyl-N-[1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-4-pyridinecarboxamide; 
 2-Methyl-N-[1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide; 
 N-[1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-4-pyridinecarboxamide; 
 3,5-dimethyl-N-[1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-4-isoxazolecarboxamide; 
 N-[1-(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide; 
 N-methyl-N-[1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide; 
 2,6-dimethyl-N-[1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide; 
 N-methyl-N-[1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide; 
 1-methyl-N-[1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-1H-imidazole-5-carboxamide; 
 N-[3-(methyloxy)-1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide; 
 N-methyl-N-[1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-4-pyridinecarboxamide; 
 N-[1-(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-N-methyl-4-pyridinecarboxamide; 
 N-{1-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-d]pyrimidin-4-yl]-4-piperidinyl}benzamide; 
 N-{1-[5-(3-furanyl)-1H-pyrrolo[2,3-d]pyrimidin-4-yl]-4-piperidinyl}benzamide; 
 N-[3-[(methyloxy)methyl]-1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide; 
 N-[1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-3-{[2-(1-pyrrolidinyl)ethyl]oxy}benzamide; 
 N-[1-(5-chloro-1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide; 
 N-[1-(5-cyano-1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide; 
 N-[1-(5-methyl-1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-3-{[2-(4-morpholinyl)ethyl]oxy}benzamide; 
 3-({2-[(3R)-3-fluoro-1-pyrrolidinyl]ethyl}oxy)-N-[1-(5-methyl-1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide; 
 3-{[2-(3,3-difluoro-1-pyrrolidinyl)ethyl]oxy}-N-[1-(5-methyl-1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide; 
 3-({2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}oxy)-N-[1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide; 
 2-(phenyloxy)-N-[1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]acetamide; and 
 2-phenyl-N-[1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]acetamide, 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         44 . The compound according to  claim 43  which is N-[1-(5-Methyl-1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide or a pharmaceutically acceptable salt thereof. 
     
     
         45 . A method of treating or preventing pain or a disease or disorder where an inhibitor of human ASK1 is required, which comprises administering to a subject in need thereof an effective amount of a compound as defined in  claim 30 , or a pharmaceutically acceptable salt thereof. 
     
     
         46 . A method according to  claim 45  where the pain indication is selected from the group consisting of: chronic articular pain (rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis or juvenile arthritis); musculoskeletal pain; lower back and neck pain; sprains and strains; neuropathic pain; sympathetically maintained pain; myositis; pain associated with cancer and fibromyalgia; pain associated with migraine; pain associated with influenza or other viral infections, such as the common cold; rheumatic fever; pain associated with functional bowel disorders such as non-ulcer dyspepsia, non-cardiac chest pain and irritable bowel syndrome; pain associated with myocardial ischemia; post operative pain; headache; toothache; dysmenorrhea; diabetic neuropathy; sciatica; non-specific lower back pain; multiple sclerosis pain; fibromyalgia; HIV-related neuropathy; post-herpetic neuralgia; trigeminal neuralgia; paraesthesias; dysesthesias; hyperesthesia; dynamic, static or thermal allodynia; thermal, cold or mechanical hyperalgesia; hyperpathia; hypoalgesia and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions. 
     
     
         47 . A method according to  claim 45  where the disease or disorder is inflammation. 
     
     
         48 . A method according to  claim 47  where the inflammation is selected from the group consisting of: skin conditions (sunburn, burns, eczema, dermatitis or psoriasis); ophthalmic diseases (glaucoma, retinitis, retinopathies, uveitis and acute injury to the eye tissue); lung disorders (asthma, bronchitis, emphysema, allergic rhinitis, respiratory distress syndrome, pigeon fancier's disease, farmer's lung, COPD); gastrointestinal tract disorders (aphthous ulcer, Crohn's disease, atopic gastritis, gastritis varialoforme, ulcerative colitis, coeliac disease, regional ileitis, irritable bowel syndrome, inflammatory bowel disease, gastrointestinal reflux disease, diarrhoea, constipation); organ transplantation; rheumatoid arthritis; vascular disease; migraine; periarteritis nodosa; thyroiditis; aplastic anaemia; Hodgkin's disease; sclerodoma; myaesthenia gravis; multiple sclerosis; sorcoidosis; nephrotic syndrome; Bechet's syndrome; polymyositis; gingivitis; myocardial ischemia; pyrexia; systemic lupus erythematosus; polymyositis; tendonitis; bursitis and Sjogren's syndrome. 
     
     
         49 . A pharmaceutical composition comprising a) the compound as defined in  claim 30 , or a pharmaceutically acceptable salt thereof, and b) a pharmaceutically acceptable carrier.