US2018208602A1PendingUtilityA1

New bicyclic compounds as atx inhibitors

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Assignee: HOFFMANN LA ROCHEPriority: Sep 24, 2015Filed: Mar 23, 2018Published: Jul 26, 2018
Est. expirySep 24, 2035(~9.2 yrs left)· nominal 20-yr term from priority
Inventors:Patrick Di GiorgioJerome HertDaniel HunzikerPatrizio MatteiMarkus RudolphPetra Schmitz
C07D 519/00A61P 27/02C07D 487/04A61K 31/407
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Claims

Abstract

The invention provides novel compounds having the general formula (I) wherein R 1 , R 2 , R 9 , Y, W, m, n, p and q are as defined herein, compositions including the compounds and methods of using the compounds.

Claims

exact text as granted — not AI-modified
1 . Compounds of formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is substituted phenyl, substituted phenyl-C 1-6 -alkyl, substituted phenoxy-C 1-6 -alkyl, substituted phenyl-C 2-6 -alkenyl, substituted phenyl-C 2-6 -alkynyl, substituted pyridinyl, substituted pyridinyl-C 1-6 -alkyl, substituted pyridinyl-C 2-6 -alkenyl, substituted pyridinyl-C 2-6 -alkynyl, substituted thiophenyl, substituted thiophenyl-C 1-6 -alkyl, substituted thiophenyl-C 2-6 -alkenyl or substituted thiophenyl-C 2-6 -alkynyl, wherein substituted phenyl, substituted phenyl-C 1-6 -alkyl, substituted phenoxy-C 1-6 -alkyl, substituted phenyl-C 2-6 -alkenyl, substituted phenyl-C 2-6 -alkynyl, substituted pyridinyl, substituted pyridinyl-C 1-6 -alkyl, substituted pyridinyl-C 2-6 -alkenyl, substituted pyridinyl-C 2-6 -alkynyl, substituted thiophenyl, substituted thiophenyl-C 1-6 -alkyl, substituted thiophenyl-C 2-6 -alkenyl and substituted thiophenyl-C 2-6 -alkynyl are substituted by R 3 , R 4  and R 5 ; 
         Y is —OC(O)— or —C(O)—; 
         W is —C(O)—, —S(O) 2 — or —CR 6 R 7 -; 
         R 2  is selected from the ring systems B, F, L, M, O, Z, AF, AG, AH, AJ, AN, AO, AP, AQ, AR, AS, AT, AU and AV; 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R 3  is halogen, hydroxy, cyano, C 1-6 -alkoxy, C 1-6 -alkoxy-C 1-6 -alkyl, halo-C 1-6 -alkoxy, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, C 3-8 -cycloalkyl-C 1-6 -alkoxy, C 3-8 -cycloalkoxy, C 3-8 -cycloalkoxy-C 1-6 -alkyl, C 1-6 -alkylamino, C 1-6 -alkylcarbonylamino, C 3-8 -cycloalkylcarbonylamino, C 1-6 -alkyltetrazolyl, C 1-6 -alkyltetrazolyl-C 1-6 -alkyl or heterocycloalkyl-C 1-6 -alkoxy; 
         R 4  and R 5  are independently selected from H, halogen, hydroxy, cyano, C 1-6 -alkoxy, C 1-6 -alkoxy-C 1-6 -alkyl, halo-C 1-6 -alkoxy, hydroxy-C 1-6 -alkyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, C 3-8 cycloalkyl-C 1-6 -alkoxy, C 3-8 -cycloalkoxy, C 3-8 -cycloalkoxy-C 1-6 -alkyl, C 1-6 -alkylcarbonylamino, C 3-8 -cycloalkylcarbonylamino, C 1-6 -alkyltetrazolyl, C 1-6 -alkyltetrazolyl-C 1-6 -alkyl or heterocycloalkyl-C 1-6 -alkoxyl; 
         R 6  is H or C 1-6 -alkyl; 
         R 7  is H, C 1-6 -alkyl, halogen, halo-C 1-6 -alkyl or C 1-6 -alkoxy; 
         R 9  is halogen, C 1-6 -alkyl or C 1-6 -alkoxy; 
         m, n, p and q are independently selected from 1 or 2; 
         r is 1, 2 or 3; 
         or pharmaceutically acceptable salts. 
       
     
     
         2 . A compound according to  claim 1 , wherein R 1  is substituted phenyl-C 1-6 -alkyl or substituted pyridinyl, wherein substituted phenyl-C 1-6 -alkyl and substituted pyridinyl-C 1-6 -alkyl are substituted by R 3 , R 4  and R 5 ;
 Y is a —OC(O)— or —C(O)—;   W is —C(O)—;   R 2  is selected from the ring systems O, AJ, AN and AO;   R 3  is halo-C 1-6 -alkoxy or tetrahydropyranyl-C 1-6 -alkoxy;   R 4  is H or C 3-8 -cycloalkyl;   R 5  is H;   R 6  is C 1-6 -alkyl;   R 9  is halogen, C 1-6 -alkyl or C 1-6 -alkoxy;   m, n, p and q are 1;   or pharmaceutically acceptable salts.   
     
     
         3 . A compound according to  claim 1  or  2 , wherein R 1  is substituted phenyl-C 1-6 -alkyl or substituted pyridinyl, wherein substituted phenyl-C 1-6 -alkyl and substituted pyridinyl-C 1-6 -alkyl are substituted by R 3 , R 4  and R 5 . 
     
     
         4 . A compound according to any one of  claims 1  to  4 , wherein Y is —C(O)—. 
     
     
         5 . A compound according to any one of  claims 1  to  2 , wherein R 2  is selected from the ring systems O, AJ, AN and AO. 
     
     
         6 . A compound according to any one of  claims 1  to  6 , wherein R 2  is selected from the ring systems AJ and AO. 
     
     
         7 . A compound according to any one of  claims 1  to  7 , wherein R 3  is halo-C 1-6 -alkoxy or tetrahydropyranyl-C 1-6 -alkoxy. 
     
     
         8 . A compound according to any one of  claims 1  to  9 , wherein R 4  is H or C 3-8 -cycloalkyl. 
     
     
         9 . A compound according to any one of  claims 1  to  11 , wherein R 5  is H. 
     
     
         10 . A compound according to any one of  claims 1  to  12 , wherein R 6  is C 1-6 -alkyl. 
     
     
         11 . A compound according to any one of  claims 1  to  13 , wherein R 7  is H. 
     
     
         12 . A compound according to any one of  claims 1  to  13 , wherein R 9  is C 1-6 -alkoxy. 
     
     
         13 . A compound according to any one of  claims 1  to  15 , wherein m, n, p and q are 1. 
     
     
         14 . A compound according to any one of  claims 1  to  17 , wherein
 R 1  is substituted phenyl-C 1-6 -alkyl or substituted pyridinyl, wherein substituted phenyl-C 1-6 -alkyl and substituted pyridinyl-C 1-6 -alkyl are substituted by R 3 , R 4  and R 5 ; 
 Y is —C(O)—; 
 W is —C(O)—; 
 R 2  is selected from the ring systems AJ and AO; 
 R 3  is halo-C 1-6 -alkoxy or tetrahydropyranyl-C 1-6 -alkoxy; 
 R 4  is H or C 3 . 8 -cycloalkyl; 
 R 5  is H; 
 R 6  is is C 1-6 -alkyl; 
 R 7  is H; 
 R 9  is C 1-6 -alkoxy; 
 m, n, p and q are 1 
 or pharmaceutically acceptable salts. 
 
     
     
         15 . A compound according to any one of  claims 1  to  20 , selected from
 trans-5-(1H-benzotriazole-5-carbonyl)-3a-fluoro-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester; 
 trans-5-(1H-benzotriazole-5-carbonyl)-3a-methoxy-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester; 
 trans-1-[5-(1H-benzotriazole-5-carbonyl)-3a-methoxy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-3-[4-(trifluoromethoxy)phenyl]propan-1-one; 
 trans-[5-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]-3a-methoxy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-(1H-benzotriazol-5-yl)methanone; 
 trans-5-(1H-benzotriazole-5-carbonyl)-3a-methyl-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester; 
 trans-5-[3a-methoxy-2-[3-[4-(trifluoromethoxy)phenyl]propanoyl]-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carbonyl]-3-methyl-1H-benzimidazol-2-one; 
 trans-5-[5-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]-3a-methoxy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-2-carbonyl]-3-methyl-1H-benzimidazol-2-one; 
 trans-[3a-m ethoxy-5-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol -2-yl]-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridin-4-yl]methanone; 
 trans-1-[3a-methoxy-5-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-3-[4-(trifluoromethoxy)phenyl]propan-1-one; 
 trans-1-[5-(3-hydroxy-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridine-6-carbonyl)-3a-methoxy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-3-[4-(trifluoromethoxy)phenyl]propan-1-one; 
 trans-[5-(3-hydroxy-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridine-6-carbonyl)-3a-methoxy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridin-4-yl]methanone; 
 trans-[3a-methoxy-5-(1,4, 6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridin-4-yl]methanone; 
 trans-[5-(3-hydroxy-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridine-6-carbonyl)-3a-methoxy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridin-4-yl]methanone; 
 (+)-trans-5-(1H-benzotriazole-5-carbonyl)-3a-methyl-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester; 
 (−)-trans-5-(1H-benzotriazole-5-carbonyl)-3a-methoxy-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester; 
 trans-[5-(3-hydroxy-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridine-6-carbonyl)-3a-methoxy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridin-4-yl]methanone; 
 (−)-trans-5-(1H-benzotriazole-5-carbonyl)-3a-methyl-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester; 
 (+)-trans-5-(1H-benzotriazole-5-carbonyl)-3a-methoxy-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid4-trifluoromethoxy-benzyl ester; 
 and pharmaceutically acceptable salts thereof. 
 
     
     
         16 . A compound according to any one of  claims 1  to  21 , selected from trans-1-[5-(1H-benzotriazole-5-carbonyl)-3a-methoxy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-3-[4-(trifluoromethoxy)phenyl]propan-1-one;
 trans-[5-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]-3a-methoxy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-(1H-benzotriazol-5-yl)methanone; 
 trans-[5-(3-hydroxy-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridine-6-carbonyl)-3a-methoxy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridin-4-yl]methanone; 
 and pharmaceutically acceptable salts thereof. 
 
     
     
         17 . A process to prepare a compound according to any one of  claims 1  to  22  comprising the reaction of a compound of formula (II) in the presence of a compound of formula (III), wherein R 1 , R 2 , R 9 , m, n, p and q are as defined in any one of  claims 1  to  22  and W is —C(O)—. 
       
         
           
           
               
               
           
         
       
     
     
         18 . A compound according to any one of  claims 1  to  22  for use as therapeutically active substance. 
     
     
         19 . A pharmaceutical composition comprising a compound according to any one of  claims 1  to  22  and a therapeutically inert carrier. 
     
     
         20 . The use of a compound according to any one of  claims 1  to  22  for the treatment or prophylaxis of ocular conditions. 
     
     
         21 . A compound according to any one of  claims 1  to  22  for the treatment or prophylaxis of ocular conditions. 
     
     
         22 . The use of a compound according to any one of  claims 1  to  22  for the preparation of a medicament for the treatment or prophylaxis of ocular conditions. 
     
     
         23 . A method for the treatment or prophylaxis ocular conditions, which method comprises administering an effective amount of a compound according to any one of  claims 1  to  22 . 
     
     
         24 . A compound according to any one of  claims 1  to  22 , when manufactured according to a process of claim  26 . 
     
     
         25 . The invention as hereinbefore described.

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