Novel compounds

Abstract

This invention relates to nicotinamide derivatives of general formula (I): in which R 1 , X, Y, Z and R 2 have the meanings defined herein, and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of such derivatives.

1 . A compound of formula (I):  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or solvate of said compound, wherein: 
 R 1  is H, halo or (C 1 -C 4 ) alkyl;  
 X is —CH 2 — and Y is S; or  
 Z is C orS 2 ;  
 R 2  is phenyl, benzyl, naphthyl, heteroaryl or (C 3 -C 8 )cycloalkyl,  
 said phenyl, benzyl, naphthyl, heteroaryl or (C 3 -C 8 )cycloalkyl each being optionally substituted independently with one to three halo; CN; CONR  3 R  4 ; (C 1 -C 6 ) alkyl optionally substituted by one to three halo; (C 1 -C 6 )alkoxy optionally substituted by one to three halo; hydroxy; hydroxy(C 1 -C 6 )alkyl; (C 3 -C 8 )cycloalkyl-(C 1 -C 6 )alkoxy; hydroxy-(C 2 -C 6 )alkoxy; (C 3 -C 8 )cycloalkyl-(C 1 -C 6 )alkyl; (C 3 -C 8 )cycloalkyloxy; phenyl optionally substituted independently by one to three hydroxy, halo or (C 1 -C 6 )alkoxy; (C 3 -C 8 )cycloalkyl or NR 3 R 4 ; and  
 R 3  and R 4  are each independently H, (C 1 -C 4 )alkyl or SO 2 (C 1 -C 4  alkyl).  
 
   
   
       2 . (canceled)  
   
   
       3 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is H, halo, CH 3  or C 2 H 5 .  
   
   
       4 . A compound of  claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 1  is H, F, Cl or CH 3 .  
   
   
       5 . A compound of  claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 1  is F.  
   
   
       6 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2  is phenyl, pyrrolyl, furanyl, furazanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, tetrazolyl, triazinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, indolyl, isoindolyl, indazolyl, purinyl, naphthyridinyl, phthalazinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzofuranyl, thiadiazolyi, benzothiadiazolyl, oxadiazolyl, benzofuranyl, dihydrobenzofuranyl, benzoxadiazolyl, benzpyrimidyl, benzothienyl, benzoxazolyi, benzothiazolyl, imidazopyridyl, benzimidazolyl, pyrazolopyridyl, pyrazolopyrimidyl, benzyl or cyclopropyl, each of which is optionally substituted independently by one to three methyl, N(CH 3 )SO2CH 3 , NHSO 2 CH 2 CH 3 , NHSO 2 CH(CH 3 ) 2 , hydroxy, hydroxymethyl, chloro, fluoro, ethyl, isopropyl, methoxy, OC 2 H 4 OH, C 2 H 4 OH, O(CH 2 ) 3 OH, trifluoromethyl, ethoxy, cyclopropylmethoxy or cyclopentyloxy.  
   
   
       7 . A compound of  claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 2  is phenyl, imidazolyl, indazolyl, quinolyl, quinazolinyl, dihydrobenzofuranyl, benzothiadiazolyl, benzoxadiazolyl, pyrazolyl, imidazopyridyl, benzimidazolyl, pyrazolopyridyl, benzyl or cyclopropyl, each of which is optionally substituted independently by one to three methyl, N(CH 3 )SO 2 CH 3 , NHSO 2 CH 2 CH 3 , NHSO 2 CH(CH 3 ) 2 , hydroxy, hydroxymethyl, chloro, fluoro, ethyl, isopropyl, methoxy, OC 2 H 4 OH, C 2 H 4 OH, O(CH 2 ) 3 OH, trifluoromethyl, ethoxy, cyclopropylmethoxy or cyclopentyloxy.  
   
   
       8 . A compound of  claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 2  is phenyl, indazolyl or imidazo[1,2-a]pyridyl, each of which is optionally substituted independently with one to three methyl, N(CH 3 )SO 2 CH 3 , NHSO 2 CH 2 CH 3 , NHSO 2 CH(CH 3 ) 2 , hydroxy, hydroxymethyl, chloro, fluoro, ethyl, isopropyl, methoxy, OC 2 H 4 OH, C 2 H 4 OH, O(CH 2 ) 3 OH, trifluoromethyl, ethoxy, cyclopropylmethoxy or cyclopentyloxy.  
   
   
       9 . A compound of  claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 2  is phenyl, indazolyl or imidazo[1 ,2-a]pyridyl, each of which is optionally substituted independently with one to three methyl or hydroxy.  
   
   
       10 . A compound of  claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 2  is 2-hydroxy-4-methylphenyl, indazol-3-yl or imidazo[1,2-a]pyridine-8-yl.  
   
   
       11 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is CO.  
   
   
       12 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein: 
 X is —CH 2 — and Y is S;    R 1  is H, halo, CH 3  or C 2 H 5 ;    R 2  is phenyl, imidazolyl, indazolyl, quinolyl, quinazolinyl, dihydrobenzofuranyl, benzothiadiazolyl, benzoxadiazolyl, pyrazolyl, imidazopyridyl, benzimidazolyl, pyrazolopyridyl, benzyl or cyclopropyl, each of which is optionally substituted independently by one to three methyl, (CH 3 )SO 2 CH 3 , NHSO 2 CH 2 CH 3 , NHSO 2 CH(CH 3 ) 2 , hydroxy, hydroxymethyl, chloro, fluoro, ethyl, isopropyl, methoxy, OC 2 H 4 OH, C 2 H 4 OH, O(CH 2 ) 3 OH, trifluoromethyl, ethoxy, cyclopropylmethoxy or cyclopentyloxy; and    Z is CO.    
   
   
       13 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein: 
 X is —CH 2 — and Y is S;    R 1  is H, F, Cl or CH 3 ;    R 2  is phenyl, indazolyl or imidazo[1,2-a]pyridyl, each of which is optionally substituted independently with one to three methyl or hydroxy; and    Z is CO.    
   
   
       14 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein: 
 X is —CH 2 — and Y is S;    R 1  is F;    R 2  is 2-hydroxy-4-methylphenyl, indazol-3-yl or imidazo[1,2-a]pyridine-8-yl;    and Z is CO.    
   
   
       15 . A compound selected from the group consisting of 
 Syn-Imidazo[1,2-a]pyridine-8-carboxylic acid (4-{[2-(2,3-dihydro-benzo[b]thiophen-6-yloxy)-5-fluoro-pyridine-3-carbonyl]-amino}-cyclohexyl)-amide;    Syn-2-(2,3-Dihydro-benzo[b]thiophen-6-yloxy)-5-fluoro-N-[4-(2-hydroxy-4-methyl-benzoylamino)-cyclohexyl]-nicotinamide;    Syn-2-(2,3-Dihydro-benzo[b]thiophen-6-yloxy)-5-fluoro-N-{4-[2-(2-hydroxyethoxy)-benzoylaminol-cyclohexyl}-nicotinamide;    Syn-Imidazo[1,2-a]pyridine-8-carboxylic acid (4-{[2-(2,3-dihydrobenzo[b]thiophen-5-yloxy)-5-fluoro-pyridine-3-carbonyl]-amino}-cyclohexyl)-amide;    Syn-2-(2,3-Dihydro-benzo[b]thiophen-6-yloxy)-5-fluoro-N-[4-(2-hydroxy-4-hydroxymethyl-benzoylamino)-cyclohexyl]-nicotinamide;    Syn-2-(2,3-Dihydro-benzo[b]thiophen-6-yloxy)-5-fluoro-N-[4-(2-hydroxy-5-hydroxymethyl-benzoylamino)-cyclohexyl]-nicotinamide;    Syn-2-(2,3-Dihydro-benzo[b]thiophen-6-yloxy)-5-fluoro-N-{4-[2-(2-hydroxyethoxy)-3-methyl-benzoylamino]-cyclohexyl}-nicotinamide;    Syn-2-(2,3-Dihydro-benzo[b]thiophen-6-yloxy)-5-fluoro-N-{4-[2-(2-hydroxyethoxy)-4-methyl-benzoylamino]-cyclohexyl}-nicotinamide;    Syn-2-(2,3-Dihydro-benzo[b]thiophen-6-yloxy)-5-fluoro-N-{4-[2-(2-hydroxyethoxy)-5-methyl-benzoylamino]-cyclohexyl}-nicotinamide;    Syn-N-{4-[4-Chloro-2-(2-hydroxy-ethoxy)-benzoylamino]-cyclohexyl}-2-(2,3-dihydro-benzo[b]thiophen-6-yloxy)-5-fluoro-nicotinamide;    Syn-N-{4-[5-Chloro-2-(2-hydroxy-ethoxy)-benzoylamino]-cyclohexyl}-2-(2,3-dihydro-benzo[b]thiophen-6-yloxy)-5-fluoro-nicotinamide;    Syn-2-(2,3-Dihydro-benzo[b]thiophen-6-yloxy)-N-[4-(5-ethyl-2-hydroxy-benzoylamino)-cyclohexyl]-5-fluoro-nicotinamide;    Syn-N-[4-(4-Chloro-2-hydroxy-benzoylamino)-cyclohexyl]-2-(2,3-dihydro-benzo[b]thiophen-6-yloxy)-5-fluoro-nicotinamide;    Syn-2-(2,3-Dihydro-benzo[b]thiophen-6-yloxy)-5-fluoro-N-[4-(2-hydroxy-4,5-dimethyl-benzoylamino)-cyclohexyl]-nicotinamide;    Syn-2-(2,3-Dihydro-benzo[b]thiophen-6-yloxy)-N-[4-(4-ethyl-2-hydroxy-benzoylamino)-cyclohexyl}-5-fluoro-nicotinamide;    Syn-2-(2,3-Dihydro-benzo[b]thiophen-6-yloxy)-5-fluoro-N-[4-(2-hydroxy-5-methyl-benzoylamino)-cyclohexyl}-nicotinamide;    Syn-2-(2,3-Dihydro-benzo[b]thiophen-6-yloxy)-5-fluoro-N-[4-(4-fluoro-2-hydroxy-benzoylamino)-cyclohexyl}-nicotinamide;    Syn-2-(2,3-Dihydro-benzo[b]thiophen-6-yloxy)-5-fluoro-N-[4-(5-fluoro-2-hydroxy-benzoylamino)-cyclohexyl]-nicotinamide;    Syn-2-(2,3-Dihydro-benzo[b]thiophen-6-yloxy)-N-{4-[5-ethyl-2-(2-hydroxyethoxy)-benzolyamino]-cyclohexyl}-5-fluoro-nicotinamide;    Syn-N-[4-(5-Chloro-2-hydroxy-benzoylamino-cyclohexyl]-2-(2,3-dihydro-benzo[b]thiophen-6-yloxy)-5-fluoro-nicotinamide;    Syn-2-(2,3-Dihydro-benzo[b]thiophen-6-yloxy)-5-fluoro-N-{4-[5-fluoro-2-(2-hydroxy-ethoxy)-benzoylamino]-cyclohexyl}-nicotinamide;    Syn-2-(2,3-Dihydro-benzo[b]thiophen-6-yloxy)-5-fluoro-N-[4-(2-hydroxy-5-trifluoromethyl-benzoylamino)-cyclohexyl}-nicotinamide; or    Syn-N-[4-(4,5-Dichloro-2-hydroxy-benzoylamino)-cyclohexyl]-2-(2,3-dihydro-benzo[b]thiophen-6-yloxy)-5-fluoro-nicotinamide;    or a pharmaceutically acceptable salt thereof.    
   
   
       16 . A compound selected from the group consisting of 
 Syn-Imidazo[1,2-a]pyridine-8-carboxylic acid (4-{[2-(2,3-dihydro-benzo[b]thiophen-6-yloxy)-5-fluoro-pyridine-3-carbonyl]-amino)-cyclohexyl)-amide;    Syn-2-(2,3-Dihydro-benzo[b]thiophen-6-yloxy)-5-fluoro-N-[4-(2-hydroxy-4-methyl-benzoylamino)-cyclohexyl}-nicotinamide;    or a pharmaceutically acceptable salt thereof.    
   
   
       17 . A pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient, diluent or carrier.  
   
   
       18 . A method of treating a disease, disorder or condition in which PDE4 inhibition is beneficial in a mammal suffering from a disease, disorder or condition in which PDE4 inhibition is beneficial, said method comprising administering to said mammal in need of such-treatment a therapeutically effective amount of a compound of  claim 1 , a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient.  
   
   
       19 .- 21 . (canceled)