Substituted 1-cyanoethylheterocyclylcarboxamide compounds 750

Abstract

The present invention provides compounds of formula (I) in which y, m, n, R 1 , R 2 and Q are as defined in the specification, a process for their preparation, pharmaceutical compositions containing them and their use in therapy.

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein
 y represents 0, 1 or 2; 
 m and n are independently 0, 1, 2 or 3 (such that the sum of m and n is equal to 1, 2 or 3); 
 R 1  is C 1-3 alkyl optionally substituted with one or more substituents selected from halogen, hydroxy or C 1-3 alkoxy;
 R 2  is selected from hydrogen, halogen, CN, CF 3 , C 1-3 alkyl or C 1-3 alkoxy; 
 
 Q represents, a 5- to 10-membered heteroaryl ring system which contains at least one ring heteroatom selected from nitrogen, oxygen and sulphur, or Q is of the formula A: 
 
       
       
         
           
           
               
               
           
         
         wherein X is CH or N and B is a 5- or 6-membered heterocyclic ring containing 1 to 3 ring heteroatoms independently selected from nitrogen, oxygen and sulphur; 
         the phenyl, heteroaryl ring system and ring system of the formula A being optionally substituted by 1 to 3 substituents independently selected from halogen, carboxyl, hydroxyl, oxo, nitro, cyano, mercapto, C 1-6 alkyl group (itself optionally substituted by hydroxyl, C 1-6 alkoxy, NR 65 R 66 , phenyl or morpholinyl), 
         C 3-6 cycloalkyl, C 2-6 alkenyl, trifluoromethyl, C 1-6 alkoxy (optionally substituted by halogen), C 1-6 alkylcarbonyl, C 1-6 alkylcarbonyloxy, C 1-6 alkoxycarbonyl, —NR 53 R 54 , —C(O)NR 55 R 56 , NR 57 C(O)R 58 , SO 2 NR 59 R 60 , NR 61 SO 2 R 62 , S(O) v R 63 , OS(O 2 )R 64 , benzyloxy and C 1-6 alkylpiperazinyl; 
         R 53  and R 54  each independently represent hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, or R 53  and R 54  together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
 v is 0, 1 or 2; 
 R 55  and R 56  each independently represent hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, or R 55  and R 56  together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring; 
 R 59  and R 60  each independently represent hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, or R 59  and R 60  together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring; 
 each R 57 , R 58 , R 61 , R 62  R 63  and R 64  independently represents a hydrogen atom or a C 1-6 alkyl or C 3-6 cycloalkyl group; 
 R 65  and R 66  each independently represent hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, or R 65  and R 66  together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring; 
 
         or a pharmaceutically-acceptable salt thereof. 
       
     
     
         2 . A compound or pharmaceutically acceptable salt thereof according to  claim 1  wherein the stereochemistry at the carbon bearing the mandatory cyano group has the S stereochemistry. 
     
     
         3 . A compound or pharmaceutically acceptable salt thereof according to  claim 1  wherein m is 1 and n is 1. 
     
     
         4 . A compound according to  claim 1  which is of the formula (I′): 
       
         
           
           
               
               
           
         
         wherein Q is as defined in  claim 1 ; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         5 . A compound according to  claim 1  or a pharmaceutically acceptable salt thereof wherein Q is optionally substituted by 1 to 3 substituents independently selected from halogen, carboxyl, hydroxyl, oxo, nitro, cyano, mercapto, C 1-6 alkyl group (optionally substituted by hydroxyl, C 2-6 alkoxy, NR 65 R 66 , phenyl or morpholinyl),
 C 3-6 cycloalkyl, C 2-6 alkenyl, trifluoromethyl, C 2-6 alkoxy, C 1-6 alkylcarbonyl, 
 C 1-6 alkylcarbonyloxy, C 1-6 alkoxycarbonyl, —NR 53 R 54 , —C(O)NR 55 R 56 , NR 57 C(O)R 58 , SO 2 NR 59 R 60 , NR 61 SO 2 R 62 , S(O) v R 63 , OS(O 2 )R 64 , benzyloxy and C 1-6 alkylpiperazinyl wherein the v and R values are as defined in  claim 1 . 
 
     
     
         6 . A compound according to  claim 1  or a pharmaceutically acceptable salt thereof wherein Q is optionally substituted pyridyl. 
     
     
         7 . A compound according to  claim 6  or a pharmaceutically acceptable salt thereof wherein Q is optionally substituted by 1 or 2 substituents independently selected from halogen, carboxyl, cyano, C 3-6 cycloalkyl, trifluoromethyl, —C(O)NR 55 R 56 , SO 2 NR 59 R 60 , S(O) 2 R 63 , OS(O 2 )R 64 , wherein the R values are as defined in  claim 1 . 
     
     
         8 . A compound according to  claim 6  or a pharmaceutically acceptable salt thereof wherein Q is substituted in the 4-position and optionally substituted in the 3-position. 
     
     
         9 . A compound according to  claim 1  or a pharmaceutically acceptable salt thereof wherein Q is selected from the following ring systems: 
       
         
           
           
               
               
           
         
       
       wherein X is CH or N and R′ is selected from hydrogen and C 1-6 alkyl optionally substituted by C 1-4 alkyoxy. 
     
     
         10 . A compound of the formula (I) according to  claim 1  selected from:
 (S)-4-amino-N-(1-cyano-2-(4-(3-(2-methoxyethyl)-2-oxo-2,3-dihydrobenzo[d]thiazol-5-yl)phenyl)ethyl)tetrahydro-2H-pyran-4-carboxamide; 
 (S)-4-amino-N-(1-cyano-2-(4-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)phenyl)ethyl)tetrahydro-2H-pyran-4-carboxamide; 
 (S)-4-amino-N-(1-cyano-2-(4-(3-(3-methoxypropyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)tetrahydro-2H-pyran-4-carboxamide; 
 (S)-4-amino-N-(1-cyano-2-(4-(1-oxoisoindolin-5-yl)phenyl)ethyl)tetrahydro-2H-pyran-4-carboxamide; 
 (S)-4-amino-N-{cyano-2-[4-(2-methyl-1,1-dioxido-2,3-dihydro-1,2-benzisothiazol-5-yl)phenyl]ethyl}tetrahydro-2H-pyran-4-carboxamide; 
 (S)-4-amino-N-(1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)tetrahydro-2H-pyran-4-carboxamide; 
 (S)-4-amino-N-(1-cyano-2-(4-(1-methyl-2-oxoindolin-6-yl)phenyl)ethyl)tetrahydro-2H-pyran-4-carboxamide; 
 (S)-4-amino-N-(1-cyano-2-(4-(3-(2-methoxyethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)tetrahydro-2H-pyran-4-carboxamide; 
 (S)-4-amino-N-(1-cyano-2-(4-(2-methoxypyridin-4-yl)phenyl)ethyl)tetrahydro-2H-pyran-4-carboxamide; 
 (S)-4-amino-N-(1-cyano-2-(4′-(morpholinosulfonyl)biphenyl-4-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide; 
 (S)-4-amino-N-(1-cyano-2-(4-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)phenyl)ethyl)tetrahydro-2H-pyran-4-carboxamide; 
 (S)-4-amino-N-(1-cyano-2-(4-(2-methyl-3-oxoisoindolin-5-yl)phenyl)ethyl)tetrahydro-2H-pyran-4-carboxamide; 
 (S)-4-amino-N-(1-cyano-2-(4-(2-methyl-1-oxoisoindolin-5-yl)phenyl)ethyl)tetrahydro-2H-pyran-4-carboxamide; 
 (S)-4-amino-N-(1-cyano-2-(4-(6-methyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)phenyl)ethyl)tetrahydro-2H-pyran-4-carboxamide; 
 (S)-4-amino-N-(1-cyano-2-(4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)tetrahydro-2H-pyran-4-carboxamide trifluoroacetatic acid salt; and 
 4-amino-N-{(1S)-1-cyano-2-[4-(2,2-dioxido-1,3-dihydro-2-benzothiophen-5-yl)phenyl]ethyl}tetrahydro-2H-pyran-4-carboxamide; 
 and pharmaceutically acceptable salts thereof. 
 
     
     
         11 . A pharmaceutical composition comprising a compound of formula (I) as claimed in  claim 1  or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable adjuvant, diluent or carrier. 
     
     
         12 . A method of treating asthma, chronic obstructive pulmonary disease or allergic rhinitis in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I) as claimed in  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         13 . A combination of a compound of formula (I) as claimed in  claim 1  or a pharmaceutically acceptable salt thereof and one or more agents independently selected from:
 a non-steroidal glucocorticoid receptor agonist; 
 a selective β 2  adrenoceptor agonist; 
 a phosphodiesterase inhibitor; 
 a protease inhibitor; 
 a glucocorticoid; 
 an anticholinergic agent; 
 a modulator of chemokine receptor function; and
 an inhibitor of kinase function.