P2X7 Receptor Antagonists and Their Use

Abstract

The invention provides compounds of formula (IA), processes for their preparation, pharmaceutical compositions containing them, and their use in therapy.

1 . A compound of formula (IA) 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt, prodrug or solvate thereof, 
       wherein 
       p is 0, 1 or 2; 
       each R 1  independently represents halogen or C 1-6  alkyl optionally substituted by at least one substituent selected from hydroxyl, halogen and C 1-6  alkoxy; 
       q is 0, 1 or 2; 
       each R 4  independently represents halogen or C 1-6  alkyl optionally substituted by at least one substituent selected from hydroxyl, halogen and C 1-6  alkoxy; 
       m is 0, 1, 2 or 3; 
       X is —C(O)NH— or —NHC(O)—; 
       n is 0, 1, 2 or 3; 
       within each grouping CR 5 R 6 , R 5  and R 6  each independently represent hydrogen, C 1-6  alkyl or R 5  and R 6  together with the carbon atom to which they are both attached can form a 3- to 6-membered cycloalkyl ring; 
       R 2  represents a 4- to 9-membered cycloalkyl ring system, which cycloakyl ring system can be optionally substituted by at least one substituent independently selected from halogen, hydroxyl, —S(O) f C 1-6 alkyl, —NR 7 R 8 , —C(O)OR 12 , —OC(O)R 13 , —C(O)NR 14 R 15 , —SO 2 NR 16 R 17 , —NR 18 SO 2 R 19 , C 1-6  alkoxy, C 1-6  hydroxyalkyl or a C 1-6  alkyl group which C 1-6  alkyl group can be optionally substituted by at least one halogen; f is 0, 1 or 2; 
       one of Y or Z is nitrogen and the other is a group CR 3  wherein R 3  is a group of formula (IIA) 
     
     
       
         
         
             
             
         
       
       wherein X 1  represents an oxygen or sulphur atom, or a group>N—R 11  wherein R 11  is hydrogen or a C 1-5  alkyl group which can be optionally substituted by one or more substituents selected from hydroxyl, halogen or C 1-6 alkoxy; s is 0 or 1; 
       R 9  represents a bond or a C 1-5  alkylene group, which can be optionally substituted by at least one substituent selected from hydroxyl, halogen and C 1 -C 6  alkoxy; 
       R 10  represents hydrogen, hydroxyl, carboxyl, —C(O)OR 20 , —NR 21 R 22 , —C(O)NOH, or a group —WR 23 ; 
       or R 10  represents a 4- to 9-membered carbocyclic or heterocyclic ring, either of which may include bridging groups, which carbocyclic and heterocyclic ring can be optionally substituted by at least one substituent selected from halogen, hydroxyl, ═O, carboxyl, cyano, C 1 -C 6  alkyl, C 1 -C 6  hydroxyalkyl, a group —W′R 24 , —C(O)NOH, —(CH 2 ) t NR 25 R 26 , —(CH 2 ) t C(O)NR 27 R 28 , —(CH 2 ) t R 29 —(CH 2 ) t NR 30 C(O)R 31 , —S(O) r R 32 , NR 33 SO 2 R 34 , NR 35 C(O)NR 36 S(O) r R 37 , —S(O) r (CH 2 ) t NR 38 R 39 , —NR 40 S(O) r NR 41 R 42 , S(O) r (CH 2 ) t C(O)OR 43 , or -M(CH 2 ) t C(O)OR 44  wherein M represents a bond, O, or a group>NR 45    
       t is 0, 1, 2, 3, 4, 5 or 6; 
       r is 0, 1 or 2; 
       R 21  and R 22  are independently selected from hydrogen, C 2-7  alkenyl, C 1-6  alkylcarbonyl, —SO 2 R 46 , —C(O)NHSO 2 R 47 , a 3- to 8-membered carbocyclic or heterocyclic ring which carbocyclic or heterocyclic ring can be optionally substituted by at least one substituent selected from halogen, hydroxyl and carboxyl, 
       or R 21  and R 22  may independently represent a C 1-7  alkyl group which C 1-7  alkyl group can be optionally substituted by at least one substituent independently selected from halogen, carboxyl, hydroxyl, —NH(CH 2 ) 2-4 OH, C 1-6  alkoxy, C 1-6  alkylthio, C 1-6  alkoxycarbonyl, —NR 48 R 49 , —C(O)NR 50 R 51 , —NR 52 C(O)R 53 , —NR 54 SO 2 R 55  and —NR 67 C(O)NR 68 SO 2 R 56 ; 
       W and W′ independently represent a bond, O, S(O) p , —NR 57 C(O)—, —C(O)NR 58 —, —SO 2 NR 59 , —NR 60 SO 2 —, >NR 61 , C 1-6  alkylene, or a group —O(CH 2 ) 1-6 —, —S(O) p (CH 2 ) 1-6 —, —NR 62 (CH 2 ) 1-6 —, —(CH 2 ) 1-3 O(CH 2 ) 1-3 —, —(CH 2 ) 1-3 S(O) p (CH 2 ) 1-3 —, —(CH 2 ) 1-3 NR 63 (CH 2 ) 1-3 —, —(CH 2 ) 1-3 NR 64 C(O)(CH 2 ) 0-3 —, —(CH 2 ) 1-3 C(O)NR 65 (CH 2 ) 0-3 —, or —S(O) p (CH 2 ) 1-6 NR 66 —; p is 0, 1 or 2; 
       R 23  and R 24  independently represent a 3- to 10-membered carbocyclic or heterocyclic ring comprising from 1 to 5 heteroatoms independently selected from nitrogen, oxygen and sulphur, which carbocyclic or heterocyclic ring can be optionally substituted with at least one substituent selected from hydroxyl, ═O, ═S, nitro, cyano, amino, halogen —SO 2 C 1-6  alkyl, C 1-6  alkylcarbonyl, C 1-6  alkoxycarbonyl, C 1-6  alkylamino, di-C 1-6  alkylamino, and a C 1-6  alkyl group which C 1-6  alkyl group can be optionally substituted by at least one substituent selected from halogen and hydroxyl; 
       R 7 , R 8 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18  and R 19  each independently represent a hydrogen atom or C 1-6  alkyl group optionally substituted by at least one substituent selected from hydroxyl, halogen and C 1-6  alkoxy, or any of R 7  and R 8 , R 14  and R 15 , R 16  and R 17  together with the nitrogen atom to which they are both attached can form a 3- to 8-membered saturated heterocyclic ring; 
       R 20 , R 34 , R 37 , R 46 , R 47 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 60 , R 61 , R 62 , R 63 , R 64 , R 65 , R 66 , R 67  and R 68  each independently represent hydrogen or a C 1-6  alkyl group which can be optionally substituted by at least one substituent selected from halogen and hydroxyl; 
       R 25 , R 26 , R 27 , R 28 , R 30 , R 31 , R 32 , R 33 , R 35 , R 36 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 48 , R 49 , R 50 , R 51 , R 52  and R 53  each independently represent a hydrogen atom or a C 1-6  alkyl, C 2-6  hydroxyalkyl or a C 3-8  cycloalkyl group, or any of R 25  and R 26 , R 27  and R 28 , R 38  and R 39 , R 41  and R 42 , R 48  and R 49 , R 50  and R 51  together with the nitrogen atom to which they are both attached can form a 3- to 8-membered saturated heterocyclic ring; and R 29  is aryl. 
     
   
   
       2 . A compound according to  claim 1  wherein Y is nitrogen and Z is a group CR 3 . 
   
   
       3 . A compound according to  claim 1  or  claim 2 , wherein n is 1 or 2. 
   
   
       4 . A compound according to any one of  claims 1  to  3 , wherein R 2  represents a cyclopentyl or cyclohexyl ring optionally substituted with a C 1-4  alkyl group. 
   
   
       5 . A compound according to any one of  claims 1  to  4 , wherein in formula (IIA) s is 0; R 9  represents a bond; and R 10  represents an optionally substituted 4- to 9-membered carbocyclic or heterocyclic ring. 
   
   
       6 . A compound according to  claim 5 , wherein in formula (IIA) s is 0; R 9  represents a bond; and R 10  represents a pyrrolidinyl, piperidinyl, piperazinyl or homopiperidinyl group, which can be optionally substituted by at least one substituent selected from hydroxyl, cyano, carboxyl, methyl, —NH 2 , —NHCH 3 , —NHCH 2 CH 2 OH, —CH 2 C(O)OH, —NHCH 2 C(O)OH, —NHCH 2 CH 2 C(O)OH, —CH 2 NHCH 3 , —CH 2 NHCH 2 CH 2 OH, —SO 2 CH 2 CH 2 OH, —N(CH 2 CH 2 OH)C(O)OC(CH 3 ) 3 , —NHSO 2 CF 3 , —NHC(O)NHSO 2 CH 3 . 
   
   
       7 . A compound according to any one of  claims 1  to  3 , wherein in formula (IIA) R 9  represents a C 1-5  alkylene group which can be optionally substituted by at least one hydroxyl; and R 10  represents hydrogen, hydroxyl, carboxyl, —C(O)OR 20 , —NR 21 R 22 , —C(O)NOH, or a group —WR 23 . 
   
   
       8 . A compound according to any one of  claims 1  to  3 , wherein R 10  represents —WR 23  or R 10  represents a 4- to 9-membered carbocyclic or heterocyclic ring, either of which may include bridging groups, which carbocyclic and heterocyclic ring is substituted by at least one substituent —W′R 24 . 
   
   
       9 . A compound of formula (IA), or pharmaceutically acceptable salt, prodrug or solvate thereof, according to  claim 1  being: 
     N-[6-Chloro-2-(4-piperidinylmethyl)-5-quinolinyl]-cyclohexaneacetamide, dihydrochloride, 
     N-[6-Chloro-2-(1-piperazinyl)-5-quinolinyl]-cyclohexaneacetamide, dihydrochloride, 
     N-[6-Chloro-2-[methyl[3-(methylamino)propyl]amino]-5-quinolinyl]-cyclohexaneacetamide, dihydrochloride, 
     6-Chloro-N-(cyclohexylmethyl)-2-methyl-5-quinolinecarboxamide, hydrochloride, 
     N-[6-Chloro-2-[(3-hydroxypropyl)amino]-5-quinolinyl]-cyclohexaneacetamide, hydrochloride, 
     N-[6-Chloro-2-[[(2R)-2,3-dihydroxypropyl]amino]-5-quinolinyl]-cyclohexaneacetamide, 
     4-[[6-Chloro-5-[(cyclohexylacetyl)amino]-2-quinolinyl]amino]-butanoic acid, 
     N-[6-Chloro-2-[methyl[3-(methylamino)propyl]amino]-5-quinolinyl]-4-(trifluoromethyl)-cyclohexaneacetamide, dihydrochloride, 
     N-[6-Chloro-2-(1-piperazinyl)-5-quinolinyl]-4-(trifluoromethyl)-cyclohexaneacetamide, 
     N-[6-Chloro-2-(hexahydro-1H-1,4-diazepin-1-yl)-5-quinolinyl]-cyclohexaneacetamide, 
     N-[6-Chloro-2-[(cis-3,5-dimethyl-1-piperazinyl]-5-quinolinyl]-cyclohexaneacetamide, 
     N-[6-Chloro-2-(4-methyl-1-piperazinyl)-5-quinolinyl]-cyclohexaneacetamide, dihydrochloride, 
     N-[6-Chloro-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-5-quinolinyl]-cyclohexaneacetamide, acetate, 
     N-[6-Chloro-2-[(3R)-3-pyrrolidinylamino]-5-quinolinyl]-cyclohexaneacetaride, dihydrochloride, 
     N-[2-[3-(Ethylamino)propyl]-6-methyl-5-quinolinyl]-cyclohexaneacetaride, dihydrochloride, 
     N-[6-Chloro-2-[3-(ethylamino)propyl]-5-quinolinyl]-cyclohexaneacetamide, dihydrochloride, 
     N-[6-Chloro-2-[[2-[(2-hydroxyethyl)amino]ethyl]amino]-5-quinolinyl]-cyclohexaneacetamide, dihydrochloride, 
     N-5-Quinolinyl-cyclohexaneacetamide, 
     1-Methyl-N-5-quinolinyl-cyclohexaneacetamide, 
     4-Methyl-N-5-quinolinyl-cyclohexaneacetamide, 
     N-5-Quinolinyl-cyclopentanepropanamide, 
     N-[6-Chloro-2-[3-[(3-hydroxypropyl)amino]propyl]-5-quinolinyl]-cyclohexaneacetamide, 
     N-[2-(3-Aminopropyl)-6-chloro-5-quinolinyl]-cyclohexaneacetamide, 
     N-[6-Chloro-2-[3-[[[(methylsulfonyl)amino]carbonyl]amino]propyl]-5-quinolinyl]-cyclohexaneacetamide, 
     N-[2-[3-(Butylamino)propyl]-6-chloro-5-quinolinyl]-cyclohexaneacetamide dihydrochloride, 
     N-[6-Chloro-2-[methyl[3-(methylamino)propyl]amino]-5-quinolinyl]-1-cyclohexyl-cyclopropanecarboxamide, hydrochloride, 
     N-[6-Chloro-2-(1-piperazinyl)-5-quinolinyl]-1-cyclohexyl-cyclopropanecarboxamide, 
     N-[6-Chloro-2-[(3R)-3-hydroxy-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide, 
     N-[6-Chloro-2-[(3S)-3-hydroxy-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide, 
     N-[2-[(3R)-3-Amino-1-pyrrolidinyl]-6-chloro-5-quinolinyl]-cyclohexaneacetamide, 
     N-[2-[(3S)-3-Amino-1-pyrrolidinyl]-6-chloro-5-quinolinyl]-cyclohexaneacetamide, 
     N-[2-(4-Amino-1-piperidinyl)-6-chloro-5-quinolinyl]-cyclohexaneacetamide, 
     N-[6-Chloro-2-[(3R)-3-(methylamino)-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide, 
     N-[6-Chloro-2-[(3R)-3-[(2-hydroxyethyl)amino]-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide, 
     N-[6-Chloro-2-[(3S)-3-(methylamino)-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide, 
     N-[6-Chloro-2-[(3S)-3-[(2-hydroxyethyl)amino]-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide, 
     N-[6-Chloro-2-[(3R)-3-hydroxy-1-piperidinyl]-5-quinolinyl]-cyclohexaneacetamide, 
     N-[2-[(3S)-3-Amino-1-pyrrolidinyl]-6-methyl-5-quinolinyl]-cyclohexaneacetamide, 
     N-[6-Methyl-2-(1-piperazinyl)-5-quinolinyl]-cyclohexaneacetamide, 
     N-[6-Chloro-5-[(cyclohexylacetyl)amino]-2-quinolinyl]-glycine, 
     N-[6-Chloro-5-[(cyclohexylacetyl)amino]-2-quinolinyl]-β-alanine, 
     6-Chloro-N-(cyclohexylmethyl)quinoline-5-carboxamide, 
     6-Chloro-N-(cyclohexylmethyl)-2-(1-piperazinyl)-5-quinolinecarboxamide, dihydrochloride, 
     2-[(3S)-3-Amino-1-pyrrolidinyl]-6-chloro-N-(cyclohexylmethyl)-5-quinolinecarboxamide, 
     6-Chloro-N-(cyclohexylmethyl)-2-[methyl[3-(methylamino)propyl]amino]-5-quinoline carboxamide, dihydrochloride, 
     6-Chloro-N-(cyclohexylmethyl)-2-[methyl[2-(methylamino)ethyl]amino]-5-quinolinecarboxamide, dihydrochloride, 
     6-Chloro-N-(cyclohexylmethyl)-2-[3-[(3-hydroxypropyl)amino]propyl]-5-quinolinecarboxamide, 
     2-[(3R)-3-Amino-1-pyrrolidinyl]-6-chloro-N-(cyclohexylmethyl)-5-quinolinecarboxamide, dihydrochloride, 
     N-(2-Amino-6-chloro-5-quinolinyl)-cyclohexaneacetamide, trifluoroacetate, 
     6-Chloro-N-(cyclohexylmethyl)-2-[(3S)-3-[(2-hydroxyethyl)amino]-1-pyrrolidinyl]-5-quinolinecarboxamide, hydrochloride, 
     2-[(3S)-3-Amino-1-piperidinyl]-6-chloro-N-(cyclohexylmethyl)-5-quinolinecarboxamide, 
     6-Chloro-N-(cyclohexylmethyl)-2-[(3S)-3-[(2-hydroxyethyl)amino]-1-piperidinyl]-5-quinolinecarboxamide, hydrochloride, 
     6-Chloro-N-(cyclohexylmethyl)-2-(3-hydroxy-1-azetidinyl)-5-quinolinecarboxamide, 
     2-[(3S)-3-Amino-1-pyrrolidinyl]-N-(cyclohexylmethyl)-5-quinolinecarboxamide, 
     6-Chloro-N-(cyclohexylmethyl)-2-[3-[(2-hydroxyethyl)amino]-1-azetidinyl]-5-quinolinecarboxamide, 
     [1-[6-Chloro-5-[(cyclohexylacetyl)amino]-2-quinolinyl]-3-pyrrolidinyl](2-hydroxyethyl)-carbamic acid 1,1-dimethylethyl ester, 
     N-(Cyclohexylmethyl)-6-methyl-5-quinolinecarboxamide, 
     2-[(3S)-3-Amino-1-pyrrolidinyl]-N-(cyclohexylmethyl)-6-methyl-5-quinolinecarboxamide, acetate, 
     N-[2-[[(3S)-3-Amino-1-pyrrolidinyl]methyl]-6-chloro-5-quinolinyl]-cyclohexaneacetamide, 
     N-[2-[(3S)-3-Amino-1-piperidinyl]-6-chloro-5-quinolinyl]-cyclohexaneacetamide, 
     N-[6-Chloro-2-[(3S)-3-[(2-hydroxyethyl)amino]-1-piperidinyl]-5-quinolinyl]-cyclohexaneacetamide, 
     N-[2-[(3S)-3-Amino-1-pyrrolidinyl]-6-chloro-5-quinolinyl]-cyclopentanepropanamide, 
     N-[6-Chloro-2-[(3S)-3-[(2-hydroxyethyl)amino]-1-pyrrolidinyl]-5-quinolinyl]-cyclopentanepropanamide, 
     N-[6-Chloro-2-[4-(1,5-dihydro-5-oxo-4H-1,2,4-triazol-4-yl)-1-piperidinyl]-5-quinolinyl]-cyclohexaneacetamide, 
     1-[6-Chloro-5-[(cyclohexylacetyl)amino]-2-quinolinyl]-D-proline, trifluoroacetate, 
     1-[6-Chloro-5-[(cyclohexylacetyl)amino]-2-quinolinyl]-4-piperidinecarboxylic acid, lithium salt, 
     6-Chloro-5-[(cyclohexylacetyl)amino]-2-quinolinebutanoic acid, 
     1-[6-Chloro-5-[(cyclohexylacetyl)amino]-2-quinolinyl]-4-piperidineacetic acid, 
     4-[6-Chloro-5-[(cyclohexylacetyl)amino]-2-quinolinyl]-1-piperazineacetic acid, lithium salt, 
     6-Chloro-5-[(cyclohexylacetyl)amino]-2-quinolinepentanoic acid, 1-[6-Chloro-5-[[(cyclohexylmethyl)amino]carbonyl]-2-quinolinyl]-D-proline, 
     1-[6-Chloro-5-[[(cyclohexylmethyl)amino]carbonyl]-2-quinolinyl]-L-proline, trifluoroacetate, 
     4-[6-Chloro-5-[[(cyclohexylmethyl)amino]carbonyl]-2-quinolinyl]-1-piperazineacetic acid, acetate, 
     1-[6-Chloro-5-[[(cyclohexylmethyl)amino]carbonyl]-2-quinolinyl]-4-piperidinecarboxylic acid, sodium salt, 
     1-[6-Chloro-5-[[(cyclohexylmethyl)amino]carbonyl]-2-quinolinyl]-4-piperidineacetic acid, trifluoroacetate, 
     1-[6-Chloro-5-[[(2-cyclohexylethyl)amino]carbonyl]-2-quinolinyl]-4-piperidinecarboxylic acid, 
     1-[6-Chloro-5-[(3-cyclopentyl-1-oxopropyl)amino]-2-quinolinyl]-4-piperidinecarboxylic acid, 
     1-[6-Chloro-5-[(3-cyclohexyl-1-oxopropyl)amino]-2-quinolinyl]-4-piperidinecarboxylic acid, potassium salt, 
     1-[6-Chloro-5-[[(1-methylcyclohexyl)acetyl]amino]-2-quinolinyl]-4-piperidinecarboxylic acid, 
     N-[6-Chloro-2-[3-[(2-hydroxyethyl)amino]-1-piperidinyl]-5-quinolinyl]-cyclohexaneacetamide, 
     N-[6-Chloro-2-[2-[[(2-hydroxyethyl)amino]methyl]-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide, 
     N-[6-Chloro-2-[3-(methylamino)-1-piperidinyl]-5-quinolinyl]-cyclohexaneacetamide, 
     N-[6-Chloro-2-[2-[(methylamino)methyl]-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide, 
     N-[2-[(3R)-3-Hydroxy-1-pyrrolidinyl]-6-methyl-5-quinolinyl]-cyclohexaneacetamide, 
     N-[(3S)-1-[6-Chloro-5-[(cyclohexylacetyl)amino]-2-quinolinyl]-3-pyrrolidinyl]-glycine, 
     N-[2-[(3S)-3-[(2-Hydroxyethyl)amino]-1-pyrrolidinyl]-6-methyl-5-quinolinyl]-cyclohexaneacetamide, 
     N-[(3S)-1-[6-Chloro-5-[(cyclohexylacetyl)amino]-2-quinolinyl]-3-pyrrolidinyl]-β-alanine, 
     N-[6-Chloro-2-[(3S)-3-[[(trifluoromethyl)sulfonyl]amino]-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide, 
     N-[6-Chloro-2-[(3S)-3-[[[(methylsulfonyl)amino]carbonyl]amino]-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide, 
     N-[2-[(3S)-3-Amino-1-pyrrolidinyl]-6-chloro-5-quinolinyl]-cyclohexanepropanamide, 
     N-[6-Chloro-2-[methyl[3-(methylamino)propyl]amino]-5-quinolinyl]-cyclohexanepropanamide, 
     N-[6-Chloro-2-(1-piperazinyl)-5-quinolinyl]-cyclohexanepropanamide, 
     N-[6-Chloro-2-[(3S)-3-[(2-hydroxyethyl)amino]-1-pyrrolidinyl]-5-quinolinyl]-cyclohexanepropanamide, 
     2-[(3S)-3-Amino-1-pyrrolidinyl]-6-chloro-N-(2-cyclohexylethyl)-5-quinolinecarboxamide, ditrifluoroacetate, 
     N-[6-Chloro-2-[(3S)-3-[(2-hydroxyethyl)sulfonyl]-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide, 
     N-[6-Chloro-2-[(3S)-3-cyano-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide, 
     N-[1-[6-Chloro-5-[[(cyclohexylmethyl)amino]carbonyl]-2-quinolinyl]-3-azetidinyl]-β-alanine, 
     6-Chloro-N-(cyclohexylmethyl)-2-[3-(1H-tetrazol-5-yl)-1-azetidinyl]-5-quinolinecarboxamide, 
     N-[6-Chloro-2-[(3S)-3-(1H-tetrazol-5-yl)-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide, 
     N-[6-Chloro-2-[(3R)-3-(1H-tetrazol-5-yl)-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide, 
     N-[6-Chloro-2-[(3S)-3-[[2-(2H-tetrazol-5-yl)ethyl]amino]-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide, 
     N-[6-Chloro-2-[4-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)-1-piperidinyl]-5-quinolinyl]-cyclohexaneacetamide, 
     N-[6-Chloro-2-[4-(4,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl)-1-piperidinyl]-5-quinolinyl]-cyclohexaneacetamide, 
     N-[6-Chloro-2-[3-(1H-tetrazol-5-yl)propyl]-5-quinolinyl]-cyclohexaneacetamide, trifluoroacetate, 
     N-[6-Chloro-2-[4-(1H-tetrazol-5-yl)butyl]-5-quinolinyl]-cyclohexaneacetamide, 
     6-Chloro-N-(cyclohexylmethyl)-2-[4-(1H-tetrazol-5-yl)butyl]-5-quinolinecarboxamide, 
     N-[6-Chloro-2-[(3S)-3-[2-(1H-tetrazol-5-yl)ethoxy]-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide, 
     N-[6-Chloro-2-[(3S)-3-[2-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)ethoxy]-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide, 
     N-[6-Chloro-2-[4-(1H-tetrazol-5-yl)-1-piperidinyl]-5-quinolinyl]cyclohexane-acetamide, 
     6-Chloro-N-(cyclohexylmethyl)-2-[4-(1H-tetrazol-5-yl)-1-piperidinyl]-5-quinolinecarboxamide, 
     6-Chloro-N-(2-cyclohexylethyl)-2-[4-(1H-tetrazol-5-yl)-1-piperidinyl]-5-quinolinecarboxamide, 
     6-Chloro-N-(cyclohexylmethyl)-2-[(3S)-3-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-1-pyrrolidinyl]-5-quinolinecarboxamide, 
     N-[6-Chloro-2-(4-cyano-1-piperidinyl)-5-quinolinyl]-cyclohexaneacetamide, or N-[6-Chloro-2-[[4-[[(trifluoromethyl)sulfonyl]amino]-1-piperidinyl]-5-quinolinyl]-cyclohexaneacetamide. 
   
   
       10 . A compound of formula (IB) 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt, prodrug or solvate thereof, 
       wherein p is 0, 1 or 2; 
       each R 1  is independently selected from halogen, or optionally substituted C 1-6  alkyl, 
       m is 0, 1, 2 or 3; 
       X is C(O)NH or NHC(O); 
       n is 0, 1, 2 or 3; 
       each R 5  and each R 6  are independently selected from hydrogen or C 1-3 alkyl, or R 5  and R 6  together with the carbon atom to which they are both attached forms a C 3-6 cycloalkyl ring, R 2  is an optionally substituted cycloalkyl group; 
       one of Y or Z is nitrogen and the other is a group CR 3  where R 3  is hydrogen, or a group R 7 , OR 7 , SR 7 , NR 7 R 8 , where R 7  and R 8  are independently selected from hydrogen, optionally substituted C 1-10 alkyl, an optionally substituted cycloalkyl or an optionally substituted heterocyclic group, or R 7  and R 8  together with the nitrogen to which they are attached form an optionally substituted heterocyclic ring which may contain additional heteroatoms, and may further comprise bridging groups; 
       q is 0, 1 or 2, 
       and each R 4  is independently selected from halogen or optionally substituted C 1-6 alkyl, with the proviso that where p is 0, q is 0, m is 0, n is 0, X is NHC(O), Y is nitrogen and Z is CR 3  and R 3  is methyl, R 2  is not a cyclopropyl group. 
     
   
   
       11 . A pharmaceutical composition comprising a compound of formula (IA), or a pharmaceutically acceptable salt, prodrug or solvate thereof, as claimed in any one of  claims 1  to  9  in association with a pharmaceutically acceptable adjuvant, diluent or carrier. 
   
   
       12 . A process for the preparation of a pharmaceutical composition as claimed in  claim 11  which comprises mixing a compound of formula (IA), or a pharmaceutically acceptable salt, prodrug or solvate thereof, as defined in any one of  claims 1  to  9  with a pharmaceutically acceptable adjuvant, diluent or carrier. 
   
   
       13 . A compound of formula (IA), or a pharmaceutically acceptable salt, prodrug or solvate thereof, as claimed in any one of  claims 1  to  9  for use in therapy. 
   
   
       14 . Use of a compound of formula (IA), or a pharmaceutically acceptable salt, prodrug or solvate thereof, as claimed in any one of  claims 1  to  9  in the manufacture of a medicament for use in the treatment of rheumatoid arthritis. 
   
   
       15 . Use of a compound of formula (IA) or a pharmaceutically acceptable salt, prodrug or solvate thereof as claimed in any one of  claims 1  to  9  in the manufacture of a medicament for use in the treatment of an obstructive airways disease. 
   
   
       16 . Use according to  claim 15 , wherein the obstructive airways disease is asthma or chronic obstructive pulmonary disease. 
   
   
       17 . Use of a compound of formula (IA) or a pharmaceutically acceptable salt, prodrug or solvate thereof as claimed in any one of  claims 1  to  9  in the manufacture of a medicament for use in the treatment of osteoarthritis. 
   
   
       18 . Use of a compound of formula (IA) or a pharmaceutically acceptable salt, prodrug or solvate thereof as claimed in any one of  claims 1  to  9  in the manufacture of a medicament for use in the treatment of rheumatoid arthritis 
   
   
       19 . Use of a compound of formula (IA) or a pharmaceutically acceptable salt, prodrug or solvate thereof as claimed in any one of  claims 1  to  9  in the manufacture of a medicament for use in the treatment of atherosclerosis. 
   
   
       20 . A method of treating rheumatoid arthritis or osteoarthritis which comprises administering to a patient a therapeutically effective amount of a compound of formula (IB) or a pharmaceutically acceptable salt, prodrug or solvate thereof as claimed in any one of  claims 1  to  9 . 
   
   
       21 . A method of treating an obstructive airways disease which comprises administering to a patient a therapeutically effective amount of a compound of formula (IB) or a pharmaceutically acceptable salt, prodrug or solvate thereof as claimed in any one of  claims 1  to  9 . 
   
   
       22 . A process for the preparation of a compound of formula (IA) as defined in  claim 1 , or a pharmaceutically acceptable salt, prodrug or solvate thereof, which comprises either:
 (a) reacting a compound of formula (IVA)   
     
       
         
         
             
             
         
       
       wherein L 1  represents a leaving group (e.g. hydroxyl or halogen) and Y, Z, R 1 , R 4 , m, p and q are as defined in formula (IA), with a compound of formula (VA),
   H 2 N—(CR 5 R 6 ) n —R 2   (VA) 
 
       R 2 , R 5 , R 6  and n are as defined in formula (IA); or 
       (b) reacting a compound of formula (VIA) 
     
     
       
         
         
             
             
         
       
       wherein Y, Z, R 1 , R 4 , m, p and q are as defined in formula (IA), with a compound of formula (VIIA)
   L 2 C(O)—(CR 5 R 6 ) n —R 2   (VIIA) 
 
       wherein L 2  represents a leaving group (e.g. hydroxyl or halogen) and R 2 , R 5 , R 6  and n are as defined in formula (IA); or 
       (c) when Y is N and Z is CR 3 , and R 3  represents a group of formula (IIA) above where s is 1 and X is >NR 11 , reacting a compound of formula (VIIIA) 
     
     
       
         
         
             
             
         
       
       wherein L 3  is a leaving group (e.g. halogen, paratoluene sulphonate or methane sulphonate), and all other variables are as defined in relation to formula (IA), with a compound of formula (IXA), H—N(R 11 )—R 9 -R 10 , wherein R 9 , R 10  and R 11  are as defined in formula (IIA); or 
       (d) when Y is N and Z is CR 3 , and R 3  is a group formula (IIA) wherein s is 0 and R 9  is a C 1 -C 5  alkylene group which may be optionally substituted as defined herein above with respect to formula (IA), reacting a compound of formula (VIIIA) as defined in (c) above with a compound of formula (XA) or (XIA) 
     
     
       
         
         
             
             
         
       
       wherein R 9′  is suitably defined such that saturation of the alkene or alkyne and combination with R 9′  gives a group of formula R 9  as defined in formula (IIA), optionally followed by a hydrogenation reaction; or 
       (e) when Y is N and Z is CR 3 , and R 3  is a group of formula (IIA) where s is 0, R 9  is (CH 2 ) 2  and R 10  is —NR 21 R 22 , reacting a compound of formula (VIIA) as defined in (c) above with a compound of formula (XIIA) 
     
     
       
         
         
             
             
         
       
       wherein L 4  is a leaving group (eg. trialkyltin, dialkylboron or zinc), followed by reaction with a compound of formula (XIIIA), HNR 21 R 22 , wherein R 21  and R 22  are as defined above; 
       (f) when Y is N and Z is CR 3 , and R 3  is a group of formula (IIA) where s is 0, R 9  is (CH 2 ) and R 10  is —NR 19 R 20 , reacting a compound of formula (VIIIA) as defined in (c) above with a compound of formula (XIIA) as defined in (e) above, followed by an oxidation reaction and then by reaction with a compound of formula (XIIIA) as defined in (e) above under reductive amination conditions; or 
       (g) when Y is N and Z is CR 3 , and R 3  is a group of formula (IIA) where s is 0, reacting a compound of formula (VIIIA) as defined in (c) above with a compound of formula (XIVA) 
     
     
       
         
         
             
             
         
       
       wherein R 9′  is suitably defined such that saturation of the alkene and combination with R 9′  gives a group of formula R 9  as defined in formula (IIA) and R 10  is as defined in formula (IIA), followed by removal of any protecting groups; or 
       (h) when Y is N and Z=CR 3 , and R 23  or R 24  represent tetrazolyl, reacting a compound of formula IIA 1  or IIA 2   
     
     
       
         
         
             
             
         
       
       with a compound of formula PN 3  wherein P is sodium, a trialkylsilyl, an alkyltin or ammonium gives a group of formula IIA 1  or IIA 2  wherein X 1 , R 9 , W, W′ are defined in IIA; or 
       (ii) when Y is N and Z=CR 3 , and R 23  or R 24  represent a group of formula (XVA) 
     
     
       
         
         
             
             
         
       
       reacting a compound of formula IIA 1  or IIA 2  wherein IIA 1  or IIA 2  are as defined in (h) above with hydroxylamine, followed by treatment with 1,1′-thiocarbonyldiimidazole and subsequent treatment with silica gives a group of formula (XVA) wherein J is S, alternatively reacting a compound of formula IIA 1  or IIA 2  wherein IIA 1  or IIA 2  are as defined in (h) above with hydroxylamine, followed by treatment with a chloroformate gives a group of formula (XVA) wherein J is O; or 
       (l) when Y is N and Z=CR 3 , and R 23  or R 24  represent a group of formula (XVIA) 
     
     
       
         
         
             
             
         
       
       reacting a compound of formula IIA 3  or IIA 4   
     
     
       
         
         
             
             
         
       
       with a source of phosgene followed by treatment with formyl hydrazine and subsequent treatment with base; or 
       (m) when Y is N and Z=CR 3 , and R 23  or R 24  represent a group of formula (XVIIA) 
     
     
       
         
         
             
             
         
       
       reacting a compound of formula IIA 3  or IIA 4  as defined above in (j) with ethyl chloroacetate, followed by reaction with (chlorosulfonyl)-carbamic acid, 1,1-dimethylethyl ester and subsequent treatment with acid and base gives the compound of formula (XVIIA); 
       (l) when Y is N, X is NHC(O) and m is 0, compounds of the formula (VIIIA) as defined above in (c) can be derived by reacting a compound of formula (XVIIIA) 
     
     
       
         
         
             
             
         
       
       with a suitable acid of formula (XIXA) 
     
     
       
         
         
             
             
         
       
       wherein L 3  is a leaving group (e.g. halogen, paratoluene sulphonate or methane sulphonate), and all other variables are as defined in relation to formula (IA); or 
       (m) when Y is N, X is C(O)NH and m is 0, compounds of the formula (VIIIA) as defined above in (c) can be derived by reacting a compound of formula (XXA) 
     
     
       
         
         
             
             
         
       
       with a suitable amine of formula (XIXA)
   H 2 N—(CR 5 R 6 )—R 2   (XXIA) 
 
       wherein L 3  is a leaving group (e.g. halogen, paratoluene sulphonate or methane sulphonate), and all other variables are as defined in relation to formula (IA); or 
       (n) when Y is N, X is C(O)NH and m is 0, compounds of the formula (VIIIA) as defined above in (c) can be derived by reacting a compound of formula (XXIIA) 
     
     
       
         
         
             
             
         
       
       with a suitable amine of formula (XXIA), wherein L 5  is a halogen (e.g. bromine or iodine) and all other variables are as defined in relation to formula (IA) with a suitable source of carbon monoxide and a suitable catalyst; 
       and optionally after (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m) or (n) carrying out one or more of the following:
 converting the compound obtained to a further compound of the invention 
 forming a pharmaceutically acceptable salt, prodrug or solvate of the compound.