Chemical Compounds

Abstract

The invention relates to a compound of formula (1) in which Q is —CO— or —C(R 4 )(R 5 )—, where R 4 is a hydrogen atom or C 1-4 alkyl and R 5 is a hydrogen atom or hydroxy group; and Ar is a 5- to 10-membered aromatic ring system where up to 4 ring atoms may be heteroatoms independently selected from nitrogen, oxygen and sulphur, the ring system being optionally substituted by one or more substituents as defined in the specification. It also relates to methods of preparing, pharmaceutical compositions containing and methods of using the compound of the formula (1), particularly in the modulation of autoimmune disease.

1 . A method of inhibiting the proliferation of T cells, comprising administering to a patient a therapeutically effective amount of a compound of formula (1) 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2  each independently represent a C 1-6 alkyl, C 3-6 alkenyl, C 3-6 cycloalkylC 1-3 alkyl or C 3-6 cycloalkyl; each of which is optionally substituted by 1 to 3 halogen atoms; 
 R 3  is a group —CON(R 10 )YR 11  or —SO 2 N(R 10 )YR 11 ; in which Y is O, S or NR 12 , R 12  being hydrogen or C 1-6 allyl; and R 10  and R 11  are independently C 1-6 allyl optionally substituted by halo, hydroxy, amino, C 1-6 alkylamino or di-(C 1-6 alkyl)amino; 
 Q is —CO— or —C(R 4 )(R 5 )—; in which R 4  is a hydrogen atom or C 1-4 alkyl and R 5  is a hydrogen atom or a hydroxy group; 
 Ar is a 5- to 10-membered aromatic ring system, in which up to 4 ring atoms are optionally heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulphur, and the ring system is optionally substituted by one or more substituents independently selected from the group consisting of C 1-4 alkyl optionally substituted by 1, 2 or 3 hydroxy groups, C 1-4 alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, C 1-4 alkoxyC 1-4 alkyl, C 1-4 alkylthio, C 1-4 alkoxycarbonyl, C 2-4 alkanoyl, oxo, thioxo, nitro, cyano, —N(R 6 )R 7 , —(CH 2 )pN(R 8 )R 9 , hydroxy, C 1-4 alkylsulphonyl, C 1-4 alkylsulphinyl, carbamoyl, C 1-4 alkylcarbamoyl, di-(C 1-4 alkyl)carbamoyl, carboxy, and a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulphur; 
 p is 1 to 4; 
 R 6  and R 7  each independently represent a hydrogen atom, C 1-4 alkanoyl or C 1-4 alkyl, or together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring; 
 R 8  and R 9  each independently represent a hydrogen atom, C 1-4 alkanoyl or C 1-4  alkyl, or together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . The method of  claim 1 , wherein R 2  is methyl or ethyl. 
     
     
         3 . The method of  claim 1 , wherein R 1  is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylpropyl, cyclopropylmethyl, trifluoromethyl 2,2,2-trifluoroethyl, 2-chloroethyl, 2-chloropropyl or 3,3,3-trifluoropropyl. 
     
     
         4 . The method of  claim 1 , wherein Q is —CO— or —CH 2 —. 
     
     
         5 . The method of  claim 1 , wherein R 10  is C 1-4 alkyl optionally substituted by hydroxy. 
     
     
         6 . The method of  claim 1 , wherein R 11  is C 1-4 alkyl optionally substituted by hydroxy. 
     
     
         7 . The method of  claim 1 , wherein Y is O. 
     
     
         8 . The method of  claim 1 , wherein R 3  is —CON(Me)OMe, —CON(Et)OMe, —CON(OEt)Me, —CON(Et)OEt, —CON(CH 2 CH 2 OH)OEt, —CON(CH 2 CH 2 OH)Me, —CON(OCH 2 CH 2 OH)Me, or —CON(OCH 2 CH 2 OH)Et. 
     
     
         9 . The method of  claim 1 , wherein Ar contains at least 1 ring nitrogen. 
     
     
         10 . The method of  claim 1 , wherein Ar contains at least 2 ring nitrogen. 
     
     
         11 . The method of  claim 1 , wherein Ar is selected from the group consisting of imidazolyl, pyrazolyl, pyrrolyl, isoxazolyl, phenyl, quinolyl, indolyl, benzimidazolyl, indazolyl, benztriazolyl, 2,3-dihydrothiazolyl, 2,3-dihydrobenzoxazolyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, imidazo[4,5-b]pyridyl, 2,3-dihydrothiazolo[5,4-b]pyridyl, 2,3-dihydropyrazinyl, 2,3-dihydrobenzothiazolyl and 2,3-dihydrobenzimidazolyl, each ring system being optionally substituted according to  claim 1 . 
     
     
         12 . The method of  claim 1 , wherein Ar is substituted by 1, 2 or 3 substituents independently selected from the group consisting of C 1-4 alkyl optionally substituted by 1 or 2 hydroxy groups, C 1-4 alkoxy, halogen, trihaloalkyl, C 1-4 alkylthio, C 1-4 alkoxycarbonyl, C 2-4 alkanoyl, oxo, thioxo, cyano, —NHR 7 , —(CH 2 )pN(R 8 )R 9  wherein p is 1 or 2, hydroxy, C 1-4 alkylsulphonyl, carbamoyl, C 1-4 alkylcarbamoyl, di-(C 1-4 alkyl)carbamoyl, carboxy, and a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulphur. 
     
     
         13 . A method of effecting immunosuppression, comprising administering to a patient a therapeutically effective amount of a compound of formula (1) 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2  each independently represent a C 1-6 alkyl, C 3-6 alkenyl, C 3-6 cycloalkylC 1-3 alkyl Our C 3-6 cycloalkyl; each of which is optionally substituted by 1 to 3 is halogen atoms; 
 R 3  is a group —CON(R 10 )YR 11  or —SO 2 N(R 10 )YR 11 ; in which Y is O S or NR 12 , R 12  being hydrogen or C 1-6 alkyl; and R 10  and R 11  are independently C 1-6 alkyl optionally substituted by halo, hydroxy, amino, C 1-6 alkylamino or di-(C 1-6 alkyl)amino; 
 Q is —CO— or —C(R 4 )(R 5 )—; in which R 4  is a hydrogen atom or C 1-4 alkyl and R 5  is a hydrogen atom or a hydroxy group; 
 Ar is a 5- to 10-membered aromatic ring system, in which up to 4 ring atoms are optionally heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulphur, and the ring system is optionally substituted by one or more substituents independently selected from the group consisting of C 1-4 alkyl optionally substituted by 1, 2 or 3 hydroxy groups, C 1-4 alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, C 1-4 alkoxyC 1-4 alkyl, C 1-4 alkylthio, C 1-4 alkoxycarbonyl, C 2-4 alkanoyl, oxo, thioxo, nitro, cyano, —N(R 6 )R 7 , —(CH 2 )pN(R 8 )R 9 , hydroxy, C 1-4 alkylsulphonyl, C 1-4 alkylsulphinyl, carbamoyl, C 1-4 alkylcarbamoyl, di-(C 1-4 alkyl)carbamoyl, carboxy, and a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulphur; 
 p is 1 to 4; 
 R 6  and R 7  each independently represent a hydrogen atom, C 1-4 alkanoyl or C 1-4 alkyl, or together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring; 
 R 8  and R 9  each independently represent a hydrogen atom, C 1-4 alkanoyl or C 1-4  alkyl, or together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         14 . The method of  claim 13 , wherein R 2  is methyl or ethyl. 
     
     
         15 . The method of  claim 13 , wherein R 1  is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylpropyl, cyclopropylmethyl, trifluoromethyl 2,2,2-trifluoroethyl, 2-chloroethyl, 2-chloropropyl or 3,3,3-trifluoropropyl. 
     
     
         16 . The method of  claim 13 , wherein Q is —CO— or —CH 2 —. 
     
     
         17 . The method of  claim 13 , wherein R 10  is C 1-4 alkyl optionally substituted by hydroxy. 
     
     
         18 . The method of  claim 13 , wherein R 11  is C 1-4 alkyl optionally substituted by hydroxy. 
     
     
         19 . The method of  claim 13 , wherein Y is O. 
     
     
         20 . The method of  claim 13 , wherein R 3  is —CON(Me)OMe, —CON(Et)OMe, —CON(OEt)Me, —CON(Et)OEt, —CON(CH 2 CH 2 OH)OEt, —CON(CH 2 CH 2 OH)Me, —CON(OCH 2 CH 2 OH)Me, or —CON(OCH 2 CH 2 OH)Et. 
     
     
         21 . The method of  claim 13 , wherein Ar contains at least 1 ring nitrogen. 
     
     
         22 . The method of  claim 13 , wherein Ar contains at least 2 ring nitrogen. 
     
     
         23 . The method of  claim 13 , wherein Ar is selected from the group consisting of imidazolyl, pyrazolyl, pyrrolyl, isoxazolyl, phenyl, quinolyl, indolyl, benzimidazolyl, indazolyl, benztriazolyl, 2,3-dihydrothiazolyl, 2,3-dihydrobenzoxazolyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, imidazo[4,5-b]pyridyl, 2,3-dihydrothiazolo[5,4-b]pyridyl, 2,3-dihydropyrazinyl, 2,3-dihydrobenzothiazolyl and 2,3-dihydrobenzimidazolyl, each ring system being optionally substituted according to  claim 13 . 
     
     
         24 . The method of  claim 13 , wherein Ar is substituted by 1, 2 or 3 substituents independently selected from the group consisting of C 1-4 alkyl optionally substituted by 1 or 2 hydroxy groups, C 1-4 alkoxy, halogen, trihaloalkyl, C 1-4 alkylthio, C 1-4 alkoxycarbonyl, C 2-4 alkanoyl, oxo, thioxo, cyano, —NHR 7 , —(CH 2 )pN(R 8 )R 9  wherein p is 1 or 2, hydroxy, C 1-4 alkylsulphonyl, carbamoyl, C 1-4 alkylcarbamoyl, di-(C 1-4 alkyl)carbamoyl, carboxy, and a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulphur. 
     
     
         25 . A method of treating or reducing the risk of a reversible obstructive airways disease in a patient suffering from, or at risk of, the disease, comprising administering to the patient a therapeutically effective amount of a compound of formula (1) 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2  each independently represent a C 1-6 alkyl, C 3-6 alkenyl, C 3-6 cycloalkylC 1-3 alkyl or C 3-6 cycloalkyl; each of which is optionally substituted by 1 to 3 halogen atoms; 
 R 3  is a group —CON(R 10 )YR 11  or —SO 2 N(R 10 )YR 11 ; in which Y is O, S or NR 12 , R 12  being hydrogen or C 1-6 alkyl; and R 10  and R 11  are independently C 1-6 alkyl optionally substituted by halo, hydroxy, amino, C 1-6 alkylamino or di-(C 1-6 alkyl)amino; 
 Q is —CO— or —C(R 4 )(R 5 )—; in which R 4  is a hydrogen atom or C 1-4 alkyl and R 5  is a hydrogen atom or a hydroxy group; 
 Ar is a 5- to 10-membered aromatic ring system, in which up to 4 ring atoms are optionally heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulphur, and the ring system is optionally substituted by one or more substituents independently selected from the group consisting of C 1-4 alkyl optionally substituted by 1, 2 or 3 hydroxy groups, C 1-4 alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, C 1-4 alkoxyC 1-4 alkyl, C 1-4 alkylthio, C 1-4 alkoxycarbonyl, C 2-4 alkanoyl, oxo, thioxo, nitro, cyano, —N(R 6 )R 7 , —(CH 2 )pN(R 8 )R 9 , hydroxy, C 1-4 alkylsulphonyl, C 1-4 alkylsulphinyl, carbamoyl, C 1-4 alkylcarbamoyl, di-(C 1-4 alkyl)carbamoyl, carboxy, and a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulphur; 
 p is 1 to 4; 
 R 6  and R 7  each independently represent a hydrogen atom, C 1-4 alkanoyl or C 1-4 alkyl, or together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring; 
 R 8  and R 9  each independently represent a hydrogen atom, C 1-4 alkanoyl or C 1-4  alkyl, or together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         26 . The method of  claim 25 , wherein the obstructive airways disease is chronic obstructive pulmonary disease (COPD). 
     
     
         27 . The method of  claim 25 , where in the obstructive airways disease is asthma. 
     
     
         28 . The method of  claim 25 , wherein R 2  is methyl or ethyl. 
     
     
         29 . The method of  claim 25 , wherein R 1  is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylpropyl, cyclopropylmethyl, trifluoromethyl 2,2,2-trifluoroethyl, 2-chloroethyl, 2-chloropropyl or 3,3,3-trifluoropropyl. 
     
     
         30 . The method of  claim 25 , wherein Q is —CO— or —CH 2 —. 
     
     
         31 . The method of  claim 25 , wherein R 10  is C 1-4 alkyl optionally substituted by hydroxy. 
     
     
         32 . The method of  claim 25 , wherein R 11  is C 1-4 alkyl optionally substituted by hydroxy. 
     
     
         33 . The method of  claim 25 , wherein Y is O. 
     
     
         34 . The method of  claim 25 , wherein R 3  is —CON(Me)OMe, —CON(Et)OMe, —CON(OEt)Me, —CON(Et)OEt, —CON(CH 2 CH 2 OH)OEt, —CON(CH 2 CH 2 OH)Me, —CON(OCH 2 CH 2 OH)Me, or —CON(OCH 2 CH 2 OH)Et. 
     
     
         35 . The method of  claim 25 , wherein Ar contains at least 1 ring nitrogen. 
     
     
         36 . The method of  claim 25 , wherein Ar contains at least 2 ring nitrogen. 
     
     
         37 . The method of  claim 25 , wherein Ar is selected from the group consisting of imidazolyl, pyrazolyl, pyrrolyl, isoxazolyl, phenyl, quinolyl, indolyl, benzimidazolyl, indazolyl, benztriazolyl, 2,3-dihydrothiazolyl, 2,3-dihydrobenzoxazolyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, imidazo[4,5-b]pyridyl, 2,3-dihydrothiazolo[5,4-b]pyridyl, 2,3-dihydropyrazinyl, 2,3-dihydrobenzothiazolyl and 2,3-dihydrobenzimidazolyl, each ring system being optionally substituted according to  claim 25 . 
     
     
         38 . The method of  claim 25 , wherein Ar is substituted by 1, 2 or 3 substituents independently selected from the group consisting of C 1-4 alkyl optionally substituted by 1 or 2 hydroxy groups, C 1-4 alkoxy, halogen, trihaloalkyl, C 1-4 alkylthio, C 1-4 alkoxycarbonyl, C 2-4 alkanoyl, oxo, thioxo, cyano, —NHR 7 , —(CH 2 )pN(R 8 )R 9  wherein p is 1 or 2, hydroxy, C 1-4 alkylsulphonyl, carbamoyl, C 1-4 alkylcarbamoyl, di-(C 1-4 alkyl)carbamoyl, carboxy, and a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulphur. 
     
     
         39 . A method of treating or reducing the risk of cancer in a patient suffering from, or at risk of, the cancer, comprising administering to a patient a therapeutically effective amount of a compound of formula (1) 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2  each independently represent a C 1-6 alkyl, C 3-6 alkenyl, C 3-6 cycloalkylC 1-3 alkyl or C 3-6 cycloalkyl; each of which is optionally substituted by 1 to 3 halogen atoms; 
 R 3  is a group —CON(R 10 )YR 11  or —SO 2 N(R 10 )YR 11 ; in which Y is O, S or NR 12 , R 12  being hydrogen or C 1-6 alkyl; and R 10  and R 11  are independently C 1-6 alkyl optionally substituted by halo, hydroxy, amino, C 1-6 alkylamino or di-(C 1-6 alkyl)amino; 
 Q is —CO— or —C(R 4 )(R 5 )—; in which R 4  is a hydrogen atom or C 1-4 alkyl and R 5  is a hydrogen atom or a hydroxy group; 
 Ar is a 5- to 10-membered aromatic ring system, in which up to 4 ring atoms are optionally heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulphur, and the ring system is optionally substituted by one or more substituents independently selected from the group consisting of C 1-4 alkyl optionally substituted by 1, 2 or 3 hydroxy groups, C 1-4 alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, C 1-4 alkoxyC 1-4 alkyl, C 1-4 alkylthio, C 1-4 alkoxycarbonyl, C 2-4 alkanoyl, oxo, thioxo, nitro, cyano, —N(R 6 )R 7 , —(CH 2 )pN(R 8 )R 9 , hydroxy, C 1-4 alkylsulphonyl, C 1-4 alkylsulphinyl, carbamoyl, C 1-4 alkylcarbamoyl, di-(C 1-4 alkyl)carbamoyl, carboxy, and a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulphur; 
 p is 1 to 4; 
 R 6  and R 7  each independently represent a hydrogen atom, C 1-4 alkanoyl or C 1-4 alkyl, or together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring; 
 R 8  and R 9  each independently represent a hydrogen atom, C 1-4 alkanoyl or C 1-4  alkyl, or together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         40 . The method of  claim 39 , wherein R 2  is methyl or ethyl. 
     
     
         41 . The method of  claim 39 , wherein R 2  is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylpropyl, cyclopropylmethyl, trifluoromethyl 2,2,2-trifluoroethyl, 2-chloroethyl, 2-chloropropyl or 3,3,3-trifluoropropyl. 
     
     
         42 . The method of  claim 39 , wherein Q is —CO— or —CH 2 —. 
     
     
         43 . The method of  claim 39 , wherein R 10  is C 1-4 alkyl optionally substituted by is hydroxy. 
     
     
         44 . The method of  claim 39 , wherein R 11  is C 1-4 alkyl optionally substituted by hydroxy. 
     
     
         45 . The method of  claim 39 , wherein Y is O. 
     
     
         46 . The method of  claim 39 , wherein R 3  is —CON(Me)OMe, —CON(Et)OMe, —CON(OEt)Me, —CON(Et)OEt, —CON(CH 2 CH 2 OH)OEt, —CON(CH 2 CH 2 OH)Me, —CON(OCH 2 CH 2 OH)Me, or —CON(OCH 2 CH 2 OH)Et. 
     
     
         47 . The method of  claim 39 , wherein Ar contains at least 1 ring nitrogen. 
     
     
         48 . The method of  claim 39 , wherein Ar contains at least 2 ring nitrogen. 
     
     
         49 . The method of  claim 39 , wherein Ar is selected from the group consisting of imidazolyl, pyrazolyl, pyrrolyl, isoxazolyl, phenyl, quinolyl, indolyl, benzimidazolyl, indazolyl, benztriazolyl, 2,3-dihydrothiazolyl, 2,3-dihydrobenzoxazolyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, imidazo[4,5-b]pyridyl, 2,3-dihydrothiazolo[5,4-b]pyridyl, 2,3-dihydropyrazinyl, 2,3-dihydrobenzothiazolyl and 2,3-dihydrobenzimidazolyl, each ring system being optionally substituted according to  claim 39 . 
     
     
         50 . The method of  claim 39 , wherein Ar is substituted by 1, 2 or 3 substituents independently selected from the group consisting of C 1-4 alkyl optionally substituted by 1 or 2 hydroxy groups, C 1-4 alkoxy, halogen, trihaloalkyl, C 1-4 alkylthio, C 1-4 alkoxycarbonyl, C 2-4 alkanoyl, oxo, thioxo, chicano, —NHR 7 , —(CH 2 )pN(R 8 )R 9  wherein p is 1 or 2, hydroxy, C 1-4 alkylsulphonyl, carbamoyl, C 1-4 alkylcarbamoyl, di-(C 1-4 alkyl)carbamoyl, carboxy, and a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulphur.