Chemical compounds

Abstract

This invention relates to novel compounds having the formula (I): and to their pharmaceutical compositions and to their methods of use. These novel compounds provide a treatment for cancer.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 2  are independently selected from hydrogen, halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkanoyloxy, N—(C 1-6 alkyl)amino, N,N—(C 1-6 alkyl) 2 amino, C 1-6 alkanoylamino, N—(C 1-6 alkyl)carbamoyl, N,N—(C 1-6 alkyl) 2 carbamoyl, C 1-6 alkylS(O) a  wherein a is 0 to 2, C 1-6 alkoxycarbonyl, N—(C 1-6 alkyl)sulphamoyl, N,N—(C 1-6 alkyl) 2 sulphamoyl, C 1-6 alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R 1  and R 2  independently of each other may be optionally substituted on carbon by one or more R 8 ; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R 9 ; 
 X 1 , X 2  and X 3  are independently ═N— or ═CR 10 —; 
 R 3  and R 10  are independently selected from hydrogen, halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkanoyloxy, N—(C 1-6 alkyl)amino, N,N—(C 1-6 alkyl) 2 amino, C 1-6 alkanoylamino, N—(C 1-6 alkyl)carbamoyl, N,N—(C 1-6 alkyl) 2 carbamoyl, C 1-6 alkylS(O) a  wherein a is 0 to 2, C 1-6 alkoxycarbonyl, N—(C 1-6 alkyl)sulphamoyl, N,N—(C 1-6 alkyl) 2 sulphamoyl, C 1-6 alkylsulphonylamino, carbocyclyl-R 11 — or heterocyclyl-R 12 —; wherein R 3  and R 10  independently of each other may be optionally substituted on carbon by one or more R 13 ; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R 14 ; 
 R 4  is hydrogen or optionally substituted C 1-6 alkyl; wherein said optional substituents are selected from one or more R 15 ; 
 R 5  and R 6  are independently selected from hydrogen, halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkanoyloxy, N—(C 1-6 alkyl)amino, N,N—(C 1-6 alkyl) 2 amino, C 1-6 alkanoylamino, N—(C 1-6 alkyl)carbamoyl, N,N—(C 1-6 alkyl) 2 carbamoyl, C 1-6 alkylS(O) a  wherein a is 0 to 2, C 1-6 alkoxycarbonyl, N—(C 1-6 alkyl)sulphamoyl, N,N—(C 1-6 alkyl) 2 sulphamoyl, C 1-6 alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R 5  and R 6  independently of each other may be optionally substituted on carbon by one or more R 16 ; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R 17 ; 
 A is a direct bond or C 1-2 alkylene; wherein said C 1-2 alkylene may be optionally substituted by one or more R 18 ; 
 Ring C is carbocyclyl or heterocyclyl; wherein if said heterocyclyl contains an —NH-moiety that nitrogen may be optionally substituted by a group selected from R 19 ; 
 R 7  is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkanoyloxy, N—(C 1-6 alkyl)amino, N,N—(C 1-6 alkyl) 2 amino, C 1-6 alkanoylamino, N—(C 1-6 alkyl)carbamoyl, N,N—(C 1-6 alkyl) 2 carbamoyl, C 1-6 alkylS(O) a  wherein a is 0 to 2, C 1-6 alkoxycarbonyl, N—(C 1-6 alkyl)sulphamoyl, N,N—(C 1-6 alkyl) 2 sulphamoyl, C 1-6 alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R 7  may be optionally substituted on carbon by one or more R 20 ; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R 21 ; 
 n is 0, 1, 2 or 3; wherein the values of R 7  may be the same or different; 
 R 8 , R 13 , R 15 , R 16 , R 18  and R 20  and are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 1-6 alkyl, C 1-2-6 alkenyl, C 1-2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkanoyloxy, N—(C 1-6 alkyl)amino, N,N—(C 1-6 alkyl) 2 amino, C 1-6 alkanoylamino, N—(C 1-6 alkyl)carbamoyl, N,N—(C 1-6 alkyl) 2 carbamoyl, C 1-6 alkylS(O) a  wherein a is 0 to 2, C 1-6 alkoxycarbonyl, N—(C 1-6 alkyl)sulphamoyl, N,N—(C 1-6 alkyl) 2 sulphamoyl, C 1-6 alkylsulphonylamino, carbocyclyl-R 22 — or heterocyclyl-R 23 —; wherein R 8 , R 13 , R 15 , R 16 , R 18  and R 20  independently of each other may be optionally substituted on carbon by one or more R 24 ; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R 25 ; 
 R 9 , R 14 , R 17 , R 19 , R 21  and R 25  are independently selected from C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkylsulphonyl, C 1-6 alkoxycarbonyl, carbamoyl, N—(C 1-6 alkyl)carbamoyl, N,N—(C 1-6 alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; wherein R 9 , R 14 , R 17 , R 19 , R 21  and R 25  independently of each other may be optionally substituted on carbon by on or more R 26 ; 
 R 24  and R 26  are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkanoyloxy, N—(C 1-6 alkyl)amino, N,N—(C 1-6 alkyl) 2 amino, C 1-6 alkanoylamino, N—(C 1-6 alkyl)carbamoyl, N,N—(C 1-6 alkyl) 2 carbamoyl, C 1-6 alkylS(O) a  wherein a is 0 to 2, C 1-6 alkoxycarbonyl, N—(C 1-6 alkyl)sulphamoyl, N,N—(C 1-6 alkyl) 2 sulphamoyl, C 1-6 alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R 24  and R 26  independently of each other may be optionally substituted on carbon by one or more R 27 ; and wherein if said heterocyclyl contains an —NH-moiety that nitrogen may be optionally substituted by a group selected from R 28 ; 
 R 11 , R 12 , R 22  and R 23  are independently selected from a direct bond, —O—, —N(R 29 )—, —C(O)—, —N(R 30 )C(O)—, —C(O)N(R 31 )—, —S(O) s —, —SO 2 N(R 32 )— or —N(R 33 )SO 2 —; wherein R 29 , R 30 , R 31 , R 32  and R 33  are independently selected from hydrogen or C 1-6 alkyl and s is 0-2; 
 R 27  is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl or N-methyl-N-ethylsulphamoyl; and 
 R 28  is selected from C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkylsulphonyl, C 1-6 alkoxycarbonyl, carbamoyl, N—(C 1-6 alkyl)carbamoyl, N,N—(C 1-6 alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in  claim 1  wherein R 1  is selected from C 1-6 alkyl, C 1-6 alkoxy and carbocyclyl. 
     
     
         3 . A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in  claim 1  wherein R 2  is hydrogen. 
     
     
         4 . A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in  claim 1  wherein R 3  is selected from hydrogen, cyano, carbamoyl, C 1-6 alkyl and C 1-6 alkoxycarbonyl; wherein R 3  may be optionally substituted on carbon by one or more R 13 ; and R 13  is hydroxy. 
     
     
         5 . A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in  claim 1  wherein R 4  is hydrogen. 
     
     
         6 . A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in  claim 1  wherein R 5  and R 6  are independently selected from hydrogen or C 1-6 alkyl; wherein R 5  and R 6  independently of each other may be optionally substituted on carbon by one or more R 16 ; wherein R 16  is hydroxy. 
     
     
         7 . A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in  claim 1  wherein A is a direct bond or C 1-2 alkylene; wherein said C 1-2 alkylene may be optionally substituted by one or more R 18 ; wherein R 18  is hydroxy. 
     
     
         8 . A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in  claim 1  wherein Ring C is phenyl, pyridyl, 1,3-benzodioxolyl or 1H-indolyl. 
     
     
         9 . A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in  claim 1  wherein R 7  is selected from halo and C 1-6 alkyl; wherein R 7  may be optionally substituted on carbon by one or more R 20 ; wherein R 20  is halo. 
     
     
         10 . A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in  claim 1  wherein n is 0, 1 or 2; wherein the values of R 7  may be the same or different. 
     
     
         11 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is selected from methyl, isopropoxy and cyclopropyl; 
 R 2  is hydrogen; 
 X 1 , X 2  and X 3  are independently ═N— or ═CR 10 —; 
 R 3  is selected from hydrogen, cyano, carbamoyl, methyl, hydroxymethyl and methoxycarbonyl; 
 R 10  is selected from hydrogen, fluoro, chloro, cyano, carbamoyl, methyl, aminomethyl and acetylaminomethyl; 
 R 4  is hydrogen; 
 R 5  is selected from hydrogen, methyl, ethyl or hydroxymethyl; 
 R 6  is selected from hydrogen or hydroxymethyl; 
 A is a direct bond, methylene or hydroxymethylene; 
 Ring C is phenyl, pyrid-2-yl, 1,3-benzodioxol-5-yl or 1H-indol-3-yl; 
 R 7  is trifluoromethyl and fluoro; and 
 n is 0, 1 or 2; wherein the values of R 7  may be the same or different; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         12 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         selected from: 
         (2R)-2-[9-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methyl-9H-purin-2-ylamino]-2-(4-fluorophenyl)ethanol; 
         (2R)-2-{[9-(5-cyclopropyl-1H-pyrazol-3-yl)-9H-purin-2-yl]amino}-2-(4-fluorophenyl)ethanol; 
         N—((S)-1-(4-fluorophenyl)ethyl)-9-(5-isopropoxy-1H-pyrazol-3-yl)-9H-purin-2-amine; 
         3-(5-cyclopropyl-1H-pyrazol-3-yl)-N—[(S)-1-(4-fluorophenyl)ethyl]-3H-imidazo[4,5-b]pyridin-5-amine; 
         3-(5-isopropoxy-1H-pyrazol-3-yl)-N—((S)-1-(pyridin-2-yl)ethyl)-3H-imidazo[4,5-b]pyridin-5-amine; 
         N—((S)-1-(4-fluorophenyl)ethyl)-3-(5-isopropoxy-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-5-amine; 
         (2R)-2-(4-fluorophenyl)-2-(3-(5-isopropoxy-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-5-ylamino)ethanol; 
         6-chloro-N—((S)-1-(4-fluorophenyl)ethyl)-3-(5-isopropoxy-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-5-amine; 
         3-(5-cyclopropyl-1H-pyrazol-3-yl)-N—[(S)-1-(4-fluorophenyl)ethyl]-3H-benzo[d]imidazol-5-amine; and 
         N-((1-(5-cyclopropyl-1H-pyrazol-3-yl)-6-((S)-1-(4-fluorophenyl)ethylamino)-1H-benzo[d]imidazol-5-yl)methyl)acetamide; 
         or a pharmaceutically acceptable salt thereof 
       
     
     
         13 . A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof which process, wherein variable groups are, unless otherwise specified, as defined in  claim 1 , wherein said process is selected from:
 Process a) reaction of a compound of formula (II):   
       
         
           
           
               
               
           
         
         wherein Pg is a nitrogen protecting group; with a compound of formula (III): 
       
       
         
           
           
               
               
           
         
         wherein L is a displaceable group; 
         Process b) for compounds of formula (I) wherein R 5  is hydroxymethyl and R 6  is hydrogen; 
         reaction of a compound of formula (II) with an epoxide of formula (IV): 
       
       
         
           
           
               
               
           
         
         Process c) for compounds of formula (I) wherein X 1  is ═CR 10 —; reacting a compound of formula (V): 
       
       
         
           
           
               
               
           
         
         with a compound of formula (VI): 
       
       
         
           
           
               
               
           
         
         Process d) for compounds of formula (I) wherein X 1  is ═N—; reacting a compound of formula (V) with aqueous NaNO 2  solution; 
         Process e) reacting a compound of formula (VII): 
       
       
         
           
           
               
               
           
         
         wherein L is a displaceable group and Pg is a nitrogen protecting group; with an amine of formula (VIII): 
       
       
         
           
           
               
               
           
         
         and thereafter if necessary: 
         i) converting a compound of the formula (I) into another compound of the formula (I); 
         ii) removing any protecting groups; 
         iii) forming a pharmaceutically acceptable salt. 
       
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . A method for the treatment or prophylaxis of cancer comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 . 
     
     
         20 . (canceled) 
     
     
         21 . A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , together with at least one pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . (canceled) 
     
     
         27 . (canceled) 
     
     
         28 . The method of use according to  claim 19  wherein said cancer is selected from congenital fibrosarcoma, mesoblastic nephroma, mesothelioma, acute myeloblastic leukemia, acute lymphocytic leukemia, multiple myeloma, melanoma, oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi sarcoma, ovarian cancer, breast cancer including secretory breast cancer, colorectal cancer, prostate cancer including hormone refractory prostate cancer, bladder cancer, melanoma, lung cancer—non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, renal cancer, lymphoma, thyroid cancer including papillary thyroid cancer, mesothelioma and leukaemia.