2,3-disubstituted 1-acyl-4-amino-1,2,3,4-tetrahydroquinoline derivatives and their use as bromodomain inhibitors

Abstract

The present invention relates to novel compounds, pharmaceutical compositions containing such compounds and to their use in therapy.

1 - 45 . (canceled) 
     
     
         46 . A method for the preparation of a compound of formula I comprising a step of reacting a compound of formula II with a compound of formula VIII: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is C 1-4 alkyl; 
 R 2  is C 1-4 alkyl, C 3-7 cycloalkyl, —CH 2 CF 3 , —CH 2 OCH 3  or heterocyclyl; 
 R 3  is C 1-4 alkyl, —CH 2 F, —CH 2 OH or —CH 2 OC(O)CH 3 ; 
 R 4  when present is H, hydroxy, halo, cyano, —CO 2 H, —CONH 2 , —OSO 2 CF 3 , —C(O)N(R 8 )C 1-4  alkyleneOH, —C(O)N(R 8 )C 1-4 alkyleneOCH 3 , —C(O)N(R 8 )C 1-4 alkyleneNR 6 R 7 , —C(O)N(R 8 )C 1-4 alkyleneSO 2 CH 3 , —C(O)N(R 8 )C 1-4 alkyleneCN, —C(O)NHOH, —C(O)NHCH(CH 2 OH) 2 , —OCH 2 CH 2 OH, —B—C 1-6 alkyl, —B—C 3-7 cycloalkyl, —B-phenyl, —B-heterocyclyl or —B-heteroaromatic, wherein the C 3-7 cycloalkyl, phenyl, heterocyclyl or heteroaromatic ring is optionally substituted by 1 or 2 substituents independently selected from ═O, C 1-6 alkyl, C 1-6 alkoxy, halo, —NH 2 , —CO 2 H, —C(O)C 1-6 alkyl, —C(O)NHC 1-6 alkyl, cyano, —CH 2 CH 2 NHCH 3 , —CH 2 CH 2 OH, —CH 2 CH 2 OCH 3 , C 3-7 cycloalkyl, phenyl, heterocyclyl and heteroaromatic; 
 R 5  when present is H, halo, hydroxy or C 1-6 alkoxy; 
 A is —NH—; 
 B is a bond, —O—, —N(R 8 )—, S, —SO—, —SO 2 —, —SO 2 N(R 8 )—, —CH 2 —, —C(O)—, —CO 2 —, —N(R 8 )C(O)—, —C(O)N(R 8 )—, —C(O)N(R 8 )CH 2 — or —C(O)N(R 8 )CH 2 CH 2 —; 
 V is phenyl, heteroaromatic or pyridone any of which may be optionally substituted by 1, 2 or 3 substituents independently selected from C 1-6 alkyl, fluorine, chlorine, C 1-6 alkoxy, hydroxy, cyclopropyl, cyano, —CO 2 CH 3 , heterocyclyl, —CO 2 H, —CH 2 NR 6 R 7 , —NR 6 R 7 , —C(O)NR 6 R 7 , —NR 6 C(O)R 7 , —CF 3 , —NO 2 , —CH 2 OCH 3 , —CH 2 OH, —CH(OH)CH 3 , —SO 2 CH 3 , —CH 2 heterocyclyl, —OCH 2 CH 2 NHC(O)CH 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 NH 2 , —C(O)NHheteroaromatic, —C(O)NHCH 2 heterocyclyl, —C(O)NHCH 2 CH 2 OH, —C(O)NHCH 2 CH 2 NH 2 , —C(O)NHCH 2 CH 2 SO 2 Me, —C(O)NHCH 2 CH(OH)CH 3 , —C(O)heterocyclyl and —C(O)NHheterocyclyl, wherein the heterocyclyl ring is optionally substituted by —OH; 
 R 6 , R 7 , R 8  are each independently selected from H and C 1-4 alkyl; 
 W is CH or N; 
 X is C or N; 
 Y is C or N; and 
 Z is CH or N; 
 Hal is fluorine, chlorine, bromine or iodine; 
 
         subject to the proviso that no more than 2 of W, X, Y and Z are N; and that the compound of formula (I) is not 1-(2-ethyl-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone or 1-(2-ethyl-3-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)propan-1-one. 
       
     
     
         47 . The method of  claim 46 , further comprising the step of preparing a compound of formula (II) comprising hydrogenation of a compound of formula (III) 
       
         
           
           
               
               
           
         
         wherein R 10  is selected from benzyl or t-butyl. 
       
     
     
         48 . The method of  claim 47 , further comprising the step of preparing a compound of formula (III), wherein R 3  is methyl and R 10  is benzyl, comprising reacting a compound of formula (IV) with a compound of formula (IX): 
       
         
           
           
               
               
           
         
       
     
     
         49 . The method of  claim 48 , wherein the reaction between the compound of formula IV and the compound of formula IX is carried out in the presence of a suitable base. 
     
     
         50 . The method of  claim 49 , wherein the suitable base is pyridine or DIPEA. 
     
     
         51 . The method of  claim 48 , further comprising the step of preparing a compound of formula IV comprising reacting a compound of formula V with a compound of formula VII and a compound of formula X: 
       
         
           
           
               
               
           
         
       
     
     
         52 . The method of  claim 51 , wherein the reaction is carried out in the presence of an acid catalyst. 
     
     
         53 . The method of  claim 52 , wherein the acid catalyst is (11bS)-2,6-bis(4-chlorophenyl)-4-hydroxy-8,9,10,11,12,13,14,15-octahydrodinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepine 4-oxide. 
     
     
         54 . The method of  claim 51 , further comprising the step of preparing a compound of formula V comprising oxidation of a compound of formula VI in the presence of an oxidising agent a phosphine ligand: 
       
         
           
           
               
               
           
         
       
     
     
         55 . The method of  claim 54 , wherein the oxidising agent is DIAD and the phosphine ligand is PPh 3 . 
     
     
         56 . The method of  claim 46 , wherein Hal is fluorine. 
     
     
         57 . The method of  claim 46 , wherein the compound of formula I is a racemic mixture of formula (Ia) 
       
         
           
           
               
               
           
         
       
     
     
         58 . The method of  claim 46 , wherein the compound of formula (I) is an enantiomer of formula (Iaa) 
       
         
           
           
               
               
           
         
       
     
     
         59 . The method of  claim 46 , wherein R 1  is methyl. 
     
     
         60 . The method of  claim 46 , wherein R 2  is cyclopropyl. 
     
     
         61 . The method of  claim 46 , wherein R 3  is methyl. 
     
     
         62 . The method of  claim 46 , wherein R 4  is fluoro, cyano, CO 2 H or —CONH 2 . 
     
     
         63 . The method of  claim 46 , wherein R 4  is —CONH 2 . 
     
     
         64 . The method of  claim 46 , wherein R 5  is H. 
     
     
         65 . The method of  claim 46 , wherein V is pyrimidinyl optionally substituted by 1 or 2 C 1-6 alkyl groups. 
     
     
         66 . The method of  claim 46 , wherein V is 
       
         
           
           
               
               
           
         
       
     
     
         67 . The method of  claim 46 , wherein W is CH; X is C; Y is C; and Z is CH. 
     
     
         68 . The method of  claim 46 , wherein the compound of formula (I) is (2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide. 
     
     
         69 . The method of  claim 51 , wherein R 4  is cyano. 
     
     
         70 . The method of  claim 51 , wherein R 2  is cyclopropyl. 
     
     
         71 . The method of  claim 47 , wherein R 10  is benzyl.