2,3-DISUBSTITUTED 1-ACYL-4-AMINO-1,2,3,4-TETRAHYDROQUINOLINE DERIVATIVES AND THEIR USE AS BROMODOMAIN INHIBITORS
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.