Bicyclic compounds and their uses as dual c-SRC / JAK inhibitors
The present invention relates to substituted aromatic bicyclic compounds containing pyrimidine and pyridine rings of formula (I) having the structure as well as pharmaceutically acceptable salts thereof. The compounds of the present invention are useful as tyrosine kinase inhibitors, preferably SRC family kinases (SFKs) inhibitors, in particular as multi SFK/JAK. kinases inhibitors and even preferably as dual c-SRC/JAK kinases inhibitors, thereby inhibiting the STAT3 activation and therefore abnormal growth of particular cell types. Notably, the compounds of the present invention are useful for the treatment or inhibition of certain diseases that are the result of deregulation of STAT3.
1. A compound of formula (I) having the structure
wherein
R1 is H, aryl, substituted aryl, alkyl, substituted alkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl or substituted heterocyclylalkyl;
X is CH 2 or C═O;
R2 is H, (C 1 -C 6 )alkyl, halogen, CF 3 , or —O—(C 1 -C 6 )alkyl;
Y is —NHCO—, —CONH—, —NHSO 2 − , —NH—, —NCH 3 —CO—, —NHCH 2 —, O, —NHCONH— or —NHCOCH 2 —;
R3 is alkyl, substituted alkyl, aryl, or substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl
or heterocycloalkyl;
or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 , of formula (II) having the structure
wherein
R1 is hydrogen, (C 1 -C 4 )alkyl, phenyl, substituted phenyl, pyridine, or substituted pyridine;
X is CH 2 or C═O;
R2 is H, (C 1 -C 6 )alkyl, halogen, or —O(C 1 -C 6 )alkyl;
R3 is (C 1 -C 6 )alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
and wherein the substituents are selected from the group consisting of C 1 -C 4 linear or branched alkyl; halo or nitrile substituted C 1 -C 4 alkyl; —O-alkyl(C 1 -C 4 ); and halogen;
or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 1 , wherein R3 is selected from the group consisting of:
4. The compound according to claim 1 , wherein
R1 is substituted phenyl or substituted pyridine;
X is CH 2 or C═O;
R2 is H, CH 3 , Cl or F;
R3 is selected from the group consisting of:
substituted phenyl, wherein the substituents are independently selected from the group consisting of Cl, F, Br, CF 3 and CH 3 .
5. The compound according to claim 1 , wherein
R1 is selected from the group consisting of:
and
R3 is selected from the group consisting of:
6. The compound according to claim 1 , selected from the group consisting of:
N-(4-Methyl-3-{2-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-7,8-dihydro-5H-pyrido[4,3-c]pyrimidin-6-yl}-phenyl)-3-trifluoromethyl-benzamide;
N-(4-Methyl-3-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-phenyl)-3-trifluoromethyl-benzamide;
5-{6-[2-Methyl-5-(3-trifluoromethyl-benzoylamino)-phenyl]-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-ylamino}-pyridine-2-carboxylic acid cyclopropylamide;
N-{3-[2-(4-Cyclopropylsulfamoyl-phenylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;
N-(4-Chloro-3-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-phenyl)-3-trifluoromethyl-benzamide;
4-Trifluoromethyl-pyridine-2-carboxylic acid {4-chloro-3-[2-(4-methylcarbamoyl-phenylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-phenyl}-amide;
4,4,4-Trifluoro-3-methyl-N-[4-methyl-3-(2-{4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenylamino}-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)-phenyl]-butyramide;
1-Cyclopentyl-3-(4-methyl-3-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-phenyl)-urea;
N-(4-Methyl-3-{5-oxo-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-phenyl)-3-trifluoromethyl-benzamide;
N-{4-Chloro-3-[2-(4-cyclopropylcarbamoylmethoxy-phenylamino)-5-oxo-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-phenyl}-3-trifluoromethyl-benzamide;
N-(4-Chloro-3-{2-[3-methyl-4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-phenyl)-3-trifluoromethyl-benzamide;
3-Bromo-N-(4-methyl-3-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-phenyl)-benzamide; and
N-(4-Chloro-3-{2-[4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-5-oxo-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-phenyl)-3-trifluoromethyl-benzamide;
or a pharmaceutically acceptable salt thereof.
7. The compound according to claim 1 , selected from the group consisting of:
N-(4-Methyl-3-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-phenyl)-3-trifluoromethyl-benzamide;
5-{6-[2-Methyl-5-(3-trifluoromethyl-benzoylamino)-phenyl]-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-ylamino}-pyridine-2-carboxylic acid cyclopropylamide; and
4-Trifluoromethyl-pyridine-2-carboxylic acid {4-chloro-3-[2-(4-methylcarbamoyl-phenylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-phenyl}-amide;
or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 1 , selected from the group consisting of:
N-(4-Chloro-3-{2-[3-methyl-4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-phenyl)-3-trifluoromethyl-benzamide; and
N-{4-Chloro-3-[2-(4-cyclopropylcarbamoylmethoxy-phenylamino)-5-oxo-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-phenyl}-3-trifluoromethyl-benzamide;
or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt according to claim 1 and at least one pharmaceutically acceptable excipient, carrier or diluent.