Factor Xa inhibitors
The invention is concerned with novel heteroaryl fused cyclic amines of formula (I) wherein A, X 1 to X 3 , Y 1 to Y 3 , Z, R 1 , R 2 , m and n are as defined in the description and in the claims, as well as physiologically acceptable salts thereof. These compounds inhibit coagulation factor Xa and can be used as medicaments.
1. A compound of formula 1 d:
or pharmaceutically acceptable salt thereof wherein:
R 1 and R 2 are independently selected from the group consisting of:
(1) hydrogen,
(2) C 1-6 alkyl,
(3) C 1-6 alkoxy,
(4) fluoro C 1-6 alkoxy,
(5) hydroxy C 1-6 alkoxy,
(6) C 1-6 alkoxy C 1-6 alkoxy,
(7) mono or di C 1-6 alkyl substituted amino C 1-6 alkoxy,
(8) halogen,
(9) cyano,
(10) nitro,
(11) —N(R′)—CO—(C 1-6 alkyl optionally substituted by one or more fluorine atoms) wherein R′ is hydrogen, C 1-6 alkyl or fluoro C 1-6 alkyl,
(12) —N(R′)—CO—O—(C 1-6 alkyl optionally substituted by one or more fluorine atoms) wherein R′ is hydrogen, C 1-6 alkyl or fluoro C 1-6 alkyl,
(13) —N(R′)—CO—N(R″) (R′″) wherein R′, R″ and R′″ are independently hydrogen, C 1-6 alkyl or fluoro C 1-6 alkyl,
(14) —N(R′)—SO 2 —(C 1-6 alkyl optionally substituted by one or more fluorine atoms) wherein R′ is hydrogen, C 1-6 alkyl or fluoro C 1-6 alkyl; and
(15) —SO 2 —N(R′)(R″), —C(O)—N(R′)(R″) or —N(R′)(R″) wherein R′ and R″ are independently selected from the group consisting of hydrogen, C 1-6 alkyl and fluoro C 1-6 alkyl, or alternatively, R′ and R″, together with the nitrogen atom to which they are attached, form a heterocycyl;
X 1 is —C(O)—NH— or —C(O)—;
—X 2 —X 3 forms phenyl or pyridyl, wherein said phenyl or pyridyl is optionally substituted by one or more halogen atoms;
Y 1 is —C(O)—NH—;
Y 2 is 1,4-phenylene optionally substituted by one or more halogen atoms;
Y 3 is hydrogen, aryl, heteroaryl or heterocyclyl, wherein one or two carbon atoms of the aryl, heteroaryl or heterocyclyl may be optionally replaced with a carbonyl group and wherein the aryl, heteroaryl or heterocyclyl may be optionally substituted by one or more substituents indepenently selected from the group consisting of:
(1) C 1-6 alkyl,
(2) C 1-6 alkoxy,
(3) halogen,
(4) cyano,
(5) nitro,
(6) amino,
(7) mono-C 1-6 alkyl substituted amino,
(8) di-C 1-6 alkyl substituted amino
(9) mono-C 1-6 alkyl substituted amino-C 1-6 alkyl,
(10) di-C 1-6 alkyl substituted amino-C 1-6 alkyl,
(11) —SO 2 —C 1-6 alkyl,
(12) —SO 2 —NH 2 ,
(13) —SO 2 —NH—C 1-6 alkyl and
(14) —SO 2 —N(C 1-6 alkyl) 2 .
2. A compound according to claim 1 , wherein X 1 is —C(O)—NH—.
3. A compound according to claim 1 , wherein X 1 is —C(O)—.
4. A compound according to claim 1 , wherein —X 2 —X 3 forms phenyl, wherein said phenyl is optionally substituted by one or more halogen atoms.
5. A compound according to claim 1 , wherein —X 2 —X 3 forms pyridyl, wherein said pyridyl is optionally substituted by one or more halogen atoms.
6. A compound according to claim 1 , wherein —X 2 —X 3 forms 4-chlorophenyl or 5-chloropyridyn-2-yl.
7. A compound according to claim 1 , wherein Y 2 is 2-fluoro-1,4 phenylene.
8. A compound according to claim 1 , wherein Y 3 is heteroaryl optionally substituted by one or more substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, halogen, cyano, nitro, amino, mono-C 1-6 alkyl substituted amino, di-C 1-6 alkyl substituted amino, mono-C 1-6 alkyl substituted amino-C 1-6 alkyl, di-C 1-6 alkyl substituted amino-C 1-6 alkyl, —SO 2 —C 1-6 alkyl, —SO 2 —NH 2 , —SO 2 —NH—C 1-6 alkyl and —SO 2 —N(C 1-6 alkyl) 2 , wherein one or two carbon atoms of said heteroaryl are optionally replaced with a carbonyl group.
9. A compound according to claim 1 , wherein Y 3 is 2-oxo-2H-pyridyn-1-yl.
10. A compound according to claim 1 , wherein one of R 1 and R 2 is hydrogen, and the other is C 1-6 alkyl.
11. A compound according to claim 1 , wherein one of R 1 and R 2 is hydrogen, and the other is C 1-6 alkyl at the 1 position of the pyrrolopyrazole ring.
12. A compound according to claim 1 , wherein one of R 1 and R 2 is hydrogen, and the other is methyl at the 1 position of the pyrrolopyrazole ring.
13. A compound according to claim 1 , selected from the group consisting of:
(R)-1-Methyl-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-4,5-dicarboxylic acid 5-[(4-chloro-phenyl)-amide]4-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},
(R)-1-Methyl-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-4,5-dicarboxylic acid 5-[(4-chloro-phenyl)-amide]4-{[4-(2-oxo-2H-pyrazin-1-yl)-phenyl]-amide},
(R)-1-Methyl-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-4,5-dicarboxylic acid 5-[(4-chloro-phenyl)-amide]4-{[2-fluoro-4-(2-oxo-2H-pyrazin-1-yl)-phenyl]-amide},
(R)-1-Methyl-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-4,5-dicarboxylic acid 5-[(4-chloro-phenyl)-amide]4-{[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide} and
(R)-1-Methyl-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-4,5-dicarboxylic acid 5-[(4-chloro-phenyl)-amide]4-{[2,6-difluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.
14. A compound according to claim 1 , wherein Y 2 is 1,4-phenylene optionally substituted by one or more halogen atoms.
15. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutically acceptable excipient.
16. A compound according to claim 1 , selected from the group consisting of:
(R)-1-Methyl-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-4,5-dicarboxylic acid 5-[(4-chloro-phenyl)-amide]-4-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};
(R)-1-Methyl-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-4,5-dicarboxylic acid 4-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}5-[(4-methoxy-phenyl)-amide];
(R)-1-Methyl-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-4,5-dicarboxylic acid 5-[(5-chloro-pyridin-2-yl)-amide]4-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};
and any pharmaceutically acceptable salt thereof.
17. A compound according to claim 1 , selected from the group consisting of:
(R)-5-(1H-Indole-6-carbonyl)-1-methyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazole-4-carboxylic acid [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide;
(S)-1-Methyl-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-4,5-dicarboxylic acid 5-[(4-chloro-phenyl)-amide]4-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};
1-Methyl-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-4,5-dicarboxylic acid 5-[(4-chloro-phenyl)-amide]4-{[4-(2-oxo-2H-pyrazin-1-yl)-phenyl]-amide};
and any pharmaceutically acceptable salt thereof.
18. A compound according to claim 1 , selected from the group consisting of:
1-Methyl-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-4,5-dicarboxylic acid 5-[(4-chloro-phenyl)-amide]4-{[2-fluoro-4-(2-oxo-2H-pyrazin-1-yl)-phenyl]-amide};
(R)-1-Methyl-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-4,5-dicarboxylic acid 5-[(4-chloro-phenyl)-amide]4-{[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenyl]-amide};
(R)-1-Methyl-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-4,5-dicarboxylic acid 5-[(4-chloro-phenyl)-amide]4-{[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};
and any pharmaceutically acceptable salt thereof.
19. A compound according to claim 1 , selected from the group consisting of:
(R)-1-Methyl-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-4,5-dicarboxylic acid 5-[(3-fluoro-4-methoxy-phenyl)-amide]4-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};
(R)-1-Methyl-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-4,5-dicarboxylic acid 5-[(4-chloro-phenyl)-amide]5-{[2,6-difluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};
(R)-1-Methyl-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-4,5-dicarboxylic acid 5-[(5-chloro-pyridin-2-yl)-amide]4-{[2-fluoro-4-(2-oxo-2H-pyrazin-1-yl)-phenyl]-amide};
and any pharmaceutically acceptable salt thereof.
20. A compound according to claim 1 , selected from the group consisting of:
(R)-1-Methyl-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-4,5-dicarboxylic acid 4-{[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenyl]-amide}5-[(4-methoxy-phenyl)-amide];
(R)-1-Methyl-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-4,5-dicarboxylic acid 5-[(5-chloro-pyridin-2-yl)-amide]4-{[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenyl]-amide}; and
(R)-1-Methyl-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-4,5-dicarboxylic acid 5-[(3-fluoro-4-methoxy-phenyl)-amide]4-{[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenyl]-amide};
and any pharmaceutically acceptable salt thereof.