Thrombin inhibitors

Patent metadata

Field	Value
Publication number	US-9469608-B2
Application number	US-201314443470-A
Country	US
Kind code	B2
Filing date	Nov 15, 2013
Priority date	Nov 20, 2012
Publication date	Oct 18, 2016
Grant date	Oct 18, 2016

Abstract

Compounds of the invention, which may be useful in inhibiting thrombin and associated thrombotic occlusions, have the following structure:

or a pharmaceutically acceptable salt thereof, wherein
m is 0 or 1; R is a heterocycle, —(CR 8 R 9 ) 1-2 NH 2 , or —(CR 8 R 9 ) 1-2 OH, wherein R 8 and R 9 , each time in which they occur, are independently H, C 1-6 alkyl, —CH 2 F, —CHF 2 , CF 3 or —CH 2 OH; W is a) —CHR 1 R 2 , where R 1 is —C(CH 3 ) 3 , and R 2 is —(CH 2 ) 1-2 OH, b) a 5- or 6-membered unsubstituted or substituted heterocycle having 1 or 2 heteroatoms selected from N and O, wherein substituted heterocycle is substituted with R 3 , c) a 9- or 10-membered unsubstituted or substituted heterocycle having 1 or 2 heteroatoms selected from N, O and S, wherein substituted heterocycle is mono-substituted with R 3 , or disubstituted with R 3 and R 4 ,

or
d) a 3-, 4-, or 5-membered carbocyclic ring which is unsubstituted, mono-substituted with R 3 , di-substituted with R 3 and R 4 , or tri-substituted with R 3 , R 4 and R 5 ; R 3 is —CF 3 , —COOH, —COOR 7 , —C(O)R 6 , —CH(OH)R 6 , —CH 2 R 6 , R 6 , ═O, halogen, R 7 , —OH, —NH 2 , or —NHSO 2 R 7 ; and R 10 is H or C 1-6 alkyl.

First claim

What is claimed is:

1. A compound of the formula I

or a pharmaceutically acceptable salt thereof, wherein
m is 0 or 1;
R is a heterocycle, —(CR 8 R 9 ) 1-2 NH 2 , or —(CR 8 R 9 ) 1-2 OH, wherein R 8 and R 9 , each time in which they occur, are independently H, C 1-6 alkyl, —CH 2 F, —CHF 2 , CF 3 or —CH 2 OH;
W is
a) —CHR 1 R 2 , where R 1 is —C(CH 3 ) 3 , and R 2 is —(CH 2 ) 1-2 OH,
b) a 5- or 6-membered unsubstituted or substituted heterocycle having 1or 2 heteroatoms selected from N and O, wherein substituted heterocycle is substituted with R 3 ,
c) a 9- or 10-membered unsubstituted or substituted heterocycle having 1or 2 heteroatoms selected from N, O and S, wherein substituted heterocycle is mono-substituted with R 3 , or disubstituted with R 3 and R 4 ,
or
d) a 3-, 4-, or 5-membered carbocyclic ring which is unsubstituted, mono-substituted with R 3 , di-substituted with R 3 and R 4 , or tri-substituted with R 3 , R 4 and R 5 ;
R 3 is —CF 3 , —COOH, —COOR 7 , —C(O)R 6 , —CH(OH)R 6 , —CH 2 R 6 , R 6 , ═O, halogen, R 7 , —OH, —NH 2 , or —NHSO 2 R 7 ;
R 4 is —OH, ═O, or C 1-6 alkyl;
R 5 is C 1-6 alkyl;
R 6 is

R 7 is C 1-6 alkyl;
R 10 is H or C 1-6 alkyl.

2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R is —CH 2 NH 2 , —CH 2 OH or tetrazole.

3. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R is —CH 2 NH 2 or tetrazole.

4. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is —CH(C(CH 3 ) 3 )CH 2 CH 2 OH, or —CH(C(CH 3 ) 3 )CH 2 OH.

5. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is

6. A compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein W is

7. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is —CF 3 , COOH, —COOCH 2 CH 3 , Cl, OH, NH 2 , NHSO 2 CH 3 ,

8. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is CH 3 .

9. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is CH 3 .

10. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is CH 3 .

11. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 10 is H.

12. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 10 is CH 3 .

13. A compound of claim 1 , or pharmaceutically acceptable salt thereof, which is
(S)—N-[2-(Aminomethyl)-5-chlorobenzyl]-1-[(R)-2-(2-hydroxyethyl)-3,3-dimethylbutanoyl]pyrrolidine-2-carboxamide-2,2,2-trifluoroacetate,
(S)—N-[2-(Aminomethyl)-5-chlorobenzyl]-1-[4-(trifluoromethyl)-1H-pyrrole-2-carbonyl]pyrrolidine-2-carboxamide-2,2,2-trifluoroacetate,
(S)-Ethyl-5-[2-{(2-(aminomethyl)-5-chlorobenzyl)carbamoyl}pyrrolidine-1-carbonyl]-1H-pyrrole-2-carboxylate-2,2,2-trifluoroacetate,
(S)—N-{2-(Aminomethyl)-5-chlorobenzyl}-1-{5-(trifluoromethyl)-1H-pyrrole-2-carbonyl}pyrrolidine-2-carboxamide,
(S)—N-{2-(Aminomethyl)-5-chlorobenzyl}-1-(4-nicotinoyl-1H-pyrrole-2-carbonyl)pyrrolidine-2-carboxamide-bis(2,2,2-trifluoro acetate),
(2S)-N-{2-(Aminomethyl)-5-chlorobenzyl}-1-[4-{hydroxyl (pyridine-4-yl)methyl}-1H-pyrrole-2-carbonyl]pyrrolidine-2-carboxamide-bis(2,2,2-trifluoroacetate),
(S)—N-{2-(Aminomethyl)-5-chlorobenzyl}-1-{4-(pyridin-4-ylmethyl)-1H-pyrrole-4-carbonyl}pyrrolidine-2-carboxamide-bis(2,2,2-trifluoroacetate),
(S)—N-{2-(aminomethyl)-5-chlorobenzyl}-1-(4-nicotinoyl-1H-pyrrole-2-carbonyl)pyrrolidine-2-carboxamide-bis(2,2,2-trifluoro acetate,
(2S)-N-{2-(Aminomethyl)-5-chlorobenzyl}-1-[4-{hydroxy (pyridine-3-yl }methyl]-1H-pyrrole-2-carbonyl)pyrrolidine-2-carboxamide,
(S)—N-{2-(Aminomethyl)-5-chlorobenzyl}-1-(4-picolinoyl-1H-pyrrole-2-carbonyl)pyrrolidine-2-carboxamide-bis(2,2,2-trifluoro acetate,
(2S)-N-{2-(Aminomethyl)-5-chlorobenzyl}-1-[4-{hydroxyl(pyridine-2-yl)methyl}-1H-pyrrole-2-carbonyl]pyrrolidine-2-carboxamide,
(S)—N-{2-(Aminomethyl)-5-chlorobenzyl}-1-{4-(pyridin-2-ylmethyl)-1H-pyrrole-2-carbonyl}pyrrolidine-2-carboxamide-bis(2,2,2-trifluoroacetate),
(S)—N-{2-(Aminomethyl)-5-chlorobenzyl)-1-}4-(pyridin-4-yl)-1H-pyrrole-2-carbonyl)pyrrolidine-2-carboxamide-bis(2,2,2-trifluoroacetate),
(S)—N-{2-(Aminomethyl)-5-chlorobenzyl}-1-{4-(pyridin-3-yl)-1H-pyrrole-2-carbonyl}pyrrolidine-2-carboxamide bis(2,2,2-trifluoroacetate),
(S)—N-[{2-(Aminomethyl)-5-chlorobenzyl}-1-{4-(pyridin-2-yl)-1H-pyrrole-2-carbonyl}]pyrrolidine-2-carboxamide bis (2,2,2-trifluoroacetate),
(S)—N-{2-(aminomethyl)-5-chlorobenzyl}-1-{(S)-2-(hydroxymethyl)-3,3-dimethylbutanoyl}pyrrolidine-2-carboxamide-2,2,2-trifluoroacetate,
(S)—N-{5-Chloro-2-(hydroxymethyl)benzyl}-1-{(R)-2-hydroxy-3,3-dimethyl butanoyl}pyrrolidine-2-carboxamide,
(S)—N-}2-(Aminomethyl)-5-chlorobenzyl}-1-(6-oxo-1,6-dihydropyridine-2-carbonyl)pyrrolidine-2-carboxamide-2,2,2-trifluoroacetate,
(2S)-N-{2-(Aminomethyl)-5-chlorobenzyl}-1-(5-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carbonyl)pyrrolidine-2-carboxamide-2,2,2-trifluoroacetate,
(2S)-N-(2-(Aminomethyl)-5-chlorobenzyl)-1-(7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonyl)pyrrolidine-2-carboxamide-bis(2,2,2-trifluoro acetate),
(2S)-N-{2-(Aminomethyl)-5chlorobenzyl}-1-(1,3-dihydroisobenzofuran-1-carbonyl)pyrrolidine-2-carboxamide-2,2,2-trifluoroacetate,
(2S)-N-{2-(Aminomethyl)-5chlorobenzyl}-1-(2,2-dioxido-1,3-dihydrobenzo[a]thiophene-1-carbonyl)pyrrolidine-2-carboxamide-2,2,2-trifluoroacetate-2,2,2-trifluoroacetate,
(2S)-N-{2-(Aminomethyl)-5-chlorobenzyl}-1-(isoindoline-1-carbonyl)pyrrolidine-2-carboxamide bis(2,2,2-trifluoroacetate),
(2S)-N-{2-(Aminomethyl)-5-chlorobenzyl}-1-(isoindoline-1-carbonyl)pyrrolidine-2-carboxamide bis(2,2,2-trifluoroacetate) Isomer A,
(2S)-N-{2-(Aminomethyl)-5-chlorobenzyl}-1-(isoindoline-1-carbonyl)pyrrolidine-2-carboxamide bis(2,2,2-trifluoroacetate) Isomer B,
(2S)-N-{2-(Aminomethyl)-5-chlorobenzyl}-1-(2,3-dihydrobenzofuran-3-carbonyl)pyrrolidine-2-carboxamide-2,2,2-trifluoroacetate,
(2S)-N-{2-(Aminomethyl)-5-chlorobenzyl}-1-(indoline-3-carbonyl)pyrrolidine-2-carboxamide bis(2,2,2-trifluoroacetate),
(2S)-N-}2-(Aminomethyl)-5-chlorobenzyl}-1-(5-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carbonyl}azetidine-2-carboxamide bis(2,2,2-trifluoroacetate),
{(2S)-N-2-(Aminomethyl)-5-chlorobenzyl}-1-(5-hydroxy-6,7-dihydro-5H-cyclopenta[c]pyridine-5-carbonyl)pyrrolidine-2-carboxamide bis(2,2,2-trifluoroacetate),
(2S)-N-{2-(aminomethyl)-5-chlorobenzyl}-1-(7-hydroxy-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carbonyl)pyrrolidine-2-carboxamide bis (2,2,2-trifluoroacetate),
(2S)-1-(7-Amino-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonyl)-N-(2-(aminomethyl)-5-chlorobenzyl)pyrrolidine-2-carboxamide tris(2,2,2-trifluoroacetate),
(2S)-1-(7-Amino-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonyl)-N-(2-(aminomethyl)-5-chlorobenzyl)pyrrolidine-2-carboxamide tris(2,2,2-trifluoroacetate) Isomer A,
(2S)-1-(7-Amino-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonyl

Assignees

• Merck Sharp & Dohme

Inventors

• Chobanian Harry
• Biftu Tesfaye
• Pio Barbara
• Wu Zhicai

Classifications

• C07D417/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D409/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D207/34

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms · CPC title

• C07D403/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title