IP Library › Granted Patent US 9,469,608
Granted Patent B2
US 9,469,608 · App. 14/443,470 · Granted Oct 18, 2016

Thrombin inhibitors

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Quick Facts
Patent No.
US 9,469,608
App. No.
14/443,470
Granted
Oct 18, 2016
Kind
B2
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.

Claims (88)

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)-N-(2-(aminomethyl)-5-chlorobenzyl)pyrrolidine-2-carboxamide tris(2,2,2-trifluoroacetate) Isomer B,

(2S)-N-{2-(Aminomethyl)-5-chlorobenzyl}-1-(5-hydroxy-5,6,7,8-tetrahydroquinoline-5-carbonyl)pyrrolidine-2-carboxamide bis(2,2,2-trifluoroacetate),

(2S)-N-{2-(Aminomethyl)-5-chlorobenzyl}-1-(5-hydroxy-5,6,7,8-tetrahydroisoquinoline-5-carbonyl)pyrrolidine-2-carboxamide bis(2,2,2-trifluoroacetate),

(2S)-N-{2-(aminomethyl)-5-chlorobenzyl}-1-(8-hydroxy-5,6,7,8-tetrahydroquinoline-8-carbonyl)pyrrolidine-2-carboxamide bis(2,2,2-trifluoroacetate),

(2S)-N-{2-(Aminomethyl)-5-chlorobenzyl}-1-(1,3-dihydroisobenzofuran-1-carbonyl)azetidine-2-carboxamide-2,2,2-trifluoroacetate,

(2S)-N-{2-(aminomethyl)-5-chlorobenzyl}-1-(isoindoline-1-carbonyl)azetidine-2-carboxamide bis(2,2,2-trifluoroacetate),

(2S)-N-{2-(Aminomethyl)-5-chlorobenzyl}-1-(indoline-3-carbonyl)azetidine-2-carboxamide bis(2,2,2-trifluoroacetate),

(2S)-N-{5-chloro-2-(1H-tetrazol-1-yl)benzyl}-1-(7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonyl)pyrrolidine-2-carboxamide,

(S)—N-{2-(Aminomethyl)-5-chlorobenzyl}-1-{(R)-1-hydroxy-2,2-dimethylcyclopropanecarbonyl)pyrrolidine-2-carboxamide-2,2,2-trifluoroacetate,

(S)—N-{2-(Aminomethyl)-5-chlorobenzyl}-1-{(R)-1-hydroxy-2,2-dimethylcyclopropanecarbonyl)pyrrolidine-2-carboxamide-2,2,2-trifluoroacetate Isomer A,

(S)—N-12-(Aminomethyl)-5-chlorobenzyl}-1-{(R)-1-hydroxy-2,2-dimethylcyclopropanecarbonyl)pyrrolidine-2-carboxamide-2,2,2-trifluoroacetate Isomer B,

(S)—N-{2-(Aminomethyl)-5-chlorobenzyl}-1-{(R)-tetrahydrofuran-2-carbonyl}pyrrolidine-2-carboxamide-2,2,2-trifluoroacetate,

(S)—N-{2-(Aminomethyl)-5-chlorobenzyl}1-(5-ethoxy-1H-pyrrole-2-carbonyl)pyrrolidine-2-carboxamide-2,2,2-trifluoroacetate,

(S)—N-{2-(Aminomethyl)-5-chlorobenzyl}1-(5-ethoxy-1H-pyrrole-2-carbonyl)pyrrolidine-2-carboxamide-2,2,2-trifluoroacetate Isomer A,

(S)—N-12-(Aminomethyl)-5-chlorobenzyl}1-(5-ethoxy-1H-pyrrole-2-carbonyl)pyrrolidine-2-carboxamide-2,2,2-trifluoroacetate Isomer B,

(S)-1-(1-Aminocyclopentanecarbonyl)-N-{2-(aminomethyl)-5-chlorobenzyl}pyrrolidine-2-carboxamide-2,2,2-trifluoroacetate,

(S)—N-{2-(Aminomethyl)-5-chlorobenzyl}-1-{1-(methylsulfonamido)cyclopentanecarbonyl}pyrrolidine-2-carboxamide-2,2,2-trifluoroacetate,

(S)—N-(2-(Aminomethyl)-5-chlorobenzyl)-1-(pyrimidine-2-carbonyl)pyrrolidine-2-carboxamide bis(2,2,2-trifluoroacetate),

(S)—N-(2-(aminomethyl)-5-chlorobenzyl)-2-methyl-1-((R)-5-oxopyrrolidine-2-carbonyl)pyrrolidine-2-carboxamide,

(S)—N-(2-(aminomethyl)-5-chlorobenzyl)-1-(5-chloro-1H-pyrrole-2-carbonyl)-2-methylpyrrolidine-2-carboxamide, or

(S)—N-(2-(aminomethyl)-5-chlorobenzyl)-2-methyl-1-(5-methyl-1H-pyrrole-2-carbonyl)pyrrolidine-2-carboxamide.

14. A composition for inhibiting thrombus formation in blood comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

15. A method for inhibiting thrombin in blood comprising adding to the blood a composition of claim 14 .

16. A method for inhibiting formation of blood platelet aggregates in blood comprising adding to the blood a composition of claim 14 .

17. A method for inhibiting thrombus formation in blood comprising adding to the blood a composition of claim 14 .

18. A method for treating venous thromboembolism and pulmonary embolism in a mammal comprising administering to the mammal a composition of claim 14 .

19. A method for treating deep vein thrombosis in a mammal comprising administering to the mammal a composition of claim 14 .

20. A method for treating thromboembolic stroke in humans and other mammals comprising administering to the mammal a composition of claim 14 .

Assignments (2)
MERGER Recorded Aug 8, 2022
From: MERCK SHARP & DOHME CORP.
To: MERCK SHARP & DOHME LLC
Reel/Frame 061102/0145 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 18, 2015
From: CHOBANIAN, HARRY; BIFTU, TESFAYE; PIO, BARBARA; WU, ZHICAI
To: MERCK SHARP & DOHME CORP.
Reel/Frame 035659/0061 →