Factor XIa inhibitors

1. A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein

R 2 is

1) phenyl,

2) R 21 ,

3) 4-7-membered saturated carbocycle,

4) —OR 21 , or

wherein R 21 is 4-7-membered unsaturated or saturated heterocycle containing one or two heteroatoms independently selected from the N, O and S,

wherein phenyl is unsubstituted or monosubstituted with CF 3 , and heterocycle is unsubstituted or monosubstituted with NH 2 , SO 2 CH 3 or COCH 3 ;

R 6 is

1) —CH═CH—R 63 ,

2) —CH 2 CH 2 —R 63 ,

3) 4-7-membered monocyclic saturated heterocycle having one or two heteroatoms independently selected from N, O and S,

4) R 62 ,

5) 7-9-membered bicyclic unsaturated carbocycle,

wherein R 63 is phenyl which is mono, di or trisubstituted with a substituent independently selected from halogen, CF 3 and tetrazole, saturated heterocycle is unsubstituted or substituted at the nitrogen atom with —C(NH)NH 2 , and R 62 is unsaturated or saturated carbocycle unsubstituted or independently substituted with one or two of —CH 2 NH 2 , NH 2 , C(CH 3 ) 2 NH 2 , C 1-6 alkyl, or C 3-8 cycloalkyl, or

wherein R 61 is —(CH 2 ) 0-1 NH 2 ;

R 4 is

1) —CH 2 OR 41 , wherein R 41 is hydrogen or —Si(C 1-6 alkyl)(C 1-6 alkyl)(C 1-6 alkyl),

2) phenyl,

3) 3-7-membered monocyclic saturated carbocycle,

4) C 1-6 alkyl, or

5) —O—R 42 , wherein R 42 is a 4-7-membered monocyclic saturated heterocycle having one or two heteroatoms independently selected from N, O and S,

wherein phenyl is unsubstituted or substituted with one or two substituents independently selected from CF 3 , halogen, NH 2 , OCF 3 , C(O)NH 2 , C 1-6 alkyl or

R 5 is

1) —C(O)NHR 51 wherein

R 51 is

a) 3-7-membered monocyclic saturated or unsaturated carbocycle,

b) 8-membered bicyclic saturated carbocycle, or

c) 9-membered bicyclic unsaturated heterocycle

wherein carbocycle is unsubstituted or substituted with one or two substituents independently selected from C(O)OC(C 1-6 alkyl)(C 1-6 alkyl)(C 1-6 alkyl) or C(O)OH, and wherein heterocycle containing one or two heteroatoms selected from N, O and S, is unsubstituted or substituted with methyl,

 wherein

R 52 is

a) 3-7-membered monocyclic saturated or unsaturated carbocycle,

b) 6-membered unsaturated heterocycle containing 1 nitrogen atom, or

c) 9-membered bicyclic unsaturated heterocycle containing 1 or 2 heteroatoms, selected from N and O

wherein carbocycle is unsubstituted or substituted with one or two substituents independently selected from CN, halogen, OC 1-6 alkyl, SO 2 C 1-6 alkyl, CF 3 , C(O)OC 1-6 alkyl, NH 2 , NHC(O)OC 1-6 alkyl, NHC(O)C 1-6 alkyl, C(O)OC(CH 3 ) 2 , C(O)OH, PO 3 H 2 , or PO 3 (C 1-6 alkyl) 2 , wherein heterocycle is unsubstituted or substituted with methyl, and wherein bicyclic heterocycle is unsubstituted or substituted with a ═O, and

R 53 is hydrogen, halogen or C 1-6 alkyl, and

 wherein

R 54 is hydrogen or halogen.

2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

R 2 is

1) phenyl

2) R 21 ,

3) 5-6-membered saturated carbocycle,

4) —OR 21 , or

wherein R 21 is 5-6-membered saturated heterocycle containing one or two N heteroatoms,

wherein phenyl is unsubstituted or monosubstituted with CF 3 , and saturated heterocycle is unsubstituted or monosubstituted with NH 2 , SO 2 CH 3 or COCH 3 ;

R 6 is

1) —CH═CH—R 63 , or

2) R 62 ,

wherein R 63 is phenyl which is mono, di or trisubstituted with a substituent independently selected from halogen, CF 3 and tetrazole, and R 62 is unsaturated carbocycle unsubstituted or substituted with one or two substituents independently selected from —CH 2 NH 2 , NH 2 , C(CH 3 ) 2 NH 2 , C 1-6 alkyl, or C 3-8 cycloalkyl;

R 4 is

1) phenyl,

2) cyclohexyl,

3) C 1-6 alkyl, or

4) —OR 42 , wherein R 42 is a 6-membered monocyclic saturated heterocycle having one or two N atoms,

wherein phenyl is unsubstituted or substituted with one or two substituents independently selected from CF 3 , halogen, NH 2 , OCF 3 , C(O)NH 2 , C 1-6 alkyl or

R 5 is

—C(O)NHR 51 wherein

R 51 is

a) 3-7 membered monocyclic saturated or unsaturated carbocycle,

b) 8 membered bicyclic saturated carbocycle, or

c) 9 membered bicyclic unsaturated heterocycle,

wherein carbocycle is unsubstituted or unsubstituted with with one or two substituents independently selected from C(O)OC(C 1-6 alkyl)(C 1-6 alkyl) or C(O)OH, wherein heterocycle contains one or two heteroatoms selected from N, O and S, and wherein heterocycle is unsubstituted or substituted with methyl.

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

1) phenyl,

2) cyclohexyl,

3) methyl or ethyl, or

4) —O—R 42 , herein R 42 is piperidinyl,

wherein phenyl is unsubstituted or substituted with one or two substituents independently selected from CF 3 , halogen, NH 2 , OCF 3 , C(O)NH 2 , C 1-6 alkyl or

4. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

R 6 is

1) —CH═CH—R 63 , or

2) R 62 ,

wherein R 63 is phenyl substituted with chloro and tetrazole, and R 62 is phenyl unsubstituted or substituted with one or two substituents independently selected from —CH 2 NH 2 , or cyclopropyl.

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

R 6 is

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

1) phenyl, or

2) cyclohexyl,

3) methyl or ethyl, or

4) —O—R 42 .

7. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

R 4 is

8. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

R 5 is

—C(O)NHR 51 , wherein R 51 is

a) phenyl, or

b) 9 membered bicyclic unsaturated, unsubstituted heterocycle containing one or two N atoms,

wherein phenyl is unsubstituted or unsubstituted with one or two of C(O)OH.

9. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

R 5 is

10. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

R 2 is

1) phenyl

2) R 21 ,

3) cyclohexyl,

4) —OR 21 , or

wherein R 21 is 6-membered saturated heterocycle containing one or two N heteroatoms,

wherein phenyl is unsubstituted or monosubstituted with CF 3 , and saturated heterocycle is unsubstituted or monosubstituted with NH 2 , SO 2 CH 3 or COCH 3 .

11. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

R 2 is

12. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is

(E)-4-(4-amino-1′-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5′-phenyl-[1,3′-bipiperidine]-6′-carboxamido)benzoic acid,

(E)-4-(1-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-3-phenyl-5-(piperazin-1-yl)piperidine-2-carboxamido)benzoic acid,

4-({[4-amino-1′-{(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}-5′-(1-methylethyl)-1,3′-bipiperidin-6′-yl]carbonyl}amino)benzoic acid,

4-{[(4-amino-1′-{(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}-5′-cyclopropyl-1,3′-bipiperidin-6′-yl)carbonyl]amino}benzoic acid,

4-{[(4-amino-1′-{(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}-5′-methyl-1,3′-bipiperidin-6′-yl)carbonyl]amino}benzoic acid,

4-({[(3′S,5′S,6′S)-4-amino-1′-{(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}-5′-phenyl-1,3′-bipiperidin-6′-yl]carbonyl}amino)benzoic acid,

4-({[(3′R,5′R,6′R)-4-amino-1′-{(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}-5′-phenyl-1,3′-bipiperidin-6′-yl]carbonyl}amino)benzoic acid,

4-(4-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylamido)-1′-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5′-phenyl-[1,3′-bipiperidine]-6′-carboxamido)benzoic acid,

4-((2S,3S,5S)-1-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-3-phenyl-5-(piperidin-4-yloxy)piperidine-2-carboxamido)benzoic acid,

4-((2R,3R,5R)-1-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-3-phenyl-5-(piperidin-4-yloxy)piperidine-2-carboxamido)benzoic acid,

(E)-4-(1-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-3-phenyl-5-(piperidin-4-yloxy)piperidine-2-carboxamido)benzoic acid,

4-(1-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-phenyl-3-(piperidin-4-yloxy)piperidine-2-carboxamido)benzoic acid,

methyl (4-{2-[4-amino-1′-{(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}-5′-(4-fluorophenyl)-1,3′-bipiperidin-6′-yl]-1H-imidazol-4-yl}phenyl)carbamate,

1′-{(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}-5′-(4-fluorophenyl)-6′-(4-pyridin-3-yl-1H-imidazol-2-yl)-1,3′-bipiperidin-4-amine,

(3′S,5′S,6′S)-1′-{(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}-5′-(4-fluorophenyl)-6′-(4-pyridin-3-yl-1H-imidazol-2-yl)-1,3′-bipiperidin-4-amine,

4-{2-[4-amino-1′-{(2E)-3-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]prop-2-enoyl}-5′-(4-fluorophenyl)-1,3′-bipiperidin-6′-yl]-1H-imidazol-5-yl}benzonitrile,

4-{2-[4-amino-1′-{(2E)-3-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]prop-2-enoyl}-5′-(4-fluorophenyl)-1,3′-bipiperidin-6′-yl]-1H-imidazol-5-yl}benzonitrile,

4-{2-[4-amino-1′-{(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}-5′-(4-fluorophenyl)-1,3′-bipiperidin-6′-yl]-1H-imidazol-5-yl}benzonitrile,

methyl (4-{2-[4-amino-1′-{(2E)-3-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]prop-2-enoyl}-5′-(4-fluorophenyl)-1,3′-bipiperidin-6′-yl]-1H-imidazol-5-yl}phenyl)carbamate,

methyl (4-{2-[4-amino-1′-{(2E)-3-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]prop-2-enoyl}-5′-(4-fluorophenyl)-1,3′-bipiperidin-6′-yl]-1H-imidazol-5-yl}phenyl)carbamate,

methyl [4-(2-{4-amino-1′-[(2E)-3-(3-chloro-2,6-difluorophenyl)prop-2-enoyl]-5′-(4-fluorophenyl)-1,3′-bipiperidin-6′-yl}-1H-imidazol-4-yl)phenyl]carbamate,

methyl (4-{2-[(3′S,5′S,6′S)-4-amino-1′-{(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}-5′-cyclopropyl-1,3′-bipiperidin-6′-yl]-1H-imidazol-4-yl}phenyl)carbamate,

4-((3R,5S,6S)-1-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-phenyl-[3,4′-bipiperidine]-6-carboxamido)benzoic acid trifluoroacetic acid salt,

4-((3R,5R,6S)-1-((E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-methyl-[3,4′-bipiperidine]-6-carboxamido)benzoic acid,

4-((3R,5R,6S)-1-(4-(aminomethyl)-3-cyclopropylbenzoyl)-5-methy-1-[3,4′-bipiperidine]-6-carboxamido)benzoic acid,

methyl (4-{2-[(3R,5S,6S)-1-{(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}-5-cyclopropyl-3,4′-bipiperidin-6-yl]-1H-imidazol-4-yl}phenyl)carbamate,

methyl (4-{2-[1-{(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}-5-(4-fluorophenyl)-3,4′-bipiperidin-6-yl]-1H-imidazol-4-yl}phenyl)carbamate,

methyl (4-{2-[(3R,5S,6S)-1-{(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}-5-cyclopropyl-1′-(methylsulfonyl)-3,4′-bipiperidin-6-yl]-1H-imidazol-4-yl}phenyl)carbamate,

(2S,3S,5S)-1-{(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}-3-(4-fluorophenyl)-N-1H-indazol-5-yl-5-morpholin-4-ylpiperidine-2-carboxamide,

(2R,3R,5R)-1-{(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}-3-(4-fluorophenyl)-N-1H-indazol-5-yl-5-piperazin-1-ylpiperidine-2-carboxamide,

(2S,3S,5S)-1-{(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}-3-(4-fluorophenyl)-N-1H-indazol-5-yl-5-piperazin-1-ylpiperidine-2-carboxamide,

(2S,3S,5S)-5-(4-acetylpiperazin-1-yl)-1-{(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}-3-(4-fluorophenyl)-N-1H-indazol-5-ylpiperidine-2-carboxamide.

13. A composition for inhibiting thrombus formation in blood comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

14. A method for inhibiting thrombin in blood comprising adding to the blood a composition of claim 13 .

15. A method for inhibiting formation of blood platelet aggregates in blood comprising adding to the blood a composition of claim 13 .

16. A method for inhibiting thrombus formation in blood comprising adding to the blood a composition of claim 13 .

17. A method for treating or preventing venous thromboembolism and pulmonary embolism in a mammal comprising administering to the mammal a composition of claim 13 .

18. A method for treating or preventing deep vein thrombosis in a mammal comprising administering to the mammal a composition of claim 13 .

19. A method for treating or preventing thromboembolic stroke in humans and other mammals comprising administering to the mammal a composition of claim 13 .