IP Library › Granted Patent US 9,062,071

Granted Patent B2

US 9,062,071 · App. 14/366,466 · Granted Jun 23, 2015

Substituted piperidines as HDM2 inhibitors

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Quick Facts

Patent No.: US 9,062,071
App. No.: 14/366,466
Granted: Jun 23, 2015
Kind: B2

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Abstract

The present invention provides a compound of Formula I (The formula should be inserted here) as described herein or a pharmaceutically acceptable salt or solvate thereof. The representative compounds are useful as inhibitors of the HDM2 protein. Also disclosed are pharmaceutical compositions comprising the above compounds and potential methods of treating cancer using the same.

Claims (269)

1. A compound of Formula I:

wherein:

X is CR 3 or N;

Y is CR 3 or N;

Ring B is a 5or 6-membered heteroaryl ring or phenyl;

R 1 is independently selected from H, halo, CN, (CR a 2 ) n R 8 , —N(R 8 ) 2 , (C 3 -C 6 )cycloalkylCOOR 8 , (CR a 2 ) n COOR 8 , (CR a 2 ) n C(O)NR a R 8 , (CR a 2 ) n C(O)NR a SO 2 R 8 , (CR a 2 ) n NR a C(O)R 8 , (CR a 2 ) n OR 8 , (CR a 2 ) n C(O)R 8 and (CR a 2 ) n O(CR a 2 ) n COOR a ;

R 2 is independently selected from H, halo, CN, amide, aryl, heterocyclic, (CR a 2 ) n COOR 8 , —N(R a ) 2 , (CR a 2 ) n OR a , (CR a 2 ) n SR a and —SO 2 R a , wherein the aryl or heterocyclic is optionally substituted with one to three substituents selected from cyano, hydroxy, amide, halo and methoxy;

Provided that R 1 and R 2 are not both H;

R 3 is independently selected from the group consisting of: H, cyano, hydroxy, and alkoxy;

R 4 is heteroaryl which is optionally substituted with halo, halo-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, or —(C 1 -C 6 )alkoxy;

R 5 is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, (C 1 -C 6 )alkynyl, (CR b 2 ) t COOH, (CR b 2 ) t N(R 9 ) 2 , (CR b 2 ) t OR 9 or (CR b 2 ) t R 9 ;

R 6 is independently (C 1 -C 6 )alkyl;

R 7 is haloalkyl, —NR a C(O)R a , or C(O)N(R a ) 2 ;

R 8 is independently selected from H, halo, OH, CN, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, heterocylic, heterocyclenyl, heteroaryl, (C 1 -C 6 )alkylheterocyclic, (C 1 -C 6 )alkylheterocyclenyl and (C1-C6)alkylheteroaryl, wherein said alkyl, cycloalkyl, heterocyclic, heterocyclenyl and heteroaryl is optionally substituted with (C 1 -C 6 )alkyl, (CR a 2 ) n OR a , —N(R a ) 2 , (CR a 2 ) n COOR a , (CR a 2 ) n C(O)NR a R a , or (CR a 2 ) n NR a C(O)R a ;

R 9 is independently H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, heteroaryl, heterocyclenyl or heterocyclic, wherein the alkyl, cycloalkyl, heteroaryl, heterocyclenyl and heterocyclic is optionally substituted with (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (CR a 2 ) n COOH, or (CR a 2 ) n OR b ;

R 10 is independently (C 1 -C 6 )alkyl;

R a is independently H or (C 1 -C 6 )alkyl, wherein the alkyl is optionally substituted with (C 0 -C 6 )alkyl-OH or —(C 0 -C 6 )alkylOMe; and

R b is independently H or (C 1 -C 6 )alkyl;

m is 1, 2, or 3;

n is independently 0, 1, 2, 3, 4 or 5;

p is 0, 1, or 2;

q is0,1,2,or 3;

r is1,2 or 3;

t is0,1,2 or 3;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein

X is CR 3 or N;

Y is CR 3 or N;

Ring B is a 5or 6-membered heteroaryl ring or phenyl;

R 1 is independently selected from halo, CN, (CR a 2 ) n R 8 , —N(R 8 ) 2 , (C 3 -C 6 )cycloalkylCOOR 8 , (CR a 2 ) n COOR 8 , (CR a 2 ) n C(O)NR a R 8 , (CR a 2 ) n C(O)NR a SO 2 R 8 , (CR a 2 ) n NR a C(O)R 8 , (CR a 2 ) n OR 8 , (CR a 2 ) n C(O)R 8 and (CR a 2 ) n O(CR a 2 ) n COOR a ;

R 3 is independently selected from the group consisting of: H, cyano, hydroxy, and alkoxy;

R 4 is heteroaryl which is optionally substituted with halo, halo-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, or —(C 1 -C 6 )alkoxy;

R 5 is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, (C 1 -C 6 )alkynyl, (CR b 2 ) t COOH, (CR b 2 ) t N(R 9 ) 2 , (CR b 2 ) t OR 9 or (CR b 2 ) t R 9 ;

R 6 is independently (C 1 -C 6 )alkyl;

R 7 is haloalkyl, —NR a C(O)R a , or C(O)N(R a ) 2 ;

R 8 is independently selected from H, halo, OH, CN, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, heterocylic, heterocyclenyl, heteroaryl, (C 1 -C 6 )alkylheterocyclic, (C 1 -C 6 )alkylheterocyclenyl and (C 1 -C 6 )alkylheteroaryl, wherein said alkyl, cycloalkyl, heterocyclic, heterocyclenyl and heteroaryl is optionally substituted with (C 1 -C 6 )alkyl, (CR a 2 ) n OR a , —N(R a ) 2 , (CR a 2 ) n COOR a , (CR a 2 ) n C(O)NR a R a , or (CR a 2 ) n NR a C(O)R a ;

R 10 is independently (C 1 -C 6 )alkyl;

R a is independently H or (C 1 -C 6 )alkyl, wherein the alkyl is optionally substituted with (C 0 -C 6 )alkyl-OH or —(C 0 -C 6 )alkylOMe; and

R b is independently H or (C 1 -C 6 )alkyl;

m is 1, 2, or 3;

n is independently 0, 1, 2, 3, 4 or 5;

p is 0,1, or 2;

q is 0,1,2, or 3;

r is 1,2 or 3;

t is 0,1,2 or 3.

3. The compound of claim 1 , wherein R 4 is thienyl, optionally substituted with CF 3 , CBr 3 , CCl 3 , CH 3 , Br, Cl, F, or —OCH 3 .

4. The compound of claim 1 , wherein R 4 is

5. The compound of claim 1 under Formula II,

wherein:

X is CH and Y is N, or Xis N and Y is CH;

Ring B is a 5or 6-membered heteroaryl ring or phenyl;

R 1 is independently selected from H, halo, CN, (CR a 2 ) n R 8 , —N(R 8 ) 2 , C 3 -C 6 cycloalkylCOOR 8 , (CR a 2 ) n COOR 8 , (CR a 2 ) n C(O)NR a R 8 , (CR a 2 ) n C(O)NR a SO 2 R 8 , (CR a 2 ) n NR a C(O)R 8 , (CR a 2 ) n OR 8 , (CR a 2 ) n C(O)R 8 and (CR a 2 ) n O(CR a 2 ) n COOR a ;

Provided that R 1 and R 2 are not both H;

R 5 is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, (C 1 -C 6 )alkynyl, (CR b 2 ) t COOH, (CR b 2 ) t N(R 9 ) 2 , (CR b 2 ) t OR 9 or (CR b 2 ) t R 9 ;

R a is independently H or (C 1 -C 6 )alkyl, wherein the alkyl is optionally substituted with (C 0 -C 6 )alkyl-OH or (C 0 -C 6 )alkylOMe; and

R b is independently H or (C 1 -C 6 )alkyl;

m is 1or 2;

n is independently 0, 1, 2, 3or 4;

r is 1or 2;

t is 0, 1 or 2.

6. The compound of claim 5 under Formula III:

wherein

R 1 is selected from (C 3 -C 6 )cycloalkylCOOR a , (CR a 2 ) n COOR a , (CR a 2 ) n O(CR a 2 ) n COOR a , and (CR a 2 ) n C(O)NR a SO 2 R 8 ;

and all other substituents are as defined in claim 5 .

7. The compound of claim 5 under Formula III:

wherein

R 1 is -cyclopentyl-COOH, (CR a 2 ) n COOH, (CR a 2 ) n O (CR a 2 ) n COOH, (CR a 2 ) n C(O)NR a SO 2 R a , methoxymethyl, morpholinylmethyl, or C(O)NH 2 , wherein n is 0, 1, 2, 3or 4, and all other substituents are as defined in claim 5 .

8. The compound of claim 1 , wherein R 1 is (CR a 2 ) n COOR a .

9. The compound of claim 7 , wherein R 1 is (CH 2 ) n COOH, and n is 2 or 3.

10. The compound of claim 1 , wherein R 2 is halo.

11. The compound of claim 10 , wherein R 2 is Cl or Br.

12. The compound of claim 5 under Formula VA:

Wherein

R 1 is selected from (C 3 -C 6 )cycloalkylCOOR a , (CR a 2 ) n COOR a , (CR a 2 ) n O(CR a 2 ) n COOR a , and (CR a 2 ) n C(O)NR a SO 2 R 8 ;

R 2 and R 2 ′are independently H, Br or Cl;

and all other substituents are as defined in claim 5 .

13. The compound of claim 1 , wherein R 5 is methyl,

CH(CH 3 )COOH, CH 2 CH 2 COOH or heterocyclic, said heterocyclic optionally substituted with (C 1 -C 3 )alkyl, (C 3 -C 5 )cycloalkyl, (CR a 2 ) n COOH, or (CR a 2 ) n OR b .

14. The compound of claim 1 selected from the group consisting of:

2-[(2R,3S)-3-[(7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]-1-{[4-(trifluoromethyl)pyridin-3-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-2-yl]-N,N-bis(2-methoxyethyl)ethanamine;

2-[(2R,3S)-3-[(6-chloro-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]-1-{[4-(trifluoromethyl)pyridin-3-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-2-yl]-N,N-bis(2-methoxyethyl)ethanamine;

7-chloro-2-{[(2R,3S)-2-(2-morpholin-4-ylethyl)-1-{[4-(trifluoromethyl)pyridin-3-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline;

6-chloro-2-{[(2R,3S)-2-(2-morpholin-4-ylethyl)-1-{[4-(trifluoromethyl)pyridin-3-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline;

2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline-7-carbonitrile;

2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;

6-fluoro-2-{[(2R,3S)-2-(2-morpholin-4-ylethyl)-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline;

5-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4,5,6,7-tetrahydrothieno [3,2-c]pyridine;

ethyl 5-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4,5,6,7-tetrahydrothieno [3,2-c]pyridine-2-carboxylate;

5-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4,5,6,7-tetrahydrothieno [3,2-c]pyridine-2-carboxylic acid;

2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-6-amine;

6-chloro-1-(morpholin-4-ylmethyl)-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline;

2-chloro-5-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4,5,6,7-tetrahydrothieno [3,2-c]pyridine-4-carboxylic acid;

6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1-(pyrrolidin-1-ylmethyl)-1,2,3,4-tetrahydroisoquinoline;

6-chloro-1-(methoxymethyl)-2-{[(2R,3S)-2-(2-pyrrolidin-1-ylethyl)-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline;

6-chloro-1-(methoxymethyl)-2-{[(2R,3S)-2-(2-morpholin-4-ylethyl)-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline;

[(2R,3S)-3-{[6-chloro-1-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-2-yl]acetic acid;

2-chloro-6-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4,5,6,7-tetrahydrothieno [2,3-c]pyridine-7-carboxylic acid;

2-(1-{2-[(2R,3S)-3-{[6-chloro-1-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-2-yl]ethyl}piperidin-4-yl)ethanol;

6-chloro-2-{[(2R,3S)-2-{2-[4-(2-methoxyethyl)piperazin-1-yl]ethyl}-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline;

N-{2-[(2R,3S)-3-{[6-chloro-1-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-2-yl]ethyl}tetrahydro-2H-pyran-4-amine;

3-(2-chloro-5-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4,5,6,7-tetrahydrothieno [3,2-c]pyridin-4-yl)propanoic acid;

ethyl 2,2-dimethyl-3-(6-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4,5,6,7-tetrahydrothieno [2,3-c]pyridin-7-yl)propanoate;

2,2-dimethyl-3-(6-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4,5,6,7-tetrahydrothieno [2,3-c]pyridin-7-yl)propanoic acid;

3-(2-chloro-6-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4,5,6,7-tetrahydrothieno [2,3-c]pyridin-7-yl)-2,2-dimethylpropanoic acid;

2-chloro-4-(3-morpholin-4-ylpropyl)-5-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4,5,6,7-tetrahydrothieno [3,2-c]pyridine;

2-chloro-5-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4-(3-pyrrolidin-1-ylpropyl)-4,5,6,7-tetrahydrothieno [3,2-c]pyridine;

2-chloro-N-methyl-5-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4,5,6,7-tetrahydrothieno [3,2-c]pyridine-4-carboxamide;

2-chloro-5-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4-(pyrrolidin-1-ylmethyl)-4,5,6,7-tetrahydrothieno [3,2-c]pyridine;

{[(3R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-3-yl]methoxy}acetic acid;

3-(6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl)propanoic acid;

5-(6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl)pentanoic acid;

3-(6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl)propanoic acid;

5-(6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl)pentanoic acid;

3-(6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl)propanoic acid;

3-[(1R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl]propanoic acid;

2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile;

6-methoxy-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquino line;

6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquino line;

6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquino line;

6-bromo-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquino line;

3-(6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl)propan-1-ol;

(6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl)acetic acid;

(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl)acetic acid;

3-(6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl)propan-1-ol;

(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl)acetic acid;

(6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl)acetic acid;

3-(6-bromo-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl)prop anoic acid;

3-(6-bromo-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl)propanoic acid;

3-(6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl)-N-(2H-tetrazol-5-ylmethyl)propanamide;

3-(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl)-N-(methylsulfonyl)propanamide;

6-phenyl-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline;

2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-6-thiophen-3-yl-1,2,3,4-tetrahydroisoquinoline;

(6-bromo-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl)acetic acid;

4-(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl)butanoic acid;

6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline-1-carboxamide;

6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile;

6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline-1-carboxamide;

6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile;

3-[(1S)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl 9 -N-cyanopropanamide;

4-[(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl)acetyl]piperazin-2-one;

1-[(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl)acetyl]piperidin-4-ol;

N,N-dimethyl-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-6-amine;

1-[(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl)acetyl]piperidin-4-ol;

5,6-dichloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline;

6,7-dichloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline;

6-(methylsulfanyl)-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline;

2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline-6-carboxamide;

6-(methylsulfonyl)-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline;

2-(4-{3-[(1R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl]propanoyl}piperazin-1-yl)ethanol;

2-{4-[(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl)carbonyl]piperazin-1-yl}ethanol;

2-{4-[(6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl)carbonyl]piperazin-1-yl}ethanol;

[(2R,3S)-3-[(1-carbamoyl-6-chloro-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-2-yl]acetic acid;

1-{3-[(1R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl]propanoyl}piperidine-4-carboxylic acid;

1-{3-[(1S)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl]propanoyl}piperidine-4-carboxylic acid;

6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid;

6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid;

6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid;

(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol;

6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid;

(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol;

6-chloro-1-(methoxymethyl)-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline;

6-chloro-1-(2-hydroxyethyl)-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline-1-carboxamide;

6-fluoro-2-[(2-propyl-3-[4-(trifluoromethoxy)phenoxy]-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}piperidin-3-yl)carbonyl]-1,2,3,4-tetrahydroisoquinoline;

3-[(1S)-6-chloro-2-{[(2R,3S)-2-propyl-3-[4-(trifluoromethoxy)phenoxy]-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl]propanoic acid;

N-{2-[(2R,3S)-3-[(6-chloro-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-2-yl]ethyl}tetrahydro-2H-pyran-4-amine;

6-chloro-2-{[(2R,3S)-2-prop-2-en-1-yl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid;

6-chloro-2-{[(2R,3S)-2-[2-(4-ethylpiperazin-1-yl)ethyl]-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline;

6-chloro-2-{[(2R,3S)-2-[2-(4-methylpiperazin-1-yl)ethyl]-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline;

6-chloro-2-{[(2R,3S)-2-{2-[4-(cyclopropylmethyl)piperazin-1-yl]ethyl}-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline;

2-[(2R,3S)-3-[(6-chloro-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-2-yl]-N-(2-methoxyethyl)-N-methylethanamine;

2-(1-{2-[(2R,3S)-3-[(6-chloro-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-2-yl]ethyl}piperidin-4-yl)-2-methylpropanoic acid;

[(3S)-2-{[(2R,3S)-2-propyl-1-{[4-(trifluoromethyl)pyridin-3-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol;

2-{[(2R,3S)-2-propyl-1-{[4-(trifluoromethyl)pyridin-3-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-8-ol;

(2-{[(2R,3S)-2-propyl-1-{[4-(trifluoromethyl)pyridin-3-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl)acetic acid;

(3R)-6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid;

3-[(3S)-6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-3-yl]propanoic acid;

(3S)-6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid;

(3R)-7-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid;

3-[(3R)-6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-3-yl]propanoic acid;

(3S)-7-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid;

(3R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid;

3-[(3S)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-3-yl]propanoic acid;

5-[(3S)-6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-3-yl]pentanoic acid;

3-[(3S)-7-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-3-yl]propanoic acid;

3-[(3R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-3-yl]butanoic acid;

(3R)-6-bromo-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid;

(2S)-3-[(3S)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-3-yl]-2-methylpropanoic acid;

7-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline;

7-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline;

7-methoxy-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline;

(3S)-6-chloro-3-(3-fluoropropyl)-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline;

7-bromo-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline;

3-[(3R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-3-yl]propanoic acid;

[(3R)-6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-3-yl]acetic acid;

4-[(3S)-6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-3-yl]butanoic acid;

3-[(3R)-7-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-3-yl]propanoic acid;

1-{[(3R)-6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-3-yl]carbonyl}piperidin-4-ol;

(3R)-6-fluoro-N-(2-hydroxyethyl)-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;

(2R)-N-{[(3R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-3-yl]methyl}-2-methoxy-N-methylpropanamide;

N-{[(3R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-3-yl]methyl}-N-methylpropanamide;

(2S)-2-{[(3R)-6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-3-yl]methyl}-3-methylbutanoic acid;

2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid;

(3S)-6-chloro-3-(3-morpholin-4-ylpropyl)-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline;

(3S)-6-chloro-3-{3-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]propyl}-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline;

3-[(3R)-6,7-difluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-3-yl]propanoic acid;

(2R)-N-{[(3S)-6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-3-yl]methyl}-2-hydroxy-N-methylpropanamide;

2,2-difluoro-N-{[(3S)-6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-3-yl]methyl}-N-methylacetamide;

(3S)-6-fluoro-3-[(4-methylpiperazin-1-yl)carbonyl]-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline;

(2R)-3-[(3S)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-3-yl]-2-(methoxymethyl)propanoic acid;

1-{[(3S)-6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-3-yl]methyl}piperidin-4-ol;

(2R)-N-{2-[(3R)-6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-3-yl]ethyl}-2-hydroxy-N-methylpropanamide;

(2S)-3-[(3R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-3-yl]-2-hydroxypropanoic acid;

(2S)-2-{[(3S)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-3-yl]methyl}butanoic acid;

(3R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-N-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;

4-[(3R)-6-fluoro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-3-yl]butan-2-ol;

1-{[(3R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-3-yl]carbonyl}piperidin-4-ol;

(3R)-6-chloro-3-[(4-methoxypiperidin-1-yl)carbonyl]-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline;

(3R)-1-{[(3R)-6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-3-yl]carbonyl}piperidin-3-ol;

6-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4,5,6,7-tetrahydrothieno [2,3-c]pyridine-5-carboxylic acid;

(5S)-2-bromo-N-(methylsulfonyl)-6-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-4,5,6,7-tetrahydrothieno [2,3-c]pyridine-5-carboxamide;

6-chloro-1-(2-methylpropyl)-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline;

2-[(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl]-3-methylbutanoic acid;

[(6-chloro-2-{[(2R,3S)-2-propyl-1-{[3-(trifluoromethyl)pyridin-2-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl)methoxy]acetic acid;

or a stereoisomer thereof;

or a pharmaceutically acceptable salt thereof;

or a pharmaceutically acceptable salt of the stereoisomer thereof.

15. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable carrier.

16. A method of inhibiting one or more HDM2 proteins in a patient comprising the step of administering a therapeutically effective amount of compound according to claim 1 to the patient.

Assignments (4)

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 Jun 25, 2014

From: VOSS, MATTHEW E.; KIROVA-SNOVER, MARGARITA; CLAYTON, W. BRENT

To: ALBANY MOLECULAR RESEARCH, INC.

Reel/Frame 033172/0435 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 25, 2014

From: ALBANY MOLECULAR RESEARCH, INC.

To: MERCK SHARP & DOHME CORP.

Reel/Frame 033172/0935 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 18, 2014

From: MA, YAO; SHIZUKA, MANAMI; GUZI, TIMOTHY J.; LIU, YUAN; TIAN, YUAN; LAHUE, BRIAN R.; GIBEAU, CRAIG R.; SHIPPS, GERALD W., JR.; WANG, YAOLIN; BOGEN, STEPHANE L.; NAIR, LATHA G.; PAN, WEIDONG; MCCOY, MARK A.

To: MERCK SHARP & DOHME CORP.

Reel/Frame 033131/0679 →