Compounds as opioid receptor modulators
The present invention is directed to novel opioid receptor modulators of Formula (I). The invention further relates to methods for preparing such compounds, pharmaceutical compositions containing them, and their use in the treatment of disorders that may be ameliorated or treated by the modulation of opioid receptors.
1. A compound of Formula (I)
wherein:
R 1 is selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocyclyl, aryl(C 1-6 )alkyl, and heteroaryl(C 1-6 )alkyl; wherein when R 1 is phenyl(C 1-6 )alkyl, phenyl is optionally fused to a heterocyclyl or cycloalkyl;
wherein when R 1 is C 1-2 alkyl, said C 1-2 alkyl is optionally substituted with one to two substituents independently selected from the group consisting of C 1-6 alkoxy, aryl, cycloalkyl, heterocyclyl, hydroxy, cyano, amino, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, trifluoromethyl, and carboxy;
and further, wherein when R 1 is C 3-6 alkyl, said C 3-6 alkyl is optionally substituted with one to three substituents independently selected from the group consisting of C 1-6 alkoxy, aryl, cycloalkyl, heterocyclyl, hydroxy, cyano, amino, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, trifluoromethyl, and carboxy;
wherein the cycloalkyl and heterocyclyl of C 1-2 alkyl and C 3-6 alkyl are optionally substituted with one to two substituents independently selected from the group consisting of C 1-6 alkyl, hydroxy(C 1-6 )alkyl, C 1-6 alkoxy, hydroxy, cyano, amino, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, trifluoromethyl, carboxy, aryl(C 1-6 )alkoxycarbonyl, C 1-6 alkoxycarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, and aminosulfonyl;
furthermore, wherein the cycloalkyl and heterocyclyl of R 1 are optionally substituted with one to two substituents independently selected from the group consisting of C 1-6 alkyl, hydroxy(C 1-6 )alkyl, C 1-6 alkoxy, hydroxy, cyano, amino, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, trifluoromethyl, carboxy, aryl(C 1-6 )alkoxycarbonyl, C 1-6 alkoxycarbonyl, aminocarbonyl,
C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, and aminosulfonyl;
furthermore, wherein the aryl and heteroaryl portion of the R 1 substituents aryl(C 1-6 )alkyl and heteroaryl(C 1-6 )alkyl, are optionally substituted with one to three R 11 substituents independently selected from the group consisting of C 1-6 alkyl; hydroxy(C 1-6 )alkyl; C 1-6 alkoxy; C 6-10 aryl(C 1-6 )alkyl; C 6-10 aryl(C 1-6 ) alkoxy; C 6-10 aryl; heteroaryl optionally substituted with one to two substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, and carboxy; cycloalkyl; heterocyclyl; C 6-10 aryloxy; heteroaryloxy; cycloalkyloxy; heterocyclyloxy; amino; C 1-6 alkylamino; (C 1-6 alkyl) 2 amino; C 3-6 cycloalkylaminocarbonyl; hydroxy(C 1-6 ) alkylaminocarbonyl; C 6-10 arylaminocarbonyl wherein C 6-10 aryl is optionally substituted with carboxy or C 1-4 alkoxycarbonyl; heterocyclylcarbonyl; carboxy; C 1-6 alkoxycarbonyl; C 1-6 alkoxycarbonyloxy; C 1-6 alkylcarbonyl; C 1-6 alkylcarbonylamino; aminocarbonyl; C 1-6 alkylaminocarbonyl; (C 1-6 alkyl) 2 aminocarbonyl; cyano; halogen; trifluoromethyl; trifluoromethoxy; and hydroxy;
provided that no more than one R 11 substituent is selected from the group consisting of C 6-10 aryl(C 1-6 )alkyl; C 6-10 aryl(C 1-6 )alkoxy; C 6-10 aryl; heteroaryl optionally substituted with one to two substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, and carboxy; cycloalkyl; heterocyclyl; C 6-10 aryloxy; heteroaryloxy; cycloalkyloxy; C 6-10 arylaminocarbonyl wherein C 6-10 aryl is optionally substituted with carboxy or C 1-4 alkoxycarbonyl; heterocyclylcarbonyl, and heterocyclyloxy;
R 2 is hydrogen, C 1-8 alkyl, hydroxy(C 1-8 )alkyl, C 6-10 aryl(C 1-6 )alkoxy(C 1-6 )alkyl, or C 6-10 aryl(C 1-8 )alkyl;
wherein the C 6-10 aryl group in the C 6-10 aryl-containing substituents of R 2 are optionally substituted with one to two substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, hydroxy, amino, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, cyano, fluoro, chloro, bromo, trifluoromethyl, and trifluoromethoxy; and, wherein the C 1-6 alkyl and C 1-6 alkoxy substituents of aryl are optionally substituted with hydroxy, amino, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, or aryl;
A is a-1, optionally substituted with R 3 and R 5 ;
wherein
A-B is N—C;
R 3 is one to two substituents independently selected from the group consisting of C 1-6 alkyl, aryl, aryl(C 1-6 )alkyl, aryl(C 2-6 )alkenyl, aryl(C 2-6 )alkynyl, heteroaryl, heteroaryl(C 1-6 )alkyl, heteroaryl(C 2-6 )alkenyl, heteroaryl(C 2-6 )alkynyl, amino, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, arylamino, heteroarylamino, aryloxy, heteroaryloxy, trifluoromethyl, and halogen;
wherein the aryl, heteroaryl, and the aryl and heteroaryl of aryl(C 1-6 )alkyl, aryl(C 2-6 )alkenyl, aryl(C 2-6 )alkynyl, heteroaryl(C 1-6 )alkyl, heteroaryl(C 2-6 )alkenyl, heteroaryl(C 2-6 )alkynyl, arylamino, heteroarylamino, aryloxy, and heteroaryloxy, are optionally substituted with one to five fluoro substituents or one to three substituents independently selected from the group consisting of C 1-6 alkyl, hydroxy(C 1-6 )alkyl, C 1-6 alkoxy, C 6-10 aryl(C 1-6 )alkyl, C 6-10 aryl(C 1-6 )alkoxy, C 6-10 aryl, C 6-10 aryloxy, heteroaryl(C 1-6 )alkyl, heteroaryl(C 1-6 )alkoxy, heteroaryl, heteroaryloxy, C 6-10 arylamino, heteroarylamino, amino, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, carboxy(C 1-6 )alkylamino, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, carboxy(C 1-6 )alkylaminocarbonyl, cyano, halogen, trifluoromethyl, trifluoromethoxy, hydroxy, C 1-6 alkylsulfonyl, and C 1-6 alkylsulfonylamino; provided that no more than one such substituent on the aryl or heteroaryl portion of R 3 is selected from the group consisting of C 6-10 aryl(C 1-6 )alkyl, C 6-10 aryl(C 1-6 )alkoxy, C 6-10 aryl, C 6-10 aryloxy, heteroaryl(C 1-6 )alkyl, heteroaryl(C 1-6 )alkoxy, heteroaryl, heteroaryloxy, C 6-10 arylamino, heteroarylamino;
and wherein C 1-6 alkyl and C 1-6 alkyl of aryl(C 1-6 )alkyl and heteroaryl(C 1-6 )alkyl are optionally substituted with a substituent selected from the group consisting of hydroxy, carboxy, C 1-4 alkoxycarbonyl, amino, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, aminocarbonyl, (C 1-4 )alkylaminocarbonyl, di(C 1-4 )alkylaminocarbonyl, aryl, heteroaryl, arylamino, heteroarylamino, aryloxy, heteroaryloxy, aryl(C 1-4 )alkoxy, and heteroaryl(C 1-4 )alkoxy;
R 4 is C 6-10 aryl or a heteroaryl selected from the group consisting of furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, indolinyl, benzofuryl, benzothienyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, quinolizinyl, quinolinyl, isoquinolinyl and quinazolinyl;
wherein R 4 is optionally substituted with one to three R 41 substituents independently selected from the group consisting of (C 1-6 )alkyl optionally substituted with amino, C 1-6 alkylamino, or (C 1-6 alkyl) 2 amino; (C 1-6 )alkoxy; phenyl(C 1-6 )alkoxy; phenyl(C 1-6 )alkylcarbonyloxy wherein C1-6 alkyl is optionally substituted with amino; a non fused 5-membered-heteroaryl(C 1-6 )alkylcarbonyloxy; a non fused 5-membered-heteroaryl; hydroxy; halogen; aminosulfonyl; formylamino; aminocarbonyl; C 1-6 alkylaminocarbonyl wherein (C 1-6 )alkyl is optionally substituted with amino, C 1-6 alkylamino, or (C 1-6 alkyl) 2 amino; (C 1-6 alkyl) 2 aminocarbonyl wherein each (C 1-6 )alkyl is optionally substituted with amino, C 1-6 alkylamino, or (C 1-6 alkyl) 2 amino; heterocyclylcarbonyl wherein heterocyclyl is a 5-7 membered nitrogen-containing ring and said heterocyclyl is attached to the carbonyl carbon via a nitrogen atom; carboxy; or cyano; and wherein the phenyl portion of phenyl(C 1-6 )alkylcarbonyloxy is optionally substituted with (C 1-6 )alkyl (C 1-6 ) alkoxy, halogen, cyano, amino, or hydroxy;
provided that no more than one R 41 is C 1-6 alkyl substituted with C 1-6 alkylamino or (C 1-6 alkyl) 2 amino; aminosulfonyl; formylamino; aminocarbonyl; C 1-6 alkylaminocarbonyl; (C 1-6 alkyl) 2 aminocarbonyl; heterocyclylcarbonyl; hydroxy; carboxy; or a phenyl- or heteroaryl-containing substituent;
R 5 is a substituent on a nitrogen atom of ring A selected from the group consisting of hydrogen and C 1-4 alkyl;
R 6 is hydrogen or C 1-6 alkyl;
R 7 is hydrogen or C 1-6 alkyl;
R a and R b are independently selected from the group consisting of hydrogen, C 1-6 alkyl, and C 1-6 alkoxycarbonyl; alternatively, when R a and R b are each other than hydrogen, R a and R b are optionally taken together with the nitrogen atom to which they are both attached to form a five to eight membered monocyclic ring;
L is O;
and pharmaceutically acceptable enantiomers, diastereomers, racemates, and salts thereof.
2. The compounds of claim 1 wherein R 1 is selected from the group consisting of hydrogen, C 1-6 alkyl, aryl(C 1-4 )alkyl, and heteroaryl(C 1-4 )alkyl;
wherein the aryl and heteroaryl portion of aryl(C 1-4 )alkyl and heteroaryl(C 1-4 ) alkyl are optionally substituted with one to three R 11 substituents independently selected from the group consisting of C 1-6 alkoxy; heteroaryl optionally substituted with one to two substitutents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, and carboxy; carboxy; C 1-4 alkoxycarbonyl; C 1-4 alkoxycarbonyloxy; aminocarbonyl; C 1-4 alkylaminocarbonyl; C 3-6 cycloalkylaminocarbonyl; hydroxy(C 1-6 ) alkylaminocarbonyl; C 6-10 arylaminocarbonyl wherein C 6-10 aryl is optionally substituted with carboxy or C 1-4 alkoxycarbonyl; heterocyclylcarbonyl; cyano; halogen; trifluoromethoxy; and hydroxy; provided that no more than one R 11 is heteroaryl (optionally substituted with one to two C 1-4 alkyl substituents); C 6-10 arylaminocarbonyl wherein C 6-10 aryl is optionally substituted with carboxy or C 1-4 alkoxycarbonyl; or heterocyclylcarbonyl.
3. The compounds of claim 1 wherein R 1 is selected from the group consisting of C 6-10 aryl(C 1-4 )alkyl, pyridinyl(C 1-4 )alkyl, and furanyl(C 1-4 )alkyl; wherein C 6-10 aryl, pyridinyl, and furanyl are optionally substituted with one to three R 11 substituents independently selected from the group consisting of C 1-3 alkoxy; tetrazolyl; carboxy; C 1-4 alkoxycarbonyl; aminocarbonyl; C 1-4 alkylaminocarbonyl; C 1-3 alkylaminocarbonyl; C 3-6 cycloalkylaminocarbonyl; hydroxy(C 1-4 )alkylaminocarbonyl; C 6-10 arylaminocarbonyl wherein C 6-10 aryl is optionally substituted with carboxy or C 1-4 alkoxycarbonyl; morpholin-4-ylcarbonyl; cyano; halogen; and trifluoromethoxyl; provided that no more than one R 11 is C 6-10 arylaminocarbonyl.
4. The compounds of claim 1 wherein R 1 is selected from the group consisting of phenyl(C 1-3 )alkyl, pyridinyl(C 1-3 )alkyl, and furanyl(C 1-3 )alkyl; wherein phenyl, pyridinyl, and furanyl are optionally substituted with one to three R 11 substituents independently selected from the group consisting of C 1-3 alkoxy; tetrazolyl, C 3-6 cycloalkylaminocarbonyl; hydroxy(C 1-4 ) alkylaminocarbonyl; C 6-10 arylaminocarbonyl wherein C 6-10 aryl is optionally substituted with carboxy or C 1-4 alkoxycarbonyl; morpholin-4-ylcarbonyl; chloro; fluoro; trifluoromethoxy; C 1-4 alkoxycarbonyl; and carboxy; provided that no more than one R 11 is C 6-10 arylaminocarbonyl.
5. The compounds of claim 1 wherein R 1 is phenylmethyl, pyridinylmethyl, or furanylmethyl; wherein phenyl, pyridinyl, and furanyl are optionally substituted with one to three R 11 substituents independently selected from the group consisting of methoxy; tetrazolyl; cyclopropylaminocarbonyl, (2-hydroxyeth-1-yl)aminocarbonyl; methoxycarbonyl; phenylaminocarbonyl wherein phenyl is optionally substituted with carboxy; morpholin-4-ylcarbonyl; and carboxy.
6. The compounds of claim 1 wherein R 2 is a substituent selected from the group consisting of hydrogen, C 1-4 alkyl, hydroxy(C 1-4 )alkyl, and phenyl(C 1-6 ) alkoxy(C 1-4 )alkyl;
wherein said phenyl is optionally substituted with one to two substituents independently selected from the group consisting of C 1-3 alkyl, C 1-3 alkoxy, hydroxy, cyano, fluoro, chloro, bromo, trifluoromethyl, and trifluoromethoxy.
7. The compounds of claim 1 wherein R 2 is a substituent selected from the group consisting of hydrogen and C 1-4 alkyl.
8. The compounds of claim 1 wherein R 2 is hydrogen or methyl.
9. The compounds of claim 1 wherein R 3 is one to two substituents independently selected from the group consisting of C 1-6 alkyl, halogen, and aryl; wherein aryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, carboxy, aminocarbonyl, C 1-3 alkylsulfonylamino, cyano, hydroxy, amino, C 1-3 alkylamino, and (C 1-3 alkyl) 2 amino.
10. The compounds of claim 1 wherein R 3 is one to two substituents independently selected from the group consisting of C 1-3 alkyl, bromo, and phenyl; wherein phenyl is optionally substituted with one to three substituents independently selected from the group consisting of chloro, fluoro, iodo, carboxy, aminocarbonyl, and cyano.
11. The compounds of claim 1 wherein R 3 is one to two substituents independently selected from the group consisting of methyl and phenyl; wherein phenyl is optionally substituted with one to three substituents independently selected from the group consisting of chloro and carboxy.
12. The compounds of claim 1 wherein at least one R 3 substituent is phenyl.
13. The compounds of claim 1 wherein R 3 is a substituent selected from the group consisting of methyl and phenyl; wherein phenyl is optionally substituted with one to two substituents independently selected from the group consisting of chloro and carboxy.
14. The compounds of claim 1 wherein R 4 is C 6-10 aryl optionally substituted with one to three R 41 substituents independently selected from the groupconsisting of (C 1-3 )alkyl, (C 1-6 )alkoxy, phenyl(C 1-6 )alkoxy; hydroxy; halogen; formylamino; aminocarbonyl; C 1-6 alkylaminocarbonyl; (C 1-6 alkyl) 2 aminocarbonyl; heterocyclylcarbonyl wherein heterocyclyl is a 5-7 membered nitrogen-containing ring and said heterocyclyl is attached to the carbonyl carbon via a nitrogen atom; carboxy; and cyano;
provided that no more than one R 41 substituent is formylamino, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, heterocyclylcarbonyl, hydroxy, carboxy, or a phenyl-containing substituent.
15. The compounds of claim 1 wherein R 4 is phenyl substituted with one to three R 41 substituents independently selected from the group consisting of (C 1-3 )alkyl, (C 1-3 )alkoxy, phenyl(C 1-3 )alkoxy, hydroxy, C 1-6 alkylaminocarbonyl, and aminocarbonyl; provided that no more than one R 41 substituent is aminocarbonyl, C 1-6 alkylaminocarbonyl, hydroxy, or a phenyl-containing substituent.
16. The compounds of claim 1 wherein R 4 is phenyl substituted at the 4-position with hydroxy, C 1-3 alkylaminocarbonyl, or aminocarbonyl, and optionally substituted with one to two substituents independently selected from the group consisting of methyl, methoxy, and benzyloxy.
17. The compounds of claim 1 wherein R 4 is phenyl substituted at the 4-position with hydroxy, C 1-3 alkylaminocarbonyl, or aminocarbonyl, and optionally substituted with one to two methyl substituents.
18. The compounds of claim 1 wherein R 4 is phenyl substituted at the 4-position with hydroxy, C 1-3 alkylaminocarbonyl, or aminocarbonyl, and substituted at the 2- and 6-positions with methyl substituents.
19. The compounds of claim 1 wherein R 5 is hydrogen or methyl.
20. The compounds of claim 1 wherein R 5 is hydrogen.
21. The compounds of claim 1 wherein R 6 is hydrogen or methyl.
22. The compounds of claim 1 wherein R 6 is hydrogen.
23. The compounds of claim 1 wherein R 7 is hydrogen or methyl.
24. The compounds of claim 1 wherein R 7 is hydrogen.
25. The compounds of claim 1 wherein R a and R b are independently selected from the group consisting of hydrogen and C 1-3 alkyl; or, when R a and R b are each other than hydrogen, R a and R b are optionally taken together with the nitrogen atom to which they are both attached to form a five to seven membered monocyclic ring.
26. The compounds of claim 1 wherein R a and R b are independently hydrogen or methyl.
27. The compounds of claim 1 wherein R a and R b are each hydrogen.
28. The compounds of claim 1 that are present in their RR, SS, RS, and SR configurations.
29. The compounds of claim 1 in their S,S configuration.
30. A compound of Formula (Ia):
wherein:
R 1 is selected from the group consisting of hydrogen, C 1-6 alkyl, aryl(C 1-4 )alkyl, and heteroaryl(C 1-4 )alkyl;
wherein the aryl and heteroaryl portion of aryl(C 1-4 )alkyl and heteroaryl(C 1-4 ) alkyl are optionally substituted with one to three R 11 substituents independently selected from the group consisting of C 1-6 alkoxy; heteroaryl optionally substituted with one to two substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, and carboxy; carboxy; C 1-4 alkoxycarbonyl; C 1-4 alkoxycarbonyloxy; aminocarbonyl; C 1-4 alkylaminocarbonyl; C 3-6 cycloalkylaminocarbonyl; hydroxy(C 1-6 ) alkylaminocarbonyl; C 6-10 arylaminocarbonyl wherein C 6-10 aryl is optionally substituted with carboxy or C 1-4 alkoxycarbonyl; heterocyclylcarbonyl; cyano; halogen; trifluoromethoxy; and hydroxy; provided that no more than one R 11 is heteroaryl (optionally substituted with one to two C 1-4 alkyl substituents); C 6-10 arylaminocarbonyl wherein C 6-10 aryl is optionally substituted with carboxy or C 1-4 alkoxycarbonyl; or heterocyclylcarbonyl;
R 2 is selected from the group consisting of hydrogen, C 1-4 alkyl, hydroxy(C 1-4 ) alkyl, and phenyl(C 1-6 )alkoxy(C 1-4 )alkyl;
wherein said phenyl is optionally substituted with one to two substituents independently selected from the group consisting of C 1-3 alkyl, C 1-3 alkoxy, hydroxy, cyano, fluoro, chloro, bromo, trifluoromethyl, and trifluoromethoxy;
R 3 is one to two substituents independently selected from the group consisting of C 1-6 alkyl, halogen, and aryl; wherein aryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, carboxy, aminocarbonyl, C 1-3 alkylsulfonylamino, cyano, hydroxy, amino, C 1-3 alkylamino, and (C 1-3 alkyl) 2 amino;
R 4 is C 6-10 aryl optionally substituted with one to three R 41 substituents independently selected from the group consisting of (C 1-3 )alkyl, (C 1-6 ) alkoxy, phenyl(C 1-6 )alkoxy; hydroxy; halogen; formylamino; aminocarbonyl; C 1-6 alkylaminocarbonyl; (C 1-6 alkyl) 2 aminocarbonyl; heterocyclylcarbonyl wherein heterocyclyl is a 5-7 membered nitrogen-containing ring and said heterocyclyl is attached to the carbonyl carbon via a nitrogen atom; carboxy; and cyano;
provided that no more than one R 41 substituent is formylamino, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, heterocyclylcarbonyl, hydroxy, carboxy, or a phenyl-containing substituent.
R 5 is hydrogen or methyl;
R a and R b are independently hydrogen or C 1-3 alkyl; or, when R a and R b are each other than hydrogen, R a and R b are optionally taken together with the nitrogen atom to which they are both attached to form a five to seven membered monocyclic ring;
and pharmaceutically acceptable enantiomers, diastereomers, racemates, and salts thereof.
31. A compound of Formula (Ia) wherein:
R 1 is selected from the group consisting of C 6-10 aryl(C 1-4 )alkyl, pyridinyl(C 1-4 ) alkyl, and furanyl(C 1-4 )alkyl; wherein C 6-10 aryl, pyridinyl, and furanyl are optionally substituted with one to three R 11 substituents independently selected from the group consisting of C 1-3 alkoxy; tetrazolyl; carboxy; C 1-3 alkoxycarbonyl; aminocarbonyl; C 1-4 alkylaminocarbonyl; C 1-3 alkylaminocarbonyl; C 3-6 cycloalkylaminocarbonyl; hydroxy(C 1-4 ) alkylaminocarbonyl; C 6-10 arylaminocarbonyl wherein C 6-10 aryl is optionally substituted with carboxy or C 1-4 alkoxycarbonyl; morpholin-4-ylcarbonyl; cyano; halogen; trifluoromethoxy; C 1-4 alkoxycarbonyl; or carboxy; provided that no more than one R 11 is C 6-10 arylaminocarbonyl;
R 2 is hydrogen or C 1-4 alkyl;
R 3 is one to two substituents independently selected from the group consisting of C 1-3 alkyl, bromo, and phenyl; wherein phenyl is optionally substituted with one to three substituents independently selected from the group consisting of chloro, fluoro, carboxy, aminocarbonyl, and cyano;
R 4 is phenyl substituted with one to three substituents independently selected from the group consisting of (C 1-3 )alkyl, (C 1-3 )alkoxy, phenyl(C 1-3 )alkoxy, hydroxy, C 1-6 alkylaminocarbonyl, and aminocarbonyl; provided that no more than one R 41 substituent is aminocarbonyl, C 1-6 alkylaminocarbonyl, hydroxy, or a phenyl-containing substituent;
R 5 is hydrogen;
R a and R b are independently hydrogen or methyl;
and pharmaceutically acceptable enantiomers, diastereomers, racemates, and salts thereof.
32. A compound of Formula (Ia) wherein:
R 1 is selected from the group consisting of phenyl(C 1-3 )alkyl, pyridinyl(C 1-3 ) alkyl, and furanyl(C 1-3 )alkyl; wherein phenyl, pyridinyl, and furanyl are optionally substituted with one to three R 11 substituents independently selected from the group consisting of is C 1-3 alkoxy; tetrazolyl, C 3-6 cycloalkylaminocarbonyl; hydroxy(C 1-4 )alkylaminocarbonyl; C 6-10 arylaminocarbonyl wherein C 6-10 aryl is optionally substituted with carboxy or C 1-4 alkoxycarbonyl; morpholin-4-ylcarbonyl; chloro; fluoro; trifluoromethoxy; methoxycarbonyl; and carboxy; provided that no more than one R 11 is C 6-10 arylaminocarbonyl;
R 2 is hydrogen or methyl;
R 3 is one to two substituents independently selected from the group consisting of methyl and phenyl; wherein phenyl is optionally substituted with one to three substituents independently selected from the group consisting of chloro and carboxy;
R 4 is phenyl substituted at the 4-position with hydroxy, C 1-3 alkylaminocarbonyl, or aminocarbonyl, and optionally substituted with one to two substituents independently selected from the group consisting of methyl, methoxy, and benzyloxy;
R 5 is hydrogen;
R a and R b are each hydrogen;
and pharmaceutically acceptable enantiomers, diastereomers, racemates, and salts thereof.
33. A compound according to claim 32 wherein R 1 is phenylmethyl, pyridinylmethyl, or furanylmethyl; wherein phenyl, pyridinyl, and furanyl are optionally substituted with one to three R 11 substituents independently selected from is the group consisting of methoxy, tetrazolyl, cyclopropylaminocarbonyl, (2-hydroxyeth-1-yl)aminocarbonyl, phenylaminocarbonyl wherein phenyl is optionally substituted with carboxy, morpholin-4-ylcarbonyl, methoxycarbonyl, and carboxy; provided that no more than one R 11 is phenylaminocarbonyl.
34. A compound according to claim 32 wherein R 4 is phenyl substituted at the 4-position with hydroxy, C 1-3 alkylaminocarbonyl, or aminocarbonyl, and optionally substituted with one to two methyl substituents.
35. A compound according to claim 32 wherein R 4 is phenyl substituted at the 4-position with hydroxy, C 1-3 alkylaminocarbonyl, or aminocarbonyl, and substituted at the 2- and 6-positions with methyl substituents.
36. A compound of Formula (Ib)
Formula (Ib)
wherein L is O and R 1 , R 2 , R 3-1 , R 3-2 , R 5 , R a ,
R b , and R 41 are dependently selected from the
group consisting of:
R 1
R 2
R 3-1
R 3-2
R 5
R 41
R a /R b
2-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
Aminocarbonyl-
aminocarbonyl
phenylmethyl
2-Cyano-phenyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
methyl
aminocarbonyl
2-Bromo-phenyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
methyl
aminocarbonyl
3-Carboxy-4-
methyl
phenyl
H
H
4-aminocarbonyl
H
methoxy-phenyl
methyl
3-Carboxy-4-
H
phenyl
H
H
4-aminocarbonyl
H
methoxy-phenyl
methyl
3-Carboxy-4-
H
phenyl
H
H
2,6-dimethyl-4-
H
methoxy-phenyl
aminocarbonyl
methyl
3-
H
phenyl
H
H
2,6-dimethyl-4-
H
Methoxycarbonyl-
aminocarbonyl
4-methoxy-
phenylmethyl
3-(1H-tetrazol-5-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
yl)-4-methoxy-
phenylmethyl
3-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
Methoxycarbonyl-
aminocarbonyl
phenylmethyl
3-Methoxy
methyl
naphthalen-
H
H
2,6-dimethyl-4-
H
carbonyl-
1-yl
aminocarbonyl
phenylmethyl
3-Carboxy-
methyl
naphthalen-
H
H
2,6-dimethyl-4-
H
phenylmethyl
1-yl
3-Carboxy-
methyl
4-chloro-
Me
H
2 ,6-dimethyl-4-
H
phenylmethyl
phenyl
4-Carboxy-
methyl
naphthalen-
H
H
2,6-dimethyl-4-
H
phenylmethyl
1-yl
3-Methoxy-4-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
carboxy-
aminocarbonyl
phenylmethyl
3,4-Dihydroxy-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
phenylmethyl
hydroxy
Piperidin-4-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
ylmethyl
hydroxy
3-Methoxy
methyl
phenyl
H
H
2,6-dimethyl-4-
H
carbonyl-4-
aminocarbonyl
methoxy-phenyl
methyl
3-Carboxy-4-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
methoxy-
aminocarbonyl
phenylmethyl
3,4-Dimethoxy-
methyl
3-bromo
H
H
2,6-dimethyl-4-
H
phenylmethyl
phenyl
aminocarbonyl
3,4-Dimethoxy-
methyl
3-carboxy
H
H
2,6-dimethyl-4-
H
phenylmethyl
phenyl
aminocarbonyl
3,4-Dimethoxy-
benzyl
phenyl
H
H
2,6-dimethyl-4-
H
phenylmethyl
oxy
hydroxy
methyl
3,4-Dimethoxy-
methyl
3-amino
H
H
2,6-dimethyl-4-
H
phenylmethyl
carbonyl
aminocarbonyl
phenyl
3,4-Dimethoxy-
methyl
3-cyano
H
H
2,6-dimethyl-4-
H
phenylmethyl
phenyl
aminocarbonyl
Isopropyl
H
quinoxalin-
Me
H
2,6-dimethyl-4-
H
8-yl
hydroxy
3,4-Dimethoxy-
methyl
2-bromo
H
H
2,6-dimethyl-4-
H
phenylmethyl
phenyl
aminocarbonyl
3,4-Dimethoxy-
methyl
2-cyano
H
H
2,6-dimethyl-4-
H
phenylmethyl
phenyl
aminocarbonyl
3,4-Dimethoxy-
methyl
2-amino
2,6-dimethyl-4-
H
phenylmethyl
carbonyl
aminocarbonyl
phenyl
3,4-Dimethoxy-
methyl
2-carboxy
H
H
2,6-dimethyl-4-
H
phenylmethyl
phenyl
aminocarbonyl
3,4-Dibenzyloxy-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
phenylmethyl
hydroxy
[1,3]benzo
methyl
phenyl
H
H
2,6-dimethyl, 4-
H
dioxal-5-yl
hydroxy
4-Methoxy-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
phenylmethyl
hydroxy
3-Methoxy-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
phenylmethyl
hydroxy
2,4-Dimethoxy-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
phenylmethyl
hydroxy
3,4-Dimethoxy-
H
phenyl
H
H
2,6-dimethyl-4-
H
phenylmethyl
hydroxy
Isopropyl
H
4-methyl
H
H
2,6-dimethyl-4-
H
carbonyl
hydroxy
phenyl
Isopropyl
H
3-fluoro, 4-
Me
H
2,6-dimethyl-4-
H
carboxy-
hydroxy
phenyl
Isopropyl
H
2-phenyl-
Me
H
2,6-dimethyl-4-
H
ethyl
hydroxy
en-1-yl
Isopropyl
H
4-hydroxy
Me
H
2,6-dimethyl-4-
H
methyl
hydroxy
phenyl
Benzhydryl
H
phenyl
H
H
2,6-dimethyl-4-
H
hydroxy
Isopropyl
H
4-cyano
Me
H
2,6-dimethyl-4-
H
phenyl
hydroxy
Benzyl
methyl
4-trifluoro
H
H
2,6-dimethyl-4-
H
methyl
aminocarbonyl
phenyl
Isopropyl
H
3-trifluoro
Me
H
2,6-dimethyl-4-
H
methoxy
hydroxy
phenyl
Isopropyl
H
4-trifluoro
Me
H
2,6-dimethyl-4-
H
methoxy
hydroxy
phenyl
Isopropyl
H
3-methane
Me
H
2,6-dimethyl-4-
H
sulfonyl
hydroxy
amino
phenyl
Isopropyl
H
4-(2-
Me
H
2,6-dimethyl-4-
H
carboxy
hydroxy
ethyl)
phenyl
Isopropyl
H
3-amino-5-
Me
H
2,6-dimethyl-4-
H
carboxy
hydroxy
phenyl
3-Carboxy-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
phenylmethyl
hydroxy
4-Carboxy-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
phenylmethyl
carboxy
4-Carboxy-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
phenylmethyl
aminocarbonyl
4-Methoxy
methyl
phenyl
H
H
2,6-dimethyl-4-
H
carbonyl-
aminocarbonyl
phenylmethyl
3-Methoxy
methyl
phenyl
H
H
2,6-dimethyl-4-
H
carbonyl-
hydroxy
phenylmethyl
1-Benzyloxy
methyl
phenyl
H
H
2,6-dimethyl-4-
H
carbonyl-
hydroxy
piperadin-4-
ylmethyl
Furan-2-yl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
methyl
hydroxy
Furan-3-yl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
methyl
hydroxy
Cyclohexyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
methyl
hydroxy
Pyridin-4-yl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
methyl
hydroxy
Benzyl
methyl
4-chloro
Me
H
2,6-dimethyl-4-
H
phenyl
aminocarbonyl
Benzyl
methyl
3-fluoro
H
H
2,6-dimethyl-4-
H
phenyl
aminocarbonyl
Isopropyl
H
3-cyano
Me
H
2,6-dimethyl-4-
H
phenyl
hydroxy
Isopropyl
H
2,5-difluoro
Me
H
2,6-dimethyl-4-
H
phenyl
hydroxy
Isopropyl
H
4-methane
Me
H
2,6-dimethyl-4-
H
sulfonyl
hydroxy
phenyl
Benzyl
benzyl
phenyl
H
H
2,6-dimethyl-4-
H
oxy
aminocarbonyl
methyl
Isopropyl
H
Br
Me
H
2,6-dimethyl-4-
H
hydroxy
Isopropyl
H
4-dimethyl
Me
H
2,6-dimethyl-4-
H
amino
hydroxy
phenyl
Isopropyl
H
3-dimethyl
Me
H
2,6-dimethyl-4-
H
amino
hydroxy
carbonyl
phenyl
Isopropyl
H
3-hydroxy
Me
H
2,6-dimethyl-4-
H
phenyl
hydroxy
Isopropyl
H
4-amino
Me
H
2,6-dimethyl-4-
H
carbonyl
hydroxy
phenyl
Isopropyl
H
3-chloro
Me
H
2,6-dimethyl-4-
H
phenyl
hydroxy
Isopropyl
H
2,4-difluoro
Me
H
2,6-dimethyl-4-
H
phenyl
hydroxy
Isopropyl
H
3-methane
Me
H
2,6-dimethyl-4-
H
sulfonyl
hydroxy
phenyl
Isopropyl
H
3-amino
Me
H
2,6-dimethyl-4-
H
carbonyl
hydroxy
phenyl
Benzyl
methyl
4-trifluoro
Me
H
2,6-dimethyl-4-
H
methyl
aminocarbonyl
phenyl
3,4-Dimethoxy-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
phenylmethyl
aminocarbonyl
Benzyl
methyl
4-fluoro
H
H
2,6-dimethyl-4-
H
phenyl
aminocarbonyl
4-Dimethylamino-
methyl
phenyl
H
Me
2,6-dimethyl-4-
H
phenylmethyl
hydroxy
4-Methylamino-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
phenylmethyl
hydroxy
4-Methylcarbonyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
amino-phenyl
hydroxy
methyl
4-Carboxy-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
phenylmethyl
hydroxy
4-Hydroxy-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
phenylmethyl
hydroxy
Benzyl
methyl
4-fluoro
H
H
2,6-dimethyl-4-
H
phenyl
hydroxy
Isopropyl
methyl
4-fluoro
H
H
2,6-dimethyl-4-
H
phenyl
hydroxy
Isopropyl
hydroxy
phenyl
H
H
2,6-dimethyl-4-
H
methyl
aminocarbonyl
Isopropyl
H
phenyl
H
H
2,6-dimethyl, 4-
H
aminocarbonyl
3,4-Dichloro-
H
phenyl
H
H
2,6-dimethyl-4-
H
phenylmethyl
hydroxy
4-Methylcarbonyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
oxy-phenyl
hydroxy
methyl
4-Methoxy
methyl
phenyl
H
H
2,6-dimethyl-4-
H
carbonyl-
hydroxy
phenylmethyl
3-Aminocarbonyl-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
phenylmethyl
hydroxy
3-Cyano-phenyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
methyl
hydroxy
Pyridin-3-yl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
methyl
hydroxy
Pyridin-2-yl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
methyl
hydroxy
1-(R)-Phenylethyl
H
phenyl
H
H
2,6-dimethyl-4-
H
aminocarbonyl
1-(R)-Phenylethyl
H
phenyl
H
H
2,6-dimethyl-4-
H
aminocarbonyl
2-Methoxy-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
phenylmethyl
hydroxy
2,6-Dichloro-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
phenylmethyl
hydroxy
3-Phenoxy-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
phenylmethyl
hydroxy
Naphthalen-1-yl-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
methyl
hydroxy
Naphthalen-2-yl-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
methyl
hydroxy
3-Bromo-phenyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
methyl
hydroxy
3,4-Dimethoxy-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
phenylmethyl
hydroxy
2,4-Dichloro-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
phenylmethyl
hydroxy
Benzyl
isobutyl
phenyl
H
H
2,6-dimethyl-4-
H
hydroxy
Benzyl
benzyl
phenyl
H
H
2,6-dimethyl-4-
H
hydroxy
Benzyl
isopropyl
phenyl
H
H
2,6-dimethyl-4-
H
hydroxy
Benzyl
H
phenyl
H
H
2,6-dimethyl-4-
H
aminocarbonyl
3-Phenyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
prop-1-yl
aminocarbonyl
2-Phenylethyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
aminocarbonyl
1-Phenylethyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
diastereomer A
aminocarbonyl
1-Phenylethyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
diasteromer B
aminocarbonyl
Benzyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
aminocarbonyl
Isopropyl
H
4-biphenyl
Me
H
2,6-dimethyl-4-
H
hydroxy
Isopropyl
H
3-fluoro
Me
H
2,6-dimethyl-4-
H
phenyl
hydroxy
Isopropyl
H
2-fluoro
Me
H
2,6-dimethyl-4-
H
phenyl
hydroxy
Isopropyl
hydroxy
phenyl
H
H
2,6-dimethyl-4-
H
methyl
hydroxy
H
hydroxy
phenyl
H
H
2,6-dimethyl-4-
H
methyl
hydroxy
Isopropyl
3-(amino
phenyl
H
H
2,6-dimethyl-4-
H
methyl)
hydroxy
phenyl
methyl
Isopropyl
3-amino
phenyl
H
H
2,6-dimethyl-4-
H
carbonyl
hydroxy
phenyl
methyl
Isopropyl
3-cyano
phenyl
H
H
2,6-dimethyl-4-
H
phenyl
hydroxy
methyl
Isopropyl
H
4-carboxy
Me
H
2,6-dimethyl-4-
H
phenyl
hydroxy
Isopropyl
H
pyridin-3-yl
Me
H
2,6-dimethyl-4-
H
hydroxy
Isopropyl
H
4-methoxy
Me
H
2,6-dimethyl-4-
H
phenyl
hydroxy
Isopropyl
H
3,5-difluoro
Me
H
2,6-dimethyl-4-
H
phenyl
hydroxy
Cyclohexyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
aminocarbonyl
Carboxymethyl
H
phenyl
H
H
2,6-dimethyl-4-
H
hydroxy
Isopropyl
H
3-hydroxy
Me
H
2,6-dimethyl-4-
H
methyl
hydroxy
phenyl
Isopropyl
H
pyrimidin-5-
Me
H
2,6-dimethyl-4-
H
yl
hydroxy
Isopropyl
H
pyrimidin-5-
Me
H
4-hydroxy
H
yl
Isopropyl
H
3-carboxy
Me
H
2,6-dimethyl-4-
H
phenyl
hydroxy
Isopropyl
H
3-biphenyl
Me
H
2,6-dimethyl-4-
H
hydroxy
Isopropyl
H
2-methoxy
Me
H
2,6-dimethyl-4-
H
phenyl
hydroxy
Isopropyl
benzyl
phenyl
H
H
3-aminocarbonyl
H
Isopropyl
isopropyl
phenyl
H
H
3-aminocarbonyl
H
Isopropyl
benzyl
phenyl
H
H
2,6-dimethyl-4-
H
oxy
hydroxy
methyl
Isopropyl
isobutyl
phenyl
H
H
2,6-dimethyl-4-[2-
H
(2,6-dimethyl-4-
hydroxyphenyl)-1-
amino-
ethylcarbonxyloxy]
phenyl
Isopropyl
isobutyl
phenyl
H
H
2,6-dimethyl-4-
H
hydroxy
Isopropyl
H
3,5-dichloro
Me
H
2,6-dimethyl-4-
H
phenyl
hydroxy
Isopropyl
H
3-methoxy
Me
H
2,6-dimethyl-4-
H
phenyl
hydroxy
Isopropyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
aminocarbonyl
Isopropyl
H
2-biphenyl
Me
H
2,6-dimethyl-4-
H
hydroxy
Isopropyl
H
thiophen-3-
Me
H
2,6-dimethyl-4-
H
yl
hydroxy
Isopropyl
H
4-chloro
Me
H
2,6-dimethyl-4-
H
phenyl
hydroxy
Isopropyl
H
3-methyl
Me
H
2,6-dimethyl-4-
H
carbonyl
hydroxy
amino
phenyl
Isopropyl
H
4-trifluoro
Me
H
2,6-dimethyl-4-
H
methyl
hydroxy
phenyl
Isopropyl
H
naphthal
Me
H
2,6-dimethyl-4-
H
en-2-yl
hydroxy
Isopropyl
H
2-trifluoro
Me
H
2,6-dimethyl-4-
H
methyl
hydroxy
phenyl
Isopropyl
H
thiophen-3-yl
Me
H
4-hydroxy
H
Isopropyl
H
pyridin-3-yl
Me
H
4-hydroxy
H
Isopropyl
H
phenyl
Me
H
4-hydroxy
H
Isopropyl
H
2-chloro
Me
H
2,6-dimethyl-4-
H
phenyl
hydroxy
Isopropyl
H
naphthal
Me
H
2,6-dimethyl-4-
H
en-1-yl
hydroxy
Isopropyl
benzyl
phenyl
H
H
3-cyano
H
Isopropyl
benzyl
phenyl
H
H
4-hydroxy
H
Isopropyl
benzyl
phenyl
H
H
2,6-dimethyl-4-
H
hydroxy
Isopropyl
isopropyl
phenyl
H
H
3-cyano
H
Isopropyl
isopropyl
phenyl
H
H
4-hydroxy
H
Isopropyl
isopropyl
phenyl
H
H
2,6-dimethyl-4-
H
hydroxy
Isopropyl
H
4-fluoro
Me
H
2,6-dimethyl-4-
H
phenyl
hydroxy
Isopropyl
H
3,5-bis-
Me
H
2,6-dimethyl-4-
H
trifluoro
hydroxy
methyl
phenyl
Isopropyl
H
2-methyl
Me
H
2,6-dimethyl-4-
H
phenyl
hydroxy
Isopropyl
H
phenyl
Me
H
2,6-dimethyl-4-
H
hydroxy
2-Dimethylamino-
H
phenyl
H
H
2,6-dimethyl-4-
H
1-methyl-eth-1-yl
hydroxy
Methyl
isobutyl
phenyl
H
H
3-aminocarbonyl
H
Methyl
isobutyl
phenyl
H
H
3-cyano
H
Ethyl
isopropyl
phenyl
H
H
2,6-dimethyl-4-
H
hydroxy
Methyl
isopropyl
phenyl
H
H
4-hydroxy
H
H
3-amino
phenyl
H
H
2,6-dimethyl-4-
H
carbonyl
hydroxy
phenyl
methyl
H
3-cyano
phenyl
H
H
2,6-dimethyl-4-
H
phenyl
hydroxy
methyl
Methyl
isobutyl
phenyl
H
H
2,6-dimethyl-4-
H
hydroxy
H
benzyl
phenyl
H
H
2,6-dimethyl-4-
H
oxy
hydroxy
methyl
H
isobutyl
phenyl
H
H
2,6-dimethyl-4-
H
hydroxy
H
benzyl
phenyl
H
H
2,6-dimethyl-4-
H
hydroxy
Isopropyl
H
phenyl
H
H
2,6-dimethyl-4-
H
aminocarbonyl
Methyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
morpholin-1-
ylcarbonyl
Methyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
ethylamino
carbonyl
Methyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
methylamino
carbonyl
H
isopropyl
phenyl
H
H
3-aminocarbonyl
H
H
isopropyl
phenyl
H
H
3-cyano
H
H
isopropyl
phenyl
H
H
2,6-dimethyl-4-
H
hydroxy
H
isopropyl
phenyl
H
H
4-hydroxy
H
Methyl
methyl
phenyl
H
H
4-aminosulfonyl
H
Cyclohexyl
H
phenyl
H
H
2,6-dimethyl-4-
H
hydroxy
Cyclohexyl
H
phenyl
H
H
2,6-dimethyl-4-
H
4-hydroxy
Cyclopropyl
H
phenyl
H
H
2,6-dimethyl-4-
H
methyl
hydroxy
Cyclopropyl
H
phenyl
H
H
4-hydroxy
H
methyl
Isopropyl
H
phenyl
H
H
2,6-dimethyl-4-
H
hydroxy
Isopropyl
H
phenyl
H
H
4-hydroxy
H
Methyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
aminocarbonyl
Ethyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
aminocarbonyl
Methyl
H
phenyl
H
H
4-hydroxy
H
Methyl
H
phenyl
H
H
2,6-dimethyl-4-
H
hydroxy
Methyl
methyl
phenyl
H
H
4-aminocarbonyl
H
Methyl
methyl
benzyl
H
H
4-hydroxy
H
Methyl
methyl
benzyl
H
H
2,6-dimethyl-4-
H
hydroxy
Methyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
hydroxy
H
methyl
phenyl
H
H
2,6-dimethyl-4-
H
hydroxy
Methyl
methyl
phenyl
H
H
4-hydroxy
H
H
methyl
phenyl
H
H
4-hydroxy
H
Ethyl
methyl
phenyl
H
H
4-hydroxy
H
Ethyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
hydroxy
Benzyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
hydroxy
Benzyl
methyl
phenyl
H
H
4-hydroxy
H
Isopropyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
hydroxy
Isopropyl
methyl
phenyl
H
H
4-hydroxy
H
2-Carboxy-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
phenyl
aminocarbonyl
methyl
3-Carboxy-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
phenyl
aminocarbonyl
methyl
2-Bromo-4,5-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
dimethoxy-
aminocarbonyl
phenylmethyl
2-Carboxy-4,5-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
dimethoxy-
aminocarbonyl
phenylmethyl
3-Carboxy-4-
methyl
phenyl
H
H
H
H
methoxy-phenyl
methyl
3-Carboxy-4-
methyl
phenyl
H
H
2,6-dimethyl
H
methoxy-phenyl
methyl
3-Methoxycarbonyl-
methyl
phenyl
H
H
2,6-dimethyl
H
4-methoxy-
phenylmethyl
3,4-Dimethoxy-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
phenylmethyl
imidazol-2-yl
3,4-Dimethoxy-
methyl
phenyl
H
H
2,6-dimethyl
H
phenylmethyl
3-Carboxy-4-
methyl
4-chloro
H
H
2,6-dimethyl-4-
H
methoxy-phenyl
aminocarbonyl
methyl
3-Carboxy-4-
methyl
4-chloro
H
H
2,6-dimethyl-4-
H
methoxy-phenyl
aminocarbonyl
methyl
3-Carboxy-4-
methyl
4-chloro
H
H
2,6-dimethyl-4-
H
methoxy-phenyl
aminocarbonyl
methyl
4-Carboxy-
methyl
4-chloro
Me
H
2,6-dimethyl-4-
H
phenylmethyl
phenyl
aminocarbonyl
3-Carboxy-4-
methyl
4-chloro
Cl
H
2,6-dimethyl-4-
H
methoxy-phenyl
phenyl
aminocarbonyl
methyl
3-(1H-tetrazol-5-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
yl)-phenylmethyl
aminocarbonyl
3-Carboxy-4-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
trifluoromethoxy-
aminocarbonyl
phenylmethyl
Bis-3,4-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
trifluoromethoxy-
aminocarbonyl
phenylmethyl
3-Carboxy-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
phenylmethyl
aminocarbonyl
Quinolin-4-yl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
methyl
hydroxy
4-Methoxy
methyl
phenyl
H
H
2,6-dimethyl-4-
H
naphthalen-1-
hydroxy
ylmethyl
4-Trifluoromethoxy-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
phenylmethyl
hydroxy
4-Trifluoromethyl-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
phenylmethyl
hydroxy
4-Isopropyloxy-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
phenylmethyl
hydroxy
3-Ethoxyphenyl-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
methyl
hydroxy
5-Methoxycarbonyl-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
pyridin-2-yl
aminocarbonyl
methyl
5-Carboxy-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
pyridin-2-
aminocarbonyl
ylmethyl
6-Carboxy-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
pyridin-3-
aminocarbonyl
ylmethyl
6-Methoxycarbonyl-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
pyridin-3-
aminocarbonyl
ylmethyl
5-Carboxy-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
furan-2-ylmethyl
aminocarbonyl
5-Methoxy
methyl
phenyl
H
H
2,6-dimethyl-4-
H
carbonyl-
aminocarbonyl
furan-2-ylmethyl
3,4-Dimethoxy-
hydroxy
phenyl
H
H
2,6-dimethyl-4-
H
phenylmethyl
methyl
aminocarbonyl
Benzyl
hydroxy
phenyl
H
H
2,6-dimethyl-4-
H
methyl
aminocarbonyl
3-Carboxy-4-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
methoxy-phenyl
hydroxy
methyl
3-Carboxy-4-
methyl
phenyl
H
H
4-hydroxy
H
methoxy-phenyl
methyl
3-Carboxy-4-
methyl
phenyl
H
H
4-hydroxy
H/Me
methoxy-phenyl
methyl
3-Carboxy-4-
H
phenyl
H
H
4-hydroxy
H
methoxy-phenyl
methyl
3-Carboxy-4-
H
phenyl
H
H
4-hydroxy
H/Me
methoxy-phenyl
methyl
3-Carboxy-4-
H
phenyl
H
H
2,6-dimethyl-4-
H
methoxy-phenyl
hydroxy
methyl
3-Methoxycarbonyl-
methyl
phenyl
H
H
H
H
4-methoxy-
phenylmethyl
3-(1H-tetrazol-5-
methyl
phenyl
H
H
4-aminocarbonyl
H
yl)-phenylmethyl
3-Methoxycarbonyl-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
4-methoxy-
hydroxy
phenylmethyl
3-Methoxycarbonyl
methyl
phenyl
H
H
4-aminocarbonyl
H
3-Carboxy
methyl
phenyl
H
H
4-aminocarbonyl
H
3-Methoxycarbonyl
H
phenyl
H
H
2,6-dimethyl-4-
H
aminocarbonyl
3-Carboxy
H
phenyl
H
H
2,6-dimethyl-4-
H
aminocarbonyl
3-Carboxy-4-
methyl
phenyl
H
H
4-benzyloxy-
H/Me
methoxy-
phenylmethyl
3-Carboxy-4-
methyl
phenyl
H
H
4-aminocarbonyl
H
methoxy-
phenylmethyl
3-Carboxy-
methyl
4-chloro
Me
H
4-aminocarbonyl
H
phenyl
3-Methoxycarbonyl-
methyl
phenyl
H
H
4-hydroxy
H
4-methoxy-
phenylmethyl
5-Methoxycarbonyl-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
furan-2-ylmethyl
hydroxy
5-Carboxy-furan-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
2-ylmethyl
hydroxy
3-Carboxy-4-
methyl
3-bromo
H
H
2,6-dimethyl-4-
H
methoxy-
phenyl
aminocarbonyl
phenylmethyl
3-Carboxy-4-
methyl
4-iodo
H
H
2,6-dimethyl-4-
H
methoxy-
aminocarbonyl
phenylmethyl
3-Carboxy-4-
methyl
2-bromo
H
H
2,6-dimethyl-4-
H
methoxy-
phenyl
aminocarbonyl
phenylmethyl
3-Carboxy-4-
methyl
4-bromo
H
H
2,6-dimethyl-4-
H
methoxy-
aminocarbonyl
phenylmethyl
3-Carboxy-4-
methyl
phenyl
H
H
2,6-dimethyl
H
methoxy-
phenylmethyl
3-Carboxy-4-
methyl
4-chloro
methyl
H
4-hydroxy
H
methoxy-
phenylmethyl
3-Aminocarbonyl-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
4-methoxy
aminocarbonyl
phenylmethyl
3-(Morpholin-4-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
ylcarbonyl)-4-
aminocarbonyl
methoxy
phenylmethyl
-3-Aminocarbonyl-
methyl
phenyl
H
H
4-hydroxy
H
4-methoxy-
phenylmethyl
3-(Morpholin-4-
methyl
phenyl
H
H
4-hydroxy
H
ylcarbonyl)-4-
methoxy-
phenylmethyl
3-(2-Hydroxy
methyl
phenyl
H
H
2,6-dimethyl-4-
H
eth-1-yl-
aminocarbonyl
aminocarbonyl)-
4-methoxy
phenylmethyl
3-(Cyclopropyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
aminocarbonyl)-
aminocarbonyl
4-methoxy-
phenylmethyl
3-(Phenylamino
methyl
phenyl
H
H
2,6-dimethyl-4-
H
carbonyl)-4-
aminocarbonyl
methoxy-
phenylmethyl
5-Methoxycarbonyl-
methyl
phenyl
H
H
4-aminocarbonyl
H
furan-2-ylmethyl
5-Carboxy-furan-
methyl
phenyl
H
H
4-aminocarbonyl
H
2-ylmethyl
3-(Phenylamino
methyl
phenyl
H
H
2,6-dimethyl-4-
H
carbonyl)-4-
hydroxy
methoxy-
phenylmethyl
3-(3-carboxyphenyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
aminocarbonyl)-
hydroxy
4-methoxy-
phenylmethyl
3-(1H-Tetrazol-5-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
yl)-4-methoxy-
hydroxy
phenylmethyl
3-(4-Carboxyphenyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
aminocarbonyl)-
hydroxy
4-methoxy-
phenylmethyl
3-(2-t-Butyl-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
tetrazol-5-yl)-4-
aminocarbonyl
methoxy-
phenylmethyl
3-Methoxycarbonyl-
methyl
phenyl
H
H
2,6-dimethyl-4-
Methoxy-
4-methoxy-
aminocarbonyl
carbonyl
phenylmethyl
2-Methoxycarbonyl-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
pyridin-4-yl
aminocarbonyl
methyl
4-Methoxycarbonyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
pyridin-2-yl
aminocarbonyl
methyl
6-Methoxycarbonyl-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
pyridin-2-
aminocarbonyl
ylmethyl
3-Methoxycarbonyl-
methyl
phenyl
H
H
2,6-dimethyl-4-
Methoxy-
4-methoxy-
aminocarbonyl
carbonyl
phenylmethyl
2-Carboxy-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
pyridin-4-
aminocarbonyl
ylmethyl
and
6-Carboxy-
methyl
phenyl
H
H
2,6-dimethyl-4-
H.
pyridin-2-
aminocarbonyl
ylmethyl
37. A compound of Formula (Ic)
Formula (Ic)
wherein L is O and R 1 , R 2 , R 3-1 , R 3-2 , R 5 , R a , R b , and R 41 are dependcently
selected from the group consisting of:
R 1
R 2
R 3-1
R 3-2
R 5
R 41
R a /R b
3,4-Dimethoxy-
benzyloxy
phenyl
H
H
2,6-dimethyl-4-
H
phenylmethyl
methyl
hydroxy
Isopropyl
hydroxy
phenyl
H
H
2,6-dimethyl-4-
H
methyl
hydroxy
Isopropyl
methyl
4-
2,6-dimethyl-4-
H
fluorophenyl
hydroxy
2-Phenylethyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
aminocarbonyl
Benzyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
aminocarbonyl
Cyclohexyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
aminocarbonyl
Methyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
aminocarbonyl
Methyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
(morpholin-4-
carbonyl)
Methyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
ethylamino
carbonyl
Methyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
methylamino
carbonyl
Methyl
methyl
phenyl
H
H
4-aminocarbonyl
H
Methyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
hydroxy
H
methyl
phenyl
H
H
2,6-dimethyl-4-
H
hydroxy
Methyl
methyl
phenyl
H
H
4-hydroxy
H
H
methyl
phenyl
H
H
4-hydroxy
H
Ethyl
methyl
phenyl
H
H
4-hydroxy
H
Ethyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
hydroxy
Benzyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
hydroxy
Benzyl
methyl
phenyl
H
H
4-hydroxy
H
Isopropyl
methyl
phenyl
H
H
4-hydroxy
H
Isopropyl
methyl
phenyl
H
H
2,6-dimethyl-4-
H
hydroxy
3-Carboxy-
methyl
4-
Me
H
2,6-dimethyl-4-
H
phenyl
chlorophenyl
aminocarbonyl
methyl
3-Carboxy-
methyl
4-
Me
H
4-aminocarbonyl
H
phenyl
chlorophenyl
3-Carboxy-4-
methyl
4-
Me
H
2,6-dimethyl-4-
H
methoxy-
chlorophenyl
aminocarbonyl
phenylmethyl
3-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
Methoxycarbon-
aminocarbonyl
yl-4-methoxy-
phenylmethyl
3-
methyl
phenyl
H
H
4-aminocarbonyl
H
Methoxycarbon-
yl-4-methoxy-
phenylmethyl
3-Carboxy-4-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
methoxy-
aminocarbonyl
phenylmethyl
3-Carboxy-4-
methyl
phenyl
H
H
4-aminocarbonyl
H
methoxy-
phenylmethyl
3-Carboxy-4-
methyl
4-
Me
H
4-hydroxy
H
methoxy-
chlorophenyl
phenylmethyl
6-Methoxy-
methyl
phenyl
H
H
2,6-dimethyl-4-
H
carbonyl-
aminocarbonyl
pyridin-2-yl
methyl
and
3-Carboxy-4-
methyl
4-
H
H
4-aminocarbonyl
H.
methoxy-
chlorophenyl
phenylmethyl
38. A compound of Formula (Id)
Formula (Id)
wherein L is O and R 1 , R 2 , R 3-1 , R 3-2 , R 5 , R a , R b , and R 41 are
dependently selected from the group consisting of:
R 1
R 2
R 3-1
R 3-2
R 5
R 41
R a /R b
3-Carboxy-4-
methyl
phenyl
H
H
4-amino-
H.
methoxyphenyl
carbonyl
methyl
39. A compound of Formula (Ie)
Formula (Ie)
wherein L is O and R 1 , R 2 , R 3-1 , R 3-2 , R 5 , R a , R b , and R 41 are
dependently selected from the group consisting of:
R 1
R 2
R 3-1
R 3-2
R 5
R 41
R a /R b
3-
methyl
phenyl
H
H
4-amino-
H
Methoxycarbon-
carbonyl
yl-4-methoxy-
phenylmethyl
and
3-Carboxy-4-
methyl
phenyl
H
H
4-amino-
H.
methoxy-
carbonyl
phenylmethyl
40. A compound selected from the group consisting of
and
41. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
42. The compound of claim 1 that is the hydrochloride salt of 5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid dihydrochloride.
43. The composition of claim 41 wherein the compound is the hydrochloride salt of 5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid.