4-amino-4-oxobutanoyl peptides as inhibitors of viral replication
The invention provides 4-amino-4-oxobutanoyl peptide compounds of Formula I and the pharmaceutically salts and hydrates thereof. The variables R 1 -R 9 , R 16 , R 18 , R 19 , n, M, n, M, and Z are defined herein. Certain compounds of Formula I are useful as antiviral agents. Certain 4-amino-4-oxobutanoyl peptide compounds disclosed herein are potent and/or selective inhibitors of viral replication, particularly Hepatitis C virus replication. The invention also provides pharmaceutical compositions containing one or more 4-amino-4-oxobutanoyl peptide compounds and one or more pharmaceutically acceptable carriers. Such pharmaceutical compositions may contain 4-amino-4-oxobutanoyl peptide compound as the only active agent or may contain a combination of 4-amino-4-oxobutanoyl peptide containing peptides compound and one or more other pharmaceutically active agents. The invention also provides methods for treating viral infections, including Hepatitis C infections, in mammals.
1. A compound of the formula:
or a pharmaceutically acceptable salt thereof, where
R 1 and R 2 are taken together to form an optionally substituted 5- to 7-membered heterocyclic ring containing 0 or 1 additional N, S, or O atoms, or an optionally substituted 5- to 7-membered heterocyclic ring containing 0 or 1 additional N, S, or O atoms fused to an optionally substituted 5- to 7-membered carbocyclic or heterocyclic ring;
R 3 , R 4 , R 5 , and R 6 are independently
(a) hydrogen, halogen, or amino, or
(b) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, (C 3 -C 7 cycloalkenyl)C 0 -C 4 alkyl, (heterocycloalkyl)C 0 -C 4 alkyl, C 2 -C 6 alkanoyl, or mono- or di-C 1 -C 6 alkylamino, each of which is optionally substituted; and
R 7 and R 8 are joined to form an optionally substituted 3- to 7-membered cycloalkyl ring or an optionally substituted 3- to 7-membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently chosen from N, S, and O;
or
R 5 is a C 7 -C 11 saturated or unsaturated hydrocarbon chain that is covalently bound to an optionally substituted cycloalkyl ring formed by R 7 and R 8 being joined to form a 3- to 7-membered optionally substituted cycloalkyl ring; wherein R 6 is hydrogen, C 1 -C 6 alkyl, or (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl;
R 9 is hydroxyl, amino, —COOH, —NR 10 R 11 , —OR 12 , —SR 12 , —NR 10 (S═O)R 11 , —NR 10 SO 2 R 11 , —NR 10 SONR 11 R 12 , —NR 10 SO 2 NR 11 R 12 , —(C═O)OR 10 , —NR 10 (C═O)OR 11 , or —CONR 10 R 11 , or
R 9 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, (C 3 -C 7 cycloalkenyl)C 0 -C 4 alkyl, (C 3 -C 7 cycloalkyl)CH 2 SO 2 —, (C 3 -C 7 cycloalkyl)CH 2 SO 2 NR 10 —, (hetero cycloalkyl)C 0 -C 4 alkyl, (aryl)C 0 -C 2 alkyl, or (5- to 10-membered heteroaryl)C 0 -C 2 alkyl, each of which is optionally substituted; R 10 , R 11 , and R 12 are independently at each occurrence hydrogen, or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (aryl)C 0 -C 2 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl, (C 3 -C 7 cycloalkenyl)C 0 -C 2 alkyl, (heterocycloalkyl)C 0 -C 2 alkyl, or (5- to 10-membered heteroaryl)C 0 -C 2 alkyl, each of which is optionally substituted;
n is 0, 1, or 2;
M is hydrogen;
Y is absent, CR 18 R 19 , NR 20 , S, O, —O(C═O)(NR 20 )—, NH(C═O)(NR 20 )—, NH(S═O)(NR 20 )—, or —O(C═O)—;
Z is (mono- or bicyclic aryl)C 0 -C 2 alkyl or (mono- or bicyclic heteroaryl)C 0 -C 2 alkyl,
each of which Z is substituted with
0 or 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, —CONH 2 , —COOH, —SO 2 NR 11 R 12 , —(C═O)NR 11 R 12 , —NR 11 (C═O)R 12 , C 1 -C 4 alkyl, C 2 -C 4 alkanoyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, mono- and di-C 1 -C 4 alkylamino, C 1 -C 4 alkylester, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy, and
0 or 1 (C 3 -C 7 cycloalkyl)C 0 C 2 alkyl, (phenyl)C 0 -C 2 alkyl, (phenyl)C 0 -C 2 alkoxy, (5- or 6-membered heteroaryl)C 0 -C 2 alkyl, (5- or 6-membered heteroaryl)C 0 -C 2 alkoxy, naphthyl, indanyl, (5- or 6-membered heterocycloalkyl)C 0 -C 2 alkyl, or 9- or 10-membered bicyclic heteroaryl, each of which is substituted with 0, 1, or 2 substituents independently chosen from:
(c) halogen, hydroxyl, amino, cyano, nitro, —COOH, —CONH 2 , CH 3 (C═O)NH—, ═NOH, C 1 -C 4 alkoxy, C 1 -C 4 hydroxyalkyl, mono- and di-C 1 -C 4 alkylamino, trifluoromethyl, and trifluoromethoxy, and
(d) phenyl and 5- or 6-membered heteroaryl, each of which is substituted with 0 or 1 or more of halogen, hydroxyl, C 1 -C 4 alkyl, and C 1 -C 2 alkoxy;
R 16 represents 0 to 4 substituents is independently chosen at from halogen, C 1 -C 2 alkyl, and C 1 -C 2 alkoxy;
R 18 and R 19 are independently hydrogen, hydroxyl, halogen, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, C 1 -C 2 haloalkyl, or C 1 -C 2 haloalkoxy; and
R 20 is hydrogen, C 1 -C 2 alkyl, C 1 -C 2 haloalkyl, or C 1 -C 2 haloalkoxy.
2. A compound or salt of claim 1 , wherein
R 1 and R 2 are joined to form a pyrrolidine, piperidine, or piperazine ring or a piperazine ring fused to a phenyl, each of which is optionally substituted with 0 to 2 substituents independently chosen from halogen, hydroxyl, amino, CONH 2 , —COOH, C 1 -C 2 alkyl, and C 1 -C 2 alkoxy.
3. A compound or salt of claim 2 , wherein
R 3 and R 4 are independently hydrogen or methyl.
4. A compound or salt of claim 3 , wherein
R 5 and R 6 are independently hydrogen, C 1 -C 4 alkyl, or (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl.
5. A compound or salt of claim 3 , wherein
R 7 and R 8 are joined to form a 3- to 7-membered cycloalkyl ring or 3- to 7-membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently chosen from N, S, and O, each of which ring is substituted with 0 to 2 substituents independently chosen from halogen, hydroxyl, amino, cyano, vinyl, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, trifluoromethyl, and trifluoromethoxy.
6. A compound or salt of claim 2 wherein
R 3 , R 4 , and R 6 , are independently hydrogen or methyl;
R 5 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, (C 3 -C 7 cycloalkenyl)C 0 -C 4 alkyl, (heterocycloalkyl)C 0 -C 4 alkyl, C 2 -C 6 alkanoyl, or mono- or di-C 1 -C 6 alkylamino; and
R 7 and R 8 are joined to form an optionally substituted 3- to 7-membered cycloalkyl ring or an optionally substituted 3- to 7-membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently chosen from N, S, and O.
7. A compound or salt of claim 6 , wherein
R 5 is C 1 -C 6 alkyl or (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl; and
R 7 and R 8 are joined to form a cyclopropyl ring, which is unsubstituted or substituted with 1 or 2 C 1 -C 6 alkyl or C 2 -C 6 alkenyl.
8. A compound or salt of claim 7 , of the formula:
9. A compound or salt of claim 2 , wherein
R 3 , R 4 , and R 6 are independently hydrogen or methyl; and
R 5 is a C 7 -C 11 saturated or unsaturated hydrocarbon chain that is covalently bound to an optionally substituted cycloalkyl ring formed by R 7 and R 8 being joined to form a 3- to 7-membered optionally substituted cycloalkyl ring.
10. A compound or salt of claim 2 , of the formula
11. A compound or salt of claim 2 , wherein
R 9 is hydroxyl, amino, —COOH, —NR 10 R 11 , —OR 12 , —NR 10 SO 2 R 11 , —(C═O)OR 10 , or —CONR 10 R 11 .
12. A compound or salt of claim 11 , wherein
R 10 , R 11 , and R 12 are independently
hydrogen, or
C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl, (heterocycloalkyl)C 0 -C 2 alkyl, (phenyl)C 0 -C 2 alkyl, or (5- to 6-membered monocyclic heteroaryl)C 0 -C 2 alkyl, each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxyl, oxo, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, trifluoromethyl, and trifluoromethoxy.
13. A compound or salt of claim 3 , wherein Z is a group of the formula
wherein
X 1 , X 2 , X 3 , X 4 , and X 5 are independently N or CH and no more than two of X 1 -X 5 are N;
G 1 , G 2 , G 3 , and G 4 are independently CH 2 , O, S, or NR 26 , wherein no more than two of G 1 to G 4 are other than hydrogen;
R 21 represents from 0 to 3 groups independently chosen from halogen, hydroxyl, amino, cyano, —CONH 2 , —COOH, C 1 -C 4 alkyl, C 2 -C 4 alkanoyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, mono- and di-C 1 -C 4 alkylamino, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy,
R 22 is hydrogen, halogen, hydroxyl, amino, cyano, —CONH 2 , —COOH, C 1 -C 4 alkyl, C 2 -C 4 alkanoyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, mono- and di-C 1 -C 4 alkylamino, C 1 -C 4 alkylester, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy, or
R 22 is (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl, (phenyl)C 0 -C 2 alkyl, (phenyl)C 0 -C 2 alkoxy, (5- or 6-membered heteroaryl)C 0 -C 2 alkyl, (5- or 6-membered heteroaryl)C 0 -C 2 alkoxy, naphthyl, indanyl, (5- or 6-membered heterocycloalkyl)C 0 -C 2 alkyl, or 9- or 10 membered bicyclic heteroaryl, each of which is substituted with 0, 1, or 2 substituents independently chosen from
(c) halogen, hydroxyl, amino, cyano, nitro, —COOH, —CONH 2 , CH 3 (C═O)NH—, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 hydroxyalkyl, mono- and di-C 1 -C 4 alkylamino, —NR 8 SO 2 R 11 , —C(O)OR 11 , —NR 8 COR 11 , —NR 8 C(O)OR 11 , trifluoromethyl, trifluoromethoxy, and
(d) phenyl and 5- or 6-membered heteroaryl, each of which is substituted with 0 or 1 or more of halogen, hydroxyl, C 1 -C 4 alkyl, C 1 -C 2 alkoxy;
R 23 is 0 to 2 substituents independently chosen from halogen, hydroxyl, C 1 -C 2 alkyl, and C 1 -C 2 alkoxy; and
R 24 is independently chosen at each occurrence from hydrogen and C 1 -C 2 alkyl.
14. A compound or salt of claim 13 , wherein R 22 is
15. A compound or salt of claim 13 , where Z is a group of the formula
wherein
X 1 , X 2 , X 3 , and X 4 , are independently N or CH and no more than two of X 1 -X 4 are N;
R 21 represents from 0 to 3 groups independently chosen from halogen, hydroxyl, amino, cyano, —CONH 2 , —COOH, C 1 -C 4 alkyl, C 2 -C 4 alkanoyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, mono- and di-C 1 -C 4 alkylamino, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy,
R 22 is hydrogen, halogen, hydroxyl, amino, cyano, —CONH 2 , —COOH, C 1 -C 4 alkyl, C 2 -C 4 alkanoyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, mono- and di-C 1 -C 4 alkylamino, C 1 -C 4 alkylester, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy, or
R 22 is (C 3 -C 7 cycloalkyl)C 0 C 2 alkyl, (phenyl)C 0 -C 2 alkyl, (phenyl)C 0 -C 2 alkoxy, (5- or 6-membered heteroaryl)C 0 -C 2 alkyl, (5- or 6-membered heteroaryl)C 0 -C 2 alkoxy, naphthyl, indanyl, (5- or 6-membered heterocycloalkyl)C 0 C 2 alkyl, or 9- or 10 membered bicyclic heteroaryl, each of which is substituted with 0, 1, or 2 substituents independently chosen from
(c) halogen, hydroxyl, amino, cyano, nitro, —COOH, —CONH 2 , CH 3 (C═O)NH—, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 hydroxyalkyl, mono- and di-C 1 -C 4 alkylamino, —NR 8 SO 2 R 11 , —C(O)OR 11 , —NR 8 COR 11 , —NR 8 C(O)OR 11 , trifluoromethyl, and trifluoromethoxy, and
(d) phenyl and 5- or 6-membered heteroaryl, each of which is substituted with 0 or 1 or more of halogen, hydroxyl, C 1 -C 4 alkyl, C 1 -C 2 alkoxy.
16. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds or salts of claim 1 and at least one pharmaceutically acceptable carrier.
17. A method of treating a hepatitis C infection in a patient, comprising providing a therapeutically effective amount of one or more compounds of claim 1 to the patient.
18. A compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 2 are joined to form a pyrrolidine, piperidine, or piperazine ring or a piperazine ring fused to a phenyl, each of which is optionally substituted with 0 to 2 substituents independently chosen from halogen, hydroxyl, amino, CONH 2 , —COOH, C 1 -C 2 alkyl, and C 1 -C 2 alkoxy;
R 3 and R 4 , are hydrogen;
R 9 is hydroxyl, amino, —COOH, —NR 10 R 11 , —OR 12 , —NR 10 SO 2 R 11 , —(C═O)OR 10 , or —CONR 10 R 11 ;
R 10 and R 12 are independently hydrogen or C 1 -C 6 alkyl,
R 11 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl, (heterocycloalkyl)C 0 -C 2 alkyl, (phenyl)C 0 -C 2 alkyl, or (5- to 6-membered monocyclic heteroaryl)C 0 -C 2 alkyl, each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxyl, oxo, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, trifluoromethyl, and trifluoromethoxy;
R 16 is 0 to 2 substituents independently chosen from halogen, C 1 -C 2 alkyl, and C 1 -C 2 alkoxy;
M is hydrogen or methyl;
Z is a quinoline of the formula
in which,
R 21 represents a substituent at the 7-position of the quinoline, and 0 to 2 additional substituents independently chosen from halogen, hydroxyl, amino, cyano, —CONH 2 , —COOH, C 1 -C 4 alkyl, C 2 -C 4 alkanoyl, C 1 -C 4 alkoxy, mono- and di-C 1 -C 4 alkylamino, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy; and
R 22 is (phenyl)C 0 -C 2 alkyl or (pyridyl)C 0 -C 2 alkyl, each of which is substituted with 0, 1, or 2 substituents independently chosen from halogen, hydroxyl, amino, cyano, —COOH,
—CONH 2 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono- and di-C 1 -C 4 alkylamino, trifluoromethyl, and trifluoromethoxy.
19. A compound or salt of claim 18 , wherein R 9 is —NR 10 SO 2 R 11 .
20. A compound or salt of claim 18 , wherein R 10 is hydrogen or methyl and R 11 is cyclopropyl.
21. A compound or salt of claim 18 , wherein M is hydrogen.
22. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds or salts of claim 18 and at least one pharmaceutically acceptable carrier.
23. A method of treating a hepatitis C infection in a patient, comprising providing a therapeutically effective amount of one or more compounds of claim 18 to the patient.