Nonpeptide HIV-1 protease inhibitors
Novel compounds and compositions for treating patients in need of relief from HIV, AIDS, and AIDS-related diseases are described. Methods for treating HIV, AIDS, and AIDS-related diseases using the compounds described herein are also described.
1. A method for treating a patient infected with a human immunodeficiency virus or in need of relief from a human immunosuppressive virus infection comprising administering a therapeutically effective amount of a composition comprising a compound of the formula
or a pharmaceutically acceptable salt thereof; wherein
R is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted;
X 2 is —C(O)— or —CH 2 — and X 3 is —C(O)—;
Q 1 is optionally substituted 1,3-phenylene;
X 1A is a bond, —N(R 17 )—, —S(O) q —, or optionally substituted alkylene; and R 1A is —S(O) 2 R 14 , —C(O)R 12 , —N(R 8 )R 9 , alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted, or R 1A and X 1A together with the attached nitrogen form an optionally substituted heterocycle;
X 4 is —C(O)— or —S(O) 2 —, and R 3 is C 3 -C 10 alkyl or cycloalkyl;
X 5 is optionally substituted alkylene;
R 2 is hydrogen; R 4 and R 5 are each independently selected from the group consisting of aryl and heteroaryl, each of which is optionally substituted;
q is independently 0, 1, or 2 in each instance;
R 20 is hydrogen;
R 8 is in each instance independently selected from the group consisting of hydrogen, —C(O)R 13 , —S(O) 2 R 14 , alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted;
R 9 is in each instance independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted;
R 12 and R 13 are each independently selected from the group consisting of hydrogen, —OR 19 , —N(R 18 )R 19 , alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted;
R 14 is in each instance independently selected from the group consisting of hydrogen, —N(R 18 )R 19 , alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted; and
R 17 , R 18 , and R 19 are in each instance independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted.
2. The method of claim 1 wherein R 1A and X 1A together with the attached nitrogen form an optionally substituted heterocycle.
3. A method for treating a patient infected with a human immunodeficiency virus or in need of relief from a human immunosuppressive virus infection comprising administering a therapeutically effective amount of a composition comprising a compound of the formula
or a pharmaceutically acceptable salt thereof; wherein
R is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted;
X 2 and X 3 are —C(O)— and Q 1 is optionally substituted 1,3-phenylene;
X 1A is a bond, —N(R 17 )—, —S(O) q —, or optionally substituted alkylene; and R 1A is —S(O) 2 R 14 , —C(O)R 12 , —N(R 8 )R 9 , alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted, or R 1A and X 1A together with the attached nitrogen form an optionally substituted heterocycle;
X 4 is —C(O)— or —S(O) 2 —, and R 3 is C 3 -C 10 alkyl or cycloalkyl;
X 5 is optionally substituted alkylene,
R 2 is hydrogen;
R 4 and R 5 are each independently selected from the group consisting of aryl and heteroaryl, each of which is optionally substituted;
q is independently 0, 1, or 2 in each instance;
R 8 is in each instance independently selected from the group consisting of hydrogen, —C(O)R 13 , —S(O) 9 R 14 , alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted;
R 9 is in each instance independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted;
R 12 and R 13 are each independently selected from the group consisting of hydrogen, —OR 19 , —N(R 18 )R 19 , alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted;
R 14 is in each instance independently selected from the group consisting of hydrogen, —N(R 18 )R 19 , alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted; and
R 17 , R 18 , and R 19 are in each instance independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted.
4. The method of claim 1 wherein R is an optionally substituted heteroaryl.
5. The method of claim 1 wherein R 5 is optionally substituted aryl.
6. A method for treating a patient infected with a human immunodeficiency virus or in need of relief from a human immunosuppressive virus infection comprising administering a therapeutically effective amount of a composition comprising a compound of the formula
or a pharmaceutically acceptable salt thereof; wherein
R is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted;
X 2 and X 3 are —C(O)— and Q 1 is optionally substituted 1,3-phenylene;
X 1A is a bond, —N(R 17 )—, —S(O) q —, or optionally substituted alkylene; and R 1A is —S(O) 2 R 14 , —C(O)R 12 , —N(R 8 )R 9 , alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted, or R 1A and X 1A together with the attached nitrogen form an optionally substituted heterocycle;
X 4 is SO 2 ; and R 4 is optionally substituted aryl;
R 3 is alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted;
X 5 is optionally substituted alkylene;
R 2 is hydrogen;
R 5 is selected from the group consisting of aryl and heteroaryl, each of which is optionally substituted;
q is independently 0, 1, or 2 in each instance;
R 8 is in each instance independently selected from the group consisting of hydrogen, —C(O)R 13 , —S(O) n R 14 , alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted;
R 9 is in each instance independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted;
R 12 and R 13 are each independently selected from the group consisting of hydrogen, —OR 19 , —N(R 18 )R 19 , alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted;
R 14 is in each instance independently selected from the group consisting of hydrogen, —N(R 18 )R 19 , alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted; and
R 17 , R 18 , and R 19 are in each instance independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted.
7. The method of claim 3 wherein R 3 is branched alkyl.
8. The method of claim 1 wherein X 5 is optionally substituted alkylene; and R 5 is optionally substituted aryl.
9. The method of claim 1 wherein R is optionally substituted heteroaryl, X 1A is alkylene, and R 1A is alkyl.
10. The method of claim 9 wherein X 1A is methylene.
11. The method of claim 6 wherein R 1A and X 1A together with the attached nitrogen form an optionally substituted heterocycle.
12. The method of claim 6 wherein R is an optionally substituted heteroaryl.
13. The method of claim 6 wherein R 5 is optionally substituted aryl.
14. The method of claim 6 wherein X 5 is optionally substituted alkylene; and R 5 is optionally substituted aryl.
15. The method of claim 6 wherein R is optionally substituted heteroaryl, X 1A is alkylene, and R 1A is alkyl.
16. The method of claim 15 wherein X 1A is methylene.
17. The method of claim 7 wherein the compound is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.