Inhibitors of human immunodeficiency virus replication
Compounds of Formula I, including pharmaceutically acceptable salts thereof, and compositions and methods for treating human immunodeficiency virus (HIV) infection are set forth:
1. A compound of Formula I, or a pharmaceutically acceptable salt thereof:
wherein:
R 0 , R 1 , and R 2 are each independently hydrogen, Cl, F, —OMe, —CN, —C 1 -C 3 alkyl, or —C 3 -C 5 cycloalkyl, wherein C 1 -C 3 alkyl may be optionally substituted with from 1-3 fluorines;
G 2 is hydrogen, 6 membered aryl, 5-6 membered heteroaryl, —C 6 -C 8 alkyl, —C 3 -C 7 cycloalkyl, or —C 1 -C 3 alkyl wherein —C 1 -C 3 alkyl is substituted with G 5 ;
G 3 is hydrogen, methyl, fluoro, chloro, phenyl, OC 1 -C 3 alkyl, or OPh;
G 4 is hydrogen, methyl, fluoro, chloro, phenyl, OC 1 -C 3 alkyl, or OPh;
G 5 is —OG 6 , —C 3 -C 7 cycloalkyl, 6 membered aryl, 5 membered heteroaryl, 4-7 membered heterocycle, —C(O)N(G 7 )(G 8 ), C(O)OH, —SO 2 (G 7 ), —N(G 7 )(G 8 ), —SO 2 -morpholine, C(O)-morpholine, or one of the following:
G 6 is —C 1 -C 6 alkyl, —C 3 -C 7 cycloalkyl, 6 membered aryl, 5 membered heteroaryl, 4-7 membered heterocycle;
G 7 is —C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;
G 8 is —C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;
R 3 is hydrogen, Cl, or F;
R 4 is hydrogen, C 1 -C 3 alkyl, or cyclopropyl wherein cyclopropyl or C 1 -C 3 cycloalkyl is optionally substituted with 1-3 fluorines;
R 5 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or N(G 7 )(G 8 );
W is selected from:
wherein R 6 is methyl optionally substituted with 1 to 3 fluorines.
2. A compound or salt according to claim 1 wherein the position of R 0 , R 1 , and R 2 are
and R 0 , R 1 , and R 2 are each independently selected from hydrogen, Cl, F, —OCH 3 , —CN, or —CH 3 with the proviso that substituents Cl, —OMe, and —CH 3 may not be used more than twice and substituent —CN may not be used more than once.
3. A compound or salt according to claim 1 wherein G 3 and G 4 are independently selected from hydrogen, methyl, fluoro, chloro, or OC 1 -C 2 alkyl with the proviso that at least one of G 3 and G 4 must be hydrogen.
4. A compound or salt according to claim 1 wherein R 3 is hydrogen, Cl, or F;
R 4 is hydrogen, C 1 -C 3 alkyl, or cyclopropyl wherein C 1 -C 3 alkyl is optionally substituted with 1-3 fluorines and cyclopropyl is optionally substituted with 1-2 fluorines; R 5 is C 1 -C 3 alkyl or C 3 -C 4 cycloalkyl.
5. A compound or salt according to claim 1 wherein W is
6. A compound or salt according to claim 1 wherein W is
7. A compound or salt according to claim 1 wherein W is one of the following:
wherein R 6 is methyl optionally substituted with one fluorine and R 7 is methyl optionally substituted with 1 to 3 fluorines.
8. A compound or salt according to claim 1 wherein G 2 is hydrogen, —C 6 -C 8 alkyl, or —C 1 -C 3 alkyl wherein —C 1 -C 3 alkyl is substituted with G 5 ; G 5 is —OG 6 , —C 3 -C 6 cycloalkyl, 6 membered aryl, 5 membered heteroaryl, 4-7 membered heterocycle, —C(O)N(G 7 )(G 8 ), —SO 2 (G 7 ), —N(G 7 )(G 8 ), —SO 2 -morpholine, C(O)-morpholine, or one of the following:
G 7 is —C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl; and
G 8 is —C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl.
9. A compound or salt according to claim 1 wherein G 2 is one of the following:
10. A compound or salt according to claim 1 wherein the position of R 0 , R 1 , and R 2 are
and R 0 , R 1 , and R 2 are each independently selected from hydrogen, F, Cl or —CH 3 with the proviso that at least one of the groups R 0 , R 1 and R 2 is hydrogen.
11. A compound or salt according to claim 10 wherein R 0 is fluorine, R 1 is fluorine, and R 2 is hydrogen.
12. A compound or salt according to claim 1 wherein R 3 is chloride, R 4 is methyl, 2,2-difluoroethyl, or 2,2,2-trifluoroethyl; and R 5 is methyl or cyclopropyl.
13. A compound or salt according to claim 1 having the stereochemistry shown below
14. A compound or salt according to claim 13 having the stereochemistry shown below
15. A compound or salt according to claim 1 , selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
16. A compound or salt according to claim 1 , selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
17. A pharmaceutical composition comprising a compound or salt according to claim 1 .
18. A composition according to claim 17 further comprising a pharmaceutically acceptable carrier, excipient, and/or diluent.
19. A method of treating HIV infection comprising administering a composition according to claim 13 to a patient.
20. The method of claim 19 wherein said administration is oral.
21. The method of claim 19 wherein said administration comprises administering by injection intramuscularly.
22. The method of claim 19 wherein said administration comprises administering by injection subcutaneously.
23. The method of claim 19 wherein said method further comprises administration of at least one other agent used for treatment of AIDS or HIV infection.
24. The method of claim 23 wherein the other agent or agents is selected from the group consisting of nucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, and HIV integrase inhibitors.
25. The method of claim 24 wherein said at least one other agent is selected from the group consisting of FTC, ibalizumab, PRO-140, dolutegravir, cabotegravir, fostemsavir, abacavir, lamivudine, fosamprenavir, rilpivirine, atazanavir, darunavir, MK-8718, MK-8591, tenofovir alfenamide, and bictegravir.