Claims for Patent: 5,413,999

Summary for Patent: 5,413,999

Title:	HIV protease inhibitors useful for the treatment of AIDS
Abstract:	Compounds of formula where R1 and R2 are independently hydrogen or optionally-substituted C1-4alkyl or aryl, or R1 and R2 are joined together to form a monocyclic or bicyclic ring system, are HIV protease inhibitors. These compounds are useful in the treatment of infection by HIV and in the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of treating infection by HIV are also described.
Inventor(s):	Joseph P. Vacca, Bruce D. Dorsey, James P. Guare, M. Katharine Holloway, Randall W. Hungate, Rhonda B. Levin
Assignee:	Merck Sharp and Dohme LLC
Application Number:	US08/059,038
Patent Claims:	1. A compound of the formula ##STR295## wherein V is absent or ##STR296## wherein Q is absent or --O--, --NR--, or heterocycle optionally sustituted with --C1-4 alkyl;R1 is:1) --C1-4 alkyl unsubstituted or substituted with one or more ofa) halo, b) C1-3 alkoxy, c) aryl unsubstituted or substituted with one or more of C1-4 alkyl, amino, hydroxy or aryl, d) --W--aryl or --W--benzyl, wherein W is --O--, --S--, or --NH--, e) a 5-7 membered cycloalkyl group unsubstituted or substituted with one or more ofi) halo, ii) C1-3 alkoxy, or iii) aryl, f) heterocycle unsubstituted or substituted with one or more of oxo, halo, C1-4 alkoxy, C1-4 alkyl; ##STR297## or Boc, ##STR298## i) --NH--SO2 C1-3 alkyl, j) --NR2, and R is hydrogen or C1-4 alkyl; k) --COOR, or l) --((CH2)m O)n R wherein in is 2, 3, 4, or 5, and n is zero, 1,2 or 3, or 2) aryl, unsubstituted or substituted with one or more ofa) halo, b) hydroxy, c) --NO2 or --NR2, d) C1-4 alkyl, e) C1-3 alkoxy, unsubstituted or substituted with one or more of C1-3 alkoxy, ##STR299## q) --R5, as defined below; or 4) heterocycle unsubstituted or substituted with one or more of oxo, halo, amino, C1-4 alkoxy, C1-4 alkyl; or Boc; 5) carbocyclic unsubstituted or substituted with one or more of halo, amino, or C1-4 alkoxy; R3 is benzyl, unsubstituted or substituted with one or more of (1) hydroxy, (2) C1-3 alkoxy substituted with one or more of --OH or (3) ##STR300## R5 is 1) --1) --W--(CH2)m --NR6 R7 wherein W is as defined above, m is 2,3,4 or 5, and R6 and R7 are independentlya) hydrogen, b) C1-6 alkyl, unsubstituted or substituted with one or more ofi) C1-3 alkoxy, or ii) --NR2, c) the smile or different and joined together to form a 5-7 member heterocycle, such as morpholino, containing up to two additional heteroatoms selected from ##STR301## the heterocycle optionally substituted with C1-4 alkyl, or d) aromatic heterocycle unsubstituted or substituted with one or more ofi) C1-4 alkyl, or ii) --NR2, 2) --(CH2)q--NR6 R7 wherein q is 1,2,3,4, or 5, and R6 and R7 are defined above, except that R6 or R 7 are not H or unsubstituted C1-6 alkyl, or 3) benzofuryl, indolyl, azacycloalkyl, azabicyclo C7-11 cycloalkyl, or benzopiperidinyl, unsubstituted or substituted with C1-4 alkyl; R12 is ##STR302## or pharmaceutically acceptable salt thereof. 2. The compound of claim 1, of the formula ##STR303## wherein V is absent;R1 is:1) --C1-4 alkyl unsubstituted or substituted with one or more ofa) halo, b) C1-3 alkoxy, c) aryl unsubstituted or substituted with one or more of C1-4 alkyl, amino, hydroxy or aryl, d) --W--aryl or --W--benzyl, wherein W is --O--, --S--, or --NH--, e) a 5-7 membered cycloalkyl group unsubstituted or substituted with one or more ofi) halo. ii) C1-3 alkoxy, or iii) aryl, f) heterocycle unsubstituted or substituted with one or more of oxo, halo, C1-4 alkoxy, C1-4 alkyl; ##STR304## or Boc, ##STR305## i) --NH--SO2 C1-3 alkyl, j) --NR2, and R is hydrogen or C1-4 alkyl; k) --COOR, or l) --((CH2)m O)n R wherein m is 2, 3, 4, or 5, and n is zero, 1,2or3, R3 is benzyl, unsubstituted or substituted with one or more of (1) hydroxy, (2) C1-3 alkoxy substituted with one or more of --OH or (3) ##STR306## or pharmaceutically acceptable salt thereof. 3. The compound of claim 2 of the formula ##STR307## wherein V is absent;R1 is:1) --C1-4 alkyl unsubstituted or substituted with one or more ofc) aryl unsubstituted or substituted with one or more of C1-4 alkyl, amino, hydroxy or aryl, e) a 5-7 membered cycloalkyl group unsubstituted or substituted with one or more ofi) halo, ii) C1-3 alkoxy, or iii) aryl, f) heterocycle unsubstituted or substituted with one or more of oxo, halo, C1-4 alkoxy, C1-4 alkyl; ##STR308## or Boc, R3 is benzyl, unsubstituted or substituted with one or more of (1) hydroxy, (2) C1-3 alkoxy substituted with one or more of --OH or (3) ##STR309## or pharmaceutically acceptable salt thereof. 4. The compound of claim 3 of the formula ##STR310## wherein V is absentR1 is:1) --C1-4 alkyl unsubstituted or substituted with one or more ofc) aryl unsubstituted or substituted with one or more of C1-4 alkyl, amino, hydroxy or aryl, e) a 5-7 membered cycloalkyl group unsubstituted or substituted with one or more ofi) halo, ii) C1-3 alkoxy, or iii) aryl, f) heterocycle, said heterocycle being piperidinyl, pyridyl, thienyl, pyrrolyl, thiazolyl, imidazolyl, furyl benzimidazolyl, pyrazinyl, isoxazolyl, pyridazinyl,or quinolinyl, said heterocycle unsubstituted or substituted with one or more of oxo, halo, C1-4 alkoxy, C1-4 alkyl; ##STR311## Boc, R3 is benzyl, unsubstituted or substituted with one or more of (1) hydroxy, (2) C1-3 alkoxy substituted with one or more of --OH or (3) ##STR312## or pharmaceutically acceptable salt thereof. 5. The compound of claim 4, of the formula ##STR313## wherein V is absent;R 1 is C1-4 alkyl substituted with pyridyl or aryl; R3 is benzyl, unsubstituted or substituted with one or more of (1) hydroxy, (2) C1-3 alkoxy substituted with one or more of-OH or (3) ##STR314## or a pharmaceutically acceptable salt thereof. 6. The compound of the formula ##STR315## or a pharmaceutically acceptable salt thereof, wherein R1 is selected from ##STR316## 7. A compound of the formula: ##STR317## or pharmaceutically acceptable salt thereof. 8. A pharmaceutical composition comprising a compound according to claims 3, 4, 5 , or 6 and a pharmaceutically acceptable carrier. 9. The pharmaceutical composition of claim 8 for use in the treatment of AIDS, in the treatment of infection of HIV, or in the inhibition of HIV protease. 10. A pharmaceutical composition comprising the compound ##STR318## or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 11. A method of treating AIDS comprising administering to a mammal in need of such treatment an effective amount of a compound according to claims 5 or 7. 12. A method of treating infection by HIV comprising administering to a mammal in need of such treatment an effective amount of a compound according to claims 5 or 7. 13. A method of inhibiting HIV protease comprising administering to a mammal in need of such treatment an effective amount of a compound according to claims 5 or 7.