Cyanamide, alkoxyamino, and urea derivatives of 4,4-disubstituted-3,4-dihydro-2(1H)-quinazolinones as HIV reverse transcriptase inhibitors

1. A compound of formula (I):

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

A is selected from NCN, NCONH 2 , and NOR 9 ;

R 1 is C 1-3 alkyl substituted with 1-7 halogen;

R 2 is selected from C 1-5 alkyl substituted with 1-2 R 4 , C 2-5 alkenyl substituted with 1-2 R 4 , and C 2-5 alkynyl substituted with 1 R 4 ;

R 3 , at each occurrence, is independently selected from C 1-4 alkyl, OH, C 1-4 alkoxy, F, Cl, Br, I, NR 5 R 5a , NO 2 , CN, C(O)R 6 , NHC(O)R 7 , and NHC(O)NR 5 R 5a ;

alternatively, if two R 3 's are present and are attached to adjacent carbons, then they may combine to form —OCH 2 O—;

R 4 is selected from C 3-5 cycloalkyl substituted with 0-2 R 3 , phenyl substituted with 0-5 R 3 , and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-2 R 3 ;

R 5 and R 5a are independently selected from H, C 1-3 alkyl;

phenyl substituted with 0-5 R 5c ;

R 5c is selected from C 1-4 alkyl, OH, C 1-4 alkoxy, F, Cl, Br, I, NO 2 , and CN;

R 6 is selected from H, OH, C 1-4 alkyl, C 1-4 alkoxy, and NR 5 R 5a ;

R 7 is selected from C 1-3 alkyl, C 1-3 alkoxy; and phenyl substituted with 0-5 R 7a ;

R 7a is selected from C 1-4 alkyl, OH, C 1-4 alkoxy, F, Cl, Br, I, NO 2 , and CN;

R 8 is selected from H, C 3-5 cycloalkyl, C 1-3 alkyl; and

phenyl optionally substituted with 0-5 R 8a ;

5 to 6 membered heterocycle optionally substituted with 0-5 R 8a ;

R 8a is selected from C 1-4 alkyl, OH, C 1-4 alkoxy, F, Cl, Br, I, NO 2 , and CN;

R 9 is selected from H and C 1-4 alkyl; and

n is selected from 0, 1, 2, 3, and 4.

2. A compound according to claim 1 , wherein:

A is selected from NCN, NCONH 2 , and NOR 9 ;

R 1 is C 1-3 alkyl substituted with 1-7 halogen;

R 2 is selected from C 1-5 alkyl substituted with 1 R 4 , C 2-5 alkenyl substituted with 1 R 4 , and C 2-5 alkynyl substituted with 1R 4 ;

R 3 , at each occurrence, is independently selected from C 1-4 alkyl, OH, C 1-4 alkoxy, F, Cl, Br, I, NR 5 R 5a , NO 2 , CN, C(O)R 6 , NHC(O)R 7 , and NHC(O)NR 5 R 5a ;

alternatively, if two R 3 's are present and are attached to adjacent carbons, then they may combine to form —OCH 2 O—;

R 4 is selected from C 3-5 cycloalkyl substituted with 0-2 R 3 , phenyl substituted with 0-2 R 3 , and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-2 R 3 ;

R 5 and R 5a are independently selected from H, CH 3 and C 2 H 5 ; phenyl substituted with 0-5 R 5c ;

R 5c is selected from C 1-4 alkyl, OH, C 1-4 alkoxy, F, Cl, Br, I, NO 2 , and CN;

R 6 is selected from H, OH, CH 3 , C 2 H 5 , OCH 3 , OC 2 H 5 , and NR 5 R 5a ;

R 7 is selected from CH 3 , C 2 H 5 , OCH 3 , OC 2 H 5 ; and phenyl substituted with 0-5 R 7a ;

R 7a is selected from C 1-4 alkyl, OH, C 1-4 alkoxy, F, Cl, Br, I, NO 2 , and CN;

R 8 is selected from H, cyclopropyl, CH 3 , C 2 H 5 ; and

phenyl optionally substituted with 0-5 R 8a ;

5 to 6 membered heterocycle optionally substituted with 0-5 R 8a ;

R 8a is selected from C 1-4 alkyl, OH, C 1-4 alkoxy, F, Cl, Br, I, NO 2 , and CN;

R 9 is selected from H and C 1-4 alkyl; and

n is selected from 0, 1, 2, and 3.

3. A compound according to claim 2 , wherein:

A is selected from NCN, NCONH 2 , and NOR 9 ;

R 1 is selected from CF 3 , and C 2 F 5 ;

R 2 is selected from C 1-3 alkyl substituted with 1 R 4 , C 2-3 alkenyl substituted with 1 R 4 , and C 2-3 alkynyl substituted with 1 R 4 ;

R 3 , at each occurrence, is independently selected from C 1-3 alkyl, OH, C 1-3 alkoxy, F, Cl, Br, I, NR 5 R 5a , NO 2 , CN, C(O)R 6 , NHC(O)R 7 , and NHC(O)NR 5 R 5a ;

alternatively, if two R 3 's are present and are attached to adjacent carbons, then they may combine to form —OCH 2 O—;

R 4 is selected from C 3-5 cycloalkyl substituted with 0-2 R 3 , phenyl substituted with 0-2 R 3 , and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-1 R 3 ;

R 5 and R 5a are independently selected from H, CH 3 and C 2 H 5 ;

R 6 is selected from H, OH, CH 3 , C 2 H 5 , OCR 3, OC 2 H 5 , and NR 5 R 5a ;

R 7 is selected from CH 3 , C 2 H 5 , OCR 3 , and OC 2 H 5 ;

R 8 is selected from H, CH 3 , C 2 H 5 , and cyclopropyl;

R 9 is selected from H, CH 3 and C 2 H 5 ; and

n is selected from 0, 1, and 2.

4. A compound according to claim 3 , wherein:

A is selected from NCN, NCONH 2 , and NOR 9 ;

R 1 is CF 3 ;

R 2 is selected from C 1-3 alkyl substituted with 1 R 4 , C 2-3 alkenyl substituted with 1 R 4 , and C 2-3 alkynyl substituted with 1 R 4 ;

R 3 , at each occurrence, is independently selected from C 1-3 alkyl, OH, C 1-3 alkoxy, F, Cl, NR 5 R 5a , NO 2 , CN, C(O)R 6 , NHC(O)R 7 , and NHC(O)NR 5 R 5a ;

alternatively, if two R 3 's are present and are attached to adjacent carbons, then they may combine to form —OCH 2 O—;

R 4 is selected from cyclopropyl substituted with 0-1 R 3 , phenyl substituted with 0-2 R 3 , and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-1 R 3 , wherein the heterocyclic system is selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-oxazolyl, 2-thiazolyl, 4-isoxazolyl, and 2-imidazolyl;

R 5 and R 5a are independently selected from H, CH 3 and C 2 H 5 ;

R 6 is selected from H, OH, CH 3 , C 2 H 5 , OCR 3, OC 2 R 5 , and NR 5 R 5a ;

R 7 is selected from CH 3 , C 2 H 5 , OCH 3 , and OC 2 H 5 ;

R 8 is selected from H, CH 3 and C 2 H 5 ;

R 9 is selected from H, CH 3 and C 2 H 5 ; and n is selected from 1 and 2.

5. A compound according to claim 4 , wherein the compound is of formula Ia:

6. A compound according to claim 4 , wherein the compound is of formula Ib:

7. A compound according to claim 1 , wherein the compound is selected from:

+/−-6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-1H-quinazolin-2-ylidene-cyanamide

or a pharmaceutically acceptable salt thereof.

8. A compound according of formula II:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

A is selected from NCN, NCONH 2 , and NOR 9 ;

R 2 is C≡C—R 4a ;

R 3 is selected from C 1-4 alkyl, OH, C 1-4 alkoxy, F, Cl, Br, I, NR 5 R 5a , NO 2 , CN, C(O)R 6 , NHC(O)R 7 , and NRC(O)NR 5 R 5a ;

R 4a is selected from methyl, ethyl, n-propyl, i-propyl, i-butyl, t-butyl, i-pentyl; cyclopropyl, cyclobutyl, and cyclopentyl;

R 5 and R 5a are independently selected from H and C 1-3 alkyl; phenyl substituted with 0-5 R 5c ;

R 5c is selected from C 1-4 alkyl, OH, C 1-4 alkoxy, F, Cl, Br, I, NO 2 , and CN;

R 6 is selected from H, OH, C 1-4 alkyl, C 1-4 alkoxy, and NR 5 R 5a ;

R 7 is selected from C 1-3 alkyl, C 1-3 alkoxy; and phenyl substituted with 0-5 R 7a ;

R 7a is selected from C 1-4 alkyl, OH, C 1-4 alkoxy, F; Cl, Br, I, NO 2 , and CN;

R 8 is selected from H, C 3-5 cycloalkyl, C 1-3 alkyl;

phenyl optionally substituted with 0-5 R 8a ; and

5 to 6 membered heterocycle optionally substituted with 0-5 R 8a ;

R 8a is selected from C 1-4 alkyl, OH, C 1-4 alkoxy, F, Cl, Br, I, NO 2 , and CN;

R 9 is selected from H and C 1-4 alkyl ; and

n is selected from 0, 1, 2, 3, and 4.

9. A compound according to claim 8 , wherein:

A is selected from NCN, NCONH 2 , and NOR 9 ;

R 2 is C≡C—R 4a ;

R 3 is selected from C 1-4 alkyl, OH, C 1-4 alkoxy, F, Cl, Br, I, NR 5 R 5a , NO 2 , CN, C(O)R 6 , and NHC (O) R 7 ;

R 4a is selected from methyl, ethyl, n-propyl, i-propyl, i-butyl, t-butyl, i-pentyl, ; cyclopropyl, cyclobutyl, and cyclopentyl;

R 5 and R 5a are independently selected from H, CH 3 and C 2 H 5 ;

R 6 is selected from H, OH, CH 3 , C 2 H 5 , OCH 3, OC 2 H 5 , and NR 5 R 5a ;

R 7 is selected from CH 3 , C 2 H 5 , OCH 3 , and OC 2 H 5 ;

R 8 is selected from H, cyclopropyl, CH 3 and C 2 H 5 ;

R 9 is selected from H, CH 3 and C 2 H 5 ; and

n is selected from 0, 1, and 2.

10. A compound according to claim 9 , wherein the compound is of formula IIa:

11. A compound according to claim 9 , wherein the compound is of formula IIb:

12. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

13. A method for treating HIV infection, comprising: administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt form thereof.

14. A method of treating HIV infection which comprises administering, in combination, to a host in need thereof a therapeutically effective amount of:

(a) a compound of claim 1 or stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salts thereof; and,

(b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.

15. A method according to claim 14 , wherein the reverse transcriptase inhibitor is selected from AZT, 3TC, ddI, ddC, d4T, delavirdine, tivirapine (8-chloro-TIBO, R86183,), BI-RG-587, nevirapine, L-697, 661, LY 73497, loviride, trovirdine, MKC-442, and HBY 097, and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, VX-478, nelfinavir, KNI-272, CGP-61755, U-140690, and ABT-378.

16. A method according to claim 15 , wherein the reverse transcriptase inhibitor is selected from AZT and 3TC and the protease inhibitor is selected from saquinavir, nelfinavir, ritonavir, and indinavir.

17. A pharmaceutical kit useful for the treatment of HIV infection, which comprises a therapeutically effective amount of:

(a) a compound of claim 1 or stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salts thereof; and,

(b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors, in one or more sterile containers.

18. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 8 or a pharmaceutically acceptable salt thereof.

19. A method for treating HIV infection, comprising: administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 8 , or a pharmaceutically acceptable salt form thereof.

20. A method of treating HIV infection which comprises administering, in combination, to a host in need thereof a therapeutically effective amount of:

(a) a compound of claim 8 or stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salts thereof; and,

(b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.

21. A method according to claim 20 , wherein the reverse transcriptase inhibitor is selected from AZT, 3TC, ddI, ddC, d4T, delavirdine, tivirapine (8-chloro-TIBO, R86183), BI-RG-587, nevirapine, L-697, 661, LY 73497, loviride, trovirdine, MKC-442, and HBY 097, and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, VX-478, nelfinavir, KNI-272, CGP-61755, U-140690, and ABT-378.

22. A method according to claim 21 , wherein the reverse transcriptase inhibitor is selected from AZT and 3TC and the protease inhibitor is selected from saquinavir, nelfinavir, ritonavir, and indinavir.

23. A pharmaceutical kit useful for the treatment of HIV infection, which comprises a therapeutically effective amount of:

(a) a compound of claim 8 or sterecisomeric forms, mixtures of sterecisomeric forms, or pharmaceutically acceptable salts thereof; and,

(b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and XIV protease inhibitors, in one or more sterile containers.