Cyanamide, alkoxyamino, and urea derivatives of 1,3-benzodiazepine as HIV reverse transcriptase inhibitors

1. A compound of formula I:

or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:

A is N—CN, NCONH 2 , or N—OR 11 ;

W is N or CR 3 ;

X is N or CR 3a ;

Y is N or CR 3b ;

Z is N or CR 3c ;

provided that if two of W, X, Y, and Z are N, then the remaining are other than N;

R 1 is selected from the group C 1-3 alkyl substituted with 0–7 halogen and cyclopropyl;

R 2 is selected from the group —R 2c , —OR 2c , —OCH 2 R 2b , —OCH 2 CH 2 R 2b , —OCH 2 C H ═CH—R 2b , —OCH 2 C≡C—R 2b , —SR 2c , —SCH 2 R 2b , —SCH 2 CH 2 R 2b , —SCH 2 C H ═CH—R 2b , and —SCH 2 C≡C—R 2b ;

R 2a is selected from the group H, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , and CH 2 CH 2 CH 3 ;

R 2b is H or R 2c ;

R 2c is selected from the group C 1-6 alkyl substituted with 0–2 R 4 , C 2-5 alkenyl substituted with 0–2 R 4 , C 2-5 alkynyl substituted with 0–1 R 4 , C 3-6 cycloalkyl substituted with 0–2 R 3d , phenyl substituted with 0–2 R 3d , and 3–6 membered heterocyclic group containing 1–3 heteroatoms selected from the group O, N, and S, substituted with 0–2 R 3d ;

alternatively, the group —NR 2a R 2c represents a 4–7 membered cyclic amine, wherein 0–1 carbon atoms are replaced by O or NR 5 ;

R 3 is selected from the group H, C 1-4 alkyl, —OH, C 1-4 alkoxy, OCF 3 , F, Cl, Br, I, —NR 5 R 5a , —NO 2 , —CN, —C(O)R 6 , —NHC(O)R 7 , —NHC(O)NR 5 R 5a , —NHSO 2 R 10 , —SO 2 NR 5 R 5a , and a 5–6 membered heteroaromatic ring containing 1–4 heteroatoms selected from the group O, N, and S;

R 3a is selected from the group H, C 1-4 alkyl, —OH, C 1-4 alkoxy, OCF 3 , F, Cl, Br, I, —NR 5 R 5a , —NO 2 , —CN, —C(O)R 6 , —NHC(O)R 7 , —NHC(O)NR 5 R 5a , —NHSO 2 R 10 , —SO 2 NR 5 R 5a , and a 5–6 membered heteroaromatic ring containing 1–4 heteroatoms selected from the group O, N, and S;

alternatively, R 3 and R 3a together form —OCH 2 O—;

R 3b , at each occurrence, is independently selected from the group H, 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, R 3a and R 3b together form —OCH 2 O—;

R 3c is selected from the group H, C 1-4 alkyl, —OH, C 1-4 alkoxy, OCF 3 , F, Cl, Br, I, —NR 5 R 5a , —NO 2 , —CN, —C(O)R 6 , —NHC(O)R 7 , —NHC(O)NR 5 R 5a , —NHSO 2 R 10 , and —SO 2 NR 5 R 5a ;

alternatively, R 3b and R 3c together form —OCH 2 O—;

R 3d , at each occurrence, is independently selected from the group C 1-4 alkyl, —OH, C 1-4 alkoxy, OCF 3 , F, Cl, Br, I, —NR 5 R 5a , —NO 2 , —CN, —C(O)R 6 , —NHC(O)R 7 , —NHC(O)NR 5 R 5a , —NHSO 2 R 10 , and —SO 2 NR 5 R 5a ;

R 3e , at each occurrence, is independently selected from the group H, C 1-4 alkyl, —OH, C 1-4 alkoxy, OCF 3 , F, Cl, Br, I, —NR 5 R 5a , —NO 2 , —CN, —C(O)R 6 , —NHC(O)R 7 , —NHC(O)NR 5 R 5a , —NHSO 2 R 10 , and —SO 2 NR 5 R 5a ;

R 3f , at each occurrence, is independently selected from the group C 1-4 alkyl, —OH, C 1-4 alkoxy, OCF 3 , F, Cl, Br, I, —NR 5 R 5a , —NO 2 , —CN, —C(O)R 6 , —NHC(O)R 7 , —NHC(O)NR 5 R 5a , —NHSO 2 R 10 , and —SO 2 NR 5 R 5a ;

R 3g , at each occurrence, is independently selected from the group C 1-4 alkyl, C 2-5 alkenyl, —OH, C 1-4 alkoxy, OCF 3 , F, Cl, Br, I, —NO 2 , —CN, —C(O)R 6 , —NHC(O)R 7 , —NHC(O)NR 5 R 5a , —NHSO 2 R 10 , —SO 2 NR 5 R 5a , C 3-10 carbocycle substituted with 0–3 R 3f and a 5–10 membered heterocyclic group containing 1–3 heteroatoms selected from the group O, N, and S, substituted with 0–3 R 3f ; and,

R 4 is selected from the group F, Cl, Br, I, C 1-6 alkyl substituted with 0–2 R 3e , C 3-10 carbocycle substituted with 0–2 R 3e , phenyl substituted with 0–5 R 3e , and a 5–10 membered heterocyclic group containing 1–3 heteroatoms selected from the group O, N, and S, substituted with 0–2 R 3e ;

R 5 and R 5a at each occurrence are independently selected from the group H and C 1-4 alkyl;

alternatively, R 5 and R 5a , together with the nitrogen to which they are attached, combine to form a 5–6 membered ring containing 0–1 O or N atoms;

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

R 7 is selected from the group C 1-3 alkyl and C 1-3 alkoxy;

R 8 is selected from the group H, OR 9 , SR 9 , NR 5 R 9 , C 1-6 alkyl substituted with 0–3 R 3g , C 2-6 alkenyl substituted with 0–3 R 3g , C 2-6 alkynyl substituted with 0–3 R 3g , C 3-5 cycloalkyl substituted with 0–2 R 3f , phenyl substituted with 0–5 R 3f , and a 5–6 membered heterocyclic group containing 1–3 heteroatoms selected from the group O, N, and S, substituted with 0–2 R 3f ;

R 9 is selected from the group C 3-10 carbocycle substituted with 0–5 R 3f and a 5–10 membered heterocyclic group containing 1–3 heteroatoms selected from the group O, N, and S, substituted with 0–2 R 3f ;

R 10 is selected from the group C 1-4 alkyl and phenyl; and

R 11 is selected from the group H and C 1-4 alkyl.

2. A compound according to claim 1 , wherein:

R 1 is selected from the group C 1-3 alkyl substituted with 1–7 halogen and cyclopropyl;

R 2a is selected from the group H, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , and CH 2 CH 2 CH 3 ;

R 2b is H or R 2c ;

R 2c is selected from the group C 1-5 alkyl substituted with 0–2 R 4 , C 2-5 alkenyl substituted with 0–2 R 4 , C 2-5 alkynyl substituted with 0–1 R 4 , C 3-6 cycloalkyl substituted with 0–2 R 3d , and phenyl substituted with 0–2 R 3d ;

R 3 , at each occurrence, is independently selected from the group H, 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 , NHC(O)NR 5 R 5a , and a 5–6 membered heteroaromatic ring containing 1–4 heteroatoms selected from the group O, N, and S;

R 3a , at each occurrence, is independently selected from the group H, 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 , NHC(O)NR 5 R 5a , and a 5–6 membered heteroaromatic ring containing 1–4 heteroatoms selected from the group O, N, and S;

alternatively, R 3 and R 3a together form —OCH 2 O—;

R 3b , at each occurrence, is independently selected from the group H, 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, R 3a and R 3b together form —OCH 2 O—;

R 4 is selected from the group Cl, F, C 1-4 alkyl substituted with 0–2 R 3e , C 3-5 carbocycle substituted with 0–2 R 3e , phenyl substituted with 0–5 R 3e , and a 5–6 membered heterocyclic group containing 1–3 heteroatoms selected from the group O, N, and S, substituted with 0–2 R 3e ;

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

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

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

R 8 is selected from the group H, cyclopropyl, CH 3 , C 2 H 5 , and CH(CH 3 ) 2 .

3. A compound according to claim 2 , wherein:

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

R 2a is selected from the group H, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , and CH 2 CH 2 CH 3 ;

R 2b is H or R 2c ;

R 2c is selected from the group C 1-3 alkyl substituted with 0–2 R 4 , C 2-3 alkenyl substituted with 0–2 R 4 , C 2-3 alkynyl substituted with 0–1 R 4 , and C 3-6 cycloalkyl substituted with 0–2 R 3d ;

R 3 , at each occurrence, is independently selected from the group H, 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, R 3 and R 3a together form —OCH 2 O—;

R 3b is H;

R 3c is H;

R 3e , at each occurrence, is independently selected from the group H, C 1-4 alkyl, —OH, C 1-4 alkoxy, OCF 3 , F, Cl, —NR 5 R 5a , —C(O)R 6 , and —SO 2 NR 5 R 5a ;

R 4 is selected from the group Cl, F, C 1-4 alkyl substituted with 0–1 R 3e , C 3-5 carbocycle substituted with 0–2 R 3e , phenyl substituted with 0–2 R 3e , and a 5–6 membered heterocyclic group containing 1–3 heteroatoms selected from the group O, N, and S, substituted with 0–1 R 3e ;

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

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

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

R 8 is selected from the group H, cyclopropyl, CH 3 , and C 2 H 5 .

4. A compound according to claim 3 , wherein:

R 1 is CF 3 ;

R 2 is selected from the group —R 2c , —OR 2c , —OCH 2 R 2b , —OCH 2 CH 2 R 2b , —OCH 2 C H ═CH—R 2b , —OCH 2 C≡C—R 2b , —SR 2c , —SCH 2 R 2b , —SCH 2 CH 2 R 2b , —SCH 2 C H ═CH—R 2b , and —SCH 2 C≡C—R 2b ;

R 2b is H or R 2c ;

R 2c is selected from the group methyl substituted with 0–2 R 4 , ethyl substituted with 0–2 R 4 , propyl substituted with 0–2 R 4 , ethenyl substituted with 0–2 R 4 , 1-propenyl substituted with 0–1 R 4 , 2-propenyl substituted with 0–1 R 4 , ethynyl substituted with 0–1 R 4 , 1-propynyl substituted with 0–1 R 4 , 2-propynyl substituted with 0–1 R 4 , and cyclopropyl substituted with 0–1 R 3d ;

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

alternatively, R 3 and R 3a together form —OCH 2 O—;

R 3d , at each occurrence, is independently selected from the group CH 3 , —OH, OCH 3 , OCF 3 , F, Cl, and —NR 5 R 5a ;

R 3e , at each occurrence, is independently selected from the group CH 3 , —OH, OCH 3 , OCF 3 , F, Cl, and —NR 5 R 5a ;

R 4 is selected from the group Cl, F, CH 3 , CH 2 CH 3 , cyclopropyl substituted with 0–1 R 3e , 1-methyl-cyclopropyl substituted with 0–1 R 3e , cyclobutyl substituted with 0–1 R 3e , phenyl substituted with 0–2 R 3e , and a 5–6 membered heterocyclic group containing 1–3 heteroatoms selected from the group O, N, and S, substituted with 0–1 R 3e , wherein the heterocyclic group is selected from the group 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 the group H, CH 3 and C 2 H 5 ;

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

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

R 8 is selected from the group H, cyclopropyl, and C 2 H 5 .

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 the group:

7-chloro-2-cyanoimino-5-(cyclopropylmethyloxy)-1,5-dihydro-5-trifluoromethyl-1,3-benzodiazepine;

7-chloro-2-cyanoimino-5-(cyclobutylmethyloxy)-1,5-dihydro-5-trifluoromethyl-1,3-benzodiazepine;

7-chloro-2-cyanoimino-5-(cyclopropylmethyloxy)-1,5-dihydro-3-ethyl-5-trifluoromethyl-1,3-benzodiazepine;

7-chloro-5-cyclopropylmethyloxy-1,5-dihydro-2-methoxyimino-5-trifluoromethyl-1,3benzodiazepine;

7-chloro-5-cyclopropylmethyloxy-1,5-dihydro-3-ethyl-2-methoxyimino-5-trifluoromethyl-1,3-benzodiazepine;

or a pharmaceutically acceptable salt form thereof.

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

(S)-7-chloro-2-cyanoimino-5-(cyclopropylmethyloxy)-1,5-dihydro-5-trifluoromethyl-1,3-benzodiazepine;

(S)-7-chloro-2-cyanoimino-5-(cyclobutylmethyloxy)-1,5-dihydro-5-trifluoromethyl-1,3-benzodiazepine;

(S)-7-chloro-2-cyanoimino-5-(cyclopropylmethyloxy)-1,5-dihydro-3-ethyl-5-trifluoromethyl-1,3-benzodiazepine;

(S)-7-chloro-5-cyclopropylmethyloxy-1,5-dihydro-2-methoxyimino-5-trifluoromethyl-1,3-benzodiazepine;

(S)-7-chloro-5-cyclopropylmethyloxy-1,5-dihydro-3-ethyl-2-methoxyimino-5-trifluoromethyl-1,3-benzodiazepine;

or a pharmaceutically acceptable salt form thereof.

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

(R)-7-chloro-2-cyanoimino-5-(cyclopropylmethyloxy)-1,5-dihydro-5-trifluoromethyl-1,3-benzodiazepine;

(R)-7-chloro-2-cyanoimino-5-(cyclobutylmethyloxy)-1,5-dihydro-5-trifluoromethyl-1,3-benzodiazepine;

(R)-7-chloro-2-cyanoimino-5-(cyclopropylmethyloxy)-1,5-dihydro-3-ethyl-5-trifluoromethyl-1,3-benzodiazepine;

(R)-7-chloro-5-cyclopropylmethyloxy-1,5-dihydro-2-methoxyimino-5-trifluoromethyl-1,3-benzodiazepine;

(R)-7-chloro-5-cyclopropylmethyloxy-1,5-dihydro-3-ethyl-2-methoxyimino-5-trifluoromethyl-1,3-benzodiazepine;

or a pharmaceutically acceptable salt form thereof.

10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 1 or pharmaceutically acceptable salt form thereof.

11. A method of treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound according to claim 1 or pharmaceutically acceptable salt form thereof.