Pyrrolo [2,3-D] pyrimidines as non-nucleoside reverse transcriptase inhibitors for treatment of HIV
View Patent ↗This application concerns certain 2-phenylamino-6-aryl amino-, 6-aryloxy-, and 6-arylthio-purines, -azapurines and -deazapurines. These compounds are non-nucleoside reverse transcriptase inhibitors and have potential as anti-HIV treatment.
1. A compound of formula
where
the dashed line represents a double bond between either A and B or B and D,
T′ is O or S;
A is NZ;
B is ═CH;
D is ═CW;
Z is H, Br, CH 3 , CH 2 CH 3 , cyclopropyl, or benzyl, the phenyl moiety of said benzyl optionally substituted with one or two groups selected independently from methyl and methoxy;
W is H, F, Cl, Br, methyl, ethyl, cyclopropyl, allyl, CH 2 CF 3 , cyanomethyl, CH 2 CH 2 CN, CH═CHCN, or benzyl, the phenyl moiety of said benzyl optionally substituted with one or two groups selected independently from methyl and methoxy,
V is F, Cl, CN, SO 2 CH 3 , SO 2 NH 2 , SO 2 NHCH 3 , C≡CCH 3 , or CH═CHCN;
Ar is (a), (b), (c), or (d) below
where
the dashed lines in (a) represent optional double bonds;
R P is Cl, Br, I, CN, methyl, ethyl, n-propyl, isopropyl, cyclopropylmethyl, C 3 -C 6 cycloalkyl, CH═CHCN, acetyl, or NH—C 1 -C 6 alkyl, said alkyl and cycloalkyl groups optionally substituted with methyl, methoxy, halogen, or cyano;
R 4 , R 5 , and R 6 are, independently, H, F, Cl, Br, CH 3 , CH 2 F, CHF 2 , CF 3 , isopropyl, cyclopropyl, OCH 3 , OH, OCF 3 , NH 2 and NHCH 3 ,
or R 6 and R P on adjacent ring atoms, together with the ring atoms to which they are attached, form an additional fused five-membered ring;
Q and Q′ are, independently, N or CH;
R 7 is Cl, Br, I, CH 3 , CF 3 , OCH 3 , isopropyl, cyclopropyl, t-butyl, or cyclobutyl; and
R 8 , R 9 , R 10 and R 11 are each, independently, H or CH 3 .
2. The compound of claim 1 , wherein Ar is (a) or (c).
3. The compound of claim 2 , where R 6 either is H or is in the 2-position.
4. The compound of claim 1 , which is a compound of formula IA-2
5. The compound of claim 4 , where Ar is 4-cyclopropyl-, 4-acetyl-, 4-methyl-, 4-bromo-, or 4-cyano-2,6-di-substituted phenyl.
6. The compound of claim 1 , where
V is CN, and where
W is, H, methyl, F, Cl, Br, or benzyl,
Z is, H, methyl, Br, or benzyl.
7. The compound of claim 3 which is a compound of formula IA-2a:
8. The compound of claim 7 , where
V is CN or CH═CHCN,
R 6 is methyl, methoxy, or chloro and
R 7 is 6-methyl, or 6-methoxy.
9. The compound of claim 8 , where R P is CN, cyclopropyl, methyl, Br, Cl, CH═CHCN, or acetyl.
10. The compound of claim 9 where
V is CN,
W is H, chloro, bromo, methyl, or ethyl and
Z is H, methyl, ethyl, or benzyl.
11. A compound of formula IB
where
the dashed line represents a double bond between either A and B or B and D, and where
A is NZ;
B is ═CH;
D is ═CW;
Z is H, Br, CH 3 , CH 2 CH 3 , cyclopropyl, or benzyl, the phenyl moiety of said benzyl optionally substituted with methyl or methoxy;
W is H, F, Cl, Br, methyl, ethyl, cyclopropyl, allyl, CH 2 CF 3 , cyanomethyl, CH 2 CH 2 CN, CH═CHCN, or benzyl, the phenyl moiety of said benzyl optionally substituted with methyl or methoxy;
V is F, Cl, CN, SO 2 CH 3 , SO 2 NH 2 , SO 2 NHCH 3 , C≡CCH 3 , or CH═CHCN,
Ar is (a), (b), or (d) below:
where
R P is Cl, Br, I, CN, methyl, ethyl, n-propyl, isopropyl, cyclopropylmethyl, C 3 -C 6 cycloalkyl, CH═CHCN, acetyl, or NH—C 1 -C 6 alkyl, said alkyl and cycloalkyl groups optionally substituted with methyl, methoxy, halogen, or cyano;
R 4 , R 5 , and R 6 are, independently, H, F, Cl, Br, CH 3 , CH 2 F, CHF 2 , CF 3 , isopropyl, cyclopropyl, OCH 3 , OH, OCF 3 , NH 2 and NHCH 3 ;
Q and Q′ are, independently, N or CH; and
R 8 , R 9 , R 10 and R 11 are each, independently, H or CH 3 .
12. A compound of formula IB-1
where
the dashed line represents a double bond between either A and B or B and D;
A is NZ;
B is ═CH;
D is ═CW;
Z is H, Br, CH 3 , CH 2 CH 3 , cyclopropyl, or benzyl, the phenyl moiety of said benzyl optionally substituted with methyl or methoxy,
W is H, F, Cl, Br, methyl, ethyl, cyclopropyl, allyl, CH 2 CF 3 , CH 2 CN, CH 2 CH 2 CN, CH═CHCN, or benzyl, the phenyl moiety of said benzyl optionally substituted with methyl or methoxy,
V is F, Cl, CN, SO 2 CH 3 , SO 2 NH 2 , SO 2 NHCH 3 , C≡CCH 3 , or CH═CHCN;
R P is Cl, Br, I, CN, CH═CHCN, methyl, ethyl, n-propyl, isopropyl, cyclopropylmethyl, C 3 -C 6 cycloalkyl, acetyl, and NH—C 3 -C 6 alkyl;
R 6 is H, F, Cl, Br, CH 3 , CH 2 F, CHF 2 , CF 3 , isopropyl, cyclopropyl, OCH 3 , OH, OCF 3 , NH 2 and NHCH 3 ; and
R 7 is Cl, Br, I, CH 3 , CF 3 , OCH 3 , isopropyl, cyclopropyl, t-butyl, or cyclobutyl.
13. The compound of claim 12 , where
V is CN or CH═CHCN,
R 6 is 2-methyl, 2-methoxy, or 2-chloro and
R 7 is 6-methyl, or 6-methoxy.
14. The compound of claim 13 , where R P is CN, cyclopropyl, methyl, Br, Cl, CH═CHCN, or acetyl.