Back to results
US 8,008,287 B2Granted
Integrase inhibitors
AssigneeGilead Sciences, Inc.
InventorsZhenhong R. Cai, Salman Y. Jabri, Haolun Jin, Rachael A. Lansdown, Samuel E. Metobo, Michael R. Mish, Richard M. Pastor
Life of this patent
Estimating the term…
Abstract
Tricyclic compounds, protected intermediates thereof, and methods for inhibition of HIV-integrase are disclosed.
Claims52
A compound of formula (II):
- wherein:
- A2 and A3 are each independently N or CRa;
- each Ra is independently H or C1-C4 alkyl;
- Rc is H, Rk, or -Q-Rn;
- Rd is H, halo, or C1-C4 alkyl that is optionally substituted with Rj;
- Re is H, halo, or C1-C4 alkyl that is optionally substituted with Rj provided that at least one of Rd and Re is C1-C4 alkyl that is substituted with Rj,
- Q is C1-C4 alkylene;
- Z is O or two hydrogens;
- each Rj is phenyl, optionally substituted with one or more F, Cl, Br, I, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, or C1-C4 alkyl;
- Rk is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, each of which is optionally substituted with one or more halo, hydroxy, C1-C6 alkoxy, dimethylamino, diethylamino, N-ethyl-N-methylamino, morpholino, thiomorpholino, piperidino, or piperazino;
- Rn is a C3-C6 carbocycle, a phenyl ring, or a 5- or 6-membered heteroaryl ring, which phenyl ring or 5- or 6-membered heteroaryl ring is optionally substituted with one or more F, Cl, Br, I, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, or C1-C4 alkyl;
- Rp is OH, C1-C4 alkyl, C1-C4 alkanoyl, C1-C4 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, —C(═O)NRxRx, —C(═NRak)Ram, NH2, —N(Ra)—C(═O)NRxRx, 4,5-dihydro-4,4-dimethyloxazole, or —N(Rs)—S(O)2—Rt, wherein each C1-C4 alkyl of Rp is substituted with —C(═O)NRxRx, —N(Rag)—C(═O)—Rah, or —N(Rag)—S(O)2—Rah;
- and wherein each C1-C4 alkoxy, C2-C6 alkenyl and C2-C6 alkynyl of Rp is optionally substituted with phenyl, hydroxy, C3-C6 carbocycle or —C(═O)NRxRx;
- Rs is —S(O)2—Rw, and Rt is C1-C4 alkyl optionally substituted with Rv;
- or Rs is C1-C4 alkyl substituted with Ru, and Rt is C1-C4 alkyl optionally substituted with Rv;
- or Rs is C1-C4 alkyl optionally substituted with Ru, and Rt is Rz, NRxRx, or C1-C4 alkyl substituted with Rv;
- each Rv is fluoro, chloro, phenyl, pyridyl, 1,4 diazepanyl, or piperazino, wherein each phenyl, pyridyl, 1,4-diazepanyl, and piperazino is optionally substituted with one or more fluoro, chloro, bromo, iodo, C1-C4 alkyl, C1-C4 alkyl-C(═O)—, C1-C4 alkyl-S(O)2—, —C(═O)NRaRa, or —C(═O)ORa;
- each Ru is independently dimethylamino, diethylamino, N-ethyl-N-methylamino, or a ring selected from C3-C6 carbocycle, pyrrolidino, morpholino, thiomorpholino, piperidino, and piperazino, which ring is optionally substituted with one or more C1-C4 alkyl;
- and
- Rw is C1-C4 alkyl;
- each Rx is independently H, C1-C4 alkyl, C3-C6 carbocycle, or C1-C4 alkyl-Ry;
- or NRxRx taken together form a piperidino, morpholino, azetidino, pyrrolidino, or piperazino ring, which ring is optionally substituted with one or more C1-C4 alkyl or halo;
- each Ry is independently cyano, phenyl or pyridyl, wherein each phenyl or pyridyl is optionally substituted with one or more fluoro, chloro, bromo, iodo, C1-C4 alkyl, C1-C4 alkyl-C(═O)—, C1-C4 alkyl-S(O)2—, —C(═O)NRaRa, or —C(═O)ORa;
- Rz is phenyl which is optionally substituted with one or more fluoro, chloro, bromo, iodo, C1-C4 alkyl, C1-C4 alkyl-C(═O)—, C1-C4 alkyl-S(O)2—, —C(═O)NRaRa, or —C(═O)ORa;
- each Rag and Rah is independently H or C1-C4 alkyl;
- each Rak is hydroxy, C1-C4 alkoxy, or NRamRan,
- each Rah is independently H or C1-C4 alkyl;
- each Ram and Ran is independently H or C1-C4 alkyl;
- or a pharmaceutically acceptable salt thereof.
26 more elements
A compound of formula (II):
- wherein:
- A2 and A3 are each independently N or CRa;
- each Ra is independently H or C1-C4 alkyl;
- Rc is H, Rk, or -Q-Rn;
- Rd is C1-C4 alkyl that is substituted with Rj;
- Re is H, halo, or C1-C4 alkyl that is optionally substituted with Rj;
- Q is C alkylene;
- Z is O or two hydrogens;
- each Rj is phenyl, optionally substituted with one or more F, Cl, Br, I, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, or C1-C4 alkyl;
- Rk is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, each of which is optionally substituted with one or more halo, hydroxy, C1-C6 alkoxy, dimethylamino, diethylamino, N-ethyl-N-methylamino, morpholino, thiomorpholino, piperidino, or piperazino;
- Rn is a C3-C6 carbocycle, a phenyl ring, or a 5- or 6-membered heteroaryl ring, which phenyl ring or 5- or 6-membered heteroaryl ring is optionally substituted with one or more F, Cl, Br, I, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, —C(═O)NRacRad, or C1-C4 alkyl;
- Rp is —N(Rae)—S(O)2—Raf;
- Rz is phenyl which is optionally substituted with one or more fluoro, chloro, bromo, iodo, C1-C4 alkyl, C1-C4 alkyl-C(═O)—, C1-C4 alkyl-S(O)2—, —C(═O)NRaRa, or —C(═O)ORa;
- each Rac and Rad is independently H or C1-C6 alkyl;
- each Rae and Raf is independently H or C1-C6 alkyl;
- or a pharmaceutically acceptable salt thereof.
13 more elements
A compound of formula (II):
- wherein:
- A2 and A3 are each independently N or CRa;
- each Ra is independently H or C1-C4 alkyl;
- Rc is H, Rk, or -Q-Rn;
- Rd is C1-C4 alkyl that is substituted with Rj;
- Re is H, halo, or C1-C4 alkyl that is optionally substituted with Rj;
- Q is C1-C4 alkylene;
- Z is O or two hydrogens;
- each Rj is phenyl, optionally substituted with one or more F, Cl, Br, I, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, or C1-C4 alkyl;
- Rk is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, each of which is optionally substituted with one or more halo, hydroxy, C1-C6 alkoxy, dimethylamino, diethylamino, N-ethyl-N-methylamino, morpholino, thiomorpholino, piperidino, or piperazino;
- Rn is a C3-C6 carbocycle, a phenyl ring, or a 5- or 6-membered heteroaryl ring, which phenyl ring or 5- or 6-membered heteroaryl ring is optionally substituted with one or more F, Cl, Br, I, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C1-C4 alkoxy, —C(═O)NRacRad, or C1-C4 alkyl;
- Rp is H, NH2, —C(═O)NRxRx, C1-C4 alkyl, pyridyl, 1,3,4-oxadiazole, 5-methyl-1,3,4-oxadiazole, or phenyl that is optionally substituted with one or more F, Cl, CN, hydroxy, or trifluoromethyl, wherein any C1-C4 alkyl of Rp is optionally substituted with one or more hydroxy, cyano, —C(═O)NRxRx, or —NRarRas,
- each Rx is independently H, C1-C4 alkyl, C3-C6 carbocycle, or C1-C4 alkyl-Ry;
- or NRxRx taken together form a piperidino, morpholino, azetidino, pyrrolidino, or piperazino ring, which ring is optionally substituted with one or more C1-C4 alkyl or halo;
- each Ry is independently cyano, trifluoromethyl, hydroxy, C1-C4 alkoxy, phenyl or pyridyl, wherein each phenyl or pyridyl is optionally substituted with one or more fluoro, chloro, bromo, iodo, C1-C4 alkyl, C1-C4 alkyl-C(═O)—, C1-C4 alkyl-S(O)2—, —C(═O)NRaRa, or —C(═O)ORa;
- each Rac and Rad is independently H or C1-C6 alkyl;
- each Rae and Raf is independently H or C1-C6 alkyl;
- each Rar and Ras is independently H, C1-C6 alkyl, or C1-C6 alkanoyl;
- or a pharmaceutically acceptable salt thereof.
16 more elements
Compound
- as described herein;
- or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.