HIV PROTEASE INHIBITORS

摘要

The present invention is directed to 5-heteroarylmorpholine derivatives and their use in the inhibition of HIV protease, the inhibition of HIV replication, the prophylaxis of infection by HIV, the treatment of infection by HIV, and the prophylaxis, treatment, and delay in the onset or progression of AIDS. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines.

主权项

1. A compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: V is CH2 or O; Y1, Y2, Y3 and Y4 are independently selected from C(R) and N; X is selected from H and NR7R8; R is selected from H, halo, hydroxy, C1-4alkyl, C1-4alkoxy, C1-4alkyl-S(O)k—, CF3, CN, and benzyl, or two R groups on adjacent atoms may be joined together with the atoms to which they are attached to form a fused phenyl, pyridine, pyridazine, pyrimidine, pyrazine, or triazine, each of which is optionally substituted with 1 to 4 substituents independently selected from the group consisting of: halo, C1-4alkyl, C1-4alkoxy, CF3 and CN; each k is independently 0, 1 or 2; Z is HetA; R6 is selected from:wherein the asterisk (*) denotes the point of attachment to the rest of the compound and U1 is selected from (1) H, (2) C1-10alkyl, wherein said C1-10alkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, C1-4alkyl, C1-4haloalkyl, hydroxy and C1-4alkoxy, (3) C3-7 cycloalkyl, wherein said C3-7 cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, C1-4alkyl, C1-4haloalkyl, hydroxy and C1-4alkoxy, (4) ArylA, (5) HetA, (6) HetB, (7) C1-10alkyl substituted with ArylA, (8) C1-10alkyl substituted with HetA, and (9) C1-10alkyl substituted with HetB; and Ring B is selected from C3-7 cycloalkyl and HetB, wherein C3-7 cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from halogen, OH, C1-4alkyl, C1-4fluoroalkyl and C1-4alkoxy;
R6A is selected from H or C1-6 alkyl; each XB, each XC, each YB and each YC are independently selected from the group consisting of:
(1) C1-6 alkyl,(2) C3-6 cycloalkyl,(3) C1-6 haloalkyl,(4) OH,(5) O—C1-6 alkyl,(6) O—C1-6 haloalkyl,(7) O—C3-6 cycloalkyl,(8) SH,(9) S—C1-6 alkyl,(10) S—C1-6 haloalkyl,(11) S—C3-6 cycloalkyl,(12) halo,(13) CN,(14) NO2,(15) NH2,(16) N(H)—C1-6 alkyl,(17) N(—C1-6 alkyl)2,(18) N(H)C(O)—C1-6 alkyl,(19) N(H)CH(O),(20) CH(O),(21) C(O)—C1-6 alkyl,(22) C(O)OH,(23) C(O)O—C1-6 alkyl,(24) C(O)NH2,(25) C(O)N(H)—C1-6 alkyl,(26) C(O)N(—C1-6 alkyl)2,(27) C(O)N(H)C(O)—C1-6 alkyl,(28) C(O)N(H)CH(O)(29) SO2H,(30) SO2—C1-6 alkyl;(31) phenyl, benzyl or phenoxy, each optionally substituted with 1 to 5 substituents selected from halogen and C1-6 alkyl,(32) HetA, —O-HetA or —CH2-HetA, optionally substituted with 1 to 5 substituents selected from halogen and C1-6 alkyl,(33) trimethylsilyl, and(34) C2-6alkenyl,wherein C1-6 alkyl in each instance of (1), (3) (5), (6), (9), (10), (16), (17), (18), (21), (23), (25), (26), (27), (30), (31) and (32) above is optionally substituted with 1 to 6 substituents as allowed by valence selected from the group consisting of:
(a) C1-6 haloalkyl,(b) OH(c) O—C1-6 alkyl,(d) O—C1-6 haloalkyl,(e) O—C3-6 cycloalkyl,(f) SH,(g) S—C1-6 alkyl,(h) halo,(i) CN,(j) NO2,(k) NH2,(l) N(H)—C1-6 alkyl,(m) N(—C1-6 alkyl)2,(n) C(O)—C1-6 alkyl,(o) C(O)OH,(p) C(O)O—C1-6 alkyl, and(q) SO2—C1-6 alkyl; T is O, S, S(O), or SO2; m is an integer equal to 0, 1, 2, or 3; n is an integer equal to 0, 1, 2, or 3; R7 is H, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkyl substituted with C3-6 cycloalkyl, C(O)—RK or SO2—RK; R8 is H, C1-6 alkyl, C1-6 haloalkyl or C3-6 cycloalkyl; RK is:
(1) C1-6 alkyl,(2) C3-6 cycloalkyl,(3) C1-6 alkyl substituted with C3-6 cycloalkyl,(4) O—C1-6 alkyl,(5) O—C1-6 alkyl substituted with O—C1-6 alkyl,(6) O—C1-6 fluoroalkyl,(7) C(O)O—C1-6 alkyl,(8) C1-6 alkyl substituted with C(O)O—C1-6 alkyl,(9) C1-6 alkyl substituted with C(O)OH,(10) C1-6 alkyl substituted with C(O)—C1-6 alkyl,(11) N(H)—C1-6 alkyl,(12) N(—C1-6 alkyl)2,(13) C1-6 alkyl substituted with NH2, N(H)—C1-6 alkyl, or N(—C1-6 alkyl)2,(14) AryA,(15) C1-6 alkyl substituted with AryA,(16) O—C1-6 alkyl substituted with AryA,(17) HetA,(18) C1-6 alkyl substituted with HetA,(19) O—C1-6 alkyl substituted with HetA,(20) HetB,(21) O-HetB, or(22) O—C1-6 alkyl substituted with HetB; each Aryl A is an aryl which is independently phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with YB from one up to the maximum number of substitutable positions as allowed by valence; each HetA is a heteroaryl which is independently (i) a 5- or 6-membered monocyclic heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, or (ii) is a 9-, 10- or 11-membered bicyclic heteroaromatic ring containing from 1 to 6 heteroatoms independently selected from N, O and S; wherein the monocyclic ring (i) or the bicyclic ring (ii) is optionally substituted with YC from one up to the maximum number of substitutable positions as allowed by valence; and each HetB is independently a 4- to 7-membered, saturated or unsaturated, non-aromatic heterocyclic ring containing at least one carbon atom and from 1 to 4 heteroatoms independently selected from N, O and S, where each S is optionally oxidized to S(O) or S(O)2, and wherein the saturated or unsaturated heterocyclic ring is optionally substituted with one or more substituents, up to the maximum number allowed by valance, each of which is independently halogen, CN, C1-6 alkyl, OH, oxo, O—C1-6 alkyl, C1-6 haloalkyl, O—C1-6 haloalkyl, C(O)NH2, C(O)N(H)—C1-6 alkyl, C(O)N(—C1-6 alkyl)2, C(O)H, C(O)—C1-6 alkyl, CO2H, CO2—C1-6 alkyl, SO2H, or SO2—C1-6 alkyl.