US 9,315,475 B2 · HIV protease inhibitors

Abstract

The compounds encompassed by Formula I include compounds which are HIV protease inhibitors and other compounds which can be metabolized in vivo to HIV protease inhibitors. The compounds and their pharmaceutically acceptable salts are useful for the prophylaxis or treatment of infection by HIV and the prophylaxis, treatment, or delay in the onset 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.

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;
each X is independently selected from H and NR7R8;
Z is selected from the group consisting of
L is a linker selected from
(a) a bond,
(b) —CH2—,
(c) —C(O)—,
(d) —CH2—C(O)—** or —C(O)—CH2—**,
(e) —CH2—CH2—C(O)—** or —C(O)—CH2—CH2—**, and
wherein ** shows the point of attachment to the morpholine and when Z is
then L is not a bond;
R is selected from H, halo, hydroxy, C1-4alkyl, C1-4alkoxy, C1-4alkyl-S(O)k—, CF3, CN, 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;
each r and t are independently 1, 2, 3 or 4;
ZA is selected from the group consisting of:
(1) hydrogen,
(2) C1-10 alkyl,
(3) C2-10alkenyl,
(4) C3-7 cycloalkyl,
(5) AryA,
(6) HetA,
(7) HetB,
wherein said C1-10 alkyl, C2-10alkenyl and C3-7 cycloalkyl are optionally substituted with 1 to 6 substituents as allowed by valence independently selected from the group consisting of:
fluoro, hydroxy, carbamoyl, C3-6 cycloalkyl, C(O)O—C1-6 alkyl, C(O)OH, C(O)—C1-6 alkyl, N(H)—C1-6 alkyl, N(—C1-6 alkyl)2, ArylA, HetA and HetB;
each RA is independently H or C1-6 alkyl;
or ZA and RA and the nitrogen atom to which they are attached may be joined together to form a 5-, 6- or 7-membered mono-cyclic, or 9- or 10-membered bi-cyclic, saturated, aromatic or partially aromatic ring, said ring optionally containing 1 to 3 additional heteroatoms selected from O, S and N, and said ring optionally substituted with from 1 to 3 XA;
each R6 independently is:
wherein the asterisk (*) denotes the point of attachment to the rest of the compound and U1 is selected from H, C1-10alkyl, ArylA, HetA and HetB;
each R6A independently is H or C1-6 alkyl;
alternatively, R6 and R6A together with the carbon to which they are attached form a C3-6 cycloalkyl which is optionally substituted with phenyl, wherein the phenyl is optionally substituted with from 1 to 3 XD;
each XA, each XB, each XC, each XD, 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 and 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 AryA is an aryl which is independently phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with from 1 to 3 YB;
each HetA is a heteroaryl which is independently (i) a 5- or 6-membered monocyclic heteroaromatic ring containing from 1 to 3 heteroatoms independently selected from N, O and S, or (ii) is a 9-, 10- or 11-membered bicyclic heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S;
wherein the monocylcic ring (i) or the bicyclic ring (ii) is optionally substituted with from 1 to 3 YC;
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 from 1 to 3 substituents 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.

115 more elements

HIV protease inhibitors

Life of this patent

HIV protease inhibitors

Life of this patent

Abstract

Claims23