US 7,125,887 B2 · Pyrrolidine modulators of CCR5 chemokine receptor activity

Abstract

Pyrrolidine compounds of Formula (I), (wherein R1, R2, R3, R4, R5, R6a, R6b, R7 and R8 are defined herein) are described. The compounds are modulators of CCR5 chemokine receptor activity. The compounds are useful, for example, in the prevention or treatment of infection by HIV and the treatment of AIDS, as compounds or pharmaceutically acceptable salts, or as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described

A compound of Formula I:

wherein:
R1 is:
(1) —CO2H,
(2) —NO2,
(3) -tetrazolyl,
(4) -hydroxyisoxazole,
(5) —SO2NHCO—(C0-3 alkyl)—Ra, or
(6) —P(O)(OH)(ORa);
wherein Ra is independently selected from hydrogen, C1-6 alkyl, C5-6 cycloalkyl, benzyl and phenyl, where any one of which except hydrogen is optionally substituted with 1–3 substituents where the substituents are independently selected from halo, C1-3 alkyl, —O—C1-3 alkyl, and —CF3,
R2 is:
wherein “” denotes the point of attachment;
R9 is selected from:
(1) hydrogen,
(2) C1-6 alkyl, which is unsubstituted or substituted with 1–4 substituents where the substituents are independently selected from hydroxy, cyano, and halo,
(3) cyano,
(4) hydroxy, and
(5) halo;
and
Y is:
(1) a direct single bond;
(2) —C1-10 alkyl- or —(C0-6 alkyl)C3-6cycloalkyl(C0-6 alkyl)-, either of which is optionally substituted with 1–7 substituents independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C1-3 alkyl,
(d) —CF3,
(e) —(C1-3 alkyl)hydroxy, and
(f) ethylenedioxy;
(3) —(C0-6 alkyl)-Z1-(C0-6 alkyl)-, wherein each alkyl is optionally substituted with 1–7 substituents independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C1-3 alkyl, and
(d) —CF3;
and where Z1 is selected from —SO2—, —N(Ru)—, —N(Ru)C(═CHRs)N(Ru)—, —N(Ru)C(═NRs)N(Ru)—, —S—, —O—, —SO—, —SO2N(Ru)—, —N(Ru)SO2—, and —PO2—;
Ru is hydrogen, C1-6 alkyl, C2-6 alkenyl, benzyl, phenyl, (CO)C1-6 alkyl, —SO2—C1-6 alkyl, —SO2-phenyl, —SO2-heterocycle, or C1-6 alkyl-C3-6 cycloalkyl;
wherein any of which except hydrogen is optionally substituted with 1–3 substituents independently selected from halo, C1-3 alkyl, —O—C1-3 alkyl, and —CF3;
Rs is hydrogen, C1-4 alkyl, —NO2 or —CN;
(4) —(C0-6 alkyl)-Z2-(C0-6 alkyl)-, wherein each alkyl is optionally substituted with 1–7 substituents independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C1-3 alkyl, and
(d) —CF3;
and where:
Z2 is selected from —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)NRv—, —NRvC(═O)—, —OC(═O)NRv—, —NRvC(═O)O—, and —NRwC(═O)NRv—;
Rv is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, benzyl, phenyl, or C1-6 alkyl-C3-6 cycloalkyl;
wherein any of which except hydrogen is optionally substituted with 1–3 substituents independently selected from halo, C1-3 alkyl, —O—C1-3 alkyl, and —CF3;
and
Rw is hydrogen or C1-6 alkyl;
R10 is:
(1) a heterocycle selected from pyrazolyl and imidazolyl, wherein the pyrazolyl or imidazolyl is substituted with three of Rd, wherein each Rd is independently selected from the group consisting of:
(a) halo,
(b) cyano,
(c) hydroxy,
(d) C1-6 alkyl, which is unsubstituted or substituted with 1–5 of Re where Re is independently selected from halo, cyano, hydroxy, —O—C1-16 alkyl, —C3-6 cycloalkyl, —CO2H, —CO2—(C1-6 alkyl), —CF3, —SO2Ra, —NRaRb (where Ra is independently as defined above and Rb is independently selected from the definitions of Ra), phenyl, naphthyl, biphenyl, and heterocycle;
wherein phenyl, naphthyl, biphenyl, or heterocycle is unsubstituted or substituted with 1–7 of Rf where Rf is independently selected from halo, cyano, hydroxy, C1-6 alkyl, C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, —CO2H, —CO2(C1-6 alkyl), —NRaRb, —(C1-6 alkyl)-NRaRb, —SO2Ra, —N(Ra)SO2Rb, —N(Ra)CORb, —(C1-6 alkyl)hydroxy, —O—C3-6 cycloalkyl, benzyloxy, phenoxy, and —NO2,
(e) —O—C1-6 alkyl, which is unsubstituted or substituted with 1–5 of Re,
(f) —O-phenyl, which is unsubstituted or substituted with 1–5 of Rf,
(g) —O-heterocycle, which is unsubstituted or substituted with 1–5 of Rf,
(h) —NO2,
(i) phenyl,
(j) —CO2Ra,
(k) tetrazolyl,
(l) —NRaRb,
(m) —NRa—CORb,
(n) —NRa—CO2Rb,
(o) —CO—NRaRb,
(p) —OCO—NRaRb,
(q) —NRaCO—NRaRb,
(r) —S(O)m—Ra, wherein m is an integer selected from 0, 1, and 2,
(s) —S(O)2—NRaRb,
(t) —NRaS(O)2—Rb,
(u) —NRaS(O)2—NRaRb,
(v) C2-6 alkenyl,
(w) furanyl, which is unsubstituted or substituted with benzyl which is unsubstituted or substituted with 1–7 of Rf wherein Rf is independently as defined above,
(x) —C3-6 cycloalkyl, and
(y) —O—C3-6 cycloalkyl;
or
(2) a heterocycle selected from:
wherein n is an integer equal to zero or 1, and
the heterocycle is mono-substituted in the pyrazolyl or imidazolyl ring with any one of Rd as defined above, and is either unsubstituted in the other ring or is substituted with 1 or more substituents where each substituent is independently selected from (a) to (y) of Rd as defined above;
R3 is phenyl, naphthyl, or heterocycle, any one of which is unsubstituted or substituted with 1–7 substituents where the substituents are independently selected from:
(a) halo,
(b) C1-4 alkyl,
(c) C1-4 haloalkyl,
(d) hydroxy,
(e) —O—C1-4 alkyl,
(f) —O—C1-4 haloalkyl,
(g) —CO2Ra,
(h) —NRaRb, and
(i) —CONRaRb;
R4 is hydrogen, C1-10 alkyl, C3-8 cycloalkyl, —(C1-3 alkyl)-C3-8 cycloalkyl, —(C0-2 alkyl)-(C3-8 cycloalkylidenyl)-(C1-2 alkyl), C2-10 alkenyl, C2-10 alkynyl, cyclohexenyl, phenyl, —(C1-6 alkyl)-phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, octahydronaphthyl, biphenyl, or heterocycle;
wherein any one of which except for hydrogen is unsubstituted or substituted with 1–7 of Rd where Rd is independently as defined above;
R5 is hydrogen or C1-6 alkyl, wherein the alkyl is unsubstituted or substituted with 1–7 substituents where the substituents are independently selected from:
(a) halo,
(b) —CF3,
(c) hydroxy,
(d) C1-3 alkyl,
(e) —O—C1-3 alkyl,
(f) —CO2Ra,
(g) —NRaRb, and
(h) —CONRaRb;
or alternatively R4 and R5 together with the carbon atom to which they are attached form a C3-8 cycloalkyl ring which may be unsubstituted or substituted with 1–7 of Rd;
R6a and R6b are each independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, phenyl, naphthyl, or heterocycle;
wherein any one of which is unsubstituted or substituted with 1–7 substituents where the substituents are independently selected from:
(a) halo,
(b) C1-4 haloalkyl,
(c) hydroxy,
(d) C1-4 alkyl,
(e) —O—C1-4alkyl,
(f) —O—C1-4 haloalkyl,
(g) C3-8 cycloalkyl,
(h) —CO2Ra,
(i) —NRaRb, and
(j)—CONRaRb;
or alternatively R6a and R6b together with the carbon atom to which they are attached form:
(a) a 3- to 8-membered saturated carbocyclic ring, in which one of the ring carbons is optionally a member of a 3- to 8-membered spiro ring containing carbon atoms and optionally 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur;
(b) a 4- to 8-membered monocyclic heterocycle containing from 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, in which one of the ring carbons is optionally a member of a 3- to 8-membered spiro ring containing carbon atoms and optionally 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur;
(c) a 5- to 8-membered saturated carbocyclic ring to which is fused a C3-8 cycloalkyl, or
(d) a 5- to 8-membered heterocyclic ring containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, to which is fused a C3-8 cycloalkyl,
wherein the ring system of (a), (b), (c) or (d) is optionally substituted with from 1 to 3 substituents selected from halo, C1-4 alkyl, C1-4 haloalkyl, —O—C1-4 alkyl, —O—C1-4 haloalkyl, and hydroxy;
R7 is hydrogen or C1-6 alkyl;
and
R8 is hydrogen or C1-6 alkyl;
or a pharmaceutically acceptable salt thereof.

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Pyrrolidine modulators of CCR5 chemokine receptor activity

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Pyrrolidine modulators of CCR5 chemokine receptor activity

Life of this patent

Abstract

Claims27