LXR modulators

A compound of formula I:

• or stereoisomers or pharmaceutically acceptable salts or N-oxides thereof, wherein:
• A is
• C(O)NR28R29, —CO2(C1-C6)-alkyl, or heterocyclyl, wherein the alkyl and heterocyclyl may be optionally substituted with one or more R10a's;
• X is CR20R20;
• R1 is —C(O)R7, —C(O)OR7, —S(O)R7, —C(O)NR28R29, (C1-C3)alkylaryl or (C1-C3)alkylheteroaryl, wherein the alkylaryl and alkylheteroaryl may be optionally substituted with one or more R10b's;
• R2a, R2b and R2c are independently hydrogen, halo, —OH, —(C1-C6)-alkyl, —O(C1-C6)-alkyl, halo(C1-C6)-alkyl-, halo(C1-C6)-alkyloxy- or cyano;
• R3a is hydrogen, (C1-C8)alkyl, aryl or heteroaryl, wherein the alkyl, aryl and heteroaryl may be optionally substituted with one or more R10b's;
• R3b is (a) hydrogen, (b) —OH, (c) R46—S(O)n—, (d) cyano, (e) aryl-(C1-C6)alkyloxy-, which may optionally be substituted with one or more substituents selected from the group consisting of:
• halo, —OH, (C1-C6)-alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkyloxy, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C1-C6)-alkyloxy, (OH)—(C1-C6)-alkyl-, R46—S(O)n—, cyano, nitro, —COOH, —(C1-C6)-alkylCOOH, —(C1-C6)-alkyl(NH2)COOH, —CO(C1-C6)-alkyl, —(C1-C6)-alkyl-CO2(C1-C6)-alkyl, —CO2(C1-C6)-alkyl, —O(C═O)—(C1-C6)-alkyl, —O(C1-C6)-alkylaryl, aryl, which may be optionally substituted with one or more R50's;
• heteroaryl, which may be optionally substituted with one or more R50's, and heterocyclo, which may be optionally substituted with one or more R50's;
• (f) heteroaryl-(C1-C6)alkyloxy-, which may optionally be substituted with one or more substituents selected from the group consisting of:
• halo, —OH, (C1-C6)-alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkyloxy, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C1-C6)-alkyloxy, (OH)—(C1-C6)-alkyl-, R46—S(O)n—, cyano, nitro, —COOH, —(C1-C6)-alkylCOOH, —(C1-C6)-alkyl(NH2)COOH, —CO(C1-C6)-alkyl, —(C1-C6)-alkyl-CO2(C1-C6)-alkyl, —CO2(C1-C6)-alkyl, —O(C═O)—(C1-C6)-alkyl, —O(C1-C6)-alkylaryl, aryl, which may be optionally substituted with one or more R50's;
• heteroaryl, which may be optionally substituted with one or more R50's, and heterocyclo, which may be optionally substituted with one or more R50's;
• (g) aryl, which may optionally be substituted with one or more substituents selected from the group consisting of:
• halo, —OH, (C1-C6)-alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkyloxy, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C1-C6)-alkyloxy, (OH)—(C1-C6)-alkyl-, cyano, nitro, —COOH, —(C1-C6)-alkylCOOH, —(C1-C6)-alkyl(NH2)COOH, —CO(C1-C6)-alkyl, —(C1-C6)-alkyl-CO2(C1-C6)-alkyl, —CO2(C1-C6)-alkyl, —O(C═O)—(C1-C6)-alkyl, —O(C1-C6)-alkylaryl, aryl, which may be optionally substituted with one or more R50's;
• heteroaryl, which may be optionally substituted with one or more R50's, and heterocyclo, which may be optionally substituted with one or more R50's;
• (h) heteroaryl optionally substituted with one or more substituents selected from the group consisting of:
• halo, —OH, (C1-C6)-alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkyloxy, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C1-C6)-alkyloxy, (OH)—(C1-C6)-alkyl-, cyano, nitro, —COOH, —(C1-C6)-alkylCOOH, —(C1-C6)-alkyl(NH2)COOH, —CO(C1-C6)-alkyl, —(C1-C6)-alkyl-CO2(C1-C6)-alkyl, —CO2(C1-C6)-alkyl, —O(C═O)—(C1-C6)-alkyl, —O(C1-C6)-alkylaryl, aryl, which may be optionally substituted with one or more R50's;
• heteroaryl, which may be optionally substituted with one or more R50's, and heterocyclo, which may be optionally substituted with one or more R50's;
• (i) —(C1-C8)-alkyl, which may optionally be substituted with one or more substituents selected from the group consisting of:
• halo, —OH, halo(C1-C6)alkyloxy, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C1-C6)-alkyloxy, (OH)—(C1-C6)-alkyl-, cyano, (C3-C6)-cycloalkyl, —COOH, —(C1-C6)-alkylCOOH, —(C1-C6)-alkyl(NH2)COOH, —CO(C1-C6)-alkyl, —(C1-C6)-alkyl-CO2(C1-C6)-alkyl, —CO2(C1-C6)-alkyl, —O(C═O)—(C1-C6)-alkyl, —O(C1-C6)-alkylaryl, aryl, which may be optionally substituted with one or more R50's, heteroaryl, which may be optionally substituted with one or more R50's, and heterocyclo, which may be optionally substituted with one or more R50's;
• (j) —O[(C═O)]saryl, which may optionally be substituted with one or more substituents selected from the group consisting of:
• halo, —OH, (C1-C6)-alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkyloxy, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C1-C6)-alkyloxy, (OH)—(C1-C6)-alkyl-, cyano, nitro, —COOH, —(C1-C6)-alkylCOOH, —(C1-C6)-alkyl(NH2)COOH, —CO(C1-C6)-alkyl, —(C1-C6)-alkyl-CO2(C1-C6)-alkyl, —CO2(C1-C6)-alkyl, —O(C═O)—(C1-C6)-alkyl, aryl, which may be optionally substituted with one or more R50's, heteroaryl, which may be optionally substituted with one or more R50's, and heterocyclo, which may be optionally substituted with one or more R50's;
• (k) —O[(C═O)]sheteroaryl, which may optionally be substituted with one or more substituents selected from the group consisting of:
• halo, —OH, (C1-C6)-alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkyloxy, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C1-C6)-alkyloxy, (OH)—(C1-C6)-alkyl-, cyano, nitro, —COOH, —(C1-C6)-alkylCOOH, —(C1-C6)-alkyl(NH2)COOH, —CO(C1-C6)-alkyl, —(C1-C6)-alkyl-CO2(C1-C6)-alkyl, —CO2(C1-C6)-alkyl, —O(C═O)—(C1-C6)-alkyl, —O(C1-C6)-alkylaryl, aryl, which may be optionally substituted with one or more R50's, heteroaryl, which may be optionally substituted with one or more R50's, and heterocyclo, which may be optionally substituted with one or more R50's;
• or (l) R46—S(O)n—O—;
• R4, R5 and R6 are independently hydroxy or halo(C1-C4)-alkyl;
• provided that (i) only one of R4, R5 or R6 is hydroxy and (ii) R5 and R6 are halo(C1-C4)-alkyl when R3a and R3b are hydrogen and R4 is hydroxy;
• R7 is alkyl, cycloalkyl, alkenyl, aryl or heterocyclyl, wherein the alkyl, cycloalkyl, aryl, or heterocyclyl may be optionally substituted with one or more R10b's;
• R10a is halo, —OH, —O[(C═O)]s(C1-C6)-alkyl, —O[(C═O)]s(C2-C6)-alkenyl, cyano, nitro, —NR28bR29b, —COOH, —CO(C1-C6)-alkyl, —CO2(C1-C6)-alkyl, —(C1-C6)-haloalkyl, —(C3-C6)-cycloalkyl or —(C1-C6)-alkyl;
• R10b is (a) halo;
• (b) —OH;
• (c) —O[(C═O)]s(C1-C6)-alkyl;
• (d) —O[(C═O)]s(C1-C6)-alkylaryl;
• (e) R46—S(O)n—;
• (f) cyano;
• (g) nitro;
• (h) —NR28bR29b;
• (i) —CO(C1-C6)-alkyl;
• (j) —CO2(C1-C6)-alkyl;
• (k) aryl, which may optionally be substituted with one or more substituents selected from the group consisting of:
• halo, —OH, (C1-C6)-alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkyloxy, (C1-C6)-alkyloxy, (OH)—(C1-C6)-alkyl-, (C1-C6)-alkyl-S(O)n—, cyano, nitro, —CO(C1-C6)-alkyl, —(C1-C3)-alkyl-CO2 (C1-C6)-alkyl, —CO2 (C1-C6)-alkyl, —NR28bR29b, —O(C═O)—(C1-C6)-alkyl, —O(C1-C6)-alkylaryl, aryl, which may be optionally substituted with one or more halo, alkyl, haloalkyl, OH, alkyloxy, haloalkyloxy, cyano, or nitro, heteroaryl, which may be optionally substituted with one or more halo, alkyl, haloalkyl, OH, alkyloxy, haloalkyloxy, cyano, or nitro;
• and heterocyclo, which may be optionally substituted with one or more halo, alkyl, haloalkyl, OH, alkyloxy, haloalkyloxy, cyano, or nitro;
• (l) heteroaryl optionally substituted with one or more substituents selected from the group consisting of:
• halo, —OH, (C1-C6)-alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkyloxy, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C1-C6)-alkyloxy, (OH)—(C1-C6)-alkyl-, cyano, nitro, —CO(C1-C6)-alkyl, —(C1-C3)-alkyl-CO2(C1-C6)-alkyl, —CO2(C1-C6)-alkyl, —O(C═O)—(C1-C6)-alkyl, —O(C1-C6)-alkylaryl, aryl, which may be optionally substituted with one or more halo, alkyl, haloalkyl, OH, alkyloxy, haloalkyloxy, cyano, or nitro;
• heteroaryl, which may be optionally substituted with one or more halo, alkyl, haloalkyl, OH, alkyloxy, haloalkyloxy, cyano, or nitro;
• and heterocyclo, which may be optionally substituted with one or more halo, alkyl, haloalkyl, OH, alkyloxy, haloalkyloxy, cyano, or nitro;
• (m) heterocyclo, other than heteroaryl, which is optionally substituted with one or more substituents selected from the group consisting of:
• halo, —OH, (C1-C6)-alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkyloxy, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C1-C6)-alkyloxy, (OH)—(C1-C6)-alkyl-, cyano, nitro, —CO(C1-C6)-alkyl, —(C1-C3)-alkyl-CO2(C1-C6)-alkyl, —CO2(C1-C6)-alkyl, —O(C═O)—(C1-C6)-alkyl, —O(C1-C6)-alkylaryl, aryl, which may be optionally substituted with one or more halo, alkyl, haloalkyl, OH, alkyloxy, haloalkyloxy, cyano, or nitro;
• heteroaryl, which may be optionally substituted with one or more halo, alkyl, haloalkyl, OH, alkyloxy, haloalkyloxy, cyano, or nitro;
• and heterocyclo, which may be optionally substituted with one or more halo, alkyl, haloalkyl, OH, alkyloxy, haloalkyloxy, cyano, or nitro;
• (n) —(C1-C6)-alkyl, which may optionally be substituted with one or more substituents selected from the group consisting of:
• halo, —OH, halo(C1-C6)alkyloxy, (C1-C6)-alkyloxy, cyano, —CO(C1-C6)-alkyl, —CO2(C1-C6)-alkyl, —O(C═O)—(C1-C6)-alkyl, aryl, which may be optionally substituted with one or more halo, alkyl, haloalkyl, OH, alkyloxy, haloalkyloxy, cyano, or nitro;
• heteroaryl, which may be optionally substituted with one or more halo, alkyl, haloalkyl, OH, alkyloxy, haloalkyloxy, cyano, or nitro, and heterocyclo, which may be optionally substituted with one or more halo, alkyl, haloalkyl, OH, alkyloxy, haloalkyloxy, cyano, or nitro;
• (o) ═O, (p) —(C3-C8)-cycloalkyl, which may optionally be substituted with one or more substituents selected from the group consisting of:
• halo, —OH, (C1-C6)-alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkyloxy, (C1-C6)-alkyloxy, (OH)—(C1-C6)-alkyl-, cyano, nitro, —CO(C1-C6)-alkyl, —(C1-C6)-alkyl-CO2(C1-C6)-alkyl, —CO2(C1-C6)-alkyl, —O(C═O)—(C1-C6)-alkyl, —O(C1-C6)-alkylaryl, aryl, which may be optionally substituted with one or more halo, alkyl, haloalkyl, OH, alkyloxy, haloalkyloxy, cyano, or nitro;
• heteroaryl, which may be optionally substituted with one or more halo, alkyl, haloalkyl, OH, alkyloxy, haloalkyloxy, cyano, or nitro, and heterocyclo, which may be optionally substituted with one or more halo, alkyl, haloalkyl, OH, alkyloxy, haloalkyloxy, cyano, or nitro;
• (q) —O[(C═O)]saryl, which may optionally be substituted with one or more substituents selected from the group consisting of:
• halo, —OH, (C1-C6)-alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkyloxy, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C1-C6)-alkyloxy, (OH)—(C1-C6)-alkyl-, cyano, nitro, —CO(C1-C6)-alkyl, —(C1-C6)-alkyl-CO2(C1-C6)-alkyl, —CO2(C1-C6)-alkyl, and —O(C═O)—(C1-C6)-alkyl;
• or (r) halo(C1-C6)alkyloxy;
• R20 is hydrogen, or (C1-C4)-alkyl;
• or the two R20's are taken together with the carbon atom to which they are attached to form a 3- to 6-membered ring;
• R28 and R29 are independently hydrogen, aryl, (C1-C6)alkyl, halo(C1-C6)alkyl, aryl(C1-C3)alkyl or heterocyclyl, wherein the aryl, alkyl, arylalkyl and heterocyclyl may be optionally substituted with one or more R50a's;
• or R28 and R29 are taken together with the nitrogen to which both are attached to form a 3- to 8-membered ring, which may optionally contain 1-4 heteroatoms selected from N, O, and S and be optionally substituted with one or more R50a's;
• R28a and R29a are independently hydrogen, —[(C═O)Or]saryl, —[(C═O)Or]sheteroaryl, —[(C═O)Or]s(C2-C8)-alkenyl, —[(C═O)Or]s(C1-C8)alkyl, —S(O)p(C1-C8)alkyl, —S(O)paryl, —S(O)pheteroaryl or heterocyclyl, wherein the aryl, heteroaryl, alkenyl, alkyl and heterocyclyl may be optionally substituted with one or more R50's;
• or R28a and R29a are taken together with the nitrogen to which both are attached to form a 3- to 8-membered ring, which may optionally contain 1-4 heteroatoms selected from N, O, and S and be optionally substituted with one or more R50's;
• R28b and R29b are independently hydrogen, alkyl or haloalkyl;
• R46 is (a) aryl, which may optionally be substituted with one or more substituents selected from the group consisting of:
• halo, —OH, (C1-C6)-alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkyloxy, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C1-C6)-alkyloxy, (OH)—(C1-C6)-alkyl-, cyano, nitro, —COOH, —(C1-C6)-alkylCOOH, —(C1-C6)-alkyl(NH2)COOH, —CO(C1-C6)-alkyl, —(C1-C6)-alkyl-CO2(C1-C6)-alkyl, —CO2(C1-C6)-alkyl, —O(C═O)—(C1-C6)-alkyl, —O(C1-C6)-alkylaryl, aryl, which may be optionally substituted with one or more R50's;
• heteroaryl, which may be optionally substituted with one or more R50's, and heterocyclo, which may be optionally substituted with one or more R50's;
• (b) heteroaryl optionally substituted with one or more substituents selected from the group consisting of:
• halo, —OH, (C1-C6)-alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkyloxy, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C1-C6)-alkyloxy, (OH)—(C1-C6)-alkyl-, cyano, nitro, —COOH, —(C1-C6)-alkylCOOH, —(C1-C6)-alkyl(NH2)COOH, —CO(C1-C6)-alkyl, —(C1-C6)-alkyl-CO2(C1-C6)-alkyl, —CO2(C1-C6)-alkyl, —O(C═O)—(C1-C6)-alkyl, —O(C1-C6)-alkylaryl, aryl, which may be optionally substituted with one or more R50's, heteroaryl, which may be optionally substituted with one or more R50's, and heterocyclo, which may be optionally substituted with one or more R50's;
• (c) heterocyclo, other than heteroaryl, which is optionally substituted with one or more substituents selected from the group consisting of:
• halo, —OH, (C1-C6)-alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkyloxy, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C1-C6)-alkyloxy, (OH)—(C1-C6)-alkyl-, cyano, nitro, —COOH, —(C1-C6)-alkylCOOH, —(C1-C6)-alkyl(NH2)COOH, —CO(C1-C6)-alkyl, —(C1-C6)-alkyl-CO2(C1-C6)-alkyl, —CO2(C1-C6)-alkyl, —O(C═O)—(C1-C6)-alkyl, —O(C1-C6)-alkylaryl, aryl, which may be optionally substituted with one or more R50's, heteroaryl, which may be optionally substituted with one or more R50's, and heterocyclo, which may be optionally substituted with one or more R50's;
• or (d) —(C1-C10)-alkyl, which may optionally be substituted with one or more substituents selected from the group consisting of:
• halo, —OH, (C1-C6)-alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkyloxy, (C1-C6)-alkyloxy, (OH)—(C1-C6)-alkyl-, cyano, nitro, —COOH, —(C1-C6)-alkylCOOH, —(C1-C6)-alkyl(NH2)COOH, —CO(C1-C6)-alkyl, —(C1-C6)-alkyl-CO2(C1-C6)-alkyl, —CO2(C1-C6)-alkyl, —O(C═O)—(C1-C6)-alkyl, —O(C1-C6)-alkylaryl, aryl, which may be optionally substituted with one or more R50's, heteroaryl, which may be optionally substituted with one or more R50's, and heterocyclo, which may be optionally substituted with one or more R50's;
• R50 is (a) hydrogen, (b) halo, (c) —OH, (d) (C1-C6)-alkyl, (e) halo(C1-C6)-alkyl, (f) halo(C1-C6)-alkyloxy, (g) —O[(C═O)]s(C1-C6)-alkyl, (h) cyano, (i) nitro, (j) —COOH, (k) —CO(C1-C6)-alkyl, (l) —CO2(C1-C6)-alkyl, (m) (OH)—(C1-C6)-alkyl-, (n)-(C1-C6)-alkylCOOH, (o) —(C1-C6)-alkyl-heteroaryl, (p) —(C1-C6)-alkyl-heterocyclyl, (q) —(C1-C6)-alkyl(NH2)COOH, (r) —(C1-C6)-alkyl-CO2(C1-C6)-alkyl, or (s) —(C3-C6)-cycloalkyl;
• R50a is halo, —OH, —O[(C═O)]s(C1-C6)-alkyl, cyano, nitro, —NR51R52, —COOH, —CO(C1-C6)-alkyl, —CO2(C1-C6)-alkyl, —(C1-C6)-haloalkyl, —(C3-C6)-cycloalkyl or —(C1-C6)-alkyl;
• R51 and R52, at each occurrence, are independently hydrogen, —(C1-C6)-alkyl, —(C3-C8)-cycloalkyl, or -halo(C1-C6)-alkyl;
• n is 0 to 2;
• p is 1 or 2;
• q is 1;
• r is 0 or 1;
• and
• s is 0 or 1;
• with the following provisos:
• a) excluding compounds wherein:
• A is
• X is CH2;
• R1 is —C(O)R7;
• R2a is hydrogen, methyl or ethyl;
• R2b, R2c, R3a and R3b are hydrogen;
• R4 and R6 are —CF3;
• R5 is hydroxy;
• and R7 is C1-5 alkyl, propenyl or cycloalkyl;
• and
• b) excluding compounds wherein:
• A is
• X is CH2;
• R1 is —S(O)R7;
• R2a, R2b, R2c, R3a and R3b are hydrogen;
• R5 is hydroxy;
• R4 and R6 are —CF3;
• R7 is phenyl optionally substituted with cyano;
• and n is 2.