US 9,040,533 B2 · Oxime-substituted-quinoxaline-type piperidine compounds as ORL-1 modulators

Abstract

The present disclosure relates to Oxime-Substituted Quinoxaline-Type Piperidine Compounds, such as those of Formula (I): and the pharmaceutically acceptable salts and solvates thereof, wherein R1, R2, R3, R4, R20, R21, Q, Y1, Z, A, B, and a are as defined herein; compositions comprising an effective amount of an Oxime-Substituted Quinoxaline-Type Piperidine Compound, and methods to treat or prevent a condition, such as pain, comprising administering to an animal in need thereof an effective amount of an Oxime-Substituted Quinoxaline-Type Piperidine Compound.

A compound of Formula (I):

wherein:
Q is fused benzo;
each R2 is independently selected from:
(a) -halo, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —NO2, —N3, —OT, —ST, —N(T)2, —C(═Y)T, —C(═Y)YT, —YC(═Y)T, —YC(═Y)YT, —C(═Y)N(T)2, —N(T)C(═Y)T, —N(T)C(═Y)N(T)2, —YC(═Y)N(T)2, —N(T)C(═Y)YT, —S(═O)pT, —S(═O)pOT, —OS(═O)pT, —OS(═O)pOT, —S(═O)pN(T)2, —N(T)S(═O)pT, —N(T)S(═O)pN(T)2, —OS(═O)pN(T)2, and —N(T)S(═O)pOT;
(b) —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C1-C6)alkoxy, —(C3-C7)cycloalkyl, —(C6-C14)bicycloalkyl, —(C7-C20)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C7-C14)bicycloalkenyl, —(C8-C20)tricycloalkenyl, —(C3-C7)cycloalkoxy, -(5- or 6-membered)heterocyclyl, and -(7- to 10-membered)bicycloheterocyclyl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R5 groups;
and
(c) -phenyl, -benzyl, -naphthyl, —(C14)aryl, and -(5- or 6-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R6 groups;
Y1 and each Y are independently selected from O and S;
denotes a double bond or a single bond at its position, provided that
(a) if denotes a double bond, then R3 and R4 are absent;
and
(b) if denotes a single bond, then R3 and R4 are present;
R3 and R4, if present, are independently selected from —H and —(C1-C4)alkyl, which is unsubstituted or substituted with 1, 2, or 3 groups independently selected from —OR7, —(C1-C4)alkoxy, —N(R7)2, —C(═O)OR7, and —C(═O)N(R7)2;
R20 is selected from:
(a) —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, and —(C2-C6)alkynyl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R5 groups;
(b) —(CH2)dC(═Y)T, —(CH2)dC(═Y)YT, —(CH2)dYC(═Y)T, —(CH2)dYC(═Y)YT, —(CH2)dC(═Y)N(T)2, —(CH2)dN(T)C(═Y)T, —(CH2)dN(T)C(═Y)N(T)2, —(CH2)dYC(═Y)N(T)2, and —(CH2)dN(T)C(═Y)YT;
(c) —Y(CH2)eYT, —(CH2)dN(T)2, —N(T)(CH2)eN(T)2, —Y(CH2)eN(T)2, and —N(T)(CH2)eYT;
and
(d) -halo, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, and —NO2;
R21 is selected from:
(a) —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, and —(C2-C6)alkynyl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R5 groups;
(b) —(CH2)dC(═Y)T, —(CH2)dC(═Y)YT, —(CH2)eYC(═Y)T, —(CH2)eYC(═Y)YT, —(CH2)dC(═Y)N(T)2, —(CH2)eN(T)C(═Y)T, —(CH2)eN(T)C(═Y)N(T)2, —(CH2)eYC(═Y)N(T)2, and —(CH2)eN(T)C(═Y)YT;
and
(c) —(CH2)eYT and —(CH2)eN(T)2;
A and B together form a (C2-C6)bridge, which is unsubstituted or substituted with 1, 2, 3, 4, 5, 6, 7, or 8 substituents independently selected from —OR7, —(C1-C6)alkyl, -halo, —C(halo)3, —CH(halo)2, and —CH2(halo) and which bridge optionally contains a carbon-carbon double bond, —O—, —S—, or —N(R7)—, wherein the 6-membered, nitrogen-containing ring that is fused to the Q ring is in the endo- or exo-configuration with respect to the A-B bridge;
Z is selected from a direct bond, —(C1-C10)alkyl-, —(C2-C10)alkenyl-, —(C2-C10)alkynyl-, —(C2-C10)alkyl-Y—, —(C1-C10)alkyl-C(═Y)Y—, —(C2-C10)alkyl-YC(═Y)—, —(C2-C10)alkyl-N(R7)—, —(C1-C10)alkyl-C(═Y)N(R7)—, and —(C2-C10)alkyl-N(R7)C(═Y)—, each of which is unsubstituted or substituted with 1, 2, or 3 independently selected R8 groups;
R1 is selected from —(C3-C14)cycloalkyl, —(C6-C14)bicycloalkyl, —(C7-C20)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C7-C14)bicycloalkenyl, —(C8-C20)tricycloalkenyl, —(C3-C7)cycloalkoxy, -(3- to 7-membered)heterocyclyl, and -(7- to 10-membered)bicycloheterocyclyl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R5 groups;
each T is independently selected from
(a) —H, —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C5-C10)cycloalkenyl, and -(5- or 6-membered)heterocyclyl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R5 groups, and, optionally, in which 1, 2, or 3 —(C1-C10)alkyl carbon atoms except the carbon atom bonded directly to the atom to which T is attached is independently replaced by —O—, —S—, or —N(R7)—;
and
(b) -phenyl, -benzyl, -naphthyl, and -(5- or 6-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R6 groups;
or
two occurrences of T attached to the same nitrogen atom together form a 4- to 8-membered (C2-C7)ring, wherein the number of atoms in the ring includes the nitrogen atom, which ring is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R5 groups, and wherein 1 or 2 of the ring carbon atoms is optionally and independently replaced by —O—, —S—, or —N(R7)—;
each R5 is independently selected from —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, -halo, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —NO2, —N3, —OR7, —SR7, —N(R7)2, ═O, ═S, —C(═O)R7, —C(═O)OR7, —OC(═O)R7, —OC(═O)OR7, —C(═O)N(R7)2, —N(R7)C(═O)R7, —N(R7)C(═O)N(R7)2, —OC(═O)N(R7)2, and —N(R7)C(═O)OR7;
each R6 is independently selected from —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, -halo, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —NO2, —N3, —OR7, —SR7, —N(R7)2, —C(═O)R7, —C(═O)OR7, —OC(═O)R7, —OC(═O)OR7, —C(═O)N(R7)2, —N(R7)C(═O)R7, —N(R7)C(═O)N(R7)2, —OC(═O)N(R7)2, —N(R7)C(═O)OR7, —S(═O)pR7, —S(═O)pOR7, —OS(═O)pR7, —OS(═O)pOR7, —S(═O)pN(R7)2, —N(R7)S(═O)pR7, —N(R7)S(═O)pN(R7)2, —OS(═O)pN(R7)2, and —N(R7)S(═O)pOR7;
each R7 is independently selected from —H, —(C1-C6)alkyl, or two occurrences of R7 attached to the same nitrogen atom together form a 4- to 7-membered (C2-C6)ring, wherein the number of atoms in the ring includes the nitrogen atom, and wherein 1 or 2 of the ring carbon atoms is optionally and independently replaced by —O—, —S—, or —N(R7)—;
each R8 is independently selected from -halo, —C(halo)3, —CH(halo)2, —CH2(halo), —OR7, —SR7, —N(R7)2, ═O, ═S, —(C1-C4)alkyl, and —(C1-C4)alkoxy;
a is an integer selected from 0, 1, 2, 3, and 4;
each d is an integer independently selected from 0, 1, 2, 3, 4, 5, and 6;
each e is an integer independently selected from 2, 3, 4, 5, and 6;
and
each p is an integer independently selected from 1 and 2;
or a pharmaceutically acceptable salt thereof.

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Oxime-substituted-quinoxaline-type piperidine compounds as ORL-1 modulators

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Oxime-substituted-quinoxaline-type piperidine compounds as ORL-1 modulators

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Abstract

Claims31