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

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- Number: US 9,040,533 B2
- Document ID: US9040533B2
- Status: Granted
- Kind: B2
- Application number: 14/138,976
- Filed: 2013-12-23
- Published: 2014-07-03
- Granted: 2015-05-26
- Earliest claimed: 2012-12-27
- Assignees: Purdue Pharma L.P.; Shionogi & Co., Ltd.
- Applicants: Purdue Pharma L.P.; Shionogi & Co., Ltd.
- Inventors: Jeffrey Michael Marra; Naoki Tsuno; Tatsuhiko Ueno; Xiaoming Zhou
- Web page: https://patentgrep.com/patent/US9040533B2

## CPC

- A61K 31/498: Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
- A61K 31/5386: spiro-condensed or forming part of bridged ring systems
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 11/14: Antitussive agents
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07D 451/04: with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D 451/14: containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
- C07D 471/08: Bridged systems
- C07D 498/08: Bridged systems
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## 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.

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

The compound of claim 1, wherein Z is a direct bond or —(C1-C10)alkyl-, which is unsubstituted or substituted with 1, 2, or 3 independently selected R8 groups.

### Claim 3 (depends on 2)

The compound of claim 2, wherein Z is a direct bond.

### Claim 4 (depends on 2)

The compound of claim 2, wherein Z is —(C1-C10)alkyl-, which is unsubstituted or substituted with 1, 2, or 3 independently selected R8 groups.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R1 is selected from —(C3-C14)cycloalkyl, —(C6-C14)bicycloalkyl, and —(C7-C20)tricycloalkyl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R5 groups.

### Claim 6 (depends on 5)

The compound of claim 5, wherein R1 is —(C6-C14)bicycloalkyl, which is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R5 groups.

### Claim 7 (depends on 5)

The compound of claim 5, wherein R1 is —(C3-C14)cycloalkyl, which is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R5 groups.

### Claim 8 (depends on 1)

The compound of claim 1, wherein denotes a double bond, and R3 and R4 are absent.

### Claim 9 (depends on 1)

The compound of claim 1, wherein denotes a single bond, and R3 and R4 are present.

### Claim 10 (depends on 1)

The compound of claim 1, wherein R20 is selected from —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.

### Claim 11 (depends on 1)

The compound of claim 1, wherein R20 is selected from —(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.

### Claim 12 (depends on 1)

The compound of claim 1, wherein R20 is selected from —Y(CH2)eYT, —(CH2)dN(T)2, —N(T)(CH2)eN(T)2, —Y(CH2)eN(T)2, and —N(T)(CH2)eYT.

### Claim 13 (depends on 1)

The compound of claim 1, wherein R20 is selected from -halo, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, and —NO2.

### Claim 14 (depends on 1)

The compound of claim 1, wherein R21 is selected from —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.

### Claim 15 (depends on 1)

The compound of claim 1, wherein R21 is selected from —(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.

### Claim 16 (depends on 1)

The compound of claim 1, wherein R21 is selected from —(CH2)eN(T)2 and —(CH2)eYT.

### Claim 17 (depends on 1)

The compound of claim 1, wherein a is 0.

### Claim 18 (depends on 1)

The compound of claim 1, wherein the compound is of Formula (Ib):
or a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 1)

The compound of claim 1, wherein —Z—R1 is:

### Claim 20 (depends on 1)

The compound of claim 1, wherein —Z—R1 is:
wherein Rz is —H or —(C1-C6)alkyl.

### Claim 21 (depends on 1)

The compound of claim 1, wherein —Z—R1 is selected from:
wherein each Rz is independently —H or —(C1-C6)alkyl.

### Claim 22 (depends on 1)

The compound of any one of claim 1, wherein —Z—R1 is:
wherein each Rz is independently selected from —H, —(C1-C6)alkyl, and —OH.

### Claim 23 (depends on 1)

The compound of claim 1, wherein —Z—R1 is selected from:

### Claim 24 (depends on 1)

The compound of claim 1, wherein A and B together form a bridge such that the bridged-piperidine is:
wherein each Rd is independently selected from —H, —(C1-C6)alkyl, -halo, —C(halo)3, —CH(halo)2, and —CH2(halo), wherein the piperidine nitrogen is optionally in pharmaceutically acceptable salt form.

### Claim 25 (depends on 24)

The compound of claim 24, wherein A and B together form a bridge such that the bridged-piperidine is:
wherein the piperidine nitrogen is optionally in pharmaceutically acceptable salt form.

### Claim 26 (depends on 1)

The compound of claim 1, wherein the compound has the structure:
wherein M1 is selected from:
and
M2 is selected from:
or a pharmaceutically acceptable salt thereof.

### Claim 27 (depends on 1)

A composition comprising an effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier or excipient.

### Claim 28 (depends on 1)

A method for modulating opioid receptor like-1 receptor function in a cell, comprising contacting a cell capable of expressing the opioid receptor like-1 receptor with an effective amount of the compound of claim 1.

### Claim 29

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) —(CH2)dN(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.

### Claim 30 (depends on 29)

A method for modulating opioid receptor like-1 receptor function in a cell, comprising contacting a cell capable of expressing the opioid receptor like-1 receptor with an effective amount of the compound of claim 29.

### Claim 31

A compound selected from:
and the pharmaceutically acceptable salts thereof.