# US 8,772,500 B2 · TRPV3 modulators

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- Number: US 8,772,500 B2
- Document ID: US8772500B2
- Status: Granted
- Kind: B2
- Application number: 13/658,374
- Filed: 2012-10-23
- Published: 2013-05-23
- Granted: 2014-07-08
- Earliest claimed: 2011-10-24
- Assignees: AbbVie Inc.
- Applicants: AbbVie Inc.
- Inventors: Erol K. Bayburt; Bruce Clapham; Phil B. Cox; Jerome F. Daanen; Michael J. Dart; Gregory A. Gfesser; Arthur Gomtsyan; Michael E. Kort; Philip R. Kym; Robert G. Schmidt
- Web page: https://patentgrep.com/patent/US8772500B2

## CPC

- C07D 213/38: having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
- A61K 31/192: having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid {(cannabinoids A61K31/658)}
- A61K 31/435: having six-membered rings with one nitrogen as the only ring hetero atom
- A61K 31/4418: having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
- A61K 31/4427: containing further heterocyclic ring systems
- A61K 31/443: containing a five-membered ring with oxygen as a ring hetero atom
- A61K 31/4433: containing a six-membered ring with oxygen as a ring hetero atom
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/47: Quinolines; Isoquinolines
- A61K 31/505: Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 213/30: Oxygen atoms
- C07D 213/34: to which a second hetero atom is attached
- C07D 213/72: Nitrogen atoms (nitro radicals C07D213/61)
- C07D 215/14: Radicals substituted by oxygen atoms
- C07D 221/04: Ortho- or peri-condensed ring systems
- C07D 239/26: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 311/04: Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 405/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 405/08: linked by a carbon chain containing alicyclic rings
- C07D 405/10: linked by a carbon chain containing aromatic rings
- C07D 417/08: linked by a carbon chain containing alicyclic rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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

## Abstract

Disclosed herein are modulators of TRPV3 of formula (II): wherein G1, X1, X2, X3, X4, X5, G2, Ra, Rb, and u are as defined in the specification. Compositions comprising such compounds and methods for treating conditions and disorders using such compounds and compositions are also presented.

## Claims

### Claim 1

A compound according to Formula (II):
or a salt thereof, wherein:
Ra and Rb are absent;
u is 0;
X3 is O; X4 is a bond, X5 is (CH2)n, and n is 2; or
X3 is O; X4 is (CH2)m, X5 is (CH2)n, m and n are each 1; or
X3 is O; X4 is (CH2)m, X5 is (CH2)n, m is 1, and n is 2; or
X3 is O; X4 is a bond, X5 is (CH2)n, and n is 3; and
X1 is —OH and X2 is hydrogen;
G1 is pyridinyl or pyrimidinyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the groups consisting of halogen C1-C6-alkyl C1-C6-haloalkyl, and N(Rgc)2;
Rgc is hydrogen or C1-C6-alkyl;
G2 is G2d;
G2d is phenyl, pyridinyl, or pyrimidinyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the groups consisting of halogen —CN, C1-C6-alkyl C1-C6-haloalkyl, and —ORf; and
Rf is C1-C6-alkyl or C1-C6-haloalkyl.

### Claim 2 (depends on 1)

The compound according to claim 1, or a salt thereof, wherein the compound has the configuration of Formula (II-i-a):

### Claim 3 (depends on 1)

The compound according to claim 1, or a salt thereof, wherein:
G1 is pyridinyl which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, and N(Rgc)2;
Rgc is hydrogen or C1-C4-alkyl;
G2d is phenyl or pyridinyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, and —ORf; and
Rf is C1-C4-alkyl or C1-C4-haloalkyl.

### Claim 4 (depends on 1)

The compound according to claim 1, or a salt thereof, wherein:
G1 is unsubstituted pyridinyl;
G2d is phenyl or pyridinyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, and —ORf; and
Rf is C1-C4-alkyl or C1-C4-haloalkyl.

### Claim 5 (depends on 1)

The compound according to claim 1, or a salt thereof, wherein:
G1 is unsubstituted pyridin-2-yl;
G2d is phenyl or pyridinyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C3-alkyl, C1-C3-haloalkyl, and —ORf; and
Rf is C1-C3-alkyl or C1-C3-haloalkyl.

### Claim 6 (depends on 5)

The compound according to claim 5, or a salt thereof, wherein:
G2d is phenyl which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C3-alkyl, C1-C3-haloalkyl, and —ORf; and
Rf is C1-C3-alkyl or C1-C3-haloalkyl.

### Claim 7 (depends on 5)

The compound according to claim 5, or a salt thereof, wherein:
G2d is phenyl which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C3-alkyl or C1-C3-haloalkyl.

### Claim 8 (depends on 5)

The compound according to claim 5, or a salt thereof, wherein:
G2d is phenyl which is substituted with 1, 2, or 3 substituents independently selected from halogen.

### Claim 9 (depends on 5)

The compound according to claim 5, or a salt thereof, wherein:
G2d is pyridinyl which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C3-alkyl, C1-C3-haloalkyl, and —ORf; and
Rf is C1-C3-alkyl or C1-C3-haloalkyl.

### Claim 10 (depends on 1)

The compound according to claim 1, or a salt thereof, wherein X3 is O; X4 is a bond, X5 is (CH2)n, and n is 2.

### Claim 11 (depends on 1)

The compound according to claim 1, or a salt thereof, wherein X3 is O; X4 is (CH2)m, X5 is (CH2)n, m and n are each 1.

### Claim 12 (depends on 1)

The compound according to claim 1, or a salt thereof, wherein X3 is O; X4 is (CH2)m, X5 is (CH2)n, m is 1, and n is 2.

### Claim 13 (depends on 1)

The compound according to claim 1, or a salt thereof, wherein X3 is O; X4 is a bond, X5 is (CH2)n, and n is 3.

### Claim 14 (depends on 1)

The compound according to claim 1, or a salt thereof, selected from the group consisting of:
pyridin-2-yl{3-[4-(trifluoromethyl)phenyl]tetrahydrofuran-3-yl}methanol;
4-{3-[hydroxy(pyridin-2-yl)methyl]tetrahydrofuran-3-yl}benzonitrile;
pyridin-2-yl {3-[3-(trifluoromethoxy)phenyl]tetrahydrofuran-3-yl}methanol;
3-{3-[hydroxy(pyridin-2-yl)methyl]tetrahydrofuran-3-yl}benzonitrile;
[3-(4-methoxyphenyl)tetrahydrofuran-3-yl](pyridin-2-yl)methanol;
[3-(3,4-dimethoxyphenyl)tetrahydrofuran-3-yl](pyridin-2-yl)methanol;
[3-(3-chlorophenyl)oxetan-3-yl](pyridin-2-yl)methanol;
[3-(3,4-dichlorophenyl)oxetan-3-yl](pyridin-2-yl)methanol;
(anti)-pyridin-2-yl{2-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methanol;
(syn)-pyridin-2-yl{2-[4-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methanol;
[2-(2-methylphenyl)tetrahydrofuran-2-yl](pyridin-2-yl)methanol;
[2-(3-methylphenyl)tetrahydrofuran-2-yl](pyridin-2-yl)methanol;
(anti)-pyridin-2-yl{2-[3-(trifluoromethoxy)phenyl]tetrahydrofuran-2-yl}methanol;
(syn)-pyridin-2-yl{2-[3-(trifluoromethoxy)phenyl]tetrahydrofuran-2-yl}methanol;
(anti)-pyridin-2-yl{2-[4-(trifluoromethoxy)phenyl]tetrahydrofuran-2-yl}methanol;
(syn)-pyridin-2-yl{2-[4-(trifluoromethoxy)phenyl]tetrahydrofuran-2-yl}methanol;
(anti)-pyridin-2-yl{2-[2-(trifluoromethoxy)phenyl]tetrahydrofuran-2-yl}methanol;
(syn)-pyridin-2-yl{2-[2-(trifluoromethoxy)phenyl]tetrahydrofuran-2-yl}methanol;
(anti)-2-(3,4-dichlorophenyl)tetrahydrofuran-2-yl](pyridin-2-yl)methanol;
(syn)-[2-(3,4-dichlorophenyl)tetrahydrofuran-2-yl](pyridin-2-yl)methanol;
(anti)-[2-(3-fluorophenyl)tetrahydrofuran-2-yl](pyridin-2-yl)methanol;
(syn)-[2-(3-fluorophenyl)tetrahydrofuran-2-yl](pyridin-2-yl)methanol;
(anti)-[2-fluorophenyl)tetrahydrofuran-2-yl](pyridin-2-yl)methanol;
(syn)-[2-(2-fluorophenyl)tetrahydrofuran-2-yl](pyridin-2-yl)methanol;
(anti)-[2-(3-chlorophenyl)tetrahydrofuran-2-yl](pyridin-2-yl)methanol;
(syn)-[2-(3-chlorophenyl)tetrahydrofuran-2-yl](pyridin-2-yl)methanol;
(anti)-pyridin-2-yl{2-[3-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methanol;
(syn)-pyridin-2-yl{2-[3-(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methanol;
(anti)-[2-(3,4-difluorophenyl)tetrahydrofuran-2-yl](pyridin-2-yl)methanol;
(syn)-[2-(3,4-difluorophenyl)tetrahydrofuran-2-yl](pyridin-2-yl)methanol;
(R)-[(2S)-2-(3,4-dichlorophenyl)oxetan-2-yl](pyridin-2-yl)methanol;
(R)-[(2R)-2-(3,4-dichlorophenyl)oxetan-2-yl](pyridin-2-yl)methanol; and
salts thereof.

### Claim 15 (depends on 1)

The compound, or a salt thereof, of claim 1, wherein the salt is a pharmaceutically acceptable salt.

### Claim 16 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

### Claim 17 (depends on 2)

The compound according to claim 2, or a salt thereof, wherein:
G1 is pyridinyl which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, and N(Rgc)2;
Rgc is hydrogen or C1-C4-alkyl;
G2d is phenyl or pyridinyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, and —ORf; and
Rf is C1-C4-alkyl or C1-C4-haloalkyl.

### Claim 18 (depends on 2)

The compound according to claim 2, or a salt thereof, wherein:
G1 is unsubstituted pyridinyl;
G2d is phenyl or pyridinyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, and —ORf; and
Rf is C1-C4-alkyl or C1-C4-haloalkyl.

### Claim 19 (depends on 2)

The compound according to claim 2, or a salt thereof, wherein:
G1 is unsubstituted pyridin-2-yl;
G2d is phenyl or pyridinyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C3-alkyl, C1-C3-haloalkyl, and —ORf; and
Rf is C1-C3-alkyl or C1-C3-haloalkyl.

### Claim 20 (depends on 19)

The compound according to claim 19, or a salt thereof, wherein:
G2d is phenyl which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C3-alkyl, C1-C3-haloalkyl, and —ORf; and
Rf is C1-C3-alkyl or C1-C3-haloalkyl.

### Claim 21 (depends on 19)

The compound according to claim 19, or a salt thereof, wherein:
G2d is pyridinyl which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C3-alkyl, C1-C3-haloalkyl, and —ORf; and
Rf is C1-C3-alkyl or C1-C3-haloalkyl.

### Claim 22 (depends on 17)

The compound according to claim 17, or a salt thereof, wherein X3 is O; X4 is a bond, X5 is (CH2)n, and n is 2.

### Claim 23 (depends on 17)

The compound according to claim 17, or a salt thereof, wherein X3 is O; X4 is (CH2)m, X5 is (CH2)n, m and n are each 1.

### Claim 24 (depends on 17)

The compound according to claim 17, or a salt thereof, wherein X3 is O; X4 is (CH2)m, X5 is (CH2)n, m is 1, and n is 2.

### Claim 25 (depends on 17)

The compound according to claim 17, or a salt thereof, wherein X3 is O; X4 is a bond, X5 is (CH2)n, and n is 3.

### Claim 26 (depends on 1)

The compound or salt of claim 1 that is (syn)-pyridin-2-yl{2-[3-(trifluoromethoxy)phenyl]tetrahydrofuran-2-yl}-methanol, or a pharmaceutically acceptable salt thereof.

### Claim 27 (depends on 16)

The pharmaceutical composition of claim 16, wherein the compound or salt is (syn)-pyridin-2-yl{2-[3-(trifluoromethoxy)phenyl]tetrahydrofuran-2-yl}-methanol, or a pharmaceutically acceptable salt thereof.

### Claim 28 (depends on 1)

The compound or salt of claim 1 that is (anti)-2-(3,4-dichlorophenyl)tetrahydrofuran-2-yl](pyridin-2-yl)methanol, or a pharmaceutically acceptable salt thereof.

### Claim 29 (depends on 16)

The pharmaceutical composition of claim 16, wherein the compound or salt is (anti)-2-(3,4-dichlorophenyl)tetrahydrofuran-2-yl](pyridin-2-yl)methanol, or a pharmaceutically acceptable salt thereof.

### Claim 30 (depends on 1)

The compound or salt of claim 1 that is (R)-[(2S)-2-(3,4-dichlorophenyl)oxetan-2-yl](pyridin-2-yl)methanol, or a pharmaceutically acceptable salt thereof.

### Claim 31 (depends on 16)

The pharmaceutical composition of claim 16, wherein the compound or salt is (R)-[(2S)-2-(3,4-dichlorophenyl)oxetan-2-yl](pyridin-2-yl)methanol, or a pharmaceutically acceptable salt thereof.

### Claim 32 (depends on 1)

The compound or salt of claim 1 that is (R)-[(2R)-2-(3,4-dichlorophenyl)oxetan-2-yl](pyridin-2-yl)methanol, or a pharmaceutically acceptable salt thereof.

### Claim 33 (depends on 16)

The pharmaceutical composition of claim 16, wherein the compound or salt is (R)-[(2R)-2-(3,4-dichlorophenyl)oxetan-2-yl](pyridin-2-yl)methanol, or a pharmaceutically acceptable salt thereof.