# US 8,772,499 B2 · TRPV3 modulators

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- Number: US 8,772,499 B2
- Document ID: US8772499B2
- Status: Granted
- Kind: B2
- Application number: 13/658,355
- Filed: 2012-10-23
- Published: 2014-03-20
- 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; Eric A. Voight
- Web page: https://patentgrep.com/patent/US8772499B2

## 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 (I) wherein p is 1, 2, 3, or 4, and G1, X1, X2, X3, X4, X5, G2, Z1, 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 (I):
or a salt thereof, wherein:
Ra and Rb are each absent;
u is 0;
X3 is CH2;
X4 is (CH2)m;
X5 is (CH2)n;
m and n are each 1;
each Z1 group is a substituent on the X3 carbon atom of the ring containing X3, X4, and X5 and is independently halogen oxo C1-C4-alkyl, or —ORc; or two Z1 groups that are situated on the X3 carbon atom, together with the carbon atom to which they are attached, form a 5-membered monocyclic heterocycle ring comprising two oxygen ring atoms;
Rc is hydrogen C1-C4-alkyl;
p is 1 or 2;
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 group 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 group 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 (I-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-C4alkyl;
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-C4alkyl or C1-C4-haloalkyl.

### Claim 5 (depends on 3)

The compound according to claim 3, 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 pyridinyl which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C3-alkyl or C1-C3-haloalkyl haloalkyl, and —ORf; and
Rf is C1-C3alkyl or C1-C3-haloalkyl.

### Claim 8 (depends on 2)

The compound according to claim 2, or a salt thereof, wherein:
p is 2;
the two Z1 groups are situated on the X3 carbon atom and, together with the carbon atom to which they are attached, form an unsubstituted 5-membered monocyclic heterocycle ring comprising two oxygen ring atoms;
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 9 (depends on 2)

The compound according to claim 2, or a salt thereof, wherein:
each Z1 group is independently halogen, oxo, C1-C3-alkyl, or —ORc;
Rc is hydrogen or C1-C3-alkyl;
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 10 (depends on 2)

The compound according to claim 2, or a salt thereof, wherein:
p is 1;
Z1 is oxo;
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 11 (depends on 2)

The compound according to claim 2, or a salt thereof, wherein:
each Z1 group is independently halogen, C1-C3-alkyl, or —ORc;
Rc is hydrogen or C1-C3-alkyl;
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 and C1-C3-haloalkyl.

### Claim 12 (depends on 2)

The compound according to claim 2, or a salt thereof, wherein:
p is 1;
Z1 is halogen, C1-C3-alkyl, or —ORc;
Rc is hydrogen or C1-C3-alkyl;
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 13 (depends on 12)

The compound according to claim 12, or a salt thereof, wherein Z1 is C1-C3-alkyl.

### Claim 14 (depends on 12)

The compound according to claim 12, or a salt thereof, wherein Z1 is methyl.

### Claim 15 (depends on 12)

The compound according to claim 12, or a salt thereof, wherein:
Z1 is —ORc; and
Rc is hydrogen.

### Claim 16 (depends on 12)

The compound according to claim 12, or a salt thereof, wherein:
Z1 is —ORc; and
Rc is C1-C3-alkyl.

### Claim 17 (depends on 12)

The compound according to claim 12, or a salt thereof, wherein:
Z1 is —ORc; and
Rc is methyl.

### Claim 18 (depends on 2)

The compound according to claim 2, or a salt thereof, wherein:
p is 2;
each Z1 group is independently halogen, C1-C3-alkyl, or —ORc;
Rc is hydrogen or C1-C3-alkyl;
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 19 (depends on 2)

The compound according to claim 2, or a salt thereof, wherein:
p is 2;
each Z1 group is independently halogen, C1-C3-alkyl, or —ORc;
Rc is hydrogen or C1-C3-alkyl, or —ORc;
G1 is unsubstituted pyridin-2-yl;
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 20 (depends on 2)

The compound according to claim 2, or a salt thereof, wherein:
p is 2;
each Z1 group is independently halogen, C1-C3-alkyl, or —ORc;
Rc is hydrogen or C1-C3-alkyl;
G1 is unsubstituted pyridin-2-yl;
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 21 (depends on 18)

The compound according to claim 18, or a salt thereof, wherein both Z1 groups are halogen.

### Claim 22 (depends on 18)

The compound according to claim 18, or a salt thereof, wherein both Z1 groups are C1-C3-alkyl.

### Claim 23 (depends on 18)

The compound according to claim 18, or a salt thereof, wherein both Z1 groups are methyl.

### Claim 24 (depends on 18)

The compound according to claim 18, or a salt thereof, wherein both Z1 groups are —ORc wherein Rc is C1-C3-alkyl.

### Claim 25 (depends on 18)

The compound according to claim 18, or a salt thereof, wherein both Z1 groups are —ORc wherein Rc is methyl.

### Claim 26 (depends on 18)

The compound according to claim 18, or a salt thereof, wherein one Z1 group is C1-C3-alkyl and the other Z1 group is —ORc wherein Rc is hydrogen.

### Claim 27 (depends on 18)

The compound according to claim 18, or a salt thereof, wherein one Z1 group is methyl and the other Z1 group is —ORc wherein Rc is hydrogen.

### Claim 28 (depends on 27)

The compound according to claim 27, or a salt thereof, wherein the substituent containing X1 and the —ORc substituent have a cis configuration.

### Claim 29 (depends on 27)

The compound according to claim 27, or a salt thereof, wherein the substituent containing X1 and the —ORc substituent have a trans configuration.

### Claim 30 (depends on 1)

The compound according to claim 1, or a salt thereof, selected from the group consisting of:
[1-(3,4-dichlorophenyl)-3,3-difluorocyclobutyl](pyridin-2-yl)methanol;
(S)-[1-(3,4-dichlorophenyl)-3,3-difluorocyclobutyl](pyridin-2-yl)methanol;
{3,3-difluoro-1-[4-(trifluoromethoxy)phenyl]cyclobutyl}(pyridin-2-yl)methanol;
{3,3-difluoro-1-[3-(trifluoromethyl)phenyl]cyclobutyl}(pyridin-2-yl)methanol;
{3,3-difluoro-1-[3-(trifluoromethoxy)phenyl]cyclobutyl}(pyridin-2-yl)methanol;
3-(3,4-dichlorophenyl)-3-[(S)-hydroxy(pyridin-2-yl)methyl]cyclobutanone;
(trans)-3-(3,4-dichlorophenyl)-3-[(S)-hydroxy(pyridin-2-yl)methyl]cyclobutanol;
(cis)-3-(3,4-dichlorophenyl)-3-[(S)-hydroxy(pyridin-2-yl)methyl]cyclobutanol;
(R)-{3,3-difluoro-1-[4-(trifluoromethyl)pyridin-2-yl]cyclobutyl}(pyridin-2-yl)-methanol;
(S)-{3,3-difluoro-1-[4-(trifluoromethyl)pyridin-2-yl]cyclobutyl}(pyridin-2-yl)-methanol;
(S)-{3,3-difluoro-1-[4-(trifluoromethoxy)phenyl]cyclobutyl}(pyridin-2-yl)-methanol;
{3,3-dimethoxy-1-[4-(trifluoromethoxy)phenyl]cyclobutyl}(pyridin-2-yl)methanol;
cis-3-[(S)-hydroxy(pyridin-2-yl)methyl]-3-[4-(trifluoromethoxy)phenyl]-cyclobutanol;
(trans)-3-[(S)-hydroxy(pyridin-2-yl)methyl]-3-[4-(trifluoromethoxy)phenyl]-cyclobutanol;
{3,3-difluoro-1-[4-(trifluoromethyl)phenyl]cyclobutyl}(pyridin-2-yl)methanol;
cis-3-[(S)-hydroxy(pyridin-2-yl)methyl]-1-methyl-3-[4-(trifluoromethoxy)phenyl]-cyclobutanol;
{3,3-difluoro-1-[5-(trifluoromethyl)pyridin-2-yl]cyclobutyl}(pyridin-2-yl)-methanol;
{1-[4-chloro-3-(trifluoromethyl)phenyl]-3,3-difluorocyclobutyl}(pyridin-2-yl)-methanol;
{3,3-difluoro-1-[4-fluoro-3-(trifluoromethyl)phenyl]cyclobutyl}(pyridin-2-yl)-methanol;
(S)-[cis-1-(3,4-dichlorophenyl)-3-methoxycyclobutyl](pyridin-2-yl)methanol;
(S)-[1-(3,4-dichlorophenyl)-3-methoxycyclobutyl](pyridin-2-yl)methanol;
(S)-{3,3-difluoro-1-[4-(trifluoromethyl)phenyl]cyclobutyl}(pyridin-2-yl)methanol;
(R)-{3,3-difluoro-1-[4-(trifluoromethoxy)phenyl]cyclobutyl}(pyridin-2-yl)-methanol;
3-[hydroxy(pyridin-2-yl)methyl]-3-[4-(trifluoromethyl)phenyl]cyclobutanone;
pyridin-2-yl{2-[4-(trifluoromethyl)phenyl]-5,8-dioxaspiro[3.4]oct-2-yl}methanol;
3-[(S)-hydroxy(pyridin-2-yl)methyl]-3-[4-(trifluoromethyl)phenyl]cyclobutanone;
3-[(R)-hydroxy(pyridin-2-yl)methyl]-3-[4-(trifluoromethyl)phenyl]cyclobutanone;
3-[(S)-hydroxy(pyridin-2-yl)methyl]-3-[4-(trifluoromethyl)phenyl]cyclobutanol;
3-[(R)-hydroxy(pyridin-2-yl)methyl]-3-[4-(trifluoromethyl)phenyl]cyclobutanol;
cis-3-[(S)-hydroxy(pyridin-2-yl)methyl]-3-[4-(trifluoromethyl)phenyl]cyclobutanol;
trans-3-[(S)-hydroxy(pyridin-2-yl)methyl]-3-[4-(trifluoromethyl)phenyl]-cyclobutanol;
pyridin-2-yl{2-[4-(trifluoromethoxy)phenyl]-5,8-dioxaspiro[3.4]oct-2-yl}methanol;
trans-3-[(S)-hydroxy(pyridin-2-yl)methyl]-1-methyl-3-[4-(trifluoromethoxy)-phenyl]-cyclobutanol;
cis-3-[(S)-hydroxy(pyridin-2-yl)methyl]-1-methyl-3-[4-(trifluoromethyl)phenyl]-cyclobutanol;
trans-3-[(S)-hydroxy(pyridin-2-yl)methyl]-1-methyl-3-[4-(trifluoromethyl)phenyl]-cyclobutanol;
pyridin-2-yl{2-[3-(trifluoromethoxy)phenyl]-5,8-dioxaspiro[3.4]oct-2-yl}methanol;
cis-3-[(S)-hydroxy(pyridin-2-yl)methyl]-1-methyl-3-[3-(trifluoromethyl)phenyl]-cyclobutanol;
3-[hydroxy(pyridin-2-yl)methyl]-3-[3-(trifluoromethoxy)phenyl]cyclobutanone;
3-[(S)-hydroxy(pyridin-2-yl)methyl]-3-[3-(trifluoromethyl)phenyl]cyclobutanone;
pyridin-2-yl{2-[3-(trifluoromethyl)phenyl]-5,8-dioxaspiro[3.4]oct-2-yl}methanol;
3-[(R)-hydroxy(pyridin-2-yl)methyl]-3-[3-(trifluoromethyl)phenyl]cyclobutanone;
trans-3-[(S)-hydroxy(pyridin-2-yl)methyl]-1-methyl-3-[3-(trifluoromethyl)phenyl]-cyclobutanol;
3-[hydroxy(pyridin-2-yl)methyl]-3-[3-(trifluoromethyl)phenyl]cyclobutanone;
cis-3-(3,4-dichlorophenyl)-3-[(R)-hydroxy(pyridin-2-yl)methyl]cyclobutanol;
cis-3-[(R)-hydroxy(pyridin-2-yl)methyl]-1-methyl-3-[4-(trifluoromethoxy)phenyl]-cyclobutanol;
3-[(S)-hydroxy(pyridin-2-yl)methyl]-3-[4-(trifluoromethoxy)phenyl]cyclobutanone;
[2-(3-chloro-4-fluorophenyl)-5,8-dioxaspiro[3.4]oct-2-yl](pyridin-2-yl)methanol;
3-[(S)-hydroxy(pyridin-2-yl)methyl]-3-[3-(trifluoromethoxy)phenyl]cyclo-butanone;
3-[(R)-hydroxy(pyridin-2-yl)methyl]-3-[3-(trifluoromethoxy)phenyl]cyclo-butanone;
3-(3-chloro-4-fluorophenyl)-3-[hydroxy(pyridin-2-yl)methyl]cyclobutanone;
cis-3-[(S)-hydroxy(pyridin-2-yl)methyl]-3-[3-(trifluoromethyl)phenyl]cyclobutanol;
cis-3-[(S)-hydroxy(pyridin-2-yl)methyl]-1-methyl-3-[3-(trifluoromethoxy)phenyl]-cyclobutanol;
trans-3-[(S)-hydroxy(pyridin-2-yl)methyl]-1-methyl-3-[3-(trifluoromethoxy)-phenyl]cyclobutanol;
trans-3-[(S)-hydroxy(pyridin-2-yl)methyl]-3-[3-(trifluoromethyl)phenyl]-cyclobutanol;
3-(3-chloro-4-fluorophenyl)-3-[(S)-hydroxy(pyridin-2-yl)methyl]cyclobutanone;
cis-3-[(S)-hydroxy(pyridin-2-yl)methyl]-3-[3-(trifluoromethoxy)phenyl]-cyclobutanol;
trans-3-[(S)-hydroxy(pyridin-2-yl)methyl]-3-[3-(trifluoromethoxy)phenyl]-cyclobutanol;
3-(3-chloro-4-fluorophenyl)-3-[(S)-hydroxy(pyridin-2-yl)methyl]cyclobutanol;
3-[(S)-hydroxy(pyridin-2-yl)methyl]-3-[4-(trifluoromethyl)pyridin-2-yl]cyclo-butanone;
3-[(R)-hydroxy(pyridin-2-yl)methyl]-3-[4-(trifluoromethyl)pyridin-2-yl]-cyclobutanone;
cis-3-[(S)-hydroxy(pyridin-2-yl)methyl]-3-[4-(trifluoromethyl)pyridin-2-yl]-cyclobutanol;
trans-3-[(S)-hydroxy(pyridin-2-yl)methyl]-3-[4-(trifluoromethyl)pyridin-2-yl]-cyclobutanol;
cis-3-[(S)-hydroxy(pyridin-2-yl)methyl]-1-methyl-3-[4-(trifluoromethyl)pyridin-2-yl]cyclobutanol;
trans-3-[(S)-hydroxy(pyridin-2-yl)methyl]-3-[4-(trifluoromethyl)pyridin-2-yl]-cyclobutanol;
cis-3-[(R)-hydroxy(pyridin-2-yl)methyl]-3-[4-(trifluoromethyl)pyridin-2-yl]-cyclobutanol;
3-[(R)-hydroxy(pyridin-2-yl)methyl]-3-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]-cyclobutanone;
3-[hydroxy(pyridin-2-yl)methyl]-3-[4-(trifluoromethyl)pyridin-2-yl]cyclobutanone;
3-[(S)-hydroxy(pyridin-2-yl)methyl]-3-[4-(trifluoromethyl)pyridin-2-yl]cyclo-butanol;
3-[hydroxy(pyridin-2-yl)methyl]-3-[5-(trifluoromethyl)pyridin-3-yl]cyclobutanone;
3-[(S)-hydroxy(pyridin-2-yl)methyl]-3-[5-(trifluoromethyl)pyridin-3-yl]cyclobutanone;
pyridin-2-yl{2-[2-(trifluoromethyl)pyridin-4-yl]-5,8-dioxaspiro[3.4]oct-2-yl}-methanol;
3-[hydroxy(pyridin-2-yl)methyl]-3-[2-(trifluoromethyl)pyridin-4-yl]cyclobutanone;
3-[(S)-hydroxy(pyridin-2-yl)methyl]-3-[2-(trifluoromethyl)pyridin-4-yl]-cyclobutanone;
cis-3-[(S)-hydroxy(pyridin-2-yl)methyl]-1-methyl-3-[2-(trifluoromethyl)pyridin-4-yl]cyclobutanol;
cis-3-[(S)-hydroxy(pyridin-2-yl)methyl]-3-[5-(trifluoromethyl)pyridin-3-yl]-cyclobutanol;
trans-3-[(S)-hydroxy(pyridin-2-yl)methyl]-3-[5-(trifluoromethyl)pyridin-3-yl]-cyclobutanol;
cis-3-[(S)-hydroxy(pyridin-2-yl)methyl]-3-[2-(trifluoromethyl)pyridin-4-yl]-cyclobutanol;
trans-3-[(S)-hydroxy(pyridin-2-yl)methyl]-3-[2-(trifluoromethyl)pyridin-4-yl]-cyclobutanol;
trans-3-[(S)-hydroxy(pyridin-2-yl)methyl]-1-methyl-3-[2-(trifluoromethyl)pyridin-4-yl]cyclobutanol;
cis-3-[(S)-hydroxy(pyridin-2-yl)methyl]-1-methyl-3-[5-(trifluoromethyl)pyridin-3-yl]cyclobutanol;
trans-3-[(S)-hydroxy(pyridin-2-yl)methyl]-1-methyl-3-[5-(trifluoromethyl)pyridin-3-yl]cyclobutanol;
(trans)-3-((S)-hydroxy(pyrimidin-2-yl)methyl)-1-methyl-3-(4-(trifluoromethoxy)-phenyl)-cyclobutanol;
(trans)-3-((R)-hydroxy(pyrimidin-2-yl)methyl)-1-methyl-3-(4-(trifluoromethoxy)-phenyl)-cyclobutanol;
(trans)-3-(3,4-dichlorophenyl)-3-((S)-hydroxy(pyrimidin-2-yl)methyl)cyclobutanol;
(trans)-3-(3,4-dichlorophenyl)-3-((R)-hydroxy(pyrimidin-2-yl)methyl)cyclobutanol; and
salts thereof.

### Claim 31 (depends on 1)

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

### Claim 32 (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 33 (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 34 (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 35 (depends on 33)

The compound according to claim 33, 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 36 (depends on 35)

The compound according to claim 35, 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 37 (depends on 35)

The compound according to claim 35, 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 38 (depends on 1)

The compound or salt of claim 1 that is cis-3-[(S)-hydroxy(pyridin-2-yl)methyl]-1-methyl-3-[4-(trifluoromethoxy)-phenyl]cyclobutanol, or a pharmaceutically acceptable salt thereof.

### Claim 39 (depends on 32)

The pharmaceutical composition of claim 32, wherein the compound or salt is cis-3-[(S)-hydroxy(pyridin-2-yl)methyl]-1-methyl-3-[4-(trifluoromethoxy)-phenyl]cyclobutanol, or a pharmaceutically acceptable salt thereof.

### Claim 40 (depends on 1)

The compound or salt of claim 1 that is cis-3-[(S)-hydroxy(pyridin-2-yl)methyl]-3-[4-(trifluoromethyl)pyridin-2-yl]cyclobutanol, or a pharmaceutically acceptable salt thereof.

### Claim 41 (depends on 32)

The pharmaceutical composition of claim 32, wherein the compound or salt is cis-3-[(S)-hydroxy(pyridin-2-yl)methyl]-3-[4-(trifluoromethyl)pyridin-2-yl]cyclobutanol, or a pharmaceutically acceptable salt thereof.

### Claim 42 (depends on 1)

The compound or salt of claim 1 that is trans-3-[(S)-hydroxy(pyridin-2-yl)methyl]-3-[4-(trifluoromethyl)pyridin-2-yl]cyclobutanol, or a pharmaceutically acceptable salt thereof.

### Claim 43 (depends on 32)

The pharmaceutical composition of claim 32, wherein the compound or salt is trans-3-[(S)-hydroxy(pyridin-2-yl)methyl]-3-[4-(trifluoromethyl)pyridin-2-yl]cyclobutanol, or a pharmaceutically acceptable salt thereof.

### Claim 44 (depends on 1)

The compound or salt of claim 1 that is cis-3-[(S)-hydroxy(pyridin-2-yl)methyl]-1-methyl-3-[4-(trifluoromethyl)-pyridin-2-yl]cyclobutanol, or a pharmaceutically acceptable salt thereof.

### Claim 45 (depends on 32)

The pharmaceutical composition of claim 32, wherein the compound or salt is cis-3-[(S)-hydroxy(pyridin-2-yl)methyl]-1-methyl-3-[4-(trifluoromethyl)-pyridin-2-yl]cyclobutanol, or a pharmaceutically acceptable salt thereof.