IP Library › Granted Patent US 9,555,050

Granted Patent B2

US 9,555,050 · App. 14/417,353 · Granted Jan 31, 2017

ATX modulating agents

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Quick Facts

Patent No.: US 9,555,050
App. No.: 14/417,353
Granted: Jan 31, 2017
Kind: B2

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Abstract

Compounds of formula (I) can modulate the activity of autotaxin (ATX).

Claims (389)

1. A compound represented by formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X 1 , X 2 , and X 3 are CH; or one of X 1 , X 2 , or X 3 is N and the other two are CH;

R 1 is

R 2 is a C 1-4 haloalkyl or cyano;

R 3 is -L 1 -J-L 2 -R 12 ; and R 4 is hydrogen or a C 1-6 alkyl; or R 3 and R 4 together with the nitrogen to which they are attached are a 3- to 8-membered heterocyclyl which is substituted with -L 2 -R 12 , and is optionally substituted with a halo, hydroxyl, amino, or a C 1-6 alkyl;

R 5 is a halo, a C 1-6 alkyl or a C 1-6 haloalkyl;

R 6 and R 7 are each independently hydrogen or C 1-6 alkyl; or R 6 and R 7 together with the carbon to which they are attached are —C(═O)—, a C 3-8 spirocycloalkyl, or a 3- to 8-membered spiroheterocyclalkyl;

R 8 and R 9 are each independently hydrogen or a C 1-6 alkyl; or R 8 and R 9 taken together with the carbon to which they are attached are —C(═O)—;

R 10 , for each occurrence, is halo;

R 11 is hydrogen, halo, or C 1-4 alkyl;

R 12 is —COOR 13 or —P(O)(OR 13 ) 2 ;

each R 13 , independently, is H, C 1-4 alkyl, aryl, or aryl-C 1-4 -alkyl;

J is a C 1-6 alkylene, a C 3-8 cycloalkylene, a 3- to 8-membered divalent monocyclic heterocyclyl, a phenylene, or a 5- to 6-membered heteroarylene, wherein J is optionally substituted with one or two substituents independently selected from a halo and a C 1-6 alkyl;

L 1 and L 2 are each independently, a C 1-3 alkylene or a direct bond;

n is 1, 2 or 3;

q is 1 or 2; and

r is 0, 1, or 2.

2. A compound represented by formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein:

X 1 , X 2 , and X 3 are CH; or one of X 1 , X 2 , or X 3 is N and the other two are CH;

R 1 is

R 2 is a C 1-4 haloalkyl or cyano;

R 3 is -L 1 -J-L 2 -R 12 ; and R 4 is hydrogen or a C 1-6 alkyl; or R 3 and R 4 together with the nitrogen to which they are attached is a 3- to 8-membered heterocyclyl which is substituted with -L 2 -R 12 , and is optionally substituted with a halo, hydroxyl, amino, or a C 1-6 alkyl;

R 5 is a halo, a C 1-6 alkyl or a C 1-6 haloalkyl;

R 6 and R 7 are each independently hydrogen, C 1-6 alkyl, a C 1-6 haloalkyl, C 3-7 cycloalkyl, or COOH; or R 6 and R 7 together with the carbon to which they are attached is —C(═O)—, a C 3-8 spirocycloalkyl, or a 3- to 8-membered spiroheterocyclalkyl;

R 8 and R 9 are each independently hydrogen or a C 1-6 alkyl; or R 8 and R 9 taken together with the carbon to which they are attached is —C(═O)—;

R 10 , for each occurrence, is halo;

R 11 is hydrogen, halo, or C 1-4 alkyl;

R 12 is —COOR 13 , —P(O)(OR 13 ) 2 , or tetrazolyl;

Each R 13 , independently, is H, C 1-4 alkyl, aryl, or aryl-C 1-4 -alkyl;

L 1 and L 2 are each independently, a C 1-3 alkylene or a direct bond;

n is 1, 2 or 3;

q is 1 or 2; and

r is 0, 1, or 2.

3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 1, and R 6 and R 7 together with the carbon to which they are attached are —C(═O)—.

4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 1 and R 6 and R 7 are both hydrogen.

5. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein n is 1 and R 6 is H and R 7 is methyl, trifluoromethyl, ethyl, isopropyl, isobutyl, or cyclopropyl.

6. The compound according to claim 5 , wherein R 12 is —COOH.

7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein

L 1 is a direct bond;

J is a C 1-6 alkylene or a phenylene, wherein J is optionally substituted with one or two substituents independently selected from a halo and a C 1-6 alkyl;

L 2 is a C 1-3 alkylene; and

R 12 is —P(O)(OR 13 ) 2 .

8. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein

R 3 and R 4 together with the nitrogen to which they are attached are a 4- to 7-membered heterocyclyl which is substituted with -L 2 -R 12 , and is optionally substituted with a halo, hydroxyl, amino, or a C 1-6 alkyl;

L 2 is a direct bond or —CH 2 —; and

R 12 is —COOR 13 .

9. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is —CHF 2 or —CF 3 .

10. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is

wherein R 5 is a halo, a C 1 alkyl, or a C 1 haloalkyl.

11. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is

wherein q is 1, R 8 and R 9 are each independently H, and each R 10 is independently H or a halo.

12. The compound of claim 2 selected from the group consisting of:

2,2-dimethyl-3-(((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclo-hexyl)oxy)naphthalen-2-yl)methyl)amino)cyclobutanecarboxylic acid;

1-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-naphthalen-2-yl)methyl)piperidine-4-carboxylic acid;

3-(((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-naphthalen-2-yl)methyl)amino)cyclopentanecarboxylic acid;

(R)-2-(1-((6-((4,4-difluorocyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)piperidin-3-yl)acetic acid;

4-(2H-tetrazol-5-yl)-1-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperidine;

2-((3R)-1-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)piperidin-3-yl)acetic acid;

2-((3R)-1-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)piperidin-3-yl)acetic acid;

2-(4-((6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)morpholin-2-yl)acetic acid;

2-(1-((6-((cis-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)piperidin-3-yl)acetic acid;

2-((3R)-1-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)piperidin-3-yl)acetic acid;

1-(Carboxy(6-((cis-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)piperidine-4-carboxylic acid;

1-(2,2,2-Trifluoro-1-(6-((cis-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)piperidine-4-carboxylic acid;

1-((5-(Difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)piperidine-4-carboxylic acid;

2-((R)-1-(((5-(trifluoromethyl)-6-(cis-4-(trifluoromethyl)cyclohexyl)oxy)quinolin-2-yl)methyl)piperidin-3-yl)acetic acid; and

2,2-dimethyl-3-(((1-(5-(trifluoromethyl)-6-(cis-4-(trifluoromethyl)cyclo-hexyl)oxy)quinolin-2-yl)ethyl)amino)cyclobutanecarboxylic acid; 2,2-dimethyl-3-((1-(6-(cis-4-methylcyclohexyl)oxy)-5-(trifluoromethyl) naphthalen-2-yl)cyclopropyl)amino)cyclobutanecarboxylic acid;

4-Acetamido-4-(5-(trifluoromethyl)-6-(cis-4-(trifluoromethyl)cyclo-hexyl)oxy)naphthalen-2-yl)pentanoic acid;

(3-(6-((3,5-dichlorobenzyl)oxy)-5-(trifluoromethyl)-2-naphthamido)propyl) phosphonic acid;

(3-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthamido)propyl)phosphonic acid;

1-((5-cyano-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperidine-4-carboxylic acid;

1-((5-(difluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperidine-4-carboxylic acid;

1-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)naphthalen-2-yl)methyl)piperidine-4-carboxylic acid;

6-((5-(trifluoromethyl)-6-((cis)-4-(trifluoromethyl)cyclohexyloxy)-2-naphthamido)methyl)nicotinic acid;

(R)-1-((5-(trifluoromethyl)-6-((cis)-4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)piperidine-3-carboxylic acid;

(trans)-4-(((5-(trifluoromethyl)-6-((cis)-4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methylamino)methyl)cyclohexanecarboxylic acid;

(S)-1-((5-(trifluoromethyl)-6-((cis)-4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)piperidine-3-carboxylic acid;

2-(1-((5-(trifluoromethyl)-6-((cis)-4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)piperidin-2-yl)acetic acid;

(trans)-4-((methyl((5-(trifluoromethyl)-6-((cis)-4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)amino)methyl)cyclohexanecarboxylic acid;

1-((5-(trifluoromethyl)-6-((cis)-4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)piperidine-2-carboxylic acid;

4-methyl-1 -((5-(trifluoromethyl)-6-((cis)-4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)piperidine-4-carboxylic acid;

1-(5-(trifluoromethyl)-6-((cis)-4-(trifluoromethyl)cyclohexyloxy)-2-naphthoyl)azepane-4-carboxylic acid;

2-(4-((5-(difluoromethyl)-6-((cis)-4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)morpholin-2-yl)acetic acid;

3-((5-(difluoromethyl)-6-((cis)-4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methylamino)-2,2-dimethylcyclobutanecarboxylic acid;

(trans)-4-(((5-(difluoromethyl)-6-((cis)-4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methylamino)methyl)cyclohexanecarboxylic acid;

4-hydroxy-1-((5-(trifluoromethyl)-6-((cis)-4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)piperidine-3-carboxylic acid;

2,2-dimethyl-3-(1-(6-((cis)-4-methylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)propylamino)cyclobutanecarboxylic acid;

2,2-dimethyl-3-(1-(5-(trifluoromethyl)-6-((cis)-4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)ethylamino)cyclobutanecarboxylic acid;

3-(cyclopropyl(6-((cis)-4-methylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methylamino)-2,2-dimethylcyclobutanecarboxylic acid;

2,2-dimethyl-3-(2-methyl-1-(5-(trifluoromethyl)-6-((cis)-4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)propylamino)cyclobutanecarboxylic acid;

2,2-dimethyl-3-(3-methyl-1-(5-(trifluoromethyl)-6-((cis)-4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)butylamino)cyclobutanecarboxylic acid;

4-(1-((5-(trifluoromethyl)-6-((cis)-4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methylamino)ethyl)cyclohexanecarboxylic acid;

3-(cyclohexyl(6-((cis)-4-methylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methylamino)-2,2-dimethylcyclobutanecarboxylic acid;

3-(cyclohexyl(5-(trifluoromethyl)-6-((cis)-4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methylamino)-2,2-dimethylcyclobutanecarboxylic acid;

3-(cyclopropyl(5-(trifluoromethyl)-6-((cis)-4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methylamino)-2,2-dimethylcyclobutanecarboxylic acid;

1-(1-(5-trifluoromethyl-6-(cis-4-methylcyclohexyloxy)naphthalene-2-yl)ethyl)-piperidine-4-carboxylic acid;

1-((5-trifluoromethyl-6-(cis-4-methylcyclohexyloxy)naphthalene-2-yl)methyl)-pyrrolidine-3-acetic acid;

1-((5-trifluoromethyl-6-(cis-4-methylcyclohexyloxy)naphthalene-2-yl)methyl)-azetidine-3-acetic acid;

1-((5-trifluoromethyl-6-(cis-4-methylcyclohexyloxy)naphthalene-2-yl)methyl)-azepane-3-carboxylic acid;

2-((3R)-1-((6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)piperidin-3-yl)acetic acid;

1-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)piperidine-4-carboxylic acid;

2-((3R)-1-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)piperidin-3-yl)acetic acid;

2-((3S)-1-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)piperidin-3-yl)acetic acid;

2-((3R)-1-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(difluoromethyl)naphthalen-2-yl)ethyl)piperidin-3-yl)acetic acid;

2-((3S)-1-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(difluoromethyl)naphthalen-2-yl)ethyl)piperidin-3-yl)acetic acid;

1-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(difluoromethyl)naphthalen-2-yl)ethyl)piperidine-4-carboxylic acid;

2-((3R)-1-((6-((cis-4-Methylcyclohexyl)oxy)-5-(difluoromethyl)naphthalen-2-yl)methyl)piperidin-3-yl)acetic acid;

2-((3R)-1-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(difluoromethyl)naphthalen-2-yl)propyl)piperidin-3-yl)acetic acid;

1-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(difluoromethyl)naphthalen-2-yl)propyl)piperidine-4-carboxylic acid;

2-((3R)-1-((S)-1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)piperidin-3-yl)acetic acid;

2-((3R)-1-((R)-1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)piperidin-3-yl)acetic acid;

1-((S)-1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(difluoromethyl)naphthalen-2-yl)ethyl)piperidine-4-carboxylic acid;

2-(1-((5-(trifluoromethyl)-6-(4-cis-(trifluoromethyl)cyclohexyloxy)naphthalene-2-yl)methyl)azetidine-3-yl)acetic acid;

3-(((5-(trifluoromethyl)-6-(cis-4-(trifluoromethyl)cyclohexyloxy)naphthalene-2-yl)methyl)amino)propylphosphonic acid;

1-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-naphthalen-2-yl)methyl)pyrrolidine-3-acetic acid;

1-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-naphthalen-2-yl)methyl)piperidine-4-acetic acid;

1-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-naphthalen-2-yl)methyl)aminocyclopentane-3-carboxylic acid;

1-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-naphthalen-2-yl)methyl)piperidine-3-acetic acid;

(4-((5-(trifluoromethyl)-6-(cis-4-(trifluoromethyl)cyclohexyloxy)naphthalene-2-yl)methyl)aminophenyl)methylphosphonic acid;

6-((((5-(trifluoromethyl)-6-((cis)-4-(trifluoromethyl)cyclohexyloxy)naphthalene-2-yl)methyl)amino)methyl)nicotinic acid;

cis-4-(((5-(trifluoromethyl)-6-((cis)-4-(trifluoromethyl)cyclohexyloxy)naphthalene-2-yl)methyl)amino)cyclohexane-l-carboxylic acid;

(S)-1-((5-(trifluoromethyl)-6-((cis)-4-(trifluoromethyl)cyclohexyloxy)naphthalene-2-yl)methyl)pyrrolidine-3-acetic acid;

(R)-1-((5-(trifluoromethyl)-6-((cis)-4-(trifluoromethyl)cyclohexyloxy)naphthalene-2-yl)methyl)pyrrolidine-3-acetic acid;

3-((4-((5-(trifluoromethyl)-6-(cis-4-(trifluoromethyl)cyclohexyloxy)naphthalene-2-yl)methyl)amino)cyclohexyl)propionic acid;

1-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-naphthalen-2-yl)methyl)-3-methylpiperidine-4-carboxylic acid;

5-((((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-naphthalen-2-yl)methyl)amino)methyl)pyridine-2-carboxylic acid;

1-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-naphthalen-2-yl)methyl)azepane-4-carboxylic acid;

4-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-naphthalen-2-yl)methyl)morpholine-2-carboxylic acid;

1-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-naphthalen-2-yl)methyl)-3-aminopyrrolidine-3-carboxylic acid;

N-methyl-cis-4-(((5-(trifluoromethyl)-6-(cis-4-(trifluoromethyl)cyclohexyloxy)naphthalene-2-yl)methyl)amino)cyclohexane-1-carboxylic acid;

2-((R)-1-((2-(cis-4-(trifluoromethyl)cyclohexyloxy)-1-(trifluoromethyl)naphthalen-6-yl)methyl)piperidin-3-yl)acetic acid;

1-((5-(trifluoromethyl)-6-(cis-4-(trifluoromethyl)cyclohexyloxy)naphthalene-2-yl)methyl)-5-hydroxypiperidine-3-carboxylic acid;

2-((S)-4-((2-(cis-4-(trifluoromethyl)cyclohexyloxy)-1-(trifluoromethyl)naphthalen-6-yl)methyl)morpholin-2-yl)acetic acid;

3-(1-((2-(cis-4-(trifluoromethyl)cyclohexyloxy)-1-(trifluoromethyl)naphthalen-6-yl)methyl)piperidine-4-yl)propionic acid;

2-((R)-1-((2-(cis-4-(ethyl)cyclohexyloxy)-1-(trifluoromethyl)naphthalen-6-yl)methyl)piperidin-3-yl)acetic acid;

2,2-dimethyl-3-((((S)-1-(5-(trifluoromethyl)-6-(cis-4-(trifluoromethyl)cyclo-hexyl)oxy)naphthalene-2-yl)ethyl)amino)cyclobutanecarboxylic acid;

2,2-dimethyl-3-((((R)-1-(5-(trifluoromethyl)-6-(cis-4-(trifluoromethyl)cyclo-hexyl)oxy)naphthalene-2-yl)ethyl)amino)cyclobutanecarboxylic acid;

2,2-dimethyl-3-((((5-(trifluoromethyl)-6-(cis-4-(trifluoromethyl)cyclo-hexyl)oxy)quinolin-2-yl)methyl)amino)cyclobutanecarboxylic acid;

2-((S)-1-(((5-(trifluoromethyl)-6-(cis-4-(trifluoromethyl)cyclohexyl)oxy)quinolin-2-yl)methyl)piperidin-3-yl)acetic acid;

2-((S)-1-(1-(2-(cis-4-(trifluoromethyl)cyclohexyloxy)-1-(trifluoromethyl)naphthalen-6-yl)propyl)piperidin-3-yl)acetic acid;

2,2-dimethyl-3-(1-(6-((cis)-4-methylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)-3-methylbutylamino)cyclobutanecarboxylic acid;

2-((3R)-1-((S)-1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(difluoromethyl)naphthalen-2-yl)ethyl)piperidin-3-yl)acetic acid;

2-((3R)-1-((R)-1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(difluoromethyl)naphthalen-2-yl)ethyl)piperidin-3-yl)acetic acid;

2-((3R)-1-((S)-1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(difluoromethyl)naphthalen-2-yl)propyl)piperidin-3-yl)acetic acid;

2-((3R)-1-((R)-1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(difluoromethyl)naphthalen-2-yl)propyl)piperidin-3-yl)acetic acid;

2-((3R)-1-((S)-1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)piperidin-3-yl)acetic acid;

2-((3R)-1-((R)-1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)piperidin-3-yl)acetic acid;

1-((5-(Difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidine-3-acetic acid;

1-(1-(5-(Difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)azetidine-3-acetic acid;

1-(1-(5-(Difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)azetidine-3-acetic acid;

2-((S)-1-((S)-1-(2-(cis-4-methylcyclohexyloxy)-1-(difluoromethyl)naphthalen-6-yl)ethyl)piperidin-3-yl)acetic acid;

2-((R)-1-((S)-1-(2-(cis-4-methylcyclohexyloxy)-1-(difluoromethyl)naphthalen-6-yl)ethyl)piperidin-3-yl)acetic acid;

(S)-2-((R)-1-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy) naphthalen-2-yl)methyl)piperidin-3-yl)propanoic acid;

2-((R)-1-((R)-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl) cyclohexyl)oxy)naphthalen-2-yl)propyl)piperidin-3-yl)acetic acid; and

2-((R)-1-((S)-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)propyl) piperidin-3-yl)acetic acid,

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

14. A method of treating, or reducing chronic pain in a mammal comprising administering to said mammal an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

15. The method of claim 14 , wherein the chronic pain is inflammatory pain.

16. The method of claim 14 , wherein the chronic pain is neuropathic pain.

17. The pharmaceutical composition of claim 13 , wherein n is 1 and R 6 and R 7 are both hydrogen.

18. The pharmaceutical composition of claim 13 , wherein:

L 2 is a direct bond or —CH 2 —; and

R 12 is —COOR 13 .

19. The pharmaceutical composition of claim 13 , wherein R 1 is

wherein R 5 is a halo, a C 1 alkyl, or a C 1 haloalkyl.

20. The pharmaceutical composition of claim 13 , wherein the compound is selected from the group consisting of: