IP Library › Granted Patent US 9,522,889

Granted Patent B2

US 9,522,889 · App. 14/417,300 · Granted Dec 20, 2016

ATX modulating agents

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Quick Facts

Patent No.: US 9,522,889
App. No.: 14/417,300
Granted: Dec 20, 2016
Kind: B2

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Abstract

Disclosed are bicyclic aryl compounds of formula (I), that can modulate the activity of the autotaxin (ATX) enzyme. This invention further relates to compounds that are ATX inhibitors, and methods of making and using such compounds in the treatment of demyelination due to injury or disease, as well as for treating proliferative disorders such as cancer.

Claims (737)

1. A compound represented by formula (II):

or a pharmaceutically acceptable salt thereof, wherein

X can be O, S(O) r , NR 12 , C(O) or CH 2 ;

R 1 is a C 6-20 alkyl, a C 3-14 carbocyclyl, a 3- to 15-membered heterocyclyl, a C 6-10 aryl, or a five- to 14-membered heteroaryl, wherein the heterocyclyl and the heteroaryl comprising from 1 to 10 heteroatoms independently selected from N, S or O, and wherein R 1 is optionally substituted with from one to six groups independently selected from groups represented by R 6 ;

R 3 is a halo, C 1-6 haloalkyl or cyano;

R 5 is a C 1-6 alkylene, C 3-8 carbocyclyl, a 3- to 8-membered heterocyclyl, C 6-10 aryl, a 5- to 10-membered heteroaryl, a bridged ring system comprising from 6 to 12 ring members, a spiro ring system comprising from 5-14 ring members, or a bicyclic ring system represented by the following formula:

wherein B′ and B″ are independently selected from the group consisting of monocyclic C 3-8 carbocyclyl, a monocyclic 3- to 8-membered heterocyclyl, phenyl or a 5- to 6-membered heteroaryl; wherein R 5 is optionally substituted with from 1 to 4 independently selected R 11 ;

R 6 , for each occurrence, is independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 6-10 aryl, C 1-6 alkoxy-C 1-6 alkyl, and tri-(C 1-6 alkyl)silyl; or two R 6 that are attached to the same carbon atom may form C 3-8 spirocycloalkyl or 3- to 8-membered spiroheterocycloalkyl;

R 7 is —OH, —C(O)OR 15 , —C(O)N(R 16 ) 2 , —C(O)N(R 15 )—S(O) 2 R 15 , —S(O) 2 OR 15 , —C(O)NHC(O)R 15 , —Si(O)OH, —B(OH) 2 , —N(R 15 )S(O) 2 R 15 , —S(O) 2 N(R 15 ) 2 , —O—P(O)(OR 15 ) 2 , —P(O)(OR 15 ) 2 , —CN, —S(O) 2 NHC(O)R 15 , —C(O)NHS(O) 2 R 15 , —C(O)NHOH, —C(O)NHCN, or a heteroaryl or a heterocyclyl selected from the group consisting of formulae (a)-(i′):

R 8 and R 9 are each independently be hydrogen, a carboxy, C 1-6 alkyl, or a C 2-6 alkenyl; or R 8 and R 9 together with the carbon to which they are attached can be —C(═O)—, a C 3-8 spirocycloalkyl, or a 3- to 8-membered spiroheterocycloalkyl;

R 10 and R 12 are each independently hydrogen or a C 1-6 alkyl;

R 11 , for each occurrence, is independently halo, hydroxyl, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, —(CR 17 R 18 )R 7 , C 1-4 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 3-8 cycloalkoxy, C 3-8 halocycloalkoxy, —NR a R b , —C(O)NR a R b , —N(R a )C(O)R b , —C(O)R a , —S(O) r R a , or —N(R a )S(O) 2 R b ;

R 15 for each occurrence is independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-10 aryl, a 5 to 14 membered heteroaryl, and a 3 to 15 membered heterocyclyl; wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, and S; and wherein R 15 is optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C 1-4 alkoxy, C 1-4 alkyl, cyano, nitro, hydroxyl, amino, N—(C 1-4 alkyl)amino, N,N-di-(C 1-4 alkyl)amino, carbamoyl, N—(C 1-4 alkyl)carbamoyl, N,N-di-(C 1-4 alkyl)carbamoyl, C 1-4 alkylamido, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonamido, sulfamoyl, N—(C 1-4 alkyl)sulfamoyl, and N,N—(C 1-4 dialkyl)-sulfamoyl;

R 16 is R 15 ; or two R 16 together with the nitrogen atom to which they are attached form a 5 to 14 membered heteroaryl or a 3 to 15 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises from 1 to 10 heteroatoms independently selected from O, N, and S; and wherein the heteroaryl or heterocyclyl is optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, C 1-4 alkoxy, C 1-4 alkyl, cyano, nitro, hydroxyl, amino, N—(C 1-4 alkyl)amino, N,N-di-(C 1-4 alkyl)amino, carbamoyl, N—(C 1-4 alkyl)carbamoyl, N,N-di-(C 1-4 alkyl)carbamoyl, C 1-4 alkylamido, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonamido, sulfamoyl, N—C 1-4 alkylsulfamoyl, and N,N—(C 1-4 dialkyl)-sulfamoyl;

R 17 and R 18 , for each occurrence, are each independently hydrogen, a halo, or a C 1-4 haloalkyl;

R a and R b , for each occurrence, are independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, or C 3-8 halocycloalkyl;

R c is hydrogen or C 1-4 alkyl;

m is 0 or 1, provided that when m is 0, R 5 comprises at least one nitrogen;

n is an integer from 1 to 6;

p is 0 or an integer from 1 to 6;

r, for each occurrence, is independently 0, 1, or 2.

2. The compound of claim 1 , wherein the compound is represented by formula (III):

or a pharmaceutically acceptable salt thereof, wherein

q is 0, 1, 2, or 3.

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:

m is 0; and

R 5 is selected from the group consisting of:

4. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:

m is 1; and

R 5 is cyclobutyl, cyclopentyl, or cyclohexyl, each of which may be optionally substituted with from 1 to 3 independently selected R 11 .

5. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 7 is —COOH.

6. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 8 is hydrogen, and R 9 is C 1-6 alkyl; or R 8 and R 9 together with the carbon to which they are attached are —C(═O)—.

7. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 are each independently hydrogen.

8. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 3 is trifluoromethyl.

9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein q is 1 and R 6 is C 1-6 alkyl.

10. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein q is 1 and R 6 is trifluoromethyl, difluoromethyl or monofluoromethyl.

11. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein q is 1 and R 6 is methyl, ethyl or isopropyl.

12. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 1 is

13. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 6 is t-butyl.

14. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein: X is NH.

15. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein: R 8 and R 9 together with the carbon to which they are attached are C(═O)—.

16. A compound of claim 1 , wherein the compound is selected from the group consisting of:

1-((8-chloro-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperidine-4-carboxylic acid;

9-((8-chloro-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;

1-(1-(8-chloro-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)piperidine-4-carboxylic acid;

8-(1-(8-chloro-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;

9-(1-(8-chloro-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;

1-(1-(8-chloro-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)propyl)piperidine-4-carboxylic acid;

(1R,3S)-3-((1-(8-chloro-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)propyl)amino)-2,2-dimethylcyclobutanecarboxylic acid;

1-((8-cyano-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperidine-4-carboxylic acid;

8-((8-cyano-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;

9-((8-cyano-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;

1-(1-(8-cyano-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)piperidine-4-carboxylic acid;

8-(1-(8-cyano-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;

9-(1-(8-cyano-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;

1-(1-(8-cyano-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)propyl)piperidine-4-carboxylic acid;

8-(1-(8-cyano-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;

9-(1-(8-cyano-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;

8-(1-(8-(difluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;

1-((8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperidine-4-carboxylic acid;

1-(1-(8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy) naphthalen-2-yl)ethyl)piperidine-4-carboxylic acid;

1-(1-(8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy) naphthalene-2-yl)propyl)piperidine-4-carboxylic acid;

8-((S)-1-(8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)-2,2,2-trideuteroethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;

1-((8-chloro-7-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)piperidine-4-carboxylic acid;

8-((8-chloro-7-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;

9-((8-chloro-7-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;

1-((7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)methyl)piperidine-4-carboxylic acid;

8-((7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;

9-((7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;

2-((R)-1-((7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)methyl)piperidin-3-yl)acetic acid;

3-(((7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)methyl)amino)-2,2-dimethylcyclobutanecarboxylic acid;

8-(1-(7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;

9-(1-(7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;

1-(1-(7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)piperidine-4-carboxylic acid;

2-((3R)-1-(1-(7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)piperidin-3-yl)acetic acid;

3-((1-(7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)amino)-2,2-dimethylcyclobutanecarboxylic acid;

1-(1-(7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)propyl)piperidine-4-carboxylic acid;

2-((3R)-1-(1-(7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)propyl)piperidin-3-yl)acetic acid;

2-((R)-1-((8-chloro-7-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)piperidin-3-yl)acetic acid;

8-(1-(8-(difluoromethyl)-7-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;

1-(1-(8-chloro-7-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)piperidine-4-carboxylic acid;

8-(1-(8-chloro-7-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;

9-(1-(8-chloro-7-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;

(1R,3S)-3-((1-(8-chloro-7-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)amino)-2,2-dimethylcyclobutanecarboxylic acid;

(1R,3S)-3-(((8-chloro-7-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)-2,2-dimethylcyclobutanecarboxylic acid;

1-((8-cyano-7-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)piperidine-4-carboxylic acid;

8-((8-cyano-7-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;

9-((8-cyano-7-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;

1-(1-(8-cyano-7-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)piperidine-4-carboxylic acid;

8-(1-(8-cyano-7-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;

9-(1-(8-cyano-7-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;

1-(1-(8-chloro-7-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)propyl)piperidine-4-carboxylic acid;

1-(1-(8-cyano-7-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)propyl)piperidine-4-carboxylic acid;

2-((R)-1-((7-((cis-4-methylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)methyl)piperidin-3-yl)acetic acid;

2,2-dimethyl-3-(((7-((cis-4-methylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)methyl)amino)cyclobutanecarboxylic acid;

1-((8-chloro-7-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)piperidine-4-carboxylic acid;

1-(1-(7-((cis-4-methylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)piperidine-4-carboxylic acid;

2-((3R)-1-(1-(7-((cis-4-methylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)piperidin-3-yl)acetic acid;

2,2-dimethyl-3-((1-(7-((cis-4-methylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)amino)cyclobutanecarboxylic acid;

8-((8-chloro-7-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;

2-((R)-1-((8-chloro-7-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)piperidin-3-yl)acetic acid;

3-(((8-chloro-7-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)-2,2-dimethylcyclobutanecarboxylic acid;

9-((8-(difluoromethyl)-7-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;

8-(1-(8-(difluoromethyl)-7-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;

9-(1-(8-(difluoromethyl)-7-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;

1-(1-(8-chloro-7-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)piperidine-4-carboxylic acid;

8-(1-(8-chloro-7-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;

9-(1-(8-chloro-7-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;

2-((3R)-1-(1-(8-chloro-7-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)piperidin-3-yl)acetic acid;

Cis-3-((1-(8-chloro-7-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)amino)-2,2-dimethylcyclobutanecarboxylic acid;

1-(1-(8-chloro-7-(cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)piperidine-4-carboxylic acid;

8-(1-(8-chloro-7-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;

8-((8-cyano-7-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;

1-((8-cyano-7-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)piperidine-4-carboxylic acid;

9-((8-cyano-7-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;

Cis-3-(((8-cyano-7-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)-2,2-dimethylcyclobutanecarboxylic acid;

1-(1-(8-cyano-7-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)piperidine-4-carboxylic acid;

8-(1-(8-cyano-7-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;

9-(1-(8-cyano-7-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;

1-(1-(8-cyano-7-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)piperidine-4-carboxylic acid;

9-(1-(7-((cis-4-methylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;

2,2-dimethyl-3-((1-(7-((cis-4-methylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)propyl)amino)cyclobutanecarboxylic acid;

1-((7-((cis-4-isopropylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)methyl)piperidine-4-carboxylic acid;

8-((7-((cis-4-isopropylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;

9-((7-((cis-4-isopropylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;

3-(((7-((cis-4-isopropylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)methyl)amino)-2,2-dimethylcyclobutanecarboxylic acid;

cis-3-((1-(7-((cis-4-methylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)amino)cyclobutanecarboxylic acid;

trans-3-((1-(7-((cis-4-methylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)amino)cyclobutanecarboxylic acid;

(1S,3R)-2,2-dimethyl-3-((1-(7-((cis-4-methylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)amino)cyclobutanecarboxylic acid;

(1R,3S)-2,2-dimethyl-3-((1-(7-((cis-4-methylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)amino)cyclobutanecarboxylic acid;

(1S,3S)-2,2-dimethyl-3-(((S)-1-(7-((cis-4-methylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)amino)cyclobutanecarboxylic acid;

((1R,3S)-2,2-dimethyl-3-(((S)-1-(7-((cis-4-methylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)amino)cyclobutanecarboxylic acid;

(1S,3S)-2,2-dimethyl-3-(((R)-1-(7-((cis-4-methylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)amino)cyclobutanecarboxylic acid;

(1R,3S)-2,2-dimethyl-3-(((R)-1-(7-((cis-4-methylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)amino)cyclobutanecarboxylic acid;

(1S,3R)-3-((1-(7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)amino)-2,2-dimethylcyclobutanecarboxylic acid;

((1R,3S)-3-((1-(7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)amino)-2,2-dimethylcyclobutanecarboxylic acid;

(1R,3R)-3-(((S)-1-(7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)amino)-2,2-dimethylcyclobutanecarboxylic acid;

(1S,3R)-3-(((S)-1-(7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)amino)-2,2-dimethylcyclobutanecarboxylic acid;

(1R,3R)-3-(((R)-1-(7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)amino)-2,2-dimethylcyclobutanecarboxylic acid;

(1S,3R)-3-(((R)-1-(7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)amino)-2,2-dimethylcyclobutanecarboxylic acid;

(1S,3S)-3-(((S)-1-(7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)amino)-2,2-dimethylcyclobutanecarboxylic acid;

(1R,3S)-3-(((S)-1-(7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)amino)-2,2-dimethylcyclobutanecarboxylic acid;

(1S,3S)-3-(((R)-1-(7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)amino)-2,2-dimethylcyclobutanecarboxylic acid;

(1R,3S)-3-(((R)-1-(7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)amino)-2,2-dimethylcyclobutanecarboxylic acid;

(1S,3R)-2,2-dimethyl-3-((1-(8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)amino)cyclobutanecarboxylic acid;

(1R,3S)-2,2-dimethyl-3-((1-(8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)amino)cyclobutanecarboxylic acid;

(1R,3R)-2,2-dimethyl-3-(((S)-1-(8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)amino)cyclobutanecarboxylic acid;

(1S,3R)-2,2-dimethyl-3-(((S)-1-(8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)amino)cyclobutanecarboxylic acid;

(1R,3R)-2,2-dimethyl-3-(((R)-1-(8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)amino)cyclobutanecarboxylic acid;

(1S,3R)-2,2-dimethyl-3-(((R)-1-(8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)amino)cyclobutanecarboxylic acid;

(1R,3R)-2,2-dimethyl-3-(((S)-1-(8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)amino)cyclobutanecarboxylic acid;

(1S,3R)-2,2-dimethyl-3-(((S)-1-(8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)amino)cyclobutanecarboxylic acid;

(1R,3R)-2,2-dimethyl-3-(((R)-1-(8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)amino)cyclobutanecarboxylic acid;

(1S,3R)-2,2-dimethyl-3-(((R)-1-(8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)amino)cyclobutanecarboxylic acid;

1-((8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy) naphthalen-2-yl)methyl)azepane-4-carboxylic acid;

cis-4-(((8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)cyclohexanecarboxylic acid;

trans-4-(((8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)cyclohexanecarboxylic acid;

2-(4-(((8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)cyclohexyl)acetic acid;

3-(((8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)cyclopentanecarboxylic acid;

3-(((8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)cyclobutanecarboxylic acid;

cis-4-((1-(8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)amino)cyclohexanecarboxylic acid;

4-((1-(7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl) naphthalen-2-yl)ethyl)amino)bicyclo[2.2.1]heptane-1-carboxylic acid;

3-((1-(7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)amino)cyclopentanecarboxylic acid;

methyl 9-(1-(7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylate;

9-((S)-1-(7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;

9-((R)-1-(7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;

cis-4-((1-(7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)amino)cyclohexanecarboxylic acid;

cis-4-(((S)-1-(7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)amino)cyclohexanecarboxylic acid;

cis-4-(((R)-1-(7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)amino)cyclohexanecarboxylic acid;

cis-4-(((S)-1-(8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)amino)cyclohexanecarboxylic acid;

cis-4-(((R)-1-(8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)amino)cyclohexanecarboxylic acid;

9-((S)-1-(8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;

9-((R)-1-(8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;

cis-4-((1-(7-((cis-4-methylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)amino)cyclohexanecarboxylic acid;

trans-4-((1-(8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)amino)cyclohexanecarboxylic acid;

8-((S)-1-(7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;

8-((R)-1-(7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;

cis-4-((1-(7-((cis-4-ethylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)propyl)amino)cyclohexanecarboxylic acid;

cis-4-((1-(7-((cis-4-methylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)propyl)amino)cyclohexanecarboxylic acid; and

cis-4-((1-(8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)propyl)amino)cyclohexanecarboxylic acid;

or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1 , wherein the compound is selected from the group consisting of:

4-((7-((cis-4-methylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)methyl)morpholine;

9-[7-(cis-4-methyl-cyclohexyloxy)-8-trifluoromethyl-naphthalen-2-ylmethyl]-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;

8-[7-(cis-4-methyl-cyclohexyloxy)-8-trifluoromethyl-naphthalen-2-ylmethyl]-8-aza-bicyclo[3.2.1]octane-3-carboxylic acid;

1-[7-(cis-4-Methyl-cyclohexyloxy)-8-trifluoromethyl-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid;

9-{1-[7-(cis-4-methyl-cyclohexyloxy)-8-trifluoromethyl-naphthalen-2-yl]-ethyl}-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;

9-{(S)-1-[7-(cis-4-methyl-cyclohexyloxy)-8-trifluoromethyl-naphthalen-2-yl]-ethyl}-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;

9-{(R)-1-[7-(cis-4-methyl-cyclohexyloxy)-8-trifluoromethyl-naphthalen-2-yl]-ethyl}-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;

8-{1-[7-(cis-4-methyl-cyclohexyloxy)-8-trifluoromethyl-naphthalen-2-yl]-ethyl}-8-aza-bicyclo[3.2.1]octane-3-carboxylic acid;

8-{(R)-1-[7-(cis-4-methyl-cyclohexyloxy)-8-trifluoromethyl-naphthalen-2-yl]-ethyl}-8-aza-bicyclo[3.2.1]octane-3-carboxylic acid;

8-{(S)-1-[7-(cis-4-methyl-cyclohexyloxy)-8-trifluoromethyl-naphthalen-2-yl]-ethyl}-8-aza-bicyclo[3.2.1]octane-3-carboxylic acid;

2-((R)-1-((8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperidin-3-yl)acetic acid;

2,2-dimethyl-3-(((8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-naphthalen-2-yl)methyl)amino)cyclobutanecarboxylic acid;

9-[8-trifluoromethyl-7-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;

9-{1-[7-(cis-4-trifluoromethyl-cyclohexyloxy)-8-trifluoromethyl-naphthalen-2-yl]-ethyl}-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;

((R)-1-{1-[8-trifluoromethyl-7-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-ethyl}-piperidin-3-yl)-acetic acid;

8-{1-[7-(cis-4-trifluoromethyl-cyclohexyloxy)-8-trifluoromethyl-naphthalen-2-yl]-ethyl}-8-aza-bicyclo[3.2.1]octane-3-carboxylic acid;

8-{(S)-1-[7-(cis-4-trifluoromethyl-cyclohexyloxy)-8-trifluoromethyl-naphthalen-2-yl]-ethyl}-8-aza-bicyclo[3.2.1]octane-3-carboxylic acid;

8-{(R)-1-[7-(cis-4-trifluoromethyl-cyclohexyloxy)-8-trifluoromethyl-naphthalen-2-yl]-ethyl}-8-aza-bicyclo[3.2.1]octane-3-carboxylic acid;

9-[7-(4-methyl-cyclohexyloxy)-8-trifluoromethyl-naphthalene-2-carbonyl]-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;

9-[8-trifluoromethyl-7-(4-trifluoromethyl-cyclohexyloxy)-naphthalene-2-carbonyl]-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;

9-[8-Chloro-7-(4-methyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;

9-[1-(8-trifluoromethyl-7-(cis-4-methylcyclohexyloxy)-naphthalen-2-yl)ethyl]-9-aza-bicyclo[3.3.1]nonan;

8-(1-(7-((cis-4-methylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;

1-(1-(7-((cis-4-methylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)propyl)piperidine-4-carboxylic acid;

2-((3R)-1-(1-(7-((cis-4-methylcyclohexyl)oxy)-8-(trifluoromethyl)naphthalen-2-yl)propyl)piperidin-3-yl)acetic acid;

((R)-1-{1-[8-trifluoromethyl-7-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-ethyl}-piperidin-3-yl)-acetic acid;

2-((S)-1-((8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperidin-3-yl)acetic acid;

8-(8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid; and

8-[7-(cis-4-methyl-cyclohexyloxy)-8-trifluoromethyl-naphthalene-2-carbonyl]-8-azabicyclo[3.2.1]octane-3-carboxylic acid;

or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

19. A method of treating a condition selected from the group consisting of rheumatoid arthritis and multiple sclerosis in a mammal comprising administering to said mammal an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

20. The method of claim 19 , wherein the condition is rheumatoid arthritis.

21. The method of claim 19 , wherein the condition is multiple sclerosis.

22. The method of claim 19 , further comprising administering to said mammal an effective amount of one or more drugs selected from the group consisting of: a corticosteroid, a bronchodilator, an antiasthmatic, an antiinflammatory, an antirheumatic, an immunosuppressant, an antimetabolite, an immunomodulator, an antipsoriatic, and an antidiabetic.

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

24. The method of claim 23 , wherein the chronic pain is inflammatory pain.

25. The method of claim 23 , wherein the chronic pain is neuropathic pain.

26. The pharmaceutical composition of claim 18 , wherein the compound is selected from the group consisting of: