Compounds that are S1P modulating agents and/or ATX modulating agents
View Patent ↗Compounds of formula (I) can modulate the activity of one or more SIP receptors and/or the activity of autotaxin (ATX).
1. A compound represented by formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X is O, or NR 12 ;
A 1 , A 2 , A 3 , A 5 , A 6 and A 7 are each independently CR 2 ;
“------” indicates a double bond;
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 R 1 may be optionally substituted with from one to six independently selected R 6 ;
R 2 , for each occurrence, is independently selected from the group consisting of hydrogen, halo, hydroxyl, nitro, cyano, carboxy, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkoxy, C 3-8 halocycloalkoxy, C 1-6 alkanoyl, amino, N—(C 1-6 alkyl)amino, N,N-di-(C 1-6 alkyl)amino, C 1-6 alkoxycarbonyl, C 1-6 alkanoyloxy, carbamoyl, N—(C 1-6 alkyl)carbamoyl, N,N-di-(C 1-6 alkyl)carbamoyl, C 1-6 alkylamido, mercapto, C 1-6 alkylthio, C 1-6 alkylsulfonyl, sulfamoyl, N—(C 1-6 alkyl)sulfamoyl, N,N-di-(C 1-6 alkyl)sulfamoyl, and C 1-6 alkylsulfonamido;
each R 3 and each R 4 are each independently hydrogen, a carboxy, C 1-6 alkyl, or a C 2-6 alkenyl; or R 3 and R 4 together with the carbon to which they are attached are —C(═O)—, a C 3-8 spirocycloalkyl, or a 3- to 8-membered spiroheterocycloalkyl;
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 8 , and R 12 are each independently hydrogen or a C 1-6 alkyl;
i is an integer from 0 to 6;
n is an integer from 1 to 6; and
(i) m is 1;
B is a ring system represented by the following formula:
and
R 5 is CO 2 H; or
(ii) m is 0;
is a ring system represented by the following formula:
wherein B is optionally further substituted by oxo, hydroxy, —NH 2 , —CONH 2 , or —CO 2 H; and
R 5 is CO 2 H.
2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
m is 1;
is a ring system represented by the following formula:
and
R 5 is CO 2 H.
3. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
is a bridged ring system represented by the following formula:
4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
m is 0;
is a ring system represented by the following formula:
wherein B is optionally further substituted by oxo, hydroxy, —NH 2 , —CONH 2 , or —CO 2 H; and
R 5 is CO 2 H.
5. The compound according to claim 1 , wherein the compound is represented by formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
A 1b , A 2b , A 3b , A 5b , and A 6b are CR 2b ;
R 2a is a halo, C 1-6 haloalkyl or cyano;
R 2b , for each occurrence, is independently selected from the group consisting of hydrogen, halo, hydroxyl, nitro, cyano, carboxy, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkoxy, C 3-8 halocycloalkoxy, C -6 alkanoyl, amino, N—(C 1-6 alkyl)amino, N,N-di-(C 1-6 alkyl)amino, C 1-6 alkoxycarbonyl, carbamoyl, N—(C 1-6 alkyl)carbamoyl, N,N-di-(C 1-6 alkyl)carbamoyl, C 1-6 alkylamido, mercapto, C 1-6 alkylthio, C 1-6 alkylsulfonyl, sulfamoyl, N—(C 1-6 alkyl)sulfamoyl, N,N-di-(C 1-6 alkyl)sulfamoyl, and C 1-6 alkylsulfonamido; and
—(CH 2 ) p —R 7 is R 5 .
6. The compound according to claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 2b , for each occurrence, is independently hydrogen or a halo.
7. The compound according to claim 6 , wherein the compound is represented by formula (IIa):
or a pharmaceutically acceptable salt thereof, wherein:
A 3c and A 5c are CH;
R 9 is a halo, an C 1-6 alkyl, or a C 1-6 haloalkyl; and
R 13 and R 14 are each independently hydrogen or a C 1-6 alkyl; and
—(CH 2 ) p —R 7 is R 5 .
8. The compound according to claim 7 , wherein the compound is represented by formula (IIb):
or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 8 , or a pharmaceutically acceptable salt thereof, wherein:
m is 0;
is a ring system represented by the following formula:
wherein B is optionally further substituted by oxo, hydroxy, —NH 2 , —CONH 2 , or —CO 2 H; and
R 5 is CO 2 H.
10. The compound according to claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 2a is —Cl, —CF 3 or —CHF 2 .
11. The compound according to claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 9 is methyl, ethyl, —CF 3 or tert-butyl.
12. The compound according to claim 1 , wherein the compound is represented by formula (III):
or a pharmaceutically acceptable salt thereof, wherein:
A 3c is CH;
R 10 and R 11 are each independently hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, tri-C 1-6 alkylsilyl, or phenyl, wherein at least one of R 10 or R 11 is not hydrogen; or R 10 and R 11 together with the carbon to which they are attached form a C 3-8 spirocycloalkyl or 3- to 8-membered spiroheterocycloalkyl; and
—(CH 2 ) p —R 7 is R 5 .
13. The compound according to claim 12 , or a pharmaceutically acceptable salt thereof, wherein:
m is 1;
is a bridged ring system represented by the following formula:
and
R 5 is CO 2 H.
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is trifluoromethyl, difluoromethyl or monofluoromethyl.
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is methyl, ethyl or isopropyl.
16. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein: X is NH.
17. The compound of claim 1 , wherein the compound is selected from the group consisting of:
4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid;
4-(((6-((trans-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl) amino)bicyclo [2.2.2]octane-1-carboxylic acid;
4-(((6-((trans-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo [2.2.2] octane-1-carboxylic acid;
4-(((6-((trans-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid;
4-(((6-((trans-4-(tert-pentyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid;
4-(((6-((trans-4-phenylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid;
4-(((6-((4,4-dimethylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo [2.2.2]octane-1-carboxylic acid;
4-(((6-(spiro [2.5]octan-6-yloxy)naphthalen-2-yl)methyl)amino)bicyclo [2.2.2]octane-1-carboxylic acid;
4-(((6-(spiro[3.5]nonan-7-yloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid;
4-(((6-(spiro [4.5]decan- 8-yloxy)naphthalen-2-yl)methyl)amino)bicyclo [2.2.2]octane-1-carboxylic acid;
4-(((6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid;
4-(((6-(heptyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid;
4-(((6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo [2.2.2] octane-1-carboxylic acid;
4-(((6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid;
4-(((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl) amino)bicyclo [2.2.2]octane-1-carboxylic acid;
4-(((6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid;
4-(((6-((cis-4-phenylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid;
4-(((6-((trans-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid;
4-(((6-((cis-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid;
4-(((6-(heptyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylate;
4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid;
3-(1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic acid;
3-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic acid;
3-(1-((6-((4,4-dimethylcyclohexyl)oxy)quinolin-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic acid;
3-(1-((6-(heptyloxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic acid;
3-(1-((6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic acid;
3-(1-((6-((4,4-dimethylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic acid;
3-((1(6-(spiro[4.5]decan-8-yloxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic acid;
4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2yl)methyl)(methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid;
8-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
9-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
3-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.3.1]nonane-9-carboxylic acid;
4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.1]heptane-1-carboxylic acid;
4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)amino)bicyclo[2.2.1]heptane-1-carboxylic acid;
4-((6-(trans-4-(Trimethylsilyl)cyclohexyloxy)naphthalen-2-yl)methylamino)bicyclo[2.2.2]octane-1-carboxylic acid;
4-(((6-((cis-4-(Trimethylsilyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid;
4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid;
or a pharmaceutically acceptable salt thereof.
18. The compound of claim 1 , wherein the compound is selected from the group consisting of:
9-((6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
3-(((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)methyl)amino)spiro[3.5]nonane-1-carboxylic acid;
9-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-((R)-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-((S)-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)ethyl)-9-azabicyclo[3.3.1]-nonane-3-carboxylic acid;
9-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid, enantiomer 1;
9-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid, enantiomer 2;
8-((6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
9-((6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-((6-((4,4-difluorocyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
8-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
9-((5-(difluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-((6-(((trans,trans)-3,5-dimethylcyclohexyl)oxy)-5-(trifluoromethyl) naphthalene-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
8-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
9-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(2-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)acetyl)-9-azabicyclo[.3.1]nonane-3-carboxylic acid;
9-(2-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-((6-((cis-4-methylcyclohexyl)amino)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-((5-Chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-((5-Chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
4-(((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)carbamoyl)bicyclo[2.2.2]octane-1-carboxylic acid;
N-(6-((cis-4-trifluoromethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-ylcarbonyl) -2-azabicyclo[1.2.3]octane-7-carboxylic acid;
N-(6-((cis-4-trifluoromethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-ylcarbonyl) -decahydroisoquinoline-5-carboxylic acid;
2-(2-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)acetyl)-2-azabicyclo[1.2.3]octane-7-carboxylic acid;
2-(2-(5-(difluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)acetyl)-2-azabicyclo[1.2.3]octane-7-carboxylic acid;
4-(((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)aminomethyl)bicyclo[2.2.2]octane-1-carboxylic acid;
8-(1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-naphthalene-2-yl)ethyl)-8-azabicyclo[.2.1]octane-3-carboxylic acid;
8-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
9-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-((6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-9-aza-7-oxa-bicyclo[3.3.1]nonane-3-carboxylic acid;
8-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
9-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-((6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-7-hydroxy-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid;
8-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid, enantiomer 1;
8-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid, enantiomer 2;
9-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
8-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
8-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
9-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
8-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl) ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid, enantiomer 1;
8-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl) ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid, enantiomer 1;
9-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid, enantiomer 1;
9-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid, enantiomer 2;
8-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid, enantiomer 1;
8-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid, enantiomer 2;
9-((6-((cis-4-trifluoromethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
3-(4-{[5-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-amino}-bicyclo[2.2.2]oct-1-yl)-carboxylic acid;
2-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-2-azaspiro[3.3]heptane-6-carboxylic acid;
N-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl) -decahydroisoquinoline-8-carboxylic acid;
3-((6-((cis-4-trifluoromethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.3.1]nonane-9-carboxylic acid;
N-(5-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-4-aminobicyclo[2.2.1]heptane-1-carboxylic acid;
3-(5-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-3-azabicyclo[3.3.0]octane-7-carboxylic acid;
8-((6-((4,4-difluorocyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
N-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-3-(azetidine-3-yl)-cyclohexane-1-carboxylic acid;
N-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-8-aminobicyclo[3.2.1]octane-3-carboxylic acid, enantiomer 1;
N-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-8-aminobicyclo[3.2.1]octane-3-carboxylic acid, enantiomer 2;
7-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-7-azabicyclo[2.2.1]heptane-2-carboxylic acid;
N-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-9-aminobicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-9-aza-7-oxabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-7-hydroxy-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-7-oxo-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-((6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
8-((6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
8-(1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid, enantiomer 1;
8-(1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid, enantiomer 2;
9-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
8-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
9-(1-(6-((cis-4-trifluoromethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl) propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
8-(1-(6-((cis-4-trifluoromethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl) propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
9-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
8-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
8-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
9-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-chloronaphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-((5-Chloro-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
8-(1-(5-Chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid; and
8-((5-Chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
or a pharmaceutically acceptable salt thereof.
19. The compound of claim 1 , wherein the compound is selected from the group consisting of:
8-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
8-(1-(5-cyano-6-((cis-4-methylcyclohexyl)oxy) naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
8-((5-cyano-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
8-(1-(5-cyano-6-((cis-4-methylcyclohexyl)oxy) naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
8-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)-2-naphthoyl)-8-azabicyclo[13.2.1]octane-3-carboxylic acid;
9-((5-cyano-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
8-((5-cyano-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
9-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
8-(1-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
8-(5-chloro-6-((cis-4-methylcyclohexyl)oxy)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
8-(1-(6-((cis-4-(1,1-difluoroethyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
8-(1-(5-chloro-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
9-(5-cyano-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-((5-cyano-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-chloro-6-((cis-4-methylcyclohexyl)oxy)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-((6-((cis-4-(1,1-difluoroethyl)cyclohexyl)oxy)-5-(trifluoro-methyl)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
8-(1-(5-chloro-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
9-(1-(5-chloro-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
8-(1-(5-cyano-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
9-(1-(5-cyano-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(1-(5-chloro-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
8-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
8-(1-(6-((cis-4-(1,1-difluoroethyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
9-(1-(6-((cis-4-(1,1-difluoroethyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(5-cyano-6-((cis-4-methylcyclohexyl)oxy)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
8-(5-cyano-6-((cis-4-methylcyclohexyl)oxy)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
8-(1-(5-cyano-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
9-(5-cyano-6-((cis-4-ethylcyclohexyl)oxy)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
8-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
8-(5-cyano-6-((cis-4-ethylcyclohexyl)oxy)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
9-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(1-(5-cyano-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
8-(1-(5-cyano-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
9-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-(1-(5-cyano-6-(((1s,4s)-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-((5-cyano-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
methyl 8-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl) amino)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylate;
8-((r)-1-(6-((cis-4-methylcyclohexyl)oxy)-5-(trifluoromethyl) naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
8-((s)-1-(6-((cis-4-methylcyclohexyl)oxy)-5-(trifluoromethyl) naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
8-(1-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy) naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
9-(1-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
8-(1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
9-(1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-((R)-1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-((S)-1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-((R)-1-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-((S)-1-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
8-((R)-1-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
8-((S)-1-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
methyl 9-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylate;
methyl 9-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylate;
8-((R)-1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
8-((S)-1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
9-((R)-1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-((S)-1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
8-((R)-1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
8-((S)-1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
methyl 8-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylate;
8-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl) amino)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
9-((6-(bicyclo[3.1.0]hexan-3-yloxy)-5-(trifluoromethyl) naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
8-((6-(bicyclo[3.1.0]hexan-3-yloxy)-5-(trifluoromethyl) naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
8-((R)-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
8-((S)-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
8-((R)-1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
8-((S)-1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
9-((R)-1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-((S)-1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
8-((R)-1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl) naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
8-((S)-1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl) naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;
9-((R)-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-((S)-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-((R)-1-(6-(((1s,4S)-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl) naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
9-((S)-1-(6-(((1s,4R)-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl) naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;
or a pharmaceutically acceptable salt thereof.
20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound, or a pharmaceutically acceptable salt thereof, according to claim 1 .
21. A method of treating or reducing symptoms of 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.
22. The method of claim 21 , 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 immunomodulating agent, an antipsoriatic, and an antidiabetic.
23. A method of treating or reducing 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.