Compounds that are S1P modulating agents and/or ATX modulating agents

1. A compound represented by structural formula (II) or (III):

or a pharmaceutically acceptable salt thereof, wherein:

X is O;

A 1 , A 2 , A 3 , A 4 , A 5 , and A 6 are CR 2 ;

“------” indicates a double;

R 1 is a cyclohexyl which is optionally substituted with one to three 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;

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

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 —COOH;

R 8 and R 9 are each independently 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 are —C(═O)—, a C 3-8 spirocycloalkyl, or a 3- to 8-membered spiroheterocycloalkyl;

R 10 is hydrogen or a C 1-6 alkyl;

R 11 , for each occurrence, is independently halo, hydroxyl, nitro, cyano, C 1-6 alkyl, —(CR 17 CR 18 ) p —R 7 , C 1-6 haloalkyl, C 1-6 alkoxy, 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 17 and R 18 , for each occurrence, are each independently hydrogen, a halo, or a C 1-4 haloalkyl;

(i) m is 0; and R 5 is selected from the group consisting of:

 or

(ii) 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 ; and

p is 0 or an integer from 1 to 6.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is represented by structural formula (II):

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is represented by structural formula (III):

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

m is 0; and

R 5 is selected from the group consisting of:

5. The compound of claim 1 , 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 .

6. A compound selected from the group consisting of:

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

8-((6-((cis-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-1-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;

9-((6-((cis-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-1-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;

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

1-(((6-((cis-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-1-yl)methyl)amino)cyclohexanecarboxylic acid;

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

8-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-1-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;

9-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-1-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;

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

1-(((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-1-yl)methyl)amino)cyclohexanecarboxylic acid;

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

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

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

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

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

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

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

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

1-((7-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-1-yl)methyl)piperidine-4-carboxylic acid;

1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-1-yl)methyl)piperidine-4-carboxylic acid; and

2-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-1-yl)methyl)piperidin-4-yl)acetic acid;

or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound according to claim 1 .

8. A method of treating a condition in a mammal comprising administering to said mammal an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the condition is selected from the group consisting of an inflammatory disorder, an autoimmune disorder, a fibrosis of the lung, or a malignancy of the lung.

9. The method of claim 8 , wherein the inflammatory disorder is rheumatoid arthritis.

10. The method of claim 8 , wherein the autoimmune disorder is multiple sclerosis.

11. The method of claim 8 , 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.

12. A method of preventing, 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.

13. The method of claim 12 , wherein the chronic pain is inflammatory pain.

14. The method of claim 12 , wherein the chronic pain is neuropathic pain.