S1P and/or ATX modulating agents

Patent metadata

Field	Value
Publication number	US-9771326-B2
Application number	US-201314443944-A
Country	US
Kind code	B2
Filing date	Nov 20, 2013
Priority date	Nov 20, 2012
Publication date	Sep 26, 2017
Grant date	Sep 26, 2017

Abstract

Compounds of formula (I), and pharmaceutically acceptable salts thereof, can modulate the activity of one or more SIP receptors and/or the activity of autotaxin (ATX).

First claim

What is claimed is:

1. A compound represented by formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
X is O;
X 1 , X 2 , and X 5 are each independently CR 4 or N;
one of X 3 or X 4 is C and is attached by a single bond to Ring A, and the other X 4 is CR 4 or N, provided that no more than two of X 1 , X 2 , X 3 , X 4 or X 5 are N;
L 1 is a direct bond, —C(O)— or C 1-7 alkylene;
Ring A is phenyl which is optionally substituted with from 1 to 3 R 5 ;
R 1 is a monocyclic C 3-8 cycloalkyl which is substituted with from 1 to 6 independently selected R 6 ;
R 2 is a C 1-7 alkyl substituted with C(O)OR 11 , or a C 3-8 cycloalkyl substituted with —C(O)OR 11 or —CH 2 C(O)OR 11 ,
R 3 is hydrogen; or
R 2 and R 3 together with the nitrogen to which they are attached form a heterocycloalkyl selected from;

 and
R 4 and R 5 , for each occurrence, are independently selected from hydrogen, halo, hydroxyl, nitro, cyano, C 1-7 alkyl, C 1-7 haloalkyl, C 1-7 alkoxy, C 1-4 haloalkoxy, C 2-7 alkenyl, C 2-7 alkynyl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 3-8 cycloalkoxy, C 3-8 halocycloalkoxy, —NR c R d , —C(O)NR c R d , —N(R c )C(O)R b , —C(O)R a , —S(O) p R a , and —N(R c )S(O) 2 R b , wherein p is 0, 1, or 2;
R 6 , for each occurrence, is independently selected from halo, hydroxyl, mercapto, nitro, C 1-7 alkyl, C 1-7 haloalkyl, C 1-7 alkoxy, C 1-4 haloalkoxy, C 1-7 alkylthio, C 2-7 alkenyl, C 2-7 alkynyl, cyano, —NR a R b ; or two R 6 on the same carbon atom together with the carbon to which they are attached form a C 3-8 spirocycloalkyl;
R 7 and R 8 , for each occurrence, are each independently hydrogen or C 1-4 alkyl;
R 9 , for each occurrence, is independently halo or C 1-4 alkyl;
R 11 for each occurrence is independently hydrogen or C 1-7 alkyl;
R a and R b for each occurrence are independently selected from hydrogen, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl;
R c and R d for each occurrence are independently selected from hydrogen, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is cyclohexyl which is substituted with from 1 to 3 independently selected R 6 .

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 4 and X 5 are CR 4 ; X 3 and X 6 are C; and X 3 is attached to Ring A by a single bond.

4. The compound of claim 1 , wherein R 4 , for each occurrence, is independently selected from hydrogen, halo and C 1-4 haloalkyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from:

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is a C 1-7 alkyl which is substituted with —C(O)OR 11 ; and R 3 is hydrogen.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is a C 3-8 cycloalkyl which is substituted with —C(O)OR 11 or —CH 2 C(O)OR 11 ; and R 3 is hydrogen.

8. A compound, or pharmaceutically acceptable salt thereof, selected from:
1-((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)piperidine-4-carboxylic acid;
3-(((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)propanoic acid;
3-(((3′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)propanoic acid;
4-(((3′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)butanoic acid;
(R)-1-((3′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)pyrrolidine-3-carboxylic acid;
(R)-1-((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)pyrrolidine-3-carboxylic acid;
3-(((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)cyclopentanecarboxylic acid;
4-(((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)butanoic acid;
3-(((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)cyclobutanecarboxylic acid;
(1S,4S)-4-(((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)cyclohexanecarboxylic acid;
(1R,4R)-4-(((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)cyclohexanecarboxylic acid;
2-(1-((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)azetidin-3-yl)acetic acid;
2-(1-((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)piperidin-3-yl)acetic acid;
2-(1-((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)piperidin-4-yl)acetic acid;
3-(((3′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)cyclopentanecarboxylic acid;
4-(((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid;
1-((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)piperidin-4-ol;
(1R,3S)-3-(((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)cyclopentanecarboxylic acid;
(1S,3R)-3-(((4′-((trans-4-(tert-Butyl)cyclohexyl)oxy)-[1,1′-biphenyl]-3-yl)methyl)amino)cyclopentanecarboxylic acid;
ethyl 1-((4′-(trans-4-tert-Butylcyclohexyloxy)biphenyl-4-yl)methyl)piperidine-4-carboxylate;
1-((4′-(trans-4-tert-Butylcyclohexyloxy)biphenyl-4-yl)methyl)piperidine-4-caboxylic acid;
3-((4′-(trans-4-tert-Butylcyclohexyloxy)biphenyl-4-yl)methylamino)propanoic acid;
3-((3′-(trans-4-tert-Butylcyclohexyloxy)-5′-methylbiphenyl-3-yl)methylamino)propanoic acid;
3-((3′-(trans-4-tert-Butylcyclohexyloxy)-5′-fluorobiphenyl-3-yl)methylamino)propanoic acid;
3-((3′-(trans-4-tert-Butylcyclohexyloxy)-5′-(trifluoromethyl)biphenyl-3-yl)methylamino)propanoic acid;
3-((3′-(trans-4-tert-Butylcyclohexyloxy)-2′-fluorobiphenyl-3-yl)methylamino)propanoic acid;
3-((3′-(trans-4-tert-Butylcyclohexyloxy)-2′-(trifluoromethyl)biphenyl-3-yl)methylamino)propanoic acid;
3-((4′-(trans-4-tert-Butylcyclohexyloxy)-2′-fluorobiphenyl-3-yl)methylamino)propanoic acid;
3-((4′-(trans-4-tert-Butylcyclohexyloxy)-2′-fluorobiphenyl-3-yl)methylamino)cyclopentanecarboxylic acid;
3-((4′-(trans-4-tert-Butylcyclohexyloxy)-3′-fluorobiphenyl-3-yl)methylamino)propanoic acid;
3-((4′-(trans-4-tert-Butylcyclohexyloxy)-3′-fluorobiphenyl-3 -yl)methylamino)cyclopentanecarboxylic acid;
3-((4′-(trans-4-tert-Butylcyclohexyloxy)-3′-(trifluoromethyl)biphenyl-3-yl)methylamino)propanoic acid;
3-((4′-(trans-4-tert-Butylcyclohexyloxy)-3′-(trifluoromethyl)biphenyl-3-yl)methylamino)cyclopentanecarboxylic acid;
3-((4′-(Spiro[4.5]decan-8-yloxy)biphenyl-3-yl)methylamino)cyclopentanecarboxylic acid;
3-((4′-(4,4-Dimethylcyclohexyloxy)biphenyl-3-yl)methylamino)cyclopentanecarboxylic acid;
3-((4′-(cis-4-Ethylcyclohexyloxy)biphenyl-3-yl)methylamino)cyclopentanecarboxylic acid;
1-(3-(5-(trans-4-tert-Butylcyclohexyloxy)pyridin-2-yl)benzyl)piperidine-4-carboxylic acid;
3-(3-(5-(trans-4-tert-Butylcyclohexyloxy)pyridin-2-yl)benzylamino)propanoic acid;
3-(3-(5-(trans-4-tert-Butylcyclohexyloxy)pyridin-2-yl)benzylamino)cyclopentanecarboxylic acid;
3-(3-(5-(trans-4-tert-Butylcyclohexyloxy)pyridin-3-yl)benzylamino)propanoic acid;
3-(3-(6-(trans-4-tert-Butylcyclohexyloxy)pyridazin-3-yl)benzylamino)propanoic acid;
3-(3-(5-(trans-4-tert-Butylcyclohexyloxy)pyrimidin-2-yl)benzylamino)propanoic acid;
3-(3-(2-(trans-4-tert-Butylcyclohexyloxy)pyrimidin-5-yl)benzylamino)propanoic acid;
3-(3-(6-(trans-4-tert-Butylcyclohexyloxy)p yrimidin-4- yl)benzylamino)prop ano

Assignees

• Biogen Ma Inc

Inventors

• Peng Hairuo
• Xin Zhili
• Sun Lihong
• Chan Timothy
• Kumaravel Gnanasambandam
• Taveras Arthur G

Classifications

• A61K31/40

  having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil · CPC title

• C07B2200/07

  Optical isomers · CPC title

• C07D401/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D277/28

  Radicals substituted by nitrogen atoms · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title