S1P and/or ATX modulating agents

Patent metadata

Field	Value
Publication number	US-9850206-B2
Application number	US-201314443912-A
Country	US
Kind code	B2
Filing date	Nov 20, 2013
Priority date	Nov 20, 2012
Publication date	Dec 26, 2017
Grant date	Dec 26, 2017

Abstract

Compounds of formula (I) wherein: X is —O—, —S(O) r —, —CH 2 —, or —NR—, wherein r is 0, 1, or 2; X 1 , X 2 , and X 5 are each independently CR 7 or N; one of X 3 or X 4 is C and is attached by a single bond to -L-, and the other is CR 7 or N, provided that no more than three of X 1 , X 2 , X 3 , X or X 5 are N; Ring A is monocyclic C 5-6 scycloalkyl or a 5- to 6-membered monocyclic heterocyclyl comprising from 1 to 5 heteroatoms independently selected from N, S, or O; wherein Ring A is further optionally substituted with from 1 to 3 R 4 ; provided that Ring A is not morpholinyl, thiomorpholinyl or tetrahydro-2H-pyranyl; L is a bond, —O—, —NR—, —S(O) n —, —CH 2 —, or —C(O)—, wherein n is 0, 1, or 2; 1 2 L 1 is an C 1-8 alkylene, C 3-s cycloalkylene, —CH 2 -L 2 -, or a 3- to 8-membered heterocyclylene comprising 1 to 5; R 1 is C 6-20 alkyl or a monocyclic C 3-8 cycloalkyl; wherein said C 3-8 cycloalkyl is substituted with at least one R 6 and may be optionally substituted with from 1 to 5 additional R 6 substituents, wherein R 6 for each occurrence is independently selected; and R 2 is —C(O)OR 3 , —C(O)N(R 3 )—S(O) 2 R 3 , —S(O) 2 OR 3 , —C(O)NHC(O)R 3 , —Si(O)OH, —B(OH) 2 , —N(R 3 )S(O) 2 R 3 , —S(O) 2 N(R 3 ) 2 , —O—P(O)(OR 3 ) 2 , or —P(O)(OR 3 ) 2 , —CN, —S(O) 2 NHC(O)R 3 , —C(O)NHS(O) 2 R3, —C(O)NHOH, —C(O)NHCN, —CH(CF 3 )OH, —C(CF 3 ) 2 OH, or a selected heteroaryl or heterocyclyl; 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—, —S(O) r —, —CH 2 —, or —NR—, wherein r is 0, 1, or 2;
X 1 , X 2 , and X 5 are each independently CR 7 or N;
X 3 is C and is attached by a single bond to -L-, and X 4 is CR 7 or N, provided that no more than three of X 1 , X 2 , X 3 , X 4 or X 5 are N;
Ring A is monocyclic C 5-6 cycloalkyl or a 5- to 6-membered monocyclic heterocyclyl comprising from 1 to 5 heteroatoms independently selected from N, S, or O; wherein Ring A is further optionally substituted with from 1 to 3 R 4 ; provided that Ring A is not morpholinyl, thiomorpholinyl or tetrahydro-2H-pyranyl;
L is a bond, —O—, —NR—, —S(O) r —, —CH 2 —, or —C(O)—, wherein n is 0, 1, or 2;
L 1 is an C 1-8 alkylene, C 3-8 cycloalkylene, —CH 2 -L 2 -, or a 3- to 8-membered heterocyclylene comprising 1 to 5 heteroatoms selected from N, S, or O; wherein L 1 may be optionally substituted with from 1 to 3 independently selected R 5 ;
L 2 is a divalent bridged ring system comprising 6-10 ring members, wherein the ring members may be all carbon atoms or may comprise 1 to 5 heteroatoms selected from N, S, or O;
R, for each occurrence, is independently hydrogen or C 1-8 alkyl;
R 1 is a monocyclic C 3-8 cycloalkyl; wherein said C 3-8 cycloalkyl is substituted with at least one R 6 and may be optionally substituted with from 1 to 5 additional R 6 substituents, wherein R 6 for each occurrence is independently selected;
R 2 is —C(O)OR 3 , —C(O)N(R 3 )—S(O) 2 R 3 , —S(O) 2 OR 3 , —C(O)NHC(O)R 3 , —Si(O)OH, —B(OH) 2 , —N(R 3 )S(O) 2 R 3 , —S(O) 2 N(R 3 ) 2 , —O—P(O)(OR 3 ) 2 , or —P(O)(OR 3 ) 2 , —CN, —S(O) 2 NHC(O)R 3 , —C(O)NHS(O) 2 R 3 , —C(O)NHOH, —C(O)NHCN, —CH(CF 3 )OH, —C(CF 3 ) 2 OH, or a heteroaryl or a heterocyclyl selected from the group consisting of formulae (a)-(i′):

R 3 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 12 membered heteroaryl, and a 3 to 12 membered heterocyclyl; wherein the heteroaryl and heterocyclyl independently comprise from 1 to 6 heteroatoms selected from O, N, or S; and wherein R 3 may be 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 alkylamino, N,N-di-(C 1-4 alkyl) amino, carbamoyl, N—C 1-4 alkylcarbamoyl, 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 4 and R 5 , for each occurrence, are independently halo, hydroxyl, nitro, cyano, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-4 haloalkoxy, C 2-8 alkenyl, C 2-8 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) p R a , or —N(R a )S(O) 2 R b , wherein p for each occurrence is independently 0, 1, or 2;
R 6 , for each occurrence, is independently halo, hydroxyl, mercapto, nitro, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-4 haloalkoxy, C 1-8 alkylthio, C 2-8 alkenyl, C 2-8 alkynyl, cyano, —NR a R b , C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 6-10 aryl, 3- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl comprise 1 to 4 heteroatoms independently selected from O, N, or S; 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 , for each occurrence, is independently 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; and
R a and R b , for each occurrence, are independently hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, or C 3-8 halocycloalkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is —O—.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is monocyclic C 5-6 cycloalkyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is 5- to 6-membered monocyclic heterocyclyl comprising from 1 to 5 heteroatoms independently selected from N, S, or O.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is 5- to 6-membered monocyclic heterocyclyl comprising from 1 to 2 heteroatoms independently selected from N.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is a bond, or —NR—.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is a bond.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 1 is an C 1-8 alkylene, C 3-8 cycloalkylene, —CH 2 -L 2 -, or a 3- to 8-membered heterocyclylene comprising 1 to 5 N.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 1 is C 1-8 alkylene.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 2 is a divalent bridged ring system comprising 6-10 ring members, wherein the ring members are all carbon atoms.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R, for each occurrence, is hydrogen.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is monocyclic C 3-8 cycloalkyl; wherein said C 3-8 cycloalkyl is substituted with at least one R 6 and may be optionally substituted with from 1 to 5 additional R 6 substituents, wherein R 6 for each occurrence is independently selected; and
R 6 , for each occurrence, is independently C 1-8 alkyl; or two R 6 on the same carbon atom together with the carbon to which they are attached form a C 3-8 spirocycloalkyl.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is —C(O)OR 3 .

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is —C(O)OR 3 , and R 3 is hydrogen.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X is —O—;
X 1 , X 2 , and X 5 are each independently CH or N;
X 3 is C and is attached by a single bond to -L-, and X 4 is CH or N, provided that no more than three of X 1 , X 2 , X 3 , X 4 or X 5 are N;
Ring A is an unsubstituted monocyclic C 5-6 cycloalkyl or a 5- to 6-membered monocyclic heterocyclyl comprising from 1 to 5 heteroatoms independently selected from N, S, or O; provided that Ring A is not morpholinyl, thiomorpholinyl or tetrahydro-2H-pyranyl;

Assignees

• Biogen Ma Inc

Inventors

• Peng Hairuo
• Lin Edward Yin-Shiang
• Chao Jianhua
• Xin Zhili
• Ma Bin
• Guckian Kevin
• Chan Timothy
• Kumaravel Gnanasambandam
• Taveras Arthur G

Classifications

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D403/04

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

• C07D295/15

  to an acyclic saturated chain · CPC title

• C07D211/22 Primary

  by oxygen atoms · CPC title

• C07D211/62

  attached in position 4 · CPC title