ATX modulating agents

Patent metadata

Field	Value
Publication number	US-9522889-B2
Application number	US-201314417300-A
Country	US
Kind code	B2
Filing date	Jul 26, 2013
Priority date	Jul 27, 2012
Publication date	Dec 20, 2016
Grant date	Dec 20, 2016

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.

First claim

What is claimed is:

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

Assignees

• Biogen Ma Inc

Inventors

• Guckian Kevin
• Kumaravel Gnanasambandam
• Ma Bin
• Mi Sha
• Peng Hairuo
• Shao Zhaohui
• Sun Lihong
• Taveras Arthur
• Wang Deping
• Xin Zhili
• Zhang Lei

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title