Heterobicyclic sphingosine 1-phosphate analogs

Patent metadata

Field	Value
Publication number	US-9708353-B2
Application number	US-201514620700-A
Country	US
Kind code	B2
Filing date	Feb 12, 2015
Priority date	Oct 30, 2008
Publication date	Jul 18, 2017
Grant date	Jul 18, 2017

Abstract

Compounds that have agonist activity at one or more of the S1P receptors are provided. The compounds are sphingosine analogs that, after phosphorylation, can behave as agonists at S1P receptors.

First claim

What is claimed is:

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
A 1 is —C(X 1 )═;
A 2 is —C(X 2 )═;
A 3 is —C(X 3 )(X 3′ )—;
A 4 is C(X 4 )(X 4′ )—;
A 5 is C(X 5 )(X 5′ )—;
A 6 is —C(X 6 )═;
X 1 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NR f R g , —N(R f )SO 2 R g , —SO 2 R f , —SO 2 NR f R g , —CO 2 R f , trialkylamino, aryl, or heteroaryl;
X 2 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NR f R g , —N(R f )SO 2 R g , —SO 2 R f , —SO 2 NR f R g , —CO 2 R f , trialkylamino, aryl, or heteroaryl;
X 3 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NR f R g , —N(R f )SO 2 R g , —SO 2 R f , —SO 2 NR f R g , —CO 2 R f , trialkylamino, aryl, or heteroaryl;
X 3′ is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NR f R g , —N(R f )SO 2 R g , —SO 2 R f , —SO 2 NR f R g , —CO 2 R f , trialkylamino, aryl, or heteroaryl;
X 4 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NR f R g , —N(R f )SO 2 R g , —SO 2 R f , —SO 2 NR f R g , —CO 2 R f , trialkylamino, aryl, or heteroaryl;
X 4′ is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NR f R g , —N(R f )SO 2 R g , —SO 2 R f , —SO 2 NR f R g , —CO 2 R f , trialkylamino, aryl, or heteroaryl;
X 5 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NR f R g , —N(R f )SO 2 R g , —SO 2 R f , —SO 2 NR f R g , —CO 2 R f , trialkylamino, aryl, or heteroaryl;
X 5′ is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NR f R g , —N(R f )SO 2 R g , —SO 2 R f , —SO 2 NR f R g , —CO 2 R f , trialkylamino, aryl, or heteroaryl;
X 6 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NR f R g , —N(R f )SO 2 R g , —SO 2 R f , —SO 2 NR f R g , —CO 2 R f , trialkylamino, aryl, or heteroaryl;
Y is —OR f , —(CR f R g )OR f , —(CR f R g ) 2 OR f , —O—P(O)(OR f )OR g , —OC(O)R c , —C(O)OR c , —(CR f R g )—P(O)(OR f )OR g , —(C(OH)R f )—P(O)(OR f )OR g , —S—P(O)(OR f )OR g , tetrazole, —SO 2 NHR f , —SO 3 , —CONHR f , —Si(OH) 2 , or —B(OH) 2 ;
W is —CR f R g —, —NR f —, —O—, —S—, —SO—, or —SO 2 —;
Cy is cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl; wherein Cy is optionally substituted by 1-6 substituents selected from the group consisting of hydrogen, halo, hydroxy, nitro, cyano, —NR f R g , alkyl, haloalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, alkoxy, haloalkoxy, cycloalkylalkoxy, cycloalkenylalkoxy, heterocyclylalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, acyl, cycloalkylacyl, cycloalkenylacyl, heterocyclylacyl, arylacyl, heteroarylacyl, thioalkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl;
L 1 is —CH 2 —, —CHF—, or —CF 2 —;
Z 4 is hydrogen, halo, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, or —OR f ;
or Z 4 is —CH 2 — bound to the carbon atom to which Y is bound;
or L 1 , Z 4 , Y, and the atoms to which they are bound form a 4-7 membered cycloalkyl group or a 4-7 membered heterocyclyl group having 1 or 2 heteroatoms selected from O and N;
R a is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl; wherein each of alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, —CN, —CHO, —CF 3 , —OH, —NO 2 , alkyl, —OCF 3 , alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
R b is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl; wherein each of alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, —CN, —CHO, —CF 3 , —OH, —NO 2 , alkyl, —OCF 3 , alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
or R b and Z 4 are taken to together to form —C(O)O— or ═C(R f )O—;
R c is alkyl, aryl, trifluoromethyl, methylsulfonyl, trifluoromethylsulfonyl, p-tolylsulfonyl, or a group selected such that —OCOR c is a good leaving group;
each R f , independently, is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl; wherein each of alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, —CN, —CHO, —CF 3 , —OH, —NO 2 , alkyl, —OCF 3 , alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
each R g , independently, is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl; wherein each of alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, —CN, —CHO, —CF 3 , —OH, —NO 2 , alkyl, —OCF 3 , alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
wherein the aryl is a monocyclic, bicyclic, or tricyclic carbocyclic ring system having one or two aromatic rings; the heteroaryl is an optionally substituted mono- or bicyclic cyclic ring system containing one, two, or three heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, and nitrogen; and the heterocyclyl is an optionally substituted mono- or bicyclic carbocyclic ring system containing one, two, three, or four heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, and nitrogen.

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

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R a and R b , independently, are each H or alkyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is —OR f .

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is —OH or —O—P(O)(OR f )OR g .

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 6 is H, halo, alkyl, cycloalkyl, or haloalkyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 3 is —C(X 3 )H—, A 4 is —C(X 4 )H—, and A 5 is —C(X 5 )H—.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy has the formula:

Assignees

• Biogen Ma Inc

Inventors

• Caldwell richard d
• Guckian Kevin
• Kumaravel Gnanasambandam
• Lee Wen-Cherng
• Lin Edward Yin-Shiang
• Liu Xiaogao
• Ma Bin
• Scott Daniel M
• Shi Zhan
• Thomas Jermaine
• Taveras Arthur G
• Zheng Guo Zhu

Classifications

• C07D215/20 Primary

  Oxygen atoms · CPC title

• C07F9/091

  with hydroxyalkyl compounds with further substituents on alkyl · CPC title

• A61P37/06

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

• C07D239/74

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring · CPC title

• C07C217/74

  with rings other than six-membered aromatic rings being part of the carbon skeleton · CPC title