Fused (hetero)cyclic compounds as S1P modulators

Patent metadata

Field	Value
Publication number	US-10280159-B2
Application number	US-201615388516-A
Country	US
Kind code	B2
Filing date	Dec 22, 2016
Priority date	Dec 22, 2015
Publication date	May 7, 2019
Grant date	May 7, 2019

Abstract

The invention relates to (hetero)cyclic compounds as S1P modulators, pharmaceutical compositions comprising such compounds, and uses thereof in the treatment, alleviation or prevention of diseases or disorders mediated by an S1P receptor.

First claim

The invention claimed is:

1. A compound of formula (I):

or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer or N-oxide thereof, wherein
X and Y are independently selected from the group consisting of O, CH 2 and CH—Z—R1, with the proviso that at most one of X and Y is O and at most one of X and Y is CH—Z—R1;
Z—R1 and R4 are selected from:
(1) Z is attached to ring A at atom 1, 2, 3 or 4 and selected from the group consisting of —O—, —NR5- and —NR5—CH 2 — whereby NR5 is attached to R1 and CH 2 is attached to ring A;
wherein R5 is selected from the group consisting of H, (C1-4)alkyl, (C1-4)alkyl substituted with one or more fluor atoms and benzyl optionally substituted with one or more substituents selected from the group consisting of a halogen atom, (C1-4)alkyl optionally substituted with one or more halogen atoms, and (C1-4)alkoxy optionally substituted with one or more halogen atoms;
R1 is selected from the group consisting of:
—(C1-6)alkylene-R6 wherein one or more carbon atoms in the alkylene group, each independently, are optionally substituted with one or more halogen atoms, with (CH 2 ) 2 to form a cyclopropyl moiety, with (CH 2 ) 3 to form a cyclobutyl moiety or with (CH 2 ) 4 to form a cyclopentyl moiety;
—(C3-6)cycloalkylene-R6, optionally substituted with (C1-4)alkyl or with (C1-4)alkyl substituted with one or more fluor atoms, and wherein one carbon atom in the (C3-6)cycloalkylene can optionally be replaced by oxygen;
—(C1-3)alkylene—(C3-6)cycloalkylene-R6, whereby said (C3-6)cycloalkylene is optionally substituted with (C1-4)alkyl or with (C1-4)alkyl substituted with one or more fluor atoms;
—(C3-6)cycloalkylene—(C1-3)alkylene-R6, whereby said (C3-6)cycloalkylene is optionally substituted with (C1-4)alkyl or with (C1-4)alkyl substituted with one or more fluor atoms; and
—C(O)—(C1-4)alkylene-R6; and

R4 is hydrogen; or

(2) Z is NR5 and attached to ring A at atom 1, 2, 3 or 4, and NR5 and R1 together form a group selected from —(C3-8)-heterocycloalkylene-R6, optionally substituted with (C1-4)alkyl or with (C1-4)alkyl substituted with one or more fluor atoms and —(C3-8)heterocycloalkylene—(C1-3)-alkylene-R6, optionally substituted with (C1-4)alkyl or with (C1-4)alkyl substituted with one or more fluor atoms; and
R4 is hydrogen; or

(3) Z is NR5 and is attached to ring A at atom 2, and NR5 and R4 together form a group selected from pyrrolidine, pyrazolidine, imidazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, piperazine, 1,2-diazinane, 1,3-diazinane, morpholine, 1,3-oxazinane, 1,2-oxazinane, thiomorpholine, 1,3-thiazinane and 1,2-thiazinane, and R1 is as defined above;
R2 is hydrogen or one or more substituents independently selected from the group consisting of a halogen atom, (C1-4)alkyl optionally substituted with one or more halogen atoms, and (C1-4)alkoxy optionally substituted with one or more halogen atoms;
R6 is selected from the group consisting of —OH, —COOH, —OPO 3 H 2, , —CO—O—(C1-4)alkyl, —CO—NH—OH, —CO—NH—O—(C1-4)alkyl, —CO—N(CH 3 )—O—(C1-4)alkyl, -isoxazol-3-one, 3-isoxazolol -dihydro-2-furanone and -tetrazol-5-yl;
L is a group —W—(CH 2 )p-T- wherein:
W is attached to ring B at atom 5, 6, 7 or 8 and
W is selected from the group consisting of —O—, —CO—, —S—, —SO—, —SO 2 —, —NH—, —CH═CH—, —C(CF 3 )═CH—, CH═C(CF 3 )—, —C≡C—, —CH 2 —O—, —O—CO—, —CO—O—, —CO—NH—, —NH—CO— and —O—CH 2 -phenyl-, or
W is —(CH 2 )n- wherein n is 1 or 2 and one or both C atoms of (CH 2 )n are optionally substituted with one or two fluoro atoms, or
W is selected from the group consisting of phenyl, pyridyl, thienyl, thiazolyl and (C3-7)cycloalkylene, each optionally substituted with one or more substituents independently selected from the group consisting of:
a halogen atom,
hydroxy,
cyano,
(C1-4)alkyl optionally substituted with one or more halogen atoms,
(C1-4)alkoxy optionally substituted with one or more halogen atoms,
(C3-6)cycloalkyl optionally substituted with one or more halogen atoms and
phenyl optionally substituted with one or more substituents independently selected from the group consisting of a halogen atom, (C1-4)alkyl optionally substituted with one or more halogen atoms, and (C1-4)alkoxy optionally substituted with one or more halogen atoms;

p is an integer from 0 to 5 and one or more C atoms of (CH 2 )p are optionally substituted with one or two methyl groups, ethyl groups or fluoro atoms;
T is absent or attached to R3 and selected from the group consisting of —O—, —S—, —SO—, —SO 2 —,—NH—, —CO—, —C═C—,C≡C—, cyclopropylene, —(CH 2 )m- and —O—(CH 2 )m- wherein m is an integer from 1 to 5 and one or more C atoms of (CH 2 )m are optionally substituted with one or two fluoro atoms;

R3 is selected from the group consisting of:
(C3-8)alkyl, (C3-8)alkenyl or (C3-8)alkynyl wherein one or more carbon atoms in the alkyl, alkenyl or alkynyl group are optionally substituted with one or more halogen atoms;
(C3-6)cycloalkyl, (C4-6)cycloalkenyl or an 8-10 membered bicyclic group, each optionally substituted with one or more substituents independently selected from the group consisting of a halogen atom, (C1-4)alkyl optionally substituted with one or more fluoro atoms and (C1-4)alkoxy optionally substituted with one or more fluoro atoms,
phenyl, biphenyl, naphthyl, pyridyl, thienyl or thiazolyl optionally substituted with one or more substituents independently selected from the group consisting of:
a halogen atom,
cyano,
(C1-4)alkyl optionally substituted with one or more fluoro atoms,
(C1-4)alkoxy optionally substituted with one or more fluoro atoms,
—S—(C1-4)-alkyl,
—SF 5, and
(C3-6)cycloalkyl optionally substituted with phenyl whereby said phenyl is optionally substituted with a substituent selected from the group consisting of (C1-4)alkyl and a halogen atom.

2. The compound according to claim 1 wherein one of X and Y is O.

3. The compound according to claim 1 wherein Z is selected from the group consisting of —NR5- and —O—.

4. The compound according to claim 1 wherein R3 is unsubstituted (C3-6)cycloalkyl or phenyl, biphenyl, naphthyl, pyridyl, thienyl or thiazolyl substituted with one or more substituents independently selected from the group consisting of:
a halogen atom,
cyano,
(C1-4)alkyl optionally substituted with one or more fluoro atoms,
(C1-4)alkoxy optionally substituted with one or more fluoro atoms,
—S—(C 1 -4)-alkyl,
—SF 5, and
(C3-6)cycloalkyl optionally substituted with phenyl whereby said phenyl is optionally substituted with a substituent selected from the group consisting of (C1-4)alkyl and a halogen atom,

wherein said one or more substituents are at one or more of the ortho and meta positions with respect to L.

5. The compound according to claim 1 wherein Z is attached to ring A at atom 1 or 2.

6. The compound according to claim 1 wherein Z is attached to ring A at atom 2 or 3.

7. The compound according to claim 1 wherein L is attached to ring B at atom 5, 6 or 7, and selected from the group consisting of —O—(CH 2 )p-, —CH═CH—, —C≡C—,—O—SO 2 —,—O—, —CO—, -Ph-(CH 2 )m-, -Ph-O—(CH 2 )m-, and —O—CH 2 -Ph-O—CH 2 —, wherein Ph is phenyl, p is an integer from 1 to 4 and m is an integer from 1 to 5.

8. The compound according to claim 1 wherein R3 is selected from the group consisting of:
(C3-6)alkyl, wherein one or more carbon atoms in the alkyl group are optionally substituted with one or more fluoro atoms;
(C3-6)cycloalkyl optionally substituted with one or more substituents selected from the group consisting of a halogen atom and (C1-4)alkyl,
phenyl, optionally substituted with one to t

Assignees

• Abbvie Deutschland

Inventors

• Amberg Wilhelm
• Lange Udo
• Geneste Herve
• Ochse Michael
• Biesinger Ralf
• Oellien Frank

Classifications

• C07D413/12 Primary

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

• C07D207/06

  with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms · CPC title

• C07C2601/04

  with a four-membered ring · CPC title

• C07D311/04

  Benzo[b]pyrans, not hydrogenated in the carbocyclic ring · CPC title

• C07C229/50

  with amino groups and carboxyl groups bound to carbon atoms being part of the same condensed ring system · CPC title