Aryl sultam derivatives as RORc modulators

Patent metadata

Field	Value
Publication number	US-10259808-B2
Application number	US-201715847407-A
Country	US
Kind code	B2
Filing date	Dec 19, 2017
Priority date	Jul 8, 2015
Publication date	Apr 16, 2019
Grant date	Apr 16, 2019

Abstract

Compounds of the formula I:

or pharmaceutically acceptable salts thereof, wherein m, n, p, q, r, X 1 , X 2 , X 3 , X 4 , Y, Z, A, Het, R 1 , R 2 , R 3 , R 4 , R 5 R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are as defined herein. Also disclosed are methods of making the compounds and using the compounds for treatment of inflammatory diseases such as arthritis, muscular sclerosis and psoriasis.

First claim

What is claimed is:

1. A compound of formula III:

wherein:
s is from 0 to 3;
p is from 0 to 3;
q is 0, 1 or 2;
r is 1, 2 or 3;
Y is: —O—; or —CR f R g —
Z is:
a bond;
—C 1-6 alkylene-;
—NR p —C 1-6 alkylene;
—C 1-6 alkylene-NR p —;
—NR p —;
—C(O)—;
—C(O)NR p —;
—C(O)NR p —C 1-6 alkylene;
—NR p C(O)—;
—NR p C(O)—C 1-6 alkylene;
—C 1-6 alkylene—O—;
—O—C 1-6 alkylene-; or
—C 1-6 alkylene-O—C 1-6 alkylene-;

Het is:
heteroaryl selected from:
oxazolyl;
isoxazolyl;
thiazolyl;
isothiazolyl;
pyrazolyl;
triazolyl;
oxadiazolyl;
thiadiazolyl;
pyridinyl;
pyrimidinyl;
pyrazinyl; or
imidazolyl;

each of which heteroaryl may be unsubstituted or substituted one or more times with R m ; or
heterocyclyl selected from:
oxetanyl;
tetrayhydrofuranyl;
tetrahydropyranyl;
pyrrolidinyl;
piperidinyl;
piperazinyl;
oxazolidinyl;
imidazolidinyl;
morpoholinyl;

each of which heterocyclyl may be unsubstituted or substituted one or more times with R n ;
R 1 and R 2 are hydrogen;

R 3 and R 4 each independently is hydrogen or C 1-6 alkyl;
each R 9 is independently:
C 1-6 alkyl;
halo;
C 1-6 alkoxy; or
cyano;
wherein the C 1-6 alkyl moieties may be unsubstituted or substituted one or more times with halo;

R 10 is:
hydrogen;
oxo;
hydroxy;
cyano;
halo; or
C 1-6 alkyl which may be unsubstituted or substituted one or more times with halo or oxo;

R 11 is:
hydrogen;
halo; or
C 1-6 alkyl which may be unsubstituted or substituted one or more times with halo or oxo;

each R e is independently:
hydrogen;
C 1-6 alkyl;
halo;
C 1-6 alkoxy; or
cyano;
wherein the C 1-6 alkyl moieties may be unsubstituted or substituted one or more times with halo, hydroxy or C 1-6 alkoxy;

R f is:
hydrogen;
halo;
C 1-6 alkoxy; or
C 1-6 alkyl which may be unsubstituted or substituted one or more times with halo, hydroxy, or C 1-6 alkoxy;

R g is:
hydrogen;
C 1-6 alkyl;
C 3-6 cycloalkyl which may be unsubstituted or substituted once or twice with C 1-6 alkyl;
C 2-6 alkenyl;
C 3-6 cycloalkenyl;
C 3-6 cycloalkyl-C 1-6 alkyl;
halo;
C 1-6 alkyl-sulfonyl;
C 3-6 cycloalkyl-sulfonyl;
C 3-6 cycloalkyl-C 1-6 alkyl-sulfonyl;
C 1-6 alkyl-sulfonyl-C 1-6 alkyl;
cyano;
cyano-C 1-6 alkyl;
C 1-6 alkoxy;
amino;
N—C 1-6 alkyl-amino;
N,N-di-C 1-6 alkyl-amino;
phenyl;
hydroxy;
wherein the C 1-6 alkyl moieties may be unsubstituted or substituted one or more times with halo;

or R f and R g together may form oxo;
each R m is independently:
C 1-6 alkyl;
oxo;
hydroxyl;
amino; or
hydroxyl-C 1-6 alkyl;

each R n is independently:
C 1-6 alkyl;
oxo;
hydroxyl;
hydroxyl-C 1-6 alkyl; or
halo;

R p is:
hydrogen; or
C 1-6 alkyl; and

R e is: C 1-6 alkyl; C 1-6 alkoxy; hydroxy; halo; hydroxy-C 1-6 alkyl; or cyano.

2. The compound of claim 1 , wherein Z is: a bond; —NR p —C 1-6 alkylene; —C(O)—; —C(O)NR p —; —C(O)NR x —C 1-6 alkylene; —NR x C(O)—; —NR x —C 1-6 alkylene; —NR x —; or —NR x C(O)—C 1-6 alkylene.

3. The compound of claim 1 , wherein Z is: a bond; —NR p —C 1-6 alkylene; —C(O)—; —C(O)NR p —; —NR x —C 1-6 alkylene; or —C(O)NR p —.

4. The compound of claim 1 , wherein Z is a bond.

5. The compound of claim 1 , wherein Het is heteroaryl selected from: oxazolyl; isoxazolyl; pyrazolyl; triazolyl; or oxadiazolyl; each of which may be unsubstituted or substituted one or more times with R m .

6. The compound of claim 1 , wherein Het is: 3H-1,3,4-oxadiazol-2-one-5-yl; 3-methyl-1,3,4-oxadiazol-2-one-5-yl; 4H-1,2,4-triazol-3-yl; 3H-1,3,4-oxadiazol-2-one-5-yl; pyrazine-2-yl; 5-methylisoxazol-3-yl; isoxazol-3-yl; 3-oxo-isoxazole-5-yl; oxazol-2-yl; 2-methyl-1,2,4-triazol-3-yl; oxazol-4-yl; 1H-pyrazol-5-yl; pyrimidin-2-yl; 1H-pyrazol-3-yl; 1,3,4-oxadiazole-2-carboxylate-5-yl; 3-aminopyrazol-1-yl; or N-methyl-1,2,4-oxadiazole-5-carboxamide-3-yl.

7. The compound of claim 1 , wherein R 3 is methyl.

8. The compound of claim 1 , wherein R f is: hydrogen; halo; C 1-6 alkyl; or halo-C 1-6 alkyl.

9. The compound of claim 1 , wherein R g is: hydrogen; halo; C 1-6 alkyl; hydroxyl; C 1-6 alkoxy; or halo-C 1-6 alkyl.

10. A compound selected from:

11. A composition comprising:
(a) a pharmaceutically acceptable carrier; and
(b) a compound of claim 1 .

Assignees

• Genentech Inc

Inventors

• Fauber Benjamin
• Gancia Emanuela
• Ladduwahetty Tammy
• Vesey David
• Winship Paul
• Rene Olivier

Classifications

• C07D417/14 Primary

  containing three or more hetero rings · CPC title

• C07D417/10

  linked by a carbon chain containing aromatic rings · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title

• C07D417/12

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

• A61K31/541

  Non-condensed thiazines containing further heterocyclic rings · CPC title