Aryl sultam derivatives as RORc modulators

Patent metadata

Field	Value
Publication number	US-10131644-B2
Application number	US-201615199447-A
Country	US
Kind code	B2
Filing date	Jun 30, 2016
Priority date	Jan 10, 2014
Publication date	Nov 20, 2018
Grant date	Nov 20, 2018

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, 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 I

or a pharmaceutically acceptable salt thereof,
wherein:
m is 0 or 1;
n is 0 or 1;
p is from 0 to 3;
q is 0, 1 or 2;
r is from 1 to 3;
A is:
a bond;

W is:
—CR b R c —;

Y is:
—O—; or
—CR f R g —;

Z is: CR m ;
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 each independently is:
hydrogen; or C 1-6 alkyl which may be unsubstituted or substituted one or more times with halo;

R 9 is
halo;
R 10 is:
hydrogen;
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;

R 12 is:
hydrogen;
halo; or
C 1-6 alkyl which may be unsubstituted or substituted one or more times with halo or oxo;

R 13 is:
hydrogen; or
C 1-6 alkyl which may be unsubstituted or substituted one or more times with halo;

R b , and R c each independently is:
hydrogen; or
C 1-6 alkyl which may be unsubstituted or substituted one or more times with halo;

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;
C 3-6 cycloalkenyl;
C 3-6 cycloalkyl-C 1-6 alkyl;
halo;
C 1-6 alkyl-carbonyl;
C 3-6 cycloalkyl-carbonyl;
C 3-6 cycloalkyl-C 1-6 alkyl-carbonyl;
cyano-C 1-6 alkyl-carbonyl;
hydroxy-C 1-6 alkyl-carbonyl;
C 1-6 alkoxy-C 1-6 alkyl-carbonyl;
carboxy;
N-cyano-aminocarbonyl;
N-cyano-N—C 1-6 alkyl-aminocarbonyl;
N—C 1-6 alkyl-acetimidamidyl;
N,N′-di-C 1-6 alkyl-acetimidamidyl;
N′-cyano-N—C 1-6 alkyl-acetimidamidyl;
N′-hydroxy-acetimidamidyl;
N′—C 1-6 alkoxy-acetimidamidyl;
N′-hydroxy-N—C 1-6 alkyl-acetimidamidyl;
N′—C 1-6 alkoxy-N—C 1-6 alkyl-acetimidamidyl;
2-nitro-1-N—C 1-6 alkylamino-vinyl; formyl;
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;
aminocarbonyl;
carbonylamino;
N-hydroxy-aminocarbonyl;
N—C 1-6 alkoxy-aminocarbonyl;
N—C 1-6 alkyl-aminocarbonyl;
aminocarbonyl-C 1-6 alkyl;
N—C 1-6 alkyl-aminocarbonyl-C 1-6 alkyl;
N,N-di-C 1-6 alkyl-aminocarbonyl-C 1-6 alkyl;
C 1-6 alkoxy-carbonyl;
N-hydroxy-N—C 1-6 alkyl-aminocarbonyl;
N—C 1-6 alkoxy-N—C 1-6 alkyl-aminocarbonyl;
N,N-di-C 1-6 alkyl-aminocarbonyl;
aminosulfonyl;
N—C 1-6 alkyl-aminosulfonyl;
N,N-di-C 1-6 alkyl-aminosulfonyl;
cyano;
C 1-6 alkoxy;
C 1-6 alkyl-sulfonylamino;
N—C 1-6 alkyl-sulfonylaminocarbonyl;
N—(C 1-6 alkyl-sulfonyl)-N—C 1-6 alkyl-aminocarbonyl;
N—(C 1-6 alkyl-sulfonyl)-amino-C 1-6 alkyl; amino;
N—C 1-6 alkyl-amino;
N,N-di-C 1-6 alkyl-amino;
halo-C 1-6 alkyl;
phenyl;
heterocyclyl;
heteroaryl;
C 1-6 alkyl-carbonylamino;
carbonylamino; or
hydroxy;
wherein the C 1-6 alkyl moieties may be unsubstituted or substituted one or more times with halo; and
wherein the phenyl, heterocyclyl, heteroaryl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl and C 3-6 cycloalkyl-C 1-6 alkyl moieties may be unsubstituted or substituted one or more times with R i ;

or R f and R g together may form oxo;
R m is: C 1-6 alkyl;
hydroxy;
halo;
hydroxy-C 1-6 alkyl;
C 1-6 alkylsulfonyl-C 1-6 alkyl;
cyano;
C 1-6 alkylsulfonyl-amino-
C 1-6 alkylsulfinyl-amino-
cyano-C 1-6 alkyl;
cyano-C 2-6 alkenyl;
amino-C 1-6 alkyl;
C 1-6 alkoxy-C 1-6 alkyl;
C 1-6 alkoxy-C 1-6 alkoxy-C 1-6 alkyl;
hydroxy-C 1-6 alkoxy;
hydroxy-C 1-6 alkoxy-C 1-6 alkyl;
hydroxy-C 1-6 alkyl-amino;
C 1-6 alkoxy-C 1-6 alkyl-amino;
N-hydroxy-carboxamidinyl;
C 1-6 alkoxy-carbonyl-C 2-6 alkenyl;
amino;
N—C 1-6 alkylamino;
N,N-di-C 1-6 alkylamino;
—(CHR t ) u —C(O)—NR p R q ;
—(CHR s ) u —O—(CHR s ) v —C(O)—NR p R q ;
—(CHR s ) u —NR a —(CHR s ) v —C(O)— NR p R q ,
(CHR t ) u —C(O)—R u ;
—(CHR s ) u —O—(CHR s ) v —C(O)—R u ; or
(CHR s ) u —NR a —(CHR s ) v —C(O)—R u ;

u is from 0 to 2;
v is from 0 to 2;
each R n is independently:
hydrogen; or
C 1-6 alkyl;

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

R q is:
hydrogen;
C 1-6 alkyl;
hydroxy-C 1-6 alkyl;
N—(C 1-6 alkylcarbonyl)-amino-C 1-6 alkyl;
C 1-6 alkylsulfonyl-C 1-6 alkyl;
amino-C 1-6 alkyl;
N—C 1-6 alkylamino-C 1-6 alkyl;
N,N-di-C 1-6 alkylamino-C 1-6 alkyl;
N,N-di-C 1-6 alkylaminocarbonyl-C 1-6 alkyl;
cyano-C 1-6 alkyl;
carboxy-C 1-6 alkyl;
aminocarbonyl-C 1-6 alkyl;
N—C 1-6 alkylaminocarbonyl-C 1-6 alkyl;
N,N-di-C 1-6 alkyl aminocarbonyl-C 1-6 alkyl;
C 1-6 alkylsulfonyl-C 1-6 alkyl; or
C 1-6 alkoxy-C 1-6 alkyl;

each R s is independently:
hydrogen; or
C 1-6 alkyl;

each R t is independently:
hydrogen;
C 1-6 alkyl;
halo; or
hydroxy; and

R u is: C 1-6 alkyl;
C 1-6 alkoxy;
hydroxy;
hydroxy-C 1-6 alkyl.

2. The compound of claim 1 , wherein R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 13 , R b and R c are hydrogen.

3. The compound of claim 1 , wherein p is 0.

4. The compound of claim 1 , wherein m is 1.

5. The compound of claim 1 , wherein n is 0.

6. The compound of claim 1 , wherein Y is —O—.

7. The compound of claim 1 , wherein each R e is independently: hydrogen; or halo.

8. The compound of claim 1 , wherein R m is selected from:

9. The compound of claim 1 , wherein the compound is of formula VII

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

11. The compound of claim 1 , wherein the compound is of formula IV:

12. The compound of claim 11 , wherein q and r are 1.

13. The compound of claim 1 , wherein the compound is of formula V:

14. The compound of claim 13 , wherein q and r are 1.

15. A compound selected from:

Assignees

• Genentech Inc

Inventors

• Van Niel Monique Bodil
• Fauber Benjamin
• Gancia Emanuela
• Gaines Simon
• Gobbi Alberto
• Hurley Christopher
• Ladduwahetty Tammy
• Rene Olivier
• Vesey David
• Ward Stuart
• Winship Paul

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/06

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

• A61P21/02

  Muscle relaxants, e.g. for tetanus or cramps · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P19/02

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