Compounds as modulators of RORγ

Patent metadata

Field	Value
Publication number	US-9242989-B2
Application number	US-201514683682-A
Country	US
Kind code	B2
Filing date	Apr 10, 2015
Priority date	Apr 14, 2014
Publication date	Jan 26, 2016
Grant date	Jan 26, 2016

Abstract

The present invention encompasses compounds of the formula (I)

wherein the variables are defined herein which are suitable for the modulation of RORγ and the treatment of diseases related to the modulation of RORγ. The present invention also encompasses processes of making compounds of formula (I) and pharmaceutical preparations containing them.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein:
R 1 is:
—CN;
—S(O) n R 6 ;
—S(O) n NR 7 R 8 ;
—S(O)(NR 9 )R 6 ;
—N(R 9 )C(O)R 6 ;
—N(R 9 )C(O)OR 6 ;
—N(R 9 )S(O) n R 6 ;
—C(O)OR 9 ;
—C(O)NR 7 R 8 ; or
—C(O)R 9 ; or

R 6 , R 7 , R 8 or R 9 of R 1 may be cyclized onto W to form a ring; and
R 2 and R 3 are each independently:
(A) —H;
(B) C 1-3 alkyl optionally substituted with one, two or three groups selected from:
a) C 3-6 cycloalkyl;
b) —OR 9 ;
c) —CN;
d) —CF 3 ;
e) -halo;
f) —C(O)OR 9 ;
g) —C(O)N(R 9 ) 2 ;
h) —S(O) n R 9 ; and
i) —S(O) n NR 7 R 8 ; or

(C) C 3-6 cycloalkyl;
(D) C 3-6 heterocyclyl; or
R 2 and R 3 are taken together with the carbon to which they are attached to form a C 3-6 carbocyclic ring; or
R 2 and R 3 are taken together with the carbon to which they are attached to form a C 3-6 heterocyclic ring; or
R 2 or R 3 may be cyclized onto W to form a ring;
R 4 is:
(A) C 1-6 alkyl optionally substituted with one, two or three groups selected from:
a) C 3-6 cycloalkyl;
b) C 3-6 heterocyclyl;
c) —OR 9 ;
d) —CN;
e) —S(O) n R 9 ;
f) -halo; and
g) —CF 3 ; or

(B) C 3-12 cycloalkyl optionally substituted with one, two or three groups selected from:
a) C 1-6 alkyl;
b) —OR 9 ;
c) —CN;
d) —S(O) n R 9 ;
e) -halo; and
f) —CF 3 ; or

(C) aryl, heteroaryl or heterocyclyl each optionally substituted with one, two or three groups selected from:
a) C 1-6 alkyl;
b) C 3-6 cycloalkyl;
c) —OR 9 ;
d) —CN;
e) —S(O) n R 9 ;
f) -halo; and
g) —CF 3 ;

R 5 is aryl, heteroaryl, heterocyclyl or C 3-12 cycloalkyl each optionally substituted with one, two or three groups selected from:
(A) C 1-6 alkyl, C 3-6 cycloalkyl or C 3-6 heterocyclyl each optionally substituted with one, two or three groups selected from:
a) C 3-6 cycloalkyl;
b) C 3-6 heterocyclyl;
c) —OR 9 ;
d) —CN;
e) —S(O) n NR 7 R 8
f) —S(O) n R 9 ;
g) -halo; and
h) —CF 3 ; or

(B) —OR 9 ;
(C) —CN;
(D) —CF 3 ;
(E) -halo;
(F) —S(O) n NR 7 R 8 ;
(G) —S(O) n R 9 ; and
(H) —NR 7 R 8 ;
W is aryl, heteroaryl, heterocyclyl, C 3-12 cycloalkyl, or alkynyl each optionally substituted with one or two groups selected from:
a) C 1-6 alkyl;
b) C 3-6 cycloalkyl;
c) —OR 9 ;
d) —CN;
e) —CF 3 ;
f) -halo;
g) —NR 7 R 8 ;
h) —C(O)OR 9 ; and
i) —C(O)N(R 9 ) 2 ;

R 6 is selected from:
(A) —OH;
(B) C 1-6 alkyl optionally substituted with one or two groups selected from:
a) C 3-6 cycloalkyl;
b) —OR 9 ;
c) —CN;
d) —CF 3 ; and
e) -halo;

(C) C 3-6 cycloalkyl; and
(D) —CF 3 ;
R 7 and R 8 are independently selected from:
(A) —H;
(B) C 1-3 alkyl optionally substituted with one or two groups selected from:
a) C 3-6 cycloalkyl;
b) —OR 9 ;
c) —CN; and
d) -halo; and

(C) C 3-6 cycloalkyl; or
R 7 and R 8 , together with the nitrogen to which they are bonded, form a saturated ring with 3-6 carbon atoms wherein one carbon atom in said saturated ring may be optionally replaced by —O—, —NR 9 —or —S(O) n —;
R 9 is selected from;
(A) —H;
(B) C 1-3 alkyl optionally substituted with one or two groups selected from:
a) C 3-6 cycloalkyl;
b) —OR 9 ;
c) —CN;
d) —CF 3
e) -halo; or

(C) C 3-6 cycloalkyl; and
n is 0, 1 or 2;
or a pharmaceutically acceptable salt thereof.

2. A compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is:
—CN,
—S(O) n R 6 ,
—S(O) n NR 7 R 8 ;
—N(H)S(O)—R 6 ; or
—S(O)(NH)R 6 ; and
wherein:
R 6 is:
(A) C 1-3 alkyl optionally substituted with one or two groups selected from:
a) C 3-6 cycloalkyl;
b) —OR 9 ; and
c) —CN; or

(B) C 3-6 cycloalkyl;
R 7 and R 8 are each independently:
(A) —H; or
(B) C 1-3 alkyl; and
R 9 is selected from;
(A) —H;
(B) C 1-3 alkyl; or
(C) C 3-6 cycloalkyl; and
n is 1 or 2.

3. A compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is:
—S(O)—R 6 ,
—S(O) n NR 7 R 8 , or
—S(O)(NH)R 6 ; and
wherein:
R 6 is:
(A) C 1-3 alkyl optionally substituted with one or two groups selected from:
a) C 3-6 cycloalkyl;
b) —OR 9 ; and
c) —CN; or

(B) C 3-6 cycloalkyl;
R 7 and R 8 are each independently:
(A) —H; or
(B) C 1-3 alkyl; and
R 9 is selected from:
(A) —H;
(B) C 1-3 alkyl; or
(C) C 3-6 cycloalkyl; and
n is 1 or 2.

4. A compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —S(O) n R 6 , —S(O) n NR 7 R 8 or —S(O)(NH)R 6 ; and
R 6 is C 1-3 alkyl; and
R 7 and R 8 are each independently:
(A) —H; or
(B) C 1-3 alkyl; and
n is 2.

5. A compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 and R 3 are each independently selected from:
(A) —H;
(B) C 1-3 alkyl optionally substituted with one, two or three groups selected from:
a) C 3-6 cycloalkyl;
b) —OR 9 ; or
c) -halo; or

R 2 and R 3 are taken together with the carbon to which they are attached to form a C 3-6 carbocyclic ring; or
R 2 and R 3 are taken together with the carbon to which they are attached to form a C 3-6 heterocyclic ring; and
R 9 is selected from:
(A) —H; and
(B) C 1-3 alkyl.

6. A compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 and R 3 are each independently selected from H and C 1-3 alkyl.

7. A compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are H.

8. A compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 4 is:
(A) C 1-6 alkyl optionally substituted with one, two or three groups selected from:
a) C 3-6 cycloalkyl;
b) a 4, 5 or 6-membered heterocyclyl;
c) —OR 9 ;
d) —CN;
e) -halo; and
f) —CF 3 ; or

(B) C 3-6 cycloalkyl optionally substituted with one, two or three groups selected from:
a) C 1-6 alkyl;
b) —OR 9 ;
c) —CN;
d) -halo; and
e) —CF 3 ; and

wherein one carbon in said C 3-6 cycloalkyl may be optionally replaced by —O—;
(C) Phenyl; or
(D) a 4, 5 or 6-membered heterocyclyl; and
R 9 is selected from:
(A) —H; and
(B) C 1-3 alkyl.

9. A compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 4 is:
(A) C 1-6 alkyl optionally substituted with one or two groups selected from:
a) C 3-6 cycloalkyl;
b) a 4, 5, or 6-membered heterocyclyl;
c) —OR 9 ;
d) —CN;
e) -halo; and
f) —CF 3 ; or

(B) C 3-6 cycloalkyl optionally substituted with one, two or three groups selected from:
a) C 1-6 alkyl;
b) —OR 9 ;
c) —CN;
d) -halo; and
e) —CF 3 ; or

(C) Phenyl; or
(D) a 5 or 6-membered heterocyclyl; and
R 9 is C 1-3 alkyl.

10. A compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 4 is:
(A) C 1-6 alkyl optionally substituted with one or two groups selected from C 3-6 cycloalkyl, halo, —CF 3 , and C 1-3 alkoxy; or
(B) C 3-6 cycloalkyl optionally substituted with one or two groups selected from C 1-6 alkyl, —CF 3 , and halo; or
(C) a 5-membered heterocyclyl.

11. A compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 5 is aryl, heteroaryl or heterocyclyl, each optionally substituted with one, two or three groups selected from:
a) C 1-6 alkyl

Assignees

• Boehringer Ingelheim Int

Inventors

• Bakonyi Johanna
• Brunette Steven Richard
• Collin Delphine
• Hughes Robert Owen
• Li Xiang
• Liang Shuang
• Sibley Robert
• Turner Michael Robert
• Wu Lifen
• Zhang Qiang

Classifications

• C07D475/10 Primary

  with an aromatic or hetero-aromatic ring directly attached in position 2 · CPC title

• A61K31/33 Primary

  Heterocyclic compounds · 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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/02

  Immunomodulators · CPC title