Compounds as ROR gamma modulators

Patent metadata

Field	Value
Publication number	US-10988467-B2
Application number	US-201916402948-A
Country	US
Kind code	B2
Filing date	May 3, 2019
Priority date	Aug 3, 2015
Publication date	Apr 27, 2021
Grant date	Apr 27, 2021

Abstract

The present disclosure is directed to compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein ring A, ring B, L, R 1 , R 2 , R 3 , R 4 , R 5 , R a , R b , n, m, p and q are as defined herein, which are active as modulators of retinoid-related orphan receptor gamma t (RORγt). These compounds prevent, inhibit, or suppress the action of RORγt and are therefore useful in the treatment of RORγt mediated diseases, disorders, syndromes or conditions such as, e.g., pain, inflammation, COPD, asthma, rheumatoid arthritis, colitis, multiple sclerosis, psoriasis, neurodegenerative diseases and cancer.

First claim

What is claimed is:

1. A process for preparing a compound of formula (Ib)

or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, the process comprising:
(i) reacting a compound of formula (1) with a compound of formula (3) to afford a compound of formula (4); and

(ii) reducing the ketone group in the compound of formula (4) to afford the compound of formula (Ib), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

wherein
ring A is selected from

ring B is selected from C 3-6 cycloalkyl, C 6-14 aryl, 3-15 membered heterocyclyl and 5 to 14 membered heteroaryl;
L is absent or is y *—CR—(CR x R y ) t —* z ;
X is selected from O, NR x1 and

each of x, y and z represents a point of attachment;
each occurrence of R 2 is independently selected from cyano, halogen, hydroxyl, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkoxyC 1-8 alkyl, haloC 1-8 alkyl, haloC 1-8 alkoxy, hydroxyC 1-8 alkyl, C(O)C 1-8 alkyl, C 3-6 cycloalkyl, C(O)C 3-6 cycloalkyl and 3 to 15 membered heterocyclic ring;
each occurrence of R 3 is independently selected from halogen, cyano, C 1-8 alkyl, haloC 1-8 alkyl and C 3-6 cycloalkyl;
each occurrence of R 4 is independently selected from halogen, cyano, C 1-8 alkyl, haloC 1-8 alkyl and C 3-6 cycloalkyl;
each occurrence of R 5 is independently selected from halogen, cyano, C 1-8 alkyl, haloC 1-8 alkyl and C 3-6 cycloalkyl;
R b is C 1-8 alkyl;
R x and R y , which may be same or different, are each independently selected from hydrogen, C 1-8 alkyl and hydroxyC 1-8 alkyl, or R x and R y together with the carbon atom to which they are attached, form a 3 to 6 membered cycloalkyl ring;
R x1 is selected from hydrogen or C 1-8 alkyl;
‘n’ is 0, 1, 2 or 3;
‘m’ is 0, 1 or 2;
‘p’ is 0, 1 or 2;
‘q’ is 0, 1, 2 or 3; and
‘t’ is 0, 1, 2 or 3.

2. The process according to claim 1 , wherein the compound of formula (1) is

the compound of formula (3) is

the compound of formula (4) is

and the compound of formula (Ib) is

3. The process according to claim 1 , wherein the compound of formula (1) is reacted with a compound of formula (3) in the presence of a coupling agent.

4. The process according to claim 3 , wherein the coupling agent is selected from 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), propylphosphonic anhydride (T3P), N,N′-dicyclohexylcarbodiimide (DCC) and (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (HATU) or combination thereof.

5. The process according to claim 1 , wherein the compound of formula (1) is reacted with a compound of formula (3) in the presence of a base.

6. The process according to claim 5 , wherein the base is selected from Et 3 N, DIPEA, pyridine or DMAP.

7. The process according to claim 1 , wherein the compound of formula (1) is reacted with a compound of formula (3) in the presence of a coupling agent and a base.

8. The process according to claim 1 , wherein the reduction of compound of formula (4) is carried out using sodium borohydride.

9. A process for preparing a compound of formula (Ib)

or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, the process comprising:
reacting a compound of formula (1) with a compound of formula (3) to afford a compound of formula (4); and

(ii) reducing the ketone group in the compound of formula (4) to afford the compound of formula (Ib), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

wherein
ring A is

ring B is selected from C 6-14 aryl, 3-15 membered heterocyclyl and 5 to 14 membered heteroaryl;
L is absent;
each of x, y and z represents a point of attachment;
each occurrence of R 2 is independently selected from cyano, halogen, hydroxyl, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkoxyC 1-8 alkyl, haloC 1-8 alkyl, haloC 1-8 alkoxy, and hydroxyC 1-8 alkyl;
each occurrence of R 3 is independently selected from halogen, cyano, C 1-8 alkyl, haloC 1-8 alkyl and C 3-6 cycloalkyl;
each occurrence of R 4 is independently selected from halogen, cyano, C 1-8 alkyl, haloC 1-8 alkyl and C 3-6 cycloalkyl;
each occurrence of R 5 is independently selected from halogen, cyano, C 1-8 alkyl, haloC 1-8 alkyl and C 3-6 cycloalkyl;
R b is C 1-8 alkyl;
‘n’ is 0, 1, 2 or 3;
‘m’ is 0, or;
‘p’ is 0, 1 or 2; and
‘q’ is 0, 1, 2 or 3.

Assignees

• Glenmark Pharmaceuticals Sa

Inventors

• Das Sanjib
• Gharat Laxmikant A
• Harde Rajendra L
• Shelke Sandeep Y
• Pardeshi Shailesh R
• Thomas Abraham
• Khairatkar-Joshi Neelima
• Shah Daisy M
• Bajpai Malini

Classifications

• C07D417/12 Primary

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

• C07D241/18

  Oxygen or sulfur atoms · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D231/12

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