ROR-gamma modulators and uses thereof

Patent metadata

Field	Value
Publication number	US-11084784-B2
Application number	US-201515128932-A
Country	US
Kind code	B2
Filing date	Mar 25, 2015
Priority date	Mar 27, 2014
Publication date	Aug 10, 2021
Grant date	Aug 10, 2021

Abstract

The present invention relates to a compound of formula I, or an isotopic form, stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a polymorph, a prodrug, N-oxide or S-oxide thereof; and processes for their preparation. The invention further relates to pharmaceutical compositions containing the compounds and their use in the treatment of diseases or disorders mediated by RORγ.

First claim

We claim:

1. A compound of formula I,

wherein:
R 1 is —S(O) m R a , —S(O) r NR b R c , —S(O) r (NR b )R a ,
R a is (C 1 -C 8 )-alkyl, (C 3 -C 12 )-cycloalkyl, (C 6 -C 10 )-aryl or heterocyclyl;
R b and R c at each occurrence are independently selected from the group consisting of hydrogen, (C 1 -C 8 )-alkyl, (C 3 -C 12 )-cycloalkyl, (C 6 -C 10 )-aryl and heterocyclyl; or
R b and R c can combine to form a saturated or unsaturated 5- or 6-membered ring, optionally containing 1 or 2 additional heteroatoms selected from the group consisting of N, S and O;
wherein the ring can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, cyano, oxo, (C 1 -C 8 )-alkyl, (C 1 -C 8 )-alkoxy and halo(C 1 -C 8 )-alkyl;
m is 0, 1 or 2;
r is 1 or 2;

R 2 at each occurrence is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, (C 1 -C 8 )-alkyl, (C 1 -C 8 )-alkoxy, (C 3 -C 12 )-cycloalkyl, halo(C 1 -C 8 )-alkyl, halo(C 1 -C 8 )-alkoxy, NR a1 R a2 , COR a3 , COOR a3 and CONR a1 R a2 ; or
R 1 and R 2 when present on adjacent carbon atoms of the phenyl can combine to form a saturated 5- or 6-membered ring containing S or SO 2 ; which ring can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, cyano, oxo, (C 1 -C 8 )-alkyl, (C 2 -C 8 )-alkenyl, (C 2 -C 8 )-alkynyl, (C 1 -C 8 )-alkoxy and halo(C 1 -C 8 )-alkyl;
R 3 and R 4 are independently selected from the group consisting of hydrogen or (C 1 -C 8 )-alkyl;
a is 1 or 2;
b is 1;
L is —CO—;
A is

R 5 is hydrogen, (C 1 -C 8 )-alkyl, halo(C 1 -C 8 )alkyl or (C 3 -C 12 )-cycloalkyl;
R 6 and R 7 are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, (C 1 -C 8 )-alkyl, (C 2 -C 8 )-alkenyl, (C 1 -C 8 )-alkoxy, halo(C 1 -C 8 )alkyl, (C 3 -C 12 )-cycloalkyl, (C 6 -C 10 )-aryl, CONR a1 R a2 , COR a3 and COOR 3 ; or
R 6 and R 7 can combine to form saturated or unsaturated 3-6 membered cyclic ring optionally containing 1 or 2 heteroatoms selected from the group consisting of O, N and S; wherein the ring can be unsubstituted or substituted with one or more groups independently selected from the group consisting of oxo, hydroxy, cyano, halogen, (C 1 -C 8 )-alkyl, halo(C 1 -C 8 )-alkyl, COR a3 , COOR a3 , CONR a2 R a3 , (C 1 -C 8 )alkoxy and halo(C 1 -C 8 )-alkoxy;

c is 0;
Q is

R 9 is (CR f R j ) f R b , (CR f R j ) f OR k , (CR f R j ) f N(R k ) 2 , (CR f R j ) f CN, (CR f R j ) f -halogen, W—(C 3 -C 12 )-cycloalkyl, W—(C 5 -C 10 )-cycloalkenyl, W 1 —(C 6 -C 10 )-aryl, W 1 -heterocyclyl or W 1 -heteroaryl;
R k is hydrogen, (C 1 -C 8 )-alkyl, (C 3 -C 12 )-cycloalkyl, (C 5 -C 10 )-cycloalkenyl, -(C 1 -C 8 )-alkylene-(C 3 -C 12 )-cycloalkyl, -(C 1 -C 8 )-alkylene-(C 5 -C 10 )-cycloalkenyl, (C 6 -C 10 )-aryl, -(C 1 -C 8 )-alkylene-(C 6 -C 10 )-aryl, heteroaryl, heterocyclyl, -(C 1 -C 8 )-alkylene-heteroaryl or -(C 1 -C 8 )-alkylene-heterocyclyl;
R x at each occurrence are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, oxo, (C 1 -C 8 )-alkyl, (C 1 -C 8 )-alkoxy, (C 3 -C 12 )-cycloalkyl, halo(C 1 -C 8 )-alkyl, halo(C 1 -C 8 )-alkoxy, NR a1 R a2 , COR a3 , COOR a3 and CONR a1 R a2 ;
W is a bond, —O—, CO, NH, (CR f R g ) f , (CR f R g ) f —C≡C— or (C 5 -C 10 )-cycloalkenyl;
W 1 is (CR f R j ) f , (CR f R g ) f —C≡C— or (C 5 -C 10 )-cycloalkenyl;
R j is (C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy, halo(C 1 -C 8 )alkyl, COOR a3 or heterocyclyl;
R f is selected from the group consisting of halogen, cyano, hydroxy, and halo(C 1 -C 8 )alkyl;
R g is selected from the group consisting of hydrogen, halogen, cyano, hydroxy, (C 1 -C 8 )alkyl and halo(C 1 -C 8 )alkyl;
e is 1 or 2;
f is 1, 2, 3 or 4;
wherein:
each of the (C 1 -C 8 )-alkyl, (C 1 -C 8 )-alkylene, (C 2 -C 8 )-alkenyl and (C 1 -C 8 )-alkoxy can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (C 1 -C 8 )-alkynyl, (C 1 -C 8 )-alkoxy, (C 3 -C 12 )-cycloalkyl, (C 6 -C 10 )-aryl, heterocyclyl, heteroaryl, halo(C 1 -C 8 )alkoxy, C(O)R h , OC(O)R h , COOR h , C(O)NR h R i , O—R i , OC(O)NR h R i , NR h R i , NR h C(O)R i , NR h C(O)NR h R i , S(O) q (C 1 -C 8 )-alkyl, S(O) r NR h R i and NR h S(O) q R i ;
each of the (C 3 -C 12 )-cycloalkyl, (C 5 -C 10 )-cycloalkenyl and (C 6 -C 10 )-aryl can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (C 1 -C 8 )-alkyl, (C 1 -C 8 )-alkoxy, (C 3 -C 12 )-cycloalkyl, (C 6 -C 10 )-aryl, heterocyclyl, heteroaryl, halo(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkoxy, C(O)R h , COOR h , C(O)NR h R i , O—R i , OC(O)R h , OC(O)NR h R i , NR h R i , NR h C(O)R i , NR h C(O)NR h R i , S(O) q (C 1 -C 8 )-alkyl, S(O) r NR h R i and NR h S(O) q R i ;
heterocyclyl is a 3- to 10-membered ring containing 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, S and O, wherein said heterocyclyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (C 1 -C 8 )-alkyl, (C 1 -C 8 )-alkoxy, (C 3 -C 12 )-cycloalkyl, (C 6 -C 10 )-aryl, heterocyclyl, heteroaryl, halo(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkoxy, C(O)R h , COOR h , C(O)NR h R i , O—R i , OC(O)R h , OC(O)NR h R i , NR h R i , NR h C(O)R i , NR h C(O)NR h R i , S(O) q (C 1 -C 8 )-alkyl, S(O) r NR h R i and NR h S(O) q R i ;
heteroaryl is a 5- to 10-membered ring containing 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, S and O, wherein said heteroaryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (C 1 -C 8 )-alkyl, (C 1 -C 8 )-alkoxy, (C 3 -C 12 )-cycloalkyl, (C 6 -C 10 )-aryl, heterocyclyl, heteroaryl, halo(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkoxy, C(O)R h , COOR h , C(O)NR h R i , O—R i , OC(O)R h , OC(O)NR h R i , NR h R i , NR h C(O)R i , NR h C(O)NR h R i , S(O) q (C 1 -C 8 )-alkyl, S(O) r NR h R i and NR h S(O) q R i ; and
R h and R i are independently selected from the group consisting of hydrogen, (C 1 -C 8 )-alkyl, (C 2 -C 8 )-alkenyl, halo(C 1 -C 8 )alkyl, (C 3 -C 12 )-cycloalkyl, (C 6 -C 10 )-aryl, (C 6 -C 10 )-aryl-(C 1 -C 8 )-alkyl, heteroaryl and heterocyclyl;
provided that,
(i) when R 1 is —S(O) r NR b R c , wherein R b and R c can combine to form a saturated or unsaturated 5- or 6-membered ring, then Q is

or an isotopic form, a stereoisomer or tautomer thereof; or a pharmaceutically acceptable salt, S oxide or N-oxide thereof.

2. The compound according to claim 1 ,
wherein:
R 1 is —S(O) m R a , —S(O) r NR b R c or —S(O) r (NR b )R a ;
provided that,
when R 1 is —S(O) r NR b R c , wherein R b and R c can combine to form a saturated or unsaturated 5- or 6-membered ring, then Q is

or an isotopic form, a stereoisomer, a tautomer, a p

Assignees

• Piramal Entpr Ltd

Inventors

• Sharma Rajiv
• Sahu Bichismita
• Mali Sunil Vasantrao
• Singh Deepak
• Kumar Pramod Bhaskar
• Dawange Mahesh
• Mistry Hitesh

Classifications

• C07C255/46 Primary

  to carbon atoms of non-condensed rings · CPC title

• C07C217/88

  the oxygen atom of at least one of the etherified hydroxy groups being further bound to a carbon atom of a ring other than a six-membered aromatic ring · CPC title

• C07C205/36

  to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system · CPC title

• C07C211/45

  Monoamines · CPC title

• C07C317/24

  having sulfone or sulfoxide groups and doubly-bound oxygen atoms bound to the same carbon skeleton · CPC title