Compounds and compositions for treating conditions associated with NLRP activity

Patent metadata

Field	Value
Publication number	US-11724992-B2
Application number	US-202117496375-A
Country	US
Kind code	B2
Filing date	Oct 7, 2021
Priority date	Jul 24, 2017
Publication date	Aug 15, 2023
Grant date	Aug 15, 2023

Abstract

In one aspect, compounds of Formula AA, or a pharmaceutically acceptable salt thereof, are featured:or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formula A can be as defined anywhere herein.

First claim

We claim:

1. A compound of Formula AA

wherein
m=0, 1, or 2;
n=0, 1, or 2;
o=1 or 2;
p=0, 1, 2, or 3;
wherein
A is a 5-10-membered heteroaryl or a C 6 -C 10 aryl;
B is a 5-10-membered heteroaryl or a C 6 -C 10 aryl;
wherein
at least one R 6 is ortho to the bond connecting the B ring to the NR 3 (CO) group of Formula AA;
R 1 and R 2 are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, halo, CN, NO 2 , COC 1 -C 6 alkyl, CO-C 6 -C 10 aryl, CO-(5- to 10-membered heteroaryl), CO 2 C 1 -C 6 alkyl, CO 2 C 3 -C 8 cycloalkyl, OCOC 1 -C 6 alkyl, OCOC 6 -C 10 aryl, OCO(5-to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C 6 -C 10 aryl, 5- to 10-membered heteroaryl, NH 2 , NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl) 2 , NHCOC 1 -C 6 alkyl, NHCOC 6 -C 10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC 2 -C 6 alkynyl, NHCOOC 1 -C 6 alkyl, NH—(C═NR 3 )NR 11 R 12 , CONR 8 R 9 , SF 5 , SC 1 -C 6 alkyl, S(O 2 )C 1 -C 6 alkyl, S(O 2 )NR 11 R 12 , S(O)C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, and 3- to 7-membered heterocycloalkyl,
wherein the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl, and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, COOC 1 -C 6 alkyl, NR 8 R 9 , CONR 8 R 9 , 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, OCOC 1 -C 6 alkyl, OCOC 6 -C 10 aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl), NHCOC 1 -C 6 alkyl, NHCOC 6 -C 10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC 2 -C 6 alkynyl;
wherein each C 1 -C 6 alkyl substituent and each C 1 -C 6 alkoxy substituent of the R 1 or R 2 C 3 -C 7 cycloalkyl or of the R 1 or R 2 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, halo, or oxo;
wherein the 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, of the R 1 or R 2 C 1 -C 6 alkyl, the R 1 or R 2 C 1 -C 6 haloalkyl, the R 1 or R 2 C 3 -C 7 cycloalkyl, or the R 1 or R 2 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from halo, C 1 -C 6 alkyl, oxo, and OC 1 -C 6 alkyl;
or at least one pair of R 1 and R 2 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C 4 -C 8 carbocyclic ring or at least one 5- to-8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 8 R 9 , ═NR 10 , COOC 1 -C 6 alkyl, C 6 -C 10 aryl, and CONR 8 R 9 , wherein the C 1 -C 6 alkyl and C 1 -C 6 alkoxy are optionally substituted with hydroxy, halo, oxo, COOC 1 -C 6 alkyl, C 6 -C 10 aryl, and CONR 8 R 9 ;
R 6 and R 7 are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, halo, CN, NO 2 , COC 1 -C 6 alkyl, CO 2 C 1 -C 6 alkyl, CO 2 C 3 -C 7 cycloalkyl, OCOC 1 -C 6 alkyl, OCOC 6 -C 10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C 6 -C 10 aryl, 5- to 10-membered heteroaryl, NH 2 , NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl) 2 , CONR 8 R 9 , SF 5 , SC 1 -C 6 alkyl, S(O 2 )C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and C 2 -C 6 alkenyl,
wherein R 6 and R 7 are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 8 R 9 , ═NR 10 , —COOC 1 -C 6 alkyl, CONR 8 R 9 , 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, OCOC 1 -C 6 alkyl, OCOC 6 -C 10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC 1 -C 6 alkyl, NHCOC 6 -C 10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC 2 -C 6 alkynyl, C 6 -C 10 aryloxy, and S(O 2 )C 1 -C 6 alkyl; and wherein the C 1 -C 6 alkyl or C 1 -C 6 alkoxy that R 6 or R 7 is substituted with is optionally substituted with one or more hydroxyl, halo, C 6 -C 10 aryl or NR 8 R 9 , or wherein R 6 or R 7 is optionally fused to a five- to-seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;
wherein the 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, NHCOC 6 -C 10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C 1 -C 6 alkyl, and OC 1 -C 6 alkyl;
or at least one pair of R 6 and R 7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C 4 -C 8 carbocyclic ring or at least one 4-to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, NR 20 , and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 8 R 9 , CH 2 NR 8 R 9 , ═NR 10 , COOC 1 -C 6 alkyl, C 6 -C 10 aryl, and CONR 8 R 9 ;
each of R 4 and R 5 is independently selected from hydrogen and C 1 -C 6 alkyl;
R 10 is C 1 -C 6 alkyl;
each of R 8 and R 9 at each occurrence is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C═NR 13 )NR 11 R 12 , S(O 2 )C 1 -C 6 alkyl, S(O 2 )NR 11 R 12 , COR 13 , CO 2 R 13 and CONR 11 R 12 ; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more hydroxy, halo, oxo, C 1 -C 6 alkoxy, C 2 -C 6 alkynyl, C 02 R 13 , C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 7 cycloalkyl, or 3- to 7-membered heterocycloalkyl; or
R 8 and R 9 taken together with the nitrogen they are attached to form a 3- to 7-membered ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to;
R 13 is C 1 -C 6 alkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl;
each of R 11 and R 12 at each occurrence is independently selected from hydrogen and C 1 -C 6 alkyl;
each R 3 is independently selected from hydrogen, cyano, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CO 2 C 1 -C 6 alkyl, and

wherein the C 1 -C 2 alkylene group is optionally substituted with oxo; and
R 14 is hydrogen, C 1 -C 6 alkyl, 5-10-membered monocyclic or bicyclic heteroaryl or C 6 -C 10 monocyclic or bicyclic aryl, wherein each C 1 -C 6 alkyl, aryl or heteroaryl is optionally independently substituted with 1, 2, or 3 R 6 ;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C 6 -C 10 monocyclic or bicyclic aryl.

3. The compound of claim 2 , wherein A is:
naphthyl optionally substituted with 1 or 2 R 1 and optionally substituted with 1 or 2 R 2 ,
pyr

Assignees

• Novartis Ag

Inventors

• Franchi Luigi
• Ghosh Shomir
• Glick Gary
• Katz Jason
• Opipari Jr Anthony William
• Roush William
• Seidel Hans Martin
• Shen Dong-Ming
• Venkatraman Shankar
• Winkler David Guenther

Classifications

• C07D277/36 Primary

  Sulfur atoms · CPC title

• A61P13/12

  of the kidneys · CPC title

• C07D333/34

  Sulfur atoms · CPC title

• C07D217/22

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring · CPC title

• C07D307/64

  Sulfur atoms · CPC title