Compounds and compositions for treating conditions associated with NLRP activity

Patent metadata

Field	Value
Publication number	US-11339136-B2
Application number	US-201716094499-A
Country	US
Kind code	B2
Filing date	Apr 18, 2017
Priority date	Apr 18, 2016
Publication date	May 24, 2022
Grant date	May 24, 2022

Abstract

In one aspect, compounds of Formulae (I) and (II), or pharmaceutically acceptable salts thereof, are featured; Formula (I), Formula (II) or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formulae (I) and (II) can be as defined anywhere herein.

First claim

We claim:

1. A compound of Formula II,

or a pharmaceutically acceptable salt thereof, wherein Formula II is selected from the group consisting of

X 2 is N;
X 3 is NH or O;
or when X 3 is NH, X 3 and R 2 taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R 16 ;
or when X 3 is NH, X 3 and R 4 taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R 16 ;
Y is N or CR 8 ;
R 8 is selected from H, CN, Cl, F, CO 2 C 1 -C 6 alkyl, CO 2 C 3 -C 8 cycloalkyl, CONR 11 R 12 , C 1 -C 6 alkyl, C 1 -C 6 haloalkoxy, and C 1 -C 6 haloalkyl;
R 8′ is selected from CN, CO 2 C 1 -C 6 alkyl, CO 2 C 3 -C 8 cycloalkyl, CONR 11 R 12 , and C 1 -C 6 haloalkyl;
R 2 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;
R 2′ is hydrogen, halo, or C 1 -C 6 alkyl optionally substituted with hydroxy;
R 2″ is hydrogen or C 1 -C 6 alkyl;
R 3 is hydrogen, CN, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;
R 3′ is hydrogen, halo, or C 1 -C 6 alkyl optionally substituted with hydroxy;
R 3″ is hydrogen, CN, or C 1 -C 6 alkyl;
R 4 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;
R 4′ is hydrogen, halo, or C 1 -C 6 alkyl optionally substituted with hydroxy;
R 4″ is hydrogen or C 1 -C 6 alkyl;
R 5 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;
R 5′ is hydrogen, halo, or C 1 -C 6 alkyl optionally substituted with hydroxy;
R 5″ is hydrogen, CN, or C 1 -C 6 alkyl;
or R 2 and R 3 taken together with the carbons connecting them form a four-membered to seven-membered ring A,
or R 2′ and R 3′ taken together with the carbons connecting them form a four-membered to seven-membered ring A,
or R 4 and R 5 taken together with the carbons connecting them form a four-membered to seven-membered ring B,
or R 4′ and R 5′ taken together with the carbons connecting them form a four-membered to seven-membered ring B,
or R 2 and R 3 taken together with the carbons connecting them form a four-membered to seven-membered ring A and R 4 and R 5 taken together with the carbons connecting them form a four-membered to seven-membered ring B,
or R 2′ and R 3′ taken together with the carbons connecting them form a four-membered to seven-membered ring A and R 4′ and R 5′ taken together with the carbons connecting them form a four-membered to seven-membered ring B,
wherein ring A is

and ring B is

wherein
ring A is a saturated carbocyclic ring;
n1 is from 2 to 5;
m1 is from 1 to 10;
wherein ring B is a saturated carbocyclic ring;
n2 is from 2 to 5;
m2 is from 1 to 10;
wherein each R 6 in each ring is the same or different and is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 11 R 12 , oxo, and ═NR 13 ;
or two R 6 taken together with the atom or atoms connecting them form a 3-to-8-membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;
R 1 is selected from H, unsubstituted C 1 -C 6 alkyl, C(R 19 ) 2 OH, C(O)C 2 -C 6 alkyl, and C 3 -C 6 cycloalkyl;
wherein each C(O)C 2 -C 6 alkyl and C 3 -C 6 cycloalkyl above is optionally substituted with one or more substituents each independently selected from hydroxy, C 1 -C 6 alkoxy, NR 11 R 12 , ═NR 13 , COOC 1 -C 6 alkyl, and CONR 11 R 12 ;
R 1′ is selected from unsubstituted C 1 -C 6 alkyl, C(R 19 ) 2 OH, C(O)C 2 -C 6 alkyl, and C 3 -C 6 cycloalkyl;
wherein each C(O)C 2 -C 6 alkyl and C 3 -C 6 cycloalkyl above is optionally substituted with one or more substituents each independently selected from hydroxy, C 1 -C 6 alkoxy, NR 11 R 12 , ═NR 13 , COOC 1 -C 6 alkyl, and CONR 11 R 12 ;
R 10 is selected from H, Cl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and C 3 -C 6 heterocycloalkyl;
wherein C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and C 3 -C 6 heterocycloalkyl substituents are optionally substituted with one or more substituents each independently selected from hydroxy, C 1 -C 6 alkoxy, NR 11 R 12 , ═NR 13 , COOC 1 -C 6 alkyl, and CONR 11 R 12 ;
R 10″ is selected from Cl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and C 3 -C 6 heterocycloalkyl;
wherein C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and C 3 -C 6 heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, C 1 -C 6 alkoxy, NR 11 R 12 , ═NR 13 , COOC 1 -C 6 alkyl, and CONR 11 R 12 ;
R 10′″ is selected from Cl, C 1 -C 6 alkyl substituted with hydroxy, C 3 -C 6 cycloalkyl, and C 3 -C 6 heterocycloalkyl;
wherein the C 3 -C 6 cycloalkyl, and C 3 -C 6 heterocycloalkyl above are each optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C 1 -C 6 alkoxy, NR 11 R 12 , ═NR 13 , COOC 1 -C 6 alkyl, and CONR 11 R 12 ;
or R 1 and R 10 taken together with the atoms connecting them form a 3-to-8-membered carbocyclic or heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the ring is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C 1 -C 6 alkoxy, NR 11 R 12 , ═NR 13 , COOC 1 -C 6 alkyl, and CONR 11 R 12 ;
R 13 is C 1 -C 6 alkyl;
each of R 11 and R 12 at each occurrence is independently selected from hydrogen, C 1 -C 6 alkyl, CO 2 R 15 and CONR 17 R 18 ;
R 15 is C 1 -C 6 alkyl;
each of R 17 and R 18 at each occurrence is independently selected from hydrogen and C 1 -C 6 alkyl;
each R 16 is the same or different and is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 11 R 12 , oxo, and ═NR 13 ;
each R 19 is the same and is C 1 -C 6 alkyl;
R 20 is selected from H, halo, or C 1 -C 6 alkyl optionally substituted with hydroxy;
R 21 is selected from H, halo, or C 1 -C 6 alkyl substituted with hydroxy.

2. A compound of Formula II,

or a pharmaceutically acceptable salt thereof, wherein Formula II is selected from the group consisting of

Y is N or CR 8 ;
R 8 is selected from H, CN, Cl, and F;
R 8′ is selected from CN and CONR 11 R 12 ;
R 2 is hydrogen or C 1 -C 6 alkyl;
R 2′ is C 1 -C 6 alkyl;
R 3 is hydrogen, CN, C 1 -C 6 alkoxy, or halo;
R 3′ is hydrogen or halo;
R 4 is hydrogen or C 1 -C 6 alkyl;
R 4′ is C 1 -C

Assignees

• Novartis Ag

Inventors

• Glick Gary
• Ghosh Shomir
• Roush William R

Classifications

• A61P31/12

  Antivirals · CPC title

• A61P31/18

  for HIV · CPC title

• C07D307/64

  Sulfur atoms · CPC title

• C07D277/36

  Sulfur atoms · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title