Compounds and compositions for treating conditions associated with NLRP activity

1. A compound of Formula A

or a pharmaceutically acceptable salt thereof, wherein:

the substituents on the compound of Formula A are the following:

Ar is a heteroaryl group

X 1 is O, S, N, CR 41 or NR 41 ;

X 10 is O, S, N, CR 10 or NR 10 ;

X 11 is O, S, N, CR 1 or NR 1 ;

X 2 is O, S, N, CR 42 or NR 42 ;

X 4 is CR 4 ;

each R 20 is the same or different and is independently selected from hydrogen and C 1 -C 6 alkyl;

Y is CR 2 ;

Z is N or CR 8 ;

R 8 is selected from H, CN, halo, 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 alkoxy, C 1 -C 6 haloalkoxy, and C 1 -C 6 haloalkyl;

R 2 is C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl or C 1 -C 6 alkyl substituted with hydroxy;

R 3 is hydrogen, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, CN, C 1 -C 6 haloalkoxy, C 3 -C 7 cycloalkyl or C 1 -C 6 alkyl optionally substituted with hydroxy;

R 4 is C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl or C 1 -C 6 alkyl substituted with hydroxy;

R 5 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, CN, C 1 -C 6 haloalkoxy, C 3 -C 7 cycloalkyl or C 1 -C 6 alkyl optionally substituted with hydroxy;

provided that at least one of R 2 , R 3 , R 4 and R 5 is not hydrogen;

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 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 carbocyclic ring or a heterocyclic ring wherein 1 or 2 members are heteroatoms independently selected from O, N, and S;

n1 is from 2 to 5;

m1 is from 1 to 10;

wherein ring B is a carbocyclic ring or a heterocyclic ring wherein 1 or 2 members are heteroatoms independently selected from O, N, and S;

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, F, 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 wherein 1 or 2 members are heteroatoms independently selected from O, N, and S;

each of R 1 , R 10 , R 41 and R 42 when bonded to carbon is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, CN, halo, CO 2 C 1 -C 6 alkyl, CO 2 C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, CONR 11 R 12 , C 3 -C 7 cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 11 R 12 , =NR 13 , COOC 1 -C 6 alkyl, C 6 -C 10 aryl, and CONR 11 R 12 ;

and each of R 1 , R 41 , R 42 when bonded to nitrogen is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, CO 2 C 1 -C 6 alkyl, CO 2 C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, CONR 11 R 12 , C 3 -C 7 cycloalkyl, S(O 2 )C 1 -C 6 alkyl and 3- to 7-membered heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 11 R 12 , =NR 13 , COOC 1 -C 6 alkyl, C 6 -C 10 aryl, 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 wherein 1 or 2 members are 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;

or

the substituents on the compound of Formula A are the following:

Ar is a heteroaryl group

X 1 is O, S, N, CR 41 or NR 41 ;

X 10 is O, S, N, CR 10 or NR 10 ;

X 11 is O, S, N, CR 10 or NR 10 ;

X 2 is O, S, N, CR 42 or NR 42 ;

X 4 is CR 4 ;

each R 20 is the same or different and is independently selected from hydrogen and C 1 -C 6 alkyl;

Y is CR 2 ;

Z 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, and C 1 -C 6 haloalkyl;

R 2 is C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl or C 1 -C 6 alkyl optionally substituted with hydroxy;

R 3 is hydrogen, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl or C 1 -C 6 alkyl optionally substituted with hydroxy;

R 4 is C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl or C 1 -C 6 alkyl substituted with hydroxy;

R 5 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl or C 1 -C 6 alkyl optionally substituted with hydroxy;

provided that at least one of R 2 , R 3 , R 4 and R 5 is not hydrogen, and that R 2 and R 4 are not both hydroxymethyl;

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 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 carbocyclic ring or a heterocyclic ring wherein 1 or 2 members are heteroatoms independently selected from O, N, and S;

n1 is from 2 to 5;

m1 is from 1 to 10;

wherein ring B is a carbocyclic ring or a heterocyclic ring wherein 1 or 2 members are heteroatoms independently selected from O, N, and S;

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 , 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 wherein 1 or 2 members are heteroatoms independently selected from O, N, and S;

each of R 1 , R 10 , R 41 and R 42 when bonded to carbon is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, CN, halo, CO 2 C 1 -C 6 alkyl, CO 2 C 3 -C 8 cycloalkyl, C 6 -C 10 aryl,

CONR 11 R 12 , C 3 -C 7 cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C 1 -C 6 alkyl,

C 3 -C 7 cycloalkyl and 3- to 7-membered heterocycloalkyl 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, C 6 -C 10 aryl, and CONR 11 R 12 ;

and each of R 1 , R 10 , R 41 and R 42 when bonded to nitrogen is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, CO 2 C 1 -C 6 alkyl, CO 2 C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, CONR 11 R 12 , C 3 -C 7 cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl and 3- to 7-membered heterocycloalkyl 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, C 6 -C 10 aryl, 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 wherein 1 or 2 members are 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.

2. The compound of claim 1 , wherein the moiety

is selected from the group consisting of:

3. The compound of claim 1 , wherein the moiety

is selected from the group consisting of:

4. A compound selected from the group consisting of:

or pharmaceutically acceptable salts thereof.

5. A pharmaceutical composition comprising a compound or salt as claimed in claim 1 , and one or more pharmaceutically acceptable excipients.

6. A pharmaceutical composition comprising a compound or salt as claimed in claim 4 , and one or more pharmaceutically acceptable excipients.