IP Library › Patent Application 17293781

Patent Application

App. No. 17/293,781

COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH NLRP ACTIVITY

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App. No.: 17/293,781

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Abstract

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

Claims (1169)

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- to 10-membered monocyclic or bicyclic heteroaryl or a C 6 -C 10 monocyclic or bicyclic aryl;

B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C 6 -C 10 monocyclic or bicyclic aryl; wherein at least one R 6 is ortho to the bond connecting the B ring to the NH(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 , 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, NR 8 R 9 , C(O)R 13 , CONR 8 R 9 , SF 5 , SC 1 -C 6 alkyl, S(O 2 )C 1 -C 6 alkyl, S(O)C 1 -C 6 alkyl, S(O 2 )NR 11 R 12 , C 3 -C 7 cycloalkyl, and 3- to 7-membered heterocycloalkyl,

wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, 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, R 15 , C 1 -C 6 haloalkoxy, NR 8 R 9 , ═NR 10 , COOC 1 -C 6 alkyl, CONR 8 R 9 , 3- to 7-membered heterocycloalkyl, C 3 -C 7 cycloalkyl, 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);

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, —O(C 0 -C 3 alkylene)C 6 -C 10 aryl, halo, NR 8 R 9 , or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C 1 -C 6 alkyl, and OC 1 -C 6 alkyl;

or one pair of R 1 and R 2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C 4 -C 12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, OC 3 -C 10 cycloalkyl, NR 8 R 9 , ═NR 10 , CN, COOC 1 -C 6 alkyl, 0S(O 2 )C 6 -C 10 aryl, S(O 2 )C 6 -C 10 aryl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR 8 R 9 ,

wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, S(O 2 )C 6 -C 10 aryl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 1 -C 6 alkoxy, oxo, NR 8 R 9 , ═NR 10 , 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 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 , 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), 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, 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 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 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, 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 ;

R 10 is C 1 -C 6 alkyl;

or R 8 and R 9 taken together with the nitrogen they are attached to form a 3- to 10-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to, wherein the ring is optionally substituted with one or more substituents independently selected from halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, oxo, N(C 1 -C 6 alkyl) 2 , NH 2 , NH(C 1 -C 6 alkyl), and hydroxy;

R 13 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or —(Z 1 —Z 2 ) a1 —Z 3 ;

each of R 11 and R 12 at each occurrence is independently selected from hydrogen, C 1 -C 6 alkyl, and —(Z 1 —Z 2 ) a1 —Z 3 ;

a1 is 0-10 (e.g., 0-4);

each Z 1 is independently C 1 -C 6 alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy;

each Z 2 is independently a bond, NH, N(C 1 -C 6 alkyl), —O—, —S—, or 5-10 membered heteroarylene;

Z 3 is independently C 6 -C 10 aryl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C 1 -C 6 alkyl, C 1-6 haloalkyl, C 1 -C 6 alkoxy, oxo, N(C 1 -C 6 alkyl) 2 , NH 2 , NH(C 1 -C 6 alkyl), and hydroxy;

R 3 is selected from hydrogen and C 1 -C 6 alkyl;

R 14 is hydrogen, C 1 -C 6 alkyl, 5- to 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 or 2 R 6 ,

R 15 is —(Z 4 —Z 5 ) a2 —Z 6 ;

a2 is an integer selected from 1-10 (e.g., 1-5);

each Z 4 is independently selected from —O—, —S—, —NH—, and —N(C 1 -C 3 alkyl)-;

provided that the Z 4 group directly attached to R 1 or R 2 is —O— or —S—;

each Z 5 is independently C 1 -C 6 alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and

Z 6 is OH, OC 1 -C 6 alkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , NHC(O)(C 1 -C 6 alkyl), NHC(O)(C 1 -C 6 alkoxy), or an optionally substituted group selected from the group consisting of:

C 6 -C 10 aryl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C 1 -C 6 alkyl, C 1-6 haloalkyl, C 1 -C 6 alkoxy, oxo, N(C 1 -C 6 alkyl) 2 , NH 2 , NH(C 1 -C 6 alkyl), and hydroxy;

or a pharmaceutically acceptable salt thereof;

provided that the compound is other than:

2 . 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- to 10-membered monocyclic or bicyclic heteroaryl or a C 6 -C 10 monocyclic or bicyclic aryl;

B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C 6 -C 10 monocyclic or bicyclic aryl;

wherein at least one R 6 is ortho to the bond connecting the B ring to the NH(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, NHCOOCC 1 -C 6 alkyl, NH—(C═NR 13 )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)C 1 -C 6 alkyl, S(O 2 )NR 11 R 12 , C 3 -C 7 cycloalkyl, and 3- to 7-membered heterocycloalkyl,

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 one pair of R 1 and R 2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C 4 -C 12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, OC 3 -C 10 cycloalkyl, NR 8 R 9 , ═NR 10 , CN, COOC 1 -C 6 alkyl, OS(O 2 )C 6 -C 10 aryl, S(O 2 )C 6 -C 10 aryl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR 8 R 9 ,

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, 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;

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 3 -C 7 cycloalkyl, (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 is optionally substituted with one or more hydroxy, halo, C 1 -C 6 alkoxy, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 7 cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR 11 R 12 ; 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 1 -C 6 haloalkyl, 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;

R 3 is selected from hydrogen and C 1 -C 6 alkyl;

R 15 is —(Z 4 —Z 5 ) a2 —Z 6 ;

a2 is an integer selected from 1-10 (e.g., 1-5);

each Z 4 is independently selected from —O—, —S—, —NH—, and —N(C 1 -C 3 alkyl)-;

provided that the Z 4 group directly attached to R 1 or R 2 is —O— or —S—;

each Z 5 is independently C 1 -C 6 alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and

Z 6 is OH, OC 1 -C 6 alkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , NHC(O)(C 1 -C 6 alkyl), NHC(O)(C 1 -C 6 alkoxy), or an optionally substituted group selected from the group consisting of:

or a pharmaceutically acceptable salt thereof;

provided that the compound is other than:

53 . A compound of Formula AA:

wherein the

moiety is as defined for (AA-1), (AA-2), (AA-3), or (AA-4) below:

(AA-1):

A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C 7 -C 10 bicyclic aryl;

m=0, 1, or 2; and

n=0, 1, or 2;

(AA-2):

A is phenyl;

m=0, 1, or 2; and

n=0, 1, or 2, provided that m+n=0, 2, 3, or 4;

(AA-3):

(AA-4):

o=1 or 2;

p=0, 1, 2, or 3;

when (AA-1), (AA-2), or (AA-3) applies,

or one pair of R 1 and R 2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C 4 -C 12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, OC 3 -C 10 cycloalkyl, NR 8 R 9 , ═NR 10 , CN, COOC 1 -C 6 alkyl, OS(O 2 )C 6 -C 10 aryl, S(O 2 )C 6 -C 10 aryl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR 8 R 9 ,

when (AA-4) applies, R 1 ′ is selected from the group consisting of:

methyl; C 2 -C 6 alkyl; C 1 -C 6 haloalkyl; C 1 -C 6 alkoxy; C 1 -C 6 haloalkoxy; halo; CN; NO 2 ; 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; NR 8 R 9 ; C(O)R 13 ; CONR 8 R 9 ; SF 5 ; SC 1 -C 6 alkyl; S(O 2 )C 1 -C 6 alkyl, S(O)C 1 -C 6 alkyl; S(O 2 )NR 11 R 12 ; C 3 -C 7 cycloalkyl; and 3- to 7-membered heterocycloalkyl,

wherein when R 1 ′ is methyl, R 1 ′ is substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, R 15 , C 1 -C 6 haloalkoxy, NR 8 R 9 , ═NR 10 , COOC 1 -C 6 alkyl, CONR 8 R 9 , 3- to 7-membered heterocycloalkyl, C 3 -C 7 cycloalkyl, 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); and

when R 1 ′ is selected from the group consisting of C 2 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 7 cycloalkyl and 3- to 7-membered heterocycloalkyl, R 1 ′ 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, R 15 , C 1 -C 6 haloalkoxy, NR 8 R 9 , ═NR 10 , COOC 1 -C 6 alkyl, CONR 8 R 9 , 3- to 7-membered heterocycloalkyl, C 3 -C 7 cycloalkyl, 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);

wherein each C 1 -C 6 alkyl substituent and each C 1 -C 6 alkoxy substituent of the R 1′ C 3 -C 7 cycloalkyl or of the R 1′ 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, halo, —O(C 0 -C 3 alkylene)C 6 -C 10 aryl, NR 8 R 9 , or oxo;

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 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl, (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 is optionally substituted with one or more hydroxy, halo, C 1 -C 6 alkoxy, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 7 cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR 11 R 12 ;

R 13 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or —(Z 1 —Z 2 ) a1 —Z 3 ;

each of R 11 and R 12 at each occurrence is independently selected from hydrogen, C 1 -C 6 alkyl, and —(Z 1 —Z 2 ) a1 —Z 3 ;

a1 is 0-10 (e.g., 0-4);

each Z 1 is independently C 1 -C 6 alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy;

each Z 2 is independently a bond, NH, N(C 1 -C 6 alkyl), —O—, —S—, or 5-10 membered heteroarylene;

R 3 is selected from hydrogen and C 1 -C 6 alkyl (e.g., R 3 is selected from hydrogen and methyl);

R 15 is —(Z 4 —Z 5 ) a2 —Z 6 ;

a2 is an integer selected from 1-10 (e.g., 1-5);

each Z 4 is independently selected from —O—, —S—, —NH—, and —N(C 1 -C 3 alkyl)-;

provided that the Z 4 group directly attached to R 1 or R 2 is —O— or —S—;

each Z 5 is independently C 1 -C 6 alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and

Z 6 is OH, OC 1 -C 6 alkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , NHC(O)(C 1 -C 6 alkyl), NHC(O)(C 1 -C 6 alkoxy), or an optionally substituted group selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

4 . A compound of Formula AA

wherein the

moiety is as defined for (AA-1), (AA-2), (AA-3), or (AA-4) below:

(AA-1):

A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C 7 -C 10 bicyclic aryl;

m=0, 1, or 2; and

n=0, 1, or 2;

(AA-2):

A is phenyl;

m=0, 1, or 2; and

n=0, 1, or 2, provided that m+n=0, 2, 3, or 4;

(AA-3):

(AA-4):

o=1 or 2;

p=0, 1, 2, or 3;

when (AA-1), (AA-2), or (AA-3) apply,

or one pair of R 1 and R 2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C 4 -C 12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, OC 3 -C 10 cycloalkyl, NR 8 R 9 , ═NR 10 , CN, COOC 1 -C 6 alkyl, OS(O 2 )C 6 -C 10 aryl, S(O 2 )C 6 -C 10 aryl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR 8 R 9 ,

when (AA-4) applies, R 1 ′ is selected from the group consisting of:

methyl; C 2 -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 13 )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)C 1 -C 6 alkyl; S(O 2 )NR 11 R 12 ; C 3 -C 7 cycloalkyl; and 3- to 7-membered heterocycloalkyl,

wherein when R 1 ′ is selected from the group consisting of C 2 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 7 cycloalkyl, and 3- to 7-membered heterocycloalkyl, R 1 ′ 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, R 15 , C 1 -C 6 haloalkoxy, NR 8 R 9 , ═NR 10 , COOC 1 -C 6 alkyl, CONR 8 R 9 , 3- to 7-membered heterocycloalkyl, C 3 -C 7 cycloalkyl, 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), 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 ′ C 3 -C 7 cycloalkyl or of the R 1 ′ 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, —O(C 0 -C 3 alkylene)C 6 -C 10 aryl, halo, NR 8 R 9 , or oxo;

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, 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;

R 10 is C 1 -C 6 alkyl;

R 13 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 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;

R 3 is selected from hydrogen and C 1 -C 6 alkyl (e.g., R 3 is selected from hydrogen and methyl);

R 15 is —(Z 4 —Z 5 ) 2a —Z 6 ;

a2 is an integer selected from 1-10 (e.g., 1-5);

each Z 4 is independently selected from —O—, —S—, —NH—, and —N(C 1 -C 3 alkyl)-;

provided that the Z 4 group directly attached to R 1 or R 2 is —O— or —S—;

each Z 5 is independently C 1 -C 6 alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and

Z 6 is OH, OC 1 -C 6 alkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , NHC(O)(C 1 -C 6 alkyl), NHC(O)(C 1 -C 6 alkoxy), or an optionally substituted group selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

5 . A compound of Formula AA

wherein

m=1 or 2;

n=1 or 2;

o=1 or 2;

p=0, 1, 2, or 3,

wherein

A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C 6 -C 10 monocyclic or bicyclic aryl;

one pair of R 1 and R 2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C 4 -C 12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, OC 3 -C 10 cycloalkyl, NR 8 R 9 , ═NR 10 , CN, COOC 1 -C 6 alkyl, OS(O 2 )C 6 -C 10 aryl, S(O 2 )C 6 -C 10 aryl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR 8 R 9 ,

each of R 1 and R 2 that are not taken together with the atoms connecting them to form at least one ring is 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 , 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, NR 8 R 9 , C(O)R 13 , CONR 8 R 9 , SF 5 , SC 1 -C 6 alkyl, S(O 2 )C 1 -C 6 alkyl, S(O)C 1 -C 6 alkyl, S(O 2 )NR 11 R 12 , C 3 -C 7 cycloalkyl, and 3- to 7-membered heterocycloalkyl,

R 10 is C 1 -C 6 alkyl;

R 13 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or —(Z 1 —Z 2 ) a1 —Z 3 ;

each of R 11 and R 12 at each occurrence is independently selected from hydrogen, C 1 -C 6 alkyl, and —(Z 1 —Z 2 ) a1 —Z 3 ;

a1 is 0-10 (e.g., 0-4);

each Z 1 is independently C 1 -C 6 alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy;

each Z 2 is independently a bond, NH, N(C 1 -C 6 alkyl), —O—, —S—, or 5-10 membered heteroarylene;

R 3 is selected from hydrogen and C 1 -C 6 alkyl (e.g., R 3 is selected from hydrogen and methyl);

R 15 is —(Z 4 —Z 5 ) a2 —Z 6 ;

a2 is an integer selected from 1-10 (e.g., 1-5);

each Z 4 is independently selected from —O—, —S—, —NH—, and —N(C 1 -C 3 alkyl)-;

provided that the Z 4 group directly attached to R 1 or R 2 is —O— or —S—;

each Z 5 is independently C 1 -C 6 alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and

Z 6 is OH, OC 1 -C 6 alkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , NHC(O)(C 1 -C 6 alkyl), NHC(O)(C 1 -C 6 alkoxy), or an optionally substituted group selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

6 . A compound of Formula AA

wherein

m=1 or 2;

n=1 or 2;

o=1 or 2;

p=0, 1, 2, or 3,

wherein

A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C 6 -C 10 monocyclic or bicyclic aryl;

B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C 6 -C 10 monocyclic or bicyclic aryl;

wherein at least one R 6 is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA;

one pair of R 1 and R 2 are on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C 4 -C 12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, OC 3 -C 10 cycloalkyl, NR 8 R 9 ,═NR 10 ,CN, COOC 1 -C 6 alkyl, OS(O 2 )C 6 -C 10 aryl, S(O 2 )C 6 -C 10 aryl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR 8 R 9 ,

each of R 1 and R 2 that are not taken together with the atoms connecting them to form at least one ring is 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, NHCOOCC 1 -C 6 alkyl, NH—(C═NR 13 )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)C 1 -C 6 alkyl, S(O 2 )NR 11 R 12 , C 3 -C 7 cycloalkyl, and 3- to 7-membered heterocycloalkyl,

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, 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;

R 10 is C 1 -C 6 alkyl;

R 13 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 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;

R 3 is selected from hydrogen and C 1 -C 6 alkyl (e.g., R 3 is selected from hydrogen and methyl);

R 15 is —(Z 4 —Z 5 ) a2 —Z 6 ;

a2 is an integer selected from 1-10 (e.g., 1-5);

each Z 4 is independently selected from —O—, —S—, —NH—, and —N(C 1 -C 3 alkyl)-;

provided that the Z 4 group directly attached to R 1 or R 2 is —O— or —S—;

each Z 5 is independently C 1 -C 6 alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and

Z 6 is OH, OC 1 -C 6 alkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , NHC(O)(C 1 -C 6 alkyl), NHC(O)(C 1 -C 6 alkoxy), or an optionally substituted group selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

7 . The compound of any one of claims 5 - 6 , provided that the compound is not selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

8 . The compound of any one of claims 1 - 7 , wherein:

(1) one or more of R 1 or R 2 , when present, is selected from N 8′ R 9′ , C(O)NR 8′ R 9′ , S(O) 2 NR 11′ R 12′ , C(O)R 13′ , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl,

wherein each of the C 3 -C 7 cycloalkyl, and 3- to 7-membered heterocycloalkyl is substituted with NR 8′ R 9′ , C(O)NR 8′ R 9′ , R 15′ , C 1 -C 6 haloalkoxy, or C 3 -C 7 cycloalkyl;

wherein each of the C 1 -C 6 alkyl and C 1 -C 6 haloalkyl is substituted with NR 8′ R 9′ , C(O)NR 8′ R 9′ , R 15 , C 1 -C 6 haloalkoxy, or C 3 -C 7 cycloalkyl;

and

each of the C 1 -C 6 alkoxy, C 6 -C 10 aryl and 5- to 10-membered heteroaryl is substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, R 15 , C 1 -C 6 haloalkoxy, NR 8 R 9 , ═NR 10 , COOC 1 -C 6 alkyl, CONR 8 R 9 , 3- to 7-membered heterocycloalkyl, C 3 -C 7 cycloalkyl, 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);

(2) one pair of R 1 and R 2 on adjacent atoms, taken together with the atoms connecting them, independently form one ring that is selected from:

(a) C 4 -C 8 carbocyclic ring or 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 independently substituted with one or more substituents each independently selected from from C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, OC 3 -C 10 cycloalkyl, CN, OS(O 2 )C 6 -C 10 aryl, S(O 2 )C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 10 cycloalkyl, and 3- to 10-membered heterocycloalkyl, wherein the S(O 2 )C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 1 -C 6 alkoxy, oxo, NR 8 R 9 , ═NR 10 , COOC 1 -C 6 alkyl, C 6 -C 10 aryl, and CONR 8 R 9 ;

(b) C 4 -C 8 carbocyclic ring or 5- to-8-membered heterocyclic ring containing 3 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 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, OC 3 -C 10 cycloalkyl, NR 8 R 9 , ═NR 10 , CN, COOC 1 -C 6 alkyl, OS(O 2 )C 6 -C 10 aryl, S(O 2 )C 6 -C 10 aryl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR 8 R 9 , wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, S(O 2 )C 6 -C 10 aryl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 1 -C 6 alkoxy, oxo, NR 8 R 9 , ═NR 10 , COOC 1 -C 6 alkyl, C 6 -C 10 aryl, and CONR 8 R 9 ; and

(c) monocyclic or bicyclic C 9 -C 12 carbocyclic ring or monocyclic or bicyclic 9- to 12-membered heterocyclic ring containing 1-3 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 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, OC 3 -C 10 cycloalkyl, NR 8 R 9 , ═NR 10 , CN, COOC 1 -C 6 alkyl, OS(O 2 )C 6 -C 10 aryl, S(O 2 )C 6 -C 10 aryl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR 8 R 9 , wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, S(O 2 )C 6 -C 10 aryl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 1 -C 6 alkoxy, oxo, NR 8 R 9 , ═NR 10 , COOC 1 -C 6 alkyl, C 6 -C 10 aryl, and CONR 8 R 9 ;

each of R 8′ and R 9′ at each occurrence is independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl, (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 is optionally substituted with one or more hydroxy, halo, C 1 -C 6 alkoxy, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 7 cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR 11 R 12 ;

or R 8′ and R 9′ taken together with the nitrogen they are attached to form a 3- to 10-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to, wherein the ring is optionally substituted with one or more substituents independently selected from halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, oxo, N(C 1 -C 6 alkyl) 2 , NH 2 , NH(C 1 -C 6 alkyl), and hydroxy;

provided that:

(1) one or more occurrences of R 8′ or R 9′ is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl, (C═NR 13′ )NR 11′ R 12′ , S(O 2 )NR 11′ R 12′ ; C(O)R 13′ , CO 2 R 13′ and CONR 11′ R 12′ ; wherein the C 1 -C 6 alkyl is substituted with NR 11 R 12 ; or

(2) one or more pairs of R 8′ and R 9′ attached to the same nitrogen taken together with the nitrogen they are attached to form:

(a) a 8- to 10-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to, wherein the ring is optionally substituted with one or more substituents independently selected from halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, oxo, N(C 1 -C 6 alkyl) 2 , NH 2 , NH(C 1 -C 6 alkyl), and hydroxy; or

(b) a 3- to 7-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to, wherein the ring is substituted with one or more substituents independently selected from halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, oxo, N(C 1 -C 6 alkyl) 2 , NH 2 , NH(C 1 -C 6 alkyl), and hydroxy;

each of R 11′ and R 12′ at each occurrence is independently selected from hydrogen, C 1 -C 6 alkyl, and —(Z 1 —Z 2 ) a1 —Z 3 , provided that one or more occurrences of R 11′ and R 12′ is —(Z 1 —Z 2 ) a1 —Z 3 ;

R 13′ is —(Z 1 —Z 2 ) a1 —Z 3′ , wherein

when a1 is 0, Z 3′ is independently C 6-10 aryl, C 3 -C 10 cycloalkyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, each of which is substituted with one or more substituents independently selected from halo, C 1 -C 6 alkyl, C 1-6 haloalkyl, C 1 -C 6 alkoxy, oxo, N(C 1 -C 6 alkyl) 2 , NH 2 , NH(C 1 -C 6 alkyl), and hydroxy;

when a1 is 1-10 (e.g., 1-4), Z 3′ is an independently selected Z 3 ;

R 15 ′ is —(Z 4 —Z 5 ) a2′ —Z 6 ;

a2′ is an integer selected from 2-10 (e.g., 2-5);

each Z 4 is independently selected from —O—, —S—, —NH—, and —N(C 1 -C 3 alkyl)-;

provided that the Z 4 group directly attached to R 1 or R 2 is —O— or —S—;

each Z 5 is independently C 1 -C 6 alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and

Z 6 is OH, OC 1 -C 6 alkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , NHC(O)(C 1 -C 6 alkyl), NHC(O)(C 1 -C 6 alkoxy), or an optionally substituted group selected from the group consisting of:

9 . The compound of any one of claims 1 - 8 , wherein when a pair of R 1 and R 2 on adjacent atoms, taken together with the atoms connecting them, independently form one C 4 -C 8 carbocyclic ring or one 5- to-8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, then the carbocyclic ring or heterocyclic ring is independently substituted with one or more substituents each independently selected from from C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, OC 3 -C 10 cycloalkyl, CN, OS(O 2 )C 6 -C 10 aryl, S(O 2 )C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 10 cycloalkyl, and 3- to 10-membered heterocycloalkyl, wherein the S(O 2 )C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 1 -C 6 alkoxy, oxo, NR 8 R 9 , ═NR 10 , COOC 1 -C 6 alkyl, C 6 -C 10 aryl, and CONR 8 R 9 .

10 . The compound of any one of claims 3 - 4 , wherein the

moiety is as defined for (AA-1).

11 . The compound of any one of claims 1 - 10 , wherein A is a 5- to 6-membered monocyclic heteroaryl optionally substituted with 1 or 2 R 1 and optionally substituted with 1 or 2 R 2 .

12 . The compound of any one of claims 1 - 11 , wherein A is furanyl optionally substituted with 1 or 2 R 1 and optionally substituted with 1 or 2 R 2 .

13 . The compound of any one of claims 1 - 11 , wherein A is thiophenyl optionally substituted with 1 or 2 R 1 and optionally substituted with 1 or 2 R 2 .

14 . The compound of any one of claims 1 - 11 , wherein A is oxazolyl optionally substituted with 1 or 2 R 1 and optionally substituted with 1 or 2 R 2 .

15 . The compound of any one of claims 1 - 11 , wherein A is thiazolyl optionally substituted with 1 or 2 R 1 and optionally substituted with 1 or 2 R 2 .

16 . The compound of any one of claims 1 - 11 , wherein A is pyrazolyl optionally substituted with 1 or 2 R 1 and optionally substituted with 1 or 2 R 2 .

17 . The compound of any one of claims 1 - 11 , wherein A is imidazolyl optionally substituted with 1 or 2 R 1 and optionally substituted with 1 or 2 R 2 .

18 . The compound of any one of claims 3 - 4 , wherein the

moiety is as defined for (AA-2), (AA-3), or (AA-4) (e.g., (AA-2) or (AA-3)).

19 . The compound of any one of claims 1 - 9 and 18 , wherein A is phenyl optionally substituted with 1 or 2 R 1 and optionally substituted with 1 or 2 R 2 .

20 . The compound of any one of claims 1 - 4 , 8 , and 10 - 19 , wherein m=1 and n=0.

21 . The compound of any one of claims 1 - 4 , 8 , 10 - 11 , 13 , and 20 , wherein A is

22 . The compound of any one of claims 1 - 4 , 8 , 10 - 11 , 13 , and 20 , wherein A is

23 . The compound of any one of claims 1 - 4 , 8 , 10 - 12 , and 20 , wherein A is

24 . The compound of any one of claims 1 - 4 , 8 , 10 - 12 , and 20 , wherein A is

25 . The compound of any one of claims 1 - 4 , 8 , 10 - 11 , 15 , and 20 , wherein A is

26 . The compound of any one of claims 1 - 4 , 8 , 10 - 11 , 15 , and 20 , wherein A is

27 . The compound of any one of claims 1 - 4 , 8 , 10 - 11 , 15 , and 20 , wherein A is

28 . The compound of any one of claims 1 - 4 , 8 , and 18 - 20 , wherein A is

29 . The compound of any one of claims 1 - 4 , 8 , and 18 - 20 , wherein A is

30 . The compound of any one of claims 1 - 4 , 8 , and 18 - 20 , wherein A is

31 . The compound of any one of claims 1 - 4 and 10 , wherein A is

32 . The compound of any one of claims 1 - 4 , 10 , 16 , and 20 , wherein A is

33 . The compound of any one of claims 1 - 4 , 8 , 10 - 11 , and 20 , wherein A is

34 . The compound of any one of claims 1 - 4 , 8 , 10 - 11 , and 20 , wherein A is

35 . The compound of any one of claims 1 - 4 , 8 , 10 - 11 , and 20 , wherein A is

36 . The compound of any one of claims 1 - 19 , wherein m=1 and n=1.

37 . The compound of any one of claims 1 - 11 , 13 , and 36 , wherein A is

38 . The compound of any one of claims 1 - 4 , 8 , 10 - 11 , 15 , and 36 , wherein A is

39 . The compound of any one of claims 1 - 4 , 8 , 10 - 11 , 15 , and 36 , wherein A is

40 . The compound of any one of claims 1 - 12 and 36 , wherein A is

41 . The compound of any one of claims 1 - 11 , 13 , and 36 , wherein A is

42 . The compound of any one of claims 1 - 4 , 10 - 11 , 13 , and 36 , wherein A is

43 . The compound of any one of claims 1 - 11 , 15 , and 36 , wherein A is

44 . The compound of any one of claims 1 - 11 , 16 , and 36 , wherein the optionally substituted ring A is

45 . The compound of any one of claims 1 - 11 , 16 , and 36 , wherein the optionally substituted ring A is

46 . The compound of any one of claims 1 - 11 , 16 , and 36 , wherein the optionally substituted ring A is

47 . The compound of any one of claims 1 - 11 , 17 , and 36 , wherein the optionally substituted ring A is

48 . The compound of any one of claims 1 - 4 , 8 , 18 - 19 , and 36 , wherein A is

49 . The compound of any one of claims 1 - 4 , 8 , 18 - 19 , and 36 , wherein A is

50 . The compound of any one of claims 1 - 9 , 18 - 19 , and 36 , wherein A is

51 . The compound of any one of claims 1 - 4 , 8 , 18 - 19 , and 36 , wherein A is

52 . The compound of any one of claims 1 - 4 , 8 , 18 - 19 , and 36 , wherein A is

53 . The compound of any one of claims 1 - 19 , wherein m=2 and n=1.

54 . The compound of any one of claims 1 - 4 , 8 , 18 - 19 and 53 , wherein A is

55 . The compound of any one of claims 1 - 9 , 18 - 19 , and 53 , wherein A is

56 . The compound of any one of claims 1 - 9 , 18 - 19 , and 53 , wherein A is

57 . The compound of any one of claims 1 - 9 , 18 - 19 , and 53 , wherein A is

58 . The compound of any one of claims 1 - 11 , 16 , and 53 , wherein A is

59 . The compound of any one of claims 1 - 4 and 10 - 58 , wherein each of R 1 and R 2 , when present, is independently selected from the group consisting of C 1 -C 6 alkyl optionally substituted with one or more hydroxy, halo, oxo, C 1 -C 6 alkoxy, 3- to 7-membered heterocycloalkyl optionally substituted with halo, C 3 -C 7 cycloalkyl, R 15 , C 1 -C 6 haloalkoxy, C 6 -C 10 aryl optionally substituted with OC 1 -C 6 alkyl, or NR 8 R 9 ; C 3 -C 7 cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, or NR 8 R 9 wherein the C 1 -C 6 alkoxy or C 1 -C 6 alkyl is further optionally substituted with one to three hydroxy, halo, NR 8 R 9 , or oxo; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C 1 -C 6 alkyl, or NR 8 R 9 wherein the C 1 -C 6 alkoxy or C 1 -C 6 alkyl is further optionally substituted with one to three hydroxy, halo, NR 8 R 9 , or oxo; C 1 -C 6 haloalkyl; C 1 -C 6 alkoxy; C 1 -C 6 haloalkoxy; halo; CN; CO—C 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 ; CONR 8 R 9 ; SF 5 ; S(O 2 )NR 11 R 12 ; S(O)C 1 -C 6 alkyl; and S(O 2 )C 1 -C 6 alkyl.

60 . The compound of any one of claims 1 - 4 and 10 - 58 , wherein R 1 is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl; isobutyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; 1,2,3-trihydroxy-2-propyl; 1-amino-2-hydroxy-prop-2-yl; 1-acetamido-2-hydroxy-prop-2-yl; 1-(tert-butoxycarbonyl)amino-2-hydroxy-prop-2-yl; 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl; 1-(2-benzyloxyethoxy)-2-hydroxy-2-propyl; 1-(2-methoxyethoxy)-2-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; pyrrolidinyl; 1,3-dioxolan-2-yl; COCH 3 ; COCH 2 CH 3 ; difluoromethoxy; 2-methoxy-2-propyl; (methylamino)methyl; (2,2-difluoroeth-1-yl)(methyl)aminomethyl; (2,2,2-trifluoroeth-1-yl)(methyl)aminomethyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; 2-((methyl)aminomethyl)-prop-2-yl; 2-((methyl)amino)-prop-2-yl; (methyl)(cyclopropylmethyl)aminomethyl; (methyl)(2-(dimethylamino)eth-1-yl)aminomethyl; (cyclobutyl)(methyl)aminomethyl; 1-(cyclobutyl)amino-eth-1-yl; isopropylaminomethyl; (cyclobutyl)aminomethyl; cycloheptylaminomethyl; tetrahydropyranylaminomethyl; sec-butylaminomethyl; ethylaminomethyl; allylaminomethyl; (2,2-difluoroeth-1-yl)aminomethyl; (2-methoxy-eth-1-yl)aminomethyl; (2-methoxy-eth-1-yl)(methyl)aminomethyl; 2-fluoro-1-dimethylamino-eth-1-yl; 1-dimethylamino-2,2-difluoroeth-1-yl; 1-dimethylamino-2,2,2-trifluoroeth-1-yl; 1-dimethylamino-2,2,2-trimethyleth-1-yl; dimethylamino(cyclopropyl)methyl; methoxymethyl; isopropyl(methyl)amino; fluoro; chloro; phenyl; pyridyl; pyrazolyl; azetidinyl; 5-methyl-oxazolidin-2-one-5-yl; S(O 2 )CH 3 ; S(O 2 )NR 11 R 12 ; (3,3-difluoropyrrolidin-1-yl)methyl; 1-(difluoromethoxyl)eth-1-yl; azetidinylmethyl; 1-((methyl)aminomethyl)-cycloprop-1-yl; 4-methoxybenzyl; 4-methyl-piperazin-1-yl; morpholinylmethyl; and cyclopentyl.

61 . The compound of any one of claims 59 - 60 , wherein R 2 is selected from the group consisting of fluoro, chloro, cyano, methyl; methoxy; ethoxy; isopropyl; 1-hydroxy-2-methylpropan-2-yl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; COCH 3 ; COPh; 2-methoxy-2-propyl; methoxymethyl; (dimethylamino)methyl; S(O 2 )CH 3 ; and S(O 2 )NR 11 R 12 .

62 . The compound of any one of claims 1 - 4 and 10 - 59 , wherein one or more R 1 when present is independently a C 1 -C 6 alkyl substituted with one or more hydroxy.

63 . The compound of claim 62 , wherein one or more R 1 is independently selected from 1-hydroxy-2-methylpropan-2-yl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; and 1,2,3-trihydroxy-2-propyl

64 . The compound of any one of claims 1 - 4 and 10 - 59 , wherein one or more R 1 when present is independently a C 1 -C 6 alkyl substituted with one or more hydroxy and further substituted with one or more (e.g., one) NR 8 R 9 .

65 . The compound of claim 64 , wherein one or more R 1 is independently selected from 1-amino-2-hydroxy-prop-2-yl; 1-acetamido-2-hydroxy-prop-2-yl; and 1-(tert-butoxycarbonyl)amino-2-hydroxy-prop-2-yl.

66 . The compound of any one of claims 1 - 4 and 10 - 59 , wherein one or more R 1 when present is independently a C 1 -C 6 alkyl substituted with one or more hydroxy and further substituted with one or more (e.g., one) R 15 .

67 . The compound of claim 66 , wherein one or more R 1 is independently selected from 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl; 1-(2-benzyloxyethoxy)-2-hydroxy-2-propyl; and 1-(2-methoxyethoxy)-2-hydroxy-2-propyl.

68 . The compound of any one of claims 1 - 4 and 10 - 59 , wherein one or more R 1 is independently C 1 -C 6 alkyl substituted with one or more (e.g., one) NR 8 R 9 and further optionally substituted with one or more halo.

69 . The compound of claim 68 , wherein one or more R 1 is independently selected from: (methylamino)methyl; (2,2-difluoroeth-1-yl)(methyl)aminomethyl; (2,2,2-trifluoroeth-1-yl)(methyl)aminomethyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; 2-((methyl)aminomethyl)-prop-2-yl; 2-((methyl)amino)-prop-2-yl; (methyl)(cyclopropylmethyl)aminomethyl; (methyl)(2-(dimethylamino)eth-1-yl)aminomethyl; (cyclobutyl)(methyl)aminomethyl; 1-(cyclobutyl)amino-eth-1-yl; isopropylaminomethyl; (cyclobutyl)aminomethyl; cycloheptylaminomethyl; tetrahydropyranylaminomethyl; sec-butylaminomethyl; ethylaminomethyl; allylaminomethyl; (2,2-difluoroeth-1-yl)aminomethyl; (2-methoxy-eth-1-yl)aminomethyl; (2-methoxy-eth-1-yl)(methyl)aminomethyl; 2-fluoro-1-dimethylamino-eth-1-yl; 1-dimethylamino-2,2-difluoroeth-1-yl; 1-dimethylamino-2,2,2-trifluoroeth-1-yl; 1-dimethylamino-2,2,2-trimethyleth-1-yl; and dimethylamino(cyclopropyl)methyl (e.g., one or more R 1 is dimethylaminomethyl or methylaminomethyl).

70 . The compound of any one of claims 62 - 69 , wherein one or more R 2 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl optionally substituted with one or more hydroxy, C 1 -C 6 alkyl optionally substituted with one or more C 1 -C 6 alkoxy, and halo.

71 . The compound of any one of claims 1 - 7 , 10 - 19 , 36 - 37 , 40 - 41 , 43 - 47 , 50 , 53 , and 55 - 58 , wherein one pair of R 1 and R 2 is on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C 4 -C 12 carbocyclic ring (e.g., C 5 or C 6 carbocyclic ring) or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 (e.g., 1-2, e.g., 2) heteroatoms independently selected from O, N, and S (e.g., tetrahydropyridine, dihydrofuran, or dihydropyran), wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C 1 -C 6 alkyl (e.g., methyl), C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy (e.g., methoxy, ethoxy, isopropoxyl), OC 3 -C 10 cycloalkyl, NR 8 R 9 , ═NR 10 , CN, COOC 1 -C 6 alkyl, S(O 2 )C 6 -C 10 aryl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 10 cycloalkyl, 3- to 10-membered heterocycloalkyl (e.g., azetidinyl or oxetanyl), and CONR 8 R 9 , wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, S(O 2 )C 6 -C 10 aryl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo (e.g., fluoro), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 1 -C 6 alkoxy, oxo, NR 8 R 9 (e.g., amino, methylamino, or dimethylamino), ═NR 10 , COOC 1 -C 6 alkyl, C 6 -C 10 aryl, and CONR 8 R 9 .

72 . The compound of any one of claims 1 - 7 , 10 - 19 , 36 - 37 , 40 - 41 , 43 - 47 , 50 , 53 , and 55 - 58 wherein one pair of R 1 and R 2 is on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C 5 -C 6 carbocyclic ring

wherein the carbocyclic is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxyl, azetidinyl, and oxetanyl are optionally substituted with one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino, and dimethylamino; or

one pair of R 1 and R 2 on adjacent atoms taken together forms a moiety selected from:

each of which is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxyl, azetidinyl, and oxetanyl are optionally substituted with one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino, and dimethylamino.

73 . The compound of any one of claims 1 - 7 , 10 - 19 , 36 - 37 , 40 - 41 , 43 - 47 , 50 , 53 , and 55 - 58 , wherein one pair of R 1 and R 2 is on adjacent atoms, and taken together with the atoms connecting them, independently form at least one bicyclic spirocyclic C 4 -C 12 carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxyl, azetidinyl, and oxetanyl are optionally substituted with one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino, and dimethylamino.

74 . The compound of any one of claims 1 - 7 , 10 - 19 , 36 - 37 , 40 - 41 , 43 - 47 , 50 , 53 , and 55 - 58 , wherein one pair of R 1 and R 2 is on adjacent atoms, and taken together with the atoms connecting them, independently form at least one bicyclic spirocyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic or heterocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxyl, azetidinyl, and oxetanyl are optionally substituted with one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino, and dimethylamino.

75 . The compound of any one of claims 1 - 6 , wherein the optionally substituted ring A is selected from the group consisting of a 5-membered heteroaryl comprising 2 or more heteroatoms, a 5-membered heteroaryl comprising 1 heteroatom or heteroatomic group selected from N, NH, and NR 1 , and a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is not bonded to the position of the heteroaryl that is bonded to the S(O)(NHR 3 )═N moiety; m is 1; n is 1; R 1 and R 2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C 4 -C 12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, OC 3 -C 10 cycloalkyl, NR 8 R 9 , ═NR 10 , COOC 1 -C 6 alkyl, S(O 2 )C 6 -C 10 aryl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR 8 R 9 , wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, S(O 2 )C 6 -C 10 aryl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 1 -C 6 alkoxy, oxo, NR 8 R 9 , ═NR 10 , COOC 1 -C 6 alkyl, C 6 -C 10 aryl, and CONR 8 R 9 .

76 . The compound of any one of claims 1 - 6 , wherein the optionally substituted ring A is a pyrazolyl; m is 1; n is 1; R 1 and R 2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C 4 -C 12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, OC 3 -C 10 cycloalkyl, NR 8 R 9 , ═NR 10 , CN, COOC 1 -C 6 alkyl, S(O 2 )C 6 -C 10 aryl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR 8 R 9 , wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, S(O 2 )C 6 -C 10 aryl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 1 -C 6 alkoxy, oxo, NR 8 R 9 , ═NR 10 , COOC 1 -C 6 alkyl, C 6 -C 10 aryl, and CONR 8 R 9 .

77 . The compound of any one of claims 1 - 6 , wherein the optionally substituted ring A is an imidazolyl; m is 1; n is 1; R 1 and R 2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C 4 -C 12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, OC 3 -C 10 cycloalkyl, NR 8 R 9 , ═NR 10 , CN, COOC 1 -C 6 alkyl, S(O 2 )C 6 -C 10 aryl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR 8 R 9 , wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, S(O 2 )C 6 -C 10 aryl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 1 -C 6 alkoxy, oxo, NR 8 R 9 , ═NR 10 , COOC 1 -C 6 alkyl, C 6 -C 10 aryl, and CONR 8 R 9 .

78 . The compound of any one of claims 1 - 6 , wherein the optionally substituted ring A is a thiophenyl; m is 1; n is 1; R 1 and R 2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C 4 -C 12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, OC 3 -C 10 cycloalkyl, NR 8 R 9 , ═NR 10 , CN, COOC 1 -C 6 alkyl, S(O 2 )C 6 -C 10 aryl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR 8 R 9 , wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, S(O 2 )C 6 -C 10 aryl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 1 -C 6 alkoxy, oxo, NR 8 R 9 , ═NR 10 , COOC 1 -C 6 alkyl, C 6 -C 10 aryl, and CONR 8 R 9 .

79 . The compound of any one of claims 1 - 6 , wherein the optionally substituted ring A is a thiazolyl; m is 1; n is 1; R 1 and R 2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C 4 -C 12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, OC 3 -C 10 cycloalkyl, NR 8 R 9 , ═NR 10 , CN, COOC 1 -C 6 alkyl, S(O 2 )C 6 -C 10 aryl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR 8 R 9 , wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, S(O 2 )C 6 -C 10 aryl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 1 -C 6 alkoxy, oxo, NR 8 R 9 , ═NR 10 , COOC 1 -C 6 alkyl, C 6 -C 10 aryl, and CONR 8 R 9 .

80 . The compound of any one of claims 1 - 6 , wherein the optionally substituted ring A is

wherein R x is selected from the group consisting of H and C 1 -C 6 alkyl (e.g., methyl); Z 1 is selected from the group consisting of O, NH, and —CH 2 — optionally substituted with 1-2 R 20 ; Z 2 is selected from the group consisting of NH and —CH 2 — optionally substituted with 1-2 R 20 ; Z 3 is selected from the group consisting of —CH 2 — optionally substituted with 1-2 R 20 , —CH 2 CH 2 — optionally substituted with 1-2 R 20 , and —CH 2 CH 2 CH 2 — optionally substituted with 1-2 R 20 ; R 20 is selected from the group consisting of hydroxy, halo (e.g., fluoro), oxo, C 1 -C 6 alkyl (e.g., methyl or ethyl) optionally substituted with one R 21 , C 1 -C 6 alkoxy (e.g., methoxy, ethoxy, or isopropoxy) optionally substituted with one R 21 , NR 8 R 9 , 3- to 10-membered heterocycloalkyl (e.g., azetidinyl or pyrrolidinyl) optionally substituted with one R 21 , or one pair of R 20 on the same atom, taken together with the atom connecting them, independently forms a monocyclic C 3 -C 4 carbocyclic ring or a monocyclic 3- to 4-membered heterocyclic ring containing 1 O atom optionally substituted with OS(O) 2 Ph; R 21 is selected from the group consisting of halo (e.g., fluoro), NR 8 R 9 , C 2 -C 6 alkynyl (e.g., ethynyl), and C 1 -C 6 alkoxy (e.g., methoxy); R 8 and R 9 at each occurrence is independently selected from hydrogen, C 1 -C 6 alkyl (e.g., methyl or ethyl), COR 13 , and CO 2 R 13 ; R 13 is selected from the group consisting of: C 1 -C 6 alkyl (e.g., methyl or t-butyl) and C 1 -C 6 haloalkyl (e.g., trifluoromethyl).

81 . The compound of any one of claims 1 - 6 , wherein the optionally substituted ring A is

wherein Z 4 is selected from the group consisting of —CH 2 —, —C(O)—, and NH; Z 5 is selected from the group consisting of O, NH, N—CH 3 , and —CH 2 —.

82 . The compound of any one of the preceding claims, wherein B is phenyl substituted with 1 or 2 R 6 and optionally substituted with 1, 2, or 3 R 7 .

83 . The compound of claim 82 , wherein o=2 and p=0.

84 . The compound of any one of claims 82 - 83 , wherein B is

85 . The compound of claim 84 , wherein each R 6 is independently selected from the group consisting of: C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, halo, CN, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, CO—C 1 -C 6 alkyl; CONR 8 R 9 , and 4- to 6-membered heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl and 4- to 6-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, NR 8 R 9 , ═NR 10 , COOC 1 -C 6 alkyl, CONR 8 R 9 , 4- to 6-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(4- to 6-membered heterocycloalkyl), NHCOC 1 -C 6 alkyl, NHCOC 6 -C 10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC 2 -C 6 alkynyl.

86 . The compound of any one of claims 84 and 85 , wherein each R 6 is independently selected from the group consisting of: C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, wherein the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 3 -C 7 cycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, or oxo.

87 . The compound of claim 82 , wherein o=1 and p=1.

88 . The compound of claim 82 , wherein o=2 and p=1.

89 . The compound of claim 88 , wherein B is

90 . The compound of claim 88 , wherein B is

91 . The compound of claim 88 , wherein B is

92 . The compound of any one of claims 89 - 91 , wherein each R 6 is independently selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, halo, CN, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, CO—C 1 -C 6 alkyl; CONR 8 R 9 , and 4- to 6-membered heterocycloalkyl,

wherein the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 7 cycloalkyl and 4- to 6-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, NR 8 R 9 , ═NR 10 , COOC 1 -C 6 alkyl, CONR 8 R 9 , 4- to 6-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(4- to 6-membered heterocycloalkyl), NHCOC 1 -C 6 alkyl, NHCOC 6 -C 10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC 2 -C 6 alkynyl;

wherein R 7 is 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, COC 1 -C 6 alkyl, CO 2 C 1 -C 6 alkyl, CO 2 C 3 -C 6 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, CONR 8 R 9 , SF 5 , S(O 2 )C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one to two C 1 -C 6 alkoxy;

or R 6 and R 7 , taken together with the atoms connecting them, independently form C 4 -C 7 carbocyclic ring or at least one 5-to-7-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 .

93 . The compound of claim 88 , wherein B is

94 . The compound of claim 93 , wherein each R 6 is independently selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, halo, CN, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, CO—C 1 -C 6 alkyl; CONR 8 R 9 , and 4- to 6-membered heterocycloalkyl,

wherein the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 7 cycloalkyl, and 4- to 6-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, NR 8 R 9 , ═NR 10 , COOC 1 -C 6 alkyl, CONR 8 R 9 , 4- to 6-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(4- to 6-membered heterocycloalkyl), NHCOC 1 -C 6 alkyl, NHCOC 6 -C 10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC 2 -C 6 alkynyl;

95 . The compound of claim 82 , wherein o=2 and p=2.

96 . The compound of claim 95 , wherein B is

97 . The compound of claim 95 , wherein B is

98 . The compound of any one of claims 96 - 97 , wherein each R 6 is independently selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, halo, CN, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, CO—C 1 -C 6 alkyl; CONR 8 R 9 , and 4- to 6-membered heterocycloalkyl,

wherein the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl and 4- to 6-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, NR 8 R 9 , ═NR 10 , COOC 1 -C 6 alkyl, CONR 8 R 9 , 4- to 6-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(4- to 6-membered heterocycloalkyl), NHCOC 1 -C 6 alkyl, NHCOC 6 -C 10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC 2 -C 6 alkynyl;

wherein each R 7 is 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, COC 1 -C 6 alkyl, CO 2 C 1 -C 6 alkyl, CO 2 C 3 -C 6 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, CONR 8 R 9 , SF 5 , S(O 2 )C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one to two C 1 -C 6 alkoxy;

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 7 carbocyclic ring or at least one 5-to-7-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 .

99 . The compound of any one of claims 95 - 98 , wherein two pairs, each of one R 6 and one R 7 , are on adjacent atoms, and each pair of one R 6 and one R 7 taken together with the atoms connecting them independently form a C 4 -C 7 carbocyclic ring or a 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein each 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 .

100 . The compound of any one of claims 96 - 99 , wherein one pair of R 6 and R 7 taken together with the atoms connecting them independently form a C 5 carbocyclic ring, wherein the carbocyclic ring is optionally 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 .

101 . The compound of claim 100 , wherein the other pair of R 6 and R 7 taken together with the atoms connecting them independently form a C 5 carbocyclic ring, wherein the carbocyclic ring is optionally 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 .

102 . The compound of any one of claims 96 and 99 - 101 , wherein the substituted ring B is:

103 . The compound of any one of claims 97 and 99 - 101 , wherein the substituted ring B is:

104 . The compound of claim 100 , wherein the other pair of R 6 and R 7 taken together with the atoms connecting them independently form a C 4 or C 6-7 (e.g., C 4 ) carbocyclic ring, wherein the carbocyclic ring is optionally 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 .

105 . The compound of claim 104 , wherein the substituted ring B is:

106 . The compound of any one of claims 96 - 99 , wherein one pair of R 6 and R 7 taken together with the atoms connecting them independently form a C 4 carbocyclic ring, wherein the carbocyclic ring is optionally 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 .

107 . The compound of claim 106 , wherein the other pair of R 6 and R 7 taken together with the atoms connecting them independently form a C 4 carbocyclic ring, wherein the carbocyclic ring is optionally 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 .

108 . The compound of claim 107 , wherein the substituted ring B is:

109 . The compound of any one claims 96 and 98 , wherein one pair of R 6 and R 7 on adjacent atoms, taken together with the atoms connecting them, independently form one C 4 -C 7 carbocyclic ring or one 5-to-7-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 ; and each of the remaining R 6 and R 7 is independently selected from C 1 -C 6 alkyl and C 3 -C 7 cycloalkyl.

110 . The compound of claim 109 , wherein one pair of R 6 and R 7 on adjacent atoms, taken together with the atoms connecting them, independently form one C 4 -C 7 (e.g., C 5 ) carbocyclic ring; and each of the remaining R 6 and R 7 is independently selected from C 1 -C 6 alkyl and C 3 -C 7 cycloalkyl.

111 . The compound of claim 110 , wherein the substituted ring B is

112 . The compound of claim 95 , wherein B is

113 . The compound of claim 112 , wherein each R 6 is independently selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, halo, CN, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, CO—C 1 -C 6 alkyl; CONR 8 R 9 , and 4- to 6-membered heterocycloalkyl,

or R 6 and R 7 , taken together with the atoms connecting them, independently form C 4 -C 7 carbocyclic ring or at least one 5-to-7-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 .

114 . The compound of claim 82 , wherein o=2 and p=3

115 . The compound of claim 114 , wherein B is

116 . The compound of claim 115 , wherein each R 6 is independently selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, halo, CN, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, CO—C 1 -C 6 alkyl; CONR 8 R 9 , and 4- to 6-membered heterocycloalkyl,

wherein each R 7 is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, halo, CN, COC 1 -C 6 alkyl, CO 2 C 1 -C 6 alkyl, CO 2 C 3 -C 6 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, CONR 8 R 9 , SF 5 , S(O 2 )C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one to two C 1 -C 6 alkoxy;

117 . The compound of any one of claims 114 - 116 , wherein two pairs, each of one R 6 and one R 7 , are on adjacent atoms, and each pair of one R 6 and one R 7 taken together with the atoms connecting them independently form a C 4 -C 7 carbocyclic ring or a 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein each 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 .

118 . The compound of any one of claims 114 - 117 , wherein one pair of R 6 and R 7 taken together with the atoms connecting them independently form a C 5 carbocyclic ring, wherein the carbocyclic ring is optionally 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 .

119 . The compound of claim 118 , wherein the other pair of R 6 and R 7 taken together with the atoms connecting them independently form a C 5 carbocyclic ring, wherein the carbocyclic ring is optionally 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 .

120 . The compound of claim 119 , wherein the substituted ring B is:

121 . The compound of claim 120 , wherein R 7 is selected from each R 7 is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, halo, and CN.

122 . The compound of any one of the preceding claims, wherein R 3 is hydrogen.

123 . The compound of any one of claims 1 - 121 , wherein R 3 is methyl.

124 . The compound of any one of claims 1 - 6 , wherein the optionally substituted ring A is

wherein R x is selected from the group consisting of H and C 1 -C 6 alkyl (e.g., methyl); Z 1 is selected from the group consisting of O, NH, and —CH 2 — optionally substituted with 1-2 R 20 ; Z 2 is selected from the group consisting of NH and —CH 2 — optionally substituted with 1-2 R 20 ; Z 3 is selected from the group consisting of —CH 2 — optionally substituted with 1-2 R 20 , —CH 2 CH 2 — optionally substituted with 1-2 R 20 , and —CH 2 CH 2 CH 2 — optionally substituted with 1-2R 20 ; R 20 is selected from the group consisting of hydroxy, halo (e.g., fluoro), oxo, C 1 -C 6 alkyl (e.g., methyl or ethyl) optionally substituted with one R 21 , C 1 -C 6 alkoxy (e.g., methoxy, ethoxy, or isopropoxy) optionally substituted with one R 21 , NR 8 R 9 , 3- to 10-membered heterocycloalkyl (e.g., azetidinyl or pyrrolidinyl) optionally substituted with one R 21 , or one pair of R 20 on the same atom, taken together with the atom connecting them, independently forms a monocyclic C 3 -C 4 carbocyclic ring or a monocyclic 3- to 4-membered heterocyclic ring containing 1 O atom optionally substituted with OS(O) 2 Ph; R 21 is selected from the group consisting of halo (e.g., fluoro), NR 8 R 9 , C 2 -C 6 alkynyl (e.g., ethynyl), and C 1 -C 6 alkoxy (e.g., methoxy); R 8 and R 9 at each occurrence is independently selected from hydrogen, C 1 -C 6 alkyl (e.g., methyl or ethyl), COR 13 , and CO 2 R 13 ; R 13 is selected from the group consisting of: C 1 -C 6 alkyl (e.g., methyl or t-butyl) and C 1 -C 6 haloalkyl (e.g., trifluoromethyl); and

the substituted ring B is selected from:

wherein

two pairs, each of one R 6 and one R 7 , are on adjacent atoms, and each pair of one R 6 and one R 7 taken together with the atoms connecting them independently form a C 4 -C 7 carbocyclic ring or a 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein each 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 ; and

the remaining R 7 that is not taken with a R 6 on adjacent atoms to form a C 4 -C 7 carbocyclic ring or a 5- to 7-membered heterocyclic ring is 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, COC 1 -C 6 alkyl, CO 2 C 1 -C 6 alkyl, CO 2 C 3 -C 6 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, CONR 8 R 9 , SF 5 , S(O 2 )C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one to two C 1 -C 6 alkoxy.

125 . The compound of any one of claims 1 - 6 , wherein the optionally substituted ring A is

wherein Z 4 is selected from the group consisting of —CH 2 —, —C(O)—, and NH; Z 5 is selected from the group consisting of O, NH, N—CH 3 , and —CH 2 —; and

the substituted ring B is selected from:

wherein

126 . The compound of any one of claims 124 - 125 , wherein the substituted ring B is

127 . The compound of any one of claims 124 - 125 , wherein the substituted ring B is

128 . The compound of any one of claims 124 - 127 , wherein one pair of R 6 and R 7 taken together with the atoms connecting them independently form a C 5 carbocyclic ring, wherein the carbocyclic ring is optionally 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 .

129 . The compound of claim 128 , wherein the other pair of R 6 and R 7 taken together with the atoms connecting them independently form a C 5 carbocyclic ring, wherein the carbocyclic ring is optionally 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 .

130 . The compound of claim 128 , wherein wherein the other pair of R 6 and R 7 taken together with the atoms connecting them independently form a C 4 carbocyclic ring, wherein the carbocyclic ring is optionally 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 .

131 . The compound of any one of claims 124 - 128 , wherein one pair of R 6 and R 7 taken together with the atoms connecting them independently form a C 4 carbocyclic ring, wherein the carbocyclic ring is optionally 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 .

132 . The compound of claim 131 , wherein wherein the other pair of R 6 and R 7 taken together with the atoms connecting them independently form a C 4 carbocyclic ring, wherein the carbocyclic ring is optionally 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 .

133 . The compound of any one of claims 126 and 128 - 129 , wherein the substituted ring B is selected from:

134 . The compound of any one of claims 126 , 128 , and 130 , wherein the substituted ring B is:

135 . The compound of any one of claims 126 and 131 - 132 , wherein the substituted ring B is:

136 . The compound of any one of claims 127 and 128 - 129 , wherein the substituted ring B is:

137 . A compound selected from the group consisting of the compounds below:

Cmpd #

Structure

101′

101

102

103′

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

163

164

165

166

167

168

169

170

171

172

172a

172b

173

173a

173b

174

175

176

176a

176b

177

177a

177b

178

178a

178b

179

179a

179b

180

180a

180b

181

181a

181b

182

182a

182b

183

183a

183b

184

185

185a

185b

186

186a

186b

187

187a

187b

188

188a

188b

189

189a

189b

190

190a

190b

191

192

192a

192b

193

193a

193b

and pharmaceutically acceptable salts thereof.

138 . A compound selected from the group consisting of the compounds below:

Cmpd

Structure

105a

105b

106a

106b

107a

107b

108a

108b

109a

109b

110a

110b

112a

112b

116a

116b

120a

120b

121a

121b

122a

122b

125a

125b

129a

129b

130a

130b

131a

131b

134a

134b

135a

135b

136a

136b

143a

143b

144a

144b

145a

145b

148a

148b

149a

149b

151a′

151b′

151a

151b

152a

152b

153a

153b

154a

154b

157b

158a

158b

161a

161b

165a

165b

167a

167b

168a

168b

170a

170b

171a

171b

174a

174b

191a

191b

195

195a

195ba

195bb

196

197

198

200

202

202a

202b

205

205a

205b

206

206a

206b

207

207a

207b

208

209

211

212

212a

212b

213

216

220

220a

220b

221

223a

223b

225a

225b

270

and pharmaceutically acceptable salts thereof.

139 . A compound selected from the group consisting of the compounds in the following table:

113a

334a

113b

335

137a

335b

137b

335a

138a

336

138b

336a

139a

336b

139b

337

159a

337b

159ba

338

159ab

338a

195e

339

207bb

339a

207aa

340

207c

340a

303

340b

303a

341

303b

341b

306

342

307

343

308

343a

308a

343b

308b

344

309

345

310

346

311

347

312

348

313

349

314

350

315

351

315b

352

315a

352b

316

352a

316b

353

317

354

317ab

354a

317aa

354b

317bb

355

317ba

356

318

357

318a

357a

318b

357b

319

358

319ab

359

319ba

359a

319aa

360ba

319bb

360bb

320

361b

320a

363b

320b

363a

321

364a

321b

364b

321a

365a

322

365b

323

366a

323ab

366b

323aa

367a

323bb

367b

323ba

369a

324

369b

325

371b

325a

372b

325b

373b

326

375

326b

375a

326a

375b

327

376

328b

376a

328a

376b

329

377

329a

378

329b

379

330

379a

330a

379b

330b

380

331

380a

332

380b

332a

380c

332b

380d

333

382

333a

382a

333b

382b

334

383

334ba

383a

334bb

383b

334aa

384a

334ab

384b

334b

387a

334a

387b

and pharmaceutically acceptable salts thereof.

140 . A compound selected from the group consisting of the compounds in the table below:

501

618

502

619

503

620

504

621

505

622

506

623

507

624

508

625

509

626

510

627

511

628

512

629

513

630

514

631

515

632

516

633

517

634

518

635

519

636

520

637

521

638

522

639

523

640

524

641

525

642

526

643

527

644

528

645

529

646

530

647

531

648

532

649

533

650

534

651

535

652

536

653

537

654

538

655

539

656

540

657

541

658

542

659

543

660

544

661

545

662

546

663

547

664

548

665

549

666

550

667

551

668

552

669

553

670

554

671

555

672

556

673

557

674

558

675

559

676

560

677

561

678

562

679

563

680

564

681

565

682

566

683

567

684

568

685

569

686

570

687

571

688

572

689

573

690

574

691

575

692

576

693

577

694

578

695

579

696

580

697

581

698

582

699

583

700

584

701

585

702

586

703

587

704

588

705

589

706

590

707

591

708

592

709

593

710

594

711

595

712

596

713

597

714

598

715

599

716

600

717

601

718

602

719

603

720

604

721

605

722

606

723

607

724

608

725

609

726

610

727

611

728

612

729

613

730

614

731

615

732

616

733

617

734

735

and pharmaceutically acceptable salts thereof.

141 . A compound selected from the group consisting of the compounds in Table 1C and pharmaceutically acceptable salts thereof.

142 . A compound selected from the group consisting of the compounds in Table 1D or Table 1E (e.g., Table 1D; e.g., Table 1E) and pharmaceutically acceptable salts thereof

143 . A compound selected from the group consisting of the following

411

412a

411a

413

412

413a

and pharmaceutically acceptable salts thereof.

144 . The compound of any one of the preceding claims, wherein the sulfur in the moiety S(═O)(NHR 3 )═N— has (S) stereochemistry.

145 . The compound of any one of claims 1 to 143 , wherein the sulfur in the moiety S(═O)(NHR 3 )═N— has (R) stereochemistry.

146 . A pharmaceutical composition comprising a compound or salt as claimed in any one of claims 1 - 145 and one or more pharmaceutically acceptable excipients.

147 . A method for modulating NLRP3 activity, the method comprising contacting NLRP3 with an effective amount of a compound as claimed in any one of claims 1 - 145 or a pharmaceutical composition as claimed in claim 146 .

148 . The method of claim 147 , wherein the modulating comprises antagonizing NLRP3.

149 . The method of any one of claim 147 or 148 , which is carried out in vitro.

150 . The method of claims 147 to 149 , wherein the method comprises contacting a sample comprising one or more cells comprising NLRP3 with the compound.

151 . The method of any one of claim 147 , 148 or 150 , which is carried out in vivo.

152 . The method of claim 151 , wherein the method comprises administering the compound to a subject having a disease in which NLRP3 signaling contributes to the pathology and/or symptoms and/or progression of the disease.

153 . The method of claim 152 , wherein the subject is a human.

154 . A method of treating a disease, disorder or condition that is a metabolic disorder, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1 - 145 or a pharmaceutical composition as claimed in claim 146 .

155 . The method of claim 154 , wherein the metabolic disorder is Type 2 diabetes, atherosclerosis, obesity or gout.

156 . A method of treating a disease, disorder or condition that is a disease of the central nervous system, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1 - 145 or a pharmaceutical composition as claimed in claim 146 .

157 . The method of claim 156 , wherein the disease of the central nervous system is Alzheimer's disease, multiple sclerosis, Amyotrophic Lateral Sclerosis or Parkinson's disease.

158 . A method of treating a disease, disorder or condition that is lung disease, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1 - 145 or a pharmaceutical composition as claimed in claim 146 .

159 . The method of claim 158 , wherein the lung disease is asthma, COPD or pulmonary idiopathic fibrosis.

160 . A method of treating a disease, disorder or condition that is liver disease, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1 - 145 or a pharmaceutical composition as claimed in claim 146 .

161 . The method of claim 160 , wherein the liver disease is NASH syndrome, viral hepatitis or cirrhosis.

162 . A method of treating a disease, disorder or condition that is pancreatic disease, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1 - 145 or a pharmaceutical composition as claimed in claim 146 .

163 . The method of claim 162 , wherein the pancreatic disease is acute pancreatitis or chronic pancreatitis.

164 . A method of treating a disease, disorder or condition that is kidney disease, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1 - 145 or a pharmaceutical composition as claimed in claim 146 .

165 . The method of claim 164 , wherein the kidney disease is acute kidney injury or chronic kidney injury.

166 . A method of treating a disease, disorder or condition that is intestinal disease, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1 - 145 or a pharmaceutical composition as claimed in claim 146 .

167 . The method of claim 166 , wherein the intestinal disease is Crohn's disease or Ulcerative Colitis.

168 . A method of treating a disease, disorder or condition that is skin disease, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1 - 145 or a pharmaceutical composition as claimed in claim 146 .

169 . The method of claim 168 , wherein the skin disease is psoriasis.

170 . A method of treating a disease, disorder or condition that is musculoskeletal disease, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1 - 145 or a pharmaceutical composition as claimed in claim 146 .

171 . The method of claim 170 , wherein the musculoskeletal disease is scleroderma.

172 . A method of treating a disease, disorder or condition that is a vessel disorder, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1 - 145 or a pharmaceutical composition as claimed in claim 146 .

173 . The method of claim 172 , wherein the vessel disorder is giant cell arteritis.

174 . A method of treating a disease, disorder or condition that is a disorder of the bones, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1 - 145 or a pharmaceutical composition as claimed in claim 146 .

175 . The method of claim 174 , wherein the disorder of the bones is osteoarthritis, osteoporosis or osteopetrosis disorders.

176 . A method of treating a disease, disorder or condition that is eye disease, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1 - 145 or a pharmaceutical composition as claimed in claim 146 .

177 . The method of claim 176 , wherein the eye disease is glaucoma or macular degeneration.

178 . A method of treating a disease, disorder or condition that is a disease caused by viral infection, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1 - 145 or a pharmaceutical composition as claimed in claim 146 .

179 . The method of claim 178 , wherein the diseases caused by viral infection is HIV or AIDS.

180 . A method of treating a disease, disorder or condition that is an autoimmune disease, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1 - 145 or a pharmaceutical composition as claimed in claim 146 .

181 . The method of claim 180 , wherein the autoimmune disease is Rheumatoid Arthritis, Systemic Lupus Erythematosus, Autoimmune Thyroiditis.

182 . A method of treating a disease, disorder or condition that is cancer or aging, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1 - 145 or a pharmaceutical composition as claimed in claim 146 .

183 . A method of treating a disease, disorder or condition that is a cancer selected from: myelodysplastic syndromes (MDS); non-small cell lung cancer, such as non-small cell lung cancer in patients carrying mutation or overexpression of NLRP3; acute lymphoblastic leukemia (ALL), such as ALL in patients resistant to glucocorticoids treatment; Langerhan's cell histiocytosis (LCH); multiple myeloma; promyelocytic leukemia; acute myeloid leukemia (AML); chronic myeloid leukemia (CML); gastric cancer; and lung cancer metastasis, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1 - 145 or a pharmaceutical composition as claimed in claim 146 .

184 . The method of claim 183 , wherein the cancer is MDS.

185 . The method of claim 183 , wherein the cancer is non-small lung cancer.

186 . The method of claim 183 , wherein the cancer is acute lymphoblastic leukemia.

187 . The method of claim 183 , wherein the cancer is LCH.

188 . The method of claim 183 , wherein the cancer is multiple myeloma.

189 . The method of claim 183 , wherein the cancer is promyelocytic leukemia.

190 . The method of claim 183 , wherein the cancer is acute myeloid leukemia (AML).

191 . The method of claim 183 , wherein the cancer is chronic myeloid leukemia (CML).

192 . The method of claim 183 , wherein the cancer is gastric cancer.

193 . The method of claim 183 , wherein the cancer is lung cancer metastasis.

194 . The method of any one of claims 152 - 193 , further comprising administering a therapeutically effective amount of an anti-TNFα agent to the subject.

195 . The method of claim 194 , wherein the NLRP3 antagonist is administered to the subject prior to administration of the anti-TNFα agent to the subject.

196 . The method of claim 194 , wherein the anti-TNFα agent is administered to the subject prior to the administration of the NLRP3 antagonist to the subject.

197 . The method of claim 194 , wherein the NLRP3 antagonist and the anti-TNFα agent are administered to the subject at substantially the same time.

198 . The method of claim 194 , wherein the NLRP3 antagonist and the anti-TNFα agent are formulated together in a single dosage form.

Assignments (3)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 29, 2021

From: FRANCHI, LUIGI; GHOSH, SHOMIR; GLICK, GARY; KATZ, JASON; OPIPARI, ANTHONY WILLIAM, JR; ROUSH, WILLIAM; SEIDEL, HANS MARTIN; SHEN, DONG-MING; VENKATRAMAN, SHANKAR; WINKLER, DAVID GUENTHER

To: IFM MANAGEMENT, INC.

Reel/Frame 057023/0522 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 29, 2021

From: IFM MANAGEMENT, INC.

To: NOVARTIS INFLAMMASOME RESEARCH, INC.

Reel/Frame 057023/0687 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 29, 2021

From: NOVARTIS INFLAMMASOME RESEARCH, INC.

To: NOVARTIS AG

Reel/Frame 057023/0839 →