IP Library › Patent Application 17293787

Patent Application

App. No. 17/293,787

THE COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH NLRP ACTIVITY

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Quick Facts

Patent No.: US None
App. No.: 17/293,787
Filed: May 13, 2021
Examiner: OTTON, ALICIA L
Art Unit: 1699
USPC: 514/367

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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 (700)

1 . A compound of Formula AA

wherein

m=0, 1, or 2;

n=0, 1, or 2;

o=1 or 2;

p=0, 1, 2, or 3;

wherein

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

B is a 5-10-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 C(R 4 R 5 ) 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 , 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), 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;

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 , S(O 2 )C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl and 3- to 10-membered heterocycloalkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl,

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;

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 ;

each of R 4 and R 5 is independently selected from hydrogen and C 1 -C 6 alkyl;

R 10 is C 1 -C 6 alkyl;

each of R 8 and R 9 at each occurrence is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 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 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 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 an integer selected from 0-10 (e.g., 0-5);

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 alkyenyl, 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, cyano, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, and

wherein the C 1 -C 2 alkylene group is optionally substituted by oxo;

R 14 is hydrogen, C 1 -C 6 alkyl, 5-10-membered monocyclic or bicyclic heteroaryl or C 6 -C 10 monocyclic or bicyclic aryl, wherein each C 1 -C 6 alkyl, aryl or heteroaryl is optionally substituted with from 1-3 independently selected R 6 ;

R 15 is —(Z 4 -Z 5 ) a2 —Z 6 ;

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

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.

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

B is a 5-10-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 C(R 4 R 5 ) group of Formula AA;

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 , 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), and NHCOC 2 -C 6 alkynyl;

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 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 4 and R 5 is independently selected from hydrogen and C 1 -C 6 alkyl;

R 10 is C 1 -C 6 alkyl;

each of R 8 and R 9 at each occurrence is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 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 or 3- to 7-membered heterocycloalkyl; or R 8 and R 9 taken together with the nitrogen they are attached to form a 3- to 7-membered ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to;

R 13 is C 1 -C 6 alkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl;

each of R 11 and R 12 at each occurrence is independently selected from hydrogen and C 1 -C 6 alkyl;

R 3 is selected from hydrogen, cyano, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, and

wherein the C 1 -C 2 alkylene group is optionally substituted by oxo;

R 15 is —(Z 4 -Z 5 ) a2 —Z 6 ;

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

or a pharmaceutically acceptable salt thereof.

3 . A compound of Formula AA

wherein

m=0, 1, or 2;

n=0, 1, or 2;

o=1 or 2;

p=0, 1, 2, or 3;

wherein

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

B is a 5-10-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 C(R 4 R 5 ) 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 2 C 1 -C 6 alkyl, CO—C 6 -C 10 aryl, CO-5- to 10-membered heteroaryl, 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 the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 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), and NHCOC 2 -C 6 alkynyl;

or at least one pair of R 1 and R 2 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C 4 -C 8 carbocyclic ring or at least one 5-to-8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 8 R 9 , ═NR 10 , COOC 1 -C 6 alkyl, C 6 -C 10 aryl, and CONR 8 R 9 ′ wherein the C 1 -C 6 alkyl and C 1 -C 6 alkoxy are optionally substituted with hydroxy, halo, oxo, NR 8 R 9 , ═NR 10 , COOC 1 -C 6 alkyl, C 6 -C 10 aryl, 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;

each of R 4 and R 5 is independently selected from hydrogen and C 1 -C 6 alkyl;

R 10 is C 1 -C 6 alkyl;

each of R 8 and R 9 at each occurrence is independently selected from hydrogen, C 1 -C 6 alkyl, (C═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 or 3- to 7-membered heterocycloalkyl; or R 8 and R 9 taken together with the nitrogen they are attached to form a 3- to 7-membered ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to;

R 13 is C 1 -C 6 alkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl;

each of R 11 and R 12 at each occurrence is independently selected from hydrogen and C 1 -C 6 alkyl;

R 3 is selected from hydrogen, cyano, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, and

wherein the C 1 -C 2 alkylene group is optionally substituted by oxo;

or a pharmaceutically acceptable salt thereof.

4 . A compound 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 5-10-membered monocyclic or bicyclic heteroaryl or a C 6 -C 10 monocyclic or bicyclic aryl;

B is a 5-10-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 C(R 4 R 5 ) group of Formula AA;

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 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 is not taken together with the atoms connecting them to form 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,

each of R 4 and R 5 is independently selected from hydrogen and C 1 -C 6 alkyl;

R 10 is C 1 -C 6 alkyl;

R 13 is C 1 -C 6 alkyl 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., 0-5);

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, cyano, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, and

wherein the C 1 -C 2 alkylene group is optionally substituted by oxo;

R 15 is —(Z 4 -Z 5 ) a2 —Z 6 ;

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

or a pharmaceutically acceptable salt thereof.

5 . A compound of Formula AA

wherein

m=0, 1, or 2;

n=0, 1, or 2;

o=1 or 2;

p=0, 1, 2, or 3;

wherein

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

B is a 5-10-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 C(R 4 R 5 ) 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 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 is not taken together with the atoms connecting them to form 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 2 C 1 -C 6 alkyl, CO—C 6 -C 10 aryl, CO-5- to 10-membered heteroaryl, 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,

each of R 4 and R 5 is independently selected from hydrogen and C 1 -C 6 alkyl;

R 10 is C 1 -C 6 alkyl;

each of R 8 and R 9 at each occurrence is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 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 or 3- to 7-membered heterocycloalkyl; or R 8 and R 9 taken together with the nitrogen they are attached to form a 3- to 7-membered ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to;

R 13 is C 1 -C 6 alkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl;

each of R 11 and R 12 at each occurrence is independently selected from hydrogen and C 1 -C 6 alkyl;

R 3 is selected from hydrogen, cyano, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, and

wherein the C 1 -C 2 alkylene group is optionally substituted by oxo;

R 15 is —(Z 4 -Z 5 ) a2 —Z 6 ;

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

or a pharmaceutically acceptable salt thereof.

6 . The compound of any one of claims 4 - 5 , wherein the compound is other than:

7 . The compound of any one of claims 4 - 5 , wherein one pair of R 1 and R 2 is on adjacent atoms, and taken together with the atoms connecting them, independently form one ring selected from:

(a) monocyclic or bicyclic C 4 -C 12 carbocyclic ring optionally 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 ,

(b) monocyclic or bicyclic 5-to-12-membered non-aromatic heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the heterocyclic ring is optionally 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 ,

(c) monocyclic or bicyclic 6-to-12-membered aromatic heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the heterocyclic ring is optionally 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 ,

(d) monocyclic 5-membered aromatic heterocyclic ring containing 2 heteroatoms independently selected from O, N, and S, wherein the heterocyclic ring is substituted with one substituent selected from hydroxy, halo, oxo, C 2 -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 ,

(e) monocyclic 5-membered aromatic heterocyclic ring containing 2 heteroatoms independently selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with two 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 ,

(f) monocyclic 5-membered aromatic heterocyclic ring containing 1 or 3 heteroatoms independently selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with two 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 ,

8 . The compound of any one of claims 1 - 6 , 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 non-aromatic carbocyclic ring or one monocyclic or bicyclic 5-to-12-membered non-aromatic 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 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, oxo, NR 8 R 9 , ═NR 10 , COOC 1 -C 6 alkyl, C 6 -C 10 aryl, and CONR 8 R 9 .

9 . The compound of any one of claims 1 - 2 and 4 - 5 , 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 1 - 9 , wherein A is a 5-6-membered monocyclic heteroaryl optionally substituted with 1 or 2 R 1 and optionally substituted with 1 or 2 R 2 .

11 . The compound of any one of claims 1 - 10 , wherein A is furanyl 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 - 10 , wherein A is thiophenyl 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 - 10 , wherein A is oxazolyl 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 - 10 , wherein A is thiazolyl 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 - 10 , wherein A is pyrazolyl 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 - 10 , wherein A is imidazolyl 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 - 9 , wherein A is phenyl 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 1 - 3 and 10 - 17 , wherein m=1 and n=0.

19 . The compound of any one of claims 1 - 3 , 10 , 12 , and 18 , wherein the substituted ring A is

20 . The compound of any one of claims 1 - 3 , 10 , 12 , and 18 , wherein the substituted ring A is

21 . The compound of any one of claims 1 - 3 , 10 , 12 , and 18 , wherein the substituted ring A is

22 . The compound of any one of claims 1 - 3 , 10 , 11 , and 18 , wherein the substituted ring A is

23 . The compound of any one of claims 1 - 3 , 10 , 11 , and 18 , wherein the substituted ring A is

24 . The compound of any one of claims 1 - 3 , 10 , 11 , and 18 , wherein the substituted ring A is

25 . The compound of any one of claims 1 - 3 , 10 , 14 , and 18 , wherein the substituted ring A is

26 . The compound of any one of claims 1 - 3 , 10 , 14 , and 18 , wherein the substituted ring A is

27 . The compound of any one of claims 1 - 3 , 10 , 14 , and 18 , wherein the substituted ring A is

28 . The compound of any one of claims 1 - 3 , 10 , 14 , and 18 , wherein the substituted ring A is

29 . The compound of any one of claims 1 - 3 , 10 , 13 , and 18 , wherein the substituted ring A is

30 . The compound of any one of claims 1 - 3 , 10 , 13 , and 18 , wherein the substituted ring A is

31 . The compound of any one of claims 1 - 3 , 10 , 13 , and 18 , wherein the substituted ring A is

32 . The compound of any one of claims 1 - 3 and 17 - 18 , wherein the substituted ring A is

33 . The compound of any one of claims 1 - 3 and 17 - 18 , wherein the substituted ring A is

34 . The compound of any one of claims 1 - 3 and 17 - 18 , wherein the substituted ring A is

35 . The compound of any one of claims 1 - 3 , wherein the substituted ring A is

36 . The compound of any one of claims 1 - 3 , 10 , and 15 , wherein the substituted ring A is

37 . The compound of any one of claims 1 - 3 , 10 , and 18 , wherein the substituted ring A is

38 . The compound of any one of claims 1 - 3 , 10 , and 18 , wherein the substituted ring A is

39 . The compound of any one of claims 1 - 3 , 10 , and 18 , wherein the substituted ring A is

40 . The compound of any one of claims 1 - 17 , wherein m=1 and n=1.

41 . The compound of any one of claims 1 - 10 , 12 , and 40 , wherein the substituted ring A is

42 . The compound of any one of claims 1 - 3 , 10 , 14 , and 40 , wherein the substituted ring A is

43 . The compound of any one of claims 1 - 3 , 10 , 14 , and 40 , wherein the substituted ring A is

44 . The compound of any one of claims 1 - 10 , 11 , and 40 , wherein the substituted ring A is

45 . The compound of any one of claims 1 - 10 , 12 , and 40 , wherein the substituted ring A is

46 . The compound of any one of claims 1 - 10 , 11 , and 40 , wherein the substituted ring A is

47 . The compound of any one of claims 1 - 3 , 10 , 12 , and 40 , wherein the substituted ring A is

48 . The compound of any one of claims 1 - 3 , 10 , 11 , and 40 , wherein the substituted ring A is

49 . The compound of any one of claims 1 - 10 , 14 , and 40 , wherein the substituted ring A is

50 . The compound of any one of claims 1 - 10 , 13 , and 40 , wherein the substituted ring A is

51 . The compound of any one of claims 1 - 10 , 15 , and 40 , wherein the optionally substituted ring A is

52 . The compound of any one of claims 1 - 10 , 15 , and 40 , wherein the optionally substituted ring A is

53 . The compound of any one of claims 1 - 10 , 15 , and 40 , wherein the optionally substituted ring A is

54 . The compound of any one of claims 1 - 10 , 16 , and 40 , wherein the optionally substituted ring A is

55 . The compound of any one of claims 1 - 3 , 17 , and 40 , wherein the substituted ring A is

56 . The compound of any one of claims 1 - 3 , 17 , and 40 , wherein the substituted ring A is

57 . The compound of any one of claims 1 - 9 , 17 , and 40 , wherein the substituted ring A is

58 . The compound of any one of claims 1 - 3 , 17 , and 40 , wherein the substituted ring A is

59 . The compound of any one of claims 1 - 9 , 17 , and 40 , wherein the substituted ring A is

60 . The compound of any one of claims 1 - 3 , 17 , and 40 , wherein the substituted ring A is

61 . The compound of any one of claims 1 - 17 , wherein m=2 and n=1.

62 . The compound of any one of claims 1 - 3 , 17 , and 61 , wherein the substituted ring A is

63 . The compound of any one of claims 1 - 9 , 17 , and 61 , wherein the substituted ring A is

64 . The compound of any one of claims 1 - 9 , 17 , and 61 , wherein the substituted ring A is

65 . The compound of any one of claims 1 - 9 , 17 , and 61 , wherein the substituted ring A is

66 . The compound of any one of claims 1 - 10 , 15 , and 61 , wherein A is

67 . The compound of any one of claims 1 - 3 and 10 - 66 , 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, 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 optionally substituted with one or more independently halo; 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.

68 . The compound of any one of claims 1 - 3 and 10 - 66 , wherein R 1 is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl; 2-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH 3 ; COCH 2 CH 3 ; 2-methoxy-2-propyl; difluoromethyl; (dimethylamino)methyl; (methylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; fluorophenyl; pyridyl; pyrazolyl; S(O 2 )CH 3 ; and S(O 2 )NR 11 R 12 .

69 . The compound of claim 67 or 68 , 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; 1,2-dihydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; COCH 3 ; COPh; 2-methoxy-2-propyl; difluoromethyl; (dimethylamino)methyl; (methylamino)methyl; S(O 2 )CH 3 ; and S(O 2 )NR 11 R 12 .

70 . The compound of any one of claims 1 - 2 , 4 - 5 , 10 - 17 , 40 - 41 , 44 - 46 , 49 - 54 , 57 , 59 , 61 , and 63 - 66 , 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 .

71 . The compound of any one of claims 1 - 2 , 4 - 5 , 10 - 17 , 40 - 41 , 44 - 46 , 49 - 54 , 57 , 59 , 61 , and 63 - 66 , 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 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; 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.

72 . The compound of any one of claims 1 - 2 , 4 - 5 , 10 - 17 , 40 - 41 , 44 - 46 , 49 - 54 , 57 , 59 , 61 , and 63 - 66 , 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.

73 . The compound of any one of claims 1 - 2 , 4 - 5 , 10 - 17 , 40 - 41 , 44 - 46 , 49 - 54 , 57 , 59 , 61 , and 63 - 66 , 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.

74 . The compound of any one of claims 1 - 2 , wherein the optionally substituted ring A is selected from the group consisting of a 5-membered heteroaryl comprising 1-3 heteroatoms independently selected from O, N, 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; and

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 .

75 . The compound of any one of claims 1 - 2 and 74 , wherein the optionally substituted ring A is a pyrazolyl;

m is 1; n is 1; and

76 . The compound of any one of claims 1 - 2 and 74 , wherein the optionally substituted ring A is an imidazolyl;

m is 1; n is 1; and

77 . The compound of any one of claims 1 - 2 and 74 , wherein the optionally substituted ring A is a thiophenyl;

m is 1; n is 1; and

78 . The compound of any one of claims 1 - 2 and 74 , wherein the optionally substituted ring A is a thiazolyl;

m is 1; n is 1; and

79 . The compound of any one of claims 1 - 2 , 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).

80 . The compound of any one of claims 1 - 2 , 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 —.

81 . 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 .

82 . The compound of claim 81 , wherein o=2 and p=0.

83 . The compound of any one of claims 81 - 82 , wherein the substituted ring B is

84 . The compound of claim 83 , 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.

85 . The compound of any one of claims 83 - 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, 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, and oxo.

86 . The compound of claim 81 , wherein o=1 and p=1.

87 . The compound of claim 81 , wherein o=2 and p=1.

88 . The compound of claim 87 , wherein the substituted ring B is

89 . The compound of claim 88 , 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 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 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein each of the C 2 -C 6 alkynyl and C 1 -C 6 alkyl is optionally substituted with from 1-2 substituents each independently selected from oxo, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, 3- to 7-membered heterocycloalkyl, and C 3 -C 10 cycloalkoxy;

or R 6 and R 7 on adjacent atoms, taken together with the atoms connecting them, independently form C 4 -C 7 carbocyclic ring or 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 .

90 . The compound of claim 87 , wherein the substituted ring B is

91 . The compound of claim 90 , 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, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl, 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;

92 . The compound of claim 81 , wherein o=2 and p=2.

93 . The compound of claim 92 , wherein the substituted ring 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,

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 .

95 . The compound of claim 94 , wherein each pair of R 6 and R 7 on adjacent atoms, taken together with the atoms connecting them, independently forms a C 4 -C 7 (e.g., C 4 -C 5 (e.g., C 5 )) carbocyclic ring.

96 . The compound of any one of claims 94 - 95 , wherein one pair of R 6 and R 7 on adjacent atoms, taken together with the atoms connecting them, independently forms a C 5 carbocyclic ring.

97 . The compound of claim 96 , wherein the second pair of R 6 and R 7 on adjacent atoms, taken together with the atoms connecting them, independently forms a C 4 -C 5 (e.g., C 4 or C 5 ) carbocyclic ring.

98 . The compound of claim 94 , wherein each pair of R 6 and R 7 on adjacent atoms, taken together with the atoms connecting them, independently forms a C 4 carbocyclic ring.

99 . The compound of claim 92 , wherein the substituted ring B is

100 . The compound of claim 99 , 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,

101 . The compound of claim 100 , wherein R 6 and R 7 on adjacent atoms, taken together with the atoms connecting them, independently form C 4 -C 7 (e.g., C 5 ) carbocyclic ring.

102 . The compound of claim 100 , wherein R 6 and R 7 on adjacent atoms, together with the atoms connecting them, independently form a 5-to-7-membered heterocyclic ring containing from 1-2 heteroatoms each independently selected from O and N (e.g., O), wherein the heterocyclic 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 .

103 . The compound of any one of claims 101 - 102 , wherein each of the remaining R 6 and R 7 is independently selected from C 1 -C 6 alkyl (e.g., isopropyl).

104 . The compound of claim 92 , wherein the substituted ring B is

105 . The compound of claim 104 , 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,

106 . The compound of any one of claims 104 - 105 , wherein each pair of R 6 and R 7 on adjacent atoms, taken together with the atoms connecting them, independently forms a C 4 -C 7 carbocyclic ring or 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 .

107 . The compound of claim 106 , wherein each pair of R 6 and R 7 on adjacent atoms, taken together with the atoms connecting them, independently forms a C 4 -C 7 (e.g., C 4 -C 5 (e.g., C 5 )) carbocyclic ring.

108 . The compound of claim 81 , wherein o=2 and p=3.

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

110 . The compound of claim 109 , 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,

111 . The compound of any one of claims 1 - 80 , wherein B is pyridyl; o=1 or 2; and p=0, 1, or 2.

112 . The compound of claim 111 , wherein o=2 and p=1.

113 . The compound of claim 112 , wherein the substituted ring B is

114 . The compound of claim 112 , wherein the substituted ring B is

115 . The compound of claim 112 , wherein the substituted ring B is

116 . The compound of any one of claims 113 - 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 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 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the C 6 -C 10 aryl is optionally substituted with one to two C 1 -C 6 alkyl optionally substituted with one to three halo; and wherein each of the C 2 -C 6 alkynyl and C 1 -C 6 alkyl is optionally substituted with from 1-2 substituents each independently selected from oxo, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, 3- to 7-membered heterocycloalkyl, and C 3 -C 10 cycloalkoxy;

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

117 . The compound of claim 111 , wherein o=2 and p=2.

118 . The compound of claim 117 , wherein the substituted ring B is

119 . The compound of claim 118 , 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 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 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the C 6 -C 10 aryl is optionally substituted with one to two C 1 -C 6 alkyl optionally substituted with one to three halo; and wherein each of the C 2 -C 6 alkynyl and C 1 -C 6 alkyl is optionally substituted with from 1-2 substituents each independently selected from oxo, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, 3- to 7-membered heterocycloalkyl, and C 3 -C 10 cycloalkoxy;

120 . The compound of any one of claims 1 - 2 , wherein the optionally substituted ring A is

the substituted ring B is selected from the group consisting of:

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,

121 . The compound of any one of claims 1 - 2 , 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 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); and

the substituted ring B is selected from:

wherein

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 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the C 6 -C 10 aryl is optionally substituted with one to two C 1 -C 6 alkyl optionally substituted with one to three halo; and wherein each of the C 2 -C 6 alkynyl and C 1 -C 6 alkyl is optionally substituted with from 1-2 substituents each independently selected from oxo, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, 3- to 7-membered heterocycloalkyl, and C 3 -C 10 cycloalkoxy;

122 . The compound of any one of claims 1 - 2 , 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 —.

the substituted ring B is selected from:

wherein

123 . The compound of any one of claims 1 - 2 , 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 —.

the substituted ring B is selected from:

wherein

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 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the C 6 -C 10 aryl is optionally substituted with one to two C 1 -C 6 alkyl optionally substituted with one to three halo; and wherein each of the C 2 -C 6 alkynyl and C 1 -C 6 alkyl is optionally substituted with from 1-2 substituents each independently selected from oxo, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, 3- to 7-membered heterocycloalkyl, and C 3 -C 10 cycloalkoxy;

124 . The compound of any one of claims 120 and 122 , wherein the substituted ring B is selected from:

wherein each pair of R 6 and R 7 on adjacent atoms taken together with the atoms connecting them, independently form C 4 -C 7 carbocyclic ring or 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 .

125 . The compound of any one of claims 120 and 122 , wherein the substituted ring B is selected from:

wherein each R 6 and R 7 is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo, —CN, C 3 -C 7 cycloalkyl.

126 . The compound of any one of claims 120 and 122 , wherein the substituted ring B is:

wherein

one pair of R 6 and R 7 on adjacent atoms taken together with the atoms connecting them, independently form C 4 -C 7 carbocyclic ring or 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 ;

each of the remaining R 6 and R 7 is independently C 1 -C 6 alkyl.

127 . The compound of any one of the preceding claims, wherein each of R 4 and R 5 is hydrogen.

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

129 . The compound of any one of claims 1 - 127 , wherein R 3 is cyano.

130 . The compound of any one of claims 1 - 127 , wherein R 3 is

wherein the C 1 -C 2 alkylene is optionally substituted by oxo.

131 . The compound of claim 130 , wherein R 3 is CHO.

132 . The compound of claim 130 , wherein R 3 C(O)C 1 -C 6 alkyl.

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

Cmpd

Structure

101

101a

101b

102

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

129a

129b

130

131

131a

131b

132

132a

132b

133

133a

133b

134

135

136

137

138

139

140

141

and pharmaceutically acceptable salts thereof.

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

Cmpd

Structure

101

101a

101b

102

103

104

104a

104b

105

106

106a

106b

107

107a

107b

108

109

110

110a

110b

111

112

112a

112b

113

114

114a

114b

115

116

116a

116b

117

117a

117b

118

119

120

121

122

123

123a

123b

124

125

126

126a

126b

127

128

129

129a

129b

130

130a

130b

131

131a

131b

132

132a

132b

133

133a

133b

134

135

136

137

138

138a

138b

139

139a

139b

140

140a

140b

141

141a

141b

142

143

144

144a

144b

145

145a

145b

(S)

146

147

147a

147b

148

148a

148b

149a

149b

150

150a

150b

151

152

152a

152b

153

154

155

158

159

160

161

162

163

164

165

168

169

170

171

172

173

176

177

178

180

181

182

183

184

185

186

189

190

191

192

194

195

196

197

197a

197b

198

198a

(R)

198b

(S)

and pharmaceutically acceptable salts thereof.

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

Cmpd #

Structure

104a

104b

106a

106b

107a

107b

110a

110b

126a

126b

130a

130b

146

147

148

149a

149b

150

151

152

152a

152b

and pharmaceutically acceptable salts thereof.

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

and a pharmaceutically acceptable salt thereof.

137 . The compound of claim 1 , wherein the compound is selected from Table 1-4.

138 . The compound ofany one of claims 1 - 2 , wherein the compound is selected from Table 1-5.

139 . The compound of any one of claims 1 - 2 , wherein the compound is selected from Table 1-6.

140 . The compound of any one of claims 1 - 2 , wherein the compound is selected from Table 1-7.

141 . The compound of any one of claims 1 - 140 , wherein the sulfur in the moiety S(═O)(NHR 3 )═N— has (S) stereochemistry.

142 . The compound of any one of claims 1 - 140 , wherein the sulfur in the moiety S(═O)(NHR 3 )═N— has (R) stereochemistry.

143 . A pharmaceutical composition comprising a compound or salt as claimed in any one of claims 1 - 142 and one or more pharmaceutically acceptable excipients.

144 . 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 - 142 or a pharmaceutical composition as claimed in claim 143 .

145 . The method of claim 144 , wherein the modulating comprises antagonizing NLRP3.

146 . The method of any one of claim 144 or 145 , which is carried out in vitro.

147 . The method of any one of claims 144 - 146 , wherein the method comprises contacting a sample comprising one or more cells comprising NLRP3 with the compound.

148 . The method of any one of claims 144 - 146 , which is carried out in vivo.

149 . The method of claim 148 , 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.

150 . The method of claim 149 , wherein the subject is a human.

151 . 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 - 142 or a pharmaceutical composition as claimed in claim 143 .

152 . The method of claim 151 , wherein the metabolic disorder is Type 2 diabetes, atherosclerosis, obesity or gout.

153 . 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 - 142 or a pharmaceutical composition as claimed in claim 143 .

154 . The method of claim 153 , wherein the disease of the central nervous system is Alzheimer's disease, multiple sclerosis, Amyotrophic Lateral Sclerosis or Parkinson's disease.

155 . 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 - 142 or a pharmaceutical composition as claimed in claim 143 .

156 . The method of claim 155 , wherein the lung disease is asthma, COPD or pulmonary idiopathic fibrosis.

157 . 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 - 142 or a pharmaceutical composition as claimed in claim 143 .

158 . The method of claim 157 , wherein the liver disease is NASH syndrome, viral hepatitis or cirrhosis.

159 . 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 - 142 or a pharmaceutical composition as claimed in claim 143 .

160 . The method of claim 159 , wherein the pancreatic disease is acute pancreatitis or chronic pancreatitis.

161 . 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 - 142 or a pharmaceutical composition as claimed in claim 143 .

162 . The method of claim 161 , wherein the kidney disease is acute kidney injury or chronic kidney injury.

163 . 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 - 142 or a pharmaceutical composition as claimed in claim 143 .

164 . The method of claim 163 , wherein the intestinal disease is Crohn's disease or Ulcerative Colitis.

165 . 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 - 142 or a pharmaceutical composition as claimed in claim 143 .

166 . The method of claim 165 , wherein the skin disease is psoriasis.

167 . 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 - 142 or a pharmaceutical composition as claimed in claim 143 .

168 . The method of claim 167 , wherein the musculoskeletal disease is scleroderma.

169 . 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 - 142 or a pharmaceutical composition as claimed in claim 143 .

170 . The method of claim 169 , wherein the vessel disorder is giant cell arteritis.

171 . 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 - 142 or a pharmaceutical composition as claimed in claim 143 .

172 . The method of claim 171 , wherein the disorder of the bones is osteoarthritis, osteoporosis or osteopetrosis disorders.

173 . 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 - 142 or a pharmaceutical composition as claimed in claim 143 .

174 . The method of claim 173 , wherein the eye disease is glaucoma or macular degeneration.

175 . 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 - 142 or a pharmaceutical composition as claimed in claim 143 .

176 . The method of claim 175 , wherein the diseases caused by viral infection is HIV or AIDS.

177 . 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 - 142 or a pharmaceutical composition as claimed in claim 143 .

178 . The method of claim 177 , wherein the autoimmune disease is Rheumatoid Arthritis, Systemic Lupus Erythematosus, Autoimmune Thyroiditis.

179 . 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 - 142 or a pharmaceutical composition as claimed in claim 143 .

180 . 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 - 142 or a pharmaceutical composition as claimed in claim 143 .

181 . The method of claim 180 , wherein the cancer is MDS.

182 . The method of claim 180 , wherein the cancer is non-small lung cancer.

183 . The method of claim 180 , wherein the cancer is acute lymphoblastic leukemia.

184 . The method of claim 180 , wherein the cancer is LCH.

185 . The method of claim 180 , wherein the cancer is multiple myeloma.

186 . The method of claim 180 , wherein the cancer is promyelocytic leukemia.

187 . The method of claim 180 , wherein the cancer is acute myeloid leukemia (AML).

188 . The method of claim 180 , wherein the cancer is chronic myeloid leukemia (CML).

189 . The method of claim 180 , wherein the cancer is gastric cancer.

190 . The method of claim 180 , wherein the cancer is lung cancer metastasis.

191 . The method of any one of claims 149 - 190 , further comprising administering a therapeutically effective amount of an anti-TNFα agent to the subject.

192 . The method of claim 191 , wherein the NLRP3 antagonist is administered to the subject prior to administration of the anti-TNFα agent to the subject.

193 . The method of claim 191 , wherein the anti-TNFα agent is administered to the subject prior to the administration of the NLRP3 antagonist to the subject.

194 . The method of claim 191 , wherein the NLRP3 antagonist and the anti-TNFα agent are administered to the subject at substantially the same time.

195 . The method of claim 191 , wherein the NLRP3 antagonist and the anti-TNFα agent are formulated together in a single dosage form.

196 . A compound of any one of claims 1 - 143 , or a method of any one of claims 144 - 195 , wherein the compound of formula AA or the NLRP3 antagonist is not:

or a pharmaceutically acceptable salt thereof.

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 057023/0001 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 29, 2021

From: IFM MANAGEMENT, INC.

To: NOVARTIS INFLAMMASOME RESEARCH, INC.

Reel/Frame 057023/0146 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 29, 2021

From: NOVARTIS INFLAMMASOME RESEARCH, INC.

To: NOVARTIS AG

Reel/Frame 057023/0300 →