1. A compound of F ormula A

Formula A

or a pharmaceutically acceptable salt thereof, wherein:

comprises at least one of CR⁴¹, CR¹⁰, CR¹, and CR⁴²;

comprises at least two of CR³⁵, CR²¹, CR³⁶, CR²⁹, and CR³⁴;

X⁴ is CR⁴, N or NR²⁴;

each R²⁰ is the same or different and is independently selected from hydrogen and C₁-C₆ alkyl;

R⁸ is selected from H, CN, halo, CO2C₁-C₆ alkyl, CO2C3-C8 cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl optionally substituted with hydroxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, and C₁-C₆ haloalkyl; R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, CN, C₁-C₆ haloalkoxy, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

R²⁴ is absent and R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, CN, C₁-C₆ haloalkoxy, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

or R²⁴ is C₁-C₆ alkyl or C3-C8 cycloalkyl and R⁵ is =0;

provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen;

or R² and R³ taken together with the carbons connecting them form a four-membered to seven- membered ring A,

or R⁴ and R⁵ taken together with the carbons connecting them form a four-membered to seven- membered ring B,

or R² and R³ taken together with the carbons connecting them form a four-membered to seven- membered ring A; and R⁴ and R⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

wherein ring A is

wherein

ring A is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S; nl is from 2 to 5;

ml is from 1 to 10;

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

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R⁶ in each ring is the same or different and is independently selected from H, F, C₁-C₆ alkyl, Ci-C₆ alkoxy, NR¹¹R¹², oxo, and =NR¹³;

or two R⁶ taken together with the atom or atoms connecting them form a 3-to-8-membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

each of R¹, R¹⁰, R⁴¹ and R⁴² when bonded to carbon is independently selected from H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, CN, halo, CO2C₁-C₆ alkyl, CO2C3-C8 cycloalkyl, C₆-C₁₀ aryl,

CONR¹¹R¹², C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹²;

and each of R¹, R¹⁰, R⁴¹ and R⁴² when bonded to nitrogen is independently selected from H, Ci- C₆ alkyl, C₁-C₆ haloalkyl, CO2C₁-C₆ alkyl, CO2C3-C8 cycloalkyl, C₆-C₁₀ aryl, CONR¹¹R¹², C₃-C₇ cycloalkyl, S(O₂)Ci-C₆ alkyl and 3- to 7-membered heterocycloalkyl, wherein the C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹²;

or any two of R⁴¹, R¹⁰, R¹, and R⁴² on adjacent atoms, taken together with the atoms connecting them form at least one monocyclic or bicyclic 3-to-l2-membered carbocyclic ring or at least one monocyclic or bicyclic 5- to l2-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, NH, NR¹³, and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, O C₃-C₁₀ cycloalkyl, NR¹¹R¹², =NR¹³, CN, COOC₁-C₆ alkyl, OS(0₂)C₆-Cio aryl, S(0₂)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to lO-membered heterocycloalkyl, and CONR¹¹R¹², wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(02)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to 10- membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to lO-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹²;

each of R³⁴, R²⁹, R³⁵, R²¹ and R³⁶ is independently selected from H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, CN, halo, CO2C₁-C₆ alkyl, CO2C3-C8 cycloalkyl, CONR¹¹R¹², C₃-C₇ cycloalkyl, 3- to 7- membered heterocycloalkyl, C₆-C₁₀ aryl, OC₁-C₆ alkyl, NH2, NHC₁-C₆ alkyl, N(CI-C₆ alkyl)2, NO2, COC₁-C₆ alkyl, SFs and S(0₂)C₁-C₆ alkyl;

wherein the C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C₁-C₆ alkoxy, C₁-C₆ alkyl, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, CONR¹¹R¹², C₃-C₇ cycloalkyl, 3- to 7- membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to lO-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl,

wherein the C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to lO-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl,

or any two of R³⁴, R²⁹, R³⁵, R²¹ and R³⁶ on adjacent atoms, taken together with the atoms connecting them form at least one monocyclic or bicyclic 3-to-l2-membered carbocyclic ring or at least one monocyclic or bicyclic 5- to l2-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, NH, NR¹³, and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC3- C₁₀ cycloalkyl, NR¹¹R¹², =NR¹³, CN, COOC₁-C₆ alkyl, OS(0₂)C₆-Cio aryl, S(0₂)C₆-Cio aryl, Ce- C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to lO-membered heterocycloalkyl, and CONR¹¹R¹², wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(02)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to 10- membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to lO-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹²;

R¹³ is C₁-C₆ alkyl;

each of R¹¹ and R¹² at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, Ci- C₆ haloalkyl, (C=NR¹⁵)NR¹⁷R¹⁸, S(0₂)C₁-C₆ alkyl, S(0₂)NR¹⁷R¹⁸, COR¹⁵, CO2R¹⁵ and CON R¹⁷R¹⁸; wherein the C₁-C₆ alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₇ cycloalkyl, or 3- to 7-membered heterocycloalkyl; or R¹¹ and R¹² 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;

R¹⁵ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, or 5- to lO-membered heteroaryl; and each of R¹⁷ and R¹⁸ at each occurrence is independently selected from hydrogen and C₁-C₆ alkyl.

2. A compound of Formula A

or a pharmaceutically acceptable salt thereof, wherein:

X³⁶ is N or CR³⁶;

X²⁹ is N or CR²⁹;

X³⁴ is N or CR³⁴; comprises at least two of CR³⁵, CR²¹, CR³⁶, CR²⁹, and CR³⁴;

X⁴ is CR⁴, N or NR²⁴;

each R²⁰ is the same or different and is independently selected from hydrogen and C₁-C₆ alkyl;

Y is N or CR²;

Z is N or CR⁸;

R⁸ is selected from H, CN, halo, CO2C₁-C₆ alkyl, CO2C3-C8 cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl optionally substituted with hydroxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, and C₁-C₆ haloalkyl;

R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, CN, C₁-C₆ haloalkoxy, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

R²⁴ is absent and R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, CN, C₁-C₆ haloalkoxy, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

or R²⁴ is C₁-C₆ alkyl or C3-C8 cycloalkyl and R⁵ is =0;

provided that at least one of R², R³, R⁴ andR⁵ is not hydrogen;

or R² and R³ taken together with the carbons connecting them form a four-membered to seven- membered ring A,

or R⁴ and R⁵ taken together with the carbons connecting them form a four-membered to seven- membered ring B,

or R² and R³ taken together with the carbons connecting them form a four-membered to seven- membered ring A; and R⁴ and R⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

wherein ring A is

wherein

ring A is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

nl is from 2 to 5;

ml is from 1 to 10;

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

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R⁶ in each ring is the same or different and is independently selected from H, F, C₁-C₆ alkyl, Ci-C₆ alkoxy, NR¹¹R¹², oxo, and =NR¹³;

or two R⁶ taken together with the atom or atoms connecting them form a 3-to-8-membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

each of R¹, R¹⁰, R⁴¹ and R⁴² when bonded to carbon is independently selected from H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, CN, halo, CO2C₁-C₆ alkyl, CO2C3-C8 cycloalkyl, C₆-C₁₀ aryl,

CONR¹¹R¹², C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹²; and each of R¹, R¹⁰, R⁴¹ and R⁴² when bonded to nitrogen is independently selected from H, Ci- C₆ alkyl, C₁-C₆ haloalkyl, CO2C₁-C₆ alkyl, CO2C3-C8 cycloalkyl, C₆-C₁₀ aryl, CONR¹¹R¹², C₃-C₇ cycloalkyl, S(O₂)Ci-C₆ alkyl and 3- to 7-membered heterocycloalkyl, wherein the C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹²;

or any two of R⁴¹, R¹⁰, R¹, and R⁴² on adjacent atoms, taken together with the atoms connecting them form at least one monocyclic or bicyclic 3-to-l2-membered carbocyclic ring or at least one monocyclic or bicyclic 5- to l2-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, NH, NR¹³, and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, O C₃-C₁₀ cycloalkyl, NR¹¹R¹², =NR¹³, CN, COOC₁-C₆ alkyl, OS(0₂)C₆-Cio aryl, S(0₂)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to lO-membered heterocycloalkyl, and CONR¹¹R¹², wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(02)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to 10- membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to lO-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹²;

each of R³⁴, R²⁹, R³⁵, R²¹ and R³⁶ is independently selected from H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, CN, halo, CO2C₁-C₆ alkyl, CO2C3-C8 cycloalkyl, CONR¹¹R¹², C₃-C₇ cycloalkyl, 3- to 7- membered heterocycloalkyl, C₆-C₁₀ aryl, OC₁-C₆ alkyl, NH2, NHC₁-C₆ alkyl, N(CI-C₆ alkyl)₂, NO2, COC₁-C₆ alkyl, SFs and S(0₂)C₁-C₆ alkyl;

wherein the C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C₁-C₆ alkoxy, C₁-C₆ alkyl, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, CONR¹¹R¹², C₃-C₇ cycloalkyl, 3- to 7- membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to lO-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl,

wherein the C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to lO-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl,

or any two of R³⁴, R²⁹, R³⁵, R²¹ and R³⁶ on adjacent atoms, taken together with the atoms connecting them form at least one monocyclic or bicyclic 3-to-l2-membered carbocyclic ring or at least one monocyclic or bicyclic 5- to l2-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, NH, NR¹³, and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC3- C₁₀ cycloalkyl, NR¹¹R¹², =NR¹³, CN, COOC₁-C₆ alkyl, OS(0₂)C₆-Cio aryl, S(0₂)C₆-Cio aryl, Ce- C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to lO-membered heterocycloalkyl, and CONR¹¹R¹², wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(02)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to 10- membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to lO-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹²;

R¹³ is C₁-C₆ alkyl;

each of R¹¹ and R¹² at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, Ci- C₆ haloalkyl, (C=NR¹⁵)NR¹⁷R¹⁸, S(0₂)C₁-C₆ alkyl, S(0₂)NR¹⁷R¹⁸, COR¹⁵, CO2R¹⁵ and CON R¹⁷R¹⁸; wherein the C₁-C₆ alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₇ cycloalkyl or 3- to 7-membered heterocycloalkyl;

R¹⁵ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, or 5- to lO-membered heteroaryl; and each of R¹⁷ and R¹⁸ at each occurrence is independently selected from hydrogen and C₁-C₆ alkyl.

3. A compound of F ormula I

or a pharmaceutically acceptable salt thereof, wherein:

X^I is O, S, N, CR⁴¹ or NR⁴¹;

X¹⁰ is O, S, N, CR¹⁰ or NR¹⁰;

X^{I I} is O, S, N, CR¹ or NR¹;

X² is O, S, N, CR⁴² or NR⁴²; comprises at least one of CR⁴¹, CR¹⁰, CR¹, and CR⁴²;

X⁴ is CR⁴, N or NR²⁴;

each R²⁰ is the same or different and is independently selected from hydrogen and C₁-C₆ alkyl;

Y is N or CR²;

Z is N or CR⁸;

R⁸ is selected from H, CN, halo, CO2C₁-C₆ alkyl, CO2C3-C8 cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl optionally substituted with hydroxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, and C₁-C₆ haloalkyl;

R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, CN, C₁-C₆ haloalkoxy, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

R²⁴ is absent and R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, CN, C₁-C₆ haloalkoxy, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

or R²⁴ is C₁-C₆ alkyl or C3-C8 cycloalkyl and R⁵ is =0;

provided that at least one of R², R³, R⁴ andR⁵ is not hydrogen;

or R² and R³ taken together with the carbons connecting them form a four-membered to seven- membered ring A,

or R⁴ and R⁵ taken together with the carbons connecting them form a four-membered to seven- membered ring B,

or R² and R³ taken together with the carbons connecting them form a four-membered to seven- membered ring A and R⁴ and R⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

wherein ring A is

Ring B

wherein

ring A is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

nl is from 2 to 5;

ml is from 1 to 10;

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

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R⁶ in each ring is the same or different and is selected from H, F, C₁-C₆ alkyl, Ci- Ce alkoxy, NR¹¹R¹², oxo, and =NR¹³;

or two R⁶ taken together with the atom or atoms connecting them form a 3-to-8-membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

each of R¹, R¹⁰, R⁴¹ and R⁴² when bonded to carbon is independently selected from H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, CN, halo, CO2C₁-C₆ alkyl, CO2C3-C8 cycloalkyl, C₆-C₁₀ aryl,

CONR¹¹R¹², C₃-C₇ cycloalkyl, S(02)Ci-C₆ alkyl and 3- to 7-membered heterocycloalkyl, wherein the C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹²; and each of R¹, R¹⁰, R⁴¹ and R⁴² when bonded to nitrogen is independently selected from H, Ci- C₆ alkyl, C₁-C₆ haloalkyl, CO2C₁-C₆ alkyl, CO2C3-C8 cycloalkyl, C₆-C₁₀ aryl, CONR¹¹R¹², C₃-C₇ cycloalkyl, S(O₂)Ci-C₆ alkyl and 3- to 7-membered heterocycloalkyl, wherein the C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, C₁-C₆ alkyl, oxo, C₁-C₆ alkoxy, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹²;

or any two of R⁴¹, R¹⁰, R¹, and R⁴² on adjacent atoms, taken together with the atoms connecting them form at least one monocyclic or bicyclic 3-to-l2-membered carbocyclic ring or at least one monocyclic or bicyclic 5- to l2-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, NH, NR¹³, and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, O C₃-C₁₀ cycloalkyl, NR¹¹R¹², =NR¹³, CN, COOC₁-C₆ alkyl, OS(0₂)C₆-Cio aryl, S(0₂)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to lO-membered heterocycloalkyl, and CONR¹¹R¹², wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(02)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to 10- membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to lO-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹²;

R¹³ is C₁-C₆ alkyl;

each of R¹¹ and R¹² at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, Ci- C₆ haloalkyl, (C=NR¹⁵)NR¹⁷R¹⁸, S(0₂)C₁-C₆ alkyl, S(0₂)NR¹⁷R¹⁸, COR¹⁵, CO2R¹⁵ and CON R¹⁷R¹⁸; wherein the C₁-C₆ alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₇ cycloalkyl or 3- to 7-membered heterocycloalkyl; or R¹¹ and R¹² 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;

R¹⁵ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, or 5- to lO-membered heteroaryl; and each of R¹⁷ and R¹⁸ at each occurrence is independently selected from hydrogen and C₁-C₆ alkyl.

4. A compound of Formula Ila

Formula lla

or a pharmaceutically acceptable salt thereof, wherein:

X³⁵ is N or CR³⁵;

X^{2 1} is N or CR²¹;

X³⁶ is N or CR³⁶;

X²⁹ is N or CR^29;

X³⁴ is N or CR³⁴: comprises at least two of CR³⁵, CR²¹, CR³⁶, CR²⁹, and CR³⁴;

X⁴ is CR⁴, N or NR²⁴;

each R²⁰ is the same or different and is independently selected from hydrogen and C₁-C₆ alkyl;

Y is N or CR²;

Z is N or CR⁸;

R⁸ is selected from H, CN, halo, CO2C₁-C₆ alkyl, CO2C3-C8 cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl optionally substituted with hydroxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, and C₁-C₆ haloalkyl;

R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, CN, C₁-C₆ haloalkoxy, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

R²⁴ is absent and R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, CN, C₁-C₆ haloalkoxy, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

or R²⁴ is C₁-C₆ alkyl or C3-C8 cycloalkyl and R⁵ is =0;

provided that at least one of R², R³, R⁴ andR⁵ is not hydrogen; or R² and R³ taken together with the carbons connecting them form a four-membered to seven- membered ring A,

or R⁴ and R⁵ taken together with the carbons connecting them form a four-membered to seven- membered ring B,

or R² and R³ taken together with the carbons connecting them form a four-membered to seven- membered ring A and R⁴ and R⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

wherein ring A is

and ring B is

wherein

ring A is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

nl is from 2 to 5;

ml is from 1 to 10;

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

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R⁶ in each ring is the same or different and is selected from H, F, C₁-C₆ alkyl, Ci- Ce alkoxy, NR¹¹R¹², oxo, and =NR¹³; or two R⁶ taken together with the atom or atoms connecting them form a 3-to-8-membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

each of R³⁴, R²⁹, R³⁵, R²¹ and R³⁶ is independently selected from H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, CN, halo, CO₂C₁-C₆ alkyl, CO2C3-C8 cycloalkyl, CONR¹¹R¹², C₃-C₇ cycloalkyl, 3- to 7- membered heterocycloalkyl, C₆-C₁₀ aryl, OC₁-C₆ alkyl, NH2, NHC₁-C₆ alkyl, N(CI-C₆ alkyl)₂, NO2, COC₁-C₆ alkyl, SFs and S(0₂)C₁-C₆ alkyl;

wherein the C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C₁-C₆ alkoxy, C₁-C₆ alkyl, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, CONR¹¹R¹², C₃-C₇ cycloalkyl, 3- to 7- membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to lO-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl,

wherein the C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to lO-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl,

or any two of R³⁴, R²⁹, R³⁵, R²¹ and R³⁶ on adjacent atoms, taken together with the atoms connecting them form at least one monocyclic or bicyclic 3-to-l2-membered carbocyclic ring or at least one monocyclic or bicyclic 5- to l2-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, NH, NR¹³, and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC3- C₁₀ cycloalkyl, NR¹¹R¹², =NR¹³, CN, COOC₁-C₆ alkyl, OS(0₂)C₆-Cio aryl, S(0₂)C₆-Cio aryl, Ce- C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to lO-membered heterocycloalkyl, and CONR¹¹R¹², wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(02)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to 10- membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to lO-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹²;

R¹³ is C₁-C₆ alkyl; each of R¹¹ and R¹² at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, Ci- C₆ haloalkyl, (C=NR¹⁵)NR¹⁷R¹⁸, S(0₂)C₁-C₆ alkyl, S(0₂)NR¹⁷R¹⁸, COR¹⁵, C0₂R¹⁵ and CON R¹⁷R¹⁸; wherein the C₁-C₆ alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₇ cycloalkyl or 3- to 7-membered heterocycloalkyl; or R¹¹ and R¹² 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;

R¹⁵ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, or 5- to lO-membered heteroaryl; and each of R¹⁷ and R¹⁸ at each occurrence is independently selected from hydrogen and C₁-C₆ alkyl.

5. A compound of Formula A

or a pharmaceutically acceptable salt thereof, wherein:

Ar is a heteroaryl group or an aryl or heteroaryl group

2;

comprises at least one of CR⁴¹, CR¹⁰, CR¹, and CR⁴²;

X⁴ is CR⁴, N or NR²⁴;

each R²⁰ is the same or different and is independently selected from hydrogen and C₁-C₆ alkyl;

Y is N or CR²;

Z is N or CR⁸;

R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl, CO2C3-C8 cycloalkyl, CONR¹¹R¹², Ci-Ce alkyl optionally substituted with hydroxy, and C₁-C₆ haloalkyl;

R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

R²⁴ is absent and R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

or R²⁴ is C₁-C₆ alkyl or C₃-C₈ cycloalkyl and R⁵ is =0;

provided that at least one of R², R³, R⁴ andR⁵ is not hydrogen, and that R² andR⁴ are not both hydroxymethyl;

or R² and R³ taken together with the carbons connecting them form a four-membered to seven- membered ring A,

or R⁴ and R⁵ taken together with the carbons connecting them form a four-membered to seven- membered ring B,

or R² and R³ taken together with the carbons connecting them form a four-membered to seven- membered ring A and R⁴ and R⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

wherein ring A is

and ring B is

Ring B

wherein

ring A is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

nl is from 2 to 5;

ml is from 1 to 10;

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

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R⁶ in each ring is the same or different and is selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and =NR¹³;

or two R⁶ taken together with the atom or atoms connecting them form a 3-to-8-membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

each of R¹, R¹⁰, R⁴¹ and R⁴² when bonded to carbon is independently selected from H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, CN, halo, CO2C₁-C₆ alkyl, CO2C3-C8 cycloalkyl, C₆-C₁₀ aryl,

CONR¹¹R¹², C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C₁-C₆ alkoxy, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹²; and each of R¹, R¹⁰, R⁴¹ and R⁴² when bonded to nitrogen is independently selected from H, Ci- C₆ alkyl, C₁-C₆ haloalkyl, CO2C₁-C₆ alkyl, CO2C3-C8 cycloalkyl, C₆-C₁₀ aryl, CONR¹¹R¹², C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C₁-C₆ alkoxy, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹²;

or any two of R⁴¹, R¹⁰, R¹, and R⁴² on adjacent atoms, taken together with the atoms connecting them form at least one monocyclic or bicyclic 3-to-l2-membered carbocyclic ring or at least one monocyclic or bicyclic 5- to l2-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, NH, NR¹³, and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, O C₃-C₁₀ cycloalkyl, NR¹¹R¹², =NR¹³, CN, COOC₁-C₆ alkyl, OS(0₂)C₆-Cio aryl, S(0₂)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to lO-membered heterocycloalkyl, and CONR¹¹R¹², wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(02)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to 10- membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to lO-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹²;

each of R³⁴, R²⁹, R³⁵, R²¹ and R³⁶ is independently selected from H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, CN, halo, CO2C₁-C₆ alkyl, CO2C3-C8 cycloalkyl, CONR¹¹R¹², C₃-C₇ cycloalkyl, 3- to 7- membered heterocycloalkyl, C₆-C₁₀ aryl, OC₁-C₆ alkyl, NH2, NHC₁-C₆ alkyl, N(CI-C₆ alkyl)₂, NO2, COC₁-C₆ alkyl,

wherein the C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C₁-C₆ alkoxy, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, CONR¹¹R¹², C₃-C₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to lO-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl,

wherein the C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to lO-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl,

or any two of R³⁴, R²⁹, R³⁵, R²¹ and R³⁶ on adjacent atoms, taken together with the atoms connecting them form at least one monocyclic or bicyclic 3-to-l2-membered carbocyclic ring or at least one monocyclic or bicyclic 5- to l2-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, NH, NR¹³, and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC3- C₁₀ cycloalkyl, NR¹¹R¹², =NR¹³, CN, COOC₁-C₆ alkyl, OS(0₂)C₆-Cio aryl, S(0₂)C₆-Cio aryl, Ce- C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to lO-membered heterocycloalkyl, and CONR¹¹R¹², wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(02)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to 10- membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to lO-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹²;

R¹³ is C₁-C₆ alkyl;

each of R¹¹ and R¹² at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, Ci- C₆ haloalkyl, (C=NR¹⁵)NR¹⁷R¹⁸, S(0₂)C₁-C₆ alkyl, S(0₂)NR¹⁷R¹⁸, COR¹⁵, CO2R¹⁵ and CON R¹⁷R¹⁸; wherein the C₁-C₆ alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₇ cycloalkyl or 3- to 7-membered heterocycloalkyl; or R¹¹ and R¹² 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;

R¹⁵ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, or 5- to lO-membered heteroaryl; and each of R¹⁷ and R¹⁸ at each occurrence is independently selected from hydrogen and C₁-C₆ alkyl.

6 A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

X^I is O, S, N, CR⁴¹ or NR⁴¹;

X¹⁰ is O, S, N, CR¹⁰ or NR¹⁰;

X^{I I} is O, S, N, CR¹ or NR¹;

X² is O, S, N, CR⁴² or NR⁴²; comprises at least one of CR⁴¹, CR¹⁰, CR¹, and CR⁴²;

X⁴ is CR⁴, N or NR²⁴;

each R²⁰ is the same or different and is independently selected from hydrogen and C₁-C₆ alkyl;

Y is N or CR²;

Z is N or CR⁸;

R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl, CO2C3-C8 cycloalkyl, CONR¹¹R¹², Ci-Ce alkyl optionally substituted with hydroxy, and C₁-C₆ haloalkyl;

R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

R²⁴ is absent and R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

or R²⁴ is C₁-C₆ alkyl or C3-C8 cycloalkyl and R⁵ is =0;

provided that at least one of R², R³, R⁴ andR⁵ is not hydrogen, and that R² andR⁴ are not both hydroxymethyl;

or R² and R³ taken together with the carbons connecting them form a four-membered to seven- membered ring A, or R⁴ and R⁵ taken together with the carbons connecting them form a four-membered to seven- membered ring B,

or R² and R³ taken together with the carbons connecting them form a four-membered to seven- membered ring A and R⁴ and R⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

wherein ring A is

wherein

ring A is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

nl is from 2 to 5;

ml is from 1 to 10;

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

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R⁶ in each ring is the same or different and is selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and =NR¹³;

or two R⁶ taken together with the atom or atoms connecting them form a 3-to-8-membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S; each of R¹, R¹⁰, R⁴¹ and R⁴² when bonded to carbon is independently selected from H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, CN, halo, CO2C₁-C₆ alkyl, CO2C3-C8 cycloalkyl, C₆-C₁₀ aryl,

CONR¹¹R¹², C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C₁-C₆ alkoxy, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹²;

or any two of R⁴¹, R¹⁰, R¹, and R⁴² on adjacent atoms, taken together with the atoms connecting them form at least one monocyclic or bicyclic 3-to-l2-membered carbocyclic ring or at least one monocyclic or bicyclic 5- to l2-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, NH, NR¹³, and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, O C₃-C₁₀ cycloalkyl, NR¹¹R¹², =NR¹³, CN, COOC₁-C₆ alkyl, OS(0₂)C₆-Cio aryl, S(0₂)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to lO-membered heterocycloalkyl, and CONR¹¹R¹², wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(02)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to 10- membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to lO-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹²;

or R¹ and R¹⁰ taken together with the atoms connecting them form a 3-to-8-membered carbocyclic or heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the ring is optionally substituted with one or more substituents each

independently selected from hydroxy, oxo, C₁-C₆ alkoxy, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, and CONR¹¹R¹²;

R¹³ is C₁-C₆ alkyl;

each of R^{1 1} and R¹² at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, Ci- C₆ haloalkyl, (C=NR¹⁵)NR¹⁷R¹⁸, S(0₂)C₁-C₆ alkyl, S(0₂)NR¹⁷R¹⁸, COR¹⁵, CO2R¹⁵ and CON R¹⁷R¹⁸; wherein the C₁-C₆ alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₇ cycloalkyl or 3- to 7-membered heterocycloalkyl; or R^{1 1} and R¹² 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;

R¹⁵ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, or 5- to lO-membered heteroaryl;

each of R¹⁷ and R¹⁸ at each occurrence is independently selected from hydrogen and C₁-C₆ alkyl.

7. A compound of Formula Ila

Formula Ila

or a pharmaceutically acceptable salt thereof, wherein:

comprises at least two of CR³⁵, CR²¹, CR³⁶, CR²⁹, and CR³⁴;

X⁴ is CR⁴, N or NR²⁴;

each R²⁰ is the same or different and is independently selected from hydrogen and C₁-C₆ alkyl; Y is N or CR²;

Z is N or CR⁸;

R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl, CO2C3-C8 cycloalkyl, CONR¹¹R¹², Ci-Ce alkyl optionally substituted with hydroxy, and C₁-C₆ haloalkyl;

R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy; R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

R²⁴ is absent and R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

or R²⁴ is C₁-C₆ alkyl or C3-C8 cycloalkyl and R⁵ is =0;

provided that at least one of R², R³, R⁴ andR⁵ is not hydrogen, and that R² andR⁴ are not both hydroxymethyl;

or R² and R³ taken together with the carbons connecting them form a four-membered to seven- membered ring A,

or R⁴ and R⁵ taken together with the carbons connecting them form a four-membered to seven- membered ring B,

or R² and R³ taken together with the carbons connecting them form a four-membered to seven- membered ring A and R⁴ and R⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

wherein ring A is

wherein

ring A is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

nl is from 2 to 5;

ml is from 1 to 10; wherein ring B is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R⁶ in each ring is the same or different and is selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and =NR¹³;

or two R⁶ taken together with the atom or atoms connecting them form a 3-to-8-membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

each of R³⁴, R²⁹, R³⁵, R²¹ and R³⁶ is independently selected from H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, CN, halo, CO₂C₁-C₆ alkyl, CO2C3-C8 cycloalkyl, CONR¹¹R¹², C₃-C₇ cycloalkyl, 3- to 7- membered heterocycloalkyl, C₆-C₁₀ aryl, OC₁-C₆ alkyl, NH2, NHC₁-C₆ alkyl, N(CI-C₆ alkyl)₂, NO₂, COC₁-C₆ alkyl,

wherein the C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C₁-C₆ alkoxy, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, CONR¹¹R¹², C₃-C₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to lO-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl,

wherein the C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to lO-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl,

or any two of R³⁴, R²⁹, R³⁵, R²¹ and R³⁶ on adjacent atoms, taken together with the atoms connecting them form at least one monocyclic or bicyclic 3-to-l2-membered carbocyclic ring or at least one monocyclic or bicyclic 5- to l2-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, NH, NR¹³, and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC3- C₁₀ cycloalkyl, NR¹¹R¹², =NR¹³, CN, COOC₁-C₆ alkyl, OS(0₂)C₆-Cio aryl, S(0₂)C₆-Cio aryl, Ce- C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to lO-membered heterocycloalkyl, and CONR¹¹R¹², wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(02)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to 10- membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to lO-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹²;

R¹³ is C₁-C₆ alkyl;

each of R^{1 1} and R¹² at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, CO2R¹⁵ and CONR¹⁷R¹⁸;

R¹⁵ is C₁-C₆ alkyl; and

each of R¹⁷ and R¹⁸ at each occurrence is independently selected from hydrogen and C₁-C₆ alkyl.

8. A compound of Formula A

Formula A

or a pharmaceutically acceptable salt thereof, wherein:

Ar is a heteroaryl group or an aryl or heteroaryl group X³⁴ is N or CR³⁴; comprises at least two of CR³⁵, CR²¹, CR³⁶, CR²⁹, and CR³⁴;

X⁴ is CR⁴, N or NR²⁴;

each R²⁰ is the same or different and is independently selected from hydrogen and C₁-C₆ alkyl;

Y is N or CR²;

Z is N or CR⁸;

R⁸ is selected from H, CN, halo, CO2C₁-C₆ alkyl, CO2C3-C8 cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl optionally substituted with hydroxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, and C₁-C₆ haloalkyl;

R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, CN, C₁-C₆ haloalkoxy, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

R²⁴ is absent and R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, CN, C₁-C₆ haloalkoxy, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

or R²⁴ is C₁-C₆ alkyl or C3-C8 cycloalkyl and R⁵ is =0;

provided that at least one of R², R³, R⁴ andR⁵ is not hydrogen;

or R² and R³ taken together with the carbons connecting them form a four-membered to seven- membered ring A,

or R⁴ and R⁵ taken together with the carbons connecting them form a four-membered to seven- membered ring B,

or R² and R³ taken together with the carbons connecting them form a four-membered to seven- membered ring A and R⁴ and R⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

wherein ring A is

and ring B is

wherein

ring A is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

nl is from 2 to 5;

ml is from 1 to 10;

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

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R⁶ in each ring is the same or different and is selected from H, F, C₁-C₆ alkyl, Ci- Ce alkoxy, NR¹¹R¹², oxo, and =NR¹³;

or two R⁶ taken together with the atom or atoms connecting them form a 3-to-8-membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

two of R⁴¹, R¹⁰, R¹, and R⁴² are present on adjacent atoms, and taken together with the atoms connecting them form at least one monocyclic or bicyclic 3 -to- 12-member ed nonaromatic carbocyclic ring or at least one monocyclic or bicyclic 5- to l2-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, NH, NR¹³, and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci- C₆ alkoxy, O C₃-C₁₀ cycloalkyl, NR¹¹R¹², =NR¹³, CN, COOC₁-C₆ alkyl, OS(0₂)C₆-Cio aryl, S(0₂)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10- membered heterocycloalkyl, and CONR¹¹R¹², wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆- C₁₀ aryl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to lO-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹²;

each of the R¹, R¹⁰, R⁴¹ and R⁴² that are not taken together with the atoms connecting them to form at least one ring, when bonded to carbon, is independently selected from H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, CN, halo, CO₂C₁-C₆ alkyl, CO2C3-C8 cycloalkyl, C₆-C₁₀ aryl, CONR¹¹R¹², C3- C7 cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹²;

each of the R¹, R¹⁰, R⁴¹ and R⁴² that are not taken together with the atoms connecting them to form at least one ring, when bonded to nitrogen, is independently selected from H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, CO2C₁-C₆ alkyl, CO2C3-C8 cycloalkyl, C₆-C₁₀ aryl, CONR¹¹R¹², C₃-C₇ cycloalkyl, S(02)Ci-C₆ alkyl and 3- to 7-membered heterocycloalkyl, wherein the C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹²; two of R³⁴, R²⁹, R³⁵, R²¹ and R³⁶ are present on adjacent atoms, and taken together with the atoms connecting them, form at least one monocyclic or bicyclic 3-to-l2-membered non aromatic carbocyclic ring or at least one monocyclic or bicyclic 5- to l2-membered (e.g., non aromatic) heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, NH, NR¹³, and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, O C₃-C₁₀ cycloalkyl, NR¹¹R¹², =NR¹³, CN, COOCi-Ce alkyl, OS(02)C₆-Cio aryl, S(O₂)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to lO-membered heterocycloalkyl, and CONR¹¹R¹², wherein the C₁-C₆ alkyl, Ci- Ce alkoxy, S(02)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to lO-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C3- C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and

CONR¹¹R¹²;

each of the R³⁴, R²⁹, R³⁵, R²¹ and R³⁶ that are not taken together with the atoms connecting them to form at least one ring, is independently selected from H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, CN, halo, CO2C₁-C₆ alkyl, CO2C3-C8 cycloalkyl, C₆-C₁₀ aryl, CONR¹¹R¹², C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, Ce- C₁₀ aryl, and CONR¹¹R¹²;

R¹³ is C₁-C₆ alkyl;

each of R^{1 1} and R¹² at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, Ci- C₆ haloalkyl, (C=NR¹⁵)NR¹⁷R¹⁸, S(0₂)C₁-C₆ alkyl, S(0₂)NR¹⁷R¹⁸, COR¹⁵, CO2R¹⁵ and CON R¹⁷R¹⁸; wherein the C₁-C₆ alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₇ cycloalkyl or 3- to 7-membered heterocycloalkyl; or R^{1 1} and R¹² 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;

R¹⁵ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, or 5- to lO-membered heteroaryl; and each of R¹⁷ and R¹⁸ at each occurrence is independently selected from hydrogen and C₁-C₆ alkyl.

9. The compound of claim 8, wherein when R¹ and R¹⁰ are taken together with the atoms connecting them to form a 3 -to- 8 -member ed carbocyclic or heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

then the carbocyclic or heterocyclic ring is substituted with one or more substituents each independently selected from halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, O C₃-C₁₀ cycloalkyl, CN, NR¹¹R¹², CONR¹¹R¹², OS(0₂)C₆-Cio aryl, S(0₂)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to lO-membered heterocycloalkyl; wherein the C₁-C₆ alkyl, S(O₂)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to lO-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹²; and

wherein R¹² is selected from C₁-C₆ haloalkyl, (C=NR¹⁵)NR¹⁷R¹⁸, S(02)Ci-C₆ alkyl, S(02)NR¹⁷R¹⁸, or C₁-C₆ alkyl substituted with one or more hydroxy, halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₇ cycloalkyl or 3- to 7-membered heterocycloalkyl; when two adjacent X²⁹, X³⁴, X²¹, and X³⁶ are other than N, and two of R³⁴, R²⁹, R³⁵, R²¹ and R³⁶ that are on adjacent ring carbon atoms taken together with the atoms connecting them form a 6-membered aromatic ring, a five-to-eight-membered carbocyclic non-aromatic ring, a five- or six-membered heteroaromatic ring or a five-to-eight-membered heterocyclic non aromatic ring, then the carbocyclic or heterocyclic ring is substituted with one or more substituents each independently selected from halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, O C₃-C₁₀ cycloalkyl, CN, NR¹¹R¹², CONR¹¹R¹², OS(0₂)C₆-Cio aryl, S(0₂)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to lO-membered heterocycloalkyl; wherein the C₁-C₆ alkyl, S(O₂)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to lO-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹²; and

wherein R¹² is selected from C₁-C₆ haloalkyl, (C=NR¹⁵)NR¹⁷R¹⁸, S(02)Ci-C₆ alkyl, S(O₂)NR¹⁷R¹⁸, or C₁-C₆ alkyl substituted with one or more hydroxy, halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₇ cycloalkyl or 3- to 7-membered heterocycloalkyl; and when two adjacent X²⁹, X³⁴, X²¹, and X³⁶ are other than N, and two of R³⁴, R²⁹, R³⁵, R²¹ and R³⁶ that are on adjacent ring carbon atoms taken together with the adjacent ring carbons form a 3-5 membered or 7-12 membered aromatic carbocyclic ring (e.g., 9-12 membered), a 3-4 membered or 9-12 membered non-aromatic carbocyclic ring, a 7-l2-membered aromatic heterocyclic ring, or a 9-l2-membered nonaromatic heterocyclic ring, then the carbocyclic or heterocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC3- C₁₀ cycloalkyl, NR¹¹R¹², =NR¹³, CN, COOC₁-C₆ alkyl, OS(0₂)C₆-Cio aryl, S(0₂)C₆-Cio aryl, Ce- C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to lO-membered heterocycloalkyl, and CONR¹¹R¹², wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(0₂)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to 10- membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to lO-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹²;

wherein each of R¹¹ and R¹² at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, (C=NR¹⁵)NR¹⁷R¹⁸, S(0₂)C₁-C₆ alkyl, S(0₂)NR¹⁷R¹⁸, COR¹⁵, C0₂R¹⁵ and CON R¹⁷R¹⁸; wherein the C₁-C₆ alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₇ cycloalkyl or 3- to 7-membered heterocycloalkyl; or R¹¹ and R¹² 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.

10. A compound of Formula A

FormuSa A

or a pharmaceutically acceptable salt thereof, wherein:

Ar is a heteroaryl group

X^I is O, S, N, CR⁴¹ or NR⁴¹;

X¹⁰ is O, S, N, CR¹⁰ or NR¹⁰;

X^{I I} is O, S, N, CR¹ or NR¹;

X² is O, S, N, CR⁴² or NR⁴²; comprises at least one of CR⁴¹, CR¹⁰, CR¹, and CR⁴²; X⁴ is CR⁴, N or NR²⁴;

each R²⁰ is the same or different and is independently selected from hydrogen and C₁-C₆ alkyl;

Y is N or CR²;

Z is N or CR⁸;

R⁸ is selected from H, CN, halo, CO2C₁-C₆ alkyl, CO2C3-C8 cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl optionally substituted with hydroxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, and C₁-C₆ haloalkyl;

R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, CN, C₁-C₆ haloalkoxy, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

R²⁴ is absent and R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, CN, C₁-C₆ haloalkoxy, C₃-C₇ cycloalkyl or C₁-C₆ alkyl optionally substituted with hydroxy;

or R²⁴ is C₁-C₆ alkyl or C3-C8 cycloalkyl and R⁵ is =0;

provided that at least one of R², R³, R⁴ andR⁵ is not hydrogen;

or R² and R³ taken together with the carbons connecting them form a four-membered to seven- membered ring A,

or R⁴ and R⁵ taken together with the carbons connecting them form a four-membered to seven- membered ring B,

or R² and R³ taken together with the carbons connecting them form a four-membered to seven- membered ring A and R⁴ and R⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

wherein ring A is

and ring B is

wherein

ring A is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

nl is from 2 to 5;

ml is from 1 to 10;

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

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R⁶ in each ring is the same or different and is selected from H, F, C₁-C₆ alkyl, Ci- Ce alkoxy, NR¹¹R¹², oxo, and =NR¹³;

or two R⁶ taken together with the atom or atoms connecting them form a 3-to-8-membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

two of R⁴¹, R¹⁰, R¹, and R⁴² are present on adjacent atoms, and taken together with the atoms connecting them form at least one monocyclic or bicyclic 3 -to- 12-member ed nonaromatic carbocyclic ring or at least one monocyclic or bicyclic 5- to l2-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, NH, NR¹³, and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci- C₆ alkoxy, O C₃-C₁₀ cycloalkyl, NR¹¹R¹², =NR¹³, CN, COOC₁-C₆ alkyl, OS(0₂)C₆-Cio aryl, S(0₂)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10- membered heterocycloalkyl, and CONR¹¹R¹², wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆- C₁₀ aryl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to lO-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹²;

each of the R¹, R¹⁰, R⁴¹ and R⁴² that are not taken together with the atoms connecting them to form at least one ring, when bonded to carbon, is independently selected from H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, CN, halo, CO2C₁-C₆ alkyl, CO2C3-C8 cycloalkyl, C₆-C₁₀ aryl, CONR¹¹R¹², C3- C7 cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹²;

each of the R¹, R¹⁰, R⁴¹ and R⁴² that are not taken together with the atoms connecting them to form at least one ring, when bonded to nitrogen, is independently selected from H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, CO2C₁-C₆ alkyl, CO2C3-C8 cycloalkyl, C₆-C₁₀ aryl, CONR¹¹R¹², C₃-C₇ cycloalkyl, S(02)Ci-C₆ alkyl and 3- to 7-membered heterocycloalkyl, wherein the C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹²;

R¹³ is C₁-C₆ alkyl;

each of R¹¹ and R¹² at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, Ci- C₆ haloalkyl, (C=NR¹⁵)NR¹⁷R¹⁸, S(0₂)C₁-C₆ alkyl, S(0₂)NR¹⁷R¹⁸, COR¹⁵, CO2R¹⁵ and CON R¹⁷R¹⁸; wherein the C₁-C₆ alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₇ cycloalkyl or 3- to 7-membered heterocycloalkyl; or R¹¹ and R¹² 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;

R¹⁵ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, or 5- to lO-membered heteroaryl;

each of R¹⁷ and R¹⁸ at each occurrence is independently selected from hydrogen and C₁-C₆ alkyl.

11. The compound of claim 10, wherein when R¹ and R¹⁰ are taken together with the atoms connecting them to form a 3-to-8-membered carbocyclic or heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S; then the carbocyclic or heterocyclic ring is substituted with one or more substituents each independently selected from halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, O C₃-C₁₀ cycloalkyl, CN, NR¹¹R¹², CONR¹¹R¹², OS(0₂)C₆-Cio aryl, S(0₂)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to lO-membered heterocycloalkyl;

wherein the C₁-C₆ alkyl, S(O₂)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to lO-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹²; and

wherein R¹² is selected from C₁-C₆ haloalkyl, (C=NR¹⁵)NR¹⁷R¹⁸, S(O₂)Ci-C₆ alkyl,

S(02)NR¹⁷R¹⁸, or C₁-C₆ alkyl substituted with one or more hydroxy, halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₇ cycloalkyl or 3- to 7-membered heterocycloalkyl.

12. The compound of any one of claims 1, 2, 3, 5, 6, and 8-11, wherein the moiety

13. The compound of any one of claims 1, 2, 3, 5, 6, and 8-11, wherein the moiety

14. The compound of any one of claims 1, 2, 3, 5, 6, and 8-11, wherein LHS3 is

15. The compound of any one of claims 1, 2, 3, 5, 6, and 8-11, wherein the moiety

16. The compound of any one of claims 1, 2, 3, 5, 6, and 8-11, wherein the moiety

17. The compound of any one of claims 1, 2, 3, 5, 6, and 8-11, wherein the moiety

18. The compound of any one of claims 1, 2, 3, 5, 6, and 8-11, wherein the moiety

19. The compound of any one of claims 1, 2, 3, 5, 6, and 8-11, wherein the moiety

20. The compound of claim 19, wherein X¹⁰ is N; and X² is S.

21. The compound of any one of claims 19-20, wherein LHS7 is

22. The compound of claim 19, wherein LHS7 is

23. The compound of any one of claims 1, 2, 3, 5, 6, and 8-11 wherein the moiety

24. The compound of claim 23, wherein X¹ is S; and X² is CH.

25. The compound of claim 1, 2, 4, 5 or 7, wherein the moiety is

26. The compound of claim 1, 2, 4, 5 or 7, wherein the moiety

(LHS10).

27. The compound of claim any one of claims 1, 2, 3, 5, 6, and 8-11, wherein the moiety

28. The compound of claim 1, 2, 4, 5 or 7, wherein the moiety is

29. The compound of claim 1, 2, 4, 5, or 7, wherein the moiety is

30. The compound of claim 1, 2, 4, 5, or 7-9, wherein the moiety is

31. The compound of claim 1, 2, 4, 5, or 7, wherein the moiety

(LHS17).

32. The compound of claim 31, wherein

33. The compound of claim 1, 2, 4, 5, or 7, wherein the moiety IS

34. The compound of any one of the preceding claims, wherein the moiety

35. The compound of claim 34, wherein the moiety

(RHS1).

36. The compound of claim 34, wherein the moiety

(RHS2).

37. The compound of claim 34, wherein the moiety

(RHS3).

38. The compound of claim 34, wherein the moiety

(RHS5).

39. The compound of claim 38, wherein

40. The compound of claim 34, wherein the moiety

(RHS6).

41. The compound of claim 34, wherein the moiety

(RHS9).

42. The compound of claim 34, wherein the moiety

(RHS12).

43. The compound of any one of claims 1-3, 5, , and 8-11, wherein X¹⁰ is CR¹⁰.

44. The compound of any one of claims 1-3, 5, , 8-11, 12-15, 17-18, 22, 23 and 43, wherein R¹⁰ is 2-hydroxy-2-propyl.

45. The compound of any one of claims 1-3, 5, , 8-11, 12-15, 17-18, 22, 23 and 43, wherein R¹⁰ is 1 -hydroxy- 1 -cyclopropyl.

46. The compound of any one of claims 1-3, 5, , 8-11, 12-15, 17-18, 22, 23 and 43, wherein R¹⁰ is dimethylaminomethyl.

47. The compound of any one of claims 1-3, 5, , 8-11, 12-15, 17-18, 22, 23 and 43, wherein R¹⁰ is S(02)CH3.

48. The compound of any one of claims 1-3, 5, ', and 8-11, wherein X¹¹ is CR¹.

49. The compound of any one of claims 1-3, 5, , 8-11, 12-16, 18-19, 22, and 48, wherein R¹ is 2-hydroxy-2-propyl.

50. The compound of any one of claims 1-3, 5, 6, 8-11, 12-16, 18-19, 22, and 48, wherein R¹ is 1 -hydroxy- 1 -cyclopropyl.

51. The compound of any one of claims 1-3, 5, 6, 8-11, 12-16, 18-19, 22, and 48, wherein R¹ is dimethylaminomethyl.

52. The compound of any one of claims 1-3, 5, 6, 8-11, 12-16, 18-19, 22, and 48, wherein R¹ is S(0₂)CH3.

53. The compound of any one of claims 1-3, 5, 6, and 8-11, wherein X¹⁰ is NR¹⁰.

54. The compound of claim 53, wherein R¹⁰ is isopropyl.

55. The compound of claim 53, wherein R¹⁰ is methyl.

56. The compound of claim 53, wherein R¹⁰ is benzyl.

57. The compound of claim 53, wherein R¹⁰ is phenyl.

58. The compound of any one of claims 1-3, 5, 6, 17, and 22, wherein R⁴¹ and R¹⁰, taken together with the atoms connecting them form a monocyclic or bicyclic 3 -to- 12- membered carbocyclic ring or a monocyclic or bicyclic 5- to l2-membered heterocyclic ring containing 1 -3 heteroatoms independently selected from O, N, NH, NR¹³, and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, O C₃-C₁₀ cycloalkyl, NR¹¹R¹², =NR¹³, CN, COOC₁-C₆ alkyl, OS(0₂)C₆-Cio aryl, S(0₂)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10- membered heterocycloalkyl, and CONR¹¹R¹², wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(0₂)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to lO-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹².

59. The compound of any one of claims 1-3, 5, 6, 12-15, 18, 22, and 23, wherein R¹⁰ and R¹, taken together with the atoms connecting them form a monocyclic or bicyclic 3- to-l2-membered carbocyclic ring or a monocyclic or bicyclic 5- to l2-membered heterocyclic ring containing 1 -3 heteroatoms independently selected from O, N, NH, NR¹³, and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, O C₃-C₁₀ cycloalkyl, NR¹¹R¹², =NR¹³, CN, COOC₁-C₆ alkyl, OS(0₂)C₆-Cio aryl, S(0₂)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10- membered heterocycloalkyl, and CONR¹¹R¹², wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(0₂)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to lO-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹².

60. The compound of any one of claims 1-3, 5, 6, and 16, wherein R¹ and R⁴², taken together with the atoms connecting them form a monocyclic or bicyclic 3 -to- 12- membered carbocyclic ring or a monocyclic or bicyclic 5- to l2-membered heterocyclic ring containing 1 -3 heteroatoms independently selected from O, N, NH, NR¹³, and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, O C₃-C₁₀ cycloalkyl, NR¹¹R¹², =NR¹³, CN, COOC₁-C₆ alkyl, OS(0₂)C₆-Cio aryl, S(0₂)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10- membered heterocycloalkyl, and CONR¹¹R¹², wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(0₂)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to lO-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹².

61. The compound of any one of claims 1, 2, 4, 5, and 7, wherein X³⁵ is CR³⁵.

62. The compound of any one of claims 1, 2, 4, 5, 7, 25, 29-30, 33, and 61 wherein R³⁵ is 2-hydroxy-2-propyl.

63. The compound of any one of claims 1, 2, 4, 5, 7, 25, 29-30, 33, and 61, wherein R³⁵ is 1 -hydroxy- 1 -cyclopropyl.

64. The compound of any one of claims 1, 2, 4, 5, 7, 25, 29-30, 33, and 61, wherein R³⁵ is dimethylaminomethyl.

65. The compound of any one of claims 1, 2, 4, 5, 7, 25, 29-30, 33, and 61, wherein R³⁵ is S(0₂)CH3.

66. The compound of any one of claims 1, 2, 4, 5, 7, 28, and 61, wherein X²¹ is CR²¹.

67. The compound of any one of claims 1, 2, 4, 5, 7, 28, 61, and 66, wherein R²¹ is 2- hydroxy-2-propyl.

68. The compound of any one of claims 1, 2, 4, 5, 7, 28, 61, and 66, wherein R²¹ is 1 - hydroxy- 1 -cyclopropyl.

69. The compound of any one of claims 1, 2, 4, 5, 7, 28, 61, and 66, wherein R²¹ is dimethylaminomethyl.

70. The compound of any one of claims 1, 2, 4, 5, 7, 28, 61, and 66, wherein R²¹ is S(0₂)CH3.

71. The compound of any one of claims 1, 2, 4, 5, 7, 28, 61, and 66, wherein R²¹ is halo.

72. The compound of any one of claims 1, 2, 4, 5, 7, 28, 61, and 66, wherein R²¹ is CH3.

73. The compound of any one of claims 1, 2, 4, 5, 7, 26, 28, 30, 31, and 61, wherein R²⁹ is 2-hydroxy-2-propyl.

74. The compound of any one of claims 1, 2, 4, 5, 7, 26, 28, 30, 31, and 61, wherein R²⁹ is 1 -hydroxy- 1 -cyclopropyl.

75. The compound of any one of claims 1, 2, 4, 5, 7, 26, 28, 30, 31, and 61, wherein R²⁹ is dimethylaminomethyl.

76. The compound of any one of claims 1, 2, 4, 5, 7, 26, 28, 30, 31, and 61, wherein R²⁹ is S(0₂)CH3.

77. The compound of any one of claims 1, 2, 4, 5, 7, 26, 28, 30, 31, and 61, wherein R²⁹ is halo.

78. The compound of any one of claims 1, 2, 4, 5, 7, 26, 28, 30, 31, and 61, wherein R²⁹ is CH3.

79. The compound of any one of claims 1, 2, 4, 5, 7, 31, and 33, wherein X³⁶ is CR³⁶.

80. The compound of any one of claims 1, 2, 4, 5, 7, 31, 33, and 79, wherein R³⁶ is halo.

81. The compound of any one of claims 1, 2, 4, 5, 7, 31, 33, and 79, wherein R³⁶ is CH3.

82. The compound of any one of claims 1, 2, 4, 5, 7, and 61, wherein R³⁴ is halo.

83. The compound of any one of claims 1, 2, 4, 5, 7, and 61, wherein R³⁴ is Ctb.

84. The compound of any one of claims 1-83, wherein Y is CR², X⁴ is CR⁴, and Z is CR⁸.

85. The compound of claim 84, wherein R² is C₁-C₆ alkyl (e.g., isopropyl), halo (e.g., chloro), or C₃-C₇ cycloalkyl (e.g., cyclopropyl); R³ is hydrogen, halo (e.g., fluoro), or C₁-C₆ alkyl (e.g., isopropyl or methyl); R⁸ is hydrogen, halo (e.g., chloro or fluoro),

CN, or C₁-C₆ haloalkyl (e.g., difluoromethyl); R⁵ is hydrogen or halo (e.g., fluoro); and R⁴ is halo (e.g., chloro), C₁-C₆ alkyl optionally substituted with hydroxy (e.g., isopropyl), or C₃-C₇ cycloalkyl (e.g., cyclopropyl);

or R² and R³ taken together with the carbons connecting them form a five-membered ring A,

or R⁴ and R⁵ taken together with the carbons connecting them form a five-membered ring B,

or R² and R³ taken together with the carbons connecting them form a five-membered ring A and R⁴ and R⁵ taken together with the carbons connecting them form a five- membered ring B,

wherein ring A is

and ring B is

wherein

ring A is a carbocyclic ring;

nl is 3;

ml is 6;

wherein ring B is a carbocyclic ring; n2 is 3;

m2 is 6;

wherein each R⁶ in each ring is the same or different and is selected from H or C₁-C₆ alkyl (e.g., methyl).

86. The compound of any one of claims 1-33 and 35-83, wherein Y is CR², X⁴ is CR⁴, and Z is N.

87. The compound of claim 86, wherein R² is C₁-C₆ alkyl (e.g., isopropyl) or halo (e.g., chloro); R³ is hydrogen or C₁-C₆ alkyl (e.g., isopropyl); R⁵ is hydrogen or halo (e.g., fluoro); R⁴ is C₁-C₆ alkyl (e.g., isopropyl);

or R² and R³ taken together with the carbons connecting them form a five-membered ring A,

or R⁴ and R⁵ taken together with the carbons connecting them form a five-membered ring B,

or R² and R³ taken together with the carbons connecting them form a five-membered ring A and R⁴ and R⁵ taken together with the carbons connecting them form a five- membered ring B,

wherein ring A is

and ring B is

wherein

ring A is a carbocyclic ring;

nl is 3;

ml is 6; wherein ring B is a carbocyclic ring;

n2 is 3;

m2 is 6;

wherein each R⁶ in each ring is the same or different and is selected from H or C₁-C₆ alkyl (e.g., methyl).

88. The compound of any one of the preceding claims, wherein each R²⁰ is hydrogen.

89. The compound of any one of claims 1-2, 3, 5, and 6, wherein

Ar is a heteroaryl group wherein

X^I is O, S, N or CH;

X¹⁰ is N, CR¹⁰ or NR¹⁰;

X^II is N, CR¹ or NR¹;

X² is O, S, N or CH;

each of R¹ and R¹⁰ when bonded to carbon is independently selected from H, C₁-C₆ alkyl, C₆-C₁₀ aryl, S(O₂)Ci-C₆ alkyl and C₃-C₇ cycloalkyl, wherein the C₁-C₆ alkyl and C₃-C₇ cycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C₁-C₆ alkoxy, and NR¹¹R¹²; and each of R¹, R¹⁰ when bonded to nitrogen is independently selected from H, C₁-C₆ alkyl, Ce- C₁₀ aryl, and C₃-C₇ cycloalkyl, wherein the C₁-C₆ alkyl and C₃-C₇ cycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy and C₁-C₆ alkoxy;

R⁸ is selected from H, CN, Cl, F, C₁-C₆ alkyl, C₁-C₆ alkoxy, Ci-C₆haloalkoxy, and C₁-C₆ haloalkyl;

R² is hydrogen, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl or C₁-C₆ alkyl;

R³ is hydrogen or halo;

R⁴ is hydrogen, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl or C₁-C₆ alkyl;

R⁵ is hydrogen or halo.

90. The compound of any one of claims 1-2, 3, 5, 6, and 8-11, wherein

the compound of formula I is a compound of formula la

wherein

X¹⁰ is N or CR¹⁰;

and

X² is O, S, or NR⁴².

91. The compound of claim 90, wherein X¹⁰ is N; and X² is O.

92. The compound of claim 90, wherein X¹⁰ is N; and X² is S.

93. The compound of claim 90, wherein X¹⁰ is CR¹⁰; and X² is O.

94. The compound of claim 90, wherein X¹⁰ is CR¹⁰; and X² is S.

95. The compound of any one of claims 1, 2, 3, 5, 6, and 8-11, wherein

the compound of formula I is a compound of formula lb:

wherein

X¹ is O, S, or NR⁴¹;

and

X² is N or CR⁴².

96. The compound of claim 95, wherein X¹ is O; and X² is N.

97. The compound of claim 95, wherein X¹ is S; and X² is N.

98. The compound of claim 95, wherein X¹ is O; and X² is CR⁴².

99. The compound of claim 95, wherein X¹ is S; and X² is CR⁴².

100. The compound of any one of claims 90-99, wherein R¹ is 2-hydroxy-2-propyl.

101. The compound of any one of claims 90 and 93-99, wherein R¹⁰ is 2-hydroxy-2- propyl.

102. The compound of any one of claims 90-99, wherein R¹ is 1 -hydroxy- 1- cyclopropyl.

103. The compound of any one of claims 90 and 93-99, wherein R¹⁰ is 1 -hydroxy- 1- cyclopropyl.

104. The compound of any one of claims 90-95, wherein R⁴¹ is 2-hydroxy-2-propyl.

105. The compound of any one of claims 90, 95 and 98-99, wherein R⁴² is 2-hydroxy - 2-propyl.

106. The compound of any one of claims 90-95, wherein R⁴¹ is 1 -hydroxy- 1- cyclopropyl.

107. The compound of any one of claims 90, 95 and 98-99, wherein R⁴² is 1 -hydroxy - 1 -cyclopropyl.

108. The compound of any one of claims 90-99, wherein R¹ is dimethylaminomethyl.

109. The compound of any one of claims 90-99, wherein R¹ is S(02)CH3.

110. The compound of any one of claims 90 and 93-99, wherein R¹⁰ is

dimethylaminomethyl.

111. The compound of any one of claims 90 and 93-99, wherein R¹⁰ is S(02)CH3.

112. The compound of any one of claims 90-95, wherein R⁴¹ is dimethylaminomethyl.

113. The compound of any one of claims 90-95, wherein R⁴¹ is S(02)CH3.

114. The compound of any one of claims 90, 95 and 98-99, wherein R⁴² is

dimethylaminomethyl.

115. The compound of any one of claims 90, 95 and 98-99, wherein R⁴² is S(02)CH3.

116. The compound of any one of claims 1, 2, 4, 5, and 7, wherein

Ar is an aryl or heteroaryl group

X³⁵ is CR³⁵;

X²¹ is N or CR²¹;

X³⁶ is CR³⁶;

each of R³⁴, R²⁹, R³⁵, R²¹ and R³⁶ is independently selected from H, C₁-C₆ alkyl, halo, C₃-C₇ cycloalkyl, 3- to 7-membered nonaromatic monocyclic heterocycloalkyl, C₆-C₁₀ aryl, and S(0₂)C₁-C₆ alkyl; wherein the C₁-C₆ alkyl, 3- to 7-membered nonaromatic monocyclic heterocycloalkyl, and C₃-C₇ cycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxyl, C₁-C₆ alkyl, oxo, NR¹¹R¹², and 3- to 7-membered heterocycloalkyl,

R⁸ is selected from H, CN, Cl, F, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, and C₁-C₆ haloalkyl;

R² is hydrogen, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl or C₁-C₆ alkyl;

R³ is hydrogen or halo;

R⁴ is hydrogen, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl or C₁-C₆ alkyl;

R⁵ is hydrogen or halo.

138. The compound of claim 116, wherein R³⁴ halo.

139. The compound of claim 1-3, 5, 6, 8, and 10, wherein the ring is

, wherein:

R^x is selected from the group consisting of H and C₁-C₆ alkyl (e.g., methyl);

Z¹ is selected from the group consisting of O, NH, NCH3, and -CH2- optionally substituted with 1 -2 R⁵⁰;

Z² is selected from the group consisting of NH, NCH3, and -CH2- optionally substituted with 1 -2 R⁵⁰;

Z³ is selected from the group consisting of -CH2- optionally substituted with 1 -2 R⁵⁰, -CH2CH2- optionally substituted with 1-2 R⁵⁰, and -CH2CH2CH2- optionally substituted with 1 -2 R⁵⁰;

R5° is selected from the group consisting of hydroxy, halo (e.g., fluoro), oxo, C₁-C₆ alkyl (e.g., methyl or ethyl) optionally substituted with one R⁵¹, C₁-C₆ alkoxy (e.g., methoxy, ethoxy, or isopropoxy) optionally substituted with one R⁵¹, NR¹¹R¹², 3- to lO-membered heterocycloalkyl (e.g., azetidinyl or pyrrolidinyl) optionally substituted with one R⁵¹, or at least one pair of R⁵⁰ on the same atom, taken together with the atom connecting them, independently forms a monocyclic C3-C4 carbocyclic ring or a monocyclic 3- to 4-membered heterocyclic ring containing 1 O atom;

R⁵¹ is selected from the group consisting of halo (e.g., fluoro), NR¹¹R¹², C₂-C₆ alkynyl (e.g., ethynyl), and C₁-C₆ alkoxy (e.g., methoxy);

R¹¹ and R¹² at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl (e.g., methyl or ethyl), COR¹⁵, and CO2R¹⁵; and

R¹⁵ is selected from the group consisting of: C₁-C₆ alkyl (e.g., methyl or /-butyl) and C₁-C₆ haloalkyl (e.g., trifluoromethyl).

140. The compound of any one of claims 1-3, 5-6, 8, and 10, wherein the ring

wherein

Z⁴ is selected from the group consisting of: -CH2- optionally substituted with 1-2 R⁵⁰, O, -C(O)-, N-CH3, and NH;

Z⁵ is selected from the group consisting of: O, -C(O)-, NH, N-CH3, -CH2- optionally substituted with 1-2 R⁵⁰, and -CH2CH2- optionally substituted with 1-2 R⁵⁰;

u is 0, 1, 2, 3, or 4;

R₅° is selected from the group consisting of: hydroxy, halo (e.g., fluoro), C₁-C₆ alkyl (e.g., methyl) optionally substituted with one R⁵¹, C₁-C₆ alkoxy (e.g., methoxy, isopropoxy, or /-butoxy) optionally substituted with one R⁵¹, NR¹¹R¹², oxo, 3- to 10- membered heterocycloalkyl (e.g., azetidinyl or pyrrolidinyl) optionally substituted with one R⁵¹;

R⁵¹ is selected from the group consisting of NR¹¹R¹², C₂-C₆ alkynyl (e.g., ethynyl), and C₁-C₆ alkoxy (e.g., methoxy);

R^{1 1} and R¹² at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl

(e.g., methyl or ethyl), COR¹⁵, and CO2R¹⁵; and

R¹⁵ is selected from the group consisting of: C₁-C₆ alkyl (e.g., /-butyl).

141. The compound of any one of claims 1-33 and 43-140, wherein the ring

, wherein:

R² is halo (e.g., chloro), C₃-C₇ cycloalkyl (e.g., cyclopropyl), or C₁-C₆ alkyl (e.g., isopropyl);

R³ is hydrogen, halo (e.g., fluoro), or C₁-C₆ alkyl (e.g., isopropyl); R⁸ is selected from H, CN, halo (e.g., chloro or fluoro), and C₁-C₆ haloalkyl (e.g., difluoromethyl);

R⁵ is hydrogen, C₁-C₆ alkyl (e.g., isopropyl), C₃-C₇ cycloalkyl (e.g., cyclopropyl), or halo (e.g., fluoro); and

R⁴ is halo (e.g., chloro), C₃-C₇ cycloalkyl (e.g., cyclopropyl), or C₁-C₆ alkyl (e.g., isopropyl).

V

142. The compound any one of claims 1-33 and 43-140, wherein the ring IS , wherein:

R² is halo (e.g., chloro) or C₁-C₆ alkyl (e.g., isopropyl);

R³ is hydrogen;

or R² and R³ taken together with the carbons connecting them form a 5 -member ed carbocyclic ring;

R⁸ is selected from H, CN, and halo (e.g., chloro or fluoro);

v is 0 or 1 ; and

R⁶ is C₁-C₆ alkyl (e.g., methyl).

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

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

410

421

and pharmaceutically acceptable salts thereof.

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

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 NRLP3 activity, the method comprising contacting NRLP3 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

NRLP3.

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

150. The method of claim any one of claims 147-149, wherein the method comprises contacting a sample comprising one or more cells comprising NRLP3 with the compound.

151. The method of any one of claims 147, 148 and 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 NRLP3 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, Addison's disease, or pernicious anemia.

182. The method of claim 180, wherein the disease is cancer or aging.

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 over expression 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. 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 over expression of NLRP3; acute lymphoblastic leukemia (ALL), such as ALL in patients resistant to glucocorticoids treatment; Langerhan’s cell histiocytosis (LCH); multiple myeloma; promyelocytic leukemia; 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.

185. The method of any one of claims 183-184, wherein the cancer is MDS.

186. The method of any one of claims 183-184, wherein the cancer is non-small lung cancer.

187. The method of any one of claims 183-184, wherein the cancer is acute lymphoblastic leukemia.

188. The method of any one of claims 183-184, wherein the cancer is LCH.

189. The method of any one of claims 183-184, wherein the cancer is multiple myeloma.

190. The method of any one of claims 183-184, wherein the cancer is promyelocytic leukemia.

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

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

193. The method of any one of claims 183-184, wherein the cancer is gastric cancer.

194. The method of any one of claims 183-184, wherein the cancer is lung cancer metastasis.

195. The method of any one of claims 147-194, further comprising administering a therapeutically effective amount of an anti-TNFa agent to the subject.

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

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

198. The method of claim 195, wherein the NLRP3 antagonist and the anti-TNFa

agent are administered to the subject at substantially the same time.

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

200. The compound of claim 1, wherein:

Ar is a heteroaryl group

wherein at least two of R⁴¹, R¹⁰, R¹, and R⁴² are present and on adjacent atoms, such that taken together with the atoms connecting them form at least one monocyclic or bicyclic 3 -to- 12-member ed carbocyclic ring or at least one monocyclic or bicyclic 5- to 12- membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, NH, NR¹³, and S, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, O C₃-C₁₀ cycloalkyl, NR¹¹R¹², =NR¹³, CN, COOC₁-C₆ alkyl, OS(0₂)C₆-Cio aryl, S(0₂)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to lO-membered

heterocycloalkyl, and CONR¹¹R¹², wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(02)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10- membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR¹¹R¹², =NR¹³, COOCi -C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹².

201. The compound of claim 200, wherein:

202. The compound of claim 201, wherein:

the at least two of R⁴¹, R¹⁰, R¹, and R⁴² present on adjacent atoms and taken together with the atoms connecting them, form a monocyclic 5- to l2-membered heterocyclic ring containing 1-3 heteroatoms selected from O and N, optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C2-

Ce alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, O C₃-C₁₀ cycloalkyl, NR¹¹R¹², =NR¹³, CN, COOC₁-C₆ alkyl, OS(02)C₆-Cio aryl, S(O₂)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to lO-membered heterocycloalkyl, and CONR¹¹R¹², wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(02)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to lO-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR¹¹R¹², =NR¹³, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹².

203. The compound of any one of claims 200 to 202, wherein

Ar is selected from

optionally substitued with one or more substituents R⁵⁵ , wherein each R⁵⁵ is

independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, O C₃-C₁₀ cycloalkyl, NR¹¹R¹², =NR¹³, CN, COOC₁-C₆ alkyl, OS(0₂)C₆-Cio aryl, S(02)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to lO-membered heterocycloalkyl, and CONR¹¹R¹², wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(02)C₆-Cio aryl, C₆-C₁₀ aryl, 5- to lO-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to lO-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR¹¹R¹², =NR¹³, COOCi- C₆ alkyl, C₆-C₁₀ aryl, and CONR¹¹R¹².

204. The compound of any one of claims 200 to 203, wherein wherein the moiety

R⁸ is selected from H, CN, halo, CO2C₁-C₆ alkyl, CO2C3-C8 cycloalkyl, CONR¹¹R¹², Ci- Ce alkyl optionally substituted with hydroxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, and C₁-C₆ haloalkyl.

205. The compound of claim 204, wherein R⁸ is CN.