Heterocyclic compounds as PARG inhibitors

Abstract

The present application provides heterocyclic compounds that modulate the activity of poly(ADP-ribose) glycohydrolase (PARG), which are useful in the treatment of various diseases, including cancer.

Description

[0001] HETEROCYCLIC COMPOUNDS AS PARG INHIBITORS

[0002] TECHNICAL FIELD

[0003] The present disclosure provides heterocyclic compounds as well as their pharmaceutical compositions that modulate the activity of poly(ADP-ribose) glycohydrolase (PARG) and are useful in the treatment of various diseases related to PARG, including cancer.

[0004] BACKGROUND

[0005] DNA repair or replication deficiency increases replication stress (RS) in cancer cells, inducing persistent DNA damage response (DDR) to stabilize replication forks and maintain genomic stability (Cybulla, E., et al., Nat Rev Cancer, 2023, 23, 6). As one of the hallmarks of cancer, RS leads to DNA breaks in S phase, triggers cell cycle checkpoints, eventually activates DNA repair or cell death pathways (Saxena, S., et al., Mol Cell, 2022, 82, 2298). Exploiting RS-related vulnerabilities by targeting DDR factors that cause additional DNA damage or prevent repair that exacerbates cellular stress emerges as an attractive strategy for treating cancers.

[0006] Development of highly potent, selective, and efficacious poly(ADP-ribose) glycohydrolase (PARG) inhibitors represents a promising avenue for targeted cancer therapy.

[0007] SUMMARY

[0008] The present disclosure provides, inter alia, compounds of Formula I: or pharmaceutically acceptable salts thereof, wherein constituent members are defined herein.

[0009] The present disclosure further provides a pharmaceutical composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0010] The present disclosure further provides methods of inhibiting poly(ADP- ribose) glycohydrolase (PARG) activity, comprising contacting the PARG with a compound described herein, or a pharmaceutically acceptable salt thereof.

[0011] The present disclosure further provides methods of treating a disease or a disorder associated with PARG in a patient by administering to the patient a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof.

[0012] The present disclosure further provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.

[0013] The present disclosure further provides use of a compound described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in any of the methods described herein.

[0014] DETAILED DESCRIPTION

[0015] The present application provides a compound of Formula I:

[0016] I or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3, 4, 5, or 6; n is 1, 2, 3, 4, 5, or 6; X1is N or CR5;

[0017] X2is N or CR6;

[0018] X3is C or N;

[0019] Z is O or NR7;

[0020] Ring A is phenyl, 6-membered heteroaryl, each = is independently a single or double bond;

[0021] Y1is C or N;

[0022] Y2is C or N;

[0023] Y3is C(-L3-R3), or N;

[0024] Ring B is Ce-io aryl or 5-10 membered heteroaryl;

[0025] Ring C is C5-10 cycloalkyl, phenyl, 5-10 membered heterocycloalkyl, or 5-6 membered heteroaryl; each L2and L3is independently selected from bond, C1-6 alkylene, C1-6 haloalkylene, C3-7 cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6 membered heteroarylene, -C3-7 cycloalkylene-Ci-4 alkyl-, -(4-7 membered heterocycloalkylene)-Ci-4 alkyl-, -phenylene-Ci-4 alkyl-, -(5-6 membered heteroarylene)-Ci-4alkyl-, -O-, -N(RL)-, -C(O)-, -N(RL)C(O)-, -N(RL)C(O)N(RL)-, - N(RL)C(O)O-, -S(O)-, -S(O)2-, -S(O)(=NRL)-, -S(O)2N(RL)-, and -N(RL)S(O)2N(RL)-, wherein the C1-6 alkylene, C1-6 haloalkylene, C3-7 cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6 membered heteroarylene, C3-7 cycloalkylene-Ci-4 alkyl, (4-7 membered heterocycloalkylene)-Ci-4 alkyl, -phenylene-Ci-4 alkyl-, and (5- 6 membered heteroarylene)-Ci-4 alkyl of L2and L3are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; or, L2and one of L3, together with the atoms to which they are attached, form a C5-30 cycloalkyl, or 5-30 membered heterocycloalkyl group, wherein the C5-30 cycloalkyl and 5-30 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R2substituents; or, two of L3, together with the atoms to which they are attached, form a 5-6 membered heteroaryl, C5-14 cycloalkyl, or 5-14 membered heterocycloalkyl group, wherein the 5-6 membered heteroaryl, C5-14 cycloalkyl and 5-14 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3substituents; or, one of L3and one of R4, together with the atoms to which they are attached, form a C5-30 cycloalkyl, or 5-30 membered heterocycloalkyl group, wherein the C5-30 cycloalkyl and 5-30 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R3substituents; each RLis independently selected from H, C1-6 alkyl, and C1-6 haloalkyl;

[0026] R1is selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci- 4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci- 4 alkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0027] R2is selected from H, oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, - ORa2, -SRa2, -NRc2Rd2, -NO2, -C(O)Ra2, -C(O)C(O)Ra2, -C(O)ORa2, -C(O)NRc2Rd2, -C(O)C(O)NRc2Rd2, -C(O)NRc2(ORa2), -OC(O)Ra2, -OC(O)NRc2Rd2, -OC(O)ORa2, - OS(O)2Rb2, -OS(O)2NRc2Rd2, -NRc2C(O)Ra2, -NRc2C(O)ORa2, -NRc2C(O)NRc2Rd2, - NRc2S(O)2Rb2, -NRc2S(O)2NRc2Rd2, -NRc2ORa2, -NRc2S(O)Rb2, -NRc2S(O)NRc2Rd2, - S(O)Rb2, -S(O)2Rb2, -S(O)NRc2Rd2, -S(O)2NRc2Rd2, -C(=NRe2)Ra2, - C(=NRe2)NRc2Rd2, -NRc2C(=NRe2)Ra2, -NRc2C(=NRe2)NRc2Rd2, - NRc2S(O)(=NRe2)Rb2, -NRc2S(O)(=NRe2)NRc2Rd2, -OS(O)(=NRe2)Rb2, - S(O)(=NRe2)Rb2, -S(O)(=NRe2)NRc2Rd2, -C(O)NRc2S(O)2Rb2, - C(O)NRc2S(O)2NRc2Rd2, -S(O)2NRc2C(O)Rb2, and -NRc2S(O)NRc2C(O)Rb2, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4- 10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; each Ra2, Rc2, and Rd2is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra2, Rc2, and Rd2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; or, any Rc2and Rd2attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; each Rb2is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; each Re2is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R2Ais independently selected from oxo, H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, -CN, -0Ra2A, -SRa2A, -NRc2ARd2A, -N02, -C(O)Ra2A, -C(O)C(O)Ra2A, - C(O)ORa2A, -C(O)NRc2ARd2A, -C(O)C(O)NRc2ARd2A, -C(O)NRc2A(ORa2A), - OC(O)Ra2A, -OC(O)NRc2ARd2A, -OC(O)ORa2A, -OS(O)2Rb2A, -OS(O)2NRc2ARd2A, - NRc2AC(O)Ra2A, -NRc2AC(O)ORa2A, -NRc2AC(O)NRc2ARd2A, -NRc2AS(O)2Rb2A, - NRc2AS(O)2NRc2ARd2A, -NRc2AORa2A, -NRc2AS(O)Rb2A, -NRc2AS(O)NRc2ARd2A, - S(O)Rb2A, -S(O)2Rb2A, -S(O)NRc2ARd2A, -S(O)2NRc2ARd2A, -C(=NRe2A)Ra2A, - C(=NRe2A)NRc2ARd2A, -NRc2AC(=NRe2A)Ra2A, -NRc2AC(=NRe2A)NRc2ARd2A, - NRc2AS(O)(=NRe2A)Rb2A, -NRc2AS(O)(=NRe2A)NRc2ARd2A, -OS(O)(=NRe2A)Rb2A, - S(O)(=NRe2A)Rb2A, -S(O)(=NRe2A)NRc2ARd2A, -C(O)NRc2AS(O)2Rb2A, - C(O)NRc2AS(O)2NRc2ARd2A, -S(O)2NRc2AC(O)Rb2A, and -NRc2AS(O)NRc2AC(O)Rb2A, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of R2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra2A, Rc2A, and Rd2Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra2A, Rc2A, and Rd2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc2Aand Rd2Aattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rb2Ais independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Re2Ais independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R3is independently selected from oxo, H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, -CN, -ORa3, -SRa3, -NRc3Rd3, -NO2, -C(O)Ra3, -C(O)C(O)Ra3, -C(O)ORa3, - C(O)NRc3Rd3, -C(O)NRc3(ORa3), -OC(O)Ra3, -OC(O)NRc3Rd3, -OC(O)ORa3, - OS(O)2Rb3, -OS(O)2NRc3Rd3, -NRc3C(O)Ra3, -NRc3C(O)ORa3, -NRc3C(O)NRc3Rd3, - NRc3S(O)2Rb3, -NRc3S(O)2NRc3Rd3, -NRc3ORa3, -NRc3S(O)Rb3, -NRc3S(O)NRc3Rd3, - S(O)Rb3, -S(O)2Rb3, -S(O)NRc3Rd3, -S(O)2NRc3Rd3, -C(=NRe3)Ra3, - C(=NRe3)NRc3Rd3, -NRc3C(=NRe3)Ra3, -NRc3C(=NRe3)NRc3Rd3, - NRc3S(O)(=NRe3)Rb3, -NRc3S(O)(=NRe3)NRc3Rd3, -OS(O)(=NRe3)Rb3, - S(O)(=NRe3)Rb3, -S(O)(=NRe3)NRc3Rd3, -C(O)NRc3S(O)2Rb3, - C(O)NRc3S(O)2NRc3Rd3, -S(O)2NRc3C(O)Rb3, -NRc3S(O)NRc3C(O)Rb3, - NRc3S(O)(=NRe3)NRc3C(O)Rb3, -C(O)C(O)NRc3Rd3, and -P(O)RfiRg3, wherein the Ci- 6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; each Ra3, Rc3, and Rd3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra3, Rc3, and Rd3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; or, any Rc3and Rd3attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; each Rb3is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; each Re3is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each Rfiand Rg3are independently selected from C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and, C1-6 haloalkoxy; each R3Ais independently selected from oxo, H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, -CN, -0Ra3A, -SRa3A, -NRc3ARd3A, -N02, -C(O)Ra3A, -C(O)C(O)Ra3A, - wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of R3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra3A, Rc3A, and Rd3Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra3A, Rc3A, and Rd3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc3Aand Rd3Aattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rb3Ais independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Re3Ais independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R4is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, (5-6 membered heteroaryl)-Ci-4 alkyl, -CN, -ORa4, -SRa4, -NRc4Rd4, -NO2, -C(O)Ra4, -C(O)ORa4, -C(O)NRc4Rd4, -C(O)NRc4(ORa4), -OC(O)Ra4, -OC(O)NRc4Rd4, -OC(O)ORa4, -OS(O)2Rb4, -OS(O)2NRc4Rd4, -NRc4C(O)Ra4, - NRc4C(O)ORa4, -NRc4C(O)NRc4Rd4, -NRc4S(O)2Rb4, -NRc4S(O)2NRc4Rd4, -NRc4ORa4, -NRc4S(O)Rb4, -NRc4S(O)NRc4Rd4, -S(O)Rb4, -S(O)2Rb4, -S(O)NRc4Rd4, - S(O)2NRc4Rd4, -C(=NRe4)Ra4, -C(=NRe4)NRc4Rd4, -NRc4C(=NRe4)Ra4, - NRc4C(=NRe4)NRc4Rd4, -NRc4S(O)(=NRe4)Rb4, -NRc4S(O)(=NRe4)NRc4Rd4, - OS(O)(=NRe4)Rb4, -S(O)(=NRe4)Rb4, -S(O)(=NRe4)NRc4Rd4, -C(O)NRc4S(O)2Rb4, - C(O)NRc4S(O)2NRc4Rd4, -S(O)2NRc4C(O)Rb4, and -NRc4S(O)NRc4C(O)Rb4, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of R4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra4, Rc4, and Rd4is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci- 4 alkyl, wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of Ra4, Rc4, and Rd4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc4and Rd4attached to the same N atom, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group, wherein the 4- 7 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rb4is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of Rb4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Re4is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl;

[0028] R5is selected from H, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and -CN;

[0029] R6is selected from H, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and -CN;

[0030] R7is selected from H, CN, ORa7, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; or, R7and R1, together with the atoms to which they are attached, form a 5-10 membered heterocycloalkyl group, wherein the 5-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0031] Ra7is selected from H, Ci-6 alkyl, and Ci-6 haloalkyl; each RGis independently selected from OH, CN, halo, oxo, Ci-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, cyano-Ci-4 alkyl, HO-C1-4 alkyl, C1-4 alkoxy-Ci-4 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-3 alkylamino, di(Ci-3 alkyl)amino, thio, C1-3 alkylthio, C1-3 alkylsulfinyl, Ci- 3 alkyl sulfonyl, carbamyl, C1-3 alkylcarbamyl, di(Ci-3 alkyl)carbamyl, carboxy, C1-3 alkylcarbonyl, C1-3 alkoxycarbonyl, C1-3 alkylcarbonyloxy, C1-3 alkylcarbonylamino, C1-3 alkoxy carbonylamino, aminocarbonyloxy, C1-3 alkylaminocarbonyloxy, di (C 1-3 alkyl)aminocarbonyloxy, C1-3 alkylsulfonylamino, aminosulfonyl, C1-3 alkylaminosulfonyl, di(Ci-3 alkyl)aminosulfonyl, aminosulfonylamino, C1-3 alkylaminosulfonylamino, di (C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C1-3 alkylaminocarbonylamino, and di(Ci-3 alkyl)aminocarbonylamino.

[0032] In some embodiments, the present application provides a compound of Formula I:

[0033] I or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3, 4, 5, or 6; n is 1, 2, 3, 4, 5, or 6;

[0034] X1is N or CR5;

[0035] X2is N or CR6;

[0036] X3is C or N;

[0037] Z is O or NR7; Ring A is phenyl, 6-membered heteroaryl, each = is independently a single or double bond;

[0038] Y1is C or N;

[0039] Y2is C or N;

[0040] Y3is C(-L3-R3), or N;

[0041] Ring B is Ce-io aryl or 5-10 membered heteroaryl;

[0042] Ring C is C5-10 cycloalkyl, phenyl, 5-10 membered heterocycloalkyl, or 5-6 membered heteroaryl; each L2and L3is independently selected from bond, C1-6 alkylene, C1-6 haloalkylene, C3-7 cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6 membered heteroarylene, -C3-7 cycloalkylene-Ci-4 alkyl-, -(4-7 membered heterocycloalkylene)-Ci-4 alkyl-, -phenylene-Ci-4 alkyl-, -(5-6 membered heteroarylene)-Ci-4alkyl-, -O-, -N(RL)-, -C(O)-, -N(RL)C(O)-, -N(RL)C(O)N(RL)-, - N(RL)C(O)O-, -S(O)-, -S(O)2-, -S(O)(=NRL)-, -S(O)2N(RL)-, and -N(RL)S(O)2N(RL)-, wherein the C1-6 alkylene, C1-6 haloalkylene, C3-7 cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6 membered heteroarylene, C3-7 cycloalkylene-Ci-4 alkyl, (4-7 membered heterocycloalkylene)-Ci-4 alkyl, -phenylene-Ci-4 alkyl-, and (5- 6 membered heteroarylene)-Ci-4 alkyl of L2and L3are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; or, L2and one of L3, together with the atoms to which they are attached, form a C5-10 cycloalkyl, or 5-10 membered heterocycloalkyl group, wherein the C5-10 cycloalkyl and 5-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2substituents; each RLis independently selected from H, C1-6 alkyl, and C1-6 haloalkyl;

[0043] R1is selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci- 4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci- 4 alkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0044] R2is selected from H, oxo, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, - S(O)2NRc2C(O)Rb2, and -NRc2S(O)NRc2C(O)Rb2, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; each Ra2, Rc2, and Rd2is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra2, Rc2, and Rd2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; or, any Rc2and Rd2attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; each Rb2is independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; each Re2is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R2Ais independently selected from oxo, H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, -CN, -ORa2A, -SRa2A, -NRc2ARd2A, -NO2, -C(O)Ra2A, -C(O)ORa2A, - C(O)NRc2ARd2A, -C(O)NRc2A(ORa2A), -OC(O)Ra2A, -OC(O)NRc2ARd2A, -OC(O)ORa2A, -OS(O)2Rb2A, -OS(O)2NRc2ARd2A, -NRc2AC(O)Ra2A, -NRc2AC(O)ORa2A, - NRc2AC(O)NRc2ARd2A, -NRc2AS(O)2Rb2A, -NRc2AS(O)2NRc2ARd2A, -NRc2AORa2A, - NRc2AS(O)Rb2A, -NRc2AS(O)NRc2ARd2A, -S(O)Rb2A, -S(O)2Rb2A, -S(O)NRc2ARd2A, - S(O)2NRc2ARd2A, -C(=NRe2A)Ra2A, -C(=NRe2A)NRc2ARd2A, -NRc2AC(=NRe2A)Ra2A, - NRc2AC(=NRe2A)NRc2ARd2A, -NRc2AS(O)(=NRe2A)Rb2A, - NRc2AS(O)(=NRe2A)NRc2ARd2A, -OS(O)(=NRe2A)Rb2A, -S(O)(=NRe2A)Rb2A, - S(O)(=NRe2A)NRc2ARd2A, -C(O)NRc2AS(O)2Rb2A, -C(O)NRc2AS(O)2NRc2ARd2A, - S(O)2NRc2AC(O)Rb2A, and -NRc2AS(O)NRc2AC(O)Rb2A, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra2A, Rc2A, and Rd2Ais independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra2A, Rc2A, and Rd2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc2Aand Rd2Aattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rb2Ais independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Re2Ais independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R3is independently selected from oxo, H, halo, Ci-6 alkyl, C2-6 alkenyl, C2-e alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, -CN, -ORa3, -SRa3, -NRc3Rd3, -NO2, -C(O)Ra3, -C(O)ORa3, -C(O)NRc3Rd3, - S(O)2NRc3C(O)Rb3, and -NRc3S(O)NRc3C(O)Rb3, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; each Ra3, Rc3, and Rd3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra3, Rc3, and Rd3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; or, any Rc3and Rd3attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; each Rb3is independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; each Re3is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R3Ais independently selected from oxo, H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, -CN, -ORa3A, -SRa3A, -NRc3ARd3A, -NO2, -C(O)Ra3A, -C(O)ORa3A, - C(O)NRc3ARd3A, -C(O)NRc3A(ORa3A), -OC(O)Ra3A, -OC(O)NRc3ARd3A, -OC(O)ORa3A, -OS(O)2Rb3A, -OS(O)2NRc3ARd3A, -NRc3AC(O)Ra3A, -NRc3AC(O)ORa3A, - NRc3AC(O)NRc3ARd3A, -NRc3AS(O)2Rb3A, -NRc3AS(O)2NRc3ARd3A, -NRc3AORa3A, - NRc3AS(O)Rb3A, -NRc3AS(O)NRc3ARd3A, -S(O)Rb3A, -S(O)2Rb3A, -S(O)NRc3ARd3A, - S(O)2NRc3ARd3A, -C(=NRe3A)Ra3A, -C(=NRe3A)NRc3ARd3A, -NRc3AC(=NRe3A)Ra3A, - NRc3AC(=NRe3A)NRc3ARd3A, -NRc3AS(O)(=NRe3A)Rb3A, - NRc3AS(O)(=NRe3A)NRc3ARd3A, -OS(O)(=NRe3A)Rb3A, -S(O)(=NRe3A)Rb3A, - S(O)(=NRe3A)NRc3ARd3A, -C(O)NRc3AS(O)2Rb3A, -C(O)NRc3AS(O)2NRc3ARd3A, - S(O)2NRc3AC(O)Rb3A, and -NRc3AS(O)NRc3AC(O)Rb3A, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra3A, Rc3A, and Rd3Ais independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra3A, Rc3A, and Rd3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc3Aand Rd3Aattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rb3Ais independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Re3Ais independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R4is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, (5-6 membered heteroaryl)-Ci-4 alkyl, -CN, -0Ra4, -SRa4, -NRc4Rd4, -NO2, -C(O)Ra4, -C(O)ORa4, -C(O)NRc4Rd4, -C(O)NRc4(ORa4), -OC(O)Ra4, -OC(O)NRc4Rd4, -OC(O)ORa4, -OS(O)2Rb4, -OS(O)2NRc4Rd4, -NRc4C(O)Ra4, - NRc4C(O)ORa4, -NRc4C(O)NRc4Rd4, -NRc4S(O)2Rb4, -NRc4S(O)2NRc4Rd4, -NRc4ORa4, -NRc4S(O)Rb4, -NRc4S(O)NRc4Rd4, -S(O)Rb4, -S(O)2Rb4, -S(O)NRc4Rd4, - S(O)2NRc4Rd4, -C(=NRe4)Ra4, -C(=NRe4)NRc4Rd4, -NRc4C(=NRe4)Ra4, - NRc4C(=NRe4)NRc4Rd4, -NRc4S(O)(=NRe4)Rb4, -NRc4S(O)(=NRe4)NRc4Rd4, - OS(O)(=NRe4)Rb4, -S(O)(=NRe4)Rb4, -S(O)(=NRe4)NRc4Rd4, -C(O)NRc4S(O)2Rb4, - C(O)NRc4S(O)2NRc4Rd4, -S(O)2NRc4C(O)Rb4, and -NRc4S(O)NRc4C(O)Rb4, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of R4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra4, Rc4, and Rd4is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci- 4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of Ra4, Rc4, and Rd4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc4and Rd4attached to the same N atom, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group, wherein the 4- 7 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rb4is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl, wherein the Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of Rb4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Re4is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl;

[0045] R5is selected from H, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and -CN;

[0046] R6is selected from H, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and -CN;

[0047] R7is selected from H, CN, ORa7, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; or, R7and R1, together with the atoms to which they are attached, form a 5-10 membered heterocycloalkyl group, wherein the 5-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0048] Ra7is selected from H, C1-6 alkyl, and C1-6 haloalkyl; each RGis independently selected from OH, CN, halo, oxo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, cyano-Ci-4 alkyl, HO-C1-4 alkyl, C1-4 alkoxy-Ci-4 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-3 alkylamino, di(Ci-3 alkyl)amino, thio, C1-3 alkylthio, C1-3 alkylsulfinyl, Ci- 3 alkyl sulfonyl, carbamyl, C1-3 alkylcarbamyl, di(Ci-3 alkyl)carbamyl, carboxy, C1-3 alkylcarbonyl, C1-3 alkoxycarbonyl, C1-3 alkylcarbonyloxy, C1-3 alkylcarbonylamino, C1-3 alkoxy carbonylamino, aminocarbonyloxy, C1-3 alkylaminocarbonyloxy, di (C 1-3 alkyl)aminocarbonyloxy, C1-3 alkylsulfonylamino, aminosulfonyl, C1-3 alkylaminosulfonyl, di(Ci-3 alkyl)aminosulfonyl, aminosulfonylamino, C1-3 alkylaminosulfonylamino, di (C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C1-3 alkylaminocarbonylamino, and di(Ci-3 alkyl)aminocarbonylamino. In some embodiments, X1is CR5.

[0049] In some embodiments, R5is H or Ci-6 alkyl.

[0050] In some embodiments, R5is H or C1-3 alkyl.

[0051] In some embodiments, R5is H.

[0052] In some embodiments, X2is CR6.

[0053] In some embodiments, R6is H or C1-6 alkyl.

[0054] In some embodiments, R6is H or C1-3 alkyl.

[0055] In some embodiments, R6is H.

[0056] In some embodiments, X1is CR5and X2is CR6.

[0057] In some embodiments, X1and X2are each CH.

[0058] In some embodiments, Z is O.

[0059] In some embodiments, R1is selected from C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci- 4 alkyl, wherein C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci-4 alkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents.

[0060] In some embodiments, R1is selected from C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci- 4 alkyl, wherein C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci-4 alkyl of R1are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.

[0061] In some embodiments, R1is selected from C3-6 cycloalkyl, and C3-6 cycloalkyl-Ci-4 alkyl, wherein the C3-6 cycloalkyl and C3-6 cycloalkyl-Ci-4 alkyl of R1are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.

[0062] In some embodiments, R1is selected from C3-6 cycloalkyl, and C3-6 cycloalkyl-Ci-4 alkyl, wherein the C3-6 cycloalkyl and C3-6 cycloalkyl-Ci-4 alkyl of R1are each optionally substituted with 1 or 2 independently selected RGsubstituents.

[0063] In some embodiments, R1is C3-6 cycloalkyl, which is optionally substituted with 1 or 2 independently selected RGsubstituents. In some embodiments, R1is C3-6 cycloalkyl, which is optionally substituted with 1 or 2 RGsubstituents independently selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and C1-4 haloalkyl.

[0064] In some embodiments, R1is C3-6 cycloalkyl, which is optionally substituted with 1 or 2 RGsubstituents independently selected from C1-4 alkyl.

[0065] In some embodiments, R1is cyclopropyl, which is optionally substituted with 1 or 2 RGsubstituents independently selected from C1-4 alkyl.

[0066] The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R1is methylcyclopropyl.

[0067] In some embodiments, L2is selected from a bond, C3-7 cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6 membered heteroarylene, -C3-7 cycloalkylene-Ci-4 alkyl-, -(4-7 membered heterocycloalkylene)-Ci-4 alkyl-, - phenylene-Ci-4 alkyl-, and -(5-6 membered heteroarylene)-Ci-4 alkyl-, wherein the C3- 7 cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6 membered heteroarylene, -C3-7 cycloalkylene-Ci-4 alkyl-, -(4-7 membered heterocycloalkylene)- C1-4 alkyl-, -phenylene-Ci-4 alkyl-, and -(5-6 membered heteroarylene)-Ci-4 alkyl- of L2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents.

[0068] In some embodiments, L2is selected from a bond, C3-7 cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6 membered heteroarylene, -C3-7 cycloalkylene-Ci-4 alkyl-, -(4-7 membered heterocycloalkylene)-Ci-4 alkyl-, - phenylene-Ci-4 alkyl-, and -(5-6 membered heteroarylene)-Ci-4 alkyl-, wherein the C3- 7 cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6 membered heteroarylene, -C3-7 cycloalkylene-Ci-4 alkyl-, -(4-7 membered heterocycloalkylene)- C1-4 alkyl-, -phenylene-Ci-4 alkyl-, and -(5-6 membered heteroarylene)-Ci-4 alkyl- of L2are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.

[0069] In some embodiments, L2is selected from a bond, C3-7 cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, and 5-6 membered heteroarylene, wherein the C3-7 cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, and 5-6 membered heteroarylene of L2are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents. In some embodiments, L2is selected from a bond and 4-7 membered heterocycloalkylene, wherein the 4-7 membered heterocycloalkylene of L2is optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.

[0070] In some embodiments, L2is selected from a bond and 4-7 membered heterocycloalkylene, wherein the 4-7 membered heterocycloalkylene of L2is optionally substituted with 1 or 2 independently selected RGsubstituents.

[0071] In some embodiments, L2is selected from a bond and 4-7 membered heterocycloalkylene, wherein the 4-7 membered heterocycloalkylene of L2is optionally substituted with 1 or 2 RGsubstituents independently selected from Ci-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and C1-4 haloalkyl.

[0072] In some embodiments, L2is selected from a bond, 1, 2,3,6- tetrahydropyridindiyl, and piperazindiyl, wherein the 1,2,3,6-tetrahydropyridindiyl and piperazindiyl of L2are each optionally substituted with 1 or 2 RGsubstituents independently selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and C1-4 haloalkyl.

[0073] In some embodiments, L2is selected from a bond, 1,2,3,6- tetrahydropyridindiyl, and piperazindiyl, wherein the 1,2,3,6-tetrahydropyridindiyl and piperazindiyl of L2are each optionally substituted with 1 or 2 RGsubstituents independently selected from C1-6 alkyl.

[0074] The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein L2is selected from a bond, 1,2,3,6-tetrahydropyridindiyl, piperazindiyl, and methylpiperazindiyl.

[0075] In some embodiments, L2is a bond.

[0076] In some embodiments, wherein s is 0, 1, or 2.

[0077] In some embodiments, , wherein s is 0, 1, or 2. N r 3-(RG)S

[0078] In some embodiments, L2is , wherein s is 0, 1, or 2. In some embodiments, s is 0 or 1.

[0079] In some embodiments, each RGis independently selected from OH, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 alkoxy, -CN, and cyano-Ci-4 alkyl.

[0080] In some embodiments, each RGis independently selected from OH, C1-4 alkyl, C1-4 alkoxy, -CN, cyano-Ci-4 alkyl.

[0081] In some embodiments, each RGis independently selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and C1-4 haloalkyl.

[0082] In some embodiments, each RGis independently selected from C1-4 alkyl and C1-4 haloalkyl.

[0083] In some embodiments, each RGis independently selected from C1-4 alkyl.

[0084] In some embodiments, each RGis independently selected from OH, methyl, cyanomethyl, methoxy, and -CN.

[0085] In some embodiments, each RGis methyl.

[0086] In some embodiments, R2is selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, -C(O)Ra2, -C(O)C(O)Ra2, -C(O)ORa2, -C(O)NRc2Rd2, - C(O)C(O)NRc2Rd2, -C(O)NRc2(ORa2), -OC(O)Ra2, -OC(O)NRc2Rd2, -NRc2C(O)Ra2, - NRc2C(O)ORa2, and -NRc2C(O)NRc2Rd2, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl of R2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

[0087] In some embodiments:

[0088] L2is a bond; and

[0089] R2is selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, -C(O)Ra2, -C(O)C(O)Ra2, -C(O)ORa2, -C(O)NRc2Rd2, - C(O)C(O)NRc2Rd2, -C(O)NRc2(ORa2), -OC(O)Ra2, -OC(O)NRc2Rd2, -NRc2C(O)Ra2, - NRc2C(O)ORa2, and -NRc2C(O)NRc2Rd2, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl of R2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents. In some embodiments, R2is selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, -C(O)Ra2, -C(O)C(O)Ra2, -C(O)ORa2, -C(O)NRc2Rd2, - C(O)C(O)NRc2Rd2, -C(O)NRc2(ORa2), -OC(O)Ra2, -OC(O)NRc2Rd2, -NRc2C(O)Ra2, - NRc2C(O)ORa2, and -NRc2C(O)NRc2Rd2, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl of R2are each optionally substituted with 1 or 2 independently selected R2Asubstituents.

[0090] In some embodiments:

[0091] L2is a bond; and

[0092] R2is selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, -C(O)Ra2, -C(O)C(O)Ra2, -C(O)ORa2, -C(O)NRc2Rd2, - C(O)C(O)NRc2Rd2, -C(O)NRc2(ORa2), -OC(O)Ra2, -OC(O)NRc2Rd2, -NRc2C(O)Ra2, - NRc2C(O)ORa2, and -NRc2C(O)NRc2Rd2, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl of R2are each optionally substituted with 1 or 2 independently selected R2Asubstituents.

[0093] In some embodiments, R2is selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, -C(O)Ra2, -C(O)ORa2, -C(O)NRc2Rd2, -C(O)NRc2(ORa2), - OC(O)Ra2, -OC(O)NRc2Rd2, -NRc2C(O)Ra2, -NRc2C(O)ORa2, and -NRc2C(O)NRc2Rd2, wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents.

[0094] In some embodiments, R2is selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, -C(O)Ra2, -C(O)C(O)Ra2, -C(O)ORa2, -C(O)NRc2Rd2, - C(O)C(O)NRc2Rd2, -C(O)NRc2(ORa2), -OC(O)Ra2, -OC(O)NRc2Rd2, -NRc2C(O)Ra2, - NRc2C(O)ORa2, and -NRc2C(O)NRc2Rd2, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl of R2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

[0095] In some embodiments:

[0096] L2is a bond; and

[0097] R2is selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, -C(O)Ra2, -C(O)C(O)Ra2, -C(O)ORa2, -C(O)NRc2Rd2, - C(O)C(O)NRc2Rd2, -C(O)NRc2(ORa2), -OC(O)Ra2, -OC(O)NRc2Rd2, -NRc2C(O)Ra2, - NRc2C(O)ORa2, and -NRc2C(O)NRc2Rd2, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl of R2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

[0098] In some embodiments, R2is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, -C(O)Ra2, -C(O)ORa2, -C(O)NRc2Rd2, -C(O)NRc2(ORa2), - OC(O)Ra2, -OC(O)NRc2Rd2, -NRc2C(O)Ra2, -NRc2C(O)ORa2, and -NRc2C(O)NRc2Rd2, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl of R2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

[0099] In some embodiments, R2is selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, 4-10 membered heterocycloalkyl, -C(O)Ra2, -C(O)C(O)NRc2Rd2, -C(O)NRc2Rd2, and - C(O)C(O)NRc2Rd2, wherein the C1-6 alkyl, C1-6 haloalkyl, and 4-10 membered heterocycloalkyl of R2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

[0100] In some embodiments:

[0101] L2is a bond; and

[0102] R2is selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, 4-10 membered heterocycloalkyl, -C(O)Ra2, -C(O)C(O)NRc2Rd2, -C(O)NRc2Rd2, and - C(O)C(O)NRc2Rd2, wherein the C1-6 alkyl, C1-6 haloalkyl, and 4-10 membered heterocycloalkyl of R2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents. In some embodiments, R2is selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, 4-10 membered heterocycloalkyl, -C(O)Ra2, and -C(O)NRc2Rd2, wherein the Ci-6 alkyl, Ci-6 haloalkyl, and 4-10 membered heterocycloalkyl of R2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

[0103] In some embodiments, R2is selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, 7-10 membered heterocycloalkyl, -C(O)Ra2, -C(O)C(O)NRc2Rd2, -C(O)NRc2Rd2, and -C(O)C(O)NRc2Rd2, wherein the Ci-6 alkyl, Ci-6 haloalkyl, and 7-10 membered heterocycloalkyl of R2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

[0104] In some embodiments:

[0105] L2is a bond; and

[0106] R2is selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, 7-10 membered heterocycloalkyl, -C(O)Ra2, -C(O)C(O)NRc2Rd2, -C(O)NRc2Rd2, and -C(O)C(O)NRc2Rd2, wherein the Ci-6 alkyl, Ci-6 haloalkyl, and 7-10 membered heterocycloalkyl of R2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

[0107] In some embodiments, R2is selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, 7-10 membered heterocycloalkyl, -C(O)Ra2, and -C(O)NRc2Rd2, wherein the Ci-6 alkyl, Ci-6 haloalkyl, and 7-10 membered heterocycloalkyl of R2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

[0108] In some embodiments, R2is selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, 6-10 membered heterocycloalkyl, -C(O)Ra2, -C(O)C(O)NRc2Rd2, -C(O)NRc2Rd2, and -C(O)C(O)NRc2Rd2, wherein the Ci-6 alkyl, Ci-6 haloalkyl, and 6-10 membered heterocycloalkyl of R2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

[0109] In some embodiments, R2is selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, 6-10 membered heterocycloalkyl, -C(O)Ra2, -C(O)C(O)NRc2Rd2, -C(O)NRc2Rd2, and -C(O)C(O)NRc2Rd2, wherein the Ci-6 alkyl, Ci-6 haloalkyl, and 6-10 membered heterocycloalkyl of R2are each optionally substituted with 1 or 2 independently selected R2Asubstituents.

[0110] In some embodiments, R2is selected from H, fluoro, chloro, bromo, methyl, isopropyl, trifluoromethyl, tetrahydropyridinyl, piperazinyl, 4,7- diazaspiro[2.5]octanyl, -C(O)Ra2, -C(O)C(O)Ra2, -C(O)NRc2Rd2, and - C(O)C(O)NRc2Rd2, wherein the methyl, isopropyl, trifluoromethyl, tetrahydropyridinyl, piperazinyl, and 4,7-diazaspiro[2.5]octanyl, of R2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

[0111] In some embodiments:

[0112] L2is a bond; and

[0113] R2is selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, 6-10 membered heterocycloalkyl, -C(O)Ra2, -C(O)C(O)NRc2Rd2, -C(O)NRc2Rd2, and -C(O)C(O)NRc2Rd2, wherein the Ci-6 alkyl, Ci-6 haloalkyl, and 6-10 membered heterocycloalkyl of R2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

[0114] In some embodiments:

[0115] L2is a bond; and

[0116] R2is selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, 6-10 membered heterocycloalkyl, -C(O)Ra2, -C(O)C(O)NRc2Rd2, -C(O)NRc2Rd2, and -C(O)C(O)NRc2Rd2, wherein the Ci-6 alkyl, Ci-6 haloalkyl, and 6-10 membered heterocycloalkyl of R2are each optionally substituted with 1 or 2 independently selected R2Asubstituents.

[0117] In some embodiments:

[0118] L2is a bond; and

[0119] R2is selected from H, fluoro, chloro, bromo, methyl, isopropyl, trifluoromethyl, tetrahydropyridinyl, piperazinyl, 4,7-diazaspiro[2.5]octanyl, - C(O)Ra2, -C(O)C(O)Ra2, -C(O)NRc2Rd2, and -C(O)C(O)NRc2Rd2, wherein the methyl, isopropyl, trifluoromethyl, tetrahydropyridinyl, piperazinyl, and 4,7- di azaspiro [2.5 ]octanyl, of R2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

[0120] In some embodiments, R2is selected from H, fluoro, chloro, bromo, methyl, isopropyl, trifluoromethyl, 4,7-diazaspiro[2.5]octanyl, -C(O)Ra2, and -C(O)NRc2Rd2, wherein the methyl, isopropyl, trifluoromethyl, and 4,7-diazaspiro[2.5]octanyl, of R2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents. In some embodiments, each Ra2, Rc2, and Rd2is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4- 10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of Ra2, Rc2, and Rd2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents.

[0121] In some embodiments, each Ra2, Rc2, and Rd2is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the C1-6 alkyl, Ci- 6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl of Ra2, Rc2, and Rd2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents.

[0122] In some embodiments, each Ra2, Rc2, and Rd2is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the C1-6 alkyl, Ci- 6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl of Ra2, Rc2, and Rd2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

[0123] In some embodiments, each Ra2, Rc2, and Rd2is independently selected from H, C1-6 alkyl, and C3-10 cycloalkyl, wherein the C1-6 alkyl and C3-10 cycloalkyl of Ra2, Rc2, and Rd2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

[0124] In some embodiments, each Ra2, Rc2, and Rd2is independently selected from C1-6 alkyl and C3-10 cycloalkyl, wherein the C1-6 alkyl and C3-10 cycloalkyl of Ra2, Rc2, and Rd2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

[0125] In some embodiments, each Ra2, Rc2, and Rd2is independently selected from H, C1-6 alkyl, and C3-7 cycloalkyl, wherein the C1-6 alkyl and C3-7 cycloalkyl of Ra2, Rc2, and Rd2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents. In some embodiments, each Ra2, Rc2, and Rd2is independently selected from Ci-6 alkyl and C3-7 cycloalkyl, wherein the C1-6 alkyl and C3-7 cycloalkyl of Ra2, Rc2, and Rd2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

[0126] In some embodiments, each Ra2, Rc2, and Rd2is independently selected from methyl, isopropyl, and cyclopropyl, wherein the methyl, isopropyl, and cyclopropyl of Ra2, Rc2, and Rd2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

[0127] In some embodiments, each Ra2, Rc2, and Rd2is independently selected from methyl, isopropyl, and cyclopropyl, wherein the methyl and cyclopropyl of Ra2, Rc2, and Rd2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

[0128] In some embodiments, each Ra2, Rc2, and Rd2is independently selected from methyl and cyclopropyl, wherein the methyl and cyclopropyl of Ra2, Rc2, and Rd2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

[0129] In some embodiments, each Ra2is independently selected from C1-6 alkyl and C3-10 cycloalkyl, wherein the C1-6 alkyl and C3-10 cycloalkyl of R2aare each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

[0130] In some embodiments, each Ra2is independently selected from C1-6 alkyl and C3-7 cycloalkyl, wherein the C1-6 alkyl and C3-10 cycloalkyl of R2aare each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

[0131] In some embodiments, each Ra2is independently selected from C1-6 alkyl and cyclopropyl, wherein the C1-6 alkyl and C3-10 cycloalkyl of R2aare each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

[0132] In some embodiments, each Ra2is C3-10 cycloalkyl, which is optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

[0133] In some embodiments, each Ra2is C3-7 cycloalkyl, which is optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

[0134] In some embodiments, each Ra2is cyclopropyl, which is optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents. In some embodiments, each Rc2and Rd2is independently selected from Ci-6 alkyl, wherein the Ci-6 alkyl of Rc2and Rd2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

[0135] In some embodiments, each R2Ais independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, -ORa2A, -C(O)Ra2A, - C(O)C(O)Ra2A, -C(O)NRc2ARd2A, and -C(O)C(O)NRc2ARd2A, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of R2Aare each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.

[0136] In some embodiments, each R2Ais independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, -ORa2A, -C(O)Ra2A, - C(O)C(O)Ra2A, -C(O)NRc2ARd2A, and -C(O)C(O)NRc2ARd2A, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci-6 haloalkyl of R2Aare each optionally substituted with 1 or 2 independently selected RGsubstituents.

[0137] In some embodiments, each R2Ais independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, -CN, -ORa2A, -C(O)Ra2A, - C(O)C(O)Ra2A, -C(O)NRc2ARd2A, and -C(O)C(O)NRc2ARd2A, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci-6 haloalkyl of R2Aare each optionally substituted with C1-4 alkoxy.

[0138] In some embodiments, each R2Ais independently selected from Ci-6 alkyl, Ci-6 haloalkyl, -CN, -ORa2A, -C(O)Ra2A, -C(O)C(O)Ra2A, -C(O)NRc2ARd2A, - C(O)C(O)NRc2ARd2A, wherein the Ci-6 alkyl is optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.

[0139] In some embodiments, each R2Ais independently selected from Ci-6 alkyl, Ci-6 haloalkyl, -CN, -ORa2A, -C(O)Ra2A, -C(O)C(O)Ra2A, -C(O)NRc2ARd2A, - C(O)C(O)NRc2ARd2A, wherein the Ci-6 alkyl is optionally substituted with 1 or 2 independently selected RGsubstituents.

[0140] In some embodiments, each R2Ais independently selected from Ci-6 alkyl, Ci-6 haloalkyl, -CN, -ORa2A, -C(O)Ra2A, -C(O)C(O)Ra2A, -C(O)NRc2ARd2A, - C(O)C(O)NRc2ARd2A, wherein the Ci-6 alkyl is optionally substituted with C1-4 alkoxy.

[0141] In some embodiments, each R2Ais independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, -CN, and -ORa2A. In some embodiments, each R2Ais independently selected from -CN and -

[0142] ORa2A

[0143] In some embodiments, each Ra2A, Rc2A, and Rd2Ais independently selected from H, Ci-6 alkyl, and C3-10 cycloalkyl, wherein the C1-6 alkyl and C3-10 cycloalkyl groups are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.

[0144] In some embodiments, each Ra2A, Rc2A, and Rd2Ais independently selected from H, C1-6 alkyl, and C3-10 cycloalkyl, wherein the C1-6 alkyl and C3-10 cycloalkyl groups are each optionally substituted with 1 or 2 independently selected RGsubstituents.

[0145] In some embodiments, each Ra2A, Rc2A, and Rd2Ais independently selected from H, C1-6 alkyl, and C3-7 cycloalkyl, wherein the C1-6 alkyl and C3-7 cycloalkyl groups are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.

[0146] In some embodiments, each Ra2A, Rc2A, and Rd2Ais independently selected from H, C1-6 alkyl, and C3-7 cycloalkyl, wherein the C1-6 alkyl and C3-7 cycloalkyl groups are each optionally substituted with 1 or 2 independently selected RGsubstituents.

[0147] In some embodiments, each Ra2A, Rc2A, and Rd2Ais independently selected from H, C1-6 alkyl, and C3-10 cycloalkyl, wherein the C1-6 alkyl and C3-10 cycloalkyl groups are each optionally substituted with C1-4 alkoxy or -CN.

[0148] In some embodiments, each Ra2A, Rc2A, and Rd2Ais independently selected from H, C1-6 alkyl, and C3-7 cycloalkyl, wherein the C1-6 alkyl and C3-7 cycloalkyl groups are each optionally substituted with C1-4 alkoxy or -CN.

[0149] In some embodiments, each Ra2Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl.

[0150] In some embodiments, each Ra2Ais independently selected from H and C1-6 alkyl.

[0151] In some embodiments, each Ra2Ais independently selected from H and C1-3 alkyl.

[0152] In some embodiments, each Ra2Ais independently selected from C1-6 alkyl.

[0153] In some embodiments, each Ra2Ais independently selected from C1-3 alkyl. In some embodiments, each Ra2Ais methyl.

[0154] In some embodiments, each R2Ais independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, -ORa2A, -C(O)Ra2A, - C(O)C(O)Ra2A, -C(O)NRc2ARd2A, and -C(O)C(O)NRc2ARd2A, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of R2Aare each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; and each Ra2A, Rc2A, and Rd2Ais independently selected from H, Ci-6 alkyl, and C3- 10 cycloalkyl, wherein the C1-6 alkyl and C3-10 cycloalkyl groups are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.

[0155] In some embodiments, each R2Ais independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, -ORa2A, -C(O)Ra2A, - C(O)C(O)Ra2A, -C(O)NRc2ARd2A, and -C(O)C(O)NRc2ARd2A, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci-6 haloalkyl of R2Aare each optionally substituted with 1 or 2 independently selected RGsubstituents; and each Ra2A, Rc2A, and Rd2Ais independently selected from H, Ci-6 alkyl, and C3- 10 cycloalkyl, wherein the Ci-6 alkyl and C3-10 cycloalkyl groups are each optionally substituted with 1 or 2 independently selected RGsubstituents.

[0156] In some embodiments, each R2Ais independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, -CN, -ORa2A, -C(O)Ra2A, - C(O)C(O)Ra2A, -C(O)NRc2ARd2A, and -C(O)C(O)NRc2ARd2A, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci-6 haloalkyl of R2Aare each optionally substituted with C1-4 alkoxy; and each Ra2A, Rc2A, and Rd2Ais independently selected from H, Ci-6 alkyl, and C3- 10 cycloalkyl, wherein the Ci-6 alkyl and C3-10 cycloalkyl groups are each optionally substituted with C1-4 alkoxy or -CN.

[0157] In some embodiments, each R2Ais independently selected from Ci-6 alkyl, Ci-6 haloalkyl, -CN, -ORa2A, -C(O)Ra2A, -C(O)C(O)Ra2A, -C(O)NRc2ARd2A, - C(O)C(O)NRc2ARd2A, wherein the Ci-6 alkyl is optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; and each Ra2A, Rc2A, and Rd2Ais independently selected from H, Ci-6 alkyl, and C3- 10 cycloalkyl, wherein the Ci-6 alkyl and C3-10 cycloalkyl groups are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents. In some embodiments, each R2Ais independently selected from Ci-6 alkyl, Ci-6 haloalkyl, -CN, -ORa2A, -C(O)Ra2A, -C(O)C(O)Ra2A, -C(O)NRc2ARd2A, - C(O)C(O)NRc2ARd2A, wherein the Ci-6 alkyl is optionally substituted with 1 or 2 independently selected RGsubstituents; and each Ra2A, Rc2A, and Rd2Ais independently selected from H, Ci-6 alkyl, and C3- 10 cycloalkyl, wherein the C1-6 alkyl and C3-10 cycloalkyl groups are each optionally substituted with 1 or 2 independently selected RGsubstituents.

[0158] In some embodiments, each R2Ais independently selected from C1-6 alkyl, C1-6 haloalkyl, -CN, -ORa2A, -C(O)Ra2A, -C(O)C(O)Ra2A, -C(O)NRc2ARd2A, - C(O)C(O)NRc2ARd2A, wherein the C1-6 alkyl is optionally substituted with C1-4 alkoxy; and each Ra2A, Rc2A, and Rd2Ais independently selected from H, C1-6 alkyl, and C3- 10 cycloalkyl, wherein the C1-6 alkyl and C3-10 cycloalkyl groups are each optionally substituted with C1-4 alkoxy or -CN.

[0159] In some embodiments, each R2Ais independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, and -ORa2A; and each Ra2Ais independently selected from H and C1-6 alkyl.

[0160] In some embodiments, each R2Ais independently selected from -CN and - ORa2A; and each Ra2Ais independently selected from H and C1-6 alkyl.

[0161] In some embodiments, each R2Ais independently selected from methyl, methoxymethyl, trifluoromethyl, -CN, methoxy, -C(O)isopropyl, - C(O)(methoxycyclopropyl), -C(O)(cyanocyclopropyl), -C(O)N(CH3)2, - C(O)C(O)N(CH3)2, and -C(O)C(O)isopropyl.

[0162] In some embodiments, each R2Ais independently selected from -CN and methoxy.

[0163] In some embodiments, each Ra2, Rc2, and Rd2is independently selected from methyl, isopropyl, cyclopropyl, cyanocyclopropyl, and methoxy cyclopropyl.

[0164] In some embodiments, each Ra2, Rc2, and Rd2is independently selected from methyl, cyclopropyl, cyanocyclopropyl, and methoxy cyclopropyl.

[0165] In some embodiments, each Ra2is independently selected from methyl, cyclopropyl, cyanocyclopropyl, and methoxycyclopropyl. In some embodiments, each Ra2is independently selected from cyclopropyl, cyanocyclopropyl, and methoxycyclopropyl.

[0166] In some embodiments, each Rc2and Rd2is methyl.

[0167] In some embodiments, R2is selected from H, fluoro, chloro, bromo, methyl, methoxymethyl, isopropyl, trifluoromethyl, dimethylpiperazinyl, 4,7- di azaspiro [2.5 ]octanyl, cyclopropylcarbonyl, (methoxycyclopropyl)carbonyl, (cyanocyclopropyl)carbonyl, (dimethylamino)carbonyl, (dimethylaminocarbonyl)piperazinyl, (dimethylaminocarbonyl)(methyl)piperazinyl, (isopropylcarbonyl)(methyl)piperazinyl, (isopropylcarbonyl)carbonyl(methyl)piperazinyl, and (dimethylaminocarbonyl)carbonyl(methyl)piperazinyl.

[0168] In some embodiments:

[0169] L2is a bond; and

[0170] R2is selected from H, fluoro, chloro, bromo, methyl, methoxymethyl, isopropyl, trifluoromethyl, dimethylpiperazinyl, 4,7-diazaspiro[2.5]octanyl, cyclopropylcarbonyl, (methoxycyclopropyl)carbonyl, (cyanocyclopropyl)carbonyl, (dimethylamino)carbonyl, (dimethylaminocarbonyl)piperazinyl, (dimethylaminocarbonyl)(methyl)piperazinyl, (isopropylcarbonyl)(methyl)piperazinyl, (isopropylcarbonyl)carbonyl(methyl)piperazinyl, and (dimethylaminocarbonyl)carbonyl(methyl)piperazinyl.

[0171] In some embodiments, R2is selected from H, fluoro, chloro, bromo, methyl, methoxymethyl, isopropyl, trifluoromethyl, 4,7-diazaspiro[2.5]octanyl, cyclopropylcarbonyl, (methoxycyclopropyl)carbonyl, (cyanocyclopropylcarbonyl), and (dimethylamino)carbonyl.

[0172] In some embodiments, Ring In some embodiments, Ring

[0173] In some embodiments, m is 0 or 1.

[0174] In some embodiments, m is 0.

[0175] In some embodiments, m is 1.

[0176] In some embodiments, Y1is N.

[0177] In some embodiments, Y2is C.

[0178] In some embodiments, Y1is N and Y2is C.

[0179] In some embodiments, Y3is CH or N.

[0180] In some embodiments, Y3is CH.

[0181] In some embodiments, Y3is N.

[0182] In some embodiments:

[0183] Y1is N;

[0184] Y2is C; and

[0185] Y3is CH.

[0186] In some embodiments:

[0187] Y1is N;

[0188] Y2is C; and

[0189] Y3is N.

[0190] In some embodiments, Ring C is 5-10 membered heterocycloalkyl or 5-6 membered heteroaryl.

[0191] In some embodiments, Ring C is 5-7 membered heterocycloalkyl or 5-6 membered heteroaryl.

[0192] In some embodiments, Ring C is selected from

[0193] In some embodiments, Ring C is selected from In some embodiments, X3is C.

[0194] In some embodiments, Ring A is a 6-membered heteroaryl.

[0195] In some embodiments, Ring A is a 6-membered heteroaryl selected from ,

[0196] In some embodiments, Ring

[0197] In some embodiments, Ring

[0198] In some embodiments, each L3is independently selected from a bond, C1-6 alkylene, -O-, and -N(RL)-.

[0199] In some embodiments, each RLis independently selected from H and Ci-6 alkyl.

[0200] In some embodiments, each L3is independently selected from a bond, Ci-6 alkylene, -O-, and -N(RL)-; and each RLis independently selected from H and Ci-6 alkyl.

[0201] In some embodiments, each L3is independently selected from a bond, Ci-6 alkylene, -O-, and -N(RL)-; and each RLis independently selected from H and C1-3 alkyl.

[0202] In some embodiments, each L3is independently selected from a bond, -O-, and -NH-.

[0203] In some embodiments, each L3is a bond. In some embodiments, each L3is -O-.

[0204] In some embodiments, each L3is -NH-.

[0205] In some embodiments, each L3is -N(RL)-.

[0206] In some embodiments, each L3is -N(RL)-; and each RLis independently selected from H and Ci-6 alkyl.

[0207] In some embodiments, each L3is -N(RL)-; and each RLis independently selected from H and C1-3 alkyl.

[0208] In some embodiments, each L3is -NH-.

[0209] In some embodiments, each R3is independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, -ORa3, -SR33, and -NRc3Rd3, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents.

[0210] In some embodiments, each R3is independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, -ORa3, -SR33, and -NRc3Rd3, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R3are each optionally substituted with 1 or 2 independently selected R3Asubstituents.

[0211] In some embodiments, each R3is independently selected from H, C1-6 alkyl, 4- 10 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-6 membered heteroaryl)-Ci-4 alkyl, - ORa3, -SRa3, and -NRc3Rd3, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents.

[0212] In some embodiments, each R3is independently selected from H, C1-6 alkyl, 4- 10 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-6 membered heteroaryl)-Ci-4 alkyl, - ORa3, -SRa3, and -NRc3Rd3, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R3are each optionally substituted with 1 or 2 independently selected R3Asubstituents.

[0213] In some embodiments, each Ra3, Rc3, and Rd3is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl.

[0214] In some embodiments, each Ra3, Rc3, and Rd3is independently selected from H and Ci -6 alkyl.

[0215] In some embodiments, each R3is independently selected from H, C1-6 alkyl, 4- 10 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-6 membered heteroaryl)-Ci-4 alkyl, - ORa3, -SRa3, and -NRc3Rd3, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R3are each optionally substituted with 1, 2, 3, or 4 independently selected R3Asubstituents; and each Ra3, Rc3, and Rd3is independently selected from H and C1-6 alkyl.

[0216] In some embodiments, each R3is independently selected from H, C1-6 alkyl, 4- 10 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-6 membered heteroaryl)-Ci-4 alkyl, - ORa3, -SRa3, and -NRc3Rd3, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R3are each optionally substituted with 1 or 2 independently selected R3Asubstituents; and each Ra3, Rc3, and Rd3is independently selected from H and C1-6 alkyl.

[0217] In some embodiments, each R3is independently selected from H, methyl, methoxy, methylthio, amino, cyclopentylmethyl, azetidinyl, 3-oxotetrahydro-3H- oxazolo[3,4-a]pyrazin-7(lH)-yl, tetrahydro-lH-pyrrolizin-7a(5H)-ylmethyl, and pyrazolyl, wherein the methyl, cyclopentylmethyl, azetidinyl, 3-oxotetrahydro-3H- oxazolo[3,4-a]pyrazin-7(lH)-yl, and tetrahydro- lH-pyrrolizin-7a(5H)-ylmethyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents.

[0218] In some embodiments, each R3is independently selected from H, methyl, methoxy, methylthio, amino, cyclopentylmethyl, azetidinyl, 3-oxotetrahydro-3H- oxazolo[3,4-a]pyrazin-7(lH)-yl, tetrahydro-lH-pyrrolizin-7a(5H)-ylmethyl, and pyrazolyl, wherein the methyl, cyclopentylmethyl, azetidinyl, 3-oxotetrahydro-3H- oxazolo[3,4-a]pyrazin-7(lH)-yl, and tetrahydro- lH-pyrrolizin-7a(5H)-ylmethyl of R3are each optionally substituted with 1 or 2 independently selected R3Asubstituents.

[0219] In some embodiments, each R3Ais independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-e alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and -CN, wherein the C1-6 alkyl, C2-6 alkenyl, C2-e alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of R3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents.

[0220] In some embodiments, each R3Ais independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-e alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and -CN, wherein the C1-6 alkyl, C2-6 alkenyl, C2-e alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of R3Aare each optionally substituted with 1 or 2 independently selected RGsubstituents. In some embodiments, each R3Ais independently selected from H, Ci-6 alkyl, C3-7 cycloalkyl, and -CN, wherein the C1-6 alkyl and C3-7 cycloalkyl of R3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents.

[0221] In some embodiments, each R3Ais independently selected from H, C1-6 alkyl, C3-7 cycloalkyl, and -CN, wherein the C1-6 alkyl and C3-7 cycloalkyl of R3Aare each optionally substituted with 1 or 2 independently selected RGsubstituents.

[0222] In some embodiments, each R3Ais independently selected from methyl, cyclobutyl, and -CN, wherein the methyl and cyclobutyl of R3Aare each optionally substituted with 1 or 2 RGsubstituents independently selected from OH and cyano-Ci- 4 alkyl.

[0223] In some embodiments, each R3Ais independently selected from methyl, hydroxymethyl, and (cyanomethyl)cyclobutyl.

[0224] In some embodiments:

[0225] X1is CR5;

[0226] X2is CR6; and

[0227] X3is C.

[0228] In some embodiments:

[0229] X1is CH;

[0230] X2is CH; and

[0231] X3is C.

[0232] In some embodiments, Ring B is 5-10 membered heteroaryl.

[0233] In some embodiments, Ring B is 5-6 membered heteroaryl.

[0234] In some embodiments, Ring B is thiadiazolyl.

[0235] In some embodiments, n is 1, 2, or 3.

[0236] In some embodiments, n is 1 or 2.

[0237] In some embodiments, n is 1.

[0238] In some embodiments, each R4is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl.

[0239] In some embodiments, each R4is independently selected from halo, C1-6 alkyl and C1-6 haloalkyl.

[0240] In some embodiments, each R4is independently selected from C1-6 alkyl and C1-6 haloalkyl. In some embodiments, each R4is independently selected from Ci-6 haloalkyl.

[0241] In some embodiments, each R4is independently selected from C1-3 alkyl and C1-3 haloalkyl.

[0242] In some embodiments, each R4is independently selected from C1-3 haloalkyl.

[0243] In some embodiments, each R4is difluoromethyl.

[0244] In some embodiments: m is 0 or 1; n is 1, 2, or 3;

[0245] X1is N or CH;

[0246] X2is N or CH;

[0247] X3is C or N;

[0248] Z is O;

[0249] Ring A is a 6-membered heteroaryl each = is independently a single or double bond;

[0250] Y1is C or N;

[0251] Y2is C or N;

[0252] Y3is C(-L3-R3), or N;

[0253] Ring B is Ce-io aryl or 5-10 membered heteroaryl;

[0254] Ring C is C5-10 cycloalkyl, phenyl, 5-10 membered heterocycloalkyl, or 5-6 membered heteroaryl; each L2and L3is independently selected from bond, C1-6 alkylene, C1-6 haloalkylene, C3-7 cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6 membered heteroarylene, -C3-7 cycloalkylene-Ci-4 alkyl-, -(4-7 membered heterocycloalkylene)-Ci-4 alkyl-, -phenylene-Ci-4 alkyl-, -(5-6 membered heteroarylene)-Ci-4alkyl-, -O-, -N(RL)-, -C(O)-, -N(RL)C(O)-, -N(RL)C(O)N(RL)-, - N(RL)C(O)O-, -S(O)-, -S(O)2-, -S(O)(=NRL)-, -S(O)2N(RL)-, and -N(RL)S(O)2N(RL)-, wherein the C1-6 alkylene, C1-6 haloalkylene, C3-7 cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6 membered heteroarylene, C3-7 cycloalkylene-Ci-4 alkyl, (4-7 membered heterocycloalkylene)-Ci-4 alkyl, -phenylene-Ci-4 alkyl-, and (5- 6 membered heteroarylene)-Ci-4 alkyl of L2and L3are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; each RLis independently selected from H, Ci-6 alkyl, and Ci-6 haloalkyl;

[0255] R1is selected from Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci- 4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci- 4 alkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0256] R2is selected from H, oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, - ORa2, -SRa2, -NRc2Rd2, -NO2, -C(O)Ra2, -C(O)C(O)Ra2, -C(O)ORa2, -C(O)NRc2Rd2, - C(O)C(O)NRc2Rd2, -C(O)NRc2(ORa2), -OC(O)Ra2, -OC(O)NRc2Rd2, -OC(O)ORa2, - OS(O)2Rb2, -OS(O)2NRc2Rd2, -NRc2C(O)Ra2, -NRc2C(O)ORa2, -NRc2C(O)NRc2Rd2, - NRc2S(O)2Rb2, -NRc2S(O)2NRc2Rd2, -NRc2ORa2, -NRc2S(O)Rb2, -NRc2S(O)NRc2Rd2, - S(O)Rb2, -S(O)2Rb2, -S(O)NRc2Rd2, -S(O)2NRc2Rd2, -C(=NRe2)Ra2, - C(=NRe2)NRc2Rd2, -NRc2C(=NRe2)Ra2, -NRc2C(=NRe2)NRc2Rd2, - NRc2S(O)(=NRe2)Rb2, -NRc2S(O)(=NRe2)NRc2Rd2, -OS(O)(=NRe2)Rb2, - S(O)(=NRe2)Rb2, -S(O)(=NRe2)NRc2Rd2, -C(O)NRc2S(O)2Rb2, - C(O)NRc2S(O)2NRc2Rd2, -S(O)2NRc2C(O)Rb2, and -NRc2S(O)NRc2C(O)Rb2, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4- 10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; each Ra2, Rc2, and Rd2is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra2, Rc2, and Rd2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; or, any Rc2and Rd2attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; each Rb2is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; each Re2is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R2Ais independently selected from oxo, H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, -CN, -ORa2A, -SRa2A, -NRc2ARd2A, -NO2, -C(O)Ra2A, -C(O)C(O)Ra2A, - C(O)ORa2A, -C(O)NRc2ARd2A, -C(O)C(O)NRc2ARd2A, -C(O)NRc2A(ORa2A), - OC(O)Ra2A, -OC(O)NRc2ARd2A, -OC(O)ORa2A, -OS(O)2Rb2A, -OS(O)2NRc2ARd2A, - NRc2AC(O)Ra2A, -NRc2AC(O)ORa2A, -NRc2AC(O)NRc2ARd2A, -NRc2AS(O)2Rb2A, - NRc2AS(O)2NRc2ARd2A, -NRc2AORa2A, -NRc2AS(O)Rb2A, -NRc2AS(O)NRc2ARd2A, - S(O)Rb2A, -S(O)2Rb2A, -S(O)NRc2ARd2A, -S(O)2NRc2ARd2A, -C(=NRe2A)Ra2A, - C(=NRe2A)NRc2ARd2A, -NRc2AC(=NRe2A)Ra2A, -NRc2AC(=NRe2A)NRc2ARd2A, - NRc2AS(O)(=NRe2A)Rb2A, -NRc2AS(O)(=NRe2A)NRc2ARd2A, -OS(O)(=NRe2A)Rb2A, - S(O)(=NRe2A)Rb2A, -S(O)(=NRe2A)NRc2ARd2A, -C(O)NRc2AS(O)2Rb2A, - C(O)NRc2AS(O)2NRc2ARd2A, -S(O)2NRc2AC(O)Rb2A, and -NRc2AS(O)NRc2AC(O)Rb2A, wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of R2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra2A, Rc2A, and Rd2Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra2A, Rc2A, and Rd2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc2Aand Rd2Aattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rb2Ais independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Re2Ais independently selected from H, OH, CN, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R3is independently selected from oxo, H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, -CN, -ORa3, -SRa3, -NRc3Rd3, -NO2, -C(O)Ra3, -C(O)ORa3, -C(O)NRc3Rd3, - S(O)2NRc3C(O)Rb3, and -NRc3S(O)NRc3C(O)Rb3, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; each Ra3, Rc3, and Rd3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; or, any Rc3and Rd3attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; each Rb3is independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each Re3is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl,

[0257] 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R3Ais independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl,

[0258] 5-10 membered heteroaryl, and -CN, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of R3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each R4is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, (5-6 membered heteroaryl)-Ci-4 alkyl, -CN, -ORa4, -SRa4, -NRc4Rd4, -NO2, -C(O)Ra4, -C(O)ORa4, -C(O)NRc4Rd4, -C(O)NRc4(ORa4), -OC(O)Ra4, -OC(O)NRc4Rd4, -OC(O)ORa4, -OS(O)2Rb4, -OS(O)2NRc4Rd4, -NRc4C(O)Ra4, - NRc4C(O)ORa4, -NRc4C(O)NRc4Rd4, -NRc4S(O)2Rb4, -NRc4S(O)2NRc4Rd4, -NRc4ORa4, -NRc4S(O)Rb4, -NRc4S(O)NRc4Rd4, -S(O)Rb4, -S(O)2Rb4, -S(O)NRc4Rd4, - S(O)2NRc4Rd4, -C(=NRe4)Ra4, -C(=NRe4)NRc4Rd4, -NRc4C(=NRe4)Ra4, - NRc4C(=NRe4)NRc4Rd4, -NRc4S(O)(=NRe4)Rb4, -NRc4S(O)(=NRe4)NRc4Rd4, - OS(O)(=NRe4)Rb4, -S(O)(=NRe4)Rb4, -S(O)(=NRe4)NRc4Rd4, -C(O)NRc4S(O)2Rb4, - C(O)NRc4S(O)2NRc4Rd4, -S(O)2NRc4C(O)Rb4, and -NRc4S(O)NRc4C(O)Rb4, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of R4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra4, Rc4, and Rd4is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci- 4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of Ra4, Rc4, and Rd4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc4and Rd4attached to the same N atom, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group, wherein the 4- 7 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rb4is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of Rb4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Re4is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl; and each RGis independently selected from OH, CN, halo, oxo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, cyano-Ci-4 alkyl, HO-C1-4 alkyl, C1-4 alkoxy-Ci-4 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-3 alkylamino, di(Ci-3 alkyl)amino, thio, C1-3 alkylthio, C1-3 alkylsulfinyl, Ci- 3 alkyl sulfonyl, carbamyl, C1-3 alkylcarbamyl, di(Ci-3 alkyl)carbamyl, carboxy, C1-3 alkylcarbonyl, C1-3 alkoxycarbonyl, C1-3 alkylcarbonyloxy, C1-3 alkylcarbonylamino, C1-3 alkoxy carbonylamino, aminocarbonyloxy, C1-3 alkylaminocarbonyloxy, di (C 1-3 alkyl)aminocarbonyloxy, C1-3 alkylsulfonylamino, aminosulfonyl, C1-3 alkylaminosulfonyl, di(Ci-3 alkyl)aminosulfonyl, aminosulfonylamino, C1-3 alkylaminosulfonylamino, di (C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C1-3 alkylaminocarbonylamino, and di(Ci-3 alkyl)aminocarbonylamino.

[0259] In some embodiments: m is 0 or 1; n is 1, 2, or 3;

[0260] X1is N or CH;

[0261] X2is N or CH;

[0262] X3is C or N;

[0263] Z is O;

[0264] Ring each = is independently a single or double bond;

[0265] Y1is C or N;

[0266] Y2is C or N;

[0267] Y3is C(-L3-R3), or N;

[0268] Ring B is Ce-io aryl or 5-10 membered heteroaryl;

[0269] Ring C is C5-10 cycloalkyl, phenyl, 5-10 membered heterocycloalkyl, or 5-6 membered heteroaryl; each L2and L3is independently selected from bond, C1-6 alkylene, C1-6 haloalkylene, C3-7 cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6 membered heteroarylene, -C3-7 cycloalkylene-Ci-4 alkyl-, -(4-7 membered heterocycloalkylene)-Ci-4 alkyl-, -phenylene-Ci-4 alkyl-, -(5-6 membered heteroarylene)-Ci-4alkyl-, -O-, -N(RL)-, -C(O)-, -N(RL)C(O)-, -N(RL)C(O)N(RL)-, - N(RL)C(O)O-, -S(O)-, -S(O)2-, -S(O)(=NRL)-, -S(O)2N(RL)-, and -N(RL)S(O)2N(RL)-, wherein the Ci-6 alkylene, Ci-6 haloalkylene, C3-7 cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6 membered heteroarylene, C3-7 cycloalkylene-Ci-4 alkyl, (4-7 membered heterocycloalkylene)-Ci-4 alkyl, -phenylene-Ci-4 alkyl-, and (5- 6 membered heteroarylene)-Ci-4 alkyl of L2and L3are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; each RLis independently selected from H, C1-6 alkyl, and C1-6 haloalkyl;

[0270] R1is selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci- 4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci- 4 alkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0271] R2is selected from H, oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, - S(O)2NRc2C(O)Rb2, and -NRc2S(O)NRc2C(O)Rb2, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; each Ra2, Rc2, and Rd2is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra2, Rc2, and Rd2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; or, any Rc2and Rd2attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; each Rb2is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; each Re2is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R2Ais independently selected from oxo, H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, -CN, -ORa2A, -SRa2A, -NRc2ARd2A, -NO2, -C(O)Ra2A, -C(O)ORa2A, - C(O)NRc2ARd2A, -C(O)NRc2A(ORa2A), -OC(O)Ra2A, -OC(O)NRc2ARd2A, -OC(O)ORa2A, -OS(O)2Rb2A, -OS(O)2NRc2ARd2A, -NRc2AC(O)Ra2A, -NRc2AC(O)ORa2A, - NRc2AC(O)NRc2ARd2A, -NRc2AS(O)2Rb2A, -NRc2AS(O)2NRc2ARd2A, -NRc2AORa2A, - NRc2AS(O)Rb2A, -NRc2AS(O)NRc2ARd2A, -S(O)Rb2A, -S(O)2Rb2A, -S(O)NRc2ARd2A, - S(O)2NRc2ARd2A, -C(=NRe2A)Ra2A, -C(=NRe2A)NRc2ARd2A, -NRc2AC(=NRe2A)Ra2A, - NRc2AC(=NRe2A)NRc2ARd2A, -NRc2AS(O)(=NRe2A)Rb2A, - NRc2AS(O)(=NRe2A)NRc2ARd2A, -OS(O)(=NRe2A)Rb2A, -S(O)(=NRe2A)Rb2A, - S(O)(=NRe2A)NRc2ARd2A, -C(O)NRc2AS(O)2Rb2A, -C(O)NRc2AS(O)2NRc2ARd2A, - S(O)2NRc2AC(O)Rb2A, and -NRc2AS(O)NRc2AC(O)Rb2A, wherein the Ci-6alkyl, C2.6alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra2A, Rc2A, and Rd2Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra2A, Rc2A, and Rd2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc2Aand Rd2Aattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rb2Ais independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Re2Ais independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R3is independently selected from oxo, H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, -CN, -ORa3, -SRa3, -NRc3Rd3, -NO2, -C(O)Ra3, -C(O)ORa3, -C(O)NRc3Rd3, - each Ra3, Rc3, and Rd3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; or, any Rc3and Rd3attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; each Rb3is independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each Re3is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R4is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, (5-6 membered heteroaryl)-Ci-4 alkyl, -CN, -ORa4, -SRa4, -NRc4Rd4, -NO2, -C(O)Ra4, -C(O)ORa4, -C(O)NRc4Rd4, -C(O)NRc4(ORa4), -OC(O)Ra4, -OC(O)NRc4Rd4, -OC(O)ORa4, -OS(O)2Rb4, -OS(O)2NRc4Rd4, -NRc4C(O)Ra4, - NRc4C(O)ORa4, -NRc4C(O)NRc4Rd4, -NRc4S(O)2Rb4, -NRc4S(O)2NRc4Rd4, -NRc4ORa4, -NRc4S(O)Rb4, -NRc4S(O)NRc4Rd4, -S(O)Rb4, -S(O)2Rb4, -S(O)NRc4Rd4, - S(O)2NRc4Rd4, -C(=NRe4)Ra4, -C(=NRe4)NRc4Rd4, -NRc4C(=NRe4)Ra4, - NRc4C(=NRe4)NRc4Rd4, -NRc4S(O)(=NRe4)Rb4, -NRc4S(O)(=NRe4)NRc4Rd4, - OS(O)(=NRe4)Rb4, -S(O)(=NRe4)Rb4, -S(O)(=NRe4)NRc4Rd4, -C(O)NRc4S(O)2Rb4, - C(O)NRc4S(O)2NRc4Rd4, -S(O)2NRc4C(O)Rb4, and -NRc4S(O)NRc4C(O)Rb4, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of R4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra4, Rc4, and Rd4is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci- 4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of Ra4, Rc4, and Rd4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc4and Rd4attached to the same N atom, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group, wherein the 4- 7 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rb4is independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of Rb4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Re4is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl; and each RGis independently selected from OH, CN, halo, oxo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, cyano-Ci-4 alkyl, HO-C1-4 alkyl, C1-4 alkoxy-Ci-4 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-3 alkylamino, di(Ci-3 alkyl)amino, thio, C1-3 alkylthio, C1-3 alkylsulfinyl, Ci- 3 alkyl sulfonyl, carbamyl, C1-3 alkylcarbamyl, di(Ci-3 alkyl)carbamyl, carboxy, C1-3 alkylcarbonyl, C1-3 alkoxycarbonyl, C1-3 alkylcarbonyloxy, C1-3 alkylcarbonylamino, C1-3 alkoxy carbonylamino, aminocarbonyloxy, C1-3 alkylaminocarbonyloxy, di (C 1-3 alkyl)aminocarbonyloxy, C1-3 alkylsulfonylamino, aminosulfonyl, C1-3 alkylaminosulfonyl, di(Ci-3 alkyl)aminosulfonyl, aminosulfonylamino, C1-3 alkylaminosulfonylamino, di (C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C1-3 alkylaminocarbonylamino, and di(Ci-3 alkyl)aminocarbonylamino. In some embodiments: m is 0 or 1; n is 1 or 2;

[0272] X1is N or CH;

[0273] X2is N or CH;

[0274] X3is C or N;

[0275] Z is O;

[0276] Ring A is a 6-membered heteroaryl each = is independently a single or double bond;

[0277] Y1is C or N;

[0278] Y2is C or N;

[0279] Y3is CH, or N;

[0280] Ring B is Ce-io aryl or 5-10 membered heteroaryl;

[0281] Ring C is 5-7 membered heterocycloalkyl or 5-6 membered heteroaryl;

[0282] L2is selected from a bond, C3-7 cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6 membered heteroarylene, -C3-7 cycloalkylene-Ci- 4 alkyl-, -(4-7 membered heterocycloalkylene)-Ci-4 alkyl-, -phenylene-Ci-4 alkyl-, and -(5-6 membered heteroarylene)-Ci-4 alkyl-, wherein the C3-7 cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6 membered heteroarylene, -C3-7 cycloalkylene-Ci-4 alkyl-, -(4-7 membered heterocycloalkylene)-Ci-4 alkyl-, - phenylene-Ci-4 alkyl-, and -(5-6 membered heteroarylene)-Ci-4 alkyl- of L2are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; each L3is independently selected from a bond, C1-6 alkylene, -O-, and -N(RL)-; each RLis independently selected from H and C1-6 alkyl;

[0283] R1is selected from C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci-4 alkyl, wherein C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci-4 alkyl of R1are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; R2is selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, -C(O)Ra2, -C(O)C(O)Ra2, -C(O)ORa2, -C(O)NRc2Rd2, - C(O)C(O)NRc2Rd2, -C(O)NRc2(ORa2), -OC(O)Ra2, -OC(O)NRc2Rd2, -NRc2C(O)Ra2, - NRc2C(O)ORa2, and -NRc2C(O)NRc2Rd2, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl of R2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents; each Ra2, Rc2, and Rd2is independently selected from H, Ci-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl of Ra2, Rc2, and Rd2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents; each R2Ais independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6haloalkyl, -CN, -ORa2A, -C(O)Ra2A, -C(O)C(O)Ra2A, -C(O)NRc2ARd2A, and -C(O)C(O)NRc2ARd2A, wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci-6 haloalkyl of R2Aare each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; each Ra2A, Rc2A, and Rd2Ais independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, wherein the Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-10 cycloalkyl of Ra2A, Rc2A, and Rd2Aare each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; each R3is independently selected from H, Ci-6 alkyl, 4-10 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-6 membered heteroaryl)-Ci-4 alkyl, -ORa3, -SRa3, and -NRc3Rd3, wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; each Ra3, Rc3, and Rd3is independently selected from H and Ci-6 alkyl; each R3Ais independently selected from H, Ci-6 alkyl, C3-7 cycloalkyl, and - CN, wherein the C1-6 alkyl and C3-7 cycloalkyl of R3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each R4is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; and each RGis independently selected from OH, CN, halo, oxo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, cyano-Ci-4 alkyl, HO-C1-4 alkyl, C1-4 alkoxy, and C1-4 alkoxy-Ci-4 alkyl.

[0284] In some embodiments: m is 0; n is 1 or 2;

[0285] X1is N or CH;

[0286] X2is N or CH;

[0287] X3is C or N;

[0288] Z is O;

[0289] Ring each = is independently a single or double bond;

[0290] Y1is C or N;

[0291] Y2is C or N;

[0292] Y3is CH, or N;

[0293] Ring B is Ce-io aryl or 5-10 membered heteroaryl;

[0294] Ring C is 5-7 membered heterocycloalkyl or 5-6 membered heteroaryl;

[0295] L2is selected from a bond, C3-7 cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6 membered heteroarylene, -C3-7 cycloalkylene-Ci- 4 alkyl-, -(4-7 membered heterocycloalkylene)-Ci-4 alkyl-, -phenylene-Ci-4 alkyl-, and -(5-6 membered heteroarylene)-Ci-4 alkyl-, wherein the C3-7 cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6 membered heteroarylene, -C3-7 cycloalkylene-Ci-4 alkyl-, -(4-7 membered heterocycloalkylene)-Ci-4 alkyl-, - phenylene-Ci-4 alkyl-, and -(5-6 membered heteroarylene)-Ci-4 alkyl- of L2are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents;

[0296] R1is selected from C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci-4 alkyl, wherein C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci-4 alkyl of R1are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents;

[0297] R2is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, -C(O)Ra2, -C(O)ORa2, -C(O)NRc2Rd2, -C(O)NRc2(ORa2), - OC(O)Ra2, -OC(O)NRc2Rd2, -NRc2C(O)Ra2, -NRc2C(O)ORa2, and -NRc2C(O)NRc2Rd2, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl of R2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents; each Ra2, Rc2, and Rd2is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl of Ra2, Rc2, and Rd2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents; each R2Ais independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, and -ORa2A; each Ra2Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; each R4is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; each RGis independently selected from OH, CN, halo, oxo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, cyano-Ci-4 alkyl, HO-C1-4 alkyl, and C1-4 alkoxy- C1-4 alkyl.

[0298] In some embodiments: n is 1 or 2;

[0299] X1is N or CH; X2is N or CH;

[0300] X3is C or N;

[0301] Z is O;

[0302] Ring A is a 6-membered heteroaryl selected from each = is independently a single or double bond;

[0303] Y1is C or N;

[0304] Y2is C or N;

[0305] Y3is CH, or N;

[0306] Ring B is 5-6 membered heteroaryl;

[0307] Ring C is 5-7 membered heterocycloalkyl or 5-6 membered heteroaryl;

[0308] L2is selected from a bond and 4-7 membered heterocycloalkylene, wherein the 4-7 membered heterocycloalkylene of L2is optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents;

[0309] R1is selected from C3-6 cycloalkyl, and C3-6 cycloalkyl-Ci-4 alkyl, wherein the C3-6 cycloalkyl and C3-6 cycloalkyl-Ci-4 alkyl of R1are each optionally substituted with 1 or 2 independently selected RGsubstituents;

[0310] R2is selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, 4-10 membered heterocycloalkyl, -C(O)Ra2, -C(O)C(O)NRc2Rd2, -C(O)NRc2Rd2, and - C(O)C(O)NRc2Rd2, wherein the C1-6 alkyl, C1-6 haloalkyl, and 4-10 membered heterocycloalkyl of R2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents; each Ra2, Rc2, and Rd2is independently selected from H, Ci-6 alkyl, and C3-7 cycloalkyl, wherein the C1-6 alkyl and C3-7 cycloalkyl of Ra2, Rc2, and Rd2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents; each R2Ais independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6haloalkyl, -CN, -ORa2A, -C(O)Ra2A, -C(O)C(O)Ra2A, -C(O)NRc2ARd2A, and -C(O)C(O)NRc2ARd2A, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of R2Aare each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; each Ra2A, Rc2A, and Rd2Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-10 cycloalkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-10 cycloalkyl groups are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; each R4is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; and each RGis independently selected from OH, CN, halo, oxo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, cyano-Ci-4 alkyl, HO-C1-4 alkyl, C1-4 alkoxy, and C1-4 alkoxy-Ci-4 alkyl.

[0311] In some embodiments: m is 0; n is 1 or 2;

[0312] X1is N or CH;

[0313] X2is N or CH;

[0314] X3is C or N;

[0315] Z is O;

[0316] Ring each = is independently a single or double bond;

[0317] Y1is C or N;

[0318] Y2is C or N;

[0319] Y3is CH, or N; Ring B is 5-6 membered heteroaryl;

[0320] Ring C is 5-7 membered heterocycloalkyl or 5-6 membered heteroaryl;

[0321] L2is selected from a bond and 4-7 membered heterocycloalkylene, wherein the 4-7 membered heterocycloalkylene of L2is optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents;

[0322] R1is selected from C3-6 cycloalkyl, and C3-6 cycloalkyl-Ci-4 alkyl, wherein the C3-6 cycloalkyl and C3-6 cycloalkyl-Ci-4 alkyl of R1are each optionally substituted with 1 or 2 independently selected RGsubstituents;

[0323] R2is selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, 4-10 membered heterocycloalkyl, -C(O)Ra2, and -C(O)NRc2Rd2, wherein the C1-6 alkyl, C1-6 haloalkyl, and 4-10 membered heterocycloalkyl of R2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents; each Ra2, Rc2, and Rd2is independently selected from H, C1-6 alkyl, and C3-7 cycloalkyl, wherein the C1-6 alkyl and C3-7 cycloalkyl of Ra2, Rc2, and Rd2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents; each R2Ais independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, and -ORa2A; each Ra2Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; each R4is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; each RGis independently selected from OH, CN, halo, oxo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, cyano-Ci-4 alkyl, HO-C1-4 alkyl, and C1-4 alkoxy- C1-4 alkyl.

[0324] In some embodiments, the compound of Formula I is a compound of Formula II:

[0325] or a pharmaceutically acceptable salt thereof.

[0326] In some embodiments, the compound of Formula I is a compound of Formula Il-a:

[0327] Il-a or a pharmaceutically acceptable salt thereof.

[0328] In some embodiments, the compound of Formula I is a compound of Formula III: or a pharmaceutically acceptable salt thereof.

[0329] In some embodiments, the compound of Formula I is a compound of Formula m-a:

[0330] III-a or a pharmaceutically acceptable salt thereof.

[0331] In some embodiments, the compound of Formula I is a compound of Formula

[0332] IV:

[0333] IV or a pharmaceutically acceptable salt thereof.

[0334] In some embodiments, the compound of Formula I is a compound of Formula

[0335] IVa:

[0336] IVa or a pharmaceutically acceptable salt thereof.

[0337] In some embodiments, the compound of Formula I is a compound of Formula V:

[0338] V or a pharmaceutically acceptable salt thereof.

[0339] In some embodiments, the compound of Formula I is a compound of Formula Va:

[0340] or a pharmaceutically acceptable salt thereof.

[0341] In some embodiments, the compound of Formula I is a compound of Formula VI:

[0342] VI or a pharmaceutically acceptable salt thereof.

[0343] In some embodiments, the compound of Formula I is a compound of Formula Via:

[0344]

[0345] Via or a pharmaceutically acceptable salt thereof.

[0346] In some embodiments, the compound of Formula I is a compound of Formula VII:

[0347] VII or a pharmaceutically acceptable salt thereof.

[0348] In some embodiments, the compound of Formula I is a compound of Formula Vila:

[0349]

[0350] Vila or a pharmaceutically acceptable salt thereof.

[0351] In some embodiments, the compound of Formula I is a compound of Formula VIII:

[0352] VIII or a pharmaceutically acceptable salt thereof.

[0353] In some embodiments, the compound of Formula I is a compound of Formula Vlll-a:

[0354] VUI-a or a pharmaceutically acceptable salt thereof.

[0355] In some embodiments, the compound of Formula I is a compound of Formula Vlll-b:

[0356] VIII-b or a pharmaceutically acceptable salt thereof.

[0357] In some embodiments, the compound of Formula I is a compound of Formula VIII-c:

[0358]

[0359] VIII-c or a pharmaceutically acceptable salt thereof.

[0360] In some embodiments, the compound of Formula I is a compound of Formula Vlll-d:

[0361] VUI-d or a pharmaceutically acceptable salt thereof.

[0362] In some embodiments, the compound of Formula I is a compound of Formula IX:

[0363] IX or a pharmaceutically acceptable salt thereof.

[0364] In some embodiments, the compound of Formula I is a compound of Formula IX-a:

[0365] IX-a or a pharmaceutically acceptable salt thereof.

[0366] In some embodiments, the compound of Formula I is a compound of Formula IX-b:

[0367]

[0368] IX-b or a pharmaceutically acceptable salt thereof.

[0369] In some embodiments, the compound provided herein is selected from:

[0370] 9-chloro-5-(5-(difhroromethyl)- 1,3, 4-thiadiazol -2 -yl)-N-(l- methylcyclopropyl)pyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0371] 5-(5-(difhroromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)-9- (l,2,3,6-tetrahydropyridin-4-yl)pyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0372] 5-(5-(difluorom ethyl)- 1,3, 4-thiadiazol -2 -yl)-9-(l-methyl-l, 2,3,6- tetrahydropyridin-4-yl)-N-(l-methylcyclopropyl)pyrazolo[l,5-a]quinazoline-7- sulfonamide;

[0373] 5-(5-(difhroromethyl)-l,3,4-thiadiazol-2-yl)-9-(l-(l-methoxycyclopropane-l- carbonyl)-l,2,3,6-tetrahydropyridin-4-yl)-N-(l-methylcyclopropyl)pyrazolo[l,5- a]quinazoline-7-sulfonamide;

[0374] 5-(5-(difhroromethyl)-l,3,4-thiadiazol-2-yl)-9-fluoro-N-(l- methylcyclopropyl)pyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0375] 5-(5-(difhroromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)-9-(3- methylpiperazin-l-yl)pyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0376] 5-(5-(difhroromethyl)-l,3,4-thiadiazol-2-yl)-9-(3,4-dimethylpiperazin-l-yl)-N- (l-methylcyclopropyl)pyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0377] 4-(5-(5 -(difluoromethyl)- 1 ,3 , 4-thiadiazol -2 -yl)-7-(N-( 1 - methylcyclopropyl)sulfamoyl)pyrazolo[l,5-a]quinazolin-9-yl)-N,N,2- trimethylpiperazine- 1 -carboxamide; 9-(4-(cyclopropanecarbonyl)-3-methylpiperazin-l-yl)-5-(5-(difluoromethyl)- l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)pyrazolo[l,5-a]quinazoline-7- sulfonamide;

[0378] 5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-9-(4-(l-methoxycyclopropane-l- carbonyl)-3-methylpiperazin-l-yl)-N-(l -methylcy clopropyl)pyrazolo[l, 5- a]quinazoline-7-sulfonamide;

[0379] 9-(4-(l -cyanocyclopropane- 1 -carbonyl)-3 -methylpiperazin- 1 -yl)-5-(5- (difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)pyrazolo[l,5- a]quinazoline-7-sulfonamide;

[0380] 9-bromo-5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l- m ethylcyclopropyl)- 1 ,2-dihydroimidazo[ 1 ,2-a]quinoline-7-sulfonamide;

[0381] 5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)-9- (piperazin-l-yl)pyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0382] 5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)-9-(4- methylpiperazin-l-yl)pyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0383] 4-(5-(5 -(difluoromethyl)- 1 ,3 ,4-thiadiazol-2-yl)-7-(N-( 1 - methylcyclopropyl)sulfamoyl)pyrazolo[l,5-a]quinazolin-9-yl)-N,N- dimethylpiperazine-1 -carboxamide;

[0384] 5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-9-(3-isopropylpiperazin-l-yl)-N- (l-methylcyclopropyl)pyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0385] 5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-9-(3-(methoxymethyl)piperazin-

[0386] 1 -yl)-N-( 1 -methylcy clopropyl)pyrazolo [ 1 , 5 -a] quinazoline-7-sulfonamide;

[0387] 5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)-9-(4,7- diazaspiro[2.5]octan-7-yl)pyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0388] 5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)-9-(3- (trifluoromethyl)piperazin-l-yl)pyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0389] 4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-(3,5-dimethylpiperazin-l-yl)-N- (1 -methylcy cl opropyl)quinazoline-6-sulfonamide;

[0390] 4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-(3,5-dimethylpiperazin-l-yl)-N- (l-methylcyclopropyl)-2-(methylthio)quinazoline-6-sulfonamide;

[0391] 4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-(3,5-dimethylpiperazin-l-yl)-2- (l-methyl-lH-pyrazol-4-yl)-N-(l-methylcyclopropyl)quinazoline-6-sulfonamide; 4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-(3,5-dimethylpiperazin-l-yl)-2- ((l-methyl-lH-pyrazol-4-yl)oxy)-N-(l-methylcyclopropyl)quinazoline-6- sulfonamide;

[0392] 2-amino-4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-(3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)quinazoline-6-sulfonamide;

[0393] 2-(3-cyanoazetidin-l-yl)-4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-(3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)quinazoline-6-sulfonamide;

[0394] 4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-(3,5-dimethylpiperazin-l-yl)-N- (l-methylcyclopropyl)-2-(3-oxotetrahydro-3H-oxazolo[3,4-a]pyrazin-7(lH)- yl)quinazoline-6-sulfonamide;

[0395] 2-(l-(l-(cyanomethyl)cyclobutyl)-lH-pyrazol-4-yl)-4-(5-(difluoromethyl)- l,3,4-thiadiazol-2-yl)-8-(3,5-dimethylpiperazin-l-yl)-N-(l- methylcyclopropyl)quinazoline-6-sulfonamide;

[0396] 4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-(3,5-dimethylpiperazin-l-yl)-N- (l-methylcyclopropyl)-2-((tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazoline- 6-sulfonamide;

[0397] 4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-(3,5-dimethylpiperazin-l-yl)-2- methoxy-N-(l-methylcyclopropyl)quinazoline-6-sulfonamide;

[0398] 4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-(3,5-dimethylpiperazin-l-yl)-2- ((l-(hydroxymethyl)cyclopentyl)methoxy)-N-(l-methylcyclopropyl)quinazoline-6- sulfonamide;

[0399] 4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-(3,5-dimethylpiperazin-l-yl)-2- methyl-N-( 1 -methylcyclopropyl)- 1 -oxo- 1 ,2-dihydrophthalazine-6-sulfonamide;

[0400] 4-(l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-3-methyl-7-(N-(l- methylcyclopropyl)sulfamoyl)-4-oxo-3,4-dihydrophthalazin-5-yl)-N,N- dimethylpiperazine-1 -carboxamide;

[0401] 4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-(4-isobutyryl-3- methylpiperazin- 1 -yl)-2-methyl-N-( 1 -methylcyclopropyl)- 1 -oxo- 1,2- dihydrophthalazine-6-sulfonamide;

[0402] 4-(l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-3-methyl-7-(N-(l- methylcyclopropyl)sulfamoyl)-4-oxo-3,4-dihydrophthalazin-5-yl)-N,N,2- trimethylpiperazine- 1 -carboxamide; 2-(4-(l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-3-methyl-7-(N-(l- methylcyclopropyl)sulfamoyl)-4-oxo-3,4-dihydrophthalazin-5-yl)-2-methylpiperazin- l-yl)-N,N-dimethyl-2-oxoacetamide; and

[0403] 4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-2-methyl-8-(3-methyl-4-(3- methyl-2-oxobutanoyl)piperazin- 1 -yl)-N-(l -methylcyclopropyl)- 1 -oxo- 1 ,2- dihydrophthalazine-6-sulfonamide; or a pharmaceutically acceptable salt thereof.

[0404] In some embodiments, the compound provided herein is selected from:

[0405] 9-chloro-5-(5-(difhroromethyl)-l,3,4-thiadiazol-2-yl)-N-(l- methylcyclopropyl)pyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0406] 5-(5-(difhroromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)-9- (l,2,3,6-tetrahydropyridin-4-yl)pyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0407] 5-(5-(difhroromethyl)-l,3,4-thiadiazol-2-yl)-9-(l-methyl-l,2,3,6- tetrahydropyridin-4-yl)-N-(l-methylcyclopropyl)pyrazolo[l,5-a]quinazoline-7- sulfonamide;

[0408] 5-(5-(difhroromethyl)-l,3,4-thiadiazol-2-yl)-9-(l-(l-methoxycyclopropane-l- carbonyl)-l,2,3,6-tetrahydropyridin-4-yl)-N-(l-methylcyclopropyl)pyrazolo[l,5- a]quinazoline-7-sulfonamide;

[0409] 5-(5-(difhroromethyl)-l,3,4-thiadiazol-2-yl)-9-fluoro-N-(l- methylcyclopropyl)pyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0410] (R)-5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)-9- (3-methylpiperazin-l-yl)pyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0411] (R)-5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-9-(3,4-dimethylpiperazin-l- yl)-N-(l-methylcyclopropyl)pyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0412] (R)-4-(5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-7-(N-(l- methylcyclopropyl)sulfamoyl)pyrazolo[l,5-a]quinazolin-9-yl)-N,N,2- trimethylpiperazine- 1 -carboxamide;

[0413] (R)-9-(4-(cyclopropanecarbonyl)-3-methylpiperazin-l-yl)-5-(5- (difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)pyrazolo[l,5- a]quinazoline-7-sulfonamide; (R)-5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-9-(4-(l- m ethoxy cyclopropane- 1 -carbonyl)-3 -methylpiperazin- 1 -yl)-N-( 1 - methylcyclopropyl)pyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0414] (R)-9-(4-( 1 -cyanocyclopropane- 1 -carbonyl)-3 -methylpiperazin- 1 -y 1 )- 5 -(5 - (difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)pyrazolo[l,5- a]quinazoline-7-sulfonamide;

[0415] 9-bromo-5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l- m ethylcyclopropyl)- 1 ,2-dihydroimidazo[ 1 ,2-a]quinoline-7-sulfonamide;

[0416] 5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)-9- (piperazin-l-yl)pyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0417] 5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)-9-(4- methylpiperazin-l-yl)pyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0418] 4-(5-(5 -(difluoromethyl)- 1 ,3 ,4-thiadiazol-2-yl)-7-(N-( 1 - methylcyclopropyl)sulfamoyl)pyrazolo[l,5-a]quinazolin-9-yl)-N,N- dimethylpiperazine-1 -carboxamide;

[0419] (R)-5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-9-(3-isopropylpiperazin-l- yl)-N-(l-methylcyclopropyl)pyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0420] (S)-5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-9-(3-

[0421] (methoxymethyl)piperazin- 1 -yl)-N-( 1 -methylcy clopropyl)pyrazolo[ 1 , 5-a]quinazoline- 7-sulfonamide;

[0422] 5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)-9-(4,7- diazaspiro[2.5]octan-7-yl)pyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0423] 5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)-9-(3- (trifluoromethyl)piperazin-l-yl)pyrazolo[l,5-a]quinazoline-7-sulfonamide;

[0424] 4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin- l-yl)-N-(l -methylcy clopropyl)quinazoline-6-sulfonamide;

[0425] 4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin- l-yl)-N-(l-methylcyclopropyl)-2-(methylthio)quinazoline-6-sulfonamide;

[0426] 4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin- l-yl)-2-(l-methyl-lH-pyrazol-4-yl)-N-(l-methylcyclopropyl)quinazoline-6- sulfonamide; 4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin- l-yl)-2-((l-methyl-lH-pyrazol-4-yl)oxy)-N-(l-methylcyclopropyl)quinazoline-6- sulfonamide;

[0427] 2-amino-4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)quinazoline-6-sulfonamide;

[0428] 2-(3-cyanoazetidin-l-yl)-4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8- ((3S,5S)-3,5-dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)quinazoline-6- sulfonamide;

[0429] 4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin- l-yl)-N-(l-methylcyclopropyl)-2-(3-oxotetrahydro-3H-oxazolo[3,4-a]pyrazin-7(lH)- yl)quinazoline-6-sulfonamide;

[0430] 2-(l-(l-(cyanomethyl)cyclobutyl)-lH-pyrazol-4-yl)-4-(5-(difluoromethyl)- l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin-l-yl)-N-(l- methylcyclopropyl)quinazoline-6-sulfonamide;

[0431] 4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin- l-yl)-N-(l-methylcyclopropyl)-2-((tetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)quinazoline-6-sulfonamide;

[0432] 4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin- l-yl)-2-methoxy-N-(l-methylcyclopropyl)quinazoline-6-sulfonamide;

[0433] 4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin- l-yl)-2-((l-(hydroxymethyl)cyclopentyl)methoxy)-N-(l- methylcyclopropyl)quinazoline-6-sulfonamide;

[0434] 4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin- 1 -yl)-2-methyl-N-(l -methylcyclopropyl)- 1 -oxo- 1 ,2-dihydrophthalazine-6- sulfonamide;

[0435] 4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3R,5R)-3,5- dimethylpiperazin- 1 -yl)-2-methyl-N-( 1 -methylcyclopropyl)- 1 -oxo- 1 ,2- dihydrophthalazine-6-sulfonamide;

[0436] 4-(l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-3-methyl-7-(N-(l- methylcyclopropyl)sulfamoyl)-4-oxo-3,4-dihydrophthalazin-5-yl)-N,N- dimethylpiperazine-1 -carboxamide; (R)-4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-(4-isobutyryl-3- methylpiperazin- 1 -yl)-2-methyl-N-( 1 -methylcyclopropyl)- 1 -oxo- 1,2- dihydrophthalazine-6-sulfonamide;

[0437] (R)-4-(l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-3-methyl-7-(N-(l- methylcyclopropyl)sulfamoyl)-4-oxo-3,4-dihydrophthalazin-5-yl)-N,N,2- trimethylpiperazine- 1 -carboxamide;

[0438] (R)-2-(4-(l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-3-methyl-7-(N-(l- methylcyclopropyl)sulfamoyl)-4-oxo-3,4-dihydrophthalazin-5-yl)-2-methylpiperazin- l-yl)-N,N-dimethyl-2-oxoacetamide; and

[0439] (R)-4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-2-methyl-8-(3-methyl-4-(3- methyl-2-oxobutanoyl)piperazin- 1 -yl)-N-(l -methylcyclopropyl)- 1 -oxo- 1 ,2- dihydrophthalazine-6-sulfonamide; or a pharmaceutically acceptable salt thereof.

[0440] It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0441] At various places in the present specification, divalent linking substituents are described. It is specifically intended that each divalent linking substituent include both the forward and backward forms of the linking substituent. For example, - NR(CR’R”)n- includes both -NR(CR’R”)n- and -(CR’R”)nNR-. Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups.

[0442] The term “n-membered” where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6- membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10- membered cycloalkyl group.

[0443] As used herein, the phrase “optionally substituted” means unsubstituted or substituted. The substituents are independently selected, and substitution may be at any chemically accessible position. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms. It is to be understood that substitution at a given atom is limited by valency.

[0444] As used herein, the phrase “each ‘variable’ is independently selected from” means substantially the same as wherein “at each occurrence ‘variable’ is selected from.”

[0445] Throughout the definitions, the terms “Cn-m” and “Cm-n” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C1-3, C1-4, C1-6, and the like.

[0446] As used herein, the term “Cn-m alkyl”, employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (iPr), n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-l- butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. The term “Cn-m alkyl” is understood to include deuterated analogs of saturated hydrocarbon groups as defined herein, including but not limited to, groups such as trideuteromethyl (CD3), pentadeuteroethyl (CD2CD3), and the like. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, from 2 to 6 carbon atoms, from 2 to 4 carbon atoms, from 2 to 3 carbon atoms, or 1 to 2 carbon atoms.

[0447] As used herein, “Cn-m alkenyl” refers to an alkyl group having one or more double carbon-carbon bonds and having n to m carbons. Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec- butenyl, and the like. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. The term “Cn-m alkenyl” is understood to include deuterated analogs of alkenyl groups as defined herein, including but not limited to, groups such as trideuteroethenyl (-CD=CD2), tetradeuteropropenyl, (-CD=CD-CD2), and the like.

[0448] As used herein, “Cn-m alkynyl” refers to an alkyl group having one or more triple carbon-carbon bonds and having n to m carbons. Example alkynyl groups include, but are not limited to, ethynyl, propyn-l-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. The term “Cn-m alkynyl” is understood to include deuterated analogs of alkynyl groups as defined herein, including but not limited to, groups such as deuteroethynyl (-C=CD), trideuteropropyn-l-yl, (-OCCD3), and the like.

[0449] As used herein, the term “Cn-m alkoxy”, employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group has n to m carbons. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tertbutoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. The term “Cn-m alkoxy” is understood to include deuterated analogs of the alkyl moiety of the alkoxy groups as defined herein, including but not limited to, groups such as trideuteromethoxy (-OCD3), pentadeuteroethoxy (-OCD2CD3), and the like.

[0450] As used herein, “Cn-m haloalkoxy”, employed alone or in combination with other terms, refers to a group of formula -O-(haloalkyl), wherein the haloalkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. An example haloalkoxy group is -OCF3. In some embodiments, the haloalkoxy group is a fluoroalkoxy group. The term “Cn-m haloalkoxy” is understood to include deuterated analogs of the haloalkoxy groups as defined herein.

[0451] As used herein, the term “carbonyl”, employed alone or in combination with other terms, refers to a -C(O)- group.

[0452] As used herein, the term “Cn-m alkylcarbonyl” refers to a group of formula -C(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. The term “Cn-malkylcarbonyl” is understood to include deuterated analogs of the alkylcarbonyl groups as defined herein.

[0453] As used herein, the term “Cn-m alkyl sulfonyl” refers to a group of formula -S(O)2-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. The term “Cn-malkyl sulfonyl” is understood to include deuterated analogs of the alkylsulfonyl groups as defined herein.

[0454] As used herein, the term “carboxy” refers to a group of formula -C(O)OH.

[0455] As used herein, the term “amino” refers to a group of formula -NH2. As used herein, the term “Cn-m alkylamino”, employed alone or in combination with other terms, refers to a group of formula -NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, alkyl group has 1 to 6 or 1 to 4 carbon atoms. Example Cn-m alkylamino groups include methylamino, ethylamino, propylamino (e.g., n-propylamino and isopropylamino), and the like. The term “Cn-m alkylamino” is understood to include deuterated analogs of the alkylamino groups as defined herein.

[0456] As used herein, the term “di(Cn-m alkyl)amino” refers to a group of formula - N(alkyl)2, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. The term “di(Cn-m alkyl)amino” is understood to include deuterated analogs of the di(Cn-m alkyl)amino groups as defined herein.

[0457] As used herein, the term “Cn-m alkoxycarbonyl”, employed alone or in combination with other terms, refers to a group of formula -C(O)O-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. The term “Cn-m alkoxy carbonyl” is understood to include deuterated analogs of the alkoxy carbonyl groups as defined herein.

[0458] As used herein, the term “Cn-m alkylcarbonyl”, employed alone or in combination with other terms, refers to a group of formula -C(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. The term “Cn-m alkylcarbonyl” is understood to include deuterated analogs of the alkylcarbonyl groups as defined herein.

[0459] As used herein, the term “Cn-m alkylcarbonylamino”, employed alone or in combination with other terms, refers to a group of formula -NHC(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. The term “Cn-m alkylcarbonylamino” is understood to include deuterated analogs of the alkylcarbonylamino groups as defined herein.

[0460] As used herein, the term “carbamyl”, employed alone or in combination with other terms, refers to a group of formula -C(0)-NH2.

[0461] As used herein, the term “Cn-m alkylcarbamyl”, employed alone or in combination with other terms, refers to a group of formula -C(O)-NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. The term “Cn-m alkylcarbamyl” is understood to include deuterated analogs of the alkylcarbamyl groups as defined herein.

[0462] As used herein, the term “di-Cn-m alkylcarbamyl”, employed alone or in combination with other terms, refers to a group of formula -C(O)-N(alkyl)2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, the alkyl group independently has 1 to 6 or 1 to 4 carbon atoms. The term “di-Cn-m alkylcarbamyl” is understood to include deuterated analogs of the dialkylcarbamyl groups as defined herein.

[0463] As used herein, the term “thio” refers to a group of formula -SH.

[0464] As used herein, the term “Cn-m alkylthio”, employed alone or in combination with other terms, refers to a group of formula -S-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. The term “Cn-m alkylthio” is understood to include deuterated analogs of the alkylthio groups as defined herein.

[0465] As used herein, the term “Cn-m alkylsulfinyl”, employed alone or in combination with other terms, refers to a group of formula -S(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. The term “Cn-m alkylsulfinyl” is understood to include deuterated analogs of the alkylsulfinyl groups as defined herein.

[0466] As used herein, the term “Cn-m alkylsulfonyl”, employed alone or in combination with other terms, refers to a group of formula -S(O)2-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. The term “Cn-m alkyl sulfonyl” is understood to include deuterated analogs of the alkylsulfonyl groups as defined herein.

[0467] As used herein, “halosulfanyl” refers to a sulfur group having one or more halogen substituents. Example halosulfanyl groups include pentahalosulfanyl groups such as SFs.

[0468] As used herein, the term “HO-C1-4 alkyl” refers to a group of formula -C1-4 alkylene-OH. The term “HO-C1-4 alkyl” is understood to include deuterated analogs of the HO-C1-4 alkyl groups as defined herein. As used herein, the term “C1-4 alkoxy-Ci-4 alkyl” refers to a group of formula - Ci-4 alkylene-O-(Ci-4 alkyl). The term “C1-4 alkoxy-Ci-4 alkyl” is understood to include deuterated analogs of the Ci-4 alkoxy-Ci-4 alkyl groups as defined herein.

[0469] As used herein, the term “aryl,” employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term “Cn-m aryl” refers to an aryl group having from n to m ring carbon atoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, aryl groups have from 5 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl. In some embodiments, the aryl is phenyl. The term “aryl” is understood to include deuterated analogs of the aryl groups as defined herein, including but not limited to, groups such as pentadeuterophenyl (z.e., perdeuterophenyl, phenyl -ds , perdeuteronaphthyl, and the like.

[0470] As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments, a halo is F, Cl, or Br. In some embodiments, a halo is F or Cl. In some embodiments, a halo is F. In some embodiments, a halo is Cl.

[0471] As used herein, “Cn-m haloalkoxy” refers to a group of formula -O-haloalkyl having n to m carbon atoms. Example haloalkoxy groups include OCF3 and OCHF2. In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. The term “Cn-mhaloalkoxy” is understood to include deuterated analogs of the haloalkyl moiety of the haloalkoxy groups as defined herein, including but not limited to, groups such as deuterodifluoromethoxy (-OCDF2), dideuterofluoromethoxy (-OCD2F), and the like.

[0472] As used herein, the term “Cn-m haloalkyl”, employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+l halogen atoms which may be the same or different, where “s” is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Example haloalkyl groups include CF3, C2F5, CHF2, CH2F, CCI3, CHCh, C2CI5 and the like. The term “Cn-m haloalkyl” is understood to include deuterated analogs of the haloalkyl groups as defined herein, including but not limited to, groups such as deuterodifluoromethyl (-CDF2), dideuterofluoromethyl (-CD2F), and the like.

[0473] As used herein, “hydroxyl” or “hydroxy” refer to a group of formula -OH.

[0474] As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and alkenyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2 fused rings) groups, spirocycles, and bridged rings (e.g., a bridged bicycloalkyl group). Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfido (e.g., C(O) or C(S)). Also included in the definition of cycloalkyl are moi eties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ringforming atom of the fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons i.e., C3-10). In some embodiments, the cycloalkyl is a C3-10 monocyclic or bicyclic cycloalkyl. In some embodiments, the cycloalkyl is a C3-7 monocyclic cycloalkyl. In some embodiments, the cycloalkyl is a C4-7 monocyclic cycloalkyl. In some embodiments, the cycloalkyl is a C4-10 spirocycle or bridged cycloalkyl (e.g., a bridged bicycloalkyl group). Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcamyl, cubane, adamantane, bicyclo[l.l. l]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl, and the like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The term “cycloalkyl” is understood to include deuterated analogs of the cycloalkyl groups as defined herein, including but not limited to, groups such as perdeuterocyclopropyl, perdeuterocyclobutyl, perdeuterocyclopentyl, perdeuterocyclohexyl, and the like.

[0475] As used herein, “heteroaryl” refers to a monocyclic or polycyclic (e.g., having 2 fused rings) aromatic heterocycle having at least one heteroatom ring member selected from N, O, S and B. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S and B. In some embodiments, any ring-forming N in a heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl is a 5-, 7-, 8-, 9-, or 10-membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl is a 5-, 7-, 8-, 9-, or 10-membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl is a 5-6 membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl is a 5 membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl is a 5 membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl group contains 5 to 10, 5 to 7, 3 to 7, or 5 to 6 ringforming atoms. In some embodiments, the heteroaryl group has 1 to 4 ring-forming heteroatoms, 1 to 3 ring-forming heteroatoms, 1 to 2 ring-forming heteroatoms or 1 ring-forming heteroatom. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. Example heteroaryl groups include, but are not limited to, thienyl (or thiophenyl), furyl (or furanyl), pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4- thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl and l,2-dihydro-l,2-azaborine, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, azolyl, triazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazofl, 2-b]thiazolyl, purinyl, triazinyl, thieno[3,2- b]pyridinyl, imidazofl, 2-a]pyridinyl, 1,5-naphthyridinyl, lH-pyrazolo[4,3- b]pyridinyl, triazolo[4,3-a]pyridinyl, lH-pyrrolo[3,2-b]pyridinyl, lH-pyrrolo[2,3- b]pyridinyl, pyrazolo[l,5-a]pyridinyl, indazolyl, and the like. The term “heteroaryl” is understood to include deuterated analogs of the heteroaryl groups as defined herein, including but not limited to, groups such as perdeuteropyridinyl, perdeuteropyrazinyl, perdeuteropyrimidinyl, and the like.

[0476] As used herein, “heterocycloalkyl” refers to monocyclic or polycyclic heterocycles having at least one non-aromatic ring (saturated or partially unsaturated ring), wherein one or more of the ring-forming carbon atoms of the heterocycloalkyl is replaced by a heteroatom selected from N, O, S, and B, and wherein the ringforming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by one or more oxo or sulfido (e.g., C(O), S(O), C(S), or S(O)2, etc.). When a ring-forming carbon atom or heteroatom of a heterocycloalkyl group is optionally substituted by one or more oxo or sulfide, the O or S of said group is in addition to the number of ring-forming atoms specified herein (e.g., a l-methyl-6- oxo-l,6-dihydropyridazin-3-yl is a 6-membered heterocycloalkyl group, wherein a ring-forming carbon atom is substituted with an oxo group, and wherein the 6- membered heterocycloalkyl group is further substituted with a methyl group). Heterocycloalkyl groups include monocyclic and polycyclic (e.g., having 2 fused rings) systems. Included in heterocycloalkyl are monocyclic and polycyclic 3 to 10, 4 to 10, 5 to 10, 4 to 7, 5 to 7, or 5 to 6 membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles and bridged rings (e.g., a 5 to 10 membered bridged biheterocycloalkyl ring having one or more of the ring-forming carbon atoms replaced by a heteroatom independently selected from N, O, S, and B). The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. The term “heterocycloalkyl” is understood to include deuterated analogs of the heterocycloalkyl groups as defined herein, including but not limited to, groups such as perdeuteroazetidinyl, perdeuteropyrrolidinyl, perdeuteropiperidinyl, and the like.

[0477] Also included in the definition of heterocycloalkyl are moi eties that have one or more aromatic rings fused (z.e., having a bond in common with) to the non- aromatic heterocyclic ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.

[0478] In some embodiments, the heterocycloalkyl group contains 3 to 10 ringforming atoms, 4 to 10 ring-forming atoms, 4 to 8 ring-forming atoms, 3 to 7 ringforming atoms, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms or 1 heteroatom. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from N, O, S and B and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 5-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, S, and B and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 5 to 10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic 5 to 6 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and having one or more oxidized ring members.

[0479] Example heterocycloalkyl groups include pyrrolidin-2-one (or 2- oxopyrrolidinyl), l,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, 1, 2,3,4- tetrahydroisoquinoline, tetrahydrothiopheneyl, tetrahydrothiopheneyl 1,1 -di oxide, benzazapene, azabicyclo[3.1.0]hexanyl, diazabicyclo[3.1.0]hexanyl, oxobicyclo[2.1.1]hexanyl, azabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.1]heptanyl, azabicyclo[3.1. l]heptanyl, diazabicyclo[3.1. l]heptanyl, azabicyclo[3.2. l]octanyl, diazabicyclo[3.2.1]octanyl, oxobicyclo[2.2.2]octanyl, azabicyclo[2.2.2]octanyl, azaadamantanyl, diazaadamantanyl, oxo-adamantanyl, azaspiro[3.3]heptanyl, 2- azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl, azaspiro[3.5]nonanyl, 7- azaspiro[3.5]nonanyl, oxo-azaspiro[3.3]heptanyl, azaspiro[3.4]octanyl, diazaspiro[3 ,4]octanyl, oxo-azaspiro[3 ,4]octanyl, azaspiro[2.5]octanyl, diazaspiro[2.5]octanyl, azaspiro[4.4]nonanyl, diazaspiro[4.4]nonanyl, oxo- azaspiro[4.4]nonanyl, azaspiro[4.5]decanyl, diazaspiro[4.5]decanyl, diazaspiro[4.4]nonanyl, oxo-diazaspiro[4.4]nonanyl, oxo-dihydropyridazinyl, oxo- 2,6-diazaspiro[3.4]octanyl, oxohexahydropyrrolo[l,2-a]pyrazinyl, 3-oxopiperazinyl, oxo-pyrrolidinyl, oxo-pyridinyl, and the like.

[0480] As used herein, “Co-Pcycloalkyl-Cn-m alkyl-” refers to a group of formula cycloalkyl-alkylene-, wherein the cycloalkyl has o to p carbon atoms and the alkylene linking group has n to m carbon atoms. The term “Co-Pcycloalkyl-Cn-m alkyl-” is understood to include deuterated analogs of the cycloalkyl and / or alkyl moieties of the Co-Pcycloalkyl-Cn-m alkyl- groups as defined herein.

[0481] As used herein “C0.paryl-Cn-m alkyl-” refers to a group of formula arylalkylene-, wherein the aryl has o to p carbon atoms and the alkylene linking group has n to m carbon atoms. The term “Co-Paryl-Cn-m alkyl-” is understood to include deuterated analogs of the aryl and / or alkyl moieties of the Co-Paryl-Cn-m alkyl- groups as defined herein.

[0482] As used herein, “heteroaryl-Cn-m alkyl-” refers to a group of formula heteroaryl-alkylene-, wherein alkylene linking group has n to m carbon atoms. The term “heteroaryl-Cn-m alkyl-” is understood to include deuterated analogs of the heteroaryl and / or alkyl moieties of the heteroaryl-Cn-m alkyl- groups as defined herein.

[0483] As used herein “heterocycloalkyl -Cn-m alkyl-” refers to a group of formula heterocycloalkyl-alkylene-, wherein alkylene linking group has n to m carbon atoms. The term “heterocycloalkyl-Cn-m alkyl-” is understood to include deuterated analogs of the heterocycloalkyl and / or alkyl moieties of the heterocycloalkyl -Cn-m alkylgroups as defined herein.

[0484] As used herein, an “alkyl linking group” or “alkylene linking group” is a bivalent straight chain or branched alkyl linking group (“alkylene group”). For example, “Co-Pcycloalkyl-Cn-m alkyl-”, “Co-Paryl-Cn-m alkyl-”, “phenyl-Cn-m alkyl-”, “heteroaryl-Cn-m alkyl-”, and “heterocycloalkyl-Cn-m alkyl-” contain alkyl linking groups. Examples of “alkyl linking groups” or “alkylene groups” include methylene, ethan- 1,1 -diyl, ethan-l,2-diyl, propan-1, 3-dilyl, propan- 1,2-diyl, propan- 1,1 -diyl and the like. The terms “alkyl linking group” and “alkylene linking group” are understood to include deuterated analogs of the alkylene groups as defined herein. As used herein, a “haloalkyl linking group” or “haloalkylene linking group” is a bivalent straight chain or branched haloalkyl linking group (“haloalkylene group”). Example haloalkylene groups include -CF2-, -C2F4-, -CHF-, -CCI2-, -CHC1-, -C2CI4-, and the like. The terms “haloalkyl linking group” and “haloalkylene linking group” are understood to include deuterated analogs of the haloalkylene groups as defined herein.

[0485] As used herein, a “cycloalkyl linking group” or “cycloalkylene linking group” is a bivalent straight chain or branched cycloalkyl linking group (“cycloalkylene group”). Examples of “cycloalkyl linking groups” or “cycloalkylene groups” include cyclopropy-l,l,-diyl, cyclopropy-l,2-diyl, cyclobut-l,3,-diyl, cyclopent-1, 3, -diyl, cyclopent- 1,4, -diyl, cyclohex- 1,2, -diyl, cyclohex-1, 3, -diyl, cyclohex- 1,4, -diyl, and the like. The terms “cycloalkyl linking group” and “cycloalkylene linking group” are understood to include deuterated analogs of the cycloalkylene groups as defined herein.

[0486] As used herein, a “heterocycloalkyl linking group” or “heterocycloalkylene linking group” is a bivalent straight chain or branched heterocycloalkyl linking group (“heterocycloalkylene group”). Examples of “heterocycloalkyl linking groups” or “heterocycloalkylene groups” include azetidin-l,2-diyl, azeti din- 1,3 -diyl, pyrrolidin- 1,2-diyl, pyrrolidin- 1,3 -diyl, pyrrolidin-2,3-diyl, piperidin-l,2-diyl, piperidin-l,3-diyl, piperidin-l,4-diyl, piperi din-2, 3 -diyl, piperi din-2, 4-diyl, and the like. The terms “heterocycloalkyl linking group” and “heterocycloalkylene linking group” are understood to include deuterated analogs of the heterocycloalkylene groups as defined herein.

[0487] As used herein, a “heteroaryl linking group” or “heteroarylene linking group” is a bivalent straight chain or branched heteroaryl linking group (“heteroarylene group”). Examples of “heteroaryl linking groups” or “heteroarylene groups” include pyrazol- 1,3 -diyl, imidazol-l,2,-diyl, pyri din-2, 3 -diyl, pyridin-2, 4-diyl, pyridin-3,4- diyl, and the like. The terms “heteroaryl linking group” and “heteroarylene linking group” are understood to include deuterated analogs of the heteroarylene groups as defined herein.

[0488] At certain places, the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring may be attached at any position of the ring, whereas a pyridin-3-yl ring is attached at the 3-position.

[0489] As used herein, the term “oxo” refers to an oxygen atom (z.e., =0) as a divalent substituent, forming a carbonyl group when attached to a carbon (e.g., C=0 or C(0)), or attached to a nitrogen or sulfur heteroatom forming a nitroso, sulfinyl, or sulfonyl group.

[0490] As used herein, the term “independently selected from” means that each occurrence of a variable or substituent (e.g., each RG) , are independently selected at each occurrence from the applicable list.

[0491] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, the compound has the (R)-configuration. In some embodiments, the compound has the (S)-configuration. The Formulas (e.g., Formula I, Formula II, etc.) provided herein include stereoisomers of the compounds.

[0492] Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. An example method includes fractional recrystallizaion using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as P-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of a-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N- m ethylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[0493] Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.

[0494] Compounds provided herein also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, 2-hydroxypyridine and 2-pyridone, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.

[0495] All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents e.g. hydrates and solvates) or can be isolated.

[0496] In some embodiments, preparation of compounds can involve the addition of acids or bases to affect, for example, catalysis of a desired reaction or formation of salt forms such as acid addition salts.

[0497] In some embodiments, the compounds provided herein, or salts thereof, are substantially isolated. By “substantially isolated” is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compounds provided herein. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds provided herein, or salt thereof. The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0498] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0499] The present application also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present disclosure include the conventional non -toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0500] Synthesis

[0501] Compounds of the invention, including salts thereof, can be prepared using known organic synthesis techniques and according to various possible synthetic routes. Example synthetic methods for preparing compounds of the invention are provided in the Schemes below.

[0502] Compounds of Formula I, such as compounds of formula 1-10, can be synthesized, for example, using a process shown in Scheme I. Compound 1-1 can be converted to 1-3 via condensation with suitable reagent (e.g., formamide 1-2). 1-3 can be converted to 1-4 via treating 1-3 with chlorosulfonic acid. 1-4 can then be converted to 1-6 after reacting with amine 1-5. Treating 1-6 with suitable reagent (e.g., POCI3) can lead to 1-7. Compound 1-8 can be obtained by treating 1-7 with palladium mediated transmetalation reaction with suitable reagent (e.g., hexamethyldi tin). 1-8 can be converted into compound 1-9 via suitable reactions (e.g., transition metal- catalyzed cross-coupling reactions). 1-9 can be converted into compounds of formula 1-10 via suitable reactions (e.g., transition metal-catalyzed cross-coupling reactions, or SNAr reactions).

[0503] Scheme I.

[0504] Compounds of Formula I, such as formula II-9, can also be synthesized, for example, using a process shown in Scheme II. Compound II-l can be converted to II-2 via reacting with amine 1-5. II-2 can be converted to II-4 via amide coupling of II-2 with II-3. II-4 can be converted to II-5 under thermal condition. Treating II-5 with suitable reagent (e.g., POCI3) can lead to II-6. II-7 can be obtained by treating II-6 with palladium mediated transmetalation reaction with suitable reagent (e.g., hexamethylditin). II-7 can be converted into compound II-8 via suitable reactions (e.g., transition metal-catalyzed cross-coupling reactions). II-8 can be converted into compound of formula II-9 via suitable reactions (e.g., transition metal-catalyzed cross-coupling reactions, or SNAr reactions).

[0505] Scheme II.

[0506] The reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.

[0507] Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[0508] Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g.,JH or13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.

[0509] The expressions, “ambient temperature,” “room temperature,” and “r.t ”, as used herein, are understood in the art, and refer generally to a temperature, e.g. a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20 °C to about 30 °C.

[0510] Methods of Use

[0511] The present disclosure provides uses for compounds and compositions described herein. The compounds described herein can inhibit the activity of poly(ADP -ribose) glycohydrolase (PARG). In some embodiments, provided compounds and compositions are for use in medicine (e.g, as therapy). In some embodiments, provided compounds and compositions are useful in treating a disease, disorder, or condition, wherein an underlying pathology is, wholly or partially, mediated by PARG. In some embodiments, provided compounds and compositions are useful in research as, for example, analytical tools and / or control compounds in biological assays.

[0512] Poly(ADP-ribosyl)ation (PARylation) is a dynamic and tightly controlled post-translational modification that plays important roles in multiple cellular processes, including DNA repair, replication, transcription, and cell death (Kang, M., et al. IntJMolSci, 2022, 23, 9826; Le May, N., et al. Mol Cell, 2012, 48, 785). The regulation of the duration and extent of PARylation involves the balance of adding poly(ADP -ribose) (PAR) chains onto target proteins by poly(ADP-ribose) polymerases (PARPs) and removing PAR chains (dePARylation) by poly(ADP- ribose) glycohydrolases. As the major PAR glycohydrolase, PARG is a monogenic protein with five splicing isoforms identified. The full-length, 976 amino acids isoform is mainly located in nucleus, with a N-terminal regulatory domain, a C- terminal catalytic and PAR-binding macrodomain. The other four shorter isoforms are mainly located in cytosol and mitochondria, the nuclear and cytosolic isoforms are shown to be involved in DNA damage repair. (Harrision, D., et al. Front Mol Biosci. 2020, 7, 191; Min, W et al. Carcinogenesis, 2010, 31, 2058).

[0513] Disruption of PAR homeostasis has been linked to increased DNA damage and cell death (Kang, M., et al. IntJMol Sci, 2022, 23, 9826; Schuhwerk, H., et al. Semin Cell Dev Biol, 2017, 63, 81). Genetic depletion of PARG delays dePARylation of target proteins, causing prolonged DNA replication fork stalling and excessive degradation, leading to accumulation of DNA lesions. In cancer cells with compromised DNA repair machinery, including those with homologous recombination repair deficiency, alteration of PARylation by depletion or inhibition of PARG is synthetic lethal (Fathers, C., et al. Cell Cycle, 2012, 11, 990).

[0514] Depletion of PARG sequesters PAR chains on target proteins, thereby blocking NAD+ recycling and leading to cellular NAD+ depletion, which can cause metabolic collapse and cell death (Berger, N., Radiat Res, 1985, 101, 4; Nie, L., et al. eLife, 2023, 12, RP89303). In IDH-mutant tumor models that are deficient in NAD+ salvage pathway, concurrent alkylator (induces hyper-PARylation) and PARG inhibitor (prevents dePARylation) treatment leads to cellular NAD+ depletion and cell death which can be rescued by supplementation of NAD+ derivatives, confirming the mechanistic basis of cytotoxicity (Nagashima, H., et al. Cancer Discov, 2020, 10, 1672). PARylation is involved in initiation and modulation of multiple DNA repair pathways, including base excision repair (BER) (Beneyton, A., et al. NAR Cancer, 2023, 5, zcad043; Ray Chaudhuri, A., et al., Nat Rev Mol Cell Biol, 2017, 18, 610). Genetic studies showed depletion of BER genes induces prolonged activation of PARylation (Koczor, C. A., et al., Cell Rep, 2021, 37, 109917) and sensitizes cells to PARG inhibition (Nie, L., et al., eLife, 2023, 12, RP89303), indicating hyper- PARylation-induced cell death.

[0515] PARP inhibitors are being used to treat cancers clinically, emerging resistance has been reported. Compared to PARP inhibition, targeting PARG prevents dePARylation, providing an alternative therapeutic pathway for disruption of PAR homeostasis. This has been shown to be effective in killing BRC Al -mutant cells that exhibit resistance to PARP inhibition (Chen, S. H., et al. Sci Adv, 2019, 5, eaav4340). PARG inhibition also potentiates the effects of other agents, such as cisplatin, temozolomide, ionizing radiation (Chen, S. H., et al. Sci Adv, 2019, 5, eaav4340; Harrision, D., et al. Front Mol Biosci, 2020, 7, 191), and cell cycle check point inhibitors (Pillay, N., et al., Cancer Cell, 2019, 35, 519), in various cancer models, potentially expand rational applications of PARG inhibition in cancers with lower cellular stress.

[0516] DePARylation is essential in maintaining PAR homeostasis. PARG genedependency data indicate vulnerabilities in cancer cell lines across lineages, including skin, ovary / fallopian tube, lymphoid, lung, CNS / brain, and breast (DepMap, Broad (2023). DepMap 23Q4 Public. Figshare+. Dataset, doi.org / 10.25452 / figshare.plus. 24667905. v2).

[0517] Inhibition or genetic attenuation of PARG selectively kills homologous recombination (HR) protein BRCA1 or BRCA2 deficient cells, indicating the application of PARG inhibitors in BRCA1 / 2 or other HR protein deficient cancers (Fathers et al. Cell Cycle, 2012, 11(5), 990-997; Chen & Yu Sci Adv 2019, 5(4), eaav4340). Synthetic lethality with PARG inhibition has been shown in base excision repair (BER) or replication deficient cells (Nie et al. eLife 2023, 12, RP89303.). These cancers include but are not limited to ovarian, gastric, colorectal, breast, prostate, uterine, pancreatic, lung, melanoma, brain, bladder, head and neck, sarcoma, liver, bile duct, kidney, lymphoma, and leukemia (Starcevic et al. Cell Cycle 2004, 3:8, 996-999; Cerami et al. 2012, 2(5):401-4).

[0518] In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject in need thereof. In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject suffering from or susceptible to a disease, disorder, or condition associated with PARG. In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject suffering from or susceptible to a disease, disorder, or condition, wherein an underlying pathology is, wholly or partially, mediated by PARG. In some embodiments, the compounds provided herein are useful as PARG inhibitors. In some embodiments, the present disclosure provides methods of inhibiting PARG in a subject comprising administering a provided compound or composition. In some embodiments, the present disclosure provides methods of inhibiting PARG in a biological sample comprising contacting the sample with a provided compound or composition.

[0519] In some embodiments, the present disclosure provides methods of treating a disease, disorder or condition associated with PARG in a subject in need thereof, comprising administering to the subject a compound, salt, or composition of the disclosure. In some embodiments, a disease, disorder or condition is associated with mutation of PARG. In some embodiments, the present disclosure provides methods of treating a disease, disorder or condition, wherein an underlying pathology is, wholly or partially, mediated by PARG, in a subject in need thereof, comprising administering to the subject a provided compound or composition.

[0520] In some embodiments, the present disclosure provides methods of treating a variety of PARG-dep endent diseases and disorders.

[0521] In some embodiments, the disease of disorder is a cancer. In some embodiments, the cancer is selected from skin cancer, ovarian cancer, fallopian tube cancer, gastric cancer, colorectal cancer, breast cancer, prostate cancer, uterine cancer, pancreatic cancer, lung cancer, melanoma, brain cancer, bladder cancer, head and neck cancer, sarcoma, liver cancer, bile duct cancer, kidney cancer, lymphoma, and leukemia.

[0522] In some embodiments, the cancer is selected from ovarian cancer, colorectal cancer, breast cancer, prostate cancer, uterine cancer, and pancreatic cancer.

[0523] In some embodiments, the cancer is ovarian cancer.

[0524] In some embodiments, the cancer is colorectal cancer.

[0525] In some embodiments, the cancer is breast cancer.

[0526] In some embodiments, the cancer is prostate cancer.

[0527] In some embodiments, the cancer is uterine cancer.

[0528] In some embodiments, the cancer is pancreatic cancer.

[0529] In some embodiments, provided herein is a method of increasing survival or progression-free survival in a patient, comprising administering a compound provided herein to the patient. In some embodiments, the patient has cancer. In some embodiments, the patient has a disease or disorder described herein. As used herein, progression-free survival refers to the length of time during and after the treatment of a solid tumor that a patient lives with the disease but it does not get worse. Progression-free survival can refer to the length of time from first administering the compound until the earlier of death or progression of the disease. Progression of the disease can be defined by RECIST v. 1.1 (Response Evaluation Criteria in Solid Tumors), as assessed by an independent centralized radiological review committee. In some embodiments, administering of the compound results in a progression free survival that is greater than about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, about 12 months, about 16 months, or about 24 months. In some embodiments, the administering of the compound results in a progression free survival that is at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, or about 12 months; and less than about 24 months, about 16 months, about 12 months, about 9 months, about 8 months, about 6 months, about 5 months, about 4 months, about 3 months, or about 2 months. In some embodiments, the administering of the compound results in an increase of progression free survival that is at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, or about 12 months; and less than about 24 months, about 16 months, about 12 months, about 9 months, about 8 months, about 6 months, about 5 months, about 4 months, about 3 months, or about 2 months.

[0530] The present disclosure further provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.

[0531] The present disclosure further provides use of a compound described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in any of the methods described herein.

[0532] As used herein, the term “cell” is meant to refer to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal.

[0533] As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” a PARG with a compound described herein includes the administration of a compound described herein to an individual or patient, such as a human, having a PARG, as well as, for example, introducing a compound described herein into a sample containing a cellular or purified preparation containing the PARG.

[0534] As used herein, the term “individual” or “patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.

[0535] As used herein, the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent such as an amount of any of the solid forms or salts thereof as disclosed herein that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. An appropriate "effective" amount in any individual case may be determined using techniques known to a person skilled in the art.

[0536] The phrase “pharmaceutically acceptable” is used herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0537] As used herein, the phrase “pharmaceutically acceptable carrier or excipient” refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipients or carriers are generally safe, non-toxic and neither biologically nor otherwise undesirable and include excipients or carriers that are acceptable for veterinary use as well as human pharmaceutical use. In one embodiment, each component is “pharmaceutically acceptable” as defined herein. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.

[0538] As used herein, the term “treating” or “treatment” refers to inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and / or symptomatology) or ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomatology) such as decreasing the severity of disease.

[0539] In some embodiments, the compounds of the invention are useful in preventing or reducing the risk of developing any of the diseases referred to herein; e.g., preventing or reducing the risk of developing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.

[0540] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment (while the embodiments are intended to be combined as if written in multiply dependent form). Conversely, various features of the disclosure which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0541] Combination Therapy

[0542] One or more additional therapeutic agents such as, for example, chemotherapeutics or other anti -cancer agents, anti-inflammatory agents, steroids, immunosuppressants, anesthetics (e.g., for use in combination with a surgical procedure), or other agents useful for treating diseases associated with PARG can be used in combination with the compounds and salts provided herein. The agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.

[0543] For example, a combination can include one or more inhibitors of the following kinases for the treatment of cancer: Aktl, Akt2, Akt3, TGF-PR, Pirn, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, CDK4 / 6, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFaR, PDGFpR, CSFIR, KIT, FLK-II, KDR / FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR / Flt2, Flt4, EphAl, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lek, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK and B-Raf.

[0544] For treating cancer and other proliferative diseases, compounds described herein can be used in combination with targeted therapies, including JAK kinase inhibitors (ruxolitinib, additional JAK1 / 2 and JAK 1 -selective, baricitinib or itacitinib), Pirn kinase inhibitors (e.g., LGH447, INCB053914 and SGI-1776), PI3 kinase inhibitors including PI3K-delta selective and broad spectrum PI3K inhibitors (e.g., parsaclisib and INCB50797), PI3K-gamma inhibitors such as PI3K-gamma selective inhibitors, MEK inhibitors, CSFIR inhibitors (e.g., PLX3397 and LY3022855), TAM receptor tyrosine kinases inhibitors (Tyro-3, Axl, and Mer; e.g., INCB81776), angiogenesis inhibitors, interleukin receptor inhibitors, Cyclin Dependent kinase inhibitors (e.g., palbociclib, riboci clib, and abemaciclib), BRAF inhibitors, mTOR inhibitors, proteasome inhibitors (Bortezomib, Carfilzomib), HD AC -inhibitors (panobinostat, vorinostat), DNA methyl transferase inhibitors, dexamethasone, bromo and extra terminal family members inhibitors (for example, bromodomain inhibitors or BET inhibitors, such as OTX015, CPI-0610, INCB54329 or INCB57643), LSD1 inhibitors (e.g., GSK2979552, INCB59872 and INCB60003), estrogen receptor modulators (e.g., fulvestrant), androgen receptor modulators (e.g., enzalutamide), BCL2 inhibitors (e.g., venetoclax), hypoxia-inducible factor-2 alpha inhibitors (e.g., belzutifan), exportin-1 (XPO-1) inhibitors (e.g., selinexor), KRAS inhibitors (e.g., sotorasib), arginase inhibitors (e.g., INCB1158), indoleamine 2,3- di oxygenase inhibitors (e.g., epacadostat, NLG919 or BMS-986205), PARP inhibitors (e.g., olaparib or rucaparib), and inhibitors of BTK such as ibrutinib. For treating cancer and other proliferative diseases, compounds described herein can be used in combination with chemotherapeutic agents, agonists or antagonists of nuclear receptors, or other anti -proliferative agents. Compounds described herein can also be used in combination with a medical therapy such as surgery or radiotherapy, e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes.

[0545] Examples of suitable chemotherapeutic agents include any of: abarelix, abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amidox, amsacrine, anastrozole, aphidicolon, arsenic trioxide, asparaginase, axitinib, azacitidine, bevacizumab, bexarotene, baricitinib, bendamustine, bicalutamide, bleomycin, bortezombi, bortezomib, brivanib, buparlisib, busulfan intravenous, busulfan oral, calusterone, camptosar, capecitabine, carboplatin, carmustine, cediranib, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dacomitinib, dactinomycin, dalteparin sodium, dasatinib, dactinomycin, daunorubicin, decitabine, degarelix, denileukin, denileukin diftitox, deoxycoformycin, dexrazoxane, didox, docetaxel, doxorubicin, droloxafine, dromostanolone propionate, eculizumab, enzalutamide, epidophyllotoxin, epirubicin, epothilones, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, flutamide, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, idelalisib, ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lonafamib, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, navelbene, necitumumab, nelarabine, neratinib, nilotinib, nilutamide, niraparib, nofetumomab, oserelin, oxaliplatin, paclitaxel, pamidronate, panitumumab, panobinostat, pazopanib, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pilaralisib, pipobroman, plicamycin, ponatinib, porfimer, prednisone, procarbazine, quinacrine, ranibizumab, rasburicase, regorafenib, reloxafine, revlimid, rituximab, rucaparib, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, tegafur, temozolomide, teniposide, testolactone, tezacitabine, thalidomide, thioguanine, thiotepa, tipifamib, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, triapine, trimidox, triptorelin, uracil mustard, valrubicin, vandetanib, vinblastine, vincristine, vindesine, vinorelbine, vorinostat, veliparib, talazoparib, and zoledronate.

[0546] Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the standard literature. For example, the administration of many of the chemotherapeutic agents is described in the “Physicians’ Desk Reference” (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if set forth in its entirety.

[0547] Example anti-inflammatory agents include, but are not limited to, aspirin, choline salicylates, celecoxib, diclofenac potassium, diclofenac sodium, diclofenac sodium with misoprostol, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, meclofenamate sodium, mefenamic acid, nabumetone, naproxen, naproxen sodium, oxaprozin, piroxican, rofecoxib, salsalate, sodium salicylate, sulindac, tolmetin sodium, and valdecoxib.

[0548] Example steroids include, but are not limited to, corticosteroids such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and prednisone.

[0549] Example immunosuppressants include, but are not limited to, azathioprine, chlorambucil, cyclophosphamide, cyclosporine, daclizumab, infliximab, methotrexate, and tacrolimus.

[0550] Example anesthetics include, but are not limited, to local anesthetics (e.g., lidocaine, procain, ropivacaine) and general anesthetics (e.g., desflurane, enflurane, halothane, isoflurane, methoxyflurane, nitrous oxide, sevoflurane, amobarbital, methohexital, thiamylal, thiopental, diazepam, lorazepam, midazolam, etomidate, ketamine, propofol, alfentanil, fentanyl, remifentanil, buprenorphine, butorphanol, hydromorphone levorphanol, meperidine, methadone, morphine, nalbuphine, oxymorphone, pentazocine).

[0551] In some embodiments, the additional therapeutic agent is administered simultaneously with a compound or salt provided herein. In some embodiments, the additional therapeutic agent is administered after administration of the compound or salt provided herein. In some embodiments, the additional therapeutic agent is administered prior to administration of the compound or salt provided herein. In some embodiments, the compound or salt provided herein is administered during a surgical procedure. In some embodiments, the compound or salt provided herein is administered in combination with an additional therapeutic agent during a surgical procedure.

[0552] As provided herein, the additional compounds, inhibitors, agents, etc. can be combined with the compounds provided herein in a single or continuous dosage form, or they can be administered simultaneously or sequentially as separate dosage forms.

[0553] Pharmaceutical Formulations and Dosage Forms

[0554] When employed as pharmaceuticals, the compounds of the invention can be administered in the form of pharmaceutical compositions which refers to a combination of a compound of the invention, or its pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral or parenteral. Methods for ocular delivery can include topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction by balloon catheter or ophthalmic inserts surgically placed in the conjunctival sac. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

[0555] This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of the invention above in combination with one or more pharmaceutically acceptable carriers. In making the compositions of the invention, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10 % by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0556] In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.

[0557] The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0558] For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid pre-formulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these pre-formulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid pre-formulation is then subdivided into unit dosage forms of the type described above.

[0559] The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.

[0560] The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils.

[0561] The compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.

[0562] The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.

[0563] The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.

[0564] The therapeutic dosage of the compounds of the present invention can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0565] The compositions of the disclosure can further include one or more additional pharmaceutical agents such as a chemotherapeutic, steroid, anti-inflammatory compound, or immunosuppressant, examples of which are provided herein.

[0566] Labeled Compounds and Assay Methods

[0567] Another aspect of the present invention relates to fluorescent dye, spin label, heavy metal or radio-labeled compounds of the invention that would be useful not only in imaging but also in assays, both in vitro and in vivo, for localizing and quantitating the PARG in tissue samples, including human, and for identifying PARG by inhibition binding of a labeled compound. Accordingly, the present invention includes PARG cellular assays that contain such labeled compounds.

[0568] The present invention further includes isotopically-labeled compounds of the invention. An “isotopically” or “radio-labeled” compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (z.e., naturally occurring). Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to2H (also written as D for deuterium),3H (also written as T for tritium),nC,13C,14C,13N,15N,15O,17O,18O,18F,35S,36C1,82Br,75Br,76Br,77Br,123I,124I,125I and131I. The radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro FGFR enzyme labeling and competition assays, compounds that incorporate3H,14C,82Br,1251 ,131I, or35S will generally be most useful. For radio-imaging applicationsnC,18F,125I,123I,124I,131I,75Br,76Br or77Br will generally be most useful.

[0569] One or more constituent atoms of the compounds presented herein can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance. In some embodiments, one or more atoms are replaced or substituted by deuterium. For example, one or more hydrogen atoms in a compound of the present disclosure can be replaced by deuterium atoms (e.g., one or more hydrogen atoms of a Ci-6 alkyl group of Formula I can be optionally substituted with deuterium atoms, such as -CD3 being substituted for -CH3). In some embodiments, alkyl groups of the disclosed Formulas (e.g., the compound of any of Formulas I- VI) can be perdeuterated.

[0570] In some embodiments, the compound provided herein (e.g., the compound of any of Formulas I-IX-b), or a pharmaceutically acceptable salt thereof, comprises at least one deuterium atom.

[0571] In some embodiments, the compound provided herein (e.g., the compound of any of Formulas I-IX-b), or a pharmaceutically acceptable salt thereof, comprises two or more deuterium atoms.

[0572] In some embodiments, the compound provided herein (e.g., the compound of any of Formulas I-IX-b), or a pharmaceutically acceptable salt thereof, comprises three or more deuterium atoms. In some embodiments, for a compound provided herein (e.g., the compound of any of Formulas I-IX-b), or a pharmaceutically acceptable salt thereof, all of the hydrogen atoms are replaced by deuterium atoms (z.e., the compound is “perdeuterated”).

[0573] It is understood that a “radio-labeled ” or “labeled compound” is a compound that has incorporated at least one radionuclide. In some embodiments the radionuclide is selected from the group consisting of3H,14C,1251 ,35S and82Br.

[0574] Synthetic methods for including isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in various studies such as NMR spectroscopy, metabolism experiments, and / or assays.

[0575] Substitution with heavier isotopes, such as deuterium, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances, (see e.g., A. Kerekes et. al. J. Med. Chem. 2011, 54, 201-210; R. Xu et. al. J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular, substitution at one or more metabolism sites may afford one or more of the therapeutic advantages.

[0576] A radio-labeled compound of the invention can be used in a screening assay to identify / evaluate compounds. In general terms, a newly synthesized or identified compound (i.e., test compound) can be evaluated for its ability to reduce binding of the radio-labeled compound of the invention to the PARG. Accordingly, the ability of a test compound to compete with the radio-labeled compound for binding to the PARG directly correlates to its binding affinity.

[0577] Kits

[0578] The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of PARG-associated diseases or disorders referred to herein which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and / or guidelines for mixing the components, can also be included in the kit.

[0579] The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of non-critical parameters which can be changed or modified to yield essentially the same results. The compounds of the Examples were found to be inhibitors of P ARG as described below.

[0580] EXAMPLES

[0581] Experimental procedures for compounds of the invention are provided below. Preparatory LC-MS purifications of some of the compounds prepared were performed on Waters mass directed fractionation systems. The basic equipment setup, protocols, and control software for the operation of these systems have been described in detail in the literature. See e.g. “Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K. Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification”, K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003); and "Preparative LC-MS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874-883 (2004). The compounds separated were typically subjected to analytical liquid chromatography mass spectrometry (LCMS) for purity check.

[0582] Some of the compounds prepared were also separated on a preparative scale by reverse-phase high performance liquid chromatography (RP-HPLC) with MS detector or flash chromatography (silica gel) as indicated in the Examples. Example 1. 9-Chloro-5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l- methylcyclopropyl)pyrazolo[l,5-a]quinazoline-7-sulfonamide

[0583] Step 1: 3-chloro-5-(chlorosulfonyl)-2-fluorobenzoic acid

[0584] To 250 mL chlorosulfonic acid was added 3-chloro-2-fluorobenzoic acid (50 g, 287 mmol) in portions at rt. The mixture was then heated to 140 °C for 3h. The mixture was allowed to cool to rt and then added dropwise on ice. The precipitated solid was filtered and dried to afford the desired product as a beige solid (62.4 g, 80%) which was used in the next step without further purification.

[0585] Step 2: 3-chloro-2-fluoro-5-(N-(l-methylcyclopropyl)sulfamoyl)benzoic acid

[0586] To a solution of 1-methylcyclopropanamine hydrochloride (10.75 g, 100 mmol) in dioxane / EEO (5:1, 400 mL) was added DIPEA (47 mL, 273 mmol), followed by 3-chloro-5-(chlorosulfonyl)-2-fluorobenzoic acid (25 g, 91 mmol) in portions at rt. The reaction mixture was stirred for 2h. The reaction mixture was then concentrated and diluted with water and IN NaOH solution which was then extracted with Et2O (2x). The aqueous phase was acidified with 4N HC1 and extracted with EtOAc. The combined organics were washed with sat. NaCl, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0587] Step 3: tert-butyl 3-(3-chloro-2-f1uoro-5-(N-(l- methylcyclopropyl)sulfamoyl)benzamido)-lH-pyrazole-l-carboxylate

[0588] To a solution of 3-chloro-2-fluoro-5-(N-(l- methylcyclopropyl)sulfamoyl)benzoic acid ( 15.0 g , 48.7 mmol) and tert-butyl 3- amino-lH-pyrazole-1 -carboxylate (9.82g, 53.6 mmol) in THF was added propanephosphonic acid anhydride (50% in THF solution, 40.3 mL, 63.4 mmol), followed by DIPEA (10.8 mL, 58.5 mmol). The reaction mixture was stirred for 4h before quenched with sat. NaHCCh solution. The mixture was extracted with EtOAc (2x), the combined organics were washed with sat. NaCl, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was redissolved in EtOAc then hexanes was added. The resulting suspension was stirred at rt overnight. The precipitate solid was collected as pure product and used in the next step without further purification. LCMS calculated for C19H23CIFN4O5S (M+H)+m / z = 473.1; found 473.1.

[0589] Step 4: 9-chloro-N-( I -methylcyclopropyl) -5-oxo-4, 5-dihydropyrazolo[ 1, 5- a quinazoline- 7 -sulfonamide

[0590] To a solution of tert-butyl 3-(3-chloro-2-fluoro-5-(N-(l- methylcyclopropyl)sulfamoyl)benzamido)-lH-pyrazole-l-carboxylate (9.2 g, 19.5 mmol) in NMP (40 mL) was added DIPEA (7.2 mL, 38.9 mmol) at rt. The mixture was then heated to 140 °C for 2h. The mixture was allowed to cool to rt and then added to a cold 0.5 N HC1 solution (300 mL). The precipitated solid was filtered and dried to afford the desired product as a beige solid (3.09 g, 45%). LCMS calculated for C14H14CIN4O3S (M+H)+m / z = 353.0; found 353.0.

[0591] Step 5: 5, 9-dichloro-N-( I -methylcyclopropyl)pyrazolo[ 1, 5 -a ]quinazoline-7- sulfonamide

[0592] 9-Chloro-N-(l-methylcyclopropyl)-5-oxo-4,5-dihydropyrazolo[l,5- a]quinazoline-7-sulfonamide (3.09 g, 8.77 mmoL) was added portion-wise to a stirring POCI3 (11 mL) at rt. After addition, the mixture was heated to 100 °C for 5h. The mixture was allowed to cool to rt and then added dropwise to stirring ice water. The precipitated solid was filtered and dried to afford the crude product, which was purified using flash column chromatography, eluting with 20-80% EtOAc in hexanes to afford the desired product as a white solid (1.3 g, 40%). LCMS calculated for C14H13CI2N4O2S (M+H)+m / z = 371.0; found 371.0.

[0593] Step 6: 9-chloro-N-( 1 -methylcyclopropyl) -5-(trimethylstannyl)pyrazolo[ 1, 5- a quinazoline- 7 -sulfonamide

[0594] To a solution of 5,9-dichloro-N-(l-methylcyclopropyl)pyrazolo[l,5- a]quinazoline-7-sulfonamide (400 mg, 1.08 mmol) in dioxane (4 mL) was added hexamethylditin (388 mg, 1.19 mmol) and bis(triphenylphosphine)palladium chloride (75.6 mg, 0.11 mmol) at rt. The mixture was then heated to 130 °C for Ih. The mixture was allowed to cool to rt and concentrated under reduced pressure, and the residue was purified using flash column chromatography, eluting with 20-80% EtOAc in hexanes to afford the desired product as a white solid (253 mg, 47%). LCMS calculated for CnE CfbW SSn (M+H)+m / z = 501.0; found 501.0. Step 7: 9-chloro-5-(5-(dijluoromethyl)-l, 3, 4-thiadiazol-2-yl)-N-( 1 - methylcyclopropyl)pyrazolo[ 1, 5 -a quinazoline- 7 -sulfonamide

[0595] To a solution of 9-chloro-N-(l-methylcyclopropyl)-5- (trimethylstannyl)pyrazolo[l,5-a]quinazoline-7-sulfonamide (253 mg, 0.51 mmol) in dioxane (2 mL) was added bis(triphenylphosphine)palladium chloride (38 mg, 0.05 mmol) and 2-bromo-5-(difluoromethyl)-l,3,4-thiadiazole (214 mg, 1 mmol) at rt. The mixture was then heated to 130 °C for Ih. The mixture was allowed to cool to rt and concentrated under reduced pressure, and the residue was purified using flash column chromatography, eluting with 20-100% EtOAc in hexanes to afford the title compound as a white solid (91 mg, 38%). LCMS calculated for C17H14CIF2N6O2S2 (M+H)+m / z = 471.0; found 471.0.

[0596] Example 2. 5-(5-(Difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)- 9-(l,2,3,6-tetrahydropyridin-4-yl)pyrazolo[l,5-a]quinazoline-7-sulfonamide

[0597] A mixture of 9-chloro-5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l- methylcyclopropyl)pyrazolo[l,5-a]quinazoline-7-sulfonamide (Example 1) (70 mg, 0.15 mmol), Xphos-PdG2 (11.7 mg, 0.01 mmol), ISfeCCE (31.5 mg, 0.3 mmol), and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)- carboxylate (46 mg, 0.15 mmol) in dioxane (2 mL) and water (0.2 mL) was heated at 100 °C for Ih under nitrogen atmosphere. Upon cooling to rt, the reaction was diluted with water and extracted with EtOAc. The combined organics were washed with sat. NaCl, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in TFA (0.2 mL), the solution was stirred at rt for 30 min, then purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C22H22F2N7O2S2 (M+H)+m / z = 518.1; found 518.1.

[0598] Example 3. 5-(5-(Difluoromethyl)-l,3,4-thiadiazol-2-yl)-9-(l-methyl-l,2,3,6- tetrahydropyridin-4-yl)-N-(l-methylcyclopropyl)pyrazolo[l,5-a]quinazoline-7- sulfonamide

[0599] A mixture of 5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l- methylcyclopropyl)-9-(l,2,3,6-tetrahydropyridin-4-yl)pyrazolo[l,5-a]quinazoline-7- sulfonamide (Example 2) (5 mg, 0.01 mmol), formaldehyde (37% water solution, 10 mg), and sodium triacetoxyborohydride (5 mg, 0.02 mmol) in DCM (0.5 mL) was stirred at rt for Ih. The reaction mixture was then diluted with MeOH and purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C23H24F2N7O2S2 (M+H)+m / z = 532.1; found 532.1.

[0600] Example 4. 5-(5-(Difluoromethyl)-l,3,4-thiadiazol-2-yl)-9-(l-(l- methoxycyclopropane-l-carbonyl)-l,2,3,6-tetrahydropyridin-4-yl)-N-(l- methylcyclopropyl)pyrazolo[l,5-a]quinazoline-7-sulfonamide

[0601]

[0602] To a mixture of 5-(5-(difhioromethyl)-l,3,4-thiadiazol-2-yl)-N-(l- methylcyclopropyl)-9-(l,2,3,6-tetrahydropyridin-4-yl)pyrazolo[l,5-a]quinazoline-7- sulfonamide (Example 2) (5 mg, 0.01 mmol) and 1 -methoxy cyclopropane- 1- carboxylic acid (4 mg, 0.03 mmol) in DMF (0.5 mL) was added HATU (11 mg, 0.03 mmol), and DIPEA (10 uL, 0.06 mmol). After stirring for 30 min, the reaction mixture was diluted with MeOH and purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C27H28F2N7O4S2 (M+H)+m / z = 616.1; found 616.2.

[0603] Example 5. 5-(5-(Difluoromethyl)-l,3,4-thiadiazol-2-yl)-9-fluoro-N-(l- methylcyclopropyl)pyrazolo[l,5-a]quinazoline-7-sulfonamide

[0604] The title compound was prepared using similar procedures as described for Example 1, with 2,3-difluorobenzoic acid replacing 3-chloro-2-fluorobenzoic acid in Step 1. The final product was purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C17H14F3N6O2S2 (M+H)+ m / z = 455.0; found 455.1.

[0605] Example 6. (R)-5-(5-(Difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l- methylcyclopropyl)-9-(3-methylpiperazin-l-yl)pyrazolo[l,5-a]quinazoline-7- sulfonamide

[0606] A mixture of 5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-9-fluoro-N-(l- methylcyclopropyl)pyrazolo[l,5-a]quinazoline-7-sulfonamide (Example 5) (40 mg, 0.09 mmol), DIPEA (33 pL, 0.18 mmol), and tert-butyl (R)-2-methylpiperazine-l- carboxylate (35 mg, 0.18 mmol) in NMP (1 mL) was heated at 110 °C for 8h under nitrogen atmosphere. Upon cooling to rt, the reaction mixture was diluted with water and extracted with EtOAc. The combined organics were washed with sat. NaCl, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in TFA (0.2 mL), the solution was stirred at rt for 30 min, then purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C22H25F2N8O2S2 (M+H)+m / z = 535.1; found 535.1.

[0607] Example 7. (R)-5-(5-(Difluoromethyl)-l,3,4-thiadiazol-2-yl)-9-(3,4- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)pyrazolo[l,5-a]quinazoline-7- sulfonamide

[0608]

[0609] A mixture of (R)-5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l- methylcyclopropyl)-9-(3-methylpiperazin-l-yl)pyrazolo[l,5-a]quinazoline-7- sulfonamide (Example 6) (5 mg, 0.01 mmol), formaldehyde (37% water solution, 10 mg), and sodium triacetoxyborohydride (5 mg, 0.02 mmol) in DCM (0.5 mL) was stirred at rt for Ih. The reaction mixture was then diluted with MeOH and purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C23H27F2N8O2S2 (M+H)+m / z = 549.2; found

[0610] 549.2.

[0611] Example 8. (R)-4-(5-(5-(Difluoromethyl)-l,3,4-thiadiazol-2-yl)-7-(N-(l- methylcyclopropyl)sulfamoyl)pyrazolo[l,5-a]quinazolin-9-yl)-N,N,2- trimethylpiperazine-l-carboxamide

[0612] To a mixture of (R)-5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l- methylcyclopropyl)-9-(3-methylpiperazin-l-yl)pyrazolo[l,5-a]quinazoline-7- sulfonamide (Example 6) (5 mg, 0.01 mmol) in DCM (0.5 mL) was added dimethylcarbamic chloride (5 mg, 0.04 mmol) and DIPEA (10 pL, 0.06 mmol) at 0 °C. The reaction was allowed to warm to rt and stirred at rt for 2h. The reaction mixture was then diluted with MeOH and purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C25H30F2N9O3S2 (M+H)+m / z = 606.2; found 606.2.

[0613] Example 9. (R)-9-(4-(Cyclopropanecarbonyl)-3-methylpiperazin-l-yl)-5-(5- (difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)pyrazolo[l,5- a] quinazoline-7-sulfonamide

[0614] The title compound was prepared using similar procedures as described for Example 8, with cyclopropanecarbonyl chloride replacing dimethylcarbamic chloride. The final product was purified by prep-HPLC (column: Sunfire prep Cl 8 column, 30*150 mm, 5 pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C26H29F2N8O3S2 (M+H)+m / z = 603.2; found 603.2.

[0615] Example 10. (R)-5-(5-(Difluoromethyl)-l,3,4-thiadiazol-2-yl)-9-(4-(l- methoxycyclopropane-l-carbonyl)-3-methylpiperazin-l-yl)-N-(l- methylcyclopropyl)pyrazolo[l,5-a]quinazoline-7-sulfonamide

[0616]

[0617] To a mixture of (R)-5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l- methylcyclopropyl)-9-(3-methylpiperazin-l-yl)pyrazolo[l,5-a]quinazoline-7- sulfonamide (Example 6) (5 mg, 0.01 mmol) and 1 -methoxy cyclopropane- 1- carboxylic acid (4 mg, 0.03 mmol) in DMF (0.5 mL) was added HATU (11 mg, 0.03 mmol), and DIPEA (10 uL, 0.06 mmol). After stirring for 30 min, the reaction mixture was diluted with MeOH and purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C27H31F2N8O4S2 (M+H)+m / z = 633.2; found 633.2.

[0618] Example 11. (R)-9-(4-(l-Cyanocyclopropane-l-carbonyl)-3-methylpiperazin-l- yl)-5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l- methylcyclopropyl)pyrazolo[l,5-a]quinazoline-7-sulfonamide The title compound was prepared using similar procedures as described for

[0619] Example 10, with 1 -cyanocyclopropane- 1 -carboxylic acid replacing 1- m ethoxy cy cl opropane-1 -carboxylic acid. The final product was purified by prep- HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C27H28F2N9O3S2 (M+H)+ m / z = 628.2; found 628.2.

[0620] Example 12. 9-Bromo-5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l- methylcyclopropyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide

[0621] Step 1: 8-bromo-2-( (2-((tert-butyldimethylsilyl)oxy)ethyl)amino)quinoline-4- carboxylic acid

[0622] To a solution of 8-bromo-2-chloroquinoline-4-carboxylic acid (3.0 g, 10.5 mmol) in dioxane (15 mL) was added 2-((tert-butyldimethylsilyl)oxy)ethan-l-amine (2.75 g, 15.7 mmol) and DIPEA (2.9 mL, 15.7 mmol) at rt. The mixture was then heated to 170 °C for 12h. The mixture was allowed to cool to rt and concentrated under reduced pressure then diluted with water and IN NaOH solution which was then extracted with Et2O (2x). The aqueous phase was acidified with IN HC1 and extracted with EtOAc. The combined organics were washed with sat. NaCl, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was used directly in the next step without further purification. Step 2: 8-bromo-2-( (2-((tert-butyldimethylsilyl)oxy)ethyl)amino)quinoline-4- carbohydrazide

[0623] To a solution of 8-bromo-2-((2-((tert- butyldimethylsilyl)oxy)ethyl)amino)quinoline-4-carboxylic acid (3.0 g, 7.05 mmol) in THF was added CDI (1.49 g, 9.17 mmol). The reaction mixture was heated at 50 °C for 3h. The reaction mixture was allowed to cool to rt and added to a hydrazine monohydrate THF solution (1:5, 5 mL) dropwise. The resulting mixture was then stirred at rt for 5h before concentrated under reduced pressure. The residue was purified using flash column chromatography, eluting with MeOH in DCM to afford the title compound as a brown solid (1.85 g, 60%). LCMS calculated for Ci8H28BrN4O2Si (M+H)+m / z = 439.1; found 439.1.

[0624] Step 3: 8-bromo-2-( (2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-N'-(2, 2- difluoroacetyl)quinoline-4-carbohydrazide

[0625] To a solution of 8-bromo-2-((2-((tert- butyldimethylsilyl)oxy)ethyl)amino)quinoline-4-carbohydrazide (1.5 g, 3.41 mmol) in EtOH (10 mL) was added methyl 2,2-difluoroacetate (751 mg, 6.8 mmol) and DBU

[0626] (1039 mg, 6.8 mmol). The reaction mixture was heated at 80 °C for 3h. The reaction mixture was allowed to cool to rt and concentrated under reduced pressure. The residue was purified using flash column chromatography, eluting with MeOH in DCM to afford the title compound as a brown solid (0.71 g, 40%). LCMS calculated for C2oH28BrF2N403Si (M+H)+m / z = 517.1; found 517.1. Step 4: 8-bromo-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-(5-(difluoromethyl)-l,3,4- thiadiazol-2-yl)quinolin-2 -amine

[0627] To a solution of 8-bromo-2-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-N'- (2,2-difluoroacetyl)quinoline-4-carbohydrazide (1.5 g, 3.41 mmol) in dioxane (5 mL) was added Lawesson's reagent (1.73 g, 4.27 mmol). The reaction mixture was heated at 80 °C for 2h. The reaction mixture was allowed to cool to rt and concentrated under reduced pressure. The residue was purified using flash column chromatography, eluting with MeOH in DCM to afford the title compound as a brown solid (1.07 g, 61%). LCMS calculated for C2oH26BrF2N4OSSi (M+H)+m / z = 515.1; found 515.1.

[0628] Step 5: 2-( (8-bromo-4-(5-(difluoromethyl)-l, 3, 4-thiadiazol-2-yl)quinolin-2- yl)amino)ethan-l-ol

[0629] To a solution of 8-bromo-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-(5- (difluoromethyl)-l,3,4-thiadiazol-2-yl)quinolin-2-amine (1.07 g, 2.08 mmol) in THF (5 mL) was added TBAF (I M THF solution, 8 mL). The reaction mixture was stirred at rt 6h before quenched with sat. NH4CI solution. The mixture was extracted with EtOAc (2x), the combined organics were washed with sat. NaCl, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified using flash column chromatography, eluting with MeOH in DCM to afford the title compound as a brown solid (665 mg, 80%). LCMS calculated for Ci4Hi2BrF2N4OS (M+H)+m / z = 401.0; found 401.0.

[0630] Step 6: 2-(9-bromo-l ,2-dihydroimidazo [ 1 ,2-a] quinolin-5-yl)-5-(dijluoromethyl)- 1, 3, 4-thiadiazole

[0631] To a solution of 2-((8-bromo-4-(5-(difluoromethyl)-l,3,4-thiadiazol-2- yl)quinolin-2-yl)amino)ethan-l-ol (130 mg, 0.32 mmol) in DCM (2 mL) was added MsCl (53 pL, 0.65 mmol), and DIPEA (119 pL, 0.65 mmol). The reaction mixture was stirred at 50 °C for Ih, then concentrated under reduced pressure. The residue was purified using flash column chromatography, eluting with MeOH in DCM to afford the title compound as a brown solid (665 mg, 80%). LCMS calculated for Ci4HioBrF2N4S (M+H)+m / z = 383.0; found 383.0.

[0632] Step 7: 9-bromo-5-(5-(difluoromethyl)-l, 3, 4-thiadiazol-2-yl)-N-( 1 - methylcyclopropyl) -1, 2-dihydroimidazo[ 1, 2 -a ] quinoline- 7 -sulfonamide

[0633] To 2-(9-bromo-l,2-dihydroimidazo[l,2-a]quinolin-5-yl)-5-(difluoromethyl)- 1,3, 4-thiadiazole (100 mg, 0.26 mmol) in 2 dram vial was added chlorosulfonic acid (0.5 mL) at 0 °C. The mixture was then heated to 100 °C for 2h. The mixture was allowed to cool to rt and then added dropwise on ice. The resulting solution was extracted with EtOAc (3x) and the combined organics were washed with sat. NaCl, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in DCM. To this solution was added 1- methylcyclopropan-1 -amine (22 mg, 0.31 mmol) and DIPEA (115 pL, 0.62 mmol). The reaction mixture was stirred at rt for Ih before diluted with MeOH and purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for CisHnB^NsChS? (M+H)+m / z = 516.0; found 516.0.

[0634] Examples 13-19.

[0635] The compounds of Examples 13-19 in Table 1 were prepared according to procedures described for Example 6 using appropriate starting materials.

[0636] Table 1.

[0637]

[0638] Example 20. 4-(5-(Difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)quinazoline-6-sulfonamide Step 1: ((2,3-Difluorophenyl)ethynyl)trimethylsilane

[0639] To a 500 mL three-necked round bottom flask were added l,2-difluoro-3- iodobenzene (33 g, 137.5 mmol), palladium(II)bis(triphenylphosphine) dichloride (1.93 g, 2.7 mmol) and cuprous iodide (1.05 g, 5.5 mmol). The flask was sealed with rubber septa, evacuated and backfilled with nitrogen (this process was repeated a total of three times). Trimethylsilylacetylene (16.2 g, 165 mmol) in triethylamine (330 mL) was added. The reaction mixture was stirred at 60 °C for 16 h. Upon cooling to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether to afford the desired product as yellow liquid (25 g, 86%).1H NMR (400 MHz, DMSO-ifc) 8 7.30 - 7.22 (m, 1H), 7.14 - 7.08 (m, 1H), 7.01 - 6.94 (m, 1H), 0.01 (s, 9H).

[0640] Step 2: l-Ethynyl-2,3-difluorobenzene

[0641] To a mixture of ((2,3-difluorophenyl)ethynyl)trimethylsilane (10 g, 47.5 mmol) in methanol (100 mL) was added potassium carbonate (19.7 g, 142.6 mmol) at room temperature. After stirring for 2 h, the reaction was diluted with water, and the mixture was extracted with petroleum ether (3 x 100 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure at 0 °C. The residue was purified by silica gel column chromatography, eluted with petroleum ether to afford the desired product as colorless liquid (5 g, 76%).1H NMR (400 MHz, DMSO-ifc) 6 7.52 - 7.42 (m, 1H), 7.36 - 7.31 (m, 1H), 7.22 - 7.15 (m, 1H), 4.62 (s, 1H).

[0642] Step 3: 2-( 1 -(2, 3 -Difluorophenyl) vinyl) -4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolane

[0643] To an oven-dried round bottom flask containing [1,3- bis(diphenylphosphino)propane]dichloronickel(II) (589 mg, 1.1 mmol) under N2 atmosphere was added anhydrous tetrahydrofuran (50 mL). The mixture was cooled to 0 °C. Diisobutylaluminum hydride (1 M in hexanes) (47.1 mL, 47.1 mmol) was added dropwise. To the above mixture, a solution of l-ethynyl-2, 3 -difluorobenzene (5 g, 36.2 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise. The resulting mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was cooled cooling back to 0 °C. 2-Methoxy-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (17.2 g, 108.6 mmol) was added dropwise. The resulting mixture was stirred under nitrogen at 80 °C for 16 h. Upon cooling to 0 °C, the reaction mixture was treated with water (300 mL). The mixture was allowed to warm to room temperature and stirred for 20 min. The mixture was poured into saturated aqueous solution of potassium sodium tartrate (300 mL) and extracted with ethyl acetate (3 x 400 mL). The combined organic phase was washed with brine (400 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with 10% ethyl acetate in petroleum ether to afford the desired product as light-yellow liquid (5 g, 52%).JH NMR (400 MHz, DMSO- e) 5 7.36 - 7.27 (m, 1H), 7.20 - 7.08 (m, 2H), 6.10 - 6.03 (m, 2H), 1.23 (s, 12H).

[0644] Step 4: 2-(Difluoromethyl)-5-( 1 -(2, 3-difluorophenyl)vinyl)-l, 3, 4-thiadiazole

[0645] To a 250 mL three-necked round bottom flask were added 2-(l-(2,3- difluorophenyl)vinyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (5 g, 18.8 mmol), 2- bromo-5-(difluoromethyl)-l, 3, 4-thiadiazole (4.04 g, 18.8 mmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1.53 g, 1.88 mmol) and potassium carbonate (7.8 g, 56.4 mmol). The flask was sealed with rubber septa, evacuated and backfilled with nitrogen (this process was repeated a total of three times). 1,4-Dioxane (50 mL) was added followed by water (10 mL). The resulting mixture was stirred at 60 °C for 3 h. Upon cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 10% ethyl acetate in petroleum ether to afford the desired product as yellow oil (3.6 g, 70%). LCMS calculated for C11H7F4N2S (M+H)+m / z = 275.0; found 274.9; 'H NMR (400 MHz, DMSO-i / ,) 8 7.89 - 7.45 (m, 2H), 7.38 - 7.29 (m, 2H), 6.58 (s, 1H), 6.14 (s, 1H).

[0646] Step 5: l-(5-(Difluoromethyl)-l,3,4-thiadiazol-2-yl)-l-(2,3-difluorophenyl)ethane-l,2- diol

[0647] To a mixture of 2-(difluoromethyl)-5-(l-(2,3-difluorophenyl)vinyl)-l,3,4- thiadiazole (2.6 g, 9.5 mmol) and potassium osmate(VI) dihydrate (350 mg, 0.95 mmol) in dichloromethane (50 mL) at 0 °C were added tert-butanol (5 mL), followed by 4-Methylmorpholine N-oxide (3.33 g, 28.4 mmol) and water (5 mL). The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 2 h. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 60% ethyl acetate in petroleum ether to afford the desired product as brown oil (1.6 g, 54%). LCMS calculated for C11H9F4N2O2S (M+H)+m / z = 309.0; found 309.0.

[0648] Step 6: (5-(Difluoromethyl)-l,3,4-thiadiazol-2-yl)(2,3-difluorophenyl)methanone

[0649] To a mixture of l-(5-(difhioromethyl)-l,3,4-thiadiazol-2-yl)-l-(2,3- difluorophenyl)ethane-l,2-diol (1.6 g, 5.2 mmol) in methanol (25 mL) was added a solution of sodium periodate (1.67 g, 7.8 mmol) in water (25 mL) at room temperature. After stirring for 2 h, the reaction mixture was diluted with water, extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with 15% ethyl acetate in petroleum ether to afford the desired product as dark yellow oil (1.1 g, 77%). LCMS calculated for CioH5F4N20S (M+H)+m / z = 277.0; found 277.1;XH NMR (400 MHz, DMSO-t / 6) 6 7.94 - 7.56 (m, 3H), 7.51-7.44 (m, 1H).

[0650] Step 7: 3-(5-(Difluoromethyl)-l,3,4-thiadiazole-2-carbonyl)-4,5- difluorobenzenesulfonyl chloride

[0651] A mixture of (5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)(2,3- difluorophenyl)methanone (1.1 g, 4.0 mmol) in chlorosulfonic acid (11 mL) was stirred at 130 °C for 3 h. Upon cooling to room temperature, the reaction mixture was poured onto ice slowly. The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layer was washed with brine (3 x 100 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford the crude product as a brown solid (1.3 g) which was used in the next step directly without further purification. Step 8: 3-(5-(Difluoromethyl)-l,3,4-thiadiazole-2-carbonyl)-4,5-difluoro-N-(l- methylcyclopropyl)benzenesulfonamide

[0652] To a mixture of 3-(5-(difluoromethyl)-l,3,4-thiadiazole-2-carbonyl)-4,5- difluorobenzenesulfonyl chloride (1.3 g, 3.5 mmol) and 1-methylcyclopropan-l- amine hydrochloride (373 mg, 3.5 mmol) in 1,4-di oxane (25 mL) at 0 °C was added water (5 mL) followed by triethylamine (1.76 g, 17.3 mmol). The mixture was allowed to warm to room temperature and stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with di chloromethane (3 x 100 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with 15% ethyl acetate in petroleum ether to afford the desired product as yellow oil (700 mg). LCMS calculated for C14H10F4N3O3S2 (M- H)’ m / z = 408.0; found 408.0; 'HNMR (400 MHz, DMSO-t / 6) 8 8.43 (s, 1H), 8.42 - 8.38 (m, 1H), 8.19 - 8.13 (m, 1H), 7.73 (t, J= 52.8 Hz, 1H), 1.16 (s, 3H), 0.71 - 0.67 (m, 2H), 0.49 - 0.45 (m, 2H).

[0653] Step 9: 4-Azido-3-(5-(difluoromethyl)-l, 3, 4-thiadiazole-2-carbonyl)-5-fluoro-N-( 1 - methylcyclopropyl)benzenesulfonamide

[0654] To a mixture of 3-(5-(difluoromethyl)-l,3,4-thiadiazole-2-carbonyl)-4,5- difluoro-7V-(l-methylcyclopropyl)benzenesulfonamide (700 mg, 1.7 mmol) in dimethyl sulfoxide (7 mL) at room temperature was added sodium azide (122 mg, 1.9 mmol). After stirring for 30 min, the resulting mixture was diluted with water (70 mL) and extracted with ethyl acetate (3 x 70 mL). The combined organic layer was washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with 25% ethyl acetate in petroleum ether to afford the desired product as a yellow solid (650 mg, 88%). LCMS calculated for C14H10F3N6O3S2 (M-H)' m / z = 431.0; found 431.0; 'HNMR (400 MHz, DMSO-t / 6) 8 8.34 (s, 1H), 8.15 (dd, J= 2.0, 0.8 Hz, 1H), 7.94 (dd, J= 10.8, 2.0 Hz, 1H), 7.71 (t, J= 52.8 Hz, 1H), 1.16 (s, 3H), 0.70 - 0.66 (m, 2H), 0.48 - 0.42 (m, 2H).

[0655] Step 10: 4-Amino-3-(5-(difluoromethyl)-l , 3, 4-thiadiazole-2-carbonyl)-5-fluoro-N-( 1 - methylcyclopropyl)benzenesulfonamide

[0656] To a screw-cap vial equipped with a magnetic stir bar was added 4-azido-3-(5- (difluoromethyl)-l,3,4-thiadiazole-2-carbonyl)-5-fluoro-7V-(l- methylcyclopropyl)benzenesulfonamide (670 mg, 1.55 mmol) followed by palladium on carbon (10 wt%, 67 mg). The vial was sealed with a Teflon-lined septum, evacuated and backfilled with hydrogen (this process was repeated a total of three times). Ethyl acetate (10 mL) was added. After stirring at room temperature under hydrogen atmosphere for 2 h, the reaction mixture was filtered. The filter-cake was rinsed with ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 30% ethyl acetate in petroleum ether to afford the desired product as a yellow solid (350 mg, 55%). LCMS calculated for C14H12F3N4O3S2 (M-H)’ m / z = 405.0; found 405.0; 'H NMR (400 MHz, DMSO-t / 6) 6 8.95 (dd, J= 2.0, 0.8 Hz, 1H), 8.06 (s, 2H), 7.96 (s, 1H), 7.76 (t, J= 52.8 Hz, 1H), 7.65 (dd, J= 10.8, 2.0 Hz, 1H), 1.13 (s, 3H), 0.70 - 0.64 (m, 2H), 0.44 - 0.38 (m, 2H).

[0657] Step 11: 4-(5-(Difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-fluoro-N-(l- methylcyclopropyl)quinazoline-6-sulfonamide

[0658] To a mixture of 4-amino-3-(5-(difluoromethyl)-l,3,4-thiadiazole-2-carbonyl)- 5-fluoro-7V-(l-methylcyclopropyl)benzenesulfonamide (70 mg, 0.17 mmol) and tri ethoxy methane (1.28 g, 8.6 mmol) was added ammonium acetate (664 mg, 8.6 mmol). The resulting mixture was stirred at 120 °C for 6 h. Upon cooling to room temperature, the reaction mixture was diluted with ethyl acetate (20 mL). The solid was filtered, and the filter cake was rinsed with ethyl acetate (3 x 15 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (20% ethyl acetate in petroleum ether) to afford the desired product as a yellow solid (35 mg, 49%). LCMS calculated for C15H13F3N5O2S2 (M+H)’ m / z = 416.0; found 416.1.

[0659] Step 12: Tert-butyl (2S,6S)-4-(4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-6-(N-(l- methylcyclopropyl)sulfamoyl)quinazolin-8-yl)-2,6-dimethylpiperazine-l-carboxylate To a mixture of 4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-fluoro-A-(l- methylcyclopropyl)quinazoline-6-sulfonamide (35 mg, 0.08 mmol) and A,A- diisopropylethylamine (54 mg, 0.42 mmol) in dimethyl sulfoxide (0.5 mL) was added tert-butyl (25,65)-2,6-dimethylpiperazine-l -carboxylate (90 mg, 0.42 mmol). The resulting mixture was stirred at 120 °C for 3 h. Upon cooling to room temperature, the reaction was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layer was washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with 30% ethyl acetate in petroleum ether to afford the desired product as a yellow solid (30 mg, 58%). LCMS calculated for C26H32F2N7O4S2 (M-H)- m / z = 608.2; found 608.3.

[0660] Step 13: 4-(5-(DifIuoromethyl)-l, 3, 4-thiadiazol-2-yl)-8-((3S, 5S)-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)quinazoline-6-sulfonamide

[0661] To a solution of tert-butyl (25,65)-4-(4-(5-(difluoromethyl)-l,3,4-thiadiazol-2- yl)-6-(7V-(l-methylcyclopropyl)sulfamoyl)quinazolin-8-yl)-2,6-dimethylpiperazine-l- carboxylate (30 mg, 0.05 mmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.1 mL). After stirring at room temperature for 1 h, the reaction was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, acetonitrile in water (0.05% trifluoroacetic acid), 5% to 35% gradient in 20 min; detector, UV 254 nm). Fractions were collected and lyophilized to provide the TFA salt of the desired product as an orange solid (13.5 mg). LCMS calculated for C21H26F2N7O2S2 (M+H)+m / z = 510.2; found 510.1; 'H NMR (400 MHz, DMSO-t / 6) 5 9.55 (s, 1H), 9.51 - 9.47 (m, 1H), 8.46 (s, 1H), 7.89 - 7.58 (m, 2H), 3.57 - 3.20 (m, 7H), 1.36 - 1.25 (m, 6H), 1.10 (s, 3H), 0.75 - 0.64 (m, 2H), 0.48 - 0.38 (m, 2H).

[0662] Example 21. 4-(5-(Difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-2-(methylthio)quinazoline-6- sulfonamide

[0663]

[0664] Step 1: 8-bromo-2, 4-dioxo-l, 2, 3, 4-tetrahydroquinazoline-6-sulfonyl chloride

[0665] To 8-bromo-4a,8a-dihydroquinazoline-2,4(lH,3H)-dione (6.00 g, 24.69 mmol) was added sulfurochloridic acid (28.76 g, 246.86 mmol) at room temperature. After stirring at 100 °C for 4 hours, the mixture was cooled to room temperature and poured into ice slowly. The solid was filtered. The filter cake was washed with water and dried under vacuum to afford the desired product which was used directly in the next step without further purification.

[0666] Step 2: 8-bromo-N-( I -methylcyclopropyl) -2, 4-dioxo-l, 2, 3, 4-tetrahydroquinazoline-6- sulfonamide

[0667] To a solution of 1-methylcyclopropanamine hydrochloride (3.17 g, 29.51 mmol) in DCM was added triethylamine (20.45 mL, 14.93 g, 147.56 mmol). 8- Bromo-2, 4-dioxo-l, 2, 3, 4-tetrahydroquinazoline-6-sulfonyl chloride (8.40 g, 24.59 mmol) was added in portion. After stirring at room temperature for 2 hours, the mixture was acidified with IN HC1 (aq). The mixture was filtered. The filter cake was rinsed with 0.2 N HC1 (aq) and dried under vacuum to afford the desired product. LCMS calculated for CnHnBrNsC S (M+H)+m / z = 374.0; found 374.0. Step 3: 8-bromo-2, 4-dichloro-N-( 1 -methylcyclopropyl)quinazoline-6-sulfonamide

[0668] To a mixture of 8-bromo-N-(l-methylcyclopropyl)-2,4-dioxo-l,2,3,4- tetrahydroquinazoline-6-sulfonamide (8.00 g, 21.26 mmol) in phosphoryl trichloride (32.60 g, 212.64 mmol) at 0 °C was added A-ethyl-A-isopropyl-propan-2-amine (9.04 mL, 6.87 g, 53.16 mmol) dropwise. The mixture was then stirred at 105 °C for 6 hours. After cooling to room temperature, the mixture was concentrated. To the residue, ice was added. The mixture was extracted with EtOAc (3 x). The combined organic phase was washed with water, sat NaHCCh (aq), dried over MgSCU, and concentrated. The residue was purified by silica gel column chromatography, eluted with 30% EtOAc in DCM to give the desired product. LCMS calculated for Ci2HnBrC12N3O2S (M+H)+m / z = 409.9; found 410.0.

[0669] Step 4: 8-bromo-2-chloro-4-( 1 -ethoxyvinyl) -N-( I -methylcyclopropyl)quinazoline-6- sulfonamide

[0670] To a solution of 8-bromo-2,4-dichloro-N-(l-methylcyclopropyl)quinazoline-6- sulfonamide (5.00 g, 12.16 mmol) in THF was added tributyl(l -ethoxy vinyl)stannane (5.27 g, 14.59 mmol) followed by bis(triphenylphosphine)palladium(II) dichloride (0.85 g , 1.22 mmol). The mixture was stirred at 60 °C under N2 atmosphere for 16 hours. After cooling to room temperature, the mixture was treated with aqueous potassium fluoride solution. EtOAc was then added. The resulting mixture was stirred at room temperature for 5 min and filtered through a celite pad. The celite pad was further rinsed with EtOAc. The combined filtrate was washed with water, brine, and concentrated to give the crude product which was used directly in the next step without further purification. LCMS calculated for CieHisBrClNsChS (M+H)+m / z = 446.0; found 446.0.

[0671] Step 5: ethyl 8-bromo-2-chlor o-6-[(l -methylcyclopropyl) sulfamoyl] quinazoline-4- carboxylate

[0672] To a solution of 8-bromo-2-chloro-4-(l-ethoxyvinyl)-7V-(l- methylcyclopropyl)quinazoline-6-sulfonamide (3.00 g, 6.72 mmol) in dioxane was added a solution of sodium periodate (2.87 g , 13.43 mmol) in water followed by potassium permanganate (1061.23 mg, 6.72 mmol). The mixture was stirred at room temperature for 3 h. The reaction mixture was treated with sat. NaHCCh (aq). The mixture was filtered through a celite pad. The celite pad was rinsed with EtOAc. The combined filtrate was washed with water, brine, and concentrated. The residue was purified by silica gel column chromatography, eluted with 50% EtOAc in Hexane to give the desired product. LCMS calculated for CisHieBrCfNf^S (M+H)+m / z = 448.0; found 448.0.

[0673] Step 6: ethyl 8-bromo-6-(N-(l-methylcyclopropyl)sulfamoyl)-2-

[0674] (methylthio)quinazoline-4-carboxylate

[0675] The mixture of ethyl 8-bromo-2-chloro-6-(N-(l- methylcyclopropyl)sulfamoyl)quinazoline-4-carboxylate (2.10 g , 4.68 mmol) in DMF (20ml) at 0 °C was added sodium methanethiolate (492.03 mg, 7.02 mmol) portion wise. The mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was diluted with sat. NaHCOs (aq) and extracted with EtOAc. The combined organic layer was washed with water, brine, and concentrated to give the crude product which was used directly in the next step without further purification. LCMS calculated for CieHigBrNsCUS? (M+H)+m / z = 460.0; found 460.0.

[0676] Step 7: 8-bromo-6-(N-( I -methylcyclopropyl)sulfamoyl)-2-(methylthio)quinazoline-4- carboxylic acid

[0677] The mixture of ethyl 8-bromo-6-(N-(l-methylcyclopropyl)sulfamoyl)-2- (methylthio)quinazoline-4-carboxylate (800.00 mg, 1.74 mmol) in THF (20 mL) was added IN aqueous sodium hydroxide (5.21 mL, 5.21 mmol). After stirring at room temperature for 1 h, the mixture was acidified with IN aqueous HC1. The mixture was extracted with EtOAc. The combined organic layer was washed with water, brine, and concentrated to give the crude product which was used directly in the next step without further purification. LCMS calculated for CwHisBrNiCUS? (M+H)+m / z = 432.0; found 432.0.

[0678] Step 8: tert-butyl 2-(8-bromo-6-(N-( 1 -methylcyclopropyl) sulfamoyl)-2- (methylthio)quinazoline-4-carbonyl)hydrazine-l-carboxylate

[0679] To a mixture of 8-bromo-6-(N-(l-methylcyclopropyl)sulfamoyl)-2- (methylthio)quinazoline-4-carboxylic acid (650.00 mg, 1.50 mmol) and tert-butyl N- aminocarbamate (298.06 mg, 2.26 mmol) in DMF was added A-ethyl-A-isopropyl- propan-2-amine (582.97 mg, 4.51 mmol) followed by HATU (1143.38 mg, 3.01 mmol). After stirring at room temperature for 2 h, the mixture was diluted with EtOAc, washed with sat. NELCl (aq), brine, and concentrated. The residue was purified by silica gel column chromatography, eluted with 50% EtOAc in Hexane. LCMS calculated for Cig^sBrNsOsS? (M+H)+m / z = 546.0; found 546.0. Step 9: 8-bromo-4-( 2-( 2, 2 -difluor oacetyl)hydr azine- l-carbonyl)-N-( I - methylcyclopropyl)-2-(methylthio)quinazoline-6-sulfonamide

[0680] To a solution of tert-butyl 2-(8-bromo-6-(N-(l-methylcyclopropyl)sulfamoyl)- 2-(methylthio)quinazoline-4-carbonyl)hydrazine-l -carboxylate (400.00 mg, 0.73 mmol) in DCM (3mL) was added 4N HC1 in dioxane (3 mL, 12 mmol). After stirring at room temperature for 4 h, the mixture was concentrated. The residue was dissolved in EtOH, ethyl 2,2-difluoroacetate (227.07 mg, 1.83 mmol) was added followed by DBU (278.59 mg, 1.83 mmol). The mixture was stirred at room temperature for 3 h, and then concentrated. The residue was dissolved in EtOAc, washed with sat. NaHCCh (aq), brine and concentrated. The residue was purified by silica gel column chromatography, eluted with 10% MeOH in DCM. LCMS calculated for Ci6Hi7BrF2N5O4S2 (M+H)+m / z = 524.0; found 524.0.

[0681] Step 10: 8-bromo-4-(5-(difluoromethyl)-l , 3, 4-thiadiazol-2-yl)-N-(l- methylcyclopropyl)-2-(methylthio)quinazoline-6-sulfonamide

[0682] To a solution of 8-bromo-4-(2-(2,2-difluoroacetyl)hydrazine-l-carbonyl)-N- (l-methylcyclopropyl)-2-(methylthio)quinazoline-6-sulfonamide (320.00 mg, 0.61 mmol) in 1,4-dioxane was added Lawesson reagent (296.20 mg, 0.73 mmol). The mixture was stirred at 100 °C for 3 hours. After cooling to room temperature, the mixture was concentrated. The residue was purified by silica gel column chromatography, eluted with 30% EtOAc in Hexane. LCMS calculated for Ci6Hi5BrF2N5O2S3 (M+H)+m / z = 522.0; found 522.0.

[0683] Step 11: 8-bromo-4-(5-(difluoromethyl)-l , 3, 4-thiadiazol-2-yl)-N-(l- methylcyclopropyl)-2-(methylthio)-N-((2-(trimethylsilyl)ethoxy)methyl)quinazoline-6- sulfonamide

[0684] To a solution of 8-bromo-4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l- methylcyclopropyl)-2-(methylthio)quinazoline-6-sulfonamide (190.00 mg, 0.36 mmol) in DMF (2mL) at 0 °C was added sodium hydride (60 % dispersion in mineral oil, 29.09 mg, 0.73 mmol). After stirring at 0 °C for 10 mins, the mixture was treated with (2-(chloromethoxy)ethyl)trimethylsilane (121.27 mg, 0.73 mmol). The mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was then treated with water and extracted with EtOAc (3 x). The combined organic layer was washed with sat. NaHCO3(aq), brine, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with 30% EtOAc in Hexane to give the desired product. LCMS calculated for C22H29BrF2N5O3S3Si (M+H)+m / z = 652.0; found 652.0.

[0685] Step 12: tert-butyl (2S,6S)-4-(4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-2-

[0686] (methylthio)quinazolin-8-yl)-2,6-dimethylpiperazine-l-carboxylate

[0687]

[0688] Boc

[0689] The mixture of 8-bromo-4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l- methylcyclopropyl)-2-(methylthio)-N-((2-(trimethylsilyl)ethoxy)methyl)quinazoline- 6-sulfonamide (10.00 mg, 0.17 mmol), tert-butyl (25,65)-2,6-dimethylpiperazine-l- carboxylate, (72.24 mg, 0.34 mmol), Pd2(dba)s (30.87 mg, 0.03 mmol), rac-BINAP (20.99 mg, 0.03 mmol) and CS2CO3 (164.74 mg, 0.51 mmol) in toluene was stirred at 80 °C for 16 h under N2 atmosphere. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography, eluted with 30% EtOAc in Hexane to give the desired product. LCMS calculated for C33H50F2N7O5S3Si (M+H)+m / z = 786.3; found 786.0.

[0690] Step 13: 4-(5-(difluoromethyl)-l , 3, 4-thiadiazol-2-yl)-8-((3S, 5S)-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-2-(methylthio)quinazoline-6- sulfonamide

[0691] To tert-butyl (2S,6S)-4-(4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-2- (methylthio)quinazolin-8-yl)-2,6-dimethylpiperazine-l-carboxylate (20.00 mg, 0.03 mmol) was added TFA (2 mL). The mixture was stirred at room temperature for 4 hours, and concentrated. The resulting residue was purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product. LCMS calculated for C22H28F2N7O2S3 (M+H)+m / z = 556.1; found 556.0. Example 22. 4-(5-(Difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5- dimethylpiperazin-l-yl)-2-(l-methyl-lH-pyrazol-4-yl)-N-(l- methylcyclopropyl)quinazoline-6-sulfonamide

[0692] To a screw-cap vial equipped with a magnetic stir bar were added tert-butyl (2S,6S)-4-(4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-6-(N-(l-methylcyclopropyl)- N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-2-(methylthio)quinazolin-8-yl)-2,6- dimethylpiperazine-1 -carboxylate (Example 21; step 12) (20.00 mg, 0.03 mmol), 1- methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (10.59 mg, 0.05 mmol), Pd(PPhs)4 (2.94 mg, 0.003 mmol) and copper(I) 2-hydroxy-3 -methylbenzoate (1.09 mg, 0.01 mmol). The vial was sealed with a Teflon-lined septum, evacuated and backfilled with nitrogen (this process was repeated a total of three times). 1,4-Dioxane (1 mL) was added. The reaction mixture was stirred at 125 °C for 40 h. Upon cooling to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was treated with TFA at room temperature for 4 h, and then concentrated. The resulting residue was purified by prep-HPLC (column: Sunfire prep Cl 8 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product. LCMS calculated for C25H30F2N9O2S2 (M+H)+m / z = 590.2; found 590.0.

[0693] Example 23. 4-(5-(Difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5- dimethylpiperazin-l-yl)-2-((l-methyl-lH-pyrazol-4-yl)oxy)-N-(l- methylcyclopropyl)quinazoline-6-sulfonamide

[0694]

[0695] Step 1: tert-butyl (2S,6S)-4-(4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-2- (methylsulfmyl) quinazolin-8-yl) -2, 6-dimethylpiper azine- 1 -carboxylate Boc

[0696] To a solution of tert-butyl (2S,6S)-4-(4-(5-(difhioromethyl)-l,3,4-thiadiazol-2- yl)-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-2- (methylthio)quinazolin-8-yl)-2,6-dimethylpiperazine-l-carboxylate (Example 21; step 12) (65.00 mg, 0.08 mmol) in DCM (2 mL) was added 3-chlorobenzenecarboperoxoic acid (21.40 mg, 0.12 mmol) at 0 °C. The mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was diluted with DCM, washed with 1 N NaOH (aq), brine, dried over MgSCU, and concentrated. The crude product was used directly in the next step without further purification. LCMS calculated for C33H50F2N7O6S3Si (M+H)+m / z = 802.3; found 802.0.

[0697] Step 2: 4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin- l-yl)-2-((l-methyl-lH-pyrazol-4-yl)oxy)-N-(l-methylcyclopropyl)quinazoline-6- sulfonamide To a mixture of l-methylpyrazol-4-ol (5.50 mg, 0.06 mmol) and tert-butyl (2S,6S)-4-(4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-6-(N-(l-methylcyclopropyl)- N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-2-(methylsulfinyl)quinazolin-8-yl)- 2,6-dimethylpiperazine-l -carboxylate (15.00 mg, 0.02 mmol) in MeCN was added potassium carbonate (5.17 mg, 0.04 mmol). After stirring at 70 °C for 2 h, the mixture was cooled to room temperature and concentrated. The residue was treated with TFA at room temperature for 4 h, and then concentrated. The resulting residue was purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product. LCMS calculated for C25H30F2N9O3S2 (M+H)+m / z = 606.2; found 606.0.

[0698] Example 24. 2-Amino-4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)quinazoline-6-sulfonamide

[0699] To a mixture of (2,4-dimethoxyphenyl)methanamine (9.38 mg, 0.06 mmol) and tert-butyl (2S,6S)-4-(4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-6-(N-(l- methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-2- (methylsulfinyl)quinazolin-8-yl)-2,6-dimethylpiperazine-l-carboxylate (Example 23; step 1) (15.00 mg, 0.02 mmol) in MeCN was added A-ethyl-A-isopropyl-propan-2- amine (7.25 mg, 0.06 mmol). After stirring at 70 °C for 2 h, the mixture was cooled to room temperature and concentrated. The residue was treated with TFA at room temperature for 4 h, and then concentrated. The resulting residue was purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product. LCMS calculated for C21H27F2N8O2S2 (M+H)+m / z = 525.2; found 525.0.

[0700] Example 25. 2-(3-Cyanoazetidin-l-yl)-4-(5-(difluoromethyl)-l,3,4-thiadiazol-2- yl)-8-((3S,5S)-3,5-dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)quinazoline-6- sulfonamide

[0701] The TFA salt of the title compound was prepared according to the procedure described in Example 24, using azetidine-3-carbonitrile;hydrochloride instead of (2,4- dimethoxyphenyl)methanamine. LCMS calculated for C25H30F2N9O2S2 (M+H)+m / z = 590.2; found 590.0.

[0702] Example 26. 4-(5-(Difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-2-(3-oxotetrahydro-3H- oxazolo[3,4-a]pyrazin-7(lH)-yl)quinazoline-6-sulfonamide

[0703] The TFA salt of the title compound was prepared according to the procedure described in Example 24, using hexahydro-3H-oxazolo[3,4-a]pyrazin-3- one;hydrochloride instead of (2,4-dimethoxyphenyl)methanamine. LCMS calculated for C27H34F2N9O4S2 (M+H) m / z = 650.2; found 650.2.

[0704] Example 27. 2-(l-(l-(Cyanomethyl)cyclobutyl)-lH-pyrazol-4-yl)-4-(5- (difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin-l-yl)-N- (l-methylcyclopropyl)quinazoline-6-sulfonamide

[0705] Step 1 : 2-( l-(4-(4,4,5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lH-pyrazol-l- yl)cyclobutyl)acetonitrile

[0706] To a solution of 4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lH-pyrazole (100.00 mg, 0.52 mmol) in MeCN (2 mL) was added 2-cyclobutylideneacetonitrile (71.99 mg, 0.77 mmol) followed by 2,3,4,6,7,8,9,10-octahydropyrimido[l,2-a]azepine (156.91 mg, 1.03 mmol). The mixture was stirred at 60 °C for 2 h and then concentrated. The residue was purified by silica gel column chromatography, eluted with 30% EtOAc in Hexane to give the desired product. LCMS calculated for C15H23BN3O2 (M+H)+m / z = 288.2; found 288.0.

[0707] Step 2: 2-(l-(l-(cyanomethyl)cyclobutyl)-lH-pyrazol-4-yl)-4-(5-(difluoromethyl)- 1, 3, 4-thiadiazol-2-yl)-8-( ( 3S, 5S)-3, 5-dimethylpiperazin-l-yl)-N-( I - methylcyclopropyl)quinazoline-6-sulfonamide The TFA salt of the title compound was prepared according to the procedure described in Example 22, using 2-(l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazol-l-yl)cyclobutyl)acetonitrile instead of l-methyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyrazole. LCMS calculated for C30H35F2N10O2S2 (M+H)+m / z = 669.2; found 669.2.

[0708] Example 28. 4-(5-(Difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-2-((tetrahydro-lH-pyrrolizin-

[0709] 7a(5H)-yl)methoxy)quinazoline-6-sulfonamide

[0710] The TFA salt of the title compound was prepared according to the procedure described in Example 23 (step 2), using (tetrahydro- 1 H-pyrrolizin-7a(5H)- yl)methanol instead of l-methylpyrazol-4-ol. LCMS calculated for C29H39F2N8O3S2 (M+H)+m / z = 649.3; found 649.2.

[0711] Example 29. 4-(5-(Difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5- dimethylpiperazin-l-yl)-2-methoxy-N-(l-methylcyclopropyl)quinazoline-6- sulfonamide To a mixture of tert-butyl (2S,6S)-4-(4-(5-(difluoromethyl)-l,3,4-thiadiazol-2- yl)-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-2- (methylsulfinyl)quinazolin-8-yl)-2,6-dimethylpiperazine-l-carboxylate (Example 23; step 1) (10.0 mg, 0.01 mmol) in MeCN ( 2 mL) was added potassium carbonate (13.8 mg, 0.1 mmol) followed by MeOH (2 mL). After stirring at 70 °C for 2 h, the mixture was cooled to room temperature and concentrated. The residue was treated with TFA(2 mL) at room temperature for 4 h, and then concentrated. The resulting residue was purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product. LCMS calculated for C22H28F2N7O3S2 (M+H)+m / z = 540.2; found 540.0.

[0712] Example 30. 4-(5-(Difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5- dimethylpiperazin-l-yl)-2-((l-(hydroxymethyl)cyclopentyl)methoxy)-N-(l- methylcyclopropyl)quinazoline-6-sulfonamide

[0713] The TFA salt of the title compound was prepared according to the procedure described in Example 23 (step 2), using cyclopentane-l,l-diyldimethanol instead of 1- methylpyrazol-4-ol. LCMS calculated for C28H38F2N7O4S2 (M+H)+m / z = 638.2; found 638.2.

[0714] Example 31. 4-(5-(Difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5- dimethylpiperazin-l-yl)-2-methyl-N-(l-methylcyclopropyl)-l-oxo-l,2- dihydrophthalazine-6-sulfonamide

[0715]

[0716] Step 1: Methyl 4-bromo-2-(dibromomethyl)-6-fhiorobenzoate

[0717] To the mixture of methyl 4-bromo-2-fluoro-6-methyl-benzoate (4.30 g, 17.40 mmol) and NBS (6.82 g, 38.29 mmol) in CCh (50 mL) at room temperature was added benzoyl peroxide(0.42 g, 1.74 mmol). The resulting suspension was stirred at 80 °C for 16 h. After cooling to room temperature, the reaction was filtered. The filter cake was rinsed with DCM (200 mL). The combined filtrate was washed with IM Na2S2C>3 (aq), sat. sodium bicarbonate solution, dried with sodium sulfate, filtered and concentrated. The residue was purified with silica gel column chromatography, eluting with 0-20% EtOAc in DCM to give desired product as colorless oil (7.51 g.)

[0718] Step 2: Methyl 4-bromo-2-fluoro-6-formylbenzoate

[0719] To methyl 4-bromo-2-(dibromomethyl)-6-fluorobenzoate (7.00 g, 17.29 mmol) was added isopropanol (60 mL), water (15 mL) followed by silver nitrate (8.81 g, 51.87 mmol). The resulting suspension was stirred at 50 °C for 16 h. After cooling to room temperature, the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was diluted with 15% MeOH / DCM and washed with water. The separated organic layer was dried with sodium sulfate, filtered and concentrated to give a 1 to 1 mixture of methyl 4-bromo-2-fluoro-6-formylbenzoate and 4-bromo-2-fluoro-6-formylbenzoic acid (4.00 g) as light-yellow solid.

[0720] Step 3: 6-bromo-8-fluorophthalazin-l(2H)-one

[0721] To the methyl 4-bromo-2-fluoro-6-formyl-benzoate (3.50 g, 13.4 mmol) was added acetic acid (35 mL) followed by hydrazine monohydrate (1.70 g, 26.82 mmol) at room temperature. The resulting mixture was stirred at 110 °C for 16 h. The reaction was then cooled to room temperature. The precipitate was collected by filtration, washed with water, and further washed with heptane to give the desired product (2.89 g) as a brown solid which was used for the next step directly. LCMS calculated for CsFEBrFlS O (M+H)+m / z = 243.0; found 243.0.

[0722] Step 4: 6-(benzylthio)-8-fluorophthalazin-l(2H)-one

[0723] To a mixture of 6-bromo-8-fhrorophthalazin-l(2J7)-one (2.83 g, 11.64 mmol) and phenylmethanethiol (2.89 g, 23.29 mmol) in anhydrous 1,4-dioxane (30 mL) was added Xantphos (0.67 g, 1.16 mmol), 7V-ethyl-7V-isopropyl-propan-2-amine (4.51 g, 34.93 mmol) followed by Pd2(dba)s (0.53 g, 0.58 mmol). The mixture was purged with N2 gas and stirred at 90 °C for 3 h. Upon cooling to room temperature, the mixture was concentrated. The residue was purified by silica gel column chromatography, eluting with 0-100% EtOAc in DCM to give the desired product as yellow solid (1.83 g, 54.9 %). LCMS calculated for C15H12FN2OS (M+H)+m / z = 287.1; found 287.1.

[0724] Step 5: 6-(benzylthio)-4-bromo-8-fluorophthalazin-l(2H)-one

[0725] To the suspension of 6-(benzylthio)-8-fluorophthalazin-l(2H)-one (1.63 g, 5.69 mmol) in anhydrous DMF (20 mL) was added potassium carbonate (1.57 g, 11.39 mmol) at room temperature. After stirring at room temperature for 5 min, the reaction mixture was treated with benzyl trimethylammonium tribromide (4.44 g, 11.39 mmol). The resulting mixture was stirred at 40 °C for 8 hours. Upon cooling to room temperature, the reaction mixture was quenched with sat. Na2S20s (aq), extracted with DCM. The separated organic layer was dried with sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography, eluting with 0-50% EtOAc in DCM to give the desired product as a white solid (1.78 g, 85.6 %). LCMS calculated for CisHnBrFN2OS (M+H)+m / z = 365.0; found 364.9.

[0726] Step 6: 6-(benzylthio)-4-bromo-8-fluoro-2-methylphthalazin-l(2H)-one

[0727] To the suspension of 6-(benzylthio)-4-bromo-8-fluorophthalazin-l(2J7)-one (690.00 mg, 1.89 mmol) in anhydrous DMF at room temperature was added iodomethane (294.98 mg, 2.08 mmol) and potassium carbonate (391.66 mg, 2.83 mmol). After stirring at room temperature for 1 hour, the reaction mixture was diluted with DCM and washed with sat. NF Cl (aq). The separated organic layer was dried with sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography, eluting with 0-100% EtOAc in DCM to give the desired product as orange solid (380.00 mg, 53.0%). LCMS calculated for CieHnBrElS OS (M+H)+m / z = 379.0; found 379.0.

[0728] Step 7. 6-(benzylthio)-4-(5-(difluoromethyl)-l, 3, 4-thiadiazol-2-yl)-8-fluoro-2- methylphthalazin-1 ( 2H)-one

[0729] To a screw-cap vial equipped with a magnetic stir bar was added 6- (benzylthio)-4-bromo-8-fluoro-2-methylphthalazin-l(2J7)-one (360.00 mg, 0.95 mmol) followed by bis(triphenylphosphine)palladium(II) dichloride (66.63 mg, 0.09 mmol). The vial was sealed with a Teflon-lined septum, evacuated and backfilled with nitrogen (this process was repeated a total of three times). A solution of hexamethylditin (342.10 mg, 1.04 mmol) in anhydrous 1,4-dioxane (3.6 mL) was added via syringe. The resulting mixture was stirred at 120 °C for 1 hour and cooled to room temperature. To the reaction mixture, bis(triphenylphosphine)palladium(II) dichloride (66.63 mg, 0.09 mmol) was added followed by copper(I) iodide (36.16 mg, 0.19 mmol) and 2-bromo-5-(difhioromethyl)-l,3,4-thiadiazole (526.05 mg, 2.37 mmol). The resulting mixture was purged with N2 gas and stirred at 130 °C for 1 hour. Upon cooling to room temperature, the reaction mixture was concentrated. The residue was purified by silica gel column chromatography, eluting with 0-20% EtOAc in DCM to give the desired product (330.00 mg, 80.0%). LCMS calculated for C19H14F3N4OS2 (M+H)+m / z = 435.1; found 435.1.

[0730] Step 8: 4-(5-(difluoromethyl)-l , 3, 4-thiadiazol-2-yl)-8-fluoro-2-methyl-N-( 1 - methylcyclopropyl)-! -oxo-1 ,2-dihydrophthalazine-6-sulfonamide

[0731] To 6-(benzylthio)-4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-fluoro-2- methylphthalazin-l(2J7)-one (90.00 mg, 0.21 mmol) was added MeCN (2 mL), water (0.1 mL) and AcOH (0.1 mL). Upon cooling to 0 °C, the mixture was treated with l,3-dichloro-5,5-dimethyl-imidazolidine-2, 4-dione (61.22 mg, 0.31 mmol) and stirred at 0 °C for 1 hour. 1-Methylcyclopropanamine hydrochloride (44.57 mg, 0.41 mmol) was added followed by A-ethyl-A-isopropyl-propan-2-amine (104.42 mg, 0.81 mmol). The resulting mixture was allowed to warm to room temperature and stirred at room temperature for 1 hour. The mixture was diluted with DCM and washed with water. The separated organic layer was dried with sodium sulfate, filtered and concentrated to give the crude product which was used in the next step directly without further purification. LCMS calculated for C16H15F3N5O3S2 (M+H)+m / z = 446.1; found 446.1.

[0732] Step 9: 4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin- l-yl)-2-methyl-N-( I -methylcyclopropyl)-l-oxo-l, 2-dihydrophthalazine-6-sulfonamide

[0733] To 4-(5-(difhioromethyl)-l,3,4-thiadiazol-2-yl)-8-fluoro-2-methyl-N-(l- methylcyclopropyl)-l-oxo-l,2-dihydrophthalazine-6-sulfonamide (20.00 mg , 0.04 mmol) was added NMP (0.2 mL), N,N-diisopropylethylamine (0.2 mL) and tert-butyl (2S,6S)-2,6-dimethylpiperazine-l -carboxylate (28.87 mg , 0.13 mmol). The resulting mixture was stirred at 90 °C for 20 minutes. Upon cooling to room temperature, the mixture was treated with 4N HC1 in 1,4-di oxane (0.2 mL). After stirring at room temperature for 10 minutes, the reaction mixture was purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a yellow solid. LCMS calculated for C22H28F2N7O3S2 (M+H)+m / z = 540.2; found 540.2.

[0734] Example 32. 4-(5-(Difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3R,5R)-3,5- dimethylpiperazin-l-yl)-2-methyl-N-(l-methylcyclopropyl)-l-oxo-l,2- dihydrophthalazine-6-sulfonamide

[0735]

[0736] The TFA salt of the title compound was prepared according to the procedure described in Example 31 (step 9), using tert-butyl (2R,6R)-2,6-dimethylpiperazine-l- carboxylate instead of tert-butyl (2S,6S)-2,6-dimethylpiperazine-l -carboxylate. LCMS calculated for C22H28F2N7O3S2 (M+H)+m / z = 540.2; found 540.2.

[0737] Example 33. 4-(l-(5-(Difluoromethyl)-l,3,4-thiadiazol-2-yl)-3-methyl-7-(N-(l- methylcyclopropyl)sulfamoyl)-4-oxo-3,4-dihydrophthalazin-5-yl)-N,N- dimethylpiperazine-l-carboxamide

[0738] The TFA salt of the title compound was prepared according to the procedure described in Example 31 (step 9), using N,N-dimethylpiperazine-l -carboxamide instead of tert-butyl (2S,6S)-2,6-dimethylpiperazine-l -carboxylate. LCMS calculated for C23H29F2N8O4S2 (M+H)+m / z = 583.2; found 583.2.

[0739] Example 34. (R)-4-(5-(Difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-(4-isobutyryl-3- methylpiperazin-l-yl)-2-methyl-N-(l-methylcyclopropyl)-l-oxo-l,2- dihydrophthalazine-6-sulfonamide

[0740]

[0741] The TFA salt of the title compound was prepared according to the procedure described in Example 31 (step 9), using (R)-2-methyl-l-(2-methylpiperazin-l- yl)propan-l-one instead of tert-butyl (2S,6S)-2,6-dimethylpiperazine-l -carboxylate. LCMS calculated for C25H32F2N7O4S2 (M+H)+m / z = 596.2; found 596.2.

[0742] Example 35. (R)-4-(l-(5-(Difluoromethyl)-l,3,4-thiadiazol-2-yl)-3-methyl-7-(N- (l-methylcyclopropyl)sulfamoyl)-4-oxo-3,4-dihydrophthalazin-5-yl)-N,N,2- trimethylpiperazine-l-carboxamide

[0743] Step 1: (R)-N,N,2-trimethylpiperazine-l-carboxamide To the solution of tert-butyl (3R)-3 -methylpiperazine- 1 -carboxylate (278.00 mg, 1.39 mmol) in DCM (10 mL) at 0 °C was added TV, A-diisopropylethylamine (280.92 mg, 2.78 mmol) and TV, A-dimethylcarbamoyl chloride (191.37 mL, 223.91 mg, 2.08 mmol). The resulting mixture was stirred at 0 °C for 1 hour. The reaction mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure. The residue was then dissolved in acetonitrile (5 mL) and treated with 4M HC1 in 1,4-di oxane (2 mL). The resulting mixture was stirred at room temperature for 30 min and concentrated. The residue was dissolved in MeOH (10 mL) and treated with NaHCCL (420 mg, 5.0 mmol). After stirring at room temperature for 30 min, the reaction was filtered. The filtrate was concentrated to give the crude product which was used directly in the next step without further purification. LCMS calculated for C8HI8N3O (M+H)+m / z = 172.1; found 172.1.

[0744] Step 2: (R)-4-( 1 -(5-(dif!uoromethyl)-l , 3, 4-thiadiazol-2-yl)-3-methyl- 7-(N-( 1 - methylcyclopropyl)sulfamoyl)-4-oxo-3,4-dihydrophthalazin-5-yl)-N,N,2- lrimelhylpiperazine-1 -carboxamide

[0745] The TFA salt of the title compound was prepared according to the procedure described in Example 31 (step 9), using (R)-N,N,2-trimethylpiperazine-l- carboxamide instead of tert-butyl (2S,6S)-2,6-dimethylpiperazine-l-carboxylate. LCMS calculated for C24H3iF2N8O4S2 (M+H)+m / z = 597.2; found 597.2.

[0746] Example 36. (R)-2-(4-(l-(5-(Difluoromethyl)-l,3,4-thiadiazol-2-yl)-3-methyl-7- (N-(l-methylcyclopropyl)sulfamoyl)-4-oxo-3,4-dihydrophthalazin-5-yl)-2- methylpiperazin-l-yl)-N,N-dimethyl-2-oxoacetamide

[0747]

[0748] Step J: (R)-N,N-dimethyl-2-(2-methylpiperazin-l-yl)-2-oxoacetamide

[0749] To the solution of 2-(dimethylamino)-2-oxo-acetic acid (133.00 mg, 1.14 mmol) in anhydrous DMF (1.3 mL) was added A-ethyl-A-isopropyl-propan-2-amine (587.15 mg, 4.54 mol), HATU (561.40 mg, 1.48 mmol) and tert-butyl (3R)-3- m ethylpiperazine- 1 -carboxylate (250.21 mg, 1.25 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic layers were dried with sodium sulfate and concentrated. The residue was dissolved in 1,4-di oxane (3 mL) and treated with 4M HC1 in 1,4-di oxane (2 mL). After stirring at room temperature for 30 min, the reaction was concentrated. The residue was dissolved in MeOH (10 mL) and treated with NaHCCL (420 mg, 5.0 mmol). After stirring at room temperature for 30 min, the reaction was filtered. The filtrate was concentrated to give the crude product which was used directly in the next step without further purification. LCMS calculated for C9H18N3O2 (M+H)+ m / z = 200.1; found 200.1.

[0750] Step 2: (R)-2-(4-( 1 -(5-(difluoromethyl)-l , 3, 4-thiadiazol-2-yl)-3-methyl-7-(N-(l- methylcyclopropyl)sulfamoyl)-4-oxo-3,4-dihydrophthalazin-5-yl)-2-methylpiperazin- l-yl)-N,N-dimethy 1-2 -oxoacetamide The TFA salt of the title compound was prepared according to the procedure described in Example 31 (step 9), using (R)-N,N-dimethyl-2-(2-methylpiperazin-l- yl)-2-oxoacetamide instead of tert-butyl (2S,6S)-2,6-dimethylpiperazine-l- carboxylate. LCMS calculated for C25H31F2N8O5S2 (M+H)+m / z = 625.2; found 625.2.

[0751] Example 37. (R)-4-(5-(Difluoromethyl)-l,3,4-thiadiazol-2-yl)-2-methyl-8-(3- methyl-4-(3-methyl-2-oxobutanoyl)piperazin-l-yl)-N-(l-methylcyclopropyl)-l- oxo-1, 2-dihydrophthalazine-6-sulfonamide

[0752] Step 1: (R)-3-methyl-l-(2-methylpiperazin-l-yl)butane- 1,2-dione

[0753] The title compound was prepared according to the procedure described in Example 36 (step 1), using 3-methyl-2-oxo-butanoic acid instead of 2- (dimethylamino)-2-oxo-acetic acid. LCMS calculated for C10H19N2O2 (M+H)+m / z = 199.1; found 199.1.

[0754] Step 2: (R)-4-(5-(dif!uoromethyl)-l , 3, 4-thiadiazol-2-yl)-2-methyl-8-( 3-methyl-4-( 3- methyl-2-oxobutanoyl)piperazin-l-yl)-N-( 1 -methylcyclopropyl)-! -oxo- 1, 2- dihydrophthalazine-6-sulfonamide

[0755] The TFA salt of the title compound was prepared according to the procedure described in Example 31 (step 9), using (R)-3 -methyl- 1 -(2 -methylpiperazin-1- yl)butane- 1,2-dione instead of tert-butyl (2S,6S)-2,6-dimethylpiperazine-l- carboxylate. LCMS calculated for C26H32F2N7O5S2 (M+H)+m / z = 624.2; found 624.2.

[0756] Example A. Cellular PARG inhibition assay

[0757] The purpose of this assay is to determine the potency of the synthesized PARG inhibitors. HeLa cells (ATCC, CCL-2) were seeded into 96 well plate at 25000 cells / well, and incubated for 24 h. Cells were pre-incubated with compounds for 1 h, stimulated with 50 pg / mL methyl methanesulfonate (MMS) for an additional 1 h, then fixed in 100% ice-cold methanol for 20 min. After fixation, cells were washed in lx PBST for 3 times, 5 min each, blocked in blocking buffer (10% goat serum, 1% BSA, 0.1% Triton X-100, in PBST) for 1 h at room temperature, then incubated with mouse anti-P AR primary antibody (Adipogen, AG-20T-0001-M001, 1 :300 in blocking buffer) for 18 h at 4 °C. Plates were washed in lx PBST for 3 times, 5 min each, incubated with IRDye 800CW conjugated goat anti-mouse IgG secondary antibody (LI-COR, 926-32210, 1 : 1000 in blocking buffer) for 1 h at room temperature, then plates were washed 3 times in lx PBST, 5 min each. Infrared signal was measured using the LI-COR Odyssey DLx Imaging system and data analyzed using GraphPad Prism.

[0758] Results of the PARG inhibition assay are presented in Table A. “++++” indicates an IC50 less than 1000 nM; “+++” indicates an IC50 greater than or equal to 1000 nM but less than 5000 nM; “++” indicates an IC50 greater than or equal to 5000 nM but less than 10000 nM; and “+” indicates an IC50 greater than or equal to 10000 nM.

[0759] Table A.

[0760] Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patent, patent applications, and publications, cited in the present application is incorporated herein by reference in its entirety.

Claims

1. WHAT IS CLAIMED IS:

1. A compound of Formula I:I or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3, 4, 5, or 6; n is 1, 2, 3, 4, 5, or 6;X1is N or CR5;X2is N or CR6;X3is C or N;Z is O or NR7;Ring A is phenyl, 6-membered heteroaryl,each = is independently a single or double bond;Y1is C or N;Y2is C or N;Y3is C(-L3-R3), or N;Ring B is Ce-io aryl or 5-10 membered heteroaryl;Ring C is C5-10 cycloalkyl, phenyl, 5-10 membered heterocycloalkyl, or 5-6 membered heteroaryl; each L2and L3is independently selected from bond, C1-6 alkylene, C1-6 haloalkylene, C3-7 cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6membered heteroarylene, -C3-7 cycloalkylene-Ci-4 alkyl-, -(4-7 membered heterocycloalkylene)-Ci-4 alkyl-, -phenylene-Ci-4 alkyl-, -(5-6 membered heteroarylene)-Ci-4alkyl-, -O-, -N(RL)-, -C(O)-, -N(RL)C(O)-, -N(RL)C(O)N(RL)-, - N(RL)C(O)O-, -S(O)-, -S(O)2-, -S(O)(=NRL)-, -S(O)2N(RL)-, and -N(RL)S(O)2N(RL)-, wherein the C1-6 alkylene, C1-6 haloalkylene, C3-7 cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6 membered heteroarylene, C3-7 cycloalkylene-Ci-4 alkyl, (4-7 membered heterocycloalkylene)-Ci-4 alkyl, -phenylene-Ci-4 alkyl-, and (5- 6 membered heteroarylene)-Ci-4 alkyl of L2and L3are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; or, L2and one of L3, together with the atoms to which they are attached, form a C5-30 cycloalkyl, or 5-30 membered heterocycloalkyl group, wherein the C5-30 cycloalkyl and 5-30 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R2substituents; or, two of L3, together with the atoms to which they are attached, form a 5-6 membered heteroaryl, C5-14 cycloalkyl, or 5-14 membered heterocycloalkyl group, wherein the 5-6 membered heteroaryl, C5-14 cycloalkyl and 5-14 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3substituents; or, one of L3and one of R4, together with the atoms to which they are attached, form a C5-30 cycloalkyl, or 5-30 membered heterocycloalkyl group, wherein the C5-30 cycloalkyl and 5-30 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R3substituents; each RLis independently selected from H, C1-6 alkyl, and C1-6 haloalkyl;R1is selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci- 4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci- 4 alkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;R2is selected from H, oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, -the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4- 10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; each Ra2, Rc2, and Rd2is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra2, Rc2, and Rd2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; or, any Rc2and Rd2attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; each Rb2is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; each Re2is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R2Ais independently selected from oxo, H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, -CN, -ORa2A, -SRa2A, -NRc2ARd2A, -NO2, -C(O)Ra2A, -C(O)C(O)Ra2A, - C(O)ORa2A, -C(O)NRc2ARd2A, -C(O)C(O)NRc2ARd2A, -C(O)NRc2A(ORa2A), - OC(O)Ra2A, -OC(O)NRc2ARd2A, -OC(O)ORa2A, -OS(O)2Rb2A, -OS(O)2NRc2ARd2A, - NRc2AC(O)Ra2A, -NRc2AC(O)ORa2A, -NRc2AC(O)NRc2ARd2A, -NRc2AS(O)2Rb2A, - NRc2AS(O)2NRc2ARd2A, -NRc2AORa2A, -NRc2AS(O)Rb2A, -NRc2AS(O)NRc2ARd2A, - S(O)Rb2A, -S(O)2Rb2A, -S(O)NRc2ARd2A, -S(O)2NRc2ARd2A, -C(=NRe2A)Ra2A, - C(=NRe2A)NRc2ARd2A, -NRc2AC(=NRe2A)Ra2A, -NRc2AC(=NRe2A)NRc2ARd2A, - NRc2AS(O)(=NRe2A)Rb2A, -NRc2AS(O)(=NRe2A)NRc2ARd2A, -OS(O)(=NRe2A)Rb2A, - S(O)(=NRe2A)Rb2A, -S(O)(=NRe2A)NRc2ARd2A, -C(O)NRc2AS(O)2Rb2A, - C(O)NRc2AS(O)2NRc2ARd2A, -S(O)2NRc2AC(O)Rb2A, and -NRc2AS(O)NRc2AC(O)Rb2A, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of R2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra2A, Rc2A, and Rd2Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra2A, Rc2A, and Rd2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc2Aand Rd2Aattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rb2Ais independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Re2Ais independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R3is independently selected from oxo, H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, -CN, -ORa3, -SRa3, -NRc3Rd3, -NO2, -C(O)Ra3, -C(O)C(O)Ra3, -C(O)ORa3, - C(O)NRc3Rd3, -C(O)NRc3(ORa3), -OC(O)Ra3, -OC(O)NRc3Rd3, -OC(O)ORa3, -NRc3S(O)(=NRe3)NRc3C(O)Rb3, -C(O)C(O)NRc3Rd3, and -P(O)RfiRg3, wherein the Ci- 6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; each Ra3, Rc3, and Rd3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra3, Rc3, and Rd3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; or, any Rc3and Rd3attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; each Rb3is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-ioaryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; each Re3is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each Rfiand Rg3are independently selected from C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and, C1-6 haloalkoxy; each R3Ais independently selected from oxo, H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, -CN, -ORa3A, -SRa3A, -NRc3ARd3A, -NO2, -C(O)Ra3A, -C(O)C(O)Ra3A, -wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of R3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra3A, Rc3A, and Rd3Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra3A, Rc3A, and Rd3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc3Aand Rd3Aattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rb3Ais independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Re3Ais independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R4is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, (5-6 membered heteroaryl)-Ci-4 alkyl, -CN, -ORa4, -SRa4, -NRc4Rd4, -NO2, -C(O)Ra4, -C(O)ORa4, -C(O)NRc4Rd4, -C(O)NRc4(ORa4), -OC(O)Ra4, -OC(O)NRc4Rd4, -OC(O)ORa4, -OS(O)2Rb4, -OS(O)2NRc4Rd4, -NRc4C(O)Ra4, -a4,n the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of R4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra4, Rc4, and Rd4is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci- 4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of Ra4, Rc4, and Rd4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc4and Rd4attached to the same N atom, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group, wherein the 4- 7 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rb4is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 memberedheteroaryl)-Ci-4 alkyl of Rb4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Re4is independently selected from H, OH, CN, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl;R5is selected from H, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and -CN;R6is selected from H, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and -CN;R7is selected from H, CN, ORa7, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; or, R7and R1, together with the atoms to which they are attached, form a 5-10 membered heterocycloalkyl group, wherein the 5-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;Ra7is selected from H, C1-6 alkyl, and C1-6 haloalkyl; each RGis independently selected from OH, CN, halo, oxo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, cyano-Ci-4 alkyl, HO-C1-4 alkyl, C1-4 alkoxy-Ci-4 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-3 alkylamino, di(Ci-3 alkyl)amino, thio, C1-3 alkylthio, C1-3 alkylsulfinyl, Ci- 3 alkyl sulfonyl, carbamyl, C1-3 alkylcarbamyl, di(Ci-3 alkyl)carbamyl, carboxy, C1-3 alkylcarbonyl, C1-3 alkoxycarbonyl, C1-3 alkylcarbonyloxy, C1-3 alkylcarbonylamino, C1-3 alkoxy carbonylamino, aminocarbonyloxy, C1-3 alkylaminocarbonyloxy, di (C 1-3 alkyl)aminocarbonyloxy, C1-3 alkylsulfonylamino, aminosulfonyl, C1-3 alkylaminosulfonyl, di(Ci-3 alkyl)aminosulfonyl, aminosulfonylamino, C1-3 alkylaminosulfonylamino, di(Ci-3 alkyl)aminosulfonylamino, aminocarbonylamino, C1-3 alkylaminocarbonylamino, and di(Ci-3 alkyl)aminocarbonylamino.

2. The compound of claim 1, wherein: m is 0, 1, 2, 3, 4, 5, or 6;n is 1, 2, 3, 4, 5, or 6;X1is N or CR5;X2is N or CR6;X3is C or N;Z is O or NR7;Ring A is phenyl, 6-membered heteroaryl,each = is independently a single or double bond;Y1is C or N;Y2is C or N;Y3is C(-L3-R3), or N;Ring B is Ce-io aryl or 5-10 membered heteroaryl;Ring C is C5-10 cycloalkyl, phenyl, 5-10 membered heterocycloalkyl, or 5-6 membered heteroaryl; each L2and L3is independently selected from bond, C1-6 alkylene, C1-6 haloalkylene, C3-7 cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6 membered heteroarylene, -C3-7 cycloalkylene-Ci-4 alkyl-, -(4-7 membered heterocycloalkylene)-Ci-4 alkyl-, -phenylene-Ci-4 alkyl-, -(5-6 membered heteroarylene)-Ci-4alkyl-, -O-, -N(RL)-, -C(O)-, -N(RL)C(O)-, -N(RL)C(O)N(RL)-, - N(RL)C(O)O-, -S(O)-, -S(O)2-, -S(O)(=NRL)-, -S(O)2N(RL)-, and -N(RL)S(O)2N(RL)-, wherein the C1-6 alkylene, C1-6 haloalkylene, C3-7 cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6 membered heteroarylene, C3-7 cycloalkylene-Ci-4 alkyl, (4-7 membered heterocycloalkylene)-Ci-4 alkyl, -phenylene-Ci-4 alkyl-, and (5- 6 membered heteroarylene)-Ci-4 alkyl of L2and L3are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; or, L2and one of L3, together with the atoms to which they are attached, form a C5-10 cycloalkyl, or 5-10 membered heterocycloalkyl group, wherein the C5-10 cycloalkyl and 5-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2substituents; each RLis independently selected from H, C1-6 alkyl, and C1-6 haloalkyl;R1is selected from Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci- 4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci- 4 alkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;R2is selected from H, oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, -S(O)2NRc2C(O)Rb2, and -NRc2S(O)NRc2C(O)Rb2, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; each Ra2, Rc2, and Rd2is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra2, Rc2,and Rd2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; or, any Rc2and Rd2attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; each Rb2is independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; each Re2is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R2Ais independently selected from oxo, H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, -CN, -ORa2A, -SRa2A, -NRc2ARd2A, -NO2, -C(O)Ra2A, -C(O)ORa2A, - C(O)NRc2ARd2A, -C(O)NRc2A(ORa2A), -OC(O)Ra2A, -OC(O)NRc2ARd2A, -OC(O)ORa2A, -OS(O)2Rb2A, -OS(O)2NRc2ARd2A, -NRc2AC(O)Ra2A, -NRc2AC(O)ORa2A, - NRc2AC(O)NRc2ARd2A, -NRc2AS(O)2Rb2A, -NRc2AS(O)2NRc2ARd2A, -NRc2AORa2A, - NRc2AS(O)Rb2A, -NRc2AS(O)NRc2ARd2A, -S(O)Rb2A, -S(O)2Rb2A, -S(O)NRc2ARd2A, - S(O)2NRc2ARd2A, -C(=NRe2A)Ra2A, -C(=NRe2A)NRc2ARd2A, -NRc2AC(=NRe2A)Ra2A, - NRc2AC(=NRe2A)NRc2ARd2A, -NRc2AS(O)(=NRe2A)Rb2A, - NRc2AS(O)(=NRe2A)NRc2ARd2A, -OS(O)(=NRe2A)Rb2A, -S(O)(=NRe2A)Rb2A, -S(O)(=NRe2A)NRc2ARd2A, -C(O)NRc2AS(O)2Rb2A, -C(O)NRc2AS(O)2NRc2ARd2A, - S(O)2NRc2AC(O)Rb2A, and -NRc2AS(O)NRc2AC(O)Rb2A, wherein the Ci-6alkyl, C2.6alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra2A, Rc2A, and Rd2Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra2A, Rc2A, and Rd2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc2Aand Rd2Aattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rb2Ais independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Re2Ais independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl,4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R3is independently selected from oxo, H, halo, C1-6 alkyl, C2-6 alkenyl, C2-e alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, -CN, -ORa3, -SRa3, -NRc3Rd3, -NO2, -C(O)Ra3, -C(O)ORa3, -C(O)NRc3Rd3, -S(O)2NRc3C(O)Rb3, and -NRc3S(O)NRc3C(O)Rb3, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; each Ra3, Rc3, and Rd3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra3, Rc3, and Rd3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents;or, any Rc3and Rd3attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; each Rb3is independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; each Re3is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R3Ais independently selected from oxo, H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, -CN, -ORa3A, -SRa3A, -NRc3ARd3A, -NO2, -C(O)Ra3A, -C(O)ORa3A, - C(O)NRc3ARd3A, -C(O)NRc3A(ORa3A), -OC(O)Ra3A, -OC(O)NRc3ARd3A, -OC(O)ORa3A, -OS(O)2Rb3A, -OS(O)2NRc3ARd3A, -NRc3AC(O)Ra3A, -NRc3AC(O)ORa3A, - NRc3AC(O)NRc3ARd3A, -NRc3AS(O)2Rb3A, -NRc3AS(O)2NRc3ARd3A, -NRc3AORa3A, - NRc3AS(O)Rb3A, -NRc3AS(O)NRc3ARd3A, -S(O)Rb3A, -S(O)2Rb3A, -S(O)NRc3ARd3A, - S(O)2NRc3ARd3A, -C(=NRe3A)Ra3A, -C(=NRe3A)NRc3ARd3A, -NRc3AC(=NRe3A)Ra3A, - NRc3AC(=NRe3A)NRc3ARd3A, -NRc3AS(O)(=NRe3A)Rb3A, - NRc3AS(O)(=NRe3A)NRc3ARd3A, -OS(O)(=NRe3A)Rb3A, -S(O)(=NRe3A)Rb3A, - S(O)(=NRe3A)NRc3ARd3A, -C(O)NRc3AS(O)2Rb3A, -C(O)NRc3AS(O)2NRc3ARd3A, - S(O)2NRc3AC(O)Rb3A, and -NRc3AS(O)NRc3AC(O)Rb3A, wherein the Ci-6alkyl, C2-6alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra3A, Rc3A, and Rd3Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra3A, Rc3A, and Rd3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc3Aand Rd3Aattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rb3Ais independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Re3Ais independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R4is independently selected from oxo, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, (5-6 membered heteroaryl)-Ci-4 alkyl, -CN, -ORa4, -SRa4, -NRc4Rd4, -NO2, -C(O)Ra4, -C(O)ORa4, -C(O)NRc4Rd4, -C(O)NRc4(ORa4), -OC(O)Ra4, -OC(O)NRc4Rd4, -OC(O)ORa4, -OS(O)2Rb4, -OS(O)2NRc4Rd4, -NRc4C(O)Ra4, - NRc4C(O)ORa4, -NRc4C(O)NRc4Rd4, -NRc4S(O)2Rb4, -NRc4S(O)2NRc4Rd4, -NRc4ORa4, -NRc4S(O)Rb4, -NRc4S(O)NRc4Rd4, -S(O)Rb4, -S(O)2Rb4, -S(O)NRc4Rd4, - S(O)2NRc4Rd4, -C(=NRe4)Ra4, -C(=NRe4)NRc4Rd4, -NRc4C(=NRe4)Ra4, - NRc4C(=NRe4)NRc4Rd4, -NRc4S(O)(=NRe4)Rb4, -NRc4S(O)(=NRe4)NRc4Rd4, - OS(O)(=NRe4)Rb4, -S(O)(=NRe4)Rb4, -S(O)(=NRe4)NRc4Rd4, -C(O)NRc4S(O)2Rb4, - C(O)NRc4S(O)2NRc4Rd4, -S(O)2NRc4C(O)Rb4, and -NRc4S(O)NRc4C(O)Rb4, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of R4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra4, Rc4, and Rd4is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci- 4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of Ra4, Rc4, and Rd4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc4and Rd4attached to the same N atom, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group, wherein the 4- 7 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;each Rb4is independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of Rb4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Re4is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl;R5is selected from H, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and -CN;R6is selected from H, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and -CN;R7is selected from H, CN, ORa7, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; or, R7and R1, together with the atoms to which they are attached, form a 5-10 membered heterocycloalkyl group, wherein the 5-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;Ra7is selected from H, C1-6 alkyl, and C1-6 haloalkyl; each RGis independently selected from OH, CN, halo, oxo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, cyano-Ci-4 alkyl, HO-C1-4 alkyl, C1-4 alkoxy-Ci-4 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-3 alkylamino, di(Ci-3 alkyl)amino, thio, C1-3 alkylthio, C1-3 alkylsulfinyl, Ci- 3 alkyl sulfonyl, carbamyl, C1-3 alkylcarbamyl, di(Ci-3 alkyl)carbamyl, carboxy, C1-3 alkylcarbonyl, C1-3 alkoxycarbonyl, C1-3 alkylcarbonyloxy, C1-3 alkylcarbonylamino, C1-3 alkoxy carbonylamino, aminocarbonyloxy, C1-3 alkylaminocarbonyloxy, di (C 1-3alkyl)aminocarbonyloxy, C1-3 alkylsulfonylamino, aminosulfonyl, C1-3 alkylaminosulfonyl, di(Ci-3 alkyl)aminosulfonyl, aminosulfonylamino, C1-3 alkylaminosulfonylamino, di (C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C1-3 alkylaminocarbonylamino, and di(Ci-3 alkyl)aminocarbonylamino.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X1is CR5.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R5is H or C1-6 alkyl.

5. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R5is H.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein X2is CR6.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R6is H or C1-6 alkyl.

8. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R6is H.

9. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X1and X2are each CH.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein Z is O.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R1is selected from C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci-4 alkyl, wherein C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci-4 alkyl of R1are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.

12. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R1is selected from C3-6 cycloalkyl, and C3-6 cycloalkyl-Ci-4 alkyl, wherein the C3-6 cycloalkyl and C3-6 cycloalkyl-Ci-4 alkyl of R1are each optionally substituted with 1 or 2 independently selected RGsubstituents.

13. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R1is C3-6 cycloalkyl, which is optionally substituted with 1 or 2 RGsubstituents independently selected from C1-6 alkyl.

14. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R1is methylcyclopropyl.

15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein L2is selected from a bond, C3-7 cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6 membered heteroarylene, -C3-7 cycloalkylene-Ci- 4 alkyl-, -(4-7 membered heterocycloalkylene)-Ci-4 alkyl-, -phenylene-Ci-4 alkyl-, and -(5-6 membered heteroarylene)-Ci-4 alkyl-, wherein the C3-7 cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6 membered heteroarylene, -C3-7 cycloalkylene-Ci-4 alkyl-, -(4-7 membered heterocycloalkylene)-Ci-4 alkyl-, - phenylene-Ci-4 alkyl-, and -(5-6 membered heteroarylene)-Ci-4 alkyl- of L2are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.

16. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein L2is selected from a bond and 4-7 membered heterocycloalkylene, wherein the 4-7 membered heterocycloalkylene of L2is optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.

17. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein L2is selected from a bond, 1,2,3,6-tetrahydropyridindiyl, and piperazindiyl, wherein the 1,2,3,6-tetrahydropyridindiyl and piperazindiyl of L2are each optionally substituted with 1 or 2 RGsubstituents independently selected from Ci-6 alkyl.

18. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein L2is selected from a bond, 1,2,3,6-tetrahydropyridindiyl, piperazindiyl, and methylpiperazindiyl.

19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R2is selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, -C(O)Ra2, -C(O)C(O)Ra2, -C(O)ORa2, -C(O)NRc2Rd2, - C(O)C(O)NRc2Rd2, -C(O)NRc2(ORa2), -OC(O)Ra2, -OC(O)NRc2Rd2, -NRc2C(O)Ra2, - NRc2C(O)ORa2, and -NRc2C(O)NRc2Rd2, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl of R2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

20. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R2is selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, 4-10 membered heterocycloalkyl, -C(O)Ra2, -C(O)C(O)NRc2Rd2, -C(O)NRc2Rd2, and - C(O)C(O)NRc2Rd2, wherein the C1-6 alkyl, C1-6 haloalkyl, and 4-10 membered heterocycloalkyl of R2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

21. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R2is selected from H, fluoro, chloro, bromo, methyl, isopropyl, trifluoromethyl, tetrahydropyridinyl, piperazinyl, 4,7-diazaspiro[2.5]octanyl, - C(O)Ra2, -C(O)C(O)Ra2, -C(O)NRc2Rd2, and -C(O)C(O)NRc2Rd2, wherein the methyl, isopropyl, trifluoromethyl, tetrahydropyridinyl, piperazinyl, and 4,7-diazaspiro[2.5]octanyl of R2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein each Ra2, Rc2, and Rd2is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl of Ra2, Rc2, and Rd2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

23. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein each Ra2, Rc2, and Rd2is independently selected from H, C1-6 alkyl, and C3-7 cycloalkyl, wherein the C1-6 alkyl and C3-7 cycloalkyl of Ra2, Rc2, and Rd2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

24. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein each Ra2, Rc2, and Rd2is independently selected from methyl, isopropyl, and cyclopropyl, wherein the methyl, isopropyl, and cyclopropyl of Ra2, Rc2, and Rd2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents.

25. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein each R2Ais independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6haloalkyl, -CN, -ORa2A, -C(O)Ra2A, -C(O)C(O)Ra2A, - C(O)NRc2ARd2A, and -C(O)C(O)NRc2ARd2A, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci-6 haloalkyl of R2Aare each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; and each Ra2A, Rc2A, and Rd2Ais independently selected from H, Ci-6 alkyl, and C3- 10 cycloalkyl, wherein the Ci-6 alkyl and C3-10 cycloalkyl groups are each optionally substituted with C1-4 alkoxy or -CN.

26. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein each R2Ais independently selected from Ci-6 alkyl, Ci-6 haloalkyl, -CN, -ORa2A, -C(O)Ra2A, -C(O)C(O)Ra2A, -C(O)NRc2ARd2A, - C(O)C(O)NRc2ARd2A, wherein the Ci-6 alkyl is optionally substituted with Ci-4 alkoxy; and each Ra2A, Rc2A, and Rd2Ais independently selected from H, Ci-6 alkyl, and C3- 7 cycloalkyl, wherein the C1-6 alkyl and C3-7 cycloalkyl groups are each optionally substituted with C1-4 alkoxy or -CN.

27. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein each R2Ais independently selected from methyl, methoxymethyl, trifluoromethyl, -CN, methoxy, -C(O)isopropyl, -C(O)(methoxycyclopropyl), - C(O)(cyanocyclopropyl), -C(O)N(CH3)2, -C(O)C(O)N(CH3)2, and -C(O)C(O)i sopropyl .

28. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein each Ra2, Rc2, and Rd2is independently selected from methyl, isopropyl, cyclopropyl, cyanocyclopropyl, and methoxy cyclopropyl.

29. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R2is selected from H, fluoro, chloro, bromo, methyl, methoxymethyl, isopropyl, trifluoromethyl, dimethylpiperazinyl, 4,7- di azaspiro [2.5 ]octanyl, cyclopropylcarbonyl, (methoxycyclopropyl)carbonyl, (cyanocyclopropyl)carbonyl, (dimethylamino)carbonyl, (dimethylaminocarbonyl)piperazinyl, (dimethylaminocarbonyl)(methyl)piperazinyl, (isopropylcarbonyl)(methyl)piperazinyl, (isopropylcarbonyl)carbonyl(methyl)piperazinyl, and (dimethylaminocarbonyl)carbonyl(methyl)piperazinyl.

30. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein Ring31. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein m is 0.

32. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein Y1is N.

33. The compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein Y2is C.

34. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein Y3is CH or N.

35. The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein Ring C is 5-10 membered heterocycloalkyl or 5-6 membered heteroaryl.

36. The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein Ring C is 5-7 membered heterocycloalkyl or 5-6 membered heteroaryl.

37. The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein Ring C is selected38. The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein Ring C is selected from39. The compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein X3is C.

40. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein Ring A is a 6-membered heteroaryl.

41. The compound of any one of claims 1 to 29 and 40, or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1.

42. The compound of any one of claims 1 to 29, 40, and 41, or a pharmaceutically acceptable salt thereof, wherein Ring A is a 6-membered heteroaryl selected from43. The compound of any one of claims 1 to 30 and 32 to 42, wherein each L3is independently selected from a bond, Ci-6 alkylene, -O-, and -N(RL)-, wherein each RLis independently selected from H and Ci-6 alkyl.

44. The compound of any one of claims 1 to 30 and 32 to 42, wherein each L3is independently selected from a bond, -O-, and -NH-.

45. The compound of any one of claims 1 to 30 and 32 to 44, wherein each R3is independently selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, C2-e alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, - ORa3, -SRa3, and -NRc3Rd3, wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents.

46. The compound of any one of claims 1 to 30 and 32 to 44, wherein each R3is independently selected from H, C1-6 alkyl, 4-10 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)- C1-4 alkyl, (5-6 membered heteroaryl)-Ci-4 alkyl, -ORa3, -SR33, and -NRc3Rd3, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4- 10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; and each Ra3, Rc3, and Rd3is independently selected from H and C1-6 alkyl.

47. The compound of any one of claims 1 to 30 and 32 to 44, wherein each R3is independently selected from H, methyl, methoxy, methylthio, amino, cyclopentylmethyl, azetidinyl, 3-oxotetrahydro-3H-oxazolo[3,4-a]pyrazin-7(lH)-yl, tetrahydro- lH-pyrrolizin-7a(5H)-ylmethyl, and pyrazolyl, wherein the methyl, cyclopentylmethyl, azetidinyl, 3-oxotetrahydro-3H-oxazolo[3,4-a]pyrazin-7(lH)-yl, and tetrahydro- lH-pyrrolizin-7a(5H)-ylmethyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents.

48. The compound of any one of claims 1 to 30 and 32 to 47, wherein each R3Ais independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and -CN, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10membered heteroaryl of R3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents.

49. The compound of any one of claims 1 to 30 and 32 to 47, wherein each R3Ais independently selected from H, Ci-6 alkyl, C3-7 cycloalkyl, and -CN, wherein the C1-6 alkyl and C3-7 cycloalkyl of R3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents.

50. The compound of any one of claims 1 to 30 and 32 to 47, wherein each R3Ais independently selected from methyl, cyclobutyl, and -CN, wherein the methyl and cyclobutyl of R3Aare each optionally substituted with 1 or 2 RGsubstituents independently selected from OH and cyano-Ci-4 alkyl.

51. The compound of any one of claims 1 to 30 and 32 to 47, wherein each R3Ais independently selected from methyl, hydroxymethyl, and (cyanomethyl)cyclobutyl.

52. The compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, wherein Ring B is 5-10 membered heteroaryl.

53. The compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, wherein Ring B is 5-6 membered heteroaryl.

54. The compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, wherein Ring B is thiadiazolyl.

55. The compound of any one of claims 1 to 54, or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3.

56. The compound of any one of claims 1 to 55, or a pharmaceutically acceptable salt thereof, wherein each R4is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-e alkynyl, and C1-6 haloalkyl.

57. The compound of any one of claims 1 to 55, or a pharmaceutically acceptable salt thereof, wherein each R4is independently selected from halo, C1-6 alkyl and C1-6 haloalkyl.

58. The compound of any one of claims 1 to 55, or a pharmaceutically acceptable salt thereof, wherein each R4is independently selected from Ci-6 haloalkyl.

59. The compound of any one of claims 1 to 55, or a pharmaceutically acceptable salt thereof, wherein each R4is difluoromethyl.

60. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: m is 0 or 1; n is 1, 2, or 3;X1is N or CH;X2is N or CH;X3is C or N;Z is O;Ring A is a 6-membered heteroaryleach = is independently a single or double bond;Y1is C or N;Y2is C or N;Y3is C(-L3-R3), or N;Ring B is Ce-io aryl or 5-10 membered heteroaryl;Ring C is C5-10 cycloalkyl, phenyl, 5-10 membered heterocycloalkyl, or 5-6 membered heteroaryl; each L2and L3is independently selected from bond, C1-6 alkylene, C1-6 haloalkylene, C3-7 cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6 membered heteroarylene, -C3-7 cycloalkylene-Ci-4 alkyl-, -(4-7 memberedheterocycloalkylene)-Ci-4 alkyl-, -phenylene-Ci-4 alkyl-, -(5-6 membered heteroarylene)-Ci-4alkyl-, -0-, -N(RL)-, -C(0)-, -N(RL)C(O)-, -N(RL)C(O)N(RL)-, - N(RL)C(O)O-, -S(0)-, -S(0)2-, -S(O)(=NRL)-, -S(O)2N(RL)-, and -N(RL)S(O)2N(RL)-, wherein the Ci-6 alkylene, Ci-6 haloalkylene, C3-7 cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6 membered heteroarylene, C3-7 cycloalkylene-Ci-4 alkyl, (4-7 membered heterocycloalkylene)-Ci-4 alkyl, -phenylene-Ci-4 alkyl-, and (5- 6 membered heteroarylene)-Ci-4 alkyl of L2and L3are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; each RLis independently selected from H, C1-6 alkyl, and C1-6 haloalkyl;R1is selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci- 4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci- 4 alkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;R2is selected from H, oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, - ORa2, -SRa2, -NRc2Rd2, -NO2, -C(O)Ra2, -C(O)C(O)Ra2, -C(O)ORa2, -C(O)NRc2Rd2, - C(O)C(O)NRc2Rd2, -C(O)NRc2(ORa2), -OC(O)Ra2, -OC(O)NRc2Rd2, -OC(O)ORa2, - OS(O)2Rb2, -OS(O)2NRc2Rd2, -NRc2C(O)Ra2, -NRc2C(O)ORa2, -NRc2C(O)NRc2Rd2, - NRc2S(O)2Rb2, -NRc2S(O)2NRc2Rd2, -NRc2ORa2, -NRc2S(O)Rb2, -NRc2S(O)NRc2Rd2, - S(O)Rb2, -S(O)2Rb2, -S(O)NRc2Rd2, -S(O)2NRc2Rd2, -C(=NRe2)Ra2, - C(=NRe2)NRc2Rd2, -NRc2C(=NRe2)Ra2, -NRc2C(=NRe2)NRc2Rd2, - NRc2S(O)(=NRe2)Rb2, -NRc2S(O)(=NRe2)NRc2Rd2, -OS(O)(=NRe2)Rb2, - S(O)(=NRe2)Rb2, -S(O)(=NRe2)NRc2Rd2, -C(O)NRc2S(O)2Rb2, - C(O)NRc2S(O)2NRc2Rd2, -S(O)2NRc2C(O)Rb2, and -NRc2S(O)NRc2C(O)Rb2, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4- 10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10membered heteroaryl)-Ci-4 alkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; each Ra2, Rc2, and Rd2is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra2, Rc2, and Rd2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; or, any Rc2and Rd2attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; each Rb2is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; each Re2is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R2Ais independently selected from oxo, H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, -CN, -ORa2A, -SRa2A, -NRc2ARd2A, -NO2, -C(O)Ra2A, -C(O)C(O)Ra2A, - C(O)ORa2A, -C(O)NRc2ARd2A, -C(O)C(O)NRc2ARd2A, -C(O)NRc2A(ORa2A), - OC(O)Ra2A, -OC(O)NRc2ARd2A, -OC(O)ORa2A, -OS(O)2Rb2A, -OS(O)2NRc2ARd2A, - NRc2AC(O)Ra2A, -NRc2AC(O)ORa2A, -NRc2AC(O)NRc2ARd2A, -NRc2AS(O)2Rb2A, - NRc2AS(O)2NRc2ARd2A, -NRc2AORa2A, -NRc2AS(O)Rb2A, -NRc2AS(O)NRc2ARd2A, - S(O)Rb2A, -S(O)2Rb2A, -S(O)NRc2ARd2A, -S(O)2NRc2ARd2A, -C(=NRe2A)Ra2A, - C(=NRe2A)NRc2ARd2A, -NRc2AC(=NRe2A)Ra2A, -NRc2AC(=NRe2A)NRc2ARd2A, - NRc2AS(O)(=NRe2A)Rb2A, -NRc2AS(O)(=NRe2A)NRc2ARd2A, -OS(O)(=NRe2A)Rb2A, - S(O)(=NRe2A)Rb2A, -S(O)(=NRe2A)NRc2ARd2A, -C(O)NRc2AS(O)2Rb2A, - C(O)NRc2AS(O)2NRc2ARd2A, -S(O)2NRc2AC(O)Rb2A, and -NRc2AS(O)NRc2AC(O)Rb2A, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of R2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra2A, Rc2A, and Rd2Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra2A, Rc2A, and Rd2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc2Aand Rd2Aattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;each Rb2Ais independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Re2Ais independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R3is independently selected from oxo, H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, -CN, -ORa3, -SRa3, -NRc3Rd3, -NO2, -C(O)Ra3, -C(O)ORa3, -C(O)NRc3Rd3, -S(O)2NRc3C(O)Rb3, and -NRc3S(O)NRc3C(O)Rb3, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents;each Ra3, Rc3, and Rd3is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; or, any Rc3and Rd3attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; each Rb3is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each Re3is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl,4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R3Ais independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, and -CN, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of R3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each R4is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, (5-6 membered heteroaryl)-Ci-4 alkyl, -CN, -ORa4, -SRa4, -NRc4Rd4, -NO2, -C(O)Ra4, -C(O)ORa4, -C(O)NRc4Rd4, -C(O)NRc4(ORa4), -OC(O)Ra4, -OC(O)NRc4Rd4, -OC(O)ORa4, -OS(O)2Rb4, -OS(O)2NRc4Rd4, -NRc4C(O)Ra4, - NRc4C(O)ORa4, -NRc4C(O)NRc4Rd4, -NRc4S(O)2Rb4, -NRc4S(O)2NRc4Rd4, -NRc4ORa4, -NRc4S(O)Rb4, -NRc4S(O)NRc4Rd4, -S(O)Rb4, -S(O)2Rb4, -S(O)NRc4Rd4, -n the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of R4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra4, Rc4, and Rd4is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci- 4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of Ra4, Rc4, and Rd4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc4and Rd4attached to the same N atom, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group, wherein the 4- 7 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rb4is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of Rb4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;each Re4is independently selected from H, OH, CN, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl; each RGis independently selected from OH, CN, halo, oxo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, cyano-Ci-4 alkyl, HO-C1-4 alkyl, C1-4 alkoxy-Ci-4 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-3 alkylamino, di(Ci-3 alkyl)amino, thio, C1-3 alkylthio, C1-3 alkylsulfinyl, Ci- 3 alkyl sulfonyl, carbamyl, C1-3 alkylcarbamyl, di(Ci-3 alkyl)carbamyl, carboxy, C1-3 alkylcarbonyl, C1-3 alkoxycarbonyl, C1-3 alkylcarbonyloxy, C1-3 alkylcarbonylamino, C1-3 alkoxy carbonylamino, aminocarbonyloxy, C1-3 alkylaminocarbonyloxy, di (C 1-3 alkyl)aminocarbonyloxy, C1-3 alkylsulfonylamino, aminosulfonyl, C1-3 alkylaminosulfonyl, di(Ci-3 alkyl)aminosulfonyl, aminosulfonylamino, C1-3 alkylaminosulfonylamino, di (C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C1-3 alkylaminocarbonylamino, and di(Ci-3 alkyl)aminocarbonylamino.

61. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: m is 0 or 1; n is 1 or 2;X1is N or CH;X2is N or CH;X3is C or N;Z is O;Ring A is a 6-membered heteroaryleach = is independently a single or double bond;Y1is C or N;Y2is C or N;Y3is CH, or N;Ring B is Ce-io aryl or 5-10 membered heteroaryl;Ring C is 5-7 membered heterocycloalkyl or 5-6 membered heteroaryl;L2is selected from a bond, C3-7 cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6 membered heteroarylene, -C3-7 cycloalkylene-Ci- 4 alkyl-, -(4-7 membered heterocycloalkylene)-Ci-4 alkyl-, -phenylene-Ci-4 alkyl-, and -(5-6 membered heteroarylene)-Ci-4 alkyl-, wherein the C3-7 cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6 membered heteroarylene, -C3-7 cycloalkylene-Ci-4 alkyl-, -(4-7 membered heterocycloalkylene)-Ci-4 alkyl-, - phenylene-Ci-4 alkyl-, and -(5-6 membered heteroarylene)-Ci-4 alkyl- of L2are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; each L3is independently selected from a bond, C1-6 alkylene, -O-, and -N(RL)-; each RLis independently selected from H and C1-6 alkyl;R1is selected from C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci-4 alkyl, wherein C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C3-6 cycloalkyl-Ci-4 alkyl, and (4-7 membered heterocycloalkyl)-Ci-4 alkyl of R1are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents;R2is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, -C(O)Ra2, -C(O)C(O)Ra2, -C(O)ORa2, -C(O)NRc2Rd2, - C(O)C(O)NRc2Rd2, -C(O)NRc2(ORa2), -OC(O)Ra2, -OC(O)NRc2Rd2, -NRc2C(O)Ra2, - NRc2C(O)ORa2, and -NRc2C(O)NRc2Rd2, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl of R2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents; each Ra2, Rc2, and Rd2is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl of Ra2, Rc2, and Rd2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents;each R2Ais independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6haloalkyl, -CN, -ORa2A, -C(O)Ra2A, -C(O)C(O)Ra2A, -C(O)NRc2ARd2A, and -C(O)C(O)NRc2ARd2A, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of R2Aare each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; each Ra2A, Rc2A, and Rd2Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-10 cycloalkyl of Ra2A, Rc2A, and Rd2Aare each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; each R3is independently selected from H, C1-6 alkyl, 4-10 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-6 membered heteroaryl)-Ci-4 alkyl, -ORa3, -SRa3, and -NRc3Rd3, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; each Ra3, Rc3, and Rd3is independently selected from H and C1-6 alkyl; each R3Ais independently selected from H, C1-6 alkyl, C3-7 cycloalkyl, and - CN, wherein the C1-6 alkyl and C3-7 cycloalkyl of R3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each R4is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; each RGis independently selected from OH, CN, halo, oxo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, cyano-Ci-4 alkyl, HO-C1-4 alkyl, C1-4 alkoxy, and C1-4 alkoxy-Ci-4 alkyl.

62. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: n is 1 or 2;X1is N or CH;X2is N or CH;X3is C or N;Z is O;Ring A is a 6-membered heteroaryl selected fromeach = is independently a single or double bond;Y1is C or N;Y2is C or N;Y3is CH, or N;Ring B is 5-6 membered heteroaryl;Ring C is 5-7 membered heterocycloalkyl or 5-6 membered heteroaryl;L2is selected from a bond and 4-7 membered heterocycloalkylene, wherein the 4-7 membered heterocycloalkylene of L2is optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents;R1is selected from C3-6 cycloalkyl, and C3-6 cycloalkyl-Ci-4 alkyl, wherein the C3-6 cycloalkyl and C3-6 cycloalkyl-Ci-4 alkyl of R1are each optionally substituted with 1 or 2 independently selected RGsubstituents;R2is selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, 4-10 membered heterocycloalkyl, -C(O)Ra2, -C(O)C(O)NRc2Rd2, -C(O)NRc2Rd2, and - C(O)C(O)NRc2Rd2, wherein the C1-6 alkyl, C1-6 haloalkyl, and 4-10 membered heterocycloalkyl of R2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents;each Ra2, Rc2, and Rd2is independently selected from H, Ci-6 alkyl, and C3-7 cycloalkyl, wherein the C1-6 alkyl and C3-7 cycloalkyl of Ra2, Rc2, and Rd2are each optionally substituted with 1, 2, 3, or 4 independently selected R2Asubstituents; each R2Ais independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6haloalkyl, -CN, -ORa2A, -C(O)Ra2A, -C(O)C(O)Ra2A, -C(O)NRc2ARd2A, and -C(O)C(O)NRc2ARd2A, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of R2Aare each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; each Ra2A, Rc2A, and Rd2Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-10 cycloalkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-10 cycloalkyl groups are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; each R4is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; each RGis independently selected from OH, CN, halo, oxo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, cyano-Ci-4 alkyl, HO-C1-4 alkyl, C1-4 alkoxy, and C1-4 alkoxy-Ci-4 alkyl.

63. The compound of claim 1, wherein the compound of Formula I is a compound of Formula II:II or a pharmaceutically acceptable salt thereof.

64. The compound of claim 1, wherein the compound of Formula I is a compound of Formula III:III or a pharmaceutically acceptable salt thereof.

65. The compound of claim 1 or 2, wherein the compound of Formula I is a compound of Formula VIII:VIII or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1.

66. The compound of claim 1 or 2, wherein the compound of Formula I is a compound of Formula IX:or a pharmaceutically acceptable salt thereof.

67. The compound of claim 1 or 2, which is selected from:9-chloro-5-(5-(difhroromethyl)-l,3,4-thiadiazol-2-yl)-N-(l- methylcyclopropyl)pyrazolo[l,5-a]quinazoline-7-sulfonamide;5-(5-(difhroromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)-9- (l,2,3,6-tetrahydropyridin-4-yl)pyrazolo[l,5-a]quinazoline-7-sulfonamide;5-(5-(difhroromethyl)-l,3,4-thiadiazol-2-yl)-9-(l-methyl-l,2,3,6- tetrahydropyridin-4-yl)-N-(l-methylcyclopropyl)pyrazolo[l,5-a]quinazoline-7- sulfonamide;5-(5-(difhroromethyl)-l,3,4-thiadiazol-2-yl)-9-(l-(l-methoxycyclopropane-l- carbonyl)-l,2,3,6-tetrahydropyridin-4-yl)-N-(l-methylcyclopropyl)pyrazolo[l,5- a]quinazoline-7-sulfonamide;5-(5-(difhroromethyl)-l,3,4-thiadiazol-2-yl)-9-fluoro-N-(l- methylcyclopropyl)pyrazolo[l,5-a]quinazoline-7-sulfonamide;(R)-5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)-9- (3-methylpiperazin-l-yl)pyrazolo[l,5-a]quinazoline-7-sulfonamide;(R)-5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-9-(3,4-dimethylpiperazin-l- yl)-N-(l-methylcyclopropyl)pyrazolo[l,5-a]quinazoline-7-sulfonamide;(R)-4-(5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-7-(N-(l- methylcyclopropyl)sulfamoyl)pyrazolo[l,5-a]quinazolin-9-yl)-N,N,2- trimethylpiperazine- 1 -carboxamide;(R)-9-(4-(cyclopropanecarbonyl)-3-methylpiperazin-l-yl)-5-(5- (difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)pyrazolo[l,5- a]quinazoline-7-sulfonamide;(R)-5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-9-(4-(l- methoxy cyclopropane- 1 -carbonyl)-3 -methylpiperazin- 1 -yl)-N-( 1 - methylcyclopropyl)pyrazolo[l,5-a]quinazoline-7-sulfonamide;(R)-9-(4-( 1 -cyanocyclopropane- 1 -carbonyl)-3 -methylpiperazin- 1 -y 1 )- 5 -(5 - (difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)pyrazolo[l,5- a]quinazoline-7-sulfonamide;9-bromo-5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l- methylcyclopropyl)- 1 ,2-dihydroimidazo[ 1 ,2-a]quinoline-7-sulfonamide;5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)-9- (piperazin-l-yl)pyrazolo[l,5-a]quinazoline-7-sulfonamide;5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)-9-(4- methylpiperazin-l-yl)pyrazolo[l,5-a]quinazoline-7-sulfonamide;4-(5-(5 -(difluoromethyl)- 1 ,3 ,4-thiadiazol-2-yl)-7-(N-( 1 - methylcyclopropyl)sulfamoyl)pyrazolo[l,5-a]quinazolin-9-yl)-N,N- dimethylpiperazine-1 -carboxamide;(R)-5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-9-(3-isopropylpiperazin-l- yl)-N-(l-methylcyclopropyl)pyrazolo[l,5-a]quinazoline-7-sulfonamide;(S)-5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-9-(3-(methoxymethyl)piperazin- 1 -yl)-N-( 1 -methylcy clopropyl)pyrazolo[ 1 , 5-a]quinazoline- 7-sulfonamide;5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)-9-(4,7- diazaspiro[2.5]octan-7-yl)pyrazolo[l,5-a]quinazoline-7-sulfonamide; and5-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)-9-(3- (trifluoromethyl)piperazin-l-yl)pyrazolo[l,5-a]quinazoline-7-sulfonamide; or a pharmaceutically acceptable salt thereof.

68. The compound of claim 1, which is selected from:4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin- l-yl)-N-(l -methylcy clopropyl)quinazoline-6-sulfonamide;4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin- l-yl)-N-(l-methylcyclopropyl)-2-(methylthio)quinazoline-6-sulfonamide;4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin- l-yl)-2-(l-methyl-lH-pyrazol-4-yl)-N-(l-methylcyclopropyl)quinazoline-6- sulfonamide;4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin- l-yl)-2-((l-methyl-lH-pyrazol-4-yl)oxy)-N-(l-methylcyclopropyl)quinazoline-6- sulfonamide;2-amino-4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)quinazoline-6-sulfonamide;2-(3-cyanoazetidin-l-yl)-4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)quinazoline-6- sulfonamide;4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin- l-yl)-N-(l-methylcyclopropyl)-2-(3-oxotetrahydro-3H-oxazolo[3,4-a]pyrazin-7(lH)- yl)quinazoline-6-sulfonamide;2-(l-(l-(cyanomethyl)cyclobutyl)-lH-pyrazol-4-yl)-4-(5-(difluoromethyl)- l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin-l-yl)-N-(l- methylcyclopropyl)quinazoline-6-sulfonamide;4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin- l-yl)-N-(l-methylcyclopropyl)-2-((tetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)quinazoline-6-sulfonamide;4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin- l-yl)-2-methoxy-N-(l-methylcyclopropyl)quinazoline-6-sulfonamide;4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin- l-yl)-2-((l-(hydroxymethyl)cyclopentyl)methoxy)-N-(l- methylcyclopropyl)quinazoline-6-sulfonamide;4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin- 1 -yl)-2-methyl-N-(l -methylcyclopropyl)- 1 -oxo- 1 ,2-dihydrophthalazine-6- sulfonamide;4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-((3R,5R)-3,5- dimethylpiperazin- 1 -yl)-2-methyl-N-( 1 -methylcyclopropyl)- 1 -oxo- 1 ,2- dihydrophthalazine-6-sulfonamide;4-(l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-3-methyl-7-(N-(l- methylcyclopropyl)sulfamoyl)-4-oxo-3,4-dihydrophthalazin-5-yl)-N,N- dimethylpiperazine-1 -carboxamide;(R)-4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-(4-isobutyryl-3- methylpiperazin- 1 -yl)-2-methyl-N-( 1 -methylcyclopropyl)- 1 -oxo- 1,2- dihydrophthalazine-6-sulfonamide;(R)-4-(l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-3-methyl-7-(N-(l- methylcyclopropyl)sulfamoyl)-4-oxo-3,4-dihydrophthalazin-5-yl)-N,N,2- trimethylpiperazine- 1 -carboxamide;(R)-2-(4-(l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-3-methyl-7-(N-(l- methylcyclopropyl)sulfamoyl)-4-oxo-3,4-dihydrophthalazin-5-yl)-2-methylpiperazin- l-yl)-N,N-dimethyl-2-oxoacetamide; and(R)-4-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-2-methyl-8-(3-methyl-4-(3- methyl-2-oxobutanoyl)piperazin- 1 -yl)-N-(l -methylcyclopropyl)- 1 -oxo- 1 ,2- dihydrophthalazine-6-sulfonamide; or a pharmaceutically acceptable salt thereof.

69. A pharmaceutical composition, comprising a compound of any one of claims 1 to 68, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

70. A method of inhibiting an activity of poly(ADP-ribose) glycohydrolase, comprising contacting the poly(ADP-ribose) glycohydrolase with a compound of any one of claims 1 to 68, or a pharmaceutically acceptable salt thereof.

71. A method of treating a poly(ADP-ribose) glycohydrolase-mediated disease or disorder in a patient, comprising administering to the patient a therapeuticallyeffective amount of a compound of any one of claims 1 to 68, or a pharmaceutically acceptable salt thereof.

72. The method of claim 71, wherein the disease or disorder is a cancer.

73. The method of claim 72, wherein the cancer is selected from skin cancer, ovarian cancer, fallopian tube cancer, gastric cancer, colorectal cancer, breast cancer, prostate cancer, uterine cancer, pancreatic cancer, lung cancer, melanoma, brain cancer, bladder cancer, head and neck cancer, sarcoma, liver cancer, bile duct cancer, kidney cancer, lymphoma, and leukemia.

74. The method of claim 72, wherein the cancer is selected from ovarian cancer, colorectal cancer, breast cancer, prostate cancer, uterine cancer, and pancreatic cancer.

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