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] 54057-0031W01 / SNV-0023W01 PATENT

[0002] HETEROCYCLIC COMPOUNDS AS PARG INHIBITORS 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 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.

[0005] Development of highly potent, selective, and efficacious poly(ADP-ribose) glycohydrolase (PARG) inhibitors represents a promising avenue for targeted cancer therapy.

[0006] SUMMARY

[0007] The present disclosure provides, inter alia, compounds of Formula I:

[0008]

[0009] I

[0010] or pharmaceutically acceptable salts thereof, wherein constituent members are defined herein.

[0011] 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.

[0012] 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. 54057-0031WO1 / SNV0023-W01 PATENT

[0013] 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.

[0014] The present disclosure further provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.

[0015] 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.

[0016] DETAILED DESCRIPTION

[0017] The present application provides a compound of Formula I:

[0018]

[0019] or a pharmaceutically acceptable salt thereof, wherein:

[0020] X1is N or CR5;

[0021] X2is N or CR6;

[0022] X3is N or C(-L2-R2);

[0023] Z is O or NR7; 54057-0031W01 / SNV0023-W01 PATENT

[0024]

[0025] each = is independently a single or double bond;

[0026] * denotes attachment to X1;

[0027] m is 0, 1, 2, 3, 4, 5, or 6;

[0028] n is 0, 1, 2, 3, 4, 5, or 6;

[0029] p is 1, 2, 3, or 4;

[0030] X4is C(-L3-R3) orN;

[0031] X5is C(-L3-R3) orN;

[0032] X6is C(-L3-R3) orN;

[0033] X7is C(-L3-R3) orN;

[0034] X8is C(-L3-R3) orN;

[0035] X9is C(-L3-R3) orN;

[0036] Y1is C orN;

[0037] Y2is C orN;

[0038] Ring B is selected from C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl;

[0039] Ring C is selected from C5-10 cycloalkyl, phenyl, 5-10 membered heterocycloalkyl, and 5-6 membered heteroaryl; 54057-0031W01 / SNV0023-W01 PATENT

[0040] each L1is independently selected from Ci-6 alkylene, Ci-6 haloalkylene, -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 and Ci-6 haloalkylene of L1are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; each L2and L3is independently selected from bond, 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-, -(5-6 membered heteroarylene)-Ci-4 alkyl-, -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;

[0041] 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;

[0042] 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;

[0043] 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;

[0044] each RLis independently selected from H, 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) -C1-4 alkyl of RLare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0045] R1is selected from -CN, C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, and 4-7 membered heterocycloalkyl, wherein the C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, and 4-7 membered heterocycloalkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; 54057-0031W01 / SNV0023-W01 PATENT

[0046] Rlaand Rlbare each independently C1-3 alkyl, wherein the C1-3 alkyl of Rlaand Rlbis optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0047] or, Rlaand Rlb, together with the carbon atom to which they are attached, form a C3-4 cycloalkyl group, wherein the C3-4 cycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0048] 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.4alkyl, -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;

[0049] 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) -C 1-4 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;

[0050] 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;

[0051] 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 54057-0031W01 / SNV0023-W01 PATENT

[0052] 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-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 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;

[0053] 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-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;

[0054] 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-Ci-4 alkyl, Ce-io aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 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;

[0055] 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, 54057-0031W01 / SNV0023-W01 PATENT

[0056] (4-10 membered heterocycloalkyl) -C 1-4 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;

[0057] 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;

[0058] 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-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 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;

[0059] 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-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;

[0060] each R3is independently 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, 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)Rf3Rg3, 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 54057-0031W01 / SNV0023-W01 PATENT

[0061] heteroaryl)-Ci-4 alkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents;

[0062] 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, 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) -C 1-4 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;

[0063] 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;

[0064] 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-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 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;

[0065] 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-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;

[0066] each Rf3and Rg3are independently selected from C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and, C1-6 haloalkoxy;

[0067] 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, -C(O)ORa3A, -C(O)NRc3ARd3A, - 54057-0031W01 / SNV0023-W01 PATENT

[0068] C(O)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 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-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 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;

[0069] 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) -C 1-4 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;

[0070] 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;

[0071] 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-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 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; 54057-0031W01 / SNV0023-W01 PATENT

[0072] each Re3Ais 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-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;

[0073] each R4is independently selected from 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, -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, -NRc4S(O)NRc4C(O)Rb4, and -P(O)Rf4Rg4, 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 R4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R4Asubstituents;

[0074] each Ra4, Rc4, and Rd4is 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) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra4, Rc4, and Rd4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R4Asubstituents;

[0075] or, any Rc4and Rd4attached 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 R4Asubstituents;

[0076] each Rb4is 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 54057-0031W01 / SNV0023-W01 PATENT

[0077] 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-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Rb4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R4Asubstituents;

[0078] 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, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;

[0079] each Rf4and Rg4are independently selected from H, 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-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;

[0080] each R4Ais 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, -ORa4A, -SRa4A, -NRc4ARd4A, -NO2, -C(O)Ra4A, -C(O)ORa4A, -C(O)NRc4ARd4A, -C(O)NRc4A(ORa4A), -OC(O)Ra4A, -OC(O)NRc4ARd4A, -OC(O)ORa4A, -OS(O)2Rb4A, -OS(O)2NRc4ARd4A, -NRc4AC(O)Ra4A, -NRc4AC(O)ORa4A, -NRc4AC(O)NRc4ARd4A, -NRc4AS(O)2Rb4A, -NRc4AS(O)2NRc4ARd4A, -NRc4AORa4A, -NRc4AS(O)Rb4A, -NRc4AS(O)NRc4ARd4A, -S(O)Rb4A, -S(O)2Rb4A, -S(O)NRc4ARd4A, -S(O)2NRc4ARd4A, -C(=NRe4A)Ra4A, -C(=NRe4A)NRc4ARd4A, -NRc4AC(=NRe4A)Ra4A, -NRc4AC(=NRe4A)NRc4ARd4A, -NRc4AS(O)(=NRe4A)Rb4A, -NRc4AS(O)(=NRe4A)NRc4ARd4A, -OS(O)(=NRe4A)Rb4A, -S(O)(=NRe4A)Rb4A, -S(O)(=NRe4A)NRc4ARd4A, -C(O)NRc4AS(O)2Rb4A, -C(O)NRc4AS(O)2NRc4ARd4A, -S(O)2NRc4AC(O)Rb4A, -NRc4AS(O)NRc4AC(O)Rb4A, and -P(O)Rf4ARg4A, 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) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R4Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; 54057-0031W01 / SNV0023-W01 PATENT

[0081] each Ra4A, Rc4A, and Rd4Ais 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) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra4A, Rc4A, and Rd4Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0082] or, any Rc4Aand Rd4Aattached 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;

[0083] each Rb4Ais 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-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Rb4Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0084] each Re4Ais 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-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;

[0085] each Rf4Aand Rg4Aare independently selected from H, 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-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;

[0086] R5is selected from H, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C 1-4 haloalkoxy, and -CN;

[0087] R6is selected from H, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C 1-4 haloalkoxy, and -CN; 54057-0031W01 / SNV0023-W01 PATENT

[0088] R7is selected from H, CN, ORa7, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;

[0089] 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;

[0090] Ra7is selected from H, C1-6 alkyl, and C1-6 haloalkyl;

[0091] 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, C1-3 alkylsulfonyl, carbamyl, C1-3 alkylcarbamyl, di(Ci-3 alkyl)carbamyl, carboxy, C1-3 alkylcarbonyl, C1-3 alkoxycarbonyl, C1-3 alkylcarbonyloxy, C1-3 alkylcarbonylamino, C1-3 alkoxycarbonylamino, aminocarbonyloxy, C1-3 alkylaminocarbonyloxy, di(Ci-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.

[0092] In some embodiments, X1is N.

[0093] In some embodiments, X1is CR5.

[0094] In some embodiments, R5is H or C1-6 alkyl.

[0095] In some embodiments, R5is H or C1-3 alkyl.

[0096] In some embodiments, R5is H.

[0097] In some embodiments, X2is N.

[0098] In some embodiments, X2is CR6.

[0099] In some embodiments, R6is selected from H, halo, and C1-6 alkyl.

[0100] In some embodiments, R6is selected from H, halo, and C1-3 alkyl.

[0101] In some embodiments, R6is H or C1-6 alkyl.

[0102] In some embodiments, R6is H or C1-3 alkyl.

[0103] In some embodiments, R6is H or halo.

[0104] In some embodiments, R6is H or fluoro.

[0105] In some embodiments, R6is H.

[0106] In some embodiments, R6is fluoro.

[0107] In some embodiments:

[0108] X1is CR5; and

[0109] X2is CR6.

[0110] In some embodiments:

[0111] X1is CR5; 54057-0031W01 / SNV0023-W01 PATENT

[0112] X2is CR6;

[0113] R5is H or Ci-6 alkyl; and

[0114] R6is selected from H, halo, and Ci-6 alkyl.

[0115] In some embodiments:

[0116] X1is CR5;

[0117] X2is CR6;

[0118] R5is H or Ci-3 alkyl; and

[0119] R6is selected from H, halo, and C1-3 alkyl.

[0120] In some embodiments:

[0121] X1is CR5;

[0122] X2is CR6;

[0123] R5is H or C1-6 alkyl; and

[0124] R6is H or C1-6 alkyl.

[0125] In some embodiments:

[0126] X1is CR5;

[0127] X2is CR6;

[0128] R5is H or C1-3 alkyl; and

[0129] R6is H or C1-3 alkyl.

[0130] In some embodiments:

[0131] X1is CR5;

[0132] X2is CR6;

[0133] R5is H; and

[0134] R6is H or halo.

[0135] In some embodiments:

[0136] X1is CR5;

[0137] X2is CR6;

[0138] R5is H; and

[0139] R6is H or fluoro.

[0140] In some embodiments X1and X2are each CH.

[0141] In some embodiments X1is CH and X2is CF.

[0142] In some embodiments, X3is N.

[0143] In some embodiments, X3is C(-L2-R2).

[0144] In some embodiments, L2is selected from a bond, 4-7 membered heterocycloalkylene, and 5-6 membered heteroarylene, wherein the 4-7 membered heterocycloalkylene and 5-6 membered heteroarylene of L2are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents. 54057-0031W01 / SNV0023-W01 PATENT

[0145] In some embodiments, L2is selected from a bond, 4-7 membered heterocycloalkylene, and 5-6 membered heteroarylene, wherein the 4-7 membered heterocycloalkylene and 5-6 membered heteroarylene of L2are each optionally substituted with 1 or 2 independently selected RGsubstituents.

[0146] 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.

[0147] 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 or 2 independently selected RGsubstituents.

[0148] 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.

[0149] 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.

[0150] 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 RGsubstituent.

[0151] A RGX N A

[0152] In some embodiments, L2is selected from a bond

[0153]

[0154] and H

[0155] N RGN R2

[0156] In some embodiments, L2is selected from a bond

[0157]

[0158] and H

[0159] In some embodiments, each RGis independently selected from OH, CN, halo, Ci-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and C1.4 haloalkyl.

[0160] In some embodiments, each RGis independently selected from OH, CN, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and C1-4 haloalkyl.

[0161] In some embodiments, each RGis independently selected from C1.4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and C1-4 haloalkyl. 54057-0031W01 / SNV0023-W01 PATENT

[0162] In some embodiments, each RGis independently selected from OH, CN, Ci-4 alkyl, and Ci.4 haloalkyl.

[0163] In some embodiments, each RGis independently selected from OH, CN, and Ci-4 alkyl.

[0164] In some embodiments, each RGis independently selected from C1.4 alkyl and C1-4 haloalkyl.

[0165] In some embodiments, each RGis independently selected from C1.4 alkyl.

[0166] In some embodiments, each RGis methyl.

[0167] In some embodiments, L2is selected from a bond, methylpiperazinyl, morpholinyl, dihydropyranyl, tetrahydropyranyl, methylmorpholinyl, pyrazolyl, and pyrimidinyl.

[0168] In some embodiments, L2is selected from a bond and methylpiperazinyl.

[0169] In some embodiments, R2is selected from H, oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, -CN, C(O)Ra2, and S(O)2Rb2, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, and 4-10 membered heterocycloalkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents.

[0170] In some embodiments, R2is selected from H, oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, -CN, C(O)Ra2, and S(O)2Rb2, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, and 4-10 membered heterocycloalkyl of R2are each optionally substituted with 1, 2, or 3 independently selected R2Asubstituents.

[0171] In some embodiments, R2is selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C(O)Ra2, and S(O)2Rb2, wherein the C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents.

[0172] In some embodiments, R2is selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C(O)Ra2, and S(O)2Rb2, wherein the C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl of R2are each optionally substituted with 1, 2, or 3 independently selected R2Asubstituents.

[0173] In some embodiments, R2is selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 4-10 membered heterocycloalkyl, C(O)Ra2, and S(O)2Rb2, wherein the C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 4-10 membered heterocycloalkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents.

[0174] In some embodiments, R2is selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 4-10 membered heterocycloalkyl, C(O)Ra2, and S(O)2Rb2, wherein the C1-6 alkyl, 54057-0031W01 / SNV0023-W01 PATENT

[0175] Ci-6 haloalkyl, C3-7 cycloalkyl, 4-10 membered heterocycloalkyl of R2are each optionally substituted with 1, 2, or 3 independently selected R2Asubstituents.

[0176] In some embodiments, each Ra2and Rb2is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-10 cycloalkyl.

[0177] In some embodiments, each Ra2and Rb2is independently selected from H, C1-6 alkyl, and C3-10 cycloalkyl.

[0178] In some embodiments, each Ra2and Rb2is independently selected from C1-6 alkyl and C3- 10 cycloalkyl.

[0179] In some embodiments, each Ra2and Rb2is independently selected from C1-6 alkyl and C3-7 cycloalkyl.

[0180] In some embodiments, each Ra2and Rb2is independently selected from C1-3 alkyl and C3-7 cycloalkyl.

[0181] In some embodiments, each Ra2and Rb2is independently selected from methyl and cyclopropyl.

[0182] In some embodiments, R2is selected from H, oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, -CN, C(O)Ra2, and S(O)2Rb2, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, and 4-10 membered heterocycloalkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; and

[0183] each Ra2and Rb2is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and C3- 10 cycloalkyl.

[0184] In some embodiments, R2is selected from H, oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, -CN, C(O)Ra2, and S(O)2Rb2, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, and 4-10 membered heterocycloalkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; and

[0185] each Ra2and Rb2is independently selected from C1-6 alkyl and C3-7 cycloalkyl.

[0186] In some embodiments, R2is selected from H, oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, -CN, C(O)Ra2, and S(O)2Rb2, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, and 4-10 membered heterocycloalkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; and

[0187] each Ra2and Rb2is independently selected from methyl and cyclopropyl.

[0188] In some embodiments, R2is selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C(O)Ra2, and S(O)2Rb2, wherein the C1-6 alkyl, 54057-0031W01 / SNV0023-W01 PATENT

[0189] Ci-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; and

[0190] each Ra2and Rb2is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and C3- 10 cycloalkyl.

[0191] In some embodiments, R2is selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C(O)Ra2, and S(O)2Rb2, wherein the C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; and

[0192] each Ra2and Rb2is independently selected from C1-6 alkyl and C3-7 cycloalkyl.

[0193] In some embodiments, R2is selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C(O)Ra2, and S(O)2Rb2, wherein the C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl of R2are each optionally substituted with 1, 2, or 3 independently selected R2Asubstituents; and

[0194] each Ra2and Rb2is independently selected from methyl and cyclopropyl.

[0195] In some embodiments, R2is selected from H, fluoro, chloro, methyl, difluoromethyl, trifluoromethyl, cyclopropyl, morpholinyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyranyl, tetrahydropyranyl, 2-oxa-7-azaspiro[3.5]nonanyl, 4-oxa-7-azaspiro[2.5]octanyl, cyclopropylcarbonyl, and isopropylsulfonyl, wherein the methyl, cyclopropyl, morpholinyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyranyl, tetrahydropyranyl, 2-oxa-7-azaspiro[3.5]nonanyl, and 4-oxa-7-azaspiro[2.5]octanyl of R2are each optionally substituted with 1, 2, or 3 independently selected R2Asubstituents.

[0196] In some embodiments, R2is selected from H, oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and -CN.

[0197] In some embodiments, R2is selected from H, oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, 4-10 membered heterocycloalkyl, and -CN, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and 4-10 membered heterocycloalkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents.

[0198] In some embodiments, R2is selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, and 4-10 membered heterocycloalkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, and 4-10 membered heterocycloalkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents.

[0199] In some embodiments, R2is selected from H, fluoro, chloro, methyl, difluoromethyl, morpholinyl, piperidinyl, piperazinyl, tetrahydropyridinyl, and 2-oxa-7-azaspiro[3.5]nonanyl, wherein the methyl, morpholinyl, piperidinyl, piperazinyl, tetrahydropyridinyl, and 2-oxa-7-azaspiro[3.5]nonanyl of R2are each optionally substituted with 1, 2, or 3 independently selected R2Asubstituents. 54057-0031W01 / SNV0023-W01 PATENT

[0200] In some embodiments, each R2Ais independently selected from 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, -CN, -ORa2A, and -C(O)Ra2A, wherein each 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 R2Ais optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents.

[0201] In some embodiments, each R2Ais independently selected from C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, -ORa2A, and -C(O)Ra2A, wherein each C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl of R2Ais optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.

[0202] In some embodiments, each R2Ais independently selected from C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, -ORa2A, and -C(O)Ra2A, wherein each C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl of R2Ais optionally substituted with 1, 2, 3, or 4 independently RGsubstituents independently selected from OH and CN.

[0203] In some embodiments, each Ra2Ais 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, and 5-10 membered heteroaryl, wherein each 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 Ra2Ais optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents.

[0204] In some embodiments, each Ra2Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein each C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl of Ra2Ais optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.

[0205] In some embodiments, each Ra2Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein each C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl of Ra2Ais optionally substituted with 1, 2, 3, or 4 independently RGsubstituents independently selected from OH and CN.

[0206] In some embodiments, each R2Ais independently selected from 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, -CN, -ORa2A, and -C(O)Ra2A, wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered 54057-0031W01 / SNV0023-W01 PATENT

[0207] heterocycloalkyl, and 5-10 membered heteroaryl of R2Ais optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; and

[0208] each Ra2Ais 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 each 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 Ra2Ais optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents.

[0209] In some embodiments, each R2Ais independently selected from C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, -ORa2A, and -C(O)Ra2A, wherein each C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl of R2Ais optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; and

[0210] each Ra2Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein each C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl of Ra2Ais optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.

[0211] In some embodiments, each R2Ais independently selected from C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, -ORa2A, and -C(O)Ra2A, wherein each C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl of R2Ais optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents selected from OH and CN; and each Ra2Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein each C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl of Ra2Ais optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents selected from OH and CN.

[0212] In some embodiments, each R2Ais independently selected from methyl, difluoromethyl, methoxy, difluoromethoxy, cyclopropylcarbonyl, cyanocyclopropylcarbonyl, tetrahydrofuranylcarbonyl, pyrazolyl, triazolyl, and thiazolyl.

[0213] In some embodiments, R2is selected from H, fluoro, chloro, methyl, difluoromethyl, trifluoromethyl, cyclopropyl, dihydropyranyl, tetrahydropyranyl, morpholinyl, (difluoromethyl)(methyl)morpholinyl, (hydroxymethyl)(methyl)morpholinyl, (methoxymethyl)(methyl)morpholinyl, (difluoromethoxymethyl)(methyl)morpholinyl, pyrazolylpiperidinyl, triazolylpiperidinyl, (cyclopropylcarbonyl)piperidinyl, thiazolylpiperazinyl, (cyclopropylcarbonyl)(methyl)piperazinyl, 54057-0031W01 / SNV0023-W01 PATENT

[0214] (cyclopropylcarbonyl)(dimethyl)piperazinyl, (cyanocyclopropylcarbonyl)(methyl)piperazinyl, (methyl)(tetrahydrofuranylcarbonyl)piperazinyl, (cyclopropylcarbonyl)tetrahydropyridinyl, 2-oxa-7-azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, cyclopropylcarbonyl, and isopropylsulfonyl.

[0215] In some embodiments, R2is selected from H, fluoro, chloro, methyl, difluoromethyl, morpholinyl, methyhnorpholinyl, (difluoromethyl)(methyl)morpholinyl, (hydroxymethyl)(methyl)morpholinyl, (methoxymethyl)(methyl)morpholinyl, (dimethyl)(methoxymethyl)morpholinyl, (difluoromethoxymethyl)(methyl)morpholinyl, pyrazolylpiperidinyl, triazolylpiperidinyl, (cyclopropylcarbonyl)piperidinyl, thiazolylpiperazinyl, (cyclopropylcarbonyl)(methyl)piperazinyl, (cyclopropylcarbonyl)(dimethyl)piperazinyl, (cyanocyclopropylcarbonyl)(methyl)piperazinyl, (methyl)(tetrahydrofuranylcarbonyl)piperazinyl, (cyclopropylcarbonyl)tetrahydropyridinyl, and 2-oxa-7-azaspiro[3.5]nonanyl.

[0216] In some embodiments, R2is selected from H, halo, and Ci-6 alkyl.

[0217] In some embodiments, R2is selected from H, fluoro, chloro, and methyl.

[0218] In some embodiments, -L2-R2is selected from -H, -F, -Cl, -CH3, -CF2,

[0219]

[0220] H

[0221]

[0222] 54057-0031W01 / SNV0023-W01 PATENT

[0223] In some embodiments, -L2-R2is selected from -H, -F, -Cl, -CH3, -CF2,

[0224]

[0225] H

[0226]

[0227] N

[0228] In some embodiments, -L2-R2is selected from -H

[0229]

[0230] , -F, -Cl, and H

[0231] N "

[0232] In some embodiments, -L2-R2is selected from -H

[0233]

[0234] , -F, -Cl, and H In some embodiments, Z is NR7.

[0235] In some embodiments, Z is O.

[0236] In some embodiments, R1is selected from -CN, C1-3 alkyl, and C1-3 haloalkyl, wherein the C1-3 alkyl and C1-3 haloalkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents.

[0237] In some embodiments, R1is selected from -CN, C1-3 alkyl, and C1-3 haloalkyl In some embodiments, R1is -CN or C1-3 alkyl.

[0238] In some embodiments, R1is C1-3 alkyl, which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents.

[0239] In some embodiments, R1is Ci- 3 alkyl. 54057-0031W01 / SNV0023-W01 PATENT

[0240] In some embodiments, R1is selected from methyl, difluoromethyl, and cyano.

[0241] In some embodiments, R1is methyl.

[0242] In some embodiments, Rlaand Rlbare each independently C1-3 alkyl, wherein the C1-3 alkyl of Rlaand Rlbis optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents.

[0243] In some embodiments, Rlaand Rlb, together with the carbon atom to which they are attached, form a C3-4 cycloalkyl group, wherein the C3-4 cycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents.

[0244] In some embodiments, Rlaand Rlb, together with the carbon atom to which they are attached, form a C3-4 cycloalkyl group, wherein the C3-4 cycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents.

[0245] In some embodiments, Rlaand Rlb, together with the carbon atom to which they are attached, form a C3-4 cycloalkyl group.

[0246] In some embodiments, Rlaand Rlb, together with the carbon atom to which they are attached, form a cyclopropyl group.

[0247] B (R4)n

[0248] In some embodiments, Ring

[0249]

[0250] A is

[0251] In some embodiments, X4is N.

[0252] In some embodiments, X4is C(-L3-R3).

[0253] In some embodiments, wherein X5is N.

[0254] In some embodiments, wherein X5is C(-L3-R3).

[0255] In some embodiments, X6is N.

[0256] In some embodiments, X6is C(-L3-R3). 54057-0031W01 / SNV0023-W01 PATENT

[0257] In some embodiments, Ring A is selected from

[0258]

[0259] In some embodiments, Ring A is

[0260]

[0261] 54057-0031W01 / SNV0023-W01 PATENT

[0262] In some embodiments, Ring

[0263]

[0264] A is

[0265] In some embodiments, Ring

[0266]

[0267] A is

[0268] In some embodiments, Ring

[0269]

[0270] A is In some embodiments, X7is N.

[0271] In some embodiments, X7is C(-L3-R3).

[0272] In some embodiments, X8is N.

[0273] In some embodiments, X8is C(-L3-R3).

[0274] In some embodiments, X9is N.

[0275] In some embodiments, X9is C(-L3-R3).

[0276] R3

[0277] In some embodiments, Ring

[0278]

[0279] A is

[0280] In some embodiments, Ring

[0281]

[0282] A is 54057-0031W01 / SNV0023-W01 PATENT

[0283] In some embodiments, wherein Ring

[0284]

[0285] A is In some embodiments, Y1is N.

[0286] In some embodiments, Y1is C.

[0287] In some embodiments, Y2is N.

[0288] In some embodiments, Y2is C.

[0289] In some embodiments, Ring

[0290]

[0291] A is 54057-0031W01 / SNV0023-W01 PATENT

[0292]

[0293] In some embodiments, Ring C is selected from C5-10 cycloalkyl, 5-10 membered heterocycloalkyl, and 5-6 membered heteroaryl.

[0294] In some embodiments, Ring C is selected from C5-7 cycloalkyl, 5-7 membered heterocycloalkyl, and 5-6 membered heteroaryl. 54057-0031W01 / SNV0023-W01 PATENT

[0295] In some embodiments, Ring C is selected from C5-10 cycloalkyl and 5-10 membered heterocycloalkyl.

[0296] In some embodiments, Ring C is selected from C5-7 cycloalkyl and 5-7 membered heterocycloalkyl.

[0297] In some embodiments, m is 0, 1, 2, 3, or 4.

[0298] In some embodiments, m is 0, 1, 2, or 3.

[0299] In some embodiments, m is 1, 2, or 3.

[0300] In some embodiments, m is 1 or 2.

[0301] I I

[0302] In some embodiments, Ring C is selected from

[0303]

[0304]

[0305] I I

[0306] In some embodiments, Ring C is selected from

[0307]

[0308] R3,

[0309]

[0310] 54057-0031W01 / SNV0023-W01 PATENT

[0311] In some embodiments, Ring C is selected from

[0312]

[0313] I

[0314]

[0315] In some embodiments, Ring C is

[0316] I

[0317] In some embodiments, Ring

[0318]

[0319] C is

[0320] In some embodiments, Ring

[0321]

[0322] C is

[0323] In some embodiments, Ring

[0324]

[0325] C is

[0326] l

[0327] In some embodiments, Ring

[0328]

[0329] C is R3 54057-0031W01 / SNV0023-W01 PATENT

[0330] I

[0331] In some embodiments, Ring

[0332]

[0333] C isu

[0334] In some embodiments, each L3is independently selected from a bond, -O-, and -C(O)-.

[0335] In some embodiments, each R3is independently selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, 4-10 membered heterocycloalkyl, -CN, and -ORa3, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and 4-10 membered heterocycloalkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents.

[0336] In some embodiments, each R3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, 4-7 membered heterocycloalkyl, -CN, and -ORa3, wherein the C1-6 alkyl, C1-6 haloalkyl, and 4-7 membered heterocycloalkyl of R3are each optionally substituted with 1, 2, 3, or 4 independently selected R3Asubstituents.

[0337] In some embodiments, each R3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, 4-7 membered heterocycloalkyl, -CN, and -ORa3, wherein the C1-6 alkyl, C1-6 haloalkyl, and 4-7 membered heterocycloalkyl of R3are each optionally substituted with 1 or 2 independently selected R3Asubstituents.

[0338] In some embodiments, each R3is independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, and -ORa3, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents.

[0339] In some embodiments, each R3is independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, and -ORa3.

[0340] In some embodiments, each R3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, -CN, and -ORa3, wherein the C1-6 alkyl and C1-6 haloalkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents.

[0341] In some embodiments, each R3Ais independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl.

[0342] In some embodiments, each R3Ais independently selected from C1-6 alkyl.

[0343] In some embodiments, each R3Ais independently selected from C1-3 alkyl.

[0344] In some embodiments, each R3Ais methyl.

[0345] In some embodiments, each R3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, -CN, and -ORa3. 54057-0031W01 / SNV0023-W01 PATENT

[0346] In some embodiments, each Ra3, Rb3, Rc3, and Rd3is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl.

[0347] In some embodiments, each Ra3, Rb3, Rc3, and Rd3is independently selected from H and Ci.6 alkyl.

[0348] In some embodiments, each Ra3, Rb3, Rc3, and Rd3is independently selected from H and C1-3 alkyl.

[0349] In some embodiments, each Ra3, Rb3, Rc3, and Rd3is methyl.

[0350] In some embodiments, each Ra3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl.

[0351] In some embodiments, each Ra3is independently selected from H and C1-6 alkyl. In some embodiments, each Ra3is independently selected from H and C1-3 alkyl. In some embodiments, each Ra3is methyl.

[0352] In some embodiments, each R3is independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, 4-10 membered heterocycloalkyl, -CN, and -ORa3, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and 4-10 membered heterocycloalkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; and

[0353] each Ra3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl.

[0354] In some embodiments, each R3is independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, 4-10 membered heterocycloalkyl, -CN, and -ORa3, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and 4-10 membered heterocycloalkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents;

[0355] each Ra3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; and

[0356] each R3Ais independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl.

[0357] In some embodiments, each R3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, 4-7 membered heterocycloalkyl, -CN, and -ORa3, wherein the C1-6 alkyl, C1-6 haloalkyl, and 4-7 membered heterocycloalkyl of R3are each optionally substituted with 1 or 2 independently selected R3Asubstituents; and

[0358] each Ra3is independently selected from H and C1-6 alkyl.

[0359] In some embodiments, each R3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, 4-7 membered heterocycloalkyl, -CN, and -ORa3, wherein the C1-6 alkyl, C1-6 54057-0031W01 / SNV0023-W01 PATENT

[0360] haloalkyl, and 4-7 membered heterocycloalkyl of R3are each optionally substituted with 1 or 2 independently selected R3Asubstituents;

[0361] each Ra3is independently selected from H and Ci-6 alkyl; and

[0362] each R3Ais independently selected from Ci -6 alkyl.

[0363] In some embodiments, each R3is independently selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, and -ORa3, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; and

[0364] each Ra3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl.

[0365] In some embodiments, each R3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, -CN, and -ORa3, wherein the C1-6 alkyl and C1-6 haloalkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; and

[0366] each Ra3is independently selected from H and C1-6 alkyl.

[0367] In some embodiments, each R3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, -CN, and -ORa3; and

[0368] each Ra3is independently selected from H and C1-6 alkyl.

[0369] In some embodiments, each R3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, -CN, and -ORa3; and

[0370] each Ra3is independently selected from H and C1-3 alkyl.

[0371] In some embodiments, each R3is independently selected from H, C1-3 alkyl, C1-3 haloalkyl, -CN, and -ORa3; and

[0372] each Ra3is independently selected from H and C1-3 alkyl.

[0373] In some embodiments, each R3is independently selected from H, C1-6 alkyl, -CN, and -ORa3; and

[0374] each Ra3is independently selected from H and C1-6 alkyl.

[0375] In some embodiments, each R3is independently selected from H, C1-3 alkyl, -CN, and -ORa3; and

[0376] each Ra3is independently selected from H and C1-3 alkyl.

[0377] In some embodiments, each R3is independently selected from H, methyl, trideuteromethyl, methoxymethyl, difluoromethyl, morpholinyl, CN, and methoxy.

[0378] In some embodiments, each R3is independently selected from H, methyl, methoxymethyl, difluoromethyl, morpholinyl, CN, and methoxy.

[0379] In some embodiments, each R3is independently selected from H, methyl, CN, and methoxy.

[0380] In some embodiments, p is 0, 1, or 2. 54057-0031W01 / SNV0023-W01 PATENT

[0381] In some embodiments, p is 1 or 2.

[0382] In some embodiments, p is 1.

[0383] In some embodiments, each L1is independently selected from -O-, -C(O)-, -C(O)N(RL)-, and C1-6 alkylene.

[0384] In some embodiments, each RLis independently selected from H and C1-6 alkyl. In some embodiments, each RLis independently selected from H and C1-3 alkyl. In some embodiments, each RLis H.

[0385] In some embodiments, each L1is independently selected from -O-, -C(O)-, -C(O)N(RL)-, and C1-6 alkylene; and

[0386] each RLis independently selected from H and C1-6 alkyl.

[0387] In some embodiments, each L1is independently selected from -O-, -C(O)-, -C(O)N(RL)-, and C1-3 alkylene; and

[0388] each RLis independently selected from H and C1-3 alkyl.

[0389] In some embodiments, each L1is independently selected from -O-, -C(O)-, -C(O)NH-, -CH2-, and -CD2-.

[0390] In some embodiments, each L1is independently selected from -O-, -C(O)-, -C(O)NH-, and -CH2-.

[0391] In some embodiments, Ring B is selected from C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl.

[0392] In some embodiments, Ring B is selected from cyclobutyl, phenyl, azetidinyl, and pyrazolyl.

[0393] In some embodiments, n is 0, 1, 2, or 3.

[0394] In some embodiments, n is 1, 2, or 3.

[0395] In some embodiments, n is 1 or 2.

[0396] In some embodiments, Ring B is selected from

[0397]

[0398] R4

[0399]

[0400] In some embodiments, each R4is independently selected from oxo, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and -CN, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of R4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R4Asubstituents. 54057-0031W01 / SNV0023-W01 PATENT

[0401] In some embodiments, each R4is independently selected from oxo, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and -CN.

[0402] In some embodiments, each R4is independently selected from halo, C1-6 alkyl, and Ci-6 haloalkyl.

[0403] In some embodiments, each R4is independently selected from halo, C1-3 alkyl, and Ci-3 haloalkyl.

[0404] In some embodiments, each R4is independently selected from fluoro, methyl, and difluoromethyl.

[0405] F

[0406] In some embodiments, Ring B is selected from

[0407]

[0408] In some embodiments:

[0409] X1is N or CR5;

[0410] X2is N or CR6;

[0411] X3is N or C(-L2-R2);

[0412] Z is O or NR7;

[0413]

[0414] 54057-0031W01 / SNV0023-W01 PATENT

[0415]

[0416] each - is independently a single or double bond;

[0417] * denotes attachment to X1;

[0418] m is 0, 1, 2, 3, 4, 5, or 6;

[0419] n is 0, 1, 2, 3, 4, 5, or 6;

[0420] p is 1, 2, 3, or 4;

[0421] X4is C(-L3-R3) orN;

[0422] X5is C(-L3-R3) orN;

[0423] X6is C(-L3-R3) orN;

[0424] X7is C(-L3-R3) orN;

[0425] X8is C(-L3-R3) orN;

[0426] X9is C(-L3-R3) orN;

[0427] Y1is C orN;

[0428] Y2is C orN;

[0429] Ring B is selected from C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl;

[0430] Ring C is selected from C5-10 cycloalkyl, phenyl, 5-10 membered heterocycloalkyl, and 5-6 membered heteroaryl;

[0431] each L1is independently selected from C1-6 alkylene, C1-6 haloalkylene, -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 and C1-6 haloalkylene of L1are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; 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-4 alkyl-, -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) -C 1-4 alkyl of L2and L3are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; 54057-0031W01 / SNV0023-W01 PATENT

[0432] each RLis independently selected from H, 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) -C1-4 alkyl of RLare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0433] R1is selected from -CN, C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, and 4-7 membered heterocycloalkyl, wherein the C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, and 4-7 membered heterocycloalkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0434] Rlaand Rlbare each independently C1-3 alkyl, wherein the C1-3 alkyl of Rlaand Rlbis optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0435] or, Rlaand Rlb, together with the carbon atom to which they are attached, form a C3-4 cycloalkyl group, wherein the C3-4 cycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0436] 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;

[0437] 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 54057-0031W01 / SNV0023-W01 PATENT

[0438] heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 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;

[0439] 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-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 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;

[0440] 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-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;

[0441] 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-Ci-4 alkyl, Ce-io aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 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; 54057-0031W01 / SNV0023-W01 PATENT

[0442] 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) -C 1-4 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;

[0443] 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-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 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;

[0444] 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-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;

[0445] 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, -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)Rf3Rg3, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 54057-0031W01 / SNV0023-W01 PATENT

[0446] 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;

[0447] 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) -C 1-4 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;

[0448] 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-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 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;

[0449] 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-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;

[0450] each Rf3and Rg3are independently selected from C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and, C1-6 haloalkoxy;

[0451] 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, -C(O)ORa3A, -C(O)NRc3ARd3A, -C(O)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, 54057-0031W01 / SNV0023-W01 PATENT

[0452] -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 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-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 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;

[0453] 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) -C 1-4 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;

[0454] 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-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 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;

[0455] 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-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;

[0456] each R4is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered 54057-0031W01 / SNV0023-W01 PATENT

[0457] 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, -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, -NRc4S(O)NRc4C(O)Rb4, and -P(O)Rf4Rg4, 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 R4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R4Asubstituents;

[0458] each Ra4, Rc4, and Rd4is 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) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra4, Rc4, and Rd4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R4Asubstituents;

[0459] each Rb4is 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-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Rb4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R4Asubstituents;

[0460] 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, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl- 54057-0031W01 / SNV0023-W01 PATENT

[0461] Ci-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;

[0462] each Rf4and Rg4are independently selected from H, 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-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;

[0463] each R4Ais 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, -ORa4A, -SRa4A, -NRc4ARd4A, -NO2, -C(O)Ra4A, -C(O)ORa4A, -C(O)NRc4ARd4A, -C(O)NRc4A(ORa4A), -OC(O)Ra4A, -OC(O)NRc4ARd4A, -OC(O)ORa4A, -OS(O)2Rb4A, -OS(O)2NRc4ARd4A, -NRc4AC(O)Ra4A, -NRc4AC(O)ORa4A, -NRc4AC(O)NRc4ARd4A, -NRc4AS(O)2Rb4A, -NRc4AS(O)2NRc4ARd4A, -NRc4AORa4A, -NRc4AS(O)Rb4A, -NRc4AS(O)NRc4ARd4A, -S(O)Rb4A, -S(O)2Rb4A, -S(O)NRc4ARd4A, -S(O)2NRc4ARd4A, -C(=NRe4A)Ra4A, -C(=NRe4A)NRc4ARd4A, -NRc4AC(=NRe4A)Ra4A, -NRc4AC(=NRe4A)NRc4ARd4A, -NRc4AS(O)(=NRe4A)Rb4A, -NRc4AS(O)(=NRe4A)NRc4ARd4A, -OS(O)(=NRe4A)Rb4A, -S(O)(=NRe4A)Rb4A, -

[0464]

[0465] S(O)(=NRe4A)NRc4ARd4A, -C(O)NRc4AS(O)2Rb4A, -C(O)NRc4AS(O)2NRc4ARd4A, -S(O)2NRc4AC(O)Rb4A, -NRc4AS(O)NRc4AC(O)Rb4A, and -P(O)Rf4ARg4A, 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) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R4Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0466] each Ra4A, Rc4A, and Rd4Ais 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) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra4A, Rc4A, and Rd4Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0467] each Rb4Ais 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 54057-0031W01 / SNV0023-W01 PATENT

[0468] 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-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Rb4Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0469] each Re4Ais 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-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;

[0470] each Rf4Aand Rg4Aare independently selected from H, 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-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;

[0471] R5is selected from H, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C 1-4 haloalkoxy, and -CN;

[0472] R6is selected from H, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C 1-4 haloalkoxy, and -CN;

[0473] R7is selected from H, CN, ORa7, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;

[0474] Ra7is selected from H, C1-6 alkyl, and C1-6 haloalkyl;

[0475] 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, C1-3 alkylsulfonyl, carbamyl, C1-3 alkylcarbamyl, di(Ci-3 alkyl)carbamyl, carboxy, C1-3 alkylcarbonyl, C1-3 alkoxycarbonyl, C1-3 alkylcarbonyloxy, C1-3 alkylcarbonylamino, C1-3 alkoxycarbonylamino, aminocarbonyloxy, C1-3 alkylaminocarbonyloxy, di(Ci-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.

[0476] In some embodiments:

[0477] X1is N or CR5; 54057-0031W01 / SNV0023-W01 PATENT

[0478] X2is N or CR6;

[0479] X3is N or C(-L2-R2);

[0480] Z is O;

[0481]

[0482] each - is independently a single or double bond;

[0483] * denotes attachment to X1;

[0484] m is 0, 1, 2, 3, or 4;

[0485] n is 1 or 2;

[0486] p is 1 or 2;

[0487] X4is C(-L3-R3) orN;

[0488] X5is C(-L3-R3) orN;

[0489] X6is C(-L3-R3) orN;

[0490] X7is C(-L3-R3) orN;

[0491] X8is C(-L3-R3) orN;

[0492] X9is C(-L3-R3) orN;

[0493] Y1is C orN;

[0494] Y2is C orN;

[0495] Ring B is selected from C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl; 54057-0031W01 / SNV0023-W01 PATENT

[0496] Ring C is selected from C5-10 cycloalkyl, 5-10 membered heterocycloalkyl, and 5-6 membered heteroarylene;

[0497] each L1is independently selected from -O-, -C(O)-, -C(O)N(RL)-, and C1-6 alkylene; 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;

[0498] each L3is independently selected from a bond, -O-, and -C(O)-;

[0499] each RLis independently selected from H and C1-6 alkyl;

[0500] R1is selected from -CN, C1-3 alkyl, and C1-3 haloalkyl;

[0501] Rlaand Rlb, together with the carbon atom to which they are attached, form a C3-4 cycloalkyl group, wherein the C3-4 cycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0502] R2is selected from H, oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, -CN, C(O)Ra2, and S(O)2Rb2, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3- 10 cycloalkyl, and 4-10 membered heterocycloalkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents;

[0503] each R2Ais independently selected from 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, -CN, -ORa2A, and -C(O)Ra2A, wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of R2Ais optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0504] each Ra2and Rb2is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-10 cycloalkyl;

[0505] each Ra2Ais 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, and 5-10 membered heteroaryl, wherein each 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 Ra2Ais optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0506] each R3is independently selected from H, halo, Ci -6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, 4-10 membered heterocycloalkyl, -CN, and -ORa3, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and 4-10 membered heterocycloalkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; 54057-0031W01 / SNV0023-W01 PATENT

[0507] each R3Ais independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;

[0508] each Ra3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;

[0509] each R4is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and -CN; and

[0510] each RGis independently selected from C1-4 alkyl, OH, and CN.

[0511] In some embodiments:

[0512] X1is N or CR5;

[0513] X2is N or CR6;

[0514] X3is N or C(-L2-R2);

[0515] Z is O;

[0516]

[0517] each - is independently a single or double bond;

[0518] * denotes attachment to X1;

[0519] m is 0, 1, 2, 3, or 4;

[0520] n is 1 or 2;

[0521] p is 1 or 2;

[0522] X4is C(-L3-R3) orN; 54057-0031W01 / SNV0023-W01 PATENT

[0523] X5is C(-L3-R3) orN;

[0524] X6is C(-L3-R3) orN;

[0525] X7is C(-L3-R3) orN;

[0526] X8is C(-L3-R3) orN;

[0527] X9is C(-L3-R3) orN;

[0528] Y1is C orN;

[0529] Y2is C orN;

[0530] Ring B is selected from C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl;

[0531] Ring C is selected from C5-10 cycloalkyl and 5-10 membered heterocycloalkyl; each L1is independently selected from -O-, -C(O)-, -C(O)N(RL)-, and C1-6 alkylene; 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;

[0532] each L3is independently selected from a bond, -O-, and -C(O)-;

[0533] each RLis independently selected from H and C1-6 alkyl;

[0534] R1is selected from -CN, C1-3 alkyl, and C1-3 haloalkyl;

[0535] Rlaand Rlb, together with the carbon atom to which they are attached, form a C3-4 cycloalkyl group, wherein the C3-4 cycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0536] R2is selected from H, oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, 4-10 membered heterocycloalkyl, and -CN, wherein the Ci -6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and 4-10 membered heterocycloalkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents;

[0537] each R2Ais independently selected from 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, -CN, -ORa2A, and -C(O)Ra2A, wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of R2Ais optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0538] each Ra2Ais 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, and 5-10 membered heteroaryl, wherein each 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 Ra2Ais optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; 54057-0031W01 / SNV0023-W01 PATENT

[0539] each R3is independently selected from H, halo, Ci -6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, 4-10 membered heterocycloalkyl, -CN, and -ORa3, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and 4-10 membered heterocycloalkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents;

[0540] each R3Ais independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;

[0541] each Ra3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;

[0542] each R4is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and -CN; and

[0543] each RGis independently selected from C1-4 alkyl, OH, and CN.

[0544] In some embodiments:

[0545] X1is N or CR5;

[0546] X2is N or CR6;

[0547] X3is N or C(-L2-R2);

[0548] Z is O;

[0549] Ring A is selected from

[0550]

[0551] each - is independently a single or double bond;

[0552] * denotes attachment to X1;

[0553] m is 0, 1, 2, 3, or 4;

[0554] n is 1 or 2;

[0555] p is 1 or 2;

[0556] X4is C(-L3-R3) orN; 54057-0031W01 / SNV0023-W01 PATENT

[0557] X5is C(-L3-R3) orN;

[0558] X6is C(-L3-R3) orN;

[0559] X7is C(-L3-R3) orN;

[0560] X8is C(-L3-R3) orN;

[0561] X9is C(-L3-R3) orN;

[0562] Y1is C orN;

[0563] Y2is C orN;

[0564] Ring B is selected from C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl;

[0565] Ring C is selected from C5-10 cycloalkyl and 5-10 membered heterocycloalkyl; each L1is independently selected from -O-, -C(O)-, -C(O)N(RL)-, and C1-6 alkylene; 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;

[0566] each L3is independently selected from a bond, -O-, and -C(O)-;

[0567] each RLis independently selected from H and C1-6 alkyl;

[0568] R1is selected from -CN, C1-3 alkyl, and C1-3 haloalkyl;

[0569] Rlaand Rlb, together with the carbon atom to which they are attached, form a C3-4 cycloalkyl group, wherein the C3-4 cycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0570] R2is selected from H, oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and -CN;

[0571] each R3is independently selected from H, halo, Ci -6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, and -ORa3, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents;

[0572] each Ra3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;

[0573] each R4is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and -CN; and

[0574] each RGis independently selected from C1-4 alkyl.

[0575] In some embodiments the compound of Formula I is a compound of Formula II: 54057-0031W01 / SNV0023-W01 PATENT

[0576]

[0577] II

[0578] or a pharmaceutically acceptable salt thereof.

[0579] In some embodiments the compound of Formula I is a compound of Formula Ila:

[0580]

[0581] Ila

[0582] or a pharmaceutically acceptable salt thereof.

[0583] In some embodiments the compound of Formula I is a compound of Formula III:

[0584] / L2

[0585]

[0586] R2

[0587] III

[0588] or a pharmaceutically acceptable salt thereof.

[0589] In some embodiments the compound of Formula I is a compound of Formula Illa: 54057-0031W01 / SNV0023-W01 PATENT

[0590]

[0591] R2

[0592] Illa

[0593] or a pharmaceutically acceptable salt thereof.

[0594] In some embodiments the compound of Formula I is a compound of Formula IV:

[0595] R3

[0596]

[0597] IV

[0598] or a pharmaceutically acceptable salt thereof.

[0599] In some embodiments the compound of Formula I is a compound of Formula IVa:

[0600] R3

[0601]

[0602] IVa

[0603] or a pharmaceutically acceptable salt thereof.

[0604] In some embodiments the compound of Formula I is a compound of Formula V: 54057-0031W01 / SNV0023-W01 PATENT

[0605]

[0606] or a pharmaceutically acceptable salt thereof.

[0607] In some embodiments the compound of Formula I is a compound of Formula Va:

[0608]

[0609] Va

[0610] or a pharmaceutically acceptable salt thereof.

[0611] In some embodiments, the compound of Formula I is a compound of Formula VI:

[0612] R3

[0613]

[0614] VI

[0615] or a pharmaceutically acceptable salt thereof.

[0616] In some embodiments, the compound of Formula I is a compound of Formula VIa: 54057-0031W01 / SNV0023-W01 PATENT

[0617] (R4)n

[0618] NC

[0619]

[0620] or a pharmaceutically acceptable salt thereof.

[0621] In some embodiments, the compound of Formula I is a compound of Formula VIb:

[0622] CN Rxzp N'S- H

[0623]

[0624] or a pharmaceutically acceptable salt thereof.

[0625] In some embodiments, the compound of Formula I is a compound of Formula Vic:

[0626] N-N

[0627] II?

[0628] CN

[0629] 2

[0630] 2

[0631]

[0632] or a pharmaceutically acceptable salt thereof.

[0633] In some embodiments, the compound provided herein is selected from:

[0634] 5 -fluoro- 1 -(( 1 -methyl- 1 H-py razol -4-y 1 )oxy )- N-( 1 -methylcyclopropyl)isoquinoline-7 -sulfonamide; 54057-0031W01 / SNV0023-W01 PATENT

[0635] 8-fluoro-4-(( 1 -methyl- I / / -py razol-4- l (oxy )- '-( 1 -methylcyclopropyl)quinoline-6-sulfonamide;

[0636] 6-(( 1 -methyl- I / / -py razol -4-y I (oxy )- '-( 1 -methylcyclopropyl)- 1,2,3,4-tetrahydrobenzo [c] [ 1,6] naphthyridine- 8 -sulfonamide;

[0637] methyl 6-(( 1 -methyl- 127-py razol-4-y 1 )oxy )-8-( N-( 1 -methylcyclopropyl)sulfamoyl)- 3.4-dihydrobcnzo|c || 1.6 |naphthyridinc-2( I / / (-carboxy late:

[0638] methyl 3 -methyl-6-(( 1 -methyl- 1 -py razol -4-y 1 )oxy )-8-( N-( 1 -mcthylcyclopropyl)sulfamoyl)-3.4-dihydrobcnzo|c || 1.6 |naphthyridinc-2( I / / (-carboxylate:

[0639] 4-(3,3-difluoroazetidine- 1 -carbonyl)-8-(3,5-dimethylpiperazin- 1 -yl)-2-methoxy-N-( 1 -methylcyclopropyl)quinazoline-6-sulfonamide;

[0640] N-(3,3-difluorocyclobutyl)-8-(3,5-dimethylpiperazin-l-yl)-2-methoxy-6-(N-(l-methylcyclopropyl) sulfamoyl)quinazoline -4-carboxamide;

[0641] methyl 10-chloro-6-(( 1 -(difluoromethyl)- I / / -py razol-4-y I )oxy)-8-(A'-( 1 -mcthylcyclopropyl)sulfamo l)-3.4-dihydrobcnzo|c || 1.6 |naphthyridinc-2( I / / (-carbox late methyl 6-(3,4-difluorophenoxy)-8-[(1-methylcyclopropyl)sulfamoyl]-3,4-dihydro-1H-benzo[c][1,6]naphthyridine-2-carboxylate;

[0642] 1 -methyl-5-(( 1 -methyl- lH-pyrazol-4-yl)oxy)-N-( 1 -methylcyclopropyl)-2,3-dihydro- 1 H-cyclopenta[c] isoquinoline -7 -sulfonamide;

[0643] 2-methyl-5-(( 1 -methyl- lH-pyrazol-4-yl)oxy)-N-( 1 -methylcyclopropyl)-2,3-dihydro-1 H-cyclopenta[c] isoquinoline -7 -sulfonamide;

[0644] 4-cyano-8-fluoro-2 -methyl -3-(( 1 -methyl- I / / -py razol-4-y I (methyl )- '-( 1 -methylcyclopropyl)quinoline-6-sulfonamide;

[0645] 4-cyano-8-(3,5 -dimethylpiperazin- 1 -yl)-2-methyl-3 -((1 -methyl- lH-pyrazol-4-yl)methyl)-N-( 1 -methylcyclopropyl)quinoline-6-sulfonamide;

[0646] 5-cyano- 1,9-dimethyl-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-N-( 1 -methylcyclopropyl) - 1,2-dihydroimidazo [ 1,2-a] quinoline -7 -sulfonamide;

[0647] 5-cyano- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-N-( 1 -methylcyclopropyl)-1,2-dihydroimidazo [ 1,2-a] quinoline-7 -sulfonamide;

[0648] 5-cyano-N-( 1 -cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-1,2-dihydroimidazo [ 1,2-a] quinoline-7 -sulfonamide;

[0649] 5-cyano-N-( 1 -cyanocyclopropyl)- 1,9-dimethyl-4-(( 1 -methyl- IH-pyrazol -4-yl)methyl) - 1,2-dihydroimidazo [ 1,2 -a] quinoline -7 -sulfonamide;

[0650] 5-cyano-N-( 1 -cyanocyclopropyl)- 1 -methyl-6-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-7a,8,10,10a-tetrahydrofuro[3',4':4,5]imidazo[l,2-a]quinoline-3-sulfonamide;

[0651] 5-cyano-N-( 1 -cyanocyclopropyl)- 1 -(methoxymethyl)-9-methyl-4-(( 1 -methyl- 1H-pyrazol-4-yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide; 54057-0031W01 / SNV0023-W01 PATENT

[0652] 5-cyano-N-( 1 -cyanocyclopropyl)-9-(difluoromethyl)- 1 -methyl -4-(( 1 -methyl-lH-pyrazol-4-yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0653] 5-cyano-N-( 1 -cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl- IH-pyrazol -4-yl)methyl)-9-morpholino- 1,2-dihydroimidazo [ 1,2-a]quinoline-7 -sulfonamide;

[0654] 4-cyano-8-(2-(hydroxymethyl)-6-methyhnorpholino)-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)quinoline-6-sulfonamide;

[0655] 4-cyano-N-(l-cyanocyclopropyl)-8-(2-(hydroxymethyl)-6-methylmorpholino)-2-methyl-3-(( 1 -methyl- lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;

[0656] 4-cyano-N-(l-(difluoromethyl)cyclopropyl)-8-(2-(hydroxymethyl)-6-methylmorpholino)-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;

[0657] 4-cyano-N-( 1 -cyanocyclopropyl)-2-methyl-3-(( 1 -methyl- IH-pyrazol -4-yl)methyl)-8-(2-oxa-7 -azaspiro [3.5]nonan-7 -yl)quinoline-6-sulfonamide;

[0658] 8-(4-( IH-pyrazol- 1 -yl)piperidin- 1 -yl)-4-cyano-N-( 1 -cyanocyclopropyl)-2-methyl-3-(( 1 -methyl- lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;

[0659] 8-(4-(2H- 1,2,3-triazol-2-yl)piperidin- 1 -yl)-4-cyano-N-( 1 -cyanocyclopropyl)-2-methyl-3-(( 1 -methyl- lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;

[0660] 4-cyano-N-( 1 -cyanocyclopropyl)-2-methyl-3-(( 1 -methyl- IH-pyrazol -4-yl)methyl)-8-(4-(thiazol-2-yl)piperazin- 1 -yl)quinoline-6-sulfonamide;

[0661] 4-cyano-N-(l-cyanocyclopropyl)-8-(2-(difluoromethyl)-6-methylmorpholino)-2-methyl-3-(( 1 -methyl- IH-pyrazol -4-yl)methyl)quinoline-6-sulfonamide;

[0662] 4-cyano-N-(l-cyanocyclopropyl)-8-(2-(methoxymethyl)-6-methyhnorpholino)-2-methyl-3-(( 1 -methyl- IH-pyrazol -4-yl)methyl)quinoline-6-sulfonamide;

[0663] 4-cyano-N-(l-cyanocyclopropyl)-8-(2-((difluoromethoxy)methyl)-6-methylmorpholino)-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;

[0664] 4-cyano-N-(l-cyanocyclopropyl)-8-(4-(cyclopropanecarbonyl)-3-methylpiperazin-l-yl)-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;

[0665] 4-cyano-N-(l-cyanocyclopropyl)-8-(4-(cyclopropanecarbonyl)-3,5-dimethylpiperazin- 1 -yl)-2-methyl-3-(( 1 -methyl- lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;

[0666] 4-cyano-8-(4-( 1 -cyanocyclopropane- 1 -carbonyl)-3-methylpiperazin- 1 -yl)-N-( 1 -cyanocyclopropyl)-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;

[0667] 4-cyano-N-( 1 -cyanocyclopropyl)-2-methyl-3-(( 1 -methyl- IH-pyrazol -4-yl)methyl)-8-(3-methyl-4-(tetrahydrofuran-3-carbonyl)piperazin-l-yl)quinoline-6-sulfonamide;

[0668] 4-cyano-N-( 1 -cyanocyclopropyl)-8-( 1 -(cyclopropanecarbonyl)piperidin-4-yl)-2-methyl-3-(( 1 -methyl- IH-pyrazol -4-yl)methyl)quinoline-6-sulfonamide; 54057-0031W01 / SNV0023-W01 PATENT

[0669] 4-cyano-N-(l-cyanocyclopropyl)-8-(2-cyclopropylpyridin-4-yl)-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;

[0670] 4-cyano-N-( 1 -cyanocyclopropyl)-8-( 1 -(cyclopropanecarbonyl)- 1,2,3,6-tetrahydropyridin-4-yl)-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;

[0671] 4-cyano-8-(4-( 1 -cyanocyclopropane- 1 -carbonyl)-3-methylpiperazin- 1 -yl)-N-( 1 -cyanocyclopropyl)-2-(difluoromethyl)-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;

[0672] 4-cyano-N-(l-cyanocyclopropyl)-2-(difluoromethyl)-8-(2-(methoxymethyl)-6-methylmorpholino)-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;

[0673] 4-cyano-N-(l-cyanocyclopropyl)-8-(2-(methoxymethyl)-6-methylmorpholino)-3-((l-methyl-lH-pyrazol-4-yl)methyl)-2-morpholinoquinoline-6-sulfonamide;

[0674] 4-cyano-N-(l-cyanocyclopropyl)-8-(4-(cyclopropanecarbonyl)-3-methylpiperazin-l-yl)-7-fluoro-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;

[0675] 4-cyano-N-(l-cyanocyclopropyl)-7-fluoro-8-(2-(methoxymethyl)-6-methylmorpholino)-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;

[0676] 5-cyano-N-( 1 -cyanocyclopropyl)-9-fluoro- 1 -methyl -4-(( 1 -methyl- IH-pyrazol -4-yl)methyl) - 1,2-dihydroimidazo [ 1,2 -a] quinoline -7 -sulfonamide;

[0677] 4-cyano-N-(l-cyanocyclopropyl)-8-(6-(methoxymethyl)-2,2-dimethyhnorpholino)-2-methyl-3-(( 1 -methyl- lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;

[0678] 5-cyano-N-( 1 -cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl- IH-pyrazol -4-yl)methyl)-9-(2-methylmorpholino)- 1,2-dihydroimidazo [ 1,2-a] quinoline-7 -sulfonamide;

[0679] 5 -cyano-N-( 1 -cyanocyclopropyl)-9-(2,2-dimethylmorpholino)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo [ 1,2-a]quinoline-7-sulfonamide;

[0680] 5 -cyano-N-( 1 -cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-9-(4-oxa-7-azaspiro [2.5] octan-7-yl)- 1,2-dihydroimidazo [ 1,2-a] quinoline-7 -sulfonamide;

[0681] 5 -cyano-N-( 1 -cyanocyclopropyl)-9-(2-(difluoromethyl)morpholino)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo [ 1,2-a]quinoline-7-sulfonamide;

[0682] 5 -cyano-N-( 1 -cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-9-(2-(trifluoromethyl)morpholino)- 1,2-dihydroimidazo [ 1,2-a]quinoline-7-sulfonamide;

[0683] 5-cyano-N-(l-cyanocyclopropyl)-9-(4-(cyclopropanecarbonyl)-3-methylpiperazin-l-yl)- 1 -methyl-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo [ 1,2-a] quinoline-7 -sulfonamide;

[0684] 5 -cyano-N-( 1 -cyanocyclopropyl)-9-(2-cyclopropylpyrimidin-4-yl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo [ 1,2-a]quinoline-7-sulfonamide; 54057-0031W01 / SNV0023-W01 PATENT

[0685] 5 -cyano-N-( 1 -cyanocyclopropyl)-9-( 1 -cyclopropyl- lH-pyrazol-4-yl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo[ 1,2-a]quinoline-7-sulfonamide;

[0686] 5-cyano-N-(l-cyanocyclopropyl)-9-(3,6-dihydro-2H-pyran-4-yl)-l-methyl-4-((l-methyl- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo[ 1,2-a]quinoline-7-sulfonamide;

[0687] 5 -cyano-N-( 1 -cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-9-(tetrahydro-2H-pyran-4-yl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0688] 5 -cyano-N-( 1 -cyanocyclopropyl)-9-(4-(isopropylsulfonyl)-3 -methylpiperazin- 1 -yl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo[ 1,2-a] quinoline-7 -sulfonamide;

[0689] 5 -cyano-N-( 1 -cyanocyclopropyl)- 1 -(methyl -d3)-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl-d2)- 1,2-dihydroimidazo[ 1,2-a] quinoline-7 -sulfonamide- 1,2,2-d3;

[0690] 5 -cyano-N-( 1 -cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl-d2)- 1,2-dihydroimidazo [ 1,2-a]quinoline-7-sulfonamide- 1,2,2-d3;

[0691] 5 -cyano-N-( 1 -cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl-d2)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0692] 5 -cyano-N-( 1 -cyanocyclopropyl)-9-(2,2-dimethylmorpholino)-4-(( 1 -methyl- 1H-pyrazol-4-yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0693] 5 -cyano-N-( 1 -cyanocyclopropyl)-9-(2,2-dimethylmorpholino)-4-(( 1 -methyl- 1H-pyrazol-4-yl)methyl)imidazo[l,2-a]quinoline-7-sulfonamide;

[0694] 5-cyano-N-( 1 -cyanocyclopropyl)-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-9-(2-methylmorpholino) - 1,2-dihydroimidazo [ 1,2-a] quinoline -7 -sulfonamide;

[0695] 5-cyano-N-( 1 -cyanocyclopropyl)-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-9-(2-methylmorpholino)imidazo[l,2-a]quinoline-7-sulfonamide;

[0696] 5-cyano-N-( 1 -cyanocyclopropyl)-9-(2-(difluoromethyl)morpholino)-4-(( 1 -methyl -lH-pyrazol-4-yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0697] 5-cyano-N-( 1 -cyanocyclopropyl)-9-(2-(difluoromethyl)morpholino)-4-(( 1 -methyl -lH-pyrazol-4-yl)methyl)imidazo[l,2-a]quinoline-7-sulfonamide;

[0698] 5-cyano-N-( 1 -cyanocyclopropyl)-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-9-(2-(trifluoromethyl)morpholino)-1,2-dihydroimidazo[1,2-a]quinoline-7-sulfonamide;

[0699] 5-cyano-N-( 1 -cyanocyclopropyl)-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-9-(2-(trifluoromethyl)morpholino)imidazo[l,2-a]quinoline-7-sulfonamide;

[0700] 5 -cyano-N-( 1 -cyanocyclopropyl)-9-(2-cyclopropylpyrimidin-4-yl)-4-(( 1 -methyl- 1H-pyrazol-4-yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0701] 5 -cyano-N-( 1 -cyanocyclopropyl)-9-(2-cyclopropylpyrimidin-4-yl)-4-(( 1 -methyl- 1H-pyrazol-4-yl)methyl)imidazo[l,2-a]quinoline-7-sulfonamide; 54057-0031W01 / SNV0023-W01 PATENT

[0702] 5-cyano-N-( 1 -cyanocyclopropyl)-8-fluoro- l-methyl-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-9-(2-methylmorpholino)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0703] 5-cyano-N-(l-cyanocyclopropyl)-9-(2,2-dimethylmorpholino)-8-fluoro-l-(methyl-d3)-4-((l-(methyl-d3)-lH-pyrazol-4-yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide- 1,2,2-d3;

[0704] 5-cyano-N-( 1 -cyanocyclopropyl)-8-fluoro- l-methyl-4-(( 1 -(methyl -d3)- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo [ 1,2-a] quinoline-7 -sulfonamide- 1,2,2-d3;

[0705] 5-cyano-N-(l-cyanocyclopropyl)-8-fluoro-l-(methyl-d3)-4-((l-(methyl-d3)-lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo [ 1,2-a] quinoline-7 -sulfonamide- 1,2,2-d3;

[0706] 5-cyano-N-(l-cyanocyclopropyl)-9-(2-cyclopropylpyrimidin-4-yl)-8-fluoro-l-methyl-4-(( 1 -(methyl -d3)- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo [ 1,2-a]quinoline-7-sulfonamide;

[0707] 5-cyano-N-(l-cyanocyclopropyl)-9-(2,2-dimethylmorpholino)-8-fluoro-4-((l-(methyl-d3)-lH-pyrazol-4-yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0708] 5-cyano-N-(l-cyanocyclopropyl)-9-(2,2-dimethylmorpholino)-8-fluoro-4-((l-(methyl-d3)-lH-pyrazol-4-yl)methyl)imidazo[l,2-a]quinoline-7-sulfonamide;

[0709] 5-cyano-N-(l-cyanocyclopropyl)-8-fluoro-4-((l-(methyl-d3)-lH-pyrazol-4-yl)methyl)-9-(2-methylmorpholino)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0710] 5-cyano-N-( 1 -cyanocyclopropyl)-8-fluoro-4-(( 1 -(methyl-d3)- lH-pyrazol-4-yl)methyl) -9-(2-methylmorpholino)imidazo [ 1,2 -a] quinoline -7 -sulfonamide;

[0711] 5-cyano-N-(l-cyanocyclopropyl)-8-fluoro-4-((l-(methyl-d3)-lH-pyrazol-4-yl)methyl)-9-(2-(trifluoromethyl)morpholino)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0712] 5-cyano-N-( 1 -cyanocyclopropyl)-8-fluoro-4-(( 1 -(methyl-d3)- lH-pyrazol-4-yl)methyl)-9-(2-(trifluoromethyl)morpholino)imidazo[1,2-a]quinoline-7-sulfonamide;

[0713] 5-cyano-N-( 1 -cyanocyclopropyl)-9-(2-cyclopropylpyrimidin-4-yl)-8-fluoro-4-(( 1 -(methyl-d3)-lH-pyrazol-4-yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0714] 5-cyano-N-( 1 -cyanocyclopropyl)-9-(2-cyclopropylpyrimidin-4-yl)-8-fluoro-4-(( 1 -(methyl-d3)-lH-pyrazol-4-yl)methyl)imidazo[l,2-a]quinoline-7-sulfonamide;

[0715] 5-cyano-N-( 1 -cyanocyclopropyl)-8-fluoro-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-9-(2-methylmorpholino)imidazo [ 1,2 -a] quinoline -7 -sulfonamide;

[0716] 5-cyano-N-( 1 -cyanocyclopropyl)-8-fluoro- l-methyl-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0717] 5 -cyano-N-( 1 -cyanocyclopropyl)-2,2-dimethyl-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl) - 1,2-dihydroimidazo [ 1,2 -a] quinoline -7 -sulfonamide; 54057-0031W01 / SNV0023-W01 PATENT

[0718] 5-cyano-N-(l-cyanocyclopropyl)-2,2-dimethyl-4-((l-methyl-lH-pyrazol-4-yl)methyl-d2)- 1,2-dihydroimidazo[ 1,2-a]quinoline-7-sulfonamide;

[0719] 5-cyano-N-( 1 -cyanocyclopropyl)-9-fluoro-2,2-dimethyl-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl) - 1,2-dihydroimidazo [ 1,2 -a] quinoline -7 -sulfonamide;

[0720] 5 -cyano-N-( 1 -cyanocyclopropyl)-2,2-dimethyl-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-9-(2-methylmorpholino)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0721] 5-cyano-N-(l-cyanocyclopropyl)-9-(2-(difluoromethyl)morpholino)-2,2-dimethyl-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo [ 1,2-a] quinoline-7 -sulfonamide;

[0722] 5 -cyano-N-( 1 -cyanocyclopropyl)-2,2-dimethyl-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-9-(2-(trifluoromethyl)morpholino)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0723] 5-cyano-N-(l-cyanocyclopropyl)-9-(2-cyclopropylpyrimidin-4-yl)-2,2-dimethyl-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo [ 1,2-a] quinoline-7 -sulfonamide;

[0724] 5-cyano-N-(l-cyanocyclopropyl)-8-fluoro-2,2-dimethyl-4-((l-(methyl-d3)-lH-pyrazol-4-yl)methyl)-9-(2-methylmorpholino)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0725] 5-cyano-N-(l-cyanocyclopropyl)-8-fluoro-2,2-dimethyl-4-((l-(methyl-d3)-lH-pyrazol-4-yl)methyl)-9-(2-(trifluoromethyl)morpholino)-1,2-dihydroimidazo[1,2-a]quinoline-7-sulfonamide;

[0726] 5-cyano-N-(l-cyanocyclopropyl)-9-(2-cyclopropylpyrimidin-4-yl)-8-fluoro-2,2-dimethyl-4-(( l-(methyl-d3)- lH-pyrazol-4-yl)methyl)- l,2-dihydroimidazo[ l,2-a]quinoline-7-sulfonamide;

[0727] 5-cyano-N-(l-cyanocyclopropyl)-8-fluoro-2,2-dimethyl-4-((l-(methyl-d3)-lH-pyrazol-4-yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0728] 5 -cyano-N-( 1 -cyanocyclopropyl)- 1 -methyl -4-((4-methyl- IH-imidazol- 1 -yl)methyl)- 1.2-dihydroimidazo [ 1,2-a] quinoline-7 -sulfonamide;

[0729] 5-cyano-N-(l-cyanocyclopropyl)-9-(2-cyclopropylpyrimidin-4-yl)-8-fluoro-l-(methyl-d3)-4-(( l-(methyl-d3)- lH-pyrazol-4-yl)methyl-d2)- 1,2-dihydroimidazo [ 1,2-a]quinoline-7-sulfonamide-l,2,2-d3;

[0730] 5-cyano-N-(l-cyanocyclopropyl)-8-fluoro-4-((l-(methyl-d3)-lH-pyrazol-4-yl)methyl-d2)-9-(2-methylmorpholino)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide- 1.1.2.2-d4; and

[0731] 5-cyano-N-(l-cyanocyclopropyl)-8-fluoro-2,2-dimethyl-4-((l-(methyl-d3)-lH-pyrazol-4-yl)methyl-d2)-9-(2-methylmorpholino)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide- 1, 1 -d2;

[0732] or a pharmaceutically acceptable salt thereof. 54057-0031W01 / SNV0023-W01 PATENT

[0733] In some embodiments, the compound provided herein is selected from:

[0734] 5 -fluoro- 1 -(( 1 -methyl- 1 H-py razol -4-y 1 )oxy )- N-( 1 -methylcyclopropyl)isoquinoline-7 -sulfonamide;

[0735] 8-fluoro-4-(( 1 -methyl- 17 / -py razol -4- l )oxy)-A'-( 1 -methylcyclopropyl)quinoline-6-sulfonamide;

[0736] 6-(( 1 -methyl- I H-py razol -4-y I )oxy )- '-( 1 -methylcyclopropyl)- 1,2,3,4-tetrahydrobenzo [c] [ 1,6] naphthyridine- 8 -sulfonamide;

[0737] methyl 6-(( 1 -methyl- 1 H-py razol-4-y 1 )oxy )-8-( N-( 1 -methylcyclopropyl)sulfamoyl)- 3.4-dihydrobcnzo|c || 1.6 |naphthyridinc-2( I / / (-carboxy late:

[0738] methyl 3 -methyl-6-(( 1 -methyl- 127-py razol -4-y 1 )oxy )-8-( N-( 1 -mcthylcyclopropyl)sulfamoyl)-3.4-dihydrobcnzo|c || 1.6 |naphthyridinc-2( I / / (-carboxylate:

[0739] 4-(3,3-difluoroazetidine-l-carbonyl)-8-[(3S,5S)-3,5-dimethylpiperazin-l-yl]-2-mcthoxy-A'-( 1 -methylcyclopropyl)quinazoline-6-sulfonamide;

[0740] '-(3.3-difliiorocyclobiityl)-8-((3. S'.5. S)-3.5-dimcthylpipcrazin-l-yl)-2-mcthoxy-6-( '-( 1 -methylcyclopropyl)sulfamoyl)quinazoline-4-carboxamide;

[0741] methyl 10-chloro-6-(( 1 -(difluoromethyl)- I / / -py razol -4- l )oxy)-8-(A'-( 1 -mcthylcyclopropyl)sulfamoyl)-3.4-dihydrobcnzo|c || 1.6 |naphthyridinc-2( I / / (-carboxylate:

[0742] methyl 6-(3,4-difluorophenoxy)-8-[(l-methylcyclopropyl)sulfamoyl]-3,4-dihydro-1 H-benzo [c] [ 1,6] naphthyridine -2 -carboxylate;

[0743] (R)- 1 -methyl-5 -((1 -methyl- I / / -py razol -4-y I (oxy )- '-( 1 -methylcyclopropyl)-2,3 -dihydro- 1 / / -cyclopenta[c]isoquinoline-7-sulfonamide;

[0744] (R)-2 -methyl-5 -((1 -methyl- I / / -py razol -4-y I (oxy )- '-( 1 -methylcyclopropyl)-2,3 -dihydro- 1 / / -cyclopenta[c]isoquinoline-7-sulfonamide;

[0745] 4-cyano-8-fluoro-2 -methyl -3-(( 1 -methyl- I / / -py razol -4- l (methyl )- '-( 1 -methylcyclopropyl)quinoline-6-sulfonamide;

[0746] 4-cyano-8-((3. S'.5. S)-3.5-dimcthylpipcrazin-l-yl)-2-mcthyl-3-(( 1 -methyl- IH-pyrazol-4-y I (mcthy l)- '-( 1 -methylcyclopropyl)quinoline-6-sulfonamide;

[0747] f / ?)-5-cyano- 1,9-dimethyl-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-N-( 1 -methylcyclopropyl) - 1,2-dihydroimidazo [ 1,2-a] quinoline -7 -sulfonamide;

[0748] f / ?)-5-cyano- 1 -methyl -4-(( 1-methyl- lH-pyrazol-4-yl)methyl)-N-( 1 -methylcyclopropyl) - 1,2-dihydroimidazo [ 1,2-a] quinoline -7 -sulfonamide;

[0749] f7?)-5-cyano-N-( 1 -cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl) - 1,2-dihydroimidazo [ 1,2 -a] quinoline -7 -sulfonamide;

[0750] f7?)-5-cyano-N-( 1 -cyanocyclopropyl)- 1,9-dimethyl-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl) - 1,2-dihydroimidazo [ 1,2 -a] quinoline -7 -sulfonamide; 54057-0031W01 / SNV0023-W01 PATENT

[0751] (7aR, 10aS)-5-cyano-N-( 1 -cyanocyclopropyl)- 1 -methyl-6-(( 1 -methyl-lH-pyrazol-4-yl)methyl)-7a,8,10,10a-tetrahydrofuro[3',4':4,5]imidazo[l,2-a]quinoline-3-sulfonamide;

[0752] (S)-5-cyano-N-( 1 -cyanocyclopropyl)- 1 -(methoxymethyl)-9-methyl-4-(( 1 -methyl-lH-pyrazol-4-yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0753] 7?)-5-cyano-N-( 1 -cyanocyclopropyl)-9-(difluoromethyl)- 1 -methyl -4-(( 1 -methyl-lH-pyrazol-4-yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0754] 7?)-5-cyano-N-( 1 -cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-9-morpholino- 1,2-dihydroimidazo[ 1,2-a]quinoline-7-sulfonamide;

[0755] 4-cyano-8-((2R,6S)-2-(hydroxymethyl)-6-methylmorpholino)-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)quinoline-6-sulfonamide;

[0756] 4-cyano-N-(l-cyanocyclopropyl)-8-((2R,6S)-2-(hydroxymethyl)-6-methylmorpholino)-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;

[0757] 4-cyano-N-(l-(difluoromethyl)cyclopropyl)-8-((2R,6S)-2-(hydroxymethyl)-6-methylmorpholino)-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;

[0758] 4-cyano-N-( 1 -cyanocyclopropyl)-2-methyl-3-(( 1 -methyl- IH-pyrazol -4-yl)methyl)-8-(2-oxa-7 -azaspiro [3.5]nonan-7 -yl)quinoline-6-sulfonamide;

[0759] 8-(4-( IH-pyrazol- 1 -yl)piperidin- 1 -yl)-4-cyano-N-( 1 -cyanocyclopropyl)-2-methyl-3-(( 1 -methyl- IH-pyrazol -4-yl)methyl)quinoline-6-sulfonamide;

[0760] 8-(4-(2H- 1,2,3-triazol-2-yl)piperidin- 1 -yl)-4-cyano-N-( 1 -cyanocyclopropyl)-2-methyl-3-(( 1 -methyl- IH-pyrazol -4-yl)methyl)quinoline-6-sulfonamide;

[0761] 4-cyano-N-( 1 -cyanocyclopropyl)-2-methyl-3-(( 1 -methyl- IH-pyrazol -4-yl)methyl)-8-(4-(thiazol-2-yl)piperazin- 1 -yl)quinoline-6-sulfonamide;

[0762] 4-cyano-N-(l-cyanocyclopropyl)-8-((2R,6S)-2-(difluoromethyl)-6-methylmorpholino)-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;

[0763] 4-cyano-N-(l-cyanocyclopropyl)-8-((2R,6S)-2-(methoxymethyl)-6-methylmorpholino)-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;

[0764] 4-cyano-N-(l-cyanocyclopropyl)-8-((2R,6S)-2-((difluoromethoxy)methyl)-6-methylmorpholino)-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;

[0765] (7^-4-cyano-N-(l-cyanocyclopropyl)-8-(4-(cyclopropanecarbonyl)-3-methylpiperazin- 1 -yl)-2-methyl-3-(( 1 -methyl- lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;

[0766] 4-cyano-N-(l-cyanocyclopropyl)-8-((cis)-4-(cyclopropanecarbonyl)-3,5-dimethylpiperazin- 1 -yl)-2-methyl-3-(( 1 -methyl- lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;

[0767] (7^-4-cyano-8-(4-( 1 -cyanocyclopropane- 1 -carbonyl) -3 -methylpiperazin- 1 -yl)-N-( 1 -cyanocyclopropyl)-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide; 54057-0031W01 / SNV0023-W01 PATENT

[0768] 4-cyano-N-( 1 -cyanocyclopropyl)-2-methyl-3-(( 1 -methyl- IH-pyrazol -4-yl)methyl)-8-(('R -3-methyl-4-((S)-tetrahydrofuran-3-carbonyl)piperazin-l-yl)quinoline-6-sulfonamide;

[0769] 4-cyano-N-( 1 -cyanocyclopropyl)-8-( 1 -(cyclopropanecarbonyl)piperidin-4-yl)-2-methyl-3-(( 1 -methyl- IH-pyrazol -4-yl)methyl)quinoline-6-sulfonamide;

[0770] 4-cyano-N-(l-cyanocyclopropyl)-8-(2-cyclopropylpyridin-4-yl)-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;

[0771] 4-cyano-N-( 1 -cyanocyclopropyl)-8-( 1 -(cyclopropanecarbonyl)- 1,2,3,6-tetrahydropyridin-4-yl)-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;

[0772] 7)-4-cyano-8-(4-( 1 -cyanocyclopropane- 1 -carbonyl) -3 -methylpiperazin- 1 -yl)-N-( 1 -cyanocyclopropyl)-2-(difluoromethyl)-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;

[0773] 4-cyano-N-(l-cyanocyclopropyl)-2-(difluoromethyl)-8-((2R,6S)-2-(methoxymethyl)-6-methylmorpholino)-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;

[0774] 4-cyano-N-(l-cyanocyclopropyl)-8-((2R,6S)-2-(methoxymethyl)-6-methylmorpholino)-3-((l-methyl-lH-pyrazol-4-yl)methyl)-2-morpholinoquinoline-6-sulfonamide;

[0775] f / )-4-cyano-N-( l-cyanocyclopropyl)-8-(4-(cyclopropanccarbonyl)-3-methylpiperazin-l-yl)-7-fluoro-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;

[0776] 4-cyano-N-(l-cyanocyclopropyl)-7-fluoro-8-((2R,6S)-2-(methoxymethyl)-6-methylmorpholino)-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;

[0777] ( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)-9-fluoro- 1 -methyl -4-(( 1 -methyl- IH-pyrazol -4-yl)methyl) - 1,2-dihydroimidazo [ 1,2 -a] quinoline -7 -sulfonamide;

[0778] ( / ?)-4-cyano-N-( 1 -cyanocyclopropyl)-8-(6-(methoxymethyl)-2,2-dimethylmorpholino)-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;

[0779] ( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-9-((R)-2-methylmorpholino)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0780] ( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)-9-(2,2-dimethylmorpholino)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo [ 1,2-a]quinoline-7-sulfonamide;

[0781] ( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl-lH-pyrazol-4-yl)methyl)-9-(4-oxa-7-azaspiro[2.5]octan-7-yl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide; 54057-0031W01 / SNV0023-W01 PATENT

[0782] ( / ?)-5-cyano-N-( 1 -cyanocyclopropy l)-9-((. S)-2-(difluoromcthy l)morphol ino)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo[ 1,2-a] quinoline-7 -sulfonamide;

[0783] ( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl-lH-pyrazol-4-yl)methyl)-9-((S)-2-(trifluoromethyl)morpholino)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0784] ( / ?)-5-cyano-N-( l-cyanocycloprop l)-9-(( / )-4-(cyclopropanccarbon l)-3-methylpiperazin- 1 -yl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo [ 1,2 -a] quinoline -7 -sulfonamide;

[0785] ( / ?)-5-cyano-N-( l-cyanocycloprop l)-9-(2-cyclopropylp rimidin-4- l)-l-mcth l-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo[ 1,2-a]quinoline-7-sulfonamide;

[0786] ( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)-9-( 1 -cyclopropyl-lH-pyrazol-4-yl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo[ 1,2-a]quinoline-7-sulfonamide;

[0787] ( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)-9-(3,6-dihydro-2H-pyran-4-yl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo[ 1,2-a]quinoline-7-sulfonamide;

[0788] ( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-9-(tetrahydro-2H-pyran-4-yl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0789] ( / )-5-cyano-N-( l-cyanocyclopropyl)-9-(( / )-4-(isopropylsiilfonyl)-3-methylpiperazin- 1 -yl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo [ 1,2 -a] quinoline -7 -sulfonamide;

[0790] 5-cyano-N-( 1 -cyanocyclopropyl)- 1 -(methyl - 3)-4-(( 1 -methyl- lH-pyrazol-4-y I )mcthy l-tA)- 1,2-dihydroimidazo[ 1,2-a] quinoline-7 -sulfonamide- 1,2,2- s;

[0791] 5-cyano-N-( 1 -cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl- 1 H-py razol-4-y I )mcthy 1-tT)-1,2-dihydroimidazo [ 1,2-a] quinoline-7 -sulfonamide- 1,2,2-t / j;

[0792] ( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-y I )m cthy I -t ) - 1,2-dihydroimidazo [ 1,2 -a] quinoline -7 -sulfonamide;

[0793] 5-cyano-N-( 1 -cyanocyclopropyl)-9-(2,2-dimethylmorpholino)-4-(( 1 -methyl- 1H-pyrazol-4-yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0794] 5-cyano-N-( 1 -cyanocyclopropyl)-9-(2,2-dimethylmorpholino)-4-(( 1 -methyl- 1H-pyrazol-4-yl)methyl)imidazo[l,2-a]quinoline-7-sulfonamide;

[0795] ( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-9-(2-methylmorpholino) - 1,2-dihydroimidazo [ 1,2-a] quinoline -7 -sulfonamide;

[0796] ( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-9-(2-methylmorpholino)imidazo[l,2-a]quinoline-7-sulfonamide;

[0797] (. S)-5-cyano-N-( 1 -cyanocyclopropyl)-9-(2-(difluoromethyl)morpholino)-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo [ 1,2-a]quinoline-7-sulfonamide; 54057-0031W01 / SNV0023-W01 PATENT

[0798] (. S')-5-cyano-N-( 1 -cyanocyclopropyl)-9-(2-(difluoromethyl)morpholino)-4-(( 1 -methyl-lH-pyrazol-4-yl)methyl)imidazo[l,2-a]quinoline-7-sulfonamide;

[0799] (. S')-5-cyano-N-( 1 -cyanocyclopropyl)-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-9-(2-(trifluoromethyl)morpholino)- 1,2-dihydroimidazo [ 1,2-a] quinoline-7 -sulfonamide;

[0800] (. S')-5-cyano-N-( 1 -cyanocyclopropyl)-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-9-(2-(trifluoromethyl)morpholino)imidazo [ 1,2 -a] quinoline -7 -sulfonamide;

[0801] 5 -cyano-N-( 1 -cyanocyclopropyl)-9-(2-cyclopropylpyrimidin-4-yl)-4-(( 1 -methyl- 1H-pyrazol-4-yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0802] 5 -cyano-N-( 1 -cyanocyclopropyl)-9-(2-cyclopropylpyrimidin-4-yl)-4-(( 1 -methyl- 1H-pyrazol-4-yl)methyl)imidazo[l,2-a]quinoline-7-sulfonamide;

[0803] ( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)-8-fluoro- 1 -methyl -4-(( 1 -methyl-lH-pyrazol-4-yl)mcthyl)-9-(( / ?)-2-mcthylmorpholino)-l.2-dihydroimidazo| l.2-a|quinolinc-7-siilfonamidc:

[0804] 5-cyano-N-(l-cyanocyclopropyl)-9-(2,2-dimethylmorpholino)-8-fluoro-l-(methyl-ds)-4-(( 1 -(methyl -d3)- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo [ 1,2-a]quinoline-7-sulfonamide- 1,2,2-ds;

[0805] 5-cyano-N-( 1 -cyanocyclopropyl)-8-fluoro- 1 -methyl -4-(( 1 -(methyl -ds)- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo [ 1,2-a] quinoline-7 -sulfonamide- 1,2,2-t / s;

[0806] 5-cyano-N-( 1 -cyanocyclopropyl)-8-fluoro- 1 -(methyl -d3)-4-(( 1 -(methyl -ds)- 1H-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo [ 1,2-a] quinoline-7 -sulfonamide- 1,2,2- s;

[0807] ( / ?)-5-cyano-N-( l-cyanocyclopropyl)-9-(2-cyclopropylpyrimidin-4-yl)-8-fliioro-l-methyl -4-(( 1 -(methyl -d3)- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo [ 1,2-a]quinoline-7-sulfonamide;

[0808] 5-cyano-N-(l-cyanocyclopropyl)-9-(2,2-dimethylmorpholino)-8-fluoro-4-((l-(methyl-d3)-lH-pyrazol-4-yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0809] 5-cyano-N-(l-cyanocyclopropyl)-9-(2,2-dimethylmorpholino)-8-fluoro-4-((l-(methyl-ds)-lH-pyrazol-4-yl)methyl)imidazo[l,2-a]quinoline-7-sulfonamide;

[0810] (J?)-5-cyano-N-( 1 -cyanocyclopropyl)-8-fluoro-4-(( 1 -(methyl -d3)- IH-pyrazol -4-yl)methyl)-9-(2-methylmorpholino)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0811] ( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)-8-fluoro-4-(( 1 -(methyl -ds)- lH-pyrazol-4-yl)methyl) -9-(2-methylmorpholino)imidazo [ 1,2 -a] quinoline -7 -sulfonamide;

[0812] (S)-5-cyano-N-( 1 -cyanocyclopropyl)-8-fluoro-4-(( 1 -(methyl -ds)- lH-pyrazol-4-yl)methyl)-9-(2-(trifluoromethyl)morpholino)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0813] (. S)-5-cyano-N-( 1 -cyanocyclopropyl)-8-fluoro-4-(( 1 -(methyl -ds)- lH-pyrazol-4-yl)methyl)-9-(2-(trifluoromethyl)morpholino)imidazo[1,2-a]quinoline-7-sulfonamide; 54057-0031W01 / SNV0023-W01 PATENT

[0814] 5-cyano-N-(l-cyanocyclopropyl)-9-(2-cyclopropylpyrimidin-4-yl)-8-fluoro-4-((l-(methyl-ds)- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo [ 1,2-a] quinoline-7 -sulfonamide;

[0815] 5-cyano-N-(l-cyanocyclopropyl)-9-(2-cyclopropylpyrimidin-4-yl)-8-fluoro-4-((l-(methyl-d3)-lH-pyrazol-4-yl)methyl)imidazo[l,2-a]quinoline-7-sulfonamide;

[0816] ( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)-8-fluoro-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl) -9-(2-methylmorpholino)imidazo [ 1,2 -a] quinoline -7 -sulfonamide;

[0817] ( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)-8-fluoro- 1 -methyl -4-(( 1 -methyl- IH-pyrazol -4-yl)methyl) - 1,2-dihydroimidazo [ 1,2 -a] quinoline -7 -sulfonamide;

[0818] 5-cyano-N-( 1 -cyanocyclopropyl)-2,2-dimethyl-4-(( 1 -methyl- IH-pyrazol -4-yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0819] 5-cyano-N-( 1 -cyanocyclopropyl)-2,2-dimethyl-4-(( 1 -methyl- IH-pyrazol -4-yl)methyl-d2)- 1,2-dihydroimidazo [ 1,2-a] quinoline-7 -sulfonamide;

[0820] 5-cyano-N-( 1 -cyanocyclopropyl)-9-fluoro-2,2-dimethyl-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl) - 1,2-dihydroimidazo [ 1,2 -a] quinoline -7 -sulfonamide;

[0821] ( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)-2,2-dimethyl-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-9-(2-methylmorpholino)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0822] (S)-5-cyano-N-(l-cyanocyclopropyl)-9-(2-(difluoromethyl)morpholino)-2,2-dimethyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0823] (. S')-5-cyano-N-( 1 -cyanocyclopropyl)-2,2-dimethyl-4-(( 1 -methyl-lH-pyrazol-4-yl)methyl)-9-(2-(trifluoromethyl)morpholino)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0824] 5-cyano-N-(l-cyanocyclopropyl)-9-(2-cyclopropylpyrimidin-4-yl)-2,2-dimethyl-4-(( 1 -methyl- IH-pyrazol -4-yl)methyl)- 1,2-dihydroimidazo [ 1,2-a]quinoline-7-sulfonamide;

[0825] ( / ?)-5-cyano-N-( l-cyanocyclopropyl)-8-fliioro-2.2-dimcthyl-4-(( l-(mcthyl-d3)-IH-pyrazol-4-yl)methyl)-9-(2-methylmorpholino)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0826] (S)-5-cyano-N-( 1 -cyanocyclopropyl)-8-fluoro-2,2-dimethyl-4-(( 1 -(methyl -d3)- 1H-pyrazol-4-yl)methyl)-9-(2-(trifluoromethyl)morpholino)-1,2-dihydroimidazo[1,2-a]quinoline-7-sulfonamide;

[0827] 5-cyano-N-(l-cyanocyclopropyl)-9-(2-cyclopropylpyrimidin-4-yl)-8-fluoro-2,2-dimethyl-4-((l-(methyl-d3)-lH-pyrazol-4-yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0828] 5-cyano-N-( 1 -cyanocyclopropyl)-8-fluoro-2,2-dimethyl-4-(( 1 -(methyl -d3)- 1H-pyrazol-4-yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide; 54057-0031W01 / SNV0023-W01 PATENT

[0829] ( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)- 1 -methyl -4-((4-methyl- IH-imidazol- 1 -yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;

[0830] 5-cyano-N-(l-cyanocyclopropyl)-9-(2-cyclopropylpyrimidin-4-yl)-8-fluoro-l-(methyl-d3)-4-(( 1 -(methyl -d3)- lH-pyrazol-4-yl)methyl-d2)- 1,2-dihydroimidazo[ 1,2-a] quinoline -7 -sulfonamide - 1,2,2-t / j;

[0831] ( / ?)-5-c ano-N-( l-cyanocyclopropyl)-8-fhioro-4-((l-(mcthyl-d3)-IH-pyrazol-4-yl)methyl-d2)-9-(2-methylmorpholino)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide-1, 1,2,2-^; and

[0832] (J?)-5-cyano-N-( 1 -cyanocyclopropyl)-8-fluoro-2,2-dimethyl-4-(( 1 -(methyl -d3)- 1H-pyrazol-4-yl)methyl-d2)-9-(2-methylmorpholino)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide- 1, 1 -d,

[0833] or a pharmaceutically acceptable salt thereof.

[0834] In some embodiments, the compound provided herein is 5-cyano-N-(l-cyanocyclopropyl)- 1 -(methyl -d3)-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl-d2)- 1,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide-l,2,2-d3, or a pharmaceutically acceptable salt thereof.

[0835] In some embodiments, the compound provided herein is 5-cyano-N-(l-cyanocyclopropyl)- 1 -(methyl -d3)-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl-d2)- 1,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide-l,2,2-d3.

[0836] In some embodiments, the compound provided herein is a pharmaceutically acceptable salt of 5-cyano-N-(l-cyanocyclopropyl)-l-(methyl-d3)-4-((l-methyl-lH-pyrazol-4-yl)methyl-d2)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide-l,2,2-d3.

[0837] In some embodiments, the compound provided herein is (J?)-5-cyano-N-(l-cyanocyclopropyl)- 1 -(methyl -d3)-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl-d2)- 1,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide-l,2,2-d3, or a pharmaceutically acceptable salt thereof.

[0838] In some embodiments, the compound provided herein is (J?)-5-cyano-N-(l-cyanocyclopropyl)- 1 -(methyl -d3)-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl-d2)- 1,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide-l,2,2-d3.

[0839] In some embodiments, the compound provided herein is a pharmaceutically acceptable salt of (J?)-5-cyano-N-(l-cyanocyclopropyl)-l-(methyl-d3)-4-((l-methyl-lH-pyrazol-4-yl)methyl-d2)- 1,2-dihydroimidazo[ 1,2 -a] quinoline -7-sulfonamide- 1,2,2-d3.

[0840] In some embodiments, the compound provided herein is (. S)-5-cyano-N-( I -cyanocyclopropyl)- 1 -(methyl -d3)-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl-d2)- 1,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide-l,2,2-d3, or a pharmaceutically acceptable salt thereof. 54057-0031W01 / SNV0023-W01 PATENT

[0841] In some embodiments, the compound provided herein is (. S)-5-cyano-N-( I -cyanocyclopropyl)- 1 -(methyl -d3)-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl-d2)- 1,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide-l,2,2-d3.

[0842] In some embodiments, the compound provided herein is a pharmaceutically acceptable salt of (. S)-5-cyano-N-( I -cyanocyclopropyl)- 1 -(mcthyl-d3)-4-(( I -methyl- 1 Pipy razol -4-yl (methyl -d2)- 1,2-dihydroimidazo [ 1,2-a] quinoline-7 -sulfonamide- 1,2,2-d3.

[0843] In some embodiments, the compound provided herein is 5-cyano-N-(l-cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl-d2)- 1,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide-l,2,2-d3, or a pharmaceutically acceptable salt thereof.

[0844] In some embodiments, the compound provided herein is 5-cyano-N-(l-cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl-d2)- 1,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide-l,2,2-d3.

[0845] In some embodiments, the compound provided herein is a pharmaceutically acceptable salt of 5-cyano-N-(l-cyanocyclopropyl)-l-methyl-4-((l-methyl-lH-pyrazol-4-yl)methyl-d2)- 1,2-dihydroimidazo[ 1,2-a] quinoline-7 -sulfonamide- 1,2,2-d3.

[0846] In some embodiments, the compound provided herein is (J?)-5-cyano-N-(l-cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl-d2)- 1,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide-l,2,2-d3, or a pharmaceutically acceptable salt thereof.

[0847] In some embodiments, the compound provided herein is (J?)-5-cyano-N-(l-cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl-d2)- 1,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide-l,2,2-d3.

[0848] In some embodiments, the compound provided herein is a pharmaceutically acceptable salt of (J?)-5-cyano-N-(l-cyanocyclopropyl)-l-methyl-4-((l-methyl-lH-pyrazol-4-yl)methyl-d2)- 1,2-dihydroimidazo[ 1,2-a] quinoline-7 -sulfonamide- 1,2,2-d3.

[0849] In some embodiments, the compound provided herein is (. S)-5-cyano-N-( I -cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl-d2)- 1,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide-l,2,2-d3, or a pharmaceutically acceptable salt thereof.

[0850] In some embodiments, the compound provided herein is (. S)-5-cyano-N-( I -cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl-d2)- 1,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide-l,2,2-d3.

[0851] In some embodiments, the compound provided herein is a pharmaceutically acceptable salt of (5)-5-cyano-N-(l-cyanocyclopropyl)-l-methyl-4-((l-methyl-lH-pyrazol-4-yl)methyl-d2)- 1,2-dihydroimidazo[ 1,2-a] quinoline-7 -sulfonamide- 1,2,2-d3. 54057-0031W01 / SNV0023-W01 PATENT

[0852] In some embodiments, the compound provided herein is 5-cyano-N-(l-cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl-d2)- 1,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide, or a pharmaceutically acceptable salt thereof.

[0853] In some embodiments, the compound provided herein is 5-cyano-N-(l-cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl-d2)- 1,2-dihydroimidazo [ 1,2 -a] quinoline -7 -sulfonamide.

[0854] In some embodiments, the compound provided herein is a pharmaceutically acceptable salt of 5-cyano-N-(l-cyanocyclopropyl)-l-methyl-4-((l-methyl-lH-pyrazol-4-yl)methyl-d2)-l,2-dihydroimidazo[I,2-a]quinoline-7-sulfonamide.

[0855] In some embodiments, the compound provided herein is ( / ?)-5-cyano-N-( I -cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl-d2)- 1,2-dihydroimidazo[I,2-a]quinoline-7-sulfonamide, or a pharmaceutically acceptable salt thereof.

[0856] In some embodiments, the compound provided herein is ( / ?)-5-cyano-N-( I -cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl-d2)- 1,2-dihydroimidazo [ 1,2 -a] quinoline -7 -sulfonamide.

[0857] In some embodiments, the compound provided herein is a pharmaceutically acceptable salt of (R)-5-cyano-N-(l-cyanocyclopropyl)-l-methyl-4-((l-methyl-lH-pyrazol-4-yl)methyl-d2)-l,2-dihydroimidazo[I,2-a]quinoline-7-sulfonamide.

[0858] In some embodiments, the compound provided herein is (. S)-5-cyano-N-( I -cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl-d2)- 1,2-dihydroimidazo[I,2-a]quinoline-7-sulfonamide, or a pharmaceutically acceptable salt thereof.

[0859] In some embodiments, the compound provided herein is (. S)-5-cyano-N-( I -cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl-d2)- 1,2-dihydroimidazo [ 1,2 -a] quinoline -7 -sulfonamide.

[0860] In some embodiments, the compound provided herein is a pharmaceutically acceptable salt of (. S)-5-cyano-N-( I -cyanocyclopropyl)- 1 -mcthyl-4-(( I -methyl- 1 H-pyrazol-4-yl)methyl-d2)-l,2-dihydroimidazo[I,2-a]quinoline-7-sulfonamide.

[0861] 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.

[0862] 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 54057-0031W01 / SNV0023-W01 PATENT

[0863] both -NR(CR’R”)n- and -(CR’R”)nNR-. Where the structure clearly requires a linking group, the Markush variables listed forthat group are understood to be linking groups.

[0864] The term “n-membered” where n is an integer typically describes the number of ringforming 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.

[0865] 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.

[0866] As used herein, the phrase “each ‘variable’ is independently selected from” means substantially the same as wherein “at each occurrence ‘variable’ is selected from.” 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.

[0867] As used herein, the term “Cn-malkyl”, 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-malkyl” is understood to include deuterated analogs of saturated hydrocarbon groups as defined herein, including but not limited to, groups such as trideuteromethyl (CDs), 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.

[0868] As used herein, “Cn-malkenyl” 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-malkenyl” 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. 54057-0031W01 / SNV0023-W01 PATENT

[0869] As used herein, “Cn-malkynyl” 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-malkynyl” 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, (-C=CCDs), and the like.

[0870] As used herein, the term “Cn-malkoxy”, 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 tert-butoxy), 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-malkoxy” 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.

[0871] As used herein, “Cn-mhaloalkoxy”, 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-mhaloalkoxy” is understood to include deuterated analogs of the haloalkoxy groups as defined herein.

[0872] As used herein, the term “carbonyl”, employed alone or in combination with other terms, refers to a -C(O)- group.

[0873] As used herein, the term “Cn-malkylcarbonyl” 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.

[0874] As used herein, the term “Cn-malkylsulfonyl” 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-malkylsulfonyl” is understood to include deuterated analogs of the alkylsulfonyl groups as defined herein.

[0875] As used herein, the term “carboxy” refers to a group of formula -C(O)OH.

[0876] As used herein, the term “amino” refers to a group of formula -NH2.

[0877] As used herein, the term “Cn-malkylamino”, 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 54057-0031W01 / SNV0023-W01 PATENT

[0878] and isopropylamino), and the like. The term “Cn-malkylamino” is understood to include deuterated analogs of the alkylamino groups as defined herein.

[0879] As used herein, the term “di(Cn-malkyl)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-malkyl)amino” is understood to include deuterated analogs of the di(Cn-malkyl)amino groups as defined herein.

[0880] As used herein, the term “Cn-malkoxycarbonyl”, 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-malkoxycarbonyl” is understood to include deuterated analogs of the alkoxycarbonyl groups as defined herein.

[0881] As used herein, the term “Cn-malkylcarbonyl”, 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-malkylcarbonyl” is understood to include deuterated analogs of the alkylcarbonyl groups as defined herein.

[0882] As used herein, the term “Cn-malkylcarbonylamino”, 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-malkylcarbonylamino” is understood to include deuterated analogs of the alkylcarbonylamino groups as defined herein.

[0883] As used herein, the term “carbamyl”, employed alone or in combination with other terms, refers to a group of formula -C(O)-NH2.

[0884] As used herein, the term “Cn-malkylcarbamyl”, 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-malkylcarbamyl” is understood to include deuterated analogs of the alkylcarbamyl groups as defined herein.

[0885] As used herein, the term “di-Cn-malkylcarbamyl”, 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-malkylcarbamyl” is understood to include deuterated analogs of the dialkylcarbamyl groups as defined herein.

[0886] As used herein, the term “thio” refers to a group of formula -SH. 54057-0031W01 / SNV0023-W01 PATENT

[0887] As used herein, the term “Cn-malkylthio”, 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.

[0888] As used herein, the term “Cn-malkylsulfinyl”, 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-malkylsulfinyl” is understood to include deuterated analogs of the alkylsulfinyl groups as defined herein.

[0889] As used herein, the term “Cn-malkylsulfonyl”, 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-malkylsulfonyl” is understood to include deuterated analogs of the alkylsulfonyl groups as defined herein.

[0890] As used herein, “halosulfanyl” refers to a sulfur group having one or more halogen substituents. Example halosulfanyl groups include pentahalosulfanyl groups such as SF5.

[0891] As used herein, the term “HO-C1-4 alkyl” refers to a group of formula -Ci-4alkylene-OH. The term “HO-C1-4 alkyl” is understood to include deuterated analogs of the HO-C1-4 alkyl groups as defined herein.

[0892] As used herein, the term “Ci-4alkoxy-Ci-4alkyl” refers to a group of formula -C1-4 alkylene-O-(Ci-4 alkyl). The term “Ci-4alkoxy-Ci-4 alkyl” is understood to include deuterated analogs of the Ci-4alkoxy-Ci-4 alkyl groups as defined herein.

[0893] 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-maryl” 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.

[0894] 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. 54057-0031W01 / SNV0023-W01 PATENT

[0895] As used herein, “Cn-mhaloalkoxy” refers to a group of formula -O-haloalkyl having n to m carbon atoms. Example haloalkoxy groups include OCFs 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.

[0896] As used herein, the term “Cn-mhaloalkyl”, 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, CHCE, C2CI5 and the like. The term “Cn-mhaloalkyl” 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.

[0897] As used herein, “hydroxyl” or “hydroxy” refer to a group of formula -OH.

[0898] 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., abridged 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 moieties that have one or more aromatic rings fused (z.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 ring -forming atom of the fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (z.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, norbomyl, norpinyl, norcamyl, cubane, adamantane, bicyclo [1.1.1 ]pentyl, bicyclo [2. l.l]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 54057-0031W01 / SNV0023-W01 PATENT

[0899] “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.

[0900] 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 ring-forming 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 ringforming 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, imidazo[l,2-a]pyridinyl, 1,5-naphthyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, triazolo[4,3-a]pyridinyl, lH-pyrrolo[3,2-b]pyridinyl, 1H-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 54057-0031W01 / SNV0023-W01 PATENT

[0901] herein, including but not limited to, groups such as perdeuteropyridinyl, perdeuteropyrazinyl, perdeuteropyrimidinyl, and the like.

[0902] 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 ring-forming 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 1-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.

[0903] Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused ( / . 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 ringforming atom including a ring -forming atom of the fused aromatic ring.

[0904] In some embodiments, the heterocycloalkyl group contains 3 to 10 ring -forming atoms, 4 to 10 ring -forming atoms, 4 to 8 ring -forming atoms, 3 to 7 ring -forming 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 54057-0031W01 / SNV0023-W01 PATENT

[0905] 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.

[0906] 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-dioxide, benzazapene, azabicyclo[3.1.0]hexanyl, diazabicyclo[3.1.0]hexanyl, oxobicyclo [2.1. l]hexanyl, azabicyclo [2.2. l]heptanyl, diazabicyclo [2.2. l]heptanyl, azabicyclo[3.1. l]heptanyl, diazabicyclo [3.1. l]heptanyl, azabicyclo[3.2. l]octanyl, diazabicyclo [3.2. l]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.

[0907] As used herein, “C0.pcycloalkyl-Cn-malkyl-” refers to a group of formula cycloalkylalkylene-, wherein the cycloalkyl has o to p carbon atoms and the alkylene linking group has n to m carbon atoms. The term “C0.pcycloalkyl-Cn-malkyl-” is understood to include deuterated analogs of the cycloalkyl and / or alkyl moieties of the C0.pcycloalkyl-Cn-malkylgroups as defined herein.

[0908] As used herein “C0.paryl-Cn-malkyl-” refers to a group of formula aryl-alkylene-, wherein the aryl has o to p carbon atoms and the alkylene linking group has n to m carbon atoms. The term “C0.paryl-Cn-malkyl-” is understood to include deuterated analogs of the aryl and / or alkyl moieties of the C0.paryl-Cn-malkyl- groups as defined herein.

[0909] As used herein, “heteroaryl-Cn-malkyl-” refers to a group of formula heteroarylalkylene-, wherein alkylene linking group has n to m carbon atoms. The term “heteroaryl -Cn-m 54057-0031W01 / SNV0023-W01 PATENT

[0910] alkyl-” is understood to include deuterated analogs of the heteroaryl and / or alkyl moieties of the heteroaryl -Cn-m alkyl- groups as defined herein.

[0911] As used herein “heterocycloalkyl -Cn-malkyl-” refers to a group of formula heterocycloalkyl-alkylene-, wherein alkylene linking group has n to m carbon atoms. The term “heterocycloalkyl -Cn-malkyl-” is understood to include deuterated analogs of the heterocycloalkyl and / or alkyl moieties of the heterocycloalkyl -Cn-malkyl- groups as defined herein.

[0912] 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, “C0.pcycloalkyl -Cn-m alkyl-”, “C0.paryl-Cn-malkyl-”, “phenyl-Cn-malkyl-”, “heteroaryl-Cn-malkyl-”, and “heterocycloalkyl-Cn-m alkyl-” contain alkyl linking groups. Examples of “alkyl linking groups” or “alkylene groups” include methylene, ethan- 1,1 -diyl, ethan- 1,2-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.

[0913] 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.

[0914] As used herein, a “cycloalkyl linking group” or “cycloalkylene linking group” is a bivalent straight chain or branched cycloalkyl linking group (“cycloalkylene group”).

[0915] Examples of “cycloalkyl linking groups” or “cycloalkylene groups” include cyclopropy-1,1,-diyl, cyclopropy- 1,2-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.

[0916] 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- 1,2-diyl, azetidin- 1,3 -diyl, pyrrolidin- 1,2-diyl, pyrrolidin-l,3-diyl, pyrrolidin-2,3-diyl, piperidin- 1,2-diyl, piperidin-l,3-diyl, piperidin-1,4-diyl, piperidin-2,3-diyl, piperidin-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. 54057-0031W01 / SNV0023-W01 PATENT

[0917] As used herein, a “heteroaryl linking group” or “heteroarylene linking group” is a bivalent straight chain or branched heteroaryl linking group (“heteroarylene group”).

[0918] Examples of “heteroaryl linking groups” or “heteroarylene groups” include pyrazol-l,3-diyl, imidazol- 1,2, -diyl, pyridin-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.

[0919] 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.

[0920] 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=O or C(O)), or attached to a nitrogen or sulfur heteroatom forming a nitroso, sulfinyl, or sulfonyl group.

[0921] 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.

[0922] 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.

[0923] 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 - 54057-0031W01 / SNV0023-W01 PATENT

[0924] 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-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[0925] 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.

[0926] 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.

[0927] 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.

[0928] 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.

[0929] 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.

[0930] 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. 54057-0031W01 / SNV0023-W01 PATENT

[0931] 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.

[0932] 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 nontoxic 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.

[0933] Synthesis

[0934] 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.

[0935] Compounds of Formula I, such as compounds of formula 1-9, can be prepared according to Scheme 1 Chlorosulfonylation of compound 1-1 can provide the sulfonyl chloride 1-2, which can react with amine 1-3 to provide the sulfonamide 1-4. Subsequent a-arylation and condensation of compound 1-4 with compound 1-5 in the presence of a transition metal (e.g. CuBr) can yield compound 1-6. Compound 1-6 can be treated with POCl3to offer compound 1-7, which can then undergo functionalization with a suitable compound 1-8 (e.g. SnAr with a nucleophile, transition-metal catalyzed cross-coupling) to provide the desired final product 1-9. 54057-0031W01 / SNV0023-W01 PATENT

[0936] Scheme I.

[0937] 1-6

[0938]

[0939] Compounds of Formula II-B can be synthesized, for example, using a process shown in Scheme II. Treating II- 1 with NBS gives II- 2 which is subsequently converted to II-3 via treating with acetyl chloride. Upon treating with KHMDS, II-3 undergoes cyclization to provide II-4 which is then converted to II-6 by treating with II-5 and Hantzsch ester. The cross-coupling of II-6 with benzyl mercaptan gives II- 7 which is converted to II-8 by refluxing with POCh. Treating II-8 with NCS followed by II- 9 yields 11-10. SEM protection of sulfonamide gives II- 11 which undergoes SnAr reaction with 11-12 to afford 11-13. Upon treating with methane sulfonic anhydride, 11-13 cyclizes to give 11-14 which is then converted into 11-15 via suitable reactions (e.g., transition metal -catalyzed cross-coupling reactions).

[0940] The cross-coupling of 11-15 with zinc cyanide gives 11-16. Removal of the SEM group of II-16 affords the desired compound of Formula II-B. 54057-0031W01 / SNV0023-W01 PATENT

[0941] Scheme II.

[0942] 11-1 II-2 H-3 II-4

[0943]

[0944] Formula ll-B Compound of Formula III-B can be synthesized using a process shown in Scheme III. Treating III-l with ethyl acetoacetate gives III-2 which is converted to III- 3 via hydrogenation. Upon heating with III-4 in polyphosphoric acid, III- 3 is converted to III-5.

[0945] The cross-coupling of III-5 with benzyl mercaptan gives III-6 which is converted to III-7 by refluxing with POCI3. Treating III-7 with NCS followed by III-8 yields III-9. SEM protection of sulfonamide gives III-10 which is then converted into III-ll via suitable reactions (e.g., transition metal -catalyzed cross-coupling reactions). The cross-coupling of III-ll with zinc cyanide gives III-12. Removal of the SEM group of III-12 affords the desired compound of formula III. 54057-0031W01 / SNV0023-W01 PATENT

[0946] Scheme III.

[0947]

[0948] Formula lll-B

[0949] 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.

[0950] 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. 54057-0031W01 / SNV0023-W01 PATENT

[0951] 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., ’H 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.

[0952] 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.

[0953] Methods of Use

[0954] 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.

[0955] 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. IntJMol Sci, 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).

[0956] 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 54057-0031W01 / SNV0023-W01 PATENT

[0957] 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).

[0958] 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.

[0959] 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 BRCA1 -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.

[0960] DePARylation is essential in maintaining PAR homeostasis. PARG gene -dependency data indicate vulnerabilities in cancer cell lines across lineages, including skin, ovary / fallopian tube, lymphoid, lung, CNS / brain, and breast (DepMap, Broad (2023).

[0961] DepMap 23Q4 Public. Figshare+. Dataset, doi.org / 10.25452 / figshare.plus. 24667905,v2).

[0962] 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 54057-0031W01 / SNV0023-W01 PATENT

[0963] 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).

[0964] 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.

[0965] 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.

[0966] 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.

[0967] In some embodiments, the present disclosure provides methods of treating a variety of PARG-dependent diseases and disorders.

[0968] 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.

[0969] In some embodiments, the cancer is selected from ovarian cancer, colorectal cancer, breast cancer, prostate cancer, uterine cancer, and pancreatic cancer.

[0970] In some embodiments, the cancer is ovarian cancer. 54057-0031W01 / SNV0023-W01 PATENT

[0971] In some embodiments, the cancer is colorectal cancer.

[0972] In some embodiments, the cancer is breast cancer.

[0973] In some embodiments, the cancer is prostate cancer.

[0974] In some embodiments, the cancer is uterine cancer.

[0975] In some embodiments, the cancer is pancreatic cancer.

[0976] 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.

[0977] The present disclosure further provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.

[0978] 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.

[0979] 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 54057-0031W01 / SNV0023-W01 PATENT

[0980] culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal.

[0981] 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.

[0982] 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.

[0983] 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.

[0984] 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.

[0985] 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.

[0986] 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 54057-0031W01 / SNV0023-W01 PATENT

[0987] 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.

[0988] 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.

[0989] 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.

[0990] Combination Therapy

[0991] 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.

[0992] For example, a combination can include one or more inhibitors of the following kinases for the treatment of cancer: Aktl, Akt2, Akt3, TGF-pR, Pim, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, CDK4 / 6, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFaR, PDGF R, 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.

[0993] 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 JAK1 -selective, baricitinib or itacitinib), Pim kinase inhibitors (e.g., 54057-0031W01 / SNV0023-W01 PATENT

[0994] 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, CSF1R 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, ribociclib, and abemaciclib), BRAF inhibitors, mTOR inhibitors, proteasome inhibitors (Bortezomib, Carfilzomib), HDAC-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), hypoxiainducible 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-dioxygenase inhibitors (e.g., epacadostat, NLG919 or BMS-986205), PARP inhibitors (e.g., olaparib or rucaparib), and inhibitors of BTK such as ibrutinib.

[0995] 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.

[0996] 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, 54057-0031W01 / SNV0023-W01 PATENT

[0997] 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, pegfdgrastim, pemetrexed disodium, pentostatin, pilaralisib, pipobroman, plicamycin, ponatinib, porfimer, prednisone, procarbazine, quinacrine, ranibizumab, rasburicase, regorafenib, reloxafme, 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.

[0998] 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.

[0999] 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.

[1000] Example steroids include, but are not limited to, corticosteroids such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and prednisone.

[1001] Example immunosuppressants include, but are not limited to, azathioprine, chlorambucil, cyclophosphamide, cyclosporine, daclizumab, infliximab, methotrexate, and tacrolimus.

[1002] 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, 54057-0031W01 / SNV0023-W01 PATENT

[1003] fentanyl, remifentanil, buprenorphine, butorphanol, hydromorphone levorphanol, meperidine, methadone, morphine, nalbuphine, oxymorphone, pentazocine).

[1004] 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.

[1005] 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.

[1006] Pharmaceutical Formulations and Dosage Forms

[1007] 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.

[1008] 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.

[1009] 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 54057-0031W01 / SNV0023-W01 PATENT

[1010] 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.

[1011] 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.

[1012] 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.

[1013] 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.

[1014] 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.

[1015] 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. 54057-0031W01 / SNV0023-W01 PATENT

[1016] 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.

[1017] 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.

[1018] 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.

[1019] 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. 54057-0031W01 / SNV0023-W01 PATENT

[1020] 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.

[1021] Labeled Compounds and Assay Methods

[1022] 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.

[1023] 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 ( / . 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 fortritium),11C,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,125I,131I, or35S will generally be most useful. For radio-imaging applications11C,18F,125I,123I,124I,131I,75Br,76Br or77Br will generally be most useful.

[1024] 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 -CDs being substituted for -CHs). In some embodiments, alkyl groups of the disclosed Formulas (e.g., the compound of any of Formulas I-V) can be perdeuterated.

[1025] In some embodiments, the compound provided herein (e.g., the compound of any of Formulas I-VI), or a pharmaceutically acceptable salt thereof, comprises at least one deuterium atom. 54057-0031W01 / SNV0023-W01 PATENT

[1026] In some embodiments, the compound provided herein (e.g., the compound of any of Formulas I-VI), or a pharmaceutically acceptable salt thereof, comprises two or more deuterium atoms.

[1027] In some embodiments, the compound provided herein (e.g., the compound of any of Formulas I-VI), or a pharmaceutically acceptable salt thereof, comprises three or more deuterium atoms.

[1028] In some embodiments, for a compound provided herein (e.g., the compound of any of Formulas I-VI), or a pharmaceutically acceptable salt thereof, all of the hydrogen atoms are replaced by deuterium atoms (z.e., the compound is “perdeuterated”).

[1029] 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.

[1030] 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.

[1031] 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.

[1032] Radiopharm. 2015, 58, 308-312). In particular, substitution at one or more metabolism sites may afford one or more of the therapeutic advantages.

[1033] 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.

[1034] Kits

[1035] 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 54057-0031W01 / SNV0023-W01 PATENT

[1036] 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.

[1037] 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 PARG as described below.

[1038] EXAMPLES

[1039] Experimental procedures for compounds of the invention are provided below.

[1040] 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.

[1041] 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.

[1042] Example 1. 5-Fluoro-l-((l-methyl-LH-pyrazol-4-yl)oxy)-A-(l-methylcyclopropyl)isoquinoline-7-sulfonamide

[1043] F

[1044]

[1045] 54057-0031W01 / SNV0023-W01 PATENT

[1046] Step 1: 7-(benzylthio)-5-fluoroisoquinolin-l(2H)-one

[1047] O

[1048] Bn / S'Y^V^'NH

[1049] F

[1050] To a mixture of 7-bromo-5-fluoroisoquinolin-l(227)-one (400 mg, 1.65 mmol), PfTdbas (75.7 mg, 0.08 mmol), and Xantphos (95.6 mg, 0.17 mmol) in dioxane (0.4 M) was added DIPEA (0.87 m, 4.96 mmol) and BnSH (0.39 m, 3.31 mmol). The mixture was evacuated and backfilled with N2, then heated at 90 °C for 5 hours. The crude reaction mixture was purified by silica gel chromatography, eluting with 0-100% EtOAc in hexanes to afford the desired product. ECMS calculated for CK. HKFNOS (M+H)+m / z = 286.1; found m / z = 286.0.

[1051] Step 2: 7-(benzylthio)-l-chloro-5-fluoroisoquinoline

[1052] Bn'

[1053]

[1054] A suspension of 7-(benzylthio)-5-fluoroisoquinolin-l(227)-one (468 mg, 1.64 mmol) in POCI3 (0.55 M) was heated at 90 °C for 90 minutes. Upon cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was diluted with ice / water, then extracted with DCM x 3. The combined organic layers were washed with brine, then dried over anhydrous MgSCh. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-100% EtOAc in hexanes to afford the desired product. LCMS calculated for CieHnCIFNS (M+H)+m / z = 304.0; found m / z = 303.9.

[1055] Step 3: l-chloro-5-fluoro-N-(l-methylcyclopropyl)isoquinoline-7-sulfonamide

[1056]

[1057] To a suspension of 7-(benzylthio)-l-chloro-5 -fluoroisoquinoline (200 mg, 0.66 mmol) in a mixture of acetonitrile / water / AcOH (200 / 1 / 1, 0.25 M) at 0 °C was added 1,3-dichloro-5, 5 -dimethylhydantoin (195 mg, 0.99 mmol). The mixture was stirred at 0 °C for 1 54057-0031W01 / SNV0023-W01 PATENT

[1058] hour, then concentrated to dryness. The residue was suspended in DCM, then added dropwise to a pre-stirred mixture of 1-methylcyclopropanamine hydrochloride (212 mg, 1.98 mmol) and DIPEA (688 pL, 3.95 mmol) in DCM (0.2 M) at 0 °C. The resultant mixture was stirred at 0 °C for 1 hour, then diluted with water. The mixture was extracted with DCM x 3. The combined organic layers were washed with brine, then dried over anhydrous MgSCE. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-100% EtOAc in hexanes to afford the desired product. LCMS calculated for C13H13CIFN2O2S (M+H)+m / z = 315.0; found m / z = 314.9.

[1059] Step 4: 5-fluoro-l-((l-methyl-lH-pyrazol-4-yl)oxy)-N-(l-methylcyclopropyl)isoquinoline-7-sulfonamide

[1060] A mixture of 1 -chloro-5-fluoro-A-( 1 -methylcyclopropyl)isoquinoline-7-sulfonamide (25 mg, 0.08 mmol), 1 -methylpyrazol-4-ol (8.6 mg, 0.09 mmol), and CS2CO3 (38.8 mg, 0.12 mmol) in acetonitrile was stirred at 45 °C for 3 hours. The mixture was diluted with water, then extracted with EtOAc x 3. The combined organic layers were washed with brine, then dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-100% EtOAc in DCM then 0-10% MeOH in DCM. Fractions containing the desired product were combined and concentrated, then purified by prep-HPLC (column: Sunfire prep Cl 8 column, 30* 150 mm, 5μm; 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 C17H18FN4O3S (M+H)+m / z = 377.1; found 377.1.

[1061] Example 2.8-Fluoro-4-((l-methyl-l. H-pyrazol-4-yl)oxy)-V-(l-methylcyclopropyl)quinoline-6-sulfonamide

[1062]

[1063] Step 1: 6-bromo-8-fluoro-4-((l -methyl- lH-pyrazol-4-yl)oxy)quinoline 54057-0031W01 / SNV0023-W01 PATENT

[1064] O

[1065]

[1066] F

[1067] A mixture of 6-bromo-4-chloro-8-fluoroquinoline (240 mg, 0.92 mmol), 1-methylpyrazol-4-ol (99.4 mg, 1.01 mmol), and CS2CO3 (450 mg, 1.38 mmol) in acetonitrile was stirred at room temperature overnight. The mixture was diluted with water, then extracted with EtOAc x 3. The combined organic layers were washed with brine, then dried over anhydrous MgSCh. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-10% MeOH in DCM then 0-10% MeOH in DCM to afford the desired product. LCMS calculated for CisHioBrFNsO (M+H)+m / z = 322.0; found m / z = 321.9.

[1068] Step 2: 6-(benzylthio)-8-fluoro-4-((l-methyl-lH-pyrazol-4-yl)oxy)quinoline

[1069]

[1070] To a mixture of 6-bromo-8-fluoro-4-(( I -methyl- l / / -pyrazol-4-yl)ox (quinoline (130 mg, 0.40 mmol), Pd2dbas (18.5 mg, 0.02 mmol), and Xantphos (23.4 mg, 0.04 mmol) in dioxane (0.4 M) was added DIPEA (0.21 mL, 1.21 mmol) and BnSH (0.09 mL, 0.81 mmol). The mixture was evacuated and backfilled with N2, then heated at 80 °C for 5 hours. The crude reaction mixture was purified by silica gel chromatography, eluting with 0-100% EtOAc in hexanes to afford the desired product. LCMS calculated for C20H17FN3OS (M+H)+m / z = 366.1; found m / z = 366.1.

[1071] Step 3: 8-fluoro-4-((l -methyl- lH-pyrazol-4-yl)oxy)-N-(l -methylcyclopropyl)quinoline-6-sulfonamide

[1072] To a suspension of 6-(benzylthio)-8-fluoro-4-((l -methyl- IH-pyrazol -4-yl)oxy)quinoline (260 mg, 0.71 mmol) in a mixture of acetonitrile / water / AcOH (200 / 1 / 1, 0.25 M) at 0 °C was added 1, 3 -dichloro-5, 5 -dimethylhydantoin (210 mg, 1.07 mmol). The mixture was stirred at 0 °C for 1 hour, then concentrated to dryness. The residue was suspended in 54057-0031W01 / SNV0023-W01 PATENT

[1073] DCM, then added dropwise to a pre-stirred mixture of 1-methylcyclopropanamine hydrochloride (230 mg, 2.13 mmol) and DIPEA (744 pL, 4.27 mmol) in DCM (0.2 M) at 0 °C. The resultant mixture was stirred at 0 °C for 1 hour, then diluted with water. The mixture was extracted with DCM x 3. The combined organic layers were washed with brine, then dried over anhydrous MgSCE. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-100% EtOAc in DCM then 0-10% MeOH in DCM. Fractions containing the desired product were combined and concentrated, then purified by prep-HPLC (column: Sunfire prep Cl 8 column, 30* 150 mm, 5μm; 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 C17H18FN4O3S (M+H)+m / z = 377.1; found 377.1.

[1074] Example 3.6-((l-Methyl-EH-pyrazol-4-yl)oxy)-A-(l-methylcyclopropyl)-l, 2,3,4-tetrahydrobenzo[c][l,6]naphthyridine-8-sulfonamide

[1075]

[1076] Step 1: 3-carbamoyl-4-iodobenzenesulfonyl chloride

[1077] °s / / 0A

[1078] er ~Y^Y^NH2

[1079] A solution of 2-iodobenzamide (15.0 g, 60.7 mmol) was heated in chlorosulfonic acid (2.1 M) at 130 °C for 4 hours. Upon cooling to room temperature, the mixture was carefully poured into ice / water. The precipitated solids were collected via filtration and washed with water. The resulting solid were dried under vacuum to afford the desired product, which was used in the next step without further purification.

[1080] Step 2: 2-iodo-5-(N-(l-methylcyclopropyl)sulfamoyl)benzamide 54057-0031W01 / SNV0023-W01 PATENT

[1081]

[1082] To a solution of 1 -methylcyclopropanamine hydrochloride (3.42 g, 31.8 mmol) and EtsN (12.0 mL, 86.8 mmol) in dioxane / water (5 / 1, 0.2 M) was added 3 -carbamoyl -4-iodobenzenesulfonyl chloride (10 g, 28.9 mmol) in portions. The resultant mixture was stirred at room temperature for 2 hours, then acidified to pH 3.0 with IN HC1. The mixture was extracted with EtOAc x 3. The combined organic layers were washed with brine, then dried over anhydrous MgSCE. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-100% EtOAc in DCM to afford the desired product. LCMS calculated for C11H14IN2O3S (M+H)+m / z = 381.0; found 381.0.

[1083] Step 3: tert-butyl 8-(N-(l-methylcyclopropyl)sulfamoyl)-6-oxo-3,4,5,6-tetrahydrobenzo[c] [1, 6 ]naphthyridine-2(lH)-carboxylate

[1084]

[1085] Boc

[1086] A mixture of 2-iodo-5-(A'-(l-mcthylcyclopropyl)sulfamoyl)bcnzamidc (140 mg, 0.37 mmol), tert-butyl 4-oxopiperidine-l -carboxylate (110 mg, 0.55 mmol), CS2CO3 (240 mg, 0.74 mmol), and CuBr (5.3 mg, 0.04 mmol) in DMSO (0.1 M) was heated at 80 °C for 3 hours. Upon cooling to room temperature, the mixture was diluted with water. The precipitated solids were collected via filtration and washed with water. The resulting solid was dried under vacuum to afford the desired product, which was used in the next step without further purification. LCMS calculated for C21H28N3O5S (M+H)+m / z = 434.2; found m / z = 434.1.

[1087] Step 4: tert-butyl 6-chloro-8-(N-(l-methylcyclopropyl)sulfamoyl)-3,4-dihydrobenzo[c] [1, 6 ]naphthyridine-2( lH)-carboxylate

[1088] Boc

[1089]

[1090] 54057-0031W01 / SNV0023-W01 PATENT

[1091] A suspension of tert-butyl 8-(A-(l-methylcyclopropyl)sulfamoyl)-6-oxo-3, 4,5,6-tetrahydrobenzo[c][l,6]naphthyridine-2(12 / )-carboxylate (600 mg, 1.38 mmol) in POCh (0.55 M) was heated at 90 °C for 90 minutes. Upon cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was diluted with dioxane / water (3 / 1, 0.2 M), then NaHC’CF (1.2 g, 13.8 mmol) was added in portions, followed by BOC2O (454 mg, 2.08 mmol). The mixture was stirred at room temperature overnight, then diluted with water. The mixture was extracted with EtOAc x 3. The combined organic layers were washed with brine, then dried over anhydrous MgSCE. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-70% EtOAc in hexanes to afford the desired product. LCMS calculated for C21H27CIN3O4S (M+H)+m / z = 452.1 found m / z = 452.1.

[1092] Step 5: 6-((l-methyl-lH-pyrazol-4-yl)oxy)-N-(l-methylcyclopropyl)-l,2, 3,4-tetrahydrobenzo [c] [1,6]naphthyridine-8-sulfonamide

[1093] A mixture of tert-butyl 6-chloro-8-(A-( l-mcthylcyclopropyl)sulfamoyl)-3.4-dihydrobcnzo|c || 1.6 |naphthyridinc-2( I / / (-carbox late (25 mg, 0.06 mmol), 1-methylpyrazol-4-ol (6.0 mg, 0.06 mmol), and CS2CO3 (27.0 mg, 0.08 mmol) in acetonitrile was stirred at 70 °C for 3 hours. The mixture was diluted with water, then extracted with EtOAc x 3. The combined organic layers were washed with brine, then dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was stirred in TFA (0.1 M) at room temperature for 1 hour, then diluted with acetonitrile and purified by prep-HPLC (column: Sunfire prep C18 column, 30* 150 mm, 5μm; 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 C20H24N5O3S (M+H)+m / z = 414.2; found 414.2.

[1094] Example 4. Methyl 6-((l-methyl-LH-pyrazol-4-yl)oxy)-8-( / V-(l-methylcyclopropyl)sulfamoyl)-3,4-dihydrobenzo[c][l,6]naphthyridine-2(LH)-carboxylate 54057-0031W01 / SNV0023-W01 PATENT

[1095]

[1096] To a solution of 6-((l-methyl-lH-pyrazol-4-yl)oxy)-A-(l-methylcyclopropyl)-l,2,3,4-tetrahydrobenzo[c][l,6]naphthyridine-8-sulfonamide (Example 3: 23 mg, 0.06 mmol) and EtsN (23.1 pL,.17 mmol) in DCM (0.1 M) was added methyl chloroformate (6.4 pL, 0.08 mmol). The mixture was stirred at room temperature for 1 hour, then diluted with methanol and purified by prep-HPLC (column: Sunfire prep C18 column, 30* 150 mm, 5μm; 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 C22H26N5O5S (M+H)+m / z = 472.2; found 472.2.

[1097] Example 5. Methyl 3-methyl-6-(( l-methyl-l / / -pyrazol-4-yl)oxy)-8-(A (l-methylcyclopropyl)sulfamoyl)-3,4-dihydrobenzo[c][l,6]naphthyridine-2(EH)-carboxylate

[1098]

[1099] Step 1: 5-(chlorosulfonyl)-2-iodobenzoic acid

[1100]

[1101] A solution of 2-iodobenzoic acid (20.0 g, 76.3 mmol) was heated in chlorosulfonic acid (2.1 M) at 120 °C for 4 hours. Upon cooling to room temperature, the mixture was carefully poured into ice / water. The precipitated solids were collected via fdtration and 54057-0031W01 / SNV0023-W01 PATENT

[1102] washed with water. The resulting solids were dried under vacuum to afford the desired product, which was used in the next step without further purification.

[1103] Step 2: 2-iodo-5-(N-(l-methylcyclopropyl)sulfamoyl)benzoic acid

[1104]

[1105] To a solution of 1 -methylcyclopropanamine hydrochloride (2.73 g, 25.4 mmol) and EtsN (9.6 mL, 69.3 mmol) in dioxane / water (5 / 1, 0.2 M) was added 5-(chlorosulfonyl)-2-iodobenzoic acid (8.0 g, 23.1 mmol) in portions. The resultant mixture was stirred at room temperature for 2 hours, then acidified with IN HC1 to pH = 3. The mixture was extracted with EtOAc x 3. The combined organic layers were washed with brine, then dried over anhydrous MgSCE. After filtration, the filtrate was concentrated under reduced pressure to afford the desired product, which was used in the next step without further purification. LCMS calculated for C11H13INO4S (M+H)+m / z = 382.0; found 382.0.

[1106] Step 3: N-(2, 4-dimethoxybenzyl)-2-iodo-5-(N-(l-methylcyclopropyl)sulfamoyl)benzamide

[1107]

[1108] To amixture of 2-iodo-5-( '-(l-mcthylcyclopropyl)siilfamoyl)bcnzoic acid (1.00 g, 2.62 mmol), HATU (1.3 g, 3.41 mmol), and DIPEA (914 pL, 5.25 mmol) in DMF (0.25 M) was added (2,4-dimethoxyphenyl)methanamine (473 pL, 3.15 mmol). The mixture was stirred at room temperature for 30 minutes, then diluted with water. The mixture was extracted with EtOAc x 3. The combined organic layers were washed with brine, then dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-50% EtOAc in hexanes to afford the desired product. LCMS calculated for C20H24IN2O5S (M+H)+m / z = 531.0 found m / z = 531.1.

[1109] Step 4: tert-butyl 5-(2,4-dimethoxybenzyl)-8-(N-(l-methylcyclopropyl)sulfamoyl)-6-oxo-3, 4,5, 6-tetrahydrobenzo[c] [1,6] naphthyridine -2(1 H) -carboxylate 54057-0031W01 / SNV0023-W01 PATENT

[1110] OMe

[1111]

[1112] Boc

[1113] A mixture of A-(2,4-dimethoxybenzyl)-2-iodo-5-(A-(l-methylcyclopropyl)sulfamoyl)benzamide (750 mg, 1.41 mmol), tert-butyl 4-oxopiperidine-l-carboxylate (0.42 g, 0.12 mmol), CS2CO3 (921 mg, 2.83 mmol), and CuBr (20.3 mg, 0.14 mmol) in DMSO (0.1 M) was heated at 80 °C for 4 hours. Upon cooling to room temperature, the mixture was diluted with a saturated aqueous solution of ammonium chloride. The mixture was extracted with EtOAc x 3. The combined organic layers were washed with water, brine, then dried over anhydrous MgSCE. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-100% EtOAc in hexanes to afford the desired product. LCMS calculated for C30H38N3O7S (M+H)+m / z = 584.2 found m / z = 583.9.

[1114] Step 5: tert-butyl 5-(2,4-dimethoxybenzyl)-8-(N-(l-methylcyclopropyl)-N-((2-( trimethylsilyl)ethoxy)methyl)sulfamoyl)-6-oxo-3, 4, 5, 6-tetrahydrobenzo[c] [1, 6 ]naphthyridine-2(lH)-carboxylate

[1115] OMe

[1116]

[1117] Boc

[1118] To a mixture of tert-butyl 5-(2,4-dimethoxybenzyl)-8-(A-(l-mcthylcyclopropyl)sulfamoyl)-6-oxo-3.4.5.6-tctrahydrobcnzo|c|| l.6|naphthyridinc-2( IH)-carboxylate (965 mg, 1.65 mmol) and DBU (742 pL, 4.96 mmol) in DCM (0.2 M) at 0 °C was added SEM-C1 (585 pL. 3.31 mmol). The mixture was stirred at room temperature overnight, then additional DBU (370 pL, 2.48 mmol) and SEM-C1 (293 pL, 1.66 mmol) were added. The mixture was stirred for an additional 4 hours, then diluted with water. The mixture was extracted with EtOAc x 3. The combined organic layers were washed with brine, then 54057-0031W01 / SNV0023-W01 PATENT

[1119] dried over anhydrous MgSC. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-100% EtOAc in hexanes to afford the desired product. LCMS calculated for CAH^NsChSSi (M+H)+m / z = 714.3 found (M+Na)+m / z = 736.1.

[1120] Step 6: tert-butyl 5-(2,4-dimethoxybenzyl)-3-methyl-8-(N-(l-methylcyclopropyl)-N-((2-( trimethylsilyl)ethoxy)methyl)sulfamoyl)-6-oxo-3, 4, 5, 6-tetrahydrobenzo[c] [1, 6 ]naphthyridine-2(lH)-carboxylate

[1121] OMe

[1122]

[1123] i

[1124] Boc

[1125] To a solution of tert-butyl 5-(2,4-dimethoxybenzyl)-8-(A-(l-methylcyclopropyl)-A-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-6-oxo-3, 4,5,6-tctrahydrobcnzo|c|| l.6|naphthyridinc-2( IH)-carboxylatc (300 mg, 0.42 mmol) in anhydrous THF (0.2 M) at 0 °C was added NaHMDS (1.0 M in THF, 925 pL, 0.93 mmol) dropwise. The mixture was stirred at 0 °C for 1 hour, then a solution of iodomethane (28.8 pL, 0.46 mmol) in anhydrous THF (0.5 M) was added dropwise. After complete addition, the mixture was allowed to warm to room temperature while stirring for 2 hours, then the mixture was diluted with a saturated aqueous solution of ammonium chloride. The mixture was extracted with EtOAc x 3. The combined organic layers were washed with water, brine, then dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-50% EtOAc in hexanes to afford the desired product. LCMS calculated for C3? H54N30sSSi (M+H)+m / z = 728.3 found (M+Na)+m / z = 750.1.

[1126] Step 7: methyl 3-methyl-8-(N-(l-methylcyclopropyl)sulfamoyl)-6-oxo-3,4,5,6-tetrahydrobenzo[c] [1, 6 ]naphthyridine-2(lH)-carboxylate 54057-0031W01 / SNV0023-W01 PATENT

[1127]

[1128] A mixture of tert-butyl 5-(2,4-dimethoxybenzyl)-3-methyl-8-(A-(l-methylcyclopropyl)-A-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-6-oxo-3,4,5,6-tetrahydrobenzo[c][l,6]naphthyridine-2(127)-carboxylate (220 mg, 0.30 mmol) in TFA (0.3 M) was heated at 60 °C for 90 minutes. Upon cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was diluted with DCM (0.25 M), then EtsN (83 pL, 0.60 mmol) was added, followed by methyl chloroformate (57.1 mg, 0.60 mmol). The mixture was stirred at room temperature overnight, then diluted with water. The mixture was extracted with DCM x 3. The combined organic layers were washed with brine, then dried over anhydrous MgSCh. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-100% EtOAc in hexanes to afford the desired product. LCMS calculated for C19H24N3O5S (M+H)+m / z = 406.1 found m / z = 406.2.

[1129] Step 8: methyl 6-chloro-3-methyl-8-(N-(l-methylcyclopropyl)sulfamoyl)-3,4-dihydrobenzo [c] [1, 6 ]naphthyridine-2( lH)-carboxylate

[1130]

[1131] A suspension of methyl 3-mcthyl-8-(A-( l-mcthylcyclopropyl)sulfamoyl)-6-oxo-3.4.5.6-tctrahydrobcnzo|c|| l.6|naphthyridinc-2( IH)-carboxylatc (85 mg, 0.21 mmol) in POCI3 (0.55 M) was heated at 90 °C for 90 minutes. Upon cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was diluted with ice / water, then extracted with DCM x 3. The combined organic layers were washed with brine, then dried over anhydrous MgSCfi. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-100% EtOAc in hexanes to afford the desired product. LCMS calculated for C19H23CIN3O4S (M+H)+m / z = 424.1; found m / z = 424.1. 54057-0031W01 / SNV0023-W01 PATENT

[1132] Step 9: methyl 3-methyl-6-((l-methyl-lH-pyrazol-4-yl)oxy)-8-(N-(l-methylcyclopropyl)sulfamoyl)-3,4-dihydrobenzo[c] [l,6]naphthyridine-2(lH)-carboxylate A mixture of methyl 6-chloro-3-mcthyl-8-(A-( l-mcthylcyclopropyl)sulfamoyl)-3.4-dihydrobcnzo|c || 1.6 |naphthyridinc-2( I / / (-carboxylate (15 mg, 0.04 mmol), 1 -methylpyrazol-4-ol (13.9 mg, 0.14 mmol), and CS2CO3 (19.6 mg, 0.14 mmol) in acetonitrile was stirred at 70 °C for 2 hours. The mixture was diluted with acetonitrile and purified by prep-HPLC (column: Sunfire prep C18 column, 30* 150 mm, 5μm; 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 C23H28N5O5S (M+H)+m / z = 486.2; found 486.2.

[1133] Example 6.4-(3,3-Difluoroazetidine-l-carbonyl)-8-[(35,5iS)-3,5-dimethylpiperazin-l-yl]-2-methoxy-A-(l-methylcyclopropyl)quinazoline-6-sulfonamide

[1134]

[1135] Step 1: 8-bromo-2,4-dioxo-l,2,3,4-tetrahydroquinazoline-6-sulfonyl chloride

[1136]

[1137] To 8-bromoquinazoline-2,4( 12,32 / )-dione (6.0 g, 24.7 mmol) was added chlorosulfonic acid (28.8 g, 246.9 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 collected via filtration. 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.

[1138] Step 2: 8-bromo-N-(l -methylcyclopropyl) -2, 4-dioxo-l,2, 3, 4-tetrahydroquinazoline-6-sulfonamide 54057-0031W01 / SNV0023-W01 PATENT

[1139]

[1140] To a solution of 1-methylcyclopropanamine hydrochloride (3.2 g, 29.5 mmol) in DCM was added triethylamine (20.5 mL, 147.6 mmol). 8-bromo-2,4-dioxo-l,2,3,4-tetrahydroquinazoline-6-sulfonyl chloride (8.40 g, 24.6 mmol) was then added in portions. 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 CnHisBrNsC S (M+H)+m / z = 374.0; found 374.0.

[1141] Step 3: 8-bromo-2, 4-dichloro-N-(l-methylcyclopropyl)quinazoline-6-sulfonamide

[1142]

[1143] To a mixture of 8-bromo-A'-( I -mcthylcyclopropyl)-2.4-dioxo- 1.2,3,4-tetrahydroquinazoline-6-sulfonamide (8.00 g, 21.3 mmol) in POCI3 (32.6 g, 212.6 mmol) at 0 °C was added DIPEA (9.04 mL, 53.2 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 NaHCOs (aq), dried over MgSCE, 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.

[1144] Step 4: 8-bromo-2-chloro-4-(l-ethoxyvinyl)-N-(l-methylcyclopropyl)quinazoline-6-sulfonamide

[1145]

[1146] 54057-0031W01 / SNV0023-W01 PATENT

[1147] To a solution of 8-bromo-2,4-dichloro-A-(l-methylcyclopropyl)quinazoline-6-sulfonamide (5.00 g, 12.2 mmol) in THF was added tributyl(l-ethoxyvinyl)stannane (5.3 g, 14.6 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 C’l. HisBrCINsOsS (M+H)+m / z = 446.0; found 446.0.

[1148] Step 5: ethyl 8-bromo-2-chloro-6-[(l-methylcyclopropyl)sulfamoyl]quinazoline-4-carboxylate

[1149]

[1150] To a solution of 8-bromo-2-chloro-4-( I -ethoxy vinyl )- '-( I -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. NaHCOs (aq). The mixture was filtered through a celite pad. The celite pad was rinsed with EtOAc. The combined fdtrate was washed with water, brine, and concentrated. The residue was purified by silica gel column chromatography, eluted with 50% EtOAc in Hexanes to give the desired product. LCMS calculated for Ci5HieBrClN3O4S (M+H)+m / z = 448.0; found 448.0.

[1151] Step 6: ethyl 8-bromo-6-(N-(l-methylcyclopropyl)sulfamoyl)-2-(methylthio)quinazoline-4-carboxylate

[1152] CK.0. /

[1153] y V Y

[1154] « Y 1 1

[1155]

[1156] Br

[1157] To a mixture of ethyl 8-bromo-2-chloro-6-(N-(l-methylcyclopropyl)sulfamoyl)quinazoline-4-carboxylate (2.10 g, 4.7 mmol) in DMF (20 mb) at 0 °C was added sodium thiomethoxide (492.0 mg, 7.0 mmol) portion wise. The mixture 54057-0031W01 / SNV0023-W01 PATENT

[1158] 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 CieHi9BrN3O4S2 (M+H)+m / z = 460.0; found 460.0.

[1159] Step 7: Ethyl 8-bromo-6-(N-(l-methylcyclopropyl)sulfamoyl)-2-(methylsulfinyl)quinazoline-4-carboxylate

[1160]

[1161] To a mixture of ethyl 8-bromo-6-(A-(l-methylcyclopropyl)sulfamoyl)-2-(methylthio)quinazoline-4-carboxylate (900 mg, 2.0 mmol) in DCM (10 mb) at 0 °C was added 3 -chloroperbenzoic acid (405 mg, 2.34 mmol) in portions. After stirring at 0 °C for 1 h, the reaction mixture was diluted with water (50 mL) and adjusted to pH 8 with saturated sodium bicarbonate (aq.). The resulting mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford the desired product (800 mg) as a light yellow solid. LCMS calculated for CieHi9BrN3O5S2 (M+H)+m / z = 476.0; found 476.0.

[1162] Step 8: 8-Bromo-2-methoxy-6-(N-(l-methylcyclopropyl)sulfamoyl)quinazoline-4-carboxylic acid

[1163]

[1164] To a mixture of ethyl 8-bromo-6-(A-( l-mcthylcyclopropyl)siilfamoyl)-2-(methylsulfmyl)quinazoline-4-carboxylate (800 mg, 1.68 mmol) in acetonitrile (4 mL) and methanol (2 mL) was added DBU (639 mg, 42 mmol) at room temperature. The resulting mixture was stirred at room temperature for 30 min. The reaction was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (0.1% formic 54057-0031W01 / SNV0023-W01 PATENT

[1165] acid), 10% to 50% gradient in 30 min; detector, UV 254 nm. Fractions were collected and lyophilized to provide the desired product as a light yellow solid. LCMS calculated for CuHisBrNsOsS (M+H)+m / z = 416.0; found 416.0.

[1166] Step 9: 8-Bromo-4-(3, 3-difluoroazetidine-l-carbonyl)-2-methoxy-N-(l-methylcyclopropyl)quinazoline-6-sulfonamide

[1167] N

[1168]

[1169] To a mixture of 8-bromo-2-methoxy-6-(A-( 1 -methylcyclopropyl)sulfamoyl)quinazoline-4-carboxylic acid (100 mg, 0.24 mmol), 3,3-difluoroazetidine hydrochloride (62 mg, 0.48 mmol) and 1 -methyl- IH-imidazole (99 mg, 1.2 mmol) in acetonitrile (1 mb) was added chloro -N, N, N', N' -tetramethylformamidinium hexafluorophosphate (81 mg, 0.29 mmol) at room temperature. After stirring at room temperature for 2 h, the reaction mixture 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 light yellow solid. LCMS calculated for Ci7Hi8BrF2N4O4S (M+H)+m / z = 491.0; found 491.1.

[1170] Step 10: 8-Bromo-4-(3, 3-difluoroazetidine-l-carbonyl)-2-methoxy-N-(l-methylcyclopropyl)- N-((2-(trimethylsilyl)ethoxy)methyl)quinazoline-6-sulfonamide

[1171] N

[1172]

[1173] To a solution of 8-bromo-4-(3,3-difluoroazetidine-l-carbonyl)-2-methoxy-A-(l-methylcyclopropyl)quinazoline-6-sulfonamide (60 mg, 0.12 mmol) and DBU (56 mg, 0.37 mmol) in DCM (1 mL) was added [2-(chloromethoxy)ethyl]trimethylsilane (102 mg, 0.61 mmol) at room temperature. After stirring at room temperature for 1 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 20% ethyl acetate in hexanes to afford the desired product as a 54057-0031W01 / SNV0023-W01 PATENT

[1174] light yellow solid. LCMS calculated for C23H32BrF2N4C>5SSi (M+H)+m / z = 621.1; found 621.1.

[1175] Step 11: Tert-butyl (2S,6S)-4-(4-(3,3-difluoroazetidine-l-carbonyl)-2-methoxy-6-(N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)quinazolin-8-yl)-2,6-dimethylpiperazine-l-carboxylcite

[1176]

[1177] Boc

[1178] To a screw-cap vial equipped with a magnetic stir bar were placed 8-bromo-4-(3,3-difluoroazetidine- 1 -carbony 1 )-2-mcthoxy-A'-( 1 -mcthylcyclopropy I )-A'-((2-(trimethylsilyl)ethoxy)methyl)quinazoline-6-sulfonamide (45 mg, 0.07 mmol), tert-butyl (2S,6S)-2,6-dimethylpiperazine-l -carboxylate (23 mg, 0.11 mmol), Pd2(dba)3 (13 mg, 0.014 mmol), BINAP (9.02 mg, 0.014 mmol) and cesium carbonate (71 mg, 0.22 mmol). The vial was sealed with a Teflon-lined septum, evacuated and backfilled with nitrogen (this process was repeated a total of three times). Toluene (1 mL) was added. The resulting mixture was stirred at 100 °C for 16 h. Upon cooling to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (20% ethyl acetate in hexanes) to afford the desired product as a light yellow solid. LCMS calculated for C34H53F2N6O7SSi (M+H)+m / z = 755.3; found 755.3.

[1179] Step 12: 4-(3,3-Difluoroazetidine-l-carbonyl)-8-((3S,5S)-3,5-dimethylpiperazin-l-yl)-2-methoxy-N-( 1 -methylcyclopropyl)quinazoline-6-sulfonamide

[1180] To a solution of tert-butyl (2S,6S)-4-(4-(3,3-difluoroazetidine-l-carbonyl)-2-methoxy-6-( N-( 1 -mcthylcyclopropy I )- '-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)quinazolin-8-yl)-2,6-dimethylpiperazine-l-carboxylate (20 mg, 0.02 mmol) in DCM (1 mL) was added TFA (1 mL) at room temperature. After stirring at room temperature for 1 h, the reaction mixture was concentrated under reduced pressure. The residue was diluted with acetonitrile (2 mL). To the above mixture was added aqueous ammonia (0.1 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 30 min, and then concentrated under reduced 54057-0031W01 / SNV0023-W01 PATENT

[1181] pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (10 mmol / L ammonium bicarbonate), 10% to 90% gradient in 30 min; detector, UV 254 nm. Fractions were collected and lyophilized to provide the desired product as an orange solid (3.6 mg). LCMS calculated for C23H31F2N6O4S (M+H)+m / z = 525.2; found 525.3. 'HNMR (400 MHz, DMSO-d6) 58.49 (d, J= 2.0 Hz, 1H), 8.28 (s, 1H), 7.51 (d, J= 2.0 Hz, 1H), 4.88 - 4.76 (m, 2H), 4.75 - 4.63 (m, 2H), 4.09 (s, 3H), 3.30 - 3.26 (m, 2H), 3.26 - 3.19 (m, 2H), 3.10 - 3.01 (m, 2H), 1.21 (d, J= 6.4 Hz, 6H), 1.06 (s, 3H), 0.70 - 0.61 (m, 2H), 0.45 - 0.36 (m, 2H).

[1182] Example 7. JV-(3,3-Difluorocyclobutyl)-8-((3iS,5iS)-3,5-dimethylpiperazin-l-yl)-2-methoxy-6-(2V-(l-methylcyclopropyl)sulfamoyl)quinazoline-4-carboxamide

[1183]

[1184] The title compound was prepared according to the procedure described in Example 6, using 3,3-difluorocyclobutan-l-amine instead of 3, 3 -difluoroazetidine hydrochloride in Step 9. LCMS calculated for C24H33F2N6O4S (M+H)+m / z = 539.2; found 539.3. 'H NMR (400 MHz, DMSO-6) 59.58 (d, J= 7.2 Hz, 1H), 8.58 (d, J= 2.0 Hz, 1H), 8.26 (s, 1H), 7.52 (d, J = 2.0 Hz, 1H), 4.45 - 4.34 (m, 1H), 4.11 (s, 3H), 3.31 - 3.27 (m, 2H), 3.24 - 3.17 (m, 2H), 3.13 - 2.96 (m, 4H), 2.92 - 2.75 (m, 2H), 2.10 (s, 1H), 1.22 (d, J= 6.4 Hz, 6H), 1.05 (s, 3H), 0.68 - 0.58 (m, 2H), 0.44 - 0.34 (m, 2H).

[1185] Example 8. Methyl 10-chloro-6-((l-(difluoromethyl)-LH-pyrazol-4-yl)oxy)-8-(JV-(l-methylcyclopropyl)sulfamoyl)-3,4-dihydrobenzo[c][l,6]naphthyridine-2(LH)-carboxylate 54057-0031W01 / SNV0023-W01 PATENT

[1186]

[1187] Step 1: 2-iodo-5-[(l-methylcyclopropyl)sulfamoyl]benzamide

[1188]

[1189] To a suspension of 2-iodo-5-(A-(l-methylcyclopropyl)sulfamoyl)benzoic acid (as prepared in Example 5, Steps 1-2, 3.70 g, 9.71 mmol) in toluene (1 M) was added thionyl chloride (4.93 mL, 68.0 mmol). The mixture was heated at 90 °C for 3 hours, then cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in small amount of acetonitrile, then added dropwise to a solution of ammonium hydroxide (28-30% solution in water, 97.1 mmol) in acetonitrile (0.5 M) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour, then acidified to pH 5 with aqueous HC1. The mixture was extracted with EtOAc x 3. The combined organic layers were washed with brine, then dried over anhydrous MgSCE. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-100% EtOAc in DCM to afford the desired product. LCMS calculated for C11H14IN2O3S (M+H)+m / z = 381.0; found 381.2.

[1190] Step 2: tert-butyl 8-(N-(l-methylcyclopropyl)sulfamoyl)-6-oxo-3,4,5,6-tetrahydrobenzo[c] [1, 6 ]naphthyridine-2(lH)-carboxylate

[1191]

[1192] Boc

[1193] A mixture of 2-iodo-5-[(l-methylcyclopropyl)sulfamoyl]benzamide (1.10 g, 2.89 mmol), tert-butyl 4-oxopiperidine-l -carboxylate (0.86 g, 4.34 mmol), CS2CO3 (1.89 g, 5.79 54057-0031W01 / SNV0023-W01 PATENT

[1194] mmol), and CuBr (41.5 mg, 0.29 mmol) in DMSO (0.1 M) was heated at 80 °C for 3 hours. Upon cooling to room temperature, the mixture was diluted with a saturated aqueous solution of ammonium chloride. The slurry was stirred at room temperature for 10 minutes, then the solids were collected via filtration and used in the next step without further purification. UCMS calculated for C21H28N3O5S (M+H)+m / z = 434.2 found m / z = 434.2.

[1195] Step 3: tert-butyl 10-chloro-8-(N-(l-methylcyclopropyl)sulfamoyl)-6-oxo-3,4,5,6-tetrahydrobenzo[c] [1, 6 ]naphthyridine-2(lH)-carboxylate

[1196]

[1197] Boc

[1198] A mixture of tert-butyl 8-( / V-(l-methylcyclopropyl)sulfamoyl)-6-oxo-3, 4,5,6-tctrahydrobcnzo|c|| l.6|naphthyridinc-2( IH)-carboxylatc (470.0 mg, 1.08 mmol) and NCS (217 mg, 1.63 mmol) in MeCN was stirred at 50 °C for 10 hours. The mixture was concentrated under reduced pressure, then purified by silica gel chromatography, eluting with 0-5% MeOH in DCM to afford the desired product. LCMS calculated for C21H27CIN3O5S (M+H)+m / z = 468.1; found 468.1.

[1199] Step 4: methyl 6,10-dichloro-8-(N-(l-methylcyclopropyl)sulfamoyl)-3,4-dihydrobenzo [c] [1, 6 ]naphthyridine-2( lH)-carboxylate

[1200]

[1201] A suspension of tert-butyl 10-chloro-8-(A-(l-methylcyclopropyl)sulfamoyl)-6-oxo-3,4,5,6-tetrahydrobenzo[c][l,6]naphthyridine-2(U7)-carboxylate (140 mg, 0.30 mmol) in POCh (0.55 M) was heated at 90 °C for 90 minutes. Upon cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was diluted with ice / water / dioxane. To this mixture was slowly added NaHCOs until pH > 7, then methyl chloroformate (84.8 mg, 0.90 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, then extracted with ethyl acetate. The combined organic layers were 54057-0031W01 / SNV0023-W01 PATENT

[1202] washed with brine, then dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-80% EtOAc in DCM to afford the desired product. LCMS calculated for CI8H2OC12N304S (M+H)+m / z = 444.1; found m / z = 444.1.

[1203] Step 5: methyl 10-chloro-6-((l-(difluoromethyl)-lH-pyrazol-4-yl)oxy)-8-(N-(l-methylcyclopropyl)sulfamoyl)-3,4-dihydrobenzo[c] [l,6]naphthyridine-2(lH)-carboxylate A mixture of methyl 6,10-dichloro-8-(A-(l-methylcyclopropyl)sulfamoyl)-3,4-dihydrobcnzo|c || 1.6 |naphthyridinc-2( I / / (-carboxylate (10 mg, 0.02 mmol), 1-(difluoromethyl)pyrazol-4-ol (12.1 mg, 0.09 mmol), and K2CO3 (12.4 mg, 0.09 mmol) in acetonitrile was stirred at 80 °C for 4 hours. The mixture was diluted with water, then extracted with EtOAc x 3. The combined organic layers were washed with brine, then dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was stirred in TFA (0.1 M) at room temperature for 1 hour, then diluted with acetonitrile and purified by prep-HPLC (column: Sunfire prep C18 column, 30* 150 mm, 5μm; 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 C22H23CIF2N5O5S (M+H)+m / z = 542.1; found 542.1

[1204] Example 9. Methyl 6-(3,4-difluorophenoxy)-8-[(l-methylcyclopropyl)sulfamoyl]-3,4-dihydro-lH-benzo[c][l,6]naphthyridine-2-carboxylate

[1205]

[1206] Step 1: methyl 6-chloro-8-(N-(l-methylcyclopropyl)sulfamoyl)-3,4-dihydrohenzo [c] [1, 6 ]naphthyridine-2( lH)-carboxylate 54057-0031W01 / SNV0023-W01 PATENT

[1207]

[1208] The title compound was prepared according to the procedure described in Example 8, Step 4, replacing tert-butyl 10-chloro-8-(JV-(l-methylcyclopropyl)sulfamoyl)-6-oxo-3, 4,5,6-tctrahydrobcnzo|c|| l.6|naphthyridinc-2(l / / )-carboxylatc with tert-butyl 8-( V-(l-mcthylcyclopropyl)sulfamoyl)-6-oxo-3.4.5.6-tctrahydrobcnzo|c|| l.6|naphthyridinc-2( I / / )-carboxylate (as prepared in Example 3). LCMS calculated for C18H21CIN3O4S (M+H)+m / z = 410.1; found m / z = 410.1.

[1209] Step 2: methyl 6-(3,4-difluorophenoxy)-8-[(l-methylcyclopropyl)sulfamoyl]-3,4-dihydro-lH-benzo [c] [1,6]naphthyridine-2-carboxylate

[1210] The title compound was prepared according to the procedure described in Example 8, Step 5, replacing l-(difluoromethyl)pyrazol-4-ol with 3,4-difluorophenol and methyl 6,10-dichloro-8-(JV-(l-methylcyclopropyl)sulfamoyl)-3,4-dihydrobenzo[c][l,6]naphthyridine-2( I / / (-carboxy late with methyl 6-chloro-8-(A'-(l-mcthylcyclopropyl)sulfamoyl)-3.4-dihydrobenzo[c][l,6]naphthyridine-2(12 / )-carboxylate. LCMS calculated for C24H24F2N3O5S (M+H)+m / z = 504.1; found m / z = 504.1.

[1211] Examples 10-11. (7?)-l-methyl-5-((l-methyl-LH-pyrazol-4-yl)oxy)-JV-(l-methylcyclopropyl)-2,3-dihydro-LH-cyclopenta[c]isoquinoline-7-sulfonamide and ( / ?)-2-methyl-5-((l-methyl-LH-pyrazol-4-yl)oxy)-JV-(l-methylcyclopropyl)-2,3-dihydro-LH-cyclopenta[c]isoquinoline-7-sulfonamide

[1212]

[1213] Step 1: (R)-l-methyl-N-(l-methylcyclopropyl)-5-oxo-2, 3, 4, 5-tetrahydro-lH-cyclopenta[c]isoquinoline-7 -sulfonamide and (R)-2-methyl-N-(l-methylcyclopropyl)-5-oxo-2, 3, 4, 5-tetrahydro-lH-cyclopenta[c ]isoquinoline-7 -sulfonamide 54057-0031W01 / SNV0023-W01 PATENT

[1214]

[1215] The title compounds were prepared according to the procedure described in Example 8, Steps 1 and 2, replacing tert-butyl 4-oxopiperidine-l -carboxylate with (R)-3-methylcyclopentan-l-one. The products were isolated as a mixture of isomers. LCMS calculated for C17H21N2O3S (M+H)+m / z = 333.1; found m / z = 333.1.

[1216] Step 2: (R)-5-chloro-l-methyl-N-( 1 -methylcyclopropyl)-2, 3-dihydro-lH-cyclopenta[c]isoquinoline-7 -sulfonamide and (R)-5-chloro-2-methyl-N-( 1-methylcyclopropyl)-2,3-dihydro-lH-cyclopenta[c]isoquinoline-7-sulfonamide

[1217]

[1218] A suspension of a mixture of ( 1 R)- 1 -methyl - '-( I -mcthy Icy clopropyl)-5 -oxo- 1,2, 3,4-tetrahydrocyclopenta[c]isoquinoline-7-sulfonamide and ( / ?)-2-mcthyl- '-(l-methylcyclopropyl)-5-oxo-2,3,4,5-tetrahydro-12 / -cyclopenta[c]isoquinoline-7-sulfonamide (60 mg, 0.18 mmol) in POCI3 (0.55 M) was heated at 90 °C for 90 minutes. Upon cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was diluted with ice / water, then extracted with EtOAc x 3. The combined organic layers were washed with brine, then dried over anhydrous MgSCE. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-80% EtOAc in DCM to afford the desired product. LCMS calculated for CI7H2OC1N202S (M+H)+m / z = 351.1 found m / z = 351.1.

[1219] Step 3: (R)-l-methyl-5-((l-methyl-lH-pyrazol-4-yl)oxy)-N-(l-methylcyclopropyl)-2, 3-dihydro-lH-cyclopenta[c]isoquinoline-7 -sulfonamide and (R)-2-methyl-5-((l-methyl-lH-pyrazol-4-yl)oxy)-N-(l-methylcyclopropyl)-2,3-dihydro-lH-cyclopenta[c]isoquinoline-7-sulfonamide

[1220] The title compounds were prepared according to the procedure described in Example 5, Step 9, replacing methyl 6-chloro-3-mcthyl-8-(A-( l-mcthylcyclopropyl)sulfamoyl)-3.4-dihydrobcnzo|c || 1.6 |naphthyridinc-2( I / / (-carbox late with a mixture of ( / ?)-5-chloro-l-mcthyl-A-(l-mcthylcyclopropyl)-2.3-dihydro-l / / -cyclopcnta|c|isoqiiinolinc-7-siilfonamidc 54057-0031W01 / SNV0023-W01 PATENT

[1221] and (A)-5-chloro-2-methyl-A-(l-methylcyclopropyl)-2,3-dihydro-lH-cyclopenta[c]isoquinoline-7-sulfonamide. The two isomers were separated by prep-HPLC (column: Sunfire prep C18 column, 30* 150 mm, 5μm; 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.

[1222] Isomer 1, peak 1: LCMS calculated for C21H25N4O3S (M+H)+m / z = 413.2; found 413.1.

[1223] Isomer 2, peak 2: LCMS calculated for C21H25N4O3S (M+H)+m / z = 413.2; found 413.1.

[1224] Example 12.4-Cyano-8-fluoro-2-methyl-3-((l-methyl-LH-pyrazol-4-yl)methyl)-JV-(l-methylcyclopropyl)quinoline-6-sulfonamide

[1225] N-N

[1226]

[1227] Step 1: Ethyl (E)-2-((l-methyl-lH-pyrazol-4-yl)methylene)-3-oxobutanoate

[1228]

[1229] To a 250 mL round botom flask was placed l-methylpyrazole-4-carbaldehyde (10 g, 90.8 mmol), ethyl acetoacetate (11.82 g, 90.8 mmol) and acetic acid (1.1 g, 18.1 mmol) in toluene (100 mL). Piperidine (0.39 g, 4.5 mmol) was added at room temperature. The flask was fited with a Dean-Stark trap and a condenser. The resulting mixture was then stirred at 120 °C for 16 h. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 50% ethyl acetate in petroleum ether to afford the desired product as light yellow oil (4.5 g, 22%). LCMS calculated for C11H15N2O3 (M+H)+m / z = 223.1; found 223.1.

[1230] Step 2: Ethyl 2-((l-methyl-lH-pyrazol-4-yl)methyl)-3-oxobutanoate 54057-0031WO1 / SNV0023-W01 PATENT

[1231]

[1232] To a 100 mb round bottom flask was placed ethyl (A')-2-(( 1 -methyl- IH-pyrazol -4-yl)methylene)-3-oxobutanoate (400 mg, 1.8 mmol) in ethyl acetate (10 mb) was added Pd / C (192 mg, 0.18 mmol, 10%). The flask was evacuated and backfilled with hydrogen (balloon) (this process was repeated a total of three times). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was filtered, and the filter-cake was washed with ethyl acetate (3 x 10 mb). The fdtrate was concentrated under reduced pressure to afford the desired product as light yellow oil (350 mg, 86%). LCMS calculated for C11H17N2O3 (M+H) m / z = 225.1; found 225.1.

[1233] Step 3: 6-Bromo-8-fluoro-2-methyl-3-( ( 1 -methyl-lH-pyrazol-4-yl)methyl)quinolin-4-ol N-N OH

[1234] Br

[1235]

[1236] F To a mixture of ethyl 2-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-3-oxobutanoate (2 g, 8.999 mmol) and 4-bromo-2-fluoroaniline (1.71 g, 8.999 mmol) was added PPA (8 g). The resulting mixture was stirred at 150 °C for 2 h. Upon cooling to room temperature, the resulting mixture was diluted with water (200 mb). The mixture was basified to pH 8 with sodium hydroxide (2 M). The precipitated solids were collected by fdtration and washed with water (3 x 20 mb) to afford the desired product as a light yellow solid (1.5 g, 47%). LCMS calculated for CisHwBrFNsO (M+H)+m / z = 350.0; found 350.0.

[1237] Step 4: 6-(Benzylthio)-8-fluoro-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinolin-4-ol N-N

[1238] BnS

[1239]

[1240] 54057-0031W01 / SNV0023-W01 PATENT

[1241] To an 100 mL three-necked round bottom flask were placed 6-bromo-8-fluoro-2-methyl-3-[(l-methylpyrazol-4-yl)methyl]quinolin-4-ol (4 g, 11.422 mmol), benzyl mercaptan (2.13 g, 17.133 mmol), Pd2(dba)3 (1.57 g, 1.713 mmol), XantPhos (0.99 g, 1.713 mmol) and DIEA (5.91 g, 45.688 mmol). The vial was sealed with a Teflon-lined septum, evacuated and backfilled with nitrogen (this process was repeated a total of three times). Toluene (40 mL) was added. The resulting mixture was stirred at 100 °C for 2 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 15% methanol in dichloromethane to afford the desired product as a light yellow solid (3.6 g, 80%). LCMS calculated for C22H21FN3OS (M+H)+m / z = 394.1; found 394.1.

[1242] Step 5: 6-(benzylthio)-4-chloro-8-fluoro-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline

[1243] N-N7

[1244]

[1245] F

[1246] To a solution of 6-(benzylthio)-8-fluoro-2-methyl-3-(( 1 -methyl- lH-pyrazol-4-yl)methyl)quinolin-4-ol (3.5 g, 8.9 mmol) in acetonitrile (35 mL) was added phosphoryl trichloride (6.14 g, 40 mmol) at 90 °C for 1 h. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (200 mL). The resulting mixture was diluted with ice water (200 mL). The mixture was basified to pH 8 with ammonium hydroxide. The resulting mixture was extracted with dichloromethane (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 10% methanol in dichloromethane to afford the desired product as a light yellow solid (3 g, 82%). LCMS calculated for C22H20CIFN3S (M+H)+m / z = 412.1; found 412.1.

[1247] Step 6: 6-(Benzylthio)-8-fluoro-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-4-carbonitrile 54057-0031W01 / SNV0023-W01 PATENT

[1248] N-N7

[1249]

[1250] F

[1251] To an 50 mL three-necked round bottom flask were placed 6-(benzylthio)-4-chloro-8-fluoro-2-methyl-3-(( 1 -methyl- lH-pyrazol-4-yl)methyl)quinoline (1.5 g, 3.6 mmol), zinc cyanide (0.86 g, 7.3 mmol), Pd2(dba)3 (0.5 g, 0.55 mmol) and XPhos (0.35 g, 0.73 mmol). The vial was sealed with a Teflon-lined septum, evacuated and backfilled with nitrogen (this process was repeated a total of three times). N,N-dimethylacetamide (15 mL) was added. The resulting mixture was stirred at 150 °C for 2 h. Upon cooling to room temperature, the resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (80 mL). The resulting mixture was extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (0.1% formic acid), 10% to 90% gradient in 40 min; detector, UV 254 nm. Fractions were collected and lyophilized to provide the desired product as a light yellow solid (280 mg, 19%). LCMS calculated for C23H20FN4S (M+H)+m / z = 403.1; found 403.2.

[1252] Step 7: 4-Cyano-8-fluoro-2-methyl-3-( ( 1 -methyl-lH-pyrazol-4-yl)methyl)-N-( 1 -methylcyclopropyl)quinoline-6-sulfonamide

[1253] To a solution of 6-(benzylthio)-8-fluoro-2-methyl-3-(( 1 -methyl- lH-pyrazol-4-yl)methyl)quinoline-4-carbonitrile (200 mg, 0.5 mmol) in acetic acid (3 mL) was added N-chlorosuccinimide (199 mg, 1.5 mmol) at room temperature. After stirring for 1 h, the resulting mixture was diluted with ethyl acetate (50 mL). The resulting mixture was washed with brine (50 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in pyridine (1 mL) and dichloromethane (4 mL). To the above mixture was added 1-methylcyclopropan-l -amine hydrochloride (107 mg, 1.0 mmol) and A'. '-diisopropylcthylaminc (257 mg, 2.0 mmol). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with ethyl acetate (100 mL). The resulting mixture was washed with 2 N hydrochloric acid (aq.) (50 mL), water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was 54057-0031W01 / SNV0023-W01 PATENT

[1254] concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (10 mmol / E ammonium bicarbonate), 10% to 90% gradient in 40 min; detector, UV 254 nm. Tractions were collected and lyophilized to provide the desired product as a white solid (90 mg, 44%). ECMS calculated for C20H21FN5O2S (M+H)+m / z = 414.1; found 414.1.

[1255] Example 13.4-Cyano-8-((3iS,5A)-3,5-dimethylpiperazin-l-yl)-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)-JV-(l-methylcyclopropyl)quinoline-6-sulfonamide

[1256] Step 1: Tert-Butyl (2S,6S)-4-(4-cyano-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)-6-(N- ( 1 -methylcyclopropyl)sulfamoyl)quinolin-8-yl)-2, 6-dimethylpiperazine-l-carboxylcite N-N7

[1257] N

[1258]

[1259] Boc

[1260] A solution of 4-cyano-8-fluoro-2-methyl-A-(l-methylcyclopropyl)-3-[(l-methylpyrazol-4-yl)methyl]quinoline-6-sulfonamide (as prepared in Example 12, 60 mg, 0.15 mmol), tert-butyl (2. S'.6. S')-2.6-dimcthylpipcrazinc-l -carboxylate (155 mg, 0.73 mmol) and '. '-di isop ropy lethy lam ine (94 mg, 0.73 mmol) in dimethyl sulfoxide (1 m ) was stirred at 120 °C for 18 h. Upon cooling to room temperature, the resulting mixture was diluted with water (50 m ). The resulting mixture was extracted with ethyl acetate (3 x 50 mb). The combined organic layers were washed with brine (100 mb), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford the desired product as a light yellow solid (40 mg). The crude product was used in the next step 54057-0031W01 / SNV0023-W01 PATENT

[1261] directly without further purification. LCMS calculated for C31H42N7O4S (M+H)+m / z = 608.3; found 608.3.

[1262] Step 2: 4-Cyano-8-((3S,5S)-3,5-dimethylpiperazin-l-yl)-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)-N-( 1 -methylcyclopropyl) quinoline -6-sulfonamide

[1263] To a mixture of tert-butyl (2. S'.6. S')-4-(4-cyano-2-mcthyl-3-((l-mcthyl-IH-pyrazol-4-y I )mcthy l)-6-( '-( 1 -methylcyclopropyl)sulfamoyl)quinolin-8-yl)-2,6-dimethylpiperazine- 1 -carboxylate (40 mg, 0.07 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 30 min. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (0.1% formic acid), 10% to 90% gradient in 30 min; detector, UV 254 nm. Fractions were collected and lyophilized to provide the desired product as a yellow solid (25.9 mg, 77%). LCMS calculated for C26H34N7O2S (M+H)+m / z = 508.2; found 508.2. 'H NMR (400 MHz, DMSO-6) 58.38 (s, 1H), 8.26 (s, 1H), 7.99 (d, J= 1.6 Hz, 1H), 7.52 (s, 1H), 7.44 (d, J= 1.6 Hz, 1H), 7.35 (s, 1H), 4.20 (s, 2H), 3.74 (s, 3H), 3.41 (s, 2H), 3.48 - 3.40 (m, 2H), 3.39 - 3.32 (m, 2H), 2.71 (s, 3H), 1.32 (d, J= 6.8 Hz, 6H), 1.06 (s, 3H), 0.71 - 0.60 (m, 2H), 0.47 - 0.37 (m, 2H).

[1264] Example 14. (7? -5-Cyano-l,9-dimethyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-l,2-dihydroimidazo[l,2-a] quinoline-7-sulfonamide

[1265]

[1266] Step 1: Methyl 2-amino-3-bromo-5-iodobenzoate

[1267]

[1268] To a mixture of methyl 2-amino-5 -iodobenzoate (5 g, 18.05 mmol) in chloroform (72 mL) was added 1 -bromopyrrolidine-2, 5-dione (4.18 g, 23.46 mmol) in portions at room temperature. The resulting mixture was stirred at the same temperature for 16 h. The reaction 54057-0031WO1 / SNV0023-W01 PATENT

[1269] was quenched with saturated sodium hyposulfite at room temperature. The resulting mixture was extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 10% ethyl acetate in petroleum ether to afford the desired product as a white solid (4.8 g, 75%). LCMS calculated for C8H7BrINO2 (M+H)+m / z = 355.9; found 355.9.

[1270] Step 2: Methyl 2-acetamido-3-bromo-5-iodobenzoate

[1271]

[1272] To a mixture of methyl 2-amino-3-bromo-5 -iodobenzoate (24 g, 67.42 mmol) in acetic anhydride (100 mL) were added pyridine (100 mL) and DMAP (824 mg, 6.74 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the reaction was diluted with water. The resulting mixture was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (300 mL). Potassium carbonate (18.64 g, 134.85 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for an additional 2 h and filtered. The filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 10% ethyl acetate in petroleum ether to afford the desired product as a white solid (20 g, 75%). LCMS calculated for C10H10BrINO3 (M+H)+m / z = 397.9; found 398.0.

[1273] Step 3: 8-Bromo-6-iodoquinoline-2,4-diol

[1274] OH

[1275]

[1276] Br

[1277] To a mixture of methyl 3 -bromo-2-acetamido-5 -iodobenzoate (20 g, 50.25 mmol) in THF (200 mL) was added KHMDS (1.0M in THF, 150.76 mL, 150.76 mmol) dropwise at -78 °C under a nitrogen atmosphere. The resulting mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was then cooled to 0 °C and acidified to 54057-0031W01 / SNV0023-W01 PATENT

[1278] pH 4 with 1 N HC1 (aq.). The precipitate was collected by filtration, washed with water, and dried under vacuum to afford the desired product as a yellow solid (14 g, 76%). LCMS calculated for C9H6BrINO2 (M+H)+m / z = 365.9; found 366.0.

[1279] Step 4: 8-Bromo-6-iodo-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinolirie-2, 4-diol

[1280]

[1281] To a mixture of 8-bromo-6-iodoquinoline-2, 4-diol (14 g, 38.26 mmol) and Hantzsch ester (9.69 g, 38.26 mmol) in pyridine (140 mL) was added 1 -methylpyrazole-4-carbaldehyde (4.63 g, 42.08 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 1 h. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with ethyl acetate to afford the desired product as a light-yellow solid (11 g, 63%). LCMS calculated for C14H13BrIN3O2 (M+H)+m / z = 459.9; found 460.1.

[1282] Step 5: 6-(Benzylthio)-8-bromo-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-2, 4-diol N-N7

[1283]

[1284] Br To a 250 mL three-necked round bottom flask were placed 8-bromo-6-iodo-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-2, 4-diol (6 g, 13.04 mmol), benzyl mercaptan (1.62 g, 13.04 mmol), Pd2(dba)3 (1.19 g, 1.3 mmol), XantPhos (1.51 g, 2.61 mmol) and DIPEA (5.06 g, 39.13 mmol). The flask was sealed with a rubber stopper, evacuated and backfilled with nitrogen (this process was repeated a total of three times). Dioxane (60 mL) was added. The resulting mixture was stirred at 60 °C for 1 h. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 10% methanol in dichloromethane to afford the desired product as a white solid (4.5 g, 76%). LCMS calculated for C2iHi9BrN3C>2S (M+H)+m / z = 456.0; found 456.0. 54057-0031W01 / SNV0023-W01 PATENT

[1285] Step 6: 6-(benzylthio)-8-bromo-2, 4-dichloro-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline N-N7

[1286]

[1287] Br To a mixture of 6-(benzylthio)-8-bromo-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-2,4-diol (6 g, 13.15 mmol) in phosphoryl trichloride (8 mL) was added DIPEA (5.10 g, 39.44 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 4 h. After cooling to room temperature, the reaction mixture was poured into ice water and stirred for 10 min. The resulting mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the desired product as a yellow solid (6 g) which was used directly in the next step without further purification. LCMS calculated for C21H17BrCl2N3S (M+H)+m / z = 492.0; found 492.0.

[1288] Step 7: 8-Bromo-2, 4-dichloro-3-( ( 1 -methyl-lH-pyrazol-4-yl)methyl)-N-( 1 -methylcyclopropyl)quinoline-6-sulfonamide

[1289] N-N7

[1290]

[1291] Br

[1292] To a mixture of 6-(benzylthio)-8-bromo-2,4-dichloro-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline (500 mg, 1.014 mmol) in acetic acid (10 mL) was added water (1 mL) followed by 1 -chloropyrrolidine-2, 5-dione (406 mg, 3.04 mmol). The reaction was stirred at the room temperature for 1.5 h. The resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (3 mL). The above solution was added to a solution of 1-methylcyclopropan-l -amine hydrochloride (218 mg, 2.03 mmol) in pyridine (8 mL) at 0 °C. The resulting mixture was allowed to warm 54057-0031WO1 / SNV0023-W01 PATENT

[1293] to room temperature and stirred for 1 h. The reaction was diluted with water and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 50% ethyl acetate in petroleum ether) to afford the desired product as a white solid (285 mg, 56%). LCMS calculated for C18H18BrCl2N4O2S (M+H)+m / z = 503.0; found 503.0.

[1294] Step 8: 8-Bromo-2, 4-dichloro-3-( ( 1 -methyl-lH-pyrazol-4-yl)methyl)-N-( 1 -methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)quinoline-6-sulfonamide

[1295] N-N7

[1296]

[1297] Br

[1298] To a stirred mixture of 8-bromo-2,4-dichloro-3-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)quinoline-6-sulfonamide (175 mg, 0.35 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (159 mg, 1.04 mmol) in dichloromethane (3 mL) was added (2-(chloromethoxy)ethyl)trimethylsilane (289 mg, 1.7 mmol) at 0 °C. After stirring at room temperature for 16 h, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 50% ethyl acetate in petroleum ether to afford the desired product as a white solid (130 mg, 59%). LCMS calculated for C24H32BrC12N4C>3SSi (M+H)+m / z = 633.1; found 633.0.

[1299] Step 9: (S)-8-bromo-4-chloro-2-((2-hydroxypropyl)amino)-3-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)quinoline-6-sulfonamide

[1300] N-N7

[1301]

[1302] To a stirred mixture of 8-bromo-2,4-dichloro-3-((l-methyl-lH-pyrazol-4-yl)methyl)- N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)quinoline-6-sulfonamide (130 54057-0031W01 / SNV0023-W01 PATENT

[1303] mg, 0.21 mmol) in DMSO (5 mL) were added (2S)-l-aminopropan-2-ol (18 mg, 0.24 mmol) followed by triethylamine (62 mg, 0.61 mmol) at room temperature. The mixture was stirred at 60 °C for 2 h. After cooling to room temperature, the reaction was diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 10% methanol in dichloromethane to afford the desired product as a white solid (120 mg, 87%). LCMS calculated for C2? H4oBrClN504SSi (M+H)+m / z = 672.1; found 672.2.

[1304] Step 10: (R)-9-bromo-5-chloro-l-methyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide

[1305] N-N7

[1306]

[1307] To a stirred mixture of (S)-8-bromo-4-chloro-2-((2-hydroxypropyl)amino)-3-((l-methyl- lH-pyrazol-4-yl)methyl)-N-( 1 -methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)quinoline-6-sulfonamide (120 mg, 0.18 mmol) and DIPEA (69 mg, 0.53 mmol) in dichloroethane (2 mL) was added methanesulfonic anhydride (62 mg, 0.36 mmol) at room temperature. The reaction mixture was stirred at 60 °C for 16 h. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 10% methanol in dichloromethane to afford the desired product as a yellow solid (90 mg, 77 %). LCMS calculated for C27H3sBrQN5O3SSi (M+H)+m / z = 654.1; found 654.2.

[1308] Step 11: (R)-5-chloro-l, 9-dimethyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide 54057-0031W01 / SNV0023-W01 PATENT

[1309]

[1310] To a screw-cap vial equipped with a magnetic stir bar were placed <7?)-9-bromo-5-chloro- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-N-( 1 -methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)- 1,2-dihydroimidazo[ 1,2-a] quinoline-7 -sulfonamide (50 mg, 0.8 mmol), trimethyl-l,3,5,2,4,6-trioxatriborinane (14 mg, 0.11 mmol), CataCXium A Pd G2 (5 mg, 0.01 mmol), di(l-adamantyl)-N-butylphosphine (5 mg, 0.01 mmol) and potassium carbonate (21 mg, 0.15 mmol). The vial was sealed with a Teflon -lined septum, evacuated and backfilled with nitrogen (this process was repeated a total of three times). Dioxane (2 mL) was added. The mixture was stirred at 80 °C for 4 h. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 10% methanol in dichloromethane to afford the desired product as a yellow solid (30 mg, 67%). LCMS calculated for C2sH4iClN5O3SSi (M+H)+m / z = 590.2; found 590.3.

[1311] Step 12: (R)-5-cyano-l,9-dimethyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)-l,2-dihydroimidazo[l,2-a]quinoline- 7-sulfonamide

[1312] N-N

[1313]

[1314] To a screw-cap vial equipped with a magnetic stir bar were placed <7?)-5-chloro- 1.9-dimethyl-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-N-( 1 -methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)- 1,2-dihydroimidazo[ 1,2-a] quinoline-7 -sulfonamide (30 mg, 0.05 mmol), zinc cyanide (30 mg, 0.26 mmol), Pd2(dba)3 (7 mg, 0.01 mmol) and XPhos (5 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). N, N -dimethylacetamide (1 mL) was added via syringe. The mixture was stirred at 150 °C for 3 h. After cooling to room temperature, the resulting mixture was diluted with ethyl acetate (50 mL). The mixture was 54057-0031W01 / SNV0023-W01 PATENT

[1315] washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 10% methanol in dichloromethane to afford the desired product as a yellow oil (15 mg, 51%). LCMS calculated for C29H4iN60sSSi (M+H)+m / z = 581.3; found 581.3.

[1316] Step 13: (R) -5 -cyano- 1, 9-dimethyl-4-( ( 1 -methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide

[1317] To a solution of <7?)-5-cyano-l.9-dimcthyl-4-(( l-mcthyl-l H-pyrazol-4- l)mcth l)-N-( 1 -methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)- 1,2-dihydroimidazo[ 1,2-a] quinoline -7-sulfonamide (15 mg, 0.03 mmol) in dichloromethane (1 mL) was added 2,2,2-trifluoroacetic acid (1 mL) at room temperature. After stirring at room temperature for 2 h, the resulting mixture was concentrated under reduced pressure. To the residue was added acetonitrile (1 mL), followed by ammonium hydroxide solution (30-33% NFF in H2O, 0.2 mL). After stirring at room temperature for 30 min, the resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: Xselect CSH Prep C18, 30* 150 mm 5μm; Mobile Phase A: water (0.1% FA), Mobile Phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 7% to 22%B over 10 min; wavelength: 254nm / 220 nm. Fractions were collected and lyophilized to provide the desired product as a yellow solid (2.3 mg). LCMS calculated for C23H27N6O2S (M+H)+m / z = 451.2; found 451.3. ’HNMR (400 MHz, DMSO-d6) 58.07 (s, 1H), 7.78 (d, J= 2.0 Hz, 1H), 7.65 (d, J= 2.4 Hz, 1H), 7.58 (s, 1H), 7.34 (s, 1H), 5.26 - 5.17 (m, 5.2 Hz, 1H), 4.03 - 3.95 (m, 1H), 3.93 - 3.80 (m, 2H), 3.76 (s, 3H), 3.71 - 3.65 (m, 1H), 2.59 (s, 3H), 1.09 (s, 3H), 1.06 (d, J= 6.4 Hz, 3H), 0.66 - 0.57 (m, 2H), 0.43 - 0.35 (m, 2H).

[1318] Example 15. (7? -5-Cyano-l-methyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-l,2-dihydroimidazo[l,2-a] quinoline-7-sulfonamide

[1319] N-N7

[1320]

[1321] Step 1: (R)-5-chloro-l-methyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)-l,2-dihydroimidazo[l,2-a]quinoline- 7-sulfonamide 54057-0031W01 / SNV0023-W01 PATENT

[1322] N-N7

[1323]

[1324] To a mixture of / ? J-9-bromo-5-chloro-l-mcthyl-4-((l-mcthyl-IH-pyrazol-4-yl)methyl)-N-( 1 -methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)- 1,2-dihydroimidazo[ 1,2 -a] quinoline -7-sulfonamide (see step 10 in Example 14, 40 mg, 0.06 mmol) in THF (2 mL) was added n-BuLi (2.5 M in n-hexane, 0.06 mL, 0.15 mmol) at -78 °C under a nitrogen atmosphere. After stirring at-78 °C for 1 h, the reaction was quenched with methanol (1 mL). The resulting mixture was allowed to warm to 0 °C and stirred for Ih. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 10% methanol in dichloromethane to afford the desired product as a yellow solid (25 mg, 71%). LCMS calculated for C^HssClNsOsSSi (M+H)+m / z = 576.2; found 576.2.

[1325] Step 2: (R)-5-cyano-l-methyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-N-( (2-(trimethylsilyl)ethoxy)methyl)-l, 2-dihydroimidazo [1, 2-a]quinoline-7 -sulfonamide N-N7

[1326]

[1327] To a screw-cap vial equipped with a magnetic stir bar were placed <7?)-5-chloro- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-N-( 1 -methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide (25 mg, 0.04 mmol), zinc cyanide (25 mg, 0.2 mmol), Pd2(dba)3(6 mg, 0.01 mmol) and XPhos (4 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). N, N -dimethylacetamide (1 mL) was added via syringe. The mixture was stirred at 150 °C for 3 h. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over 54057-0031W01 / SNV0023-W01 PATENT

[1328] anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 10% methanol in dichloromethane to afford the desired product as a yellow solid (20 mg, 81%). LCMS calculated for C28H39NeO3SSi (M+H)+m / z = 567.2; found 567.3.

[1329] Step 3: (R)-5-cyano-l-methyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide

[1330] To a solution of <7?)-5-cyano-l-mcthyl-4-(( l-mcthyl-l H-pyrazol-4-yl)mcth l)-N-( I-methylcyclopropyl)-N-((2-(trimethylsilyl)ethoxy)methyl)- 1,2-dihydroimidazo[ 1,2-a] quinoline -7-sulfonamide (20 mg, 0.035 mmol) in dichloromethane (1 mL) was added 2,2,2-trifluoroacetic acid (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. To the residue was added acetonitrile (1 mL), followed by ammonium hydroxide solution (30-33% NH3 in H2O, 0.2 mL). After stirring at room temperature for 30 min, the resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (0.1% FA), 10% to 40% gradient over 20 min; detector, UV 254 nm. Fractions were collected and lyophilized to provide the desired product as a yellow solid (5.3 mg). LCMS calculated for C22H25N6O2S (M+H)+m / z = 437.2; found 437.1. 'HNMR (400 MHz, DMSO-d6) 58.13 (s, 1H), 7.91 (d, J= 2.0 Hz, 1H), 7.83 (d, J= 8.4 Hz, 1H), 7.60 (s, 1H), 7.36 (s, 1H), 7.34 (s, 1H), 4.95 - 4.80 (m, 1H), 4.21 - 4.12 (m, 1H), 3.87 (s, 2H), 3.76 (s, 3H), 3.74 - 3.68 (m, 1H), 1.30 (d, J = 6.4 Hz, 3H), 1.08 (s, 3H), 0.65 - 0.57 (m, 2H), 0.42 -0.36 (m, 2H).

[1331] Example 16. (R)-5-Cyano-N-(l-cyanocyclopropyl)-l-methyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide

[1332]

[1333] '(R)

[1334] Step 1: 6-Iodo-3-( ( 1 -methyl- lH-pyrazol-4-yl)methyl)quinoline-2, 4-diol 54057-0031W01 / SNV0023-W01 PATENT

[1335] N-N7

[1336]

[1337] To a mixture of 6-iodoquinoline-2,4-diol (15 g, 52.26 mmol) and Hantzsch ester (13.24 g, 52.26 mmol) in pyridine (150 mL) was added l-methylpyrazole-4-carbaldehyde (6.9 g, 62.71 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 1 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by trituration with ethyl acetate to afford the desired product as a white solid (17 g, 85%). LCMS calculated for C14H13IN3O2 (M+H)+m / z = 382.0; found 382.0.

[1338] Step 2: 6-(Benzylthio)-3-( ( 1 -methyl-lH-pyrazol-4-yl)methyl)quinoline-2, 4-diol

[1339] N-NZ

[1340] OHV

[1341]

[1342] To a 100 mL three-necked round bottom flask were placed 6-iodo-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-2, 4-diol (1 g, 2.62 mmol), benzyl mercaptan (0.33 g, 2.62 mmol), Pd2(dba)3 (0.36 g, 0.39 mmol), XantPhos (0.3 g, 0.5 mmol) and DIPEA (1.02 g, 7.87 mmol). The flask was sealed with a rubber stopper, evacuated and backfilled with nitrogen (this process was repeated a total of three times). Dioxane (10 mL) was added. The resulting mixture was stirred at 60 °C for 4 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 15% methanol in dichloromethane to afford the desired product as a yellow solid (700 mg, 71%). LCMS calculated for C21H20N3O2S (M+H)+m / z = 378.1; found 378.0.

[1343] Step 3: 6-(Benzylthio)-2, 4-dichloro-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline

[1344]

[1345] 54057-0031W01 / SNV0023-W01 PATENT

[1346] To a solution of 6-(benzylthio)-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-2,4-diol (1 g, 2.65 mmol) and in phosphoryl trichloride (8 mL) was added DIPEA (1.03 g, 7.95 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 1 h. After cooling to room temperature, the mixture was poured onto ice water. After stirring at room temperature for 10 min, the mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 50% ethyl acetate in petroleum ether to afford the desired product as a yellow solid (600 mg, 55%). LCMS calculated for C2IHI8C12N3S (M+H)+m / z = 414.1; found 414.0.

[1347] Step 4: 2,4-Dichloro-N-(l-cyanocyclopropyl)-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinolirie- 6-sulfonamide

[1348] N-NZ

[1349]

[1350] To a solution of 6-(benzylthio)-2,4-dichloro-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline (650 mg, 1.32 mmol) in acetic acid (6.5 mL) and water (0.65 mL) was added 1 -chloropyrrolidine-2, 5-dione (528 mg, 3.95 mmol) at room temperature. After stirring at room temperature for 1.5 h, the reaction mixture was diluted with ethyl acetate (100 mL). The resulting mixture was washed with brine (2 x 60 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (5 mL). The above solution was added to a solution of 1-aminocyclopropane-1 -carbonitrile (216 mg, 2.64 mmol) in pyridine (10 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL) and washed with aqueous HC1 (IN, 2 x 60 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 25% ethyl acetate in dichloromethane to afford the desired product as a light-yellow solid (400 mg, 59%). LCMS calculated for CisHieChNsC S (M+H)+m / z = 436.0; found 436.0.

[1351] Step 5: (S)-4-chloro-N-(l-cyanocyclopropyl)-2-((2-hydroxypropyl)amino)-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfoncimide 54057-0031WO1 / SNV0023-W01 PATENT

[1352]

[1353] To a mixture of 2,4-dichloro-N-(l-cyanocyclopropyl)-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide (400 mg, 0.92 mmol) and (2. S)-l-aminopropan-2-ol (103 mg, 1.4 mmol) in DMSO (5 mL) was added DIPEA (355 mg, 2.75 mmol) at room temperature. The resulting mixture was stirred at 60 °C for 16 h. After cooling to room temperature, the mixture was diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 15% methanol in dichloromethane to afford the desired product as a yellow solid (300 mg, 69%). LCMS calculated for C21H24CIN6O3S (M+H)+m / z = 475.1; found 475.1.

[1354] Step 6: (R)-5-chloro-N-(l-cyanocyclopropyl)-l-methyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide

[1355] N-N7

[1356]

[1357] To a mixture of (S)-4-chloro-N-(l-cyanocyclopropyl)-2-((2-hydroxypropyl)amino)-3-((1 -methyl- lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide (300 mg, 0.63 mmol) and DIPEA (245 mg, 1.9 mmol) in dichloroethane (5 mL) was added methanesulfonic anhydride (220 mg, 1.26 mmol) at room temperature. The resulting mixture was stirred at 60 °C for 16 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 15% methanol in dichloromethane to afford the desired product as a yellow solid (220 mg, 76%). LCMS calculated for C21H22CIN6O2S (M+H)+m / z = 457.1; found 457.1. 54057-0031W01 / SNV0023-W01 PATENT

[1358] Step 7: (R)-5-cyano-N-(l-cyanocyclopropyl)-l-methyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)- I,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide

[1359] To a screw-cap vial equipped with a magnetic stir bar were placed <7? J-5-chloro-N-( I -cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo[ 1,2-a] quinoline -7-sulfonamide (220 mg, 0.48 mmol), zinc cyanide (283 mg, 2.4 mmol), Pd2(dba)3 (66 mg, 0.07 mmol) and XPhos (46 mg, 0.1 mmol). The vial was sealed with a Teflon-lined septum, evacuated and backfilled with nitrogen (this process was repeated a total of three times). N, N -dimethylacetamide (4 m ) was added. The resulting mixture was stirred at 120 °C for 2 h. After cooling to room temperature, the mixture was diluted with water (50 mb). The resulting mixture was extracted with ethyl acetate (3 x 50 mb). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (0.1% TFA), 5% to 50% gradient over 20 min; detector, UV 254 nm. Fractions were collected and lyophilized to provide the TFA salt of the desired product as a yellow solid (104.6 mg). LCMS calculated for C22H22N7O2S (M+H)+m / z = 448.2; found 448.3. 'H NMR (400 MHz, DMSO-6) 59.54 (s, 1H), 8.38 (d, J= 2.4 Hz, 1H), 8.26 (dd, J = II.6, 2.4 Hz, 1H), 8.13 (d, J= 12.0 Hz, 1H), 7.68 (s, 1H), 7.45 (d, J = 0.9 Hz, 1H), 5.64 -5.54 (m, 1H), 4.39 - 4.28 (m, lH), 4.12 (s, 2H), 3.99 - 3.90 (m, 1H), 3.78 (s, 3H), 1.52 (d, J= 8.4 Hz, 3H), 1.50 - 1.46 (m, 2H), 1.37 - 1.29 (m, 2H).

[1360] Example 17. (R)-5-Cyano-N-(l-cyanocyclopropyl)-l,9-dimethyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide

[1361] N-N

[1362] NO

[1363]

[1364] Step 1: 8-Bromo-2, 4-dichloro-N-(l -cyanocyclopropyl)-3-(( 1 -methyl- lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide 54057-0031W01 / SNV0023-W01 PATENT

[1365]

[1366] Br

[1367] To a solution of 6-(benzylthio)-8-bromo-2,4-dichloro-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline (see step 6 in Example 14, 2 g, 4.06 mmol) in acetic acid (20 m ) and water (2 m ) was added 1 -chloropyrrolidine-2, 5-dione (1.62 g, 12.17 mmol) at room temperature. After stirring at room temperature for 1.5 h, the reaction mixture was diluted with ethyl acetate (200 mb). The resulting mixture was washed with brine (2 x 100 mb), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 mL). The resulting solution was added to a solution of 1 -aminocyclopropane- 1 -carbonitrile (666 mg, 8.11 mmol) in pyridine (20 mb) at 0 °C. After stirring at room temperature for 1 h, the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mb) and washed with aqueous HC1 (IN, 2 x 60 mb) followed by brine...

Claims

1. 54057-0031W01 / SNV0023-W01 PATENT2.WHAT IS CLAIMED IS:

1. A compound of F ormula I:

5. 7.I8.or a pharmaceutically acceptable salt thereof, wherein:9.X1is N or CR5;10.X2is N or CR6;11.X3is N or C(-L2-R2);12.Z is O or NR7;13.Ring A is selected from14., and16.

19.

20. * denotes attachment to X1;21.m is 0, 1, 2, 3, 4, 5, or 6;22.n is 0, 1, 2, 3, 4, 5, or 6; 54057-0031W01 / SNV0023-W01 PATENT23.p is 1, 2, 3, or 4;24.X4is C(-L3-R3) orN;25.X5is C(-L3-R3) orN;26.X6is C(-L3-R3) orN;27.X7is C(-L3-R3) orN;28.X8is C(-L3-R3) orN;29.X9is C(-L3-R3) orN;30.Y1is C orN;31.Y2is C orN;32.Ring B is selected from C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl;33.Ring C is selected from C5-10 cycloalkyl, phenyl, 5-10 membered heterocycloalkyl, and 5-6 membered heteroaryl;34.each L1is independently selected from C1-6 alkylene, C1-6 haloalkylene, -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 and C1-6 haloalkylene of L1are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; 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-4 alkyl-, -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) -C 1-4 alkyl of L2and L3are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents;35.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;36.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; 54057-0031W01 / SNV0023-W01 PATENT37.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;38.each RLis independently selected from H, 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) -C1-4 alkyl of RLare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;39.R1is selected from -CN, C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, and 4-7 membered heterocycloalkyl, wherein the C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, and 4-7 membered heterocycloalkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;40.Rlaand Rlbare each independently C1-3 alkyl, wherein the C1-3 alkyl of Rlaand Rlbis optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;41.or, Rlaand Rlb, together with the carbon atom to which they are attached, form a C3-4 cycloalkyl group, wherein the C3-4 cycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;42.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; 54057-0031W01 / SNV0023-W01 PATENT43.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) -C 1-4 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;44.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;45.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-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 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;46.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-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;47.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, - 54057-0031W01 / SNV0023-W01 PATENT48.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-Ci-4 alkyl, Ce-io aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 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;49.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) -C 1-4 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;50.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;51.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-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 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;52.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-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; 54057-0031W01 / SNV0023-W01 PATENT53.each R3is independently 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, 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)Rf3Rg3, 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;54.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) -C 1-4 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;55.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;56.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-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, 54057-0031W01 / SNV0023-W01 PATENT57.(4-10 membered heterocycloalkyl) -C 1-4 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;58.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-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;59.each Rf3and Rg3are independently selected from C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and, C1-6 haloalkoxy;60.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, -C(O)ORa3A, -C(O)NRc3ARd3A, -C(O)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 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-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 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;61.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) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of 54057-0031W01 / SNV0023-W01 PATENT62.Ra3A, Rc3A, and Rd3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;63.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;64.each Rb3Ais 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-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 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;65.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-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;66.each R4is independently selected from 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, -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, -NRc4S(O)NRc4C(O)Rb4, and -P(O)Rf4Rg4, 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 R4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R4Asubstituents; 54057-0031W01 / SNV0023-W01 PATENT67.each Ra4, Rc4, and Rd4is 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) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra4, Rc4, and Rd4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R4Asubstituents;68.or, any Rc4and Rd4attached 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 R4Asubstituents;69.each Rb4is 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-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Rb4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R4Asubstituents;70.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, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;71.each Rf4and Rg4are independently selected from H, 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-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;72.each R4Ais 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, -ORa4A, -SRa4A, - 54057-0031W01 / SNV0023-W01 PATENT73.-NRc4ARd4A, -NO2, -C(O)Ra4A, -C(O)ORa4A, -C(O)NRc4ARd4A, -C(O)NRc4A(ORa4A), -OC(O)Ra4A, -OC(O)NRc4ARd4A, -OC(O)ORa4A, -OS(O)2Rb4A, -OS(O)2NRc4ARd4A, -NRc4AC(O)Ra4A, -NRc4AC(O)ORa4A, -NRc4AC(O)NRc4ARd4A, -NRc4AS(O)2Rb4A, -NRc4AS(O)2NRc4ARd4A, -NRc4AORa4A, -NRc4AS(O)Rb4A, -NRc4AS(O)NRc4ARd4A, -S(O)Rb4A, -S(O)2Rb4A, -S(O)NRc4ARd4A, -S(O)2NRc4ARd4A, -C(=NRe4A)Ra4A, -C(=NRe4A)NRc4ARd4A, -NRc4AC(=NRe4A)Ra4A, -NRc4AC(=NRe4A)NRc4ARd4A, -NRc4AS(O)(=NRe4A)Rb4A, -NRc4AS(O)(=NRe4A)NRc4ARd4A, -OS(O)(=NRe4A)Rb4A, -S(O)(=NRe4A)Rb4A, -S(O)(=NRe4A)NRc4ARd4A, -C(O)NRc4AS(O)2Rb4A, -C(O)NRc4AS(O)2NRc4ARd4A, -S(O)2NRc4AC(O)Rb4A, -NRc4AS(O)NRc4AC(O)Rb4A, and -P(O)Rf4ARg4A, 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, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R4Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;74.each Ra4A, Rc4A, and Rd4Ais 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) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra4A, Rc4A, and Rd4Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;75.or, any Rc4Aand Rd4Aattached 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;76.each Rb4Ais 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-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Rb4Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; 54057-0031W01 / SNV0023-W01 PATENT77.each Re4Ais 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-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;78.each Rf4Aand Rg4Aare independently selected from H, 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-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;79.R5is selected from H, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C 1-4 haloalkoxy, and -CN;80.R6is selected from H, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C 1-4 haloalkoxy, and -CN;81.R7is selected from H, CN, ORa7, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;82.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;83.Ra7is selected from H, C1-6 alkyl, and C1-6 haloalkyl;84.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, C1-3 alkylsulfonyl, carbamyl, C1-3 alkylcarbamyl, di(Ci-3 alkyl)carbamyl, carboxy, C1-3 alkylcarbonyl, C1-3 alkoxycarbonyl, C1-3 alkylcarbonyloxy, C1-3 alkylcarbonylamino, C1-3 alkoxycarbonylamino, aminocarbonyloxy, C1-3 alkylaminocarbonyloxy, di(Ci-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, or a pharmaceutically acceptable salt thereof, wherein X1is CR5.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R5is H or C1-6 alkyl.54057-0031W01 / SNV0023-W01 PATENT4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R5is H.

5. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein X2is CR6.

6. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R6is selected from H, halo, and Ci-6 alkyl.

7. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R6is H or fluoro.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein X3is C(-L2-R2).

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

10. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein L2is selected from a bond, 4-7 membered heterocycloalkylene, and 5-6 membered heteroarylene, wherein the 4-7 membered heterocycloalkylene and 5-6 membered heteroarylene of L2are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents.

11. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein L2is selected from a bond, methylpiperazinyl, morpholinyl, dihydropyranyl, tetrahydropyranyl, methylmorpholinyl, pyrazolyl, and pyrimidinyl.

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R2is selected from H, oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, -CN, C(O)Ra2, and S(O)2Rb2,54057-0031W01 / SNV0023-W01 PATENT96.wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, and 4-10 membered heterocycloalkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; and97.each Ra2and Rb2is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and C3- 10 cycloalkyl.

13. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R2is selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C(O)Ra2, and S(O)2Rb2, wherein the C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents; and99.each Ra2and Rb2is independently selected from C1-6 alkyl and C3-7 cycloalkyl.

14. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R2is selected from H, fluoro, chloro, methyl, difluoromethyl, trifluoromethyl, cyclopropyl, morpholinyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyranyl, tetrahydropyranyl, 2-oxa-7-azaspiro[3.5]nonanyl, 4-oxa-7-azaspiro[2.5]octanyl, cyclopropylcarbonyl, and isopropylsulfonyl, wherein the methyl, cyclopropyl, morpholinyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyranyl, tetrahydropyranyl, 2-oxa-7-azaspiro[3.5]nonanyl, and 4-oxa-7-azaspiro[2.5]octanyl of R2are each optionally substituted with 1, 2, or 3 independently selected R2Asubstituents.

15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein each R2Ais independently selected from 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, -CN, -ORa2A, and -C(O)Ra2A, wherein each 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 R2Ais optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; and102.each Ra2Ais 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, and 5-10 membered heteroaryl, wherein each 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 Ra2Ais optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents. 54057-0031W01 / SNV0023-W01 PATENT16. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein each R2Ais independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, -ORa2A, and -C(O)Ra2A, wherein each C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl of R2Ais optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents selected from OH and CN; and104.each Ra2Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein each C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl of Ra2Ais optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents selected from OH and CN.

17. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein each R2Ais independently selected from methyl, difluoromethyl, methoxy, difluoromethoxy, cyclopropylcarbonyl, cyanocyclopropylcarbonyl, tetrahydrofuranylcarbonyl, pyrazolyl, triazolyl, and thiazolyl.

18. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R2is selected from H, fluoro, chloro, methyl, difluoromethyl, trifluoromethyl, cyclopropyl, dihydropyranyl, tetrahydropyranyl, morpholinyl, (difluoromethyl)(methyl)morpholinyl, (hydroxymethyl)(methyl)morpholinyl, (methoxymethyl)(methyl)morpholinyl, (difluoromethoxymethyl)(methyl)morpholinyl, pyrazolylpiperidinyl, triazolylpiperidinyl, (cyclopropylcarbonyl)piperidinyl, thiazolylpiperazinyl, (cyclopropylcarbonyl)(methyl)piperazinyl, (cyclopropylcarbonyl)(dimethyl)piperazinyl, (cyanocyclopropylcarbonyl)(methyl)piperazinyl, (methyl)(tetrahydrofuranylcarbonyl)piperazinyl, (cyclopropylcarbonyl)tetrahydropyridinyl, 2-oxa-7-azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, cyclopropylcarbonyl, and isopropylsulfonyl.

19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein Z is O.

20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R1is selected from -CN, C1-3 alkyl, and C1-3 haloalkyl.54057-0031W01 / SNV0023-W01 PATENT21. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R1is -CN or C1-3 alkyl.

22. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R1is selected from methyl, difluoromethyl, and cyano.

23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein Rlaand Rlb, together with the carbon atom to which they are attached, form a C3-4 cycloalkyl group, wherein the C3-4 cycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents.

24. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein Rlaand Rlb, together with the carbon atom to which they are attached, form a C3-4 cycloalkyl group.

25. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein Rlaand Rlb, together with the carbon atom to which they are attached, form a cyclopropyl group.

26. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt115.B 4-(R4)n116.thereof, wherein Ring A117.

118. is27. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein X4is N.

28. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein X4is C(-L3-R3).

29. The compound of any one of claims 26 to 28, or a pharmaceutically acceptable salt thereof, wherein X5is C(-L3-R3).54057-0031W01 / SNV0023-W01 PATENT30. The compound of any one of claims 25 to 29, or a pharmaceutically acceptable salt thereof, wherein X6is N.

31. The compound of any one of claims 25 to 29, or a pharmaceutically acceptable salt thereof, wherein X6is C(-L3-R3).

32. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt126.

33. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt129.thereof, wherein Ring A130.

131. is34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein X7is C(-L3-R3).

35. The compound of claim 33 or 34, or a pharmaceutically acceptable salt thereof, wherein X8is C(-L3-R3).54057-0031W01 / SNV0023-W01 PATENT36. The compound of any one of claims 33 to 35, or a pharmaceutically acceptable salt thereof, wherein X9is N.

37. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt136.thereof, wherein Ring A137.

138. is38. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt140.thereof, wherein Ring A141.

142. is39. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein X4is N.

40. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt145.thereof, wherein Ring A146.

147. is41. The compound of claim 40, or a pharmaceutically acceptable salt thereof, wherein X7is C(-L3-R3).54057-0031W01 / SNV0023-W01 PATENT42. The compound of any one of claims 38 to 41, or a pharmaceutically acceptable salt thereof, wherein Y1is C.

43. The compound of any one of claims 38 to 41, or a pharmaceutically acceptable salt thereof, wherein Y1is N.

44. The compound of any one of claims 38 to 43, or a pharmaceutically acceptable salt thereof, wherein Y2is C.

45. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt153.thereof, wherein Ring A154.

155. is46. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt157.thereof, wherein Ring A158.

159. is47. The compound of any one of claims 1 to 25 and 38 to 46, or a pharmaceutically acceptable salt thereof, wherein Ring C is selected from C5-10 cycloalkyl, 5-10 membered heterocycloalkyl, and 5-6 membered heteroaryl.

48. The compound of any one of claims 1 to 25 and 38 to 46, or a pharmaceutically acceptable salt thereof, wherein Ring C is selected from C5-7 cycloalkyl, 5-7 membered heterocycloalkyl, and 5-6 membered heteroaryl.54057-0031W01 / SNV0023-W01 PATENT49. The compound of any one of claims 1 to 25 and 38 to 48, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, or 4.

50. The compound of any one of claims 1 to 25 and 38 to 49, or a pharmaceutically165.

51. The compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, wherein each L3is independently selected from a bond, -O-, and -C(O)-.

52. The compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, wherein each R3is independently selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, 4-10 membered heterocycloalkyl, -CN, and -ORa3, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and 4-10 membered heterocycloalkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; and each Ra3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl.

53. The compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, wherein each R3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, 4-7 membered heterocycloalkyl, -CN, and -ORa3, wherein the C1-6 alkyl, C1-6 haloalkyl, and 4-7 membered heterocycloalkyl of R3are each optionally substituted with 1 or 2 independently selected R3Asubstituents; and54057-0031W01 / SNV0023-W01 PATENT170.each Ra3is independently selected from H and Ci-6 alkyl.

54. The compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, wherein each R3Ais independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl.

55. The compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, wherein each R3Ais independently selected from C1-6 alkyl.

56. The compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, wherein each R3Ais methyl.

57. The compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, wherein each R3is independently selected from H, methyl, trideuteromethyl, methoxymethyl, difluoromethyl, morpholinyl, CN, and methoxy.

58. The compound of any one of claims 1 to 57, or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2.

59. The compound of any one of claims 1 to 57, or a pharmaceutically acceptable salt thereof, wherein p is 1.

60. The compound of any one of claims 1 to 59, or a pharmaceutically acceptable salt thereof, wherein each L1is independently selected from -O-, -C(O)-, -C(O)N(RL)-, and C1-6 alkylene; and178.each RLis independently selected from H and C1-6 alkyl.

61. The compound of any one of claims 1 to 59, or a pharmaceutically acceptable salt thereof, wherein each L1is independently selected from -O-, -C(O)-, -C(O)NH-, -CH2-, and -CD2-.

62. The compound of any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl.54057-0031W01 / SNV0023-W01 PATENT63. The compound of any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from cyclobutyl, phenyl, azetidinyl, and pyrazolyl.

64. The compound of any one of claims 1 to 63, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.

65. The compound of any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof, wherein each R4is independently selected from oxo, halo, Ci- 6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and -CN.

66. The compound of any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof, wherein each R4is independently selected from halo, Ci-6 alkyl, and Ci-6 haloalkyl.

67. The compound of any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof, wherein each R4is independently selected from fluoro, methyl, and difluoromethyl.

68. The compound of any one of claims 1 to 61, or a pharmaceutically acceptable salt187.thereof, wherein Ring B is selected from188.

191.

69. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:194.X1is N or CR5;195.X2is N or CR6;196.X3is N or C(-L2-R2);197.Z is O or NR7; 54057-0031W01 / SNV0023-W01 PATENT199. 201.each - is independently a single or double bond;202.* denotes attachment to X1;203.m is 0, 1, 2, 3, 4, 5, or 6;204.n is 0, 1, 2, 3, 4, 5, or 6;205.p is 1, 2, 3, or 4;206.X4is C(-L3-R3) orN;207.X5is C(-L3-R3) orN;208.X6is C(-L3-R3) orN;209.X7is C(-L3-R3) orN;210.X8is C(-L3-R3) orN;211.X9is C(-L3-R3) orN;212.Y1is C orN;213.Y2is C orN;214.Ring B is selected from C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl;215.Ring C is selected from C5-10 cycloalkyl, phenyl, 5-10 membered heterocycloalkyl, and 5-6 membered heteroaryl; 54057-0031W01 / SNV0023-W01 PATENT216.each L1is independently selected from Ci-6 alkylene, Ci-6 haloalkylene, -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 and Ci-6 haloalkylene of L1are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents; each L2and L3is independently selected from bond, 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-, -(5-6 membered heteroarylene)-Ci-4 alkyl-, -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) -C 1-4 alkyl of L2and L3are each optionally substituted with 1, 2, 3, or 4 independently selected RGsubstituents;217.each RLis independently selected from H, 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) -C1-4 alkyl of RLare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;218.R1is selected from -CN, C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, and 4-7 membered heterocycloalkyl, wherein the C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, and 4-7 membered heterocycloalkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;219.Rlaand Rlbare each independently C1-3 alkyl, wherein the C1-3 alkyl of Rlaand Rlbis optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;220.or, Rlaand Rlb, together with the carbon atom to which they are attached, form a C3-4 cycloalkyl group, wherein the C3-4 cycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;221.R2is selected from H, oxo, halo, C1-6 alkyl, C2.6 alkenyl, C2-ealkynyl, 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, - 54057-0031W01 / SNV0023-W01 PATENT222.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;223.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) -C 1-4 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;224.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-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 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;225.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-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;226.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, - 54057-0031W01 / SNV0023-W01 PATENT227.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, 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-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 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;228.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) -C 1-4 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;229.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-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 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;230.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- 54057-0031W01 / SNV0023-W01 PATENT231.Ci-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;232.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, -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)Rf3Rg3, 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;233.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) -C 1-4 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;234.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-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of 54057-0031W01 / SNV0023-W01 PATENT235.Rb3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents;236.each Re3is 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-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;237.each Rf3and Rg3are independently selected from C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and, C1-6 haloalkoxy;238.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, -C(O)ORa3A, -C(O)NRc3ARd3A, -C(O)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 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-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 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;239.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) -C 1-4 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; 54057-0031W01 / SNV0023-W01 PATENT240.each Rb3Ais 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-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 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;241.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-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;242.each R4is independently selected from 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, -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, -NRc4S(O)NRc4C(O)Rb4, and -P(O)Rf4Rg4, 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 R4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R4Asubstituents;243.each Ra4, Rc4, and Rd4is 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, 54057-0031W01 / SNV0023-W01 PATENT244.(4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra4, Rc4, and Rd4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R4Asubstituents;245.each Rb4is 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-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Rb4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R4Asubstituents;246.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, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;247.each Rf4and Rg4are independently selected from H, 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-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;248.each R4Ais 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, -ORa4A, -SRa4A, -NRc4ARd4A, -NO2, -C(O)Ra4A, -C(O)ORa4A, -C(O)NRc4ARd4A, -C(O)NRc4A(ORa4A), -OC(O)Ra4A, -OC(O)NRc4ARd4A, -OC(O)ORa4A, -OS(O)2Rb4A, -OS(O)2NRc4ARd4A, -NRc4AC(O)Ra4A, -NRc4AC(O)ORa4A, -NRc4AC(O)NRc4ARd4A, -NRc4AS(O)2Rb4A, -NRc4AS(O)2NRc4ARd4A, -NRc4AORa4A, -NRc4AS(O)Rb4A, -NRc4AS(O)NRc4ARd4A, -S(O)Rb4A, -S(O)2Rb4A, -S(O)NRc4ARd4A, -S(O)2NRc4ARd4A, -C(=NRe4A)Ra4A, -C(=NRe4A)NRc4ARd4A, -NRc4AC(=NRe4A)Ra4A, -NRc4AC(=NRe4A)NRc4ARd4A, -NRc4AS(O)(=NRe4A)Rb4A, -NRc4AS(O)(=NRe4A)NRc4ARd4A, -OS(O)(=NRe4A)Rb4A, -S(O)(=NRe4A)Rb4A, -249.

250. S(O)(=NRe4A)NRc4ARd4A, -C(O)NRc4AS(O)2Rb4A, -C(O)NRc4AS(O)2NRc4ARd4A, -S(O)2NRc4AC(O)Rb4A, -NRc4AS(O)NRc4AC(O)Rb4A, and -P(O)Rf4ARg4A, wherein the Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered 54057-0031W01 / SNV0023-W01 PATENT251.heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R4Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;252.each Ra4A, Rc4A, and Rd4Ais 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) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra4A, Rc4A, and Rd4Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;253.each Rb4Ais 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-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Rb4Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;254.each Re4Ais 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-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;255.each Rf4Aand Rg4Aare independently selected from H, 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-C1-4 alkyl, (4-10 membered heterocycloalkyl) -C 1-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;256.R5is selected from H, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C 1-4 haloalkoxy, and -CN;257.R6is selected from H, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C 1-4 haloalkoxy, and -CN; 54057-0031W01 / SNV0023-W01 PATENT258.R7is selected from H, CN, ORa7, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;259.Ra7is selected from H, C1-6 alkyl, and C1-6 haloalkyl;260.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, C1-3 alkylsulfonyl, carbamyl, C1-3 alkylcarbamyl, di(Ci-3 alkyl)carbamyl, carboxy, C1-3 alkylcarbonyl, C1-3 alkoxycarbonyl, C1-3 alkylcarbonyloxy, C1-3 alkylcarbonylamino, C1-3 alkoxycarbonylamino, aminocarbonyloxy, C1-3 alkylaminocarbonyloxy, di(Ci-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.

70. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:262.X1is N or CR5;263.X2is N or CR6;264.X3is N or C(-L2-R2);265.Z is O; 54057-0031W01 / SNV0023-W01 PATENT267. 269.each - is independently a single or double bond;270.* denotes attachment to X1;271.m is 0, 1, 2, 3, or 4;272.n is 1 or 2;273.p is 1 or 2;274.X4is C(-L3-R3) orN;275.X5is C(-L3-R3) orN;276.X6is C(-L3-R3) orN;277.X7is C(-L3-R3) orN;278.X8is C(-L3-R3) orN;279.X9is C(-L3-R3) orN;280.Y1is C orN;281.Y2is C orN;282.Ring B is selected from C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl;283.Ring C is selected from C5-10 cycloalkyl, 5-10 membered heterocycloalkyl, and 5-6 membered heteroarylene;284.each L1is independently selected from -O-, -C(O)-, -C(O)N(RL)-, and C1.6 alkylene; 54057-0031W01 / SNV0023-W01 PATENT285.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;286.each L3is independently selected from a bond, -O-, and -C(O)-;287.each RLis independently selected from H and C1-6 alkyl;288.R1is selected from -CN, C1-3 alkyl, and C1-3 haloalkyl;289.Rlaand Rlb, together with the carbon atom to which they are attached, form a C3-4 cycloalkyl group, wherein the C3-4 cycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;290.R2is selected from H, oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, -CN, C(O)Ra2, and S(O)2Rb2, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3- 10 cycloalkyl, and 4-10 membered heterocycloalkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents;291.each R2Ais independently selected from 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, -CN, -ORa2A, and -C(O)Ra2A, wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of R2Ais optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;292.each Ra2and Rb2is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-10 cycloalkyl;293.each Ra2Ais 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, and 5-10 membered heteroaryl, wherein each 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 Ra2Ais optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;294.each R3is independently selected from H, halo, Ci -6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, 4-10 membered heterocycloalkyl, -CN, and -ORa3, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and 4-10 membered heterocycloalkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents;295.each R3Ais independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;296.each Ra3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; 54057-0031W01 / SNV0023-W01 PATENT297.each R4is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, and -CN; and298.each RGis independently selected from C1-4 alkyl, OH, and CN.

71. The compound of claim 1, wherein the compound of Formula l is a compound of Formula II:

301. 303.or a pharmaceutically acceptable salt thereof.

72. The compound of claim 1, wherein the compound of Formula I is a compound of Formula III:

305. / L2306.R2308. 310.or a pharmaceutically acceptable salt thereof.

73. The compound of claim 1, wherein the compound of Formula I is a compound of Formula IV:54057-0031W01 / SNV0023-W01 PATENT312.R3314. 316.IV317.or a pharmaceutically acceptable salt thereof.

74. The compound of claim 1, wherein the compound of Formula I is a compound of Formula V:

320. 322.or a pharmaceutically acceptable salt thereof.

75. The compound of claim 1, wherein the compound of Formula I is a compound of Formula VI:324.R3326.

327. 54057-0031W01 / SNV0023-W01 PATENT328.VI329.or a pharmaceutically acceptable salt thereof.

76. The compound of claim 1, which is selected from:331.5 -fluoro- 1 -(( 1 -methyl- 127-py razol -4-y 1 )oxy )- N-( 1 -methylcyclopropyl)isoquinoline-7 -sulfonamide;332.8-fluoro-4-(( 1 -methyl- I / / -py razol -4- l (oxy )- '-( 1 -methylcyclopropyl)quinoline-6-sulfonamide;333.6-(( 1 -methyl- I / / -py razol -4-y I (oxy )- '-( 1 -methylcyclopropyl)- 1,2,3,4-tetrahydrobenzo [c] [ 1,6] naphthyridine- 8 -sulfonamide;334.methyl 6-(( 1 -methyl- 127-py razol-4-y 1 )oxy )-8-( N-( 1 -methylcyclopropyl)sulfamoyl)- 3.4-dihydrobcnzo|c || 1.6 |naphthyridinc-2( I / / (-carboxy late:335.methyl 3 -methyl-6-(( 1 -methyl- 1 -py razol -4-y 1 )oxy )-8-( N-( 1 -mcthylcyclopropyl)sulfamoyl)-3.4-dihydrobcnzo|c || 1.6 |naphthyridinc-2( I / / (-carboxylate:336.4-(3,3-difluoroazetidine-l-carbonyl)-8-[(3S,5S)-3,5-dimethylpiperazin-l-yl]-2-mcthoxy-A'-( 1 -methylcyclopropyl)quinazoline-6-sulfonamide;337.V-(3,3-difluorocyclobutyl)-8-((3S,5S)-3,5-dimethylpiperazin-l-yl)-2-methoxy-6-( / V-( 1 -methylcyclopropyl)sulfamoyl)quinazoline-4-carboxamide;338.methyl 10-chloro-6-(( 1 -(difluoromethyl)- I / / -py razol -4- l )oxy)-8-(A'-( 1 -mcthylcyclopropyl)sulfamo l)-3.4-dihydrobcnzo|c || 1.6 |naphthyridinc-2( I / / (-carbox late:339.methyl 6-(3,4-difluorophenoxy)-8-[(l-methylcyclopropyl)sulfamoyl]-3,4-dihydro-1 H-benzo [c] [ 1,6] naphthyridine -2 -carboxylate;340.(R)- 1 -methyl-5 -((1 -methyl- I / / -py razol -4-y I (oxy )- '-( 1 -methylcyclopropyl)-2,3 -dihydro- 1 / / -cyclopenta[c]isoquinoline-7-sulfonamide;341.(R)-2 -methyl-5 -((1 -methyl- I / / -py razol -4-y I (oxy )- '-( 1 -methylcyclopropyl)-2,3 -dihydro- 1 / / -cyclopenta[c]isoquinoline-7-sulfonamide;342.4-cyano-8-fluoro-2 -methyl -3-(( 1 -methyl- I / / -py razol -4- l (methyl )- '-( 1 -methylcyclopropyl)quinoline-6-sulfonamide; and343.4-cyano-8-((3. S'.5, S)-3.5-dimcthylpipcrazin-l-yl)-2-mcthyl-3-(( l-mcthyl-l / / -pyrazol-4-yl)methyl)- / V-( 1 -methylcyclopropyl)quinoline-6-sulfonamide;344.or a pharmaceutically acceptable salt thereof.

77. The compound of claim 1, which is selected from:

346. / 7 / -5-cyano- 1,9-dimethyl-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-N-( 1 -methylcyclopropyl) - 1,2-dihydroimidazo [ 1,2-a] quinoline -7 -sulfonamide; 54057-0031W01 / SNV0023-W01 PATENT347.7? J-5-cyano- 1 -methyl -4-(( 1-methyl- lH-pyrazol-4-yl)methyl)-N-( 1 -methylcyclopropyl) - 1,2-dihydroimidazo [ 1,2-a] quinoline -7 -sulfonamide;348.<7)-5-cyano-N-( 1 -cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl) - 1,2-dihydroimidazo [ 1,2 -a] quinoline -7 -sulfonamide;349.<7)-5-cyano-N-( 1 -cyanocyclopropyl)- 1,9-dimethyl-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl) - 1,2-dihydroimidazo [ 1,2 -a] quinoline -7 -sulfonamide;350.(7aR, 10aS)-5-cyano-N-( 1 -cyanocyclopropyl)- 1 -methyl-6-(( 1 -methyl-lH-pyrazol-4-yl)methyl)-7a,8,10,10a-tetrahydrofuro[3',4':4,5]imidazo[l,2-a]quinoline-3-sulfonamide;351.(S)-5-cyano-N-( 1 -cyanocyclopropyl)- 1 -(methoxymethyl)-9-methyl-4-(( 1 -methyl-lH-pyrazol-4-yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;352.<7)-5-cyano-N-( 1 -cyanocyclopropyl)-9-(difluoromethyl)- 1 -methyl -4-(( 1 -methyl-lH-pyrazol-4-yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;353.<7)-5-cyano-N-( 1 -cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-9-morpholino- 1,2-dihydroimidazo[ 1,2-a]quinoline-7-sulfonamide;354.4-cyano-8-((2R,6S)-2-(hydroxymethyl)-6-methylmorpholino)-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)-N-(l-methylcyclopropyl)quinoline-6-sulfonamide;355.4-cyano-N-(l-cyanocyclopropyl)-8-((2R,6S)-2-(hydroxymethyl)-6-methylmorpholino)-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;356.4-cyano-N-(l-(difhioromethyl)cyclopropyl)-8-((2R,6S)-2-(hydroxymethyl)-6-methylmorpholino)-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;357.4-cyano-N-( 1 -cyanocyclopropyl)-2-methyl-3-(( 1 -methyl- IH-pyrazol -4-yl)methyl)-8-(2-oxa-7 -azaspiro [3.5]nonan-7 -yl)quinoline-6-sulfonamide;358.8-(4-( IH-pyrazol- 1 -yl)piperidin- 1 -yl)-4-cyano-N-( 1 -cyanocyclopropyl)-2-methyl-3-(( 1 -methyl- IH-pyrazol -4-yl)methyl)quinoline-6-sulfonamide;359.8-(4-(2H- 1,2,3-triazol-2-yl)piperidin- 1 -yl)-4-cyano-N-( 1 -cyanocyclopropyl)-2-methyl-3-(( 1 -methyl- IH-pyrazol -4-yl)methyl)quinoline-6-sulfonamide;360.4-cyano-N-( 1 -cyanocyclopropyl)-2-methyl-3-(( 1 -methyl- IH-pyrazol -4-yl)methyl)-8-(4-(thiazol-2-yl)piperazin- 1 -yl)quinoline-6-sulfonamide;361.4-cyano-N-(l-cyanocyclopropyl)-8-((2R,6S)-2-(difluoromethyl)-6-methylmorpholino)-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;362.4-cyano-N-(l-cyanocyclopropyl)-8-((2R,6S)-2-(methoxymethyl)-6-methylmorpholino)-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;363.4-cyano-N-(l-cyanocyclopropyl)-8-((2R,6S)-2-((difluoromethoxy)methyl)-6-methylmorpholino)-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide; 54057-0031W01 / SNV0023-W01 PATENT364.f / ?)-4-cyano-N-( l-cyanocyclopropyl)-8-(4-(cyclopropanccarbonyl)-3-methylpiperazin- 1 -yl)-2-methyl-3-(( 1 -methyl- lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;365.4-cyano-N-(l-cyanocyclopropyl)-8-((cis)-4-(cyclopropanecarbonyl)-3,5-dimethylpiperazin- 1 -yl)-2-methyl-3-(( 1 -methyl- lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;366.f7?)-4-cyano-8-(4-( 1 -cyanocyclopropane- 1 -carbonyl) -3 -methylpiperazin- 1 -yl)-N-( 1 -cyanocyclopropyl)-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;367.4-cyano-N-( 1 -cyanocyclopropyl)-2-methyl-3-(( 1 -methyl- IH-pyrazol -4-yl)methyl)-8-(<7?)-3-mcthyl-4-((S)-tctrahydrofiiran-3-carbonyl)pipcrazin-l-yl)quinolinc-6-siilfonamidc:368.4-cyano-N-( 1 -cyanocyclopropyl)-8-( 1 -(cyclopropanecarbonyl)piperidin-4-yl)-2-methyl-3-(( 1 -methyl- IH-pyrazol -4-yl)methyl)quinoline-6-sulfonamide;369.4-cyano-N-(l-cyanocyclopropyl)-8-(2-cyclopropylpyridin-4-yl)-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;370.4-cyano-N-( 1 -cyanocyclopropyl)-8-( 1 -(cyclopropanecarbonyl)- 1,2,3,6-tetrahydropyridin-4-yl)-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;371.f7?)-4-cyano-8-(4-( 1 -cyanocyclopropane- 1 -carbonyl) -3 -methylpiperazin- 1 -yl)-N-( 1 -cyanocyclopropyl)-2-(difluoromethyl)-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;372.4-cyano-N-(l-cyanocyclopropyl)-2-(difluoromethyl)-8-((2R,6S)-2-(methoxymethyl)-6-methylmorpholino)-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;373.4-cyano-N-(l-cyanocyclopropyl)-8-((2R,6S)-2-(methoxymethyl)-6-methylmorpholino)-3-((l-methyl-lH-pyrazol-4-yl)methyl)-2-morpholinoquinoline-6-sulfonamide;374.f / ?)-4-cyano-N-( l-cyanocyclopropyl)-8-(4-(cyclopropanccarbonyl)-3-methylpiperazin-l-yl)-7-fluoro-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;375.4-cyano-N-(l-cyanocyclopropyl)-7-fluoro-8-((2R,6S)-2-(methoxymethyl)-6-methylmorpholino)-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide;376.( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)-9-fluoro- 1 -methyl -4-(( 1 -methyl- IH-pyrazol -4-yl)methyl) - 1,2-dihydroimidazo [ 1,2 -a] quinoline -7 -sulfonamide;377.( / ?)-4-cyano-N-( 1 -cyanocyclopropyl)-8-(6-(methoxymethyl)-2,2-dimethylmorpholino)-2-methyl-3-((l-methyl-lH-pyrazol-4-yl)methyl)quinoline-6-sulfonamide; and 54057-0031W01 / SNV0023-W01 PATENT378.( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl-lH-pyrazol-4-yl)methyl)-9-((R)-2-methylmorpholino)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;379.or a pharmaceutically acceptable salt thereof.

78. The compound of claim 1, which is selected from:381.( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)-9-(2,2-dimethylmorpholino)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo[ 1,2-a]quinoline-7-sulfonamide;382.( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl-lH-pyrazol-4-yl)methyl)-9-(4-oxa-7-azaspiro[2.5]octan-7-yl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;383.( / ?)-5-cyano-N-( 1 -cyanocyclopropy l)-9-((. S)-2-(difluoromcthy l)morphol ino)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo[ 1,2-a] quinoline-7 -sulfonamide;384.( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl-lH-pyrazol-4-yl)mcthyl)-9-((. S)-2-(trifhioromcthyl)morpholino)-l.2-dihydroimidazo| l.2-a|qtiinolinc-7-sulfonamide;385.( / )-5-cyano-N-( l-cyanocyclopropyl)-9-(( / )-4-(cyclopropanccarbonyl)-3-methylpiperazin- 1 -yl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo [ 1,2 -a] quinoline -7 -sulfonamide;386.( / ?)-5-cyano-N-( l-cyanocyclopropyl)-9-(2-cyclopropylpyrimidin-4-yl)-l-mcthyl-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo[ 1,2-a]quinoline-7-sulfonamide;387.( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)-9-( 1 -cyclopropyl-lH-pyrazol-4-yl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo[ 1,2-a]quinoline-7-sulfonamide;388.( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)-9-(3,6-dihydro-2H-pyran-4-yl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo[ 1,2-a]quinoline-7-sulfonamide;389.( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-9-(tetrahydro-2H-pyran-4-yl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;390.( / )-5-cyano-N-( l-cyanocyclopropyl)-9-(( / )-4-(isopropylsiilfonyl)-3-methylpiperazin- 1 -yl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo [ 1,2 -a] quinoline -7 -sulfonamide;391.5-cyano-N-( 1 -cyanocyclopropyl)- 1 -(methyl - 3)-4-(( 1 -methyl- lH-pyrazol-4-y I )mcthy l-tA)- 1,2-dihydroimidazo[ 1,2-a] quinoline-7 -sulfonamide- 1,2,2- s;392.5-cyano-N-( 1 -cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl- 1 H-py razol-4-y I )mcthy 1-tT)-1,2-dihydroimidazo [ 1,2-a] quinoline-7 -sulfonamide- 1,2,2-t / j;393.( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)- 1 -methyl -4-(( 1 -methyl- lH-pyrazol-4-y I )m cthy I -t ) - 1,2-dihydroimidazo [ 1,2 -a] quinoline -7 -sulfonamide; 54057-0031W01 / SNV0023-W01 PATENT394.5-cyano-N-( 1 -cyanocyclopropyl)-9-(2,2-dimethylmorpholino)-4-(( 1 -methyl-lH-pyrazol-4-yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;395.5-cyano-N-( 1 -cyanocyclopropyl)-9-(2,2-dimethylmorpholino)-4-(( 1 -methyl- 1H-pyrazol-4-yl)methyl)imidazo[l,2-a]quinoline-7-sulfonamide;396.( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-9-(2-methylmorpholino) - 1,2-dihydroimidazo [ 1,2-a] quinoline -7 -sulfonamide;397.( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-9-(2-methylmorpholino)imidazo[l,2-a]quinoline-7-sulfonamide;398.(. S')-5-cyano-N-( 1 -cyanocyclopropyl)-9-(2-(difluoromethyl)morpholino)-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo [ 1,2-a]quinohne-7-sulfonamide;399.(. S')-5-cyano-N-( 1 -cyanocyclopropyl)-9-(2-(difluoromethyl)morpholino)-4-(( 1 -methyl-lH-pyrazol-4-yl)methyl)imidazo[l,2-a]quinoline-7-sulfonamide;400.(. S')-5-cyano-N-( 1 -cyanocyclopropyl)-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-9-(2-(trifluoromethyl)morpholino)- 1,2-dihydroimidazo [ 1,2-a] quinoline-7 -sulfonamide;401.(. S')-5-cyano-N-( 1 -cyanocyclopropyl)-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-9-(2-(trifluoromethyl)morpholino)imidazo [ 1,2 -a] quinoline -7 -sulfonamide;402.5 -cyano-N-( 1 -cyanocyclopropyl)-9-(2-cyclopropylpyrimidin-4-yl)-4-(( 1 -methyl- 1H-pyrazol-4-yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;403.5 -cyano-N-( 1 -cyanocyclopropyl)-9-(2-cyclopropylpyrimidin-4-yl)-4-(( 1 -methyl- 1H-pyrazol-4-yl)methyl)imidazo[l,2-a]quinoline-7-sulfonamide;404.( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)-8-fluoro- 1 -methyl -4-(( 1 -methyl-lH-pyrazol-4-yl)mcthyl)-9-(( / ?)-2-mcthylmorpholino)-l.2-dihydroimidazo| l.2-a|quinolinc-7-siilfonamidc:405.5-cyano-N-(l-cyanocyclopropyl)-9-(2,2-dimethylmorpholino)-8-fluoro-l-(methyl-ds)-4-(( 1 -(methyl -d3)- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo [ 1,2-a]quinoline-7-sulfonamide- 1,2,2-ds;406.5-cyano-N-( 1 -cyanocyclopropyl)-8-fluoro- 1 -methyl -4-(( 1 -(methyl -ds)- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo [ 1,2-a] quinoline-7 -sulfonamide- 1,2,2-t / s;407.5-cyano-N-( 1 -cyanocyclopropyl)-8-fluoro- 1 -(methyl -d3)-4-(( 1 -(methyl -ds)- 1H-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo [ 1,2-a] quinoline-7 -sulfonamide- 1,2,2- s;408.( / ?)-5-cyano-N-( l-cyanocyclopropyl)-9-(2-cyclopropylpyrimidin-4-yl)-8-fliioro-l-methyl -4-(( 1 -(methyl -d3)- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo [ 1,2-a]quinoline-7-sulfonamide;409.5-cyano-N-(l-cyanocyclopropyl)-9-(2,2-dimethylmorpholino)-8-fluoro-4-((l-(methyl-d3)-lH-pyrazol-4-yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;410.5-cyano-N-(l-cyanocyclopropyl)-9-(2,2-dimethylmorpholino)-8-fluoro-4-((l-(methyl-ds)-lH-pyrazol-4-yl)methyl)imidazo[l,2-a]quinoline-7-sulfonamide; 54057-0031W01 / SNV0023-W01 PATENT411.( / ?)-5-cyano-N-( l-cyanocyclopropyl)-8-fliioro-4-((l-(mcthyl-d3)-IH-pyrazol-4-yl)methyl)-9-(2-methylmorpholino)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;412.( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)-8-fluoro-4-(( 1 -(methyl -ds)- lH-pyrazol-4-yl)methyl) -9-(2-methylmorpholino)imidazo [ 1,2 -a] quinoline -7 -sulfonamide;413.(S)-5-cyano-N-( 1 -cyanocyclopropyl)-8-fluoro-4-(( 1 -(methyl -ds)- lH-pyrazol-4-yl)methyl)-9-(2-(trifluoromethyl)morpholino)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;414.(. S)-5-cyano-N-( 1 -cyanocyclopropyl)-8-fluoro-4-(( 1 -(methyl -ds)- lH-pyrazol-4-yl)methyl)-9-(2-(trifluoromethyl)morpholino)imidazo[l,2-a]quinoline-7-sulfonamide;415.5-cyano-N-(l-cyanocyclopropyl)-9-(2-cyclopropylpyrimidin-4-yl)-8-fluoro-4-((l-(methyl-ds)- lH-pyrazol-4-yl)methyl)- 1,2-dihydroimidazo [ 1,2-a] quinoline-7 -sulfonamide;416.5-cyano-N-(l-cyanocyclopropyl)-9-(2-cyclopropylpyrimidin-4-yl)-8-fluoro-4-((l-(methyl-ds)-lH-pyrazol-4-yl)methyl)imidazo[l,2-a]quinoline-7-sulfonamide;417.( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)-8-fluoro-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl) -9-(2-methylmorpholino)imidazo [ 1,2 -a] quinoline -7 -sulfonamide;418.( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)-8-fluoro- 1 -methyl -4-(( 1 -methyl- IH-pyrazol -4-yl)methyl) - 1,2-dihydroimidazo [ 1,2 -a] quinoline -7 -sulfonamide;419.5-cyano-N-( 1 -cyanocyclopropyl)-2,2-dimethyl-4-(( 1 -methyl- IH-pyrazol -4-yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;420.5-cyano-N-( 1 -cyanocyclopropyl)-2,2-dimethyl-4-(( 1 -methyl- IH-pyrazol -4-yl)methyl-d2)- 1,2-dihydroimidazo [ 1,2-a] quinoline-7 -sulfonamide;421.5-cyano-N-( 1 -cyanocyclopropyl)-9-fluoro-2,2-dimethyl-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl) - 1,2-dihydroimidazo [ 1,2 -a] quinoline -7 -sulfonamide;422.( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)-2,2-dimethyl-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl)-9-(2-methylmorpholino)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;423.(S)-5-cyano-N-(l-cyanocyclopropyl)-9-(2-(difluoromethyl)morpholino)-2,2-dimethyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;424.(. S)-5-cyano-N-( 1 -cyanocyclopropyl)-2,2-dimethyl-4-(( 1 -methyl-lH-pyrazol-4-yl)methyl)-9-(2-(trifluoromethyl)morpholino)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;425.5-cyano-N-(l-cyanocyclopropyl)-9-(2-cyclopropylpyrimidin-4-yl)-2,2-dimethyl-4-(( 1 -methyl- IH-pyrazol -4-yl)methyl)- 1,2-dihydroimidazo [ 1,2-a]quinoline-7-sulfonamide;426.( / ?)-5-cyano-N-( l-cyanocyclopropyl)-8-fliioro-2.2-dimcthyl-4-(( l-(mcthyl-d3)-IH-pyrazol-4-yl)methyl)-9-(2-methylmorpholino)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide; 54057-0031W01 / SNV0023-W01 PATENT427.(. S')-5-cyano-N-( l-cyanocyclopropyl)-8-fliioro-2.2-dimcthyl-4-(( l-(mcthyl-d3)-IH-pyrazol-4-yl)methyl)-9-(2-(trifluoromethyl)morpholino)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;428.5-cyano-N-(l-cyanocyclopropyl)-9-(2-cyclopropylpyrimidin-4-yl)-8-fluoro-2,2-dimethyl-4-((l-(methyl-d3)-lH-pyrazol-4-yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;429.5-cyano-N-(l-cyanocyclopropyl)-8-fluoro-2,2-dimethyl-4-((l-(methyl-d3)-lH-pyrazol-4-yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;430.( / ?)-5-cyano-N-( 1 -cyanocyclopropyl)- 1 -methyl -4-((4-methyl- IH-imidazol- 1 -yl)methyl)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide;431.5-cyano-N-(l-cyanocyclopropyl)-9-(2-cyclopropylpyrimidin-4-yl)-8-fluoro-l-(methyl-d3)-4-(( 1 -(methyl -d3)- lH-pyrazol-4-yl)methyl-d2)- 1,2-dihydroimidazo[ 1,2-a] quinoline -7 -sulfonamide - 1,2,2-t / j;432.(J?)-5-cyano-N-( 1 -cyanocyclopropyl)-8-fluoro-4-(( 1 -(methyl -d3)- IH-pyrazol -4-yl)methyl-d2)-9-(2-methylmorpholino)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide- 1.1.2.2-<; and433.( / ?)-5-cyano-N-( l-cyanocyclopropyl)-8-fliioro-2.2-dimcthyl-4-(( l-(mcthyl-d3)-IH-pyrazol-4-yl)methyl-d2)-9-(2-methylmorpholino)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide- 1, 1 -d,434.or a pharmaceutically acceptable salt thereof.

79. A compound, which is 5-cyano-N-(l-cyanocyclopropyl)-l-(methyl- 3)-4-((l-methyl- I H-py razol-4-y I )mcthy l-tA)- 1,2-dihydroimidazo[ 1,2-a]quinoline-7-sulfonamide- 1,2,2-< A, or a pharmaceutically acceptable salt thereof.

80. A compound, which is 5-cyano-N-(l-cyanocyclopropyl)-l-methyl-4-((l-methyl-lH-pyrazol-4-yl)methyl-d2)- 1,2-dihydroimidazo[ 1,2 -a] quinoline -7-sulfonamide- 1,2,2-t / j, or a pharmaceutically acceptable salt thereof.

81. A compound, which is ( / ?)-5-cyano-N-( I -cyanocyclopropyl)- 1 -mcthyl-4-(( I -mcthyl-lH-pyrazol-4-yl)methyl-d2)-l,2-dihydroimidazo[l,2-a]quinoline-7-sulfonamide, or a pharmaceutically acceptable salt thereof.

82. The compound of claim 79, which is 5-cyano-N-(l-cyanocyclopropyl)-l-(methyl- 3)-4-(( 1 -methyl- 1 H-pyrazol -4-yl (mcthyl-tA)- 1,2-dihydroimidazo[ 1,2-a]quinoline-7-sulfonamide- 1.2.2-3.54057-0031W01 / SNV0023-W01 PATENT83. The compound of claim 80, which is 5-cyano-N-(l-cyanocyclopropyl)-l-methyl-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl-d2)- 1,2-dihydroimidazo[ 1,2-a]quinoline-7-sulfonamide-1,2, 2-6 / 3.

84. The compound of claim 81, which is (A)-5-cyano-N-(l-cyanocyclopropyl)-l-methyl-4-(( 1 -methyl- lH-pyrazol-4-yl)methyl-d2)- 1,2-dihydroimidazo[ 1,2-a]quinoline-7-sulfonamide.

85. A pharmaceutical composition, comprising a compound of any one of claims 1 to 81, or a pharmaceutically acceptable salt thereof, or a compound of any one of claims 82 to 84, and a pharmaceutically acceptable carrier.

86. 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 81, or a pharmaceutically acceptable salt thereof, or a compound of any one of claims 82 to 84.

87. A method of treating a poly(ADP-ribose) glycohydrolase -mediated disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 81, or a pharmaceutically acceptable salt thereof, or a compound of any one of claims 82 to 84.

88. The method of claim 87, wherein the disease or disorder is a cancer.

89. The method of claim 88, 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.

90. The method of claim 88, wherein the cancer is selected from ovarian cancer, colorectal cancer, breast cancer, prostate cancer, uterine cancer, and pancreatic cancer.

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