NRF2 degrader for the treatment of cancer

Abstract

The present application discloses NRF2 degrader of formula (I), wherein NRF2L is a NRF2 (nuclear factor-erythroid-derived 2-related factor 2) binding moiety, L is a linker and E3L is the ubiquitin E3 ligase moiety. Preferred compounds are of formula (IV). A specific example is e.g. The present compounds are for use in methods of treatment of cancer.

Description

[0001] 54057-0024W01 / SNV0019-W01 PATENT

[0002] NRF2 Degrader Compounds

[0003] TECHNICAL FIELD

[0004] The present disclosure provides heterocyclic compounds as well as their pharmaceutical compositions that modulate the activity of nuclear factor-erythroid- derived 2-related factor 2 (NRF2) and are useful in the treatment of various diseases related to NRF2, including cancer.

[0005] BACKGROUND

[0006] Nuclear factor-erythroid-derived 2-related factor 2 (NRF2) is a key transcription factor (TF) encoded by the NFE2L2 gene in human genome. This TF controls expression of a battery of genes important for detoxification and antioxidant response (see e.g., Cancers (Basel), 2020;13(l):46). Induction of phase II detoxification and antioxidant enzymes through activation of NRF2 has been recognized as one of the major cellular defense mechanisms against oxidative or xenobiotic stresses. In addition, NRF2 is also involved in energy metabolism and inflammation (see e.g., Annu. Rev. Pharmacol. Toxicol., 2013; 53:401-426).

[0007] Most clinically used pharmaceutical agents are based upon small-molecule inhibition of protein function. However, alternative approaches that provide for protein degradation, rather than inhibition, also have the potential to provide clinical efficacy. Accordingly, targeted protein degradation through ubiquitination of protein targets has emerged as an effective strategy in drug discovery. Heterobifunctional small molecules, which simultaneously bind to target proteins and recruit an ubiquitin ligase (e.g., ubiquitin E3 ligase) have been shown to result in the target protein’s ubiquitination and degradation (Bondeson, D.P. et al., Nat. Chem. Biol. 2015, 11(8):611-617).

[0008] Inhibition or degradation of NRF2 can alter metabolic processes and thus suppress tumor growth, prevent metastasis, and / or increase sensitivity of chemotherapy. There is a need for the development of new drugs, such as small molecules that can bind to both NRF2 and ubiquitin E3 ligase to cause NRF2 degradation, which are useful in the treatment of cancer of other diseases.

[0009] SUMMARY 54057-0024W01 / SNV0019-W01 PATENT

[0010] The present disclosure provides, inter alia, compounds of Formula I:

[0011] I or pharmaceutically acceptable salts thereof, wherein constituent members are defined herein.

[0012] 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.

[0013] The present disclosure further provides methods of inhibiting nuclear factor- erythroid-derived 2-related factor 2 (NRF2) activity, comprising contacting the NRF2 with a compound described herein, or a pharmaceutically acceptable salt thereof.

[0014] The present disclosure further provides methods of treating a disease or a disorder associated with nuclear factor-erythroid-derived 2-related factor 2 (NRF2) in a patient by administering to the patient a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof.

[0015] The present disclosure further provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.

[0016] 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.

[0017] DETAILED DESCRIPTION

[0018] The present application provides a compound of Formula I:

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

[0020] NRF2L is a NRF2 binding moiety of the following formula: 54057-0024W01 / SNV0019-W01 PATENT m is 0, 1, 2, 3, 4, 5, or 6; n is 0, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, 5, or 6;

[0021] Ring A is selected from C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl;

[0022] Ring B is selected from bicyclic or tricyclic Ce-14 cycloalkyl, bicyclic or tricyclic C10-14 aryl, bicyclic or tricyclic 7-14 membered heterocycloalkyl, and bicyclic or tricyclic 6-14 membered heteroaryl;

[0023] Ring C is selected from C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl;

[0024] L1and L2are each independently selected from bond or C1-6 alkylene wherein 1-3 methylene units of the C1-6 alkylene are independently and optionally replaced with -O-, -N(RL1)-, -C(O)-, -N(RL1)C(O)-, -N(RL1)C(O)N(RL1)-, -N(RL1)C(O)O-, - S(O)-, -S(O)2-, -S(O)(=NRL1)-, -S(O)2N(RL1)-, and -N(RL1)S(O)2N(RL1)-, wherein the C1-6 alkylene of L1and L2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each RL1is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, (5-6 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, (5-6 membered heteroaryl)-Ci-4 alkyl of RL1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0025] L is selected from a covalent bond and k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; 54057-0024W01 / SNV0019-W01 PATENT each L’ is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cn 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, -O-, - O)N(RL’)-, -N(RL’)C(O)O-, -S(O)-, -S(O)2-, ’)S(O)2N(RL’)-, wherein the C1-6 alkyl, C2.6alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Cn 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of L’ are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each RLis independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, (5-6 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, (5-6 membered heteroaryl)-Ci-4 alkyl of RLare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0026] E3L is an E3 ubiquitin ligase ligand of the following formula: q is 0, 1, 2, 3, 4, 5, or 6;

[0027] X is N or CR5;

[0028] L3is selected from a bond and C1-3 alkylene, wherein 1-2 methylene units of the C1-3 alkylene are independently and optionally replaced with -O-, -S-, -N(RL3)-, - C(O)-, -N(RL3)C(O)-, -N(RL3)C(O)N(RL3)-, -N(RL3)C(O)O-, -S(O)-, -S(O)2-, - S(O)(=NRL3)-, -S(O)2N(RL3)-, and -N(RL3)S(O)2N(RL3)-, wherein the C1-3 alkylene of L3is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; 54057-0024W01 / SNV0019-W01 PATENT each RL3is independently selected from H, Ci-6 alkyl, and Ci-6 haloalkyl;

[0029] Ring D is C3-14 cycloalkyl, Ce-io aryl, 4-14 membered heterocycloalkyl, 5-10 membered heteroaryl;

[0030] R1is 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, - ORal, -SRal, -NRclRdl, -NO2, -C(O)Ral, -C(O)ORal, -C(O)NRclRdl, - C(O)NRcl(ORal), -OC(O)Ral, -OC(O)NRclRdl, -OC(O)ORal, -OS(O)2Rbl, - OS(O)2NRclRdl, -NRclC(O)Ral, -NRclC(O)ORal, -NRclC(O)NRclRdl, -NRclS(O)2Rbl, -NRclS(O)2NRclRdl, -NRclORal, -NRclS(O)Rbl, -NRclS(O)NRclRdl, -S(O)Rbl, - S(O)2Rbl, -S(O)NRclRdl, -S(O)2NRclRdl, -C(=NRel)Ral, -C(=NRel)NRclRdl, - NRclC(=NRel)Ral, -NRclC(=NRel)NRclRdl, -NRclS(O)(=NRel)Rbl, - NRclS(O)(=NRel)NRclRdl, -OS(O)(=NRel)Rbl, -S(O)(=NRel)Rbl, - S(O)(=NRel)NRclRdl, -C(O)NRclS(O)2Rbl, -C(O)NRclS(O)2NRclRdl, - S(O)2NRclC(O)Rbl, -NRclS(O)NRclC(O)Rbl, and -P(O)RflRgl, 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 R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1Asubstituents; each Ral, Rcl, and Rdlis 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-Cn 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ral, Rcl, and Rdlare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1Asubstituents; 54057-0024W01 / SNV0019-W01 PATENT or, any Rcland Rdlattached 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 R1Asubstituents; each Rblis independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rblare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1Asubstituents; each Relis 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,

[0031] 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each Rfland Rglare independently selected from H, C1-6 alkyl, C1-6 alkoxy, Cn 6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4- 10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R1Ais 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,

[0032] 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, - ORalA, -SRalA, -NRclARdlA, -NO2, -C(O)RalA, -C(O)ORalA, -C(O)NRclARdlA, - C(O)NRclA(ORalA), -OC(O)RalA, -OC(O)NRclARdlA, -OC(O)ORalA, -OS(O)2RblA, - OS(O)2NRclARdlA, -NRclAC(O)RalA, -NRclAC(O)ORalA, -NRclAC(O)NRclARdlA, - NRclAS(O)2RblA, -NRclAS(O)2NRclARdlA, -NRclA0RalA, -NRclAS(O)RblA, - NRclAS(O)NRclARdlA, -S(O)RblA, -S(O)2RblA, -S(O)NRclARdlA, -S(O)2NRclARdlA, - 54057-0024W01 / SNV0019-W01 PATENT

[0033] C(=NRelA)RalA, -C(=NRelA)NRclARdlA, -NRclAC(=NRelA)RalA, - NRclAC(=NRelA)NRclARdlA, -NRclAS(O)(=NRelA)RblA, - NRclAS(O)(=NRelA)NRclARdlA, -OS(O)(=NRelA)RblA, -S(O)(=NRelA)RblA, - S(O)(=NRelA)NRclARdlA, -C(O)NRclAS(O)2RblA, -C(O)NRclAS(O)2NRclARdlA, - S(O)2NRclAC(O)RblA, -NRclAS(O)NRclAC(O)RblA, and -P(O)RflARglA, wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R1Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each RalA, RclA, and RdlAis 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-Cn 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of RalA, RclA, and RdlAare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any RclAand RdlAattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each RblAis independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 54057-0024W01 / SNV0019-W01 PATENT

[0034] 10 membered heteroaryl)-Ci-4 alkyl of RblAare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each RelAis independently selected from H, OH, CN, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each RflAand RglAare 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-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R2, R3and R4are independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, (5-6 membered heteroaryl)-Ci-4 alkyl, -CN, -ORa2, -SRa2, -NRc2Rd2, -NO2, -C(O)Ra2, -C(O)ORa2, -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, -NRc2S(O)NRc2C(O)Rb2, and -P(O)Rf2Rg2, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci- 4 alkyl of R2, R3and R4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra2, Rc2, and Rd2is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered 54057-0024W01 / SNV0019-W01 PATENT heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci- 4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of Ra2, Rc2, and Rd2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc2and Rd2attached to the same N atom, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group, wherein the 4- 7 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rb2is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of Rb2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; 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, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl; each R12and Rg2are independently selected from H, C1-6 alkyl, C1-6 alkoxy, Cn 6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl;

[0035] R5is H, D, halo, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, or C1-4 haloalkoxy; 54057-0024W01 / SNV0019-W01 PATENT each RGis independently selected from OH, CN, halo, oxo, Ci-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, cyano-Ci-4 alkyl, HO-C1-4 alkyl, C1-4 alkoxy-Ci-4 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-3 alkylamino, di(Ci-3 alkyl)amino, thio, C1-3 alkylthio, C1-3 alkylsulfinyl, Ci- 3 alkyl sulfonyl, carbamyl, C1-3 alkylcarbamyl, di (C 1-3 alkyl)carbamyl, carboxy, C1-3 alkylcarbonyl, C1-3 alkoxycarbonyl, C1-3 alkylcarbonyloxy, C1-3 alkylcarbonylamino, C1-3 alkoxy carbonylamino, aminocarbonyloxy, C1-3 alkylaminocarbonyloxy, di (C 1-3 alkyl)aminocarbonyloxy, C1-3 alkylsulfonylamino, aminosulfonyl, C1-3 alkylaminosulfonyl, di(Ci-3 alkyl)aminosulfonyl, aminosulfonylamino, C1-3 alkylaminosulfonylamino, di(Ci-3 alkyl)aminosulfonylamino, aminocarbonylamino, C1-3 alkylaminocarbonylamino, and di(Ci-3 alkyl)aminocarbonylamino.

[0036] In some embodiments, Ring A is selected from C3-7 cycloalkyl, phenyl, 8-10 membered heterocycloalkyl, and 5-6 membered heteroaryl.

[0037] In some embodiments, Ring A is selected from C3-7 cycloalkyl, phenyl, bicyclic 8-10 membered heterocycloalkyl, and 5-6 membered heteroaryl.

[0038] In some embodiments, Ring A is selected from phenyl, pyrazolyl, and indolinyl.

[0039] In some embodiments, m is 0, 1, or 2.

[0040] In some embodiments, m is 0 or 1.

[0041] In some embodiments, m is 0.

[0042] In some embodiments, m is 1. In some embodiments, Ring A is selected from

[0043] In some embodiments, each R1is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, -ORal, -SRal, -NRclRdl, -NO2, -C(O)Ral, -C(O)ORal, and -C(O)NRclRdl.

[0044] In some embodiments, each R1is independently selected from oxo, C1-6 alkyl, -ORal, -NRclRdl, -C(O)Ral, -C(O)ORal, and -C(O)NRclRdl.

[0045] In some embodiments, each R1is independently selected from C1-6 alkyl, - NRclRdl, and -C(O)Ral. 54057-0024W01 / SNV0019-W01 PATENT

[0046] In some embodiments, each Ral, Rcl, and Rdlis independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4- 10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of Ral, Rcl, and Rdlare each optionally substituted with 1, 2, 3, or 4 independently selected R1Asubstituents.

[0047] In some embodiments, each Ral, Rcl, and Rdlis independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl of Ral, Rcl, and Rdlare each optionally substituted with 1, 2, 3, or 4 independently selected R1Asubstituents.

[0048] In some embodiments, each Ral, Rcl, and Rdlis independently selected from H, C1-6 alkyl, C3-10 cycloalkyl, and Ce-io aryl, wherein the C1-6 alkyl, C3-10 cycloalkyl, and Ce-io aryl of Ral, Rcl, and Rdlare each optionally substituted with 1, 2, 3, or 4 independently selected R1Asubstituents.

[0049] In some embodiments, each Ral, Rcl, and Rdlis independently selected from H, C1-6 alkyl, C3-7 cycloalkyl, and phenyl, wherein the C3-7 cycloalkyl and phenyl of Ral, Rcl, and Rdlare each optionally substituted with 1 or 2 independently selected R1Asubstituents.

[0050] In some embodiments, each R1Ais independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of R1Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents.

[0051] In some embodiments, each R1Ais independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl.

[0052] In some embodiments, each R1Ais independently selected from C1-6 alkyl, which is optionally substituted with 1, 2, 3 or 4 independently selected RGsubstituents.

[0053] In some embodiments, each R1Ais independently selected from C1-6 alkyl.

[0054] In some embodiments, each R1Ais independently selected from C1-3 alkyl.

[0055] In some embodiments, each R1Ais methyl. 54057-0024W01 / SNV0019-W01 PATENT

[0056] In some embodiments, each R1is independently selected from oxo, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, -ORal, -SRal, -NRclRdl, -NO2, -C(O)Ral, -C(O)ORal, and -C(O)NRclRdl; each Ral, Rcl, and Rdlis independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl of Ral, Rcl, and Rdlare each optionally substituted with 1, 2, 3, or 4 independently selected R1Asubstituents; and each R1Ais independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl.

[0057] In some embodiments, each R1is independently selected from C1-6 alkyl, - NRclRdl, and -C(O)Ral; each Ral, Rcl, and Rdlis independently selected from H, C1-6 alkyl, C3-7 cycloalkyl, and phenyl, wherein the C3-7 cycloalkyl and phenyl of Ral, Rcl, and Rdlare each optionally substituted with 1 or 2 independently selected R1Asubstituents; and each R1Ais independently selected from C1-6 alkyl.

[0058] In some embodiments, each R1is independently selected from methyl, dimethylamino, methylcarbonyl, (methylphenyl)carbonyl, and cyclopropylcarbonyl.

[0059] In some embodiments, L1is a bond.

[0060] In some embodiments, Ring B is selected from bicyclic Ce-14 cycloalkyl, bicyclic Cio-u aryl, bicyclic 7-14 membered heterocycloalkyl, and tricyclic 6-14 membered heteroaryl.

[0061] In some embodiments, Ring B is selected from bicyclic 7-14 membered heterocycloalkyl and bicyclic 8-14 membered heteroaryl.

[0062] In some embodiments, Ring B is a bicyclic 7-14 membered heterocycloalkyl.

[0063] In some embodiments, Ring B is a bicyclic 8-14 membered heteroaryl.

[0064] The compound of claim 1, wherein Ring B is selected from 3,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-one, 5,6,7,8-tetrahydroimidazo[l,2-a]pyrazinyl, imidazo[l,2-a]pyrazin-8(7H)-one, imidazo[l,2-c]pyrimidinyl, lH-imidazo[4,5- b]pyrazinyl, imidazo[l,2-a]pyrazinyl, imidazo[l,2-a]pyridinyl, and isoquinolinyl. 54057-0024W01 / SNV0019-W01 PATENT

[0065] In some embodiments, Ring B is selected from

[0066] In some embodiments, Ring B is selected from

[0067] In some embodiments, n is 0, 1, or 2.

[0068] In some embodiments, n is 0 or 1.

[0069] In some embodiments, n is 0. In some embodiments, n is 1.

[0070] In some embodiments, each R2is independently selected from oxo, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents. In some embodiments, each R2is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl.

[0071] In some embodiments, each R2is independently selected from oxo and C1-6 alkyl. 54057-0024W01 / SNV0019-W01 PATENT

[0072] In some embodiments, each R2is independently selected from oxo and C1-3 alkyl.

[0073] In some embodiments, each R2is independently selected from oxo and methyl.

[0074] In some embodiments, each R2is oxo.

[0075] In some embodiments, each R2is methyl.

[0076] In some embodiments, Ring B is selected from

[0077] In some embodiments, L2is C1-6 alkylene, wherein 1-3 methylene units of the C1-6 alkylene are independently and optionally replaced with -N(RL1)-.

[0078] In some embodiments, L2is C1-6 alkylene, wherein 1 or 2 methylene units of the C1-6 alkylene are independently and optionally replaced with -N(RL1)-.

[0079] In some embodiments, L2is C1-6 alkylene, wherein 1 methylene unit of the C1-6 alkylene are independently and optionally replaced with -N(RL1)-.

[0080] In some embodiments, L2is C1-3 alkylene, wherein 1 or 2 methylene units of the C1-6 alkylene are independently and optionally replaced with -N(RL1)-.

[0081] In some embodiments, L2is C1-3 alkylene, wherein 1 methylene unit of the C1-6 alkylene are independently and optionally replaced with -N(RL1)-.

[0082] In some embodiments, each RL1is independently selected from H and C1-6 alkyl.

[0083] In some embodiments, each RL1is independently selected from H and C1-3 alkyl.

[0084] In some embodiments, each RL1is H.

[0085] In some embodiments, L2is C1-6 alkylene, wherein 1-3 methylene units of the C1-6 alkylene are independently and optionally replaced with -N(RL1)-; and 54057-0024W01 / SNV0019-W01 PATENT each RL1is independently selected from H and Ci-6 alkyl.

[0086] In some embodiments, L2is Ci-6 alkylene, wherein 1-3 methylene units of the Ci-6 alkylene are independently and optionally replaced with -N(RL1)-; and each RL1is independently selected from H and C1-3 alkyl.

[0087] In some embodiments, L2is C1-6 alkylene, wherein 1-3 methylene units of the C1-6 alkylene are independently and optionally replaced with -NH-.

[0088] In some embodiments, L2is C1-6 alkylene, wherein 1 or 2 methylene units of the C1-6 alkylene are independently and optionally replaced with -NH-.

[0089] In some embodiments, L2is C1-6 alkylene, wherein 1 methylene unit of the C1-6 alkylene are independently and optionally replaced with -NH-.

[0090] In some embodiments, L2is C1-3 alkylene, wherein 1 or 2 methylene units of the C1-6 alkylene are independently and optionally replaced with -NH-.

[0091] In some embodiments, L2is C1-3 alkylene, wherein 1 methylene unit of the C1-6 alkylene are independently and optionally replaced with -NH-.

[0092] In some embodiments, L2is selected from -CH2- and -NHCH2-.

[0093] In some embodiments, L2is selected from -CH2-.

[0094] In some embodiments, L2is selected -NHCH2-.

[0095] In some embodiments, Ring C is Ce-io aryl.

[0096] In some embodiments, Ring C is phenyl.

[0097] In some embodiments, Ring C is JO .

[0098] In some embodiments, p is 0, 1, or 2.

[0099] In some embodiments, p is 0 or 1.

[0100] In some embodiments, p is 0.

[0101] In some embodiments, L is a bond.

[0102] In some embodiments,

[0103] In some embodiments, k is 3, 4, 5, 6, or 7.

[0104] In some embodiments, k is 4, 5, or 6.

[0105] In some embodiments, k is 4.

[0106] In some embodiments, k is 5. 54057-0024W01 / SNV0019-W01 PATENT

[0107] In some embodiments, k is 6.

[0108] In some embodiments, each L’ is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -O-, and -N(RL)-.

[0109] In some embodiments, each L’ is independently selected from C1-6 alkyl, -O-, and -N(RL)-.

[0110] In some embodiments, each RLis independently selected from H and C1-6 alkyl.

[0111] In some embodiments, each RLis independently selected from H and C1-3 alkyl.

[0112] In some embodiments, each RLis H.

[0113] In some embodiments, each L’ is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -O-, and -N(RL)-; and each RLis independently selected from H and C1-6 alkyl.

[0114] In some embodiments, each L’ is independently selected from C1-6 alkyl, -O-, and -N(RL)-; and each RLis independently selected from H and C1-3 alkyl.

[0115] In some embodiments, each L’ is independently selected from -CH2CH2-, -O-, and -NH-.

[0116] In some embodiments, L is -O-C1-6 alkylene-O-Ci-6 alkylene-N(RL)-.

[0117] In some embodiments, L is -O-C1-3 alkylene-O-Ci-3 alkylene-N(RL)-.

[0118] In some embodiments, L is -O-C1-6 alkylene-O-Ci-6 alkylene-NH-.

[0119] In some embodiments, L is -O-C1-3 alkylene-O-Ci-3 alkylene-NH-.

[0120] In some embodiments, L is -OCH2CH2OCH2CH2N(RL)-.

[0121] In some embodiments, L is -OCH2CH2OCH2CH2NH-.

[0122] In some embodiments, Ring D is 4-14 membered heterocycloalkyl.

[0123] In some embodiments, Ring D is bicyclic 8-14 membered heterocycloalkyl.

[0124] In some embodiments, Ring D is bicyclic 8-10 membered heterocycloalkyl.

[0125] In some embodiments, q is 1, 2, or 3.

[0126] In some embodiments, q is 2.

[0127] In some embodiments, each R4is oxo.

[0128] In some embodiments, Ring D is isoindoline-1, 3-dionyl. 54057-0024W01 / SNV0019-W01 PATENT

[0129] In some embodiments, Ring

[0130] In some embodiments, L3is a bond.

[0131] In some embodiments, X is N.

[0132] In some embodiments, X is CR5.

[0133] In some embodiments, R5is selected from H, D, halo, C1-4 alkyl, and C1-4 haloalkyl.

[0134] In some embodiments, R5is selected from H, D, halo, C1-4 alkyl, and C1-4 haloalkyl.

[0135] In some embodiments, R5is selected from H, D, and C1-4 alkyl.

[0136] In some embodiments, R5is selected from H and D.

[0137] In some embodiments, R5is selected from H.

[0138] In some embodiments:

[0139] NRF2L is a NRF2 binding moiety of the following formula: m is 0, 1, or 2; n is 0 or 1; p is 0 or 1;

[0140] Ring A is selected from C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl;

[0141] Ring B is selected from bicyclic or tricyclic Ce-14 cycloalkyl, bicyclic or tricyclic C10-14 aryl, bicyclic or tricyclic 7-14 membered heterocycloalkyl, and bicyclic or tricyclic 6-14 membered heteroaryl;

[0142] Ring C is selected from C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl;

[0143] L1is a bond;

[0144] L2is C1-6 alkylene, wherein 1-3 methylene units of the C1-6 alkylene are independently and optionally replaced with -N(RL1)-; each RL1is independently selected from H and C1-6 alkyl; 54057-0024W01 / SNV0019-W01 PATENT

[0145] L is selected from a covalent bond and k is 4, 5, or 6; each L’ is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 haloalkyl, -O-, and -N(RL)-; each RLis independently selected from H and C1-6 alkyl;

[0146] E3L is an E3 ubiquitin ligase ligand of the following formula: q is 1, 2, or 3;

[0147] X is N or CR5;

[0148] L3is a bond;

[0149] Ring D is C3-14 cycloalkyl, Ce-io aryl, 4-14 membered heterocycloalkyl, 5-10 membered heteroaryl; each R1is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, -ORal, -SRal, -NRclRdl, -NO2, -C(O)Ral, -C(O)ORal, and -C(O)NRclRdl; each Ral, Rcl, and Rdlis independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl of Ral, Rcl, and Rdlare each optionally substituted with 1, 2, 3, or 4 independently selected R1Asubstituents; each R1Ais independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; each R2is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; each R4is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; and

[0150] R5is selected from H, D, halo, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy.

[0151] In some embodiments: 54057-0024W01 / SNV0019-W01 PATENT

[0152] NRF2L is a NRF2 binding moiety of the following formula: m is 0, 1, or 2; n is 0 or 1; p is 0 or 1;

[0153] Ring A is selected from C3-7 cycloalkyl, phenyl, 8-10 membered heterocycloalkyl, and 5-6 membered heteroaryl;

[0154] Ring B is selected from bicyclic 7-14 membered heterocycloalkyl and bicyclic 8-14 membered heteroaryl;

[0155] Ring C is Ce-io aryl;

[0156] L1is a bond;

[0157] L2is C1-6 alkylene, wherein 1-3 methylene units of the C1-6 alkylene are independently and optionally replaced with -N(RL1)-; each RL1is independently selected from H and C1-6 alkyl; k is 4, 5, or 6; each L’ is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cn 6 haloalkyl, -O-, and -N(RL)-; each RLis independently selected from H and C1-6 alkyl;

[0158] E3L is an E3 ubiquitin ligase ligand of the following formula: q is 1, 2, or 3;

[0159] X is N or CR5;

[0160] L3is a bond;

[0161] Ring D is 4-14 membered heterocycloalkyl; 54057-0024W01 / SNV0019-W01 PATENT each R1is independently selected from oxo, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, -ORal, -SRal, -NRclRdl, -NO2, -C(O)Ral, -C(O)ORal, and -C(O)NRclRdl; each Ral, Rcl, and Rdlis independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl of Ral, Rcl, and Rdlare each optionally substituted with 1, 2, 3, or 4 independently selected R1Asubstituents; each R1Ais independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; each R2is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; each R4is oxo; and

[0162] R5is selected from H, D, halo, C1-4 alkyl, and C 1-4 haloalkyl.

[0163] In some embodiments, the compound of Formula I is a compound of Formula

[0164] II: or a pharmaceutically acceptable salt thereof.

[0165] In some embodiments, the compound of Formula I is a compound of Formula

[0166] III: or a pharmaceutically acceptable salt thereof. 54057-0024W01 / SNV0019-W01 PATENT

[0167] In some embodiments, the compound of Formula I is a compound of Formula

[0168] III: or a pharmaceutically acceptable salt thereof.

[0169] In some embodiments, the compound provided herein is selected from:

[0170] 2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(3-((3-methyl-2-(l-(2- methylbenzoyl)indolin-5-yl)imidazo[l,2-c]pyrimidin-7- yl)methyl)phenoxy)ethoxy)ethyl)amino)isoindoline-l,3-dione;

[0171] 5-((2-(2-(3-((6-(l-(cyclopropanecarbonyl)indolin-5-yl)-l-oxo-3,4- dihydropyrrolo[l,2-a]pyrazin-2(177)-yl)methyl)phenoxy)ethoxy)ethyl)amino)-2-(2,6- dioxopiperi din-3 -yl)isoindoline- 1 ,3 -di one;

[0172] 2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(3-((6-(l-(2-methylbenzoyl)indolin-5-yl)- l / 7-imidazo[4,5-Z>]pyrazin-2-yl)methyl)phenoxy)ethoxy)ethyl)amino)isoindoline-l,3- dione;

[0173] 4-((2-(2-(3-(((2-(l-(cyclopropanecarbonyl)indolin-5-yl)imidazo[l,2- a]pyrazin-8-yl)amino)methyl)phenoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline- 1 ,3 -di one;

[0174] 4-((2-(2-(3-((3-(l-(cyclopropanecarbonyl)indolin-5-yl)-5,6- dihydroimidazo[l,2-a]pyrazin-7(8J7)-yl)methyl)phenoxy)ethoxy)ethyl)amino)-2-(2,6- dioxopiperi din-3 -yl)isoindoline- 1 ,3 -di one;

[0175] 2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(3-((8-(l-(2-methylbenzoyl)indolin-5- yl)isoquinolin-3-yl)methyl)phenoxy)ethoxy)ethyl)amino)isoindoline-l, 3-dione;

[0176] 2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(3-((6-(p-tolyl)-lJ / -imidazo[4,5- Z»]pyrazin-2-yl)methyl)phenoxy)ethoxy)ethyl)amino)isoindoline-l, 3-dione;

[0177] 2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(3-((6-(l-methyl-l / 7-pyrazol-4-yl)-lZ7- imidazo[4,5-Z>]pyrazin-2-yl)methyl)phenoxy)ethoxy)ethyl)amino)isoindoline-l,3- dione; 54057-0024W01 / SNV0019-W01 PATENT

[0178] 4-((2-(2-(3-((6-(4-(dimethylamino)phenyl)-l#-imidazo[4,5-Z>]pyrazin-2- yl)methyl)phenoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3- dione;

[0179] 4-((2-(2-(3-((6-(l-acetylindolin-5-yl)-l -imidazo[4,5-Z>]pyrazin-2- yl)methyl)phenoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3- dione;

[0180] 2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(3-((3-(l-(2-methylbenzoyl)indolin-5- yl)imidazo[l,2-a]pyridin-7-yl)methyl)phenoxy)ethoxy)ethyl)amino)isoindoline-l,3- dione; and

[0181] 2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(3-((3-(l-(2-methylbenzoyl)indolin-5-yl)- 8-oxoimidazo[l,2-a]pyrazin-7(8Z / )- yl)methyl)phenoxy)ethoxy)ethyl)amino)isoindoline-l,3-dione; or a pharmaceutically acceptable salt thereof.

[0182] In some embodiments, the present application provides a compound of Formula V: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring, B, Ring C, and variables R1, R2, R3, L1, L2, m, n, and p are defined according to the definitions provided herein for compounds of Formula I.

[0183] In some embodiments, the present application provides a compound of Formula VI: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring, B, Ring C, and variables R1, R2, R3, L1, L2, m, n, and p are defined according to the definitions provided herein for compounds of Formula I; k is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; 54057-0024W01 / SNV0019-W01 PATENT each L’ is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -O-, - O)N(RL’)-, -N(RL’)C(O)O-, -S(O)-, -S(O)2-, ’)S(O)2N(RL’)-, 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 L’ are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; and each RGis independently selected from OH, CN, halo, oxo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, cyano-Ci-4 alkyl, HO-C1-4 alkyl, C1-4 alkoxy-Ci-4 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-3 alkylamino, di(Ci-3 alkyl)amino, thio, C1-3 alkylthio, C1-3 alkylsulfinyl, Cn 3 alkyl sulfonyl, carbamyl, C1-3 alkylcarbamyl, di (C 1-3 alkyl)carbamyl, carboxy, C1-3 alkylcarbonyl, C1-3 alkoxycarbonyl, C1-3 alkylcarbonyloxy, C1-3 alkylcarbonylamino, C1-3 alkoxy carbonylamino, aminocarbonyloxy, C1-3 alkylaminocarbonyloxy, di (C 1-3 alkyl)aminocarbonyloxy, C1-3 alkylsulfonylamino, aminosulfonyl, C1-3 alkylaminosulfonyl, di(Ci-3 alkyl)aminosulfonyl, aminosulfonylamino, C1-3 alkylaminosulfonylamino, di (C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C1-3 alkylaminocarbonylamino, and di(Ci-3 alkyl)aminocarbonylamino.

[0184] 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.

[0185] 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, -N(RL)C(O)- includes both -N(RL)C(O)- and -C(O)N(RL)- (e.g. -NHC(O)- includes both -NHC(O)- 54057-0024W01 / SNV0019-W01 PATENT and -C(O)NH-). Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups.

[0186] The term “n-membered” where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6- membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10- membered cycloalkyl group.

[0187] 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.

[0188] As used herein, the phrase “each ‘variable’ is independently selected from” means substantially the same as wherein “at each occurrence ‘variable’ is selected from.”

[0189] 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, C , C1-6, and the like.

[0190] As used herein, the term “Cn-m alkyl”, employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (iPr), n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-l- butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. 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.

[0191] As used herein, “Cn-m alkenyl” refers to an alkyl group having one or more double carbon-carbon bonds and having n to m carbons. Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec- 54057-0024W01 / SNV0019-W01 PATENT butenyl, and the like. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0192] As used herein, “Cn-m alkynyl” refers to an alkyl group having one or more triple carbon-carbon bonds and having n to m carbons. Example alkynyl groups include, but are not limited to, ethynyl, propyn-l-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0193] As used herein, the term “Cn-m alkoxy”, employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group has n to m carbons. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tertbutoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0194] As used herein, the term “amino” refers to a group of formula -NH2.

[0195] As used herein, the term “aryl,” employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term “Cn-m aryl” refers to an aryl group having from n to m ring carbon atoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, aryl groups have from 5 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl. In some embodiments, the aryl is phenyl.

[0196] 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.

[0197] As used herein, “Cn-m haloalkoxy” refers to a group of formula -O-haloalkyl having n to m carbon atoms. Example haloalkoxy groups include OCF3 and OCHF2. In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0198] As used herein, the term “Cn-m haloalkyl”, employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+l halogen atoms which may be the same or different, where “s” is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the alkyl 54057-0024W01 / SNV0019-W01 PATENT group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Example haloalkyl groups include CF3, C2F5, CHF2, CH2F, CCI3, CHC12, C2C15and the like.

[0199] As used herein, the term “Cn-m alkylamino” refers to a group of formula -NH(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.

[0200] As used herein, the term “Cn-m alkoxycarbonyl” 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, 1 to 4, or 1 to 3 carbon atoms.

[0201] As used herein, the term “Cn-m alkylcarbonyl” refers to a group of formula -C(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0202] As used herein, the term “Cn-m alkylcarbonylamino” 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, 1 to 4, or 1 to 3 carbon atoms.

[0203] As used herein, the term “Cn-m alkylsulfonylamino” refers to a group of formula -NHS(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.

[0204] As used herein, the term “aminosulfonyl” refers to a group of formula -S(O)2NH2.

[0205] As used herein, the term “Cn-m alkylaminosulfonyl” refers to a group of formula -S(O)2NH(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.

[0206] As used herein, the term “di(Cn-m alkyl)aminosulfonyl” refers to a group of formula -S(O)2N(alkyl)2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0207] As used herein, the term “aminosulfonylamino” refers to a group of formula - NHS(O)2NH2.

[0208] As used herein, the term “Cn-m alkylaminosulfonylamino” refers to a group of formula -NHS(O)2NH(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. 54057-0024W01 / SNV0019-W01 PATENT

[0209] As used herein, the term “di(Cn-m alkyl)aminosulfonylamino” refers to a group of formula -NHS(O)2N(alkyl)2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0210] As used herein, the term “aminocarbonylamino”, employed alone or in combination with other terms, refers to a group of formula -NHC(O)NH2.

[0211] As used herein, the term “Cn-m alkylaminocarbonylamino” refers to a group of formula -NHC(O)NH(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.

[0212] As used herein, the term “di(Cn-m alkyl)aminocarbonylamino” refers to a group of formula -NHC(O)N(alkyl)2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0213] As used herein, the term “Cn-m alkylcarbamyl” 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, 1 to 4, or 1 to 3 carbon atoms.

[0214] As used herein, the term “thio” refers to a group of formula -SH.

[0215] As used herein, the term “Cn-m alkylthio” 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, 1 to 4, or 1 to 3 carbon atoms.

[0216] As used herein, the term “Cn-m alkylsulfinyl” 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, 1 to 4, or 1 to 3 carbon atoms.

[0217] As used herein, the term “Cn-m alkyl sulfonyl” refers to a group of formula -S(O)2-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0218] As used herein, the term “amino” refers to a group of formula -NH2.

[0219] As used herein, the term “carbamyl” to a group of formula -C(O)NH2.

[0220] As used herein, the term “carbonyl”, employed alone or in combination with other terms, refers to a -C(O)- group.

[0221] As used herein, the term “cyano-Ci-3 alkyl” refers to a group of formula -(C1-3 alkylene)-CN. 54057-0024W01 / SNV0019-W01 PATENT

[0222] As used herein, the term “HO-C1-3 alkyl” refers to a group of formula -(C1-3 alkylene)-OH.

[0223] As used herein, the term “C1-3 alkoxy-Ci-3 alkyl” refers to a group of formula - (C1-3 alkylene)-O(Ci-3 alkyl).

[0224] As used herein, the term “carboxy” refers to a group of formula -C(O)OH.

[0225] As used herein, the term “di(Cn-m-alkyl)amino” refers to a group of formula - N(alkyl)2, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0226] As used herein, the term “di(Cn-m-alkyl)carbamyl” refers to a group of formula -C(O)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.

[0227] As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and alkenyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2 fused rings) groups, spirocycles, and bridged rings (e.g, a bridged bicycloalkyl group). Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfido (e.g, C(O) or C(S)). Also included in the definition of cycloalkyl are moi eties that have one or more aromatic rings fused (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 ringforming 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, norbornyl, norpinyl, norcamyl, cubane, adamantane, bicyclo[l.l. l]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, 54057-0024W01 / SNV0019-W01 PATENT spiro[3.3]heptanyl, and the like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0228] As used herein, “heteroaryl” refers to a monocyclic or polycyclic (e.g., having 2 fused rings) aromatic heterocycle having at least one heteroatom ring member selected from N, O, S and B. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S and B. In some embodiments, any ring-forming N in a heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl is a 5-, 7-, 8-, 9-, or 10-membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl is a 5-, 7-, 8-, 9-, or 10-membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl is a 5-6 membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl is a 5 membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl is a 5 membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl group contains 5 to 10, 5 to 7, 3 to 7, or 5 to 6 ringforming atoms. In some embodiments, the heteroaryl group has 1 to 4 ring-forming heteroatoms, 1 to 3 ring-forming heteroatoms, 1 to 2 ring-forming heteroatoms or 1 ring-forming heteroatom. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. Example heteroaryl groups include, but are not limited to, thienyl (or thiophenyl), furyl (or furanyl), pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4- thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl and l,2-dihydro-l,2-azaborine, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, azolyl, 54057-0024W01 / SNV0019-W01 PATENT triazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazofl, 2-b]thiazolyl, purinyl, triazinyl, thieno[3,2- b]pyridinyl, imidazofl, 2-a]pyridinyl, 1,5-naphthyridinyl, lH-pyrazolo[4,3- b]pyridinyl, triazolo[4,3-a]pyridinyl, lH-pyrrolo[3,2-b]pyridinyl, lH-pyrrolo[2,3- b]pyridinyl, pyrazolo[l,5-a]pyridinyl, indazolyl, and the like.

[0229] As used herein, “heterocycloalkyl” refers to monocyclic or polycyclic heterocycles having at least one non-aromatic ring (saturated or partially unsaturated ring), wherein one or more of the ring-forming carbon atoms of the heterocycloalkyl is replaced by a heteroatom selected from N, O, S, and B, and wherein the ringforming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by one or more oxo or sulfido (e.g., C(O), S(O), C(S), or S(O)2, etc.). When a ring-forming carbon atom or heteroatom of a heterocycloalkyl group is optionally substituted by one or more oxo or sulfide, the O or S of said group is in addition to the number of ring-forming atoms specified herein (e.g., a l-methyl-6- oxo-l,6-dihydropyridazin-3-yl is a 6-membered heterocycloalkyl group, wherein a ring-forming carbon atom is substituted with an oxo group, and wherein the 6- membered heterocycloalkyl group is further substituted with a methyl group). Heterocycloalkyl groups include monocyclic and polycyclic (e.g., having 2 fused rings) systems. Included in heterocycloalkyl are monocyclic and polycyclic 3 to 10, 4 to 10, 5 to 10, 4 to 7, 5 to 7, or 5 to 6 membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles and bridged rings (e.g., a 5 to 10 membered bridged biheterocycloalkyl ring having one or more of the ring-forming carbon atoms replaced by a heteroatom independently selected from N, O, S, and B). The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds.

[0230] Also included in the definition of heterocycloalkyl are moi eties that have one or more aromatic rings fused ( / .< ., 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 54057-0024W01 / SNV0019-W01 PATENT can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.

[0231] In some embodiments, the heterocycloalkyl group contains 3 to 10 ringforming atoms, 4 to 10 ring-forming atoms, 4 to 8 ring-forming atoms, 3 to 7 ringforming atoms, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms or 1 heteroatom. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from N, O, S and B and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 5-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, S, and B and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 5 to 10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic 5 to 6 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and having one or more oxidized ring members.

[0232] Example heterocycloalkyl groups include pyrrolidin-2-one (or 2- oxopyrrolidinyl), l,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, 1, 2,3,4- tetrahydroisoquinoline, tetrahydrothiopheneyl, tetrahydrothiopheneyl 1,1 -di oxide, benzazapene, azabicyclo[3.1.0]hexanyl, diazabicyclo[3.1.0]hexanyl, oxobicyclo[2.1.1]hexanyl, azabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.1]heptanyl, azabicyclo[3.1. l]heptanyl, diazabicyclo[3.1. l]heptanyl, azabicyclo[3.2. l]octanyl, diazabicyclo[3.2.1]octanyl, oxobicyclo[2.2.2]octanyl, azabicyclo[2.2.2]octanyl, azaadamantanyl, diazaadamantanyl, oxo-adamantanyl, azaspiro[3.3]heptanyl, 2- azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl, azaspiro[3.5]nonanyl, 7- azaspiro[3.5]nonanyl, oxo-azaspiro[3.3]heptanyl, azaspiro[3.4]octanyl, diazaspiro[3 ,4]octanyl, oxo-azaspiro[3 ,4]octanyl, azaspiro[2.5]octanyl, 54057-0024W01 / SNV0019-W01 PATENT 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.

[0233] As used herein, “Co-Pcycloalkyl-Cn-m alkyl-” refers to a group of formula cycloalkyl-alkylene-, wherein the cycloalkyl has o to p carbon atoms and the alkylene linking group has n to m carbon atoms.

[0234] As used herein “Co-Paryl-Cn-m alkyl-” refers to a group of formula arylalkylene-, wherein the aryl has o to p carbon atoms and the alkylene linking group has n to m carbon atoms.

[0235] As used herein, “heteroaryl-Cn-m alkyl-” refers to a group of formula heteroaryl-alkylene-, wherein alkylene linking group has n to m carbon atoms.

[0236] As used herein “heterocycloalkyl -Cn-m alkyl-” refers to a group of formula heterocycloalkyl-alkylene-, wherein alkylene linking group has n to m carbon atoms.

[0237] As used herein, an “alkyl linking group” or “alkylene linking group” is a bivalent straight chain or branched alkyl linking group (“alkylene group”). For example, “Co-Pcycloalkyl-Cn-m alkyl-”, “Co-Paryl-Cn-m alkyl-”, “phenyl-Cn-m alkyl-”, “heteroaryl-Cn-m alkyl-”, and “heterocycloalkyl-Cn-m alkyl-” contain alkyl linking groups. Examples of “alkyl linking groups” or “alkylene groups” include methylene, ethan- 1,1 -diyl, ethan- 1,2-diyl, propan-1, 3-dilyl, propan- 1,2-diyl, propan- 1,1 -diyl and the like.

[0238] 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.

[0239] As used herein, a “cycloalkyl linking group” or “cycloalkylene linking group” is a bivalent straight chain or branched cycloalkyl linking group (“cycloalkylene group”). Examples of “cycloalkyl linking groups” or “cycloalkylene groups” include cyclopropy-l,l,-diyl, cy cl opropy- 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. 54057-0024W01 / SNV0019-W01 PATENT

[0240] As used herein, a “heterocycloalkyl linking group” or “heterocycloalkylene linking group” is a bivalent straight chain or branched heterocycloalkyl linking group (“heterocycloalkylene group”). Examples of “heterocycloalkyl linking groups” or “heterocycloalkylene groups” include azetidin-l,2-diyl, azeti din- 1,3 -diyl, pyrrolidin- 1,2-diyl, pyrrolidin- 1,3 -diyl, pyrrolidin-2,3-diyl, piperidin-l,2-diyl, piperidin-l,3-diyl, piperidin-l,4-diyl, piperi din-2, 3 -diyl, piperidin-2,4-diyl, and the like.

[0241] As used herein, a “heteroaryl linking group” or “heteroarylene linking group” is a bivalent straight chain or branched heteroaryl linking group (“heteroarylene group”). Examples of “heteroaryl linking groups” or “heteroarylene groups” include pyrazol- 1,3 -diyl, imidazol-l,2,-diyl, pyri din-2, 3 -diyl, pyridin-2,4-diyl, pyridin-3,4- diyl, and the like.

[0242] 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.

[0243] As used herein, the term “oxo” refers to an oxygen atom ( / .< ., =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.

[0244] 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.

[0245] 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 54057-0024W01 / SNV0019-W01 PATENT 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 ( / ^-configuration. In some embodiments, the compound has the (^-configuration. The Formulas (e.g., Formula I, Formula II, etc.) provided herein include stereoisomers of the compounds.

[0246] Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. An example method includes fractional recrystallizaion using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as P-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of a-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N- m ethylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[0247] 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.

[0248] 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. 54057-0024W01 / SNV0019-W01 PATENT

[0249] 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.

[0250] 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.

[0251] 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.

[0252] 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.

[0253] 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.

[0254] The present application also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present disclosure include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically 54057-0024W01 / SNV0019-W01 PATENT 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.

[0255] Synthesis

[0256] 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.

[0257] Compounds of formula 1-12, wherein E3L is an E3 ubiquitin ligase binding moiety, can be prepared according to the process shown in Scheme I. Compound 1-3 can be synthesized by a combination of 1-1 and 1-2 under Friedel-Crafts conditions (e.g. in the presence of AlCh). Condensation of compound 1-3 with an appropriate 1-4 provides the bicyclic compound 1-5. Dependent on the desired L2, 1-5 can be functionalized with 1-6 via suitable reaction conditions (e.g., transition metal- catalyzed cross-coupling, SnAr) to provide 1-7. If present, removal of the protecting group on 1-7 yields 1-8, which can then be furnished with 1-9 via SN2 or other appropriate synthetic methods to offer 1-10. The E3L group can then be appended to 1-10 under suitable reaction conditions (e.g. SnAr, SN2) to provide the desired product 1-12. Analogs of 1-12 can be obtained by replacing reagents 1-1, 1-4, 1-6, 1-9, and I- 11, respectively. 54057-0024W01 / SNV0019-W01 PATENT

[0258] Compounds of formula 11-12, wherein E3L is an E3 ubiquitin ligase binding moiety, can be prepared according to the process shown in Scheme II. Compound II- 3 can be synthesized by a combination of II-l and II-2 under suitable conditions (e.g. transition metal-catalyzed cross-coupling). If present, removal of the protecting group on II-3 and subsequent functionalization (e.g. reductive amination, SN2) with II-5 provides II-6. Condensation under suitable reaction conditions (e.g. sodium methoxide, ammonia in methanol, acetic acid) allows the conversion of II-6 to II-7. If present, removal of the protecting group on II-7 yields II-8, which can then be furnished with II-9 via SN2 or other appropriate synthetic methods to offer 11-10. The E3L group can then be appended to 11-10 under suitable reaction conditions (e.g. SnAr, SN2) to provide the desired product 1-12. Analogs of 11-12 can be obtained by replacing reagents II-l, II-2, II-5, II-9, and 11-11, respectively. 54057-0024W01 / SNV0019-W01 PATENT

[0259] Scheme II.

[0260] 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.

[0261] 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 54057-0024W01 / SNV0019-W01 PATENT

[0262] 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.

[0263] 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.,XH 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.

[0264] 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.

[0265] Methods of Use

[0266] The present disclosure provides uses for compounds and compositions described herein. The compounds described herein can inhibit the activity of nuclear factor-erythroid-derived 2-related factor 2 (NRF2). 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 NRF2. In some embodiments, provided compounds and compositions are useful in research as, for example, analytical tools and / or control compounds in biological assays.

[0267] NRF2 protein expression is controlled in human tissues by a complex of Kelch-like ECH-associated protein 1 (KEAP1) and Cullin 3 (Cul3) E3 ligase (see e.g, Physiol. Rev. 2018;98(3): 1169-1203). Under normal homeostatic conditions, KEAP1 forms part of an E3 ubiquitin ligase, which regulates NRF2 protein level in the cytosol by targeting it for protein ubiquitination and subsequent degradation. In response to stress, NRF2 is released from the E3 ligase complex escaping degradation and accumulating in the nucleus, where it initiates expression of genes critical for detoxification and antioxidant response that are cytoprotective and pro-survival. 54057-0024W01 / SNV0019-W01 PATENT

[0268] Tumor cells can hijack the KEAP1-NRF2 system through multiple molecular mechanisms (see e.g., Physiol. Rev. 2018;98(3): 1169-1203). Somatic mutation in any of NRF2, KEAP1, or Cul3 contributes to upregulated NRF2 signaling. These genetic alterations include gain-of-function mutations of NRF2 and loss-of-function mutations of KEAP1 and Cul3. NRF2 exon 2 shipping disrupts interaction between NRF2 and KEAP1, leading to activation of the pathway (see e.g., Cell Rep., 2016; 16(10):2605-2617). Similar outcomes can also be caused by epigenic silencing of KEAP1 or Cul3. Germline mutations in fumarate hydratase and aberrant accumulation of p62 cause NRF2 activation, and these two have been documented in renal cell carcinoma and hepatocellular carcinoma, respectively. In addition, genetic alterations in oncogenic drivers including KRAS, BRAF, and MYC can also lead to accumulated expression of NRF2 through increasing its gene transcription.

[0269] KEAP1-NRF2 is an independent biomarker of poor prognosis for cancers (see e.g., Genes Dev. 2013;27(20):2179-91). Mounting evidence suggest that dysregulated NRF2 signaling contributed to resistance mechanisms of chemotherapy, radiotherapy, targeted therapy, and immune checkpoint inhibitor therapies, and is a well -recognized marker of poor prognosis for a variety of human malignancies. Co-mutation of KRAS and KEAP1 / NFE2L2 predicted shorter survival, duration of response to initial platinum-based chemotherapy, and survival from the start of immune therapy (see e.g., Clin. Cancer Res. 2018;24(2):334-340], Accordingly, there is a need for new therapeutic agents capable of inhibiting the activity of the NRF2 protein.

[0270] When used as a single agent for monotherapy, the compounds provided herein may be useful for selectively killing tumor cells characterized by NRF2 addiction due to a variety of genetic alteration including, but not limited to, NRF2 gain-of-function mutation, KEAP1 or CUL3 loss-of-function mutation, NRF2 exon 2 skipping, germline mutations in fumarate hydratase, aberrant accumulation of p62 protein, transcriptional upregulation of the NRF2 gene by oncogenes including but not limited to KRAS mutation, BRAF mutation, and MYC activation etc., and epigenetic silencing or KE API or CUL3.

[0271] 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 54057-0024W01 / SNV0019-W01 PATENT provided compounds or compositions to a subject suffering from or susceptible to a disease, disorder, or condition associated with NRF2. 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 NRF2.

[0272] In some embodiments, the compounds provided herein are useful as NRF2 inhibitors. In some embodiments, the present disclosure provides methods of inhibiting NRF2 in a subject comprising administering a provided compound or composition. In some embodiments, the present disclosure provides methods of inhibiting NRF2 in a biological sample comprising contacting the sample with a provided compound or composition.

[0273] In some embodiments, the present disclosure provides methods of treating a disease, disorder or condition associated with NRF2 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 NRF2. 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 NRF2, in a subject in need thereof, comprising administering to the subject a provided compound or composition.

[0274] In some embodiments, the present disclosure provides methods of treating a variety of NRF2-dependent diseases and disorders. In some embodiments, the disease, disorder, or condition associated with NRF2 is a cancer. Exemplary cancers include, but are not limited to squamous cell lung cancer, lung adenocarcinoma, esophageal cancer, endometrial cancer, head and neck cancer, bladder cancer, ovarian cancer, liver cancer (e.g., hepatocellular carcinoma), cervical cancer, cholangiocarcinoma, gastric cancer, melanoma, kidney cancer (e.g., renal cell carcinoma), colorectal carcinoma, breast cancer, pancreatic cancer, thyroid cancer, brain and central nervous system cancers, glioblastoma, neuroblastoma, neuroendocrine cancer, rhabdoid cancer, keratoacanthoma, epidermoid carcinoma, myeloid disorders (e.g., acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome and promyelocytic leukemia), and lymphoid disorders (e.g., leukemia, multiple myeloma, 54057-0024W01 / SNV0019-W01 PATENT mantle cell lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, and hairy cell lymphoma).

[0275] In some embodiments, the cancer is selected from squamous cell lung cancer, lung adenocarcinoma, esophageal cancer, endometrial cancer, head and neck cancer, bladder cancer, ovarian cancer, liver cancer, cervical cancer, cholangiocarcinoma, gastric cancer, melanoma, kidney cancer, colorectal carcinoma, breast cancer, pancreatic cancer, thyroid cancer, brain and central nervous system cancers, glioblastoma, neuroblastoma, neuroendocrine cancer, rhabdoid cancer, keratoacanthoma, epidermoid carcinoma, acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome, promyelocytic leukemia, leukemia, multiple myeloma, mantle cell lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, and hairy cell lymphoma.

[0276] 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, 54057-0024W01 / SNV0019-W01 PATENT 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.

[0277] The present disclosure further provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.

[0278] 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.

[0279] As used herein, the term “cell” is meant to refer to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal.

[0280] 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” NRF2 with a compound described herein includes the administration of a compound described herein to an individual or patient, such as a human, having NRF2, as well as, for example, introducing a compound described herein into a sample containing a cellular or purified preparation containing the NRF2.

[0281] 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.

[0282] 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" 54057-0024W01 / SNV0019-W01 PATENT amount in any individual case may be determined using techniques known to a person skilled in the art.

[0283] 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.

[0284] 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.

[0285] As used herein, the term “treating” or “treatment” refers to inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (z.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.

[0286] 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 54057-0024W01 / SNV0019-W01 PATENT 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.

[0287] 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.

[0288] Combination Therapy

[0289] One or more additional therapeutic agents such as, for example, chemotherapeutic agents, radiotherapy, anti-inflammatory agents, steroids, immunosuppressants, immune-oncology agents, metabolic enzyme inhibitors, chemokine receptor inhibitors, phosphatase inhibitors, and targeted therapies such as kinase inhibitors useful for treating diseases associated with NRF2 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.

[0290] The compounds and salts described herein can be used in combination with one or more other chemotherapeutic agents for the treatment of disease, such as cancer. Example chemotherapeutic agents include, but are not limited to, platinumbased therapy, taxane-based therapy, albumin bound paclitaxel, altretamine, capecitabine, cyclophosphamide, gemcitabine, ifosfamide, irinotecan, liposomal doxorubicin, melphalan, pemetrexed, topotecan, and vinorelbine. For example, in the treatment of of non-small cell lung cancer, the compounds and salts of the present disclosure can be combined with chemotherapeutic agents including, but not limited, to cisplatin, carboplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, and vinorelbine.

[0291] The compounds and salts provided herein may be useful, for example, in improving the effectiveness of radiation therapy. In some embodiments, a compound or salt provided herein can be combined with one or more radiotherapies for the treatment of cancer. Example radiotherapies include, but are not limited to, external 54057-0024W01 / SNV0019-W01 PATENT beam radiation therapy (EBRT), intensity-modulated radiation therapy (IMRT), image-guided radiation therapy (IGRT), proton therapy, brachytherapy, stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT).

[0292] Immunotherapies, such as antibodies of PD1, PD-L1, and CTLA4, have been successfully used for the treatment of cancer. Despite this success, resistance and relapse remain a challenge for majority of cancer patients. In some embodiments, the compounds and salts provided herein can be combined with one or more immunotherapies. In some embodiments, the compounds and salts provided herein may be useful, for example, in improving the effectiveness of antibody-medicated immunotherapies. Exemplary immunotherapies that can be used for combination therapy with the compounds and salts provided herein include, but are not limited to, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, cemiplimab, dostarlimab, retifanlimab, toripalimab, and ipilimumab.

[0293] In some embodiments, the compounds and salts provided herein can be combined with targeted therapies of well-established therapeutic targets including, but not limited to, PARP1 inhibitors (e.g., olaparib, rucaparib, niraparib, SNV1521, and the like), PI3K inhibitors (e.g., alpelisib, inavolisib, SNV4818, and the like), KRAS inhibitors (e.g., sotorasib, adagrasib, RMC6236, and the like), CDK4 / 6 inhibitors (e.g., palbociclib, ribociclib, abemaciclib, and the like), BRAF inhibitors (e.g., vemurafenib, dabrafenib,encorafenib, and the like), MEK inhibitors, androgen receptor inhibitors, selective estrogen receptor modulators, proteosome inhibitors, mTOR inhibitors, EGFR inhibitors, FGFR inhibitors, MET inhibitors, PDGFR inhibitors, VEGFR inhibitors, EZH2 inhibitors, BTK inhibitors, and BCL2 inhibitors for treatment of cancer.

[0294] In some embodiments, the compounds and salts provided herein can be combined with antibody-drug conjugates (ADCs). Exemplary ADCs include, but are not limited to, gemtuzumab ozogamicin, brentuximab vedotin, ado-trastuzumab emtansine, inotuzumab ozogamicin, moxetumomab pasudotox, polatuzumab vedotin, enfortumab vedotin, trastuzumab deruxtecan, sacituzumab govitecan, belantamab mafodotin, cetuximab saratolacan sodium, loncastuximab tesirine, disitamab vedotin, tisotumab vedotin, and mirvetuximab soravtansine. 54057-0024W01 / SNV0019-W01 PATENT

[0295] In some embodiments, the compounds and salts provided herein can be combined with peptide receptor radionuclide therapy (PRRT), radioligand therapy, or a combination of PRRT and radioligand therapy. Exemplary PRRTs include but not limited to Lutetium Lu 177 dotatate (lutetium oxodotreotide), a radiolabeled somatostatin analog. Exemplary radioligand therapy includes, but is not limited to, lutetium (177Lu) vipivotide tetraxetan.

[0296] The compounds and salts provided herein can also be used, for example, in combination with one or more other kinase inhibitors for the treatment of diseases, such as cancer, that are impacted by multiple signaling pathways. For example, a combination can include one or more inhibitors of the following kinases for the treatment of cancer: radiation therapies, DNA damage pathway inhibitors (including, but not limited to, PARP inhibitors, ATR inhibitors, DNAPK inhibitors, CHK1 / 2 inhibitors, and WEE1 inhibitors), immune checkpoint antibodies or inhibitors, or other immune activating therapies.

[0297] 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.

[0298] 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. 54057-0024W01 / SNV0019-W01 PATENT

[0299] 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.

[0300] Pharmaceutical Formulations and Dosage Forms

[0301] When employed as pharmaceuticals, the compounds of the invention can be administered in the form of pharmaceutical compositions which refers to a combination of a compound of the invention, or its pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral or parenteral. Methods for ocular delivery can include topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction by balloon catheter or ophthalmic inserts surgically placed in the conjunctival sac. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

[0302] This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of the invention above in combination with one or more pharmaceutically acceptable carriers. In making the compositions of the invention, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a 54057-0024W01 / SNV0019-W01 PATENT 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.

[0303] 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.

[0304] 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.

[0305] 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.

[0306] 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 54057-0024W01 / SNV0019-W01 PATENT in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.

[0307] 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.

[0308] 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

[0309] 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.

[0310] 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 54057-0024W01 / SNV0019-W01 PATENT foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.

[0311] 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.

[0312] 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..

[0313] Labeled Compounds and Assay Methods

[0314] 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 NRF2 in tissue samples, including human, and for identifying NRF2 ligands by inhibition binding of a labeled compound. Accordingly, the present invention includes NRF2 biochemical assays that contain such labeled compounds.

[0315] 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 (i.e., naturally occurring). Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to2H (also written as D for deuterium),3H (also written as T for tritium),nC,13C,14C,13N, 54057-0024W01 / SNV0019-W01 PATENT

[0316] 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 NRF2 labeling and competition assays, compounds that incorporate3H,14C,82Br,125I ,131I, or35S will generally be most useful. For radio-imaging applicationsnC,18F,125I,123I,124I,131I,75Br,76Br or77Br will generally be most useful.

[0317] One or more constituent atoms of the compounds presented herein can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance. In some embodiments, one or more atoms are replaced or substituted by deuterium. For example, one or more hydrogen atoms in a compound of the present disclosure can be replaced by deuterium atoms (e.g., one or more hydrogen atoms of a Ci-6 alkyl group of Formula I can be optionally substituted with deuterium atoms, such as -CD3 being substituted for -CH3). In some embodiments, alkyl groups of the disclosed Formulas (e.g., the compound of any of Formulas I-IVe) can be perdeuterated.

[0318] In some embodiments, the compound provided herein (e.g., the compound of any of Formulas I-IVe), or a pharmaceutically acceptable salt thereof, comprises at least one deuterium atom.

[0319] In some embodiments, the compound provided herein (e.g., the compound of any of Formulas I-IVe), or a pharmaceutically acceptable salt thereof, comprises two or more deuterium atoms.

[0320] In some embodiments, the compound provided herein (e.g., the compound of any of Formulas I-IVe), or a pharmaceutically acceptable salt thereof, comprises three or more deuterium atoms.

[0321] In some embodiments, for a compound provided herein (e.g., the compound of any of Formulas I-IVe), or a pharmaceutically acceptable salt thereof, all of the hydrogen atoms are replaced by deuterium atoms ( / .< ., the compound is “perdeuterated”).

[0322] 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.

[0323] Synthetic methods for including isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, 54057-0024W01 / SNV0019-W01 PATENT

[0324] 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.

[0325] Substitution with heavier isotopes, such as deuterium, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances, (see e.g., A. Kerekes et. al. J. Med. Chem. 2011, 54, 201-210; R. Xu et. al. J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular, substitution at one or more metabolism sites may afford one or more of the therapeutic advantages.

[0326] 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 ( / .< ., test compound) can be evaluated for its ability to reduce binding of the radio-labeled compound of the invention to the NRF2. Accordingly, the ability of a test compound to compete with the radio-labeled compound for binding to the NRF2 directly correlates to its binding affinity.

[0327] Kits

[0328] The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of NRF2-associated diseases or disorders referred to herein which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and / or guidelines for mixing the components, can also be included in the kit. 54057-0024W01 / SNV0019-W01 PATENT

[0329] 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.

[0330] EXAMPLES

[0331] Experimental procedures for compounds of the invention are provided below. Preparatory LC-MS purifications of some of the compounds prepared are 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 are typically subjected to analytical liquid chromatography mass spectrometry (LCMS) for purity check.

[0332] Some of the compounds prepared are also separated on a preparative scale by reverse-phase high performance liquid chromatography (RP-HPLC) with MS detector or flash chromatography (silica gel).

[0333] Intermediate 1. (5-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)indolin-l-yl)(o- tolyl)methanone

[0334] Step 1: (5-bromoindolin-l-yl)(o-tolyl)methanone 54057-0024W01 / SNV0019-W01 PATENT

[0335] To a solution of 5 -bromoindoline (5.0 g, 25.2 mmol), triethylamine (10.6 mL, 75.7 mmol) in DCM (50 mL) was added 2-methylbenzoyl chloride (3.29 mL, 25.2 mmol) at 0 °C. The mixture was stirred at room temperature for 2 hours. The mixture was then quenched with water (100 mL) and extracted with DCM (50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the desired product as a yellow solid. LCMS calculated for CieHisBrNO (M+H)+m / z = 316.0; found 316.1.

[0336] Step 2: (5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indolin-l-yl)(o- tolyl)methanone

[0337] A mixture of (5-bromoindolin-l-yl)(o-tolyl)methanone (3.0 g, 9.49 mmol), KOAc (2.33 g, 23.7 mmol), bis(pinacolato)diboron (2.89 g, 11.4 mmol) and Pd(dppf)C12 • DCM (0.77 g, 0.95 mmol) in dioxane (30 mL) was stirred at 90 °C under N2 atmosphere. After 12 hours, the mixture was cooled to room temperature. The mixture was quenched with water (100 mL) and extracted with EtOAc (60 mL x 2). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with EtOAc in hexanes (0- 90%) to provide the title product as a light-yellow solid. LCMS calculated for C22H27BNO3 (M+H)+m / z =364.2; found 364.2.

[0338] Intermediate 2. Cyclopropyl(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)indolin-l-yl)methanone 54057-0024W01 / SNV0019-W01 PATENT

[0339] The title compound was prepared using a similar procedure as described for the synthesis of Intermediate 1, with cyclopropanecarbonyl chloride replacing 2- methylbenzoyl chloride in Step 1 to afford the title product. LCMS calculated for C18H25BNO3 (M+H)+m / z =314.2; found 314.2.

[0340] Intermediate 3. (3-((tert-Butyldimethylsilyl)oxy)benzyl)zinc(II) bromide

[0341] To a solution of (3-((tert-butyldimethylsilyl)oxy)phenyl)methanol (1.0 g, 4.2 mmol) in DCM (20 mL) was added tribromophosphane (0.26 mL, 2.73 mmol) at 0 °C. The mixture was warmed to room temperature and stirred for 2 hours. The mixture was then quenched with a saturated aqueous solution of sodium bicarbonate (50 mL) and extracted with DCM (20 mL x 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with EtOAc in hexanes (0-40%) to give the desired product as a colorless oil. LCMS calculated for CisH^BrOSi (M+H)+m / z = 301.1; found 301.1.

[0342] Step 2: (3-((tert-butyldimethylsilyl)oxy)benzyl)zinc(II) bromide

[0343] To a stirred suspension of zinc dust (196.2 mg, 3.0 mmol) in THF (2.0 mL) was added 1,2-dibromoethane (14.1 mg, 0.07 mmol) at room temperature. The mixture was refluxed for 10 minutes, then chloro(trimethyl)silane (8.2 mg, 0.07 mmol) was added to the hot suspension. The mixture was vigorously stirred at 60 °C for 15 minutes, then cooled to 0°C before a solution of (3- (bromomethyl)phenoxy)(terLbutyl)dimethylsilane (451.9 mg, 1.5 mmol) in THF (1.0 mL) was added dropwise. The resulting mixture was stirred at room temperature for 4 hours. The stirring was discontinued, the unreacted zinc was allowed to settle down 54057-0024W01 / SNV0019-W01 PATENT and the reaction mixture was cooled to room temperature. The reaction mixture was filtered through a syringe filter (pore size: 0.45 pM, PTFE) and the filtrate was used as is.

[0344] Intermediate 4. 2-(3-(2-(2-((tert-

[0345] Butoxycarbonyl)amino)ethoxy)ethoxy)phenyl)acetic acid

[0346] Step J: methyl 2-(3-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethoxy)phenyl)acetate

[0347] A solution of methyl 2-(3-hydroxyphenyl)acetate (4.0 g, 24.1 mmol), 2-(2- (( / c / 7-butoxycarbonyl)amino)ethoxy)ethyl 4-methylbenzenesulfonate (17.3 g, 48.1 mmol) and K2CO3 (9.98 g, 72.2 mmol) in DMF (24 mL) was stirred at 40 °C for 16 hours. The mixture was then quenched with water (120 mL) and extracted with EtOAc (60 mL x 2). The combined organic layer was washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by flash column chromatography, eluting with EtOAc in DCM (0-80%) to give the desired product as a yellow oil. LCMS calculated for CisEEsNOe (M+H)+m / z = 354.2; found 354.2.

[0348] Step 2: 2-(3-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethoxy)phenyl)acetic acid

[0349] A solution of methyl 2-(3-(2-(2-(( / c77- butoxycarbonyl)amino)ethoxy)ethoxy)phenyl)acetate (4.0 g, 11.3 mmol) in aqueous sodium hydroxide solution (2 M, 20 mL), MeOH (10 mL) and tetrahydrofuran (10 mL) was stirred at 50 °C for 1 hour. The pH of the reaction was adjusted to 5 - 7 with aqueous HC1 solution (2 M). The mixture was then diluted with water (60 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was washed with brine (80 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give the title product as a white solid. LCMS calculated for C17H26NO6 (M+H)+m / z = 340.2; found 340.2. 54057-0024W01 / SNV0019-W01 PATENT

[0350] Intermediate 5. 2-(2-((2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)ethoxy)ethyl 4-methylbenzenesulfonate

[0351] A solution of 2-(2, 6-dioxopiperi din-3 -yl)-4-((2-(2- hydroxyethoxy)ethyl)amino)isoindoline-l, 3-dione (2.7 g, 7.47 mmol) and triethylamine (2.08 mL, 14.9 mmol) in DCM (270 mL) was cooled to 0 °C before a solution of 4-methylbenzenesulfonyl chloride (1.57 g, 8.21 mmol) in DCM was added slowly. The mixture was stirred at room temperature overnight, then quenched with water and extracted with DCM. The combined organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with MeOH in DCM (0-10%) to give the desired product as a bright yellow solid. LCMS calculated for C24H26N3O8S (M+H)+m / z = 516.1 ; found 516.1.

[0352] Example 1. 2-(2,6-Dioxopiperidin-3-yl)-4-((2-(2-(3-((3-methyl-2-(l-(2- methylbenzoyl)indolin-5-yl)imidazo[l,2-c]pyrimidin-7- yl)methyl)phenoxy)ethoxy)ethyl)amino)isoindoline-l, 3-dione

[0353] Step 1: indolin-l-yl(o-tolyl)methanone 54057-0024W01 / SNV0019-W01 PATENT

[0354] To a solution of indoline (20.0 g, 167.8 mmol), triethylamine (94.4 mL, 671.4 mmol) in DCM (500 mL) was added 2-methylbenzoly chloride (22.0 mL, 167.8 mmol) at 0 °C. The reaction was warmed to room temperature and stirred for 2 hours. The mixture was then quenched with water (300 mL) and extracted with DCM (300 mL x 2). The combined organic layer was washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with MTBE (100 mL) to give the title product as a white solid. LCMS calculated for CI6HI6NO (M+H)+m / z = 238.1; found 238.1.

[0355] Step 2: 2-bromo-l-( 1 -(2-methylbenzoyl)indolin-5-yl)propan-l-one

[0356] To a solution of indolin-l-yl(o-tolyl)m ethanone (3.0 g, 12.6 mmol) and aluminum chloride (5.06 g, 37.9 mmol) in DCM (50 mL) was added 2- bromopropanoyl bromide (3.97 mL, 37.9 mmol) at 0 °C. After addition, the mixture was stirred at 50 °C for 4 hours. The mixture was then quenched with water (30 mL) and basified to pH between 8 -10 with aqueous sodium hydroxide solution (6 N). The mixture was extracted with DCM (100 mL x 2). The combined organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo to yield a yellow oil. The concentrated residue was used in the next step without purification. LCMS calculated for C H BrNCh (M+H)+m / z = 372.1; found 372.1.

[0357] Step 3: (5-(7-chloro-3-methylimidazo[l,2-c]pyrimidin-2-yl)indolin-l-yl)(o- tolyl)methanone 54057-0024W01 / SNV0019-W01 PATENT

[0358] A mixture of 2-bromo-l-(l-(2-methylbenzoyl)indolin-5-yl)propan-l-one (2.65 g, 7.12 mmol) and 6-chloropyrimidin-4-amine (1.84 g, 14.2 mmol) in acetonitrile (100 mL) was stirred at 100 °C in a sealed tube for 3 days. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with MeOH in DCM (0-20%), to give the product as a yellow solid. LCMS calculated for C23H20CIN4O (M+H)+m / z = 403.1; found 403.2.

[0359] Step 4: (5-(7-( 3-( f tert-butyldimethylsilyl)oxy)benzyl)-3-methylimidazo[ 1, 2- c ]pyrimidin-2-yl)indolin-l-yl)(o-tolyl)methanone

[0360] To a solution of (3-(( / c / 7-butyldimethylsilyl)oxy)benzyl)zinc(II) bromide (Intermediate 3, 273.1 mg, 0.74 mmol) in THF (1.5 mL) was added (5-(7-chloro-3- methylimidazo[l,2-c]pyrimidin-2-yl)indolin-l-yl)(o-tolyl)m ethanone (150 mg, 0.37 mmol) and Pd(PPhs)4 (43.0 mg, 0.04 mmol) under N2 atomsphere. The resulting mixture was stirred at 70 °C for 2 hours. Upon cooling to room temperature, the reaction mixture was concentrated in vacuo and purified by flash column chromatography, eluting with EtOAc in DCM (0-90%) to give the product as a yellow solid. LCMS calculated for C36H4iN4O2Si (M+H)+m / z = 589.3; found 589.2.

[0361] Step 5: (5-(7-( 3-hydroxybenzyl)-3-methylimidazo[ 1, 2-c ]pyrimidin-2-yl)indolin-l- yl)(o-tolyl)methanone 54057-0024W01 / SNV0019-W01 PATENT

[0362] A solution of (5-(7-(3-(( / erLbutyldimethylsilyl)oxy)benzyl)-3- methylimidazo[l,2-c]pyrimidin-2-yl)indolin-l-yl)(o-tolyl)m ethanone (125 mg, 0.21 mg) and tetrabutylammonium fluoride (1.0 M in THF, 3 mL, 3.0 mmol) was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to give the crude product, which was used in the next step without purification. LCMS calculated for C30H27N4O2 (M+H)+m / z = 475.2; found 475.2.

[0363] Step 6: tert-butyl (2-(2-(3-((3-methyl-2-(l-(2-methylbenzoyl)indolin-5-yl)imidazo [ 1 ,2- c Jpyrimidin- 7 -yl)methyl)phenoxy) ethoxy) ethyl) carbamate

[0364] A solution of (5-(7-(3-hydroxybenzyl)-3-methylimidazo[l,2-c]pyrimidin-2- yl)indolin-l-yl)(o-tolyl)methanone (80 mg, 0.17 mmol), 2-(2- (tert- butoxycarbonyl)amino)ethoxy)ethyl 4-methylbenzenesulfonate (97.0 mg, 0.27 mmol) and potassium / c / 7-butoxide (75.7 mg, 0.67 mmol) in DMF (2 mL) was stirred at 30 °C for 16 hours. The mixture was then quenched with water (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by flash column chromatography, eluting with EtOAc in DCM (0-90%) to give the product as a yellow solid. LCMS calculated for C39H44N5O5 (M+H)+m / z = 662.3; found 662.2.

[0365] Step 7: (5-(7-( 3-(2-(2-aminoethoxy)ethoxy)benzyl)-3-methylimidazo[ 1, 2-c Jpyrimidin- 2-yl)indolin-l-yl) ( o-tolyl)methanone 54057-0024W01 / SNV0019-W01 PATENT

[0366] A solution of tert-butyl (2-(2-(3-((3-methyl-2-(l-(2-methylbenzoyl)indolin-5- yl)imidazo[l,2-c]pyrimidin-7-yl)methyl)phenoxy)ethoxy)ethyl)carbamate (28 mg, 0.04 mmol) and HC1 in dioxane (4.0 M, 2.0 mL) was stirred at room temperature for 1 hour. Upon completion, the reaction mixture was concentrated in vacuo to give the crude product, which was used in the next step without purification. LCMS calculated for C34H36N5O3 (M+H)+m / z = 562.3; found 562.2.

[0367] Step 8: 2-(2, 6-dioxopiperidin-3-yl)-4-( (2-(2-( 3-( ( 3-methyl-2-( 1 -(2- methylbenzoyl)indolin-5-yl)imidazo[ 1, 2-c Jpyrimidin- 7- yl)methyl)phenoxy)ethoxy)ethyl)amino)isoindoline-l, 3-dione

[0368] A solution of (5-(7-(3-(2-(2-aminoethoxy)ethoxy)benzyl)-3- methylimidazo[l,2-c]pyrimidin-2-yl)indolin-l-yl)(o-tolyl)m ethanone (23 mg, 0.04 mmol), 2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-l, 3-dione (13.6 mg, 0.05 mmol) and A, A-diisopropylethylamine (21.5 pL, 0.12 mmol) in DMF (1.0 mL) was stirred at 100 °C for 16 hours. The reaction mixture was diluted with MeOH and purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide a TFA salt of the title product as a yellow solid. LCMS calculated for C47H44N7O7 (M+H)+m / z = 818.3; found 818.2.

[0369] Example 2. 5-((2-(2-(3-((6-(l-(Cyclopropanecarbonyl)indolin-5-yl)-l-oxo-3,4- dihydropyrrolo[l,2-a]pyrazin-2(lH)-yl)methyl)phenoxy)ethoxy)ethyl)amino)-2-

[0370] (2, 6-dioxopiperidin-3-yl)isoindoline-l, 3-dione

[0371] Step 1: ethyl 5-bromo-l-(2-((tert-butoxycarbonyl)amino)ethyl)-lH-pyrrole-2- carboxylate 54057-0024W01 / SNV0019-W01 PATENT

[0372] To a solution of ethyl 5-bromo-U / -pyrrole-2-carboxylate (1.5 g, 6.88 mmol) in DMF (15 mL) was added sodium hydride (60% dispersion in mineral oil, 0.43 g, 11.0 mmol) at 0 °C. The resulting mixture was then warmed to room temperature and stirred for 30 minutes, tert-butyl (2-bromoethyl)carbamate (3.85 g, 17.2 mmol) was added and the reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (80 mL) and extracted with EtOAc (50 mL x 2). The combined organic layer was washed with brine (80 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The mixture was purified by flash column chromatography, eluting with EtOAc in hexanes (0-90%), to give the product as a yellow solid. LCMS calculated for Ci4H22BrN2O4 (M+H)+m / z = 361.1; found 361.1.

[0373] Step 2: ethyl l-(2-((tert-butoxycarbonyl)amino)ethyl)-5-(l- ( cyclopropanecarbonyl) indolin-5-yl) -lH-pyrrole-2-carboxylate

[0374] To a solution of ethyl 5-bromo-l-(2-((tert-butoxycarbonyl)amino)ethyl)-UT- pyrrole-2-carboxylate (1.60 g, 4.43 mmol) in dioxane (16 mL) and water (4 mL) was added cyclopropyl(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indolin-l- yl)methanone (Intermediate 2, 2.08 g, 6.64 mmol), potassium carbonate (1.53 g, 11.07 mmol) and Pd(PPh3)4 (0.51 g, 0.44 mmol) under N2 atmosphere. The resulting mixture was stirred at 90 °C for 8 hours. Upon completion, the mixture was diluted with water (50 mL) and extracted with EtOAc (40 mL x 2). The combined organics were washed with brine (50 mL) and dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with EtOAc in DCM (0-90%), to provide the desired product 54057-0024W01 / SNV0019-W01 PATENT as a yellow solid. LCMS calculated for C26H34N3O5 (M+H)+m / z = 468.2; found 468.2.

[0375] Step 3: ethyl l-(2-aminoethyl)-5-(l-(cyclopropanecarbonyl)indolin-5-yl)-lH-pyrrole- 2-carboxylate

[0376] A solution of ethyl l-(2-((terLbutoxycarbonyl)amino)ethyl)-5-(l- (cyclopropanecarbonyl)indolin-5-yl)-U / -pyrrole-2-carboxylate (1.54 g, 3.30 mmol) and HC1 in dioxane (4.0 M, 15 mL) was stirred at room temperature for 1 hour. Upon completion, the reaction mixture was concentrated in vacuo to give the crude product, which was used in the next step without purification. LCMS calculated for C21H26N3O3 (M+H)+m / z = 368.2; found 368.2.

[0377] Step 4: ethyl 5-(l-(cyclopropanecarbonyl)indolin-5-yl)-l-(2-((3- hydroxybenzyl)amino)ethyl)-lH-pyrrole-2-carboxylate

[0378] To a solution of ethyl l-(2-aminoethyl)-5-(l-(cyclopropanecarbonyl)indolin-5- yl)-U / -pyrrole-2-carboxylate (1.20 g, 3.27 mmol) in MeOH (12 mL) was added 3- hydroxybenzaldehyde (0.40 g, 3.27 mmol) at room temperature. The reaction was stirred at room temperature for 4 hours, then sodium triacetoxyborohydride (1.38 g, 6.53 mmol) was added and the reaction was stirred for 30 minutes. Upon completion, the reaction mixture was diluted with water (60 mL) and extracted with EtOAc (50 mL x 2). The combined organic layer was washed with brine (50 mL), dried over 54057-0024W01 / SNV0019-W01 PATENT sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was used in the next without purification. LCMS calculated for C28H32N3O4 (M+H)+m / z = 474.2; found 474.2.

[0379] Step 5: 6-( I -(cyclopropanecarbonyl)indolin-5-yl)-2-( 3-hydroxybenzyl)-3, 4- dihydropyrrolo[ 1, 2 -a ]pyrazin-l( 2H) -one

[0380] A solution of ethyl 5-(l-(cyclopropanecarbonyl)indolin-5-yl)-l-(2-((3- hydroxybenzyl)amino)ethyl)- IT / -pyrrole-2-carboxylate (1.55 g, 3.27 mmol) and ammonia solution in MeOH (7.0 N, 20 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0-15%), to provide the desired product as a yellow solid. LCMS calculated for C26H26N3O3 (M+H)+m / z = 428.2; found 428.2.

[0381] Step 6: tert-butyl (2-(2-(3-((6-(l-(cyclopropanecarbonyl)indolin-5-yl)-l-oxo-3,4- dihydropyrrolo [ 1 ,2-a]pyrazin-2(lH)-yl)methyl)phenoxy)ethoxy)ethyl)carbamate

[0382] A solution of 6-(l-(cyclopropanecarbonyl)indolin-5-yl)-2-(3-hydroxybenzyl)- 3,4-dihydropyrrolo[l,2-a]pyrazin-l(2J7)-one (100 mg, 0.23 mmol), 2-(2-(( / c / 7- butoxycarbonyl)amino)ethoxy)ethyl 4-methylbenzenesulfonate (126.1 mg, 0.35 mmol) and potassium / cvV-butoxide (105.0 mg, 0.94 mmol) in DMF (2.5 mL) was stirred at 30 °C for 16 hours. The mixture was then quenched with water (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by flash column chromatography, eluting with 54057-0024W01 / SNV0019-W01 PATENT

[0383] MeOH in DCM (0-20%), to give the product as a yellow solid. LCMS calculated for C35H43N4O6 (M+H)+m / z = 615.3; found 615.3.

[0384] Step 7: 2-(3-(2-(2-aminoethoxy)ethoxy)benzyl)-6-(l-(cyclopropanecarbonyl)indolin- 5-yl)-3,4-dihydropyrrolo [ 1 ,2-a]pyrazin-l (2H)-one

[0385] A solution of tert-butyl (2-(2-(3-((6-(l-(cyclopropanecarbonyl)indolin-5-yl)-l- oxo-3, 4-dihydropyrrolo[l,2-a]pyrazin-2(lrt)- yl)methyl)phenoxy)ethoxy)ethyl)carbamate (52 mg, 0.08 mmol) and HC1 in dioxane (4.0 M, 2.0 mL) was stirred at room temperature for 1 hour. Upon completion, the reaction mixture was concentrated in vacuo to give the crude product, which was used in the next step without purification. LCMS calculated for C30H35N4O4 (M+H)+m / z = 515.3; found 515.2.

[0386] Step 8: 5-( (2-(2-(3-((6-(l-( cyclopropanecarbonyl) indolin-5-yl)-l-oxo-3, 4- dihydropyrrolo[l,2-a]pyrazin-2(lH)-yl)methyl)phenoxy)ethoxy)ethyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-l, 3-dione

[0387] A solution of 2-(3-(2-(2-aminoethoxy)ethoxy)benzyl)-6-(l- (cyclopropanecarbonyl)indolin-5-yl)-3,4-dihydropyrrolo[l,2-a]pyrazin-l(2rt)-one (43 mg, 0.08 mmol), 2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-l, 3-dione (27.7 mg, 0.10 mmol) and A, A-diisopropylethylamine (43.8 pL, 0.25 mmol) in DMF (2.0 mL) was stirred at 100 °C for 16 hours. The reaction mixture was diluted with MeOH and purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide a TFA salt of the desired product as a yellow solid. LCMS calculated for C43H43N6O8 (M+H)+m / z = 771.3; found 771.3. 54057-0024W01 / SNV0019-W01 PATENT

[0388] Example 3. 2-(2,6-Dioxopiperidin-3-yl)-4-((2-(2-(3-((6-(l-(2- inetliylbeiizoyl)indolin-5-yl)-l / / -imidazo [4,5-6] pyrazin-2- yl)methyl)phenoxy)ethoxy)ethyl)amino)isoindoline-l, 3-dione

[0389] Step 1: (5-(5, 6-diaminopyrazin-2-yl)indolin-l-yl)(o-tolyl)methanone

[0390] To a solution of 5-bromopyrazine-2,3-diamine (1.42 g, 7.50 mmol) in dioxane (16 mL) and water (4 mL) was added (5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)indolin-l-yl)(o-tolyl)methanone (Intermediate 1, 3.27 g, 9.0 mmol), potassium carbonate (2.59 g, 18.7 mmol) and Pd(PPh3)4 (0.87 g, 0.75 mmol) under N2 atmosphere. The resulting mixture was stirred at 90 °C for 8 hours. Upon completion, the mixture was diluted with water (50 mL) and extracted with EtOAc (40 mL x 2). The combined organic layers were washed with brine (50 mL) and dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0-20%), to provide the desired product as a yellow solid. LCMS calculated for C20H20N5O (M+H)+m / z = 346.2; found 346.2.

[0391] Step 2: tert-butyl (2-(2-(3-(2-((3-amino-6-(l-(2-methylbenzoyl)indolin-5-yl)pyrazin-2- y I) amino) -2 -oxoethyl)phenoxy) ethoxy) ethyl) carbamate 54057-0024W01 / SNV0019-W01 PATENT

[0392] A solution of (5-(5,6-diaminopyrazin-2-yl)indolin-l-yl)(o-tolyl)methanone (291 mg, 0.84 mmol) in DMF (8.0 mL) was added 2-(3-(2-(2-((tert- butoxycarbonyl)amino)ethoxy)ethoxy)phenyl)acetic acid (Intermediate 4, 220 mg, 065 mmol), HATU (443 mg, 1.17 mmol) and A,A-diisopropylethylamine (0.34 mL, 1.94 mmol) was stirred at room temperature for 2 hours. The reaction mixture was then diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The mixture was purified by flash column chromatography, eluting with MeOH in DCM (0-20%) to give the product as a yellow solid. LCMS calculated for C37H43N6O6 (M+H)+m / z = 667.3; found 667.2.

[0393] Step 3: (5-(2-( 3-(2-(2-aminoethoxy)ethoxy)benzyl)-lH-imidazo[ 4, 5-b ]pyrazin-6- yl)indolin-l-yl) ( o-tolyl)methanone

[0394] A solution of tert-butyl (2-(2-(3-(2-((3-amino-6-(l-(2-methylbenzoyl)indolin- 5-yl)pyrazin-2-yl)amino)-2-oxoethyl)phenoxy)ethoxy)ethyl)carbamate (100 mg, 0.15 mmol) was dissolved in trifluoroacetic acid (3.0 mL) and the resulting solution was heated at 100 °C for 16 hours. The reaction mixture was concentrated in vacuo to give the crude product, which was used in the next step without purification. LCMS calculated for C32H33N6O3 (M+H)+m / z = 549.3; found 549.2.

[0395] Step 4: 2-(2, 6-dioxopiperidin-3-yl)-4-( (2-(2-( 3-( 6-( 1 -(2-methylbenzoyl)indolin-5-yl)- lH-imidazo[ 4, 5-b ]pyrazin-2-yl)methyl)phenoxy)ethoxy)ethyl)amino)isoindoline-l, 3- dione 54057-0024W01 / SNV0019-W01 PATENT

[0396] A solution of (5-(2-(3-(2-(2-aminoethoxy)ethoxy)benzyl)-17 / -imidazo[4,5- Z»]pyrazin-6-yl)indolin-l-yl)(o-tolyl)methanone (45 mg, 0.08 mmol), 2-(2,6-dioxo-3- piperidyl)-4-fluoro-isoindoline-l, 3-dione (27.2 mg, 0.10 mmol) and N, N- diisopropylethylamine (43.0 pL, 0.25 mmol) in DMF (2.0 mL) was stirred at 100 °C for 16 hours. The reaction mixture was diluted with MeOH and purified by prep- HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a yellow solid. LCMS calculated for C45H41N8O7 (M+H)+m / z = 805.3; found 805.3.

[0397] Example 4. 4-((2-(2-(3-(((2-(l-(Cyclopropanecarbonyl)indolin-5-yl)imidazo[l,2- a]pyrazin-8-yl)amino)methyl)phenoxy)ethoxy)ethyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-l, 3-dione

[0398] The title compound was prepared using a similar procedure as described for the synthesis of Example 1 Step 1, with cyclopropanecarbonyl chloride replacing 2- m ethylbenzoyl chloride to afford the title product. LCMS calculated for C12H14NO (M+H)+m / z = 188.1; found 188.1.

[0399] Step 2: 2-bromo-l-( 1 -(cyclopropanecarbonyl)indolin-5-yl)ethan-l-one 54057-0024W01 / SNV0019-W01 PATENT

[0400] To a solution of cyclopropyl(indolin-l-yl)methanone (4.0 g, 21.4 mmol) and aluminium chloride (8.55 g, 64.1 mmol) in DCM (70 mL) was added 2-bromoacetyl chloride (5.34 mL, 64.1 mmol) at 0 °C. After addition, the mixture was stirred at 50 °C for 4 hours. The mixture was then quenched with water (30 mL) and basified to pH between 8 -10 with aqueous sodium hydroxide solution (6 N). The mixture was extracted with DCM (100 mL x 2). The combined organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with EtOAc in hexanes (0-80%) to give the product as a white solid. LCMS calculated for CuHisBrNCh (M+H)+m / z = 308.0; found 308.1.

[0401] Step 3: (5-(8-chloroimidazo[ 1, 2-a]pyrazin-2-yl)indolm-l-yl)(cyclopropyl)methanone

[0402] To a solution of 2-bromo-l-(l-(cyclopropanecarbonyl)indolin-5-yl)ethan-l- one (0.45 g, 1.46 mmol) in acetonitrile (6 mL) was added 3-chloropyrazin-2-amine (189.2 mg, 1.46 mmol) and diethylaniline (0.23 mL, 1.46 mmol). The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was cooled to room temperature and filtered to give the crude product, which was used in the next step without purification. LCMS calculated for CisHieCllS O (M+H)+m / z = 339.1; found 339.1.

[0403] Step 4: cyclopropyl(5-(8-((3-hydroxybenzyl)amino)imidazo[l,2-a]pyrazin-2- yl)indolin-l-yl)methanone 54057-0024W01 / SNV0019-W01 PATENT

[0404] A solution of (5-(8-chloroimidazo[l,2-a]pyrazin-2-yl)indolin-l- yl)(cyclopropyl)methanone (20 mg, 0.06 mmol), 3-(aminomethyl)phenol (10.9 mg, 0.09 mmol) and potassium carbonate (24.5 mg, 0.18 mmol) in NMP (2 mL) was stirred at 100 °C for 16 hours. Upon cooling to room temperature, the mixture was diluted with MeOH and purified by prep-HPLC (column: Sunfire prep Cl 8 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide a TFA salt of the desired product as a yellow solid. LCMS calculated for C25H24N5O2 (M+H)+m / z = 426.2; found 426.2.

[0405] Step 5: tert-butyl (2-(2-(3-(((2-(l-(cyclopropanecarbonyl)indolin-5-yl)imidazo [ 1 ,2- a]pyrazin-8-yl)amino)methyl)phenoxy)ethoxy)ethyl)carbamate

[0406] A solution of cyclopropyl(5-(8-((3-hydroxybenzyl)amino)imidazo[l,2- a]pyrazin-2-yl)indolin-l-yl)m ethanone (70 mg, 0.16 mmol), 2-(2-((terf- butoxycarbonyl)amino)ethoxy)ethyl 4-methylbenzenesulfonate (36.9 mg, 0.33 mmol) and potassium / c / 7-butoxide (118.3 mg, 0.33 mmol) in DMF (3 mL) was stirred at 30 °C for 16 hours. The mixture was then quenched with water (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by flash column chromatography, eluting with MeOH in DCM (0-20%) to give the product as a yellow solid. LCMS calculated for C34H41N6O5 (M+H)+m / z = 613.3; found 613.2.

[0407] Step 6: (5-(8-((3-(2-(2-aminoethoxy)ethoxy)benzyl)amino)imidazo [ 1 ,2-a]pyrazin-2- yl)indolin-l-yl) ( cyclopropyl) methanone 54057-0024W01 / SNV0019-W01 PATENT

[0408] A solution of tert-butyl (2-(2-(3-(((2-(l-(cyclopropanecarbonyl)indolin-5- yl)imidazo[l,2-a]pyrazin-8-yl)amino)methyl)phenoxy)ethoxy)ethyl)carbamate (36 mg, 0.06 mmol) and HC1 in dioxane (4.0 M, 2.0 mL) was stirred at room temperature for 1 hour. Upon completion, the reaction mixture was concentrated in vacuo to give the crude product, which was used in the next step without purification. LCMS calculated for C29H33N6O3 (M+H)+m / z = 513.2; found 513.2.

[0409] Step 7: 4-( (2-(2-(3-(((2-( 1 -(cyclopropanecarbonyl)indolin-5-yl)imidazo[ 1,2- a]pyrazin-8-yl)amino)methyl)phenoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-l, 3-dione

[0410] A solution of (5-(8-((3-(2-(2-aminoethoxy)ethoxy)benzyl)amino)imidazo[l,2- a]pyrazin-2-yl)indolin-l-yl)(cyclopropyl)methanone (30 mg, 0.06 mmol), 2-(2,6- dioxo-3-piperidyl)-4-fluoro-isoindoline-l, 3-dione (32.3 mg, 0.12 mmol) and N- diisopropylethylamine (40.9 pL, 0.23 mmol) in DMF (2.0 mL) was stirred at 100 °C for 16 hours. The reaction mixture was diluted with MeOH and purified by prep- HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a yellow solid. LCMS calculated for C42H41N8O7 (M+H)+m / z = 769.3; found 769.2.

[0411] Example 5. 4-((2-(2-(3-((3-(l-(Cyclopropanecarbonyl)indolin-5-yl)-5,6- dihydroimidazo[l,2-a]pyrazin-7(&H)-yl)methyl)phenoxy)ethoxy)ethyl)amino)-2-

[0412] (2, 6-dioxopiperidin-3-yl)isoindoline-l, 3-dione 54057-0024W01 / SNV0019-W01 PATENT

[0413] Step 1: tert-butyl 3-(l-(cyclopropanecarbonyl)indolin-5-yl)-5,6-dihydroimidazo[l,2- a ] pyrazine- 7 ( 8H) -carboxylate

[0414] To a solution of tert-butyl 3-bromo-5,6-dihydroimidazo[l,2-a]pyrazine-7(8rt)- carboxylate (500 mg, 1.65 mmol) in dioxane (5 mL) and water (1 mL) was added cyclopropyl(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indolin-l-yl)methanone (Intermediate 2, 622 mg, 2.0 mmol), cesium carbonate (1.35 g, 4.14 mmol) and Pd(PPh3)4 (135 mg, 0.17 mmol) under N2 atmosphere. The resulting mixture was stirred at 90 °C for 4 hours. Upon completion, the mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (30 mL) and dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with EtOAc in DCM (0-90%) to provide the desired product as a yellow solid. LCMS calculated for C23H29N4O3 (M+H)+m / z = 409.2; found 409.2.

[0415] Step 2: cyclopropyl(5-(5,6, 7,8-tetrahydroimidazo[l,2-a]pyrazin-3-yl)indolin-l- yl)methanone

[0416] To a solution of tert-butyl 3-(l-(cyclopropanecarbonyl)indolin-5-yl)-5,6- dihydroimidazo[l,2-a]pyrazine-7(8rt)-carboxylate in DCM (5 mL) was added TFA (5 mL) at 0 °C. The resulting solution was warmed to room temperature and stirred for 2 hours. The reaction was concentrated in vacuo to give the crude product, which was used in the next step without purification. LCMS calculated for C18H21N4O (M+H)+m / z = 309.2; found 309.2.

[0417] Step 3: cyclopropyl(5-(7-(3-hydroxybenzyl)-5,6, 7 ,8-tetrahydroimidazo [ 1 ,2-a]pyrazin- 3-yl)indolin-l-yl)methanone 54057-0024W01 / SNV0019-W01 PATENT

[0418] A solution of cyclopropyl(5-(5,6,7,8-tetrahydroimidazo[l,2-a]pyrazin-3- yl)indolin-l-yl)methanone (462 mg, 1.5 mmol) and 3 -hydroxybenzaldehyde (183 mg, 1.5 mmol) in methanol (15 mL) was stirred at room temperature for 12 hours. Sodium cyanoborohydride (141 mg, 2.25 mmol) was added to the reaction and the mixture was stirred for 1 hour before concentrating in vacuo. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0-25%) to provide the desired product as a yellow solid. LCMS calculated for C25H27N4O2 (M+H)+m / z = 415.2; found 415.2.

[0419] Step 4: tert-butyl (2-(2-(3-((3-(l-(cyclopropanecarbonyl)indolin-5-yl)-5,6- dihydroimidazo [ 1 ,2-a]pyrazin-7(8H)-yl)methyl)phenoxy)ethoxy)ethyl)carbamate

[0420] A solution of cyclopropyl(5-(7-(3-hydroxybenzyl)-5,6,7,8- tetrahydroimidazo[l,2-a]pyrazin-3-yl)indolin-l-yl)m ethanone (100 mg, 0.24 mmol), 2-(2-(( / c / 7-butoxycarbonyl)amino)ethoxy)ethyl 4-methylbenzenesulfonate (86.7 mg, 0.24 mmol) and potassium / c / V-butoxide (40.6 mg, 0.36 mmol) in DMF (3 mL) was stirred at 30 °C for 16 hours. The mixture was then quenched with water (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by flash column chromatography, eluting with MeOH in DCM (0-20%) to give the product as a yellow solid. LCMS calculated for C34H44N5O5 (M+H)+m / z = 602.3; found 602.2.

[0421] Step 5: (5-(7-(3-(2-(2-aminoethoxy)ethoxy)benzyl)-5,6, 7,8-tetrahydroimidazo[l,2- a ]pyrazin-3-yl)indolin-l-yl) ( cyclopropyl) methanone 54057-0024W01 / SNV0019-W01 PATENT

[0422] A solution of tert-butyl (2-(2-(3-((3-(l-(cyclopropanecarbonyl)indolin-5-yl)- 5,6-dihydroimidazo[l,2-a]pyrazin-7(8rt)-yl)methyl)phenoxy)ethoxy)ethyl)carbamate (42 mg, 0.07 mmol) and HC1 in dioxane (4.0 M, 2.0 mL) was stirred at room temperature for 1 hour. Upon completion, the reaction mixture was concentrated in vacuo to give the crude product, which was used in the next step without purification. LCMS calculated for C29H36N5O3 (M+H)+m / z = 502.3; found 502.2.

[0423] Step 6: 4-( (2-(2-(3-((3-(l-( cyclopropanecarbonyl) indolin-5-yl)-5, 6- dihydroimidazo[l,2-a]pyrazin-7(8H)-yl)methyl)phenoxy)ethoxy)ethyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-l, 3-dione

[0424] A solution of (5-(7-(3-(2-(2-aminoethoxy)ethoxy)benzyl)-5,6,7,8- tetrahydroimidazo[l,2-a]pyrazin-3-yl)indolin-l-yl)(cy cl opropyl)m ethanone (40 mg, 0.08 mmol), 2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-l, 3-dione (33.0 mg, 0.12 mmol) and N, A-diisopropylethylamine (41 mg, 0.32 mmol) in DMF (2.0 mL) was stirred at 100 °C for 16 hours. The reaction mixture was diluted with MeOH and purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide a TFA salt of the title product as a yellow solid. LCMS calculated for C42H44N7O7 (M+H)+m / z = 758.3; found 758.2.

[0425] Example 6: 2-(2,6-Dioxopiperidin-3-yl)-4-((2-(2-(3-((8-(l-(2- methylbenzoyl)indolin-5-yl)isoquinolin-3- yl)methyl)phenoxy)ethoxy)ethyl)amino)isoindoline-l, 3-dione 54057-0024W01 / SNV0019-W01 PATENT

[0426] Step 1: 8-bromo-3-(3-methoxybenzyl)isoquinoline

[0427] To a solution of 8-bromo-3-chloroisoquinoline (275 mg, 1.13 mmol) and Pd(dppf)C12 • DCM (93 mg, 0.11 mmol) in THF (6 mL) at 70 °C was added (3- methoxybenzyl)zinc(II) chloride (0.5 M in THF, 2.72 mL, 1.36 mmol) under N2 atomsphere. The resulting mixture was stirred at 70 °C for 2 hours. Upon cooling to room temperature, the mixture was then quenched with a saturated aqueous solution of ammonium chloride and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with EtOAc in hexanes (0-100%) to give the desired product. LCMS calculated for CnHisBrNO (M+H)+m / z = 328.0; found 328.0.

[0428] Step 2: 3-((8-bromoisoquinolin-3-yl)methyl)phenol

[0429] To a solution of 8-bromo-3-(3-methoxybenzyl)isoquinoline (151 mg, 0.46 mmol) in DCM at 0 °C was added a boron tribromide (1.0 M in DCM, 0.92 mL, 0.92 mmol). The mixture was stirred at room temperature overnight, then quenched with MeOH. The mixture was concentrated in vacuo then purified by silica gel column chromatography, eluting with EtOAc in hexanes (0-100%) to give the desired product. LCMS calculated for CieHnBrNO (M+H)+m / z = 314.0; found 314.0. 54057-0024W01 / SNV0019-W01 PATENT

[0430] Step 3: (5-(3-(3-hydroxybenzyl)isoquinolin-8-yl)indolin-l-yl)(o-tolyl)methanone

[0431] To a solution of 3-((8-bromoisoquinolin-3-yl)methyl)phenol (144 mg, 0.46 mmol) in dioxane (5 mL) and water (1 mL) was added (5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)indolin-l-yl)(o-tolyl)methanone (Intermediate 1, 184 mg, 0.51 mmol), sodium carbonate (127 mg, 0.92 mmol) and Pd(dppf)C12 • DCM (38 mg, 0.05 mmol) under N2 atmosphere. The resulting mixture was stirred at 90 °C for 1 hour. Upon completion, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried with anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with EtOAc in hexanes (0-100%) to provide the desired product as a yellow solid. LCMS calculated for C32H27N2O2 (M+H)+m / z = 471.2; found 471.2.

[0432] Step 4: 2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(3-((8-(l-(2-methylbenzoyl)indolin-5- yl)isoquinolin-3-yl)methyl)phenoxy)ethoxy)ethyl)amino)isoindoline-l, 3-dione

[0433] To a solution of (5-(3-(3-hydroxybenzyl)isoquinolin-8-yl)indolin-l-yl)(o- tolyl)methanone (150 mg, 0.32 mmol) in DMF (5 mL) was added sodium hydride (60% dispersion in mineral oil, 26 mg, 0.64 mmol) at 0 °C. The resulting mixture was then warmed to room temperature and stirred for 10 minutes, then 2-(2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)ethoxy)ethyl 4- methylbenzenesulfonate (Intermediate 5, 330 mg, 0.64 mmol) was added. The mixture was stirred at room temperature overnight. The reaction mixture was quenched with aqueous HC1 (1.0 M) and acetonitrile, then purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide a TFA salt of the title product as a yellow solid. LCMS calculated for C49H44N5O7 (M+H)+m / z = 814.3; found 814.3. 54057-0024W01 / SNV0019-W01 PATENT

[0434] Example 7. 2-(2,6-Dioxopiperidin-3-yl)-4-((2-(2-(3-((6-( / i-tolyl)-lH-imidazo[4,5-

[0435] / >]pyrazin-2-yl)methyl)phenoxy)ethoxy)ethyl)amino)isoindoline-l, 3-dione

[0436] Step 1: tert-butyl (2-(2-(3-(2-((3-amino-5-bromopyrazin-2-yl)amino)-2- oxoethyl)phenoxy)ethoxy)ethyl)carbamate

[0437] To a solution of 2-(3-(2-(2- (tert- butoxycarbonyl)amino)ethoxy)ethoxy)phenyl)acetic acid (Intermediate 4, 1.32 g, 3.90 mmol) in DMF (20.0 mL) was added 5-bromopyrazine-2, 3 -diamine (0.96 g, 5.07 mmol), HATU (2.67 g, 7.02 mmol) and A,A-diisopropylethylamine (2.04 mL, 11.7 mmol) was stirred at room temperature for 2 hours. The reaction mixture was then diluted with water (100 mL) and extracted with EtOAc (80 mL x 2). The combined organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The mixture was purified by flash column chromatography, eluting with MeOH in DCM (0-20%) to give the product as a yellow solid. LCMS calculated for C2iH29BrNsO5 (M+H)+m / z = 510.1; found 510.1.

[0438] Step 2: 2-(2-(3-((6-bromo-lH-imidazo[4,5-b]pyrazin-2- yl)methyl)phenoxy) ethoxy) ethan-1 -amine

[0439] A solution of tert-butyl (2-(2-(3-(2-((3-amino-5-bromopyrazin-2-yl)amino)-2- oxoethyl)phenoxy)ethoxy)ethyl)carbamate (1.0 g, 1.96 mmol) was dissolved TFA (10.0 mL) and the resulting solution was heated at 100 °C for 16 hours. The reaction 54057-0024W01 / SNV0019-W01 PATENT mixture was concentrated in vacuo to give the crude product, which was used in the next step without purification. LCMS calculated for CieH BrNsCh (M+H)+m / z = 392.1; found 392.1.

[0440] Step 3: 2-(2-(3-((6-(p-tolyl)-lH-imidazo[4,5-b]pyrazin-2- yl)methyl)phenoxy) ethoxy) ethan-1 -amine

[0441] Under N2 atmosphere, to a suspension of 2-(2-(3-((6-bromo-IT / -imidazo[4,5- Z»]pyrazin-2-yl)methyl)phenoxy)ethoxy)ethan-l -amine (30 mg, 0.08 mmol) in dioxane (1 mL) and water (0.2 mL) was added / ?-tolylboronic acid (13.5 mg, 0.10 mmol), Pd(dppf)C12 • DCM (6.3 mg, 0.01 mmol) and potassium carbonate (31.7 mg, 0.23 mmol). The resulting mixture was stirred at 90 °C for 16 hours. The reaction mixture was diluted with MeOH and purified by prep-HPLC (column: Sunfire prep Cl 8 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide a TFA salt of the title product as a yellow solid. LCMS calculated for C23H26N5O2 (M+H)+m / z = 404.2; found 404.2.

[0442] Step 4: 2-(2, 6-dioxopiperidin-3-yl)-4-( (2-(2-( 3-( f 6-(p-tolyl)-lH-imidazo[ 4, 5- b]pyrazin-2-yl)methyl)phenoxy)ethoxy)ethyl)amino)isoindoline-l, 3-dione

[0443] A solution of 2-(2-(3-((6-( / ?-tolyl)-U / -imidazo[4,5-Z>]pyrazin-2- yl)methyl)phenoxy)ethoxy)ethan-l -amine (15 mg, 0.04 mmol), 2-(2,6-dioxo-3- piperidyl)-4-fluoro-isoindoline-l, 3-dione (30.8 mg, 0.11 mmol) and A, N- diisopropylethylamine (14.4 mg, 0.11 mmol) in DMF (2.0 mL) was stirred at 100 °C for 16 hours. The reaction mixture was diluted with MeOH and purified by prep- HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide a TFA salt of the title product as a yellow solid. LCMS calculated for C36H34N7O6 (M+H)+m / z = 660.3; found 660.2. 54057-0024W01 / SNV0019-W01 PATENT

[0444] Examples 8-10.

[0445] The following compounds in Table 1 were prepared similarly according to the procedures described for Example 7 using appropriate intermediates.

[0446] Table 1. 54057-0024W01 / SNV0019-W01 PATENT

[0447] Example 11. 2-(2,6-Dioxopiperidin-3-yl)-4-((2-(2-(3-((3-(l-(2- methylbenzoyl)indolin-5-yl)imidazo[l,2-a]pyridin-7- yl)methyl)phenoxy)ethoxy)ethyl)amino)isoindoline-l, 3-dione

[0448] Step 1: (5-(7-chloroimidazo[l,2-a]pyridin-3-yl)mdolm-l-yl)(o-tolyl)methanone

[0449] To a solution of 7-chloro-3-iodoimidazo[l,2-a]pyridine (300 mg, 1.08 mmol) in dioxane (5 mL) and water (1 mL) was added (5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)indolin-l-yl)(o-tolyl)methanone (Intermediate 1, 391 mg, 1.08 mmol), potassium carbonate (372 mg, 2.69 mmol) and Pd(PPhs)4 (124 mg, 0.11 mmol) under N2 atmosphere. The resulting mixture was stirred at 80 °C for 16 hours. Upon completion, the mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (30 mL) and dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with ethyl acetate in DCM (0-90%), to provide the desired product (260 mg, 62% yield) as a yellow solid. LCMS calculated for C23H19CIN3O (M+H)+m / z = 388.1; found 388.1.

[0450] Step 2: (5-(7-(3-methoxybenzyl)imidazo[l,2-a]pyridin-3-yl)mdolm-l-yl)(o- tolyl)methanone

[0451] To a mixture of (5-(7-chloroimidazo[l,2-a]pyridin-3-yl)indolin-l-yl)(o- tolyl)methanone (255 mg, 0.66 mmol) and Pd(PPh3)4 (76 mg, 0.07 mmol) was added 3 -methoxybenzylzinc chloride (0.5 M in THF, 2.0 mL, 1.0 mmol) under N2 54057-0024W01 / SNV0019-W01 PATENT atmosphere. The resulting mixture was stirred at 70 °C for 16 hours. Upon completion, the mixture was diluted with water (20 mL) and extracted with EtOAc (15 mL x 2). The combined organic layers were washed with brine (20 mL) and dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with ethyl acetate in DCM (0- 90%), to provide the desired product (272 mg, 87% yield) as a yellow solid. LCMS calculated for C31H28N3O2 (M+H)+m / z = 474.2; found 474.2.

[0452] Step 3: (5-(7-(3-hydroxybenzyl)imidazo[l,2-a]pyridin-3-yl)indolin-l-yl)(o- tolyl)methanone

[0453] To a solution of (5-(7-(3-methoxybenzyl)imidazo[l,2-a]pyridin-3-yl)indolin- l-yl)(o-tolyl)methanone (240 mg, 0.51 mmol) in dichloromethane (3 mL) was added BBr3 (381 mg, 1.52 mmol) at 0 °C. The mixture was then warmed to room temperature and stirred for 16 hours. The reaction mixture was then quenched with saturated sodium bicarbonate solution (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (30 mL) and dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product, which was used in the next step without purification. LCMS calculated for C30H26N3O2 (M+H)+m / z = 460.2; found 460.2.

[0454] Step 4: 2-(2, 6-dioxopiperidin-3-yl)-4-( (2-(2-( 3-( 3-( 1 -(2-methylbenzoyl)indolin-5- yl)imidazo[ 1, 2-a]pyridin-7-yl)methyl)phenoxy)ethoxy)ethyl)amino)isoindoline-l, 3- dione

[0455] To a solution of (5-(7-(3-hydroxybenzyl)imidazo[l,2-a]pyridin-3-yl)indolin-l- yl)(o-tolyl)methanone (100 mg, 0.22 mmol) in DMF (4 mL) was added sodium hydride (60 % dispersion in mineral oil, 26 mg, 0.65 mmol) at 0 °C. The mixture was then warmed to room temperature and stirred for 15 minutes. Then 2-(2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)ethoxy)ethyl 4- methylbenzenesulfonate (Intermediate 5, 336 mg, 0.65 mmol) was added and the 54057-0024W01 / SNV0019-W01 PATENT reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with MeOH and purified by prep-HPLC (column: Sunfire prep Cl 8 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide a TFA salt of the title product as a yellow solid. LCMS calculated for C47H43N6O7 (M+H)+m / z = 803.3; found 803.2.

[0456] Example 12. 2-(2,6-Dioxopiperidin-3-yl)-4-((2-(2-(3-((3-(l-(2- methylbenzoyl)indolin-5-yl)-8-oxoimidazo[l,2-a]pyrazin-7(&H)- yl)methyl)phenoxy)ethoxy)ethyl)amino)isoindoline-l, 3-dione

[0457] Step 1: (5-(8-hydroxyimidazo[l,2-a]pyrazin-3-yl)mdolm-l-yl)(o-tolyl)methanone

[0458] To a solution of 3-bromoimidazo[l,2-a]pyrazin-8-ol (300 mg, 1.40 mmol) in dioxane (5 mL) and water (1 mL) was added (5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)indolin-l-yl)(o-tolyl)methanone (Intermediate 1, 611 mg, 1.68 mmol), potassium carbonate (484 mg, 3.50 mmol) and Pd(dppf)C12 • DCM (114 mg, 0.14 mmol) under N2 atmosphere. The resulting mixture was stirred at 90 °C for 16 hours. Upon completion, the mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (30 mL) and dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with methanol in DCM (0-20%), to provide the desired product (272 mg, 52% yield) as a yellow solid. LCMS calculated for C22H19N4O2 (M+H)+m / z = 371.2; found 371.1. 54057-0024W01 / SNV0019-W01 PATENT

[0459] Step 2: 7-(3-methoxybenzyl)-3-(l-(2-methylbenzoyl)indolin-5-yl)imidazo[l,2- a ]pyrazin-8(7H)-one

[0460] To a solution of (5-(8-hydroxyimidazo[l,2-a]pyrazin-3-yl)indolin-l-yl)(o- tolyl)methanone (255 mg, 0.69 mmol) and 1 -(brom omethyl)-3 -methoxy -benzene (277 mg, 1.38 mmol) in DMF (5 mL) was added potassium carbonate (285 mg, 2.07 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction was then diluted with water (30 mL) and EtOAc (30 mL). The aqueous layer was then extracted with EtOAc (30 mL). The combined organic layers were washed with brine (30 mL) and dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with EtOAc in DCM (0-90%), to provide the desired product (210 mg, 62% yield) as a yellow solid. LCMS calculated for C30H27N4O3 (M+H)+m / z = 491.2; found 491.2.

[0461] Step 3: 7-( 3-hydroxybenzyl)-3-( 1 -(2-methylbenzoyl)indolin-5-yl)imidazo[ 1, 2- a ]pyrazin-8(7H)-one

[0462] To a solution of 7-(3-methoxybenzyl)-3-(l-(2-methylbenzoyl)indolin-5- yl)imidazo[l,2-a]pyrazin-8(7J7)-one (115 mg, 0.23 mmol) in dichloromethane (3 mL) was added BBr? (176 mg, 0.70 mmol) at 0 °C. The mixture was then warmed to room temperature and stirred for 16 hours. The reaction mixture was then quenched with saturated sodium bicarbonate solution (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (30 mL) and dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product, which was used in the next step without purification. LCMS calculated for C29H25N4O3 (M+H)+m / z = 477.2; found 477.2. 54057-0024W01 / SNV0019-W01 PATENT

[0463] Step 4: 2-(2, 6-dioxopiperidin-3-yl)-4-( (2-(2-( 3-( f 3-( 1 -(2-methylbenzoyl)indolin-5-yl)- 8-oxoimidazo[ 1, 2-a]pyrazin-7(8H)~ yl)methyl)phenoxy)ethoxy)ethyl)amino)isoindoline-l, 3-dione

[0464] To a solution of 7-(3-hydroxybenzyl)-3-(l-(2-methylbenzoyl)indolin-5- yl)imidazo[l,2-a]pyrazin-8(7J7)-one (110 mg, 0.23 mmol) in DMF (4 mL) was added sodium hydride (60 % dispersion in mineral oil, 28 mg, 0.69 mmol) at 0 °C. The mixture was then warmed to room temperature and stirred for 15 minutes. Then 2-(2- ((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)ethoxy)ethyl 4- methylbenzenesulfonate (Intermediate 5, 357 mg, 0.69 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with MeOH and purified by prep-HPLC (column: Sunfire prep Cl 8 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide a TFA salt of the title product as a yellow solid. LCMS calculated for C46H42N7O8 (M+H)+m / z = 820.3; found 820.3.

[0465] Example A. ARE Luciferase Reporter Assay

[0466] KYSE-70 cells are cultured following DSMZ instruction in RPMI 1640 medium supplemented with 10% fetal bovine serum. Cells are transduced with lentiviral vectors carrying the firefly luciferase gene driven by antioxidant response element (ARE) located upstream of the minimal TATA promoter. Positive cells are selected through puromycin treatment and used for the ARE Luciferase Reporter Assay. One day before compound treatment, cells are seeded into 96-well plates at 40,000 cells per well. Compounds are dissolved in DMSO and directly dotted into wells using Thermo-Fisher Multidrop Pico-8 digital dispenser with 3-fold serial dilution. Cells are treated with compounds for 18 h before measuring reporter activity using the One-Step Luciferase Assay System following instruction from the manufacturer. Luminescence signal are detected using an SpectraMax i3x multi-mode microplate reader. Half-maximal inhibitory concentration (IC50) is established using GraphPad Prism software.

[0467] Percentage of inhibition is calculated, according to Equation 1, wherein BC = background control; and VC = vehicle control. 54057-0024W01 / SNV0019-W01 PATENT

[0468] Equation 1.

[0469] % Inhibition (Signal compound - Signal_BC) / (Signal_VC - Signal BC) x 100 IC50 is calculated by fitting % inhibition values and log of compound concentrations to nonlinear regression (normalized dose response-variable slope 4PL) with GraphPad 11.0, according to Equation 2, wherein X = log of inhibitor concentration; and Y = % inhibition.

[0470] Equation 2.

[0471] Y=Bottom + (Top-Bottom) / (l+10A((LogIC50-X)*HillSlope))

[0472] Results of the assay described above are presented in Table A. “+” indicates an IC50 less than 100 nM; “++” indicates an IC50 greater than or equal to 100 nM but less than 1000 nM; “+++” indicates an IC50 greater than or equal to 1000 nM but less than 5000 nM; and “++++” indicates an IC50 greater than or equal to 5000 nM.

[0473] Table A.

[0474] Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patent, patent applications, and publications, cited in the present application is incorporated herein by reference in its entirety.

Claims

54057-0024W01 / SNV0019-W01 PATENTWHAT IS CLAIMED IS:

1. A compound of Formula I:I or a pharmaceutically acceptable salt thereof, wherein:NRF2L is a NRF2 binding moiety of the following formula:m is 0, 1, 2, 3, 4, 5, or 6; n is 0, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, 5, or 6;Ring A is selected from C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl;Ring B is selected from bicyclic or tricyclic Ce-14 cycloalkyl, bicyclic or tricyclic C10-14 aryl, bicyclic or tricyclic 7-14 membered heterocycloalkyl, and bicyclic or tricyclic 6-14 membered heteroaryl;Ring C is selected from C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl;L1and L2are each independently selected from bond or C1-6 alkylene wherein 1-3 methylene units of the C1-6 alkylene are independently and optionally replaced with -O-, -N(RL1)-, -C(O)-, -N(RL1)C(O)-, -N(RL1)C(O)N(RL1)-, -N(RL1)C(O)O-, - S(O)-, -S(O)2-, -S(O)(=NRL1)-, -S(O)2N(RL1)-, and -N(RL1)S(O)2N(RL1)-, wherein the C1-6 alkylene of L1and L2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each RL1is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, (5-6 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered54057-0024W01 / SNV0019-W01 PATENT heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, (5-6 membered heteroaryl)-Ci-4 alkyl of RL1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;L is selected from a covalent bond andk is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each L’ is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -O-, - O)N(RL’)-, -N(RL’)C(O)O-, -S(O)-, -S(O)2-,’)S(O)2N(RL’)-, 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 L’ are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each RLis independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, (5-6 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, (5-6 membered heteroaryl)-Ci-4 alkyl of RLare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;E3L is an E3 ubiquitin ligase ligand of the following formula:54057-0024W01 / SNV0019-W01 PATENTX is N or CR5;L3is selected from a bond and C1-3 alkylene, wherein 1-2 methylene units of the C1-3 alkylene are independently and optionally replaced with -O-, -S-, -N(RL3)-, - C(O)-, -N(RL3)C(O)-, -N(RL3)C(O)N(RL3)-, -N(RL3)C(O)O-, -S(O)-, -S(O)2-, - S(O)(=NRL3)-, -S(O)2N(RL3)-, and -N(RL3)S(O)2N(RL3)-, wherein the C1-3 alkylene of L3is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each RL3is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl;Ring D is C3-14 cycloalkyl, Ce-io aryl, 4-14 membered heterocycloalkyl, 5-10 membered heteroaryl;R1is 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, - ORal, -SRal, -NRclRdl, -NO2, -C(O)Ral, -C(O)ORal, -C(O)NRclRdl, - C(O)NRcl(ORal), -OC(O)Ral, -OC(O)NRclRdl, -OC(O)ORal, -OS(O)2Rbl, - OS(O)2NRclRdl, -NRclC(O)Ral, -NRclC(O)ORal, -NRclC(O)NRclRdl, -NRclS(O)2Rbl, -NRclS(O)2NRclRdl, -NRcl0Ral, -NRclS(O)Rbl, -NRclS(O)NRclRdl, -S(O)Rbl, - S(O)2Rbl, -S(O)NRclRdl, -S(O)2NRclRdl, -C(=NRel)Ral, -C(=NRel)NRclRdl, - NRclC(=NRel)Ral, -NRclC(=NRel)NRclRdl, -NRclS(O)(=NRel)Rbl, - NRclS(O)(=NRel)NRclRdl, -OS(O)(=NRel)Rbl, -S(O)(=NRel)Rbl, - S(O)(=NRel)NRclRdl, -C(O)NRclS(O)2Rbl, -C(O)NRclS(O)2NRclRdl, - S(O)2NRclC(O)Rbl, -NRclS(O)NRclC(O)Rbl, and -P(O)RflRgl, 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-Cn 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1Asubstituents; each Ral, Rcl, and Rdlis 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-Cn 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered54057-0024W01 / SNV0019-W01 PATENT heteroaryl)-Ci-4 alkyl, wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ral, Rcl, and Rdlare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1Asubstituents; or, any Rcland Rdlattached 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 R1Asubstituents; each Rblis independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rblare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1Asubstituents; each Relis independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl,4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each Rfland Rglare independently selected from H, C1-6 alkyl, C1-6 alkoxy, Cn 6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4- 10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R1Ais 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, (4-1054057-0024W01 / SNV0019-W01 PATENT membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, - ORalA, -SRalA, -NRclARdlA, -NO2, -C(O)RalA, -C(O)ORalA, -C(O)NRclARdlA, - C(O)NRclA(ORalA), -OC(O)RalA, -OC(O)NRclARdlA, -OC(O)ORalA, -OS(O)2RblA, - OS(O)2NRclARdlA, -NRclAC(O)RalA, -NRclAC(O)ORalA, -NRclAC(O)NRclARdlA, - NRclAS(O)2RblA, -NRclAS(O)2NRclARdlA, -NRclAORalA, -NRclAS(O)RblA, - NRclAS(O)NRclARdlA, -S(O)RblA, -S(O)2RblA, -S(O)NRclARdlA, -S(O)2NRclARdlA, - C(=NRelA)RalA, -C(=NRelA)NRclARdlA, -NRclAC(=NRelA)RalA, - NRclAC(=NRelA)NRclARdlA, -NRclAS(O)(=NRelA)RblA, - NRclAS(O)(=NRelA)NRclARdlA, -OS(O)(=NRelA)RblA, -S(O)(=NRelA)RblA, - S(O)(=NRelA)NRclARdlA, -C(O)NRclAS(O)2RblA, -C(O)NRclAS(O)2NRclARdlA, - S(O)2NRclAC(O)RblA, -NRclAS(O)NRclAC(O)RblA, and -P(O)RflARglA, 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 R1Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each RalA, RclA, and RdlAis 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-Cn 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of RalA, RclA, and RdlAare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any RclAand RdlAattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each RblAis 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, 5-54057-0024W01 / SNV0019-W01 PATENT10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of RblAare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each RelAis independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each RflAand RglAare 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-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R2, R3and R4are independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, (5-6 membered heteroaryl)-Ci-4 alkyl, -CN, -ORa2, -SRa2, -NRc2Rd2, -NO2, -C(O)Ra2, -C(O)ORa2, -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, -NRc2S(O)NRc2C(O)Rb2, and -P(O)Rf2Rg2, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-454057-0024W01 / SNV0019-W01 PATENT alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci- 4 alkyl of R2, R3and R4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra2, Rc2, and Rd2is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci- 4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of Ra2, Rc2, and Rd2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc2and Rd2attached to the same N atom, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group, wherein the 4- 7 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rb2is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of Rb2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; 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, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl; each R12and Rg2are independently selected from H, C1-6 alkyl, C1-6 alkoxy, Cn 6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-754057-0024W01 / SNV0019-W01 PATENT membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl;R5is H, D, halo, CN, C1-4 alkyl, Ci-4haloalkyl, C1-4 alkoxy, or C1-4 haloalkoxy; each RGis independently selected from OH, CN, halo, oxo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, cyano-Ci-4 alkyl, HO-C1-4 alkyl, C1-4 alkoxy-Ci-4 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-3 alkylamino, di(Ci-3 alkyl)amino, thio, C1-3 alkylthio, C1-3 alkylsulfinyl, Ci- 3 alkyl sulfonyl, carbamyl, C1-3 alkylcarbamyl, di (C 1-3 alkyl)carbamyl, carboxy, C1-3 alkylcarbonyl, C1-3 alkoxycarbonyl, C1-3 alkylcarbonyloxy, C1-3 alkylcarbonylamino, C1-3 alkoxy carbonylamino, aminocarbonyloxy, C1-3 alkylaminocarbonyloxy, di (C 1-3 alkyl)aminocarbonyloxy, C1-3 alkylsulfonylamino, aminosulfonyl, C1-3 alkylaminosulfonyl, di(Ci-3 alkyl)aminosulfonyl, aminosulfonylamino, C1-3 alkylaminosulfonylamino, di(Ci-3 alkyl)aminosulfonylamino, aminocarbonylamino, C1-3 alkylaminocarbonylamino, and di(Ci-3 alkyl)aminocarbonylamino.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from C3-7 cycloalkyl, phenyl, 8-10 membered heterocycloalkyl, and 5-6 membered heteroaryl.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from phenyl, pyrazolyl, and indolinyl.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein each R1is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, -ORal, -SRal, -NRclRdl, -NO2, -C(O)Ral, - C(O)ORal, and -C(O)NRclRdl; each Ral, Rcl, and Rdlis independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered54057-0024W01 / SNV0019-W01 PATENT heterocycloalkyl, and 5-6 membered heteroaryl, wherein the C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl of Ral, Rcl, and Rdlare each optionally substituted with 1, 2, 3, or 4 independently selected R1Asubstituents; and each R1Ais independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl.

6. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein each R1is independently selected from C1-6 alkyl, -NRclRdl, and -C(O)Ral; each Ral, Rcl, and Rdlis independently selected from H, C1-6 alkyl, C3-7 cycloalkyl, and phenyl, wherein the C3-7 cycloalkyl and phenyl of Ral, Rcl, and Rdlare each optionally substituted with 1 or 2 independently selected R1Asubstituents; and each R1Ais independently selected from C1-6 alkyl.

7. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein each R1is independently selected from methyl, dimethylamino, methylcarbonyl, (methylphenyl)carbonyl, and cyclopropyl carbonyl.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein L1is a bond.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from bicyclic 7-14 membered heterocycloalkyl and bicyclic 8-14 membered heteroaryl.

10. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from 3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)- one, 5,6,7, 8-tetrahydroimidazo[ 1 ,2-a]pyrazinyl, imidazof 1 ,2-a]pyrazin-8(7H)-one, imidazof 1 ,2-c]pyrimidinyl, lH-imidazo[4, 5-b]pyrazinyl, imidazof 1 ,2-a]pyrazinyl, imidazof l,2-a]pyridinyl, and isoquinolinyl.54057-0024W01 / SNV0019-W01 PATENT11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein each R2is independently selected from oxo, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl.

13. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein each R2is independently selected from oxo, and C1-6 alkyl.

14. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein each R2is independently selected from oxo and methyl.

15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein L2is C1-6 alkylene, wherein 1-3 methylene units of the C1-6 alkylene are independently and optionally replaced with -N(RL1)-; and each RL1is independently selected from H and C1-6 alkyl.

16. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein L2is selected from -CH2- and -NHCH2-.

17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein Ring C is Ce-io aryl.

18. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein Ring C is phenyl.

19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein p is 0.

20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein54057-0024W01 / SNV0019-W01 PATENT21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein k is 4, 5, or 6.

22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein each L’ is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -O-, and -N(RL)-; and each RLis independently selected from H and C1-6 alkyl.

23. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein each L’ is independently selected from C1-6 alkyl, -O-, and - N(RL)-; and each RLis independently selected from H and C1-3 alkyl.

24. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein each L’ is independently selected from -CH2CH2-, -O-, and -NH-.

25. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein L is -OCH2CH2OCH2CH2NH-.

26. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein Ring D is 4-14 membered heterocycloalkyl.

27. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein Ring D is bicyclic 8-10 membered heterocycloalkyl.

28. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein Ring D is isoindoline- 1, 3-dionyl.

29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein q is 1, 2, or 3.54057-0024W01 / SNV0019-W01 PATENT30. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein each R4is oxo.

31. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein L3is a bond.

32. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein X is CR5.

33. The compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R5is selected from H, D, halo, Ci-4 alkyl, and Ci-4 haloalkyl.

34. The compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R5is selected from H, D, and Ci-4 alkyl.

35. The compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R5is selected from H.

36. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:NRF2L is a NRF2 binding moiety of the following formula:m is 0, 1, or 2; n is 0 or 1; p is 0 or 1;Ring A is selected from C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl;Ring B is selected from bicyclic or tricyclic Ce-14 cycloalkyl, bicyclic or tricyclic C10-14 aryl, bicyclic or tricyclic 7-14 membered heterocycloalkyl, and bicyclic or tricyclic 6-14 membered heteroaryl;54057-0024W01 / SNV0019-W01 PATENTRing C is selected from C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl;L1is a bond;L2is C1-6 alkylene, wherein 1-3 methylene units of the C1-6 alkylene are independently and optionally replaced with -N(RL1)-; each RL1is independently selected from H and C1-6 alkyl;L is selected from a covalent bond andk; k is 4, 5, or 6; each L’ is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cn 6 haloalkyl, -O-, and -N(RL)-; each RLis independently selected from H and C1-6 alkyl;E3L is an E3 ubiquitin ligase ligand of the following formula:q is 1, 2, or 3;X is N or CR5;L3is a bond;Ring D is C3-14 cycloalkyl, Ce-io aryl, 4-14 membered heterocycloalkyl, 5-10 membered heteroaryl; each R1is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, -ORal, -SRal, -NRclRdl, -NO2, -C(O)Ral, -C(O)ORal, and -C(O)NRclRdl; each Ral, Rcl, and Rdlis independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl of Ral, Rcl, and Rdlare each optionally substituted with 1, 2, 3, or 4 independently selected R1Asubstituents; each R1Ais independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;54057-0024W01 / SNV0019-W01 PATENT each R2is independently selected from oxo, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; each R4is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; andR5is selected from H, D, halo, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy.

37. The compound of claim 1, wherein:NRF2L is a NRF2 binding moiety of the following formula:m is 0, 1, or 2; n is 0 or 1; p is 0 or 1;Ring A is selected from C3-7 cycloalkyl, phenyl, 8-10 membered heterocycloalkyl, and 5-6 membered heteroaryl;Ring B is selected from bicyclic 7-14 membered heterocycloalkyl and bicyclic 8-14 membered heteroaryl;Ring C is Ce-io aryl;L1is a bond;L2is C1-6 alkylene, wherein 1-3 methylene units of the C1-6 alkylene are independently and optionally replaced with -N(RL1)-; each RL1is independently selected from H and C1-6 alkyl;k is 4, 5, or 6; each L’ is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cn 6 haloalkyl, -O-, and -N(RL)-; each RLis independently selected from H and C1-6 alkyl;E3L is an E3 ubiquitin ligase ligand of the following formula:54057-0024W01 / SNV0019-W01 PATENTq is 1, 2, or 3;X is N or CR5;L3is a bond;Ring D is 4-14 membered heterocycloalkyl; each R1is independently selected from oxo, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, -ORal, -SRal, -NRclRdl, -NO2, -C(O)Ral, -C(O)ORal, and -C(O)NRclRdl; each Ral, Rcl, and Rdlis independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl of Ral, Rcl, and Rdlare each optionally substituted with 1, 2, 3, or 4 independently selected R1Asubstituents; each R1Ais independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; each R2is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; each R4is oxo; andR5is selected from H, D, halo, C1-4 alkyl, and C 1-4 haloalkyl.

38. The compound of claim 1, wherein the compound of Formula I is a compound of Formula II:or a pharmaceutically acceptable salt thereof.54057-0024W01 / SNV0019-W01 PATENT39. The compound of claim 1, wherein the compound of Formula I is a compound of Formula III:III or a pharmaceutically acceptable salt thereof.

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

41. The compound of claim 1, which is selected from:2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(3-((3-methyl-2-(l-(2- methylbenzoyl)indolin-5-yl)imidazo[l,2-c]pyrimidin-7- yl)methyl)phenoxy)ethoxy)ethyl)amino)isoindoline-l,3-dione;5-((2-(2-(3-((6-(l-(cyclopropanecarbonyl)indolin-5-yl)-l-oxo-3,4- dihydropyrrolo[l,2-a]pyrazin-2(177)-yl)methyl)phenoxy)ethoxy)ethyl)amino)-2-(2,6- dioxopiperi din-3 -yl)isoindoline- 1 ,3 -di one;2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(3-((6-(l-(2-methylbenzoyl)indolin-5-yl)- 17 / -imidazo[4,5-Z>]pyrazin-2-yl)methyl)phenoxy)ethoxy)ethyl)amino)isoindoline-l,3- dione;54057-0024W01 / SNV0019-W01 PATENT4-((2-(2-(3-(((2-(l-(cyclopropanecarbonyl)indolin-5-yl)imidazo[l,2- a]pyrazin-8-yl)amino)methyl)phenoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline- 1 ,3 -di one;4-((2-(2-(3-((3-(l-(cyclopropanecarbonyl)indolin-5-yl)-5,6- dihydroimidazo[l,2-a]pyrazin-7(8J7)-yl)methyl)phenoxy)ethoxy)ethyl)amino)-2-(2,6- dioxopiperi din-3 -yl)isoindoline- 1 ,3 -di one;2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(3-((8-(l-(2-methylbenzoyl)indolin-5- yl)isoquinolin-3-yl)methyl)phenoxy)ethoxy)ethyl)amino)isoindoline-l, 3-dione;2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(3-((6-(p-tolyl)-lJ / -imidazo[4,5- Z»]pyrazin-2-yl)methyl)phenoxy)ethoxy)ethyl)amino)isoindoline-l, 3-dione;2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(3-((6-(l-methyl-lJH-pyrazol-4-yl)-lJH- imidazo[4,5-Z>]pyrazin-2-yl)methyl)phenoxy)ethoxy)ethyl)amino)isoindoline-l,3- dione;4-((2-(2-(3-((6-(4-(dimethylamino)phenyl)-lJH-imidazo[4,5-Z>]pyrazin-2- yl)methyl)phenoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3- dione;4-((2-(2-(3-((6-(l-acetylindolin-5-yl)-l / 7-imidazo[4,5-Z>]pyrazin-2- yl)methyl)phenoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3- dione;2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(3-((3-(l-(2-methylbenzoyl)indolin-5- yl)imidazo[l,2-a]pyridin-7-yl)methyl)phenoxy)ethoxy)ethyl)amino)isoindoline-l,3- dione; and2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(3-((3-(l-(2-methylbenzoyl)indolin-5-yl)- 8-oxoimidazo[l,2-a]pyrazin-7(8Z / )- yl)methyl)phenoxy)ethoxy)ethyl)amino)isoindoline-l,3-dione; or a pharmaceutically acceptable salt thereof.

42. A pharmaceutical composition, comprising a compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.54057-0024W01 / SNV0019-W01 PATENT43. A method of inhibiting an activity of NRF2, comprising contacting the NRF2 with a compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof.

44. A method of treating a NRF2-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 41, or a pharmaceutically acceptable salt thereof.

45. The method of claim 44, wherein the disease is cancer.

46. The method of claim 45, wherein the cancer is selected from squamous cell lung cancer, lung adenocarcinoma, esophageal cancer, endometrial cancer, head and neck cancer, bladder cancer, ovarian cancer, liver cancer, cervical cancer, cholangiocarcinoma, gastric cancer, melanoma, kidney cancer, colorectal carcinoma, breast cancer, pancreatic cancer, thyroid cancer, brain and central nervous system cancers, glioblastoma, neuroblastoma, neuroendocrine cancer, rhabdoid cancer, keratoacanthoma, epidermoid carcinoma, acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome, promyelocytic leukemia, leukemia, multiple myeloma, mantle cell lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, and hairy cell lymphoma.

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