Benzimidazole derivatives which avr as modulators of TNF-alpha

Abstract

The present disclosure provides heterocyclic compounds as well as their pharmaceutical compositions that modulate the activity of tumor necrosis factor-alpha (TNFα) and are useful in the treatment of various diseases related to TNFα, including autoimmune diseases and inflammatory diseases.

Description

[0001] 54057-0034W01 / SNV0025-W01 PATENT

[0002] HETEROCYCLIC COMPOUNDS AS MODULATORS OF TNFa ACTIVITY TECHNICAL FIELD

[0003] The present disclosure provides heterocyclic compounds as well as their pharmaceutical compositions that modulate the activity of tumor necrosis factor-alpha (TNFa) and are useful in the treatment of various diseases related to TNFa, including autoimmune diseases and inflammatory diseases.

[0004] BACKGROUND

[0005] Tumor Necrosis Factor-alpha (TNF-a) is a pro-inflammatory cytokine primarily produced by monocytes and macrophages. It plays a key role in the regulation of immune cells, inflammation, and apoptosis (see e.g., Nat. Rev.

[0006] Rheumatol. 2016;12(l):49-62). TNF-a functions by binding to its receptors, TNFR1 and TNFR2, which activate multiple signaling pathways including NF-KB, MAPKs, and apoptotic pathways (see e.g., Physiol. Rev. 2019;99(l): 115-160). These pathways lead to the production of other cytokines, chemokines, and adhesion molecules, amplifying the inflammatory response.

[0007] SUMMARY

[0008] The present disclosure provides, inter alia, compounds of Formula I:

[0009]

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

[0011] The present disclosure further provides a pharmaceutical composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.54057-0034W01 / SNV0025-W01 PATENT

[0012] The present disclosure further provides methods of inhibiting tumor necrosis factor-alpha (TNFa) activity, comprising contacting the TNFa with a compound described herein, or a pharmaceutically acceptable salt thereof.

[0013] The present disclosure further provides methods of treating a disease or a disorder associated with TNFa in a patient by administering to the patient a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof.

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

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

[0016] DETAILED DESCRIPTION

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

[0018] >

[0019]

[0020] or a pharmaceutically acceptable salt thereof, wherein:

[0021] m is 1, 2, 3, 4, 5, or 6;

[0022] n is 1, 2, 3, 4, 5, or 6;

[0023] p is 1, 2, 3, 4, 5, or 6;

[0024] q is 1, 2, 3, 4, 5, or 6;

[0025] X1is N or C;

[0026] X2is N or C;

[0027] X3is N or C;

[0028] X4is N or C;

[0029] wherein one of X1, X2, X3, and X4is N, and three of X1, X2, X3, and X4are C;54057-0034W01 / SNV0025-W01 PATENT

[0030] Y1is N or C;

[0031] Y2is N or C;

[0032] Ring A is a 5-membered heteroaryl;

[0033] Ring B is selected from Ce-io aryl, 5-10 membered heteroaryl, bicyclic Cs-14 cycloalkyl, and bicyclic 8-14 membered heterocycloalkyl;

[0034] Ring C is selected from C5-14 cycloalkyl, phenyl, 5-14 membered heterocycloalkyl, and 5-10 membered heteroaryl;

[0035] each L1and L2are independently selected from C1-6 alkylene, C2-6 alkenylene, C3-10 cycloalkylene, 4-10 membered heterocycloalkylene, phenylene, 5-10 membered heteroarylene, -O-, -S-, -N(RL2c)-, -C(O)-, -S(O)-, -S(O)2-, and -S(O)(=NRL2e)-, wherein the C1-6 alkylene, C2-6 alkenylene, C3-10 cycloalkylene, 4-10 membered heterocycloalkylene, phenylene, and 5-10 membered heteroarylene of L1and L2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RL2substituents;

[0036] or, one of L1and one of L2, together with the atoms to which they are attached to, form a C5-14 cycloalkyl, or 5-14 membered heterocycloalkyl, wherein the C5-14 cycloalkyl, and 5-14 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RL2substituents;

[0037] L4is selected from -CRL4=CRL5- and C2-4 alkylene, wherein 1-2 methylene units of the C2-4 alkylene are independently and optionally replaced with -O-, C3-4 cycloalkylene, or 4-5 membered heterocycloalkylene, and wherein the C2-4 alkylene, C3-4 cycloalkylene, and 4-5 membered heterocycloalkylene are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0038] RL4and RL5are each independently selected from H, halo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;

[0039] each RL2Cis independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkylidenyl, 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, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, -ORaL2, -NRcL2RdL2, -C(O)RaL2, -C(O)ORaL2, -C(O)NRcL2RdL2, -C(O)NRcL2(ORaL2), -S(O)RbL2, -S(O)2RbL2, -S(O)NRcL2RdL2, -S(O)2NRcL2RdL2, -S(O)(=NReL2)RbL2, -S(O)(=NReL2)NRcL2RdL2, -C(O)NRcL2S(O)2RbL2, -54057-0034W01 / SNV0025-W01 PATENT

[0040] C(O)NRcL2S(O)2NRcL2RdL2, and -S(O)2NRcL2C(O)RbL2, wherein the Ci-6alkyl, Ci-6alkylidenyl, 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 RL2care each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RL2substituents;

[0041] each RL2eis 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;

[0042] each RL2is independently selected from H, oxo, halo, Ci-6 alkyl, Ci-6 alkylidenyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4alkyl, -CN, -ORaL2, -SRaL2, -NRcL2RdL2, -NO2, -C(O)RaL2, -C(O)ORaL2, -C(O)NRcL2RdL2, -C(O)NRcL2(ORaL2), -OC(O)RaL2, -OC(O)NRcL2RdL2, -OC(O)ORaL2, -OS(O)2RbL2, -OS(O)2NRcL2RdL2, -NRcL2C(O)RaL2, -NRcL2C(O)ORaL2, -NRcL2C(O)NRcL2RdL2, -NRcL2S(O)2RbL2, -NRcL2S(O)2NRcL2RdL2, -NRcL2ORaL2, -NRcL2S(O)RbL2, -NRcL2S(O)NRcL2RdL2, -S(O)RbL2, -S(O)2RbL2, -S(O)NRcL2RdL2, -S(O)2NRcL2RdL2, -C(=NReL2)RaL2, -C(=NReL2)NRcL2RdL2, -NRcL2C(=NReL2)RaL2, -NRcL2C(=NReL2)NRcL2RdL2, -NRcL2S(O)(=NReL2)RbL2, -NRcL2S(O)(=NReL2)NRcL2RdL2, -OS(O)(=NReL2)RbL2, -S(O)(=NReL2)RbL2, -S(O)(=NReL2)NRcL2RdL2, -C(O)NRcL2S(O)2RbL2, -C(O)NRcL2S(O)2NRcL2RdL2, -S(O)2NRcL2C(O)RbL2, -NRcL2S(O)NRcL2C(O)RbL2, and -P(O)RfL2RgL2, wherein the Cn 6 alkyl, Ci-6 alkylidenyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of RL2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0043] each RaL2, RcL2, and RdL2is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered54057-0034W01 / SNV0025-W01 PATENT

[0044] 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 RaL2, RcL2, and RdL2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0045] or, any RcL2and RdL2attached 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;

[0046] each RbL2is 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 RbL2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0047] each ReL2is 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;

[0048] each11'2and RgL2are independently selected from H, 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;

[0049] each R1is independently selected from oxo, halo, C1-6 alkyl, C1-6 alkylidenyl, C 2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered54057-0034W01 / SNV0025-W01 PATENT

[0050] 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, -SF5, -SRal, -NRclRdl, -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, Ci-ealkylidenyl, 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;

[0051] 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;

[0052] 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;

[0053] 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, 5-1054057-0034W01 / SNV0025-W01 PATENT

[0054] 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;

[0055] 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;

[0056] 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;

[0057] each R1Ais independently selected from oxo, halo, C1-6 alkyl, C1-6 alkylidenyl, 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, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, -ORalA, -SF5, -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, C1-6 alkylidenyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl,54057-0034W01 / SNV0025-W01 PATENT

[0058] Ce-io aryl, 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 R1Bsubstituents;

[0059] 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 R1Bsubstituents;

[0060] 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 R1Bsubstituents;

[0061] 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 (5-10 membered heteroaryl)-Ci-4 alkyl of RblAare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1Bsubstituents;

[0062] 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;54057-0034W01 / SNV0025-W01 PATENT

[0063] each RflAand RglAare independently selected from H, 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;

[0064] each R1Bis independently selected from oxo, halo, C1-6 alkyl, C1-6 alkylidenyl, 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, -ORalB, -SF5, -SRalB, -NRclBRdlB, -NO2, -C(O)RalB, -C(O)ORalB, -C(O)NRclBRdlB, -C(O)NRclB(ORalB), -OC(O)RalB, -OC(O)NRclBRdlB, -OC(O)ORalB, -OS(O)2RblB, -OS(O)2NRclBRdlB, -NRclBC(O)RalB, -NRclBC(O)ORalB, -NRclBC(O)NRclBRdlB, -NRclBS(O)2RblB, -NRclBS(O)2NRclBRdlB, -NRclBORalB, -NRclBS(O)RblB, -NRclBS(O)NRclBRdlB, -S(O)RblB, -S(O)2RblB, -S(O)NRclBRdlB, -S(O)2NRclBRdlB, -C(=NRelB)RalB, -C(=NRelB)NRclBRdlB, -NRclBC(=NRelB)RalB, -NRclBC(=NRelB)NRclBRdlB, -NRclBS(O)(=NRelB)RblB, -NRclBS(O)(=NRelB)NRclBRdlB, -OS(O)(=NRelB)RblB, -S(O)(=NRelB)RblB, -S(O)(=NRelB)NRclBRdlB, -C(O)NRclBS(O)2RblB, -C(O)NRclBS(O)2NRclBRdlB, -S(O)2NRclBC(O)RblB, -NRclBS(O)NRclBC(O)RblB, and -P(O)RflBRglB, wherein the C1-6 alkyl, C1-6 alkylidenyl, 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 R1Bare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0065] each RalB, RclB, and RdlBis 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 RalB, RclB,54057-0034W01 / SNV0025-W01 PATENT

[0066] and RdlBare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0067] or, any RclBand RdlBattached 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;

[0068] each RblBis 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 RblBare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0069] each RelBis 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;

[0070] each RflBand RglBare 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;

[0071] R2is selected from H, halo, C1-6 alkyl, C1-6 alkylidenyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, -ORa2, -SF5, -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)2Rb2,54057-0034W01 / SNV0025-W01 PATENT

[0072] -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 Ci-6alkyl, Ci-6 alkylidenyl, 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 R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents;

[0073] or, R2and one of R1, together with the atoms to which they are attached to, form a Ce-30 cycloalkyl, or 6-30 membered heterocycloalkyl, wherein the Ce-30 cycloalkyl, and 6-30 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1Asubstituents;

[0074] each Ra2, Rc2, and Rd2is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-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 Ra2, Rc2, and Rd2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents;

[0075] or, any Rc2and Rd2attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents;

[0076] each Rb2is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-1054057-0034W01 / SNV0025-W01 PATENT

[0077] membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Rb2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents;

[0078] each Re2is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;

[0079] 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, C3-10 cycloalkyl, Ce-io aryl, 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;

[0080] each R2Ais independently selected from oxo, halo, C1-6 alkyl, C1-6 alkylidenyl, 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, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, -ORa2A, -SF5, -SRa2A, -NRc2ARd2A, -NO2, -C(O)Ra2A, -C(O)ORa2A, -C(O)NRc2ARd2A, -C(O)NRc2A(ORa2A), -OC(O)Ra2A, -OC(O)NRc2ARd2A, -OC(O)ORa2A, -OS(O)2Rb2A, -OS(O)2NRc2ARd2A, -NRc2AC(O)Ra2A, -NRc2AC(O)ORa2A, -NRc2AC(O)NRc2ARd2A, -NRc2AS(O)2Rb2A, -NRc2AS(O)2NRc2ARd2A, -NRc2AORa2A, -NRc2AS(O)Rb2A, -NRc2AS(O)NRc2ARd2A, -S(O)Rb2A, -S(O)2Rb2A, -S(O)NRc2ARd2A, -S(O)2NRc2ARd2A, -C(=NRe2A)Ra2A, -C(=NRe2A)NRc2ARd2A, -NRc2AC(=NRe2A)Ra2A, -NRc2AC(=NRe2A)NRc2ARd2A, -NRc2AS(O)(=NRe2A)Rb2A, -NRc2AS(O)(=NRe2A)NRc2ARd2A, -OS(O)(=NRe2A)Rb2A, -S(O)(=NRe2A)Rb2A, -S(O)(=NRe2A)NRc2ARd2A, -C(O)NRc2AS(O)2Rb2A, -C(O)NRc2AS(O)2NRc2ARd2A, -S(O)2NRc2AC(O)Rb2A, -NRc2AS(O)NRc2AC(O)Rb2A, and -P(O)Rf2ARg2A, wherein the C1-6 alkyl, C1-6 alkylidenyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-1054057-0034W01 / SNV0025-W01 PATENT

[0081] cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0082] each Ra2A, Rc2A, and Rd2Ais independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-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 Ra2A, Rc2A, and Rd2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0083] or, any Rc2Aand Rd2Aattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0084] each Rb2Ais independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Rb2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0085] each Re2Ais independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;54057-0034W01 / SNV0025-W01 PATENT

[0086] each RGAand Rg2Aare independently selected from H, 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;

[0087] L3is selected from bond, C1-6 alkylene, C2-6 alkenylene, C3-10 cycloalkylene, 4-10 membered heterocycloalkylene, phenylene, and 5-10 membered heteroarylene, wherein the C1-6 alkylene, C2-6 alkenylene, C3-10 cycloalkylene, 4-10 membered heterocycloalkylene, phenylene, and 5-10 membered heteroarylene of L3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0088] or, two L3, together with the atoms to which they are attached to, form a C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, wherein the C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3substituents;

[0089] each R3is independently selected from H, oxo, halo, C1-6 alkyl, C1-6 alkylidenyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4alkyl, -CN, -ORa3, -SF5, -SRa3, -NRc3Rd3, -NO2, -C(O)Ra3, -C(O)ORa3, -C(O)NRc3Rd3, -C(O)NRc3(ORa3), -OC(O)Ra3, -OC(O)NRc3Rd3, -OC(O)ORa3, -OS(O)2Rb3, -OS(O)2NRc3Rd3, -NRc3C(O)Ra3, -NRc3C(O)ORa3, -NRc3C(O)NRc3Rd3, -NRc3S(O)2Rb3, -NRc3S(O)2NRc3Rd3, -NRc3ORa3, -NRc3S(O)Rb3, -NRc3S(O)NRc3Rd3, -S(O)Rb3, -S(O)2Rb3, -S(O)NRc3Rd3, -S(O)2NRc3Rd3, -C(=NRe3)Ra3, -C(=NRe3)NRc3Rd3, -NRc3C(=NRe3)Ra3, -NRc3C(=NRe3)NRc3Rd3, -NRc3S(O)(=NRe3)Rb3, -NRc3S(O)(=NRe3)NRc3Rd3, -OS(O)(=NRe3)Rb3, -S(O)(=NRe3)Rb3, -S(O)(=NRe3)NRc3Rd3, -C(O)NRc3S(O)2Rb3, -C(O)NRc3S(O)2NRc3Rd3, -S(O)2NRc3C(O)Rb3, -NRc3S(O)NRc3C(O)Rb3, and -P(O)RfiRg3, wherein the C1-6 alkyl, C1-6 alkylidenyl, 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 of54057-0034W01 / SNV0025-W01 PATENT

[0090] R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents;

[0091] each Ra3, Rc3, and Rd3is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-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 Ra3, Rc3, and Rd3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents;

[0092] or, any Rc3and Rd3attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents;

[0093] each Rb3is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Rb3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents;

[0094] each Re3is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;

[0095] each R13and Rg3are 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, 4-54057-0034W01 / SNV0025-W01 PATENT

[0096] 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;

[0097] each R3Ais independently selected from oxo, halo, C1-6 alkyl, C1-6 alkylidenyl, C2-6 alkenyl, C2-6alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, -ORa3A, -SF5, -SRa3A, -NRc3ARd3A, -NO2, -C(O)Ra3A, -C(O)ORa3A, -C(O)NRc3ARd3A, -C(O)NRc3A(ORa3A), -OC(O)Ra3A, -OC(O)NRc3ARd3A, -OC(O)ORa3A, -OS(O)2Rb3A, -OS(O)2NRc3ARd3A, -NRc3AC(O)Ra3A, -NRc3AC(O)ORa3A, -NRc3AC(O)NRc3ARd3A, -NRc3AS(O)2Rb3A, -NRc3AS(O)2NRc3ARd3A, -NRc3AORa3A, -NRc3AS(O)Rb3A, -NRc3AS(O)NRc3ARd3A, -S(O)Rb3A, -S(O)2Rb3A, -S(O)NRc3ARd3A, -S(O)2NRc3ARd3A, -C(=NRe3A)Ra3A, -C(=NRe3A)NRc3ARd3A, -NRc3AC(=NRe3A)Ra3A, -NRc3AC(=NRe3A)NRc3ARd3A, -NRc3AS(O)(=NRe3A)Rb3A, -NRc3AS(O)(=NRe3A)NRc3ARd3A, -OS(O)(=NRe3A)Rb3A, -S(O)(=NRe3A)Rb3A, -S(O)(=NRe3A)NRc3ARd3A, -C(O)NRc3AS(O)2Rb3A, -C(O)NRc3AS(O)2NRc3ARd3A, -S(O)2NRc3AC(O)Rb3A, -NRc3AS(O)NRc3AC(O)Rb3A, and -P(O)RCARg3A, wherein the C1-6 alkyl, C1-6 alkylidenyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Bsubstituents;

[0098] each Ra3A, Rc3A, and Rd3Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-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 Ra3A, Rc3A, and Rd3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Bsubstituents;54057-0034W01 / SNV0025-W01 PATENT

[0099] or, any Rc3Aand Rd3Aattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Bsubstituents;

[0100] each Rb3Ais independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Rb3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Bsubstituents;

[0101] each Re3Ais independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;

[0102] each RfiAand Rg3Aare 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;

[0103] each R3Bis independently selected from oxo, halo, C1-6 alkyl, C1-6 alkylidenyl, 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, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, -ORa3B, -SF5, -SR3313, -NRc3BRd3B, -NO2, -C(O)Ra3B, -C(O)ORa3B, -C(O)NRc3BRd3B, -C(O)NRc3B(ORa3B), -OC(O)Ra3B, -OC(O)NRc3BRd3B, -OC(O)ORa3B, -OS(O)2Rb3B, -OS(O)2NRc3BRd3B, -NRc3BC(O)Ra3B, -NRc3BC(O)ORa3B, -NRc3BC(O)NRc3BRd3B, -NRc3BS(O)2Rb3B, -NRc3BS(O)2NRc3BRd3B, -NRc3BORa3B, -NRc3BS(O)Rb3B, -NRc3BS(O)NRc3BRd3B, -S(O)Rb3B, -S(O)2Rb3B, -S(O)NRc3BRd3B, -54057-0034W01 / SNV0025-W01 PATENT

[0104] S(O)2NRc3BRd3B, -C(=NRe3B)Ra3B, -C(=NRe3B)NRc3BRd3B, -NRc3BC(=NRe3B)Ra3B, -NRc3BC(=NRe3B)NRc3BRd3B, -NRc3BS(O)(=NRe3B)Rb3B, -NRc3BS(O)(=NRe3B)NRc3BRd3B, -OS(O)(=NRe3B)Rb3B, -S(O)(=NRe3B)Rb3B, -S(O)(=NRe3B)NRc3BRd3B, -C(O)NRc3BS(O)2Rb3B, -C(O)NRc3BS(O)2NRc3BRd3B, -S(O)2NRc3BC(O)Rb3B, -NRc3BS(O)NRc3BC(O)Rb3B, and -P(O)Rf3BRg3B, wherein the Ci-6 alkyl, Ci-6 alkylidenyl, 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 R3Bare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0105] each Ra3B, Rc3B, and Rd3Bis 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 Ra3B, Rc3B, and Rd3Bare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0106] or, any Rc3Band Rd3Battached 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;

[0107] each Rb3Bis 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 (5-54057-0034W01 / SNV0025-W01 PATENT

[0108] 10 membered heteroaryl)-Ci-4 alkyl of Rb3Bare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;

[0109] each Re3Bis 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;

[0110] each RfiBand Rg3Bare 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;

[0111] each RGis independently selected from H, OH, CN, halo, oxo, C1-4 alkyl, C1-4 alkylidenyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, cyano-Ci-4 alkyl, HO-C1-4 alkyl, C1-4 alkoxy-Ci-4 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-3 alkylamino, di(Ci-3 alkyl)amino, thio, C1-3 alkylthio, C1-3 alkylsulfinyl, C1-3 alkyl sulfonyl, carbamyl, C1-3 alkylcarbamyl, di(Ci-3 alkyl)carbamyl, carboxy, C1-3 alkyl carbonyl, C1-3 alkoxycarbonyl, C1-3 alkylcarbonyloxy, C1-3 alkylcarbonylamino, C1-3 alkoxycarbonylamino, aminocarbonyloxy, C1-3 alkylaminocarbonyloxy, di(Ci-3 alkyl)aminocarbonyloxy, C1-3 alkylsulfonylamino, aminosulfonyl, C1-3 alkylaminosulfonyl, di(Ci-3 alkyl)aminosulfonyl, aminosulfonylamino, C1-3 alkylaminosulfonylamino, di(Ci-3 alkyl)aminosulfonylamino, aminocarbonylamino, C1-3 alkylaminocarbonylamino, and di (C 1 -3 alky 1 )aminocarb onyl amino ;

[0112] provided that -(L2)n-R2is not NH2 or OH.

[0113] In some embodiments, X1is C.

[0114] In some embodiments, X1is N.

[0115] In some embodiments, X2is C.

[0116] In some embodiments, X2is N.

[0117] In some embodiments, X3is C.

[0118] In some embodiments, X3is N.

[0119] In some embodiments, X4is C.54057-0034W01 / SNV0025-W01 PATENT

[0120] In some embodiments, X4is N.

[0121] In some embodiments, X1, X3, and X4are each C; and X2is N.

[0122] In some embodiments, m is 0, 1, 2, or 3.

[0123] In some embodiments, m is 1 or 2.

[0124] In some embodiments, m is 1.

[0125] In some embodiments, each L1is independently selected from Ci-6 alkylene, wherein each Ci-6 alkylene is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RL2substituents.

[0126] In some embodiments, each L1is independently selected from Ci-6 alkylene. In some embodiments, each L1is independently selected from C1-3 alkylene, wherein each C1-3 alkylene is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RL2substituents.

[0127] In some embodiments, each L1is independently selected from C1-3 alkylene. In some embodiments, each L1is -CH2-.

[0128] In some embodiments, n is 0, 1, 2, or 3.

[0129] In some embodiments, n is 1 or 2.

[0130] In some embodiments, n is 1.

[0131] In some embodiments, each L2is independently selected from C1-6 alkylene, wherein each C1-6 alkylene is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RL2substituents.

[0132] In some embodiments, each L2is independently selected from C1-6 alkylene. In some embodiments, each L2is independently selected from C1-3 alkylene, wherein each C1-3 alkylene is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RL2substituents.

[0133] In some embodiments, each L2is independently selected from C1-3 alkylene. In some embodiments, each L2is -CH2-.

[0134] In some embodiments, each R2is independently selected from H, halo, 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 R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents.

[0135] In some embodiments, each R2is independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl.54057-0034W01 / SNV0025-W01 PATENT

[0136] In some embodiments, each R2is independently selected from H and Ci-6 alkyl.

[0137] In some embodiments, each R2is independently selected from H and C1-3 alkyl.

[0138] In some embodiments, each R2is H.

[0139] In some embodiments, n is 1 and -L2-R2is -CH3.

[0140] In some embodiments, Ring B is selected from Ce-io aryl and 5-10 membered heteroaryl.

[0141] In some embodiments, Ring B is selected from phenyl and 5-6 membered heteroaryl.

[0142] In some embodiments, Ring B is Ce-io aryl.

[0143] In some embodiments, Ring B is phenyl.

[0144] In some embodiments, p is 0, 1, 2, 3, or 4.

[0145] In some embodiments, p is 1, 2, or 3.

[0146] In some embodiments, p is 1 or 2.

[0147] In some embodiments, p is 1.

[0148] In some embodiments, p is 2.

[0149] In some embodiments, each R1is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, and -ORal, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1Asubstituents.

[0150] In some embodiments, each R1is independently selected from halo, C1-6 alkyl, C 2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, and -ORal.

[0151] In some embodiments, each R1is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, and -ORal, wherein the C1-6 alkyl and C1-6 haloalkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1Asubstituents.

[0152] In some embodiments, each R1is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, and -ORal.

[0153] In some embodiments, each R1is independently selected from halo and -ORal. In some embodiments, each Ralis independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl.54057-0034W01 / SNV0025-W01 PATENT

[0154] In some embodiments, each Ralis independently selected from H, Ci-6 alkyl, and Ci-6 haloalkyl.

[0155] In some embodiments, each Ralis independently selected from Ci-6 alkyl and Ci-6 haloalkyl.

[0156] In some embodiments, each Ralis independently selected from Ci-6 haloalkyl. In some embodiments, each Ralis independently selected from C1-3 haloalkyl. In some embodiments, each Ralis independently selected from

[0157] difluorom ethyl.

[0158] In some embodiments, each R1is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, and -ORal, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1Asubstituents; and

[0159] each Ralis independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl.

[0160] In some embodiments, each R1is independently selected from halo, C1-6 alkyl, C 2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, and -ORal; and

[0161] each Ralis independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl.

[0162] In some embodiments, each R1is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, and -ORal, wherein the C1-6 alkyl and C1-6 haloalkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1Asubstituents; and

[0163] each Ralis independently selected from H, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, each R1is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, and -ORal; and

[0164] each Ralis independently selected from H, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, each R1is independently selected from halo and -ORal; and

[0165] each Ralis independently selected from H and C1-6 haloalkyl.

[0166] In some embodiments, each R1is independently selected from halo and -ORal; and

[0167] each Ralis independently selected from C1-6 haloalkyl.54057-0034W01 / SNV0025-W01 PATENT

[0168] In some embodiments, each R1is independently selected from halo and -ORal; and

[0169] each Ralis independently selected from C1-3 haloalkyl.

[0170] In some embodiments, each R1is independently selected from fluoro and difluorom ethoxy.

[0171] In some embodiments, R2and one of R1, together with the atoms to which they are attached to, form a 6-14 membered heterocycloalkyl group, wherein the 6-14 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1Asubstituents.

[0172] In some embodiments, R2and one of R1, together with the atoms to which they are attached to, form a 6-14 membered heterocycloalkyl group.

[0173] In some embodiments, R2and one of R1, together with the atoms to which they are attached to, form a 6-10 membered heterocycloalkyl group.

[0174] In some embodiments, R2and one of R1, together with the atoms to which they are attached to, form a tetrahydrooxazocine group.

[0175] In some embodiments, Ring C is selected from phenyl and 5-14 membered heterocycloalkyl.

[0176] In some embodiments, Ring C is selected from phenyl and 5-7 membered heterocycloalkyl.

[0177] In some embodiments, Ring C is selected from phenyl and piperidinyl.

[0178] In some embodiments, Ring C is phenyl.

[0179] In some embodiments, Ring C is 5-14 membered heterocycloalkyl.

[0180] In some embodiments, Ring C is 5-7 membered heterocycloalkyl.

[0181] In some embodiments, Ring C is 6-membered heterocycloalkyl.

[0182] In some embodiments, Ring C is piperidinyl.

[0183] In some embodiments, Y1is C.

[0184] In some embodiments, Y1is N.

[0185] In some embodiments, Y2is C.

[0186] In some embodiments, Y2is N.

[0187] In some embodiments, L4is -CRL4=CRL5-.

[0188] In some embodiments, RL4is H or C1-6 alkyl.

[0189] In some embodiments, RL4is H or C1-3 alkyl.54057-0034W01 / SNV0025-W01 PATENT

[0190] In some embodiments, RL4is H.

[0191] In some embodiments, RL5is H or Ci-6 alkyl.

[0192] In some embodiments, RL5is H or C1-3 alkyl.

[0193] In some embodiments, RL5is H.

[0194] In some embodiments:

[0195] L4is -CRL4=CRL5-;

[0196] RL4is H or C1-6 alkyl; and

[0197] RL5is H or C1-6 alkyl.

[0198] In some embodiments:

[0199] L4is -CRL4=CRL5-;

[0200] RL4is H or C1-3 alkyl; and

[0201] RL5is H or C1-3 alkyl.

[0202] In some embodiments, L4is -CH=CH-.

[0203] In some embodiments, q is 0, 1, 2, or 3.

[0204] In some embodiments, q is 1 or 2.

[0205] In some embodiments, q is 1.

[0206] In some embodiments, q is 2.

[0207] In some embodiments, each L3is a bond.

[0208] In some embodiments, each R3is independently selected from C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -ORa3, -NRc3Rd3, -C(O)Ra3, -C(O)ORa3, and -C(O)NRc3Rd3, wherein the C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents.

[0209] In some embodiments, each R3is independently selected from C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -ORa3, -NRc3Rd3, -C(O)Ra3, -C(O)ORa3, and -C(O)NRc3Rd3, wherein the C3-10 cycloalkyl, Ce-io aryl, 4-1054057-0034W01 / SNV0025-W01 PATENT

[0210] membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R3are each optionally substituted with 1 or 2 independently selected R3Asubstituents.

[0211] In some embodiments, each R3is independently selected from C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and -C(O)Ra3, wherein the C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents.

[0212] In some embodiments, each R3is independently selected from C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and -C(O)Ra3, wherein the C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of R3are each optionally substituted with 1 or 2 independently selected R3Asubstituents.

[0213] In some embodiments, each R3is independently selected from Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and -C(O)Ra3, wherein the Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of R3are each optionally substituted with 1 or 2 independently selected R3Asubstituents.

[0214] In some embodiments, each R3is independently selected from phenyl, 4-7 membered heterocycloalkyl, 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl, and -C(O)Ra3, wherein the phenyl, 4-7 membered heterocycloalkyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered bicyclic heteroaryl of R3are each optionally substituted with 1 or 2 independently selected R3Asubstituents.

[0215] In some embodiments, each Ra3, Rc3, and Rd3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl of Ra3, Rc3, and Rd3are each optionally substituted with 1, 2, 3, or 4 independently selected R3Bsubstituents

[0216] In some embodiments, each Ra3, Rc3, and Rd3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl of Ra3, Rc3, and Rd3are each optionally substituted with 1, 2, 3, or 4 independently selected R3Bsubstituents.54057-0034W01 / SNV0025-W01 PATENT

[0217] In some embodiments, each Ra3, Rc3, and Rd3is independently selected from H and Ci-6 alkyl, wherein the Ci-6 alkyl of Ra3, Rc3, and Rd3is optionally substituted with amino.

[0218] In some embodiments, each Ra3is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl of Ra3are each optionally substituted with 1, 2, 3, or 4 independently selected R3Bsubstituents.

[0219] In some embodiments, each Ra3is independently selected from H and C1-6 alkyl, wherein the C1-6 alkyl of Ra3is optionally substituted with amino.

[0220] In some embodiments, each R3is independently selected from phenyl, pyrrolidinyl, pyrazolyl, pyrimidinyl, oxazolyl, thiazolyl, triazolyl, indazolyl, and aminomethylcarbonyl, wherein the phenyl, pyrrolidinyl, pyrazolyl, pyrimidinyl, oxazolyl, thiazolyl, triazolyl, and indazolyl of R3are each optionally substituted with 1 or 2 independently selected R3Asubstituents.

[0221] In some embodiments, each R3is independently selected from C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -ORa3, -NRc3Rd3, -C(O)Ra3, -C(O)ORa3, and -C(O)NRc3Rd3, wherein the C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; and

[0222] each Ra3, Rc3, and Rd3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl of Ra3, Rc3, and Rd3are each optionally substituted with 1, 2, 3, or 4 independently selected R3Bsubstituents.

[0223] In some embodiments, each R3is independently selected from C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and -C(O)Ra3, wherein the C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents;54057-0034W01 / SNV0025-W01 PATENT

[0224] each Ra3is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl of Ra3are each optionally substituted with 1, 2, 3, or 4 independently selected R3Bsubstituents.

[0225] In some embodiments, each R3is independently selected from Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and -C(O)Ra3, wherein the C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of R3are each optionally substituted with 1 or 2 independently selected R3Asubstituents;

[0226] each Ra3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl of Ra3are each optionally substituted with 1, 2, 3, or 4 independently selected R3Bsubstituents.

[0227] In some embodiments, each R3is independently selected from Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and -C(O)Ra3, wherein the C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of R3are each optionally substituted with 1 or 2 independently selected R3Asubstituents;

[0228] each Ra3is independently selected from H and C1-6 alkyl, wherein the C1-6 alkyl of Ra3is optionally substituted with amino.

[0229] In some embodiments, each R3is independently selected from phenyl, 4-7 membered heterocycloalkyl, 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl, and -C(O)Ra3, wherein the phenyl, 4-7 membered heterocycloalkyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered bicyclic heteroaryl of R3are each optionally substituted with 1 or 2 independently selected R3Asubstituents; and

[0230] each Ra3is independently selected from H and C1-6 alkyl, wherein the C1-6 alkyl of Ra3is optionally substituted with amino.

[0231] In some embodiments, each R3is independently selected from phenyl, pyrrolidinyl, pyrazolyl, pyrimidinyl, oxazolyl, thiazolyl, triazolyl, indazolyl, and aminomethylcarbonyl, wherein the phenyl, pyrrolidinyl, pyrazolyl, pyrimidinyl,54057-0034W01 / SNV0025-W01 PATENT

[0232] oxazolyl, thiazolyl, triazolyl, and indazolyl of R3are each optionally substituted with 1 or 2 independently selected R3Asubstituents.

[0233] In some embodiments, each R3Ais independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, -ORa3A, and -NRc3ARd3A, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of R3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Bsubstituents.

[0234] In some embodiments, each R3Ais independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, -ORa3A, and -NRc3ARd3A, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of R3Aare each optionally substituted with 1 or 2 independently selected R3Bsubstituents.

[0235] In some embodiments, each R3Ais independently selected from C1-6 alkyl and -ORa3A, wherein the C1-6 alkyl of R3Aare each optionally substituted with 1 or 2 independently selected R3Bsubstituents.

[0236] In some embodiments, each R3Ais independently selected from hydroxy, methyl, isopropyl, and isobutyl, wherein the methyl, isopropyl, and isobutyl of R3Aare each optionally substituted with 1 or 2 independently selected R3Bsubstituents.

[0237] In some embodiments, each R3Ais independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, -ORa3A, and -NRc3ARd3A, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of R3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Bsubstituents; and each Ra3A, Rc3A, and Rd3Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl.

[0238] In some embodiments, each R3Ais independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, -ORa3A, and -NRc3ARd3A, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of R3Aare each optionally substituted with 1 or 2 independently selected R3Bsubstituents; and

[0239] each Ra3A, Rc3A, and Rd3Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl.

[0240] In some embodiments, each R3Ais independently selected from C1-6 alkyl and -ORa3A, wherein the C1-6 alkyl of R3Aare each optionally substituted with 1 or 2 independently selected R3Bsubstituents; and

[0241] each Ra3Ais independently selected from H and C1-6 alkyl.54057-0034W01 / SNV0025-W01 PATENT

[0242] In some embodiments, each R3Ais independently selected from hydroxy, methyl, isopropyl, and isobutyl, wherein the methyl, isopropyl, and isobutyl of R3Aare each optionally substituted with 1 or 2 independently selected R3Bsubstituents.

[0243] In some embodiments, each R3Bis independently selected from -CN, -ORa3B, -NRc3BRd3B, -C(O)Ra3B, -C(O)ORa3B, and -C(O)NRc3BRd3B

[0244] In some embodiments, each R3Bis independently selected from -CN, -ORa3B, -NRc3BRd3B, and -C(O)NRc3BRd3B

[0245] In some embodiments, each Ra3B, Rc3B, and Rd3Bis independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl

[0246] In some embodiments, each Ra3B, Rc3B, and Rd3Bis independently selected from H and C1-6 alkyl.

[0247] In some embodiments, each R3Bis independently selected from -CN, -ORa3B, -NRc3BRd3B, -C(O)Ra3B, -C(O)ORa3B, and -C(O)NRc3BRd3B; and

[0248] each R.a3B, Rc3B, and Rd3Bis independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl.

[0249] In some embodiments, each R3Bis independently selected from -CN, -ORa3B, -NRc3BRd3B, and -C(O)NRc3BRd3B; and

[0250] each R.a3B, R.c3B, and Rd3Bis independently selected from H and C1-6 alkyl. In some embodiments, each R3Bis independently selected from -CN, -OH, -NH2, C(O)NH2, C(O)NHCH3, and C(O)N(CH3)2.

[0251] In some embodiments, each R3is independently selected from

[0252]

[0253]

[0254] 54057-0034W01 / SNV0025-W01 PATENT

[0255] In some embodiments:

[0256] m is 1, 2, or 3;

[0257] n is 1, 2, or 3;

[0258] p is 1, 2, or 3;

[0259] q is 1, 2, or 3;

[0260] X1is N or C;

[0261] X2is N or C;

[0262] X3is N or C;

[0263] X4is N or C;

[0264] wherein one of X1, X2, X3, and X4is N, and three of X1, X2, X3, and X4are C; Y1is N or C;

[0265] Y2is N or C;

[0266] Ring A is a 5-membered heteroaryl;

[0267] Ring B is selected from Ce-io aryl and 5-10 membered heteroaryl;

[0268] Ring C is selected from phenyl and 5-14 membered heterocycloalkyl; each L1and L2are each independently selected from Ci-6 alkylene, wherein each Ci-6 alkylene is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RL2substituents;

[0269] each L3is a bond;

[0270] L4is -CRL4=CRL5-;

[0271] RL4is H or Ci-6 alkyl;

[0272] RL5is H or Ci-6 alkyl;

[0273] each R1is independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, and -ORal, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1Asubstituents;

[0274] each Ralis independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;

[0275] each R2is independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; or54057-0034W01 / SNV0025-W01 PATENT

[0276] R2and one of R1, together with the atoms to which they are attached to, form a 6-14 membered heterocycloalkyl group, wherein the 6-14 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1Asubstituents each R3is independently selected from C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4alkyl, -ORa3, -NRc3Rd3, -C(O)Ra3, -C(O)ORa3, and -C(O)NRc3Rd3, wherein the C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents;

[0277] each Ra3, Rc3, and Rd3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl of Ra3, Rc3, and Rd3are each optionally substituted with 1, 2, 3, or 4 independently selected R3Bsubstituents;

[0278] each R3Ais independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, -ORa3A, and -NRc3ARd3A, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of R3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Bsubstituents;

[0279] each Ra3A, Rc3A, and Rd3Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl;

[0280] each R3Bis independently selected from -CN, -ORa3B, -NRc3BRd3B, -C(O)Ra3B, -C(O)ORa3B, and -C(O)NRc3BRd3B; and

[0281] each Ra3B, Rc3B, and Rd3Bis independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl.

[0282] In some embodiments:

[0283] m is 1 or 2;

[0284] n is 1 or 2;

[0285] p is 1 or 2;

[0286] q is 1 or 2;

[0287] X1, X3, and X4are each C; and X2is N;54057-0034W01 / SNV0025-W01 PATENT

[0288] Y1is C;

[0289] Y2is C;

[0290] Ring A is a 5-membered heteroaryl;

[0291] Ring B is phenyl;

[0292] Ring C is selected from phenyl and piperidinyl;

[0293] each L1and L2are each independently selected from C1-3 alkylene;

[0294] each L3is a bond;

[0295] L4is -CRL4=CRL5-;

[0296] RL4is H or C1-6 alkyl;

[0297] RL5is H or C1-6 alkyl;

[0298] each R1is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, and -ORal, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1Asubstituents;

[0299] each Ralis independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;

[0300] each R2is independently selected from H and C1-6 alkyl; or

[0301] R2and one of R1, together with the atoms to which they are attached to, form a 6-14 membered heterocycloalkyl group, wherein the 6-14 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1Asubstituents each R3is independently selected from C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4alkyl, -ORa3, -NRc3Rd3, -C(O)Ra3, -C(O)ORa3, and -C(O)NRc3Rd3, wherein the C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents;

[0302] each Ra3, Rc3, and Rd3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-654057-0034W01 / SNV0025-W01 PATENT

[0303] alkenyl, and C2-6 alkynyl of Ra3, Rc3, and Rd3are each optionally substituted with 1, 2, 3, or 4 independently selected R3Bsubstituents;

[0304] each R3Ais independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, -ORa3A, and -NRc3ARd3A, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of R3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Bsubstituents;

[0305] each Ra3A, Rc3A, and Rd3Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl;

[0306] each R3Bis independently selected from -CN, -ORa3B, -NRc3BRd3B, -C(O)Ra3B, -C(O)ORa3B, and -C(O)NRc3BRd3B; and

[0307] each Ra3B, Rc3B, and Rd3Bis independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl.

[0308] In some embodiments, the compound of Formula I is a compound of Formula II:

[0309]

[0310] or a pharmaceutically acceptable salt thereof.

[0311] In some embodiments, the compound of Formula I is a compound of Formula Ila:

[0312]

[0313] Ila

[0314] or a pharmaceutically acceptable salt thereof.54057-0034W01 / SNV0025-W01 PATENT

[0315] In some embodiments, the compound of Formula I is a compound of Formula III:

[0316]

[0317] or a pharmaceutically acceptable salt thereof.

[0318] In some embodiments, the compound of Formula I is a compound of Formula Illa:

[0319]

[0320] or a pharmaceutically acceptable salt thereof.

[0321] In some embodiments, the compound of Formula I is a compound of Formula IV:

[0322]

[0323] or a pharmaceutically acceptable salt thereof.

[0324] In some embodiments, the compound of Formula I is a compound of Formula IVa:54057-0034W01 / SNV0025-W01 PATENT

[0325]

[0326] or a pharmaceutically acceptable salt thereof.

[0327] In some embodiments, the compound of Formula I is a compound of Formula V:

[0328]

[0329] or a pharmaceutically acceptable salt thereof.

[0330] In some embodiments, the compound of Formula I is a compound of Formula Va:

[0331]

[0332] or a pharmaceutically acceptable salt thereof.

[0333] In some embodiments, the compound provided herein is selected from:

[0334] 2-(5-(l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH-naphtho[l,2-d]imidazol-7-yl)pyrimidin-2-yl)propan-2-ol;54057-0034W01 / SNV0025-W01 PATENT

[0335] l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-7-(l -methyl- lH-pyrazol-4-yl)- lH-naphtho[ 1 ,2-d]imidazole;

[0336] 1 -(4-(l -(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl- lH-naphtho[ 1 ,2-d]imidazol-7-yl)-lH-pyrazol-l-yl)-2-methylpropan-2-ol;

[0337] 1-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-7-(lH-pyrazol-4-yl)-lH-naphthof 1 ,2-d]imidazole;

[0338] (3 -( 1 -(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl- lH-naphtho[ 1 ,2-d]imidazol-7-yl)phenyl)methanamine;

[0339] 2-(4-(l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH-naphtho[l,2-d]imidazol-7-yl)-lH-pyrazol-l-yl)-2-methylpropanenitrile;

[0340] 2-(4-(l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH-naphtho[l,2-d]imidazol-7-yl)-lH-pyrazol-l-yl)-2-methylpropanamide;

[0341] l-(2-(difluoromethoxy)-6-fluorobenzyl)-7-(l-isopropyl-lH-pyrazol-4-yl)-2-m ethyl- lH-naphtho[ 1 ,2-d]imidazole;

[0342] 5-(l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH-naphtho[l,2-d]imidazol-7-yl)-2-methyloxazole;

[0343] 5-(l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH-naphtho[l,2-d]imidazol-7-yl)-2-methylthi azole;

[0344] l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-7-(2-methyl-2H-l,2,3-tri azol -4-yl)- lH-naphtho[ 1 ,2-d]imidazole;

[0345] l-(2-(difluoromethoxy)-6-fluorobenzyl)-7-(lH-indazol-6-yl)-2-methyl-lH-naphthof 1 ,2-d]imidazole;

[0346] (5-(l -(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl- lH-naphtho[ 1 ,2-d]imidazol-7-yl)oxazol-2-yl)methanol;

[0347] 1-(l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH-naphtho[l,2-d]imidazol-7-yl)pyrrolidin-3-ol;

[0348] 2-(4-(l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH-naphtho[l,2-d]imidazol-7-yl)-lH-pyrazol-l-yl)-N,N,2-trimethylpropanamide;

[0349] 2-(4-(l-(difluoromethoxy)-5,16-dihydro-7H-benzo[f]naphtho[2',r:4,5]imidazo[2,l-c][l,4]oxazocin-12-yl)-lH-pyrazol-l-yl)-N,2-dimethylpropanamide;54057-0034W01 / SNV0025-W01 PATENT

[0350] 2-(4-(l-(difluoromethoxy)-5,16-dihydro-7H-benzo[f]naphtho[2',r:4,5]imidazo[2,l-c][l,4]oxazocin-12-yl)-lH-pyrazol-l-yl)-N,N,2-trimethylpropanamide;

[0351] 2-(4-(l-(difluoromethoxy)-5,16-dihydro-7H-benzo[f]naphtho[2',r:4,5]imidazo[2,l-c][l,4]oxazocin-12-yl)-lH-pyrazol-l-yl)-2-methylpropanamide; and

[0352] 2-amino-l-(l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-l, 6,8,9-tetrahydro-7H-imidazo[4,5-f]isoquinolin-7-yl)ethan-l-one;

[0353] or a pharmaceutically acceptable salt thereof.

[0354] In some embodiments, the compound provided herein is selected from:

[0355] 2-(5-(l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH-naphtho[l,2-d]imidazol-7-yl)pyrimidin-2-yl)propan-2-ol;

[0356] l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-7-(l -methyl- lH-pyrazol-4-yl)- lH-naphtho[ 1 ,2-d]imidazole;

[0357] 1 -(4-(l -(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl- lH-naphtho[ 1 ,2-d]imidazol-7-yl)-lH-pyrazol-l-yl)-2-methylpropan-2-ol;

[0358] 1-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-7-(lH-pyrazol-4-yl)-lH-naphthof 1 ,2-d]imidazole;

[0359] (3 -( 1 -(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl- lH-naphtho[ 1 ,2-d]imidazol-7-yl)phenyl)methanamine;

[0360] 2-(4-(l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH-naphtho[l,2-d]imidazol-7-yl)-lH-pyrazol-l-yl)-2-methylpropanenitrile;

[0361] 2-(4-(l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH-naphtho[l,2-d]imidazol-7-yl)-lH-pyrazol-l-yl)-2-methylpropanamide;

[0362] l-(2-(difluoromethoxy)-6-fluorobenzyl)-7-(l-isopropyl-lH-pyrazol-4-yl)-2-m ethyl- lH-naphtho[ 1 ,2-d]imidazole;

[0363] 5-(l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH-naphtho[l,2-d]imidazol-7-yl)-2-methyloxazole;

[0364] 5-(l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH-naphtho[l,2-d]imidazol-7-yl)-2-methylthi azole;

[0365] l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-7-(2-methyl-2H-l,2,3-tri azol -4-yl)- lH-naphtho[ 1 ,2-d]imidazole;54057-0034W01 / SNV0025-W01 PATENT

[0366] 1-(2-(difluoromethoxy)-6-fluorobenzyl)-7-(lH-indazol-6-yl)-2-methyl-lH-naphthof 1 ,2-d]imidazole;

[0367] (5-(l -(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl- lH-naphtho[ 1 ,2-d]imidazol-7-yl)oxazol-2-yl)methanol;

[0368] (R)-l -(1 -(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl- lH-naphtho[ 1 ,2-d]imidazol-7-yl)pyrrolidin-3-ol;

[0369] 2-(4-(l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH-naphtho[l,2-d]imidazol-7-yl)-lH-pyrazol-l-yl)-N,N,2-trimethylpropanamide;

[0370] 2-(4-(l-(difluoromethoxy)-5,16-dihydro-7H-benzo[f]naphtho[2',r:4,5]imidazo[2,l-c][l,4]oxazocin-12-yl)-lH-pyrazol-l-yl)-N,2-dimethylpropanamide;

[0371] 2-(4-(l-(difluoromethoxy)-5,16-dihydro-7H-benzo[f]naphtho[2',r:4,5]imidazo[2,l-c][l,4]oxazocin-12-yl)-lH-pyrazol-l-yl)-N,N,2-trimethylpropanamide;

[0372] 2-(4-(l-(difluoromethoxy)-5,16-dihydro-7H-benzo[f]naphtho[2',r:4,5]imidazo[2,l-c][l,4]oxazocin-12-yl)-lH-pyrazol-l-yl)-2-methylpropanamide; and

[0373] 2-amino-l-(l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-l, 6,8,9-tetrahydro-7H-imidazo[4,5-f]isoquinolin-7-yl)ethan-l-one;

[0374] or a pharmaceutically acceptable salt thereof.

[0375] 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.

[0376] At various places in the present specification, divalent linking substituents are described. It is specifically intended that each divalent linking substituent include both the forward and backward forms of the linking substituent. For example, -NR(CR’R”)n- includes both -NR(CR’R”)n- and -(CR’R”)nNR-. Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups.54057-0034W01 / SNV0025-W01 PATENT

[0377] 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.

[0378] 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.

[0379] As used herein, the phrase “each ‘variable’ is independently selected from” means substantially the same as wherein “at each occurrence ‘variable’ is selected from.”

[0380] 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.

[0381] As used herein, the term “Cn-m alkyl”, employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (iPr), n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-l-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. The term “Cn-m alkyl” is understood to include deuterated analogs of saturated hydrocarbon groups as defined herein, including but not limited to, groups such as trideuteromethyl (CD3), pentadeuteroethyl (CD2CD3), and the like. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, from 2 to 6 carbon atoms, from 2 to 4 carbon atoms, from 2 to 3 carbon atoms, or 1 to 2 carbon atoms.

[0382] As used herein, “Cn-m alkylidenyl” refers to an alkylidene group of formula R= and having n to m carbons, wherein R refers to an alkyl group as defined above.54057-0034W01 / SNV0025-W01 PATENT

[0383] Example alkylidenyl groups include, but are not limited to, methylidenyl (H2C=), ethylidenyl (CH3CH=), n-propylidenyl (CH3CH2CH=), 2-propylidenyl ((CH3)2C=), and the like. For example, in the compound below, the alkylidene group (methylidenyl) is enclosed by the box which is indicated by the arrow.

[0384]

[0385] The term “Cn-m alkylidenyl” is understood to include deuterated analogs of alkylidene groups as defined herein, including but not limited to, groups such as dideuteromethylidenyl (D2C=), tetradeuteroethylidenyl (CD3CD=), and the like.

[0386] As used herein, “Cn-m alkenyl” refers to an alkyl group having one or more double carbon-carbon bonds and having n to m carbons. Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. The term “Cn-m alkenyl” is understood to include deuterated analogs of alkenyl groups as defined herein, including but not limited to, groups such as trideuteroethenyl (-CD=CD2), tetradeuteropropenyl, (-CD=CD-CD2), and the like.

[0387] As used herein, “Cn-m alkynyl” refers to an alkyl group having one or more triple carbon-carbon bonds and having n to m carbons. Example alkynyl groups include, but are not limited to, ethynyl, propyn-l-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. The term “Cn-m alkynyl” is understood to include deuterated analogs of alkynyl groups as defined herein, including but not limited to, groups such as deuteroethynyl (-C=CD), trideuteropropyn-l-yl, (-OCCD3), and the like.

[0388] As used herein, the term “Cn-m alkoxy”, employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group has n to m carbons. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tertbutoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. The term “Cn-m alkoxy” is understood to include deuterated analogs of the alkyl moiety of the alkoxy groups as defined herein, including but not limited54057-0034W01 / SNV0025-W01 PATENT

[0389] to, groups such as trideuteromethoxy (-OCD3), pentadeuteroethoxy (-OCD2CD3), and the like.

[0390] As used herein, “Cn-m haloalkoxy”, employed alone or in combination with other terms, refers to a group of formula -O-(haloalkyl), wherein the haloalkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. An example haloalkoxy group is -OCF3. In some embodiments, the haloalkoxy group is a fluoroalkoxy group. The term “Cn-m haloalkoxy” is understood to include deuterated analogs of the haloalkoxy groups as defined herein.

[0391] As used herein, the term “carbonyl”, employed alone or in combination with other terms, refers to a -C(O)- group.

[0392] As used herein, the term “Cn-m alkylcarbonyl” refers to a group of formula -C(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. The term “Cn-m alkylcarbonyl” is understood to include deuterated analogs of the alkylcarbonyl groups as defined herein.

[0393] As used herein, the term “Cn-m alkyl sulfonyl” refers to a group of formula -S(O)2-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. The term “Cn-m

[0394] alkyl sulfonyl” is understood to include deuterated analogs of the alkylsulfonyl groups as defined herein.

[0395] As used herein, the term “carboxy” refers to a group of formula -C(O)OH. As used herein, the term “amino” refers to a group of formula -NH2.

[0396] As used herein, the term “Cn-m alkylamino”, employed alone or in combination with other terms, refers to a group of formula -NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, alkyl group has 1 to 6 or 1 to 4 carbon atoms. Example Cn-m alkylamino groups include methylamino, ethylamino, propylamino (e.g., n-propylamino and isopropylamino), and the like. The term “Cn-m alkylamino” is understood to include deuterated analogs of the alkylamino groups as defined herein.

[0397] 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 154057-0034W01 / SNV0025-W01 PATENT

[0398] to 3 carbon atoms. The term “di(Cn-m alkyl)amino” is understood to include deuterated analogs of the di(Cn-m alkyl)amino groups as defined herein.

[0399] As used herein, the term “Cn-m alkoxycarbonyl”, employed alone or in combination with other terms, refers to a group of formula -C(O)O-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. The term “Cn-m alkoxycarbonyl” is understood to include deuterated analogs of the alkoxycarbonyl groups as defined herein.

[0400] As used herein, the term “Cn-m alkylcarbonyl”, employed alone or in combination with other terms, refers to a group of formula -C(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. The term “Cn-m alkylcarbonyl” is understood to include deuterated analogs of the alkylcarbonyl groups as defined herein.

[0401] As used herein, the term “Cn-m alkylcarbonylamino”, employed alone or in combination with other terms, refers to a group of formula -NHC(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. The term “Cn-m alkylcarbonylamino” is understood to include deuterated analogs of the alkylcarbonylamino groups as defined herein.

[0402] As used herein, the term “carbamyl”, employed alone or in combination with other terms, refers to a group of formula -C(O)-NH2.

[0403] As used herein, the term “Cn-m alkylcarbamyl”, employed alone or in combination with other terms, refers to a group of formula -C(O)-NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. The term “Cn-m alkylcarbamyl” is understood to include deuterated analogs of the alkylcarbamyl groups as defined herein.

[0404] As used herein, the term “di-Cn-m alkylcarbamyl”, employed alone or in combination with other terms, refers to a group of formula -C(O)-N(alkyl)2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, the alkyl group independently has 1 to 6 or 1 to 4 carbon atoms. The term “di-Cn-m alkylcarbamyl” is understood to include deuterated analogs of the dialkylcarbamyl groups as defined herein.

[0405] As used herein, the term “thio” refers to a group of formula -SH.54057-0034W01 / SNV0025-W01 PATENT

[0406] As used herein, the term “Cn-m alkylthio”, employed alone or in combination with other terms, refers to a group of formula -S-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. The term “Cn-m alkylthio” is understood to include deuterated analogs of the alkylthio groups as defined herein.

[0407] As used herein, the term “Cn-m alkylsulfinyl”, employed alone or in combination with other terms, refers to a group of formula -S(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. The term “Cn-m alkylsulfinyl” is understood to include deuterated analogs of the alkylsulfinyl groups as defined herein.

[0408] As used herein, the term “Cn-m alkylsulfonyl”, employed alone or in combination with other terms, refers to a group of formula -S(O)2-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. The term “Cn-m alkyl sulfonyl” is understood to include deuterated analogs of the alkylsulfonyl groups as defined herein.

[0409] As used herein, “halosulfanyl” refers to a sulfur group having one or more halogen substituents. Example halosulfanyl groups include pentahalosulfanyl groups such as SFs.

[0410] As used herein, the term “HO-C1-4 alkyl” refers to a group of formula -C1-4 alkylene-OH. The term “HO-C1-4 alkyl” is understood to include deuterated analogs of the HO-C1-4 alkyl groups as defined herein.

[0411] As used herein, the term “C1-4 alkoxy-Ci-4 alkyl” refers to a group of formula -C1-4 alkylene-O-(Ci-4 alkyl). The term “C1-4 alkoxy-Ci-4 alkyl” is understood to include deuterated analogs of the Ci-4alkoxy-Ci-4 alkyl groups as defined herein.

[0412] As used herein, the term “aryl,” employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term “Cn-maryl” refers to an aryl group having from n to m ring carbon atoms. Aryl groups include, e.g, phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, aryl groups have from 5 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl. In some embodiments, the aryl is phenyl. The term “aryl” is understood to include deuterated analogs of the aryl groups as defined herein, including but not54057-0034W01 / SNV0025-W01 PATENT

[0413] limited to, groups such as pentadeuterophenyl (z.e., perdeuterophenyl, phenyl -ds), perdeuteronaphthyl, and the like.

[0414] 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.

[0415] As used herein, “Cn-m haloalkoxy” refers to a group of formula -O-haloalkyl having n to m carbon atoms. Example haloalkoxy groups include OCF3 and OCHF2. In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. The term “Cn-mhaloalkoxy” is understood to include deuterated analogs of the haloalkyl moiety of the haloalkoxy groups as defined herein, including but not limited to, groups such as deuterodifluoromethoxy (-OCDF2), dideuterofluoromethoxy (-OCD2F), and the like.

[0416] As used herein, the term “Cn-m haloalkyl”, employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+l halogen atoms which may be the same or different, where “s” is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Example haloalkyl groups include CF3, C2F5, CHF2, CH2F, CCI3, CHCI2, C2CI5 and the like. The term “Cn-m haloalkyl” is understood to include deuterated analogs of the haloalkyl groups as defined herein, including but not limited to, groups such as deuterodifluoromethyl (-CDF2), dideuterofluoromethyl (-CD2F), and the like.

[0417] As used herein, “hydroxyl” or “hydroxy” refer to a group of formula -OH. 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 ring-54057-0034W01 / SNV0025-W01 PATENT

[0418] forming atom of the fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (i.e., C3-10). In some embodiments, the cycloalkyl is a C3-10 monocyclic or bicyclic cycloalkyl. In some embodiments, the cycloalkyl is a C3-7 monocyclic cycloalkyl. In some embodiments, the cycloalkyl is a C4-7 monocyclic cycloalkyl. In some embodiments, the cycloalkyl is a C4-10 spirocycle or bridged cycloalkyl (e.g., abridged bicycloalkyl group). Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcamyl, cubane, adamantane, bicyclo[l.l.l]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl, and the like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The term “cycloalkyl” is understood to include deuterated analogs of the cycloalkyl groups as defined herein, including but not limited to, groups such as perdeuterocyclopropyl, perdeuterocyclobutyl, perdeuterocyclopentyl, perdeuterocyclohexyl, and the like.

[0419] 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 254057-0034W01 / SNV0025-W01 PATENT

[0420] heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl is a 5 membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl group contains 5 to 10, 5 to 7, 3 to 7, or 5 to 6 ringforming atoms. In some embodiments, the heteroaryl group has 1 to 4 ring-forming heteroatoms, 1 to 3 ring-forming heteroatoms, 1 to 2 ring-forming heteroatoms or 1 ring-forming heteroatom. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. Example heteroaryl groups include, but are not limited to, thienyl (or thiophenyl), furyl (or furanyl), pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl and l,2-dihydro-l,2-azaborine, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, azolyl, triazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazofl, 2-b]thiazolyl, purinyl, triazinyl, thieno[3,2-b]pyridinyl, imidazofl, 2-a]pyridinyl, 1,5-naphthyridinyl, lH-pyrazolo[4,3-b]pyridinyl, triazolo[4,3-a]pyridinyl, lH-pyrrolo[3,2-b]pyridinyl, lH-pyrrolo[2,3-b]pyridinyl, pyrazolo[l,5-a]pyridinyl, indazolyl, and the like. The term “heteroaryl” is understood to include deuterated analogs of the heteroaryl groups as defined herein, including but not limited to, groups such as perdeuteropyridinyl, perdeuteropyrazinyl, perdeuteropyrimidinyl, and the like.

[0421] 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 6-54057-0034W01 / SNV0025-W01 PATENT

[0422] membered heterocycloalkyl group is further substituted with a methyl group).

[0423] 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.

[0424] Heterocycloalkyl groups can also include spirocycles and bridged rings (e.g., a 5 to 10 membered bridged biheterocycloalkyl ring having one or more of the ring-forming carbon atoms replaced by a heteroatom independently selected from N, O, S, and B). The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. The term “heterocycloalkyl” is understood to include deuterated analogs of the heterocycloalkyl groups as defined herein, including but not limited to, groups such as perdeuteroazetidinyl, perdeuteropyrrolidinyl, perdeuteropiperidinyl, and the like.

[0425] 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 nonaromatic heterocyclic ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.

[0426] 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 having54057-0034W01 / SNV0025-W01 PATENT

[0427] 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.

[0428] 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. l]hexanyl, azabicyclo[2.2. l]heptanyl, diazabicyclo[2.2. l]heptanyl, azabicyclo[3.1. l]heptanyl, diazabicyclo[3.1. l]heptanyl, azabicyclo[3.2. l]octanyl, diazabicyclo[3.2.1]octanyl, oxobicyclo[2.2.2]octanyl, azabicyclo[2.2.2]octanyl, azaadamantanyl, diazaadamantanyl, oxo-adamantanyl, azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl, azaspiro[3.5]nonanyl, 7-azaspiro[3.5]nonanyl, oxo-azaspiro[3.3]heptanyl, azaspiro[3.4]octanyl, diazaspiro[3 ,4]octanyl, oxo-azaspiro[3 ,4]octanyl, azaspiro[2.5]octanyl, diazaspiro[2.5]octanyl, azaspiro[4.4]nonanyl, diazaspiro[4.4]nonanyl, oxo-azaspiro[4.4]nonanyl, azaspiro[4.5]decanyl, diazaspiro[4.5]decanyl, diazaspiro[4.4]nonanyl, oxo-diazaspiro[4.4]nonanyl, oxo-dihydropyridazinyl, oxo-2,6-diazaspiro[3.4]octanyl, oxohexahydropyrrolo[l,2-a]pyrazinyl, 3-oxopiperazinyl, oxo-pyrrolidinyl, oxo-pyridinyl, and the like.

[0429] As used herein, “Co-Pcycloalkyl-Cn-m alkyl-” refers to a group of formula cycloalkyl-alkylene-, wherein the cycloalkyl has o to p carbon atoms and the alkylene linking group has n to m carbon atoms. The term “Co-Pcycloalkyl-Cn-m alkyl-” is understood to include deuterated analogs of the cycloalkyl and / or alkyl moieties of the Co-Pcycloalkyl-Cn-m alkyl- groups as defined herein.

[0430] 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. The term “Co-Paryl-Cn-m alkyl-” is understood to include deuterated analogs of the aryl and / or alkyl moieties of the Co-Paryl-Cn-m alkyl- groups54057-0034W01 / SNV0025-W01 PATENT

[0431] as defined herein. Example Co-Paryl-Cn-m alkyl- groups include, but are not limited to, phenyl-CH2- (z.e., benzyl).

[0432] As used herein, “heteroaryl-Cn-m alkyl-” refers to a group of formula heteroaryl-alkylene-, wherein alkylene linking group has n to m carbon atoms. The term “heteroaryl-Cn-m alkyl-” is understood to include deuterated analogs of the heteroaryl and / or alkyl moieties of the heteroaryl-Cn-m alkyl- groups as defined herein.

[0433] As used herein “heterocycloalkyl -Cn-m alkyl-” refers to a group of formula heterocycloalkyl-alkylene-, wherein alkylene linking group has n to m carbon atoms. The term “heterocycloalkyl-Cn-m alkyl-” is understood to include deuterated analogs of the heterocycloalkyl and / or alkyl moieties of the heterocycloalkyl -Cn-m alkylgroups as defined herein.

[0434] 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. The terms “alkyl linking group” and “alkylene linking group” are understood to include deuterated analogs of the alkylene groups as defined herein.

[0435] As used herein, a “haloalkyl linking group” or “haloalkylene linking group” is a bivalent straight chain or branched haloalkyl linking group (“haloalkylene group”). Example haloalkylene groups include -CF2-, -C2F4-, -CHF-, -CCI2-, -CHC1-, -C2CI4-, and the like. The terms “haloalkyl linking group” and “haloalkylene linking group” are understood to include deuterated analogs of the haloalkylene groups as defined herein.

[0436] 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. The terms “cycloalkyl linking group” and “cycloalkylene linking group” are54057-0034W01 / SNV0025-W01 PATENT

[0437] understood to include deuterated analogs of the cycloalkylene groups as defined herein.

[0438] As used herein, a “heterocycloalkyl linking group” or “heterocycloalkylene linking group” is a bivalent straight chain or branched heterocycloalkyl linking group (“heterocycloalkylene group”). Examples of “heterocycloalkyl linking groups” or “heterocycloalkylene groups” include azetidin-l,2-diyl, azeti din- 1,3 -diyl, pyrrolidin-1,2-diyl, pyrrolidin- 1,3 -diyl, pyrrolidin-2,3-diyl, piperidin-l,2-diyl, piperidin-l,3-diyl, piperidin-l,4-diyl, piperi din-2, 3 -diyl, piperi din-2, 4-diyl, and the like. The terms “heterocycloalkyl linking group” and “heterocycloalkylene linking group” are understood to include deuterated analogs of the heterocycloalkylene groups as defined herein.

[0439] As used herein, a “heteroaryl linking group” or “heteroarylene linking group” is a bivalent straight chain or branched heteroaryl linking group (“heteroarylene group”). Examples of “heteroaryl linking groups” or “heteroarylene groups” include pyrazol- 1,3 -diyl, imidazol-l,2,-diyl, pyri din-2, 3 -diyl, pyridin-2, 4-diyl, pyridin-3,4-diyl, and the like. The terms “heteroaryl linking group” and “heteroarylene linking group” are understood to include deuterated analogs of the heteroarylene groups as defined herein.

[0440] 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.

[0441] 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.

[0442] 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.

[0443] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended54057-0034W01 / SNV0025-W01 PATENT

[0444] unless otherwise indicated. Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, the compound has the (R)-configuration. In some embodiments, the compound has the (S)-configuration. The Formulas (e.g., Formula I, Formula II, etc.) provided herein include stereoisomers of the compounds.

[0445] 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.

[0446] 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.

[0447] 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 forms54057-0034W01 / SNV0025-W01 PATENT

[0448] 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.

[0449] 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.

[0450] 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.

[0451] 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.

[0452] 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.

[0453] 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.

[0454] 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 of54057-0034W01 / SNV0025-W01 PATENT

[0455] pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present disclosure include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0456] Synthesis

[0457] 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.

[0458] Compounds of formula 1-8 can be synthesized, for example, using a process shown in Scheme I. Compound 1-1 can be converted to 1-2 via nitration reaction with suitable reagents (e.g., fuming HNO3). 1-2 can then be converted to 1-3 via reduction reaction with suitable reagents (e.g., Zn powder). Treating 1-3 with aldehyde 1-4 and suitable reductants (e.g., NaBEECN) can lead to 1-5. 1-5 then can be converted to 1-6 via deprotection reaction with suitable reagents (e.g., HC1). 1-7 can be obtained by treating 1-6 with suitable reagents (e.g., AcOH). 1-7 can be converted to 1-8 via suitable reactions (e.g., transition metal -catalyzed cross-coupling reactions).54057-0034W01 / SNV0025-W01 PATENT

[0459]

[0460] Compounds of formula 11-13 can be synthesized, for example, using a process shown in Scheme II. Compound 1-3 can be converted to II-2 via transition metal-catalyzed cross-coupling reactions (e.g., Suzuki reaction) with suitable reagents (e.g., boronic acid pinacol ester II-l). Treating II-2 with aldehyde II-3 and suitable reductants (e.g., NaBHsCN) can lead to II-4. II-4 can then be converted to II-5 via transition metal-catalyzed cross-coupling reactions with suitable reagents. II-5 can be converted to II-6 via deprotection reaction with suitable reagents (e.g., HC1). II-8 can be obtained by treating II-6 with suitable condensation reagents (e.g., chloride II-7). II-8 can then be converted to II-9 via oxidative cleavage reaction with suitable reagents (e.g., NalCh and OsCh). Treating II-9 with suitable reductants (e.g., NaBT ) can lead to alcohol 11-10. 11-10 can then be converted to 11-11 with suitable bases (e.g., CS2CO3). 11-11 can be hydrolyzed to 11-12 via suitable reagents (e.g., lithium hydroxide monohydrate). 11-12 can be converted to 11-13 via amide coupling reaction with suitable amines.54057-0034W01 / SNV0025-W01 PATENT

[0461] Scheme II.

[0462]

[0463] 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.

[0464] 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 one54057-0034W01 / SNV0025-W01 PATENT

[0465] skilled in the art. The chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[0466] 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.

[0467] 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.

[0468] Methods of Use

[0469] The present disclosure provides uses for compounds and compositions described herein. The compounds described herein can inhibit the activity of tumor necrosis factor-alpha (TNFa). 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 TNFa. In some embodiments, provided compounds and compositions are useful in research as, for example, analytical tools and / or control compounds in biological assays.

[0470] In autoimmune diseases, TNF-a is often overproduced, leading to chronic inflammation and tissue damage. For example, in rheumatoid arthritis, TNF-a contributes to synovial inflammation and joint destruction. Inflammatory bowel disease involves TNF-a-driven inflammation of the gastrointestinal tract.

[0471] Overexpression of TNF-a is also involved in the pathogenesis of psoriasis, a chronic inflammatory skin disorder characterized by hyperproliferation of keratinocytes and an influx of immune cells into the skin. In addition to above-mentioned diseases,54057-0034W01 / SNV0025-W01 PATENT

[0472] overproduction of TNF-a is also implicated in many other human diseases related to chronic inflammation and cell apoptosis, particularly for some neurodegenerative diseases (see e.g., Nat. Rev. Immunol. 2023;23(5):289-303).

[0473] Therapeutic strategies targeting TNF-a, such as monoclonal antibodies (e.g., infliximab, adalimumab, golimumab, and certrolizumab) or receptor decoys (e.g., etanercept), have been effective in treating rheumatoid arthritis, inflammatory bowel disease, and psoriasis by reducing inflammation and mitigating tissue damage [see e.g., Pharmacol. Ther. 2008; 117(2):244-79). These biologies have revolutionized the treatment of many autoimmune diseases and significantly improved clinical outcomes for many patients. However, use of these biologies is also associated with several significant issues (see e.g., Drug Discov. Today. 2022;27(l):3-7). First, patients may develop anti -drug antibodies that lead to diminished efficacy and drug failure.

[0474] Second, TNF-a blockers can increase the risk of infections, which is presumably related to blockade of the TNFR2 that is involved in immune regulation. Third, TNF-a blockers can cause adverse reactions such as injection site reactions due to the immunogenicity of large immune complexes formed by TNF-a and the biologies. Finally, the high cost of TNF-a blockers can be a barrier for many patients, limiting accessibility and long-term treatment sustainability.

[0475] In addition to biologies, small molecule inhibitors have also been explored for blockade of the TNF-a signaling. Recent progress in this area has shown promising advancements, offering potential alternatives to biological TNF-a inhibitors (see e.g., Drug Discov. Today. 2023;28(6): 103575). Unlike biologies, small molecules can be administered orally and are generally less costly to produce, making them more accessible to patients. One significant development in this area is the identification of small molecules that disrupt the TNF-a trimer, preventing its binding to TNF receptors (see e.g., Science. 2005;310(5750): 1022-5). These molecules work by stabilizing TNF-a in an inactive conformation, thereby blocking its ability to initiate inflammatory signaling. Some other small molecule inhibitors have also been designed to lock TNF-a in an inactive conformation that cannot initiate downstream chronic inflammatory signal (see e.g, Nat. Commun. 2019; 10(1): 5795). Despite these advances, it remains challenging to discover a potent and effective drug-like small54057-0034W01 / SNV0025-W01 PATENT

[0476] molecule inhibitor of TNF-a for autoimmune and inflammatory diseases. Thus, there is a need for developing new molecular inhibitors of TNFa.

[0477] Accordingly, in some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject in need thereof. In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject suffering from or susceptible to a disease, disorder, or condition associated with TNFa. 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 TNFa.

[0478] When used as a single agent for monotherapy, the compounds, salts, and compositions of the present disclosure are expected to suppress overexpression of TNF-a induced production of proinflammatory cytokines and chemokines including IL1, IL6, IL8, IL12, IL17, IL22, IL23, MCP1, IFN-y, and GM-CSF etc.

[0479] Overproduction of these proinflammatory proteins play a pivotal role in the initiation and progression of a variety of autoimmune and chronic inflammatory conditions listed above. When used as a single agent for monotherapy, provided compounds and compositions of the present disclosure are expected to block TNF-a induced downstream signaling, inhibit immune cell activation, suppress cell apoptosis, and thereby help restore the balance between pro-inflammatory and anti-inflammatory pathways.

[0480] In some embodiments, the compounds provided herein are useful as TNFa inhibitors. In some embodiments, the present disclosure provides methods of inhibiting TNFa in a subject comprising administering a provided compound or composition. In some embodiments, the present disclosure provides methods of inhibiting TNFa in a biological sample comprising contacting the sample with a provided compound or composition.

[0481] In some embodiments, the present disclosure provides methods of treating a disease, disorder or condition associated with TNFa 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 with54057-0034W01 / SNV0025-W01 PATENT

[0482] mutation of TNFa. 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 TNFa, in a subject in need thereof, comprising administering to the subject a provided compound or composition.

[0483] In some embodiments, the present disclosure provides methods of treating a variety of TNFa-dependent diseases and disorders. For example, in some embodiments the present disclosure provides methods of treating TNF-a overproduction related autoimmune and chronic inflammatory diseases, comprising administering a provided compound or composition to a subject in need thereof. Exemplary diseases include, but are not limited, to plaque psoriasis, rheumatoid arthritis (RA), psoriatic arthritis (PsA), Crohn’s disease (CD), ulcerative colitis (UC), juvenile idiopathic arthritis (JIA), ankylosing spondylitis (AS), hidradenitis suppurativa (HS), uveitis, sarcoidosis, Behcet's disease, granulomatosis with polyangiitis, and neurodegenerative diseases associated with TNF-a related inflammation and apoptosis, including Alzheimer's disease, Parkinson's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Huntington's disease, traumatic brain injury, and neuromyelitis optica spectrum disorder (NMOSD).

[0484] 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.

[0485] 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 least54057-0034W01 / SNV0025-W01 PATENT

[0486] about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, or about 12 months; and less than about 24 months, about 16 months, about 12 months, about 9 months, about 8 months, about 6 months, about 5 months, about 4 months, about 3 months, or about 2 months. In some embodiments, the administering of the compound results in an increase of progression free survival that is at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, or about 12 months; and less than about 24 months, about 16 months, about 12 months, about 9 months, about 8 months, about 6 months, about 5 months, about 4 months, about 3 months, or about 2 months.

[0487] The present disclosure further provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.

[0488] 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.

[0489] 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.

[0490] As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” a TNFa with a compound described herein includes the administration of a compound described herein to an individual or patient, such as a human, having a TNFa, as well as, for example, introducing a compound described herein into a sample containing a cellular or purified preparation containing the TNFa.

[0491] 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.

[0492] 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 the54057-0034W01 / SNV0025-W01 PATENT

[0493] solid forms or salts thereof as disclosed herein that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. An appropriate "effective" amount in any individual case may be determined using techniques known to a person skilled in the art.

[0494] 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.

[0495] 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;

[0496] 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.

[0497] 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.54057-0034W01 / SNV0025-W01 PATENT

[0498] In some embodiments, the compounds of the invention are useful in preventing or reducing the risk of developing any of the diseases referred to herein; e.g., preventing or reducing the risk of developing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.

[0499] 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.

[0500] Combination Therapy

[0501] One or more additional therapeutic agents such as, for example, chemotherapeutics or other anti -cancer agents, anti-inflammatory agents, steroids, immunosuppressants, anesthetics (e.g., for use in combination with a surgical procedure), or other agents useful for treating diseases associated with TNFa 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.

[0502] In some embodiments, a compound, salt, or composition of the present disclosure is administered as part of a combination therapy. As used herein, the term “combination therapy” refers to those situations in which a subject is simultaneously exposed to two or more therapeutic or prophylactic regimens (e.g., two or more therapeutic or prophylactic agents). Exemplary additional therapies include but are not limited to small molecules, biologies, and gene and cell therapies. In some embodiments, the two or more therapeutic agents are administered simultaneously. In some embodiments, the two or more therapeutic agents are administered sequentially.

[0503] In some embodiments, compound, salt, or composition of the present disclosure can be combined with other therapies for treatment of rheumatoid arthritis (RA). Exemplary therapies include, but are not limited to, conventional diseasemodifying antirheumatic drugs (DMARDs), biologies, targeted synthetic DMARDs54057-0034W01 / SNV0025-W01 PATENT

[0504] (small molecules), and supportive treatments. Conventional DMARDs include methotrexate, sulfasalazine, leflunomide, and hydroxychloroquine etc. Biologic DMARDs include etanercept, infliximab, adalimumab, certolizumab pegol, and golimumab and all those available biosimilars. Targeted synthetic DMARDs are mainly JAK inhibitors including tofacitinib, baricitinib, upadacitinib, and filgotinib. The compounds, salts, and compositions of the present disclosure can also be combined with nonsteroidal anti-inflammatory drugs (NSAIDs) including, but not limited to, ibuprofen, naproxen, and celecoxib, and the like. Other potential combination partners include, but are not limited to, tocilizumab, sarilumab, rituximab, abatacept, and anakinra.

[0505] In some embodiments, compound, salt, or composition of the present disclosure can be combined with other therapies for treatment of inflammatory bowel diseases (IBD). Exemplary therapies include, but are not limited to, conventional therapies, biologic therapies, small molecule therapies, and emerging and experimental therapies. Conventional therapies include, but are not limited to, sulfasalazine, mesalamine (5-ASA), olsalazine, balsalazide, prednisone, methylprednisolone, budesonide, hydrocortisone, azathioprine, 6-mercaptopurine (6-MP), methotrexate, cyclosporine, and tacrolimus. Biologic therapies include, but are not limited to, infliximab, adalimumab, certolizumab pegol (e.g., for treatment of Crohn's disease), golimumab (c.g. for treatment of ulcerative colitis), natalizumab, vedolizumab, and ustekinumab. Small molecule therapies include, but are not limited to, JAK inhibitors. Emerging and experimental therapies include, but are not limited to, sphingosine- 1 -phosphate (SIP) receptor modulators, and JAK inhibitors including, but not limited to, tofacitinib, filgotinib, and upadacitinib. In addition, the compounds, salt, and compositions of the present disclosure can also be combined with additional other therapies including, but not limited to, stem cell therapy and fecal microbiota transplantation.

[0506] In some embodiments, a compound, salt, or composition of the present disclosure can be combined with other additional therapies for treatment of psoriasis. Exemplary therapies include, but are not limited to, topical treatments, systemic treatments, biologic therapies, and emerging and experimental therapies. Topical treatments include, but are not limited to, hydrocortisone, betamethasone, clobetasol,54057-0034W01 / SNV0025-W01 PATENT

[0507] triamcinolone, calcipotriene, calcitriol, tazarotene, tacrolimus, and pimecrolimus. Systemic treatments include, but are not limited to, methotrexate, cyclosporine, and acitretin. Biologic therapies include, but are not limited to, etanercept, infliximab, adalimumab, certolizumab pegol, and golimumab, and all those available biosimilars, ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab, tildrakizumab, and risankizumab. Emerging and experimental therapies include, but are not limited to, JAK inhibitors and TYK2 inhibitors including, but not limited to, deucravacitinib, ropsacitinib, and brepocitinib.

[0508] Methods for the safe and effective administration of most of these agents are known to those skilled in the art. In addition, their administration is described in the standard literature.

[0509] In some embodiments, the additional therapeutic agent is administered simultaneously with a compound, salt, or composition provided herein. In some embodiments, the additional therapeutic agent is administered after administration of the compound, salt, or composition provided herein. In some embodiments, the additional therapeutic agent is administered prior to administration of the compound, salt, or composition provided herein. In some embodiments, the compound, salt, or composition provided herein is administered during a surgical procedure. In some embodiments, the compound, salt, or composition provided herein is administered in combination with an additional therapeutic agent during a surgical procedure.

[0510] As provided herein, the additional compounds, inhibitors, agents, etc. can be combined with the compounds, salts, or compositions provided herein in a single or continuous dosage form, or they can be administered simultaneously or sequentially as separate dosage forms.

[0511] Pharmaceutical Formulations and Dosage Forms

[0512] 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 desired54057-0034W01 / SNV0025-W01 PATENT

[0513] 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.

[0514] This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of the invention above in combination with one or more pharmaceutically acceptable carriers. In making the compositions of the invention, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10 % by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0515] 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 be54057-0034W01 / SNV0025-W01 PATENT

[0516] adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.

[0517] 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.

[0518] 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.

[0519] The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.

[0520] 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.

[0521] 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, the54057-0034W01 / SNV0025-W01 PATENT

[0522] 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.

[0523] 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.

[0524] The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.

[0525] 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 status54057-0034W01 / SNV0025-W01 PATENT

[0526] 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.

[0527] 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.

[0528] Labeled Compounds and Assay Methods

[0529] 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 TNFa in tissue samples, including human, and for identifying TNFa by inhibition binding of a labeled compound. Accordingly, the present invention includes TNFa cellular assays that contain such labeled compounds.

[0530] 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,15N,15O,17O,18O,18F,35S,36C1,82Br,75Br,76Br,77Br,123I,124I,125I and131I. The radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro FGFR enzyme labeling and competition assays, compounds that incorporate3H,14C,82Br,1251 ,131I, or35S will generally be most useful. For radio-imaging applicationsnC,18F,125I,123I,124I,131I,75Br,76Br or77Br will generally be most useful.

[0531] 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 disclosure54057-0034W01 / SNV0025-W01 PATENT

[0532] 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-Va) can be perdeuterated.

[0533] In some embodiments, the compound provided herein (e.g., the compound of any of Formulas I-Va), or a pharmaceutically acceptable salt thereof, comprises at least one deuterium atom.

[0534] In some embodiments, the compound provided herein (e.g., the compound of any of Formulas I-Va), or a pharmaceutically acceptable salt thereof, comprises two or more deuterium atoms.

[0535] In some embodiments, the compound provided herein (e.g., the compound of any of Formulas I-Va), or a pharmaceutically acceptable salt thereof, comprises three or more deuterium atoms.

[0536] In some embodiments, for a compound provided herein (e.g., the compound of any of Formulas I-Va), or a pharmaceutically acceptable salt thereof, all of the hydrogen atoms are replaced by deuterium atoms (i.e., the compound is “perdeuterated”).

[0537] 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.

[0538] Synthetic methods for including isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in various studies such as NMR spectroscopy, metabolism experiments, and / or assays.

[0539] 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, 54,54057-0034W01 / SNV0025-W01 PATENT

[0540] 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.

[0541] 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 TNFa. Accordingly, the ability of a test compound to compete with the radio-labeled compound for binding to the TNFa directly correlates to its binding affinity.

[0542] Kits

[0543] The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of TNFa-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.

[0544] The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of non-critical parameters which can be changed or modified to yield essentially the same results. The compounds of the Examples were found to be inhibitors of TNFa as described below.

[0545] EXAMPLES

[0546] Experimental procedures for compounds of the invention are provided below. Preparatory LC-MS purifications of some of the compounds prepared were performed54057-0034W01 / SNV0025-W01 PATENT

[0547] on Waters mass directed fractionation systems. The basic equipment setup, protocols, and control software for the operation of these systems have been described in detail in the literature. See e.g. “Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K. Blom, J. Combi. Chem.„ 4, 295 (2002); “Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification”, K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003); and "Preparative LC-MS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874-883 (2004). The compounds separated were typically subjected to analytical liquid chromatography mass spectrometry (LCMS) for purity check.

[0548] Some of the compounds prepared were also separated on a preparative scale by reverse-phase high performance liquid chromatography (RP-HPLC) with MS detector or flash chromatography (silica gel) as indicated in the Examples.

[0549] Example 1.2-(5-(l-(2-(Difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH-naphtho[l,2-d]imidazol-7-yl)pyrimidin-2-yl)propan-2-ol

[0550]

[0551] Step 1: tert-butyl (6-bromo-l-nitronaphthalen-2-yl)carbamate

[0552]

[0553] "

[0554] To a solution of tert-butyl (6-bromonaphthalen-2-yl)carbamate (22.85 g, 70.92 mmol) in acetic acid (200 mL) was added fuming nitric acid (10.65 mL, 255.31 mmol) dropwise over 20 min at 0 °C. The mixture was stirred at 23 °C for 2 h. Then the mixture was poured to ice and the precipitated yellow solid was filtered and washed with water and dried to give the desired product (23.70 g, 91%) which was used for the next step without further purification.54057-0034W01 / SNV0025-W01 PATENT

[0555] Step 2: tert-butyl (l-amino-6-bromonaphthalen-2-yl)carbamate

[0556]

[0557] To a solution of tert-butyl (6-bromo-l-nitronaphthalen-2-yl)carbamate (6.87 g, 18.71 mmol) in THF (100 mL) and water (20 mL) was added ammonium chloride (5.01 g, 93.57 mmol), followed by zinc (6.12 g, 93.57 mmol) at 0 °C. The mixture was stirred at 23 °C for 1 h. The mixture was filtered and the filtrate is washed with water and extracted with EtOAc. The combined organics were washed with sat. NaCl, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product (5.31 g, 84%) was used directly in the next step without further purification. LCMS calculated for CisHi8BrN2O2+(M+H)+m / z = 337.1; found 337.0.

[0558] Step 3: tert-butyl (6-bromo-l-((2-(difluoromethoxy)-6-fluorobenzyl)amino)naphthalen-2-yl)carbamate

[0559]

[0560] To a solution of tert-butyl (l-amino-6-bromonaphthalen-2-yl)carbamate (1.04 g, 3.07 mmol) in DCM (9 mL) was added 2-(difluoromethoxy)-6-fluorobenzaldehyde (1.75 g, 9.21 mmol). The mixture was stirred at 23 °C for 15 min. Then sodium cyanoborohydride (0.96 g, 15.35 mmol) was added and the mixture was stirred at 50 °C for 14 h. The reaction was quenched with water and the mixture was extracted with DCM. The combined organics were washed with sat. NaCl, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified using flash column chromatography, eluting with 5-100% EtOAc in hexanes to afford the title compound as a light yellow solid (1.14 g, 73%). LCMS calculated for C23H23BrF3N2O3+(M+H)+m / z = 511.1; found 511.0.

[0561]

[0562] 54057-0034W01 / SNV0025-W01 PATENT

[0563]

[0564] To a solution of tert-butyl (6-bromo-l-((2-(difluoromethoxy)-6-fluorobenzyl)amino)naphthalen-2-yl)carbamate (1.14 g, 2.23 mmol) in MeOH (30 mL) was added 4 N HC1 in 1,4-dioxane (15 mL). The mixture was stirred at 50 °C for 2 h. The mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS calculated for Ci8Hi5BrF3N2O+(M+H)+m / z = 411.0; found 411.1.

[0565] Step 5: 7-bromo-l -(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH-naphtho [ 1 ,2-d]imidazole

[0566]

[0567] The 6-bromo-Nl-(2-(difluoromethoxy)-6-fluorobenzyl)naphthalene-l,2-diamine (crude, 2.23 mmol) was dissolved in acetic acid (30 mL) and the mixture was stirred at 120 °C for 14 h. The mixture was concentrated under reduced pressure. The residue was purified using flash column chromatography, eluting with 10-100% EtOAc in hexanes to afford the title compound as a light yellow solid (0.86 g, 89% for 2 steps). LCMS calculated for C2oHisBrF3N20+(M+H)+m / z = 435.0; found 435.1.

[0568] Step 6: 2-(5-( 1 -(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH-naphtho[ 1, 2-d]imidazol-7-yl)pyrimidin-2-yl)propan-2-ol

[0569] To a solution of 7-bromo-l -(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH-naphtho[l,2-d]imidazole (9.0 mg, 0.021 mmol) in 1,4-dioxane (1 mL) and water (0.1 mL) was added (2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)boronic acid (4.5 mg, 0.025 mmol), followed by sodium carbonate (6.6 mg, 0.062 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.5 mg, 0.002 mmol). The54057-0034W01 / SNV0025-W01 PATENT

[0570] mixture was degassed with nitrogen and stirred at 100 °C for 1 h. Then the reaction mixture was cooled to 23 °C and diluted with MeOH. The mixture was filtered

[0571] through Celite 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 the TFA salt of the desired product as a white solid. LCMS calculated for C27H24FsN4O2+(M+H)+m / z = 493.2; found 493.2.

[0572] Examples 2-12.

[0573] The compounds of Examples 2-12 in Table 1 were prepared according to procedures described for Example 1, using appropriate starting materials.

[0574] Table 1.

[0575]

[0576] 54057-0034W01 / SNV0025-W01 PATENT

[0577] >

[0578]

[0579] 54057-0034W01 / SNV0025-W01 PATENT

[0580] Example 13. (5-(l-(2-(Difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH- naphtho[l,2-d]imidazol-7-yl)oxazol-2-yl)methanol

[0581]

[0582] Step 1: 2-( ((tert-butyldimethylsilyl)oxy)methyl)-5-( 1 -(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH-naphtho[ 1, 2-d]imidazol- 7-yl) oxazole

[0583]

[0584] To a solution of 7-bromo-l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl- lH-naphtho[l,2-d]imidazole (16.7 mg, 0.04 mmol) in 1,4-dioxane (1 mL) and water (0.1 mL) was added 2-(tert-butyl-dimethyl-silanyloxymethyl)-oxazole-5-boronic acid pinacol ester (19.5 mg, 0.06 mmol), followed by cesium carbonate (37.5 mg, 0.12 mmol) and [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.8 mg, 0.004 mmol). The mixture was degassed with nitrogen and stirred at 100 °C for 1 h. Then the reaction mixture was cooled to 23 °C and diluted with MeOH. The mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified using flash column chromatography, eluting with 5-100% EtOAc in hexanes to afford the title compound as a light yellow solid (20.8 mg, 95%). LCMS calculated for C30H33F3N3O3Si+(M+H)+m / z = 568.2; found 568.2.

[0585] Step 2: (5-(l -(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH-naphtho [ 1 ,2- d]imidazol-7-yl)oxazol-2-yl)methanol

[0586] To a solution of 2-(((tert-butyldimethylsilyl)oxy)methyl)-5-(l-(2- (difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH-naphtho[l,2-d]imidazol-7- yl)oxazole (13.3 mg, 0.02 mmol) in DCM (1 mL) was added trifluoroacetic acid (0.4 mL). The mixture was stirred at 23 °C for 12 h. The mixture was concentrated and purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile54057-0034W01 / SNV0025-W01 PATENT

[0587] phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C24Hi9F3N3C>3+(M+H)+m / z = 454.1; found 454.1.

[0588] Example 14. (7?)-l-(l-(2-(Difluorometho y)-6-fluorobenzyl)-2-methyl-lH-naphtho[l,2-d]imidazol-7-yl)pyrrolidin-3-ol

[0589]

[0590] To a solution of 7-bromo-l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH-naphtho[l,2-d]imidazole (9.0 mg, 0.021 mmol) in THF (1 mL) was added (R)-Pyrrolidin-3-ol (3.6 mg, 0.041 mmol), followed by sodium trimethylsilanolate (7.0 mg, 0.062 mmol) and GPhos Pd G6 TES (2.0 mg, 0.002 mmol). The mixture was degassed with nitrogen and stirred at 65 °C for 1 h. Then the reaction mixture was cooled to 23 °C and diluted with MeOH. The mixture was filtered through Celite and purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C24H23F3N3C>2+(M+H)+m / z = 442.2; found 442.2.

[0591] Example 15.2-(4-(l-(2-(Difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH-naphtho[l,2-d]imidazol-7-yl)-lH-pyrazol-l-yl)-N,N,2-trimethylpropanamide

[0592]

[0593] Step 1: ethyl 2-(4-(l-(2-(difhioromethoxy)-6-fhiorobenzyl)-2-methyl-lH-naphtho[l,2-d]imidazol-7-yl)-lH-pyrazol-l-yl)-2-methylpropanoate54057-0034W01 / SNV0025-W01 PATENT

[0594]

[0595] To a solution of 7-bromo-l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH-naphtho[l,2-d]imidazole (52.4 mg, 0.12 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was added ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)propanoate (55.7 mg, 0.18 mmol), followed by cesium carbonate (117.7 mg, 0.36 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8.8 mg, 0.01 mmol). The mixture was degassed with Nitrogen and stirred at 100 °C for 1 h. Then the reaction mixture was cooled to 23 °C and diluted with MeOH. The mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified using flash column chromatography, eluting with 5-100% EtOAc in hexanes to afford the title compound as a light yellow solid (49.9 mg, 77%). LCMS calculated for C29H28F3N4O3+(M+H)+m / z = 537.2; found 537.2.

[0596] Step 2: 2-( 4-( 1 -(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH-naphtho[ 1, 2-d]imidazol- 7-yl)-lH-pyrazol-l-yl)-2-methylpropanoic acid

[0597]

[0598] To a solution of ethyl 2-(4-(l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH-naphtho[l,2-d]imidazol-7-yl)-lH-pyrazol-l-yl)-2-methylpropanoate (45.0 mg, 0.08 mmol) in a mixed solvent (THF 2 mL, water 1 mL, MeOH 1 mL)) was added lithium hydroxide monohydrate (10.6 mg, 0.25 mmol). The reaction mixture was stirred at 23 °C for 12 h. Then the mixture was concentrated under reduced pressure. The residue was purified using flash column chromatography, eluting with 0-10% MeOH in DCM to afford the title compound as a white solid (42.3 mg, 99%). LCMS calculated for C2?H24F3N4O3+(M+H)+m / z = 509.2; found 509.1.54057-0034W01 / SNV0025-W01 PATENT

[0599] Step 3: 2-( 4-( I -(2-(difhioromethoxy)-6-fhiorobenzyl)-2-methyl-lH-naphtho[ 1, 2- d]imidazol- 7-yl)-lH-pyrazol-l-yl)-N,N, 2-trimethylpropanamide

[0600] To a solution of 2-(4-(l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH- naphtho[l,2-d]imidazol-7-yl)-lH-pyrazol-l-yl)-2-methylpropanoic acid (10.0 mg, 0.02 mmol) in DMF (1 mL) was added triethylamine (8.2 uL, 0.06 mmol) and HATU (15.0 mg, 0.04 mmol) at 23 °C. Then dimethylamine (2 M in THF, 49.2 uL, 0.1 mmol) was added. The mixture was stirred at 23 °C for 1 h. The mixture was filtered through Celite 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 the TFA salt of the desired product as a white solid. LCMS calculated for C29H29F3NsO2+(M+H)+m / z = 536.2; found 536.2.

[0601] Example 16.2-(4-(l-(Difluoromethoxy)-5,16-dihydro-7H- benzo[f|naphtho[2',l':4,5]imidazo[2,l-c][l,4]oxazocin-12-yl)-lH-pyrazol-l-yl)-

[0602]

[0603] Step 1: ethyl 2-(4-(5-amino-6-((tert-butoxycarbonyl)amino)naphthalen-2-yl)-lH-pyrazol-l-yl)-2-methylpropanoate

[0604]

[0605] To a solution of tert-butyl (l-amino-6-bromonaphthalen-2-yl)carbamate (314.0 mg, 0.93 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added ethyl 2- methyl-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l- yl)propanoate (430.5 mg, 1.40 mmol), followed by cesium carbonate (910.2 mg, 2.7954057-0034W01 / SNV0025-W01 PATENT

[0606] mmol) and [l,T-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (68.1 mg, 0.09 mmol). The mixture was degassed with nitrogen and stirred at 100 °C for 1 h. Then the reaction mixture was cooled to 23 °C and diluted with MeOH. The mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified using flash column chromatography, eluting with 5-100% EtOAc in hexanes to afford the title compound as a light yellow solid (337.8 mg, 83%). LCMS calculated for C24H3iN4O4+(M+H)+m / z = 439.2; found 439.2.

[0607] Step 2: ethyl 2-(4-(5-((2-bromo-6-(difluoromethoxy)benzyl)amino)-6-((tert-butoxycarbonyl)amino)naphthalen-2-yl)-lH-pyrazol-l-yl)-2-methylpropanoate

[0608]

[0609] To a solution of ethyl 2-(4-(5-amino-6-((tert-butoxycarbonyl)amino)naphthalen-2-yl)-lH-pyrazol-l-yl)-2-methylpropanoate (337.8 mg, 0.77 mmol) in DCM (8 mL) was added 2-bromo-6-(difluoromethoxy)benzaldehyde (580.1 mg, 2.31 mmol). The mixture was stirred at 23 °C for 15 min. Then sodium cyanoborohydride (242.0 mg, 3.85 mmol) was added and the mixture was stirred at 50 °C for 14 h. The reaction was quenched with water and the mixture was extracted with DCM. The combined organics were washed with sat. NaCl, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified using flash column chromatography, eluting with 5-100% EtOAc in hexanes to afford the title compound as a light yellow solid (394.3 mg, 63%). LCMS calculated for C32H36BrF2N4O5+(M+H)+m / z = 673.2; found 673.2.

[0610] Step 3: ethyl 2-(4-(6-((tert-butoxycarbonyl)amino)-5-((2-(difluoromethoxy)-6-vinylbenzyl)amino)naphthalen-2-yl)-lH-pyrazol-l-yl)-2-methylpropanoate54057-0034W01 / SNV0025-W01 PATENT

[0611]

[0612] To a solution of ethyl 2-(4-(5-((2-bromo-6-(difluoromethoxy)benzyl)amino)-6-((tert-butoxycarbonyl)amino)naphthalen-2-yl)-lH-pyrazol-l-yl)-2-methylpropanoate (45.9 mg, 0.07 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was added pinacol vinylboronate (21.0 mg, 0.14 mmol), followed by cesium carbonate (66.6 mg, 0.20 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5.0 mg, 0.01 mmol). The mixture was degassed with nitrogen and stirred at 100 °C for 1 h. Then the reaction mixture was cooled to 23 °C and diluted with MeOH. The mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified using flash column chromatography, eluting with 5-100% EtOAc in hexanes to afford the title compound as a light yellow solid (40.2 mg, 95%). LCMS calculated for C34H39F2N4O5+(M+H)+m / z = 621.3; found 621.2.

[0613] Step 4: ethyl 2-(4-(6-amino-5-((2-(difluoromethoxy)-6-vmylbenzyl)ammo)naphthalen-2-yl)-lH-pyrazol-l-yl)-2-methylpropanoate

[0614]

[0615] To a solution of ethyl 2-(4-(6-((tert-butoxycarbonyl)amino)-5-((2-(difluoromethoxy)-6-vinylbenzyl)amino)naphthalen-2-yl)-lH-pyrazol-l-yl)-2-methylpropanoate (40.2 mg, 0.06 mmol) in EtOH (2 mL) was added 4 N HC1 in 1,4-dioxane (0.4 mL). The mixture was stirred at 50 °C for 2 h. The mixture was concentrated under reduced pressure. The crude product was used directly in the next54057-0034W01 / SNV0025-W01 PATENT

[0616] step without further purification. LCMS calculated for C29H3iF2N4C>3+(M+H)+m / z = 521.2; found 521.2.

[0617] Step 5: ethyl 2-(4-(2-(chloromethyl)-l-(2-(difluoromethoxy)-6-vinylbenzyl)-lH-naphtho[ 1, 2-d]imidazol- 7-yl)-lH-pyrazol-l-yl)-2-methylpropanoate

[0618]

[0619] To a solution of ethyl 2-(4-(6-amino-5-((2-(difluoromethoxy)-6-vinylbenzyl)amino)naphthalen-2-yl)-lH-pyrazol-l -yl)-2-methylpropanoate (33.7 mg, 0.06 mmol) in THF (1 mL) was added p-toluenesulfonic acid monohydrate (0.62 mg, 0.003 mmol), followed by 2-chl oro-1, 1,1 -trimethoxy ethane (13.1 uL, 0.097 mmol). The mixture was stirred at 50 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified using flash column chromatography, eluting with 5-100% EtOAc in hexanes to afford the title compound as a light yellow solid (36.2 mg, 97% for 2 steps). LCMS calculated for C3iH3oClF2N4C>3+(M+H)+m / z = 579.2; found 579.2.

[0620] Step 6: ethyl 2-(4-(2-(chloromethyl)-l-(2-(difluoromethoxy)-6-formylbenzyl)-lH-naphtho[ 1, 2-d]imidazol- 7-yl)-lH-pyrazol-l-yl)-2-methylpropanoate

[0621]

[0622] To a solution of ethyl 2-(4-(2-(chloromethyl)-l-(2-(difluoromethoxy)-6-vinylbenzyl)- lH-naphtho[ 1 ,2-d]imidazol-7-yl)- IH-pyrazol- 1 -yl)-2-methylpropanoate (36.2 mg, 0.063 mmol) in a mixed solvent (THF 1 mL, water 0.2 mL) was added osmium tetroxide (4% in water, 39.7 uL, 0.01 mmol), followed by sodium periodate (40.1 mg, 0.19 mmol). The mixture was stirred at 23 °C for 1 h. The mixture was54057-0034W01 / SNV0025-W01 PATENT

[0623] diluted with water and extracted with EtOAc. The combined organics were washed with sat. NaCl, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS calculated for C3OH2SC1F2N404+(M+H)+m / z = 581.2; found 581.2.

[0624] Step 7: ethyl 2-(4-(2-(chloromethyl)-l-(2-(difhioromethoxy)-6-(hydroxymethyl)benzyl)-lH-naphtho[l,2-d]imidazol-7-yl)-lH-pyrazol-l-yl)-2-methylpropanoate

[0625]

[0626] To a solution of ethyl 2-(4-(2-(chloromethyl)-l-(2-(difluoromethoxy)-6-formylbenzyl)-lH-naphtho[l,2-d]imidazol-7-yl)-lH-pyrazol-l-yl)-2-methylpropanoate (36.6 mg, 0.063 mmol) in MeOH (2 mL) was added sodium borohydride (3.4 mg, 0.09 mmol) at 0 °C. Then the mixture was stirred at 23 °C for 1 h. The reaction was quenched with water and extracted with EtOAc. The combined organics were washed with sat. NaCl, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS calculated for C3OH3OC1F2N4C>4+(M+H)+m / z = 583.2; found 583.2.

[0627] Step 8: ethyl 2-(4-(l-(difluoromethoxy)-5, 16-dihydro-7H-benzo[f]naphtho[2', 1 ':4,5]imidazo[2, l-c][ 1, 4 ]oxazocin-12-yl)-lH-pyrazol-l-yl)-2-methylpropanoate

[0628]

[0629] 54057-0034W01 / SNV0025-W01 PATENT

[0630] To a solution of ethyl 2-(4-(2-(chloromethyl)-l-(2-(difluoromethoxy)-6-(hydroxymethyl)benzyl)- lH-naphtho[ 1 ,2-d]imidazol-7-yl)- IH-pyrazol- 1 -yl)-2-methylpropanoate (36.7 mg, 0.063 mmol) in DMF (2 mL) was added cesium carbonate (58.7 mg, 0.18 mmol) at 23 °C. Then the mixture was stirred at 50 °C for 3 h. The reaction was quenched with water and extracted with EtOAc. The combined organics were washed with sat. NaCl, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified using flash column chromatography, eluting with 0-10% MeOH in DCM to afford the title compound as a light yellow solid (33.1 mg, 97% for 3 steps). LCMS calculated for C3oH29F2N404+(M+H)+m / z = 547.2; found 547.2.

[0631] Step 9: 2-(4-(l-(difluoromethoxy)-5,16-dihydro-7H-benzo[f]naphtho[2', 1 ':4,5]imidazo[2, l-c][ 1, 4 ]oxazocin-12-yl)-lH-pyrazol-l-yl)-2-methylpropanoic acid

[0632]

[0633] To a solution of ethyl 2-(4-(l-(difluoromethoxy)-5,16-dihydro-7H-benzo[f]naphtho[2',T:4,5]imidazo[2,l-c][l,4]oxazocin-12-yl)-lH-pyrazol-l-yl)-2-methylpropanoate (33.1 mg, 0.061 mmol) in a mixed solvent (THF 1 mL, water 0.5 mL, MeOH 0.5 mL)) was added lithium hydroxide monohydrate (5.1 mg, 0.12 mmol). The reaction mixture was stirred at 23 °C for 12 h. Then the mixture was concentrated under reduced pressure. The residue was purified using flash column chromatography, eluting with 0-10% MeOH in DCM to afford the title compound as a white solid (30.1 mg, 96%). LCMS calculated for C28H2sF2N4O4+(M+H)+m / z = 519.2; found 519.1.

[0634] Step 10: 2-(4-(l-(difluoromethoxy)-5,16-dihydro-7H-benzo[f]naphtho[2', 1 ':4,5]imidazo[2, l-c][ 1, 4 ]oxazocin-12-yl)-lH-pyrazol-l-yl)-N, 2-dimethylpropanamide54057-0034W01 / SNV0025-W01 PATENT

[0635] To a solution of2-(4-(l-(difluoromethoxy)-5,16-dihydro-7H-benzo[f]naphtho[2',T:4,5]imidazo[2,l-c][l,4]oxazocin-12-yl)-lH-pyrazol-l-yl)-2-methylpropanoic acid (8.0 mg, 0.02 mmol) in DMF (1 mL) was added triethylamine (6.5 uL, 0.05 mmol) and HATU (11.7 mg, 0.03 mmol) at 23 °C. Then methylamine (2 M in THF, 38.6 uL, 0.08 mmol) was added. The mixture was stirred at 23 °C for 1 h. The mixture was filtered through Celite and purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C29H28F2N5O3+(M+H)+m / z = 532.2; found 532.2.

[0636] Example 17.2-(4-(l-(Difluoromethoxy)-5,16-dihydro-7H-benzo[f|naphtho[2',l':4,5]imidazo[2,l-c][l,4]oxazocin-12-yl)-lH-pyrazol-l-yl)- N,N,2-trimethylpropanamide

[0637]

[0638] To a solution of2-(4-(l-(difluoromethoxy)-5,16-dihydro-7H-benzo[f]naphtho[2',r:4,5]imidazo[2,l-c][l,4]oxazocin-12-yl)-lH-pyrazol-l-yl)-2-methylpropanoic acid (8.0 mg, 0.02 mmol) in DMF (1 mL) was added triethylamine (6.5 uL, 0.05 mmol) and HATU (11.7 mg, 0.03 mmol) at 23 °C. Then dimethylamine (2 M in THF, 38.6 uL, 0.08 mmol) was added. The mixture was stirred at 23 °C for 1 h. The mixture was filtered through Celite and purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for CsoHsoFzNsOs (M+H)+m / z = 546.2; found 546.2.54057-0034W01 / SNV0025-W01 PATENT

[0639] Example 18.2-(4-(l-(Difluoromethoxy)-5,16-dihydro-7H-benzo[f|naphtho[2',l':4,5]imidazo[2,l-c][l,4]oxazocin-12-yl)-lH-pyrazol-l-yl)-2-methylpropanamide

[0640]

[0641] To a solution of2-(4-(l-(difluoromethoxy)-5,16-dihydro-7H-benzo[f]naphtho[2',r:4,5]imidazo[2,l-c][l,4]oxazocin-12-yl)-lH-pyrazol-l-yl)-2-methylpropanoic acid (8.0 mg, 0.02 mmol) in DMF (1 mL) was added DIPEA (8.1 uL, 0.05 mmol) and HATU (8.8 mg, 0.02 mmol) at 23 °C. Then ammonium chloride (2.5 mg, 0.05 mmol) was added. The mixture was stirred at 23 °C for 1 h. The mixture was filtered through Celite and purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C28H26F2N5O3+(M+H)+m / z = 518.2; found 518.1.

[0642] Example 19.2-Amino-l-(l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-l,6,8,9-tetrahydro-7H-imidazo[4,5-f|isoquinolin-7-yl)ethan-l-one

[0643]

[0644] Step 1: 6-bromo-5-nitro-l,2,3,4-tetrahydroisoquinoline

[0645]

[0646] To a solution of 6-bromo-5-nitroisoquinoline (539.4 mg, 2.13 mmol) in acetic acid (4 mL) was added sodium borohydride (322.6 mg, 8.53 mmol) in small portions at 0 °C. The mixture was stirred at 0 °C for an additional 15 min. Then the mixture54057-0034W01 / SNV0025-W01 PATENT

[0647] was stirred at 23 °C for 1 h. The mixture was quenched with 5 mL cold water, basified with 4 N NaOH (20 mL) and extracted with DCM. The combined organics were washed with sat. NaCl, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS calculated for C9HioBrN2C>2+(M+H)+m / z = 257.0; found 257.0.

[0648] Step 2: tert-butyl 6-bromo-5-nitro-3,4-dihydroisoquinoline-2(lH)-carboxylate

[0649]

[0650] To a solution of 6-bromo-5-nitro-l,2,3,4-tetrahydroisoquinoline (2.13 mmol) in 1,4-dioxane (10 mL) was added NaOH (426.0 mg, 10.65 mmol, dissolved in 2 mL water), followed by di-tert-butyl decarbonate (697.3 mg, 3.19 mmol). The mixture was stirred at 23 °C for 12 h. The reaction was quenched with water and extracted with DCM. The combined organics were washed with sat. NaCl, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified using flash column chromatography, eluting with 0-10% MeOH in DCM to afford the title compound as a light yellow solid (686.4 mg, 90% for 2 steps). LCMS calculated for CioHioBrN204+(M-56)+m / z = 301.0; found 300.9.

[0651] Step 3: tert-butyl 6-((tert-butoxycarbonyl)amino)-5-nitro-3,4-dihydroisoquinoline-2( lH)-carboxylate

[0652]

[0653] To a solution of tert-butyl 6-bromo-5-nitro-3,4-dihydroisoquinoline-2(lH)-carboxylate (585.0 mg, 1.64 mmol) in 1,4-dioxane (10 mL) was added tert-butyl carbamate (383.7 mg, 3.28 mmol), followed by cesium carbonate (1.6 g, 4.91 mmol), XPhos (78.1 mg, 0.16 mmol) and palladium (II) acetate (18.4 mg, 0.08 mmol). The mixture was degassed with nitrogen and stirred at 100 °C for 12 h. Then the reaction mixture was cooled to 23 °C and diluted with MeOH. The mixture was filtered54057-0034W01 / SNV0025-W01 PATENT

[0654] through Celite and concentrated under reduced pressure. The residue was purified using flash column chromatography, eluting with 5-100% EtOAc in hexanes to afford the title compound as a light yellow solid (490.9 mg, 76%). LCMS calculated for C14H20N3O (M-100)+m / z = 294.1; found 294.1.

[0655] Step 4: tert-butyl 5-amino-6-((tert-butoxycarbonyl)amino)-3,4-dihydroisoquinoline- 2( lH)-carboxylate

[0656]

[0657] To a solution of tert-butyl 6-((tert-butoxycarbonyl)amino)-5-nitro-3,4- dihydroisoquinoline-2(lH)-carboxylate (490.9 mg, 1.25 mmol) in a mixed solvent (THF 12.5 mL, water 2.5 mL) was added ammonium chloride (333.7 mg, 6.24 mmol), followed by zinc powder (408.1 mg, 6.24 mmol) at 23 °C. The mixture was stirred at 23 °C for 1 h. The mixture was filtered through Celite and concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with water and extracted with EtOAc. The combined organics were washed with sat. NaCl, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS calculated for C19H30N3O (M+H)+m / z = 364.2; found 364.2.

[0658] Step 5: tert-butyl 6-((tert-butoxycarbonyl)amino)-5-((2-(difluoromethoxy)-6-fluorobenzyl)amino)-3, 4-dihydroisoquinoline-2 (1H) -carboxylate

[0659]

[0660] To a solution of tert-butyl 5-amino-6-((tert-butoxycarbonyl)amino)-3,4- dihydroisoquinoline-2(lH)-carboxylate (1.25 mmol) in DCM (5 mL) was added 2- (difluoromethoxy)-6-fluorobenzaldehyde (713.0 mg, 3.75 mmol). The mixture was stirred at 23 °C for 15 min. Then sodium cyanoborohydride (392.8 mg, 6.25 mmol) was added and the mixture was stirred at 50 °C for 14 h. The reaction was quenched54057-0034W01 / SNV0025-W01 PATENT

[0661] with water and the mixture was extracted with DCM. The combined organics were washed with sat. NaCl, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified using flash column chromatography, eluting with 5-100% EtOAc in hexanes to afford the title compound as a light yellow solid (565.0 mg, 84% for 2 steps). LCMS calculated for C27H35F3N3O5+(M+H)+m / z = 538.3; found 538.2.

[0662] Step 6: N5-(2-(difluoromethoxy)-6-fluorobenzyl)-l, 2, 3, 4-tetrahydroisoquinoline-5, 6-diamine

[0663]

[0664] To a solution of tert-butyl 6-((tert-butoxycarbonyl)amino)-5-((2-(difluoromethoxy)-6-fluorobenzyl)amino)-3,4-dihydroisoquinoline-2(lH)-carboxylate (565.0 mg, 1.05 mmol) in MeOH (20 mL) was added 4 N HC1 in 1,4-dioxane (10 mL). The mixture was stirred at 50 °C for 3 h. The mixture was concentrated under reduced pressure. The residue was purified using flash column chromatography, eluting with 0-10% MeOH in DCM to afford the title compound as a light yellow solid (329.8 mg, 93%). LCMS calculated for Ci7Hi9F3N3O+(M+H)+m / z = 338.1; found 338.1.

[0665] Step 7: l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-6, 7,8,9-tetrahydro-lH-imidazo[ 4, 5-f] isoquinoline

[0666]

[0667] The N5-(2-(difluoromethoxy)-6-fluorobenzyl)-l,2,3,4-tetrahydroisoquinoline-5,6-diamine (53.2 mg, 0.16 mmol) was dissolved in acetic acid (1.6 mL) and the mixture was stirred at 120 °C for 14 h. The mixture was concentrated under reduced54057-0034W01 / SNV0025-W01 PATENT

[0668] pressure. The residue was purified using flash column chromatography, eluting with 0-10% MeOH in DCM to afford the title compound as a light yellow solid (37.8 mg, 66%). LCMS calculated for Ci9Hi9F3N3O+(M+H)+m / z = 362.1; found 362.1.

[0669] Step 8: tert-butyl (2-(l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-l, 6,8,9-tetrahydro- 7H-imidazo[ 4, 5-f]isoquinolin- 7 -yl) -2 -oxoethyl) carbamate

[0670]

[0671] To a solution of l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-6, 7,8,9-tetrahydro-lH-imidazo[4,5-f]isoquinoline (9.5 mg, 0.03 mmol) in DCM (1 mL) was added Boc-Gly-OH (6.9 mg, 0.04 mmol), followed by triethylamine (11.0 uL, 0.08 mmol). Then HATU (20.0 mg, 0.05 mmol) was added. The mixture was stirred at 23 °C for 1 h. The reaction was quenched with water and the mixture was extracted with DCM. The combined organics were washed with sat. NaCl, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified using flash column chromatography, eluting with 0-10% MeOH in DCM to afford the title compound as a light yellow solid (7.4 mg, 54%). LCMS calculated for C26H30F3N4O (M+H)+m / z = 519.2; found 519.2.

[0672] Step 9: 2-amino-l-(l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-l, 6,8,9-tetrahydro- 7H-imidazo[ 4, 5-f]isoquinolin- 7-yl)ethan-l-one

[0673] To a solution of tert-butyl (2-(l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-l,6,8,9-tetrahydro-7H-imidazo[4,5-f]isoquinolin-7-yl)-2-oxoethyl)carbamate (7.4 mg, 0.014 mmol) in DCM (1 mL) was added trifluoroacetic acid (0.2 mL). The mixture was stirred at 23 °C for 1 h. The mixture was concentrated and purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5pm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C2iH22F3N4C>2+(M+H)+m / z = 419.2; found 419.2.54057-0034W01 / SNV0025-W01 PATENT

[0674] Example A. HEK-Blue TNFa reporter assay

[0675] The purpose of this assay is to determine the potency of the synthesized TNFa inhibitors. HEK-blue CD40L cells were generated by stable expression of the human CD40 gene and an NF-KB-inducible SEAP construct in HEK293 host cells. In these cells, the binding of CD40L to its receptor CD40 triggers a signaling cascade leading to activation of NF-KB and subsequent production of SEAP. HEK293 host cells also express endogenously the receptors for TNF-a which shares a common signaling pathway with CD40L. Therefore, HEK-blue CD40L cells also respond to TNF-a. Interaction of TNF-a ligand with its receptor in this cell line can be monitored by assessing the levels of SEAP in the supernatant using QUANTI-Blue Solution, a detection reagent. The complete medium for cell culture includes DMEM, 4.5 g / 1 glucose, 2 mM L-glutamine, 10% heat-inactivated fetal bovine serum, 100 U / ml penicillin, 100 pg / ml streptomycin, and 100 pg / ml Zeocin. Assay medium is the complete medium without Zeocin.

[0676] Recombinant human TNF-a was diluted to a final concentration of 0.2 ng / ml using assay medium and added into 96-well plates at 50 uL per well. Compounds were dispensed using the Multidrop PICO8 digital dispenser into assay medium containing TNF-a. Compounds were preincubated with TNF-a at 37 °C for 1 hour. Reporter cells were then added to the assay plates at 10,000 cells per well to a final volume of 100 uL per well. These assay plates were then kept in the cell culture incubator for 24 hours before SEAP measurement using QUANTI-Blue colorimetric assay. Absorbance measurements were performed in the SpectraMax i3x Multi-Mode Microplate Reader purchased from Molecular Devices. Half-maximal inhibitory concentration (IC50) was established using GraphPad Prism software.

[0677] 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.

[0678] Table A.

[0679]

[0680] 54057-0034W01 / SNV0025-W01 PATENT

[0681]

[0682] 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

54057-0034W01 / SNV0025-W01 PATENTWHAT IS CLAIMED IS:

1. A compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein:m is 1, 2, 3, 4, 5, or 6;n is 1, 2, 3, 4, 5, or 6;p is 1, 2, 3, 4, 5, or 6;q is 1, 2, 3, 4, 5, or 6;X1is N or C;X2is N or C;X3is N or C;X4is N or C;wherein one of X1, X2, X3, and X4is N, and three of X1, X2, X3, and X4are C; Y1is N or C;Y2is N or C;Ring A is a 5-membered heteroaryl;Ring B is selected from Ce-io aryl, 5-10 membered heteroaryl, bicyclic Cs-14 cycloalkyl, and bicyclic 8-14 membered heterocycloalkyl;Ring C is selected from C5-14 cycloalkyl, phenyl, 5-14 membered heterocycloalkyl, and 5-10 membered heteroaryl;each L1and L2are independently selected from C1-6 alkylene, C2-6 alkenylene, C3-10 cycloalkylene, 4-10 membered heterocycloalkylene, phenylene, 5-10 membered heteroarylene, -O-, -S-, -N(RL2c)-, -C(O)-, -S(O)-, -S(O)2-, and -S(O)(=NRL2e)-, wherein the C1-6 alkylene, C2-6 alkenylene, C3-10 cycloalkylene, 4-10 membered heterocycloalkylene, phenylene, and 5-10 membered heteroarylene of L1and L2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RL2substituents;54057-0034W01 / SNV0025-W01 PATENTor, one of L1and one of L2, together with the atoms to which they are attached to, form a C5-14 cycloalkyl, or 5-14 membered heterocycloalkyl, wherein the C5-14 cycloalkyl, and 5-14 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RL2substituents;L4is selected from -CRL4=CRL5- and C2-4 alkylene, wherein 1-2 methylene units of the C2-4 alkylene are independently and optionally replaced with -O-, C3-4 cycloalkylene, or 4-5 membered heterocycloalkylene, and wherein the C2-4 alkylene, C3-4 cycloalkylene, and 4-5 membered heterocycloalkylene are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;RL4and RL5are each independently selected from H, halo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;each RL2Cis independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkylidenyl, 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, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, -ORaL2, -NRcL2RdL2, -C(O)RaL2, -C(O)ORaL2, -C(O)NRcL2RdL2, -C(O)NRcL2(ORaL2), -S(O)RbL2, -S(O)2RbL2, -S(O)NRcL2RdL2, -S(O)2NRcL2RdL2, -S(O)(=NReL2)RbL2, -S(O)(=NReL2)NRcL2RdL2, -C(O)NRcL2S(O)2RbL2, -C(O)NRcL2S(O)2NRcL2RdL2, and -S(O)2NRcL2C(O)RbL2, wherein the C1-6 alkyl, C1-6 alkylidenyl, 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 RL2care each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RL2substituents;each RL2eis 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 RL2is independently selected from H, oxo, halo, C1-6 alkyl, C1-6 alkylidenyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl,54057-0034W01 / SNV0025-W01 PATENTphenyl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4alkyl, -CN, -ORaL2, -SRaL2, -NRcL2RdL2, -NO2, -C(O)RaL2, -C(O)ORaL2, -C(O)NRcL2RdL2, -C(O)NRcL2(ORaL2), -OC(O)RaL2, -OC(O)NRcL2RdL2, -OC(O)ORaL2, -OS(O)2RbL2, -OS(O)2NRcL2RdL2, -NRcL2C(O)RaL2, -NRcL2C(O)ORaL2, -NRcL2C(O)NRcL2RdL2, -NRcL2S(O)2RbL2, -NRcL2S(O)2NRcL2RdL2, -NRcL2ORaL2, -NRcL2S(O)RbL2, -NRcL2S(O)NRcL2RdL2, -S(O)RbL2, -S(O)2RbL2, -S(O)NRcL2RdL2, -S(O)2NRcL2RdL2, -C(=NReL2)RaL2, -C(=NReL2)NRcL2RdL2, -NRcL2C(=NReL2)RaL2, -NRcL2C(=NReL2)NRcL2RdL2, -NRcL2S(O)(=NReL2)RbL2, -NRcL2S(O)(=NReL2)NRcL2RdL2, -OS(O)(=NReL2)RbL2, -S(O)(=NReL2)RbL2, -S(O)(=NReL2)NRcL2RdL2, -C(O)NRcL2S(O)2RbL2, -C(O)NRcL2S(O)2NRcL2RdL2, -S(O)2NRcL2C(O)RbL2, -NRcL2S(O)NRcL2C(O)RbL2, and -P(O)RfL2RgL2, wherein the Ci- 6 alkyl, C1-6 alkylidenyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of RL2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;each RaL2, RcL2, and RdL2is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of RaL2, RcL2, and RdL2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;or, any RcL2and RdL2attached 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 RbL2is 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 membered54057-0034W01 / SNV0025-W01 PATENTheterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl, wherein the Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of RbL2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;each ReL2is 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;each11'2and RgL2are independently selected from H, 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 R1is independently selected from oxo, halo, C1-6 alkyl, C1-6 alkylidenyl, 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, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, -ORal, -SF5, -SRal, -NRclRdl, -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, C 1-6 alkylidenyl, 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 (5-1054057-0034W01 / SNV0025-W01 PATENTmembered 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, 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-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;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, 4-54057-0034W01 / SNV0025-W01 PATENT10 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, C1-6 alkylidenyl, C2-6 alkenyl, C2-6alkynyl, 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, -ORalA, -SF5, -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, -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, C1-6 alkylidenyl, 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 R1Bsubstituents;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 R1Bsubstituents;54057-0034W01 / SNV0025-W01 PATENTor, 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 R1Bsubstituents;each RblAis 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 RblAare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1Bsubstituents;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 R1Bis independently selected from oxo, halo, C1-6 alkyl, C1-6 alkylidenyl, 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, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, -ORalB, -SF5, -SRalB, -NRclBRdlB, -NO2, -C(O)RalB, -C(O)ORalB, -C(O)NRclBRdlB, -C(O)NRclB(ORalB), -OC(O)RalB, -OC(O)NRclBRdlB, -OC(O)ORalB, -OS(O)2RblB, -OS(O)2NRclBRdlB, -NRclBC(O)RalB, -NRclBC(O)ORalB, -NRclBC(O)NRclBRdlB, -NRclBS(O)2RblB, -NRclBS(O)2NRclBRdlB, -NRclB0RalB, -NRclBS(O)RblB, -NRclBS(O)NRclBRdlB, -S(O)RblB, -S(O)2RblB, -S(O)NRclBRdlB, -54057-0034W01 / SNV0025-W01 PATENTS(O)2NRclBRdlB, -C(=NRelB)RalB, -C(=NRelB)NRclBRdlB, -NRclBC(=NRelB)RalB, -NRclBC(=NRelB)NRclBRdlB, -NRclBS(O)(=NRelB)RblB, -NRclBS(O)(=NRelB)NRclBRdlB, -OS(O)(=NRelB)RblB, -S(O)(=NRelB)RblB, -S(O)(=NRelB)NRclBRdlB, -C(O)NRclBS(O)2RblB, -C(O)NRclBS(O)2NRclBRdlB, -S(O)2NRclBC(O)RblB, -NRclBS(O)NRclBC(O)RblB, and -P(O)RflBRglB, wherein the Ci-6 alkyl, Ci-6 alkylidenyl, 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 R1Bare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;each RalB, RclB, and RdlBis 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 RalB, RclB, and RdlBare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;or, any RclBand RdlBattached 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 RblBis 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 (5-54057-0034W01 / SNV0025-W01 PATENT10 membered heteroaryl)-Ci-4 alkyl of RblBare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;each RelBis 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 RflBand RglBare 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;R2is selected from H, halo, C1-6 alkyl, C1-6 alkylidenyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, -ORa2, -SF5, -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, C1-6 alkylidenyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents;or, R2and one of R1, together with the atoms to which they are attached to, form a Ce-30 cycloalkyl, or 6-30 membered heterocycloalkyl, wherein the Ce-3054057-0034W01 / SNV0025-W01 PATENTcycloalkyl, and 6-30 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1Asubstituents;each Ra2, Rc2, and Rd2is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-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 Ra2, Rc2, and Rd2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents;or, any Rc2and Rd2attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents;each Rb2is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Rb2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R2Asubstituents;each Re2is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;each R12and Rg2are independently selected from H, C1-6 alkyl, C1-6 alkoxy, Cn 6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-54057-0034W01 / SNV0025-W01 PATENT10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;each R2Ais independently selected from oxo, halo, C1-6 alkyl, C1-6 alkylidenyl, C2-6 alkenyl, C2-6alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, -ORa2A, -SF5, -SRa2A, -NRc2ARd2A, -NO2, -C(O)Ra2A, -C(O)ORa2A, -C(O)NRc2ARd2A, -C(O)NRc2A(ORa2A), -OC(O)Ra2A, -OC(O)NRc2ARd2A, -OC(O)ORa2A, -OS(O)2Rb2A, -OS(O)2NRc2ARd2A, -NRc2AC(O)Ra2A, -NRc2AC(O)ORa2A, -NRc2AC(O)NRc2ARd2A, -NRc2AS(O)2Rb2A, -NRc2AS(O)2NRc2ARd2A, -NRc2AORa2A, -NRc2AS(O)Rb2A, -NRc2AS(O)NRc2ARd2A, -S(O)Rb2A, -S(O)2Rb2A, -S(O)NRc2ARd2A, -S(O)2NRc2ARd2A, -C(=NRe2A)Ra2A, -C(=NRe2A)NRc2ARd2A, -NRc2AC(=NRe2A)Ra2A, -NRc2AC(=NRe2A)NRc2ARd2A, -NRc2AS(O)(=NRe2A)Rb2A, -NRc2AS(O)(=NRe2A)NRc2ARd2A, -OS(O)(=NRe2A)Rb2A, -S(O)(=NRe2A)Rb2A, -S(O)(=NRe2A)NRc2ARd2A, -C(O)NRc2AS(O)2Rb2A, -C(O)NRc2AS(O)2NRc2ARd2A, -S(O)2NRc2AC(O)Rb2A, -NRc2AS(O)NRc2AC(O)Rb2A, and -P(O)Rf2ARg2A, wherein the C1-6 alkyl, C1-6 alkylidenyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;each Ra2A, Rc2A, and Rd2Ais independently selected from H, 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 Ra2A, Rc2A, and Rd2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;54057-0034W01 / SNV0025-W01 PATENTor, any Rc2Aand Rd2Aattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;each Rb2Ais independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Rb2Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;each Re2Ais independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;each R12and Rg2Aare 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;L3is selected from bond, C1-6 alkylene, C2-6 alkenylene, C3-10 cycloalkylene, 4-10 membered heterocycloalkylene, phenylene, and 5-10 membered heteroarylene, wherein the C1-6 alkylene, C2-6 alkenylene, C3-10 cycloalkylene, 4-10 membered heterocycloalkylene, phenylene, and 5-10 membered heteroarylene of L3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;or, two L3, together with the atoms to which they are attached to, form a C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, wherein the C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-654057-0034W01 / SNV0025-W01 PATENTmembered heteroaryl are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3substituents;each R3is independently selected from H, oxo, halo, Ci-6 alkyl, Ci-6 alkylidenyl, C2-6 alkenyl, C2-6alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4alkyl, -CN, -ORa3, -SF5, -SRa3, -NRc3Rd3, -NO2, -C(O)Ra3, -C(O)ORa3, -C(O)NRc3Rd3, -C(O)NRc3(ORa3), -OC(O)Ra3, -OC(O)NRc3Rd3, -OC(O)ORa3, -OS(O)2Rb3, -OS(O)2NRc3Rd3, -NRc3C(O)Ra3, -NRc3C(O)ORa3, -NRc3C(O)NRc3Rd3, -NRc3S(O)2Rb3, -NRc3S(O)2NRc3Rd3, -NRc3ORa3, -NRc3S(O)Rb3, -NRc3S(O)NRc3Rd3, -S(O)Rb3, -S(O)2Rb3, -S(O)NRc3Rd3, -S(O)2NRc3Rd3, -C(=NRe3)Ra3, -C(=NRe3)NRc3Rd3, -NRc3C(=NRe3)Ra3, -NRc3C(=NRe3)NRc3Rd3, -NRc3S(O)(=NRe3)Rb3, -NRc3S(O)(=NRe3)NRc3Rd3, -OS(O)(=NRe3)Rb3, -S(O)(=NRe3)Rb3, -S(O)(=NRe3)NRc3Rd3, -C(O)NRc3S(O)2Rb3, -C(O)NRc3S(O)2NRc3Rd3, -S(O)2NRc3C(O)Rb3, -NRc3S(O)NRc3C(O)Rb3, and -P(O)RfiRg3, wherein the C1-6 alkyl, C1-6 alkylidenyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents;each Ra3, Rc3, and Rd3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-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 Ra3, Rc3, and Rd3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents;54057-0034W01 / SNV0025-W01 PATENTor, any Rc3and Rd3attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents;each Rb3is independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Rb3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents;each Re3is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;each R13and Rg3are 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 R3Ais independently selected from oxo, halo, C1-6 alkyl, C1-6 alkylidenyl, 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, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, -ORa3A, -SF5, -SRa3A, -NRc3ARd3A, -NO2, -C(O)Ra3A, -C(O)ORa3A, -C(O)NRc3ARd3A, -C(O)NRc3A(ORa3A), -OC(O)Ra3A, -OC(O)NRc3ARd3A, -OC(O)ORa3A, -OS(O)2Rb3A, -OS(O)2NRc3ARd3A, -NRc3AC(O)Ra3A, -NRc3AC(O)ORa3A, -NRc3AC(O)NRc3ARd3A, -NRc3AS(O)2Rb3A, -NRc3AS(O)2NRc3ARd3A, -NRc3AORa3A, -NRc3AS(O)Rb3A, -NRc3AS(O)NRc3ARd3A, -S(O)Rb3A, -S(O)2Rb3A, -S(O)NRc3ARd3A, -54057-0034W01 / SNV0025-W01 PATENTS(O)2NRc3ARd3A, -C(=NRe3A)Ra3A, -C(=NRe3A)NRc3ARd3A, -NRc3AC(=NRe3A)Ra3A, -NRc3AC(=NRe3A)NRc3ARd3A, -NRc3AS(O)(=NRe3A)Rb3A, -NRc3AS(O)(=NRe3A)NRc3ARd3A, -OS(O)(=NRe3A)Rb3A, -S(O)(=NRe3A)Rb3A, -S(O)(=NRe3A)NRc3ARd3A, -C(O)NRc3AS(O)2Rb3A, -C(O)NRc3AS(O)2NRc3ARd3A, -S(O)2NRc3AC(O)Rb3A, -NRc3AS(O)NRc3AC(O)Rb3A, and -P(O)RCARg3A, wherein the Ci-6 alkyl, Ci-6 alkylidenyl, 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 R3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Bsubstituents;each Ra3A, Rc3A, and Rd3Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-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 Ra3A, Rc3A, and Rd3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Bsubstituents;or, any Rc3Aand Rd3Aattached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Bsubstituents;each Rb3Ais independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-54057-0034W01 / SNV0025-W01 PATENT10 membered heteroaryl)-Ci-4 alkyl of Rb3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Bsubstituents;each Re3Ais independently selected from H, OH, CN, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;each RfiAand Rg3Aare 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 R3Bis independently selected from oxo, halo, C1-6 alkyl, C1-6 alkylidenyl, 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, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, -ORa3B, -SF5, -SR3313, -NRc3BRd3B, -NO2, -C(O)Ra3B, -C(O)ORa3B, -C(O)NRc3BRd3B, -C(O)NRc3B(ORa3B), -OC(O)Ra3B, -OC(O)NRc3BRd3B, -OC(O)ORa3B, -OS(O)2Rb3B, -OS(O)2NRc3BRd3B, -NRc3BC(O)Ra3B, -NRc3BC(O)ORa3B, -NRc3BC(O)NRc3BRd3B, -NRc3BS(O)2Rb3B, -NRc3BS(O)2NRc3BRd3B, -NRc3BORa3B, -NRc3BS(O)Rb3B, -NRc3BS(O)NRc3BRd3B, -S(O)Rb3B, -S(O)2Rb3B, -S(O)NRc3BRd3B, -S(O)2NRc3BRd3B, -C(=NRe3B)Ra3B, -C(=NRe3B)NRc3BRd3B, -NRc3BC(=NRe3B)Ra3B, -NRc3BC(=NRe3B)NRc3BRd3B, -NRc3BS(O)(=NRe3B)Rb3B, -NRc3BS(O)(=NRe3B)NRc3BRd3B, -OS(O)(=NRe3B)Rb3B, -S(O)(=NRe3B)Rb3B, -S(O)(=NRe3B)NRc3BRd3B, -C(O)NRc3BS(O)2Rb3B, -C(O)NRc3BS(O)2NRc3BRd3B, -S(O)2NRc3BC(O)Rb3B, -NRc3BS(O)NRc3BC(O)Rb3B, and -P(O)Rf3BRg3B, wherein the C1-6 alkyl, C1-6 alkylidenyl, 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 R3Bare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;54057-0034W01 / SNV0025-W01 PATENTeach Ra3B, Rc3B, and Rd3Bis independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra3B, Rc3B, and Rd3Bare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;or, any Rc3Band Rd3Battached 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 Rb3Bis 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 Rb3Bare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents;each Re3Bis 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 RfiBand Rg3Bare 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-454057-0034W01 / SNV0025-W01 PATENTalkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl;each RGis independently selected from H, OH, CN, halo, oxo, Ci-4 alkyl, Ci-4 alkylidenyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, cyano-Ci-4 alkyl, HO-C1-4 alkyl, C1-4 alkoxy-Ci-4 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-3 alkylamino, di(Ci-3 alkyl)amino, thio, C1-3 alkylthio, C1-3 alkylsulfinyl, C1-3 alkyl sulfonyl, carbamyl, C1-3 alkylcarbamyl, di(Ci-3 alkyl)carbamyl, carboxy, C1-3 alkyl carbonyl, C1-3 alkoxycarbonyl, C1-3 alkylcarbonyloxy, C1-3 alkylcarbonylamino, C1-3 alkoxycarbonylamino, aminocarbonyloxy, C1-3 alkylaminocarbonyloxy, di(Ci-3 alkyl)aminocarbonyloxy, C1-3 alkylsulfonylamino, aminosulfonyl, C1-3 alkylaminosulfonyl, di(Ci-3 alkyl)aminosulfonyl, aminosulfonylamino, C1-3 alkylaminosulfonylamino, di(Ci-3 alkyl)aminosulfonylamino, aminocarbonylamino, C1-3 alkylaminocarbonylamino, and di (C 1 -3 alky 1 )aminocarb onyl amino ;provided that -(L2)n-R2is not NH2 or OH.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X1, X3, and X4are each C; and X2is N.

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

4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein m is 1.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein each L1is independently selected from C1-6 alkylene, wherein each C1-6 alkylene is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RL2substituents.

6. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein each L1is independently selected from C1-6 alkylene.54057-0034W01 / SNV0025-W01 PATENT7. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein each L1is -CH2-.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.

9. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein n is i.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein L2is C1-6 alkylene.

11. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein L2is C1-3 alkylene.

12. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein L2is -CH2-.

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

14. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein each R2is independently selected from H and C1-6 alkyl.

15. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein each R2is H.

16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from Ce-io aryl and 5-10 membered heteroaryl.54057-0034W01 / SNV0025-W01 PATENT17. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from phenyl and 5-6 membered heteroaryl.

18. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein Ring B is phenyl.

19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein p is 1, 2, or 3.

20. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2.

21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein each R1is independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, and -ORal, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1Asubstituents; andeach Ralis independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl.

22. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein each R1is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, and -ORal, wherein the C1-6 alkyl and C1-6 haloalkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1Asubstituents; andeach Ralis independently selected from H, C1-6 alkyl, and C1-6 haloalkyl.

23. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein each R1is independently selected from halo and -ORal; and each Ralis independently selected from H and C1-6 haloalkyl.54057-0034W01 / SNV0025-W01 PATENT24. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein each R1is independently selected from fluoro and difluorom ethoxy.

25. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R2and one of R1, together with the atoms to which they are attached to, form a 6-14 membered heterocycloalkyl group, wherein the 6-14 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1Asubstituents.

26. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R2and one of R1, together with the atoms to which they are attached to, form a 6-10 membered heterocycloalkyl group.

27. The compound of any one of claims 1 to 20, wherein R2and one of R1, together with the atoms to which they are attached to, form a tetrahydrooxazocine group.

28. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein Ring C is selected from phenyl and 5-14 membered heterocycloalkyl.

29. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein Ring C is selected from phenyl and 5-7 membered heterocycloalkyl.

30. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein Ring C is selected from phenyl and piperidinyl.

31. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein Y1is C.54057-0034W01 / SNV0025-W01 PATENT32. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein Y2is C.

33. The compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein L4is -CRL4=CRL5-.

34. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein RL4is H or Ci-6 alkyl.

35. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein RL4is H.

36. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein RL5is H or Ci-6 alkyl.

37. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein RL5is H.

38. The compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein L4is -CH=CH-.

39. The compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein q is 1 or 2.

40. The compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein q is 1.

41. The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein each L3is a bond.

42. The compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein each R3is independently selected from C3-10 cycloalkyl, Ce-io54057-0034W01 / SNV0025-W01 PATENTaryl, 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, (5-10 membered heteroaryl)-Ci-4 alkyl, -ORa3, -NRc3Rd3, -C(O)Ra3, -C(O)ORa3, and -C(O)NRc3Rd3, wherein the C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents; andeach Ra3, Rc3, and Rd3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl of Ra3, Rc3, and Rd3are each optionally substituted with 1, 2, 3, or 4 independently selected R3Bsubstituents.

43. The compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein each R3is independently selected from C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and -C(O)Ra3, wherein the C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents;each Ra3is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl of Ra3are each optionally substituted with 1, 2, 3, or 4 independently selected R3Bsubstituents.

44. The compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein each R3is independently selected from phenyl, 4-7 membered heterocycloalkyl, 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl, and -C(O)Ra3, wherein the phenyl, 4-7 membered heterocycloalkyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered bicyclic heteroaryl of R3are each optionally substituted with 1 or 2 independently selected R3Asubstituents; and each Ra3is independently selected from H and C1-6 alkyl, wherein the C1-6 alkyl of Ra3is optionally substituted with amino.54057-0034W01 / SNV0025-W01 PATENT45. The compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein each R3is independently selected from phenyl, pyrrolidinyl, pyrazolyl, pyrimidinyl, oxazolyl, thiazolyl, triazolyl, indazolyl, and aminomethylcarbonyl, wherein the phenyl, pyrrolidinyl, pyrazolyl, pyrimidinyl, oxazolyl, thiazolyl, triazolyl, and indazolyl of R3are each optionally substituted with 1 or 2 independently selected R3Asubstituents.

46. The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, wherein each R3Ais independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, -ORa3A, and -NRc3ARd3A, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of R3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Bsubstituents; and each Ra3A, Rc3A, and Rd3Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl.

47. The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, wherein each R3Ais independently selected from C1-6 alkyl and -ORa3A, wherein the C1-6 alkyl of R3Aare each optionally substituted with 1 or 2 independently selected R3Bsubstituents; andeach Ra3Ais independently selected from H and C1-6 alkyl.

48. The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, wherein each R3Ais independently selected from hydroxy, methyl, isopropyl, and isobutyl, wherein the methyl, isopropyl, and isobutyl of R3Aare each optionally substituted with 1 or 2 independently selected R3Bsubstituents.

49. The compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, wherein each R3Bis independently selected from -CN, -ORa3B, -NRc3BRd3B, -C(O)Ra3B, -C(O)ORa3B, and -C(O)NRc3BRd3B; andeach Ra3B, Rc3B, and Rd3Bis independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl.54057-0034W01 / SNV0025-W01 PATENT50. The compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, wherein each R3Bis independently selected from -CN, -ORa3B, -NRc3BRd3B, and -C(O)NRc3BRd3B; andeach Ra3B, Rc3B, and Rd3Bis independently selected from H and C1-6 alkyl.

51. The compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, wherein each R3Bis independently selected from -CN, -OH, -NH2, C(O)NH2, C(O)NHCH3, and C(O)N(CH3)2.

52. The compound of any one of claims 1 to 41, or a pharmaceutically acceptablesalt thereof, wherein each R3is independently selected from53. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:m is 1, 2, or 3;n is 1, 2, or 3;p is 1, 2, or 3;q is 1, 2, or 3;X1is N or C;X2is N or C;54057-0034W01 / SNV0025-W01 PATENTX3is N or C;X4is N or C;wherein one of X1, X2, X3, and X4is N, and three of X1, X2, X3, and X4are C; Y1is N or C;Y2is N or C;Ring A is a 5-membered heteroaryl;Ring B is selected from Ce-io aryl and 5-10 membered heteroaryl;Ring C is selected from phenyl and 5-14 membered heterocycloalkyl; each L1and L2are each independently selected from Ci-6 alkylene, wherein each Ci-6 alkylene is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RL2substituents;each L3is a bond;L4is -CRL4=CRL5-;RL4is H or Ci-6 alkyl;RL5is H or Ci-6 alkyl;each R1is independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, and -ORal, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1Asubstituents;each Ralis independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;each R2is independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; orR2and one of R1, together with the atoms to which they are attached to, form a 6-14 membered heterocycloalkyl group, wherein the 6-14 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1Asubstituents each R3is independently selected from C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4alkyl, -ORa3, -NRc3Rd3, -C(O)Ra3, -C(O)ORa3, and -C(O)NRc3Rd3, wherein the C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-1054057-0034W01 / SNV0025-W01 PATENTmembered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Asubstituents;each Ra3, Rc3, and Rd3is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl of Ra3, Rc3, and Rd3are each optionally substituted with 1, 2, 3, or 4 independently selected R3Bsubstituents;each R3Ais independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, -ORa3A, and -NRc3ARd3A, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of R3Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R3Bsubstituents;each Ra3A, Rc3A, and Rd3Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl;each R3Bis independently selected from -CN, -ORa3B, -NRc3BRd3B, -C(O)Ra3B, -C(O)ORa3B, and -C(O)NRc3BRd3B; andeach Ra3B, Rc3B, and Rd3Bis independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl.

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

55. The compound of claim 1, wherein the compound of Formula I is a compound of Formula III:54057-0034W01 / SNV0025-W01 PATENTor a pharmaceutically acceptable salt thereof.

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

57. The compound of claim 1, wherein the compound of Formula I is a compound of Formula V:or a pharmaceutically acceptable salt thereof.54057-0034W01 / SNV0025-W01 PATENT58. The compound of claim 1, which is selected from:2-(5-(l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH-naphtho[l,2-d]imidazol-7-yl)pyrimidin-2-yl)propan-2-ol;l-(2-(difhioromethoxy)-6-fluorobenzyl)-2-methyl-7-(l -methyl- lH-pyrazol-4-yl)- lH-naphtho[ 1 ,2-d]imidazole;1 -(4-(l -(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl- lH-naphtho[ 1 ,2-d]imidazol-7-yl)-lH-pyrazol-l-yl)-2-methylpropan-2-ol;1-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-7-(lH-pyrazol-4-yl)-lH-naphthof 1 ,2-d]imidazole;(3 -( 1 -(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl- lH-naphtho[ 1 ,2-d]imidazol-7-yl)phenyl)methanamine;2-(4-(l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH-naphtho[l,2-d]imidazol-7-yl)-lH-pyrazol-l-yl)-2-methylpropanenitrile;2-(4-(l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH-naphtho[l,2-d]imidazol-7-yl)-lH-pyrazol-l-yl)-2-methylpropanamide;l-(2-(difluoromethoxy)-6-fluorobenzyl)-7-(l-isopropyl-lH-pyrazol-4-yl)-2-m ethyl- lH-naphtho[ 1 ,2-d]imidazole;5-(l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH-naphtho[l,2-d]imidazol-7-yl)-2-methyloxazole;5-(l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH-naphtho[l,2-d]imidazol-7-yl)-2-methylthi azole;l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-7-(2-methyl-2H-l,2,3-triazol-4-yl)- lH-naphtho[ 1 ,2-d]imidazole;1-(2-(difluoromethoxy)-6-fluorobenzyl)-7-(lH-indazol-6-yl)-2-methyl-lH-naphthof 1 ,2-d]imidazole;(5-(l -(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl- lH-naphtho[ 1 ,2-d]imidazol-7-yl)oxazol-2-yl)methanol;(R)-l -(1 -(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl- lH-naphtho[ 1 ,2-d]imidazol-7-yl)pyrrolidin-3-ol;2-(4-(l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-lH-naphtho[l,2-d]imidazol-7-yl)-lH-pyrazol-l-yl)-N,N,2-trimethylpropanamide;54057-0034W01 / SNV0025-W01 PATENT2-(4-(l-(difluoromethoxy)-5,16-dihydro-7H-benzo[f]naphtho[2',r:4,5]imidazo[2,l-c][l,4]oxazocin-12-yl)-lH-pyrazol-l-yl)-N,2-dimethylpropanamide;2-(4-(l-(difluoromethoxy)-5,16-dihydro-7H-benzo[f]naphtho[2',r:4,5]imidazo[2,l-c][l,4]oxazocin-12-yl)-lH-pyrazol-l-yl)-N,N,2-trimethylpropanamide;2-(4-(l-(difluoromethoxy)-5,16-dihydro-7H-benzo[f]naphtho[2',r:4,5]imidazo[2,l-c][l,4]oxazocin-12-yl)-lH-pyrazol-l-yl)-2-methylpropanamide; and2-amino-l-(l-(2-(difluoromethoxy)-6-fluorobenzyl)-2-methyl-l, 6,8,9-tetrahydro-7H-imidazo[4,5-f]isoquinolin-7-yl)ethan-l-one;or a pharmaceutically acceptable salt thereof.

59. A pharmaceutical composition, comprising a compound of any one of claims 1 to 58, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

60. A method of inhibiting an activity of tumor necrosis factor-alpha (TNFa), comprising contacting the TNFa with a compound of any one of claims 1 to 58, or a pharmaceutically acceptable salt thereof.

61. A method of treating a TNFa-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 58, or a pharmaceutically acceptable salt thereof.

62. The method of claim 61, wherein the disease or disorder is and autoimmune disease or inflammatory disease.

63. The method of claim 62, wherein the inflammatory disease is a chronic inflammatory disease.54057-0034W01 / SNV0025-W01 PATENT64. The method of any one of claims 61 to 63, wherein the disease or disorder is neurodegenerative disease associated with TNF-a related inflammation and apoptosis.

65. The method of any one of claims 61 to 64, wherein the disease or disorder is selected from plaque psoriasis, rheumatoid arthritis (RA), psoriatic arthritis (PsA), Crohn’s disease (CD), ulcerative colitis (UC), juvenile idiopathic arthritis (JIA), ankylosing spondylitis (AS), hidradenitis suppurativa (HS), uveitis, sarcoidosis, Behcet's disease, granulomatosis with polyangiitis, Alzheimer's disease, Parkinson's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Huntington's disease, traumatic brain injury, and neuromyelitis optica spectrum disorder(NMOSD).

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