Heterocyclic compounds as modulators of TNFα activity

Abstract

The present application provides heterocyclic compounds that modulate the activity of tumor necrosis factor-alpha (TNFα), which are useful in the treatment of various diseases, including autoimmune diseases and inflammatory diseases.

Description

[0001] 54057-0027WO1 / SNV0020-WO1 PATENT HETEROCYCLIC COMPOUNDS AS MODULATORS OF TNFα ACTIVITY TECHNICAL FIELD 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. BACKGROUND Tumor Necrosis Factor-alpha (TNF-α) 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. Rheumatol.2016;12(1):49-62). TNF-α functions by binding to its receptors, TNFR1 and TNFR2, which activate multiple signaling pathways including NF-κB, MAPKs, and apoptotic pathways (see e.g., Physiol. Rev.2019;99(1):115-160). These pathways lead to the production of other cytokines, chemokines, and adhesion molecules, amplifying the inflammatory response. SUMMARY The present disclosure provides, inter alia, compounds of Formula I: I or pharmaceutically acceptable salts thereof, wherein constituent members are defined herein. 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. 54057-0027WO1 / SNV0020-WO1 PATENT The present disclosure further provides methods of inhibiting tumor necrosis factor-alpha (TNFα) activity, comprising contacting the TNFα with a compound described herein, or a pharmaceutically acceptable salt thereof. The present disclosure further provides methods of treating a disease or a disorder associated with TNFα in a patient by administering to the patient a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof. The present disclosure further provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein. 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. DETAILED DESCRIPTION The present application provides a compound of Formula I: I or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, 5, or 6; q is 0, 1, 2, 3, or, 4; X1, X2, X3, X4are each independently N or C, wherein one of X1, X2, X3, and X4is N, and three of X1, X2, X3, and X4are C; Y1is N or CR4; Y2is N or CR5; Y3is N or CR6; 54057-0027WO1 / SNV0020-WO1 PATENT Y4is N or CR7; Ring A is selected from a C5-14 bicyclic cycloalkyl, C6-14 membered tricyclic cycloalkyl, 5-14 membered bicyclic heterocycloalkyl, 6-14 membered tricyclic heterocycloalkyl, naphthyl, 8-10 membered bicyclic heteroaryl, and 11-14 membered tricyclic heteroaryl; Ring B is a 5-membered heteroaryl; each L1and L2is independently selected from C1-6alkylene, C2-6alkenylene, 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 C1-6alkylene, C2-6alkenylene, C3-10cycloalkylene, 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; each RL2cis independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4alkyl, - 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 C1-6alkyl, C2-6alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4alkyl of RL2care each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RL2substituents; each RL2eis independently selected from H, OH, CN, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4alkyl; 54057-0027WO1 / SNV0020-WO1 PATENT each RL2is independently selected from oxo, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, (4-7 membered heterocycloalkyl)-C1-4alkyl, (5-6 membered heteroaryl)-C1-4alkyl, -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 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-C1-4 alkyl, phenyl-C1-4alkyl, (4-7 membered heterocycloalkyl)-C1-4alkyl, and (5-6 membered heteroaryl)-C1-4alkyl 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, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, (4-7 membered heterocycloalkyl)-C1-4 alkyl, and (5-6 membered heteroaryl)-C1-4alkyl, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-7cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, (4-7 membered heterocycloalkyl)-C1-4 alkyl, and (5-6 membered heteroaryl)-C1-4alkyl 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; 54057-0027WO1 / SNV0020-WO1 PATENT each RbL2is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, (4-7 membered heterocycloalkyl)-C1-4alkyl, and (5-6 membered heteroaryl)-C1-4alkyl, 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-C1-4 alkyl, phenyl-C1-4alkyl, (4-7 membered heterocycloalkyl)-C1-4alkyl, and (5-6 membered heteroaryl)-C1-4 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, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, (4-7 membered heterocycloalkyl)-C1-4 alkyl, and (5-6 membered heteroaryl)-C1-4alkyl; each RfL2and 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, C3-7cycloalkyl-C1-4alkyl, phenyl-C1-4alkyl, (4-7 membered heterocycloalkyl)-C1-4alkyl, and (5-6 membered heteroaryl)-C1-4 alkyl; each R1is independently selected from oxo, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4 alkyl, -CN, - ORa1, -SRa1, -NRc1Rd1, -NO2, -C(O)Ra1, -C(O)ORa1, -C(O)NRc1Rd1, - C(O)NRc1(ORa1), -OC(O)Ra1, -OC(O)NRc1Rd1, -OC(O)ORa1, -OS(O)2Rb1, - OS(O)2NRc1Rd1, -NRc1C(O)Ra1, -NRc1C(O)ORa1, -NRc1C(O)NRc1Rd1, -NRc1S(O)2Rb1, -NRc1S(O)2NRc1Rd1, -NRc1ORa1, -NRc1S(O)Rb1, -NRc1S(O)NRc1Rd1, -S(O)Rb1, - S(O)2Rb1, -S(O)NRc1Rd1, -S(O)2NRc1Rd1, -C(=NRe1)Ra1, -C(=NRe1)NRc1Rd1, - NRc1C(=NRe1)Ra1, -NRc1C(=NRe1)NRc1Rd1, -NRc1S(O)(=NRe1)Rb1, - NRc1S(O)(=NRe1)NRc1Rd1, -OS(O)(=NRe1)Rb1, -S(O)(=NRe1)Rb1, - S(O)(=NRe1)NRc1Rd1, -C(O)NRc1S(O)2Rb1, -C(O)NRc1S(O)2NRc1Rd1, - S(O)2NRc1C(O)Rb1, -NRc1S(O)NRc1C(O)Rb1, and -P(O)Rf1Rg1, wherein the C1-6 alkyl, 54057-0027WO1 / SNV0020-WO1 PATENT C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1- 4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4alkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1Asubstituents; or, two R1, 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 R1Asubstituents; each Ra1, Rc1, and Rd1is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-4alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4alkyl of Ra1, Rc1, and Rd1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1Asubstituents; or, any Rc1and Rd1attached 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 Rb1is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10cycloalkyl-C1-4alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5- 54057-0027WO1 / SNV0020-WO1 PATENT 10 membered heteroaryl)-C1-4alkyl of Rb1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1Asubstituents; each Re1is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4alkyl; each Rf1and Rg1are 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, C6-10 aryl, 4- 10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-4alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl; each R1Ais independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4 alkyl, -CN, - ORa1A, -SRa1A, -NRc1ARd1A, -NO2, -C(O)Ra1A, -C(O)ORa1A, -C(O)NRc1ARd1A, - C(O)NRc1A(ORa1A), -OC(O)Ra1A, -OC(O)NRc1ARd1A, -OC(O)ORa1A, -OS(O)2Rb1A, - OS(O)2NRc1ARd1A, -NRc1AC(O)Ra1A, -NRc1AC(O)ORa1A, -NRc1AC(O)NRc1ARd1A, - NRc1AS(O)2Rb1A, -NRc1AS(O)2NRc1ARd1A, -NRc1AORa1A, -NRc1AS(O)Rb1A, - NRc1AS(O)NRc1ARd1A, -S(O)Rb1A, -S(O)2Rb1A, -S(O)NRc1ARd1A, -S(O)2NRc1ARd1A, - C(=NRe1A)Ra1A, -C(=NRe1A)NRc1ARd1A, -NRc1AC(=NRe1A)Ra1A, - NRc1AC(=NRe1A)NRc1ARd1A, -NRc1AS(O)(=NRe1A)Rb1A, - NRc1AS(O)(=NRe1A)NRc1ARd1A, -OS(O)(=NRe1A)Rb1A, -S(O)(=NRe1A)Rb1A, - S(O)(=NRe1A)NRc1ARd1A, -C(O)NRc1AS(O)2Rb1A, -C(O)NRc1AS(O)2NRc1ARd1A, - S(O)2NRc1AC(O)Rb1A, -NRc1AS(O)NRc1AC(O)Rb1A, and -P(O)Rf1ARg1A, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-4alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl of R1Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; 54057-0027WO1 / SNV0020-WO1 PATENT each Ra1A, Rc1A, and Rd1Ais independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-4alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl of Ra1A, Rc1A, and Rd1Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc1Aand Rd1Aattached 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 Rb1Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10cycloalkyl-C1-4alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10cycloalkyl- C1-4alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5- 10 membered heteroaryl)-C1-4 alkyl of Rb1Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Re1Ais independently selected from H, OH, CN, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4alkyl; each Rf1Aand Rg1Aare 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, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-4 54057-0027WO1 / SNV0020-WO1 PATENT alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl; R2and R3are independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-7cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, (4-7 membered heterocycloalkyl)-C1-4 alkyl, (5-6 membered heteroaryl)-C1-4 alkyl, -CN, -ORa2, -SRa2, -NRc2Rd2, -NO2, -C(O)Ra2, -C(O)ORa2, -C(O)NRc2Rd2, -C(O)NRc2(ORa2), -OC(O)Ra2, -OC(O)NRc2Rd2, -OC(O)ORa2, -OS(O)2Rb2, -OS(O)2NRc2Rd2, -NRc2C(O)Ra2, - NRc2C(O)ORa2, -NRc2C(O)NRc2Rd2, -NRc2S(O)2Rb2, -NRc2S(O)2NRc2Rd2, -NRc2ORa2, -NRc2S(O)Rb2, -NRc2S(O)NRc2Rd2, -S(O)Rb2, -S(O)2Rb2, -S(O)NRc2Rd2, - S(O)2NRc2Rd2, -C(=NRe2)Ra2, -C(=NRe2)NRc2Rd2, -NRc2C(=NRe2)Ra2, - NRc2C(=NRe2)NRc2Rd2, -NRc2S(O)(=NRe2)Rb2, -NRc2S(O)(=NRe2)NRc2Rd2, - OS(O)(=NRe2)Rb2, -S(O)(=NRe2)Rb2, -S(O)(=NRe2)NRc2Rd2, -C(O)NRc2S(O)2Rb2, - C(O)NRc2S(O)2NRc2Rd2, -S(O)2NRc2C(O)Rb2, -NRc2S(O)NRc2C(O)Rb2, and - P(O)Rf2Rg2, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4alkyl, phenyl-C1-4alkyl, (4-7 membered heterocycloalkyl)-C1-4alkyl, and (5-6 membered heteroaryl)-C1-4alkyl of R2and R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra2, Rc2, and Rd2is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, (4-7 membered heterocycloalkyl)-C1-4 alkyl, and (5-6 membered heteroaryl)-C1-4alkyl, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-7cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, (4-7 membered heterocycloalkyl)-C1-4 alkyl, and (5-6 membered heteroaryl)-C1-4alkyl of Ra2, Rc2, and Rd2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc2and Rd2attached to the same N atom, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group, wherein the 4- 7 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; 54057-0027WO1 / SNV0020-WO1 PATENT each Rb2is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, (4-7 membered heterocycloalkyl)-C1-4alkyl, and (5-6 membered heteroaryl)-C1-4alkyl, 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-C1-4 alkyl, phenyl-C1-4alkyl, (4-7 membered heterocycloalkyl)-C1-4alkyl, and (5-6 membered heteroaryl)-C1-4 alkyl of Rb2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Re2is independently selected from H, OH, CN, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, (4-7 membered heterocycloalkyl)-C1-4 alkyl, and (5-6 membered heteroaryl)-C1-4alkyl; each Rf2and Rg2are 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, C3-7cycloalkyl-C1-4alkyl, phenyl-C1-4alkyl, (4-7 membered heterocycloalkyl)-C1-4alkyl, and (5-6 membered heteroaryl)-C1-4 alkyl; R4, R5, and R6are independently selected from H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1- 4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4alkyl, -CN, -ORa5, -SRa5, -NRc5Rd5, -NO2, -C(O)Ra5, -C(O)ORa5, -C(O)NRc5Rd5, - C(O)NRc5(ORa5), -OC(O)Ra5, -OC(O)NRc5Rd5, -OC(O)ORa5, -OS(O)2Rb5, - OS(O)2NRc5Rd5, -NRc5C(O)Ra5, -NRc5C(O)ORa5, -NRc5C(O)NRc5Rd5, -NRc5S(O)2Rb5, -NRc5S(O)2NRc5Rd5, -NRc5ORa5, -NRc5S(O)Rb5, -NRc5S(O)NRc5Rd5, -S(O)Rb5, - S(O)2Rb5, -S(O)NRc5Rd5, -S(O)2NRc5Rd5, -C(=NRe5)Ra5, -C(=NRe5)NRc5Rd5, - NRc5C(=NRe5)Ra5, -NRc5C(=NRe5)NRc5Rd5, -NRc5S(O)(=NRe5)Rb5, - NRc5S(O)(=NRe5)NRc5Rd5, -OS(O)(=NRe5)Rb5, -S(O)(=NRe5)Rb5, - S(O)(=NRe5)NRc5Rd5, -C(O)NRc5S(O)2Rb5, -C(O)NRc5S(O)2NRc5Rd5, - S(O)2NRc5C(O)Rb5, -NRc5S(O)NRc5C(O)Rb5, and -P(O)Rf5Rg5, wherein the C1-6 alkyl, 54057-0027WO1 / SNV0020-WO1 PATENT C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1- 4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4alkyl of R4, R5, and R6are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R5Asubstituents; each Ra5, Rc5, and Rd5is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1- 4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4alkyl, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl of Ra5, Rc5, and Rd5are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R5Asubstituents; or, any Rc5and Rd5attached 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 R5Asubstituents; each Rb5is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl, wherein the C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10cycloalkyl- C1-4 alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5- 10 membered heteroaryl)-C1-4alkyl of Rb5are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R5Asubstituents; each Re5is 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, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-4 54057-0027WO1 / SNV0020-WO1 PATENT alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl; each Rf5and Rg5are independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 4- 10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4alkyl; each R5Ais independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-4alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, (5-10 membered heteroaryl)-C1-4alkyl, -CN, - S(O)2NRc5AC(O)Rb5A, -NRc5AS(O)NRc5AC(O)Rb5A, and -P(O)Rf5ARg5A, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4alkyl of R5Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R5Bsubstituents; each Ra5A, Rc5A, and Rd5Ais independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1- 4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4alkyl, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered 54057-0027WO1 / SNV0020-WO1 PATENT heteroaryl, C3-10cycloalkyl-C1-4alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl of Ra5A, Rc5A, and Rd5Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R5Bsubstituents; or, any Rc5Aand Rd5Aattached 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 R5Bsubstituents; each Rb5Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10cycloalkyl-C1-4alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10cycloalkyl- C1-4 alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5- 10 membered heteroaryl)-C1-4 alkyl of Rb5Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R5Bsubstituents; each Re5Ais independently selected from H, OH, CN, C1-6alkyl, C1-6alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-4alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl; each Rf5Aand Rg5Aare independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-4alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4alkyl; each R5Bis independently selected from oxo, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, (5-10 membered heteroaryl)-C1-4alkyl, -CN, - ORa5B, -SRa5B, -NRc5BRd5B, -NO2, -C(O)Ra5B, -C(O)ORa5B, -C(O)NRc5BRd5B, - 54057-0027WO1 / SNV0020-WO1 PATENT S(O)2NRc5BC(O)Rb5B, -NRc5BS(O)NRc5BC(O)Rb5B, and -P(O)Rf5BRg5B, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-4alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl of R5Bare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra5B, Rc5B, and Rd5Bis independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-4alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-4alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl of Ra5B, Rc5B, and Rd5Bare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc5Band Rd5Battached 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 Rb5Bis independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10cycloalkyl-C1-4alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl, 54057-0027WO1 / SNV0020-WO1 PATENT wherein the C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5- 10 membered heteroaryl)-C1-4alkyl of Rb5Bare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Re5Bis independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4alkyl; each Rf5Band Rg5Bare independently selected from H, C1-6alkyl, C1-6alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl; R7is selected from H, halo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6haloalkoxy; each RGis independently selected from OH, CN, halo, oxo, C1-4alkyl, C2-4alkenyl, C2-4 alkynyl, C1-4 haloalkyl, cyano-C1-4 alkyl, HO-C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, C1-4alkoxy, C1-4haloalkoxy, amino, C1-3alkylamino, di(C1-3alkyl)amino, thio, C1-3alkylthio, C1-3alkylsulfinyl, C1-3 alkylsulfonyl, carbamyl, C1-3 alkylcarbamyl, di(C1-3 alkyl)carbamyl, carboxy, C1-3 alkylcarbonyl, C1-3 alkoxycarbonyl, C1-3 alkylcarbonyloxy, C1-3 alkylcarbonylamino, C1-3alkoxycarbonylamino, aminocarbonyloxy, C1-3alkylaminocarbonyloxy, di(C1-3alkyl)aminocarbonyloxy, C1-3alkylsulfonylamino, aminosulfonyl, C1-3alkylaminosulfonyl, di(C1-3 alkyl)aminosulfonyl, aminosulfonylamino, C1-3 alkylaminosulfonylamino, di(C1-3alkyl)aminosulfonylamino, aminocarbonylamino, C1-3alkylaminocarbonylamino, and di(C1-3alkyl)aminocarbonylamino. In some embodiments, X1is C. In some embodiments, X1is N. In some embodiments, X2is C. In some embodiments, X2is N. 54057-0027WO1 / SNV0020-WO1 PATENT In some embodiments, X3is C. In some embodiments, X3is N. In some embodiments, X4is C. In some embodiments, X4is N. In some embodiments, Y1is N. In some embodiments, Y1is CR4. In some embodiments, R4is selected from H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C1-6 haloalkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of R4are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R5Asubstituents. In some embodiments, R4is selected from H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C1-6 haloalkyl. In some embodiments, R4is H or C1-6 alkyl. In some embodiments, R4is H. In some embodiments, Y2is N. In some embodiments, Y2is CR5. In some embodiments, R5is C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-4alkyl, C6-10aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, or (5-10 membered heteroaryl)- C1-4alkyl, wherein the C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-4alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl of R5are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R5Asubstituents. In some embodiments, R5is C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, or (5-10 membered heteroaryl)- C1-4alkyl, wherein the C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl of R5are each optionally substituted with 1 or 2 independently selected R5Asubstituents. 54057-0027WO1 / SNV0020-WO1 PATENT In some embodiments, R5is C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, wherein the C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of R5are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R5Asubstituents. In some embodiments, R5is C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, wherein the C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of R5are each optionally substituted with 1 or 2 independently selected R5Asubstituents. In some embodiments, R5is C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, wherein the C3-7cycloalkyl, phenyl, 4- 7 membered heterocycloalkyl, or 5-6 membered heteroaryl of R5are each optionally substituted with 1, 2, 3, or 4 independently selected R5Asubstituents. In some embodiments, R5is C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, wherein the C3-7cycloalkyl, phenyl, 4- 7 membered heterocycloalkyl, or 5-6 membered heteroaryl of R5are each optionally substituted with 1 or 2 independently selected R5Asubstituents. In some embodiments, R5is 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R5is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R5Asubstituents. In some embodiments, R5is 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R5is optionally substituted with 1, 2, 3, or 4 independently selected R5Asubstituents. In some embodiments, R5is 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R5is optionally substituted with 1 or 2 independently selected R5Asubstituents. In some embodiments, R5is 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl of R5is optionally substituted with 1, 2, 3, or 4 independently selected R5Asubstituents. In some embodiments, R5is 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl of R5is optionally substituted with 1 or 2 independently selected R5Asubstituents. 54057-0027WO1 / SNV0020-WO1 PATENT In some embodiments, R5is pyrimidinyl, which is optionally substituted with 1 or 2 independently selected R5Asubstituents. In some embodiments, R5is pyrimidinyl, which is optionally substituted with 1 R5Asubstituent. In some embodiments, R5is pyrimidinyl, which is substituted with 1 R5Asubstituent. In some embodiments, In some embodiments, each R5Ais independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of R5Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R5Bsubstituents. In some embodiments, each R5Ais independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of R5Aare each optionally substituted with 1 or 2 independently selected R5Bsubstituents. In some embodiments, each R5Ais independently selected from C1-6 alkyl, C1-6 haloalkyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of R5Aare each optionally substituted with 1 or 2 independently selected R5Bsubstituents. In some embodiments, each R5Ais independently selected from C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of R5Aare each optionally substituted with 1, 2, 3, or 4 independently selected R5Bsubstituents. In some embodiments, each R5Ais independently selected from C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 54057-0027WO1 / SNV0020-WO1 PATENT membered heteroaryl, wherein the C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl of R5Aare each optionally substituted with 1, 2, 3, or 4 independently selected R5Bsubstituents. In some embodiments, each R5Ais independently selected from C1-6alkyl, C1-6haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl of R5Aare each optionally substituted with 1 or 2 independently selected R5Bsubstituents. In some embodiments, each R5Ais independently selected from C1-6 alkyl and C3-10cycloalkyl, wherein the C1-6alkyl and C3-10cycloalkyl of R5Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R5Bsubstituents. In some embodiments, each R5Ais independently selected from C1-6 alkyl and C3-10 cycloalkyl, wherein the C1-6 alkyl and C3-10 cycloalkyl of R5Aare each optionally substituted with 1 or 2 independently selected R5Bsubstituents. In some embodiments, each R5Ais independently selected from C1-6 alkyl and C3-7 cycloalkyl, wherein the C1-6 alkyl and C3-7 cycloalkyl of R5Aare each optionally substituted with 1 or 2 independently selected R5Bsubstituents. In some embodiments, each R5Ais independently selected from isopropyl and cyclobutyl, wherein the isopropyl and cyclobutyl of R5Aare each optionally substituted with 1 or 2 independently selected R5Bsubstituents. In some embodiments, each R5Bis independently selected from C1-6alkyl, C2-6alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, -ORa5B, and -NRc5BRd5B. In some embodiments, each R5Bis independently selected from -ORa5Band - NRc5BRd5B. In some embodiments, each Ra5B, Rc5B, and Rd5Bis independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl. In some embodiments, each Ra5B, Rc5B, and Rd5Bis independently selected from H and C1-6alkyl. In some embodiments, each Ra5B, Rc5B, and Rd5Bis independently selected from H and C1-3 alkyl. In some embodiments, each R5Bis independently selected from C1-6alkyl, C2-6alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, -ORa5B, and -NRc5BRd5B; and 54057-0027WO1 / SNV0020-WO1 PATENT each Ra5B, Rc5B, and Rd5Bis independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6 alkenyl, and C2-6 alkynyl. In some embodiments, each R5Bis independently selected from -ORa5Band - NRc5BRd5B; and each Ra5B, Rc5B, and Rd5Bis independently selected from H and C1-6 alkyl. In some embodiments, each R5Bis independently selected from hydroxy and amino. In some embodiments, each R5Ais independently selected from hydroxyisopropyl and aminocyclobutyl. In some embodiments, R5is selected from and In some embodiments, In some embodiments, Y3is CR6. In some embodiments, R6is H or C1-6alkyl. In some embodiments, R6is H. In some embodiments, Y4is N. In some embodiments, Y4is CR7. In some embodiments, R7is H or C1-6 alkyl. In some embodiments, R7is H. In some embodiments: X1is C; X2is N; X3is C; Y1is CR4; Y2is CR5; 54057-0027WO1 / SNV0020-WO1 PATENT Y3is CR6; Y4is CR7; R4is H or C1-3 alkyl; R6is H or C1-3alkyl; and R7is H or C1-3 alkyl. In some embodiments, q is 0, 1, 2, or 3. In some embodiments, q is 0, 1, or 2. In some embodiments, q is 0 or 1. In some embodiments, q is 0. In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 1 or 2. In some embodiments, p is 1. In some embodiments, each L1and L2is independently selected from C1-6alkylene, C3-10 cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6 membered heteroarylene, -O-, -N(RL2c)-, and -C(O)-. In some embodiments, each L1and L2is independently selected from C1-6alkylene, C3-10cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6 membered heteroarylene, -O-, -N(RL2c)-, and -C(O)-. In some embodiments, each L2is independently selected from C1-6alkylene, C3-10cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6 membered heteroarylene, -O-, -N(RL2c)-, and -C(O)-. In some embodiments: q is 0; p is 1; and L2is independently selected from C1-6 alkylene, C3-10 cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6 membered heteroarylene, -O-, - N(RL2c)-, and -C(O)-. In some embodiments, each L2is independently -N(RL2c)-. In some embodiments: q is 0; p is 1; and 54057-0027WO1 / SNV0020-WO1 PATENT L2is -N(RL2c)-. In some embodiments, each RL2cis 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, C3-7cycloalkyl-C1-4alkyl, phenyl-C1-4alkyl, (4-7 membered heterocycloalkyl)-C1-4 alkyl, and (5-6 membered heteroaryl)-C1- 4 alkyl, wherein each C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, (4-7 membered heterocycloalkyl)-C1-4 alkyl, and (5-6 membered heteroaryl)-C1-4 alkyl of RL2cis optionally substituted with 1, 2, 3, or 4 independently selected RL2substituents. In some embodiments, each RL2cis independently selected from H, C1-6alkyl, phenyl, and phenyl-C1-4 alkyl, wherein each C1-6 alkyl, phenyl, and phenyl-C1-4 alkyl of RL2cis optionally substituted with 1, 2, 3, or 4 independently selected RL2substituents. In some embodiments, each RL2cis independently selected from H, methyl, benzyl, wherein each methyl and benzyl of RL2cis optionally substituted with 1 or 2 RL2substituents. In some embodiments, each RL2is independently selected from C1-6alkyl, C2-6alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, and -ORaL2. In some embodiments, each RL2is independently selected from -ORaL2. In some embodiments, each RaL2is independently selected from H, C1-6alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl. In some embodiments, each RaL2is independently selected from H and C1-6 alkyl. In some embodiments, each RaL2is independently selected from H and C1-3alkyl. In some embodiments, each RaL2is independently selected from H and methyl. In some embodiments, each RL2cis independently selected from H, C1-6alkyl, phenyl, and phenyl-C1-4 alkyl, wherein each C1-6 alkyl, phenyl, and phenyl-C1-4 alkyl of RL2cis optionally substituted with 1, 2, 3, or 4 independently selected RL2substituents; and 54057-0027WO1 / SNV0020-WO1 PATENT each RL2is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6 haloalkyl, -CN, and -ORaL2. In some embodiments, each RL2cis independently selected from H, methyl, benzyl, wherein each methyl and benzyl of RL2cis optionally substituted with 1 or 2 RL2substituents independently selected from -ORaL2. In some embodiments, each RL2cis independently selected from H, C1-6 alkyl, phenyl, and phenyl-C1-4alkyl, wherein each C1-6alkyl, phenyl, and phenyl-C1-4alkyl of RL2cis optionally substituted with 1, 2, 3, or 4 independently selected RL2substituents; each RL2is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, -CN, and -ORaL2; and each RaL2is independently selected from H and C1-6 alkyl. In some embodiments, each RL2cis independently selected from H, methyl, benzyl, wherein each methyl and benzyl of RL2cis optionally substituted with 1 or 2 RL2substituents independently selected from -ORaL2; and each RaL2is independently selected from H and C1-3 alkyl. In some embodiments, each RL2cis independently selected from H, methyl, and methoxybenzyl. In some embodiments, Ring A is an 8-10 membered bicyclic heteroaryl. In some embodiments, Ring A is indazolyl. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 2. In some embodiments, each R1is independently selected from oxo, halo, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, -ORa1, and -NRc1Rd1. In some embodiments, each R1is independently selected from halo, C1-6alkyl, C1-6haloalkyl, and -ORa1. In some embodiments, each Ra1, Rc1, and Rd1is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl. In some embodiments, each Ra1, Rc1, and Rd1is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl. 54057-0027WO1 / SNV0020-WO1 PATENT In some embodiments, each R1is independently selected from oxo, halo, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, -ORa1, and -NRc1Rd1; and each Ra1, Rc1, and Rd1is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6alkenyl, and C2-6alkynyl. In some embodiments, each R1is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, and -ORa1; and each Ra1, Rc1, and Rd1is independently selected from H, C1-6alkyl, and C1-6haloalkyl. In some embodiments, each R1is independently selected from methyl and difluoromethoxy. In some embodiments, R2is selected from H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C1-6 haloalkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents. In some embodiments, R2is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl. In some embodiments, R2is selected from H and C1-6alkyl. In some embodiments, R2is selected from H and C1-3alkyl. In some embodiments, R2is H. In some embodiments, R3is selected from H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C1-6haloalkyl, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C1-6haloalkyl of R2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents. In some embodiments, R3is selected from H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C1-6haloalkyl. In some embodiments, R3is selected from H and C1-6 alkyl. In some embodiments, R3is selected from H and C1-3alkyl. In some embodiments, R3is H. In some embodiments: X1is C; X2is N; X3is C; 54057-0027WO1 / SNV0020-WO1 PATENT Y1is CR4; Y2is CR5; Y3is CR6; Y4is CR7; Ring A is a 5-14 membered bicyclic heterocycloalkyl or 8-10 membered bicyclic heteroaryl; Ring B is a 5-membered heteroaryl; m is 0, 1, 2, or 3; p is 1 or 2; q is 0, 1, or 2; each L1and L2is independently selected from C1-6alkylene, C3-10cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6 membered heteroarylene, -O-, -N(RL2c)-, and -C(O)-; each RL2cis independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, (4-7 membered heterocycloalkyl)-C1-4alkyl, and (5-6 membered heteroaryl)-C1-4alkyl, wherein each C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4alkyl, (4-7 membered heterocycloalkyl)-C1-4alkyl, and (5-6 membered heteroaryl)-C1-4alkyl of RL2cis optionally substituted with 1, 2, 3, or 4 independently selected RL2substituents; each RL2is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6haloalkyl, -CN, and -ORaL2; each RaL2is independently selected from H and C1-6alkyl; each R1is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6haloalkyl, -CN, -ORa1, and -NRc1Rd1; each Ra1, Rc1, and Rd1is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; R2is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; 54057-0027WO1 / SNV0020-WO1 PATENT R3is selected from H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C1-6haloalkyl; R4is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; R6is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; and R7is selected from H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C1-6haloalkyl. In some embodiments, the compound of Formula I is a compound of Formula II: or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula IIa: or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula IIb: 54057-0027WO1 / SNV0020-WO1 PATENT or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula IIc: or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula III: or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula IIIa: 54057-0027WO1 / SNV0020-WO1 PATENT IIIa or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula IIIb: or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula IIIc: IIIc or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula IV: 54057-0027WO1 / SNV0020-WO1 PATENT or a pharmaceutically acceptable salt thereof, wherein s is 0, 1, 2, or 3. In some embodiments, the compound of Formula I is a compound of Formula IVa: or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula IVb: or a pharmaceutically acceptable salt thereof. 54057-0027WO1 / SNV0020-WO1 PATENT In some embodiments, the compound of Formula I is a compound of Formula IVc or a pharmaceutically acceptable salt thereof. In some embodiments, the compound provided herein is selected from: 2-(5-(1-(difluoromethoxy)-6-(4-methoxybenzyl)-4-methyl-4,6,7,14- tetrahydro-7,14-methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7- cd]indazol-11-yl)pyrimidin-2-yl)propan-2-ol; 1-(5-(1-(difluoromethoxy)-6-(4-methoxybenzyl)-4-methyl-4,6,7,14- tetrahydro-7,14-methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7- cd]indazol-11-yl)pyrimidin-2-yl)cyclobutan-1-amine; 2-(5-(1-(difluoromethoxy)-4-methyl-4,6,7,14-tetrahydro-7,14- methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7-cd]indazol-11- yl)pyrimidin-2-yl)propan-2-ol; 1-(5-(1-(difluoromethoxy)-4-methyl-4,6,7,14-tetrahydro-7,14- methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7-cd]indazol-11- yl)pyrimidin-2-yl)cyclobutan-1-amine; 2-(5-(1-(difluoromethoxy)-4,6-dimethyl-4,6,7,14-tetrahydro-7,14- methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7-cd]indazol-11- yl)pyrimidin-2-yl)propan-2-ol; and 1-(5-(1-(difluoromethoxy)-4,6-dimethyl-4,6,7,14-tetrahydro-7,14- methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7-cd]indazol-11- yl)pyrimidin-2-yl)cyclobutan-1-amine; or a pharmaceutically acceptable salt thereof. In some embodiments, the compound provided herein is selected from: 54057-0027WO1 / SNV0020-WO1 PATENT 2-(5-((7R,14R)-1-(difluoromethoxy)-6-(4-methoxybenzyl)-4-methyl-4,6,7,14- tetrahydro-7,14-methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7- cd]indazol-11-yl)pyrimidin-2-yl)propan-2-ol; 1-(5-((7R,14R)-1-(difluoromethoxy)-6-(4-methoxybenzyl)-4-methyl-4,6,7,14- tetrahydro-7,14-methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7- cd]indazol-11-yl)pyrimidin-2-yl)cyclobutan-1-amine; 2-(5-((7R,14R)-1-(difluoromethoxy)-4-methyl-4,6,7,14-tetrahydro-7,14- methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7-cd]indazol-11- yl)pyrimidin-2-yl)propan-2-ol; 1-(5-((7R,14R)-1-(difluoromethoxy)-4-methyl-4,6,7,14-tetrahydro-7,14- methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7-cd]indazol-11- yl)pyrimidin-2-yl)cyclobutan-1-amine; 2-(5-((7R,14R)-1-(difluoromethoxy)-4,6-dimethyl-4,6,7,14-tetrahydro-7,14- methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7-cd]indazol-11- yl)pyrimidin-2-yl)propan-2-ol; and 1-(5-((7R,14R)-1-(difluoromethoxy)-4,6-dimethyl-4,6,7,14-tetrahydro-7,14- methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7-cd]indazol-11- yl)pyrimidin-2-yl)cyclobutan-1-amine; or a pharmaceutically acceptable salt thereof. 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. 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. 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 54057-0027WO1 / SNV0020-WO1 PATENT 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. 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. As used herein, the phrase “each ‘variable’ is independently selected from” means substantially the same as wherein “at each occurrence ‘variable’ is selected from.” Throughout the definitions, the terms “Cn-m” and “Cm-n” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C1-3, C1-4, C1-6, and the like. As used herein, the term “Cn-malkyl”, employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (iPr), n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-1- 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. 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, 54057-0027WO1 / SNV0020-WO1 PATENT or 2 to 3 carbon atoms. The term “Cn-malkenyl” is understood to include deuterated analogs of alkenyl groups as defined herein, including but not limited to, groups such as trideuteroethenyl (-CD=CD2), tetradeuteropropenyl, (-CD=CD-CD2), and the like. As used herein, “Cn-malkynyl” refers to an alkyl group having one or more triple carbon-carbon bonds and having n to m carbons. Example alkynyl groups include, but are not limited to, ethynyl, propyn-1-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-1-yl, (-C≡CCD3), and the like. As used herein, the term “Cn-malkoxy”, employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group has n to m carbons. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert- butoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. The term “Cn-m alkoxy” is understood to include deuterated analogs of the alkyl moiety of the alkoxy groups as defined herein, including but not limited to, groups such as trideuteromethoxy (-OCD3), pentadeuteroethoxy (-OCD2CD3), and the like. As used herein, “Cn-mhaloalkoxy”, employed alone or in combination with other terms, refers to a group of formula -O-(haloalkyl), wherein the haloalkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. An example haloalkoxy group is -OCF3. In some embodiments, the haloalkoxy group is a fluoroalkoxy group. The term “Cn-mhaloalkoxy” is understood to include deuterated analogs of the haloalkoxy groups as defined herein. As used herein, the term “carbonyl”, employed alone or in combination with other terms, refers to a -C(O)- group. As used herein, the term “Cn-malkylcarbonyl” refers to a group of formula -C(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. The term “Cn-m alkylcarbonyl” is understood to include deuterated analogs of the alkylcarbonyl groups as defined herein. 54057-0027WO1 / SNV0020-WO1 PATENT As used herein, the term “Cn-malkylsulfonyl” refers to a group of formula -S(O)2-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. The term “Cn-m alkylsulfonyl” is understood to include deuterated analogs of the alkylsulfonyl groups as defined herein. 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. 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-malkylamino 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. As used herein, the term “di(Cn-m alkyl)amino” refers to a group of formula - N(alkyl)2, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. The term “di(Cn-malkyl)amino” is understood to include deuterated analogs of the di(Cn-m alkyl)amino groups as defined herein. As used herein, the term “Cn-malkoxycarbonyl”, employed alone or in combination with other terms, refers to a group of formula -C(O)O-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. The term “Cn-m alkoxycarbonyl” is understood to include deuterated analogs of the alkoxycarbonyl groups as defined herein. As used herein, the term “Cn-malkylcarbonyl”, employed alone or in combination with other terms, refers to a group of formula -C(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. The term “Cn-malkylcarbonyl” is understood to include deuterated analogs of the alkylcarbonyl groups as defined herein. 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 54057-0027WO1 / SNV0020-WO1 PATENT to 6 or 1 to 4 carbon atoms. The term “Cn-malkylcarbonylamino” is understood to include deuterated analogs of the alkylcarbonylamino groups as defined herein. As used herein, the term “carbamyl”, employed alone or in combination with other terms, refers to a group of formula -C(O)-NH2. 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. As used herein, the term “di-Cn-malkylcarbamyl”, employed alone or in combination with other terms, refers to a group of formula -C(O)-N(alkyl)2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, the alkyl group independently has 1 to 6 or 1 to 4 carbon atoms. The term “di-Cn-m alkylcarbamyl” is understood to include deuterated analogs of the dialkylcarbamyl groups as defined herein. As used herein, the term “thio” refers to a group of formula -SH. As used herein, the term “Cn-malkylthio”, employed alone or in combination with other terms, refers to a group of formula -S-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. The term “Cn-malkylthio” is understood to include deuterated analogs of the alkylthio groups as defined herein. 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-malkylsulfinyl” is understood to include deuterated analogs of the alkylsulfinyl groups as defined herein. As used herein, the term “Cn-malkylsulfonyl”, employed alone or in combination with other terms, refers to a group of formula -S(O)2-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. The term “Cn-m alkylsulfonyl” is understood to include deuterated analogs of the alkylsulfonyl groups as defined herein. 54057-0027WO1 / SNV0020-WO1 PATENT As used herein, “halosulfanyl” refers to a sulfur group having one or more halogen substituents. Example halosulfanyl groups include pentahalosulfanyl groups such as SF5. As used herein, the term “HO-C1-4alkyl” refers to a group of formula -C1-4alkylene-OH. The term “HO-C1-4 alkyl” is understood to include deuterated analogs of the HO-C1-4 alkyl groups as defined herein. As used herein, the term “C1-4alkoxy-C1-4alkyl” refers to a group of formula - C1-4 alkylene-O-(C1-4 alkyl). The term “C1-4 alkoxy-C1-4 alkyl” is understood to include deuterated analogs of the C1-4 alkoxy-C1-4 alkyl groups as defined herein. As used herein, the term “aryl,” employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term “Cn-m aryl” refers to an aryl group having from n to m ring carbon atoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, aryl groups have from 5 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl. In some embodiments, the aryl is phenyl. The term “aryl” is understood to include deuterated analogs of the aryl groups as defined herein, including but not limited to, groups such as pentadeuterophenyl (i.e., perdeuterophenyl, phenyl-d5), perdeuteronaphthyl, and the like. 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. As used herein, “Cn-m haloalkoxy” refers to a group of formula –O-haloalkyl having n to m carbon atoms. Example haloalkoxy groups include OCF3and 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. 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+1 halogen atoms which may be the same or different, where “s” is the number of carbon 54057-0027WO1 / SNV0020-WO1 PATENT 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, CCl3, CHCl2, C2Cl5and the like. The term “Cn-mhaloalkyl” is understood to include deuterated analogs of the haloalkyl groups as defined herein, including but not limited to, groups such as deuterodifluoromethyl (-CDF2), dideuterofluoromethyl (-CD2F), and the like. 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 moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring- 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 C3-10monocyclic or bicyclic cycloalkyl. In some embodiments, the cycloalkyl is a C3-7monocyclic cycloalkyl. In some embodiments, the cycloalkyl is a C4-7monocyclic cycloalkyl. In some embodiments, the cycloalkyl is a C4-10 spirocycle or bridged cycloalkyl (e.g., a bridged bicycloalkyl group). Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, cubane, adamantane, bicyclo[1.1.1]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. 54057-0027WO1 / SNV0020-WO1 PATENT As used herein, “heteroaryl” refers to a monocyclic or polycyclic (e.g., having 2 fused rings) aromatic heterocycle having at least one heteroatom ring member selected from N, O, S and B. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S and B. In some embodiments, any ring-forming N in a heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl is a 5-, 7-, 8-, 9-, or 10-membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl is a 5-, 7-, 8-, 9-, or 10-membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl is a 5-6 membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl is a 5 membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl is a 5 membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl group contains 5 to 10, 5 to 7, 3 to 7, or 5 to 6 ring- forming atoms. In some embodiments, the heteroaryl group has 1 to 4 ring-forming heteroatoms, 1 to 3 ring-forming heteroatoms, 1 to 2 ring-forming heteroatoms or 1 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 1,2-dihydro-1,2-azaborine, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, azolyl, triazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazo[1, 2-b]thiazolyl, purinyl, triazinyl, thieno[3,2- 54057-0027WO1 / SNV0020-WO1 PATENT b]pyridinyl, imidazo[1,2-a]pyridinyl, 1,5-naphthyridinyl, 1H-pyrazolo[4,3- b]pyridinyl, triazolo[4,3-a]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3- b]pyridinyl, pyrazolo[1,5-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. As used herein, “heterocycloalkyl” refers to monocyclic or polycyclic heterocycles having at least one non-aromatic ring (saturated or partially unsaturated ring), wherein one or more of the ring-forming carbon atoms of the heterocycloalkyl is replaced by a heteroatom selected from N, O, S, and B, and wherein the ring- forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by one or more oxo or sulfido (e.g., C(O), S(O), C(S), or S(O)2, etc.). When a ring-forming carbon atom or heteroatom of a heterocycloalkyl group is optionally substituted by one or more oxo or sulfide, the O or S of said group is in addition to the number of ring-forming atoms specified herein (e.g., a 1-methyl-6- oxo-1,6-dihydropyridazin-3-yl is a 6-membered heterocycloalkyl group, wherein a ring-forming carbon atom is substituted with an oxo group, and wherein the 6- membered heterocycloalkyl group is further substituted with a methyl group). Heterocycloalkyl groups include monocyclic and polycyclic (e.g., having 2 fused rings) systems. Included in heterocycloalkyl are monocyclic and polycyclic 3 to 10, 4 to 10, 5 to 10, 4 to 7, 5 to 7, or 5 to 6 membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles and bridged rings (e.g., a 5 to 10 membered bridged biheterocycloalkyl ring having one or more of the ring-forming carbon atoms replaced by a heteroatom independently selected from N, O, S, and B). The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. The term “heterocycloalkyl” is understood to include deuterated analogs of the heterocycloalkyl groups as defined herein, including but not limited to, groups such as perdeuteroazetidinyl, perdeuteropyrrolidinyl, perdeuteropiperidinyl, and the like. 54057-0027WO1 / SNV0020-WO1 PATENT Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the non- aromatic heterocyclic ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. In some embodiments, the heterocycloalkyl group contains 3 to 10 ring- forming atoms, 4 to 10 ring-forming atoms, 4 to 8 ring-forming atoms, 3 to 7 ring- forming atoms, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms or 1 heteroatom. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from N, O, S and B and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 5-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, S, and B and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 5 to 10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic 5 to 6 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and having one or more oxidized ring members. Example heterocycloalkyl groups include pyrrolidin-2-one (or 2- oxopyrrolidinyl), 1,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, 1,2,3,4- tetrahydroisoquinoline, tetrahydrothiopheneyl, tetrahydrothiopheneyl 1,1-dioxide, benzazapene, azabicyclo[3.1.0]hexanyl, diazabicyclo[3.1.0]hexanyl, oxobicyclo[2.1.1]hexanyl, azabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.1]heptanyl, azabicyclo[3.1.1]heptanyl, diazabicyclo[3.1.1]heptanyl, azabicyclo[3.2.1]octanyl, diazabicyclo[3.2.1]octanyl, oxobicyclo[2.2.2]octanyl, azabicyclo[2.2.2]octanyl, 54057-0027WO1 / SNV0020-WO1 PATENT 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[1,2-a]pyrazinyl, 3-oxopiperazinyl, oxo-pyrrolidinyl, oxo-pyridinyl, and the like. As used herein, “Co-pcycloalkyl-Cn-malkyl-” 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-p cycloalkyl-Cn-m alkyl-” is understood to include deuterated analogs of the cycloalkyl and / or alkyl moieties of the Co-pcycloalkyl-Cn-malkyl- groups as defined herein. As used herein “Co-p aryl-Cn-m alkyl-” refers to a group of formula aryl- alkylene-, wherein the aryl has o to p carbon atoms and the alkylene linking group has n to m carbon atoms. The term “Co-paryl-Cn-malkyl-” is understood to include deuterated analogs of the aryl and / or alkyl moieties of the Co-paryl-Cn-malkyl- groups as defined herein. Example Co-p aryl-Cn-m alkyl- groups include, but are not limited to, phenyl-CH2- (i.e., benzyl). As used herein, “heteroaryl-Cn-malkyl-” 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-malkyl- groups as defined herein. As used herein “heterocycloalkyl-Cn-malkyl-” refers to a group of formula heterocycloalkyl-alkylene-, wherein alkylene linking group has n to m carbon atoms. The term “heterocycloalkyl-Cn-malkyl-” is understood to include deuterated analogs of the heterocycloalkyl and / or alkyl moieties of the heterocycloalkyl-Cn-malkyl- groups as defined herein. 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-p cycloalkyl-Cn-m alkyl-”, “Co-p aryl-Cn-m alkyl-”, “phenyl-Cn-m alkyl-”, 54057-0027WO1 / SNV0020-WO1 PATENT “heteroaryl-Cn-malkyl-”, and “heterocycloalkyl-Cn-malkyl-” 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. 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-, -CCl2-, -CHCl-, -C2Cl4-, 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. 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-1,1,-diyl, cyclopropy-1,2-diyl, cyclobut-1,3,-diyl, cyclopent-1,3,-diyl, cyclopent-1,4,-diyl, cyclohex-1,2,-diyl, cyclohex-1,3,-diyl, cyclohex-1,4,-diyl, and the like. The terms “cycloalkyl linking group” and “cycloalkylene linking group” are understood to include deuterated analogs of the cycloalkylene groups as defined herein. As used herein, a “heterocycloalkyl linking group” or “heterocycloalkylene linking group” is a bivalent straight chain or branched heterocycloalkyl linking group (“heterocycloalkylene group”). Examples of “heterocycloalkyl linking groups” or “heterocycloalkylene groups” include azetidin-1,2-diyl, azetidin-1,3-diyl, pyrrolidin- 1,2-diyl, pyrrolidin-1,3-diyl, pyrrolidin-2,3-diyl, piperidin-1,2-diyl, piperidin-1,3-diyl, piperidin-1,4-diyl, piperidin-2,3-diyl, piperidin-2,4-diyl, and the like. The terms “heterocycloalkyl linking group” and “heterocycloalkylene linking group” are understood to include deuterated analogs of the heterocycloalkylene groups as defined herein. 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-1,2,-diyl, pyridin-2,3-diyl, pyridin-2,4-diyl, pyridin-3,4- 54057-0027WO1 / SNV0020-WO1 PATENT 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. 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. As used herein, the term “oxo” refers to an oxygen atom (i.e., =O) 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. 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. The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, the compound has the (R)-configuration. In some embodiments, the compound has the (S)-configuration. The Formulas (e.g., Formula I, Formula II, etc.) provided herein include stereoisomers of the compounds. 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 54057-0027WO1 / SNV0020-WO1 PATENT 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 β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N- methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like. 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. Compounds provided herein also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone – enol pairs, amide - imidic acid pairs, lactam – lactim pairs, enamine – imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, 2-hydroxypyridine and 2-pyridone, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. 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. 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. 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 54057-0027WO1 / SNV0020-WO1 PATENT compounds provided herein. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds provided herein, or salt thereof. The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified. 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. The present application also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present disclosure include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety. 54057-0027WO1 / SNV0020-WO1 PATENT Synthesis 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. Compounds of Formula I, such as compounds of formula I-16, can be synthesized, for example, using a process shown in Scheme I. Compound I-1 can be converted to I-2 via treating I-2 with 4-methoxybenzyl bromide (i.e., “para- methoxybenzyl bromide” or “PMB-Br”, wherein “PMB” refers to the “para- methoxybenzyl” or “4-methoxybenzyl” group). I-2 can be converted to I-3 via Suzuki coupling with potassium trifluoro(vinyl)borate. I-3 can then be converted to I-4 via treating I-3 with osmium tetroxide and NaIO4. I-4 can be converted to I-5 via condensation with 2-methylpropane-2-sulfinamide. I-5 can then be converted to I-6 via a Reformatsky reaction with ethyl 2-bromoacetate. Treating I-6 with HCl can lead to I-7. Compound I-9 can be obtained by treating I-7 with I-8. I-9 can be converted to the aldehyde I-10 via reduction with suitable reagent (e.g., DIABL-H). Treating I-10 with TMSCN and ZnI2can lead to I-11. I-12 can be obtained by treating I-11 with suitable reagent (e.g., tin(II) chloride dihydrate). Deprotection of I-12 with TFA to give I -13. I-13 can be converted to I-15 via alkylation or amidation with suitable reagent (e.g., I-14). I-15 can be converted into compounds of formula I-16 via suitable reactions (e.g., transition metal-catalyzed cross-coupling reactions).

[0002] 54057-0027WO1 / SNV0020-WO1 PATENT Scheme I. 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. 54057-0027WO1 / SNV0020-WO1 PATENT Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety. 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.,1H 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. 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 ºC to about 30 ºC. Methods of Use The present disclosure provides uses for compounds and compositions described herein. The compounds described herein can inhibit the activity of tumor necrosis factor-alpha (TNFα). 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 TNFα. In some embodiments, provided compounds and compositions are useful in research as, for example, analytical tools and / or control compounds in biological assays. In autoimmune diseases, TNF-α is often overproduced, leading to chronic inflammation and tissue damage. For example, in rheumatoid arthritis, TNF-α contributes to synovial inflammation and joint destruction. Inflammatory bowel disease involves TNF-α-driven inflammation of the gastrointestinal tract. 54057-0027WO1 / SNV0020-WO1 PATENT Overexpression of TNF-α 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, overproduction of TNF-α 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). Therapeutic strategies targeting TNF-α, 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 biologics have revolutionized the treatment of many autoimmune diseases and significantly improved clinical outcomes for many patients. However, use of these biologics is also associated with several significant issues (see e.g., Drug Discov. Today.2022;27(1):3-7). First, patients may develop anti-drug antibodies that lead to diminished efficacy and drug failure. Second, TNF-α blockers can increase the risk of infections, which is presumably related to blockade of the TNFR2 that is involved in immune regulation. Third, TNF- α blockers can cause adverse reactions such as injection site reactions due to the immunogenicity of large immune complexes formed by TNF-α and the biologics. Finally, the high cost of TNF-α blockers can be a barrier for many patients, limiting accessibility and long-term treatment sustainability. In addition to biologics, small molecule inhibitors have also been explored for blockade of the TNF-α signaling. Recent progress in this area has shown promising advancements, offering potential alternatives to biological TNF-α inhibitors (see e.g., Drug Discov. Today.2023;28(6):103575). Unlike biologics, 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-α trimer, preventing its binding to TNF receptors (see e.g., Science.2005;310(5750):1022-5). These molecules work by stabilizing TNF-α in an inactive conformation, thereby blocking its ability to initiate inflammatory signaling. Some other small molecule inhibitors have also been designed to lock TNF-α in an inactive conformation that cannot initiate downstream 54057-0027WO1 / SNV0020-WO1 PATENT 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 small molecule inhibitor of TNF-α for autoimmune and inflammatory diseases. Thus, there is a need for developing new molecular inhibitors of TNFα. 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 TNFα. 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 TNFα. When used as a single agent for monotherapy, the compounds, salts, and compositions of the present disclosure are expected to suppress overexpression of TNF-α induced production of proinflammatory cytokines and chemokines including IL1, IL6, IL8, IL12, IL17, IL22, IL23, MCP1, IFN-γ, and GM-CSF etc. 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-α induced downstream signaling, inhibit immune cell activation, suppress cell apoptosis, and thereby help restore the balance between pro-inflammatory and anti-inflammatory pathways. In some embodiments, the compounds provided herein are useful as TNFα inhibitors. In some embodiments, the present disclosure provides methods of inhibiting TNFα in a subject comprising administering a provided compound or composition. In some embodiments, the present disclosure provides methods of inhibiting TNFα in a biological sample comprising contacting the sample with a provided compound or composition. In some embodiments, the present disclosure provides methods of treating a disease, disorder or condition associated with TNFα in a subject in need thereof, 54057-0027WO1 / SNV0020-WO1 PATENT comprising administering to the subject a compound, salt, or composition of the disclosure. In some embodiments, a disease, disorder or condition is associated with mutation of TNFα. 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 TNFα, in a subject in need thereof, comprising administering to the subject a provided compound or composition. In some embodiments, the present disclosure provides methods of treating a variety of TNFα-dependent diseases and disorders. For example, in some embodiments the present disclosure provides methods of treating TNF-α 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, Behçet's disease, granulomatosis with polyangiitis, and neurodegenerative diseases associated with TNF-α 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). In some embodiments, provided herein is a method of increasing survival or progression-free survival in a patient, comprising administering a compound provided herein to the patient. In some embodiments, the patient has cancer. In some embodiments, the patient has a disease or disorder described herein. As used herein, progression-free survival refers to the length of time during and after the treatment of a solid tumor that a patient lives with the disease but it does not get worse. Progression-free survival can refer to the length of time from first administering the compound until the earlier of death or progression of the disease. Progression of the disease can be defined by RECIST v.1.1 (Response Evaluation Criteria in Solid Tumors), as assessed by an independent centralized radiological review committee. In some embodiments, administering of the compound results in a progression free survival that is greater than about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, about 12 54057-0027WO1 / SNV0020-WO1 PATENT months, about 16 months, or about 24 months. In some embodiments, the administering of the compound results in a progression free survival that is at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, or about 12 months; and less than about 24 months, about 16 months, about 12 months, about 9 months, about 8 months, about 6 months, about 5 months, about 4 months, about 3 months, or about 2 months. In some embodiments, the administering of the compound results in an increase of progression free survival that is at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, or about 12 months; and less than about 24 months, about 16 months, about 12 months, about 9 months, about 8 months, about 6 months, about 5 months, about 4 months, about 3 months, or about 2 months. The present disclosure further provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein. 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. 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. 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 TNFα with a compound described herein includes the administration of a compound described herein to an individual or patient, such as a human, having a TNFα, as well as, for example, introducing a compound described herein into a sample containing a cellular or purified preparation containing the TNFα. 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. 54057-0027WO1 / SNV0020-WO1 PATENT As used herein, the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent such as an amount of any of the solid forms or salts thereof as disclosed herein that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. An appropriate "effective" amount in any individual case may be determined using techniques known to a person skilled in the art. 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. As used herein, the phrase “pharmaceutically acceptable carrier or excipient” refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipients or carriers are generally safe, non-toxic and neither biologically nor otherwise undesirable and include excipients or carriers that are acceptable for veterinary use as well as human pharmaceutical use. In one embodiment, each component is “pharmaceutically acceptable” as defined herein. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009. As used herein, the term “treating” or “treatment” refers to inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and / or symptomatology) or ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology 54057-0027WO1 / SNV0020-WO1 PATENT or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomatology) such as decreasing the severity of disease. 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. 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. Combination Therapy 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 TNFα 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. 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, biologics, 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. In some embodiments, compound, salt, or composition of the present disclosure can be combined with other therapies for treatment of rheumatoid arthritis 54057-0027WO1 / SNV0020-WO1 PATENT (RA). Exemplary therapies include, but are not limited to, conventional disease- modifying antirheumatic drugs (DMARDs), biologics, targeted synthetic DMARDs (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. 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 (e.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 (S1P) 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. 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 54057-0027WO1 / SNV0020-WO1 PATENT treatments, biologic therapies, and emerging and experimental therapies. Topical treatments include, but are not limited to, hydrocortisone, betamethasone, clobetasol, 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. 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. 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. 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. Pharmaceutical Formulations and Dosage Forms 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 54057-0027WO1 / SNV0020-WO1 PATENT prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral or parenteral. Methods for ocular delivery can include topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction by balloon catheter or ophthalmic inserts surgically placed in the conjunctival sac. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. 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. 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 54057-0027WO1 / SNV0020-WO1 PATENT mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh. 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. 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. 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. 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. 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 54057-0027WO1 / SNV0020-WO1 PATENT pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner. 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. 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. 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 54057-0027WO1 / SNV0020-WO1 PATENT the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems. 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. Labeled Compounds and Assay Methods 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 TNFα in tissue samples, including human, and for identifying TNFα by inhibition binding of a labeled compound. Accordingly, the present invention includes TNFα cellular assays that contain such labeled compounds. 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),11C,13C,14C,13N,15N,15O,17O,18O,18F,35S,36Cl,82Br,75Br,76Br,77Br,123I,124I,125I and131I. The radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro FGFR enzyme labeling and competition assays, compounds that incorporate3H,14C,82Br,125I ,131I, or35S will generally be most useful. For radio-imaging applications11C,18F,125I,123I,124I,131I,75Br,76Br or77Br will generally be most useful. 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. 54057-0027WO1 / SNV0020-WO1 PATENT For example, one or more hydrogen atoms in a compound of the present disclosure can be replaced by deuterium atoms (e.g., one or more hydrogen atoms of a C1-6 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-IVc) can be perdeuterated. In some embodiments, the compound provided herein (e.g., the compound of any of Formulas I-IVc), or a pharmaceutically acceptable salt thereof, comprises at least one deuterium atom. In some embodiments, the compound provided herein (e.g., the compound of any of Formulas I-IVc), or a pharmaceutically acceptable salt thereof, comprises two or more deuterium atoms. In some embodiments, the compound provided herein (e.g., the compound of any of Formulas I-IVc), or a pharmaceutically acceptable salt thereof, comprises three or more deuterium atoms. In some embodiments, for a compound provided herein (e.g., the compound of any of Formulas I-IVc), or a pharmaceutically acceptable salt thereof, all of the hydrogen atoms are replaced by deuterium atoms (i.e., the compound is “perdeuterated”). 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,125I ,35S and82Br. 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. 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 54057-0027WO1 / SNV0020-WO1 PATENT preferred in some circumstances. (see e.g., A. Kerekes et. al. J. Med. Chem.2011, 54, 201-210; R. Xu et. al. J. Label Compd. Radiopharm.2015, 58, 308-312). In particular, substitution at one or more metabolism sites may afford one or more of the therapeutic advantages. A radio-labeled compound of the invention can be used in a screening assay to identify / evaluate compounds. In general terms, a newly synthesized or identified compound (i.e., test compound) can be evaluated for its ability to reduce binding of the radio-labeled compound of the invention to the TNFα. Accordingly, the ability of a test compound to compete with the radio-labeled compound for binding to the TNFα directly correlates to its binding affinity. Kits The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of TNFα-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. 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 TNFα as described below. EXAMPLES 54057-0027WO1 / SNV0020-WO1 PATENT Experimental procedures for compounds of the invention are provided below. Preparatory LC-MS purifications of some of the compounds prepared were performed on Waters mass directed fractionation systems. The basic equipment setup, protocols, and control software for the operation of these systems have been described in detail in the literature. See e.g. “Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K. Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification”, K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003); and "Preparative LC-MS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874-883 (2004). The compounds separated were typically subjected to analytical liquid chromatography mass spectrometry (LCMS) for purity check. Some of the compounds prepared were also separated on a preparative scale by reverse-phase high performance liquid chromatography (RP-HPLC) with MS detector or flash chromatography (silica gel) as indicated in the Examples. Example 1.2-(5-((7R,14R)-1-(Difluoromethoxy)-6-(4-methoxybenzyl)-4-methyl- 4,6,7,14-tetrahydro-7,14- methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7-cd]indazol-11- yl)pyrimidin-2-yl)propan-2-ol Step 1: 2-bromo-6-fluoro-3-hydroxybenzonitrile Triflic acid (1.2 mL, 13.7 mmol) was added to a well-stirred solution of 2- bromo-6-fluoro-3-hydroxybenzaldehyde (1.0 g, 4.57 mmol) and sodium azide (0.45 g, 6.85 mmol) in 10 mL of MeCN, and the mixture was stirred at room temperature until 54057-0027WO1 / SNV0020-WO1 PATENT the reaction was completed (monitored by LCMS, about 5 min). After removal of the solvent under reduced pressure, the mixture was diluted with water and extracted with EtOAc (3 x 30 mL). The combined organic fractions were washed with brine, dried over anhydrous sodium sulfate, filtered, then concentrated under reduced pressure. The residue was used in the next step directly without further purification. LCMS calculated for C7H4BrFNO (M+H)+m / z = 215.9; found 216.0. Step 2: 2-bromo-3-(difluoromethoxy)-6-fluorobenzonitrile To a solution of 2-bromo-6-fluoro-3-hydroxybenzonitrile (3.90 g, 18.05 mmol) in 90 mL of ACN and 90 mL of water was added potassium hydroxide (5.06 g, 90.27 mmol) at 0 °C. Then slowly added diethyl (bromodifluoromethyl)phosphonate (6.43 mL, 9.64 g, 36.11 mmol) to the mixture. After stirring at room temperature for 2 hours, the reaction mixture was diluted with water and extracted with EtOAc (3 x 300 mL). The combined organic fractions were washed with brine, dried over anhydrous sodium sulfate, filtered, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc in hexane to provide the desired product as a yellow oil. (2.85 g, 59%). LCMS calculated for C8H4BrF3NO (M+H)+m / z = 265.9; found 266.0. Step 3: 4-bromo-5-(difluoromethoxy)-1-methyl-1H-indazol-3-amine The mixture of 2-bromo-3-(difluoromethoxy)-6-fluorobenzonitrile (2.85 g, 10.7 mmol) and methylhydrazine (2.8 mL, 53.6 mmol) in 50 mL of EtOH was refluxed for 5 hours. Then the solvent was removed under reduced pressure. The residue was recrystallized from cold EtOH to give the desired product as a white solid (3.0 g, 96%). LCMS calculated for C9H9BrF2N3O (M+H)+m / z = 292.0; found 292.0. 54057-0027WO1 / SNV0020-WO1 PATENT Step 4: 4-bromo-5-(difluoromethoxy)-N,N-bis(4-methoxybenzyl)-1-methyl-1H- indazol-3-amine To a solution of 4-bromo-5-(difluoromethoxy)-1-methyl-1H-indazol-3-amine (1.27 g, 4.35 mmol) in 20 mL of DMF was added 4-methoxybenzyl bromide (1.9 mL, 13.0 mmol), potassium iodide (2.16 g, 13 mmol) and potassium carbonate (1.8 g, 13 mmol). After stirring at 100 °C overnight, the mixture was diluted with water and extracted with EtOAc (3 x 50 mL). The combined organic fractions were washed with brine, dried over anhydrous sodium sulfate, filtered, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc in hexane to provide the desired product as a yellow solid (2.18 g, 94%). LCMS calculated for C25H25BrF2N3O3(M+H)+m / z = 532.1; found 532.0. Step 5: 5-(difluoromethoxy)-N,N-bis(4-methoxybenzyl)-1-methyl-4-vinyl-1H-indazol- 3-amine To a solution of 4-bromo-5-(difluoromethoxy)-N,N-bis(4-methoxybenzyl)-1- methyl-1H-indazol-3-amine (1.34 g, 2.52 mmol) in 25 mL of 1,4-dioxane and 5 mL of water was added potassium trifluoro(vinyl)borate (0.67 g, 5.0 mmol), cesium carbonate (1.64 g, 5.0 mmol) and (1,1'- bis(diphenylphosphino)ferrocene)palladium(II) dichloride (210 mg, 0.25 mmol). The reaction mixture was stirred at 90 °C under nitrogen atmosphere overnight. Then the mixture was diluted with water and extracted with EtOAc (3 x 50 mL). The combined organic fractions were washed with brine, dried over anhydrous sodium sulfate, filtered, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc in hexane to provide the desired 54057-0027WO1 / SNV0020-WO1 PATENT product as a yellow solid (969 mg, 80%). LCMS calculated for C27H28F2N3O3(M+H)+m / z = 480.2; found 480.2. Step 6: 3-(bis(4-methoxybenzyl)amino)-5-(difluoromethoxy)-1-methyl-1H-indazole-4- carbaldehyde To a solution of 5-(difluoromethoxy)-N,N-bis(4-methoxybenzyl)-1-methyl-4- vinyl-1H-indazol-3-amine (969 mg, 2.0 mmol) in 10 mL of THF and 5 mL of water was added sodium periodate (2.16 g, 10 mmol) and 4% OsO4 in water (2.57 mL, 0.4 mmol) at 0 °C. After stirring at rt for 3h, the reaction mixture was diluted with water and extracted with EtOAc (3 x 30 mL). The combined organic fractions were washed with brine, dried over anhydrous sodium sulfate, filtered, then concentrated under reduced pressure. The residue was used in the next step directly without further purification. LCMS calculated for C26H26F2N3O4(M+H)+m / z = 482.2; found 482.3. Step 7: (S)-N-((3-(bis(4-methoxybenzyl)amino)-5-(difluoromethoxy)-1-methyl-1H- indazol-4-yl)methylene)-2-methylpropane-2-sulfinamide To a solution of 3-(bis(4-methoxybenzyl)amino)-5-(difluoromethoxy)-1- methyl-1H-indazole-4-carbaldehyde (963 mg, 2.0 mmol) in 10 mL of DCM was added (S)-2-methylpropane-2-sulfinamide (242 mg, 2.0 mmol) and cesium carbonate (1.3 g, 4.0 mmol). After stirring at rt overnight, the reaction mixture was diluted with water and extracted with EtOAc (3 x 50 mL). The combined organic fractions were washed with brine, dried over anhydrous sodium sulfate, filtered, then concentrated 54057-0027WO1 / SNV0020-WO1 PATENT under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc in hexane to provide the desired product as a yellow solid (1.12 g, 96%). LCMS calculated for C30H35F2N4O4S (M+H)+m / z = 585.2; found 585.3. Step 8: ethyl (R)-3-(3-(bis(4-methoxybenzyl)amino)-5-(difluoromethoxy)-1-methyl- 1H-indazol-4-yl)-3-(((S)-tert-butylsulfinyl)amino)propanoate To a stirred mixture of zinc powder (632 mg, 9.66 mmol) in 5 mL of THF was added anhydrous CuCl (96 mg, 0.97 mmol) at rt. The resulting mixture was stirred for 0.5 h at 70 °C. The mixture was allowed to cool down to room temperature. To the above mixture was added solution of ethyl bromoacetate (0.38 mL, 3.38 mmol) in 5 mL of THF dropwise at rt. The resulting mixture was stirred for additional 0.5 h at 50 °C. The resulting mixture was filtered. To the above filtrate was added a solution of (S)-N-((3-(bis(4-methoxybenzyl)amino)-5-(difluoromethoxy)-1-methyl-1H-indazol-4- yl)methylene)-2-methylpropane-2-sulfinamide (565 mg, 0.97 mmol) in 1 mL of THF dropwise at 0 °C. The resulting mixture was stirred overnight at rt. The reaction was quenched with sat. NH4Cl (aq.). The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 x 5 mL). The filtrate was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc in hexane to provide the desired product as a yellow solid (576 mg, 88.6%). LCMS calculated for C34H43F2N4O6S (M+H)+m / z = 673.3; found 673.2. Step 9: ethyl (R)-3-amino-3-(3-(bis(4-methoxybenzyl)amino)-5-(difluoromethoxy)-1- methyl-1H-indazol-4-yl)propanoate 54057-0027WO1 / SNV0020-WO1 PATENT To a stirred solution of ethyl (R)-3-(3-(bis(4-methoxybenzyl)amino)-5- (difluoromethoxy)-1-methyl-1H-indazol-4-yl)-3-(((S)-tert- butylsulfinyl)amino)propanoate (576 mg, 0.86 mmol) in 2 mL of Et2O and 1 mL of EtOH was added 4N HCl in 1,4-dioxane (1.1 mL, 4.28 mmol) at rt. The resulting mixture was stirred for 3 h at rt. The resulting mixture was concentrated under reduced pressure. The residue was used in the next step directly without further purification. LCMS calculated for C30H35F2N4O5 (M+H)+m / z = 569.3; found 569.2. Step 10: ethyl (R)-3-(3-(bis(4-methoxybenzyl)amino)-5-(difluoromethoxy)-1-methyl- 1H-indazol-4-yl)-3-((5-bromo-2-nitrophenyl)amino)propanoate To a stirred solution of ethyl (R)-3-amino-3-(3-(bis(4-methoxybenzyl)amino)- 5-(difluoromethoxy)-1-methyl-1H-indazol-4-yl)propanoate (480 mg, 0.84 mmol) in 5 mL of ACN was added 4-bromo-2-fluoro-1-nitrobenzene (223 mg, 1.0 mmol) and potassium carbonate (350 mg, 2.53 mmol) at rt. The mixture was stirred for 16 h at 80 °C. The resulting mixture was diluted with water and extracted with EtOAc (3 x 10 mL). The combined organic fractions were washed with brine, dried over anhydrous sodium sulfate, filtered, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc in hexane to provide the desired product as a yellow solid (423 mg, 65%). LCMS calculated for C36H37BrF2N5O7 (M+H)+m / z = 768.2; found 768.3. 54057-0027WO1 / SNV0020-WO1 PATENT Step 11: (R)-3-(3-(bis(4-methoxybenzyl)amino)-5-(difluoromethoxy)-1-methyl-1H- indazol-4-yl)-3-((5-bromo-2-nitrophenyl)amino)propanal To a solution of ethyl (R)-3-(3-(bis(4-methoxybenzyl)amino)-5- (difluoromethoxy)-1-methyl-1H-indazol-4-yl)-3-((5-bromo-2- nitrophenyl)amino)propanoate (423 mg, 0.55 mmol) in 5 mL of DCM was added 1.0 M DIBAL-H in THF (1.1 mL, 1.1 mmol) dropwise at -78 °C under nitrogen atmosphere. The reaction was stirred for 30 minutes at -78 °C under nitrogen atmosphere. The resulting mixture was quenched with sat. NH4Cl (aq.) at -78 °C, then extracted with DCM (3 x 10 mL). The combined organic fractions were washed with brine, dried over anhydrous sodium sulfate, filtered, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc in hexane to provide the desired product as a yellow solid (320 mg, 80%). LCMS calculated for C34H33BrF2N5O6(M+H)+m / z = 724.2; found 724.1. Step 12: (R)-6-((5-bromo-2-nitrophenyl)amino)-5-(difluoromethoxy)-9-(4- methoxybenzyl)-2-methyl-6,7,8,9-tetrahydro-2H-azepino[2,3,4-cd]indazole-8- carbonitrile To a solution of (R)-3-(3-(bis(4-methoxybenzyl)amino)-5-(difluoromethoxy)- 1-methyl-1H-indazol-4-yl)-3-((5-bromo-2-nitrophenyl)amino)propanal (129 mg, 0.18 mmol) in 2 mL of DCM was added ZnI2(28.4 mg, 0.09 mmol) and TMSCN (44.6 uL, 0.36 mmol) at rt. After stirring at rt for 16 h, the resulting mixture was diluted with 54057-0027WO1 / SNV0020-WO1 PATENT water and extracted with EtOAc (3 x 10 mL). The combined organic fractions were washed with brine, dried over anhydrous sodium sulfate, filtered, then concentrated under reduced pressure. The residue was used in the next step directly without further purification. LCMS calculated for C27H24BrF2N6O4(M+H)+m / z = 613.1; found 613.1. Step 13: (7R,14R)-11-bromo-1-(difluoromethoxy)-6-(4-methoxybenzyl)-4-methyl- 4,6,7,14-tetrahydro-7,14-methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7- cd]indazole To a solution of (R)-6-((5-bromo-2-nitrophenyl)amino)-5-(difluoromethoxy)- 9-(4-methoxybenzyl)-2-methyl-6,7,8,9-tetrahydro-2H-azepino[2,3,4-cd]indazole-8- carbonitrile (110 mg, 0.18 mmol) in 5 mL of EtOH was added tin(II) chloride dihydrate (203 mg, 0.9 mmol) at rt. The mixture was stirred for 3 h at 80 °C. The reaction was quenched by the addition of water (2.5 mL) and basified to pH 8 with 1N NaOH (aq.). The mixture was filtered, the filter cake was washed with EtOAc (3 x 3 mL), the filtrate was extracted with EtOAc (3 x 5 mL). The combined organic fractions were washed with brine, dried over anhydrous sodium sulfate, filtered, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc in hexane to provide the desired product as a yellow solid (45 mg, 44%). LCMS calculated for C27H23BrF2N5O2 (M+H)+m / z = 566.1; found 566.2. Step 14: 2-(5-((7R,14R)-1-(difluoromethoxy)-6-(4-methoxybenzyl)-4-methyl-4,6,7,14- tetrahydro-7,14-methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7- cd]indazol-11-yl)pyrimidin-2-yl)propan-2-ol To a solution of (7R,14R)-11-bromo-1-(difluoromethoxy)-6-(4- methoxybenzyl)-4-methyl-4,6,7,14-tetrahydro-7,14- 54057-0027WO1 / SNV0020-WO1 PATENT methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7-cd]indazole (5 mg, 0.01 mmol) in 1 mL of 1,4-dioxane and 0.2 mL of water was added 2-(5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)propan-2-ol (4.7 mg, 0.02 mmol), cesium carbonate (8.6 mg, 0.03 mmol) and (1,1'- bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.72 mg, 0.001 mmol). The mixture was stirred at 80 °C under nitrogen atmosphere for 1 h. Then the mixture was diluted with water and extracted with EtOAc (3 x 50 mL). The combined organic fractions were washed with brine, dried over anhydrous sodium sulfate, filtered, then concentrated under reduced pressure. The residue was diluted with MeOH and purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C34H32F2N7O3 (M+H)+m / z = 624.2; found 624.3. Example 2.1-(5-((7R,14R)-1-(Difluoromethoxy)-6-(4-methoxybenzyl)-4-methyl- 4,6,7,14-tetrahydro-7,14- methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7-cd]indazol-11- yl)pyrimidin-2-yl)cyclobutan-1-amine Step 1: (7R,14R)-1-(difluoromethoxy)-6-(4-methoxybenzyl)-4-methyl-11-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-4,6,7,14-tetrahydro-7,14- methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7-cd]indazole 54057-0027WO1 / SNV0020-WO1 PATENT To a solution of (7R,14R)-11-bromo-1-(difluoromethoxy)-6-(4- methoxybenzyl)-4-methyl-4,6,7,14-tetrahydro-7,14- methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7-cd]indazole (Example 1, Step 13: 20 mg, 0.04 mmol) in 1 mL of 1,4-dioxane was added bis(pinacolato)diboron (18 mg, 0.07 mmol), potassium acetate (10.4 mg, 0.11 mmol) and (1,1'- bis(diphenylphosphino)ferrocene)palladium(II) dichloride (5.8 mg, 0.01 mmol). The reaction mixture was stirred at 90 °C under nitrogen atmosphere for 2 h. The reaction mixture was partitioned between EtOAc and water and extracted with further EtOAc. The combined organic phases were filtered through a phase separator, and the solvent was removed in vacuo to give the titled compound which was used without further purification. LCMS calculated for C33H35BF2N5O4(M+H)+m / z = 614.3; found 614.2. Step 2: tert-butyl (1-(5-((7R,14R)-1-(difluoromethoxy)-6-(4-methoxybenzyl)-4-methyl- 4,6,7,14-tetrahydro-7,14-methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7- cd]indazol-11-yl)pyrimidin-2-yl)cyclobutyl)carbamate To a solution of (7R,14R)-1-(difluoromethoxy)-6-(4-methoxybenzyl)-4- methyl-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,6,7,14-tetrahydro-7,14- methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7-cd]indazole (24 mg, 0.04 mmol) in 1 mL of 1,4-dioxane and 0.2 mL of water was added tert-butyl (1-(5- bromopyrimidin-2-yl)cyclobutyl)carbamate (16 mg, 0.05 mmol), cesium carbonate (39 mg, 0.12 mmol) and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (3.27 mg, 0.004 mmol). The reaction mixture was stirred at 80 °C under nitrogen atmosphere for 1 h. The reaction mixture was partitioned between EtOAc and water and extracted with further EtOAc. The combined organic phases were filtered through a phase separator, and the solvent was removed in vacuo to give titled compound which was used without further purification. LCMS calculated for C40H41F2N8O4 (M+H)+m / z = 735.3; found 735.2. 54057-0027WO1 / SNV0020-WO1 PATENT Step 3: 1-(5-((7R,14R)-1-(difluoromethoxy)-6-(4-methoxybenzyl)-4-methyl-4,6,7,14- tetrahydro-7,14-methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7- cd]indazol-11-yl)pyrimidin-2-yl)cyclobutan-1-amine To a solution of tert-butyl (1-(5-((7R,14R)-1-(difluoromethoxy)-6-(4- methoxybenzyl)-4-methyl-4,6,7,14-tetrahydro-7,14- methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7-cd]indazol-11- yl)pyrimidin-2-yl)cyclobutyl)carbamate in 0.5 mL DCM was added 0.2 mL of 4N HCl in dioxane. After stirring for 2 h at rt, the mixture was concentrated under reduced pressure. The residue was diluted with MeOH and purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C35H33F2N8O2(M+H)+m / z = 635.3; found 635.2. Example 3: 2-(5-((7R,14R)-1-(Difluoromethoxy)-4-methyl-4,6,7,14-tetrahydro- 7,14-methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7-cd]indazol-11- yl)pyrimidin-2-yl)propan-2-ol To a solution of 2-(5-((7R,14R)-1-(difluoromethoxy)-6-(4-methoxybenzyl)-4- methyl-4,6,7,14-tetrahydro-7,14- methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7-cd]indazol-11- yl)pyrimidin-2-yl)propan-2-ol (Example 1: 10 mg, 0.02 mmol) in 0.5 mL of DCM was added 0.5 mL of TFA. After stirring for 1 h at rt, the mixture was concentrated under reduced pressure. The residue was diluted with MeOH and purified by prep- HPLC (column: Sunfire prep C18 column, 30*150 mm, 5μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions 54057-0027WO1 / SNV0020-WO1 PATENT were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C26H24F2N7O2 (M+H)+m / z = 504.2; found 504.2. Example 4.1-(5-((7R,14R)-1-(Difluoromethoxy)-4-methyl-4,6,7,14-tetrahydro- 7,14-methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7-cd]indazol-11- yl)pyrimidin-2-yl)cyclobutan-1-amine To a solution of tert-butyl (1-(5-((7R,14R)-1-(difluoromethoxy)-6-(4- methoxybenzyl)-4-methyl-4,6,7,14-tetrahydro-7,14- methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7-cd]indazol-11- yl)pyrimidin-2-yl)cyclobutyl)carbamate (Example 2, Step 2: 10 mg, 0.014 mmol) in 0.5 mL of DCM was added 0.5 mL of TFA. After stirring for 1 h at rt, the mixture was concentrated under reduced pressure. The residue was diluted with MeOH and purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C27H25F2N8O (M+H)+m / z = 515.2; found 515.3. Example 5.2-(5-((7R,14R)-1-(Difluoromethoxy)-4,6-dimethyl-4,6,7,14- tetrahydro-7,14-methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7- cd]indazol-11-yl)pyrimidin-2-yl)propan-2-ol 54057-0027WO1 / SNV0020-WO1 PATENT Step 1: (7R,14R)-11-bromo-1-(difluoromethoxy)-4-methyl-4,6,7,14-tetrahydro-7,14- methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7-cd]indazole To a solution of (7R,14R)-11-bromo-1-(difluoromethoxy)-6-(4- methoxybenzyl)-4-methyl-4,6,7,14-tetrahydro-7,14- methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7-cd]indazole (Example 1, Step 13: 20 mg, 0.04 mmol) in 1 mL of DCM was added 1 mL of TFA. After stirring at rt for 1 h, the solvent was removed in vacuo to give titled compound which was used without further purification. LCMS calculated for C19H15BrF2N5O (M+H)+m / z = 446.0; found 446.0. Step 2: (7R,14R)-11-bromo-1-(difluoromethoxy)-4,6-dimethyl-4,6,7,14-tetrahydro- 7,14-methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7-cd]indazole To a solution of (7R,14R)-11-bromo-1-(difluoromethoxy)-4-methyl-4,6,7,14- tetrahydro-7,14-methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7- cd]indazole (10 mg, 0.02 mmol) in 0.5 mL of DMF was added NaH (1.8 mg, 0.04 mmol, 60 % dispersion in mineral oil) at 0 °C. After stirring for 30 min at rt, the mixture was added MeI (2.8 uL, 0.04 mmol) at 0 °C. After stirring an additional 1 h at rt, the resulting mixture was quenched with water and extracted with EtOAc (3 x 2 mL). The combined organic fractions were washed with brine, dried over anhydrous sodium sulfate, filtered, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc in hexane to 54057-0027WO1 / SNV0020-WO1 PATENT provide the desired product as a yellow solid (8 mg, 78%). LCMS calculated for C20H17BrF2N5O (M+H)+m / z = 460.1; found 460.0. Step 3: 2-(5-((7R,14R)-1-(difluoromethoxy)-4,6-dimethyl-4,6,7,14-tetrahydro-7,14- methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7-cd]indazol-11- yl)pyrimidin-2-yl)propan-2-ol To a solution of (7R,14R)-11-bromo-1-(difluoromethoxy)-4,6-dimethyl- 4,6,7,14-tetrahydro-7,14-methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7- cd]indazole (8 mg, 0.017 mmol) in 1 mL of 1,4-dioxane and 0.2 mL of water was added 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)propan-2-ol (9.2 mg, 0.03 mmol), cesium carbonate (17 mg, 0.05 mmol) and (1,1'- bis(diphenylphosphino)ferrocene)palladium(II) dichloride (1.42 mg, 0.002 mmol). The reaction mixture was stirred at 80 °C under nitrogen atmosphere for 1 h. Then the mixture was diluted with water and extracted with EtOAc (3 x 50 mL). The combined organic fractions were washed with brine, dried over anhydrous sodium sulfate, filtered, then concentrated under reduced pressure. The residue was diluted with MeOH and purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C27H26F2N7O2(M+H)+m / z = 518.2; found 518.3. Example 6.1-(5-((7R,14R)-1-(Difluoromethoxy)-4,6-dimethyl-4,6,7,14- tetrahydro-7,14-methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7- cd]indazol-11-yl)pyrimidin-2-yl)cyclobutan-1-amine

[0003] 54057-0027WO1 / SNV0020-WO1 PATENT Step 1: (7R,14R)-1-(difluoromethoxy)-4,6-dimethyl-11-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-4,6,7,14-tetrahydro-7,14- methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7-cd]indazole To a solution of (7R,14R)-11-bromo-1-(difluoromethoxy)-4,6-dimethyl- 4,6,7,14-tetrahydro-7,14-methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7- cd]indazole (Example 5, Step 2: 10 mg, 0.02 mmol) in 1 mL of 1,4-dioxane was added bis(pinacolato)diboron (11 mg, 0.04 mmol), potassium acetate (6.4 mg, 0.07 mmol) and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (3.6 mg, 0.004 mmol). The mixture was stirred at 90 °C under nitrogen atmosphere for 2 h. The reaction mixture was partitioned between EtOAc and water and extracted with further EtOAc. The combined organic phases were filtered through a phase separator and the solvent removed in vacuo to give the titled compound which was used without further purification. LCMS calculated for C26H29BF2N5O3 (M+H)+m / z = 508.2; found 508.2. Step 2: tert-butyl (1-(5-((7R,14R)-1-(difluoromethoxy)-4,6-dimethyl-4,6,7,14- tetrahydro-7,14-methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7- cd]indazol-11-yl)pyrimidin-2-yl)cyclobutyl)carbamate To a solution of (7R,14R)-1-(difluoromethoxy)-4,6-dimethyl-11-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-4,6,7,14-tetrahydro-7,14- methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7-cd]indazole (10 mg, 0.02 mmol) in 1 mL of 1,4-dioxane and 0.2 mL of water was added tert-butyl (1-(5- 54057-0027WO1 / SNV0020-WO1 PATENT bromopyrimidin-2-yl)cyclobutyl)carbamate (9.7 mg, 0.03 mmol), cesium carbonate (19 mg, 0.06 mmol) and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (1.6 mg, 0.002 mmol). The mixture was stirred at 80 °C under nitrogen atmosphere for 1 h. The reaction mixture was partitioned between EtOAc and water and extracted with further EtOAc. The combined organic phases were filtered through a phase separator and the solvent removed in vacuo to give the titled compound which was used without further purification. LCMS calculated for C33H35F2N8O3(M+H)+m / z = 629.3; found 629.2. Step 3: 1-(5-((7R,14R)-1-(difluoromethoxy)-4,6-dimethyl-4,6,7,14-tetrahydro-7,14- methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7-cd]indazol-11- yl)pyrimidin-2-yl)cyclobutan-1-amine To a solution of tert-butyl (1-(5-((7R,14R)-1-(difluoromethoxy)-4,6-dimethyl- 4,6,7,14-tetrahydro-7,14-methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7- cd]indazol-11-yl)pyrimidin-2-yl)cyclobutyl)carbamate in 0.5 mL DCM was added 0.1 mL of TFA. After stirring for 30 min at rt, the mixture was concentrated under reduced pressure. The residue was diluted with MeOH and purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); eluted fractions were collected and lyophilized to provide the TFA salt of the desired product as a white solid. LCMS calculated for C28H27F2N8O (M+H)+m / z = 529.2; found 529.3. Example A. HEK-Blue TNFα reporter assay The purpose of this assay is to determine the potency of the synthesized TNFα inhibitors. HEK-blue CD40L cells were generated by stable expression of the human CD40 gene and an NF-κB-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-κB and subsequent production of SEAP. HEK293 host cells also express endogenously the receptors for TNF-α which shares a common signaling pathway with CD40L. Therefore, HEK-blue CD40L cells also respond to TNF-α. Interaction of TNF-α 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 54057-0027WO1 / SNV0020-WO1 PATENT detection reagent. The complete medium for cell culture includes DMEM, 4.5 g / l glucose, 2 mM L-glutamine, 10% heat-inactivated fetal bovine serum, 100 U / ml penicillin, 100 µg / ml streptomycin, and 100 µg / ml Zeocin. Assay medium is the complete medium without Zeocin. Recombinant human TNF-α 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-α. Compounds were preincubated with TNF-α 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. 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 IC50greater than or equal to 1000 nM but less than 5000 nM; and “++++” indicates an IC50greater than or equal to 5000 nM. Table A. 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

54057-0027WO1 / SNV0020-WO1 PATENT WHAT IS CLAIMED IS:

1. A compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, 5, or 6; q is 0, 1, 2, 3, or, 4; X1, X2, X3, X4are each independently N or C, wherein one of X1, X2, X3, and X4is N, and three of X1, X2, X3, and X4are C; Y1is N or CR4; Y2is N or CR5; Y3is N or CR6; Y4is N or CR7; Ring A is selected from a C5-14 bicyclic cycloalkyl, C6-14 membered tricyclic cycloalkyl, 5-14 membered bicyclic heterocycloalkyl, 6-14 membered tricyclic heterocycloalkyl, naphthyl, 8-10 membered bicyclic heteroaryl, and 11-14 membered tricyclic heteroaryl; Ring B is a 5-membered heteroaryl; each L1and L2is independently selected from C1-6alkylene, C2-6alkenylene, 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 C1-6alkylene, C2-6alkenylene, C3-10cycloalkylene, 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;54057-0027WO1 / SNV0020-WO1 PATENT each RL2cis independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4alkyl, - 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, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-4alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4 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, C1-6alkyl, C1-6alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4alkyl; each RL2is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6haloalkyl, C3-7cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7cycloalkyl-C1-4alkyl, phenyl-C1-4alkyl, (4-7 membered heterocycloalkyl)-C1-4 alkyl, (5-6 membered heteroaryl)-C1-4 alkyl, -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 C1-54057-0027WO1 / SNV0020-WO1 PATENT6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-7cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, (4-7 membered heterocycloalkyl)-C1-4 alkyl, and (5-6 membered heteroaryl)-C1-4alkyl 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, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, (4-7 membered heterocycloalkyl)-C1-4 alkyl, and (5-6 membered heteroaryl)-C1-4alkyl, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-7cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, (4-7 membered heterocycloalkyl)-C1-4 alkyl, and (5-6 membered heteroaryl)-C1-4 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 H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6alkynyl, C3-7cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7cycloalkyl-C1-4alkyl, phenyl-C1-4alkyl, (4-7 membered heterocycloalkyl)-C1-4 alkyl, and (5-6 membered heteroaryl)-C1-4 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, C3-7cycloalkyl-C1-4alkyl, phenyl-C1-4alkyl, (4-7 membered heterocycloalkyl)-C1-4alkyl, and (5-6 membered heteroaryl)-C1-4 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, C1-6alkyl, C1-6alkoxy, 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-C1-4 alkyl, phenyl-C1-4alkyl, (4-7 membered heterocycloalkyl)-C1-4alkyl, and (5-6 membered heteroaryl)-C1-4 alkyl;54057-0027WO1 / SNV0020-WO1 PATENT each RfL2and RgL2are independently selected from H, C1-6alkyl, C1-6alkoxy, 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-C1-4 alkyl, phenyl-C1-4alkyl, (4-7 membered heterocycloalkyl)-C1-4alkyl, and (5-6 membered heteroaryl)-C1-4 alkyl; each R1is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4 alkyl, -CN, - ORa1, -SRa1, -NRc1Rd1, -NO2, -C(O)Ra1, -C(O)ORa1, -C(O)NRc1Rd1, - C(O)NRc1(ORa1), -OC(O)Ra1, -OC(O)NRc1Rd1, -OC(O)ORa1, -OS(O)2Rb1, - OS(O)2NRc1Rd1, -NRc1C(O)Ra1, -NRc1C(O)ORa1, -NRc1C(O)NRc1Rd1, -NRc1S(O)2Rb1, -NRc1S(O)2NRc1Rd1, -NRc1ORa1, -NRc1S(O)Rb1, -NRc1S(O)NRc1Rd1, -S(O)Rb1, - S(O)2Rb1, -S(O)NRc1Rd1, -S(O)2NRc1Rd1, -C(=NRe1)Ra1, -C(=NRe1)NRc1Rd1, - NRc1C(=NRe1)Ra1, -NRc1C(=NRe1)NRc1Rd1, -NRc1S(O)(=NRe1)Rb1, - NRc1S(O)(=NRe1)NRc1Rd1, -OS(O)(=NRe1)Rb1, -S(O)(=NRe1)Rb1, - S(O)(=NRe1)NRc1Rd1, -C(O)NRc1S(O)2Rb1, -C(O)NRc1S(O)2NRc1Rd1, - S(O)2NRc1C(O)Rb1, -NRc1S(O)NRc1C(O)Rb1, and -P(O)Rf1Rg1, wherein the C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-4alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl of R1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1Asubstituents; or, two R1, together with the atoms to which they are attached to, form a C3-7cycloalkyl, 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 R1Asubstituents; each Ra1, Rc1, and Rd1is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-4alkyl, C6-10aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered54057-0027WO1 / SNV0020-WO1 PATENT heteroaryl)-C1-4alkyl, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4alkyl of Ra1, Rc1, and Rd1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1Asubstituents; or, any Rc1and Rd1attached 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 Rb1is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5- 10 membered heteroaryl)-C1-4alkyl of Rb1are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1Asubstituents; each Re1is independently selected from H, OH, CN, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4alkyl; each Rf1and Rg1are independently selected from H, C1-6alkyl, C1-6alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4- 10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-4alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl; each R1Ais independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4 alkyl, (4-1054057-0027WO1 / SNV0020-WO1 PATENT membered heterocycloalkyl)-C1-4alkyl, (5-10 membered heteroaryl)-C1-4alkyl, -CN, - ORa1A, -SRa1A, -NRc1ARd1A, -NO2, -C(O)Ra1A, -C(O)ORa1A, -C(O)NRc1ARd1A, - C(O)NRc1A(ORa1A), -OC(O)Ra1A, -OC(O)NRc1ARd1A, -OC(O)ORa1A, -OS(O)2Rb1A, - OS(O)2NRc1ARd1A, -NRc1AC(O)Ra1A, -NRc1AC(O)ORa1A, -NRc1AC(O)NRc1ARd1A, - NRc1AS(O)2Rb1A, -NRc1AS(O)2NRc1ARd1A, -NRc1AORa1A, -NRc1AS(O)Rb1A, - NRc1AS(O)NRc1ARd1A, -S(O)Rb1A, -S(O)2Rb1A, -S(O)NRc1ARd1A, -S(O)2NRc1ARd1A, - C(=NRe1A)Ra1A, -C(=NRe1A)NRc1ARd1A, -NRc1AC(=NRe1A)Ra1A, - NRc1AC(=NRe1A)NRc1ARd1A, -NRc1AS(O)(=NRe1A)Rb1A, - NRc1AS(O)(=NRe1A)NRc1ARd1A, -OS(O)(=NRe1A)Rb1A, -S(O)(=NRe1A)Rb1A, - S(O)(=NRe1A)NRc1ARd1A, -C(O)NRc1AS(O)2Rb1A, -C(O)NRc1AS(O)2NRc1ARd1A, - S(O)2NRc1AC(O)Rb1A, -NRc1AS(O)NRc1AC(O)Rb1A, and -P(O)Rf1ARg1A, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl of R1Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra1A, Rc1A, and Rd1Ais independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4alkyl, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4alkyl of Ra1A, Rc1A, and Rd1Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc1Aand Rd1Aattached 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 Rb1Ais independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-54057-0027WO1 / SNV0020-WO1 PATENT 10 membered heteroaryl, C3-10cycloalkyl-C1-4alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10cycloalkyl- C1-4 alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5- 10 membered heteroaryl)-C1-4 alkyl of Rb1Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Re1Ais 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, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-4alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl; each Rf1Aand Rg1Aare independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4alkyl; R2and R3are independently selected from H, halo, C1-6alkyl, C2-6alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7cycloalkyl-C1-4alkyl, phenyl-C1-4alkyl, (4-7 membered heterocycloalkyl)-C1-4alkyl, (5-6 membered heteroaryl)-C1-4alkyl, -CN, -ORa2, -SRa2,P(O)Rf2Rg2, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, (4-7 membered heterocycloalkyl)-C1-4 alkyl,54057-0027WO1 / SNV0020-WO1 PATENT and (5-6 membered heteroaryl)-C1-4alkyl of R2and R3are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra2, Rc2, and Rd2is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, (4-7 membered heterocycloalkyl)-C1-4 alkyl, and (5-6 membered heteroaryl)-C1-4alkyl, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-7cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, (4-7 membered heterocycloalkyl)-C1-4 alkyl, and (5-6 membered heteroaryl)-C1-4alkyl of Ra2, Rc2, and Rd2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc2and Rd2attached to the same N atom, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group, wherein the 4- 7 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Rb2is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6alkynyl, C3-7cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7cycloalkyl-C1-4alkyl, phenyl-C1-4alkyl, (4-7 membered heterocycloalkyl)-C1-4 alkyl, and (5-6 membered heteroaryl)-C1-4 alkyl, wherein the C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7cycloalkyl-C1-4alkyl, phenyl-C1-4 alkyl, (4-7 membered heterocycloalkyl)-C1-4 alkyl, and (5-6 membered heteroaryl)-C1-4 alkyl of Rb2are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Re2is independently selected from H, OH, CN, C1-6alkyl, C1-6alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7cycloalkyl-C1-4alkyl, phenyl-C1-4alkyl, (4-7 membered heterocycloalkyl)-C1-4alkyl, and (5-6 membered heteroaryl)-C1-4 alkyl; each Rf2and Rg2are independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl,54057-0027WO1 / SNV0020-WO1 PATENT phenyl-C1-4alkyl, (4-7 membered heterocycloalkyl)-C1-4alkyl, and (5-6 membered heteroaryl)-C1-4 alkyl; R4, R5, and R6are independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1- 4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4alkyl, -CN, -ORa5, -SRa5, -NRc5Rd5, -NO2, -C(O)Ra5, -C(O)ORa5, -C(O)NRc5Rd5, - C(O)NRc5(ORa5), -OC(O)Ra5, -OC(O)NRc5Rd5, -OC(O)ORa5, -OS(O)2Rb5, - OS(O)2NRc5Rd5, -NRc5C(O)Ra5, -NRc5C(O)ORa5, -NRc5C(O)NRc5Rd5, -NRc5S(O)2Rb5, -NRc5S(O)2NRc5Rd5, -NRc5ORa5, -NRc5S(O)Rb5, -NRc5S(O)NRc5Rd5, -S(O)Rb5, - S(O)2Rb5, -S(O)NRc5Rd5, -S(O)2NRc5Rd5, -C(=NRe5)Ra5, -C(=NRe5)NRc5Rd5, - NRc5C(=NRe5)Ra5, -NRc5C(=NRe5)NRc5Rd5, -NRc5S(O)(=NRe5)Rb5, - NRc5S(O)(=NRe5)NRc5Rd5, -OS(O)(=NRe5)Rb5, -S(O)(=NRe5)Rb5, - S(O)(=NRe5)NRc5Rd5, -C(O)NRc5S(O)2Rb5, -C(O)NRc5S(O)2NRc5Rd5, - S(O)2NRc5C(O)Rb5, -NRc5S(O)NRc5C(O)Rb5, and -P(O)Rf5Rg5, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-4alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl of R4, R5, and R6are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R5Asubstituents; each Ra5, Rc5, and Rd5is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4alkyl, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-4alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4alkyl of Ra5, Rc5, and Rd5are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R5Asubstituents; or, any Rc5and Rd5attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the54057-0027WO1 / SNV0020-WO1 PATENT 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R5Asubstituents; each Rb5is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl, wherein the C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5- 10 membered heteroaryl)-C1-4alkyl of Rb5are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R5Asubstituents; each Re5is 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, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-4alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl; each Rf5and Rg5are independently selected from H, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 4- 10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4alkyl; each R5Ais independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-4alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, (5-10 membered heteroaryl)-C1-4alkyl, -CN, -54057-0027WO1 / SNV0020-WO1 PATENT NRc5AS(O)(=NRe5A)NRc5ARd5A, -OS(O)(=NRe5A)Rb5A, -S(O)(=NRe5A)Rb5A, - S(O)(=NRe5A)NRc5ARd5A, -C(O)NRc5AS(O)2Rb5A, -C(O)NRc5AS(O)2NRc5ARd5A, - S(O)2NRc5AC(O)Rb5A, -NRc5AS(O)NRc5AC(O)Rb5A, and -P(O)Rf5ARg5A, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4alkyl of R5Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R5Bsubstituents; each Ra5A, Rc5A, and Rd5Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-4alkyl, C6-10aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl of Ra5A, Rc5A, and Rd5Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R5Bsubstituents; or, any Rc5Aand Rd5Aattached 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 R5Bsubstituents; each Rb5Ais independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10cycloalkyl-C1-4alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl, wherein the C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10cycloalkyl- C1-4 alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5- 10 membered heteroaryl)-C1-4 alkyl of Rb5Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R5Bsubstituents;54057-0027WO1 / SNV0020-WO1 PATENT each Re5Ais independently selected from H, OH, CN, C1-6alkyl, C1-6alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl; each Rf5Aand Rg5Aare independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4alkyl; each R5Bis independently selected from oxo, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, (5-10 membered heteroaryl)-C1-4alkyl, -CN, - ORa5B, -SRa5B, -NRc5BRd5B, -NO2, -C(O)Ra5B, -C(O)ORa5B, -C(O)NRc5BRd5B, - C(O)NRc5B(ORa5B), -OC(O)Ra5B, -OC(O)NRc5BRd5B, -OC(O)ORa5B, -OS(O)2Rb5B, - OS(O)2NRc5BRd5B, -NRc5BC(O)Ra5B, -NRc5BC(O)ORa5B, -NRc5BC(O)NRc5BRd5B, - NRc5BS(O)2Rb5B, -NRc5BS(O)2NRc5BRd5B, -NRc5BORa5B, -NRc5BS(O)Rb5B, - NRc5BS(O)NRc5BRd5B, -S(O)Rb5B, -S(O)2Rb5B, -S(O)NRc5BRd5B, -S(O)2NRc5BRd5B, - C(=NRe5B)Ra5B, -C(=NRe5B)NRc5BRd5B, -NRc5BC(=NRe5B)Ra5B, - NRc5BC(=NRe5B)NRc5BRd5B, -NRc5BS(O)(=NRe5B)Rb5B, - NRc5BS(O)(=NRe5B)NRc5BRd5B, -OS(O)(=NRe5B)Rb5B, -S(O)(=NRe5B)Rb5B, - S(O)(=NRe5B)NRc5BRd5B, -C(O)NRc5BS(O)2Rb5B, -C(O)NRc5BS(O)2NRc5BRd5B, - S(O)2NRc5BC(O)Rb5B, -NRc5BS(O)NRc5BC(O)Rb5B, and -P(O)Rf5BRg5B, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4alkyl of R5Bare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Ra5B, Rc5B, and Rd5Bis independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-54057-0027WO1 / SNV0020-WO1 PATENT4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-4alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl of Ra5B, Rc5B, and Rd5Bare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; or, any Rc5Band Rd5Battached 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 Rb5Bis independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10cycloalkyl-C1-4alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10cycloalkyl- C1-4alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5- 10 membered heteroaryl)-C1-4 alkyl of Rb5Bare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RGsubstituents; each Re5Bis independently selected from H, OH, CN, C1-6alkyl, C1-6alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4alkyl; each Rf5Band Rg5Bare independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-4alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl, and (5-10 membered heteroaryl)-C1-4 alkyl; R7is selected from H, halo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C1-6 haloalkoxy;54057-0027WO1 / SNV0020-WO1 PATENT each RGis independently selected from OH, CN, halo, oxo, C1-4alkyl, C2-4alkenyl, C2-4 alkynyl, C1-4 haloalkyl, cyano-C1-4 alkyl, HO-C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-3alkylamino, di(C1-3alkyl)amino, thio, C1-3alkylthio, C1-3alkylsulfinyl, C1-3 alkylsulfonyl, carbamyl, C1-3 alkylcarbamyl, di(C1-3 alkyl)carbamyl, carboxy, C1-3 alkylcarbonyl, C1-3 alkoxycarbonyl, C1-3 alkylcarbonyloxy, C1-3 alkylcarbonylamino, C1-3alkoxycarbonylamino, aminocarbonyloxy, C1-3alkylaminocarbonyloxy, di(C1-3alkyl)aminocarbonyloxy, C1-3 alkylsulfonylamino, aminosulfonyl, C1-3 alkylaminosulfonyl, di(C1-3 alkyl)aminosulfonyl, aminosulfonylamino, C1-3 alkylaminosulfonylamino, di(C1-3alkyl)aminosulfonylamino, aminocarbonylamino, C1-3alkylaminocarbonylamino, and di(C1-3alkyl)aminocarbonylamino.

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

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X2is N.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein X3is C.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein X4is C.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein Y1is CR4.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R4is H or C1-6 alkyl.

8. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R4is H.54057-0027WO1 / SNV0020-WO1 PATENT 9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein Y2is CR5.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein Y3is CR6.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R6is H or C1-6 alkyl.

12. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R6is H.

13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein Y4is CR7.

14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R7is H or C1-6alkyl.

15. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R7is H.

16. The compound of any claim 1, or a pharmaceutically acceptable salt thereof, wherein: X1is C; X2is N; X3is C; Y1is CR4; Y2is CR5; Y3is CR6; Y4is CR7; R4is H or C1-3 alkyl;54057-0027WO1 / SNV0020-WO1 PATENT R6is H or C1-3alkyl; and R7is H or C1-3 alkyl.

17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R5is C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, or (5-10 membered heteroaryl)- C1-4 alkyl, wherein the C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4alkyl, and (5-10 membered heteroaryl)-C1-4alkyl of R5are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R5Asubstituents.

18. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R5is C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, wherein the C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of R5are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R5Asubstituents.

19. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R5is C3-7cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, wherein the C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl of R5are each optionally substituted with 1, 2, 3, or 4 independently selected R5Asubstituents.

20. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R5is 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl of R5is optionally substituted with 1, 2, 3, or 4 independently selected R5Asubstituents.54057-0027WO1 / SNV0020-WO1 PATENT 21. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R5is pyrimidinyl, which is optionally substituted with 1 or 2 independently selected R5Asubstituents.

22. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein each R5Ais independently selected from C1-6alkyl, C2-6alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of R5Aare each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R5Bsubstituents.

24. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein each R5Ais independently selected from C1-6 alkyl, C1-6 haloalkyl, C3-7cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl of R5Aare each optionally substituted with 1, 2, 3, or 4 independently selected R5Bsubstituents.

25. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein each R5Ais independently selected from C1-6 alkyl and C3-7 cycloalkyl, wherein the C1-6alkyl and C3-7cycloalkyl of R5Aare each optionally substituted with 1 or 2 independently selected R5Bsubstituents.

26. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein each R5Ais independently selected from isopropyl and cyclobutyl, wherein the isopropyl and cyclobutyl of R5Aare each optionally substituted with 1 or 2 independently selected R5Bsubstituents.54057-0027WO1 / SNV0020-WO1 PATENT 27. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein each R5Bis independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C1-6haloalkyl, -CN, -ORa5B, and -NRc5BRd5B; and each Ra5B, Rc5B, and Rd5Bis independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl.

28. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein each R5Bis independently selected from -ORa5Band -NRc5BRd5B; and each Ra5B, Rc5B, and Rd5Bis independently selected from H and C1-6alkyl.

29. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein each R5Bis independently selected from hydroxy and amino.

30. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein each R5Ais independently selected from hydroxyisopropyl and aminocyclobutyl.

31. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R5is selected from.

32. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein q is 0.

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

34. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein each L2is independently selected from C1-6 alkylene, C3-1054057-0027WO1 / SNV0020-WO1 PATENT cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6 membered heteroarylene, -O-, -N(RL2c)-, and -C(O)-.

35. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein each L2is independently -N(RL2c)-.

36. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein each RL2cis 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, C3-7cycloalkyl-C1-4alkyl, phenyl-C1-4alkyl, (4-7 membered heterocycloalkyl)-C1-4alkyl, and (5-6 membered heteroaryl)-C1-4 alkyl, wherein each 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-C1-4alkyl, phenyl-C1-4alkyl, (4-7 membered heterocycloalkyl)-C1-4alkyl, and (5-6 membered heteroaryl)-C1-4 alkyl of RL2cis optionally substituted with 1, 2, 3, or 4 independently selected RL2substituents.

37. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein each RL2cis independently selected from H, C1-6 alkyl, phenyl, and phenyl-C1-4alkyl, wherein each C1-6alkyl, phenyl, and phenyl-C1-4alkyl of RL2cis optionally substituted with 1, 2, 3, or 4 independently selected RL2substituents; each RL2is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, and -ORaL2; and each RaL2is independently selected from H and C1-6alkyl.

38. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein each RL2cis independently selected from H, methyl, benzyl, wherein each methyl and benzyl of RL2cis optionally substituted with 1 or 2 RL2substituents independently selected from -ORaL2; and each RaL2is independently selected from H and C1-3 alkyl.54057-0027WO1 / SNV0020-WO1 PATENT 39. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein each RL2cis independently selected from H, methyl, and methoxybenzyl.

40. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein Ring A is an 8-10 membered bicyclic heteroaryl.

41. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein Ring A is indazolyl.

42. The compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, or 3.

43. The compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein m is 2.

44. The compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein each R1is independently selected from oxo, halo, C1-6alkyl, C2-6alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -CN, -ORa1, and -NRc1Rd1; and each Ra1, Rc1, and Rd1is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, and C2-6alkynyl.

45. The compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein each R1is independently selected from halo, C1-6alkyl, C1-6haloalkyl, and -ORa1; and each Ra1, Rc1, and Rd1is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl.

46. The compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein each R1is independently selected from methyl and difluoromethoxy.54057-0027WO1 / SNV0020-WO1 PATENT 47. The compound of any one of claims 1 to 46, or a pharmaceutically acceptable salt thereof, wherein R2is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl.

48. The compound of any one of claims 1 to 46, or a pharmaceutically acceptable salt thereof, wherein R2is selected from H and C1-6 alkyl.

49. The compound of any one of claims 1 to 46, or a pharmaceutically acceptable salt thereof, wherein R2is H.

50. The compound of any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof, wherein R3is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl.

51. The compound of any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof, wherein R3is selected from H and C1-6 alkyl.

52. The compound of any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof, wherein R3is H.

53. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: X1is C; X2is N; X3is C; Y1is CR4; Y2is CR5; Y3is CR6; Y4is CR7; Ring A is a 5-14 membered bicyclic heterocycloalkyl or 8-10 membered bicyclic heteroaryl; Ring B is a 5-membered heteroaryl;54057-0027WO1 / SNV0020-WO1 PATENT m is 0, 1, 2, or 3; p is 1 or 2; q is 0, 1, or 2; each L1and L2is independently selected from C1-6alkylene, C3-10cycloalkylene, 4-7 membered heterocycloalkylene, phenylene, 5-6 membered heteroarylene, -O-, -N(RL2c)-, and -C(O)-; each RL2cis independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, (4-7 membered heterocycloalkyl)-C1-4alkyl, and (5-6 membered heteroaryl)-C1-4alkyl, wherein each C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, (4-7 membered heterocycloalkyl)-C1-4 alkyl, and (5-6 membered heteroaryl)-C1-4alkyl of RL2cis optionally substituted with 1, 2, 3, or 4 independently selected RL2substituents; each RL2is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6haloalkyl, -CN, and -ORaL2; each RaL2is independently selected from H and C1-6alkyl; each R1is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6haloalkyl, -CN, -ORa1, and -NRc1Rd1; each Ra1, Rc1, and Rd1is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; R2is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; R3is selected from H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C1-6haloalkyl; R4is selected from H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C1-6haloalkyl; R6is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; and R7is selected from H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C1-6haloalkyl.54057-0027WO1 / SNV0020-WO1 PATENT 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:or a pharmaceutically acceptable salt thereof.

56. The compound of claim 1, wherein the compound of Formula I is a compound of Formula IV:54057-0027WO1 / SNV0020-WO1 PATENTIV or a pharmaceutically acceptable salt thereof.

57. The compound of claim 1, which is selected from: 2-(5-((7R,14R)-1-(difluoromethoxy)-6-(4-methoxybenzyl)-4-methyl-4,6,7,14- tetrahydro-7,14-methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7- cd]indazol-11-yl)pyrimidin-2-yl)propan-2-ol; 1-(5-((7R,14R)-1-(difluoromethoxy)-6-(4-methoxybenzyl)-4-methyl-4,6,7,14- tetrahydro-7,14-methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7- cd]indazol-11-yl)pyrimidin-2-yl)cyclobutan-1-amine; 2-(5-((7R,14R)-1-(difluoromethoxy)-4-methyl-4,6,7,14-tetrahydro-7,14- methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7-cd]indazol-11- yl)pyrimidin-2-yl)propan-2-ol; 1-(5-((7R,14R)-1-(difluoromethoxy)-4-methyl-4,6,7,14-tetrahydro-7,14- methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7-cd]indazol-11- yl)pyrimidin-2-yl)cyclobutan-1-amine; 2-(5-((7R,14R)-1-(difluoromethoxy)-4,6-dimethyl-4,6,7,14-tetrahydro-7,14- methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7-cd]indazol-11- yl)pyrimidin-2-yl)propan-2-ol; and 1-(5-((7R,14R)-1-(difluoromethoxy)-4,6-dimethyl-4,6,7,14-tetrahydro-7,14- methanobenzo[4',5']imidazo[1',2':1,2][1,4]diazocino[5,6,7-cd]indazol-11- yl)pyrimidin-2-yl)cyclobutan-1-amine; or a pharmaceutically acceptable salt thereof.54057-0027WO1 / SNV0020-WO1 PATENT 58. A pharmaceutical composition, comprising a compound of any one of claims 1 to 57, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

59. A method of inhibiting an activity of tumor necrosis factor-alpha (TNFα), comprising contacting the TNFα with a compound of any one of claims 1 to 57, or a pharmaceutically acceptable salt thereof.

60. A method of treating a TNFα-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 57, or a pharmaceutically acceptable salt thereof.

61. The method of claim 60, wherein the disease or disorder is and autoimmune disease or inflammatory disease.

62. The method of claim 61, wherein the inflammatory disease is a chronic inflammatory disease.

63. The method of any one of claims 60 to 62, wherein the disease or disorder is neurodegenerative disease associated with TNF-α related inflammation and apoptosis.

64. The method of any one of claims 60 to 63, 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, Behçet'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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