Combination therapy

Abstract

Described herein is a composition or a kit comprising a therapeutically effective amount of a TEAD inhibitor and a therapeutically effective amount of other types of inhibitors that are useful for treating cancer, including relapsed or refractory cancer. Also, described herein is a method of treating cancer in a patient in need thereof, including administering to the patient a therapeutically effective amount of a TEAD inhibitor and a therapeutically effective amount of other types of inhibitors. Specific cancer, such as relapsed or refractory cancers, includes those that are mediated by YAP / TAZ or those that are modulated by the interaction between YAP / TAZ and TEAD.

Description

COMBINATION THERAPYCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 607,831 filed on December 8, 2023, which is herein incorporated by reference in its entirety.BACKGROUND OF THE DISCLOSURE

[0002] YAP and TAZ are transcriptional co-activators of the Hippo pathway network and regulate cell proliferation, migration, and apoptosis. Inhibition of the Hippo pathway promotes YAP / TAZ translocation to the nucleus, wherein YAP / TAZ interact with transcriptional enhancer associate domain (TEAD) transcription factors and coactivate the expression of target genes and promote cell proliferation. Hyperactivation of YAP and TAZ and / or mutations in one or more members of the Hippo pathway network have been implicated in numerous cancers. Described herein are inhibitors associated with one or more members of the Hippo pathway network, such as inhibitors of YAP / TAZ or inhibitors that modulate the interaction between YAP / TAZ and TEAD.

[0003] Combinations of therapeutic agents (e.g., drugs) can improve overall efficacies and targeting tumor robustness and complexity to minimize resistance. Although it is not clear how many therapeutic agents are required and what processes need to be targeted in combination to a certain type of cancer, it usually requires inhibition of different pathways or drivers. A number of treatment options for patients with specific types of cancer exist, but it is necessary to develop effective and safe combination therapies that can be administered for the treatment of cancer.SUMMARY OF THE DISCLOSURE

[0004] In one aspect, provided herein are compositions and kits comprising a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent, wherein the second therapeutic agent is selected from a c-MET inhibitor, a BRAF inhibitor, an EGFR inhibitor, a MEK inhibitor, a KRAS inhibitor, and a mTOR inhibitor. In some embodiments, the subject compositions and kits are useful for the treatment of cancer. In some embodiments, the cancer is a relapsed or refractory cancer.

[0005] In one aspect, provided herein are methods of treating cancer in a patient in need thereof by administering to a patient a composition comprising a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent, wherein the second therapeutic agent is selected from a c-MET inhibitor, a BRAF inhibitor, an EGFR inhibitor, a MEK inhibitor, a KRAS inhibitor, and a mTOR inhibitor. In some embodiments, the cancer is a relapsed or refractory cancer. In some embodiments, the methods disclosed herein cause synergistic effects in treating cancer.

[0006] In one aspect, disclosed herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent, wherein the cancer is a relapsed or refractory cancer. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 1 mg to about 300 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 25 mg to about 200 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 25 mg to about 100 mg per day.

[0007] In another aspect, disclosed herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent, wherein the therapeutically effective amount of the TEAD inhibitor is about 1 mg to about 300 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 25 mg to about 200 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 25 mg to about 100 mg per day. In some embodiments, the cancer is a relapsed or refractory cancer. In some embodiments, the second therapeutic agent is selected from a c-MET inhibitor, a BRAF inhibitor, an EGFR inhibitor, a MEK inhibitor, a KRAS inhibitor, and a mTOR inhibitor. In some embodiments, the second therapeutic agent is a c-MET inhibitor. In some embodiments, the therapeutically effective amount of the c- MET inhibitor is about 1 mg to about 800 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 1 mg to about 400 mg per day. In some embodiments, the c-MET inhibitor is selected from cabozantinib, crizotinib, foretinib, tivantinib, savolitinib, capmatinib, and tepotinib, or a combination thereof. In some embodiments, the c-MET inhibitor is selected from savolitinib and capmatinib, or a combination thereof. In some embodiments, the relapsed or refractory cancer is a c-MET mutant cancer. In some embodiments, the relapsed or refractory cancer is a c-MET amplified cancer. In some embodiments, the second therapeutic agent is a BRAF inhibitor. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 1 mg to about 400 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 1 mg to about 200 mg per day. In some embodiments, the BRAF inhibitor is selected from vemurafenib, dabrafenib, encorafenib, and sorafenib, or a combination thereof. In some embodiments, the BRAF inhibitor is sorafenib. In some embodiments, the relapsed or refractory cancer is a BRAF mutant cancer. In some embodiments, the second therapeutic agent is an EGFR inhibitor. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 1 mg to about 80 mg per day. Insome embodiments, the therapeutically effective amount of the EGFR inhibitor is about 1 mg to about 40 mg per day. In some embodiments, the EGFR inhibitor comprises a monoclonal antibody. In some embodiments, the EGFR inhibitor comprises a tyrosine kinase inhibitor. In some embodiments, the EGFR inhibitor is selected from cetuximab, necitumumab, panitumumab, zalutumumab, nimotuzumab, matuzumab, osimertinib, gefitinib, erlotinib, lapatinib, neratinib, vandetanib, afatinib, brigatinib, dacomitinib, lazertinib, amivantamab, and icotinib, or a combination thereof. In some embodiments, the EGFR inhibitor is selected from osimertinib, lazertinib, and amivantamab, or a combination thereof. In some embodiments, the relapsed or refractory cancer is an EGFR mutant cancer. In some embodiments, the relapsed or refractory cancer is an EGFR mutant lung cancer or an EGFR mutant non-small cell lung cancer (NSCLC). In some embodiments, the second therapeutic agent is a MEK inhibitor. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 1 mg to about 60 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 1 mg to about 30 mg per day. In some embodiments, the MEK inhibitor is selected from refametinib, selumetinib, trametinib, cobimetinib, binimetinib, mirdametinib, and pimasertib, or a combination thereof. In some embodiments, the MEK inhibitor is selected from cobimetinib and trametinib, or a combination thereof. In some embodiments, the second therapeutic agent is a KRAS inhibitor. In some embodiments, the therapeutically effective amount of the KRAS inhibitor about 1 mg to about 1200 mg per day. Th In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 1 mg to about 600 mg per day. In some embodiments, the KRAS inhibitor is selected from an inhibitor of a KRAS G12C mutant, an inhibitor of a KRAS G12D mutant, an inhibitor of a KRAS G12V mutant, and an inhibitor of a KRAS G13 mutant, or a combination thereof. In some embodiments, the KRAS inhibitor is selected from adagrasib and sotorasib, or a combination thereof. In some embodiments, the relapsed or refractory cancer is a KRAS mutant cancer. In some embodiments, the KRAS mutant cancer harbors one or more KRAS mutations selected from a KRAS G12C mutation, a KRAS G12D mutation, a KRAS G12V mutation, and a KRAS G13 mutation. In some embodiments, the second therapeutic agent is a mTOR inhibitor. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 1 mg to about 10 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 1 mg to about 5 mg per day. In some embodiments, the mTOR inhibitor is selected from mTORCl inhibitor and mTORC2 inhibitor, or a combination thereof. In some embodiments, the mTOR inhibitor is selected from temsirolimus, everolimus, ridaforolimus, sirolimus, umirolimus, and zotarolimus, or a combination thereof. In some embodiments, the mTOR inhibitor is everolimus. In some embodiments, the therapeutically effective amount of thefirst therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent are administered simultaneously. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent are formulated together in a single composition. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent are administered sequentially. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent are formulated in separate compositions. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent is administered daily for at least a week. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent is administered daily for at least two weeks. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent is administered daily for at least three weeks. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent is administered daily for at least 24 days. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent is administered in a cycle length of three weeks, wherein the therapeutically effective amount is administered daily for one week, and then not administered for the following two weeks. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent is administered in a cycle length of three weeks, wherein the therapeutically effective amount is administered daily for two weeks, and then not administered for the following one week. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent is administered in a cycle length of four weeks, wherein the therapeutically effective amount is administered daily for one week, and then not administered for the following three weeks. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent is administered in a cycle length of four weeks, wherein the therapeutically effective amount isadministered daily for two weeks, and then not administered for the following two weeks. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent is administered in at least two cycles. In some embodiments, administering a combination of the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent provides a synergistic effect to the patient.

[0008] In some embodiments, the TEAD inhibitor comprises a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:wherein, each X1, X4, X5, and X6is independently N or CRX; each X2and X3is independently N or CRY; each Rxis independently hydrogen, halogen, nitro, -OR3, -SR3, -CN, -C(=O)R3, - C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, - NR3C(=O)R3, -NR3C(=O)OR3, C1-C6 alkyl, Ci-C6fluoroalkyl, C2-C4alkenyl, C2- C4alkynyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2-cCy1c0hloeatelkroyl, C6-10aryl, - CEk-C6-10aryl, Ci-9heteroaryl, or -CH2-Ci-9heteroaryl, wherein C1-C6alkyl, Ci- Cefluoroalkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2- Cioheterocycloalkyl, C6-10aryl, -CEk-C6-10aryl, Ci-9heteroaryl, and -CEk-Ci-gheteroaryl are optionally substituted with 1-5 R5groups; each RYis independently hydrogen, halogen, nitro, -CN, -C(=O)R3, -C(=O)N(R3)2, - C(=O)OR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, - NR3C(=O)OR3, C1-C6 alkyl, Ci-C6fluoroalkyl, C2-C4alkenyl, C2-C4alkynyl, Ci- Ceheteroalkyl, C3-C10cycloalkyl, C2-C10chyectleoraolkyl, C6-10aryl, -CEk-C6-10aryl, Ci- 9heteroaryl, or -CEk-Ci-gheteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C2- C4alkenyl, C2-C4alkynyl, C1-C6heteroalkyl, C3-C10cycloalkyl, cCy2c-lCoa10lhkeytle,roC6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups;R is halogen, nitro, -CN, -OR3, -SR3, -C(=O)R3, -C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, - S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, -NR3C(=O)OR3, or Ci- Cefluoroalkyl optionally substituted with 1-5 R5groups;R1is C1-C6alkyl, C1-C6fluoroalkyl, C2-Cealkenyl, C2-Cealkynyl, C3-C10cycloalkyl, C2- Cioheterocycloalkyl, C1-C6heteroalkyl, -CN, or -S(=O)2R4, wherein C1-C6alkyl, Ci- Cefluoroalkyl, C2-Cealkenyl, C2-Cealkynyl, C3-C10cycloalkyl, C2-Cioheterocycloalkyl, and C1-C6heteroalkyl are optionally substituted with 1-5 R5groups; each R2is independently halogen, nitro, -Ns, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, - C(=O)OR3, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, C2- Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, or -CH2-Ci-9heteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, C2- Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, C2-Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, or - CH2-Ci-9heteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, C2-Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and - CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups;R4is C1-C6alkyl, C1-C6fluoroalkyl, C3-C10cycloalkyl, or -NH2, wherein C1-C6alkyl, Ci- Cefluoroalkyl, and C3-C10cycloalkyl are optionally substituted with 1-5 R5groups; each R5is independently selected from halogen, oxo, -CN, -OR10, -SR10, -N(R10)(Rn), - C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(Rn), -N(R12)C(O)OR13, - N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(Rn), - C(O)C(O)N(R10)(Rn), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, Ci- ehaloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, cycloalkyl,C -3C-6H2-C3- ecycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-Ce- waryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2- eheteroalkyl, C2-6alkenyl, C2-6alkynyl, cycloalCk3y-6l, -CH2-C3-ecycloalkyl, C2- 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl,and -CH2-Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, cycloalkCy3l,-6C2- 9heterocycloalkyl, C6-10aryl, Ci-9heteroaryl, -OR10, and -N(R10)(Rn); or two R5are combined to form a Cs-scycloalkyl ring; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, cycClo3-a6lkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl,C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, Ci- ealkyl, C 1 -ehaloalky 1, C1-6alkoxy, cycloalkCy3l-,6C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl,C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with Ci- C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; each R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl,C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- ealkynyl, C3c-6ycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, cycloalkyl, C2C-3-69heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, SFs, -CN, hydroxy, C1-6alkyl, Ci- ehaloalkyl, C1-6alkoxy, cyCc3l-o6alkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci- 9heteroaryl; and n is 0, 1, 2, 3, or 4.

[0009] In some embodiments, the TEAD inhibitor comprises a compound of Formula (I-A), or a pharmaceutically acceptable salt or solvate thereof:wherein, each Rxis independently hydrogen, halogen, -OR3, -SR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, - NR3S(=O)2R3, -NR3C(=O)R3, C1-C6alkyl, C1-C6fluoroalkyl, or C2-C4alkynyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, and C2-C4alkynyl are optionally substituted with 1-5 R5groups; each RYis independently hydrogen, halogen, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, C1-C6alkyl, C1-C6fluoroalkyl, or C2-C4alkynyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, and C2-C4alkynyl are optionally substituted with 1-5 R5groups;R is halogen, nitro, -CN, -OR3, -C(=O)R3, -C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, - S(=O)2R3, -NR3S(=O)2R3, -NR3C(=O)R3, -NR3C(=O)OR3, or C1-C6fluoroalkyl optionally substituted with 1-5 R5groups;R1is C1-C6alkyl optionally substituted with 1-5 R5groups; each R2is independently halogen, nitro, -Ns, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, - C(=O)OR3, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2- Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, or -CH2-Ci-9heteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2- Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, C2-C10hetercoycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, or - CH2-Ci-9heteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, C2-C10hetercoycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and - CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups;R4is C1-C6alkyl, C1-C6fluoroalkyl, C3-C10cycloalkyl, or -NH2, wherein C1-C6alkyl, Ci- Cefluoroalkyl, and C3-C10cycloalkyl are optionally substituted with 1-5 R5groups; each R5is independently selected from halogen, oxo, -CN, -OR10, -SR10, -N(R10)(Rn), - C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(Rn), -N(R12)C(O)OR13, - N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(Rn), - C(O)C(O)N(R10)(Rn), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(RU)-, C1-6alkyl, Ci- ehaloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, cycloalkyl,C -3C-6H2-C3- ecycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-Ce- waryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2- eheteroalkyl, C2-6alkenyl, C2-6alkynyl, cycloalCk3y-6l, -CH2-C3-6cycloalkyl, C2- 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, cycloalkCy3l-,6C2- 9heterocycloalkyl, C6-10aryl, Ci-9heteroaryl, -OR10, and -N(R10)(Rn); or two R5are combined to form a C3-5cycloalkyl ring; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, cycClo3-a6lkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl,C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalky 1, C1-6alkoxy, cycloalkCy3l-6, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl,C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with Ci- C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; each R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl,C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- ealkynyl, C3-66ycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, cycloalkyl, C3-69heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, SFs, -CN, hydroxy, C1-6alkyl, Ci- ehaloalkyl, C1-6alkoxy, cyCc3l-o6alkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci- 9heteroaryl; and n is 0, 1, or 2.

[0010] In some embodiments, each Rxis independently hydrogen, F, Cl, Br, -CH3, -OH, -OCH3, or -OCF3. In some embodiments, each Rxis hydrogen. In some embodiments, each RYis independently hydrogen, F, Cl, or -CH3. In some embodiments, each RYis hydrogen. In some embodiments, R is F, Cl, -CN, -OCF3, -CHF2, or -CF3. In some embodiments, R is F, Cl, or -CF3. In some embodiments, R is -CF3. In some embodiments, R1is C1-C6alkyl substituted with -OH. In some embodiments, R1is C1-C6alkyl substituted with 6-membered heteroaryl ring selected from pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl, wherein pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl are optionally substituted with 1-5 R5groups. In some embodiments, R1is C1-C6alkyl substituted with pyridinyl optionally substituted with 1-5 R5groups. In some embodiments, R1is C1-C6alkyl substituted with 1, 2, or 3 substituents each independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, and pyridinyl. In some embodiments, each R2is independently F, Cl, -OCF3, or -CF3. In some embodiments, each R2is independently F or Cl. In some embodiments, n is 0. In some embodiments, n is 1 or 2.

[0011] In some embodiments, the TEAL) inhibitor is selected from:pharmaceutically acceptable salt or solvate thereof.

[0012] In some embodiments, the TEAD inhibitor comprises a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:Formula (II) wherein, each X1, X2, X3, X4, X5, and X6is independently N or CRX; each Rxis independently hydrogen, halogen, nitro, -OR3, -SR3, -CN, -C(=O)R3, - C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, - NR3C(=O)R3, -NR3C(=O)OR3, C1-C6 alkyl, C1-C6fluoroalkyl, C2-C4alkenyl, C2- C4alkynyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2-Ccy10chloetaelrkoyl, C6-10aryl, - CH2-C6-10aryl, Ci-9heteroaryl, or -CH2-Ci-9heteroaryl, wherein C1-C6alkyl, Ci- Cefluoroalkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2- Cioheterocycloalkyl, C6-10aryl, -CFb-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups;R is halogen, nitro, -CN, -OR3, -SR3, -C(=O)R3, -C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, - S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, -NR3C(=O)OR3, or Ci- Cefluoroalkyl optionally substituted with 1-5 R5groups;R1is C1-C6alkyl, C1-C6fluoroalkyl, C2-Cealkenyl, C2-Cealkynyl, C3-C10cycloalkyl, C2- Cioheterocycloalkyl, C1-C6heteroalkyl, -CN, or -S(=O)2R4, wherein C1-C6alkyl, Ci- Cefluoroalkyl, C2-Cealkenyl, C2-Cealkynyl, C3-C10cycloalkyl, cCy2c-Clo1a0lhkeytle,ro and C1-C6heteroalkyl are optionally substituted with 1-5 R5groups; each R2is independently halogen, nitro, -N3, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, - C(=O)OR3, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2- Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, or -CH2-Ci-9heteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2- Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, C2-C10hetercoycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, or - CH2-Ci-9heteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-Ciocycloalkyl, C2-C10hetercoycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and - CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups;R4is C1-C6alkyl, C1-C6fluoroalkyl, C3-C10cycloalkyl, or -NH2, wherein C1-C6alkyl, Ci- Cefluoroalkyl, and C3-C10cycloalkyl are optionally substituted with 1-5 R5groups; each R5is independently selected from halogen, oxo, -CN, -OR10, -SR10, -N(R10)(Rn), - C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(Rn), -N(R12)C(O)OR13, - N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(Rn), - C(O)C(O)N(R10)(Rn), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, Ci- ehaloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, cycloalkyl,C -3C-6H2-C3- ecycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6- waryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2- eheteroalkyl, C2-6alkenyl, C2-6alkynyl, cycloalCk3y-6l, -CH2-C3-6cycloalkyl, C2- 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, cycloalkCy3l-,6C2- 9heterocycloalkyl, C6-10aryl, Ci-9heteroaryl, -OR10, and -N(R10)(Rn); or two R5are combined to form a Cs-scycloalkyl ring; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, cycClo3-a6lkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl,C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, Ci- ealkyl, C 1 -ehaloalky 1, C1-6alkoxy, cycloalkCy3l-6, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl,C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with Ci- C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl;each R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl,C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- ealkynyl, C3c-6ycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, cycloalkyl, C3-69heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, SF5, -CN, hydroxy, C1-6alkyl, Ci- ehaloalkyl, C1-6alkoxy, cyCc3l-o6alkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci- 9heteroaryl; and n is 0, 1, 2, 3, or 4.

[0013] In some embodiments, the TEAD inhibitor comprises a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:wherein, each X3, X5, and X6is independently N or CRX;X4is CRX; each Rxis independently hydrogen, halogen, nitro, -OR3, -SR3, -CN, -C(=O)R3, - C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, - NR3C(=O)R3, -NR3C(=O)OR3, C1-C6 alkyl, Ci-C6fluoroalkyl, C2-C4alkenyl, C2- C4alkynyl, C1-C6heteroalkyl, C3-CiocycloalkyCl,2-C10hetero cycloalkyl, C6-10aryl, - CEk-C6-10aryl, Ci-9heteroaryl, or -CH2-Ci-9heteroaryl, wherein C1-C6alkyl, Ci- Cefluoroalkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C6heteroalkyl, C3-Ciocycloalkyl, C2- Cioheterocycloalkyl, C6-10aryl, -CEk-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups;R is halogen, nitro, -CN, -OR3, -SR3, -C(=O)R3, -C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, - S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, -NR3C(=O)OR3, or Ci- Cefluoroalkyl optionally substituted with 1-5 R5groups;R1is C1-C6alkyl, C1-C6fluoroalkyl, C2-Cealkenyl, C2-Cealkynyl, C3-Ciocycloalkyl, C2- Cioheterocycloalkyl, C1-C6heteroalkyl, -CN, or -S(=O)2R4, wherein C1-C6alkyl, Ci-Cefluoroalkyl, C2-Cealkenyl, C2-Cealkynyl, C3-C10cycloalkyl, cCy2c-Clo1a0lhkeytle,ro and C1-C6heteroalkyl are optionally substituted with 1-5 R5groups; each R2is independently halogen, nitro, -N3, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, - C(=O)OR3, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2- Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, or -CH2-Ci-9heteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2- Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, C2-C10hetercoycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, or - CH2-Ci-9heteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, C2-C10hetercoycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and - CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups;R4is C1-C6alkyl, C1-C6fluoroalkyl, C3-Ciocycloalkyl, or -NH2, wherein C1-C6alkyl, Ci- Cefluoroalkyl, and C3-Ciocycloalkyl are optionally substituted with 1-5 R5groups; each R5is independently selected from halogen, oxo, -CN, -OR10, -SR10, -N(R10)(Rn), - C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(Rn), -N(R12)C(O)OR13, - N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(Rn), - C(O)C(O)N(R10)(Rn), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, Ci- ehaloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, cycloalkyl,C -3C-6H2-C3- ecycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6- waryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2- eheteroalkyl, C2-6alkenyl, C2-6alkynyl, cycloalCk3y-6l, -CH2-Cs-ecycloalkyl, C2- 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, cycloalkCy3l-,6C2- 9heterocycloalkyl, C6-10aryl, Ci-9heteroaryl, -OR10, and -N(R10)(Rn); or two R5are combined to form a Cs-scycloalkyl ring; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, cycClo3-a6lkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl,C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, Ci- ealkyl, C i -ehaloalky 1, C1-6alkoxy, cycloalCk3y-l6, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl,C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with Ci- C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; each R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl,C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- ealkynyl, C3c-6ycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, cycloalkyl, C2C-3-69heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, SFs, -CN, hydroxy, C1-6alkyl, Ci- ehaloalkyl, C1-6alkoxy, cyCc3l-o6alkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci- 9heteroaryl; and n is 0, 1, 2, 3, or 4.

[0014] In some embodiments, the method further comprises administering to the patient one or more pharmaceutically acceptable excipients. In some embodiments, the relapsed or refractory cancer is a relapsed or refractory solid tumor. In some embodiments, the relapsed or refractory cancer is a tumor comprising a mutation in a neurofibromatosis type 2 (NF2) gene. In some embodiments, the relapsed or refractory cancer is a solid tumor. In some embodiments, the relapsed or refractory cancer is a hematologic malignancy. In some embodiments, the solid tumor is a sarcoma or carcinoma. In some embodiments, the solid tumor is a sarcoma. In some embodiments, the solid tumor is a carcinoma. In some embodiments, the relapsed or refractory cancer is selected from mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma, lung cancer, bladder carcinoma, cutaneous neurofibromas, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, breast cancer, head and neck cancer, and renal cell carcinoma.

[0015] In another aspect, disclosed herein is a kit, comprising (i) a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent; and (ii) instructions for administering the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent to treat cancer in a subject in need thereof, wherein the cancer is a relapsed or refractory cancer. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 1 mg to about 300 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 25 mg to about 200 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 25 mg to about 100 mg per day.

[0016] In another aspect, disclosed herein is a kit, comprising (i) a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent; and (ii) instructions for administering the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent to treat cancer in a subject in need thereof, wherein the therapeutically effective amount of the TEAD inhibitor is about 1 mg to about 300 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 25 mg to about 200 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 25 mg to about 100 mg per day. In some embodiments, the cancer is a relapsed or refractory cancer. In some embodiments, the second therapeutic agent is selected from a c-MET inhibitor, a BRAF inhibitor, an EGFR inhibitor, a MEK inhibitor, a KRAS inhibitor, and a mTOR inhibitor. In some embodiments, the second therapeutic agent is a c-MET inhibitor. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 1 mg to about 800 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 1 mg to about 400 mg per day. In some embodiments, the c-MET inhibitor is selected from cabozantinib, crizotinib, foretinib, tivantinib, savolitinib, capmatinib, and tepotinib, or a combination thereof. In some embodiments, the c-MET inhibitor is selected from savolitinib and capmatinib, or a combination thereof. In some embodiments, the relapsed or refractory cancer is a c-MET mutant cancer. In some embodiments, the relapsed or refractory cancer is a c-MET amplified cancer. In some embodiments, the second therapeutic agent is a BRAF inhibitor. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 1 mg to about 400 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 1 mg to about 200 mg per day. In some embodiments, the BRAF inhibitor is selected from vemurafenib, dabrafenib, encorafenib, and sorafenib, or a combination thereof. In someembodiments, the BRAF inhibitor is sorafenib. In some embodiments, the relapsed or refractory cancer is a BRAF mutant cancer. In some embodiments, the second therapeutic agent is an EGFR inhibitor. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 1 mg to about 80 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 1 mg to about 40 mg per day. In some embodiments, the EGFR inhibitor comprises a monoclonal antibody. In some embodiments, the EGFR inhibitor comprises a tyrosine kinase inhibitor. In some embodiments, the EGFR inhibitor is selected from cetuximab, necitumumab, panitumumab, zalutumumab, nimotuzumab, matuzumab, osimertinib, gefitinib, erlotinib, lapatinib, neratinib, vandetanib, afatinib, brigatinib, dacomitinib, lazertinib, amivantamab, and icotinib, or a combination thereof. In some embodiments, the EGFR inhibitor is selected from osimertinib, lazertinib, and amivantamab, or a combination thereof. In some embodiments, the relapsed or refractory cancer is an EGFR mutant cancer. In some embodiments, the relapsed or refractory cancer is an EGFR mutant lung cancer or an EGFR mutant non-small cell lung cancer (NSCLC). In some embodiments, the second therapeutic agent is a MEK inhibitor. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 1 mg to about 60 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 1 mg to about 30 mg per day. In some embodiments, the MEK inhibitor is selected from refametinib, selumetinib, trametinib, cobimetinib, binimetinib, mirdametinib, and pimasertib, or a combination thereof. In some embodiments, the MEK inhibitor is selected from cobimetinib and trametinib, or a combination thereof. In some embodiments, the second therapeutic agent is a KRAS inhibitor. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 1 mg to about 1200 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 1 mg to about 600 mg per day. In some embodiments, the KRAS inhibitor is selected from an inhibitor of a KRAS G12C mutant, an inhibitor of a KRAS G12D mutant, an inhibitor of a KRAS G12V mutant, and an inhibitor of a KRAS G13 mutant, or a combination thereof. In some embodiments, the KRAS inhibitor is selected from adagrasib and sotorasib, or a combination thereof. In some embodiments, the relapsed or refractory cancer is a KRAS mutant cancer. In some embodiments, the KRAS mutant cancer harbors one or more KRAS mutations selected from a KRAS G12C mutation, a KRAS G12D mutation, a KRAS G12V mutation, and a KRAS G13 mutation. In some embodiments, the second therapeutic agent is a mTOR inhibitor. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 1 mg to about 10 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 1 mg to about 5 mg per day. In some embodiments, the mTOR inhibitor is selected from mTORCl inhibitor and mTORC2 inhibitor, or a combination thereof. Insome embodiments, the mTOR inhibitor is selected from temsirolimus, everolimus, ridaforolimus, sirolimus, umirolimus, and zotarolimus, or a combination thereof. In some embodiments, the mTOR inhibitor is everolimus. In some embodiments, the TEAD inhibitor comprises a compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof.

[0017] In some embodiments, the TEAD inhibitor is selected from:pharmaceutically acceptable salt or solvate thereof.

[0018] In some embodiments, the kit further comprises one or more pharmaceutically acceptable excipients. In some embodiments, the relapsed or refractory cancer is a relapsed or refractory solid tumor. In some embodiments, the relapsed or refractory cancer is a tumor comprising a mutation in a neurofibromatosis type 2 (NF2) gene. In some embodiments, the relapsed or refractory cancer is a solid tumor. In some embodiments, the relapsed or refractory cancer is a hematologic malignancy. In some embodiments, the solid tumor is a sarcoma or carcinoma. In some embodiments, the solid tumor is a sarcoma. In some embodiments, the solid tumor is a carcinoma. In some embodiments, the relapsed or refractory cancer is selected from mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma, lung cancer, bladder carcinoma, cutaneous neurofibromas, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, breast cancer, head and neck cancer, and renal cell carcinoma. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent is administered daily for at least a week. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent isadministered daily for at least two weeks. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent is administered daily for at least three weeks. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent is administered daily for at least 24 days. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent is administered in a cycle length of three weeks, wherein the therapeutically effective amount is administered daily for one week, and then not administered for the following two weeks. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent is administered in a cycle length of three weeks, wherein the therapeutically effective amount is administered daily for two weeks, and then not administered for the following one week. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent is administered in a cycle length of four weeks, wherein the therapeutically effective amount is administered daily for one week, and then not administered for the following three weeks. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent is administered in a cycle length of four weeks, wherein the therapeutically effective amount is administered daily for two weeks, and then not administered for the following two weeks. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent is administered in at least two cycles.INCORPORATION BY REFERENCE

[0019] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Various aspects of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0021] Fig. 1 illustrates a schematic representation of the Hippo signaling network. Hippo pathway components shaded in dark gray indicate components that inhibit YAP / TAZ activity. Hippo pathway components shaded in light gray indicate components that promote YAP / TAZ activity. Pointed and blunt arrowheads indicate activating and inhibitory interactions, respectively. Abbreviations: a-CAT (a-Catenin), AJUB (Ajuba), AMOT (Angiomotin), P-TRCP (P-transducing repeat containing protein), CK1 (Casein Kinase 1), CRB (Crumbs), E-C D (E-cadherin), EX (Expanded), GPCR (G-protein coupled receptor), HIPK (Homeodomain interacting protein kinase), KIBRA (Kidney brain), LATS (Large tumor suppressor), LGL (Lethal giant larvae), MASK (Multiple ankyrin single KH), MER (Merlin), MOB (Mps one binder), MST (Mammalian sterile 20 like), PALS (Protein Associated with Lin-7), PATJ (Pals 1 -associated tight junction protein), PP2A (Protein phosphatase 2A), PTPN14 (Protein tyrosine phosphatase non-receptor type 14), RASSF (Ras associated factor), SAV (Salvador), SCRIB (Scribble), SIK (Salt inducible kinase), TAO (Thousand and one amino acid protein), TAZ (transcriptional coactivator with PDZ-binding motif), TEAL) (TEA domain protein), VGL4 (Vestigial-like 4), WBP2 (WW domain binding protein 2), YAP (Yes associated protein), ZO (Zonula occludens), and ZYX (Zyxin).

[0022] Fig. 2 illustrates a schematic representation of the Hippo signaling pathway regulated by G alpha proteins.

[0023] Figs. 3A and 3B illustrate the biological data of in vivo efficacy study (change in average tumor volume (Fig. 3A) and percentage survival (Fig. 3B)) of Compound 42, osimertinib, and a combination of Compound 42 and osimertinib in NCLH1975 NSCLC CDX model; NCI-H1975 harbors EGFR p.L858R; p.T790M mutations.

[0024] Figs. 4A and 4B illustrate the biological data of in vivo efficacy study (change in average tumor volume (Fig. 4A) and body weight change (Fig. 4B)) of Compound 42, osimertinib, and a combination of Compound 42 and osimertinib in NCLH1975 NSCLC CDX model; NCI-H1975 harbors EGFR p.L858R; p.T790M mutations.

[0025] Figs. 5A, 5B, and 5C illustrate the biological data of in vivo efficacy study (change in average tumor volume), comparing Compound 42, osimertinib, and a combination of Compound 42 and osimertinib, in HCC827 NSCLC CDX model; HCC827 harbors EGFR p.ELREA701del mutation: 1 or 2.5 mg / kg of osimertinib for Fig. 5A; 1 mg / kg of osimertinib for Fig. 5B; and 2.5 mg / kg of osimertinib for Fig. 5C.

[0026] Fig. 6 illustrates the biological data of in vivo efficacy study (change in average tumor volume when monitored for 93 days), comparing Compound 42, osimertinib, and a combination of Compound 42 and osimertinib, in LU-01-1291 NSCLC PDX model, which harbors EGFR Exon 19del. The study started with n = 12 mice per group.

[0027] Figs. 7A and 7B illustrate the biological data of in vivo efficacy study (change in average tumor volume (Fig. 7A) and body weight change (Fig. 7B)) of Compound 42, osimertinib, and a combination of Compound 42 and osimertinib in LU-01-1137 NSCLC PDX model, which harbors EGFR Exon 19del.

[0028] Figs. 8A and 8B illustrate the biological data of in vivo efficacy study (change in average tumor volume (Fig. 8A) and body weight change (Fig. 8B)) of Compound 42, osimertinib, and a combination of Compound 42 and osimertinib in LUI 868 NSCLC PDX model, which harbors EGFR pL858R; pT790M mutations.

[0029] Fig. 9 illustrates the biological data of in vivo efficacy study (change in average tumor volume when monitored for 63 days), comparing osimertinib and combinations of osimertinib and Compound 6, Compound 42, Compound 47, Compound 48, or Compound 49, in NCI-H1975 NSCLC CDX model.

[0030] Figs. 10A and 10B illustrate the biological data of in vivo efficacy study (change in average tumor volume (Fig. 10A) and body weight change (Fig. 10B)), comparing Compound 42, osimertinib, lazertinib, and a combination of Compound 42 and lazertinib, in NCI-H1975 NSCLC CDX model.

[0031] Fig. 11 illustrates the biological data of in vivo efficacy study (change in average tumor volume when monitored for 74 days), comparing Compound 42, amivantamab, and a combination of Compound 42 and amivantamab, in NCI-H1975 NSCLC CDX model. All treatments were stopped on Day 23. TEAD inhibitor 1 dosing resumed on Day 39 and stopped on Day 53 in combination group.

[0032] Fig. 12 illustrates the biological data of in vivo efficacy study (change in average tumor volume when monitored for 91 days), comparing Compound 42, amivantamab, and a combination of Compound 42 and amivantamab, in NCI-H820 NSCLC CDX model. All treatments were stopped on Day 23. Compound 42 dosing resumed on Day 39 and stopped on Day 53 in combination group.

[0033] Fig. 13 illustrates the biological data of in vivo efficacy study (change in average tumor volume when monitored for 138 days), comparing Compound 42, a combination of lazertinib and amivantamab, and a combination of lazertinib, amivantamab, and Compound 42, in LU-01-1291 NSCLC PDX model.

[0034] Fig. 14 illustrates the biological data of in vivo efficacy study (change in average tumor volume when monitored for 48 days), comparing Compound 42, savolitinib, and a combination of Compound 42 and savolitinib, in Hs746T gastric carcinoma CDX model. All treatments (PO, QD) were stopped on Day 12.

[0035] Fig. 15 illustrates the biological data of in vivo efficacy study (change in average tumor volume when monitored for 70 days), comparing Compound 42, savolitinib, and a combination of Compound 42 and savolitinib, in EBC1 NSCLC CDX model. All treatments (PO, QD) were stopped on Day 43.

[0036] Fig. 16 illustrates the biological data of in vivo efficacy study (change in average tumor volume when monitored for 56 days), comparing Compound 42, adagrasib, and a combination of Compound 42 and adagrasib, in CR6243 CRC PDX model. All treatments (PO, QD) were stopped on Day 31.

[0037] Fig. 17 illustrates the biological data of in vivo efficacy study (change in average tumor volume when monitored for 49 days), comparing Compound 42, sotorasib, and a combination of Compound 42 and sotorasib, in LU-01-1185 NSCLC PDX model.

[0038] Figs. 18A and 18B illustrate the biological data of in vivo efficacy study (change in average tumor volume (Fig. 18A) and body weight change (Fig. 18B)), comparing Compound 42, trametinib, and a combination of Compound 42 and trametinib, in NCI-H2030 NSCLC CDX model.

[0039] Figs. 19A and 19B illustrate the biological data of in vivo efficacy study (change in average tumor volume (Fig. 19A) and body weight change (Fig. 19B)), comparing Compound 42, trametinib, and a combination of Compound 42 and trametinib, in LU-01-0407 PDX model; NF2 deficient NSCLC (NF2 CNV<1).

[0040] Figs. 20A and 20B illustrate the biological data of in vivo efficacy study (change in average tumor volume (Fig. 20A) and body weight change (Fig. 20B)), comparing Compound 42, trametinib, and a combination of Compound 42 and trametinib, in LU-01-0236 PDX model; Merlin p.E265X (homozygous) NSCLC.

[0041] Fig. 21 illustrates the biological data of in vivo efficacy study (change in average tumor volume when monitored for 84 days), comparing Compound 42, trametinib, and a combination of Compound 42 and trametinib, in NCI-H226 mesothelioma CDX model; NF2 deficient.

[0042] Figs. 22A and 22B illustrate the biological data of in vivo efficacy study (change in average tumor volume (Fig. 22A) and mean % change inhibition, tumor volume (Fig. 22B)), comparing Compound 42, trametinib, and a combination of Compound 42 and trametinib, in BL9216 bladder cancer PDX model; Merlin pE106X (100%); EGFR CNV = 6.93; Combination Efficacy: TGI = 70%.

[0043] Fig. 23 illustrates the biological data of in vivo efficacy study (change in average tumor volume when monitored for 85 days), comparing Compound 42, everolimus, and a combination of Compound 42 and everolimus, in NCI-H226 mesothelioma CDX model.

[0044] Fig. 24 illustrates the biological data of in vivo efficacy study (change in average tumor volume when monitored for 54 days), comparing Compound 42, everolimus, and a combination of Compound 42 and everolimus, in LI 1098 HCC PDX model.

[0045] Fig. 25 illustrates the biological data of in vivo efficacy study (change in average tumor volume when monitored for 54 days), comparing Compound 42, sorafenib, and a combination of Compound 42 and sorafenib, in LI 1098 HCC PDX model.

[0046] Figs. 26A and 26B illustrate the biological data of in vivo efficacy study (change in average tumor volume (Fig. 26A) and body weight change (Fig. 26B) when monitored for 47 days), comparing Compound 42, encorafenib, and a combination of Compound 42 and encorafenib, in HT-29 colorectal adenocarcinoma CDX model harboring BRAF p.V600E mutation.DETAILED DESCRIPTION OF THE DISCLOSURECertain Terminology

[0047] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and / or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting.

[0048] As used herein, in some embodiments, ranges and amounts are expressed as “about” a particular value or range. About also includes the exact amount. Hence “about 5 pL” means “about 5 pL” and also “5 pL.” Generally, the term “about” includes an amount that is expected to be within experimental error.

[0049] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0050] As used herein, the terms “individual(s),” “subject(s),” and “patient(s)” mean any mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is a nonhuman. None of the terms require or are limited to situations characterized by the supervision (e.g., constant or intermittent) of a health care worker (e.g., a doctor, a registered nurse, a nurse practitioner, a physician’s assistant, an orderly, or a hospice worker).

[0051] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0052] In one aspect, a TEAD inhibitor is a transcriptional enhancer associate domain inhibitor.

[0053] In one aspect, a c-MET inhibitor is a mesenchymal-epithelial transition factor inhibitor. The c-MET inhibitors inhibit the enzymatic activity of the c-MET tyrosine kinase, the receptor of hepatocyte growth factor / scatter factor (HGF / SF). These inhibitors may have therapeutic application in the treatment of various types of cancers.

[0054] In one aspect, a BRAF inhibitor is a v-raf murine sarcoma viral oncogene homolog Bl inhibitor. In some embodiments, the BRAF inhibitors can be used in the treatment of patients with BRAF-mutant melanoma. They selectively target BRAF kinase and interfere with the mitogen- activated protein kinase signaling pathway that regulates the proliferation and survival of melanoma cells. In some embodiments, in addition to their molecularly targeted activity, BRAF inhibitors have immunomodulatory effects.

[0055] In one aspect, an EGFR inhibitor is an epidermal growth factor receptor inhibitor. In some embodiments, the EGFR inhibitor blocks the activity of an epidermal growth factor receptor (EGFR). In some embodiments, the EGFR may be found on the surface of some normal cells and is involved in cell growth. In some embodiments, the EGFR may also be found at high levels on some types of cancer cells, which causes these cells to grow and divide. In some embodiments, blocking EGFR may keep cancer cells from growing. In some embodiments, the EGFR inhibitor may also be called an EGFR tyrosine kinase inhibitor or an epidermal growth factor receptor tyrosine kinase inhibitor.

[0056] In one aspect, a MEK inhibitor is a mitogen-activated protein kinase kinase inhibitor. In some embodiments, a MEK inhibitor inhibits the mitogen-activated protein kinase kinase enzymes MEK1 or MEK2. In some embodiments, the MEK inhibitors can be used to affect the MAPK / ERK pathway which is often overactive in some cancers. In some embodiments, the MEK inhibitors can be used for treatment of cancers, such as BRAF-mutated melanoma and KRAS / BRAF mutated colorectal cancer.

[0057] In one aspect, a KRAS inhibitor is a Kirsten rat sarcoma viral oncogene homolog (KRAS) inhibitor. In some embodiments, KRAS acts as an on / off switch for cell growth. When KRAS is mutated, the cells may develop into cancers. In some embodiments, the KRAS inhibitors may be used to treat people with cancer, such as non-small cell lung cancer, which has this specific KRAS mutation.

[0058] In one aspect, a mTOR inhibitor is a mechanistic target of rapamycin (mTOR) inhibitor. In some embodiments, the mTOR inhibitors are a class of drugs that inhibit the mechanistic target ofrapamycin (mTOR), which is a serine / threonine-specific protein kinase that belongs to the family of phosphatidylinositol-3 kinase (PI3K) related kinases (PIKKs). In some embodiments, mTOR regulates cellular metabolism, growth, and proliferation by forming and signaling through two protein complexes, mTORCl and mT0RC2.

[0059] " Amino" refers to the -NH2 radical.

[0060] "Cyano" refers to the -CN radical.

[0061] “Hydroxyl” refers to the -OH radical.

[0062] "Nitro" refers to the -NO2 radical.

[0063] " Oxa" refers to the -O- radical.

[0064] " Oxo" refers to the =0 radical.

[0065] " Thioxo" refers to the =S radical.

[0066] " Imino" refers to the =N-H radical.

[0067] " Oximo" refers to the =N-0H radical.

[0068] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., Ci- C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., Ci-Cs alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C3-C5alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl ( / / -propyl), 1 -methyl ethyl ( / .w-propyl), 1 -butyl ( / / -butyl), 1 -methylpropyl (.scc-butyl), 2-methylpropyl ( / .w-butyl),1,1 -dimethylethyl (Zc / 7-butyl), and 1 -pentyl (w-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa,SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORf, -OC(O)- NRaRf, -N( Ra)C(O)Rf, -N(Ra)S(O)tRf(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRf(where t is 1 or 2), and -S(O)tN(Ra)2 (where t is 1 or 2), where each Rais independently hydrogen, alkyl, fluoroalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and each Rfis independently alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0069] " Amino-alkyl" refers to a radical of the formula: -alkyl-NBfc.

[0070] "Hydroxyl-alkyl" refers to a radical of the formula: -alkyl-OH.

[0071] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0072] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl i.e., allyl), but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, - SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORf, -OC(O)- NRaRf, -N( Ra)C(O)Rf, -N(Ra)S(O)tRf(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRf(where t is 1 or 2), and -S(O)tN(Ra)2 (where t is 1 or 2), where each Rais independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and each Rfis independently alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0073] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl has two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, - SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORf, -OC(O)- NRaRf, -N(Ra)C(O)Rf, -N(Ra)S(O)tRf(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRf(where t is 1 or 2), and -S(O)tN(Ra)2 (where t is 1 or 2), where each Rais independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaryl alkyl, and each Rfis independently alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0074] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, w-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In some embodiments, the points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., Ci-Cs alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C3-C5alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORf, -OC(O)- NRaRf, -N( Ra)C(O)Rf, -N(Ra)S(O)tRf(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRf(where t is 1 or 2), and -S(O)tN(Ra)2 (where t is 1 or 2), where each Rais independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and each Rfis independently alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0075] "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, / .<?., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance with the Hiickel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless stated otherwise specifically in thespecification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-CN, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb- N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0076] "Aryloxy" refers to a radical bonded through an oxygen atom of the formula -O-aryl, where aryl is as defined above.

[0077] "Aralkyl" refers to a radical of the formula -Rc-aryl where Rcis an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0078] "Aralkenyl" refers to a radical of the formula -Rd-aryl where Rdis an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0079] "Aralkynyl" refers to a radical of the formula -Re-aryl, where Reis an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0080] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, and in some embodiments, include fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond.In some embodiments, the carbocyclyl is saturated, (z.e., containing single C-C bonds only) or unsaturated i.e., containing one or more double bonds or triple bonds.) A fully saturated carbocyclyl radical is also referred to as "cycloalkyl." Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In certain embodiments, a cycloalkyl comprises three to eight carbon atoms (e.g., C3-C5cycloalkyl). In other embodiments, a cycloalkyl comprises three to seven carbon atoms (e.g., C3-C7 cycloalkyl). In other embodiments, a cycloalkyl comprises three to six carbon atoms (e.g., C3-C6 cycloalkyl). In other embodiments, a cycloalkyl comprises three to five carbon atoms (e.g., C3-C5 cycloalkyl). In other embodiments, a cycloalkyl comprises three to four carbon atoms (e.g., C3-C4 cycloalkyl). An unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -CN, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, - Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0081] "Carbocyclylalkyl" refers to a radical of the formula -Rc-carbocyclyl where Rcis an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0082] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo substituents.

[0083] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl,2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0084] "Heterocyclyl" or “heterocycle” refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which include fused or bridged ring systems in some embodiments. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. In some embodiments, the heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). In some embodiments, the heterocyclyl is saturated, (i.e., containing single bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds.) A fully saturated heterocyclyl radical is also referred to as "heterocycloalkyl." Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -CN, -Rb-CN , -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N-(Ra)2, -Rb- N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, - Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), -Rb- S(O)tRa(where t is 1 or 2), and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0085] “Heteroalkyl” refers to an alkyl group as defined above in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, - N(alkyl)-, sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6heteroalkyl. In some embodiments, the heteroalkyl comprises 1, 2, or 3 heteroatoms. In some embodiments, the alkyl part of the heteroalkyl radical is optionally substituted as defined for an alkyl group. Representative heteroalkyl groups include, but are not limited to -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2OH, -CH2OCH3, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, -CH2CH2OH, -CH2CH2OCH3, - CH2CH2OCH2CH2NH2, or -CH2CH2OCH2CH2OH.

[0086] "Heterocyclylalkyl" refers to a radical of the formula -Rc-heterocyclyl where Rcis an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

[0087] "Heterocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O- Rc-heterocyclyl where Rcis an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0088] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, in some embodiments, the heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, ie., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance with the Hiickel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 4-6 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl is monocyclic heteroaryl. In some embodiments, the monocyclic heteroaryl is a 5-membered or 6- membered heteroaryl. In some embodiments, heteroaryl is a C1-C9 heteroaryl. In someembodiments, monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, a bicyclic heteroaryl is a C5-C9 heteroaryl. Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[Z»][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodi oxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotri azolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5.6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H- benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1.6-naphthyri dinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1 -phenyl- IT / -pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4- d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3- d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5, 6,7,8- tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl ( / .< ., thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Raisindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0089] "A-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An A-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0090] " C-heteroaryl" refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0091] "Heteroaryloxy" refers to radical bonded through an oxygen atom of the formula -O- heteroaryl, where heteroaryl is as defined above.

[0092] "Heteroarylalkyl" refers to a radical of the formula -Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0093] "Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O- Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0094] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (5)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or irons'). Likewise, all possible isomers, as well as their racemic and optically pure forms,and all tautomeric forms are also intended to be included. The term "geometric isomer" refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term "positional isomer" refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0095] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0096] "Optional" or "optionally" means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.

[0097] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Pharmaceutically acceptable salts of the compounds described herein are optionally pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0098] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid,and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997), which is hereby incorporated by reference in its entirety). In some embodiments, acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0099] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, A,A-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N- methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, A-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.

[0100] As used herein, "treatment" or "treating " or "palliating" or "ameliorating" are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired resultsincluding, but not limited to, therapeutic benefit and / or a prophylactic benefit. By "therapeutic benefit" is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in a patient, notwithstanding that the patient is afflicted with the underlying disorder in some embodiments. For prophylactic benefit, in some embodiments, the compositions are administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.

[0101] "Prodrug" is meant to indicate a compound that is converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharmaceutically acceptable. In some embodiments, a prodrug is inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).

[0102] A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein.

[0103] The term "prodrug" is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. In some embodiments, prodrugs of an active compound, as described herein, are prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino, or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino, or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol or amine functional groups in the active compounds and the like.COMPOSITIONS

[0104] In one aspect, the present disclosure provides compositions, comprising a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeuticallyeffective amount of a second therapeutic agent, wherein the second therapeutic agent is selected from a c-MET inhibitor, a BRAF inhibitor, an EGFR inhibitor, a MEK inhibitor, a KRAS inhibitor, and a mTOR inhibitor. In some embodiments, the present disclosure provides compositions, comprising a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent, wherein the second therapeutic agent is selected from a c-MET inhibitor, a BRAF inhibitor, an EGFR inhibitor, a MEK inhibitor, a KRAS inhibitor, and a mTOR inhibitor.

[0105] In some embodiments, the present disclosure provides compositions, comprising a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of a c-MET inhibitor. In some embodiments, the present disclosure provides compositions, comprising a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a c-MET inhibitor.

[0106] In some embodiments, the present disclosure provides compositions, comprising a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of a BRAF inhibitor. In some embodiments, the present disclosure provides compositions, comprising a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a BRAF inhibitor.

[0107] In some embodiment, the present disclosure provides compositions, comprising a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of an EGFR inhibitor. In some embodiments, the present disclosure provides compositions, comprising a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of an EGFR inhibitor.

[0108] In one aspect, the present disclosure provides compositions, comprising a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of a MEK inhibitor. In some embodiments, the present disclosure provides compositions, comprising a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a MEK inhibitor.

[0109] In one aspect, the present disclosure provides compositions, comprising a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeuticallyeffective amount of a KRAS inhibitor. In some embodiments, the present disclosure provides compositions, comprising a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a KRAS inhibitor.

[0110] In one aspect, the present disclosure provides compositions, comprising a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of a mTOR inhibitor. In some embodiments, the present disclosure provides compositions, comprising a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a mTOR inhibitor.[OHl] In some embodiments, the present disclosure provides compositions for use in treating cancer in a subject in need thereof comprising administering to the subject in need thereof the composition comprising a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent, wherein the second therapeutic agent is selected from a c-MET inhibitor, a BRAF inhibitor, an EGFR inhibitor, a MEK inhibitor, a KRAS inhibitor, and a mTOR inhibitor. In some embodiments, the present disclosure provides compositions for use in treating cancer in a subject in need thereof comprising administering to the subject in need thereof the composition comprising a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (LA), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent, wherein the second therapeutic agent is selected from a c-MET inhibitor, a BRAF inhibitor, an EGFR inhibitor, a MEK inhibitor, a KRAS inhibitor, and a mTOR inhibitor. In some embodiments, the compositions disclosed herein are useful for treating cancer.

[0112] In some embodiments, the composition further comprises one or more pharmaceutically acceptable excipients.TEAD inhibitors

[0113] In one aspect, the first therapeutic agent comprises a TEAD inhibitor. In some embodiments, the TEAD inhibitor comprises a compound of Formula (I), (LA), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof.

[0114] In one aspect, the TEAD inhibitor comprises a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:wherein, each X1, X4, X5, and X6is independently N or CRX; each X2and X3is independently N or CRY; each Rxis independently hydrogen, halogen, nitro, -OR3, -SR3, -CN, -C(=O)R3, - C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, - NR3C(=O)R3, -NR3C(=O)OR3, C1-C6 alkyl, C1-C6fluoroalkyl, C2-C4alkenyl, C2- C4alkynyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2-cCy1c0hloeatelkryol, C6-10aryl, -CH2- C6-10aryl, Ci-9heteroaryl, or -CH2-Ci-9heteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2- Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; each RYis independently hydrogen, halogen, nitro, -CN, -C(=O)R3, -C(=O)N(R3)2, - C(=O)OR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, - NR3C(=O)OR3, C1-C6 alkyl, C1-C6fluoroalkyl, C2-C4alkenyl, C2-C4alkynyl, Ci- Ceheteroalkyl, C3-C10cycloalkyl, C2-C10chyectleoraolkyl, C6-10aryl, -CH2-C6-10aryl, Ci- 9heteroaryl, or -CH2-Ci-9heteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C2- C4alkenyl, C2-C4alkynyl, C1-C6heteroalkyl, C3-C10cycloalkyl, cCy2c-lCoa10lhkeytle,ro C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups;R is halogen, nitro, -CN, -OR3, -SR3, -C(=O)R3, -C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, - S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, -NR3C(=O)OR3, or C1-C6fluoroalkyl optionally substituted with 1-5 R5groups;R1is C1-C6alkyl, C1-C6fluoroalkyl, C2-Cealkenyl, C2-Cealkynyl, C3-C10cycloalkyl, C2- Cioheterocycloalkyl, C1-C6heteroalkyl, -CN, or -S(=O)2R4, wherein C1-C6alkyl, Ci- Cefluoroalkyl, C2-Cealkenyl, C2-Cealkynyl, C3-C10cycloalkyl, cCy2c-lCoa10lhkeytle,ro and C1-C6heteroalkyl are optionally substituted with 1-5 R5groups;each R2is independently halogen, nitro, -N3, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, - C(=O)OR3, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, C2- Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, or -CH2-Ci-9heteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, C2- Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, C2-C10hetecryocloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, or - CH2-Ci-9heteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, C2-C10hetecryocloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and - CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups;R4is C1-C6alkyl, C1-C6fluoroalkyl, C3-Ciocycloalkyl, or -NH2, wherein C1-C6alkyl, Ci- Cefluoroalkyl, and C3-Ciocycloalkyl are optionally substituted with 1-5 R5groups; each R5is independently selected from halogen, oxo, -CN, -OR10, -SR10, -N(R10)(Rn), - C(O)OR10, -OC(O)N(R10)(Rn), -N(R12)C(O)N(R10)(Rn), -N(R12)C(O)OR13, - N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(Rn), - C(O)C(O)N(R10)(Rn), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, Ci-6alkyl, Ci- ehaloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3- ecycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2- eheteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2- 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, Ci-9heteroaryl, -OR10, and -N(R10)(Rn); or two R5are combined to form a Cs-scycloalkyl ring; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, Ci-ealkyl, C1-6haloalkyl, C1-6alkoxy, cyclCo3a-l6kyl, C2-9heterocycloalkyl, C6-10aryl, and Ci- gheteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl,C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; each R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl,C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- ealkynyl, C3c-y6cloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl, wherein Ci- ealkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, cycloalkyl, C2C-3-69heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, SFs, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, Ci- ealkoxy, C3c-y6cloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl; and n is 0, 1, 2, 3, or 4.

[0115] For any and all of the embodiments of a compound of Formula (I), substituents are selected from among a subset of the listed alternatives. For example, in some embodiments X1is N or CRX. In other embodiments, X1is N. In some embodiments, X1is CRX.

[0116] In some embodiments, X1is CRX; and each X2and X3is CRY. In some embodiments, X1is N; and each X2and X3is CRY. In some embodiments, X1is CRX; X2is CRY; and X3is N

[0117] In some embodiments, each X4, X5, and X6is CRX. In some embodiments, X4is N; and each X5and X6is CRX. In some embodiments, each X4and X5is CRX; and X6is N.

[0118] In some embodiments, each Rxis independently hydrogen, halogen, -OR3, -SR3, -CN, - S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, C1-C6alkyl, C1-C6fluoroalkyl, C2- C4alkenyl, C2-C4alkynyl, or C1-C6heteroalkyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C2-C4alkenyl, C2-C4alkynyl, and C1-C6heteroalkyl are optionally substituted with 1-5 R5groups; and each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-Ciocycloalkyl, or C2- Cioheterocycloalkyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-Ciocycloalkyl, and C2-C10heterocycloalkyl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups. In someembodiments, each Rxis independently hydrogen, halogen, -OR3, -SR3, -S(=O)R3, -S(=O)2R3, - N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, C1-C6alkyl, C1-C6fluoroalkyl, or C2-C4alkynyl, wherein Ci- Cealkyl, C1-C6fluoroalkyl, and C2-C4alkynyl are optionally substituted with 1-5 R5groups; and each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, or C3-C10cycloalkyl, wherein Ci- Cealkyl, C1-C6fluoroalkyl, and C3-C10cycloalky are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0119] In some embodiments, each Rxis independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, - CH2OH, -CH2CH2OH, -CH2CN, -CH2C(=O)OH, -CH2C(=O)OCH3, -CH2C(=O)OCH2CH3, - CH2C(=O)NH2, -CH2C(=O)NHCH3, -CH2C(=O)N(CH3)2, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, - CH2F, -CHF2, -CF3, -CH=CH2, -C=CH, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, oxetanyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy, azetidinyl, pyrrolidinyl, tetrazolyl, -CN, -OH, -OCH3, -OCH2CH3, -OCH2CH2OH, -OCH2CN, -OCF3, -C(=O)OH, -C(=O)OCH3, - C(=O)OCH2CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -NH2, -NHCH3, -N(CH3)2, - NHC(=O)CH3, -N(CH3)C(=O)CH3, -NHC(=O)OCH3, -N(CH3)C(=O)OCH3, -S(=O)CH3, - S(=O)2CH3, -NHS(=O)2CH3, or -N(CH3)S(=O)2CH3. In some embodiments, each Rxis independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, cyclopropyl, -C=CH, -OH, -OCH3, - OCH2CH3, -OCF3, -SCH3, cyclopropyloxy, -NH2, -NHC(=O)CH3, -N(CH3)C(=O)CH3, - NHS(=O)2CH3, -N(CH3)S(=O)2CH3, -S(=O)CH3, or -S(=O)2CH3. In some embodiments, each Rxis independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, cyclopropyl, -OH, -OCH3, -OCH2CH3, - OCF3, cyclopropyloxy, -NH2, -NHC(=O)CH3, -NHS(=O)2CH3, -S(=O)CH3, or -S(=O)2CH3. In some embodiments, each Rxis independently hydrogen, F, Cl, Br, -CH3, -OH, -OCH3, or -OCF3. In some embodiments, each Rxis independently hydrogen, F, Cl, -CH3, -OCH3, or -OCF3. In some embodiments, each Rxis independently hydrogen, F, or -OCH3. In some embodiments, each Rxis hydrogen.

[0120] In some embodiments, each RYis independently hydrogen, halogen, -CN, -S(=O)R3, - S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, C1-C6alkyl, C1-C6fluoroalkyl, C2-C4alkenyl, C2- C4alkynyl, or C1-C6heteroalkyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C2-C4alkenyl, C2-C4alkynyl, and C1-C6heteroalkyl are optionally substituted with 1-5 R5groups; and each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-Ciocycloalkyl, or C2- Cioheterocycloalkyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-Ciocycloalkyl, and C2-C10heterocycloalkyl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups. In someembodiments, each RYis independently hydrogen, halogen, -S(=O)R3, -S(=O)2R3, -N(R3)2, - NR3S(=O)2R3, -NR3C(=O)R3, C1-C6alkyl, C1-C6fluoroalkyl, or C2-C4alkynyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, and C2-C4alkynyl are optionally substituted with 1-5 R5groups; and each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, or C3-C10cycloalkyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, and C3-C10cycloalkyl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0121] In some embodiments, each RYis independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, - CH2OH, -CH2CH2OH, -CH2CN, -CH2C(=O)OH, -CH2C(=O)OCH3, -CH2C(=O)OCH2CH3, - CH2C(=O)NH2, -CH2C(=O)NHCH3, -CH2C(=O)N(CH3)2, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, - CH2F, -CHF2, -CF3, -CH=CH2, -C=CH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -NH2, - NHCH3, -N(CH3)2, -NHC(=O)CH3, -N(CH3)C(=O)CH3, -NHC(=O)OCH3, -N(CH3)C(=O)OCH3, - S(=O)CH3, -S(=O)2CH3, -NHS(=O)2CH3, or -N(CH3)S(=O)2CH3. In some embodiments, each RYis independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, cyclopropyl, -C=CH -NH2, - NHC(=O)CH3, -N(CH3)C(=O)CH3, -NHS(=O)2CH3, -N(CH3)S(=O)2CH3, -S(=O)CH3, or - S(=O)2CH3. In some embodiments, each RYis independently hydrogen, F, Cl, Br, I, -CH3, - CH2CH3, cyclopropyl, -NH2, -NHC(=O)CH3, -NHS(=O)2CH3, -S(=O)CH3, or -S(=O)2CH3. In some embodiments, each RYis independently hydrogen, F, Cl, or -CH3. In some embodiments, each RYis independently hydrogen or F. In some embodiments, each RYis hydrogen.

[0122] In some embodiments, R1is C1-C6alkyl optionally substituted with 1-5 R5groups.

[0123] In some embodiments, R1is C1-C6alkyl substituted with C2-Cealkenyl, C2-Cealkynyl, or - CN, wherein C2-Cealkenyl and C2-Cealkynyl optionally substituted with 1-5 R5groups.

[0124] In some embodiments, R1is C1-C6alkyl substituted with -OR3; and R3is hydrogen, Ci- Cealkyl, C1-C6fluoroalkyl, or C3-Ciocycloalkyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, and C3- Ciocycloalkyl are optionally substituted with 1-5 R5groups.

[0125] In some embodiments, R1is C1-C6alkyl substituted with -C(=O)N(R5)2 or -N(R5)2; wherein each R5is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C3-Ciocycloalkyl, C2-Cealkenyl, C2-Cealkynyl, or -CN, wherein C1-C6alkyl, C1-C6fluoroalkyl, C3-Ciocycloalkyl, C2-Cealkenyl, and C2-Cealkynyl are optionally substituted with 1-5 R5groups; or two R5are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0126] In some embodiments, R1is C1-C6alkyl substituted with C3-C5cycloalkyl or C2- C7heterocycloalkyl, wherein Ci-Cxcycloalkyl and C2-C7heterocycloalkyl are optionally substituted with 1-5 R5groups.

[0127] In some embodiments, R1is C1-C6alkyl substituted with cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0128] In some embodiments, R1is C1-C6alkyl substituted with oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, or piperidinyl.

[0129] In some embodiments, R1is C1-C6alkyl substituted with phenyl optionally substituted with 1-5 R5groups, wherein if phenyl is substituted, then it is substituted with 1, 2, 3, or 4 substituents selected from halogen, nitro, -CN, -OR3, -N(R3)2, -C(=O)R3, -C(=O)N(R3)2, -C(=O)OR3, Ci- Cealkyl, and C1-C6fluoroalkyl, wherein C1-C6alkyl and C1-C6fluoroalkyl are optionally substituted with 1-5 R5groups; and each R3is independently hydrogen, C1-C6alkyl, or C3-C10cycloalkyl, wherein C1-C6alkyl and C3-C10cycloalkyl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0130] In some embodiments, R1is C1-C6alkyl substituted with 5-membered heteroaryl ring containing at least one nitrogen atom.

[0131] In some embodiments, R1is C1-C6alkyl substituted with 5-membered heteroaryl ring selected from pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, and thiadiazolyl, wherein pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, and thiadiazolyl are optionally substituted with 1-5 R5groups.

[0132] In some embodiments, R1is C1-C6alkyl substituted with 5-membered heteroaryl ring selected from:each Rzis independently hydrogen, halogen, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, -C(=O)OR3, Ci- Cealkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, Cc2y-cClo10ahlketyelr,o Ce- waryl, -Clfc-C6-10aryl, Ci-9heteroaryl, or -CH2-Ci-9heteroaryl, wherein C1-C6alkyl, Ci- Cefluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2-cCyc10lhoeatlekryol, C6-10aryl, -CH2-C6- waryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; and each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, or C2-C10hetecryocloalkyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, Ci- Ceheteroalkyl, C3-C10cycloalkyl, and C2-Cc1y0hcelotearlokyl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0133] In some embodiments, R1is C1-C6alkyl substituted with a monocyclic 6-membered heteroaryl ring containing at least one nitrogen atom and optionally substituted with 1-5 R5groups. In some embodiments, R1is C1-C6alkyl substituted with a monocyclic 6-membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms and optionally substituted with 1-5 R5groups. In some embodiments, R1is C1-C6alkyl substituted with 6-membered heteroaryl ring selected from pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazinyl, wherein pyridinyl, pyrazinyl,pyrimidinyl, pyridazinyl, and triazinyl are optionally substituted with 1-5 R5groups. In some embodiments, R1is C1-C6alkyl substituted with pyridinyl optionally substituted with 1-5 R5groups. In some embodiments, R1is C1-C6alkyl substituted with 2-pyridinyl optionally substituted with 1-5 R5groups.

[0134] In some embodiments, R1is C1-C6alkyl substituted with 6-membered heteroaryl ring selected from:each Rzis independently hydrogen, halogen, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, -C(=O)OR3, Ci- Cealkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, Cc2y-cClo10ahlketyelr,o Ce- waryl, -CH2-C6-10aryl, Ci-9heteroaryl, or -CH2-Ci-9heteroaryl, wherein C1-C6alkyl, Ci- Cefluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2-cCyc10lhoeatlekryol, C6-10aryl, -CH2-C6- waryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; and each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, or C2-C10hetecryocloalkyl, wherein -Cealkyl, C1-C6fluoroalkyl, Ci- Ceheteroalkyl, C3-C10cycloalkyl, and C2-Cc1y0hcelotearlokyl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0135] In some embodiments, R1is C1-C6alkyl substituted with bicyclic 6 / 5 fused heteroaryl ring. In some embodiments, R1is C1-C6alkyl substituted with bicyclic 6 / 5 fused heteroaryl ring selected from indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzoimidazolyl, benzooxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotri azolyl, benzooxadiazolyl, benzothiadiazolyl, indolizinyl, and imidazopyridinyl, wherein indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzoimidazolyl, benzooxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzooxadiazolyl, benzothiadiazolyl, indolizinyl, and imidazopyridinyl are optionally substituted with 1-5 R5groups.

[0136] In some embodiments, R1is C1-C6alkyl substituted with bicyclic 6 / 5 fused heteroaryl ring selected from:each Rzis independently hydrogen, halogen, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, -C(=O)OR3, Ci- Cealkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, Ccy2-cClo10ahlkeytelr,o Ce- waryl, -Clfc-C6-10aryl, Ci-9heteroaryl, or -CH2-Ci-9heteroaryl, wherein C1-C6alkyl, Ci- Cefluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2-cCyc10lhoeatlekryol, C6-10aryl, -CH2-C6- waryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-Ciocycloalkyl, or C2-C10hetecryocloalkyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, Ci-Ceheteroalkyl, C3-C10cycloalkyl, and C2-Cc1y0hcelotearlokyl are optionally substituted with 1-5R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with thenitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0137] In some embodiments, R1is C1-C6alkyl substituted with a bicyclic 6 / 6 fused heteroaryl ring containing at least one nitrogen atom and optionally substituted with 1-5 R5groups. In some embodiments, R1is C1-C6alkyl substituted with a bicyclic 6 / 6 fused heteroaryl ring containing 1, 2, 3, or 4 nitrogen atoms and optionally substituted with 1-5 R5groups. In some embodiments, R1is C1-C6alkyl substituted with bicyclic 6 / 6 fused heteroaryl ring selected from quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl, pyrimidopyrimidinyl, and pteridinyl, wherein quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl, pyrimidopyrimidinyl, and pteridinyl are optionally substituted with 1-5 R5groups.

[0138] In some embodiments, R1is C1-C6alkyl substituted with 6 / 6 fused heteroaryl ring selected from:each Rzis independently hydrogen, halogen, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, -C(=O)OR3, Ci- Cealkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, Cc2y-cClo10ahlketyelr,o Ce- waryl, -Clfc-C6-10aryl, Ci-9heteroaryl, or -CH2-Ci-9heteroaryl, wherein C1-C6alkyl, Ci- Cefluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2-cCyc10lhoeatlekryol, C6-10aryl, -CH2-C6- waryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; and each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, or C2-C10hetecryocloalkyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, Ci- Ceheteroalkyl, C3-C10cycloalkyl, and C2-Cc1y0hcelotearlokyl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0139] In some embodiments, R1is C1-C6alkyl substituted with 1, 2, or 3 substituents each independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, and pyridinyl. In some embodiments, R1is C1-C6alkyl substituted with 1 or 2 substituents each independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, and pyridinyl. In some embodiments, R1is Ci- Cealkyl substituted with 1 or 2 substituents each independently selected from -OH and pyridinyl. In some embodiments, R1is C1-C6alkyl substituted with 1 or 2 substituents each independently selected from -NH2 and pyridinyl. In some embodiments, R1is C1-C6alkyl substituted with 1 or 2 substituents each independently selected from -OH and -NH2. In some embodiments, R1is Ci- Cealkyl substituted with -OH. In some embodiments, R1is C1-C6alkyl substituted with -NH2.

[0140] In some embodiments, each Rzis independently hydrogen, F, Cl, Br, -CH3, -CH2CH3, - CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCH2CH3, -OCF3, -NH2, -NHCH3, or -N(CH3)2. In some embodiments, each Rzis independently hydrogen, F, Cl, Br, -CH3, -CN, -OCH3, -NH2, -NHCH3, or -N(CH3)2. In some embodiments, each Rzis independently hydrogen, Cl, Br, -CH3, -OCH3, -NH2, or -N(CH3)2. In some embodiments, each Rzis hydrogen.

[0141] In some embodiments, R1is C1-C6alkyl substituted with halogen, -CN, -OR3, -SR3, -S(=O) R3, -S(=O)2R3, -N(R3)2, -C(=O)OR3, -C(=O)N(R3)2, -CR3=C(R3)2, -OCR3, C3-C10cycloalkyl, C2- Cioheterocycloalkyl, or aryl, wherein C3-C10cycloalkylC,2-C10hetero cycloalkyl, and aryl are optionally substituted with 1-5 R5groups; and each R3is independently hydrogen, C1-C6alkyl, Ci- Cefluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, orC2-C10hetero cycloalkyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, andC2-C10hetero cycloalkyl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0142] In some embodiments, R1is C3-C10cycloalkyl orC2-C10hetero cycloalkyl, wherein C3- Ciocycloalkyl andC2-C10hetero cycloalkyl are optionally substituted with 1-5 R5groups. In some embodiments, R1is C3-C6cycloalkyl or C3-C5heterocycloalkyl substituted with C1-C6alkyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazinyl. In some embodiments, R1is C3- C6cycloalkyl or C3-C5heterocycloalkyl substituted with C1-C6alkyl, phenyl, or pyridinyl.

[0143] In some embodiments, R1is selected from:

[0144] In some embodiments, R is halogen, nitro, -CN, -OR3, -C(=O)R3, -C(=O)N(R3)2, - C(=O)OR3, -S(=O)R3, -S(=O)2R3, -NR3S(=O)2R3, -NR3C(=O)R3, -NR3C(=O)OR3, or Ci- Cefluoroalkyl optionally substituted with 1-5 R5groups; and each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, or C2-Cioheterocycloalkyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, and C2- Cioheterocycloalkyl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0145] In some embodiments, R is F, Cl, Br, I, nitro, -CN, -OCH2F, -OCHF2, -OCF3, -C(=O)CH3, - C(=O)OCH3-C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -S(=O)CH3, -S(=O)2CH3, - NHS(=O)2CH3, -N(CH3)S(=O)2CH3, -NHC(=O)CH3, -N(CH3)C(=O)CH3, -NHC(=O)OCH3, - N(CH3)C(=O)OCH3, -CH2F, -CHF2, or -CF3. In some embodiments, R is F, Cl, -CN, -OCF3, - CHF2, or -CF3. In some embodiments, R is F, Cl, -OCF3, -CHF2, or -CF3. In some embodiments, R is F, Cl, or -CF3. In some embodiments, R is -OCF3. In some embodiments, R is -CF3.

[0146] In some embodiments, each R2is independently halogen, nitro, -CN, -OR3, -SR3, - S(=O)2R3, -N(R3)2, -C(=O)OR3, C1-C6alkyl, or C1-C6fluoroalkyl, wherein C1-C6alkyl and Ci- Cefluoroalkyl are optionally substituted with 1-5 R5groups; and each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-Ciocycloalkyl, or C2- Cioheterocycloalkyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-Ciocycloalkyl, and C2-Cioheterocycloalkyl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0147] In some embodiments, each R2is independently F, Cl, Br, nitro, -CN, -OH, -OCH3, - OCH2CH3, -OCH2CH2OH, -OCH2CN, -0CF3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, - C(=O)OCH3, -CH3, -CH2CH3, -CH2F, -CHF2, or -CF3. In some embodiments, each R2is independently F, Cl, -CN, -OCH3, -OCF3, -C(=O)OCH3, -CH3, or -CF3. In some embodiments, each R2is independently F, Cl, -OCF3, or -CF3. In some embodiments, each R2is independently F or Cl.

[0148] In some embodiments, R4is C1-C6alkyl, C1-C6fluoroalkyl, C3-Ciocycloalkyl, or -NH2, wherein C1-C6alkyl, C1-C6fluoroalkyl, and C3-Ciocycloalkyl are optionally substituted with 1-5 R5groups. In some embodiments, R4is C1-C6alkyl optionally substituted with 1-5 R5groups. In some embodiments, R4is C1-C6fluoroalkyl optionally substituted with 1-5 R5groups. In some embodiments, R4is C3-Ciocycloalkyl optionally substituted with 1-5 R5groups. In some embodiments, R4is -NH2.

[0149] In some embodiments, each R5is independently selected from halogen, oxo, -CN, -OR10, - SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(Rn), -N(R12)C(O)N(R10)(Rn), -N(R12)C(O)OR13, - N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(RI0)(Rn), -C(O)C(O)N(R10)(Rn), - N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(RU)-, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2- ealkenyl, C2-6alkynyl, cyCc3l-o6alkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl, wherein Ci- ealkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, cycloalkyl, -CCH3-26-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and - CH2-Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, cyCcl3o-6alkyl, C2-9heterocycloalkyl, C6-10aryl, Ci-9heteroaryl, -OR10, and -N(R10)(Rn); or two R5are combined to form a Cs-scycloalkyl ring. In some embodiments, each R5is independently selected from -OR10, -N(R10)(Rn), C1-6alkyl, and Ci-9heteroaryl, wherein C1-6alkyl and Ci-9heteroaryl are optionally substituted with halogen or -N(R10)(R11). In some embodiments, each R5is independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, and Ci-9heteroaryl optionally substituted with halogen or -N(R10)(Rn).

[0150] In some embodiments, each R5is -OH. In some embodiments, each R5is -OCH3. In some embodiments, each R5is -NH2. In some embodiments, each R5is -NHCH3. In some embodiments, each R5is -N(CH3)2. In some embodiments, each R5is -NHCH2CH3. In some embodiments, each R5is -NHCH2CH2OH. In some embodiments, each R5is -NHCH2CH2F. In some embodiments, each R5is -NHCH2CHF2. In some embodiments, each R5is Ci-9heteroaryl optionally substituted with halogen or -N(R10)(R11). In some embodiments, each R5is pyridinyl or pyrazinyl, wherein pyridinyl or pyrazinyl are optionally substituted with halogen or -N(R10)(Rn). In some embodiments, each R5is pyridinyl or pyrazinyl, wherein pyridinyl or pyrazinyl are optionally substituted with -Br, -NH2, or -N(CH3)2. In some embodiments, each R5is pyridinyl optionally substituted with -Br, -NH2, or -N(CH3)2. In some embodiments, each R5is pyrazinyl optionally substituted with -Br, -NH2, or -N(CH3)2.

[0151] In some embodiments, each R10is independently selected from hydrogen, C1-6alkyl, Ci- ehaloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, cycloalkyl,C C32-6-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, Cs- ecycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, Cs- ecycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl.

[0152] In some embodiments, each R10is independently selected from hydrogen and C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, Ci- ealkyl, C1-6haloalkyl, C1-6alkoxy, cycClo3a-6lkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl.

[0153] In some embodiments, each R10is independently selected from hydrogen and C1-6alkyl optionally substituted with F, Cl, Br, I, or hydroxy.

[0154] In some embodiments, each R11is independently selected from hydrogen, C1-6alkyl, Ci- ehaloalkyl, C2-6heteroalkyl, cycClo3a-6lkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl. In some embodiments, each R11is hydrogen. In some embodiments, each R11is C1-6alkyl.

[0155] In some embodiments, each R12is independently selected from hydrogen, C1-6alkyl, Ci- ehaloalkyl C2-6heteroalkyl, cycClo3a-6lkyl, and C2-9heterocycloalkyl.

[0156] In some embodiments, each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2- eheteroalkyl, C2-6alkenyl, C2-6alkynyl, cycloalCk3y-l6, C2-9heterocycloalkyl, C6-10aryl, and Ci- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, Cs- ecycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, SFs, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, Cs-ecycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl.

[0157] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments, n is 2 or 3. In some embodiments, n is 3 or 4. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 1, 2, 3, or 4.

[0158] In another aspect, the TEAL) inhibitor comprises a compound of Formula (I-A), or a pharmaceutically acceptable salt or solvate thereof:Formula (I- A) wherein, each Rxis independently hydrogen, halogen, -OR3, -SR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, - NR3S(=O)2R3, -NR3C(=O)R3, C1-C6alkyl, C1-C6fluoroalkyl, or C2-C4alkynyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, and C2-C4alkynyl are optionally substituted with 1-5 R5groups; each RYis independently hydrogen, halogen, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, C1-C6alkyl, C1-C6fluoroalkyl, or C2-C4alkynyl, wherein C1-C6alkyl, Ci- Cefluoroalkyl, and C2-C4alkynyl are optionally substituted with 1-5 R5groups;R is halogen, nitro, -CN, -OR3, -C(=O)R3, -C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, - S(=O)2R3, -NR3S(=O)2R3, -NR3C(=O)R3, -NR3C(=O)OR3, or C1-C6fluoroalkyl optionally substituted with 1-5 R5groups;R1is C1-C6alkyl optionally substituted with 1-5 R5groups; each R2is independently halogen, nitro, -Ns, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, - C(=O)OR3, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2- Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, or -CH2-C1-9heteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl,C2-C10hetero cycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-C1- 9heteroaryl are optionally substituted with 1-5 R5groups; each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, C2-C10hetecryocloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, or - CH2-Ci-9heteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, C2-C10hetecryocloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and - CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups;R4is C1-C6alkyl, C1-C6fluoroalkyl, C3-C10cycloalkyl, or -NH2, wherein C1-C6alkyl, Ci- Cefluoroalkyl, and C3-C10cycloalkyl are optionally substituted with 1-5 R5groups; each R5is independently selected from halogen, oxo, -CN, -OR10, -SR10, -N(R10)(Rn), - C(O)OR10, -OC(O)N(R10)(Rn), -N(R12)C(O)N(R10)(Rn), -N(R12)C(O)OR13, - N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(Rn), - C(O)C(O)N(R10)(Rn), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, Ci-6alkyl, Ci- ehaloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, cycloalkyl,C -C3-H62-C3-ecycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2- eheteroalkyl, C2-6alkenyl, C2-6alkynylC,3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -Clfc-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl,C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, Ci-9heteroaryl, -OR10, and -N(R10)(Rn); or two R5are combined to form a Cs-scycloalkyl ring; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynylC,3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl,C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy,C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci- 9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C3-ecycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; each R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- ealkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl, wherein Ci- ealkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynylC,3-6cycloalkyl, C2- 9heterocycloalkyl, C6-1010aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, SFs, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, Ci- ealkoxyC,3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl; and n is 0, 1, or 2.

[0159] In some embodiments, each Rxis independently hydrogen, F, Cl, Br, -CH3, -OH, -OCH3, or -OCF3. In some embodiments, each Rxis hydrogen. In some embodiments, each Rxis F. In some embodiments, each Rxis Cl. In some embodiments, each Rxis Br. In some embodiments, each Rxis -CH3. In some embodiments, each Rxis -OH. In some embodiments, each Rxis -OCH3. In some embodiments, each Rxis -OCF3.

[0160] In some embodiments, R is F, Cl, -CN, -OCF3, -CHF2, or -CF3. In some embodiments, R is F, Cl, or -CF3. In some embodiments, R is -CF3.

[0161] In some embodiments, R1is C1-C6alkyl substituted with -OH.

[0162] In some embodiments, R1is C1-C6alkyl substituted with 6-membered heteroaryl ring selected from pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl, wherein pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl are optionally substituted with 1-5 R5groups. In some embodiments, R1is C1-C6alkyl substituted with pyridinyl optionally substituted with 1-5 R5groups.

[0163] In some embodiments, R1is C1-C6alkyl substituted with 1, 2, or 3 substituents each independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, and pyridinyl.

[0164] In some embodiments, each R2is independently F, Cl, -OCF3, or -CF3. In some embodiments, each R2is independently F or Cl.

[0165] In some embodiments, n is 0.

[0166] In some embodiments, n is 1 or 2.

[0167] In some embodiments, the TEAL) inhibitor is selected from:pharmaceutically acceptable salt or solvate thereof.

[0168] In another aspect, the TEAD inhibitor comprises a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:Formula (II) wherein, each X1, X2, X3, X4, X5, and X6is independently N or CRX; each Rxis independently hydrogen, halogen, nitro, -OR3, -SR3, -CN, -C(=O)R3, - C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, - NR3C(=O)R3, -NR3C(=O)OR3, C1-C6 alkyl, C1-C6fluoroalkyl, C2-C4alkenyl, C2- C4alkynyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2-cCy1c0hloeatelkryol, C6-10aryl, -CH2- C6-10aryl, Ci-9heteroaryl, or -CH2-Ci-9heteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2- Cioheterocycloalkyl, C6-10aryl, -CFb-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups;R is halogen, nitro, -CN, -OR3, -SR3, -C(=O)R3, -C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, - S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, -NR3C(=O)OR3, or C1-C6fluoroalkyl optionally substituted with 1-5 R5groups;R1is C1-C6alkyl, C1-C6fluoroalkyl, C2-Cealkenyl, C2-Cealkynyl, C3-C10cycloalkyl, C2- Cioheterocycloalkyl, C1-C6heteroalkyl, -CN, or -S(=O)2R4, wherein C1-C6alkyl, Ci- Cefluoroalkyl, C2-Cealkenyl, C2-Cealkynyl, C3-C10cycloalkyl, cCy2c-lCoa10lhkeytle,ro and C1-C6heteroalkyl are optionally substituted with 1-5 R5groups; each R2is independently halogen, nitro, -N3, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, - C(=O)OR3, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2- Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, or -CH2-Ci-9heteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2- Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, C2-C10hetecryocloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, or - CH2-Ci-9heteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-CiocycloalkyCl,2-C10hetero cycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and - CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups;R4is C1-C6alkyl, C1-C6fluoroalkyl, C3-C10cycloalkyl, or -NH2, wherein C1-C6alkyl, Ci- Cefluoroalkyl, and C3-C10cycloalkyl are optionally substituted with 1-5 R5groups; each R5is independently selected from halogen, oxo, -CN, -OR10, -SR10, -N(R10)(Rn), - C(O)OR10, -OC(O)N(R10)(Rn), -N(R12)C(O)N(R10)(Rn), -N(R12)C(O)OR13, - N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(RI0)(Rn), - C(O)C(O)N(R10)(Rn), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, Ci-6alkyl, Ci- ehaloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, cycloalkyl,C -C3-H62-C3- ecycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2- eheteroalkyl, C2-6alkenyl, C2-6alkynyl, cycloalCky3-l6, -CH2-C3-6cycloalkyl, C2- 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, cycloalkCy3l,-6C2- 9heterocycloalkyl, C6-10aryl, Ci-9heteroaryl, -OR10, and -N(R10)(Rn); or two R5are combined to form a Cs-scycloalkyl ring; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, cycClo3-a6lkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl,C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, Ci- ealkyl, C1-6haloalkyl, C1-6alkoxy, cyclCo3a-l6kyl, C2-9heterocycloalkyl, C6-10aryl, and Ci- 9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl,C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl;each R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl,C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- ealkynyl, C3c-y6cloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl, wherein Ci- ealkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, cycloalkyl, C2C-3-69heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, SFs, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, Ci- ealkoxy, C3c-y6cloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl; and n is 0, 1, 2, 3, or 4.

[0169] For any and all of the embodiments of a compound of Formula (II), substituents are selected from among a subset of the listed alternatives. For example, in some embodiments X1is N or CRX. In other embodiments, X1is N. In some embodiments, X1is CRX.

[0170] In some embodiments, each X1, X2, and X3is CRX. In some embodiments, X1is N; and each X2and X3is CRX. In some embodiments, each X1and X2is CRX; and X3is N.

[0171] In some embodiments, each X4, X5, and X6is CRX. In some embodiments, X4is N; and each X5and X6is CRX. In some embodiments, each X4and X5is CRX; and X6is N.

[0172] In some embodiments, each Rxis independently hydrogen, halogen, -OR3, -SR3, -CN, - S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, C1-C6alkyl, C1-C6fluoroalkyl, C2- C4alkenyl, C2-C4alkynyl, or C1-C6heteroalkyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C2-C4alkenyl, C2-C4alkynyl, and C1-C6heteroalkyl are optionally substituted with 1-5 R5groups; and each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-Ciocycloalkyl, or C2- Cioheterocycloalkyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-Ciocycloalkyl, and C2-C10heterocycloalkyl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0173] In some embodiments, each Rxis independently hydrogen, halogen, -OR3, -SR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, C1-C6alkyl, C1-C6fluoroalkyl, or C2-C4alkynyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, and C2-C4alkynyl are optionally substituted with 1-5 R5groups; and each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, or C3-Ciocycloalkyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, and C3-Ciocycloalkyl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0174] In some embodiments, each Rxis independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, - CH2OH, -CH2CH2OH, -CH2CN, -CH2C(=O)OH, -CH2C(=O)OCH3, -CH2C(=O)OCH2CH3, - CH2C(=O)NH2, -CH2C(=O)NHCH3, -CH2C(=O)N(CH3)2, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, - CH2F, -CHF2, -CF3, -CH=CH2, -C=CH, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, oxetanyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy, azetidinyl, pyrrolidinyl, tetrazolyl, -CN, -OH, -OCH3, -OCH2CH3, -OCH2CH2OH, -OCH2CN, -OCF3, -C(=O)OH, -C(=O)OCH3, - C(=O)OCH2CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -NH2, -NHCH3, -N(CH3)2, - NHC(=O)CH3, -N(CH3)C(=O)CH3, -NHC(=O)OCH3, -N(CH3)C(=O)OCH3, -S(=O)CH3, - S(=O)2CH3, -NHS(=O)2CH3, or -N(CH3)S(=O)2CH3. In some embodiments, each Rxis independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, cyclopropyl, -C=CH, -OH, -OCH3, - OCH2CH3, -OCF3, -SCH3, cyclopropyloxy, -NH2, -NHC(=O)CH3, -N(CH3)C(=O)CH3, - NHS(=O)2CH3, -N(CH3)S(=O)2CH3, -S(=O)CH3, or -S(=O)2CH3. In some embodiments, each Rxis independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, cyclopropyl, -OH, -OCH3, -OCH2CH3, - OCF3, cyclopropyloxy, -NH2, -NHC(=O)CH3, -NHS(=O)2CH3, -S(=O)CH3, or -S(=O)2CH3. In some embodiments, each Rxis independently hydrogen, F, Cl, Br, -CH3, -OH, -OCH3, or -OCF3. In some embodiments, each Rxis independently hydrogen, F, Cl, -CH3, -OCH3, or -OCF3. In some embodiments, each Rxis independently hydrogen, F, or -OCH3. In some embodiments, each Rxis hydrogen.

[0175] In some embodiments, R1is C1-C6alkyl optionally substituted with 1-5 R5groups.

[0176] In some embodiments, R1is C1-C6alkyl substituted with C2-Cealkenyl, C2-Cealkynyl, or - CN, wherein Cealkenyl and C2-Cealkynyl are optionally substituted with 1-5 R5groups.

[0177] In some embodiments, R1is C1-C6alkyl substituted with -OR3; and R3is hydrogen, Ci- Cealkyl, C1-C6fluoroalkyl, or C3-Ciocycloalkyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, and C3- Ciocycloalkyl are optionally substituted with 1-5 R5groups.

[0178] In some embodiments, R1is C1-C6alkyl substituted with -C(=O)N(R5)2 or -N(R5)2; wherein each R5is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C3-Ciocycloalkyl, C2-Cealkenyl, C2-Cealkynyl, or -CN, wherein C1-C6alkyl, C1-C6fluoroalkyl, C3-Ciocycloalkyl, C2-Cealkenyl, and C2-Cealkynyl are optionally substituted with 1-5 R5groups; or two R5are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0179] In some embodiments, R1is C1-C6alkyl substituted with C3-C5cycloalkyl or C2- Cvheterocycloalkyl, wherein Ci-Cxcycloalkyl and C2-C7heterocycloalkyl are optionally substituted with 1-5 R5groups.

[0180] In some embodiments, R1is C1-C6alkyl substituted with cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0181] In some embodiments, R1is C1-C6alkyl substituted with oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, or piperidinyl.

[0182] In some embodiments, R1is C1-C6alkyl substituted with phenyl optionally substituted with 1-5 R5groups, wherein if phenyl is substituted, then it is substituted with 1, 2, 3, or 4 substituents selected from halogen, nitro, -CN, -OR3, -N(R3)2, -C(=O)R3, -C(=O)N(R3)2, -C(=O)OR3, Ci- Cealkyl, and C1-C6fluoroalkyl, wherein C1-C6alkyl and C1-C6fluoroalkyl are optionally substituted with 1-5 R5groups; and each R3is independently hydrogen, C1-C6alkyl, or C3-C10cycloalkyl, wherein C1-C6alkyl, and C3-C10cycloalkyl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0183] In some embodiments, R1is C1-C6alkyl substituted with 5-membered heteroaryl ring containing at least one nitrogen atom.

[0184] In some embodiments, R1is C1-C6alkyl substituted with 5-membered heteroaryl ring selected from pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, and thiadiazolyl, wherein pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, and thiadiazolyl are optionally substituted with 1-5 R5groups.

[0185] In some embodiments, R1is C1-C6alkyl substituted with 5-membered heteroaryl ring selected from:Each Rzis independently hydrogen, halogen, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, -C(=O)OR3, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, Cc2y-cClo10ahlketyelr,o Ce- waryl, -CEb-C6-10aryl, Ci-9heteroaryl, or -CH2-Ci-9heteroaryl, wherein C1-C6alkyl, Ci- Cefluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2-cCyc10lhoeatlekryol, C6-10aryl, -CH2-C6- waryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, or C2-C10hetecryocloalkyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, Ci- Ceheteroalkyl, C3-C10cycloalkyl, and C2-Cc1y0hcelotearlokyl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0186] In some embodiments, R1is C1-C6alkyl substituted with a monocyclic 6-membered heteroaryl ring containing at least one nitrogen atom and optionally substituted with 1-5 R5groups. In some embodiments, R1is C1-C6alkyl substituted with a monocyclic 6-membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms and optionally substituted with 1-5 R5groups. In some embodiments, R1is C1-C6alkyl substituted with 6-membered heteroaryl ring selected from pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl, wherein pyridinyl, pyrazinyl,pyrimidinyl, pyridazinyl, and triazinyl are optionally substituted with 1-5 R5groups. In some embodiments, R1is C1-C6alkyl substituted with pyridinyl optionally substituted with 1-5 R5groups. In some embodiments, R1is C1-C6alkyl substituted with pyridinyl optionally substituted with 1-5 R5groups. In some embodiments, R1is C1-C6alkyl substituted with 2-pyridinyl optionally substituted with 1-5 R5groups.

[0187] In some embodiments, R1is C1-C6alkyl substituted with 6-membered heteroaryl ring selected from:each Rzis independently hydrogen, halogen, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, -C(=O)OR3, Ci- Cealkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, Cc2y-cClo10ahlketyelr,o Ce- waryl, -Clfc-C6-10aryl, Ci-9heteroaryl, or -CH2-Ci-9heteroaryl, wherein C1-C6alkyl, Ci- Cefluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2-cCyc10lhoeatlekryol, C6-10aryl, -CH2-C6- waryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; and each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, or C2-C10hetecryocloalkyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, Ci- Ceheteroalkyl, C3-C10cycloalkyl, and C2-Cc1y0hcelotearlokyl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0188] In some embodiments, R1is C1-C6alkyl substituted with bicyclic 6 / 5 fused heteroaryl ring. In some embodiments, R1is C1-C6alkyl substituted with bicyclic 6 / 5 fused heteroaryl ring selected from indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzoimidazolyl, benzooxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotri azolyl, benzooxadiazolyl, benzothiadiazolyl, indolizinyl, and imidazopyridinyl, wherein indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzoimidazolyl, benzooxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl,benzooxadi azolyl, benzothiadiazolyl, indolizinyl, and imidazopyridinyl are optionally substituted with 1-5 R5groups.

[0189] In some embodiments, R1is C1-C6alkyl substituted with bicyclic 6 / 5 fused heteroaryl ring selected from:each Rzis independently hydrogen, halogen, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, -C(=O)OR3, Ci-Cealkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, Cc2y-cClo10ahlketyelr,o Ce- waryl, -CH2-C6-10aryl, Ci-9heteroaryl, or -CH2-Ci-9heteroaryl, wherein C1-C6alkyl, Ci- Cefluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2-cCyc10lhoeatlekryol, C6-10aryl, -CH2-C6- waryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; and each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-Ciocycloalkyl, or C2-C10hetecryocloalkyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, Ci-Ceheteroalkyl, C3-C10cycloalkyl, and C2-Cc1y0hcelotearlokyl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0190] In some embodiments, R1is C1-C6alkyl substituted with a bicyclic 6 / 6 fused heteroaryl ring containing at least one nitrogen atom and optionally substituted with 1-5 R5groups. In some embodiments, R1is C1-C6alkyl substituted with a bicyclic 6 / 6 fused heteroaryl ring containing 1, 2, 3, or 4 nitrogen atoms and optionally substituted with 1-5 R5groups. In some embodiments, R1is C1-C6alkyl substituted with bicyclic 6 / 6 fused heteroaryl ring selected from quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl, pyrimidopyrimidinyl, and pteridinyl, wherein quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl, pyrimidopyrimidinyl, and pteridinyl are optionally substituted with 1-5 R5groups.

[0191] In some embodiments, R1is C1-C6alkyl substituted with 6 / 6 fused heteroaryl ring selected from:each Rzis independently hydrogen, halogen, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, -C(=O)OR3, Ci-Cealkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, Cc2y-cClo10ahlketyelr,o Ce- waryl, -CH2-C6-10aryl, Ci-9heteroaryl, or -CH2-Ci-9heteroaryl, wherein C1-C6alkyl, Ci-Cefluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2-cCyc10lhoeatlekryol, C6-10aryl, -CH2-C6- waryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; and each R3is independently hydrogen, C1-C6alkyl, Ci -Cefluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, or C2-C10hetecryocloalkyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, Ci- Ceheteroalkyl, C3-C10cycloalkyl, and C2-Cc1y0hcelotearlokyl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0192] In some embodiments, R1is C1-C6alkyl substituted with 1, 2, or 3 substituents each independently selected from -OH, -OCH3, -NH2, -NHCH3, N(CH3)2, and pyridinyl. In some embodiments, R1is C1-C6alkyl substituted with 1 or 2 substituents each independently selected from -OH, -OCH3, -NH2, -NHCH3, N(CH3)2, and pyridinyl. In some embodiments, R1is C1-C6alkyl substituted with 1 or 2 substituents each independently selected from -OH and pyridinyl. In some embodiments, R1is C1-C6alkyl substituted with 1 or 2 substituents each independently selected from -NH2 and pyridinyl. In some embodiments, R1is C1-C6alkyl substituted with 1 or 2 substituents each independently selected from -OH and -NH2. In some embodiments, R1is Ci- Cealkyl substituted with -OH. In some embodiments, R1is C1-C6alkyl substituted with -NH2.

[0193] In some embodiments, each Rzis independently hydrogen, F, Cl, Br, -CH3, -CH2CH3, - CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCH2CH3, -OCF3, -NH2, -NHCH3, or -N(CH3)2. In some embodiments, each Rzis independently hydrogen, F, Cl, Br, -CH3, -CN, -OCH3, -NH2, -NHCH3, or -N(CH3)2. In some embodiments, each Rzis independently hydrogen, Cl, Br, -CH3, -OCH3, -NH2, or -N(CH3)2. In some embodiments, each Rzis hydrogen.

[0194] In some embodiments, R1is C1-C6alkyl substituted with halogen, -CN, -OR3, -SR3, -S(=O) R3, -S(=O)2R3, -N(R3)2, -C(=O)OR3, -C(=O)N(R3)2, -CR3=C(R3)2, -OCR3, C3-Ciocycloalkyl, C2- Cioheterocycloalkyl, or aryl, wherein C3-C10cycloalkyl, Cc2y-Ccl1o0ahlektyerl,o and aryl are optionally substituted with 1-5 R5groups; and each R3is independently hydrogen, C1-C6alkyl, Ci- Cefluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, or C2c-yCc1l0ohaeltkeyrol, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, and C2c-yCcl10ohaelkteyrlo are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0195] In some embodiments, R1is C3-C10cycloalkyl or Cc2y-cClo10ahlketyelr,o wherein C3- Ciocycloalkyl and C2-C10hetecyrocloalkyl are optionally substituted with 1-5 R5groups. In some embodiments, R1is Cs-Cecycloalkyl or C3-C5heterocycloalkyl substituted with C1-C6alkyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazinyl. In some embodiments, R1is C3- Cecycloalkyl or C3-C5heterocycloalkyl substituted with C1-C6alkyl, phenyl, or pyridinyl.

[0196] In some embodiments, R is halogen, nitro, -CN, -OR3, -C(=O)R3, -C(=O)N(R3)2, - C(=O)OR3, -S(=O)R3, -S(=O)2R3, -NR3S(=O)2R3, -NR3C(=O)R3, -NR3C(=O)OR3, or Ci- Cefluoroalkyl optionally substituted with 1-5 R5groups; and each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-Ciocycloalkyl, or cCy2c-Clo1a0lhkeytle,ro wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-Ciocycloalkyl, and C2- Cioheterocycloalkyl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0197] In some embodiments, R is F, Cl, Br, I, nitro, -CN, -OCH2F, -OCHF2, -OCF3, -C(=O)CH3, - C(=O)OCH3-C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -S(=O)CH3, -S(=O)2CH3, - NHS(=O)2CH3, -N(CH3)S(=O)2CH3, -NHC(=O)CH3, -N(CH3)C(=O)CH3, -NHC(=O)OCH3, - N(CH3)C(=O)OCH3, -CH2F, -CHF2, or -CF3. In some embodiments, R is F, Cl, -CN, -OCF3, - CHF2, or -CF3. In some embodiments, R is F, Cl, -OCF3, -CHF2, or -CF3. In some embodiments, R is F, Cl, or -CF3. In some embodiments, R is -OCF3. In some embodiments, R is -CF3.

[0198] In some embodiments, each R2is independently halogen, nitro, -CN, -OR3, -SR3, - S(=O)2R3, -N(R3)2, -C(=O)OR3, C1-C6alkyl, or C1-C6fluoroalkyl, wherein C1-C6alkyl and Ci- Cefluoroalkyl are optionally substituted with 1-5 R5groups; and each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-Ciocycloalkyl, or C2- Cioheterocycloalkyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-Ciocycloalkyl, and C2-C10heterocycloalkyl are optionally substituted with 1-5 R5groups; or if two R3are on thesame nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0199] In some embodiments, each R2is independently F, Cl, Br, nitro, -CN, -OH, -OCH3, - OCH2CH3, -OCH2CH2OH, -OCH2CN, -OCF3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, - C(=O)OCH3, -CH3, -CH2CH3, -CH2F, -CHF2, or -CF3. In some embodiments, each R2is independently F, Cl, -CN, -OCH3, -OCF3, -C(=O)OCH3, -CH3, or -CF3. In some embodiments, each R2is independently F, Cl, -OCF3, or -CF3. In some embodiments, each R2is independently F or Cl.\

[0200] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments, n is 2 or 3. In some embodiments, n is 3 or 4. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 1, 2, 3, or 4.

[0201] In another aspect, the TEAL) inhibitor comprises a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:wherein, each X3, X5, and X6is independently N or CRX;X4is CRX; each Rxis independently hydrogen, halogen, nitro, -OR3, -SR3, -CN, -C(=O)R3, - C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, - NR3C(=O)R3, -NR3C(=O)OR3, C1-C6 alkyl, Ci-C6fluoroalkyl, C2-C4alkenyl, C2- C4alkynyl, C1-C6heteroalkyl, C3-Ciocycloalkyl, C2-cCyc10lhoeatlekryol, C6-10aryl, -CH2- C6-10aryl, Ci-9heteroaryl, or -CH2-Ci-9heteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C6heteroalkyl, C3-Ciocycloalkyl, C2- Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups;R is halogen, nitro, -CN, -OR3, -SR3, -C(=O)R3, -C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, - S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, -NR3C(=O)OR3, or Ci-C6fluoroalkyl optionally substituted with 1-5 R5groups;R1is C1-C6alkyl, C1-C6fluoroalkyl, C2-Cealkenyl, C2-Cealkynyl, C3-C10cycloalkyl, C2- Cioheterocycloalkyl, C1-C6heteroalkyl, -CN, or -S(=O)2R4, wherein C1-C6alkyl, Ci- Cefluoroalkyl, C2-Cealkenyl, C2-Cealkynyl, C3-C10cycloalkyl, C2-Cioheterocycloalkyl, and C1-C6heteroalkyl are optionally substituted with 1-5 R5groups; each R2is independently halogen, nitro, -Ns, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, - C(=O)OR3, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2- Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, or -CH2-Ci-9heteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2- Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, C2-Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, or - CH2-Ci-9heteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, C2-Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and - CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups;R4is C1-C6alkyl, C1-C6fluoroalkyl, C3-C10cycloalkyl, or -NH2, wherein C1-C6alkyl, Ci- Cefluoroalkyl, and C3-C10cycloalkyl are optionally substituted with 1-5 R5groups; each R5is independently selected from halogen, oxo, -CN, -OR10, -SR10, -N(R10)(Rn), - C(O)OR10, -OC(O)N(R10)(Rn), -N(R12)C(O)N(R10)(Rn), -N(R12)C(O)OR13, - N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(Rn), - C(O)C(O)N(R10)(Rn), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(RU)-, Ci-6alkyl, Ci- ehaloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, cycloalkyl,C -C3-H6 2-C3- ecycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2- eheteroalkyl, C2-6alkenyl, C2-6alkynyl, cycloalCky3-l6, -CH2-C3-6cycloalkyl, C2- 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, cycloalkCy3l,-6C2-9heterocycloalkyl, C6-10aryl, Ci-9heteroaryl, -OR10, and -N(R10)(Rn); or two R5are combined to form a Cs-scycloalkyl ring; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, cycCl3o-a6lkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl,C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, Ci- ealkyl, C1-6haloalkyl, C1-6alkoxy, cycClo3a-6lkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci- 9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl,C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; each R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl,C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- ealkynyl, C3-c6ycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl, wherein Ci- ealkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, cycloalkyl, CC2-3-69heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, SFs, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, Ci- ealkoxy, C3-c6ycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl; and n is 0, 1, 2, 3, or 4.

[0202] For any and all of the embodiments of a compound of Formula (III), substituents are selected from among a subset of the listed alternatives. For example, in some embodiments X5is N or CRX. In other embodiments, X5is N. In some embodiments, X5is CRX.

[0203] In some embodiments, X3is CRX. In some embodiments, X3is N.

[0204] In some embodiments, each X5and X6is CRX. In some embodiments, X5is N; and X6is CRX. In some embodiments, X5is CRX; and X6is N.

[0205] In some embodiments, each Rxis independently hydrogen, halogen, -OR3, -SR3, -CN, - S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, Ci-C6alkyl, Ci-C6fluoroalkyl, C2- C4alkenyl, C2-C4alkynyl, or C1-C6heteroalkyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C2-C4alkenyl,C2-C4alkynyl, and C1-C6heteroalkyl are optionally substituted with 1-5 R5groups; and each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, or C2- Cioheterocycloalkyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, and C2-C10heterocycloalkyl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0206] In some embodiments, each Rxis independently hydrogen, halogen, -OR3, -SR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, C1-C6alkyl, C1-C6fluoroalkyl, or C2-C4alkynyl; and each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, or C3-C10cycloalkyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, and C2-C4alkynyl are optionally substituted with 1-5 R5groups; and each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C3-C10cycloalkyl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0207] In some embodiments, each Rxis independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, - CH2OH, -CH2CH2OH, -CH2CN, -CH2C(=O)OH, -CH2C(=O)OCH3, -CH2C(=O)OCH2CH3, - CH2C(=O)NH2, -CH2C(=O)NHCH3, -CH2C(=O)N(CH3)2, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, - CH2F, -CHF2, -CF3, -CH=CH2, -C=CH, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, oxetanyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy, azetidinyl, pyrrolidinyl, tetrazolyl, -CN, -OH, -OCH3, -OCH2CH3, -OCH2CH2OH, -OCH2CN, -OCF3, -C(=O)OH, -C(=O)OCH3, - C(=O)OCH2CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -NH2, -NHCH3, -N(CH3)2, - NHC(=O)CH3, -N(CH3)C(=O)CH3, -NHC(=O)OCH3, -N(CH3)C(=O)OCH3, -S(=O)CH3, - S(=O)2CH3, -NHS(=O)2CH3, or -N(CH3)S(=O)2CH3. In some embodiments, each Rxis independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, cyclopropyl, -C=CH, -OH, -OCH3, - OCH2CH3, -OCF3, -SCH3, cyclopropyloxy, -NH2, -NHC(=O)CH3, -N(CH3)C(=O)CH3, - NHS(=O)2CH3, -N(CH3)S(=O)2CH3, -S(=O)CH3, or -S(=O)2CH3. In some embodiments, each Rxis independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, cyclopropyl, -OH, -OCH3, -OCH2CH3, - OCF3, cyclopropyloxy, -NH2, -NHC(=O)CH3, -NHS(=O)2CH3, -S(=O)CH3, or -S(=O)2CH3. In some embodiments, each Rxis independently hydrogen, F, Cl, Br, -CH3, -OH, -OCH3, or -OCF3. In some embodiments, each Rxis independently hydrogen, F, Cl, -CH3, -OCH3, or -OCF3. In some embodiments, each Rxis independently hydrogen, F, or -OCH3. In some embodiments, each Rxis hydrogen.

[0208] In some embodiments, R1is C1-C6alkyl optionally substituted with 1-5 R5groups.

[0209] In some embodiments, R1is C1-C6alkyl substituted with C2-Cealkenyl, C2-Cealkynyl, or - CN, C2-Cealkenyl, and C2-Cealkynyl are optionally substituted with 1-5 R5groups.

[0210] In some embodiments, R1is C1-C6alkyl substituted with -OR3; and R3is hydrogen, Ci- Cealkyl, C1-C6fluoroalkyl, or C3-C10cycloalkyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, and C3- Ciocycloalkyl are optionally substituted with 1-5 R5groups.

[0211] In some embodiments, R1is C1-C6alkyl substituted with -C(=O)N(R5)2 or -N(R5)2; wherein each R5is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C3-C10cycloalkyl, C2-Cealkenyl, C2-Cealkynyl, or -CN, wherein C1-C6alkyl, C1-C6fluoroalkyl, C3-C10cycloalkyl, C2-Cealkenyl, and C2-Cealkynyl are optionally substituted with 1-5 R5groups; or two R5are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0212] In some embodiments, R1is C1-C6alkyl substituted with C3-C5cycloalkyl or C2- Cvheterocycloalkyl, wherein Ci-Cxcycloalkyl and C2-C7heterocycloalkyl are optionally substituted with 1-5 R5groups.

[0213] In some embodiments, R1is C1-C6alkyl substituted with cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0214] In some embodiments, R1is C1-C6alkyl substituted with oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, or piperidinyl.

[0215] In some embodiments, R1is C1-C6alkyl substituted with phenyl optionally substituted with 1-5 R5groups, wherein if phenyl is substituted, then it is substituted with 1, 2, 3, or 4 substituents selected from halogen, nitro, -CN, -OR3, -N(R3)2, -C(=O)R3, -C(=O)N(R3)2, -C(=O)OR3, Ci- Cealkyl, and C1-C6fluoroalkyl, wherein C1-C6alkyl and C1-C6fluoroalkyl are optionally substituted with 1-5 R5groups; and each R3is independently hydrogen, C1-C6alkyl, or C3-Ciocycloalkyl, wherein C1-C6alkyl and C3-Ciocycloalkyl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0216] In some embodiments, R1is C1-C6alkyl substituted with 5-membered heteroaryl ring containing at least one nitrogen atom. In some embodiments, R1is C1-C6alkyl substituted with 5- membered heteroaryl ring selected from pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, and thiadiazolyl, wherein pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, and thiadiazolyl are optionally substituted with 1-5 R5groups.

[0217] In some embodiments, R1is C1-C6alkyl substituted with 5-membered heteroaryl ring selected from:wherein each Rzis independently hydrogen, halogen, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, -C(=O)OR3, Ci- Cealkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, Cc2y-cClo10ahlketyelr,o substitute C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, or -CH2-Ci-9heteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2-cCyc10lhoeatlekryol, substitute Ce- waryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; and each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, or C2-C10hetecryocloalkyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, Ci- Ceheteroalkyl, C3-C10cycloalkyl, and C2-Cc1y0hcelotearlokyl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with thenitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0218] In some embodiments, R1is C1-C6alkyl substituted with a monocyclic 6-membered heteroaryl ring containing at least one nitrogen atom and optionally substituted with 1-5 R5groups. In some embodiments, R1is C1-C6alkyl substituted with a monocyclic 6-membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms and optionally substituted with 1-5 R5groups. In some embodiments, R1is C1-C6alkyl substituted with 6-membered heteroaryl ring selected from pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl, wherein pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl are optionally substituted with 1-5 R5groups. In some embodiments, R1is C1-C6alkyl substituted with pyridinyl optionally substituted with 1-5 R5groups. In some embodiments, R1is C1-C6alkyl substituted with 2-pyridinyl optionally substituted with 1-5 R5groups.

[0219] In some embodiments, R1is C1-C6alkyl substituted with 6-membered heteroaryl ring selected from:each Rzis independently hydrogen, halogen, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, -C(=O)OR3, Ci- Cealkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-Ciocycloalkyl, Ccy2-cClo10ahlkeytelr,o Ce- waryl, -Clfc-C6-10aryl, Ci-9heteroaryl, or -CH2-Ci-9heteroaryl, wherein C1-C6alkyl, Ci- Cefluoroalkyl, C1-C6heteroalkyl, C3-Ciocycloalkyl, C2c-Cyc10lohaeltkeryol, C6-10aryl, -CH2-C6- waryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; and each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, or C2-C10hetecryocloalkyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, Ci- Ceheteroalkyl, C3-C10cycloalkyl, and C2-Cc1y0hcelotearlokyl are C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, or C2-C1c0yhceltoearolkyl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0220] In some embodiments, R1is C1-C6alkyl substituted with bicyclic 6 / 5 fused heteroaryl ring. In some embodiments, R1is C1-C6alkyl substituted with bicyclic 6 / 5 fused heteroaryl ring selected from indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzoimidazolyl, benzooxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotri azolyl, benzooxadiazolyl, benzothiadiazolyl, indolizinyl, and imidazopyridinyl, wherein indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzoimidazolyl, benzooxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotri azolyl, benzooxadiazolyl, benzothiadiazolyl, indolizinyl, and imidazopyridinyl are optionally substituted with 1-5 R5groups.

[0221] In some embodiments, R1is C1-C6alkyl substituted with bicyclic 6 / 5 fused heteroaryl ring selected from:each Rzis independently hydrogen, halogen, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, -C(=O)OR3, Ci- Cealkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, Cc2y-cClo10ahlketyelr,o aralkyl, C6-10aryl, -Clfc-C6-10aryl, Ci-9heteroaryl, or -CH2-Ci-9heteroaryl, wherein C1-C6alkyl, Ci- Cefluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2-cCyc10lhoeatlekryol, aralkyl, C6-10aryl, - CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; and each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, or C2-C10hetecryocloalkyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, Ci- Ceheteroalkyl, C3-C10cycloalkyl, and C2-Cc1y0hcelotearlokyl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0222] In some embodiments, R1is C1-C6alkyl substituted with a bicyclic 6 / 6 fused heteroaryl ring containing at least one nitrogen atom and optionally substituted with 1-5 R5groups. In some embodiments, R1is C1-C6alkyl substituted with a bicyclic 6 / 6 fused heteroaryl ring containing 1, 2, 3, or 4 nitrogen atoms and optionally substituted with 1-5 R5groups. In some embodiments, R1is C1-C6alkyl substituted with bicyclic 6 / 6 fused heteroaryl ring selected from quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl, pyrimidopyrimidinyl, and pteridinyl, wherein quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl, pyrimidopyrimidinyl, and pteridinyl are optionally substituted with 1-5 R5groups.

[0223] In some embodiments, R1is C1-C6alkyl substituted with 6 / 6 fused heteroaryl ring selected from:each Rzis independently hydrogen, halogen, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, -C(=O)OR3, Ci- Cealkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, Cc2y-cClo10ahlketyelr,o Ce- waryl, -Clfc-C6-10aryl, Ci-9heteroaryl, or -CH2-Ci-9heteroaryl, wherein C1-C6alkyl, Ci- Cefluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2-cCyc10lhoeatlekryol, C6-10aryl, -CH2-C6- waryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; and each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, or C2-C10hetecryocloalkyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, Ci- Ceheteroalkyl, C3-C10cycloalkyl, and C2-Cc1y0hcelotearlokyl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0224] In some embodiments, R1is C1-C6alkyl substituted with 1, 2, or 3 substituents each independently selected from -OH, -OCH3, -NH2, -NHCH3, N(CH3)2, and pyridinyl. In some embodiments, R1is C1-C6alkyl substituted with 1 or 2 substituents each independently selected from -OH, -OCH3, -NH2, -NHCH3, N(CH3)2, and pyridinyl. In some embodiments, R1is C1-C6alkyl substituted with 1 or 2 substituents each independently selected from -OH and pyridinyl. In some embodiments, R1is C1-C6alkyl substituted with 1 or 2 substituents each independently selected from -NH2 and pyridinyl. In some embodiments, R1is C1-C6alkyl substituted with 1 or 2substituents each independently selected from -OH and -NH2. In some embodiments, R1is Ci- Cealkyl substituted with -OH. In some embodiments, R1is C1-C6alkyl substituted with -NH2.

[0225] In some embodiments, each Rzis independently hydrogen, F, Cl, Br, -CH3, -CH2CH3, - CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCH2CH3, -OCF3, -NH2, -NHCH3, or -N(CH3)2. In some embodiments, each Rzis independently hydrogen, F, Cl, Br, -CH3, -CN, -OCH3, -NH2, -NHCH3, or -N(CH3)2. In some embodiments, each Rzis independently hydrogen, Cl, Br, -CH3, -OCH3, -NH2, or -N(CH3)2. In some embodiments, each Rzis hydrogen.

[0226] In some embodiments, R1is C1-C6alkyl substituted with halogen, -CN, -OR3, -SR3, -S(=O) R3, -S(=O)2R3, -N(R3)2, -C(=O)OR3, -C(=O)N(R3)2, -CR3=C(R3)2, -C=CR3, C3-Ciocycloalkyl, C2- Cioheterocycloalkyl, or aryl, wherein C3-Ciocycloalkyl, Cc2y-cClo10ahlektyelr,o and aryl are optionally substituted with 1-5 R5groups; and each R3is independently hydrogen, C1-C6alkyl, Ci- Cefluoroalkyl, C1-C6heteroalkyl, C3-Ciocycloalkyl, or C2c-yCc1l0ohaeltkeyrol, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-Ciocycloalkyl, and Cc2y-Ccl1o0halekteyrlo are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0227] In some embodiments, R1is C3-Ciocycloalkyl or Ccy2-cClo10ahlkeytelr, o wherein C3- Ciocycloalkyl and C2-C10hetecyrocloalkyl optionally substituted with 1-5 R5groups. In some embodiments, R1is Cs-Cecycloalkyl or C3-C5heterocycloalkyl substituted with C1-C6alkyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazinyl. In some embodiments, R1is C3- Cecycloalkyl or C3-C5heterocycloalkyl substituted with C1-C6alkyl, phenyl, or pyridinyl.

[0228] In some embodiments, R is halogen, nitro, -CN, -OR3, -C(=O)R3, -C(=O)N(R3)2, - C(=O)OR3, -S(=O)R3, -S(=O)2R3, -NR3S(=O)2R3, -NR3C(=O)R3, -NR3C(=O)OR3, or Ci- Cefluoroalkyl optionally substituted with 1-5 R5groups; and each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-Ciocycloalkyl, or cCy2c-Clo1a0lhkeytle,ro wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-Ciocycloalkyl, and C2- Cioheterocycloalkyl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0229] In some embodiments, R is F, Cl, Br, I, nitro, -CN, -OCH2F, -OCHF2, -OCF3, -C(=O)CH3, - C(=O)OCH3-C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -S(=O)CH3, -S(=O)2CH3, - NHS(=O)2CH3, -N(CH3)S(=O)2CH3, -NHC(=O)CH3, -N(CH3)C(=O)CH3, -NHC(=O)OCH3, - N(CH3)C(=O)OCH3, -CH2F, -CHF2, or -CF3. In some embodiments, R is F, Cl, -CN, -OCF3, -CHF2, or -CF3. In some embodiments, R is F, Cl, -OCF3, -CHF2, or -CF3. In some embodiments, R is F, Cl, or -CF3. In some embodiments, R is -OCF3. In some embodiments, R is -CF3.

[0230] In some embodiments, each R2is independently halogen, nitro, -CN, -OR3, -SR3, - S(=O)2R3, -N(R3)2, -C(=O)OR3, C1-C6alkyl, or C1-C6fluoroalkyl, wherein C1-C6alkyl and Ci- Cefluoroalkyl are optionally substituted with 1-5 R5groups; and each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-Ciocycloalkyl, or C2- Cioheterocycloalkyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-Ciocycloalkyl, and C2-C10heterocycloalkyl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups.

[0231] In some embodiments, each R2is independently F, Cl, Br, nitro, -CN, -OH, -OCH3, - OCH2CH3, -OCH2CH2OH, -OCH2CN, -OCF3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, - C(=O)OCH3, -CH3, -CH2CH3, -CH2F, -CHF2, or -CF3. In some embodiments, each R2is independently F, Cl, -CN, -OCH3, -OCF3, -C(=O)OCH3, -CH3, or -CF3. In some embodiments, each R2is independently F, Cl, -OCF3, or -CF3. In some embodiments, each R2is independently F or Cl.

[0232] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments, n is 2 or 3. In some embodiments, n is 3 or 4. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 1, 2, 3, or 4.

[0233] In one aspect, the therapeutically effective amount of the TEAL) inhibitor is about 1 mg to about 500 mg per day. In some embodiments, therapeutically effective amount of the TEAL) inhibitor is about 1 mg to about 450 mg per day. In some embodiments, therapeutically effective amount of the TEAL) inhibitor is about 1 mg to about 400 mg per day. In some embodiments, therapeutically effective amount of the TEAL) inhibitor is about 1 mg to about 350 mg per day. In some embodiments, therapeutically effective amount of the TEAL) inhibitor is about 1 mg to about 300 mg per day. In some embodiments, therapeutically effective amount of the TEAL) inhibitor is about 1 mg to about 250 mg per day. In some embodiments, therapeutically effective amount of the TEAL) inhibitor is about 10 mg to about 250 mg per day. In some embodiments, therapeutically effective amount of the TEAL) inhibitor is about 25 mg to about 250 mg per day. In some embodiments, therapeutically effective amount of the TEAL) inhibitor is about 25 mg to about 200 mg per day. In some embodiments, therapeutically effective amount of the TEAL) inhibitor is about 25 mg to about 150 mg per day. In some embodiments, therapeutically effective amount of theTEAD inhibitor is about 25 mg to about 100 mg per day. In some embodiments, therapeutically effective amount of the TEAD inhibitor is about 25 mg to about 90 mg per day. In some embodiments, therapeutically effective amount of the TEAD inhibitor is about 25 mg to about 80 mg per day. In some embodiments, therapeutically effective amount of the TEAD inhibitor is about 25 mg to about 70 mg per day. In some embodiments, therapeutically effective amount of the TEAD inhibitor is about 25 mg to about 60 mg per day. In some embodiments, therapeutically effective amount of the TEAD inhibitor is about 25 mg to about 50 mg per day.

[0234] In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 5 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 10 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 15 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 20 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 25 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 30 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 40 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 45 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 50 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 55 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 60 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 65 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 70 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 75 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 80 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 85 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 90 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 95 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 100 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 110 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 120 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 130 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 140 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 150 mg per day. In some embodiments, the therapeutically effectiveamount of the TEAD inhibitor is about 160 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 170 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 180 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 190 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 200 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 210 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 220 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 230 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 240 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 250 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 300 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 350 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 400 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 450 mg per day. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is about 500 mg per day.

[0235] In some embodiments, the TEAD inhibitor disclosed herein has the structure provided in Table 1Table 1Preparation of the Compounds

[0236] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and / or from compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0237] Methods known to one of ordinary skill in the art are identified through various reference books and databases. Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin,Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471- 60180-2; Otera, J. (editor) "Modem Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871- 1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley- Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[0238] In some instances, specific and analogous reactants are identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (the American Chemical Society, Washington, D.C., is contacted for more details). Chemicals that are known but not commercially available in catalogs are prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0239] In some embodiments, the compounds disclosed herein are prepared as described in the Examples section. c-MET inhibitors

[0240] In some aspects, the second therapeutic agent is a c-MET inhibitor.

[0241] In some aspects, the c-Met inhibitors are a class of small molecules that inhibit the enzymatic activity of the c-Met tyrosine kinase, the receptor of hepatocyte growth factor / scatter factor (HGF / SF).

[0242] In some aspects, the c-MET inhibitor is selected from cabozantinib, crizotinib, foretinib, tivantinib, savolitinib, capmatinib, and tepotinib, or a combination thereof. In some embodiments, the c-MET inhibitor is selected from savolitinib and capmatinib, or a combination thereof. In some embodiments, the c-MET inhibitor is cabozantinib. In some embodiments, the c-MET inhibitor is crizotinib. In some embodiments, the c-MET inhibitor is foretinib. In some embodiments, the c- MET inhibitor is tivantinib. In some embodiments, the c-MET inhibitor is savolitinib. In some embodiments, the c-MET inhibitor is capmatinib. In some embodiments, the c-MET inhibitor is tepotinib.

[0243] In some embodiments, cabozantinib is a kinase inhibitor indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC).

[0244] In some embodiments, crizotinib is used to treat patients with non-small cell lung cancer (NSCLC) that has spread to other parts of the body and is caused by a defect in either a gene called ALK (anaplastic lymphoma kinase) or a gene called ROSE

[0245] In some embodiments, tivantinib is indicated for the treatment of adult patients with relapsed or refractory advanced renal cell carcinoma (RCC) following two or more prior systemic therapies.

[0246] In some embodiments, capmatinib is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 skipping as detected by an FDA-approved test.

[0247] In some embodiments, tepotinib is a kinase inhibitor indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) harboring mesenchymal epithelial transition (MET) exon 14 skipping alterations.

[0248] In some aspects, the therapeutically effective amount of the c-MET inhibitor is about 1 mg to about 1000 mg per day. In some embodiments, the therapeutically effective amount of the c- MET inhibitor is about 1 mg to about 950 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 1 mg to about 900 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 1 mg to about 850 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 1 mg to about 800 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 1 mg to about 750 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 1 mg to about 700 mg per day. Insome embodiments, the therapeutically effective amount of the c-MET inhibitor is about 1 mg to about 650 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 1 mg to about 600 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 1 mg to about 550 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 1 mg to about 500 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 1 mg to about 450 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 1 mg to about 400 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 1 mg to about 350 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 1 mg to about 300 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 1 mg to about 250 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 1 mg to about 200 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 1 mg to about 150 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 1 mg to about 100 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 1 mg to about 50 mg per day.

[0249] In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 5 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 10 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 20 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 30 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 40 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 50 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 60 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 70 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 80 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 90 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 100 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 120 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 140 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 160 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 180 mg per day. In some embodiments, thetherapeutically effective amount of the c-MET inhibitor is about 200 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 220 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 240 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 260 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 280 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 300 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 320 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 340 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 360 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 380 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 400 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 420 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 440 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 460 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 480 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 500 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 520 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 540 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 560 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 580 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 600 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 620 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 640 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 660 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 680 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 700 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 720 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 740 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 760 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 780 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about800 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 850 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 900 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 950 mg per day. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is about 1000 mg per day.BRAF inhibitors

[0250] In some aspects, the second therapeutic agent is a BRAF inhibitor.

[0251] In some aspects, the BRAF inhibitors selectively target BRAF kinase and thus interfere with the mitogen-activated protein kinase (MAPK) signaling pathway that regulates the proliferation and survival of melanoma cells. In some embodiments, the BRAF inhibitors have immunomodulatory effects as well as molecularly targeted activity. In some embodiments, the MAPK pathway is involved in T-cell receptor signaling, and interference in the pathway by BRAF inhibitors can have beneficial effects on the tumor microenvironment and anti -turn or immune response in BRAF- mutant cancer, including increased immune-stimulatory cytokine levels, decreased immunosuppressive cytokine levels, enhanced cancer differentiation antigen expression and presentation of tumor antigens by HL A 1, and increased intra-tumoral T-cell infiltration and activity. In some embodiments, such effects can promote recognition of the tumor by the immune system and enhance anti -turn or T-cell responses.

[0252] In some aspects, the BRAF inhibitor is selected from vemurafenib, dabrafenib, encorafenib, and sorafenib, or a combination thereof. In some embodiments, the BRAF inhibitor is vemurafenib. In some embodiments, the BRAF inhibitor is dabrafenib. In some embodiments, the BRAF inhibitor is encorafenib. In some embodiments, the BRAF inhibitor is sorafenib.

[0253] In some embodiments, vemurafenib is a kinase inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. In some embodiments, vemurafenib is indicated for the treatment of patients with Erdheim-Chester Disease (ECD) with BRAF V600 mutation.

[0254] In some embodiments, dabrafenib is a kinase inhibitor indicated as a single agent for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. In some embodiments, dabrafenib in combination with trametinib is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test.

[0255] In some embodiments, encorafenib is indicated, in combination with binimetinib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test.

[0256] In some embodiments, encorafenib is indicated, in combination with cetuximab, for the treatment of adult patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy.

[0257] In some embodiments, sorafenib is a kinase inhibitor indicated for the treatment of (1) unresectable hepatocellular carcinoma; (2) advanced renal cell carcinoma; or (3) locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) refractory to radioactive iodine treatment.

[0258] In some aspects, the therapeutically effective amount of the BRAF inhibitor is about 1 mg to about 500 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 1 mg to about 450 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 1 mg to about 400 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 1 mg to about 350 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 1 mg to about 300 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 1 mg to about 250 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 1 mg to about 200 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 1 mg to about 150 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 1 mg to about 100 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 1 mg to about 50 mg per day.

[0259] In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 5 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 10 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 20 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 30 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 40 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 50 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 60 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 70 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 80 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 90 mgper day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 100 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 120 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 140 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 160 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 180 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 200 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 220 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 240 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 260 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 280 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 300 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 320 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 340 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 360 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 380 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 400 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 420 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 440 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 460 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 480 mg per day. In some embodiments, the therapeutically effective amount of the BRAF inhibitor is about 500 mg per day.EFGR inhibitors

[0260] In some aspects, the second therapeutic agent is an EGFR inhibitor.

[0261] In some aspects, the EGFR inhibitor can block the extracellular ligand binding domain by which signal molecules can no longer attach to the domain and activate the tyrosine kinase. In some embodiments, the EGFR inhibitor can inhibit the EGFR tyrosine kinase, which is on the cytoplasmic side of the receptor. Without kinase activity, EGFR is unable to activate itself and to bind to downstream adaptor proteins. In some embodiments, the EGFR inhibitor can raise antibodies against EGF itself, thereby denying EGFR-dependent cancers of a proliferative stimulus.

[0262] In some aspects, the EGFR inhibitor comprises a monoclonal antibody.

[0263] In some aspects, the EGFR inhibitor comprises a tyrosine kinase inhibitor.

[0264] In some aspects, the EGFR inhibitor is selected from cetuximab, necitumumab, panitumumab, zalutumumab, nimotuzumab, matuzumab, osimertinib, gefitinib, erlotinib, lapatinib, neratinib, vandetanib, afatinib, brigatinib, dacomitinib, lazertinib, amivantamab, and icotinib, or a combination thereof. In some embodiments, the EGFR inhibitor is selected from osimertinib, lazertinib, and amivantamab, or a combination thereof, or a combination thereof. In some embodiments, the EGFR inhibitor is cetuximab. In some embodiments, the EGFR inhibitor is necitumumab. In some embodiments, the EGFR inhibitor is panitumumab. In some embodiments, the EGFR inhibitor is zalutumumab. In some embodiments, the EGFR inhibitor is nimotuzumab. In some embodiments, the EGFR inhibitor is matuzumab. In some embodiments, the EGFR inhibitor is osimertinib. In some embodiments, the EGFR inhibitor is gefitinib. In some embodiments, the EGFR inhibitor is erlotinib. In some embodiments, the EGFR inhibitor is lapatinib. In some embodiments, the EGFR inhibitor is neratinib. In some embodiments, the EGFR inhibitor is vandetanib. In some embodiments, the EGFR inhibitor is afatinib. In some embodiments, the EGFR inhibitor is brigatinib. In some embodiments, the EGFR inhibitor is dacomitinib. In some embodiments, the EGFR inhibitor is lazertinib. In some embodiments, the EGFR inhibitor is amivantamab. In some embodiments, the EGFR inhibitor is icotinib.

[0265] In some embodiments, cetuximab, used in combination with irinotecan, is indicated for the treatment of EGFR expressing, metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy.

[0266] In some embodiments, cetuximab administered as a single agent is indicated for the treatment of EGFR expressing, metastatic colorectal carcinoma in patients who are intolerant to irinotecan-based chemotherapy.

[0267] In some embodiments, cetuximab is indicated for the treatment of KRAS wild-type, epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use: (1) in combination with FOLFIRI (irinotecan, fluorouracil, leucovorin) for first-line treatment; or (2) in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy; or as a single agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan.

[0268] In some embodiments, necitumumab is an epidermal growth factor receptor (EGFR) antagonist indicated, in combination with gemcitabine and cisplatin, for first-line treatment of patients with metastatic squamous non-small cell lung cancer.

[0269] In some embodiments, panitumumab is an epidermal growth factor receptor (EGFR) antagonist indicated for the treatment of wild-type RAS (defined as wild-type in both KRAS andNRAS as determined by an FDA-approved test for this use) metastatic colorectal cancer (mCRC): (1) in combination with FOLFOX for first-line treatment; or (2) as monotherapy following disease progression after prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan-containing chemotherapy.

[0270] In some embodiments, osimertinib is a kinase inhibitor indicated for: (1) as adjuvant therapy after tumor resection in adult patients with non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test; (2) the first-line treatment of adult patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test; or (3) the treatment of adult patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR TKI therapy.

[0271] In some embodiments, gefitinib is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.

[0272] In some embodiments, gefitinib is a tyrosine kinase inhibitor indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.

[0273] In some embodiments, erlotinib is indicated for patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test receiving first-line, maintenance, or >second-line treatment after progression following at least 1 prior chemotherapy regimen.

[0274] In some embodiments, erlotinib is indicated for first-line treatment in patients with locally advanced, unresectable, or metastatic pancreatic cancer.

[0275] In some embodiments, lapatinib is a kinase inhibitor indicated in combination with: (1) capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress human epidermal growth factor receptor 2 (HER2) and who have received prior therapy, including an anthracycline, a taxane, and trastuzumab; or (2) letrozole for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer that overexpresses the HER2 receptor for whom hormonal therapy is indicated.

[0276] In some embodiments, neratinib is a kinase inhibitor indicated: (1) as a single agent, for the extended adjuvant treatment of adult patients with early-stage HER2 -positive breast cancer, tofollow adjuvant trastuzumab-based therapy; or (2) in combination with capecitabine, for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 based regimens in the metastatic setting.

[0277] In some embodiments, vandetanib is a kinase inhibitor indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease.

[0278] In some embodiments, afatinib is a kinase inhibitor indicated for: (1) first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have non-resistant epidermal growth factor receptor (EGFR) mutations as detected by an FDA-approved test; or (2) treatment of patients with metastatic, squamous NSCLC progressing after platinum-based chemotherapy.

[0279] In some embodiments, brigatinib is a kinase inhibitor indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test.

[0280] In some embodiments, dacomitinib is a kinase inhibitor indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA- approved test.

[0281] In some embodiments, amivantamab is a bispecific EGF receptor-directed and MET receptor-directed antibody indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.

[0282] In some embodiments, icotinib is an EGFR-tyrosine kinase inhibitor and exhibits efficacy and tolerability in patients with advanced non-small-cell lung cancer (NSCLC) who failed previous chemotherapy.

[0283] In some aspects, the therapeutically effective amount of the EGFR inhibitor is about 1 mg to about 200 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 1 mg to about 190 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 1 mg to about 180 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 1 mg to about 170 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 1 mg to about 160 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 1 mg to about 150 mg per day. In some embodiments, thetherapeutically effective amount of the EGFR inhibitor is about 1 mg to about 140 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 1 mg to about 130 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 1 mg to about 120 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 1 mg to about 110 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 1 mg to about 100 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 1 mg to about 90 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 1 mg to about 80 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 1 mg to about 70 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 1 mg to about 60 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 1 mg to about 50 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 1 mg to about 40 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 1 mg to about 30 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 1 mg to about 20 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 1 mg to about 10 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 1 mg to about 5 mg per day.

[0284] In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 5 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 10 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 20 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 30 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 40 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 50 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 60 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 70 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 80 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 90 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 100 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 110 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 120 mg per day. In some embodiments, the therapeutically effective amount ofthe EGFR inhibitor is about 130 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 140 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 150 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 160 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 170 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 180 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 190 mg per day. In some embodiments, the therapeutically effective amount of the EGFR inhibitor is about 200 mg per day.MEK inhibitors

[0285] In some aspects, the second therapeutic agent is a MEK inhibitor.

[0286] In some aspects, the MEK inhibitor can inhibit the mitogen-activated protein kinase kinase enzymes MEK1 and / or MEK2. In some embodiments, the MEK inhibitor can be used to affect the MAPKZERK pathway which is often overactive in some cancers.

[0287] In some aspects, the MEK inhibitor is selected from refametinib, selumetinib, trametinib, cobimetinib, binimetinib, mirdametinib, and pimasertib, or a combination thereof. In some embodiments, the MEK inhibitor is selected from cobimetinib and trametinib, or a combination thereof. In some embodiments, the MEK inhibitor is refametinib. In some embodiments, the MEK inhibitor is selumetinib. In some embodiments, the MEK inhibitor is trametinib. In some embodiments, the MEK inhibitor is cobimetinib. In some embodiments, the MEK inhibitor is binimetinib. In some embodiments, the MEK inhibitor is mirdametinib. In some embodiments, the MEK inhibitor is pimasertib.

[0288] In some embodiments, selumetinib is a kinase inhibitor indicated for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN).

[0289] In some embodiments, trametinib is a kinase inhibitor indicated as a single agent for the treatment of BRAF-inhibitor treatment-naive patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test.

[0290] In some embodiments, trametinib is indicated, in combination with dabrafenib, for: (1) the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test; (2) the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection; (3) the treatment of patients withIllmetastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test; (4) the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation and with no satisfactory locoregional treatment options; (5) the treatment of adult and pediatric patients 6 years of age and older with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options; or (6) the treatment of pediatric patients 1 year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy.

[0291] In some embodiments, cobimetinib is a kinase inhibitor indicated: (1) for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in combination with vemurafenib; or (2) as a single agent for the treatment of adult patients with histiocytic neoplasms.

[0292] In some embodiments, binimetinib is a kinase inhibitor indicated, in combination with encorafenib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test.

[0293] In some aspects, the therapeutically effective amount of the MEK inhibitor is about 1 mg to about 200 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 1 mg to about 190 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 1 mg to about 180 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 1 mg to about 170 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 1 mg to about 160 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 1 mg to about 150 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 1 mg to about 140 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 1 mg to about 130 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 1 mg to about 120 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 1 mg to about 110 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 1 mg to about 100 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 1 mg to about 90 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 1 mg to about 80 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 1 mg to about 70 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 1 mg to about 60mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 1 mg to about 50 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 1 mg to about 40 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 1 mg to about 30 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 1 mg to about 20 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 1 mg to about 10 mg per day.

[0294] In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 5 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 10 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 20 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 30 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 40 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 50 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 60 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 70 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 80 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 90 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 100 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 110 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 120 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 130 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 140 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 150 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 160 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 170 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 180 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 190 mg per day. In some embodiments, the therapeutically effective amount of the MEK inhibitor is about 200 mg per day.KRAS inhibitors

[0295] In some aspects, the second therapeutic agent is a KRAS inhibitor.

[0296] In some aspects, the KRAS inhibitor is selected from an inhibitor of a KRAS G12C mutant, an inhibitor of a KRAS G12D mutant, an inhibitor of a KRAS G12V mutant, and an inhibitor of a KRAS G13 mutant, or a combination thereof. In some embodiments, the KRAS inhibitor is an inhibitor of a KRAS G12C mutant. In some embodiments, the KRAS inhibitor is an inhibitor of a KRAS G12D mutant. In some embodiments, the KRAS inhibitor is an inhibitor of a KRAS G12V mutant. In some embodiments, the KRAS inhibitor is an inhibitor of a KRAS G13 mutant.

[0297] In some embodiments, the KRAS inhibitor is selected from adagrasib and sotorasib, or a combination thereof. In some embodiments, the KRAS inhibitor is adagrasib. In some embodiments, the KRAS inhibitor is sotorasib.

[0298] In some embodiments, Adagrasib is an inhibitor of the RAS GTPase family indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA approved test, who have received at least one prior systemic therapy.

[0299] In some embodiments, sotorasib is an inhibitor of the RAS GTPase family indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy.

[0300] In some aspects, the therapeutically effective amount of the KRAS inhibitor is about 1 mg to about 1500 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 1 mg to about 1400 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 1 mg to about 1300 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 1 mg to about 1200 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 1 mg to about 1100 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 1 mg to about 1000 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 1 mg to about 900 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 1 mg to about 800 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 1 mg to about 700 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 1 mg to about 600 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 1 mg to about 500 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 1 mg to about 400 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 1 mg to about 300 mg per day. In someembodiments, the therapeutically effective amount of the KRAS inhibitor is about 1 mg to about 200 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 1 mg to about 100 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 1 mg to about 90 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 1 mg to about 80 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 1 mg to about 70 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 1 mg to about 60 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 1 mg to about 50 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 1 mg to about 40 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 1 mg to about 30 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 1 mg to about 20 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 1 mg to about 10 mg per day.

[0301] In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 10 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 20 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 30 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 40 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 50 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 60 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 70 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 80 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 90 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 100 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 200 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 300 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 400 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 500 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 600 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 700 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 800 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 900 mg per day.In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 1000 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 1100 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 1200 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 1300 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 1400 mg per day. In some embodiments, the therapeutically effective amount of the KRAS inhibitor is about 1500 mg per day. mTOR inhibitors

[0302] In some aspects, the second therapeutic agent is a mTOR inhibitor.

[0303] In some aspects, the mTOR inhibitor can inhibit the mechanistic target of rapamycin (mTOR), which is a serine / threonine-specific protein kinase that belongs to the family of phosphatidylinositol-3 kinase (PI3K) related kinases (PIKKs). In some embodiments, mTOR regulates cellular metabolism, growth, and proliferation by forming and signaling through two protein complexes, mTORCl and mTORC2.

[0304] In some aspects, the mTOR inhibitor is selected from mTORCl inhibitor and mTORC2 inhibitor, or a combination thereof. In some embodiments, the mTOR inhibitor is mTORCl inhibitor. In some embodiments, the mTOR inhibitor is mTORC2 inhibitor.

[0305] In some aspects, the mTOR inhibitor is selected from temsirolimus, everolimus, ridaforolimus, sirolimus, umirolimus, and zotarolimus, or a combination thereof. In some embodiments, the mTOR inhibitor is temsirolimus. In some embodiments, the mTOR inhibitor is everolimus. In some embodiments, the mTOR inhibitor is ridaforolimus. In some embodiments, the mTOR inhibitor is sirolimus. In some embodiments, the mTOR inhibitor is umirolimus. In some embodiments, the mTOR inhibitor is zotarolimus.

[0306] In some embodiments, temsirolimus is a kinase inhibitor indicated for the treatment of advanced renal cell carcinoma.

[0307] In some embodiments, everolimus is a kinase inhibitor indicated for the treatment of:• postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole.• adults with progressive neuroendocrine tumors of pancreatic origin (PNET) that is unresectable, locally advanced or metastatic. The safety and effectiveness of everolimus in the treatment of patients with carcinoid tumors have not been established.• adults with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib.• adults with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery. The effectiveness of everolimus in treatment of renal angiomyolipoma is based on an analysis of durable objective responses in patients treated for a median of 8.3 months. Further follow-up of patients is required to determine long-term outcomes.• adults and children > 3 years of age with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TSC) who require therapeutic intervention but are not candidates for curative surgical resection. The effectiveness of everolimus is based on an analysis of change in SEGA volume. Clinical benefit such as improvement in disease-related symptoms or increase in overall survival has not been demonstrated.

[0308] In some embodiments, sirolimus is an immunosuppressive agent indicated for the prophylaxis of organ rejection in patients aged >13 years receiving renal transplants.• Patients at low- to moderate-immunologic risk: Use initially with cyclosporine (CsA) and corticosteroids. CsA withdrawal is recommended 2-4 months after transplantation.• Patients at high-immunologic risk: Use in combination with cyclosporine and corticosteroids for the first 12 months following transplantation. Safety and efficacy of CsA withdrawal has not been established in high-risk patients.• Therapeutic drug monitoring is recommended for all patients.

[0309] In some aspects, the therapeutically effective amount of the mTOR inhibitor is about 1 mg to about 100 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 1 mg to about 90 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 1 mg to about 80 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 1 mg to about 70 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 1 mg to about 60 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 1 mg to about 50 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 1 mg to about 40 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 1 mg to about 30 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 1 mg to about 20 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 1 mg to about 10 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 1 mg to about 9 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 1 mg to about 8 mg per day. Insome embodiments, the therapeutically effective amount of the mTOR inhibitor is about 1 mg to about 7 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 1 mg to about 6 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 1 mg to about 5 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 1 mg to about 4 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 1 mg to about 3 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 1 mg to about 2 mg per day.

[0310] In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 100 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 90 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 80 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 70 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 60 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 50 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 40 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 30 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 20 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 10 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 9 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 8 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 7 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 6 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 5 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 4 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 3 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 2 mg per day. In some embodiments, the therapeutically effective amount of the mTOR inhibitor is about 1 mg per day.Further Forms of CompoundsIsomers

[0311] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (£), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, disclosed herein are dissociable complexes (e.g., crystalline diastereomeric salts). In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that does not result in racemization.Labeled compounds

[0312] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. In some embodiments, examples of isotopes that are incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36C1, respectively. Compounds described herein, and the metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates, or derivatives thereof which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this disclosure. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e.,2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compounds, pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof is prepared by any suitable method.

[0313] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.Pharmaceutically acceptable salts

[0314] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0315] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds of the disclosure, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.Solvates

[0316] In some embodiments, the compounds described herein exist as solvates. The disclosure provides for methods of treating diseases by administering such solvates. The disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0317] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent iswater, or alcoholates are formed when the solvent is alcohol. In some embodiments, solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous / organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or methanol. In some embodiments, the compounds provided herein exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.Prodrugs

[0318] In some embodiments, the compounds described herein exist in prodrug form. The disclosure provides for methods of treating diseases by administering such prodrugs. The disclosure further provides for methods of treating diseases by administering such prodrugs as pharmaceutical compositions.

[0319] In some embodiments, prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy, or carboxylic acid group of compounds of the present disclosure. The amino acid residues include, but are not limited to, the 20 naturally occurring amino acids and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, ornithine, and methionine sulfone. In other embodiments, prodrugs include compounds wherein a nucleic acid residue, or an oligonucleotide of two or more (e.g., two, three or four) nucleic acid residues is covalently joined to a compound of the present disclosure.

[0320] Pharmaceutically acceptable prodrugs of the compounds described herein also include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, metal salts, and sulfonate esters. In some embodiments, compounds having free amino, amido, hydroxy, or carboxylic groups are converted into prodrugs. For instance, free carboxyl groups are derivatized as amides or alkyl esters. In certain instances, all of these prodrug moieties incorporate groups including, but not limited to, ether, amine, and carboxylic acid functionalities.

[0321] Hydroxy prodrugs include esters such as, though not limited to, acyloxyalkyl (e.g., acyloxymethyl, acyloxyethyl) esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, sulfonate esters, sulfate esters and disulfide containing esters, ethers, amides, carbamates, hemi succinates, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews 1996, 19, 115.

[0322] Amine derived prodrugs include, but are not limited to, the following groups andas well as sulfonamides and phosphonamides.

[0323] In certain instances, sites on any aromatic ring portions are susceptible to various metabolic reactions, therefore incorporation of appropriate substituents on the aromatic ring structures reduce, minimize, or eliminate this metabolic pathway.Metabolites

[0324] In some embodiments, compounds described herein are susceptible to various metabolic reactions. Therefore, in some embodiments, incorporation of appropriate substituents into the structure will reduce, minimize, or eliminate a metabolic pathway. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of an aromatic ring to metabolic reactions is, by way of example only, a halogen or an alkyl group.

[0325] In some embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.METHODS

[0326] In one aspect, the present disclosure provides methods of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent, wherein the cancer is a relapsed or refractory cancer. In some embodiments, the methods comprise administering to the patient a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent, wherein the cancer is a relapsed cancer. In some embodiments, the methods comprise administering to the patient a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent, wherein the cancer is a refractory cancer.

[0327] In another aspect, the present disclosure provides methods of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent, wherein the cancer is a relapsed or refractory cancer. In some embodiments, the methods comprise administering to the patient a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent, wherein the cancer is a relapsed cancer. In some embodiments, the methods comprise administering to the patient a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent, wherein the cancer is a refractory cancer.

[0328] In another aspect, the present disclosure provides use of a composition comprising a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent disclosed herein in the manufacture of a medicament for treating cancer. In some embodiments, the present disclosure provides use of a composition comprising a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent disclosed herein in the manufacture of a medicament for treating cancer.

[0329] In another aspect, the present disclosure provides methods of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent, wherein the therapeutically effective amount of the TEAD inhibitor is about 1 mg to about 300 mg per day.

[0330] In some embodiments, the present disclosure provides methods of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent, wherein the therapeutically effective amount of the compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, is about 1 mg to about 300 mg per day.

[0331] In another aspect, the present disclosure provides methods of inhibiting one or more of proteins encompassed by, or related to, the Hippo pathway, comprising administering to a subject in need thereof a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent disclosed herein.

[0332] In another aspect, the present disclosure provides methods of inhibiting one or more of proteins encompassed by, or related to, the Hippo pathway, comprising administering to a subject in need thereof a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent disclosed herein.

[0333] In another aspect, the present disclosure provides methods of inhibiting transcriptional coactivator with PDZ binding motif / Yes-associated protein transcriptional coactivator (TAZ / YAP) comprising administering to a subject in need thereof a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent disclosed herein.

[0334] In another aspect, the present disclosure provides methods of inhibiting transcriptional coactivator with PDZ binding motif / Yes-associated protein transcriptional coactivator (TAZ / YAP) comprising administering to a subject in need thereof a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent disclosed herein.

[0335] In another aspect, the present disclosure provides methods of treating polycystic kidney disease or liver fibrosis in a subject in need thereof comprising administering to a subject in need thereof a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent disclosed herein.

[0336] In another aspect, the present disclosure provides methods of treating polycystic kidney disease or liver fibrosis in a subject in need thereof comprising administering to a subject in need thereof a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent disclosed herein.

[0337] In some aspects, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent are administered simultaneously. In some aspects, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent are administered sequentially. In some embodiments, thetherapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent are formulated together in a single composition. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent are formulated in separate compositions.

[0338] In some aspects, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the c-MET inhibitor are administered simultaneously. In some aspects, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the c- MET inhibitor are administered sequentially. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the c-MET inhibitor are formulated together in a single composition. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the c-MET inhibitor are formulated in separate compositions.

[0339] In some aspects, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the BRAF inhibitor are administered simultaneously. In some aspects, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the BRAF inhibitor are administered sequentially. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the BRAF inhibitor are formulated together in a single composition. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the BRAF inhibitor are formulated in separate compositions.

[0340] In some aspects, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the EGFR inhibitor are administered simultaneously. In some aspects, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the EGFR inhibitor are administered sequentially. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the EGFR inhibitor are formulated together in a single composition. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising theTEAD inhibitor and the therapeutically effective amount of the EGFR inhibitor are formulated in separate compositions.

[0341] In some aspects, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the MEK inhibitor are administered simultaneously. In some aspects, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the MEK inhibitor are administered sequentially. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the MEK inhibitor are formulated together in a single composition. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the MEK inhibitor are formulated in separate compositions.

[0342] In some aspects, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the KRAS inhibitor are administered simultaneously. In some aspects, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the KRAS inhibitor are administered sequentially. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the KRAS inhibitor are formulated together in a single composition. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the KRAS inhibitor are formulated in separate compositions.

[0343] In some aspects, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the mTOR inhibitor are administered simultaneously. In some aspects, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the mTOR inhibitor are administered sequentially. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the mTOR inhibitor are formulated together in a single composition. In some embodiments, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the mTOR inhibitor are formulated in separate compositions.

[0344] In some aspects, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent is administered daily for at least a week.

[0345] In some aspects, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent is administered daily for at least two weeks.

[0346] In some aspects, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent is administered daily for at least three weeks.

[0347] In some aspects, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent is administered daily for at least 24 days.

[0348] In some aspects, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent is administered in a cycle length of three weeks, wherein the therapeutically effective amount is administered daily for one week, and then not administered for the following two weeks.

[0349] In some aspects, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent is administered in a cycle length of three weeks, wherein the therapeutically effective amount is administered daily for two weeks, and then not administered for the following one week.

[0350] In some aspects, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent is administered in a cycle length of four weeks, wherein the therapeutically effective amount is administered daily for one week, and then not administered for the following three weeks.

[0351] In some aspects, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent is administered in a cycle length of four weeks, wherein the therapeutically effective amount is administered daily for two weeks, and then not administered for the following two weeks.

[0352] In some aspects, the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent is administered in at least two cycles.

[0353] In some embodiments, administering a combination of the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent provides a synergistic effect to the patient.

[0354] In some embodiments, administering a combination of the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the c-MET inhibitor provides a synergistic effect to the patient. In some embodiments, administering a combination of the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the BRAF inhibitor provides a synergistic effect to the patient. In some embodiments, administering a combination of the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the EGFR inhibitor provides a synergistic effect to the patient. In some embodiments, administering a combination of the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the MEK inhibitor provides a synergistic effect to the patient. In some embodiments, administering a combination of the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the KRAS inhibitor provides a synergistic effect to the patient. In some embodiments, administering a combination of the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the mTOR inhibitor provides a synergistic effect to the patient.

[0355] In some embodiments, the methods disclosed herein further comprises administering to the patient one or more pharmaceutically acceptable excipients.KITS

[0356] In one aspect, the present disclosure provides kits, comprising (i) a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent; and (ii) instructions for administering the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent to treat cancer in a subject in need thereof, wherein the cancer is a relapsed or refractory cancer.

[0357] In another aspect, the present disclosure provides kits, comprising (i) a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I -A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent; and (ii) instructions for administering the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent to treat cancer in a subject in need thereof, wherein the cancer is a relapsed or refractory cancer.

[0358] In some embodiments, the present disclosure provides kits, comprising (i) a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a c-MET inhibitor; and (ii) instructions for administering the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the c-MET inhibitor to treat cancer in a subject in need thereof, wherein the cancer is a relapsed or refractory cancer.

[0359] In some embodiments, the present disclosure provides kits, comprising (i) a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a BRAF inhibitor; and (ii) instructions for administering the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the BRAF inhibitor to treat cancer in a subject in need thereof, wherein the cancer is a relapsed or refractory cancer.

[0360] In some embodiments, the present disclosure provides kits, comprising (i) a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of an EGFR inhibitor; and (ii) instructions for administering the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the EGFR inhibitor to treat cancer in a subject in need thereof, wherein the cancer is a relapsed or refractory cancer.

[0361] In some embodiments, the present disclosure provides kits, comprising (i) a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a MEK inhibitor; and (ii) instructions for administering the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the MEK inhibitor to treat cancer in a subject in need thereof, wherein the cancer is a relapsed or refractory cancer.

[0362] In some embodiments, the present disclosure provides kits, comprising (i) a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a KRAS inhibitor; and (ii) instructions for administering the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amountof the KRAS inhibitor to treat cancer in a subject in need thereof, wherein the cancer is a relapsed or refractory cancer.

[0363] In some embodiments, the present disclosure provides kits, comprising (i) a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a mTOR inhibitor; and (ii) instructions for administering the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the mTOR inhibitor to treat cancer in a subject in need thereof, wherein the cancer is a relapsed or refractory cancer.

[0364] In another aspect, the present disclosure provides kits, comprising (i) a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent; and (ii) instructions for administering the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent to treat cancer in a subject in need thereof, wherein the therapeutically effective amount of the TEAD inhibitor is about 1 mg to about 300 mg per day.

[0365] In another aspect, the present disclosure provides kits, comprising (i) a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent; and (ii) instructions for administering the therapeutically effective amount of the compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and the therapeutically effective amount of the second therapeutic agent to treat cancer in a subject in need thereof, wherein the therapeutically effective amount of the compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, is about 1 mg to about 300 mg per day.

[0366] In some embodiments, the present disclosure provides kits, comprising (i) a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a c-MET inhibitor; and (ii) instructions for administering the therapeutically effective amount of the compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and the therapeutically effective amount of the c-MET inhibitor to treat cancer in a subject in need thereof, wherein the therapeutically effective amount of the compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, is about 1 mg to about 300 mg per day.

[0367] In some embodiments, the present disclosure provides kits, comprising (i) a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I -A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a BRAF inhibitor; and (ii) instructions for administering the therapeutically effective amount of the compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and the therapeutically effective amount of the BRAF inhibitor to treat cancer in a subject in need thereof, wherein the therapeutically effective amount of the compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, is about 1 mg to about 300 mg per day.

[0368] In some embodiments, the present disclosure provides kits, comprising (i) a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I -A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of an EGFR inhibitor; and (ii) instructions for administering the therapeutically effective amount of the compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and the therapeutically effective amount of the EGFR inhibitor to treat cancer in a subject in need thereof, wherein the therapeutically effective amount of the compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, is about 1 mg to about 300 mg per day.

[0369] In some embodiments, the present disclosure provides kits, comprising (i) a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I -A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a MEK inhibitor; and (ii) instructions for administering the therapeutically effective amount of the compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and the therapeutically effective amount of the MEK inhibitor to treat cancer in a subject in need thereof, wherein the therapeutically effective amount of the compound of Formula (I), (I- A),(II), or (III), or a pharmaceutically acceptable salt or solvate thereof, is about 1 mg to about 300 mg per day.

[0370] In some embodiments, the present disclosure provides kits, comprising (i) a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (LA), (II), or(III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a KRAS inhibitor; and (ii) instructions for administering the therapeutically effective amount of the compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and the therapeutically effective amount of the KRAS inhibitor to treat cancer in a subject in need thereof, wherein the therapeutically effective amount of the compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, is about 1 mg to about 300 mg per day.

[0371] In some embodiments, the present disclosure provides kits, comprising (i) a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I -A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a mTOR inhibitor; and (ii) instructions for administering the therapeutically effective amount of the compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and the therapeutically effective amount of the mTOR inhibitor to treat cancer in a subject in need thereof, wherein the therapeutically effective amount of the compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, is about 1 mg to about 300 mg per day.

[0372] In some embodiments, the kits disclosed herein further comprise one or more pharmaceutically acceptable excipients.PHARMACEUTICAL COMPOSITIONS

[0373] In one aspect, the present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent, wherein the second therapeutic agent is selected from a c-MET inhibitor, a BRAF inhibitor, an EGFR inhibitor, a MEK inhibitor, a KRAS inhibitor, and a mTOR inhibitor, and a pharmaceutically acceptable excipient.

[0374] In another aspect, the present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent, wherein the second therapeutic agent is selected from a c-MET inhibitor, a BRAF inhibitor, an EGFR inhibitor, a MEK inhibitor, a KRAS inhibitor, and a mTOR inhibitor, and a pharmaceutically acceptable excipient.

[0375] In some aspects, the present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of a c-MET inhibitor, and a pharmaceutically acceptable excipient.

[0376] In some aspects, the present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a c-MET inhibitor, and a pharmaceutically acceptable excipient.

[0377] In some aspects, the present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of a BRAF inhibitor, and a pharmaceutically acceptable excipient.

[0378] In some aspects, the present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a BRAF inhibitor, and a pharmaceutically acceptable excipient.

[0379] In some aspects, the present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of an EGFR inhibitor, and a pharmaceutically acceptable excipient.

[0380] In some aspects, the present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of an EGFR inhibitor, and a pharmaceutically acceptable excipient.

[0381] In some embodiments, the present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of a MEK inhibitor, and a pharmaceutically acceptable excipient.

[0382] In some aspects, the present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a MEK inhibitor, and a pharmaceutically acceptable excipient.

[0383] In some aspects, the present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of a KRAS inhibitor, and a pharmaceutically acceptable excipient.

[0384] In some aspects, the present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a KRAS inhibitor, and a pharmaceutically acceptable excipient.

[0385] In some aspects, the present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of a mTOR inhibitor, and a pharmaceutically acceptable excipient.

[0386] In some aspects, the present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a mTOR inhibitor, and a pharmaceutically acceptable excipient.

[0387] In some aspects, the present disclosure provides pharmaceutical compositions comprising a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent, wherein the second therapeutic agent is selected from a c-MET inhibitor, a BRAF inhibitor, an EFGR inhibitor, a MEK inhibitor, a KRAS inhibitor, and a mTOR inhibitor, together with one or more pharmaceutically acceptable carriers.

[0388] In some aspects, the present disclosure provides pharmaceutical compositions comprising a therapeutically effective amount of a first therapeutic agent comprising a compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent, wherein the second therapeutic agent is selected from a c-MET inhibitor, a BRAF inhibitor, an EFGR inhibitor, a MEK inhibitor, a KRAS inhibitor, and a mTOR inhibitor, together with one or more pharmaceutically acceptable carriers.

[0389] In some aspects, the carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject) of the composition.

[0390] In one aspect, the pharmaceutical compositions as often further can comprise more than one active compound (e.g., a compound, salt or conjugate and other agents) as necessary for the particular indication being treated. The active compounds can have complementary activities that do not adversely affect each other. Such molecules can be present in combination in amounts that are effective for the purpose intended.

[0391] In another aspect, a first therapeutic agent comprising a TEAD inhibitor and a second therapeutic agent may be formulated in any suitable pharmaceutical formulation.

[0392] In another aspect, a first therapeutic agent comprising a compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a second therapeutic agent may be formulated in any suitable pharmaceutical formulation.

[0393] In some aspects, a first therapeutic agent disclosed herein is formulated with a second therapeutic agent disclosed herein, as described in the International Application No. PCT / US2022 / 070330, filed January 25, 2022, and published as WO2022159986A1; International Application No. PCT / US2022 / 072452, filed May 19, 2022, and published as WO2022246459A1;and International Application No. PCT / IB2022 / 058104, filed August 30, 2022, and published as WO2023031781A1; each of which is hereby incorporated by reference in its entirety.

[0394] In some embodiments, a pharmaceutical formulation of the present disclosure typically contains an active ingredient (e.g., compound or salt of any one Formula I) and one or more pharmaceutically acceptable excipients or carriers, including but not limited to: inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, antioxidents, solubilizers, and adjuvants.

[0395] In some aspects, a first therapeutic agent comprising a TEAD inhibitor and a second therapeutic agent is formulated with a chelating agent or other material capable of binding metal ions, such as ethylene diamine tetra acetic acid (EDTA) and its salts are capable of enhancing the stability of the first therapeutic agent comprising the TEAD inhibitor and the second therapeutic agent.

[0396] In some aspects, a first therapeutic agent comprising a compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a second therapeutic agent is formulated with a chelating agent or other material capable of binding metal ions, such as ethylene diamine tetra acetic acid (EDTA) and its salts are capable of enhancing the stability of the first therapeutic agent comprising the compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof and the second therapeutic agent.

[0397] In some aspects, pharmaceutical compositions can be formulated using one or more physiologically-acceptable carriers comprising excipients and auxiliaries. Formulation can be modified depending upon the route of administration chosen. Pharmaceutical compositi...

Claims

CLAIMSWhat is claimed is:

1. A method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent, wherein the cancer is a relapsed or refractory cancer.2 The method of claim 1, wherein the therapeutically effective amount of the TEAD inhibitor is about 1 mg to about 300 mg per day.3 The method of claim 1 or 2, wherein the therapeutically effective amount of the TEAD inhibitor is about 25 mg to about 200 mg per day.4 The method of any one of claims 1 to 3, wherein the therapeutically effective amount of the TEAD inhibitor is about 25 mg to about 100 mg per day.5 A method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent, wherein the therapeutically effective amount of the TEAD inhibitor is about 1 mg to about 300 mg per day.6 The method of claim 5, wherein the therapeutically effective amount of the TEAD inhibitor is about 25 mg to about 200 mg per day.7 The method of claim 5 or 6, wherein the therapeutically effective amount of the TEAD inhibitor is about 25 mg to about 100 mg per day.8 The method of any one of claims 5 to 7, wherein the cancer is a relapsed or refractory cancer.9 The method of any one of claims 1 to 8, wherein the second therapeutic agent is selected from a c-MET inhibitor, a BRAF inhibitor, an EGFR inhibitor, a MEK inhibitor, a KRAS inhibitor, and a mTOR inhibitor.10 The method of any one of claims 1 to 9, wherein the second therapeutic agent is a c-MET inhibitor.11 The method of claim 10, wherein the therapeutically effective amount of the c-MET inhibitor is about 1 mg to about 800 mg per day.12 The method of claim 10 or 11, wherein the therapeutically effective amount of the c-MET inhibitor is about 1 mg to about 400 mg per day.13 The method of any one of claims 9 to 12, wherein the c-MET inhibitor is selected from cabozantinib, crizotinib, foretinib, tivantinib, savolitinib, capmatinib, and tepotinib, or a combination thereof.

14. The method of claim 13, wherein the c-MET inhibitor is selected from savolitinib and capmatinib, or a combination thereof.

15. The method of any one of claims 1 to 4 or 8, wherein the relapsed or refractory cancer is a c- MET mutant cancer.

16. The method of any one of claims 1 to 4 or 8, wherein the relapsed or refractory cancer is a c- MET amplified cancer.

17. The method of any one of claims 1 to 9, wherein the second therapeutic agent is a BRAF inhibitor.

18. The method of claim 17, wherein the therapeutically effective amount of the BRAF inhibitor is about 1 mg to about 400 mg per day.

19. The method of claim 17 or 18, wherein the therapeutically effective amount of the BRAF inhibitor is about 1 mg to about 200 mg per day.

20. The method of any one of claims 17 to 19, wherein the BRAF inhibitor is selected from vemurafenib, dabrafenib, encorafenib, and sorafenib, or a combination thereof.

21. The method of claim 20, wherein the BRAF inhibitor is sorafenib.

22. The method of any one of claims 1 to 4 or 8, wherein the relapsed or refractory cancer is a BRAF mutant cancer.

23. The method of any one of claims 1 to 9, wherein the second therapeutic agent is an EGFR inhibitor.

24. The method of claim 23, wherein the therapeutically effective amount of the EGFR inhibitor is about 1 mg to about 80 mg per day.

25. The method of claim 23 or 24, wherein the therapeutically effective amount of the EGFR inhibitor is about 1 mg to about 40 mg per day.

26. The method of any one of claims 23 to 25, wherein the EGFR inhibitor comprises a monoclonal antibody.

27. The method of any one of claims 23 to 25, wherein the EGFR inhibitor comprises a tyrosine kinase inhibitor.

28. The method of any one of claims 23 to 25, wherein the EGFR inhibitor is selected from cetuximab, necitumumab, panitumumab, zalutumumab, nimotuzumab, matuzumab, osimertinib, gefitinib, erlotinib, lapatinib, neratinib, vandetanib, afatinib, brigatinib, dacomitinib, lazertinib, amivantamab, and icotinib, or a combination thereof.

29. The method of claim 28, wherein the EGFR inhibitor is selected from osimertinib, lazertinib, and amivantamab, or a combination thereof.

30. The method of any one of claims 1 to 4 or 8, wherein the relapsed or refractory cancer is an EGFR mutant cancer.

31. The method of any one of claims 1 to 4 or 8, wherein the relapsed or refractory cancer is an EGFR mutant lung cancer or an EGFR mutant non-small cell lung cancer (NSCLC).

32. The method of any one of claims 1 to 9, wherein the second therapeutic agent is a MEK inhibitor.

33. The method of claim 32, wherein the therapeutically effective amount of the MEK inhibitor is about 1 mg to about 60 mg per day.

34. The method of claim 32 or 33, wherein the therapeutically effective amount of the MEK inhibitor is about 1 mg to about 30 mg per day.

35. The method of any one of claims 32 to 34, wherein the MEK inhibitor is selected from refametinib, selumetinib, trametinib, cobimetinib, binimetinib, mirdametinib, and pimasertib, or a combination thereof.

36. The method of claim 35, wherein the MEK inhibitor is selected from cobimetinib and trametinib, or a combination thereof.

37. The method of any one of claims 1 to 9, wherein the second therapeutic agent is a KRAS inhibitor.

38. The method of claim 37, wherein the therapeutically effective amount of the KRAS inhibitor about 1 mg to about 1200 mg per day.

39. The method of claim 37 or 38, wherein the therapeutically effective amount of the KRAS inhibitor is about 1 mg to about 600 mg per day.

40. The method of any one of claims 37 to 39, wherein the KRAS inhibitor is selected from an inhibitor of a KRAS G12C mutant, an inhibitor of a KRAS G12D mutant, an inhibitor of a KRAS G12V mutant, and an inhibitor of a KRAS G13 mutant, or a combination thereof.

41. The method of any one of claims 37 to 40, wherein the KRAS inhibitor is selected from adagrasib and sotorasib, or a combination thereof.

42. The method of any one of claims 1 to 4 or 8, wherein the relapsed or refractory cancer is a KRAS mutant cancer.

43. The method of claim 42, wherein the KRAS mutant cancer harbors one or more KRAS mutations selected from a KRAS G12C mutation, a KRAS G12D mutation, a KRAS G12V mutation, and a KRAS G13 mutation.

44. The method of any one of claims 1 to 9, wherein the second therapeutic agent is a mTOR inhibitor.

45. The method of claim 44, wherein the therapeutically effective amount of the mTOR inhibitor is about 1 mg to about 10 mg per day.

46. The method of claim 44 or 45, wherein the therapeutically effective amount of the mTOR inhibitor is about 1 mg to about 5 mg per day.

47. The method of any one of claims 44 to 46, wherein the mTOR inhibitor is selected from mTORCl inhibitor and mT0RC2 inhibitor, or a combination thereof.

48. The method of any one of claims 44 to 47, wherein the mTOR inhibitor is selected from temsirolimus, everolimus, ridaforolimus, sirolimus, umirolimus, and zotarolimus, or a combination thereof.

49. The method of claim 48, wherein the mTOR inhibitor is everolimus.

50. The method of any one of claims 1 to 49, wherein the therapeutically effective amount of the first therapeutic agent comprising the TEAL) inhibitor and the therapeutically effective amount of the second therapeutic agent are administered simultaneously.

51. The method of any one of claims 1 to 50, wherein the therapeutically effective amount of the first therapeutic agent comprising the TEAL) inhibitor and the therapeutically effective amount of the second therapeutic agent are formulated together in a single composition.

52. The method of any one of claims 1 to 49, wherein the therapeutically effective amount of the first therapeutic agent comprising the TEAL) inhibitor and the therapeutically effective amount of the second therapeutic agent are administered sequentially.

53. The method of claim 50 or 52, wherein the therapeutically effective amount of the first therapeutic agent comprising the TEAL) inhibitor and the therapeutically effective amount of the second therapeutic agent are formulated in separate compositions.

54. The method of any one of claims 1 to 53, wherein the therapeutically effective amount of the first therapeutic agent comprising the TEAL) inhibitor and the therapeutically effective amount of the second therapeutic agent is administered daily for at least a week.

55. The method of any one of claims 1 to 53, wherein the therapeutically effective amount of the first therapeutic agent comprising the TEAL) inhibitor and the therapeutically effective amount of the second therapeutic agent is administered daily for at least two weeks.

56. The method of any one of claims 1 to 53, wherein the therapeutically effective amount of the first therapeutic agent comprising the TEAL) inhibitor and the therapeutically effective amount of the second therapeutic agent is administered daily for at least three weeks.

57. The method of any one of claims 1 to 53, wherein the therapeutically effective amount of the first therapeutic agent comprising the TEAL) inhibitor and the therapeutically effective amount of the second therapeutic agent is administered daily for at least 24 days.

58. The method of any one of claims 1 to 53, wherein the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent is administered in a cycle length of three weeks, wherein the therapeutically effective amount is administered daily for one week, and then not administered for the following two weeks.

59. The method of any one of claim 1 to 53, wherein the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent is administered in a cycle length of three weeks, wherein the therapeutically effective amount is administered daily for two weeks, and then not administered for the following one week.

60. The method of any one of claims 1 to 53, wherein the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent is administered in a cycle length of four weeks, wherein the therapeutically effective amount is administered daily for one week, and then not administered for the following three weeks.

61. The method of any one of claims 1 to 53, wherein the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent is administered in a cycle length of four weeks, wherein the therapeutically effective amount is administered daily for two weeks, and then not administered for the following two weeks.

62. The method of any one of claims 58 to 61, wherein the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent is administered in at least two cycles.

63. The method of any one of claims 1 to 62, wherein administering a combination of the therapeutically effective amount of the first therapeutic agent comprising the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent provides a synergistic effect to the patient.

64. The method of any one of claims 1 to 63, wherein the TEAD inhibitor comprises a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:wherein, each X1, X4, X5, and X6is independently N or CRX; each X2and X3is independently N or CRY; each Rxis independently hydrogen, halogen, nitro, -OR3, -SR3, -CN, -C(=O)R3, - C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, - NR3C(=O)R3, -NR3C(=O)OR3, C1-C6 alkyl, C1-C6fluoroalkyl, C2-C4alkenyl, C2- C4alkynyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2-cCy1c0hloeatelkryol, C6-10aryl, -CH2- C6-10aryl, Ci-9heteroaryl, or -CH2-Ci-9heteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2- Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; each RYis independently hydrogen, halogen, nitro, -CN, -C(=O)R3, -C(=O)N(R3)2, - C(=O)OR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, - NR3C(=O)OR3, C1-C6 alkyl, C1-C6fluoroalkyl, C2-C4alkenyl, C2-C4alkynyl, Ci- Ceheteroalkyl, C3-C10cycloalkyl, C2-C10chyectleoraolkyl, C6-10aryl, -CH2-C6-10aryl, Ci- 9heteroaryl, or -CH2-Ci-9heteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C2- C4alkenyl, C2-C4alkynyl, C1-C6heteroalkyl, C3-C10cycloalkyl, cCy2c-lCoa10lhkeytle,ro C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups;R is halogen, nitro, -CN, -OR3, -SR3, -C(=O)R3, -C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, - S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, -NR3C(=O)OR3, or C1-C6fluoroalkyl optionally substituted with 1-5 R5groups;R1is C1-C6alkyl, C1-C6fluoroalkyl, C2-Cealkenyl, C2-Cealkynyl, C3-C10cycloalkyl, C2- Cioheterocycloalkyl, C1-C6heteroalkyl, -CN, or -S(=O)2R4, wherein C1-C6alkyl, Ci- Cefluoroalkyl, C2-Cealkenyl, C2-Cealkynyl, C3-C10cycloalkyl, cCy2c-lCoa10lhkeytle,ro and C1-C6heteroalkyl are optionally substituted with 1-5 R5groups;each R2is independently halogen, nitro, -N3, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, - C(=O)OR3, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, C2- Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, or -CH2-Ci-9heteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, C2- Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, C2-C10hetecryocloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, or - CH2-Ci-9heteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, C2-C10hetecryocloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and - CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups;R4is C1-C6alkyl, C1-C6fluoroalkyl, C3-Ciocycloalkyl, or -NH2, wherein C1-C6alkyl, Ci- Cefluoroalkyl, and C3-Ciocycloalkyl are optionally substituted with 1-5 R5groups; each R5is independently selected from halogen, oxo, -CN, -OR10, -SR10, -N(R10)(Rn), - C(O)OR10, -OC(O)N(R10)(Rn), -N(R12)C(O)N(R10)(Rn), -N(R12)C(O)OR13, - N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(Rn), - C(O)C(O)N(R10)(Rn), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, Ci-6alkyl, Ci- ehaloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3- ecycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2- eheteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2- 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, Ci-9heteroaryl, -OR10, and -N(R10)(Rn); or two R5are combined to form a Cs-scycloalkyl ring; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, Ci-ealkyl, C1-6haloalkyl, C1-6alkoxy, cycClo3a-6lkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci- gheteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl,C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; each R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl,C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- ealkynyl, C3-c6ycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl, wherein Ci- ealkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, cycloalkyl, CC2-3-69heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, SFs, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, Ci- ealkoxy, C3-c6ycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl; and n is 0, 1, 2, 3, or 4.

65. The method of any one of claims 1 to 64, wherein the TEAD inhibitor comprises a compound of Formula (I-A), or a pharmaceutically acceptable salt or solvate thereof:Formula (I-A) wherein, each Rxis independently hydrogen, halogen, -OR3, -SR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, - NR3S(=O)2R3, -NR3C(=O)R3, C1-C6alkyl, C1-C6fluoroalkyl, or C2-C4alkynyl, wherein C1-C6alkyl, C1-C6fluoroalkyl, and C2-C4alkynyl are optionally substituted with 1-5 R5groups;each RYis independently hydrogen, halogen, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, C1-C6alkyl, C1-C6fluoroalkyl, or C2-C4alkynyl, wherein C1-C6alkyl, Ci- Cefluoroalkyl, and C2-C4alkynyl are optionally substituted with 1-5 R5groups;R is halogen, nitro, -CN, -OR3, -C(=O)R3, -C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, - S(=O)2R3, -NR3S(=O)2R3, -NR3C(=O)R3, -NR3C(=O)OR3, or C1-C6fluoroalkyl optionally substituted with 1-5 R5groups;R1is C1-C6alkyl optionally substituted with 1-5 R5groups; each R2is independently halogen, nitro, -Ns, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, - C(=O)OR3, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2- Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, or -CH2-C1-9heteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2- Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, C2-C10hetero cycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, or - CH2-Ci-9heteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, C2-C10heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and - CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups;R4is C1-C6alkyl, C1-C6fluoroalkyl, C3-C10cycloalkyl, or -NH2, wherein C1-C6alkyl, Ci- Cefluoroalkyl, and C3-C10cycloalkyl are optionally substituted with 1-5 R5groups; each R5is independently selected from halogen, oxo, -CN, -OR10, -SR10, -N(R10)(Rn), - C(O)OR10, -OC(O)N(R10)(Rn), -N(R12)C(O)N(R10)(Rn), -N(R12)C(O)OR13, - N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(Rn), - C(O)C(O)N(R10)(Rn), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, Ci-6alkyl, Ci- ehaloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, cycloalkyl,C -C3-H62-C3- ecycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2- eheteroalkyl, C2-6alkenyl, C2-6alkynyl, cycloalCky3-l6, -CH2-Cs-ecycloalkyl, C2- 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, cycloalkCy3l,-6C2-9heterocycloalkyl, C6-10aryl, Ci-9heteroaryl, -OR10, and -N(R10)(Rn); or two R5are combined to form a Cs-scycloalkyl ring; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, cycCl3o-a6lkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl,C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, Ci- ealkyl, C1-6haloalkyl, C1-6alkoxy, cycClo3a-6lkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci- 9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl,C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; each R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl,C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- ealkynyl, C3-c6ycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl, wherein Ci- ealkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, cycloalkyl, CC2-3-69heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, SFs, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, Ci- ealkoxy, C3-c6ycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl; and n is 0, 1, or 2.

66. The method of claim 64 or 65, wherein each Rxis independently hydrogen, F, Cl, Br, -CH3, - OH, -OCH3, or -OCF3.

67. The method of any one of claims 64 to 66, wherein each Rxis hydrogen.

68. The method of any one of claims 64 to 67, wherein each RYis independently hydrogen, F, Cl, or -CH3.

69. The method of any one of claims 64 to 68, wherein each RYis hydrogen.

70. The method of any one of claims 64 to 69, wherein R is F, Cl, -CN, -OCF3, -CHF2, or -CF3.

71. The method of any one of claims 64 to 70, wherein R is F, Cl, or -CF3.

72. The method of any one of claims 64 to 71, wherein R is -CF3.

73. The method of any one of claims 64 to 72, wherein R1is C1-C6alkyl substituted with -OH.

74. The method of any one of claims 64 to 72, wherein R1is C1-C6alkyl substituted with 6- membered heteroaryl ring selected from pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl, wherein pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl are optionally substituted with 1-5 R5groups.

75. The method of claim 74, wherein R1is C1-C6alkyl substituted with pyridinyl optionally substituted with 1-5 R5groups.

76. The method of any one of claims 64 to 72, wherein R1is C1-C6alkyl substituted with 1, 2, or 3 substituents each independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, and pyridinyl.

77. The method of any one of claims 64 to 76, wherein each R2is independently F, Cl, -OCF3, or - CF3.

78. The method of any one of claims 64 to 77, wherein each R2is independently F or Cl.

79. The method of any one of claims 64 to 78, wherein n is 0.

80. The method of any one of claims 64 to 78, wherein n is 1 or 2.

81. The method of any one of claims 1 to 80, wherein the TEAD inhibitor is selected from:pharmaceutically acceptable salt or solvate thereof.

82. The method of any one of claims 1 to 63, wherein the TEAD inhibitor comprises a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:wherein, each X1, X2, X3, X4, X5, and X6is independently N or CRX; each Rxis independently hydrogen, halogen, nitro, -OR3, -SR3, -CN, -C(=O)R3, - C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, - NR3C(=O)R3, -NR3C(=O)OR3, C1-C6 alkyl, C1-C6fluoroalkyl, C2-C4alkenyl, C2- C4alkynyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2-Ccy10chloetaelrkoyl, C6-10aryl, -CH2- C6-10aryl, Ci-9heteroaryl, or -CH2-Ci-9heteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2- Cioheterocycloalkyl, C6-10aryl, -CEk-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups;R is halogen, nitro, -CN, -OR3, -SR3, -C(=O)R3, -C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, - S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, -NR3C(=O)OR3, or C1-C6fluoroalkyl optionally substituted with 1-5 R5groups;R1is C1-C6alkyl, C1-C6fluoroalkyl, C2-Cealkenyl, C2-Cealkynyl, C3-C10cycloalkyl, C2- Cioheterocycloalkyl, C1-C6heteroalkyl, -CN, or -S(=O)2R4, wherein C1-C6alkyl, Ci- Cefluoroalkyl, C2-Cealkenyl, C2-Cealkynyl, C3-C10cycloalkyl, cCy2c-Clo1a0lhkeytle,ro and C1-C6heteroalkyl are optionally substituted with 1-5 R5groups; each R2is independently halogen, nitro, -N3, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, - C(=O)OR3, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2-Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, or -CH2-Ci-9heteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2- Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, C2-C10hetecryocloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, or - CH2-Ci-9heteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, C2-C10hetecryocloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and - CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups;R4is C1-C6alkyl, C1-C6fluoroalkyl, C3-Ciocycloalkyl, or -NH2, wherein C1-C6alkyl, Ci- Cefluoroalkyl, and C3-Ciocycloalkyl are optionally substituted with 1-5 R5groups; each R5is independently selected from halogen, oxo, -CN, -OR10, -SR10, -N(R10)(Rn), - C(O)OR10, -OC(O)N(R10)(Rn), -N(R12)C(O)N(R10)(Rn), -N(R12)C(O)OR13, - N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(Rn), - C(O)C(O)N(R10)(Rn), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, Ci-6alkyl, Ci- ehaloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3- ecycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2- eheteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2- 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, Ci-9heteroaryl, -OR10, and -N(R10)(Rn); or two R5are combined to form a Cs-scycloalkyl ring; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, Ci- ealkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci- 9heteroaryl;each R11is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl,C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; each R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl,C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- ealkynyl, C3-c6ycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl, wherein Ci- ealkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, cycloalkyl, CC2-3-69heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, SFs, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, Ci- ealkoxy, C3-c6ycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl; and n is 0, 1, 2, 3, or 4.

83. The method of any one of claims 1 to 63, wherein the TEAD inhibitor comprises a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:wherein, each X3, X5, and X6is independently N or CRX;X4is CRX; each Rxis independently hydrogen, halogen, nitro, -OR3, -SR3, -CN, -C(=O)R3, - C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, - NR3C(=O)R3, -NR3C(=O)OR3, C1-C6 alkyl, Ci-C6fluoroalkyl, C2-C4alkenyl, C2- C4alkynyl, C1-C6heteroalkyl, C3-Ciocycloalkyl, C2-Ccy1c0hloeatelkroyl, C6-10aryl, -CH2- C6-10aryl, Ci-9heteroaryl, or -CEk-Ci-gheteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C6heteroalkyl, C3-Ciocycloalkyl, C2-Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups;R is halogen, nitro, -CN, -OR3, -SR3, -C(=O)R3, -C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, - S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, -NR3C(=O)OR3, or Ci-C6fluoroalkyl optionally substituted with 1-5 R5groups;R1is C1-C6alkyl, C1-C6fluoroalkyl, C2-Cealkenyl, C2-Cealkynyl, C3-C10cycloalkyl, C2- Cioheterocycloalkyl, C1-C6heteroalkyl, -CN, or -S(=O)2R4, wherein C1-C6alkyl, Ci- Cefluoroalkyl, C2-Cealkenyl, C2-Cealkynyl, C3-C10cycloalkyl, C2-Cioheterocycloalkyl, and C1-C6heteroalkyl are optionally substituted with 1-5 R5groups; each R2is independently halogen, nitro, -Ns, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, - C(=O)OR3, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2- Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, or -CH2-Ci-9heteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C10cycloalkyl, C2- Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; each R3is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, C2-Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, or - CH2-Ci-9heteroaryl, wherein C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3- Ciocycloalkyl, C2-Cioheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, Ci-9heteroaryl, and - CH2-Ci-9heteroaryl are optionally substituted with 1-5 R5groups; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a C3-C7 heterocycloalkyl optionally substituted with 1-5 R5groups;R4is C1-C6alkyl, C1-C6fluoroalkyl, C3-C10cycloalkyl, or -NH2, wherein C1-C6alkyl, Ci- Cefluoroalkyl, and C3-C10cycloalkyl are optionally substituted with 1-5 R5groups; each R5is independently selected from halogen, oxo, -CN, -OR10, -SR10, -N(R10)(Rn), - C(O)OR10, -OC(O)N(R10)(Rn), -N(R12)C(O)N(R10)(Rn), -N(R12)C(O)OR13, - N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(Rn), - C(O)C(O)N(R10)(Rn), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, Ci-6alkyl, Ci- ehaloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, cycloalkyl,C -C3-H6 2-C3- ecycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-ioaryl, Ci-9heteroaryl, and -CH2-Ci-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2- eheteroalkyl, C2-6alkenyl, C2-6alkynyl, cycloalCky3-l6, -CH2-C3-6cycloalkyl, C2- 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-ioaryl, Ci-9heteroaryl,and -CH2-Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, cycloalkCy3l-,6C2- 9heterocycloalkyl, C6-10aryl, Ci-9heteroaryl, -OR10, and -N(R10)(Rn); or two R5are combined to form a Cs-scycloalkyl ring; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, cycClo3-a6lkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl,C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, Ci- ealkyl, C1-6haloalkyl, C1-6alkoxy, cycClo3a-6lkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci- 9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl,C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; each R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl,C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- ealkynyl, C3-c6ycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl, wherein Ci- ealkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, cycloalkyl, CC2-3-69heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, SFs, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, Ci- ealkoxy, C3-c6ycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl; and n is 0, 1, 2, 3, or 4.

84. The method of any one of claims 1 to 83, further comprising administering to the patient one or more pharmaceutically acceptable excipients.

85. The method of any one of claims 1 to 84, wherein the relapsed or refractory cancer is a relapsed or refractory solid tumor.

86. The method of any one of claims 1 to 84, wherein the relapsed or refractory cancer is a tumor comprising a mutation in a neurofibromatosis type 2 (NF2) gene.

87. The method of any one of claims 1 to 84, wherein the relapsed or refractory cancer is a solid tumor.

88. The method of any one of claims 1 to 84, wherein the relapsed or refractory cancer is a hematologic malignancy.

89. The method of claim 87, wherein the solid tumor is a sarcoma or carcinoma.

90. The method of claim 87, wherein the solid tumor is a sarcoma.

91. The method of claim 87, wherein the solid tumor is a carcinoma.

92. The method of any one of claims 1 to 91, wherein the relapsed or refractory cancer is selected from mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma, lung cancer, bladder carcinoma, cutaneous neurofibromas, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, breast cancer, head and neck cancer, and renal cell carcinoma.

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