Combination therapy

Abstract

This article describes a composition or kit comprising a therapeutically effective amount of a TEAD inhibitor and a therapeutically effective amount of another type of inhibitor that can be used to treat cancers, including recurrent or refractory cancers. Furthermore, this article describes a method of treating cancer in a patient in need, comprising administering to the patient a therapeutically effective amount of a TEAD inhibitor and a therapeutically effective amount of another type of inhibitor. Specific cancers, such as recurrent or refractory cancers, include cancers mediated by YAP / TAZ or cancers regulated by the interaction between YAP / TAZ and TEAD.

Description

[0001] Cross-references This application claims the benefit of U.S. Provisional Application No. 63 / 607,831, filed December 8, 2023, which is incorporated herein by reference in its entirety. Background Technology

[0002] YAP and TAZ are transcriptional coactivators of the Hippo pathway network and regulate cell proliferation, migration, and apoptosis. Inhibition of the Hippo pathway promotes YAP / TAZ translocation to the nucleus, where YAP / TAZ interacts with transcription enhancer-associated domain (TEAD) transcription factors, coactivating target gene expression and promoting cell proliferation. Overactivation of YAP and TAZ and / or mutations in one or more members of the Hippo pathway network are associated with many cancers. This article describes inhibitors associated with one or more members of the Hippo pathway network, such as inhibitors of YAP / TAZ or inhibitors regulating the interaction between YAP / TAZ and TEAD.

[0003] Combinations of therapeutic agents (e.g., drugs) can improve overall efficacy and target tumor tolerability and complexity to minimize resistance. While it remains unclear how many therapeutic agents are needed for a particular type of cancer and which processes need to be targeted in combination, it is generally necessary to inhibit different pathways or driving factors. Many treatment options exist for patients with specific types of cancer, but there is a need to develop effective and safe combination therapies that can be administered to treat cancer. Summary of the Invention

[0004] In one aspect, this document provides 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 c-MET inhibitors, BRAF inhibitors, EGFR inhibitors, MEK inhibitors, KRAS inhibitors, and mTOR inhibitors. In some embodiments, the compositions and kits disclosed herein can be used to treat cancer. In some embodiments, the cancer is a recurrent or refractory cancer.

[0005] In one aspect, this document provides a method for treating cancer in a patient of need by administering a composition to the patient, said 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 said second therapeutic agent is selected from c-MET inhibitors, BRAF inhibitors, EGFR inhibitors, MEK inhibitors, KRAS inhibitors, and mTOR inhibitors. In some embodiments, said cancer is recurrent or refractory cancer. In some embodiments, the method disclosed herein induces a synergistic effect in treating cancer.

[0006] In one aspect, this document discloses a method of treating cancer in a patient in need, 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 recurrent or refractory cancer. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is from about 1 mg to about 300 mg daily. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is from about 25 mg to about 200 mg daily. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is from about 25 mg to about 100 mg daily.

[0007] In another embodiment, this document discloses a method for treating cancer in a patient in need, 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 from about 1 mg to about 300 mg daily. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is from about 25 mg to about 200 mg daily. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is from about 25 mg to about 100 mg daily. In some embodiments, the cancer is a recurrent or refractory cancer. In some embodiments, the second therapeutic agent is selected from c-MET inhibitors, BRAF inhibitors, EGFR inhibitors, MEK inhibitors, KRAS inhibitors, and mTOR inhibitors. 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 from about 1 mg to about 800 mg daily. In some embodiments, the therapeutically effective amount of the c-MET inhibitor is from about 1 mg to about 400 mg daily. In some embodiments, the c-MET inhibitor is selected from cabozantinib, crizotinib, foretinib, tivantinib, savolitinib, capmatinib, and tepotinib, or combinations thereof. In some embodiments, the c-MET inhibitor is selected from savolitinib and capmatinib, or combinations thereof. In some embodiments, the recurrent or refractory cancer is a c-MET-mutant cancer. In some embodiments, the recurrent 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 dose of the BRAF inhibitor is about 1 mg to about 400 mg daily. In some embodiments, the therapeutically effective dose of the BRAF inhibitor is about 1 mg to about 200 mg daily. In some embodiments, the BRAF inhibitor is selected from vemurafenib, dabrafenib, encorafenib, and sorafenib, or combinations thereof. In some embodiments, the BRAF inhibitor is sorafenib. In some embodiments, the recurrent 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 dose of the EGFR inhibitor is about 1 mg to about 80 mg daily.In some embodiments, the therapeutically effective dose of the EGFR inhibitor is about 1 mg to about 40 mg daily. 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 combinations thereof. In some embodiments, the EGFR inhibitor is selected from osimertinib, lazertinib, and amivantamab, or combinations thereof. In some embodiments, the recurrent or refractory cancer is an EGFR-mutant cancer. In some embodiments, the recurrent or refractory cancer is EGFR-mutant lung cancer or 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 dose of the MEK inhibitor is about 1 mg to about 60 mg daily. In some embodiments, the therapeutically effective dose of the MEK inhibitor is about 1 mg to about 30 mg daily. In some embodiments, the MEK inhibitor is selected from refametinib, selumetinib, trametinib, cobimetinib, binimetinib, mirdametinib, and pimasertib, or combinations thereof. In some embodiments, the MEK inhibitor is selected from cobimetinib and trametinib, or combinations thereof. In some embodiments, the second therapeutic agent is a KRAS inhibitor. In some embodiments, the therapeutically effective dose of the KRAS inhibitor is from about 1 mg to about 1200 mg daily. In some embodiments, the therapeutically effective dose of the KRAS inhibitor is from about 1 mg to about 600 mg daily.In some embodiments, the KRAS inhibitor is selected from inhibitors of KRAS G12C mutations, KRAS G12D mutations, KRAS G12V mutations, and KRAS G13 mutations, or combinations thereof. In some embodiments, the KRAS inhibitor is selected from adagrasib and sotorasib, or combinations thereof. In some embodiments, the recurrent or refractory cancer is a KRAS-mutant cancer. In some embodiments, the KRAS-mutant cancer carries one or more KRAS mutations selected from KRAS G12C, KRAS G12D, KRAS G12V, and KRAS G13 mutations. In some embodiments, the second therapeutic agent is an mTOR inhibitor. In some embodiments, the therapeutically effective dose of the mTOR inhibitor is about 1 mg to about 10 mg daily. In some embodiments, the therapeutically effective dose of the mTOR inhibitor is about 1 mg to about 5 mg daily. In some embodiments, the mTOR inhibitor is selected from mTORC1 inhibitors and mTORC2 inhibitors, or combinations thereof. In some embodiments, the mTOR inhibitor is selected from temsirolimus, everolimus, ridaforolimus, sirolimus, umirolimus, and zotarolimus, or combinations thereof. In some embodiments, the mTOR inhibitor is everolimus. In some embodiments, a therapeutically effective amount of the first therapeutic agent containing the TEAD inhibitor and a therapeutically effective amount of the second therapeutic agent are administered simultaneously. In some embodiments, a therapeutically effective amount of the first therapeutic agent containing the TEAD inhibitor and a therapeutically effective amount of the second therapeutic agent are co-formulated in a single composition. In some embodiments, a therapeutically effective amount of the first therapeutic agent containing the TEAD inhibitor and a therapeutically effective amount of the second therapeutic agent are administered sequentially. In some embodiments, a therapeutically effective amount of the first therapeutic agent containing the TEAD inhibitor and a therapeutically effective amount of the second therapeutic agent are formulated in a separate composition. In some embodiments, a therapeutically effective amount of the first therapeutic agent containing the TEAD inhibitor and a therapeutically effective amount of the second therapeutic agent are administered daily for at least one week. In some embodiments, a therapeutically effective amount of the first therapeutic agent containing the TEAD inhibitor and a therapeutically effective amount of the second therapeutic agent are administered daily for at least two weeks.In some embodiments, a therapeutically effective amount of the first therapeutic agent containing the TEAD inhibitor and a therapeutically effective amount of the second therapeutic agent are administered daily for at least three weeks. In some embodiments, a therapeutically effective amount of the first therapeutic agent containing the TEAD inhibitor and a therapeutically effective amount of the second therapeutic agent are administered daily for at least 24 days. In some embodiments, a therapeutically effective amount of the first therapeutic agent containing the TEAD inhibitor and a therapeutically effective amount of the second therapeutic agent are administered in three-week cycles, wherein the therapeutically effective amount is administered daily for one week, followed by a two-week gap. In some embodiments, a therapeutically effective amount of the first therapeutic agent containing the TEAD inhibitor and a therapeutically effective amount of the second therapeutic agent are administered in three-week cycles, wherein the therapeutically effective amount is administered daily for two weeks, followed by a one-week gap. In some embodiments, a therapeutically effective amount of the first therapeutic agent containing the TEAD inhibitor and a therapeutically effective amount of the second therapeutic agent are administered in four-week cycles, wherein the therapeutically effective amount is administered daily for one week, followed by a three-week gap. In some embodiments, a therapeutically effective amount of the first therapeutic agent containing the TEAD inhibitor and a therapeutically effective amount of the second therapeutic agent are administered in a four-week cycle, wherein the therapeutically effective amount is administered daily for two weeks, followed by a two-week period without administration. In some embodiments, a therapeutically effective amount of the first therapeutic agent containing the TEAD inhibitor and a therapeutically effective amount of the second therapeutic agent are administered in at least two cycles. In some embodiments, the combination of administering a therapeutically effective amount of the first therapeutic agent containing the TEAD inhibitor and a 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: in, Each X 1 X 4 X 5 and X 6 Independently N or CR X ; Each X 2 and X 3 Independently N or CR Y ; Each R X Independently hydrogen, halogen, nitro, -OR 3 -SR 3-CN, -C(=O)R 3 -C(=O)N(R) 3 2. -C(=O)OR 3 -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 -NR 3 C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by groups; Each R Y Independently hydrogen, halogen, nitro, -CN, -C(=O)R 3 -C(=O)N(R) 3 2. -C(=O)OR 3 -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 -NR 3 C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by groups; R represents halogen, nitro, -CN, or -OR. 3 -SR 3 -C(=O)R 3 -C(=O)N(R) 3 2. -C(=O)OR 3 -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 -NR 3 C(=O)OR 3 Or optionally by 1-5 R 5 C1-C6 fluoroalkyl groups substituted by the radical; R 1 It is C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C1-C6 heteroalkyl, -CN or -S(=O)2R 4 Among them, C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl groups and C1-C6 heteroalkyl groups are optionally surrounded by 1-5 R groups. 5 Substituted by groups; Each R 2 Independently halogen, nitro, -N3, -CN, -OR 3 -SR 3 -S(=O)2R 3 -N(R) 3 2. -C(=O)OR 3C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by groups; Each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by a group; or If two R 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group; R 4 It is a C1-C6 alkyl, C1-C6 fluoroalkyl, or C3-C 10 Cycloalkyl or -NH2, wherein C1-C6 alkyl, C1-C6 fluoroalkyl and C3-C 10 The cycloalkyl group is optionally surrounded by 1-5 Rs. 5 Substituted by groups; Each R 5 Independently selected from halogen, oxo, -CN, -OR 10-SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, -CH2-C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, -CH2-C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 and -N(R) 10 (R) 11 The group is replaced by ) or two R groups. 5 Combine to form C 3-5 cycloalkyl rings; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Substituted with heteroaryl groups; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl; or R 10 and R 11Together with the nitrogen atoms to which they are attached, they independently form 4- to 7-membered heterocycles, wherein the heterocycles optionally contain an additional 1-2 heteroatoms selected from N, O and S, and wherein each heterocycle nitrogen atom, if present, is independently and optionally substituted by a C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN or C2-C3 heteroalkyl. Each R 12 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl groups; Each R 13 Selected independently from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogen, SF5, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is replaced; and n can be 0, 1, 2, 3, or 4.

[0009] In some embodiments, the TEAD inhibitor comprises a compound of formula (IA), or a pharmaceutically acceptable salt or solvate thereof: in, Each R X Independently hydrogen, halogen, -OR 3 -SR 3 -S(=O)R3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 C1-C6 alkyl, C1-C6 fluoroalkyl, or C2-C4 ynyl, wherein the C1-C6 alkyl, C1-C6 fluoroalkyl, and C2-C4 ynyl are optionally surrounded by 1-5 R groups. 5 Substituted by groups; Each R Y Independently hydrogen, halogen, -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 C1-C6 alkyl, C1-C6 fluoroalkyl, or C2-C4 ynyl, wherein the C1-C6 alkyl, C1-C6 fluoroalkyl, and C2-C4 ynyl are optionally surrounded by 1-5 R groups. 5 Substituted by groups; R represents halogen, nitro, -CN, or -OR. 3 -C(=O)R 3 -C(=O)N(R) 3 2. -C(=O)OR 3 -S(=O)R 3 -S(=O)2R 3 -NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 -NR 3 C(=O)OR 3 Or optionally by 1-5 R 5 C1-C6 fluoroalkyl groups substituted by the radical; R 1 For optional use by 1-5 R 5 C1-C6 alkyl groups substituted by the radical; Each R 2 Independently halogen, nitro, -N3, -CN, -OR 3 -SR 3 -S(=O)2R 3 -N(R) 3 2. -C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by groups; Each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by a group; or If two R 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group; R 4 It is a C1-C6 alkyl, C1-C6 fluoroalkyl, or C3-C 10 Cycloalkyl or -NH2, wherein C1-C6 alkyl, C1-C6 fluoroalkyl and C3-C 10 The cycloalkyl group is optionally surrounded by 1-5 Rs. 5 Substituted by groups; Each R 5 Independently selected from halogen, oxo, -CN, -OR 10 -SR 10 -N(R) 10(R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, -CH2-C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, -CH2-C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C1-6 Haloalkyl, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 and -N(R) 10 (R) 11 The group is replaced by ) or two R groups. 5 Combine to form C 3-5 cycloalkyl rings; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Substituted with heteroaryl groups; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl; or R 10 and R 11 Together with the nitrogen atoms to which they are attached, they independently form 4- to 7-membered heterocycles, wherein the heterocycles optionally contain an additional 1-2 heteroatoms selected from N, O and S, and wherein each heterocycle nitrogen atom, if present, is independently and optionally substituted by a C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN or C2-C3 heteroalkyl. Each R 12 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl groups; Each R 13 Selected independently from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogen, SF5, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is replaced; and n is 0, 1, or 2.

[0010] In some implementations, each R X Independently, it can be hydrogen, F, Cl, Br, -CH3, -OH, -OCH3, or -OCF3. In some embodiments, each R... X It is hydrogen. In some implementations, each R... Y Independently, it can be hydrogen, F, Cl, or -CH3. In some embodiments, each R... Y It is 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, R... 1 It is a C1-C6 alkyl group substituted with -OH. In some embodiments, R 1The alkyl group is a C1-C6 alkyl group substituted with a 6-membered heteroaryl ring, wherein the 6-membered heteroaryl ring is selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl, wherein the pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl are optionally replaced by 1-5 R groups. 5 The group is replaced. In some embodiments, R 1 The alkyl group is a C1-C6 alkyl group substituted with a pyridinyl group, wherein the pyridinyl group is optionally replaced by 1-5 R groups. 5 The group is replaced. In some embodiments, R 1 It is a C1-C6 alkyl group substituted with 1, 2, or 3 substituents, each substituent independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, and pyridyl. In some embodiments, each R... 2 Independently, it can be F, Cl, -OCF3, or -CF3. In some implementations, each R... 2 Independently, it is either F or Cl. In some implementations, n is 0. In some implementations, n is 1 or 2.

[0011] In some implementations, the TEAD inhibitor is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or Or, or a 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: in, Each X 1 X 2 X 3 X 4 X 5 and X 6 Independently N or CR X ; Each R X Independently hydrogen, halogen, nitro, -OR 3 -SR 3 -CN, -C(=O)R 3 -C(=O)N(R) 3 2. -C(=O)OR 3 -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 -NR 3 C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5Substituted by groups; R represents halogen, nitro, -CN, or -OR. 3 -SR 3 -C(=O)R 3 -C(=O)N(R) 3 2. -C(=O)OR 3 -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 -NR 3 C(=O)OR 3 Or optionally by 1-5 R 5 C1-C6 fluoroalkyl groups substituted by the radical; R 1 It is C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C1-C6 heteroalkyl, -CN or -S(=O)2R 4 Among them, C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl groups and C1-C6 heteroalkyl groups are optionally surrounded by 1-5 R groups. 5 Substituted by groups; Each R 2 Independently halogen, nitro, -N3, -CN, -OR 3 -SR 3 -S(=O)2R 3 -N(R) 3 2. -C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by groups; Each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by a group; or If two R 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group; R 4 It is a C1-C6 alkyl, C1-C6 fluoroalkyl, or C3-C 10 Cycloalkyl or -NH2, wherein C1-C6 alkyl, C1-C6 fluoroalkyl and C3-C 10 The cycloalkyl group is optionally surrounded by 1-5 Rs. 5 Substituted by groups; Each R 5 Independently selected from halogen, oxo, -CN, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13-S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, -CH2-C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, -CH2-C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 and -N(R) 10 (R) 11 The group is replaced by ) or two R groups. 5 Combine to form C 3-5 cycloalkyl rings; Each R 10 Independently selected from hydrogen and C1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Substituted with heteroaryl groups; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl; or R 10 and R 11 Together with the nitrogen atoms to which they are attached, they independently form 4- to 7-membered heterocycles, wherein the heterocycles optionally contain an additional 1-2 heteroatoms selected from N, O and S, and wherein each heterocycle nitrogen atom, if present, is independently and optionally substituted by a C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN or C2-C3 heteroalkyl. Each R 12 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl groups; Each R 13 Selected independently from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogen, SF5, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is replaced; and n can be 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: in, Each X 3 X 5 and X 6 Independently N or CR X ; X 4 For CR X ; Each R X Independently hydrogen, halogen, nitro, -OR 3 -SR 3 -CN, -C(=O)R 3 -C(=O)N(R) 3 2. -C(=O)OR 3 -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 -NR 3 C(=O)OR 3C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by groups; R represents halogen, nitro, -CN, or -OR. 3 -SR 3 -C(=O)R 3 -C(=O)N(R) 3 2. -C(=O)OR 3 -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 -NR 3 C(=O)OR 3 Or optionally by 1-5 R 5 C1-C6 fluoroalkyl groups substituted by the radical; R 1 It is C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C1-C6 heteroalkyl, -CN or -S(=O)2R 4 Among them, C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl groups and C1-C6 heteroalkyl groups are optionally surrounded by 1-5 R groups. 5 Substituted by groups; Each R 2 Independently halogen, nitro, -N3, -CN, -OR3 -SR 3 -S(=O)2R 3 -N(R) 3 2. -C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by groups; Each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by a group; or If two R 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group; R 4 It is a C1-C6 alkyl, C1-C6 fluoroalkyl, or C3-C 10 Cycloalkyl or -NH2, wherein C1-C6 alkyl, C1-C6 fluoroalkyl and C3-C 10The cycloalkyl group is optionally surrounded by 1-5 Rs. 5 Substituted by groups; Each R 5 Independently selected from halogen, oxo, -CN, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, -CH2-C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, -CH2-C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 and -N(R) 10 (R) 11 The group is replaced by ) or two R groups. 5 Combine to form C 3-5 cycloalkyl rings; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Substituted with heteroaryl groups; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl; or R 10 and R 11Together with the nitrogen atoms to which they are attached, they independently form 4- to 7-membered heterocycles, wherein the heterocycles optionally contain an additional 1-2 heteroatoms selected from N, O and S, and wherein each heterocycle nitrogen atom, if present, is independently and optionally substituted by a C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN or C2-C3 heteroalkyl. Each R 12 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl groups; Each R 13 Selected independently from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogen, SF5, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is replaced; and n can be 0, 1, 2, 3, or 4.

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

[0015] On the other hand, this document discloses a kit comprising (i) a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent; and (ii) instructions for administering the therapeutically effective amounts of the first therapeutic agent containing the TEAD inhibitor and the second therapeutic agent to treat cancer in a subject of need, wherein the cancer is a recurrent or refractory cancer. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is from about 1 mg to about 300 mg daily. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is from about 25 mg to about 200 mg daily. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is from about 25 mg to about 100 mg daily.

[0016] In another aspect, this document discloses a kit comprising (i) a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent; and (ii) instructions for administering the therapeutically effective amounts of the first therapeutic agent containing the TEAD inhibitor and the second therapeutic agent to treat cancer in a subject of need, wherein the therapeutically effective amount of the TEAD inhibitor is from about 1 mg to about 300 mg daily. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is from about 25 mg to about 200 mg daily. In some embodiments, the therapeutically effective amount of the TEAD inhibitor is from about 25 mg to about 100 mg daily. In some embodiments, the cancer is a recurrent or refractory cancer. In some embodiments, the second therapeutic agent is selected from c-MET inhibitors, BRAF inhibitors, EGFR inhibitors, MEK inhibitors, KRAS inhibitors, and mTOR inhibitors. 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 from about 1 mg to about 800 mg daily. In some embodiments, the therapeutically effective dose of the c-MET inhibitor is about 1 mg to about 400 mg daily. In some embodiments, the c-MET inhibitor is selected from cabozantinib, crizotinib, folatinib, tevantinib, cevotinib, carmatinib, and terpoxtinib, or combinations thereof. In some embodiments, the c-MET inhibitor is selected from cevotinib and carmatinib, or combinations thereof. In some embodiments, the recurrent or refractory cancer is a c-MET-mutant cancer. In some embodiments, the recurrent 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 dose of the BRAF inhibitor is about 1 mg to about 400 mg daily. In some embodiments, the therapeutically effective dose of the BRAF inhibitor is about 1 mg to about 200 mg daily. In some embodiments, the BRAF inhibitor is selected from vemurafenib, dabrafenib, cannefenib, and sorafenib, or combinations thereof. In some embodiments, the BRAF inhibitor is sorafenib. In some embodiments, the recurrent 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 dose of the EGFR inhibitor is about 1 mg to about 80 mg daily. In some embodiments, the therapeutically effective dose of the EGFR inhibitor is about 1 mg to about 40 mg daily. 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, nexituzumab, panitumumab, zarumumab, nimotuzumab, materutuzumab, osimertinib, gefitinib, erlotinib, lapatinib, neratinib, vandetanib, afatinib, brigatinib, dacomitinib, lazatinib, ervantumab, and icotinib, or combinations thereof. In some embodiments, the EGFR inhibitor is selected from osimertinib, lazatinib, and ervantumab, or combinations thereof. In some embodiments, the relapsed or refractory cancer is EGFR-mutant cancer. In some embodiments, the relapsed or refractory cancer is EGFR-mutant lung cancer or 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 dose of the MEK inhibitor is about 1 mg to about 60 mg daily. In some embodiments, the therapeutically effective dose of the MEK inhibitor is about 1 mg to about 30 mg daily. In some embodiments, the MEK inhibitor is selected from refatinib, selumetinib, trametinib, cobimetinib, bimetinib, midametinib, and pimazatinib, or combinations thereof. In some embodiments, the MEK inhibitor is selected from cobimetinib and trametinib, or combinations thereof. In some embodiments, the second therapeutic agent is a KRAS inhibitor. In some embodiments, the therapeutically effective dose of the KRAS inhibitor is about 1 mg to about 1200 mg daily. In some embodiments, the therapeutically effective dose of the KRAS inhibitor is about 1 mg to about 600 mg daily. In some embodiments, the KRAS inhibitor is selected from inhibitors of KRAS G12C mutations, KRAS G12D mutations, KRAS G12V mutations, and KRAS G13 mutations, or combinations thereof. In some embodiments, the KRAS inhibitor is selected from adagraxib and sotorasib, or combinations thereof. In some embodiments, the recurrent or refractory cancer is a KRAS-mutant cancer. In some embodiments, the KRAS-mutant cancer carries one or more KRAS mutations selected from KRAS G12C, KRAS G12D, KRAS G12V, and KRAS G13. In some embodiments, the second therapeutic agent is an mTOR inhibitor. In some embodiments, the therapeutically effective dose of the mTOR inhibitor is about 1 mg to about 10 mg daily. In some embodiments, the therapeutically effective dose of the mTOR inhibitor is about 1 mg to about 5 mg daily. In some embodiments, the mTOR inhibitor is selected from mTORC1 inhibitors and mTORC2 inhibitors, or a combination thereof.In some embodiments, the mTOR inhibitor is selected from tesirobolimus, everolimus, lidafomus, sirolimus, umimilimus, and zotalimus, or combinations thereof. In some embodiments, the mTOR inhibitor is everolimus. In some embodiments, the TEAD inhibitor comprises a compound of formula (I), (IA), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof.

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

[0018] In some embodiments, the kit further comprises one or more pharmaceutically acceptable excipients. In some embodiments, the recurrent or refractory cancer is a recurrent or refractory solid tumor. In some embodiments, the recurrent or refractory cancer is a tumor containing a mutation in the neurofibromatosis type 2 (NF2) gene. In some embodiments, the recurrent or refractory cancer is a solid tumor. In some embodiments, the recurrent 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 carcinoma. In some embodiments, the recurrent or refractory cancer is selected from mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma, lung cancer, bladder cancer, cutaneous neurofibroma, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, undifferentiated 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, a therapeutically effective amount of the first therapeutic agent containing the TEAD inhibitor and a therapeutically effective amount of the second therapeutic agent are administered daily for at least one week. In some embodiments, a therapeutically effective amount of the first therapeutic agent containing the TEAD inhibitor and a therapeutically effective amount of the second therapeutic agent are administered daily for at least two weeks. In some embodiments, a therapeutically effective amount of the first therapeutic agent containing the TEAD inhibitor and a therapeutically effective amount of the second therapeutic agent are administered daily for at least three weeks. In some embodiments, a therapeutically effective amount of the first therapeutic agent containing the TEAD inhibitor and a therapeutically effective amount of the second therapeutic agent are administered daily for at least 24 days. In some embodiments, a therapeutically effective amount of the first therapeutic agent containing the TEAD inhibitor and a therapeutically effective amount of the second therapeutic agent are administered in three-week cycles, wherein the therapeutically effective amount is administered daily for one week, followed by a two-week gap. In some embodiments, a therapeutically effective amount of the first therapeutic agent containing the TEAD inhibitor and a therapeutically effective amount of the second therapeutic agent are administered daily in three-week cycles, wherein the therapeutically effective amount is administered daily for two weeks, followed by a one-week gap. In some embodiments, the therapeutically effective amount of the first therapeutic agent containing the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent are administered in a four-week cycle, wherein the therapeutically effective amount is administered daily for one week, followed by a three-week period without administration. In some embodiments, the therapeutically effective amount of the first therapeutic agent containing the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent are administered in a four-week cycle, wherein the therapeutically effective amount is administered daily for two weeks, followed by a two-week period without administration.In some embodiments, the therapeutically effective amount of the first therapeutic agent containing the TEAD inhibitor and the therapeutically effective amount of the second therapeutic agent are administered over at least two cycles.

[0019] Incorporation All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the extent that each individual publication, patent or patent application is specifically and individually cited and incorporated herein by reference. Attached Figure Description

[0020] The various aspects of this disclosure are set forth in detail in the appended claims. A better understanding of the features and advantages of this disclosure will be gained by referring to the following detailed description and accompanying drawings, which illustrate embodiments utilizing the principles of this disclosure, in which: Figure 1A schematic diagram of the Hippo signaling network is shown. Dark gray shaded Hippo pathway components represent those that inhibit YAP / TAZ activity. Light gray shaded Hippo pathway components represent those that promote YAP / TAZ activity. Pointed and blunt arrows represent activation and inhibition interactions, respectively. Abbreviations: α-CAT (α-catenin), AJUB (Ajuba), AMOT (Angiomotin), β-TRCP (protein containing β-transduction repeat sequence), CK1 (casein kinase 1), CRB (Crumbs), E-CAD (E-cadherin), EX (extended), GPCR (G protein-coupled receptor), HIPK (homology-interacting protein kinase), KIBRA (Kidney brain), LATS (large tumor suppressor), LGL (Lethal giant larvae gene), MASK (Multiple ankyrinsingle KH), MER (Merlin), MOB (Mps one conjugate), MST (Mammalian sterility 20), PALS (Lin-7 associated protein), PATJ (Pals1 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 (a protein of 101 amino acids), TAZ (a transcriptional coactivator with a PDZ-binding motif), TEAD (TEA domain protein), VGL4 (Vestigial-like 4), WBP2 (WW domain-binding protein 2), YAP (Yes-associated protein), ZO (closed band), and ZYX (pixelated protein).

[0021] Figure 2 A schematic diagram of the Hippo signaling pathway regulated by the Gα protein is shown.

[0022] Figure 3A and Figure 3B This study illustrates the in vivo efficacy of compound 42, osimertinib, and the combination of compound 42 and osimertinib in the NCI-H1975 NSCLC CDX model (change in mean tumor volume). Figure 3A ) and survival percentage ( Figure 3B Biological data; NCI-H1975 carries the EGFR p.L858R; p.T790M mutation.

[0023] Figure 4A and Figure 4B This study illustrates the in vivo efficacy of compound 42, osimertinib, and the combination of compound 42 and osimertinib in the NCI-H1975 NSCLC CDX model (change in mean tumor volume). Figure 4A ) and weight change ( Figure 4B Biological data; NCI-H1975 carries the EGFR p.L858R; p.T790M mutation.

[0024] Figure 5A , Figure 5B and Figure 5C Biological data (changes in mean tumor volume) from in vivo efficacy studies comparing compound 42, osimertinib, and the combination of compound 42 and osimertinib in an HCC827 NSCLC CDX model are presented; HCC827 carries the EGFR p.ELREA701del mutation: for Figure 5A 1 or 2.5 mg / kg osimertinib; for Figure 5B 1 mg / kg osimertinib; and for Figure 5C 2.5 mg / kg osimertinib.

[0025] Figure 6 Biological data are presented from an in vivo efficacy study (monitoring changes in mean tumor volume over 93 days) comparing compound 42, osimertinib, and the combination of compound 42 and osimertinib in a LU-01-1291 NSCLC PDX model carrying EGFR exon 19 deletion. The study began with n = 12 mice per group.

[0026] Figure 7A and Figure 7B This study illustrates the in vivo efficacy of compound 42, osimertinib, and the combination of compound 42 and osimertinib in a LU-01-1137 NSCLC PDX model with EGFR exon 19 deletion (change in mean tumor volume). Figure 7A ) and weight change ( Figure 7B Biological data.

[0027] Figure 8A and Figure 8B This study illustrates the in vivo efficacy of compound 42, osimertinib, and the combination of compound 42 and osimertinib in a LU1868 NSCLC PDX model carrying the EGFR pL858R;pT790M mutation (change in mean tumor volume). Figure 8A ) and weight change ( Figure 8B Biological data.

[0028] Figure 9Biological data are presented in an in vivo efficacy study (monitoring changes in mean tumor volume over 63 days) comparing osimertinib and combinations of osimertinib with compounds 6, 42, 47, 48, or 49 in the NCI-H1975 NSCLC CDX model.

[0029] Figure 10A and Figure 10B This study demonstrates the in vivo efficacy of compound 42, osimertinib, lazatinib, and the combination of compound 42 and lazatinib in the NCI-H1975 NSCLC CDX model (change in mean tumor volume). Figure 10A ) and weight change ( Figure 10B Biological data.

[0030] Figure 11 Biological data from an in vivo efficacy study (monitoring changes in mean tumor volume over 74 days) comparing compound 42, ervantumab, and the combination of compound 42 and ervantumab in the NCI-H1975 NSCLC CDX model are presented. All treatments were discontinued on day 23. In the combination group, TEAD inhibitor 1 was resumed on day 39 and discontinued on day 53.

[0031] Figure 12 Biological data from an in vivo efficacy study (monitoring changes in mean tumor volume over 91 days) comparing compound 42, ervaltumab, and the combination of compound 42 and ervaltumab in the NCI-H820 NSCLC CDX model are presented. All treatments were discontinued on day 23. In the combination group, compound 42 administration was resumed on day 39 and discontinued on day 53.

[0032] Figure 13 Biological data are presented in an in vivo efficacy study (monitoring changes in mean tumor volume over 138 days) comparing compound 42, the combination of lazatinib and ervantumab, and the combination of lazatinib, ervantumab, and compound 42 in the LU-01-1291 NSCLC PDX model.

[0033] Figure 14 Biological data from an in vivo efficacy study (monitoring changes in mean tumor volume over 48 days) comparing compound 42, cerivitinib, and the combination of compound 42 and cerivitinib in an Hs746T gastric cancer model are presented. All treatments were discontinued on day 12 (PO, QD).

[0034] Figure 15Biological data from an in vivo efficacy study (monitoring changes in mean tumor volume over 70 days) comparing compound 42, cerivitinib, and the combination of compound 42 and cerivitinib in an EBC1 NSCLC CDX model are presented. All treatments were discontinued on day 43 (PO, QD).

[0035] Figure 16 Biological data from an in vivo efficacy study (monitoring changes in mean tumor volume over 56 days) comparing compound 42, adagraxibu, and the combination of compound 42 and adagraxibu in a CR6243 CRC PDX model are presented. All treatments were discontinued on day 31 (PO, QD).

[0036] Figure 17 Biological data are presented for an in vivo efficacy study (monitoring changes in mean tumor volume over 49 days) comparing compound 42, sotorasirb, and the combination of compound 42 and sotorasirb in the LU-01-1185 NSCLC PDX model.

[0037] Figure 18A and Figure 18B This study demonstrates the in vivo efficacy of compound 42, trametinib, and the combination of compound 42 and trametinib in the NCI-H2030 NSCLC CDX model (change in mean tumor volume). Figure 18A ) and weight change ( Figure 18B Biological data.

[0038] Figure 19A and Figure 19B This study demonstrates the in vivo efficacy of compound 42, trametinib, and the combination of compound 42 and trametinib in the LU-01-0407 PDX model (change in mean tumor volume). Figure 19A ) and weight change ( Figure 19B Biological data; the model is NF2-deficient NSCLC (NF2 CNV < 1).

[0039] Figure 20A and Figure 20B This study demonstrates the in vivo efficacy of compound 42, trametinib, and the combination of compound 42 and trametinib in the LU-01-0236 PDX model (change in mean tumor volume). Figure 20A ) and weight change ( Figure 20B Biological data; the model is Merlin p.E265X (homozygous) NSCLC.

[0040] Figure 21Biological data are presented in an in vivo efficacy study (monitoring changes in mean tumor volume over 84 days) comparing compound 42, trametinib, and the combination of compound 42 and trametinib in the NCI-H226 mesothelioma CDX model, which is NF2 deficient.

[0041] Figure 22A and Figure 22B This study illustrates the in vivo efficacy of compound 42, trametinib, and the combination of compound 42 and trametinib in a BL9216 bladder cancer PDX model (change in mean tumor volume). Figure 22A ) and the percentage change in mean tumor volume inhibition ( Figure 22B Biological data for the model: Merlin pE106X (100%); EGFR CNV = 6.93; combined efficacy: TGI = 70%.

[0042] Figure 23 Biological data are presented in an in vivo efficacy study (monitoring changes in mean tumor volume over 85 days) comparing compound 42, everolimus, and the combination of compound 42 and everolimus in the NCI-H226 mesothelioma CDX model.

[0043] Figure 24 Biological data are presented in an in vivo efficacy study (monitoring changes in mean tumor volume over 54 days) comparing compound 42, everolimus, and the combination of compound 42 and everolimus in the LI1098 HCC PDX model.

[0044] Figure 25 Biological data are presented for an in vivo efficacy study (monitoring changes in mean tumor volume over 54 days) comparing compound 42, sorafenib, and the combination of compound 42 and sorafenib in the LI1098 HCC PDX model.

[0045] Figure 26A and Figure 26B This study demonstrates the in vivo efficacy comparison of compound 42, cannefenib, and the combination of compound 42 and cannefenib in an HT-29 colorectal adenocarcinoma CDX model carrying the BRAF p.V600E mutation (monitoring changes in mean tumor volume over 47 days). Figure 26A ) and weight change ( Figure 26B Biological data. Detailed Implementation

[0046] certain terms Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. It should be understood that the foregoing general description and the following detailed description are exemplary and illustrative only and are not intended to limit any of the claimed subject matter. In this application, the use of the singular form includes the plural form unless otherwise specified. It must be noted that, unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” used in this specification and the appended claims include the plural form. In this application, the use of “or” means “and / or” unless otherwise specified. Furthermore, the use of the term “comprising” and other forms such as “including,” “containing,” and “having” is not restrictive.

[0047] As used herein, in some embodiments, ranges and quantities are expressed as “about” a specific value or range. “About” also includes the exact quantity. Therefore, “about 5 µL” means “about 5 µL” and also “5 µL”. Typically, the term “about” includes the quantity expected to be within experimental error.

[0048] The chapter titles used in this article are for organizational purposes only and should not be construed as limiting the topics described.

[0049] As used herein, the terms “individual,” “object,” and “patient” refer to any mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is a non-human mammal. None of these terms require or are limited to situations characterized by care (e.g., long-term or intermittent) provided by healthcare workers (e.g., physicians, registered nurses, nurse practitioners, physician assistants, caregivers, or hospice staff).

[0050] As used in this specification and the appended claims, unless otherwise stated, the following terms have the meanings described below.

[0051] In one respect, TEAD inhibitors are inhibitors of transcription enhancer-related domains.

[0052] In one respect, c-MET inhibitors are mesenchymal-epithelial transition factor (MEFT) inhibitors. c-MET inhibitors inhibit the enzymatic activity of c-MET tyrosine kinase (the receptor for hepatocyte growth factor / hepatocyte scavenging factor (HGF / SF)). These inhibitors have therapeutic applications in treating various types of cancer.

[0053] In one respect, BRAF inhibitors are inhibitors of the v-raf mouse sarcoma virus oncogene homolog B1. In some embodiments, BRAF inhibitors can be used to treat patients with BRAF-mutant melanoma. They selectively target BRAF kinase and interfere with the mitogen-activated protein kinase signaling pathway that regulates melanoma cell proliferation and survival. In some embodiments, in addition to their molecular targeting activity, BRAF inhibitors also have immunomodulatory effects.

[0054] In one aspect, EGFR inhibitors are epidermal growth factor receptor inhibitors. In some embodiments, EGFR inhibitors block the activity of the epidermal growth factor receptor (EGFR). In some embodiments, EGFR can be found on the surface of some normal cells and participates in cell growth. In some embodiments, EGFR can also be found at high levels in some types of cancer cells, leading to the growth and division of these cells. In some embodiments, blocking EGFR can prevent cancer cell growth. In some embodiments, EGFR inhibitors may also be referred to as EGFR tyrosine kinase inhibitors or epidermal growth factor receptor tyrosine kinase inhibitors.

[0055] In one aspect, MEK inhibitors are mitogen-activated protein kinase inhibitors. In some embodiments, MEK inhibitors inhibit mitogen-activated protein kinase kinases MEK1 or MEK2. In some embodiments, MEK inhibitors can be used to affect the MAPK / ERK pathway, which is typically overactive in some cancers. In some embodiments, MEK inhibitors can be used to treat cancers such as BRAF-mutant melanoma and KRAS / BRAF-mutant colorectal cancer.

[0056] In one aspect, KRAS inhibitors are inhibitors of the Kirsten rat sarcoma virus oncogene homolog (KRAS). In some embodiments, KRAS acts as an on / off switch for cell growth. When KRAS is mutated, cells can develop into cancer. In some embodiments, KRAS inhibitors can be used to treat people with cancers such as non-small cell lung cancer with that specific KRAS mutation.

[0057] In one aspect, mTOR inhibitors are inhibitors of the mechanistic target of rapamycin (mTOR). In some embodiments, mTOR inhibitors are a class of drugs that inhibit the mechanistic target of rapamycin (mTOR), which is a serine / threonine-specific protein kinase belonging to the phosphatidylinositol-3 kinase (PI3K)-associated kinase (PIKK) family. In some embodiments, mTOR regulates cell metabolism, growth, and proliferation by forming two protein complexes, mTORC1 and mTORC2, and by signal transduction through these two protein complexes.

[0058] "Amino" refers to the -NH2 group.

[0059] "Cyano" refers to the -CN group.

[0060] "Hydroxy group" refers to the -OH group.

[0061] "Nitro" refers to the -NO2 group.

[0062] "O-" refers to the -O- group.

[0063] "Oxo" refers to the =O group.

[0064] "Thio" refers to the =S group.

[0065] "Imine" refers to the =NH group.

[0066] "Oxime group" refers to the =N-OH group.

[0067] "Alkyl" refers to a compound consisting only of carbon and hydrogen atoms, without any degree of unsaturation, and having 1 to 15 carbon atoms (e.g., C1-C1). 15 Alkyl groups are straight-chain or branched hydrocarbon chain groups. In some embodiments, the alkyl group comprises 1 to 13 carbon atoms (e.g., C1-C1). 13 Alkyl group. In some embodiments, the alkyl group comprises 1 to 8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl group comprises 1 to 5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, the alkyl group comprises 1 to 4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl group comprises 1 to 3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl group comprises 1 to 2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl group comprises one carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl group comprises 5 to 15 carbon atoms (e.g., C5-C6 alkyl). 15Alkyl group. In other embodiments, the alkyl group comprises 5 to 8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl group comprises 2 to 5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl group comprises 3 to 5 carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). The alkyl group is connected to the remainder of the molecule by a single bond. Unless otherwise specified in this specification, the alkyl group is optionally substituted with one or more of the following substituents: halogenated, cyano, nitro, oxo, thio, imino, oxime (oximo), trimethylsilyl, -OR a -SR a -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)N(R) a )2、-N(R a )C(O)OR f -OC(O)- NR a R f -N(R) a )C(O)R f -N(R) a S(O) t R f (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R f (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a Independently hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic, heterocyclic alkyl, heteroaryl, or heteroarylalkyl, and each R f It is independently an alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic, heterocyclic alkyl, heteroaryl, or heteroarylalkyl.

[0068] "Amino-alkyl" refers to the group with the following formula: -alkyl-NH2.

[0069] "Hydroxy-alkyl" refers to the group with the following formula: -alkyl-OH.

[0070] "Alkoxy" refers to a group of the formula -O-alkyl that is bonded by an oxygen atom, wherein the alkyl group is an alkyl chain as defined above.

[0071] "Alkenyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having 2 to 12 carbon atoms. In some embodiments, the alkenyl group contains 2 to 8 carbon atoms. In other embodiments, the alkenyl group contains 2 to 4 carbon atoms. The alkenyl group is connected to the rest of the molecule by a single bond, such as ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentenyl, pent-1,4-dienyl, etc. Unless otherwise specified in this specification, the alkenyl group may optionally be substituted with one or more of the following substituents: halogenated, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a -SR a -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)N(R) a )2、-N(R a )C(O)OR f -OC(O)-NR a R f -N(R) a )C(O)R f -N(R) a S(O) t R f (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R f (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a Independently hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic, heterocyclic alkyl, heteroaryl, or heteroarylalkyl, and each R f It is independently an alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic, heterocyclic alkyl, heteroaryl, or heteroarylalkyl.

[0072] "Alynyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and having 2 to 12 carbon atoms. In some embodiments, the alkynyl group contains 2 to 8 carbon atoms. In other embodiments, the alkynyl group has 2 to 4 carbon atoms. The alkynyl group is connected to the rest of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentylyl, hexynyl, etc. Unless otherwise specified in this specification, the alkynyl group may optionally be substituted with one or more of the following substituents: halogenated, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a -SR a -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)N(R) a )2、-N(R a )C(O)OR f -OC(O)-NR a R f -N(R) a )C(O)R f -N(R) a S(O) t R f (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R f (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a Independently hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic, heterocyclic alkyl, heteroaryl, or heteroarylalkyl, and each R f It is independently an alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic, heterocyclic alkyl, heteroaryl, or heteroarylalkyl.

[0073] "alkylene" or "alkylene chain" refers to a straight-chain or branched divalent hydrocarbon chain that connects the rest of a molecule to a group, consisting only of carbon and hydrogen, without unsaturation, and having 1 to 12 carbon atoms, such as methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is connected to the rest of the molecule by a single bond and to the group by a single bond. In some embodiments, the connection point between the alkylene chain and the rest of the molecule, and to the group, is through one carbon atom in the alkylene chain or through any two carbons within the chain. In some embodiments, the alkylene contains 1 to 8 carbon atoms (e.g., C1-C8 alkylene). In other embodiments, the alkylene contains 1 to 5 carbon atoms (e.g., C1-C5 alkylene). In other embodiments, the alkylene contains 1 to 4 carbon atoms (e.g., C1-C4 alkylene). In other embodiments, the alkylene contains 1 to 3 carbon atoms (e.g., C1-C3 alkylene). In other embodiments, the alkylene contains 1 to 2 carbon atoms (e.g., C1-C2 alkylene). In other embodiments, the alkylene group comprises one carbon atom (e.g., C1 alkylene). In other embodiments, the alkylene group comprises five to eight carbon atoms (e.g., C5-C8 alkylene). In other embodiments, the alkylene group comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, the alkylene group comprises three to five carbon atoms (e.g., C3-C5 alkylene). Unless otherwise specifically stated in this specification, the alkylene chain is optionally substituted with one or more of the following substituents: halogenated, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a -SR a -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)N(R) a )2、-N(R a )C(O)OR f -OC(O)- NR a R f -N(R) a )C(O)R f -N(R) a S(O) t R f (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R f (where t is 1 or 2) and -S(O) t N(R a)2 (where t is 1 or 2), where each R a Independently hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic, heterocyclic alkyl, heteroaryl, or heteroarylalkyl, and each R f It is independently an alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic, heterocyclic alkyl, heteroaryl, or heteroarylalkyl.

[0074] "Aryl" refers to a group derived from aromatic monocyclic or polycyclic hydrocarbon ring systems by removing a hydrogen atom from a ring carbon atom. Aromatic monocyclic or polycyclic hydrocarbon ring systems contain only hydrogen and carbon atoms from 5 to 18 carbon atoms, wherein at least one ring in the ring system is completely unsaturated, that is, it contains a cyclic, delocalized (4n+2) π-electron system according to Hückel theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indene, indene, tetrahydronaphthalene, and naphthalene. Unless otherwise specified in this specification, the term "aryl" or the prefix "aromatic-" (as in "arylalkyl") is intended to include an aryl group optionally substituted with one or more substituents independently selected from: alkyl, alkenyl, ynyl, halogen, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted arenel, optionally substituted arynyl, optionally substituted carbocyclic, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -CN、-R b -OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(R a )2、-R b -OR c -C(O)N(R a )2、-R b -N(R a )C(O)OR a -R b -N(R a )C(O)R a -Rb -N(R a S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R a Independently, each R is hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted by one or more halogenated groups), aralkyl, heterocyclic, heterocyclic alkyl, heteroaryl, or heteroarylalkyl. b Independently, it is a direct bond or a straight-chain or branched alkylene or alkenylene chain, and R c It is a straight-chain or branched alkylene or alkenylene chain, and unless otherwise stated, each of the above substituents is unsubstituted.

[0075] "Aryloxy group" refers to a group of formula -O-aryl bonded by an oxygen atom, wherein the aryl group is as defined above.

[0076] "Aryl group" refers to the formula -R c -aryl groups, where R c The alkylene chain is as defined above, for example, methylene, ethylene, etc. The alkylene chain portion of the aralkyl group is optionally substituted as described above for the alkylene chain. The aryl portion of the aralkyl group is optionally substituted as described above for the aryl group.

[0077] "Aryl" refers to the formula -R d -aryl groups, where R d It is an alkenyl chain as defined above. The aryl portion of the aryl group is optionally substituted as described above for the aryl group. The alkenyl chain portion of the aryl group is optionally substituted as defined above for the alkenyl group.

[0078] "Arotyne group" refers to the formula -R e -aryl groups, where R e The aryynyl chain is as defined above. The aryl portion of the aryynyl group is optionally substituted as described above for the aryl group. The aryynyl chain portion of the aryynyl group is optionally substituted as defined above for the aryynyl chain.

[0079] A "carbocyclic group" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, and in some embodiments includes a fused ring or bridged ring system having 3 to 15 carbon atoms. In some embodiments, the carbocyclic group contains 3 to 10 carbon atoms. In other embodiments, the carbocyclic group contains 5 to 7 carbon atoms. The carbocyclic group is connected to the rest of the molecule by a single bond. In some embodiments, the carbocyclic group is saturated (i.e., containing only a single C-C bond) or unsaturated (i.e., containing one or more double or triple bonds). Fully saturated carbocyclic groups are also referred to as "cycloalkyl groups". Examples of monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the cycloalkyl group contains 3 to 8 carbon atoms (e.g., C3-C8 cycloalkyl). In other embodiments, the cycloalkyl group contains 3 to 7 carbon atoms (e.g., C3-C7 cycloalkyl). In other embodiments, the cycloalkyl group contains 3 to 6 carbon atoms (e.g., C3-C6 cycloalkyl). In other embodiments, the cycloalkyl group comprises 3 to 5 carbon atoms (e.g., C3-C5 cycloalkyl). In other embodiments, the cycloalkyl group comprises 3 to 4 carbon atoms (e.g., C3-C4 cycloalkyl). Unsaturated carbocyclic groups are also referred to as "cycloalkenyl". Examples of monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclic groups include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptyl), norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Unless otherwise specified in this specification, the term "carbocyclic" is intended to include a carbocyclic group optionally substituted with one or more substituents independently selected from: alkyl, alkenyl, ynyl, halogenated, fluoroalkyl, oxo, thiolated, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted arenel, optionally substituted arynyl, optionally substituted carbocyclic, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -CN, -R b -OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(Ra )2、-R b -OR c -C(O)N(R a )2、-R b -N(R a )C(O)OR a -R b -N(R a )C(O)R a -R b -N(R a S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R a Independently, each R is hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclic, heterocyclic alkyl, heteroaryl, or heteroarylalkyl. b Independently, it is a direct bond or a straight-chain or branched alkylene or alkenylene chain, and R c It is a straight-chain or branched alkylene or alkenylene chain, and unless otherwise stated, each of the above substituents is unsubstituted.

[0080] "Carbocycloalkyl" refers to the formula -R c - A carbocyclic group, wherein R c It is an alkylene chain as defined above. The alkylene chain and the carbocyclic group as defined above may optionally be substituted.

[0081] "Halogen" or "halogen" refers to bromine, chlorine, fluorine, or iodine substituents.

[0082] "Fluoroalkyl" refers to an alkyl group as defined above, which is substituted with one or more fluorinated groups as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl group may optionally be substituted as described above for alkyl groups.

[0083] "Heterocyclic group" or "heterocycle" refers to a stable 3- to 18-membered non-aromatic cyclic group containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise expressly stated in the specification, a heterocyclic group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and in some embodiments, it includes fused or bridged ring systems. The heteroatoms in the heterocyclic group are optionally oxidized. If one or more nitrogen atoms are present, they are optionally quaternized. The heterocyclic group is partially or fully saturated. In some embodiments, the heterocyclic group is connected to the remainder of the molecule by any atom in the ring. In some embodiments, the heterocyclic group is saturated (i.e., containing only single bonds) or unsaturated (i.e., containing one or more double or triple bonds). A fully saturated heterocyclic group is also called a "heterocyclic alkyl group". Examples of such heterocyclic groups include, but are not limited to, dioxolane, thiophene[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperylalkyl, oxazolyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolylalkyl, pyrazolylalkyl, quininecycloyl, thiazoalkyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropyranyl, thiomorpholinyl, thio-morpholinyl, 1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl. Unless otherwise specified in this specification, the term "heterocyclic" is intended to include heterocyclic groups as defined above, optionally substituted with one or more substituents selected from the following: alkyl, alkenyl, ynyl, halogenated, fluoroalkyl, oxo, thiolated, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted arenel, optionally substituted arynyl, optionally substituted carbocyclic, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -CN, -R b -CN、-R b -OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(R a )2、-R b -OR c -C(O)N(Ra )2、-R b -N(R a )C(O)OR a -R b -N(R a )C(O)R a -R b -N(R a S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R a Independently, each R is hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclic, heterocyclic alkyl, heteroaryl, or heteroarylalkyl. b Independently, it is a direct bond or a straight-chain or branched alkylene or alkenylene chain, and R c It is a straight-chain or branched alkylene or alkenylene chain, and unless otherwise stated, each of the above substituents is unsubstituted.

[0084] "Heteroalkyl" means an alkyl group as defined above, wherein one or more skeletal atoms of the alkyl group are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. The heteroalkyl group is attached to the remainder of the molecule at a carbon atom of the heteroalkyl group. In one aspect, the heteroalkyl group is a C1-C6 heteroalkyl group. In some embodiments, the heteroalkyl group contains 1, 2, or 3 heteroatoms. In some embodiments, the alkyl portion of the heteroalkyl group is optionally substituted as described with respect to the 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.

[0085] "Heterocyclic alkyl" refers to formula -R c - A heterocyclic group, wherein R cThe heterocyclic group is an alkylene chain as defined above. If the heterocyclic group is a nitrogen-containing heterocyclic group, it is optionally linked to an alkyl group at the nitrogen atom. The alkylene chain of the heterocyclic alkyl group is optionally substituted as described above for the alkylene chain. The heterocyclic moiety of the heterocyclic alkyl group is optionally substituted as described above for the heterocyclic group.

[0086] "Heterocyclic alkoxy" refers to the formula -OR c Heterocyclic groups are groups bonded by oxygen atoms, where R c The heterocyclic chain is as defined above. If the heterocyclic group is a nitrogen-containing heterocyclic group, it is optionally linked to an alkyl group at the nitrogen atom. The alkylene chain of the heterocyclic alkoxy group is optionally substituted as described above for the alkylene chain. The heterocyclic moiety of the heterocyclic alkoxy group is optionally substituted as described above for the heterocyclic group.

[0087] "Heteroaryl" refers to a group derived from a 3- to 18-membered aromatic ring group comprising 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, in some embodiments, the heteroaryl group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring in the ring system is fully unsaturated, i.e., it comprises a cyclic, delocalized (4n+2) π-electron system according to Hückel theory. Heteroaryls include fused or bridged ring systems. The heteroatoms in the heteroaryl group are optionally oxidized. If one or more nitrogen atoms are present, they are optionally quaternized. The heteroaryl group is connected to the rest of the molecule through any atom in the ring. In some embodiments, the heteroaryl group contains 1-4 N atoms in the ring. In some embodiments, the heteroaryl group contains 4-6 N atoms in the ring. In some embodiments, the heteroaryl group contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl group is a monocyclic heteroaryl group. In some embodiments, the monocyclic heteroaryl group is a 5- or 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a C1-C9 heteroaryl group. In some embodiments, the monocyclic heteroaryl group is a C1-C5 heteroaryl group. In some embodiments, the bicyclic heteroaryl group is a C5-C9 heteroaryl group. Examples of heteroaryl groups include, but are not limited to, azathiol, acridinel, benzimidazolyl, benzoindolyl, 1,3-benzodioxolane, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxazolyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxane, benzonaphthofuranyl, benzooxazolyl, benzodioxolane, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, and benzothienyl. hiophenyl), benzothiopheno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazole, cenolinyl, cyclopentano[d]pyrimidinyl, 6,7-dihydro-5H-cyclopentano[4,5]thiopheno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h] Crazinyl, 6,7-dihydro-5H-benzo[6,7]cycloheptano[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanoneyl, furano[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocyclooctano[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocyclooctano[d]pyridazinyl, 5,6,7,8,9,10-Hexahydrocyclooctano[d]pyridinyl, isothiazolyl, imidazolyl, indazole, indole, indazole, isoindole, dihydroindole, isodihydroindole, isoquinolinyl, indazinyl, isoxazolyl, 5,8-methylbridged-5,6,7,8-tetrahydroquinazolinyl, naphridinyl, 1,6-naphthyridinonyl, oxadiazole 2-Oxazolidinyl, oxazolyl, ethylene oxide, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl The following are listed: pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrroleyl, 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-cycloheptano[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 (i.e., thienyl). Unless otherwise specified in this specification, the term "heteroaryl" is intended to include heteroaryl groups as defined above, optionally substituted with one or more substituents selected from the following: alkyl, alkenyl, ynyl, halo, fluoroalkyl, haloalkenyl, haloynyl, oxo, thio, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted arenel, optionally substituted arynyl, optionally substituted carbocyclic, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R, b -OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(R a)2、-R b -OR c -C(O)N(R a )2、-R b -N(R a )C(O)OR a -R b -N(R a )C(O)R a -R b -N(R a S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R a Independently, each R is hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclic, heterocyclic alkyl, heteroaryl, or heteroarylalkyl. b Independently, it is a direct bond or a straight-chain or branched alkylene or alkenylene chain, and R c It is a straight-chain or branched alkylene or alkenylene chain, and unless otherwise stated, each of the above substituents is unsubstituted.

[0088] “ N "-Heteroaryl" refers to a heteroaryl group as defined above containing at least one nitrogen atom, wherein the connection point between the heteroaryl group and the rest of the molecule is through a nitrogen atom in the heteroaryl group. N - The heteroaryl group is optionally substituted as described above for the heteroaryl group.

[0089] “ C "-Heteroaryl" refers to a heteroaryl group as defined above, wherein the connection point between the heteroaryl group and the rest of the molecule is through a carbon atom in the heteroaryl group. C - The heteroaryl group is optionally substituted as described above for the heteroaryl group.

[0090] "Heteroaryloxy group" refers to a group of formula -O-heteroaryl bonded by an oxygen atom, wherein the heteroaryl group is as defined above.

[0091] "Heteroarylalkyl" refers to the formula -R c - A heteroaryl group, wherein R cThe alkylene chain is as defined above. If the heteroaryl group is a nitrogen-containing heteroaryl group, it is optionally linked to an alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkyl group is optionally substituted as defined above for the alkylene chain. The heteroaryl portion of the heteroarylalkyl group is optionally substituted as defined above for the heteroaryl group.

[0092] "Heteroarylalkoxy" refers to the formula -OR c - A heteroaryl group bonded by an oxygen atom, wherein R c The alkylene chain is as defined above. If the heteroaryl group is a nitrogen-containing heteroaryl group, it is optionally linked to an alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkoxy group is optionally substituted as defined above for the alkylene chain. The heteroaryl portion of the heteroarylalkoxy group is optionally substituted as defined above for the heteroaryl group.

[0093] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers, thus yielding enantiomers, diastereomers, and isomers defined by absolute stereochemistry as ( R )-or( S Other stereoisomers of )-. Unless otherwise stated, this disclosure is intended to cover all stereoisomers of the compounds disclosed herein. When the compounds described herein contain an alkene double bond, unless otherwise stated, this disclosure is intended to also include E And Z geometric isomers (e.g., cis or trans). Similarly, it is intended to include all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms. The term "geometric isomer" refers to the olefin double bond... E Or Z-geometric isomers (e.g., cis or trans). The term "positional isomer" refers to structural isomers around the central ring, such as the ortho, meta, and para isomers around the benzene ring.

[0094] A "tautomer" is a molecule in which it is possible for a proton to move from one atom of the molecule to another atom of the same molecule. In some embodiments, the compounds presented herein exist as tautomers. A chemical equilibrium of tautomers will exist where tautomerization is possible. The exact proportions of tautomers depend on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibria include: .

[0095] "Optional" or "optionally" means that the event or situation described below may or may not occur, and that the description includes both the occurrence and non-occurrence of the event or situation. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and that the description includes both substituted and unsubstituted aryl groups.

[0096] "Pharmaceutically acceptable salt" includes both acid addition salts and base addition salts. A pharmaceutically acceptable salt of any compound described herein is intended to include any and all pharmaceutically suitable salt forms. Optionally, a pharmaceutically acceptable salt of the compounds described herein is a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable base addition salt.

[0097] "Pharmaceutically acceptable acid addition salts" refer to those salts that retain the biological effectiveness and properties of the free base, are not biologically or otherwise undesirable, and are formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, and phosphorous acid. It also includes salts formed from organic acids such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanes, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and including, 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, and salicylic acid. Therefore, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, caprylates, sebacic acid salts, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, etc. Salts of amino acids such as arginine salts, gluconates, and galacturons are also involved (see, for example, Berge SM et al., "Pharmaceutical Salts") Journal of Pharmaceutical Science , 66:1-19 (1997), which is incorporated herein by reference in its entirety. In some embodiments, the acid addition salt of a basic compound is prepared by contacting its free basic form with a sufficient amount of the desired acid in accordance with methods and techniques familiar to a skilled craftsman to produce the salt.

[0098] "Pharmaceutically acceptable base addition salts" refer to those salts that retain the bioavailability and properties of the free acid and are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed using metals or amines such as alkali metals 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, and aluminum salts. Salts derived from organic bases include, but are not limited to, salts of the following organic bases: primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and base ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, etc. N , N -Dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenediphenylamine, N methylglucosamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N - Ethylpiperidine, polyamine resins, etc. See Berge et al., ibid.

[0099] As used herein, the terms "treatment," "management," "relief," or "improvement" are used interchangeably. These terms refer to the means of obtaining a beneficial or desired outcome (including, but not limited to, therapeutic and / or preventive benefits). A "therapeutic benefit" refers to the eradication or improvement of an underlying condition that is being treated. Alternatively, a therapeutic benefit may be achieved by the eradication or improvement of one or more physical symptoms associated with the underlying condition, resulting in an observed improvement in a patient, even if, in some embodiments, the patient is suffering from the underlying condition. For preventive benefits, in some embodiments, the composition is administered to a patient at risk of developing a specific disease, or to a patient who reports one or more physical symptoms of a disease, even if the disease has not yet been diagnosed.

[0100] The term "prodrug" is intended to refer to a compound that is converted into the bioactive compound described herein under physiological conditions or by solvent degradation. Therefore, the term "prodrug" refers to a precursor of a pharmaceutically acceptable bioactive compound. In some embodiments, the prodrug is inactive when administered to a subject, but is converted into the active compound in vivo, for example, by hydrolysis. Prodrug compounds often have the advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)).

[0101] Discussions of prodrugs are provided in Higuchi, T. et al., “Pro-drugs as Novel Delivery Systems,” ACS Symposium Series, Volume 14, and Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entirety.

[0102] The term "prodrug" is also intended to include any covalently bonded carrier that, when administered to a mammalian subject, releases the active compound in vivo. In some embodiments, as described herein, a prodrug of the active compound is prepared by modifying a functional group present in the active compound in such a way that the modification cleaves into the parent active compound in conventional operation or in vivo. Prodrugs include compounds in which a hydroxyl, amino, or thiol group is bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free thiol 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 compound, etc.

[0103] Composition In one aspect, this disclosure provides 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 c-MET inhibitors, BRAF inhibitors, EGFR inhibitors, MEK inhibitors, KRAS inhibitors, and mTOR inhibitors. In some embodiments, this disclosure provides compositions comprising a therapeutically effective amount of a first therapeutic agent comprising a compound of formula (I), (IA), (II), or (III) or a pharmaceutically acceptable salt or solvation thereof, and a therapeutically effective amount of a second therapeutic agent, wherein the second therapeutic agent is selected from c-MET inhibitors, BRAF inhibitors, EGFR inhibitors, MEK inhibitors, KRAS inhibitors, and mTOR inhibitors.

[0104] In some embodiments, this 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, this disclosure provides compositions comprising a therapeutically effective amount of a first therapeutic agent comprising a compound of formula (I), (IA), (II), or (III) or a pharmaceutically acceptable salt or solvation thereof and a therapeutically effective amount of a c-MET inhibitor.

[0105] In some embodiments, this 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, this disclosure provides compositions comprising a therapeutically effective amount of a first therapeutic agent comprising a compound of formula (I), (IA), (II), or (III) or a pharmaceutically acceptable salt or solvation thereof and a therapeutically effective amount of a BRAF inhibitor.

[0106] In some embodiments, this 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, this disclosure provides compositions comprising a therapeutically effective amount of a first therapeutic agent comprising a compound of formula (I), (IA), (II), or (III) or a pharmaceutically acceptable salt or solvation thereof and a therapeutically effective amount of an EGFR inhibitor.

[0107] In one aspect, this 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, this disclosure provides compositions comprising a therapeutically effective amount of a first therapeutic agent comprising a compound of formula (I), (IA), (II), or (III) or a pharmaceutically acceptable salt or solvation thereof, and a therapeutically effective amount of a MEK inhibitor.

[0108] In one aspect, this disclosure provides compositions comprising a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of a KRAS inhibitor. In some embodiments, this disclosure provides compositions comprising a therapeutically effective amount of a first therapeutic agent comprising a compound of formula (I), (IA), (II), or (III) or a pharmaceutically acceptable salt or solvation thereof and a therapeutically effective amount of a KRAS inhibitor.

[0109] In one aspect, this disclosure provides compositions comprising a therapeutically effective amount of a first therapeutic agent comprising a TEAD inhibitor and a therapeutically effective amount of an mTOR inhibitor. In some embodiments, this disclosure provides compositions comprising a therapeutically effective amount of a first therapeutic agent comprising a compound of formula (I), (IA), (II), or (III) or a pharmaceutically acceptable salt or solvation thereof, and a therapeutically effective amount of an mTOR inhibitor.

[0110] In some embodiments, this disclosure provides compositions for treating cancer in a subject of need, comprising administering to the subject of need 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 c-MET inhibitors, BRAF inhibitors, EGFR inhibitors, MEK inhibitors, KRAS inhibitors, and mTOR inhibitors. In some embodiments, this disclosure provides compositions for treating cancer in a subject of need, comprising administering to the subject of need a composition comprising a first therapeutic agent comprising a compound of formula (I), (IA), (II), or (III) or a pharmaceutically acceptable salt or solvation thereof and a therapeutically effective amount of a second therapeutic agent, wherein the second therapeutic agent is selected from c-MET inhibitors, BRAF inhibitors, EGFR inhibitors, MEK inhibitors, KRAS inhibitors, and mTOR inhibitors. In some embodiments, the compositions disclosed herein can be used to treat cancer.

[0111] In some embodiments, the composition also includes one or more pharmaceutically acceptable excipients.

[0112] TEAD inhibitors In one aspect, the first therapeutic agent comprises a TEAD inhibitor. In some embodiments, the TEAD inhibitor comprises a compound of formula (I), (IA), (II), or (III), or a pharmaceutically acceptable salt or solvation thereof.

[0113] In one respect, TEAD inhibitors comprise compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof: in, Each X1 X 4 X 5 and X 6 Independently N or CR X ; Each X 2 and X 3 Independently N or CR Y ; Each R X Independently hydrogen, halogen, nitro, -OR 3 -SR 3 -CN, -C(=O)R 3 -C(=O)N(R) 3 2. -C(=O)OR 3 -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 -NR 3 C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by groups; Each R Y Independently hydrogen, halogen, nitro, -CN, -C(=O)R 3 -C(=O)N(R) 3 2. -C(=O)OR 3 -S(=O)R 3 -S(=O)2R 3 -N(R) 3)2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 -NR 3 C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by groups; R represents halogen, nitro, -CN, or -OR. 3 -SR 3 -C(=O)R 3 -C(=O)N(R) 3 2. -C(=O)OR 3 -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 -NR 3 C(=O)OR 3 Or optionally by 1-5 R 5 C1-C6 fluoroalkyl groups substituted by the radical; R 1 It is C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C1-C6 heteroalkyl, -CN or -S(=O)2R 4 Among them, C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10cycloalkyl, C2-C 10 Heterocyclic alkyl groups and C1-C6 heteroalkyl groups are optionally surrounded by 1-5 R groups. 5 Substituted by groups; Each R 2 Independently halogen, nitro, -N3, -CN, -OR 3 -SR 3 -S(=O)2R 3 -N(R) 3 2. -C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by groups; Each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by a group; or If two R 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5The C3-C7 heterocyclic alkyl group substituted by the group; R 4 It is a C1-C6 alkyl, C1-C6 fluoroalkyl, or C3-C 10 Cycloalkyl or -NH2, wherein C1-C6 alkyl, C1-C6 fluoroalkyl and C3-C 10 The cycloalkyl group is optionally surrounded by 1-5 Rs. 5 Substituted by groups; Each R 5 Independently selected from halogen, oxo, -CN, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, -CH2-C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, -CH2-C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 and -N(R) 10 (R) 11 The group is replaced by ) or two R groups. 5 Combine to form C 3-5 cycloalkyl rings; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Substituted with heteroaryl groups; Each R 11 Independently selected from hydrogen and C1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl; or R 10 and R 11 Together with the nitrogen atoms to which they are attached, they independently form 4- to 7-membered heterocycles, wherein the heterocycle optionally contains 1-2 additional heteroatoms selected from N, O and S, and wherein each heterocycle nitrogen atom, if present, is independently and optionally substituted by a C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN or C2-C3 heteroalkyl. Each R 12 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl groups; Each R 13 Selected independently from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogen, SF5, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is replaced; and n can be 0, 1, 2, 3, or 4.

[0114] For any and all embodiments of compounds of formula (I), the substituents are selected from a subset of the listed options. For example, in some embodiments, X1 For N or CR X In other implementations, X 1 For N. In some implementations, X 1 For CR X .

[0115] In some implementation schemes, X 1 For CR X And each X 2 and X 3 For CR Y In some implementations, X 1 Let N be the number of X; and each X 2 and X 3 For CR Y In some implementations, X 1 For CR X ;X 2 For CR Y And X 3 Let N be the number of elements in the array.

[0116] In some implementations, each X 4 X 5 and X 6 For CR X In some implementations, X 4 Let N be the number of X; and each X 5 and X 6 For CR X In some implementations, each X 4 and X 5 For CR X And X 6 Let N be the number of elements in the array.

[0117] In some implementations, each R X Independently hydrogen, halogen, -OR 3 -SR 3 -CN, -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C4 alkenyl, C2-C4 ynyl or C1-C6 heteroalkyl, wherein the C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C4 alkenyl, C2-C4 ynyl and C1-C6 heteroalkyl are optionally surrounded by 1-5 R 5 The group is replaced; and each R 3Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl or C2-C 10 Heterocyclic alkyl groups, including C1-C6 alkyl groups, C1-C6 fluoroalkyl groups, C1-C6 heteroalkyl groups, and C3-C6 heteroalkyl groups. 10 cycloalkyl and C2-C 10 Heterocyclic alkyl groups are optionally surrounded by 1-5 R groups. 5 The group is replaced; or if two R groups are replaced. 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group. In some embodiments, each R X Independently hydrogen, halogen, -OR 3 -SR 3 -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 C1-C6 alkyl, C1-C6 fluoroalkyl, or C2-C4 ynyl, wherein the C1-C6 alkyl, C1-C6 fluoroalkyl, and C2-C4 ynyl are optionally surrounded by 1-5 R groups. 5 The group is replaced; and each R 3 It is independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl or C3-C 10 Cycloalkyl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl and C3-C6 alkyl groups. 10 The cycloalkyl group is optionally surrounded by 1-5 Rs. 5 The group is replaced; or if two R groups are replaced. 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0118] In some implementations, each R XIndependently, it can be 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, oxacyclobutyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy, aziridine, pyrrole Alkyl, 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 R X Independently, it is 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 R X Independently, it is 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 R X Independently, it can be hydrogen, F, Cl, Br, -CH3, -OH, -OCH3, or -OCF3. In some embodiments, each R... X Independently, it can be hydrogen, F, Cl, -CH3, -OCH3, or -OCF3. In some embodiments, each R... X Independently hydrogen, F, or -OCH3. In some embodiments, each RX It is hydrogen.

[0119] In some implementations, each R Y Independently hydrogen, halogen, -CN, -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C4 alkenyl, C2-C4 ynyl or C1-C6 heteroalkyl, wherein the C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C4 alkenyl, C2-C4 ynyl and C1-C6 heteroalkyl are optionally surrounded by 1-5 R 5 The group is replaced; and each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl or C2-C 10 Heterocyclic alkyl groups, including C1-C6 alkyl groups, C1-C6 fluoroalkyl groups, C1-C6 heteroalkyl groups, and C3-C6 heteroalkyl groups. 10 cycloalkyl and C2-C 10 Heterocyclic alkyl groups are optionally surrounded by 1-5 R groups. 5 The group is replaced; or if two R groups are replaced. 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group. In some embodiments, each R Y Independently hydrogen, halogen, -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 C1-C6 alkyl, C1-C6 fluoroalkyl, or C2-C4 ynyl, wherein the C1-C6 alkyl, C1-C6 fluoroalkyl, and C2-C4 ynyl are optionally surrounded by 1-5 R groups. 5 The group is replaced; and each R 3 It is independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl or C3-C 10 Cycloalkyl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl and C3-C6 alkyl groups. 10 The cycloalkyl group is optionally surrounded by 1-5 Rs. 5 The group is replaced; or if two R groups are replaced.3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0120] In some implementations, each R Y Independently, it is 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 R Y Independently, it is 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 R Y Independently, it is 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 R Y Independently, it can be hydrogen, F, Cl, or -CH3. In some embodiments, each R... Y Independently hydrogen or F. In some implementations, each R Y It is hydrogen.

[0121] In some implementation schemes, R 1 For optional use by 1-5 R 5 The C1-C6 alkyl group substituted by the group.

[0122] In some implementation schemes, R 1It is a C1-C6 alkyl group substituted with C2-C6 alkenyl, C2-C6 ynyl or -CN, wherein the C2-C6 alkenyl and C2-C6 ynyl groups are optionally replaced by 1-5 R groups. 5 The group is replaced.

[0123] In some implementation schemes, R 1 For OR 3 The substituted C1-C6 alkyl group; and R 3 It is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl or C3-C 10 Cycloalkyl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl and C3-C6 alkyl groups. 10 The cycloalkyl group is optionally surrounded by 1-5 Rs. 5 The group is replaced.

[0124] In some implementation schemes, R 1 For -C(=O)N(R) 5 )2 or -N(R 5 )2 replaced by C1-C6 alkyl groups; wherein each R 5 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 ynyl or -CN, wherein C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl and C2-C6 ynyl groups are optionally separated by 1-5 R groups. 5 Substituted by a group; or two R groups 5 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0125] In some implementation schemes, R 1 C1-C6 alkyl groups substituted with C3-C8 cycloalkyl or C2-C7 heterocycloalkyl, wherein the C3-C8 cycloalkyl and C2-C7 heterocycloalkyl groups are optionally replaced by 1-5 R groups. 5 The group is replaced.

[0126] In some implementation schemes, R 1 It is a C1-C6 alkyl group substituted with cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0127] In some implementation schemes, R 1 It is a C1-C6 alkyl group substituted with oxetane, tetrahydrofuranyl, tetrahydropyranyl, azirnebutane, pyrrolidinyl or piperidinyl.

[0128] In some implementation schemes, R 1It is a C1-C6 alkyl group substituted with a phenyl group, which is optionally replaced by 1-5 R groups. 5 The group is substituted, wherein if the phenyl group is substituted, it is replaced by 1, 2, 3 or 4 groups selected from halogen, nitro, -CN, -OR. 3 -N(R) 3 )2、-C(=O)R 3 -C(=O)N(R) 3 2. -C(=O)OR 3 The C1-C6 alkyl and C1-C6 fluoroalkyl groups are substituted with substituents, wherein the C1-C6 alkyl and C1-C6 fluoroalkyl groups are optionally replaced by 1-5 R groups. 5 The group is replaced; and each R 3 It is independently hydrogen, C1-C6 alkyl or C3-C 10 Cycloalkyl groups, wherein C1-C6 alkyl groups and C3-C6 alkyl groups are cycloalkyl groups. 10 The cycloalkyl group is optionally surrounded by 1-5 Rs. 5 The group is replaced; or if two R groups are replaced. 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0129] In some implementation schemes, R 1 It is a C1-C6 alkyl group substituted with a 5-membered heteroaryl ring containing at least one nitrogen atom.

[0130] In some implementation schemes, R 1 The alkyl group is a C1-C6 alkyl group substituted with a 5-membered heteroaryl ring, wherein the 5-membered heteroaryl ring is selected from pyrroloyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, and thiadiazolyl, wherein the pyrroloyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, and thiadiazolyl groups are optionally replaced by 1-5 R groups. 5 The group is replaced.

[0131] In some implementation schemes, R 1 The alkyl group is a C1-C6 alkyl group substituted with a 5-membered heteroaryl ring, which is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and ;in Each R z Independently hydrogen, halogen, -CN, -OR 3 -SR 3 -S(=O)2R 3 -N(R) 3 2. -C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups.5 The group is replaced; and Each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl or C2-C 10 Heterocyclic alkyl groups, including C1-C6 alkyl groups, C1-C6 fluoroalkyl groups, C1-C6 heteroalkyl groups, and C3-C6 heteroalkyl groups. 10 cycloalkyl and C2-C 10 Heterocyclic alkyl groups are optionally surrounded by 1-5 R groups. 5 The group is replaced; or if two R groups are replaced. 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0132] In some implementation schemes, R 1 It is a C1-C6 alkyl group substituted by a monocyclic 6-membered heteroaryl ring, which contains at least one nitrogen atom and is optionally replaced by 1-5 R atoms. 5 The group is replaced. In some embodiments, R 1 It is a C1-C6 alkyl group substituted by a monocyclic 6-membered heteroaryl ring, which contains 1, 2, or 3 nitrogen atoms and is optionally replaced by 1-5 R atoms. 5 The group is replaced. In some embodiments, R 1 The alkyl group is a C1-C6 alkyl group substituted with a 6-membered heteroaryl ring, which is selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazinyl, wherein the pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl groups are optionally replaced by 1-5 R groups. 5 The group is replaced. In some embodiments, R 1 It is a C1-C6 alkyl group substituted with a pyridinyl group, which is optionally replaced by 1-5 R groups. 5 The group is replaced. In some embodiments, R 1 It is a C1-C6 alkyl group substituted with a 2-pyridinyl group, which is optionally replaced by 1-5 R groups. 5 The group is replaced.

[0133] In some implementation schemes, R 1 The alkyl group is a C1-C6 alkyl group substituted with a 6-membered heteroaryl ring, which is selected from: ; in Each R z Independently hydrogen, halogen, -CN, -OR 3 -SR 3-S(=O)2R 3 -N(R) 3 2. -C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 The group is replaced; and Each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl or C2-C 10 Heterocyclic alkyl groups, including -C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl and C2-C 10 Heterocyclic alkyl groups are optionally surrounded by 1-5 R groups. 5 The group is replaced; or if two R groups are replaced. 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0134] In some implementation schemes, R 1 It is a C1-C6 alkyl group substituted with a bicyclic 6 / 5 fused heteroaryl ring. In some embodiments, R 1The alkyl group is a C1-C6 alkyl group substituted by a bicyclic 6 / 5 fused heteroaryl ring, wherein the bicyclic 6 / 5 fused heteroaryl ring is selected from indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophene, indazole, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, inazinyl, and imidazopyridyl, wherein the indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiaphene, indazole, benzimidazolyl, benzoxazolyl, benzoisothiazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, inazinyl, and imidazopyridyl are optionally replaced by 1-5 R groups. 5 The group is replaced.

[0135] In some implementation schemes, R 1 The C1-C6 alkyl group is replaced by a bicyclic 6 / 5 fused heteroaryl ring, which is selected from: , , , , , , , , , , , , , , , , , , , , , , , , and ;in Each R z Independently hydrogen, halogen, -CN, -OR 3 -SR 3 -S(=O)2R 3 -N(R) 3 2. -C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 The group is replaced; and Each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl or C2-C 10 Heterocyclic alkyl groups, including C1-C6 alkyl groups, C1-C6 fluoroalkyl groups, C1-C6 heteroalkyl groups, and C3-C6 heteroalkyl groups. 10 cycloalkyl and C2-C 10 Heterocyclic alkyl groups are optionally surrounded by 1-5 R groups. 5 The group is replaced; or if two R groups are replaced. 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0136] In some implementation schemes, R 1 It is a C1-C6 alkyl group substituted by a bicyclic 6 / 6 fused heteroaryl ring, which contains at least one nitrogen atom and is optionally replaced by 1-5 R atoms. 5 The group is replaced. In some embodiments, R 1 It is a C1-C6 alkyl group substituted by a bicyclic 6 / 6 fused heteroaryl ring containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted by 1-5 R atoms. 5 The group is replaced. In some embodiments, R 1 The alkyl group is a C1-C6 alkyl group substituted by a bicyclic 6 / 6 fused heteroaryl ring, wherein the bicyclic 6 / 6 fused heteroaryl ring is selected from quinolinyl, isoquinolinyl, cenolinyl, quinazolinyl, quinoxalinyl, naphridinyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl, and pteridinyl, wherein quinolinyl, isoquinolinyl, cenolinyl, quinazolinyl, quinoxalinyl, naphridinyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyrimidinyl, and pteridinyl is optionally replaced by 1-5 R... 5 The group is replaced.

[0137] In some implementation schemes, R 1The bicyclic 6 / 6 fused heteroaryl ring is a C1-C6 alkyl group substituted with a 6 / 6 fused heteroaryl ring, selected from: ; in Each R z Independently hydrogen, halogen, -CN, -OR 3 -SR 3 -S(=O)2R 3 -N(R) 3 2. -C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 The group is replaced; and Each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl or C2-C 10 Heterocyclic alkyl groups, including C1-C6 alkyl groups, C1-C6 fluoroalkyl groups, C1-C6 heteroalkyl groups, and C3-C6 heteroalkyl groups. 10 cycloalkyl and C2-C 10 Heterocyclic alkyl groups are optionally surrounded by 1-5 R groups. 5 The group is replaced; or if two R groups are replaced. 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0138] In some implementation schemes, R 1 It is a C1-C6 alkyl group substituted with 1, 2, or 3 substituents, each substituent independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, and pyridyl. In some embodiments, R 1It is a C1-C6 alkyl group substituted with one or two substituents, each substituent being independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, and pyridyl. In some embodiments, R 1 It is a C1-C6 alkyl group substituted with one or two substituents, each substituent independently selected from -OH and pyridyl groups. In some embodiments, R 1 It is a C1-C6 alkyl group substituted with one or two substituents, each substituent independently selected from -NH2 and pyridyl groups. In some embodiments, R 1 It is a C1-C6 alkyl group substituted with one or two substituents, each substituent independently selected from -OH and -NH2. In some embodiments, R 1 It is a C1-C6 alkyl group substituted with -OH. In some embodiments, R 1 It is a C1-C6 alkyl group substituted with -NH2.

[0139] In some implementations, each R z Independently, it is hydrogen, F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCH2CH3, -OCF3, -NH2, -NHCH3, or -N(CH3)2. In some embodiments, each R z Independently, it is hydrogen, F, Cl, Br, -CH3, -CN, -OCH3, -NH2, -NHCH3, or -N(CH3)2. In some embodiments, each R z Independently, it is hydrogen, Cl, Br, -CH3, -OCH3, -NH2, or -N(CH3)2. In some embodiments, each R z It is hydrogen.

[0140] In some implementation schemes, R 1 For halogenated, -CN, -OR 3 -SR 3 -S(=O) R 3 -S(=O)2R 3 -N(R) 3 2. -C(=O)OR 3 -C(=O)N(R) 3 )2、-CR 3 =C(R 3 2. -C≡CR 3 C3-C 10 cycloalkyl, C2-C 10 C1-C6 alkyl groups substituted with heterocyclic alkyl or aryl groups, wherein C3-C6 10 cycloalkyl, C2-C 10Heterocyclic alkyl and aryl groups are optionally surrounded by 1-5 R groups. 5 The group is replaced; and each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl or C2-C 10 Heterocyclic alkyl groups, including C1-C6 alkyl groups, C1-C6 fluoroalkyl groups, C1-C6 heteroalkyl groups, and C3-C6 heteroalkyl groups. 10 cycloalkyl and C2-C 10 Heterocyclic alkyl groups are optionally surrounded by 1-5 R groups. 5 The group is replaced; or if two R groups are replaced. 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0141] In some implementation schemes, R 1 For C3-C 10 cycloalkyl or C2-C 10 Heterocyclic alkyl groups, wherein C3-C 10 cycloalkyl and C2-C 10 Heterocyclic alkyl groups are optionally surrounded by 1-5 R groups. 5 The group is replaced. In some embodiments, R 1 It is a C3-C6 cycloalkyl or C3-C5 heterocycloalkyl group substituted with C1-C6 alkyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazinyl. In some embodiments, R 1 It is a C3-C6 cycloalkyl or C3-C5 heterocycloalkyl that has been substituted with C1-C6 alkyl, phenyl or pyridyl.

[0142] In some implementation schemes, R 1 Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0143] In some implementations, R is halogen, nitro, -CN, or -OR. 3 -C(=O)R 3 -C(=O)N(R) 3 2. -C(=O)OR 3 -S(=O)R 3 -S(=O)2R 3 -NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 -NR 3 C(=O)OR 3 Or optionally by 1-5 R 5 The C1-C6 fluoroalkyl group substituted by the group; and each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl or C2-C 10 Heterocyclic alkyl groups, including C1-C6 alkyl groups, C1-C6 fluoroalkyl groups, C1-C6 heteroalkyl groups, and C3-C6 heteroalkyl groups. 10 cycloalkyl and C2-C 10 Heterocyclic alkyl groups are optionally surrounded by 1-5 R groups. 5 The group is replaced; or if two R groups are replaced. 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0144] 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 implementations, R is F, Cl, or -CF3. In some implementations, R is -OCF3. In some implementations, R is -CF3.

[0145] In some implementations, each R 2 Independently halogen, nitro, -CN, -OR 3 -SR 3 -S(=O)2R 3 -N(R) 3 2. -C(=O)OR 3 C1-C6 alkyl or C1-C6 fluoroalkyl, wherein the C1-C6 alkyl and C1-C6 fluoroalkyl are optionally surrounded by 1-5 R... 5 The group is replaced; and each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl or C2-C 10 Heterocyclic alkyl groups, including C1-C6 alkyl groups, C1-C6 fluoroalkyl groups, C1-C6 heteroalkyl groups, and C3-C6 heteroalkyl groups. 10 cycloalkyl and C2-C 10 Heterocyclic alkyl groups are optionally surrounded by 1-5 R groups. 5 The group is replaced; or if two R groups are replaced. 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0146] In some implementations, each R 2Independently, it can be 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 R 2 Independently, it can be F, Cl, -CN, -OCH3, -OCF3, -C(=O)OCH3, -CH3, or -CF3. In some implementations, each R 2 Independently, it can be F, Cl, -OCF3, or -CF3. In some implementations, each R... 2 It can be F or Cl independently.

[0147] In some implementation schemes, R 4 It is a C1-C6 alkyl, C1-C6 fluoroalkyl, or C3-C 10 Cycloalkyl or -NH2, wherein C1-C6 alkyl, C1-C6 fluoroalkyl and C3-C 10 The cycloalkyl group is optionally surrounded by 1-5 Rs. 5 The group is replaced. In some embodiments, R 4 For optional use by 1-5 R 5 The C1-C6 alkyl group substituted by the group. In some embodiments, R 4 For optional use by 1-5 R 5 The C1-C6 fluoroalkyl group substituted by the radical. In some embodiments, R 4 For optional use by 1-5 R 5 The C3-C group substituted by the group 10 Cycloalkyl. In some embodiments, R 4 It is -NH2.

[0148] In some implementations, each R 5 Independently selected from halogen, oxo, -CN, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13-C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, -CH2-C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, -CH2-C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 and -N(R) 10 (R) 11 The group is replaced by ) or two R groups. 5 Combine to form C 3-5 Cycloalkyl ring. In some embodiments, each R 5Independently selected from -OR 10 -N(R) 10 (R) 11 C 1-6 Alkyl and C 1-9 heteroaryl, of which C 1-6 Alkyl and C 1-9 Heteroaryl groups are optionally coated with halogens or -N(R) 10 (R) 11 Replaced by ) . In some implementations, each R 5 Independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2 and optionally halogenated or -N(R 10 (R) 11 The C replaced by ) 1-9 Mixed aromatic compounds.

[0149] In some implementations, each R 5 For -OH. In some implementations, each R 5 For -OCH3. In some implementations, each R 5 For -NH2. In some implementations, each R 5 For -NHCH3. In some implementations, each R 5 It is -N(CH3)2. In some implementations, each R 5 For -NHCH2CH3. In some implementations, each R 5 For -NHCH2CH2OH. In some embodiments, each R 5 For -NHCH2CH2F. In some implementations, each R 5 For -NHCH2CHF2. In some implementations, each R 5 To be optionally halogenated or -N(R) 10 (R) 11 The C replaced by ) 1-9 Heteroaryl. In some implementations, each R 5 It is pyridyl or pyrazinyl, wherein the pyridyl or pyrazinyl group is optionally halogenated or -N(R) 10 (R) 11 Replaced by ) . In some implementations, each R 5 It is pyridyl or pyrazinyl, wherein the pyridyl or pyrazinyl group is optionally substituted with -Br, -NH2, or -N(CH3)2. In some embodiments, each R 5 The pyridinyl group is optionally substituted with -Br, -NH2, or -N(CH3)2. In some embodiments, each R 5 The pyrazin group is optionally substituted with -Br, -NH2 or -N(CH3)2.

[0150] In some implementations, each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is replaced.

[0151] In some implementations, each R 10 Independently selected from hydrogen and optionally selected by one, two or three elements selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The C group substituted by the heteroaryl group 1-6 alkyl.

[0152] In some implementations, each R 10 Independently selected from hydrogen and C atoms optionally substituted with F, Cl, Br, I or a hydroxyl group. 1-6 alkyl.

[0153] In some implementations, each R 11 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl; or R10 and R 11 Together with the nitrogen atoms to which they are attached, they independently form 4- to 7-membered heterocycles, wherein the heterocycle optionally contains 1-2 additional heteroatoms selected from N, O, and S, and wherein each heterocycle nitrogen atom, if present, is independently and optionally substituted with a C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl. In some embodiments, each R 11 It is hydrogen. In some implementations, each R... 11 C 1-6 alkyl.

[0154] In some implementations, each R 12 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl groups.

[0155] In some implementations, each R 13 Selected independently from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogen, SF5, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is replaced.

[0156] In some implementations, n is 0. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3. In some implementations, n is 4. In some implementations, n is 0 or 1. In some implementations, n is 1 or 2. In some implementations, n is 2 or 3. In some implementations, n is 3 or 4. In some implementations, n is 1, 2, or 3. In some implementations, n is 2, 3, or 4. In some implementations, n is 1, 2, 3, or 4.

[0157] On the other hand, TEAD inhibitors include compounds of formula (IA), or pharmaceutically acceptable salts or solvates thereof: in, Each R X Independently hydrogen, halogen, -OR 3 -SR 3 -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 C1-C6 alkyl, C1-C6 fluoroalkyl, or C2-C4 ynyl, wherein the C1-C6 alkyl, C1-C6 fluoroalkyl, and C2-C4 ynyl are optionally surrounded by 1-5 R groups. 5 Substituted by groups; Each R Y Independently hydrogen, halogen, -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 C1-C6 alkyl, C1-C6 fluoroalkyl, or C2-C4 ynyl, wherein the C1-C6 alkyl, C1-C6 fluoroalkyl, and C2-C4 ynyl are optionally surrounded by 1-5 R groups. 5 Substituted by groups; R represents halogen, nitro, -CN, or -OR. 3 -C(=O)R 3 -C(=O)N(R) 3 2. -C(=O)OR 3 -S(=O)R 3 -S(=O)2R 3 -NR 3S(=O)2R 3 -NR 3 C(=O)R 3 -NR 3 C(=O)OR 3 Or optionally by 1-5 R 5 C1-C6 fluoroalkyl groups substituted by the radical; R 1 For optional use by 1-5 R 5 C1-C6 alkyl groups substituted by the radical; Each R 2 Independently halogen, nitro, -N3, -CN, -OR 3 -SR 3 -S(=O)2R 3 -N(R) 3 2. -C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by groups; Each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by a group; or If two R 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group; R 4 It is a C1-C6 alkyl, C1-C6 fluoroalkyl, or C3-C 10 Cycloalkyl or -NH2, wherein C1-C6 alkyl, C1-C6 fluoroalkyl and C3-C 10 The cycloalkyl group is optionally surrounded by 1-5 Rs. 5 Substituted by groups; Each R 5 Independently selected from halogen, oxo, -CN, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, -CH2-C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, -CH2-C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 and -N(R) 10 (R) 11 The group is replaced by ) or two R groups. 5 Combine to form C 3-5 cycloalkyl rings; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Substituted with heteroaryl groups; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl; or R 10 and R 11 Together with the nitrogen atoms to which they are attached, they independently form 4- to 7-membered heterocycles, wherein the heterocycle optionally contains 1-2 additional heteroatoms selected from N, O and S, and wherein each heterocycle nitrogen atom, if present, is independently and optionally substituted by a C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN or C2-C3 heteroalkyl. Each R 12 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl groups; Each R 13 Selected independently from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogen, SF5, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9The heteroaryl group is replaced; and n is 0, 1, or 2.

[0158] In some implementations, each R X Independently, it can be hydrogen, F, Cl, Br, -CH3, -OH, -OCH3, or -OCF3. In some embodiments, each R... X It is hydrogen. In some implementations, each R... X For F. In some implementations, each R X For Cl. In some implementations, each R X For Br. In some implementations, each R X For -CH3. In some implementations, each R X For -OH. In some implementations, each R X For -OCH3. In some implementations, each R X It is -OCF3.

[0159] In some implementations, R is F, Cl, -CN, -OCF3, -CHF2, or -CF3. In some implementations, R is F, Cl, or -CF3. In some implementations, R is -CF3.

[0160] In some implementation schemes, R 1 It is a C1-C6 alkyl group substituted with -OH.

[0161] In some implementation schemes, R 1 The alkyl group is a C1-C6 alkyl group substituted with a 6-membered heteroaryl ring, which is selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl, wherein the pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl are optionally replaced by 1-5 R groups. 5 The group is replaced. In some embodiments, R 1 It is a C1-C6 alkyl group substituted with a pyridinyl group, which is optionally replaced by 1-5 R groups. 5 The group is replaced.

[0162] In some implementation schemes, R 1 It is a C1-C6 alkyl group substituted with 1, 2 or 3 substituents, each substituent being independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2 and pyridyl.

[0163] In some implementations, each R 2 Independently, it can be F, Cl, -OCF3, or -CF3. In some implementations, each R... 2 It can be F or Cl independently.

[0164] In some implementations, n is 0.

[0165] In some implementations, n is 1 or 2.

[0166] In some implementation schemes, the TEAD inhibitor is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or Or, or a pharmaceutically acceptable salt or solvate thereof.

[0167] On the other hand, TEAD inhibitors include compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof: in, Each X 1 X 2 X 3 X 4 X 5 and X 6 Independently N or CRX ; Each R X Independently hydrogen, halogen, nitro, -OR 3 -SR 3 -CN, -C(=O)R 3 -C(=O)N(R) 3 2. -C(=O)OR 3 -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 -NR 3 C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by groups; R represents halogen, nitro, -CN, or -OR. 3 -SR 3 -C(=O)R 3 -C(=O)N(R) 3 2. -C(=O)OR 3 -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 -NR 3 C(=O)OR 3 Or optionally by 1-5 R5 C1-C6 fluoroalkyl groups substituted by the radical; R 1 It is C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C1-C6 heteroalkyl, -CN or -S(=O)2R 4 Among them, C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl groups and C1-C6 heteroalkyl groups are optionally surrounded by 1-5 R groups. 5 Substituted by groups; Each R 2 Independently halogen, nitro, -N3, -CN, -OR 3 -SR 3 -S(=O)2R 3 -N(R) 3 2. -C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by groups; Each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by a group; or If two R 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group; R 4 It is a C1-C6 alkyl, C1-C6 fluoroalkyl, or C3-C 10 Cycloalkyl or -NH2, wherein C1-C6 alkyl, C1-C6 fluoroalkyl and C3-C 10 The cycloalkyl group is optionally surrounded by 1-5 Rs. 5 Substituted by groups; Each R 5 Independently selected from halogen, oxo, -CN, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-6 cycloalkyl, -CH2-C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, -CH2-C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 and -N(R) 10 (R) 11 The group is replaced by ) or two R groups. 5 Combine to form C 3-5 cycloalkyl rings; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Substituted with heteroaryl groups; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl; or R 10 and R 11 Together with the nitrogen atoms to which they are attached, they independently form 4- to 7-membered heterocycles, wherein the heterocycle optionally contains 1-2 additional heteroatoms selected from N, O and S, and wherein each heterocycle nitrogen atom, if present, is independently and optionally substituted by a C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN or C2-C3 heteroalkyl. Each R 12 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl groups; Each R 13 Selected independently from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogen, SF5, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is replaced; and n can be 0, 1, 2, 3, or 4.

[0168] For any and all embodiments of compounds of formula (II), the substituents are selected from a subset of the listed options. For example, in some embodiments, X 1 For N or CR X In other implementations, X 1 For N. In some implementations, X 1 For CR X .

[0169] In some implementations, each X 1 X 2 and X 3 For CR X In some implementations, X 1 Let N be the number of X; and each X 2 and X 3 For CR X In some implementations, each X 1 and X 2 For CR X And X 3 Let N be the number of elements in the array.

[0170] In some implementations, each X 4 X 5 and X 6 For CR X In some implementations, X 4 Let N be the number of X; and each X 5 and X 6 For CR X In some implementations, each X 4 and X 5 For CR X And X 6 Let N be the number of elements in the array.

[0171] In some implementations, each R X Independently hydrogen, halogen, -OR 3 -SR 3 -CN, -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR3 C(=O)R 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C4 alkenyl, C2-C4 ynyl or C1-C6 heteroalkyl, wherein the C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C4 alkenyl, C2-C4 ynyl and C1-C6 heteroalkyl are optionally surrounded by 1-5 R 5 The group is replaced; and each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl or C2-C 10 Heterocyclic alkyl groups, including C1-C6 alkyl groups, C1-C6 fluoroalkyl groups, C1-C6 heteroalkyl groups, and C3-C6 heteroalkyl groups. 10 cycloalkyl and C2-C 10 Heterocyclic alkyl groups are optionally surrounded by 1-5 R groups. 5 The group is replaced; or if two R groups are replaced. 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0172] In some implementations, each R X Independently hydrogen, halogen, -OR 3 -SR 3 -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 C1-C6 alkyl, C1-C6 fluoroalkyl, or C2-C4 ynyl, wherein the C1-C6 alkyl, C1-C6 fluoroalkyl, and C2-C4 ynyl are optionally surrounded by 1-5 R groups. 5 The group is replaced; and each R 3 It is independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl or C3-C 10 Cycloalkyl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl and C3-C6 alkyl groups. 10 The cycloalkyl group is optionally surrounded by 1-5 Rs. 5 The group is replaced; or if two R groups are replaced. 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0173] In some implementations, each R X Independently, it can be 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, oxacyclobutyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy, aziridine, pyrrole Alkyl, 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 R X Independently, it is 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 R X Independently, it is 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 R X Independently, it can be hydrogen, F, Cl, Br, -CH3, -OH, -OCH3, or -OCF3. In some embodiments, each R... X Independently, it can be hydrogen, F, Cl, -CH3, -OCH3, or -OCF3. In some embodiments, each R... XIndependently hydrogen, F, or -OCH3. In some embodiments, each R X It is hydrogen.

[0174] In some implementation schemes, R 1 For optional use by 1-5 R 5 The C1-C6 alkyl group substituted by the group.

[0175] In some implementation schemes, R 1 It is a C1-C6 alkyl group substituted with C2-C6 alkenyl, C2-C6 ynyl or -CN, wherein the C6 alkenyl and C2-C6 ynyl groups are optionally replaced by 1-5 R groups. 5 The group is replaced.

[0176] In some implementation schemes, R 1 For OR 3 The substituted C1-C6 alkyl group; and R 3 It is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl or C3-C 10 Cycloalkyl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl and C3-C6 alkyl groups. 10 The cycloalkyl group is optionally surrounded by 1-5 Rs. 5 The group is replaced.

[0177] In some implementation schemes, R 1 For -C(=O)N(R) 5 )2 or -N(R 5 )2 replaced by C1-C6 alkyl groups; wherein each R 5 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 ynyl or -CN, wherein C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl and C2-C6 ynyl groups are optionally separated by 1-5 R groups. 5 Substituted by a group; or two R groups 5 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0178] In some implementation schemes, R 1 C1-C6 alkyl groups substituted with C3-C8 cycloalkyl or C2-C7 heterocycloalkyl, wherein the C3-C8 cycloalkyl and C2-C7 heterocycloalkyl groups are optionally replaced by 1-5 R groups. 5 The group is replaced.

[0179] In some implementation schemes, R 1It is a C1-C6 alkyl group substituted with cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0180] In some implementation schemes, R 1 It is a C1-C6 alkyl group substituted with oxetane, tetrahydrofuranyl, tetrahydropyranyl, azirnebutane, pyrrolidinyl or piperidinyl.

[0181] In some implementation schemes, R 1 It is a C1-C6 alkyl group substituted with a phenyl group, which is optionally replaced by 1-5 R groups. 5 The group is substituted, wherein if the phenyl group is substituted, it is replaced by 1, 2, 3 or 4 groups selected from halogen, nitro, -CN, -OR. 3 -N(R) 3 )2、-C(=O)R 3 -C(=O)N(R) 3 2. -C(=O)OR 3 The C1-C6 alkyl and C1-C6 fluoroalkyl groups are substituted with substituents, wherein the C1-C6 alkyl and C1-C6 fluoroalkyl groups are optionally replaced by 1-5 R groups. 5 The group is replaced; and each R 3 It is independently hydrogen, C1-C6 alkyl or C3-C 10 Cycloalkyl groups, wherein C1-C6 alkyl groups and C3-C6 alkyl groups are cycloalkyl groups. 10 The cycloalkyl group is optionally surrounded by 1-5 Rs. 5 The group is replaced; or if two R groups are replaced. 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0182] In some implementation schemes, R 1 It is a C1-C6 alkyl group substituted with a 5-membered heteroaryl ring containing at least one nitrogen atom.

[0183] In some implementation schemes, R 1 The alkyl group is a C1-C6 alkyl group substituted with a 5-membered heteroaryl ring, wherein the 5-membered heteroaryl ring is selected from pyrroloyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, and thiadiazolyl, wherein the pyrroloyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, and thiadiazolyl groups are optionally replaced by 1-5 R groups. 5 The group is replaced.

[0184] In some implementation schemes, R 1 The alkyl group is a C1-C6 alkyl group substituted with a 5-membered heteroaryl ring, which is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and ;in Each R z Independently hydrogen, halogen, -CN, -OR 3 -SR 3 -S(=O)2R 3 -N(R) 3 2. -C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 The group is replaced; and Each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl or C2-C 10 Heterocyclic alkyl groups, including C1-C6 alkyl groups, C1-C6 fluoroalkyl groups, C1-C6 heteroalkyl groups, and C3-C6 heteroalkyl groups. 10 cycloalkyl and C2-C 10 Heterocyclic alkyl groups are optionally surrounded by 1-5 R groups. 5 The group is replaced; or if two R groups are replaced. 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0185] In some implementation schemes, R 1 It is a C1-C6 alkyl group substituted by a monocyclic 6-membered heteroaryl ring, which contains at least one nitrogen atom and is optionally replaced by 1-5 R atoms. 5 The group is replaced. In some embodiments, R 1 It is a C1-C6 alkyl group substituted by a monocyclic 6-membered heteroaryl ring, which contains 1, 2, or 3 nitrogen atoms and is optionally replaced by 1-5 R atoms. 5 The group is replaced. In some embodiments, R 1 The alkyl group is a C1-C6 alkyl group substituted with a 6-membered heteroaryl ring, which is selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl, wherein the pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl are optionally replaced by 1-5 R groups. 5 The group is replaced. In some embodiments, R 1 It is a C1-C6 alkyl group substituted with a pyridinyl group, which is optionally replaced by 1-5 R groups. 5 The group is replaced. In some embodiments, R 1 It is a C1-C6 alkyl group substituted with a pyridinyl group, which is optionally replaced by 1-5 R groups. 5 The group is replaced. In some embodiments, R 1It is a C1-C6 alkyl group substituted with a 2-pyridinyl group, which is optionally replaced by 1-5 R groups. 5 The group is replaced.

[0186] In some implementation schemes, R 1 The alkyl group is a C1-C6 alkyl group substituted with a 6-membered heteroaryl ring, which is selected from: ; in Each R z Independently hydrogen, halogen, -CN, -OR 3 -SR 3 -S(=O)2R 3 -N(R) 3 2. -C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 The group is replaced; and Each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl or C2-C 10 Heterocyclic alkyl groups, including C1-C6 alkyl groups, C1-C6 fluoroalkyl groups, C1-C6 heteroalkyl groups, and C3-C6 heteroalkyl groups. 10 cycloalkyl and C2-C 10 Heterocyclic alkyl groups are optionally surrounded by 1-5 R groups. 5 The group is replaced; or if two R groups are replaced. 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0187] In some implementation schemes, R 1It is a C1-C6 alkyl group substituted with a bicyclic 6 / 5 fused heteroaryl ring. In some embodiments, R 1 The alkyl group is a C1-C6 alkyl group substituted by a bicyclic 6 / 5 fused heteroaryl ring, wherein the bicyclic 6 / 5 fused heteroaryl ring is selected from indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophene, indazole, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, inazinyl, and imidazopyridyl, wherein the indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiaphene, indazole, benzimidazolyl, benzoxazolyl, benzoisothiazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, inazinyl, and imidazopyridyl are optionally replaced by 1-5 R groups. 5 The group is replaced.

[0188] In some implementation schemes, R 1 The C1-C6 alkyl group is replaced by a bicyclic 6 / 5 fused heteroaryl ring, which is selected from: , , , , , , , , , , , , , , , , , , , , , , , , and ;in Each R z Independently hydrogen, halogen, -CN, -OR 3 -SR 3 -S(=O)2R 3 -N(R) 3 2. -C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 The group is replaced; and Each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl or C2-C 10 Heterocyclic alkyl groups, including C1-C6 alkyl groups, C1-C6 fluoroalkyl groups, C1-C6 heteroalkyl groups, and C3-C6 heteroalkyl groups. 10 cycloalkyl and C2-C 10 Heterocyclic alkyl groups are optionally surrounded by 1-5 R groups. 5 The group is replaced; or if two R groups are replaced. 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0189] In some implementation schemes, R 1 It is a C1-C6 alkyl group substituted by a bicyclic 6 / 6 fused heteroaryl ring, which contains at least one nitrogen atom and is optionally replaced by 1-5 R atoms. 5 The group is replaced. In some embodiments, R 1 It is a C1-C6 alkyl group substituted by a bicyclic 6 / 6 fused heteroaryl ring containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted by 1-5 R atoms. 5 The group is replaced. In some embodiments, R 1 The alkyl group is a C1-C6 alkyl group substituted by a bicyclic 6 / 6 fused heteroaryl ring, wherein the bicyclic 6 / 6 fused heteroaryl ring is selected from quinolinyl, isoquinolinyl, cenolinyl, quinazolinyl, quinoxalinyl, naphridinyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl, and pteridinyl, wherein quinolinyl, isoquinolinyl, cenolinyl, quinazolinyl, quinoxalinyl, naphridinyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyrimidinyl, and pteridinyl is optionally replaced by 1-5 R... 5 The group is replaced.

[0190] In some implementation schemes, R 1 The bicyclic 6 / 6 fused heteroaryl ring is a C1-C6 alkyl group substituted with a 6 / 6 fused heteroaryl ring, selected from: ; in Each R z Independently hydrogen, halogen, -CN, -OR 3 -SR 3 -S(=O)2R 3 -N(R) 3 2. -C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 The group is replaced; and Each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl or C2-C 10 Heterocyclic alkyl groups, including C1-C6 alkyl groups, C1-C6 fluoroalkyl groups, C1-C6 heteroalkyl groups, and C3-C6 heteroalkyl groups. 10 cycloalkyl and C2-C 10 Heterocyclic alkyl groups are optionally surrounded by 1-5 R groups. 5 The group is replaced; or if two R groups are replaced. 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0191] In some implementation schemes, R 1It is a C1-C6 alkyl group substituted with 1, 2, or 3 substituents, each substituent independently selected from -OH, -OCH3, -NH2, -NHCH3, N(CH3)2, and pyridyl. In some embodiments, R 1 It is a C1-C6 alkyl group substituted with one or two substituents, each substituent independently selected from -OH, -OCH3, -NH2, -NHCH3, N(CH3)2, and pyridyl. In some embodiments, R 1 It is a C1-C6 alkyl group substituted with one or two substituents, each substituent independently selected from -OH and pyridyl groups. In some embodiments, R 1 It is a C1-C6 alkyl group substituted with one or two substituents, each substituent independently selected from -NH2 and pyridyl groups. In some embodiments, R 1 It is a C1-C6 alkyl group substituted with one or two substituents, each substituent independently selected from -OH and -NH2. In some embodiments, R 1 It is a C1-C6 alkyl group substituted with -OH. In some embodiments, R 1 It is a C1-C6 alkyl group substituted with -NH2.

[0192] In some implementations, each R z Independently, it is hydrogen, F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCH2CH3, -OCF3, -NH2, -NHCH3, or -N(CH3)2. In some embodiments, each R z Independently, it is hydrogen, F, Cl, Br, -CH3, -CN, -OCH3, -NH2, -NHCH3, or -N(CH3)2. In some embodiments, each R z Independently, it is hydrogen, Cl, Br, -CH3, -OCH3, -NH2, or -N(CH3)2. In some embodiments, each R z It is hydrogen.

[0193] In some implementation schemes, R 1 For halogenated, -CN, -OR 3 -SR 3 -S(=O) R 3 -S(=O)2R 3 -N(R) 3 2. -C(=O)OR 3 -C(=O)N(R) 3 )2、-CR 3 =C(R 3 2. -C≡CR 3 C3-C10 cycloalkyl, C2-C 10 C1-C6 alkyl groups substituted with heterocyclic alkyl or aryl groups, wherein C3-C6 10 cycloalkyl, C2-C 10 Heterocyclic alkyl and aryl groups are optionally surrounded by 1-5 R groups. 5 The group is replaced; and each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl or C2-C 10 Heterocyclic alkyl groups, including C1-C6 alkyl groups, C1-C6 fluoroalkyl groups, C1-C6 heteroalkyl groups, and C3-C6 heteroalkyl groups. 10 cycloalkyl and C2-C 10 Heterocyclic alkyl groups are optionally surrounded by 1-5 R groups. 5 The group is replaced; or if two R groups are replaced. 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0194] In some implementation schemes, R 1 For C3-C 10 cycloalkyl or C2-C 10 Heterocyclic alkyl groups, wherein C3-C 10 cycloalkyl and C2-C 10 Heterocyclic alkyl groups are optionally surrounded by 1-5 R groups. 5 The group is replaced. In some embodiments, R 1 It is a C3-C6 cycloalkyl or C3-C5 heterocycloalkyl group substituted with C1-C6 alkyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazinyl. In some embodiments, R 1 It is a C3-C6 cycloalkyl or C3-C5 heterocycloalkyl that has been substituted with C1-C6 alkyl, phenyl or pyridyl.

[0195] In some implementations, R is halogen, nitro, -CN, or -OR. 3 -C(=O)R 3 -C(=O)N(R) 3 2. -C(=O)OR 3 -S(=O)R 3 -S(=O)2R 3 -NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 -NR 3 C(=O)OR 3Or optionally by 1-5 R 5 The C1-C6 fluoroalkyl group substituted by the group; and each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl or C2-C 10 Heterocyclic alkyl groups, including C1-C6 alkyl groups, C1-C6 fluoroalkyl groups, C1-C6 heteroalkyl groups, and C3-C6 heteroalkyl groups. 10 cycloalkyl and C2-C 10 Heterocyclic alkyl groups are optionally surrounded by 1-5 R groups. 5 The group is replaced; or if two R groups are replaced. 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0196] 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 implementations, R is F, Cl, or -CF3. In some implementations, R is -OCF3. In some implementations, R is -CF3.

[0197] In some implementations, each R 2 Independently halogen, nitro, -CN, -OR 3 -SR 3 -S(=O)2R 3 -N(R) 3 2. -C(=O)OR 3 C1-C6 alkyl or C1-C6 fluoroalkyl, wherein the C1-C6 alkyl and C1-C6 fluoroalkyl are optionally surrounded by 1-5 R... 5 The group is replaced; and each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10cycloalkyl or C2-C 10 Heterocyclic alkyl groups, including C1-C6 alkyl groups, C1-C6 fluoroalkyl groups, C1-C6 heteroalkyl groups, and C3-C6 heteroalkyl groups. 10 cycloalkyl and C2-C 10 Heterocyclic alkyl groups are optionally surrounded by 1-5 R groups. 5 The group is replaced; or if two R groups are replaced. 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0198] In some implementations, each R 2 Independently, it can be 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 R 2 Independently, it can be F, Cl, -CN, -OCH3, -OCF3, -C(=O)OCH3, -CH3, or -CF3. In some implementations, each R 2 Independently, it can be F, Cl, -OCF3, or -CF3. In some implementations, each R... 2 It can be F or Cl independently.

[0199] In some implementations, n is 0. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3. In some implementations, n is 4. In some implementations, n is 0 or 1. In some implementations, n is 1 or 2. In some implementations, n is 2 or 3. In some implementations, n is 3 or 4. In some implementations, n is 1, 2, or 3. In some implementations, n is 2, 3, or 4. In some implementations, n is 1, 2, 3, or 4.

[0200] On the other hand, TEAD inhibitors include compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof: in, Each X 3 X 5 and X 6 Independently N or CR X ; X 4 For CR X ; Each R X Independently hydrogen, halogen, nitro, -OR 3 -SR 3 -CN, -C(=O)R 3 -C(=O)N(R) 3 2. -C(=O)OR 3 -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 -NR 3 C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by groups; R represents halogen, nitro, -CN, or -OR. 3 -SR 3 -C(=O)R 3 -C(=O)N(R) 3 2. -C(=O)OR 3 -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 -NR 3 C(=O)OR 3 Or optionally by 1-5 R 5C1-C6 fluoroalkyl groups substituted by the radical; R 1 It is C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C1-C6 heteroalkyl, -CN or -S(=O)2R 4 Among them, C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl groups and C1-C6 heteroalkyl groups are optionally surrounded by 1-5 R groups. 5 Substituted by groups; Each R 2 Independently halogen, nitro, -N3, -CN, -OR 3 -SR 3 -S(=O)2R 3 -N(R) 3 2. -C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by groups; Each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by a group; or If two R 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group; R 4 It is a C1-C6 alkyl, C1-C6 fluoroalkyl, or C3-C 10 Cycloalkyl or -NH2, wherein C1-C6 alkyl, C1-C6 fluoroalkyl and C3-C 10 The cycloalkyl group is optionally surrounded by 1-5 Rs. 5 Substituted by groups; Each R 5 Independently selected from halogen, oxo, -CN, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6cycloalkyl, -CH2-C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, -CH2-C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 and -N(R) 10 (R) 11 The group is replaced by ) or two R groups. 5 Combine to form C 3-5 cycloalkyl rings; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Substituted with heteroaryl groups; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl; or R 10 and R 11 Together with the nitrogen atoms to which they are attached, they independently form 4- to 7-membered heterocycles, wherein the heterocycle optionally contains 1-2 additional heteroatoms selected from N, O and S, and wherein each heterocycle nitrogen atom, if present, is independently and optionally substituted by a C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN or C2-C3 heteroalkyl. Each R 12 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl groups; Each R 13 Selected independently from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogen, SF5, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is replaced; and n can be 0, 1, 2, 3, or 4.

[0201] For any and all embodiments of compounds of formula (III), the substituents are selected from a subset of the listed options. For example, in some embodiments, X 5 For N or CR X In other implementations, X 5 For N. In some implementations, X 5 For CR X .

[0202] In some implementation schemes, X 3 For CR X In some implementations, X 3 Let N be the number of elements in the array.

[0203] In some implementations, each X 5 and X 6 For CR X In some implementations, X 5 Let N be the number of elements; and X be the number of elements. 6 For CR X In some implementations, X 5 For CR X And X 6 Let N be the number of elements in the array.

[0204] In some implementations, each R X Independently hydrogen, halogen, -OR 3 -SR 3 -CN, -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C4 alkenyl, C2-C4 ynyl or C1-C6 heteroalkyl, wherein the C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C4 alkenyl, C2-C4 ynyl and C1-C6 heteroalkyl are optionally surrounded by 1-5 R 5 The group is replaced; and each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10cycloalkyl or C2-C 10 Heterocyclic alkyl groups, including C1-C6 alkyl groups, C1-C6 fluoroalkyl groups, C1-C6 heteroalkyl groups, and C3-C6 heteroalkyl groups. 10 cycloalkyl and C2-C 10 Heterocyclic alkyl groups are optionally surrounded by 1-5 R groups. 5 The group is replaced; or if two R groups are replaced. 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0205] In some implementations, each R X Independently hydrogen, halogen, -OR 3 -SR 3 -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 C1-C6 alkyl, C1-C6 fluoroalkyl, or C2-C4 alkynyl; and each R 3 It is independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl or C3-C 10 Cycloalkyl, wherein C1-C6 alkyl, C1-C6 fluoroalkyl and C2-C4 ynyl are optionally surrounded by 1-5 R groups. 5 The group is replaced; and each R 3 Independently hydrogen, optionally surrounded by 1-5 R 5 The C1-C6 alkyl, C1-C6 fluoroalkyl and C3-C groups substituted 10 cycloalkyl; or if two R 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0206] In some implementations, each R XIndependently, it can be 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, oxacyclobutyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy, aziridine, pyrrole Alkyl, 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 R X Independently, it is 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 R X Independently, it is 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 R X Independently, it can be hydrogen, F, Cl, Br, -CH3, -OH, -OCH3, or -OCF3. In some embodiments, each R... X Independently, it can be hydrogen, F, Cl, -CH3, -OCH3, or -OCF3. In some embodiments, each R... X Independently hydrogen, F, or -OCH3. In some embodiments, each RX It is hydrogen.

[0207] In some implementation schemes, R 1 For optional use by 1-5 R 5 The C1-C6 alkyl group substituted by the group.

[0208] In some implementation schemes, R 1 It is a C1-C6 alkyl group substituted with C2-C6 alkenyl, C2-C6 ynyl or -CN, wherein the C2-C6 alkenyl and C2-C6 ynyl groups are optionally replaced by 1-5 R groups. 5 The group is replaced.

[0209] In some implementation schemes, R 1 For OR 3 The substituted C1-C6 alkyl group; and R 3 It is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl or C3-C 10 Cycloalkyl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl and C3-C6 alkyl groups. 10 The cycloalkyl group is optionally surrounded by 1-5 Rs. 5 The group is replaced.

[0210] In some implementation schemes, R 1 For -C(=O)N(R) 5 )2 or -N(R 5 )2 replaced by C1-C6 alkyl groups; wherein each R 5 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 ynyl or -CN, wherein C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl and C2-C6 ynyl groups are optionally separated by 1-5 R groups. 5 Substituted by a group; or two R groups 5 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0211] In some implementation schemes, R 1 C1-C6 alkyl groups substituted with C3-C8 cycloalkyl or C2-C7 heterocycloalkyl, wherein the C3-C8 cycloalkyl and C2-C7 heterocycloalkyl groups are optionally replaced by 1-5 R groups. 5 The group is replaced.

[0212] In some implementation schemes, R 1 It is a C1-C6 alkyl group substituted with cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0213] In some implementation schemes, R 1 It is a C1-C6 alkyl group substituted with oxetane, tetrahydrofuranyl, tetrahydropyranyl, azirnebutane, pyrrolidinyl or piperidinyl.

[0214] In some implementation schemes, R 1 It is a C1-C6 alkyl group substituted with a phenyl group, which is optionally replaced by 1-5 R groups. 5 The group is substituted, wherein if the phenyl group is substituted, it is replaced by 1, 2, 3 or 4 groups selected from halogen, nitro, -CN, -OR. 3 -N(R) 3 )2、-C(=O)R 3 -C(=O)N(R) 3 2. -C(=O)OR 3 The C1-C6 alkyl and C1-C6 fluoroalkyl groups are substituted with substituents, wherein the C1-C6 alkyl and C1-C6 fluoroalkyl groups are optionally replaced by 1-5 R groups. 5 The group is replaced; and each R 3 It is independently hydrogen, C1-C6 alkyl or C3-C 10 Cycloalkyl groups, wherein C1-C6 alkyl groups and C3-C6 alkyl groups are cycloalkyl groups. 10 The cycloalkyl group is optionally surrounded by 1-5 Rs. 5 The group is replaced; or if two R groups are replaced. 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0215] In some implementation schemes, R 1 It is a C1-C6 alkyl group substituted with a 5-membered heteroaryl ring containing at least one nitrogen atom. In some embodiments, R 1 The alkyl group is a C1-C6 alkyl group substituted with a 5-membered heteroaryl ring, wherein the 5-membered heteroaryl ring is selected from pyrroloyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, and thiadiazolyl, wherein the pyrroloyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, and thiadiazolyl groups are optionally replaced by 1-5 R groups. 5 The group is replaced.

[0216] In some implementation schemes, R 1 The alkyl group is a C1-C6 alkyl group substituted with a 5-membered heteroaryl ring, which is selected from: ;in Each R zIndependently hydrogen, halogen, -CN, -OR 3 -SR 3 -S(=O)2R 3 -N(R) 3 2. -C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, substituted C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, substituted C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 The group is replaced; and Each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl or C2-C 10 Heterocyclic alkyl groups, including C1-C6 alkyl groups, C1-C6 fluoroalkyl groups, C1-C6 heteroalkyl groups, and C3-C6 heteroalkyl groups. 10 cycloalkyl and C2-C 10 Heterocyclic alkyl groups are optionally surrounded by 1-5 R groups. 5 The group is replaced; or if two R groups are replaced. 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0217] In some implementation schemes, R 1 It is a C1-C6 alkyl group substituted by a monocyclic 6-membered heteroaryl ring, which contains at least one nitrogen atom and is optionally replaced by 1-5 R atoms. 5 The group is replaced. In some embodiments, R 1 It is a C1-C6 alkyl group substituted by a monocyclic 6-membered heteroaryl ring, which contains 1, 2, or 3 nitrogen atoms and is optionally replaced by 1-5 R atoms. 5 The group is replaced. In some embodiments, R 1The alkyl group is a C1-C6 alkyl group substituted with a 6-membered heteroaryl ring, which is selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl, wherein the pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl are optionally replaced by 1-5 R groups. 5 The group is replaced. In some embodiments, R 1 It is a C1-C6 alkyl group substituted with a pyridinyl group, which is optionally replaced by 1-5 R groups. 5 The group is replaced. In some embodiments, R 1 It is a C1-C6 alkyl group substituted with a 2-pyridinyl group, which is optionally replaced by 1-5 R groups. 5 The group is replaced.

[0218] In some implementation schemes, R 1 The alkyl group is a C1-C6 alkyl group substituted with a 6-membered heteroaryl ring, which is selected from: , , , , , , , , , and ;in Each R z Independently hydrogen, halogen, -CN, -OR 3 -SR 3 -S(=O)2R 3 -N(R) 3 2. -C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 The group is replaced; and Each R 3Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl or C2-C 10 Heterocyclic alkyl groups, including C1-C6 alkyl groups, C1-C6 fluoroalkyl groups, C1-C6 heteroalkyl groups, and C3-C6 heteroalkyl groups. 10 cycloalkyl and C2-C 10 Heterocyclic alkyl groups are optionally marked with 1-5 R's. 5 The substituted C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl and C2-C 10 Heterocyclic alkyl; or if two R 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0219] In some implementation schemes, R 1 It is a C1-C6 alkyl group substituted with a bicyclic 6 / 5 fused heteroaryl ring. In some embodiments, R 1 The alkyl group is a C1-C6 alkyl group substituted by a bicyclic 6 / 5 fused heteroaryl ring, wherein the bicyclic 6 / 5 fused heteroaryl ring is selected from indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophene, indazole, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, inazinyl, and imidazopyridyl, wherein the indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiaphene, indazole, benzimidazolyl, benzoxazolyl, benzoisothiazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, inazinyl, and imidazopyridyl are optionally replaced by 1-5 R groups. 5 The group is replaced.

[0220] In some implementation schemes, R 1 The C1-C6 alkyl group is replaced by a bicyclic 6 / 5 fused heteroaryl ring, which is selected from: , , , , , , , , , , , , , , , , , , , , , , , , and ;in Each R z Independently hydrogen, halogen, -CN, -OR 3 -SR 3 -S(=O)2R 3 -N(R) 3 2. -C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, aralkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, aralkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 The group is replaced; and Each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl or C2-C 10 Heterocyclic alkyl groups, including C1-C6 alkyl groups, C1-C6 fluoroalkyl groups, C1-C6 heteroalkyl groups, and C3-C6 heteroalkyl groups. 10 cycloalkyl and C2-C 10 Heterocyclic alkyl groups are optionally surrounded by 1-5 R groups. 5 The group is replaced; or if two R groups are replaced. 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0221] In some implementation schemes, R1 It is a C1-C6 alkyl group substituted by a bicyclic 6 / 6 fused heteroaryl ring, which contains at least one nitrogen atom and is optionally replaced by 1-5 R atoms. 5 The group is replaced. In some embodiments, R 1 It is a C1-C6 alkyl group substituted by a bicyclic 6 / 6 fused heteroaryl ring containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted by 1-5 R atoms. 5 The group is replaced. In some embodiments, R 1 The alkyl group is a C1-C6 alkyl group substituted by a bicyclic 6 / 6 fused heteroaryl ring, wherein the bicyclic 6 / 6 fused heteroaryl ring is selected from quinolinyl, isoquinolinyl, cenolinyl, quinazolinyl, quinoxalinyl, naphridinyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl, and pteridinyl, wherein quinolinyl, isoquinolinyl, cenolinyl, quinazolinyl, quinoxalinyl, naphridinyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyrimidinyl, and pteridinyl is optionally replaced by 1-5 R... 5 The group is replaced.

[0222] In some implementation schemes, R 1 The bicyclic 6 / 6 fused heteroaryl ring is a C1-C6 alkyl group substituted with a 6 / 6 fused heteroaryl ring, selected from: ; in Each R z Independently hydrogen, halogen, -CN, -OR 3 -SR 3 -S(=O)2R 3 -N(R) 3 2. -C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 The group is replaced; and Each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl or C2-C 10 Heterocyclic alkyl groups, including C1-C6 alkyl groups, C1-C6 fluoroalkyl groups, C1-C6 heteroalkyl groups, and C3-C6 heteroalkyl groups. 10 cycloalkyl and C2-C 10 Heterocyclic alkyl groups are optionally surrounded by 1-5 R groups. 5 The group is replaced; or if two R groups are replaced. 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0223] In some implementation schemes, R 1 It is a C1-C6 alkyl group substituted with 1, 2, or 3 substituents, each substituent independently selected from -OH, -OCH3, -NH2, -NHCH3, N(CH3)2, and pyridyl. In some embodiments, R 1 It is a C1-C6 alkyl group substituted with one or two substituents, each substituent independently selected from -OH, -OCH3, -NH2, -NHCH3, N(CH3)2, and pyridyl. In some embodiments, R 1 It is a C1-C6 alkyl group substituted with one or two substituents, each substituent independently selected from -OH and pyridyl groups. In some embodiments, R 1 It is a C1-C6 alkyl group substituted with one or two substituents, each substituent independently selected from -NH2 and pyridyl groups. In some embodiments, R 1 It is a C1-C6 alkyl group substituted with one or two substituents, each substituent independently selected from -OH and -NH2. In some embodiments, R 1 It is a C1-C6 alkyl group substituted with -OH. In some embodiments, R 1 It is a C1-C6 alkyl group substituted with -NH2.

[0224] In some implementations, each R z Independently, it is hydrogen, F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCH2CH3, -OCF3, -NH2, -NHCH3, or -N(CH3)2. In some embodiments, each R zIndependently, it is hydrogen, F, Cl, Br, -CH3, -CN, -OCH3, -NH2, -NHCH3, or -N(CH3)2. In some embodiments, each R z Independently, it is hydrogen, Cl, Br, -CH3, -OCH3, -NH2, or -N(CH3)2. In some embodiments, each R z It is hydrogen.

[0225] In some implementation schemes, R 1 For halogenated, -CN, -OR 3 -SR 3 -S(=O) R 3 -S(=O)2R 3 -N(R) 3 2. -C(=O)OR 3 -C(=O)N(R) 3 )2、-CR 3 =C(R 3 2. -C≡CR 3 C3-C 10 cycloalkyl, C2-C 10 C1-C6 alkyl groups substituted with heterocyclic alkyl or aryl groups, wherein C3-C6 10 cycloalkyl, C2-C 10 Heterocyclic alkyl and aryl groups are optionally surrounded by 1-5 R groups. 5 The group is replaced; and each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl or C2-C 10 Heterocyclic alkyl groups, including C1-C6 alkyl groups, C1-C6 fluoroalkyl groups, C1-C6 heteroalkyl groups, and C3-C6 heteroalkyl groups. 10 cycloalkyl and C2-C 10 Heterocyclic alkyl groups are optionally surrounded by 1-5 R groups. 5 The group is replaced; or if two R groups are replaced. 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0226] In some implementation schemes, R 1 For C3-C 10 cycloalkyl or C2-C 10 Heterocyclic alkyl groups, wherein C3-C 10 cycloalkyl and C2-C 10 Heterocyclic alkyl groups are optionally surrounded by 1-5 R groups. 5 The group is replaced. In some embodiments, R1 It is a C3-C6 cycloalkyl or C3-C5 heterocycloalkyl group substituted with C1-C6 alkyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazinyl. In some embodiments, R 1 It is a C3-C6 cycloalkyl or C3-C5 heterocycloalkyl that has been substituted with C1-C6 alkyl, phenyl or pyridyl.

[0227] In some implementations, R is halogen, nitro, -CN, or -OR. 3 -C(=O)R 3 -C(=O)N(R) 3 2. -C(=O)OR 3 -S(=O)R 3 -S(=O)2R 3 -NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 -NR 3 C(=O)OR 3 Or optionally by 1-5 R 5 The C1-C6 fluoroalkyl group substituted by the group; and each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl or C2-C 10 Heterocyclic alkyl groups, including C1-C6 alkyl groups, C1-C6 fluoroalkyl groups, C1-C6 heteroalkyl groups, and C3-C6 heteroalkyl groups. 10 cycloalkyl and C2-C 10 Heterocyclic alkyl groups are optionally surrounded by 1-5 R groups. 5 The group is replaced; or if two R groups are replaced. 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0228] 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 implementations, R is F, Cl, or -CF3. In some implementations, R is -OCF3. In some implementations, R is -CF3.

[0229] In some implementations, each R 2 Independently halogen, nitro, -CN, -OR 3 -SR 3 -S(=O)2R 3 -N(R) 3 2. -C(=O)OR 3 C1-C6 alkyl or C1-C6 fluoroalkyl, wherein the C1-C6 alkyl and C1-C6 fluoroalkyl are optionally surrounded by 1-5 R... 5 The group is replaced; and each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl or C2-C 10 Heterocyclic alkyl groups, including C1-C6 alkyl groups, C1-C6 fluoroalkyl groups, C1-C6 heteroalkyl groups, and C3-C6 heteroalkyl groups. 10 cycloalkyl and C2-C 10 Heterocyclic alkyl groups are optionally surrounded by 1-5 R groups. 5 The group is replaced; or if two R groups are replaced. 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group.

[0230] In some implementations, each R 2Independently, it can be 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 R 2 Independently, it can be F, Cl, -CN, -OCH3, -OCF3, -C(=O)OCH3, -CH3, or -CF3. In some implementations, each R 2 Independently, it can be F, Cl, -OCF3, or -CF3. In some implementations, each R... 2 It can be F or Cl independently.

[0231] In some implementations, n is 0. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3. In some implementations, n is 4. In some implementations, n is 0 or 1. In some implementations, n is 1 or 2. In some implementations, n is 2 or 3. In some implementations, n is 3 or 4. In some implementations, n is 1, 2, or 3. In some implementations, n is 2, 3, or 4. In some implementations, n is 1, 2, 3, or 4.

[0232] In one aspect, the effective therapeutic dose of a TEAD inhibitor is about 1 mg to about 500 mg daily. In some embodiments, the effective therapeutic dose of a TEAD inhibitor is about 1 mg to about 450 mg daily. In some embodiments, the effective therapeutic dose of a TEAD inhibitor is about 1 mg to about 400 mg daily. In some embodiments, the effective therapeutic dose of a TEAD inhibitor is about 1 mg to about 350 mg daily. In some embodiments, the effective therapeutic dose of a TEAD inhibitor is about 1 mg to about 300 mg daily. In some embodiments, the effective therapeutic dose of a TEAD inhibitor is about 1 mg to about 250 mg daily. In some embodiments, the effective therapeutic dose of a TEAD inhibitor is about 10 mg to about 250 mg daily. In some embodiments, the effective therapeutic dose of a TEAD inhibitor is about 25 mg to about 250 mg daily. In some embodiments, the effective therapeutic dose of a TEAD inhibitor is about 25 mg to about 200 mg daily. In some embodiments, the effective therapeutic dose of a TEAD inhibitor is about 25 mg to about 150 mg daily. In some embodiments, the effective therapeutic dose of a TEAD inhibitor is about 25 mg to about 100 mg daily. In some embodiments, the effective therapeutic dose of a TEAD inhibitor is about 25 mg to about 90 mg daily. In some embodiments, the effective therapeutic dose of a TEAD inhibitor is about 25 mg to about 80 mg daily. In some embodiments, the effective therapeutic dose of a TEAD inhibitor is about 25 mg to about 70 mg daily. In some embodiments, the effective therapeutic dose of a TEAD inhibitor is about 25 mg to about 60 mg daily. In some embodiments, the effective therapeutic dose of a TEAD inhibitor is about 25 mg to about 50 mg daily.

[0233] In some embodiments, the effective therapeutic dose of the TEAD inhibitor is about 5 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is about 10 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is about 15 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is about 20 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is about 25 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is about 30 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is about 40 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is about 45 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is about 50 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is about 55 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is about 60 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is about 65 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is about 70 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is approximately 75 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is approximately 80 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is approximately 85 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is approximately 90 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is approximately 95 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is approximately 100 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is approximately 110 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is approximately 120 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is approximately 130 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is approximately 140 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is approximately 150 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is approximately 160 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is approximately 170 mg daily. In some embodiments, the effective therapeutic dose of a TEAD inhibitor is approximately 180 mg daily. In some embodiments, the effective therapeutic dose of a TEAD inhibitor is approximately 190 mg daily. In some embodiments, the effective therapeutic dose of a TEAD inhibitor is approximately 200 mg daily. In some embodiments, the effective therapeutic dose of a TEAD inhibitor is approximately 210 mg daily.In some embodiments, the effective therapeutic dose of the TEAD inhibitor is approximately 220 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is approximately 230 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is approximately 240 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is approximately 250 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is approximately 300 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is approximately 350 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is approximately 400 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is approximately 450 mg daily. In some embodiments, the effective therapeutic dose of the TEAD inhibitor is approximately 500 mg daily.

[0234] In some implementations, the TEAD inhibitors disclosed herein have the structures provided in Table 1.

[0235] Table 1 Preparation of compounds The compounds used in the reactions described herein are prepared from commercially available chemicals and / or compounds described in chemical literature, according to organic synthesis techniques known to those skilled in the art."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).

[0236] Methods known to those skilled in the art have been determined through various reference books and databases. Suitable reference books and papers that detail the synthesis of reactants useful in the preparation of the compounds described herein or that provide reference to articles describing such preparations include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; SR Sandler et al., "Organic Functional Group Preparations", 2nd ed., Academic Press, New York, 1983; HO House, "Modern Synthetic Reactions", 2nd ed., WA Benjamin, Inc., Menlo Park, Calif. 1972; TL 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. Other suitable reference books and papers that detail the synthesis of reactants useful in the preparation of the compounds described herein or that provide reference to articles describing such preparations 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, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC"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. (Ed.) "Modern 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, total 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, total more than 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, total 73 volumes..

[0237] In some cases, specific and similar reactants are identified using an index of known chemicals compiled by the American Chemical Society's Chemical Abstracts Service, which is available from most public and university libraries as well as online databases (contact the American Chemical Society (Washington, DC) for more details). Known but not commercially available chemicals in the index are prepared by custom chemical synthesis houses, many of which offer custom synthesis services, including those from standard chemical supply rooms (e.g., those listed above). A reference for the preparation and selection of pharmaceutical salts for the compounds described herein is PH Stahl and CGWermuth, "Handbook of Pharmaceutical Salts," Verlag Helvetica Chimica Acta, Zurich, 2002.

[0238] In some embodiments, the compounds disclosed herein are prepared as described in the Examples section.

[0239] c-MET inhibitors In some respects, the second treatment is a c-MET inhibitor.

[0240] In some respects, c-Met inhibitors are a class of small molecules that inhibit the enzymatic activity of c-Met tyrosine kinase (the receptor for hepatocyte growth factor / scattering factor (HGF / SF)).

[0241] In some aspects, the c-MET inhibitor is selected from cabozantinib, crizotinib, furatinib, tevantinib, cevotinib, carmatinib, and terpoxtinib, or combinations thereof. In some embodiments, the c-MET inhibitor is selected from cevotinib and carmatinib, or combinations 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 furatinib. In some embodiments, the c-MET inhibitor is tevantinib. In some embodiments, the c-MET inhibitor is cevotinib. In some embodiments, the c-MET inhibitor is carmatinib. In some embodiments, the c-MET inhibitor is terpoxtinib.

[0242] In some implementations, cabozantinib is a kinase inhibitor indicated for the treatment of patients with progressive, metastatic medullary thyroid carcinoma (MTC).

[0243] In some implementations, 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 a gene called ALK (anaplastic lymphoma kinase) or a gene called ROS1.

[0244] In some implementations, tevantinib is indicated for the treatment of adult patients with recurrent or refractory advanced renal cell carcinoma (RCC) following two or more prior systemic therapies.

[0245] In some implementations, carmatinib is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have mutations that cause mesenchymal-epithelial transition (MET) exon 14 skipping, as detected by an FDA-approved test.

[0246] In some implementations, terpoxtinib is a kinase inhibitor indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) carrying mesenchymal-epithelial transition (MET) exon 14 skipping alterations.

[0247] In some embodiments, the effective therapeutic dose of a c-MET inhibitor is about 1 mg to about 1000 mg daily. In some embodiments, the effective therapeutic dose of a c-MET inhibitor is about 1 mg to about 950 mg daily. In some embodiments, the effective therapeutic dose of a c-MET inhibitor is about 1 mg to about 900 mg daily. In some embodiments, the effective therapeutic dose of a c-MET inhibitor is about 1 mg to about 850 mg daily. In some embodiments, the effective therapeutic dose of a c-MET inhibitor is about 1 mg to about 800 mg daily. In some embodiments, the effective therapeutic dose of a c-MET inhibitor is about 1 mg to about 750 mg daily. In some embodiments, the effective therapeutic dose of a c-MET inhibitor is about 1 mg to about 700 mg daily. In some embodiments, the effective therapeutic dose of a c-MET inhibitor is about 1 mg to about 650 mg daily. In some embodiments, the effective therapeutic dose of a c-MET inhibitor is about 1 mg to about 600 mg daily. In some embodiments, the effective therapeutic dose of a c-MET inhibitor is about 1 mg to about 550 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is about 1 mg to about 500 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is about 1 mg to about 450 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is about 1 mg to about 400 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is about 1 mg to about 350 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is about 1 mg to about 300 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is about 1 mg to about 250 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is about 1 mg to about 200 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is about 1 mg to about 150 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is about 1 mg to about 100 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is about 1 mg to about 50 mg daily.

[0248] In some embodiments, the effective therapeutic dose of the c-MET inhibitor is about 5 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is about 10 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is about 20 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is about 30 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is about 40 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is about 50 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is about 60 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is about 70 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is about 80 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is about 90 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is about 100 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is about 120 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 140 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 160 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 180 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 200 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 220 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 240 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 260 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 280 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 300 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 320 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 340 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 360 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 380 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 400 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 420 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 440 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 460 mg daily.In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 480 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 500 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 520 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 540 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 560 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 580 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 600 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 620 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 640 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 660 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 680 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 700 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 720 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 740 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 760 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 780 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 800 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 850 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 900 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 950 mg daily. In some embodiments, the effective therapeutic dose of the c-MET inhibitor is approximately 1000 mg daily.

[0249] BRAF inhibitors In some respects, the second treatment is a BRAF inhibitor.

[0250] In some embodiments, BRAF inhibitors selectively target BRAF kinase and thus interfere with the mitogen-activated protein kinase (MAPK) signaling pathway, which regulates melanoma cell proliferation and survival. In some embodiments, BRAF inhibitors possess immunomodulatory and molecularly targeted activity. In some embodiments, the MAPK pathway is involved in T cell receptor signaling, and interference with this pathway by BRAF inhibitors can have beneficial effects on the tumor microenvironment and antitumor immune response in BRAF-mutant cancers, including: increased levels of immunostimulatory cytokines, decreased levels of immunosuppressive cytokines, enhanced expression of cancer differentiation antigens and enhanced HLA-1 presentation of tumor antigens, as well as increased intratumoral T cell infiltration and activity. In some embodiments, such effects can promote the immune system's recognition of tumors and enhance antitumor T cell responses.

[0251] In some embodiments, the BRAF inhibitor is selected from vemurafenib, dabrafenib, cannefenib, and sorafenib, or combinations thereof. In some embodiments, the BRAF inhibitor is vemurafenib. In some embodiments, the BRAF inhibitor is dabrafenib. In some embodiments, the BRAF inhibitor is cannefenib. In some embodiments, the BRAF inhibitor is sorafenib.

[0252] In some implementations, vemurafenib is a kinase inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma having a BRAF V600E mutation, as detected by an FDA-approved test. In some implementations, vemurafenib is indicated for the treatment of patients with Erdheim-Chester disease (ECD) having a BRAF V600 mutation.

[0253] In some implementations, dabrafenib is a kinase inhibitor indicated as monotherapy for the treatment of patients with unresectable or metastatic melanoma having a BRAF V600E mutation as detected by an FDA-approved test. In some implementations, dabrafenib in combination with trametinib is indicated for the treatment of patients with unresectable or metastatic melanoma having a BRAF V600E or V600K mutation as detected by an FDA-approved test.

[0254] In some implementations, cannefenib is indicated in combination with bimetinib for the treatment of patients with unresectable or metastatic melanoma having a BRAF V600E or V600K mutation as detected by an FDA-approved test.

[0255] In some implementations, cannefenib is indicated in combination with cetuximab for the treatment of adult patients with metastatic colorectal cancer (CRC) having a BRAF V600E mutation as detected by an FDA-approved test, following prior therapy.

[0256] In some implementations, 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 cancer (DTC) refractory to radioactive iodine therapy.

[0257] In some embodiments, the effective therapeutic dose of a BRAF inhibitor is about 1 mg to about 500 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is about 1 mg to about 450 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is about 1 mg to about 400 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is about 1 mg to about 350 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is about 1 mg to about 300 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is about 1 mg to about 250 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is about 1 mg to about 200 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is about 1 mg to about 150 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is about 1 mg to about 100 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is about 1 mg to about 50 mg daily.

[0258] In some embodiments, the effective therapeutic dose of a BRAF inhibitor is about 5 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is about 10 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is about 20 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is about 30 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is about 40 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is about 50 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is about 60 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is about 70 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is about 80 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is about 90 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is about 100 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is about 120 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is about 140 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is approximately 160 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is approximately 180 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is approximately 200 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is approximately 220 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is approximately 240 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is approximately 260 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is approximately 280 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is approximately 300 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is approximately 320 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is approximately 340 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is approximately 360 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is approximately 380 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is approximately 400 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is approximately 420 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is approximately 440 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is approximately 460 mg daily. In some embodiments, the effective therapeutic dose of a BRAF inhibitor is approximately 480 mg daily.In some implementations, the effective therapeutic dose of a BRAF inhibitor is approximately 500 mg per day.

[0259] EFGR inhibitors In some cases, the second treatment is an EGFR inhibitor.

[0260] In some embodiments, EGFR inhibitors can block the extracellular ligand-binding domain, thereby preventing signaling molecules from attaching to this domain and activating tyrosine kinases. In some implementations, EGFR inhibitors can inhibit EGFR tyrosine kinases located on the cytoplasmic side of the receptor. Without kinase activity, EGFR cannot activate itself and bind to downstream adaptor proteins. In some implementations, EGFR inhibitors can generate antibodies against EGF itself, thereby depriving EGFR-dependent cancers of proliferative stimulation.

[0261] In some respects, EGFR inhibitors contain monoclonal antibodies.

[0262] In some respects, EGFR inhibitors include tyrosine kinase inhibitors.

[0263] In some embodiments, the EGFR inhibitor is selected from cetuximab, nexituzumab, panitumumab, zarumumab, nimotuzumab, materutuzumab, osimertinib, gefitinib, erlotinib, lapatinib, neratinib, vandetanib, afatinib, brigatinib, dacomitinib, lazaitinib, ervantumab, and icotinib, or combinations thereof. In some embodiments, the EGFR inhibitor is selected from osimertinib, lazaitinib, and ervantumab, or combinations thereof. In some embodiments, the EGFR inhibitor is cetuximab. In some embodiments, the EGFR inhibitor is nexituzumab. In some embodiments, the EGFR inhibitor is panitumumab. In some embodiments, the EGFR inhibitor is zarumumab. In some embodiments, the EGFR inhibitor is nimotuzumab. In some embodiments, the EGFR inhibitor is materutuzumab. 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 lazazetinib. In some embodiments, the EGFR inhibitor is erlotinib. In some embodiments, the EGFR inhibitor is icotinib.

[0264] In some implementations, cetuximab, used in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients refractory to irinotecan-based chemotherapy.

[0265] In some implementations, cetuximab, administered as a single agent, is indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients intolerant to irinotecan-based chemotherapy.

[0266] In some implementations, cetuximab is indicated for the treatment of metastatic colorectal cancer (mCRC) that is KRAS wild-type and expresses epidermal growth factor receptor (EGFR) as determined by an FDA-approved test for this use: (1) in combination with FOLFIRI (irinotecan, fluorouracil, leucovorin) as first-line treatment; or (2) in combination with irinotecan in patients refractory to irinotecan-based chemotherapy; or as monotherapy in patients who have failed or are intolerant to irinotecan-based chemotherapy and oxaliplatin-based chemotherapy.

[0267] In some implementations, nexituzumab 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.

[0268] In some implementations, panitumumab is an epidermal growth factor receptor (EGFR) antagonist indicated for the treatment of wild-type RAS (defined as having both KRAS and NRAS wild-type, as determined by an FDA-approved test for this use) metastatic colorectal cancer (mCRC): (1) in combination with FOLFOX as first-line treatment; or (2) as monotherapy after disease progression following prior chemotherapy with fluoropyrimidine, oxaliplatin, and irinotecan.

[0269] In some implementations, 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 deletion or exon 21 L858R mutation as detected by an FDA-approved test; (2) as first-line treatment in adult patients with metastatic NSCLC whose tumors have EGFR exon 19 deletion or exon 21 L858R mutation as detected by an FDA-approved test; or (3) as treatment in adult patients with metastatic EGFR T790M mutation-positive NSCLC as detected by an FDA-approved test whose disease has progressed during or after EGFR TKI therapy.

[0270] In some implementations, 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.

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

[0272] In some implementations, erlotinib is indicated for patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 (L858R) substitution mutations as detected by an FDA-approved test, and who have received first-line therapy, maintenance therapy, or ≥ second-line therapy after progression following at least one prior chemotherapy regimen.

[0273] In some implementations, erlotinib is indicated as first-line treatment for patients with locally advanced, unresectable, or metastatic pancreatic cancer.

[0274] In some implementations, lapatinib is a kinase inhibitor indicated for use 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 anthracyclines, taxanes, and trastuzumab); or (2) letrozole for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer that overexpresses the HER2 receptor and who are eligible for hormone therapy.

[0275] In some implementations, neratinib is a kinase inhibitor indicated for: (1) as monotherapy for adult patients with early HER2-positive breast cancer as adjuvant therapy following trastuzumab-based adjuvant 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 at the metastatic stage.

[0276] In some implementations, vandetanib is a kinase inhibitor indicated for the treatment of symptomatic or progressive medullary thyroid carcinoma in patients with unresectable locally advanced or metastatic disease.

[0277] In some implementations, afatinib is a kinase inhibitor indicated for: (1) first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a non-resistant epidermal growth factor receptor (EGFR) mutation as detected by an FDA-approved test; or (2) treatment of patients with metastatic squamous NSCLC that has progressed following platinum-based chemotherapy.

[0278] In some implementations, brigatinib is a kinase inhibitor indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) that is positive for anaplastic lymphoma kinase (ALK) as detected by an FDA-approved test.

[0279] In some implementations, dacomitinib is a kinase inhibitor indicated for first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) having epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations as detected by FDA-approved tests.

[0280] In some implementations, ervantuzumab is a bispecific EGF receptor- and MET receptor-guided antibody indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) having an epidermal growth factor receptor (EGFR) exon 20 insertion mutation as detected by an FDA-approved test, whose disease has progressed during or after platinum-based chemotherapy.

[0281] In some implementations, icotinib is an EGFR-tyrosine kinase inhibitor and has demonstrated efficacy and tolerability in patients with advanced non-small cell lung cancer (NSCLC) who have failed prior chemotherapy.

[0282] In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 1 mg to about 200 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 1 mg to about 190 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 1 mg to about 180 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 1 mg to about 170 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 1 mg to about 160 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 1 mg to about 150 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 1 mg to about 140 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 1 mg to about 130 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 1 mg to about 120 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 1 mg to about 110 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 1 mg to about 100 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 1 mg to about 90 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 1 mg to about 80 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 1 mg to about 70 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 1 mg to about 60 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 1 mg to about 50 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 1 mg to about 40 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 1 mg to about 30 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 1 mg to about 20 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 1 mg to about 10 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 1 mg to about 5 mg daily.

[0283] In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 5 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 10 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 20 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 30 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 40 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 50 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 60 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 70 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 80 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 90 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 100 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 110 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is about 120 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is approximately 130 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is approximately 140 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is approximately 150 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is approximately 160 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is approximately 170 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is approximately 180 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is approximately 190 mg daily. In some embodiments, the effective therapeutic dose of an EGFR inhibitor is approximately 200 mg daily.

[0284] MEK inhibitors In some respects, the second treatment is a MEK inhibitor.

[0285] In some respects, MEK inhibitors can inhibit mitogen-activated protein kinase kinases MEK1 and / or MEK2. In some implementations, MEK inhibitors can be used to affect the MAPK / ERK pathway, which is typically overactive in some cancers.

[0286] In some embodiments, the MEK inhibitor is selected from refatinib, selumetinib, trametinib, cobimetinib, bimetinib, midametinib, and pimachitinib, or combinations thereof. In some embodiments, the MEK inhibitor is selected from cobimetinib and trametinib, or combinations thereof. In some embodiments, the MEK inhibitor is refatinib. 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 bimetinib. In some embodiments, the MEK inhibitor is midametinib. In some embodiments, the MEK inhibitor is pimachitinib.

[0287] In some implementations, selumetinib is a kinase inhibitor indicated for the treatment of pediatric patients aged 2 years and older with symptomatic, inoperable plexiform neurofibromatosis (PN) and neurofibromatosis type 1 (NF1).

[0288] In some implementations, trametinib is a kinase inhibitor indicated as monotherapy for the treatment of patients with unresectable or metastatic melanoma who have not been treated with BRAF inhibitors and have BRAF V600E or V600K mutations detected by an FDA-approved test.

[0289] In some implementations, trametinib is indicated in combination with dabrafenib for: (1) the treatment of patients with unresectable or metastatic melanoma having a BRAF V600E or V600K mutation as detected by an FDA-approved test; (2) adjuvant therapy in patients with melanoma having a BRAF V600E or V600K mutation and involving lymph nodes as detected by an FDA-approved test; (3) the treatment of patients with metastatic non-small cell lung cancer (NSCLC) having a BRAF V600E mutation as detected by an FDA-approved test; (4) the treatment of patients with locally advanced or metastatic undifferentiated thyroid cancer (ATC) having a BRAF V600E mutation and no satisfactory local regional treatment option; (5) the treatment of adult and pediatric patients aged 6 years and older with unresectable or metastatic solid tumors having a BRAF V600E mutation who have progressed after prior treatment and have no satisfactory alternative treatment option; or (6) patients aged 1 year and older with BRAF V600E mutations who require systemic therapy. Treatment of pediatric patients with low-grade glioma (LGG) with V600E mutation.

[0290] In some implementations, cobimetinib is a kinase inhibitor indicated for: (1) in combination with vemurafenib for the treatment of adult patients with unresectable or metastatic melanoma having BRAF V600E or V600K mutations; or (2) as monotherapy for the treatment of adult patients with histiocytic tumors.

[0291] In some implementations, bimetinib is a kinase inhibitor indicated in combination with cannefenib for the treatment of patients with unresectable or metastatic melanoma having BRAF V600E or V600K mutations as detected by an FDA-approved test.

[0292] In some embodiments, the effective therapeutic dose of a MEK inhibitor is about 1 mg to about 200 mg daily. In some embodiments, the effective therapeutic dose of a MEK inhibitor is about 1 mg to about 190 mg daily. In some embodiments, the effective therapeutic dose of a MEK inhibitor is about 1 mg to about 180 mg daily. In some embodiments, the effective therapeutic dose of a MEK inhibitor is about 1 mg to about 170 mg daily. In some embodiments, the effective therapeutic dose of a MEK inhibitor is about 1 mg to about 160 mg daily. In some embodiments, the effective therapeutic dose of a MEK inhibitor is about 1 mg to about 150 mg daily. In some embodiments, the effective therapeutic dose of a MEK inhibitor is about 1 mg to about 140 mg daily. In some embodiments, the effective therapeutic dose of a MEK inhibitor is about 1 mg to about 130 mg daily. In some embodiments, the effective therapeutic dose of a MEK inhibitor is about 1 mg to about 120 mg daily. In some embodiments, the effective therapeutic dose of a MEK inhibitor is about 1 mg to about 110 mg daily. In some embodiments, the effective therapeutic dose of a MEK inhibitor is about 1 mg to about 100 mg daily. In some embodiments, the therapeutically effective dose of the MEK inhibitor is about 1 mg to about 90 mg daily. In some embodiments, the therapeutically effective dose of the MEK inhibitor is about 1 mg to about 80 mg daily. In some embodiments, the therapeutically effective dose of the MEK inhibitor is about 1 mg to about 70 mg daily. In some embodiments, the therapeutically effective dose of the MEK inhibitor is about 1 mg to about 60 mg daily. In some embodiments, the therapeutically effective dose of the MEK inhibitor is about 1 mg to about 50 mg daily. In some embodiments, the therapeutically effective dose of the MEK inhibitor is about 1 mg to about 40 mg daily. In some embodiments, the therapeutically effective dose of the MEK inhibitor is about 1 mg to about 30 mg daily. In some embodiments, the therapeutically effective dose of the MEK inhibitor is about 1 mg to about 20 mg daily. In some embodiments, the therapeutically effective dose of the MEK inhibitor is about 1 mg to about 10 mg daily.

[0293] In some embodiments, the effective therapeutic dose of the MEK inhibitor is about 5 mg daily. In some embodiments, the effective therapeutic dose of the MEK inhibitor is about 10 mg daily. In some embodiments, the effective therapeutic dose of the MEK inhibitor is about 20 mg daily. In some embodiments, the effective therapeutic dose of the MEK inhibitor is about 30 mg daily. In some embodiments, the effective therapeutic dose of the MEK inhibitor is about 40 mg daily. In some embodiments, the effective therapeutic dose of the MEK inhibitor is about 50 mg daily. In some embodiments, the effective therapeutic dose of the MEK inhibitor is about 60 mg daily. In some embodiments, the effective therapeutic dose of the MEK inhibitor is about 70 mg daily. In some embodiments, the effective therapeutic dose of the MEK inhibitor is about 80 mg daily. In some embodiments, the effective therapeutic dose of the MEK inhibitor is about 90 mg daily. In some embodiments, the effective therapeutic dose of the MEK inhibitor is about 100 mg daily. In some embodiments, the effective therapeutic dose of the MEK inhibitor is about 110 mg daily. In some embodiments, the effective therapeutic dose of the MEK inhibitor is about 120 mg daily. In some embodiments, the effective therapeutic dose of the MEK inhibitor is approximately 130 mg daily. In some embodiments, the effective therapeutic dose of the MEK inhibitor is approximately 140 mg daily. In some embodiments, the effective therapeutic dose of the MEK inhibitor is approximately 150 mg daily. In some embodiments, the effective therapeutic dose of the MEK inhibitor is approximately 160 mg daily. In some embodiments, the effective therapeutic dose of the MEK inhibitor is approximately 170 mg daily. In some embodiments, the effective therapeutic dose of the MEK inhibitor is approximately 180 mg daily. In some embodiments, the effective therapeutic dose of the MEK inhibitor is approximately 190 mg daily. In some embodiments, the effective therapeutic dose of the MEK inhibitor is approximately 200 mg daily.

[0294] KRAS inhibitors In some respects, the second treatment is a KRAS inhibitor.

[0295] In some aspects, the KRAS inhibitor is selected from inhibitors of the KRAS G12C mutation, the KRAS G12D mutation, the KRAS G12V mutation, and the KRAS G13 mutation, or combinations thereof. In some embodiments, the KRAS inhibitor is an inhibitor of the KRAS G12C mutation. In some embodiments, the KRAS inhibitor is an inhibitor of the KRAS G12D mutation. In some embodiments, the KRAS inhibitor is an inhibitor of the KRAS G12V mutation. In some embodiments, the KRAS inhibitor is an inhibitor of the KRAS G13 mutation.

[0296] In some embodiments, the KRAS inhibitor is selected from adagraxibu and sotorasibu, or a combination thereof. In some embodiments, the KRAS inhibitor is adagraxibu. In some embodiments, the KRAS inhibitor is sotorasibu.

[0297] In some implementations, adagraxibue is an inhibitor of the RAS GTPase family and is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a KRAS G12C mutation as determined by an FDA-approved test, who have received at least one prior systemic therapy.

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

[0299] In some embodiments, the effective therapeutic dose of a KRAS inhibitor is about 1 mg to about 1500 mg daily. In some embodiments, the effective therapeutic dose of a KRAS inhibitor is about 1 mg to about 1400 mg daily. In some embodiments, the effective therapeutic dose of a KRAS inhibitor is about 1 mg to about 1300 mg daily. In some embodiments, the effective therapeutic dose of a KRAS inhibitor is about 1 mg to about 1200 mg daily. In some embodiments, the effective therapeutic dose of a KRAS inhibitor is about 1 mg to about 1100 mg daily. In some embodiments, the effective therapeutic dose of a KRAS inhibitor is about 1 mg to about 1000 mg daily. In some embodiments, the effective therapeutic dose of a KRAS inhibitor is about 1 mg to about 900 mg daily. In some embodiments, the effective therapeutic dose of a KRAS inhibitor is about 1 mg to about 800 mg daily. In some embodiments, the effective therapeutic dose of a KRAS inhibitor is about 1 mg to about 700 mg daily. In some embodiments, the effective therapeutic dose of a KRAS inhibitor is about 1 mg to about 600 mg daily. In some embodiments, the effective therapeutic dose of a KRAS inhibitor is about 1 mg to about 500 mg daily. In some embodiments, the effective therapeutic dose of a KRAS inhibitor is about 1 mg to about 400 mg daily. In some embodiments, the effective therapeutic dose of a KRAS inhibitor is about 1 mg to about 300 mg daily. In some embodiments, the effective therapeutic dose of a KRAS inhibitor is about 1 mg to about 200 mg daily. In some embodiments, the effective therapeutic dose of a KRAS inhibitor is about 1 mg to about 100 mg daily. In some embodiments, the effective therapeutic dose of a KRAS inhibitor is about 1 mg to about 90 mg daily. In some embodiments, the effective therapeutic dose of a KRAS inhibitor is about 1 mg to about 80 mg daily. In some embodiments, the effective therapeutic dose of a KRAS inhibitor is about 1 mg to about 70 mg daily. In some embodiments, the effective therapeutic dose of a KRAS inhibitor is about 1 mg to about 60 mg daily. In some embodiments, the effective therapeutic dose of a KRAS inhibitor is about 1 mg to about 50 mg daily. In some embodiments, the therapeutically effective dose of a KRAS inhibitor is about 1 mg to about 40 mg daily. In some embodiments, the therapeutically effective dose of a KRAS inhibitor is about 1 mg to about 30 mg daily. In some embodiments, the therapeutically effective dose of a KRAS inhibitor is about 1 mg to about 20 mg daily. In some embodiments, the therapeutically effective dose of a KRAS inhibitor is about 1 mg to about 10 mg daily.

[0300] In some embodiments, the effective therapeutic dose of a KRAS inhibitor is about 10 mg daily. In some embodiments, the effective therapeutic dose of a KRAS inhibitor is about 20 mg daily. In some embodiments, the effective therapeutic dose of a KRAS inhibitor is about 30 mg daily. In some embodiments, the effective therapeutic dose of a KRAS inhibitor is about 40 mg daily. In some embodiments, the effective therapeutic dose of a KRAS inhibitor is about 50 mg daily. In some embodiments, the effective therapeutic dose of a KRAS inhibitor is about 60 mg daily. In some embodiments, the effective therapeutic dose of a KRAS inhibitor is about 70 mg daily. In some embodiments, the effective therapeutic dose of a KRAS inhibitor is about 80 mg daily. In some embodiments, the effective therapeutic dose of a KRAS inhibitor is about 90 mg daily. In some embodiments, the effective therapeutic dose of a KRAS inhibitor is about 100 mg daily. In some embodiments, the effective therapeutic dose of a KRAS inhibitor is about 200 mg daily. In some embodiments, the effective therapeutic dose of a KRAS inhibitor is about 300 mg daily. In some embodiments, the effective therapeutic dose of the KRAS inhibitor is approximately 400 mg daily. In some embodiments, the effective therapeutic dose of the KRAS inhibitor is approximately 500 mg daily. In some embodiments, the effective therapeutic dose of the KRAS inhibitor is approximately 600 mg daily. In some embodiments, the effective therapeutic dose of the KRAS inhibitor is approximately 700 mg daily. In some embodiments, the effective therapeutic dose of the KRAS inhibitor is approximately 800 mg daily. In some embodiments, the effective therapeutic dose of the KRAS inhibitor is approximately 900 mg daily. In some embodiments, the effective therapeutic dose of the KRAS inhibitor is approximately 1000 mg daily. In some embodiments, the effective therapeutic dose of the KRAS inhibitor is approximately 1100 mg daily. In some embodiments, the effective therapeutic dose of the KRAS inhibitor is approximately 1200 mg daily. In some embodiments, the effective therapeutic dose of the KRAS inhibitor is approximately 1300 mg daily. In some embodiments, the effective therapeutic dose of the KRAS inhibitor is approximately 1400 mg daily. In some implementations, the effective therapeutic dose of a KRAS inhibitor is approximately 1500 mg per day.

[0301] mTOR inhibitors In some respects, the second treatment is an mTOR inhibitor.

[0302] In some respects, mTOR inhibitors can inhibit the mechanistic target of rapamycin (mTOR), a serine / threonine-specific protein kinase belonging to the phosphatidylinositol-3 kinase (PI3K)-associated kinase (PIKK) family. In some embodiments, mTOR regulates cell metabolism, growth, and proliferation by forming two protein complexes, mTORC1 and mTORC2, and by signal transduction through these two protein complexes.

[0303] In some aspects, the mTOR inhibitor is selected from mTORC1 inhibitors and mTORC2 inhibitors, or combinations thereof. In some embodiments, the mTOR inhibitor is an mTORC1 inhibitor. In some embodiments, the mTOR inhibitor is an mTORC2 inhibitor.

[0304] In some aspects, the mTOR inhibitor is selected from tesimolimus, everolimus, lidafomus, sirolimus, umimilimus, and zotalimus, or combinations thereof. In some embodiments, the mTOR inhibitor is tesimolimus. In some embodiments, the mTOR inhibitor is everolimus. In some embodiments, the mTOR inhibitor is lidafomus. In some embodiments, the mTOR inhibitor is sirolimus. In some embodiments, the mTOR inhibitor is umimilimus. In some embodiments, the mTOR inhibitor is zotalimus.

[0305] In some implementations, tesimolimus is a kinase inhibitor indicated for the treatment of advanced renal cell carcinoma.

[0306] In some implementations, everolimus is a kinase inhibitor suitable for the treatment of: ● In combination with exemestane for postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) after failure of treatment with fritillary or anastrozole.

[0307] ● Adults with unresectable, locally advanced, or metastatic progressive neuroendocrine tumors of pancreatic origin (PNET). The safety and efficacy of everolimus in treating patients with carcinoid tumors have not been established.

[0308] ● Adults with advanced renal cell carcinoma (RCC) who have failed treatment with sunitinib or sorafenib. ● Adults with renal angiomyolipoma and tuberous sclerosis complex (TSC) who do not require immediate surgery. The efficacy of everolimus in treating renal angiomyolipoma is based on an analysis of durable objective responses in patients with a median treatment duration of 8.3 months. Further follow-up of patients is needed to determine long-term outcomes.

[0309] ● Adults and children aged ≥3 years with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TSC) who require therapeutic intervention but are not candidates for radical surgical resection. The efficacy of everolimus is based on an analysis of changes in SEGA volume. No clinical benefit, such as improvement in disease-related symptoms or increased overall survival, has been demonstrated.

[0310] In some implementations, sirolimus is an immunosuppressant used to prevent organ rejection in patients aged ≥13 years who have received a kidney transplant.

[0311] ● Patients at low to moderate immune risk: Initially used with cyclosporine (CsA) and corticosteroids. It is recommended to discontinue CsA 2–4 months after transplantation.

[0312] ● Patients at high immune risk: Use in combination with cyclosporine and corticosteroids for the first 12 months post-transplantation. The safety and efficacy of CsA discontinuation in high-risk patients have not been established.

[0313] ● It is recommended that all patients undergo treatment drug monitoring.

[0314] In some embodiments, the effective therapeutic dose of an mTOR inhibitor is about 1 mg to about 100 mg daily. In some embodiments, the effective therapeutic dose of an mTOR inhibitor is about 1 mg to about 90 mg daily. In some embodiments, the effective therapeutic dose of an mTOR inhibitor is about 1 mg to about 80 mg daily. In some embodiments, the effective therapeutic dose of an mTOR inhibitor is about 1 mg to about 70 mg daily. In some embodiments, the effective therapeutic dose of an mTOR inhibitor is about 1 mg to about 60 mg daily. In some embodiments, the effective therapeutic dose of an mTOR inhibitor is about 1 mg to about 50 mg daily. In some embodiments, the effective therapeutic dose of an mTOR inhibitor is about 1 mg to about 40 mg daily. In some embodiments, the effective therapeutic dose of an mTOR inhibitor is about 1 mg to about 30 mg daily. In some embodiments, the effective therapeutic dose of an mTOR inhibitor is about 1 mg to about 20 mg daily. In some embodiments, the effective therapeutic dose of an mTOR inhibitor is about 1 mg to about 10 mg daily. In some embodiments, the effective therapeutic dose of an mTOR inhibitor is about 1 mg to about 9 mg daily. In some embodiments, the therapeutically effective dose of the mTOR inhibitor is about 1 mg to about 8 mg daily. In some embodiments, the therapeutically effective dose of the mTOR inhibitor is about 1 mg to about 7 mg daily. In some embodiments, the therapeutically effective dose of the mTOR inhibitor is about 1 mg to about 6 mg daily. In some embodiments, the therapeutically effective dose of the mTOR inhibitor is about 1 mg to about 5 mg daily. In some embodiments, the therapeutically effective dose of the mTOR inhibitor is about 1 mg to about 4 mg daily. In some embodiments, the therapeutically effective dose of the mTOR inhibitor is about 1 mg to about 3 mg daily. In some embodiments, the therapeutically effective dose of the mTOR inhibitor is about 1 mg to about 2 mg daily.

[0315] In some embodiments, the effective therapeutic dose of the mTOR inhibitor is approximately 100 mg daily. In some embodiments, the effective therapeutic dose of the mTOR inhibitor is approximately 90 mg daily. In some embodiments, the effective therapeutic dose of the mTOR inhibitor is approximately 80 mg daily. In some embodiments, the effective therapeutic dose of the mTOR inhibitor is approximately 70 mg daily. In some embodiments, the effective therapeutic dose of the mTOR inhibitor is approximately 60 mg daily. In some embodiments, the effective therapeutic dose of the mTOR inhibitor is approximately 50 mg daily. In some embodiments, the effective therapeutic dose of the mTOR inhibitor is approximately 40 mg daily. In some embodiments, the effective therapeutic dose of the mTOR inhibitor is approximately 30 mg daily. In some embodiments, the effective therapeutic dose of the mTOR inhibitor is approximately 20 mg daily. In some embodiments, the effective therapeutic dose of the mTOR inhibitor is approximately 10 mg daily. In some embodiments, the effective therapeutic dose of the mTOR inhibitor is approximately 9 mg daily. In some embodiments, the effective therapeutic dose of the mTOR inhibitor is approximately 8 mg daily. In some embodiments, the effective therapeutic dose of the mTOR inhibitor is approximately 7 mg daily. In some embodiments, the effective therapeutic dose of the mTOR inhibitor is about 6 mg daily. In some embodiments, the effective therapeutic dose of the mTOR inhibitor is about 5 mg daily. In some embodiments, the effective therapeutic dose of the mTOR inhibitor is about 4 mg daily. In some embodiments, the effective therapeutic dose of the mTOR inhibitor is about 3 mg daily. In some embodiments, the effective therapeutic dose of the mTOR inhibitor is about 2 mg daily. In some embodiments, the effective therapeutic dose of the mTOR inhibitor is about 1 mg daily.

[0316] Other forms of compounds Isomers In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis, trans, cis, trans, and engegen ( E ) and zusammen ( ZIsomers and their corresponding mixtures. In some cases, the compounds exist as tautomers. The compounds described herein include all possible tautomers within the general formulas described herein. In some cases, the compounds described herein have one or more chiral centers, and each center exists in an R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms, and their corresponding mixtures. In other embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers produced by a single preparation 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 compounds with an optically resolving agent to form a pair of diastereomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, separable complexes (e.g., crystalline diastereomeric salts) are disclosed herein. In some embodiments, diastereomers possess different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by utilizing these dissimilarity. In some embodiments, diastereomers are separated by chiral chromatography, or preferably by a separation / resolution technique based on solubility differences. In some embodiments, the optically pure enantiomers are subsequently recovered, along with the resolving agent, by any practical means that do not cause racemization.

[0317] Labeled compounds In some embodiments, the compounds described herein are present in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds in the form of a pharmaceutical composition. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to those listed herein, except that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. In some embodiments, examples of isotopes incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36Cl. The compounds described herein, their metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates, or derivatives containing the aforementioned isotopes and / or other isotopes are all within the scope of this disclosure. Certain isotope-labeled compounds, such as those doped with radioactive isotopes, are also included. 3 H and 14 Compounds of C are useful in drug and / or substrate tissue distribution assays. Tritium (i.e. 3 H) and carbon-14 (i.e., ... 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, the use of heavy isotopes (such as deuterium, i.e., deuterium) is also advantageous due to better metabolic stability, for example, prolonged in vivo half-life, or reduced dose requirements. 2 H) substitution produces certain therapeutic advantages. In some embodiments, the isotopically labeled compound, its pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative is prepared by any suitable method.

[0318] 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 markers, or chemiluminescent markers.

[0319] Pharmaceutically acceptable salts In some embodiments, the compounds described herein are present as pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts in the form of a pharmaceutical composition.

[0320] In some embodiments, the compounds described herein have acidic or basic groups, and thus react with any base or acid, either inorganic or organic, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by reacting the purified compounds in their free form with suitable acids or bases, and then isolating the resulting salts.

[0321] solvates In some embodiments, the compounds described herein are present as solvates. This disclosure provides a method of treating a disease by administering such solvates. This disclosure further provides a method of treating a disease by administering such solvates in the form of a pharmaceutical composition.

[0322] The solvate contains a stoichiometric or non-stoichiometric amount of solvent, and in some embodiments, the solvate is formed during crystallization with a pharmaceutically acceptable solvent such as water, ethanol, etc. A hydrate is formed when the solvent is water, or an alcohol is formed when the solvent is an alcohol. In some embodiments, the solvate of the compounds described herein is conveniently prepared or formed in the process described herein. By way of example only, the hydrate of the compounds described herein is conveniently prepared by recrystallization from an aqueous / organic solvent mixture using an organic solvent including, but not limited to, dioxane, tetrahydrofuran, or methanol. In some embodiments, the compounds provided herein are present in both unsolvated and solvated forms. Generally, for the compounds and methods provided herein, the solvated form is considered equivalent to the unsolvated form.

[0323] prodrug In some embodiments, the compounds described herein are in the form of prodrugs. This disclosure provides methods for treating diseases by administering such prodrugs. This disclosure also provides methods for treating diseases by administering such prodrugs in the form of pharmaceutical compositions.

[0324] In some embodiments, the prodrug comprises a compound in which an amino acid residue or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues is covalently linked to a free amino, hydroxy, or carboxylic acid group of the disclosed compound via an amide or ester bond. The amino acid residues include, but are not limited to, 20 naturally occurring amino acids, and also include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, valine, β-alanine, γ-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone. In other embodiments, the prodrug comprises a compound in which a nucleic acid residue or an oligonucleotide (e.g., two, three, or four) nucleic acid residues is covalently linked to a compound of the disclosed compound.

[0325] 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 ammonium derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, metal salts, and sulfonates. In some embodiments, compounds having free amino, amide, hydroxyl, or carboxyl groups are converted into prodrugs. For example, a free carboxyl group is derived into an amide or alkyl ester. In some cases, all these prodrug moieties contain functional groups, including but not limited to ether, amine, and carboxylic acid functional groups.

[0326] Hydroxyl prodrugs include esters, such as, but not limited to, acyloxyalkyl (e.g., acyloxymethyl, acyloxyethyl) esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, sulfonates, sulfate esters, and disulfide-containing esters, ethers, amides, carbamates, hemisuccinates, dimethylaminoacetate, and phosphoryloxymethoxycarbonyl, such as Advanced Drug Delivery Reviews 1996, 19 As outlined in , 115.

[0327] Amine-derived prodrugs include, but are not limited to, the following groups and combinations thereof: In addition, sulfonamides and phosphonamides.

[0328] In some cases, sites on any aromatic ring moiety are prone to various metabolic reactions. Therefore, introducing appropriate substituents into the aromatic ring structure can reduce, minimize, or eliminate this metabolic pathway.

[0329] Metabolites In some embodiments, the compounds described herein are susceptible to a variety of metabolic reactions. Therefore, in some embodiments, introducing suitable substituents into the structure will reduce, minimize, or eliminate metabolic pathways. In specific embodiments, by way of example only, suitable substituents for reducing or eliminating the sensitivity of the aromatic ring to metabolic reactions are halogenated or alkyl groups.

[0330] In some embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce metabolites, which are then used to produce desired effects, including desired therapeutic effects.

[0331] method In one aspect, this disclosure provides a method of treating cancer in a patient in need, comprising administering to the patient a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent, wherein the cancer is a recurrent or refractory cancer. In some embodiments, the method comprises administering to the patient a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent, wherein the cancer is a recurrent cancer. In some embodiments, the method comprises administering to the patient a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent, wherein the cancer is a refractory cancer.

[0332] In another aspect, this disclosure provides a method of treating cancer in a patient in need, comprising administering to the patient a therapeutically effective amount of a first therapeutic agent containing a compound of formula (I), (IA), (II), or (III) or a pharmaceutically acceptable salt or solvation thereof, and a therapeutically effective amount of a second therapeutic agent, wherein the cancer is a recurrent or refractory cancer. In some embodiments, the method comprises administering to the patient a therapeutically effective amount of a first therapeutic agent containing a compound of formula (I), (IA), (II), or (III) or a pharmaceutically acceptable salt or solvation thereof, and a therapeutically effective amount of a second therapeutic agent, wherein the cancer is a recurrent cancer. In some embodiments, the method comprises administering to the patient a therapeutically effective amount of a first therapeutic agent containing a compound of formula (I), (IA), (II), or (III) or a pharmaceutically acceptable salt or solvation thereof, and a therapeutically effective amount of a second therapeutic agent, wherein the cancer is a refractory cancer.

[0333] On the other hand, this disclosure provides the 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, this disclosure provides the use of a composition comprising a therapeutically effective amount of a first therapeutic agent comprising a compound of formula (I), (IA), (II), or (III) or a pharmaceutically acceptable salt or solvation thereof and a therapeutically effective amount of a second therapeutic agent disclosed herein in the manufacture of a medicament for treating cancer.

[0334] On the other hand, this disclosure provides a method of treating cancer in patients in need, comprising administering to the patient a therapeutically effective amount of a first therapeutic agent containing 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.

[0335] In some embodiments, this disclosure provides a method of treating cancer in a patient in need, comprising administering to the patient a therapeutically effective amount of a first therapeutic agent comprising a compound of formula (I), (IA), (II), or (III) or a pharmaceutically acceptable salt or solvation thereof, and a therapeutically effective amount of a second therapeutic agent, wherein the therapeutically effective amount of the compound of formula (I), (IA), (II), or (III) or a pharmaceutically acceptable salt or solvation thereof is about 1 mg to about 300 mg per day.

[0336] In another aspect, this disclosure provides a method for inhibiting one or more proteins covered by or associated with the Hippo pathway, comprising administering to a subject in need a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent disclosed herein.

[0337] In another aspect, this disclosure provides a method for inhibiting one or more proteins covered by or associated with the Hippo pathway, comprising administering to a subject in need a therapeutically effective amount of a first therapeutic agent comprising a compound of formula (I), (IA), (II), or (III) or a pharmaceutically acceptable salt or solvation thereof, and a therapeutically effective amount of a second therapeutic agent disclosed herein.

[0338] On the other hand, this disclosure provides a method for inhibiting transcriptional coactivator / Yes-related protein transcriptional coactivator (TAZ / YAP) having a PDZ binding motif, comprising administering to a subject in need a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent disclosed herein.

[0339] On the other hand, this disclosure provides a method for inhibiting transcriptional coactivator / Yes-related protein transcriptional coactivator (TAZ / YAP) having a PDZ binding motif, comprising administering to a subject in need a therapeutically effective amount of a first therapeutic agent comprising a compound of formula (I), (IA), (II) or (III) or a pharmaceutically acceptable salt or solvation thereof, and a therapeutically effective amount of a second therapeutic agent disclosed herein.

[0340] On the other hand, this disclosure provides a method for treating polycystic kidney disease or liver fibrosis in subjects in need, comprising administering to the subject in need 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.

[0341] On the other hand, this disclosure provides a method for treating polycystic kidney disease or liver fibrosis in a subject in need, comprising administering to the subject in need a therapeutically effective amount of a first therapeutic agent comprising a compound of formula (I), (IA), (II) or (III) or a pharmaceutically acceptable salt or solvation thereof, and a therapeutically effective amount of a second therapeutic agent disclosed herein.

[0342] In some aspects, a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent are administered simultaneously. In some aspects, a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent are administered sequentially. In some embodiments, a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent are co-formulated in a single composition. In some embodiments, a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent are formulated in separate compositions.

[0343] In some aspects, a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of a c-MET inhibitor are administered simultaneously. In some aspects, a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of a c-MET inhibitor are administered sequentially. In some embodiments, a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of a c-MET inhibitor are co-formulated in a single composition. In some embodiments, a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of a c-MET inhibitor are formulated in separate compositions.

[0344] In some aspects, a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of a BRAF inhibitor are administered simultaneously. In some aspects, a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of a BRAF inhibitor are administered sequentially. In some embodiments, a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of a BRAF inhibitor are co-formulated in a single composition. In some embodiments, a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of a BRAF inhibitor are formulated in separate compositions.

[0345] In some aspects, a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of an EGFR inhibitor are administered simultaneously. In some aspects, a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of an EGFR inhibitor are administered sequentially. In some embodiments, a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of an EGFR inhibitor are co-formulated in a single composition. In some embodiments, a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of an EGFR inhibitor are formulated in separate compositions.

[0346] In some aspects, a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of a MEK inhibitor are administered simultaneously. In some aspects, a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of a MEK inhibitor are administered sequentially. In some embodiments, a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of a MEK inhibitor are co-formulated in a single composition. In some embodiments, a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of a MEK inhibitor are formulated in separate compositions.

[0347] In some aspects, a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of a KRAS inhibitor are administered simultaneously. In some aspects, a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of a KRAS inhibitor are administered sequentially. In some embodiments, a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of a KRAS inhibitor are co-formulated in a single composition. In some embodiments, a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of a KRAS inhibitor are formulated in separate compositions.

[0348] In some aspects, a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of an mTOR inhibitor are administered simultaneously. In some aspects, a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of an mTOR inhibitor are administered sequentially. In some embodiments, a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of an mTOR inhibitor are co-formulated in a single composition. In some embodiments, a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of an mTOR inhibitor are formulated in separate compositions.

[0349] In some cases, a therapeutically effective dose of a first-line treatment containing a TEAD inhibitor and a therapeutically effective dose of a second-line treatment are administered daily for at least one week.

[0350] In some cases, a therapeutically effective dose of a first-line treatment containing a TEAD inhibitor and a therapeutically effective dose of a second-line treatment are administered daily for at least two weeks.

[0351] In some cases, a therapeutically effective dose of a first-line treatment containing a TEAD inhibitor and a therapeutically effective dose of a second-line treatment are administered daily for at least three weeks.

[0352] In some cases, a therapeutically effective dose of a first-line treatment containing a TEAD inhibitor and a therapeutically effective dose of a second-line treatment are administered daily for at least 24 days.

[0353] In some cases, a therapeutically effective dose of a first treatment agent containing a TEAD inhibitor and a therapeutically effective dose of a second treatment agent are administered in a three-week cycle, with the therapeutically effective dose administered daily for one week, followed by a two-week period without administration.

[0354] In some cases, a therapeutically effective dose of a first treatment agent containing a TEAD inhibitor and a therapeutically effective dose of a second treatment agent are administered in a three-week cycle, with the therapeutically effective dose administered daily for two weeks, followed by a week without administration.

[0355] In some cases, a therapeutically effective dose of a first treatment agent containing a TEAD inhibitor and a therapeutically effective dose of a second treatment agent are administered in a four-week cycle, with the therapeutically effective dose administered daily for one week, followed by a three-week period without administration.

[0356] In some cases, a therapeutically effective dose of a first treatment agent containing a TEAD inhibitor and a therapeutically effective dose of a second treatment agent are administered in a four-week cycle, with the therapeutically effective dose administered daily for two weeks, followed by a two-week period without administration.

[0357] In some respects, a therapeutically effective amount of a first therapeutic agent containing a TEAD inhibitor and a therapeutically effective amount of a second therapeutic agent are administered over at least two cycles.

[0358] In some implementations, a combi...

Claims

1. A method of treating cancer in a patient in need, 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 recurrent or refractory cancer.

2. The method of claim 1, wherein the therapeutically effective dose of the TEAD inhibitor is about 1 mg to about 300 mg per day.

3. The method according to claim 1 or 2, wherein the therapeutically effective dose of the TEAD inhibitor is about 25 mg to about 200 mg per day.

4. The method according to 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, 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 dose of the TEAD inhibitor is about 25 mg to about 200 mg per day.

7. The method according to 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 according to any one of claims 5 to 7, wherein the cancer is a recurrent or refractory cancer.

9. The method according to any one of claims 1 to 8, wherein the second therapeutic agent is selected from c-MET inhibitors, BRAF inhibitors, EGFR inhibitors, MEK inhibitors, KRAS inhibitors, and mTOR inhibitors.

10. The method according to 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 dose 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 dose of the c-MET inhibitor is about 1 mg to about 400 mg per day.

13. The method according to any one of claims 9 to 12, wherein the c-MET inhibitor is selected from cabozantinib, crizotinib, furatinib, tevantinib, cevotinib, carmatinib, and terpoxtinib, or combinations thereof.

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

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

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

17. The method according to 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 dose of the BRAF inhibitor is about 1 mg to about 200 mg per day.

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

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

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

23. The method according to 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 dose 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 dose of the EGFR inhibitor is about 1 mg to about 40 mg per day.

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

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

28. The method according to any one of claims 23 to 25, wherein the EGFR inhibitor is selected from cetuximab, nexituzumab, panitumumab, zarumumab, nimotuzumab, mateuzumab, osimertinib, gefitinib, erlotinib, lapatinib, nellatinib, vandetanib, afatinib, brigatinib, dacomitinib, lazetinib, ervantumab, and icotinib, or combinations thereof.

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

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

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

32. The method according to 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 according to any one of claims 32 to 34, wherein the MEK inhibitor is selected from refatinib, selmetinib, trametinib, cobimetinib, bimetinib, midametinib, and pimazatinib or combinations thereof.

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

37. The method according to 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 is 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 according to any one of claims 37 to 39, wherein the KRAS inhibitor is selected from inhibitors of KRAS G12C mutant, KRAS G12D mutant, KRAS G12V mutant, and KRAS G13 mutant, or combinations thereof.

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

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

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

44. The method according to any one of claims 1 to 9, wherein the second therapeutic agent is an 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 according to any one of claims 44 to 46, wherein the mTOR inhibitor is selected from mTORC1 inhibitors and mTORC2 inhibitors or combinations thereof.

48. The method according to any one of claims 44 to 47, wherein the mTOR inhibitor is selected from tesimolimus, everolimus, lidafomus, sirolimus, umimimus, and zotalimus or combinations thereof.

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

50. The method according to any one of claims 1 to 49, wherein 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.

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

52. The method according to any one of claims 1 to 49, wherein 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.

53. The method of claim 50 or 52, wherein 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.

54. The method according to 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 are administered daily for at least one week.

55. The method according to 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 are administered daily for at least two weeks.

56. The method according to 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 are administered daily for at least three weeks.

57. The method according to 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 are administered daily for at least 24 days.

58. The method according to 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 are administered in a three-week cycle, wherein the therapeutically effective amount is administered daily for one week, and then not administered for the next two weeks.

59. The method according to 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 are administered in a three-week cycle, wherein the therapeutically effective amount is administered daily for two weeks, followed by a week without administration.

60. The method according to 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 are administered in a four-week cycle, wherein the therapeutically effective amount is administered daily for one week, and then not administered for the next three weeks.

61. The method according to 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 are administered in a four-week cycle, wherein the therapeutically effective amount is administered daily for two weeks, and then not administered for the next two weeks.

62. The method according to 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 are administered for at least two cycles.

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

64. The method according to 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: in, Each X 1 X 4 X 5 and X 6 Independently N or CR X ; Each X 2 and X 3 Independently N or CR Y ; Each R X Independently hydrogen, halogen, nitro, -OR 3 -SR 3 -CN, -C(=O)R 3 -C(=O)N(R) 3 2. -C(=O)OR 3 -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 -NR 3 C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by groups; Each R Y Independently hydrogen, halogen, nitro, -CN, -C(=O)R 3 -C(=O)N(R) 3 2. -C(=O)OR 3 -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 -NR 3 C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by groups; R represents halogen, nitro, -CN, or -OR. 3 -SR 3 -C(=O)R 3 -C(=O)N(R) 3 2. -C(=O)OR 3 -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 -NR 3 C(=O)OR 3 Or optionally by 1-5 R 5 C1-C6 fluoroalkyl groups substituted by the radical; R 1 It is C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C1-C6 heteroalkyl, -CN or -S(=O)2R 4 Among them, C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl groups and C1-C6 heteroalkyl groups are optionally surrounded by 1-5 R groups. 5 Substituted by groups; Each R 2 Independently halogen, nitro, -N3, -CN, -OR 3 -SR 3 -S(=O)2R 3 -N(R) 3 2. -C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by groups; Each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by a group; or If two R 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group; R 4 It is a C1-C6 alkyl, C1-C6 fluoroalkyl, or C3-C 10 Cycloalkyl or -NH2, wherein C1-C6 alkyl, C1-C6 fluoroalkyl and C3-C 10 The cycloalkyl group is optionally surrounded by 1-5 Rs. 5 Substituted by groups; Each R 5 Independently selected from halogen, oxo, -CN, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, -CH2-C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, -CH2-C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 and -N(R) 10 (R) 11 The group is replaced by ) or two R groups. 5 Combine to form C 3-5 cycloalkyl rings; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Substituted with heteroaryl groups; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl; or R 10 and R 11 Together with the nitrogen atoms to which they are attached, they independently form 4- to 7-membered heterocycles, wherein the heterocycles optionally contain an additional 1-2 heteroatoms selected from N, O and S, and wherein each heterocycle nitrogen atom, if present, is independently and optionally substituted by a C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN or C2-C3 heteroalkyl. Each R 12 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl groups; Each R 13 Selected independently from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogen, SF5, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is replaced; and n can be 0, 1, 2, 3, or 4.

65. The method according to any one of claims 1 to 64, wherein the TEAD inhibitor comprises a compound of formula (IA), or a pharmaceutically acceptable salt or solvate thereof: in, Each R X Independently hydrogen, halogen, -OR 3 -SR 3 -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 C1-C6 alkyl, C1-C6 fluoroalkyl, or C2-C4 ynyl, wherein the C1-C6 alkyl, C1-C6 fluoroalkyl, and C2-C4 ynyl are optionally surrounded by 1-5 R groups. 5 Substituted by groups; Each R Y Independently hydrogen, halogen, -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 C1-C6 alkyl, C1-C6 fluoroalkyl, or C2-C4 ynyl, wherein the C1-C6 alkyl, C1-C6 fluoroalkyl, and C2-C4 ynyl are optionally surrounded by 1-5 R groups. 5 Substituted by groups; R represents halogen, nitro, -CN, or -OR. 3 -C(=O)R 3 -C(=O)N(R) 3 2. -C(=O)OR 3 -S(=O)R 3 -S(=O)2R 3 -NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 -NR 3 C(=O)OR 3 Or optionally by 1-5 R 5 C1-C6 fluoroalkyl groups substituted by the radical; R 1 For optional use by 1-5 R 5 C1-C6 alkyl groups substituted by the radical; Each R 2 Independently halogen, nitro, -N3, -CN, -OR 3 -SR 3 -S(=O)2R 3 -N(R) 3 2. -C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by groups; Each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by a group; or If two R 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group; R 4 It is a C1-C6 alkyl, C1-C6 fluoroalkyl, or C3-C 10 Cycloalkyl or -NH2, wherein C1-C6 alkyl, C1-C6 fluoroalkyl and C3-C 10 The cycloalkyl group is optionally surrounded by 1-5 Rs. 5 Substituted by groups; Each R 5 Independently selected from halogen, oxo, -CN, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, -CH2-C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, -CH2-C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 and -N(R) 10 (R) 11 The group is replaced by ) or two R groups. 5 Combine to form C 3-5 cycloalkyl rings; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Substituted with heteroaryl groups; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl; or R 10 and R 11 Together with the nitrogen atoms to which they are attached, they independently form 4- to 7-membered heterocycles, wherein the heterocycles optionally contain an additional 1-2 heteroatoms selected from N, O and S, and wherein each heterocycle nitrogen atom, if present, is independently and optionally substituted by a C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN or C2-C3 heteroalkyl. Each R 12 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl groups; Each R 13 Selected independently from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogen, SF5, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is replaced; and n is 0, 1, or 2.

66. The method according to claim 64 or 65, wherein each R X It can be hydrogen, F, Cl, Br, -CH3, -OH, -OCH3 or -OCF3 independently.

67. The method according to any one of claims 64 to 66, wherein each R X It is hydrogen.

68. The method according to any one of claims 64 to 67, wherein each R Y It can be hydrogen, F, Cl or -CH3 independently.

69. The method according to any one of claims 64 to 68, wherein each R Y It is hydrogen.

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

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

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

73. The method according to any one of claims 64 to 72, wherein R 1 It is a C1-C6 alkyl group substituted with -OH.

74. The method according to any one of claims 64 to 72, wherein R 1 The alkyl group is a C1-C6 alkyl group substituted with a 6-membered heteroaryl ring, wherein the 6-membered heteroaryl ring is selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl, wherein the pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl are optionally replaced by 1-5 R groups. 5 The group is replaced.

75. The method of claim 74, wherein R 1 The alkyl group is a C1-C6 alkyl group substituted with a pyridinyl group, wherein the pyridinyl group is optionally replaced by 1-5 R groups. 5 The group is replaced.

76. The method according to any one of claims 64 to 72, wherein R 1 It is a C1-C6 alkyl group substituted with 1, 2 or 3 substituents, each substituent being independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2 and pyridyl.

77. The method according to any one of claims 64 to 76, wherein each R 2 It can be F, Cl, -OCF3 or -CF3 independently.

78. The method according to any one of claims 64 to 77, wherein each R 2 It can be F or Cl independently.

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

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

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

82. The method according to 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: in, Each X 1 X 2 X 3 X 4 X 5 and X 6 Independently N or CR X ; Each R X Independently hydrogen, halogen, nitro, -OR 3 -SR 3 -CN, -C(=O)R 3 -C(=O)N(R) 3 2. -C(=O)OR 3 -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 -NR 3 C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by groups; R represents halogen, nitro, -CN, or -OR. 3 -SR 3 -C(=O)R 3 -C(=O)N(R) 3 2. -C(=O)OR 3 -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 -NR 3 C(=O)OR 3 Or optionally by 1-5 R 5 C1-C6 fluoroalkyl groups substituted by the radical; R 1 It is C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C1-C6 heteroalkyl, -CN or -S(=O)2R 4 Among them, C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl groups and C1-C6 heteroalkyl groups are optionally surrounded by 1-5 R groups. 5 Substituted by groups; Each R 2 Independently halogen, nitro, -N3, -CN, -OR 3 -SR 3 -S(=O)2R 3 -N(R) 3 2. -C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by groups; Each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by a group; or If two R 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group; R 4 It is a C1-C6 alkyl, C1-C6 fluoroalkyl, or C3-C 10 Cycloalkyl or -NH2, wherein C1-C6 alkyl, C1-C6 fluoroalkyl and C3-C 10 The cycloalkyl group is optionally surrounded by 1-5 Rs. 5 Substituted by groups; Each R 5 Independently selected from halogen, oxo, -CN, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, -CH2-C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, -CH2-C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 and -N(R) 10 (R) 11 The group is replaced by ) or two R groups. 5 Combine to form C 3-5 cycloalkyl rings; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Substituted with heteroaryl groups; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl; or R 10 and R 11 Together with the nitrogen atoms to which they are attached, they independently form 4- to 7-membered heterocycles, wherein the heterocycles optionally contain an additional 1-2 heteroatoms selected from N, O and S, and wherein each heterocycle nitrogen atom, if present, is independently and optionally substituted by a C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN or C2-C3 heteroalkyl. Each R 12 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl groups; Each R 13 Selected independently from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogen, SF5, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is replaced; and n can be 0, 1, 2, 3, or 4.

83. The method according to 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: in, Each X 3 X 5 and X 6 Independently N or CR X ; X 4 For CR X ; Each R X Independently hydrogen, halogen, nitro, -OR 3 -SR 3 -CN, -C(=O)R 3 -C(=O)N(R) 3 2. -C(=O)OR 3 -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 -NR 3 C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by groups; R represents halogen, nitro, -CN, or -OR. 3 -SR 3 -C(=O)R 3 -C(=O)N(R) 3 2. -C(=O)OR 3 -S(=O)R 3 -S(=O)2R 3 -N(R) 3 )2、-NR 3 S(=O)2R 3 -NR 3 C(=O)R 3 -NR 3 C(=O)OR 3 Or optionally by 1-5 R 5 C1-C6 fluoroalkyl groups substituted by the radical; R 1 It is C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C1-C6 heteroalkyl, -CN or -S(=O)2R 4 Among them, C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl groups and C1-C6 heteroalkyl groups are optionally surrounded by 1-5 R groups. 5 Substituted by groups; Each R 2 Independently halogen, nitro, -N3, -CN, -OR 3 -SR 3 -S(=O)2R 3 -N(R) 3 2. -C(=O)OR 3 C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by groups; Each R 3 Independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl or -CH2-C 1-9 Heteroaryl groups, including C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, and C3-C 10 cycloalkyl, C2-C 10 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is selectively coated with 1-5 R groups. 5 Substituted by a group; or If two R 3 On the same nitrogen atom, then the two R 3 Together with the nitrogen atoms they are attached to, they form optional groups of 1-5 R atoms. 5 The C3-C7 heterocyclic alkyl group substituted by the group; R 4 It is a C1-C6 alkyl, C1-C6 fluoroalkyl, or C3-C 10 Cycloalkyl or -NH2, wherein C1-C6 alkyl, C1-C6 fluoroalkyl and C3-C 10 The cycloalkyl group is optionally surrounded by 1-5 Rs. 5 Substituted by groups; Each R 5 Independently selected from halogen, oxo, -CN, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR 10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, -CH2-C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, -CH2-C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 heteroaryl and -CH2-C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 and -N(R) 10 (R) 11 The group is replaced by ) or two R groups. 5 Combine to form C 3-5 cycloalkyl rings; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Substituted with heteroaryl groups; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl; or R 10 and R 11 Together with the nitrogen atoms to which they are attached, they independently form 4- to 7-membered heterocycles, wherein the heterocycles optionally contain an additional 1-2 heteroatoms selected from N, O and S, and wherein each heterocycle nitrogen atom, if present, is independently and optionally substituted by a C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN or C2-C3 heteroalkyl. Each R 12 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-6 cycloalkyl and C 2-9 Heterocyclic alkyl groups; Each R 13 Selected independently from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogen, SF5, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is replaced; and n can be 0, 1, 2, 3, or 4.

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

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

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

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

88. The method according to any one of claims 1 to 84, wherein the recurrent 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 cancer.

92. The method according to any one of claims 1 to 91, wherein the recurrent or refractory cancer is selected from mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma, lung cancer, bladder cancer, cutaneous neurofibroma, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, undifferentiated 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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