Compounds and methods for treating cancer

Abstract

Provided herein are compounds and pharmaceutical compositions containing the compounds that are useful for treating cancer, such as mesothelioma. Also, provided herein are methods of using the compounds or the pharmaceutical compositions for treating cancer, such as mesothelioma. Specific cancers include those that are mediated by YAP / TAZ or those that are modulated by the interaction between YAP / TAZ and TEAD, such as mesothelioma.

Description

COMPOUNDS AND METHODS FOR TREATING CANCERCROSS-REFERENCE

[0001] This application claims benefit of U.S. Provisional Patent Application No. 63 / 517,799 filed on August 4, 2023 and U.S. Provisional Patent Application No. 63 / 592,448 filed on October 23, 2023, each of which is incorporated herein by reference in its entirety.BACKGROUND OF THE DISCLOSURE

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

[0003] In one aspect, provided herein are compounds and pharmaceutical compositions comprising said compounds. In some embodiments, the compounds and pharmaceutical compositions disclosed herein comprise a therapeutically effective amount of a TEAD inhibitor. In some embodiments, the subject compounds and pharmaceutical compositions are useful for the treatment of cancer, such as mesothelioma.

[0004] In another aspect, provided herein are methods of treating cancer, such as mesothelioma, in a patient by administering to the patient the compounds or the pharmaceutical compositions described herein.

[0005] In one aspect, described herein is a method for treating mesothelioma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount a TEAD inhibitor, wherein the TEAD inhibitor associates with one or more components of the Hippo pathway network comprising TEAD, transcriptional coactivator with PDZ binding motif (TAZ), or Yes-associated protein transcriptional coactivator (YAP); and wherein the TEAD inhibitor is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereofFormula (I) wherein, each X1, X4, X5, and X6is independently N or CRX; each X2and X3is independently N or CRY; each Rxis independently hydrogen, halogen, nitro, -OR3, -SR3, -CN, -C(=O)R3, - C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, - NR3C(=O)R3, -NR3C(=O)OR3, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C2-C4alkenyl, substituted or unsubstituted C2-C4alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2- Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each RYis independently hydrogen, halogen, nitro, -CN, -C(=O)R3, -C(=O)N(R3)2, - C(=O)OR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, - NR3C(=O)OR3, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C2-C4alkenyl, substituted or unsubstituted C2-C4alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2- Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R is halogen, nitro, -CN, -OR3, -SR3, -C(=O)R3, -C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, - S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, -NR3C(=O)OR3, or substituted or unsubstituted C1-C6fluoroalkyl;R1is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C2-Cealkenyl, substituted or unsubstituted C2-Cealkynyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2- Cioheterocycloalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, or - S(=O)2R4;each R2is independently halogen, nitro, -N3, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, - C(=O)OR3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2- Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl;R4is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or -NH2; and n is 0, 1, 2, 3, or 4.

[0006] In some embodiments, the TEAD inhibitor is a compound of Formula (I- A), or a pharmaceutically acceptable salt or solvate thereof:Formula (I- A) wherein, each Rxis independently hydrogen, halogen, -OR3, -SR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, - NR3S(=O)2R3, -NR3C(=O)R3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C2-C4alkynyl; each RYis independently hydrogen, halogen, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C2-C4alkynyl;R is halogen, nitro, -CN, -OR3, -C(=O)R3, -C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, - S(=O)2R3, -NR3S(=O)2R3, -NR3C(=O)R3, -NR3C(=O)OR3, or substituted or unsubstituted C1-C6fluoroalkyl;R1is C1-C6alkyl optionally substituted with(a) -OR3; and R3is hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C3-C10cycloalkyl;(b) 6-membered heteroaryl ring selected from substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, and substituted or unsubstituted triazinyl; or(c) 1, 2, or 3 substituents each independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, and pyridinyl; each R2is independently halogen, nitro, -N3, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, - C(=O)OR3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2- Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl; and n is 0, 1, or 2.

[0007] In some embodiments, the TEAD inhibitor is selected from:pharmaceutically acceptable salt or solvate thereof. In some embodiments, the TEAD inhibitor ipharmaceutically acceptable salt or solvate thereof. In some embodiments, the mesothelioma is a relapsed or refractory mesothelioma. In some embodiments, the mesothelioma comprises a mutation in a neurofibromatosis type 2 (NF2) gene. In some embodiments, the mesothelioma comprises pleural mesothelioma, peritoneal mesothelioma, or pericardial mesothelioma, or any combination thereof. In some embodiments, the mesothelioma comprises epithelioid mesothelioma, sarcomatoid mesothelioma, or dermoplastic mesothelioma, or any combination thereof. In some embodiments, administering the TEAD inhibitor inhibits transcriptional coactivator with PDZ binding motif / Yes-associated protein transcriptional coactivator (TAZ / YAP). In some embodiments, administering the TEAD inhibitor inhibits one or more of proteins encompassed by, or related to, the Hippo pathway in the subject. In some embodiments, X1is CRX; and each X2and X3is CRY. In some embodiments, each X4, X5, and X6is CRX. In some embodiments, each Rxis independently hydrogen, halogen, -OR3, -SR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, - NR3C(=O)R3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci-Cefluoroalkyl, or substituted or unsubstituted C2-C4alkynyl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C3-C10cycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl. In some embodiments, each Rxis independently hydrogen, F, Cl, Br, -CH3, -OH, -OCH3, or -OCF3. In some embodiments, each Rxis hydrogen. In some embodiments, each RYis independently hydrogen, halogen, -S(=O)R3, -S(=O)2R3, -N(R3)2, - NR3S(=O)2R3, -NR3C(=O)R3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C2-C4alkynyl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C3-C10cycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl. In some embodiments, each RYis independently hydrogen, F, Cl, or -CH3. In some embodiments, each RYis hydrogen. In some embodiments, R1is substituted or unsubstituted C1-C6alkyl. In some embodiments, R1is C1-C6alkyl substituted with -OR3; and R3is hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C3-C10cycloalkyl. In some embodiments, R1is C1-C6alkyl substituted with -OH. In some embodiments, R1is C1-C6alkyl substituted with 6-membered heteroaryl ring selected from substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, and substituted or unsubstituted triazinyl. In some embodiments, R1is C1-C6alkyl substituted with pyridinyl. In some embodiments, R1is C1-C6alkyl substituted with 1, 2, or 3 substituents each independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, and pyridinyl. In some embodiments, R is halogen, nitro, -CN, -OR3, -C(=O)R3, -C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, - S(=O)2R3, -NR3S(=O)2R3, -NR3C(=O)R3, -NR3C(=O)OR3, or substituted or unsubstituted Ci- Cefluoroalkyl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted C2- Cioheterocycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl. 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, each R2is independently F, Cl, -OCF3, or -CF3. In some embodiments, each R2is independently F or Cl. In some embodiments, n is 0. In some embodiments, n is 1 or 2. In some embodiments, the compoundof Formula (I) or (I- A), or the pharmaceutically acceptable salt or solvate thereof, is administered as an oral formulation. In some embodiments, the compound of Formula (I) or (I- A), or the pharmaceutically acceptable salt or solvate thereof, is administered in a capsule. In some embodiments, the compound of Formula (I) or (I- A), or the pharmaceutically acceptable salt or solvate thereof, is administered in a 15 mg, 25 mg, 50 mg, 70 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg amount. In some embodiments, the compound of Formula (I) or (I- A), or the pharmaceutically acceptable salt or solvate thereof, is administered in a 15 mg amount. In some embodiments, the compound of Formula (I) or (I- A), or the pharmaceutically acceptable salt or solvate thereof, is administered in a 25 mg amount. In some embodiments, the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered in a 50 mg amount. In some embodiments, the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered in a 70 mg amount. In some embodiments, the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered in a 100 mg amount. In some embodiments, the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for at least a week. In some embodiments, the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for at least two weeks. In some embodiments, the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for at least three weeks. In some embodiments, the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of three weeks, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for one week, and not administered for the following two weeks. In some embodiments, the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of four weeks, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for one week, and then not administered for the following three weeks. In some embodiments, the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of three weeks, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for two weeks, and then not administered for the following week. In some embodiments, the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of four weeks, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for two weeks, and then not administered for the following two weeks. In some embodiments, thecompound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for 15 days, and then administered on days 1, 8, and 15 thereof. In some embodiments, the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of four weeks, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for two weeks, and then not administered for the following two weeks, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered at 50 mg. In some embodiments, the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of four weeks, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for two weeks, and then not administered for the following two weeks, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered at 100 mg.INCORPORATION BY REFERENCE

[0008] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Various aspects of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0010] Fig. 1 illustrates a schematic representation of the Hippo signaling network. Hippo pathway components shaded in dark gray indicate components that inhibit YAP / TAZ activity. Hippo pathway components shaded in light gray indicate components that promote YAP / TAZ activity. Pointed and blunt arrowheads indicate activating and inhibitory interactions, respectively. Abbreviations: a-CAT (a-Catenin), AJUB (Ajuba), AMOT (Angiomotin), P-TRCP (P-transducing repeat containing protein), CK1 (Casein Kinase 1), CRB (Crumbs), E-CAD (E-cadherin), EX (Expanded), GPCR (G-protein coupled receptor), HIPK (Homeodomain interacting protein kinase), KIBRA (Kidney brain), LATS (Large tumor suppressor), LGL (Lethal giant larvae), MASK (Multiple ankyrin single KH), MER (Merlin), MOB (Mps one binder), MST (Mammalian sterile 20 like), PALS (Protein Associated with Lin-7), PATJ (Palsl -associated tight junction protein), PP2A (Protein phosphatase 2 A), PTPN14 (Protein tyrosine phosphatase non -receptor type 14), RASSF(Ras associated factor), SAV (Salvador), SCRIB (Scribble), SIK (Salt inducible kinase), TAO (Thousand and one amino acid protein), TAZ (transcriptional coactivator with PDZ-binding motif), TEAD (TEA domain protein), VGL4 (Vestigial-like 4), WBP2 (WW domain binding protein 2), YAP (Yes associated protein), ZO (Zonula occludens), ZYX (Zyxin).

[0011] Fig. 2 illustrates a schematic representation of the Hippo signaling pathway regulated by G alpha proteins.

[0012] Figs. 3A-3E illustrate selectivity of Compound 42 in five different mesothelioma lines showing selectivity for NF2 deficiency (NCI-H226 (NF2 deficient) in Fig. 3A; NCI-H2052 (NF2 homozygous mutant) in Fig. 3B; NCI-H2373 (NF2 homozygous deletion) in Fig. 3C; NCI-H28 (NF2 wild-type) in Fig. 3D; and NCI-H2452 (NF2 wild-type) in Fig. 3E).

[0013] Figs. 4A-4C illustrate the pharmacokinetics of Compound 42 (mean Cmax vs. dose in Fig. 4A; mean AUCiast vs. dose in Fig. 4B; and mean concentration vs. time in Fig. 4C).

[0014] Fig. 5 is a waterfall plot describing the % change in target lesions in mesothelioma patients with at least one post-baseline evaluation (n = 32). Schedule A: continuous daily dosing; Schedule B: 2 weeks on, 1 week off; Schedule C: 1 week on, 2 weeks off; Schedule D: 2 weeks on, 2 weeks off; Schedule E: 1 week on, 3 weeks off; and Schedule F: daily for 15 days then weekly thereafter.

[0015] Fig. 6 is a waterfall plot describing the % change in target lesions in solid tumor patients excluding mesothelioma, meningioma, schwannoma and MPNST, with at least one post-baseline evaluation (n=13). Schedule A: continuous daily dosing; Schedule B: 2 weeks on, 1 week off; Schedule C: 1 week on, 2 weeks off; Schedule D: 2 weeks on, 2 weeks off; Schedule E: 1 week on, 3 weeks off; and Schedule F: daily for 15 days then weekly thereafter.

[0016] Figs. 7A-7C are images of peritoneal mesothelioma with no NF2 mutation, taken at different time points and used for the measurement of longest diameters (mm) and response. Fig. 7A for baseline; Fig. 7B for the follow-up after three months; and Fig. 7C for the follow-up after 13 months. Details of the longest diameters (mm) and response evaluation criteria in solid tumors (RECIST) in a patient with peritoneal mesothelioma without NF2 mutation are shown in Table 6.

[0017] Figs. 8A and 8B are images of pleural and peritoneal mesothelioma with unknown NF2 mutation status, taken at different time points and used for the measurement of longest diameters (mm) and response. Fig. 8A for baseline; and Fig. 8B for the follow-up after three months. Details of the longest diameters (mm) of the pleural rind target lesions and modified response evaluation criteria in solid tumors (mRECIST) in a patient with pleural and peritoneal mesothelioma with unknown NF2 mutation status are shown in Table 7.DETAILED DESCRIPTION OF THE DISCLOSURECertain Terminology

[0018] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and / or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting.

[0019] As used herein, in some embodiments, ranges and amounts are expressed as “about” a particular value or range. “About” also includes the exact amount. Hence, “about 5 pL” means “about 5 pL” and also “5 pL.” Generally, the term “about” includes an amount that is expected to be within experimental error.

[0020] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0021] As used herein, the terms “individual(s)”, “subject(s)” and “patient(s)” mean any mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is a nonhuman. None of the terms require or are limited to situations characterized by the supervision (e.g., constant or intermittent) of a health care worker (e.g., a doctor, a registered nurse, a nurse practitioner, a physician’s assistant, an orderly, or a hospice worker).

[0022] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0023] " Amino" refers to the -NH2 radical.

[0024] "Cyano" refers to the -CN radical.

[0025] “Hydroxyl” refers to the -OH radical.

[0026] "Nitro" refers to the -NO2 radical.

[0027] " Oxa" refers to the -O- radical.

[0028] " Oxo" refers to the =0 radical.

[0029] " Thioxo" refers to the =S radical.

[0030] " Imino" refers to the =N-H radical.

[0031] " Oximo" refers to the =N-0H radical.

[0032] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., Ci-Cs alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., Cs-Cs alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl (n-propyl), 1 -methylethyl (isopropyl), 1 -butyl (n-butyl), 1 -methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1 -dimethylethyl (tert-butyl), 1 -pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SIU, -OC(O)Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORf, -OC(O)NRaRf, -N(Ra)C(O)Rf, -N(Ra)S(O)tRf(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRf(where t is 1 or 2), and -S(O)tN(Ra)2 (where t is 1 or 2), where each Rais independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and each Rfis independently alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0033] " Amino-alkyl" refers to a radical of the formula: -alkyl-NTU

[0034] "Hydroxyl-alkyl" refers to a radical of the formula: -alkyl-OH.

[0035] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0036] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (z.e., vinyl), prop-l-enyl (z.e., allyl), but- 1-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like. Unless stated otherwise specifically in thespecification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORf, -OC(O)NRaRf, -N(Ra)C(O)Rf, -N(Ra)S(O)tRf(where t is 1 or 2), S(O)tORa(where t is 1 or 2), S(O)tRf(where t is 1 or 2), and S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and each Rf is independently alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0037] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl has two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORf, -OC(O)NRaRf, -N(Ra)C(O)Rf, -N(Ra)S(O)tRf(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRf(where t is 1 or 2), and -S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and each Rfis independently alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0038] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, ^-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In some embodiments, the points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., Ci-Cs alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2 alkylene). In otherembodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., Cs-Cs alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, - SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORf, -OC(O)- NRaRf, -N( Ra)C(O)Rf, -N(Ra)S(O)tRf(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRf(where t is 1 or 2), and -S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and each Rfis independently alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0039] "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance with the Hiickel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-CN, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra) C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0040] "Aryloxy" refers to a radical bonded through an oxygen atom of the formula -O-aryl, where aryl is as defined above.

[0041] "Aralkyl" refers to a radical of the formula -Rc-aryl where Rcis an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0042] "Aralkenyl" refers to a radical of the formula -Rd-aryl where Rdis an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0043] "Aralkynyl" refers to a radical of the formula -Re-aryl, where Reis an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0044] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, and in some embodiments, include fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. In some embodiments, the carbocyclyl is saturated, (z.e., containing single C-C bonds only) or unsaturated (z.e., containing one or more double bonds or triple bonds.) A fully saturated carbocyclyl radical is also referred to as "cycloalkyl." Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In certain embodiments, a cycloalkyl comprises three to eight carbon atoms (e.g., Cs-Cs cycloalkyl). In other embodiments, a cycloalkyl comprises three to seven carbon atoms (e.g., C3-C7 cycloalkyl). In other embodiments, a cycloalkyl comprises three to six carbon atoms (e.g., C3-C6 cycloalkyl). In other embodiments, a cycloalkyl comprises three to five carbon atoms (e.g., C3-C5 cycloalkyl). In other embodiments, a cycloalkyl comprises three to four carbon atoms (e.g., C3-C4 cycloalkyl). An unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbomyl (z.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo,fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -CN, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O )Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0045] "Carbocyclylalkyl" refers to a radical of the formula -Rc-carbocyclyl where Rcis an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0046] " Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo substituents.

[0047] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0048] "Heterocyclyl" or “heterocycle” refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which include fused or bridged ring systems in some embodiments. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heterocyclyl radical is partially or fully saturated. In some embodiments, the heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). In some embodiments, the heterocyclyl is saturated, (z.e., containing single bonds only) or unsaturated (z.e., containing one or more double bonds or triple bonds.) A fully saturated heterocyclyl radical is also referred to as "heterocycloalkyl. " Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl,pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -CN, -Rb-CN , -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)O Ra, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)t Ra(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0049] “Heteroalkyl” refers to an alkyl group as defined above in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, - N(alkyl)-, sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6heteroalkyl. In some embodiments, the heteroalkyl comprises 1, 2, or 3 heteroatoms. In some embodiments, the alkyl part of the heteroalkyl radical is optionally substituted as defined for an alkyl group. Representative heteroalkyl groups include, but are not limited to -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2OH, -CH2OCH3, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, -CH2CH2OH, -CH2CH2OCH3, - CH2CH2OCH2CH2NH2, or -CH2CH2OCH2CH2OH.

[0050] "Heterocyclylalkyl" refers to a radical of the formula -Rc-heterocyclyl where Rcis an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

[0051] "Heterocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O- Rc-heterocyclyl where Rcis an alkylene chain as defined above. If the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0052] "Heteroaryl" refers to a radical derived from a 3 - to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, in some embodiments, the heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, z.e., it contains a cyclic, delocalized (4n+2) 7i-electron system in accordance with the Hiickel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 4-6 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl is monocyclic heteroaryl. In some embodiments, the monocyclic heteroaryl is a 5-membered or 6- membered heteroaryl. In some embodiments, heteroaryl is a C1-C9 heteroaryl. In some embodiments, monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, a bicyclic heteroaryl is a C5-C9 heteroaryl. Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[Z>][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodi oxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotri azolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5.6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H- benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1.6-naphthyri dinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1 -phenyl- 177-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl,5.6.7.8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6.7.8.9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O )Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, - Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0053] "A-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An / f-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0054] " C-heteroaryl" refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0055] "Heteroaryl oxy" refers to radical bonded through an oxygen atom of the formula -O- heteroaryl, where heteroaryl is as defined above.

[0056] "Heteroarylalkyl" refers to a radical of the formula -Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl isoptionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroaryl alkyl radical is optionally substituted as defined above for a heteroaryl group.

[0057] "Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O- Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroaryl alkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0058] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (5)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans). Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term "geometric isomer" refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term "positional isomer" refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0059] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0060] "Optional" or "optionally" means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.

[0061] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Pharmaceutically acceptable salts of the compounds described herein are optionally pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0062] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates,methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997), which is hereby incorporated by reference in its entirety). In some embodiments, acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0063] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, 7V,7V-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N- methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, TV-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.

[0064] As used herein, "treatment" or "treating " or "palliating" or "ameliorating" are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including, but not limited to, therapeutic benefit and / or a prophylactic benefit. By "therapeutic benefit" is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is afflicted with the underlying disorder in some embodiments. For prophylactic benefit, in some embodiments, the compositions are administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.

[0065] "Prodrug" is meant to indicate a compound that is converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharmaceutically acceptable. In some embodiments, a prodrug is inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).

[0066] A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein.

[0067] The term "prodrug" is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. In some embodiments, prodrugs of an active compound, as described herein, are prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino, or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino, or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol or amine functional groups in the active compounds and the like.COMPOUNDS

[0068] In one apsect, the compounds disclosed herein are TEAD inhibitors.

[0069] In one aspect, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:Formula (I) wherein,each X1, X4, X5, and X6is independently N or CRX; each X2and X3is independently N or CRY; each Rxis independently hydrogen, halogen, nitro, -OR3, -SR3, -CN, -C(=O)R3, - C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, - NR3C(=O)R3, -NR3C(=O)OR3, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C2-C4alkenyl, substituted or unsubstituted C2-C4alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each RYis independently hydrogen, halogen, nitro, -CN, -C(=O)R3, -C(=O)N(R3)2, - C(=O)OR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, - NR3C(=O)OR3, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted C2-C4alkenyl, substituted or unsubstituted C2-C4alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R is halogen, nitro, -CN, -OR3, -SR3, -C(=O)R3, -C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, - S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, -NR3C(=O)OR3, or substituted or unsubstituted Ci-Cefluoroalkyl;R1is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C2-Cealkenyl, substituted or unsubstituted C2-Cealkynyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2- Cioheterocycloalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, or -S(=O)2R4; each R2is independently halogen, nitro, -N3, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, - C(=O)OR3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl;R4is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or -NH2; and n is 0, 1, 2, 3, or 4.

[0070] For any and all of the embodiments of a compound of Formula (I), substituents are selected from among a subset of the listed alternatives. For example, in some embodiments X1is N or CRX. In other embodiments, X1is N. In some embodiments, X1is CRX.

[0071] In some embodiments, X1is CRX; and each X2and X3is CRY. In some embodiments, X1is N; and each X2and X3is CRY. In some embodiments, X1is CRX; X2is CRY; and X3is N.

[0072] In some embodiments, each X4, X5, and X6is CRX. In some embodiments, X4is N; and each X5and X6is CRX. In some embodiments, each X4and X5is CRX; and X6is N.

[0073] In some embodiments, each Rxis independently hydrogen, halogen, -OR3, -SR3, -CN, - S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, substituted or unsubstituted Ci- Cealkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C2-C4alkenyl, substituted or unsubstituted C2-C4alkynyl, or substituted or unsubstituted C1-C6heteroalkyl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted C2-Cioheterocycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl. In some embodiments, each Rxis independently hydrogen, halogen, -OR3, -SR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, - NR3S(=O)2R3, -NR3C(=O)R3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C2-C4alkynyl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C3-C10cycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0074] In some embodiments, each Rxis independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, - CH2OH, -CH2CH2OH, -CH2CN, -CH2C(=O)OH, -CH2C(=O)OCH3, -CH2C(=O)OCH2CH3, - CH2C(=O)NH2, -CH2C(=O)NHCH3, -CH2C(=O)N(CH3)2, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, - CH2F, -CHF2, -CF3, -CH=CH2, -C=CH, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,oxetanyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy, azetidinyl, pyrrolidinyl, tetrazolyl, -CN, -OH, -OCH3, -OCH2CH3, -OCH2CH2OH, -OCH2CN, -OCF3, -C(=O)OH, -C(=O)OCH3, - C(=O)OCH2CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -NH2, -NHCH3, -N(CH3)2, - NHC(=O)CH3, -N(CH3)C(=O)CH3, -NHC(=O)OCH3, -N(CH3)C(=O)OCH3, -S(=O)CH3, - S(=O)2CH3, -NHS(=O)2CH3, or -N(CH3)S(=O)2CH3. In some embodiments, each Rxis independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, cyclopropyl, -C=CH, -OH, -OCH3, - OCH2CH3, -OCF3, -SCH3, cyclopropyloxy, -NH2, -NHC(=O)CH3, -N(CH3)C(=O)CH3, - NHS(=O)2CH3, -N(CH3)S(=O)2CH3, -S(=O)CH3, or -S(=O)2CH3. In some embodiments, each Rxis independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, cyclopropyl, -OH, -OCH3, -OCH2CH3, - OCF3, cyclopropyloxy, -NH2, -NHC(=O)CH3, -NHS(=O)2CH3, -S(=O)CH3, or -S(=O)2CH3. In some embodiments, each Rxis independently hydrogen, F, Cl, Br, -CH3, -OH, -OCH3, or -OCF3. In some embodiments, each Rxis independently hydrogen, F, Cl, -CH3, -OCH3, or -OCF3. In some embodiments, each Rxis independently hydrogen, F, or -OCH3. In some embodiments, each Rxis hydrogen.

[0075] In some embodiments, each RYis independently hydrogen, halogen, -CN, -S(=O)R3, - S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C2-C4alkenyl, substituted or unsubstituted C2-C4alkynyl, or substituted or unsubstituted C1-C6heteroalkyl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3- Ciocycloalkyl, or substituted or unsubstituted C2-Cioheterocycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl. In some embodiments, each RYis independently hydrogen, halogen, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C2-C4alkynyl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C3-C10cycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0076] In some embodiments, each RYis independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, - CH2OH, -CH2CH2OH, -CH2CN, -CH2C(=O)OH, -CH2C(=O)OCH3, -CH2C(=O)OCH2CH3, - CH2C(=O)NH2, -CH2C(=O)NHCH3, -CH2C(=O)N(CH3)2, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, - CH2F, -CHF2, -CF3, -CH=CH2, -C=CH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -NHC(=O)CH3, -N(CH3)C(=O)CH3, -NHC(=O)OCH3, -N(CH3)C(=O)OCH3, - S(=O)CH3, -S(=O)2CH3, -NHS(=O)2CH3, or -N(CH3)S(=O)2CH3. In some embodiments, each RYis independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH5, cyclopropyl, -C=CH -NH2, - NHC(=O)CH3, -N(CH3)C(=O)CH3, -NHS(=O)2CH3, -N(CH3)S(=O)2CH3, -S(=O)CH3, or - S(=O)2CH3. In some embodiments, each RYis independently hydrogen, F, Cl, Br, I, -CH3, - CH2CH3, cyclopropyl, -NH2, -NHC(=O)CH3, -NHS(=O)2CH3, -S(=O)CH3, or -S(=O)2CH3. In some embodiments, each RYis independently hydrogen, F, Cl, or -CH3. In some embodiments, each RYis independently hydrogen or F. In some embodiments, each RYis hydrogen.

[0077] In some embodiments, R1is substituted or unsubstituted C1-C6alkyl.

[0078] In some embodiments, R1is C1-C6alkyl substituted with substituted or unsubstituted C2- Cealkenyl, substituted or unsubstituted C2-Cealkynyl, or -CN.

[0079] In some embodiments, R1is C1-C6alkyl substituted with -OR3; and R3is hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci-Cefluoroalkyl, or substituted or unsubstituted C3-Ciocycloalkyl.

[0080] In some embodiments, R1is C1-C6alkyl substituted with -C(=O)N(R5)2 or -N(R5)2; wherein each R5is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C2-Cealkenyl, substituted or unsubstituted C2-Cealkynyl, or -CN; or two R5are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C? heterocycloalkyl.

[0081] In some embodiments, R1is C1-C6alkyl substituted with substituted or unsubstituted C3- Cscycloalkyl or substituted or unsubstituted C2-C7heterocycloalkyl.

[0082] In some embodiments, R1is C1-C6alkyl substituted with cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0083] In some embodiments, R1is C1-C6alkyl substituted with oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, or piperidinyl.

[0084] In some embodiments, R1is C1-C6alkyl substituted with substituted or unsubstituted phenyl, wherein if phenyl is substituted, then it is substituted with 1, 2, 3, or 4 substituents selected from halogen, nitro, -CN, -OR3, -N(R3)2, -C(=O)R3, -C(=O)N(R3)2, -C(=O)OR3, substituted or unsubstituted C1-C6alkyl, and substituted or unsubstituted C1-C6fluoroalkyl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C3- Ciocycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C? heterocycloalkyl.

[0085] In some embodiments, R1is C1-C6alkyl substituted with 5-membered heteroaryl ring containing at least one nitrogen atom.

[0086] In some embodiments, R1is C1-C6alkyl substituted with 5-membered heteroaryl ring selected from substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted oxadiazolyl, and substituted or unsubstituted thiadiazolyl.

[0087] In some embodiments, R1is C1-C6alkyl substituted with 5-membered heteroaryl ring selected from:whereineach Rzis independently hydrogen, halogen, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, -C(=O)OR3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted C2-Cioheterocycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0088] In some embodiments, R1is C1-C6alkyl substituted with a substituted or unsubstituted monocyclic 6-membered heteroaryl ring containing at least one nitrogen atom. In some embodiments, R1is C1-C6alkyl substituted with a substituted or unsubstituted monocyclic 6- membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms. In some embodiments, R1is Ci- Cealkyl substituted with 6-membered heteroaryl ring selected from substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, and substituted or unsubstituted triazinyl. In some embodiments, R1is C1-C6alkyl substituted with substituted or unsubstituted pyridinyl. In some embodiments, R1is C1-C6alkyl substituted with pyridinyl. In some embodiments, R1is C1-C6alkyl substituted with 2-pyridinyl.

[0089] In some embodiments, R1is C1-C6alkyl substituted with 6-membered heteroaryl ring selected from:each Rzis independently hydrogen, halogen, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, -C(=O)OR3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; andeach R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted C2-Cioheterocycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0090] In some embodiments, R1is C1-C6alkyl substituted with bicyclic 6 / 5 fused heteroaryl ring. In some embodiments, R1is C1-C6alkyl substituted with bicyclic 6 / 5 fused heteroaryl ring selected from substituted or unsubstituted indolyl, substituted or unsubstituted isoindolyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted isobenzofuranyl, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted indazolyl, substituted or unsubstituted benzoimidazolyl, substituted or unsubstituted benzooxazolyl, substituted or unsubstituted benzoisoxazolyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted benzoisothiazolyl, substituted or unsubstituted benzotri azolyl, substituted or unsubstituted benzooxadi azolyl, substituted or unsubstituted benzothiadi azolyl, substituted or unsubstituted indolizinyl, and substituted or unsubstituted imidazopyridinyl.

[0091] In some embodiments, R1is C1-C6alkyl substituted with bicyclic 6 / 5 fused heteroaryl ring selected from:each Rzis independently hydrogen, halogen, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, -C(=O)OR3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted C2-Cioheterocycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0092] In some embodiments, R1is C1-C6alkyl substituted with a substituted or unsubstituted bicyclic 6 / 6 fused heteroaryl ring containing at least one nitrogen atom. In some embodiments, R1is C1-C6alkyl substituted with a substituted or unsubstituted bicyclic 6 / 6 fused heteroaryl ring containing 1, 2, 3, or 4 nitrogen atoms. In some embodiments, R1is C1-C6alkyl substituted with bicyclic 6 / 6 fused heteroaryl ring selected from substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted cinnolinyl, substituted or unsubstituted quinazolinyl, substituted or unsubstituted quinoxalinyl, substituted or unsubstituted naphthyridinyl, substituted or unsubstituted pyridopyrimidinyl, substituted or unsubstituted pyridopyrazinyl, substituted or unsubstituted pyridopyridazinyl, substituted or unsubstituted pyrimidopyrimidinyl, and substituted or unsubstituted pteridinyl.

[0093] In some embodiments, R1is C1-C6alkyl substituted with 6 / 6 fused heteroaryl ring selected from:each Rzis independently hydrogen, halogen, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, -C(=O)OR3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted C2-Cioheterocycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0094] In some embodiments, R1is C1-C6alkyl substituted with 1, 2, or 3 substituents each independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, and pyridinyl. In someembodiments, R1is C1-C6alkyl substituted with 1 or 2 substituents each independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, and pyridinyl. In some embodiments, R1is Ci- Cealkyl substituted with 1 or 2 substituents each independently selected from -OH and pyridinyl. In some embodiments, R1is C1-C6alkyl substituted with 1 or 2 substituents each independently selected from -NH2 and pyridinyl. In some embodiments, R1is C1-C6alkyl substituted with 1 or 2 substituents each independently selected from -OH and -NH2. In some embodiments, R1is Ci- Cealkyl substituted with -OH. In some embodiments, R1is C1-C6alkyl substituted with -NH2.

[0095] In some embodiments, each Rzis independently hydrogen, F, Cl, Br, -CH3, -CH2CH3, - CH2F, -CHF2, -CF3, -CN, -OH, -0CH3, -OCH2CH3, -0CF3, -NH2, -NHCH3, or -N(CH3)2. In some embodiments, each Rzis independently hydrogen, F, Cl, Br, -CH3, -CN, -OCH3, -NH2, -NHCH3, or -N(CH3)2. In some embodiments, each Rzis independently hydrogen, Cl, Br, -CH3, -OCH3, -NH2, or -N(CH3)2. In some embodiments, each Rzis hydrogen.

[0096] In some embodiments, R1is C1-C6alkyl substituted with halogen, -CN, -OR3, -SR3, -S(=O) R3, -S(=O)2R3, -N(R3)2, -C(=O)OR3, -C(=O)N(R3)2, -CR3=C(R3)2, -C=CR3, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, or substituted or unsubstituted aryl; and each R3is independently hydrogen, substituted or unsubstituted Ci- Cealkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted Ci- Ceheteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted C2- Cioheterocycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0097] In some embodiments, R1is substituted or unsubstituted C3-C10cycloalkyl or substituted or unsubstituted C2-Cioheterocycloalkyl. In some embodiments, R1is Cs-Cecycloalkyl or C3- Csheterocycloalkyl substituted with C1-C6alkyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazinyl. In some embodiments, R1is Cs-Cecycloalkyl or Cs-Csheterocycloalkyl substituted with C1-C6alkyl, phenyl, or pyridinyl.

[0098] In some embodiments, R is halogen, nitro, -CN, -OR3, -C(=O)R3, -C(=O)N(R3)2, - C(=O)OR3, -S(=O)R3, -S(=O)2R3, -NR3S(=O)2R3, -NR3C(=O)R3, -NR3C(=O)OR3, or substituted or unsubstituted C1-C6fluoroalkyl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted C2- Cioheterocycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0099] In some embodiments, R is F, Cl, Br, I, nitro, -CN, -OCH2F, -OCHF2, -OCF3, -C(=O)CH3, - C(=O)OCH3-C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -S(=O)CH3, -S(=O)2CH3, - NHS(=O)2CH3, -N(CH3)S(=O)2CH3, -NHC(=O)CH3, -N(CH3)C(=O)CH3, -NHC(=O)OCH3, - N(CH3)C(=O)OCH3, -CH2F, -CHF2, or -CF3. In some embodiments, R is F, Cl, -CN, -OCF3, - CHF2, or -CF3. In some embodiments, R is F, Cl, -OCF3, -CHF2, or -CF3. In some embodiments, R is F, Cl, or -CF3. In some embodiments, R is -OCF3. In some embodiments, R is -CF3.

[0100] In some embodiments, each R2is independently halogen, nitro, -CN, -OR3, -SR3, - S(=O)2R3, -N(R3)2, -C(=O)OR3, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted Ci-Cefluoroalkyl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, or substituted or unsubstituted C2- Cioheterocycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C? heterocycloalkyl.

[0101] In some embodiments, each R2is independently F, Cl, Br, nitro, -CN, -OH, -OCH3, - OCH2CH3, -OCH2CH2OH, -0CH2CN, -OCF3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, - C(=O)OCH3, -CH3, -CH2CH3, -CH2F, -CHF2, or -CF3. In some embodiments, each R2is independently F, Cl, -CN, -OCH3, -OCF3, -C(=O)OCH3, -CH3, or -CF3. In some embodiments, each R2is independently F, Cl, -OCF3, or -CF3. In some embodiments, each R2is independently F or Cl.

[0102] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments, n is 2 or 3. In some embodiments, n is 3 or 4. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 1, 2, 3, or 4.

[0103] In another aspect, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:wherein, each X1, X4, X5, and X6is independently CRX; each X2and X3is independently CRY; each Rxis independently hydrogen, halogen, nitro, -OR3, -SR3, -CN, -C(=O)R3, - C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Cefluoroalkyl, or substituted or unsubstituted Cs-Cecycloalkyl; each RYis independently hydrogen, halogen, nitro, -CN, -C(=O)R3, -C(=O)N(R3)2, - C(=O)OR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C3- Cecycloalkyl;R is halogen, nitro, -CN, or Ci-C4fluoroalkyl;R1is substituted or unsubstituted C1-C6alkyl or substituted or unsubstituted C3- Ciocycloalkyl; each R2is independently halogen, nitro, -N3, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, - C(=O)OR3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci- Cefluoroalkyl, or substituted or unsubstituted Cs-Cecycloalkyl; each R3is independently hydrogen or substituted or unsubstituted C1-C6alkyl; and n is 0, 1, 2, 3, or 4.

[0104] In some embodiments, each Rxis independently hydrogen, F, Cl, Br, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -OCF3. -OCF2CH3, or -OCH2CF3. In some embodiments, each X1, X4, X5, and X6is CH. In some embodiments, each RYis independently hydrogen, F, Cl, Br, -CH3, -CH2CH3. In some embodiments, each X2and X3is CH. In some embodiments, R1is substituted or unsubstituted C1-C6alkyl. In some embodiments, R1is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, - CH2CH2CH2CH3, -CH(CH3)CH2CH3, -CH2CH(CH3)2, or -C(CH3)3. In some embodiments, R1is - CH3. In some embodiments, R1is -CH2CH3. In some embodiments, R1is -CH2CH2CH3. In some embodiments, R1is -CH(CH3)2. In some embodiments, R1is -CH2CH2CH2CH3. In some embodiments, R1is -CH(CH3)CH2CH3. In some embodiments, R1is -CH2CH(CH3)2. In some embodiments, R1is -C(CH3)3. In some embodiments, R1is C1-C6alkyl substituted with 0, 1, 2, or 3 substituents each independently selected from F, -CN, -NH2, -NH(Ci-C6alkyl), -N(C1-C6alkyl)2, - OH, -O(C1-C6alkyl), C1-C6fluoroalkyl, amino-C1-C6alkyl, hydroxyl-C1-C6alkyl, Cs-Cscycloalkyl, C2-C7heterocycloalkyl, or heteroaryl; wherein C2-C7heterocycloalkyl is having 1, 2, or 3 heteroatom ring members each independently selected from N, O, or S; wherein heteroaryl is 3-6 membered monocyclic or 9-10 membered bicyclic ring system having 1, 2, 3, or 4 heteroatom ringmembers each independently selected from N, O, and S; and wherein each instance of C3- Cscycloalkyl, C2-C7heterocycloalkyl, and heteroaryl is substituted with 0, 1, 2, or 3 substituents each independently selected from halogen, oxo, -CN, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, - OH, -O(C1-C6alkyl), C1-C6alkyl, C1-C6fluoroalkyl, amino-C1-C6alkyl, hydroxyl-C1-C6alkyl, and Cs-Cscycloalkyl. In some embodiments, R1is C1-C6alkyl substituted with -N(R3)2 or -OR3; and each R3is independently hydrogen or C1-C6alkyl. In some embodiments, R1is C1-C6alkyl substituted with -N(R3)2; and R3is hydrogen or C1-C6alkyl. In some embodiments, R1is C1-C6alkyl substituted with -OR3; and R3is hydrogen or C1-C6alkyl. In some embodiments, R1is C1-C6alkyl substituted with -NH2, -NHCH3, -N(CH3)2, -OH, or -OCH3. In some embodiments, R1is C1-C6alkyl substituted with -NH2. In some embodiments, R1is -CH2NH2, -CH2CH2NH2, -CH(NH2)CH3, - CH2CH2CH2NH2, -CH2CH(NH2)CH3, -CH(NH2)CH2CH3, -CH(CH3)CH2NH2, or -C(CH3)2NH2. In some embodiments, R1is -CH2NH2. In some embodiments, R1is -CH(NH2)CH3. In some embodiments, R1is -CH2CH2CH2NH2. In some embodiments, R1is -CH2CH(NH2)CH3. In some embodiments, R1is -CH(NH2)CH2CH3. In some embodiments, R1is -CH(CH3)CH2NH2. In some embodiments, R1is -C(CH3)2NH2. In some embodiments, R1is C1-C6alkyl substituted with - NHCH3. In some embodiments, R1is -CH2NHCH3, -CH2CH2NHCH3, -CH(NHCH3)CH3, - CH2CH2CH2NHCH3, -CH2CH(NHCH3)CH3, -CH(NHCH3)CH2CH3, -CH(CH3)CH2NHCH3, or - C(CH3)2NHCH3. In some embodiments, R1is -CH2NHCH3. In some embodiments, R1is - CH(NHCH3)CH3. In some embodiments, R1is -CH2CH2CH2NHCH3. In some embodiments, R1is - CH2CH(NHCH3)CH3. In some embodiments, R1is -CH(NHCH3)CH2CH3. In some embodiments, R1is -CH(CH3)CH2NHCH3. In some embodiments, R1is -C(CH3)2NHCH3. In some embodiments, R1is C1-C6alkyl substituted with -N(CH3)2. In some embodiments, R1is -CH2N(CH3)2, - CH2CH2N(CH3)2, -CH(N(CH3)2)CH3, -CH2CH2CH2N(CH3)2, -CH2CH(N(CH3)2)CH3, - CH(N(CH3)2)CH2CH3, -CH(CH3)CH2N(CH3)2, or -C(CH3)2N(CH3)2. In some embodiments, R1is - CH2N(CH3)2. In some embodiments, R1is -CH(N(CH3)2)CH3. In some embodiments, R1is - CH2CH2CH2N(CH3)2. In some embodiments, R1is -CH2CH(N(CH3)2)CH3. In some embodiments, R1is -CH(N(CH3)2)CH2CH3. In some embodiments, R1is -CH(CH3)CH2N(CH3)2. In some embodiments, R1is -C(CH3)2N(CH3)2. In some embodiments, R1is C1-C6alkyl substituted with - OH. In some embodiments, R1is -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CH2CH2OH, - CH2CH(OH)CH3, -CH(OH)CH2CH3, -CH(CH3)CH2OH, or -C(CH3)2OH. In some embodiments, R1is -CH2OH. In some embodiments, R1is -CH(OH)CH3. In some embodiments, R1is - CH2CH2CH2OH. In some embodiments, R1is -CH2CH(OH)CH3. In some embodiments, R1is - CH(OH)CH2CH3. In some embodiments, R1is -CH(CH3)CH2OH. In some embodiments, R1is - C(CH3)2OH. In some embodiments, R1is C1-C6alkyl substituted with -OCH3. In someembodiments, R1is -CH2OCH3, -CH2CH2OCH3, -CH(OCH3)CH3, -CH2CH2CH2OCH3, - CH2CH(OCH3)CH3, -CH(OCH3)CH2CH3, -CH(CH3)CH2OCH3, or -C(CH3)2OCH3. In some embodiments, R1is -CH2OCH3. In some embodiments, R1is -CH(OCH3)CH3. In some embodiments, R1is -CH2CH2CH2OCH3. In some embodiments, R1is -CH2CH(OCH3)CH3. In some embodiments, R1is -CH(OCH3)CH2CH3. In some embodiments, R1is -CH(CH3)CH2OCH3. In some embodiments, R1is -C(CH3)2OCH3. In some embodiments, R1is C1-C6alkyl substituted with heteroaryl. In some embodiments, R1is C1-C6alkyl substituted with 6-membered heteroaryl ring. In some embodiments, R1is C1-C6alkyl substituted with 6-membered heteroaryl ring selected from substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, and substituted or unsubstituted triazinyl. In some embodiments, R1is C1-C6alkyl substituted with substituted or unsubstituted pyridinyl. In some embodiments, R1is C1-C6alkyl substituted with pyridinyl. In some embodiments, the pyridinyl is 2-pyridinyl. In some embodiments, R is F, Cl, or -CF3. In some embodiments, R is F. In some embodiments, R is Cl. In some embodiments, R is -CF3. In some embodiments, each R2is independently F, Cl, -OCF3, or -CF3. In some embodiments, each R2is independently F or Cl. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 1 or 2.

[0105] In some embodiments, the present disclosure provides a compound of Formula (I-A), or a pharmaceutically acceptable salt or solvate thereof:wherein, each Rxis independently hydrogen, halogen, -OR3, -SR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, - NR3S(=O)2R3, -NR3C(=O)R3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C2-C4alkynyl; each RYis independently hydrogen, halogen, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci- Cefluoroalkyl, or substituted or unsubstituted C2-C4alkynyl;R is halogen, nitro, -CN, -OR3, -C(=O)R3, -C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, - S(=O)2R3, -NR3S(=O)2R3, -NR3C(=O)R3, -NR3C(=O)OR3, or substituted or unsubstituted C1-C6fluoroalkyl;R1is C1-C6alkyl optionally substituted with(a) -OR3; and R3is hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C3-C10cycloalkyl;(b) 6-membered heteroaryl ring selected from substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, and substituted or unsubstituted triazinyl; or(c) 1, 2, or 3 substituents each independently selected from -OH, -OCH3, -NH2, - NHCH3, -N(CH3)2, and pyridinyl; each R2is independently halogen, nitro, -N3, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, - C(=O)OR3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2- Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl; and n is 0, 1, or 2.

[0106] In some embodiments, the present disclosure provides a compound selected from:pharmaceutically acceptable salt or solvate thereof. In some embodiments, the present disclosure provides a compoundpharmaceutically acceptable salt or solvate thereof.

[0107] In another aspect, the present disclosure provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:Formula (II) wherein, each X1, X2, X3, X4, X5, and X6is independently N or CRX; each Rxis independently hydrogen, halogen, nitro, -OR3, -SR3, -CN, -C(=O)R3, - C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, - NR3C(=O)R3, -NR3C(=O)OR3, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C2-C4alkenyl, substituted or unsubstituted C2-C4alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R is halogen, nitro, -CN, -OR3, -SR3, -C(=O)R3, -C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, - S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, -NR3C(=O)OR3, or substituted or unsubstituted C1-C6fluoroalkyl;R1is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C2-Cealkenyl, substituted or unsubstituted C2-Cealkynyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2- Cioheterocycloalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, or -S(=O)2R4; each R2is independently halogen, nitro, -N3, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, - C(=O)OR3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2- Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl;R4is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or -NH2; and n is 0, 1, 2, 3, or 4.

[0108] For any and all of the embodiments of a compound of Formula (II), substituents are selected from among a subset of the listed alternatives. For example, in some embodiments X1is N or CRX. In other embodiments, X1is N. In some embodiments, X1is CRX.

[0109] In some embodiments, each X1, X2, and X3is CRX. In some embodiments, X1is N; and each X2and X3is CRX. In some embodiments, each X1and X2is CRX; and X3is N.

[0110] In some embodiments, each X4, X5, and X6is CRX. In some embodiments, X4is N; and each X5and X6is CRX. In some embodiments, each X4and X5is CRX; and X6is N.

[0111] In some embodiments, each Rxis independently hydrogen, halogen, -OR3, -SR3, -CN, - S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, substituted or unsubstituted Ci- Cealkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C2-C4alkenyl, substituted or unsubstituted C2-C4alkynyl, or substituted or unsubstituted C1-C6heteroalkyl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted C2-Cioheterocycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl. In some embodiments, each Rxis independently hydrogen, halogen, -OR3, -SR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, - NR3S(=O)2R3, -NR3C(=O)R3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C2-C4alkynyl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C3-C10cycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0112] In some embodiments, each Rxis independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, - CH2OH, -CH2CH2OH, -CH2CN, -CH2C(=O)OH, -CH2C(=O)OCH3, -CH2C(=O)OCH2CH3, - CH2C(=O)NH2, -CH2C(=O)NHCH3, -CH2C(=O)N(CH3)2, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, - CH2F, -CHF2, -CF3, -CH=CH2, -C=CH, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, oxetanyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy, azetidinyl, pyrrolidinyl, tetrazolyl, -CN, -OH, -OCH3, -OCH2CH3, -OCH2CH2OH, -OCH2CN, -OCF3, -C(=O)OH, -C(=O)OCH3, - C(=O)OCH2CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -NH2, -NHCH3, -N(CH3)2, - NHC(=O)CH3, -N(CH3)C(=O)CH3, -NHC(=O)OCH3, -N(CH3)C(=O)OCH3, -S(=O)CH3, - S(=O)2CH3, -NHS(=O)2CH3, or -N(CH3)S(=O)2CH3. In some embodiments, each Rxis independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, cyclopropyl, -C=CH, -OH, -OCH3, - OCH2CH3, -OCF3, -SCH3, cyclopropyloxy, -NH2, -NHC(=O)CH3, -N(CH3)C(=O)CH3, - NHS(=O)2CH3, -N(CH3)S(=O)2CH3, -S(=O)CH3, or -S(=O)2CH3. In some embodiments, each Rxis independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, cyclopropyl, -OH, -OCH3, -OCH2CH3, - OCF3, cyclopropyloxy, -NH2, -NHC(=O)CH3, -NHS(=O)2CH3, -S(=O)CH3, or -S(=O)2CH3. In some embodiments, each Rxis independently hydrogen, F, Cl, Br, -CH3, -OH, -OCH3, or -OCF3. In some embodiments, each Rxis independently hydrogen, F, Cl, -CH3, -OCH3, or -OCF3. In some embodiments, each Rxis independently hydrogen, F, or -OCH3. In some embodiments, each Rxis hydrogen.

[0113] In some embodiments, R1is substituted or unsubstituted C1-C6alkyl.

[0114] In some embodiments, R1is C1-C6alkyl substituted with substituted or unsubstituted C2- Cealkenyl, substituted or unsubstituted C2-Cealkynyl, or -CN.

[0115] In some embodiments, R1is C1-C6alkyl substituted with -OR3; and R3is hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C3-C10cycloalkyl.

[0116] In some embodiments, R1is C1-C6alkyl substituted with -C(=O)N(R5)2 or -N(R5)2; wherein each R5is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-Cealkenyl, substituted or unsubstituted C2-Cealkynyl, or -CN; or two R5are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0117] In some embodiments, R1is C1-C6alkyl substituted with substituted or unsubstituted C3- Cscycloalkyl or substituted or unsubstituted C2-C7heterocycloalkyl.

[0118] In some embodiments, R1is C1-C6alkyl substituted with cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0119] In some embodiments, R1is C1-C6alkyl substituted with oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, or piperidinyl.

[0120] In some embodiments, R1is C1-C6alkyl substituted with substituted or unsubstituted phenyl, wherein if phenyl is substituted, then it is substituted with 1, 2, 3, or 4 substituents selected from halogen, nitro, -CN, -OR3, -N(R3)2, -C(=O)R3, -C(=O)N(R3)2, -C(=O)OR3, substituted or unsubstituted C1-C6alkyl, and substituted or unsubstituted C1-C6fluoroalkyl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C3- Ciocycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0121] In some embodiments, R1is C1-C6alkyl substituted with 5-membered heteroaryl ring containing at least one nitrogen atom.

[0122] In some embodiments, R1is C1-C6alkyl substituted with 5-membered heteroaryl ring selected from substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted oxadiazolyl, and substituted or unsubstituted thiadiazolyl.

[0123] In some embodiments, R1is C1-C6alkyl substituted with 5-membered heteroaryl ring selected from:wherein each Rzis independently hydrogen, halogen, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, -C(=O)OR3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted C2-Cioheterocycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0124] In some embodiments, R1is C1-C6alkyl substituted with a substituted or unsubstituted monocyclic 6-membered heteroaryl ring containing at least one nitrogen atom. In some embodiments, R1is C1-C6alkyl substituted with a substituted or unsubstituted monocyclic 6- membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms. In some embodiments, R1is Ci- Cealkyl substituted with 6-membered heteroaryl ring selected from substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, and substituted or unsubstituted triazinyl. In some embodiments, R1is C1-C6alkyl substituted with substituted or unsubstituted pyridinyl. In some embodiments, R1is C1-C6alkyl substituted with pyridinyl. In some embodiments, R1is C1-C6alkyl substituted with substituted or unsubstituted pyridinyl. In some embodiments, R1is C1-C6alkyl substituted with pyridinyl. In some embodiments, R1is C1-C6alkyl substituted with 2-pyridinyl.

[0125] In some embodiments, R1is C1-C6alkyl substituted with 6-membered heteroaryl ring selected from:each Rzis independently hydrogen, halogen, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, -C(=O)OR3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted C2-Cioheterocycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0126] In some embodiments, R1is C1-C6alkyl substituted with bicyclic 6 / 5 fused heteroaryl ring. In some embodiments, R1is C1-C6alkyl substituted with bicyclic 6 / 5 fused heteroaryl ring selected from substituted or unsubstituted indolyl, substituted or unsubstituted isoindolyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted isobenzofuranyl, substituted orunsubstituted benzothiophenyl, substituted or unsubstituted indazolyl, substituted or unsubstituted benzoimidazolyl, substituted or unsubstituted benzooxazolyl, substituted or unsubstituted benzoisoxazolyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted benzoisothiazolyl, substituted or unsubstituted benzotri azolyl, substituted or unsubstituted benzooxadi azolyl, substituted or unsubstituted benzothiadi azolyl, substituted or unsubstituted indolizinyl, and substituted or unsubstituted imidazopyridinyl.

[0127] In some embodiments, R1is C1-C6alkyl substituted with bicyclic 6 / 5 fused heteroaryl ring selected from:each Rzis independently hydrogen, halogen, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, -C(=O)OR3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl,substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted C2-Cioheterocycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0128] In some embodiments, R1is C1-C6alkyl substituted with a substituted or unsubstituted bicyclic 6 / 6 fused heteroaryl ring containing at least one nitrogen atom. In some embodiments, R1is C1-C6alkyl substituted with a substituted or unsubstituted bicyclic 6 / 6 fused heteroaryl ring containing 1, 2, 3, or 4 nitrogen atoms. In some embodiments, R1is C1-C6alkyl substituted with bicyclic 6 / 6 fused heteroaryl ring selected from substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted cinnolinyl, substituted or unsubstituted quinazolinyl, substituted or unsubstituted quinoxalinyl, substituted or unsubstituted naphthyridinyl, substituted or unsubstituted pyridopyrimidinyl, substituted or unsubstituted pyridopyrazinyl, substituted or unsubstituted pyridopyridazinyl, substituted or unsubstituted pyrimidopyrimidinyl, and substituted or unsubstituted pteridinyl.

[0129] In some embodiments, R1is C1-C6alkyl substituted with 6 / 6 fused heteroaryl ring selectedeach Rzis independently hydrogen, halogen, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, -C(=O)OR3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted C2-Cioheterocycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0130] In some embodiments, R1is C1-C6alkyl substituted with 1, 2, or 3 substituents each independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, and pyridinyl. In some embodiments, R1is C1-C6alkyl substituted with 1 or 2 substituents each independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, and pyridinyl. In some embodiments, R1is Ci- Cealkyl substituted with 1 or 2 substituents each independently selected from -OH and pyridinyl. In some embodiments, R1is C1-C6alkyl substituted with 1 or 2 substituents each independently selected from -NH2 and pyridinyl. In some embodiments, R1is C1-C6alkyl substituted with 1 or 2 substituents each independently selected from -OH and -NH2. In some embodiments, R1is Ci- Cealkyl substituted with -OH. In some embodiments, R1is C1-C6alkyl substituted with -NH2.

[0131] In some embodiments, each Rzis independently hydrogen, F, Cl, Br, -CH3, -CH2CH3, - CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCH2CH3, -OCF3, -NH2, -NHCH3, or -N(CH3)2. In some embodiments, each Rzis independently hydrogen, F, Cl, Br, -CH3, -CN, -OCH3, -NH2, -NHCH3, or -N(CH3)2. In some embodiments, each Rzis independently hydrogen, Cl, Br, -CH3, -OCH3, -NH2, or -N(CH3)2. In some embodiments, each Rzis hydrogen.

[0132] In some embodiments, R1is C1-C6alkyl substituted with halogen, -CN, -OR3, -SR3, -S(=O) R3, -S(=O)2R3, -N(R3)2, -C(=O)OR3, -C(=O)N(R3)2, -CR3=C(R3)2, -C=CR3, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, or substitutedor unsubstituted aryl; and each R3is independently hydrogen, substituted or unsubstituted Ci- Cealkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted Ci- Ceheteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted C2- Cioheterocycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0133] In some embodiments, R1is substituted or unsubstituted C3-C10cycloalkyl or substituted or unsubstituted C2-Cioheterocycloalkyl. In some embodiments, R1is Cs-Cecycloalkyl or C3- Csheterocycloalkyl substituted with C1-C6alkyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazinyl. In some embodiments, R1is Cs-Cecycloalkyl or Cs-Csheterocycloalkyl substituted with C1-C6alkyl, phenyl, or pyridinyl.

[0134] In some embodiments, R is halogen, nitro, -CN, -OR3, -C(=O)R3, -C(=O)N(R3)2, - C(=O)OR3, -S(=O)R3, -S(=O)2R3, -NR3S(=O)2R3, -NR3C(=O)R3, -NR3C(=O)OR3, or substituted or unsubstituted C1-C6fluoroalkyl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted C2- Cioheterocycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0135] In some embodiments, R is F, Cl, Br, I, nitro, -CN, -OCH2F, -OCHF2, -OCF3, -C(=O)CH3, - C(=O)OCH3-C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -S(=O)CH3, -S(=O)2CH3, - NHS(=O)2CH3, -N(CH3)S(=O)2CH3, -NHC(=O)CH3, -N(CH3)C(=O)CH3, -NHC(=O)OCH3, - N(CH3)C(=O)OCH3, -CH2F, -CHF2, or -CF3. In some embodiments, R is F, Cl, -CN, -OCF3, - CHF2, or -CF3. In some embodiments, R is F, Cl, -OCF3, -CHF2, or -CF3. In some embodiments, R is F, Cl, or -CF3. In some embodiments, R is -OCF3. In some embodiments, R is -CF3.

[0136] In some embodiments, each R2is independently halogen, nitro, -CN, -OR3, -SR3, - S(=O)2R3, -N(R3)2, -C(=O)OR3, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6fluoroalkyl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted C2- Cioheterocycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0137] In some embodiments, each R2is independently F, Cl, Br, nitro, -CN, -OH, -OCH3, - OCH2CH3, -OCH2CH2OH, -0CH2CN, -0CF3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, - C(=O)OCH3, -CH3, -CH2CH3, -CH2F, -CHF2, or -CF3. In some embodiments, each R2is independently F, Cl, -CN, -OCH3, -OCF3, -C(=O)OCH3, -CH3, or -CF3. In some embodiments, each R2is independently F, Cl, -OCF3, or -CF3. In some embodiments, each R2is independently F or Cl.

[0138] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments, n is 2 or 3. In some embodiments, n is 3 or 4. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 1, 2, 3, or 4.

[0139] In another aspect, the present disclosure provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:Formula (III) wherein, each X3, X5, and X6is independently N or CRX;X4is CRX; each Rxis independently hydrogen, halogen, nitro, -OR3, -SR3, -CN, -C(=O)R3, - C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, - NR3C(=O)R3, -NR3C(=O)OR3, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C2-C4alkenyl, substituted or unsubstituted C2-C4alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R is halogen, nitro, -CN, -OR3, -SR3, -C(=O)R3, -C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, - S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, -NR3C(=O)OR3, or substituted or unsubstituted C1-C6fluoroalkyl;R1is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C2-Cealkenyl, substituted or unsubstituted C2-Cealkynyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2- Cioheterocycloalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, or -S(=O)2R4; each R2is independently halogen, nitro, -N3, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, - C(=O)OR3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2- Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl;R4is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or -NH2; and n is 0, 1, 2, 3, or 4.

[0140] For any and all of the embodiments of a compound of Formula (III), substituents are selected from among a subset of the listed alternatives. For example, in some embodiments X5is N or CRX. In other embodiments, X5is N. In some embodiments, X5is CRX.

[0141] In some embodiments, X3is CRX. In some embodiments, X3is N.

[0142] In some embodiments, each X5and X6is CRX. In some embodiments, X5is N; and X6is CRX. In some embodiments, X5is CRX; and X6is N.

[0143] In some embodiments, each Rxis independently hydrogen, halogen, -OR3, -SR3, -CN, - S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, substituted or unsubstituted Ci- Cealkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C2-C4alkenyl, substituted or unsubstituted C2-C4alkynyl, or substituted or unsubstituted C1-C6heteroalkyl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted C2-Cioheterocycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0144] In some embodiments, each Rxis independently hydrogen, halogen, -OR3, -SR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C2-C4alkynyl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C3-C10cycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0145] In some embodiments, each Rxis independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, - CH2OH, -CH2CH2OH, -CH2CN, -CH2C(=O)OH, -CH2C(=O)OCH3, -CH2C(=O)OCH2CH3, - CH2C(=O)NH2, -CH2C(=O)NHCH3, -CH2C(=O)N(CH3)2, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, - CH2F, -CHF2, -CF3, -CH=CH2, -C=CH, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, oxetanyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy, azetidinyl, pyrrolidinyl, tetrazolyl, -CN, -OH, -OCH3, -OCH2CH3, -OCH2CH2OH, -OCH2CN, -OCF3, -C(=O)OH, -C(=O)OCH3, - C(=O)OCH2CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -NH2, -NHCH3, -N(CH3)2, - NHC(=O)CH3, -N(CH3)C(=O)CH3, -NHC(=O)OCH3, -N(CH3)C(=O)OCH3, -S(=O)CH3, - S(=O)2CH3, -NHS(=O)2CH3, or -N(CH3)S(=O)2CH3. In some embodiments, each Rxis independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, cyclopropyl, -C=CH, -OH, -OCH3, - OCH2CH3, -OCF3, -SCH3, cyclopropyloxy, -NH2, -NHC(=O)CH3, -N(CH3)C(=O)CH3, - NHS(=O)2CH3, -N(CH3)S(=O)2CH3, -S(=O)CH3, or -S(=O)2CH3. In some embodiments, each Rxis independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, cyclopropyl, -OH, -OCH3, -OCH2CH3, - OCF3, cyclopropyloxy, -NH2, -NHC(=O)CH3, -NHS(=O)2CH3, -S(=O)CH3, or -S(=O)2CH3. In some embodiments, each Rxis independently hydrogen, F, Cl, Br, -CH3, -OH, -OCH3, or -OCF3. In some embodiments, each Rxis independently hydrogen, F, Cl, -CH3, -OCH3, or -OCF3. In some embodiments, each Rxis independently hydrogen, F, or -OCH3. In some embodiments, each Rxis hydrogen.

[0146] In some embodiments, R1is substituted or unsubstituted C1-C6alkyl.

[0147] In some embodiments, R1is C1-C6alkyl substituted with substituted or unsubstituted C2- Cealkenyl, substituted or unsubstituted C2-Cealkynyl, or -CN.

[0148] In some embodiments, R1is C1-C6alkyl substituted with -OR3; and R3is hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C3-C10cycloalkyl.

[0149] In some embodiments, R1is C1-C6alkyl substituted with -C(=O)N(R5)2 or -N(R5)2; wherein each R5is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-Cealkenyl, substituted or unsubstituted C2-Cealkynyl, or -CN; or two R5are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0150] In some embodiments, R1is C1-C6alkyl substituted with substituted or unsubstituted C3- Cscycloalkyl or substituted or unsubstituted C2-C7heterocycloalkyl.

[0151] In some embodiments, R1is C1-C6alkyl substituted with cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0152] In some embodiments, R1is C1-C6alkyl substituted with oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, or piperidinyl.

[0153] In some embodiments, R1is C1-C6alkyl substituted with substituted or unsubstituted phenyl, wherein if phenyl is substituted, then it is substituted with 1, 2, 3, or 4 substituents selected from halogen, nitro, -CN, -OR3, -N(R3)2, -C(=O)R3, -C(=O)N(R3)2, -C(=O)OR3, substituted or unsubstituted C1-C6alkyl, and substituted or unsubstituted C1-C6fluoroalkyl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C3- Ciocycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0154] In some embodiments, R1is C1-C6alkyl substituted with 5-membered heteroaryl ring containing at least one nitrogen atom. In some embodiments, R1is C1-C6alkyl substituted with 5- membered heteroaryl ring selected from substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted oxadiazolyl, and substituted or unsubstituted thiadiazolyl.

[0155] In some embodiments, R1is C1-C6alkyl substituted with 5-membered heteroaryl ring selected from:wherein each Rzis independently hydrogen, halogen, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, -C(=O)OR3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted C2-Cioheterocycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0156] In some embodiments, R1is C1-C6alkyl substituted with a substituted or unsubstituted monocyclic 6-membered heteroaryl ring containing at least one nitrogen atom. In some embodiments, R1is C1-C6alkyl substituted with a substituted or unsubstituted monocyclic 6- membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms. In some embodiments, R1is Ci- Cealkyl substituted with 6-membered heteroaryl ring selected from substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, and substituted or unsubstituted triazinyl. In some embodiments, R1is C1-C6alkyl substituted with substituted or unsubstituted pyridinyl. In some embodiments, R1is C1-C6alkyl substituted with pyridinyl. In some embodiments, R1is C1-C6alkyl substituted with 2-pyridinyl.

[0157] In some embodiments, R1is C1-C6alkyl substituted with 6-membered heteroaryl ring selected from:each Rzis independently hydrogen, halogen, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, -C(=O)OR3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted C2-Cioheterocycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0158] In some embodiments, R1is C1-C6alkyl substituted with bicyclic 6 / 5 fused heteroaryl ring. In some embodiments, R1is C1-C6alkyl substituted with bicyclic 6 / 5 fused heteroaryl ring selected from substituted or unsubstituted indolyl, substituted or unsubstituted isoindolyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted isobenzofuranyl, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted indazolyl, substituted or unsubstitutedbenzoimidazolyl, substituted or unsubstituted benzooxazolyl, substituted or unsubstituted benzoisoxazolyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted benzoisothiazolyl, substituted or unsubstituted benzotri azolyl, substituted or unsubstituted benzooxadi azolyl, substituted or unsubstituted benzothiadi azolyl, substituted or unsubstituted indolizinyl, and substituted or unsubstituted imidazopyridinyl.

[0159] In some embodiments, R1is C1-C6alkyl substituted with bicyclic 6 / 5 fused heteroaryl ring selected from:each Rzis independently hydrogen, halogen, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, -C(=O)OR3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; andeach R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted C2-Cioheterocycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0160] In some embodiments, R1is C1-C6alkyl substituted with a substituted or unsubstituted bicyclic 6 / 6 fused heteroaryl ring containing at least one nitrogen atom. In some embodiments, R1is C1-C6alkyl substituted with a substituted or unsubstituted bicyclic 6 / 6 fused heteroaryl ring containing 1, 2, 3, or 4 nitrogen atoms. In some embodiments, R1is C1-C6alkyl substituted with bicyclic 6 / 6 fused heteroaryl ring selected from substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted cinnolinyl, substituted or unsubstituted quinazolinyl, substituted or unsubstituted quinoxalinyl, substituted or unsubstituted naphthyridinyl, substituted or unsubstituted pyridopyrimidinyl, substituted or unsubstituted pyridopyrazinyl, substituted or unsubstituted pyridopyridazinyl, substituted or unsubstituted pyrimidopyrimidinyl, and substituted or unsubstituted pteridinyl.

[0161] In some embodiments, R1is C1-C6alkyl substituted with 6 / 6 fused heteroaryl ring selected from:each Rzis independently hydrogen, halogen, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, -C(=O)OR3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted C2-Cioheterocycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0162] In some embodiments, R1is C1-C6alkyl substituted with 1, 2, or 3 substituents each independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, and pyridinyl. In some embodiments, R1is C1-C6alkyl substituted with 1 or 2 substituents each independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, and pyridinyl. In some embodiments, R1is Ci- Cealkyl substituted with 1 or 2 substituents each independently selected from -OH and pyridinyl. In some embodiments, R1is C1-C6alkyl substituted with 1 or 2 substituents each independently selected from -NH2 and pyridinyl. In some embodiments, R1is C1-C6alkyl substituted with 1 or 2 substituents each independently selected from -OH and -NH2. In some embodiments, R1is Ci- Cealkyl substituted with -OH. In some embodiments, R1is C1-C6alkyl substituted with -NH2.

[0163] In some embodiments, each Rzis independently hydrogen, F, Cl, Br, -CH3, -CH2CH3, - CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCH2CH3, -OCF3, -NH2, -NHCH3, or -N(CH3)2. In some embodiments, each Rzis independently hydrogen, F, Cl, Br, -CH3, -CN, -OCH3, -NH2, -NHCH3, or -N(CH3)2. In some embodiments, each Rzis independently hydrogen, Cl, Br, -CH3, -OCH3, -NH2, or -N(CH3)2. In some embodiments, each Rzis hydrogen.

[0164] In some embodiments, R1is C1-C6alkyl substituted with halogen, -CN, -OR3, -SR3, -S(=O) R3, -S(=O)2R3, -N(R3)2, -C(=O)OR3, -C(=O)N(R3)2, -CR3=C(R3)2, -C=CR3, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, or substitutedor unsubstituted aryl; and each R3is independently hydrogen, substituted or unsubstituted Ci- Cealkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted Ci- Ceheteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted C2- Cioheterocycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0165] In some embodiments, R1is substituted or unsubstituted C3-C10cycloalkyl or substituted or unsubstituted C2-Cioheterocycloalkyl. In some embodiments, R1is Cs-Cecycloalkyl or C3- Csheterocycloalkyl substituted with C1-C6alkyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazinyl. In some embodiments, R1is Cs-Cecycloalkyl or Cs-Csheterocycloalkyl substituted with C1-C6alkyl, phenyl, or pyridinyl.

[0166] In some embodiments, R is halogen, nitro, -CN, -OR3, -C(=O)R3, -C(=O)N(R3)2, - C(=O)OR3, -S(=O)R3, -S(=O)2R3, -NR3S(=O)2R3, -NR3C(=O)R3, -NR3C(=O)OR3, or substituted or unsubstituted C1-C6fluoroalkyl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted C2- Cioheterocycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0167] In some embodiments, R is F, Cl, Br, I, nitro, -CN, -OCH2F, -OCHF2, -OCF3, -C(=O)CH3, - C(=O)OCH3-C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -S(=O)CH3, -S(=O)2CH3, - NHS(=O)2CH3, -N(CH3)S(=O)2CH3, -NHC(=O)CH3, -N(CH3)C(=O)CH3, -NHC(=O)OCH3, - N(CH3)C(=O)OCH3, -CH2F, -CHF2, or -CF3. In some embodiments, R is F, Cl, -CN, -OCF3, - CHF2, or -CF3. In some embodiments, R is F, Cl, -OCF3, -CHF2, or -CF3. In some embodiments, R is F, Cl, or -CF3. In some embodiments, R is -OCF3. In some embodiments, R is -CF3.

[0168] In some embodiments, each R2is independently halogen, nitro, -CN, -OR3, -SR3, - S(=O)2R3, -N(R3)2, -C(=O)OR3, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6fluoroalkyl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted C2- Cioheterocycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0169] In some embodiments, each R2is independently F, Cl, Br, nitro, -CN, -OH, -OCH3, - OCH2CH3, -OCH2CH2OH, -0CH2CN, -0CF3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, - C(=O)OCH3, -CH3, -CH2CH3, -CH2F, -CHF2, or -CF3. In some embodiments, each R2is independently F, Cl, -CN, -OCH3, -OCF3, -C(=O)OCH3, -CH3, or -CF3. In some embodiments, each R2is independently F, Cl, -OCF3, or -CF3. In some embodiments, each R2is independently F or Cl.

[0170] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments, n is 2 or 3. In some embodiments, n is 3 or 4. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 1, 2, 3, or 4.

[0171] In another aspect, the present disclosure provides a compound or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is a compound from Table 1, or a pharmaceutically acceptable salt or solvate thereof.Table 1Synthesis of Compounds

[0172] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and / or from compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0173] Methods known to one of ordinary skill in the art are identified through various reference books and databases. Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modem Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471- 60180-2; Otera, J. (editor) "Modem Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871- 1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley- Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[0174] In some instances, specific and analogous reactants are identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (the American Chemical Society, Washington, D.C., is contacted for more details). Chemicals that are known but not commercially available in catalogs are prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0175] In some embodiments, the compounds disclosed herein are prepared as described in the Examples section.Further Forms of CompoundsIsomers

[0176] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (£), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, disclosed herein are dissociable complexes (e.g., crystalline diastereomeric salts). In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that does not result in racemization.Labeled compounds

[0177] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number usually found in nature. In some embodiments, examples of isotopes that are incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as2H,3H,13C,14C,15N,18O,170,31P,32P,35S,18F, and36C1, respectively. Compounds described herein, and the metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates, or derivatives thereof which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this disclosure. Certain isotopically-labeled compounds, for example, those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e.,2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compounds, pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof is prepared by any suitable method.

[0178] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.Pharmaceutically acceptable salts

[0179] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0180] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds of the disclosure, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.Solvates

[0181] In some embodiments, the compounds described herein exist as solvates. The disclosure provides for methods of treating diseases by administering such solvates. The disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0182] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In some embodiments, solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous / organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or methanol. In some embodiments, the compounds provided herein exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.Prodrugs

[0183] In some embodiments, the compounds described herein exist in prodrug form. The disclosure provides for methods of treating diseases by administering such prodrugs. The disclosure further provides for methods of treating diseases by administering such prodrugs as pharmaceutical compositions.

[0184] In some embodiments, prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy, or carboxylic acid group of compounds of the present disclosure. The amino acid residues include, but are not limited to, the 20 naturally occurring amino acids and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, ornithine, and methionine sulfone. In other embodiments, prodrugs include compounds wherein a nucleic acid residue, or an oligonucleotide of two or more (e.g., two, three or four) nucleic acid residuies is covalently joined to a compound of the present disclosure.

[0185] Pharmaceutically acceptable prodrugs of the compounds described herein also include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxy alkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, metal salts, and sulfonate esters. In some embodiments, compounds having free amino, amido, hydroxy, or carboxylic groups are converted into prodrugs. For instance, free carboxyl groups are derivatized as amides or alkyl esters. In certain instances, all of these prodrug moieties incorporate groups including, but not limited to, ether, amine, and carboxylic acid functionalities.

[0186] Hydroxy prodrugs include esters such as, though not limited to, acyloxyalkyl (e.g., acyloxymethyl or acyloxyethyl) esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters,sulfonate esters, sulfate esters and disulfide containing esters, ethers, amides, carbamates, hemi succinates, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews 1996, 19, 115.

[0187] Amine derived prodrugs include, but are not limited to, the following groups and combinations of groups:as well as sulfonamides and phosphonamides.

[0188] In certain instances, sites on any aromatic ring portions are susceptible to various metabolic reactions, therefore incorporation of appropriate substituents on the aromatic ring structures reduce, minimize, or eliminate this metabolic pathway.Metabolites

[0189] In some embodiments, compounds described herein are susceptible to various metabolic reactions. Therefore, in some embodiments, incorporation of appropriate substituents into the structure will reduce, minimize, or eliminate a metabolic pathway. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of an aromatic ring to metabolic reactions is, by way of example only, a halogen or an alkyl group.

[0190] In some embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.METHODS

[0191] In one aspect, the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount a TEAD inhibitor disclosed herein. In some embodiments, the methods comprise administering to the subject a therapeutically effective amount a TEAD inhibitor disclosed herein.

[0192] In some embodiments, the TEAD inhibitor associates with one or more components of the Hippo pathway network comprising TEAD, transcriptional coactivator with PDZ binding motif (TAZ), or Yes-associated protein transcriptional coactivator (YAP). In some embodiments, theTEAD inhibitor associates with one or more components of the Hippo pathway network comprising TEAD. In some embodiments, the TEAD inhibitor associates with one or more components of the Hippo pathway network comprising transcriptional coactivator with PDZ binding motif (TAZ). In some embodiments, the TEAD inhibitor associates with one or more components of the Hippo pathway network comprising Yes-associated protein transcriptional coactivator (YAP).

[0193] In some embodiments, a TEAD inhibitor disclosed herein is a compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the TEAD inhibitor disclosed herein is a compound selected from:pharmaceutically acceptable salt or solvate thereof. In some embodiments, the TEAD inhibitor disclosed hereina pharmaceutically acceptable salt or solvate thereof.

[0194] In one aspect, a mesothelioma is a relapsed or refractory mesothelioma. In some embodiments, a mesothelioma is a relapsed mesothelioma. In some embodiments, a mesothelioma is a refractory mesothelioma.

[0195] In one aspect, a mesothelioma comprises a mutation in a neurofibromatosis type 2 (NF2) gene.

[0196] In one aspect, a mesothelioma comprises pleural mesothelioma, peritoneal mesothelioma, or pericardial mesothelioma, or any combination thereof. In some embodiments, the mesothelioma is pleural mesothelioma. In some embodiments, the mesothelioma is peritoneal mesothelioma. In some embodiments, the mesothelioma is pericardial mesothelioma.

[0197] In one aspect, a mesothelioma comprises epithelioid mesothelioma, sarcomatoid mesothelioma, or dermoplastic mesothelioma, or any combination thereof. In some embodiments, the mesothelioma is epithelioid mesothelioma. In some embodiments, the mesothelioma is sarcomatoid mesothelioma. In some embodiments, the mesothelioma is dermoplastic mesothelioma.

[0198] In one aspect, administering a TEAD inhibitor inhibits transcriptional coactivator with PDZ binding motif / Yes-associated protein transcriptional coactivator (TAZ / YAP).

[0199] In one aspect, administering a TEAD inhibitor inhibits one or more of proteins encompassed by, or related to, the Hippo pathway in the subject.

[0200] In one aspect, a compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, is administered as an oral formulation.

[0201] In one aspect, a compound of (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, is administered in a capsule.

[0202] In one aspect, a compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, is administered in a 15 mg, 25 mg, 50 mg, 70 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg amount. In some embodiments, the compound of Formula (I), (I- A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered in a 15 mg amount. In some embodiments, the compound of Formula (I), (I-A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered in a 25 mg amount. In some embodiments, the compound of Formula (I), (I-A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered in a 50 mg amount. In some embodiments, the compound of Formula (I), (I-A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered in a 70 mg amount. In some embodiments, the compound of Formula (I), (I-A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered in a 100 mg amount. In some embodiments, the compound of Formula (I), (I-A), (II), or (III), or thepharmaceutically acceptable salt or solvate thereof, is administered in a 125 mg amount. In some embodiments, the compound of Formula (I), (I-A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered in a 150 mg amount. In some embodiments, the compound of Formula (I), (I-A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered in a 175 mg amount. In some embodiments, the compound of Formula (I), (I-A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered in a 200 mg amount.

[0203] In one aspect, a compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, is administered daily for at least a week. In some embodiments, the compound of Formula (I), (I-A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for at least two weeks. In some embodiments, the compound of Formula (I), (I-A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for at least three weeks. In some embodiments, the compound of Formula (I), (I- A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for at least four weeks.

[0204] In one aspect, a compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of three weeks, wherein the compound of Formula (I), (I-A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for one week, and not administered for the following two weeks. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of three weeks, wherein the compound of Formula (I), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for one week, and not administered for the following two weeks. In some embodiments, a compound of Formula (I-A), or a pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of three weeks, wherein the compound of Formula (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for one week, and not administered for the following two weeks. In some embodiments, a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of three weeks, wherein the compound of Formula (II), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for one week, and not administered for the following two weeks. In some embodiments, a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of three weeks, wherein the compound of Formula (III), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for one week, and not administered for the following two weeks.

[0205] In one aspect, a compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of four weeks, wherein the compound of Formula (I), (I- A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for one week, and then not administered for the following three weeks. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of four weeks, wherein the compound of Formula(I), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for one week, and then not administered for the following three weeks. In some embodiments, a compound of Formula (I-A), or a pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of four weeks, wherein the compound of Formula (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for one week, and then not administered for the following three weeks. In some embodiments, a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of four weeks, wherein the compound of Formula (II), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for one week, and then not administered for the following three weeks. In some embodiments, a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of four weeks, wherein the compound of Formula (III), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for one week, and then not administered for the following three weeks.

[0206] In one aspect, a compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of three weeks, wherein the compound of Formula (I), (I-A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for two weeks, and then not administered for the following week. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of three weeks, wherein the compound of Formula (I), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for two weeks, and then not administered for the following week. In some embodiments, a compound of Formula (I- A), or a pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of three weeks, wherein the compound of Formula (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for two weeks, and then not administered for the following week. In some embodiments, a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of three weeks, wherein the compound of Formula(II), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for two weeks, and then not administered for the following week. In some embodiments, a compound of Formula(III), or a pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of three weeks, wherein the compound of Formula (III), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for two weeks, and then not administered for the following week.

[0207] In one aspect, a compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of four weeks, wherein the compound of Formula (I), (I- A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for two weeks, and then not administered for the following two weeks. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of four weeks, wherein the compound of Formula (I), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for two weeks, and then not administered for the following two weeks. In some embodiments, a compound of Formula (I-A), or a pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of four weeks, wherein the compound of Formula (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for two weeks, and then not administered for the following two weeks. In some embodiments, a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of four weeks, wherein the compound of Formula (II), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for two weeks, and then not administered for the following two weeks. In some embodiments, a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of four weeks, wherein the compound of Formula (III), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for two weeks, and then not administered for the following two weeks.

[0208] In one aspect, a compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, is administered daily for 15 days, and then administered on days 1, 8, and 15 thereof. In one aspect, a compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, is administered daily for 15 days, and then administered on day 1 thereof. In one aspect, a compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, is administered daily for 15 days, and then administered on day 8 thereof. In one aspect, a compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, is administered daily for 15 days, and then administered on day 15 thereof.

[0209] In one aspect, a compound of Formula (I), (I-A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of four weeks, wherein thecompound of Formula (I), (I- A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for two weeks, and then not administered for the following two weeks, wherein the compound of Formula (I), (I- A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered at 15 mg.

[0210] In one aspect, a compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of four weeks, wherein the compound of Formula (I), (I- A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for two weeks, and then not administered for the following two weeks, wherein the compound of Formula (I), (I- A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered at 25 mg.

[0211] In one aspect, a compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of four weeks, wherein the compound of Formula (I), (I- A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for two weeks, and then not administered for the following two weeks, wherein the compound of Formula (I), (I- A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered at 50 mg.

[0212] In one aspect, a compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of four weeks, wherein the compound of Formula (I), (I- A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for two weeks, and then not administered for the following two weeks, wherein the compound of Formula (I), (I- A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered at 70 mg.

[0213] In one aspect, a compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of four weeks, wherein the compound of Formula (I), (I- A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for two weeks, and then not administered for the following two weeks, wherein the compound of Formula (I), (I- A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered at 100 mg.

[0214] In one aspect, a compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of four weeks, wherein the compound of Formula (I), (I- A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for two weeks, and then not administered for the following two weeks, wherein the compound of Formula (I), (I- A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered at 125 mg.

[0215] In one aspect, a compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of four weeks, wherein the compound of Formula (I), (I- A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for two weeks, and then not administered for the following two weeks, wherein the compound of Formula (I), (I- A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered at 150 mg.

[0216] In one aspect, a compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of four weeks, wherein the compound of Formula (I), (I- A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for two weeks, and then not administered for the following two weeks, wherein the compound of Formula (I), (I- A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered at 175 mg.

[0217] In one aspect, a compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of four weeks, wherein the compound of Formula (I), (I- A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for two weeks, and then not administered for the following two weeks, wherein the compound of Formula (I), (I- A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, is administered at 200 mg.PHARMACEUTICAL COMPOSITIONS

[0218] In certain embodiments, the compound as described herein is administered as a pure chemical. In other embodiments, the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)), the disclosure of which is hereby incorporated herein by reference in its entirety.

[0219] Accordingly, provided herein is a pharmaceutical composition comprising at least one compound described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject) of the composition.

[0220] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, disclosed herein.

[0221] Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (I), (I- A), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, disclosed herein.

[0222] In certain embodiments, the compound as described herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1% of other organic small molecules, such as contaminating intermediates or by-products that are created, for example, in one or more of the steps of a synthesis method.

[0223] These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used. For example, disclosed compositions are formulated as a unit dose, and / or are formulated for oral or subcutaneous administration.

[0224] In some instances, exemplary pharmaceutical compositions are used in the form of a pharmaceutical preparation, for example, in solid, semisolid, or liquid form, which includes one or more of a compound disclosed herein, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral applications. In some embodiments, the active ingredient is compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.

[0225] For preparing solid compositions such as tablets in some instances, the principal active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a disclosed compound or a non-toxic pharmaceutically acceptable salt or solvate thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition is readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0226] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions also comprise buffering agents in some embodiments. Solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0227] In some instances, a tablet is made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets are prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets are made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills, and granules, are optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceuticalformulating art.

[0228] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, the liquid dosage forms contain optionally inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins, and mixtures thereof.

[0229] Suspensions, in addition to the subject composition, optionally contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0230] In some embodiments, formulations for rectal or vaginal administration are presented as a suppository, which are prepared by mixing a subject composition with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.

[0231] Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component is optionally mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which are required in some embodiments.

[0232] In some embodiments, the ointments, pastes, creams and gels contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0233] In some embodiments, powders and sprays contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0234] Compositions and compounds disclosed herein are alternatively administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers are used because they minimize exposing the agent to shear, which result in degradation of the compounds contained in the subject compositions in some embodiments. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (e.g., Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.

[0235] Pharmaceutical compositions suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which are reconstituted into sterile injectable solutions or dispersions just prior to use, which optionally contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0236] Examples of suitable aqueous and non-aqueous carriers employed in the pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. In some embodiments, proper fluidity is maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0237] Also contemplated are enteral pharmaceutical formulations including a disclosed compound and an enteric material and a pharmaceutically acceptable carrier or excipient thereof. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs. The small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenumjejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5 and the pH of the distal ileum is about 7.5. Accordingly, enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal collophorium, and several commercially available enteric dispersion systems (e.g., Eudragit L30D55, Eudragit FS30D, Eudragit LIOO, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric). Thesolubility of each of the above materials is either known or is readily determinable in vitro. The foregoing is a list of possible materials, but one of skill in the art with the benefit of the disclosure will recognize that it is not comprehensive and that there are other enteric materials that meet the objectives of the present disclosure.

[0238] In some embodiments, the doses of the composition comprising at least one compound as described herein differ, depending upon the patient's (e.g., human) condition, that is, stage of the disease, general health status, age, and other factors that a person skilled in the medical art will use to determine dose.

[0239] In some instances, pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented) as determined by persons skilled in the medical arts. An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and / or clinical trials. In some embodiments, the optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0240] In some embodiments, oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.The Hippo Signaling Network

[0241] The Hippo signaling network (also known as the Salvador / Warts / Hippo (SWH) pathway) is a master regulator of cell proliferation, death, and differentiation. In some embodiments, the main function of the Hippo signaling pathway is to regulate negatively the transcriptional co-activators Yes-associated protein (YAP) and its paralogue, the transcriptional co-activator with PDZ-binding motif (TAZ; also known as WWTR1) (Fig. 1). The Hippo kinase cascade phosphorylates and inhibits YAP / TAZ by promoting its cytoplasmic retention and degradation, thereby inhibiting the growth promoting function regulated under the YAP / TAZ control. In an un-phosphorylated / de- phosphorylated state, YAP, also known as YAP1 or YAP65, together with TAZ, are transported into the nucleus where they interact with TEAD family of transcription factors to upregulate genes that promote proliferation and migration and inhibit apoptosis. In some instances, unregulatedupregulation of these genes involved in proliferation, migration, and anti-apoptosis leads to development of cancer. In some instances, overexpression of YAP / TAZ is associated with cancer.

[0242] Additional core members of the Hippo signaling pathway comprise the serine / threonine kinases MST1 / 2 (homologues of Hippo / Hpo in Drosophila), Latsl / 2 (homologues of Warts / Wts), and their adaptor proteins Savl (homologue of Salvador / Sav) and Mob (MOBKL1 A and MOBKL1B; homologues of Mats), respectively (Fig. 1). In general, MST1 / 2 kinase complexes with the scaffold protein Savl, which in turn phosphorylates and activates Latsl / 2 kinase. Latsl / 2 is also activated by the scaffold protein Mob. The activated Latsl / 2 then phosphorylates and inactivates YAP or its paralog TAZ. The phosphorylation of YAP / TAZ leads to their nuclear export, retention within the cytoplasm, and degradation by the ubiquitin proteasome system.

[0243] In some instances, Latsl / 2 phosphorylates YAP at the [HXRXXS] consensus motifs. YAP comprises five [HXRXXS] consensus motifs, wherein X denotes any amino acid residue. In some instances, Latsl / 2 phosphorylates YAP at one or more of the consensus motifs. In some instances, Latsl / 2 phosphorylates YAP at all five of the consensus motifs. In some instances, Latsl / 2 phosphorylate at the S127 amino acid position. The phosphorylation of YAP SI 27 promotes 14-3-3 protein binding and results in cytoplasmic sequestration of YAP. Mutation of YAP at the S127 position thereby disrupts its interaction with 14-3-3 and subsequently promotes nuclear translocation.

[0244] Additional phosphorylation occurs at the S381 amino acid position in YAP. Phosphorylation of YAP at the S381 position and on the corresponding site in TAZ primes both proteins for further phosphorylation events by CK15 / s in the degradation motif, which then signals for interaction with the P-TRCP E3 ubiquitin ligase, leading to polyubiquitination and degradation of YAP.

[0245] In some instances, Latsl / 2 phosphorylates TAZ at the [HXRXXS] consensus motifs. TAZ comprises four [HXRXXS] consensus motifs, wherein X denotes any amino acid residues. In some instances, Latsl / 2 phosphorylates TAZ at one or more of the consensus motifs. In some instances, Latsl / 2 phosphorylates TAZ at all four of the consensus motifs. In some instances, Latsl / 2 phosphorylate at the S89 amino acid position. The phosphorylation of TAZ S89 promotes 14-3-3 protein binding and results in cytoplasmic sequestration of TAZ. Mutation of TAZ at the S89 position thereby disrupts its interaction with 14-3-3 and subsequently promotes nuclear translocation.

[0246] In some embodiments, phosphorylated YAP / TAZ accumulates in the cytoplasm, and undergoes SCFp'TRCP-mediated ubiquitination and subsequent proteasomal degradation. In some instances, the Skp, Cullin, F-box containing complex (SCF complex) is a multi-protein E3 ubiquitinligase complex that comprises a F-box family member protein (e.g., Cdc4), Skpl, a bridging protein, and RBX1, which contains a small RING Finger domain which interacts with E2 -ubiquitin conjugating enzyme. In some cases, the F-box family comprises more than 40 members, in which exemplary members include F-box / WD repeat-containing protein 1A (FBXW1A, pTrCPl, Fbxwl, hsSlimb, plkappaBalpha-E3 receptor subunit) and S-phase kinase-associated proteins 2 (SKP2). In some embodiments, the SCF complex (e.g., SCFpTrCP1) interacts with an El ubiquitin-activating enzyme and an E2 ubiquitin-conjugating enzyme to catalyze the transfer of ubiquitin to the YAP / TAZ substrate. Exemplary El ubiquitin-activating enzymes include those encoded by the following genes: UBA1, UBA2, UBA3, UBA5, UBA5, UBA7, ATG7, NAE1, mA SAEl . Exemplary E2 ubiquitin-conjugating enzymes include those encoded by the following genes: UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE2G1, UBE2G2, UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2L6, UBE2M, UBE2N, UBE2O, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2Z, ATG2, BIRC5, and UFC1. In some embodiments, the ubiquitinated YAP / TAZ further undergoes the degradation process through the 26S proteasome.

[0247] In some embodiments, the Hippo pathway is regulated upstream by several different families of regulators (Fig. 1). In some instances, the Hippo pathway is regulated by the G-protein and its coupled receptors, the Crumbs complex, regulators upstream of the MST kinases, and the adherens junction.YAP / TAZ Interaction with TEAD

[0248] In some embodiments, un-phosphorylated and / or dephosphorylated YAP / TAZ accumulates in the nucleus. Within the nucleus, YAP / TAZ interacts with the TEAD family of transcription factors (e.g., TEAD1, TEAD2, TEAD3, or TEAD4) to activate genes involved in anti-apoptosis and proliferation, such as for example, CTFG, Cyr61, and FGF1.

[0249] In some embodiments, the compounds disclosed herein modulate the interaction between YAP / TAZ and TEAD. In some embodiments, the compounds disclosed herein bind to TEAD, YAP, or TAZ and prevent the interaction between YAP / TAZ and TEAD.YAP / TAZ regulation mediated by G-proteins / GPCRs

[0250] In some embodiments, the Hippo pathway is regulated by the G protein-coupled receptor (GPCR) and G protein (also known as guanine nucleotide-binding proteins) family of proteins (Fig. 2). G proteins are molecular switches that transmit extracellular stimuli into the cell through GPCRs. In some instances, there are two classes of G proteins: monomeric small GTPases and heterotrimeric G protein complexes. In some instances, the latter class of complexes comprise ofalpha (Ga), beta (Gp), and gamma (Gy) subunits. In some cases, there are several classes of Gasubunits: Gq / na, G12 / 1301, Gi / Oa (G inhibitory, G other), and Gsa (G stimulatory).

[0251] In some instances, Ga (G inhibitory), Goa (G other), Gq / na, and Gi2 / i3a coupled GPCRs activate YAP / TAZ and promote nuclear translocation. In other instances, Gsa (G stimulatory) coupled GPCRs suppress YAP / TAZ activity, leading to YAP / TAZ degradation.

[0252] In some cases, Ga (G inhibitory), Goa (G other), Gq / na, and Gi2 / i3a coupled GPCRs activate YAP / TAZ through repression of Latsl / 2 activities. In contrast, Gsa, in some embodiments, induces Latsl / 2 activity, thereby promoting YAP / TAZ degradation.Gq Family

[0253] Gqa (also known as Gq / n protein), participates in the inositol trisphosphate (IP3) signal transduction pathway and calcium (Ca2+) release from intracellular storage through the activation of phospholipase C (PLC). The activated PLC hydrolyzes phosphatidylinositol 4, 5 -bisphosphate (PIP2) to diacyl glycerol (DAG) and IP3. In some instances, IP3 then diffuses through the cytoplasm into the ER or the sarcoplasmic reticulum (SR) in the case of muscle cells, and then binds to inositol trisphosphate receptor (InsP3R), which is a Ca2+channel. In some cases, the binding triggers the opening of the Ca2+channel, and thereby increases the release of Ca2+into the cytoplasm.

[0254] In some embodiments, the GPCRs that interact with Gqa include, but are not limited to, 5- hydroxytryptamine receptor (5-HT receptor) types 5-HT2 and 5-HT3; alpha-1 adrenergic receptor; vasopressin type 1 receptors 1 A and IB; angiotensin II receptor type 1; calcitonin receptor; histamine Hl receptor; metabotropic glutamate receptor, group I; muscarinic receptors Mi, M3, and Ms; and trace amine-associated receptor 1.

[0255] In some instances, there are several types of Gqa: Gq, Gq / n, Gq / i4, and Gq / is. The Gqprotein is encoded by GNAQ. Gq / n is encoded by GNA11. Gq / i4 is encoded by GNA14. Gq / is is encoded by GNA15.

[0256] In some instances, mutations or modifications of the Gqa genes have been associated with cancer. Indeed, studies have shown that mutations in Gqa promote uveal melanoma (UM) tumorigenesis. In some instances, about 80% of UM cases have been detected to contain a mutation in GNAQ and / or GNA11.

[0257] In some instances, mutations or modifications of the Gqa genes have been associated with congenital diseases. In some instances, mutations of Gqa have been observed in congenital diseases such as Port-Wine Stain and / or Sturge-Weber Syndrome. In some instances, about 92% of Port- Wine stain cases harbors a mutation in GNAQ. In some instances, about 88% of Sturge-Weber Syndrome harbors a mutation in GNAQ.Gn / 13 Family

[0258] G12 / 1301 modulates actin cytoskeletal remodeling in cells and regulates cell processes through guanine nucleotide exchange factors (GEFs). GEFs participate in the activation of small GTPases which acts as molecular switches in a variety of intracellular signaling pathways. Examples of small GTPases include the Ras-related GTPase superfamily (e.g., Rho family, such as Cdc42), which is involved in cell differentiation, proliferation, cytoskeletal organization, vesicle trafficking, and nuclear transport.

[0259] In some embodiments, the GPCRs that interact with G12 / 1301 include, but are not limited to, purinergic receptors (e.g. P2Yi, P2Y2, P2Y4, P2Ye); muscarinic acetylcholine receptors Ml and M3; receptors for thrombin [protease-activated receptor (PAR)-1, PAR-2]; thromboxane (TXA2); sphingosine 1 -phosphate (e.g. SIP2, SIP3, SIP4 and SIP5); lysophosphatidic acid (e.g. LPAi, LPA2, LPA3); angiotensin II (ATI); serotonin (5-HT2Cand 5-HT4); somatostatin (ssts); endothelin (ETA and ETB); cholecystokinin (CCKi); Via vasopressin receptors; D5 dopamine receptors; fMLP formyl peptide receptors; GAL2 galanin receptors; EP3 prostanoid receptors; Ai adenosine receptors; ai adrenergic receptors; BB2 bombesin receptors; B2 bradykinin receptors; calcium- sensing receptors; KSHV-ORF74 chemokine receptors; NKi tachykinin receptors; and thyroid- stimulating hormone (TSH) receptors.

[0260] In some instances, G12 / 1301 is further subdivided into G12 and G13 types which are encoded by GNA12 and GNA13, respectively.Gj / o Family

[0261] G,oa (G inhibitory, G other) (also known as Gi / Go or Gi protein) suppresses the production of 3 ’,5 ’-cyclic AMP (cAMP) from adenosine triphosphate (ATP) through an inhibition of adenylate cyclase activity, which converts ATP to cAMP.

[0262] In some embodiments, the GPCRs that interact with Ga include, but are not limited to, 5- hydroxytryptamine receptor (5-HT receptor) types 5-HTi and 5-HTs; muscarinic acetylcholine receptors such as M2 and M4; adenosine receptors such as Ai and A3; adrenergic receptors such as ct2A, ct2B, and 012c; apelin receptors; calcium-sensing receptor; cannabinoid receptors CB 1 and CB2; chemokine CXCR4 receptor; dopamines D2, D3, and D4; GAB AB receptor; glutamate receptors such as metabotropic glutamate receptor 2 (mGluR2), metabotropic glutamate receptor 3 (mGluR3), metabotropic glutamate receptor 4 (mGluR4), metabotropic glutamate receptor 6 (mGluR6), metabotropic glutamate receptor 7 (mGluR7), and metabotropic glutamate receptor 8 (mGluR8); histamine receptors such as H3 and H4 receptors; melatonin receptors such as melatonin receptor type 1 (MT1), melatonin receptor type 2 (MT2), and melatonin receptor type 3 (MT3); niacin receptors such as NIACR1 and NIACR2; opioid receptors such as 5, K, p, and nociceptinreceptors; prostaglandin receptors such as prostaglandin E receptor 1 (EPi), prostaglandin E receptor 3 (EP3), prostaglandin F receptor (FP), and thromboxane receptor (TP); somatostatin receptors sstl, sst2, sst3, sst4, and sst5; and trace amine-associated receptor 8.

[0263] In some instances, there are several types of Gia: Gal, Ga2, Ga3, Ga4, Goa, Gt, Ggust, and Gz. Gal is encoded by GNAI1. Ga2 is encoded by GNAI2. Ga3 is encoded by GN Al 3. Goa, the a0subunit, is encoded by GNAO1. Gt is encoded by GNAT1 and GNAT2. Ggust is encoded by GNAT3. Gzis encoded by GN AZ.GsFamily

[0264] Gsa (also known as G stimulatory, Gsalpha subunit, or Gsprotein) activates the cAMP- dependent pathway through the activation of adenylate cyclase, which convers adenosine triphosphate (ATP) to 3 ’,5 ’-cyclic AMP (cAMP) and pyrophosphate. In some embodiments, the GPCRs that interact with Gsa include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HT4, 5-HTe, and 5-HT?; adrenocorticotropic hormone receptor (ACTH receptor) (also known as melanocortin receptor 2 or MC2R); adenosine receptor types A2a and A2b; arginine vasopressin receptor 2 (AVPR2); P-adrenergic receptors Pi, P2, and P3; calcitonin receptor; calcitonin gene-related peptide receptor; corticotropin-releasing hormone receptor; dopamine receptor Di-like family receptors such as Di and D5; follicle-stimulating hormone receptor (FSH- receptor); gastric inhibitory polypeptide receptor; glucagon receptor; histamine EE receptor; luteinizing hormone / choriogonadotropin receptor; melanocortin receptors such as MC1R, MC2R, MC3R, MC4R, and MC5R; parathyroid hormone receptor 1; prostaglandin receptor types D2 and I2; secretin receptor; thyrotropin receptor; trace amine-associated receptor 1; and box jellyfish opsin.

[0265] In some instances, there are two types of Gsa: Gsand Golf. Gsis encoded by GNAS. Goif is encoded by GN AL.Additional Regulators of the Hippo signaling network

[0266] In some embodiments, the additional regulator of the Hippo signaling pathway is the Crumbs (Crb) complex. The Crumbs complex is a key regulator of cell polarity and cell shape. In some instances, the Crumbs complex comprises transmembrane CRB proteins which assemble multi-protein complexes that function in cell polarity. In some instances, CRB complexes recruit members of the Angiomotin (AMOT) family of adaptor proteins that interact with the Hippo pathway components. In some instances, studies have shown that AMOT directly binds to YAP, promotes YAP phosphorylation, and inhibits its nuclear localization.

[0267] In some instances, the additional regulator of the Hippo signaling pathway comprises regulators of the MST kinase family. MST kinases monitor actin cytoskeletal integrity. In some instances, the regulators include TAO kinases and cell polarity kinase PAR-1.

[0268] In some instances, the additional regulator of the Hippo signaling pathway comprises molecules of the adherens junction. In some instances, E-Cadherin (E-cad) suppresses YAP nuclear localization and activity through regulating MST activity. In some embodiments, E-cad-associated protein a-catenin regulates YAP through sequestering YAP / 14-3-3 complexes in the cytoplasm. In other instances, Ajuba protein family members interact with Latsl / 2 kinase activity, thereby preventing inactivation of YAP / TAZ.

[0269] In some embodiments, additional proteins that interact with YAP / TAZ either directly or indirectly include, but are not limited to, Merlin, protocadherin Fat 1, MASK1 / 2, HIPK2, PTPN14, RASSF, PP2A, Salt-inducible kinases (SIKs), Scribble (SCRIB), the Scribble associated proteins Discs large (Dig), KIBRA, PTPN14, NPHP3, LKB1, Ajuba, and ZO1 / 2.

[0270] In some embodiments, the compounds described herein are inhibitors of transcriptional coactivator with PDZ binding motif / Yes- associated protein transcriptional coactivator(TAZ / YAP). In some embodiments, the compounds described herein increase the phosphorylation of transcriptional coactivator with PDZ binding motif / Yes- associated protein transcriptional coactivator (TAZ / YAP) or decrease the dephosphorylation of transcriptional coactivator with PDZ binding motif / Yes- associated protein transcriptional coactivator (TAZ / YAP). In some embodiments, the compounds increase the ubiquitination of transcriptional coactivator with PDZ binding motif / Yes- associated protein transcriptional coactivator (TAZ / YAP) or decrease the deubiquitination of transcriptional coactivator with PDZ binding motif / Yes- associated protein transcriptional coactivator (TAZ / YAP).

[0271] In some embodiments, the compounds disclosed herein are inhibitors of one or more of the proteins encompassed by, or related to, the Hippo pathway. In some instances, the one or more proteins comprise a protein shown in Fig. 1 or Fig. 2. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a G-protein and / or its coupled GPCR. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a G-protein. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of the Gqa family proteins such as Gq, Gq / n, Gq / i4, and Gq / is; the Gn / isa family of proteins such as G12 and G13; or the Gia family of proteins such as Gial, Ga2, Ga3, Ga4, Goa, Gt, Ggust, and Gz. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gq. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gq / n. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gq / i4. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gq / 15. In some embodiments, aninhibitor of the Hippo pathway is an inhibitor of G12. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G13. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Giod. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Ga2. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Ga3. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Ga4. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Goa. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gt. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Ggust. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gz.

[0272] In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a core protein of the Hippo pathway. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Savl. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Mob. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of YAP. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of TAZ. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of TEAD.

[0273] In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a protein associated with the ubiquitination and proteasomal degradation pathway. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a proteasomal degradation pathway protein (e.g., 26 S proteasome).

[0274] In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a protein of the Ras superfamily of proteins. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a protein of the Rho family of proteins. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Cdc42.

[0275] Cdc42 is a member of the Ras superfamily of small GTPases. Specifically, Cdc42 belongs to the Rho family of GTPases, in which the family members participate in diverse and critical cellular processes such as gene transcription, cell-cell adhesion, and cell cycle progression. Cdc42 is involved in cell growth and polarity, and in some instances, Cdc42 is activated by guanine nucleotide exchange factors (GEFs). In some cases, an inhibitor of Cdc42 is a compound disclosed herein.

[0276] In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a deubiquitinating enzyme. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a cysteine protease or a metalloprotease. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a ubiquitin-specific protease. USP47 is a member of the ubiquitinspecific protease (USP / UBP) superfamily of cysteine proteases. In some embodiments, the compounds disclosed herein are inhibitors of USP47.

[0277] Further embodiments provided herein include combinations of one or more of the particular embodiments set forth above.DiseasesCancer

[0278] In some embodiments, the compounds of Formula (I), (I- A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, disclosed herein are useful for treating cancer. In some embodiments, provided herein is methods for treating a cancer in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided herein is a compound for use in treating a cancer in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided herein is use of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for treating cancer.

[0279] In some embodiments, the cancer is mediated by activation of transcriptional coactivator with PDZ binding motif / Yes- associated protein transcription coactivator (TAZ / YAP). In some embodiments, the cancer is mediated by modulation of the interaction of YAP / TAZ with TEAD. In some embodiments, the cancer is characterized by a mutant Ga-protein. In some embodiments, the mutant Ga-protein is selected from G12, G13, Gq, G11, Gi, Go, and Gs. In some embodiments, the mutant Ga-protein is G12. In some embodiments, the mutant Ga-protein is G13. In some embodiments, the mutant Ga-protein is Gq. In some embodiments, the mutant Ga-protein is Gl 1. In some embodiments, the mutant Ga-protein is Gi. In some embodiments, the mutant Ga-protein is Go. In some embodiments, the mutant Ga-protein is Gs.

[0280] In some embodiments, the cancer is a solid tumor. In some instances, the cancer is a hematologic malignancy. In some instances, the solid tumor is a sarcoma or carcinoma. In some instances, the solid tumor is a sarcoma. In some instances, the solid tumor is a carcinoma.

[0281] Exemplary sarcoma includes, but is not limited to, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastoma, angiosarcoma, chondrosarcoma, chordoma, clear cell sarcoma of soft tissue, dedifferentiated liposarcoma, desmoid, desmoplastic small round cell tumor, embryonal rhabdomyosarcoma, epithelioid fibrosarcoma, epithelioid hemangioendothelioma, epithelioid sarcoma, esthesioneuroblastoma, Ewing sarcoma, extrarenal rhabdoid tumor, extraskeletal myxoid chondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma, giant cell tumor, hemangiopericytoma, infantile fibrosarcoma, inflammatory myofibroblastic tumor, Kaposi sarcoma, leiomyosarcoma ofbone, liposarcoma, liposarcoma of bone, malignant fibrous histiocytoma (MFH), malignant fibrous histiocytoma (MFH) of bone, malignant mesenchymoma, malignant peripheral nerve sheath tumor, mesenchymal chondrosarcoma, myxofibrosarcoma, myxoid liposarcoma, myxoinflammatory fibroblastic sarcoma, neoplasms with perivascular epithelioid cell differentiation, osteosarcoma, parosteal osteosarcoma, neoplasm with perivascular epithelioid cell differentiation, periosteal osteosarcoma, pleomorphic liposarcoma, pleomorphic rhabdomyosarcoma, PNET / extraskeletal Ewing tumor, rhabdomyosarcoma, round cell liposarcoma, small cell osteosarcoma, solitary fibrous tumor, synovial sarcoma, and telangiectatic osteosarcoma.

[0282] Exemplary carcinoma includes, but is not limited to, adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, anal cancer, appendix cancer, bile duct cancer (i.e., cholangiocarcinoma), bladder cancer, brain tumor, breast cancer, cervical cancer, colon cancer, cancer of Unknown Primary (CUP), esophageal cancer, eye cancer, fallopian tube cancer, gastroenterological cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer. In some instances, the liver cancer is primary liver cancer.

[0283] In some instances, the cancer is selected from uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer, and meningioma. In some cases, the cancer is uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer, or meningioma. In some cases, the cancer is uveal melanoma, mesothelioma, esophageal cancer, or liver cancer. In some cases, the cancer is uveal melanoma. In some cases, the cancer is mesothelioma. In some cases, the cancer is esophageal cancer. In some cases, the cancer is liver cancer. In some cases, the cancer is primary liver cancer.

[0284] In some instances, the cancer is a hematologic malignancy. In some embodiments, a hematologic malignancy is a leukemia, a lymphoma, a myeloma, a non-Hodgkin’s lymphoma, a Hodgkin’s lymphoma, a T-cell malignancy, or a B-cell malignancy. In some instances, a hematologic malignancy is a T-cell malignancy. Exemplary T-cell malignancy includes, but is not limited to, peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), anaplastic large celllymphoma, angioimmunoblastic lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia / lymphoma (ATLL), blastic NK-cell lymphoma, enteropathy -type T-cell lymphoma, hematosplenic gamma-delta T-cell lymphoma, lymphoblastic lymphoma, nasal NK / T-cell lymphomas, and treatment-related T-cell lymphomas.

[0285] In some instances, a hematologic malignancy is a B-cell malignancy. Exemplary B-cell malignancy includes, but is not limited to, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, and a non-CLL / SLL lymphoma. In some embodiments, the cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt’s lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.

[0286] In some instances, the cancer is a relapsed or refractory cancer. In some embodiments, the relapsed or refractory cancer is a relapsed or refractory solid tumor. In some embodiments, the relapsed or refractory solid tumor is a relapsed or refractory sarcoma or a relapsed or refractory carcinoma. In some embodiments, the relapsed or refractory carcinoma includes adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, anal cancer, appendix cancer, bile duct cancer (i.e., cholangiocarcinoma), bladder cancer, brain tumor, breast cancer, cervical cancer, colon cancer, cancer of Unknown Primary (CUP), esophageal cancer, eye cancer, fallopian tube cancer, gastroenterological cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer.

[0287] In some instances, the relapsed or refractory cancer is selected from relapsed or refractory uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer, and meningioma. In some cases, the relapsed or refractory cancer is relapsed or refractory uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectalcancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer, or meningioma. In some cases, the relapsed or refractory cancer is relapsed or refractory uveal melanoma, mesothelioma, esophageal cancer, or liver cancer. In some cases, the relapsed or refractory cancer is relapsed or refractory uveal melanoma. In some cases, the relapsed or refractory cancer is relapsed or refractory mesothelioma. In some cases, the relapsed or refractory cancer is relapsed or refractory esophageal cancer. In some cases, the relapsed or refractory cancer is relapsed or refractory liver cancer. In some cases, the relapsed or refractory cancer is relapsed or refractory primary liver cancer.

[0288] In some instances, the relapsed or refractory cancer is a relapsed or refractory hematologic malignancy. In some embodiments, a relapsed or refractory hematologic malignancy is a relapsed or refractory leukemia, a relapsed or refractory lymphoma, a relapsed or refractory myeloma, a relapsed or refractory non-Hodgkin’s lymphoma, a relapsed or refractory Hodgkin’s lymphoma, a relapsed or refractory T-cell malignancy, or a relapsed or refractory B-cell malignancy. In some instances, a relapsed or refractory hematologic malignancy is a relapsed or refractory T-cell malignancy. In some instances, a relapsed or refractory hematologic malignancy is a relapsed or refractory B-cell malignancy, such as for example, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, or a non-CLL / SLL lymphoma. In some embodiments, the cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt’ s lymphoma, nonBurkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.

[0289] In some instances, the cancer is a metastasized cancer. In some instances, the metastasized cancer is a metastasized solid tumor. In some instances, the metastasized solid tumor is a metastasized sarcoma or a metastasized carcinoma. In some embodiments, the metastasized carcinoma includes adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, anal cancer, appendix cancer, bile duct cancer (i.e., cholangiocarcinoma), bladder cancer, brain tumor, breast cancer, cervical cancer, colon cancer, cancer of Unknown Primary (CUP), esophageal cancer, eye cancer, fallopian tube cancer, gastroenterological cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer,pituitary tumor, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer.

[0290] In some instances, the metastasized cancer is selected from metastasized uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer, and meningioma. In some cases, the metastasized cancer is metastasized uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer, or meningioma. In some cases, the metastasized cancer is metastasized uveal melanoma, mesothelioma, esophageal cancer, or liver cancer. In some cases, the metastasized cancer is metastasized uveal melanoma. In some cases, the metastasized cancer is metastasized mesothelioma. In some cases, the metastasized cancer is metastasized esophageal cancer. In some cases, the metastasized cancer is metastasized liver cancer. In some cases, the metastasized cancer is metastasized primary liver cancer.

[0291] In some instances, the metastasized cancer is a metastasized hematologic malignancy. In some embodiments, the metastasized hematologic malignancy is a metastasized leukemia, a metastasized lymphoma, a metastasized myeloma, a metastasized non -Hodgkin’s lymphoma, a metastasized Hodgkin’s lymphoma, a metastasized T-cell malignancy, or a metastasized B-cell malignancy. In some instances, a metastasized hematologic malignancy is a metastasized T-cell malignancy. In some instances, a metastasized hematologic malignancy is a metastasized B-cell malignancy, such as for example, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, or a non-CLL / SLL lymphoma. In some embodiments, the cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt’s lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.

[0292] In some instances, the cancer is mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma, lung cancer, bladder carcinoma, cutaneousneurofibromas, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, or breast cancer.Non-Cancer Indications

[0293] In some embodiments, the compounds of Formula (I), (I- A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, disclosed herein are useful for treating polycystic kidney disease. In some embodiments, the compounds of Formula (I), (I- A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, disclosed herein are useful for treating liver fibrosis. In some embodiments, provided herein is a method for treating polycystic kidney disease in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided herein is a compound for use in treating polycystic kidney disease in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided herein is use of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for treating polycystic kidney disease. In some embodiments, provided herein is a method for treating liver fibrosis in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided herein is a compound for use in treating liver fibrosis in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided herein is use of a compound or a pharmaceutically acceptable salt or solvate thereof disclosed herein in the manufacture of a medicament for treating liver fibrosis.

[0294] In some embodiments, the compounds of Formula (I), (I- A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, disclosed herein are useful for treating kidney fibrosis, cardiac fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), heart failure, cardiac diseases associated with pathological remodeling, diastolic heart failure, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, autosomal dominant polycystic kidney disease, interstitial lung diseases, progressive osseous heteroplasia, heterotopic ossification, osteoma cutis, fibrodysplasia ossificans progressive, crescentic glomerulopathies, or osteoporosis. In some embodiments, the compounds of Table 1, or the pharmaceutically acceptable salt or solvate thereof, disclosed herein are useful for treating kidney fibrosis, cardiac fibrosis,pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), heart failure, cardiac diseases associated with pathological remodeling, diastolic heart failure, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, autosomal dominant polycystic kidney disease, interstitial lung diseases, progressive osseous heteroplasia, heterotopic ossification, osteoma cutis, fibrodysplasia ossificans progressive, crescentic glomerulopathies, or osteoporosis. In some embodiments, provided herein is a method for treating kidney fibrosis, cardiac fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), heart failure, cardiac diseases associated with pathological remodeling, diastolic heart failure, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, autosomal dominant polycystic kidney disease, interstitial lung diseases, progressive osseous heteroplasia, heterotopic ossification, osteoma cutis, fibrodysplasia ossificans progressive, crescentic glomerulopathies, or osteoporosis in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided herein is a compound for use in treating kidney fibrosis, cardiac fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), heart failure, cardiac diseases associated with pathological remodeling, diastolic heart failure, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, autosomal dominant polycystic kidney disease, interstitial lung diseases, progressive osseous heteroplasia, heterotopic ossification, osteoma cutis, fibrodysplasia ossificans progressive, crescentic glomerulopathies, or osteoporosis in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided herein is use of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for treating kidney fibrosis, cardiac fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), heart failure, cardiac diseases associated with pathological remodeling, diastolic heart failure, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, autosomal dominant polycystic kidney disease, interstitial lung diseases, progressive osseous heteroplasia, heterotopic ossification, osteoma cutis, fibrodysplasia ossificans progressive, crescentic glomerulopathies, or osteoporosis.Congenital Diseases

[0295] In some embodiments, the compounds of Formula (I), (I- A), (II), or (III), or the pharmaceutically acceptable salt or solvate thereof, disclosed herein are useful for treating a congenital disease. In some embodiments, provided herein is a method for treating congenital disease in a subject in need thereof comprising administering to the subject in need thereof atherapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided herein is a compound for use in treating congenital disease in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided herein is use of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for treating congenital disease. In some embodiments, the congenital disease is mediated by activation of transcriptional coactivator with PDZ binding motif / Yes- associated protein transcription coactivator (TAZ / YAP). In some embodiments, the congenital disease is characterized by a mutant Ga-protein. In some embodiments, the mutant Ga-protein is selected from G12, G13, Gq, G11, Gi, Go, and Gs. In some embodiments, the mutant Ga-protein is G12. In some embodiments, the mutant Ga-protein is G13. In some embodiments, the mutant Ga-protein is Gq. In some embodiments, the mutant Ga-protein is Gl 1. In some embodiments, the mutant Ga- protein is Gi. In some embodiments, the mutant Ga-protein is Go. In some embodiments, the mutant Ga-protein is Gs.

[0296] In some embodiments, the congenital disease is the result of a genetic abnormality, an intrauterine environment, errors related to morphogenesis, infection, epigenetic modifications on a parental germline, or a chromosomal abnormality. Exemplary congenital diseases include, but are not limited to, Sturge-Weber Syndrome, Port-Wine stain, Holt-Oram syndrome, abdominal wall defects, Becker muscular dystrophy (BMD), biotinidase deficiency, Charcot-Marie-Tooth (CMT), cleft lip, cleft palate, congenital adrenal hyperplasia, congenital heart defects, congenital hypothyroidism, congenital muscular dystrophy, cystic fibrosis, Down syndrome, Duchenne muscular dystrophy, Fragile X syndrome, Friedreich’s ataxia, galactosemia, hemoglobinopathies, Krabbe disease, limb-girdle muscular dystrophy, medium chain acyl-CoA dehydrogenase deficiency, myasthenia gravis, neural tube defects, phenylketonuria, Pompe disease, severe combined immunodeficiency (SCID), Stickler syndrome (or hereditary progressive arthro- ophthalmopathy), spinal muscular atrophy, and trisomy 18. In some embodiments, the congenital disease is Sturge-Weber Syndrome or Port-Wine stain. In some embodiments, the congenital disease is Sturge-Weber Syndrome. In some embodiments, the congenital disease is Port-Wine stain.EXAMPLES

[0297] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.List of abbreviations

[0298] As used above, and throughout the disclosure, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:ACN or MeCN acetonitrileAc acetylBn benzylBOC or Boc tert-butyl carbamateZ-Bu tert-butylCy cyclohexyl°C degrees CelsiusDBA or dba dib enzy li deneacetoneDCE di chloroethane (CICH2CH2CI)DCM dichloromethane (CH2Q2)DIAD diisopropyl azodi carb oxy lateDIPEA or DIEA diisopropylethylamineDMAP 4-(A A-dimethylamino)pyridineDMF dimethylformamideDMA M-V-di methyl acetamideDMSO dimethylsulfoxideDppf or dppf l,l'-bis(diphenylphosphino)ferroceneEA or EtO Ac ethyl acetate eq equivalent(s)Et ethylEt2O diethyl etherEtOH ethanol g gram(s) h hour(s)HPLC high performance liquid chromatographyHz hertzLAH lithium aluminum anhydrideLCMS liquid chromatography mass spectrometry m / z mass-to-charge ratioM molarMe methylMel methyl iodideMeOH methanol mg milligram(s)MHz megahertz umol micromole(s) uL microliter(s) mL milliliter(s) mmol millimole(s) MS mass spectroscopy MsCl methanesulfonyl chloride MW micro wave radiation NCS A-chlorosuccinimideNMM A-methyl-morpholineNMP A-methyl-pyrrolidin-2-oneNMR nuclear magnetic resonancePE petroleum etherPh phenyl prep-HPLC preparative high pressure liquid chromatography prep-TLC preparative thin layer chromatography Py pyridineRP-HPLC reverse phase-high pressure liquid chromatographyRT retention timeTEA tri ethylamineTFA trifluoroacetic acidTHF tetrahydrofuranTLC thin layer chromatographyTMSC1 trimethyl silyl chloride Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene XPhos 2-dicy clohexylphosphino-2 ',4 6 ' -tri i sopropylbiphenylXPhos Pd G II chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'- biphenyl)[2-(2'-amino-l, 1 '-biphenyl)]palladium(II)I. Chemical Synthesis

[0299] The present disclosure relates to a compound of Formula (I), (LA), (II), or (III), or a pharmaceutical acceptable salt or solvate thereof, as described in the International Application No. PCT / US2020 / 028363, filed April 15, 2020, and published as WO2020 / 214734A1, which is hereby incorporated by reference in its entirety.

[0300] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for synthetic transformations sensitive to moisture and / or oxygen. Yields were not optimized. Reaction times were approximate and were not optimized. Column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise noted. In some embodiments, in case of a discrepancy between a reaction scheme and a written procedure, the written procedure should be followed.Example 1: N-isopropyl-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 1) 5-[4-(Trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid

[0301] To a mixture of methyl 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylate (200 mg, 0.58 mmol, 1 eq) in methanol (1.5 mL), tetrahydrofuran (0.5 mL) and H2O (0.5 mL) was added sodium hydroxide (2 M, 2.89 mL, 10 eq.). The mixture was stirred at 30 °C for 1 h. The mixture was concentrated. The residue was diluted with H2O (20 mL) and adjusted pH = 6-7 with IN hydrochloric acid. The mixture was extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (220 mg, crude).N-isopropyl-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 1)

[0302] To a solution of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (0.1, 0.30 mmol, 1 eq) in DMF (2 mL) was added HATU (228.8 mg, 0.60 mmol, 2 eq) and TEA (152.2 mg, 1.50 mmol, 0.20 mL, 5 eq). The mixture was stirred for 0.5 hrs at 25 °C. Tso-propylamine (35.5 mg, 0.60 mmol, 51.7 uL, 2 eq) was added to the mixture and the mixture was stirred for 0.5 hr at 25 °C. The mixture was quenched by H2O (30 mL), and the mixture was extracted with EA (20 mL*3). The combined organic phase was washed with brine (20 mL*3), dried with anhydrous Na2SO4,filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Xtimate C18 150*25mm*5um;mobile phase: [water(0.05%HCl)-ACN];B%: 60%-90%,9.5min) to give the title compound (13.26 mg, 35.5 umol, 11.8% yield). LCMS (ESI): RT = 0.881 min, mass calc, for: C2iHi8F3NO2 373.37, m / z found 373.9;1H NMR (400MHz, METHANOL-d4) Shift = 8.45 (d, J= 1.5 Hz, 1H), 8.10 (d, J= 8.9 Hz, 1H), 7.91 (d, J= 8.7 Hz, 2H), 7.71 - 7.64 (m, J= 8.5 Hz, 2H), 7.59 (t, J= 7.9 Hz, 1H), 7.23 (dd, J= 0.8, 7.6 Hz, 1H), 7.18 - 7.12 (m, J= 8.6 Hz, 2H), 4.34 - 4.24 (m, 1H), 1.31 (d, J = 6.6 Hz, 6H).Example 2: N-(2-hydroxy-l-(pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide (Compound 2)

[0303] The mixture of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (60 mg, 0.18 mmol, 1 eq), HATU (102.9 mg, 0.27 mmol, 1.5 eq) and DIPEA (70 mg, 0.54 mmol, 94.3 uL, 3 eq) in DCM (2 mL) was stirred at 25 °C for 1 hr. Then 2-amino-2-pyridin-2-yl-ethanol (50 mg, 0.23 mmol, 1.31 eq, 2 HC1) was added at the mixture and the mixture was stirred at 25 °C for another 1 hr. The reaction mixture was diluted with H2O (10 mL) and the mixture was extracted with EA (10 mL * 3). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Xtimate C18 150*25mm*5um;mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN];B%: 60%-90%,7.8min) to give the title compound (32 mg, 70.7 umol, 39.1% yield). LCMS (ESI): RT = 0.868 min, mass calcd for C25H19F3N2O3 452.34 m / z found 453.0 [M+H]+; 'HNMR (400 MHz, DMSO-d6) 8 8.90 (d, J= 7.8 Hz, 1H), 8.67 (s, 1H), 8.58 - 8.53 (m, 1H), 8.04 - 7.97 (m, 3H), 7.80 - 7.73 (m, 4H), 7.69 - 7.62 (m, 1H), 7.47 (d, J= 7.8 Hz, 1H), 7.34 (d, J= 7.5 Hz, 1H), 7.31 - 7.21 (m, 2H), 7.18 (d, J= 8.5 Hz, 2H), 5.26 - 5.18 (m, 1H), 4.98 (br s, 1H), 3.85 (br dd, J = 5.8, 12.0 Hz, 2H).Example 3: (R)-N-(l-methoxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 3)

[0304] The mixture of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (50 mg, 0.15 mmol, 1 eq), DIPEA (58.3 mg, 0.45 mmol, 78.6 uL, 3 eq) and HATU (85.8 mg, 0.22 mmol, 1.5 eq) in DCM (2 mL) was stirred at 25 °C for 1 hr. Then (2R)-l-methoxypropan-2-amine hydrochloride (22.6 mg, 0.18 mmol, 1.2 eq) was added at the mixture and the mixture was stirred at 25 °C for 2 hr. The reaction mixture was diluted with H2O (10 mL) and the mixture was extracted with EA (10 mL * 3). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Xtimate C18 150*25mm*5um;mobile phase: [water(0.05%HCl)-ACN];B%: 60%-90%,7min) to give the title compound (40 mg, 99.1 umol, 65.9% yield). LCMS (ESI): RT = 0.863 min, mass calcd for C22H20F3NO3 403.39 m / z found 404.0 [M+H]+; 'HNMR (400 MHz, CD3OD) 5 8.46 (d, J = 1.3 Hz, 1H), 8.10 (d, J= 8.8 Hz, 1H), 7.94 - 7.87 (m, 2H), 7.68 (d, J= 8.5 Hz, 2H), 7.60 (t, J= 7.9 Hz, 1H), 7.26 - 7.20 (m, 1H), 7.15 (d, J= 8.5 Hz, 2H), 4.40 (sxt, J= 6.5 Hz, 1H), 3.59 - 3.53 (m, 1H), 3.50 - 3.45 (m, 1H), 3.42 (s, 3H), 1.30 (d, J= 6.8 Hz, 4H).Example 4: N-[(lR)-l-(2-pyridyl)ethyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2- carboxamide (Compound 4)

[0305] The mixture of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (50 mg, 0.15 mmol, 1 eq), DIPEA (58.3 mg, 0.45 mmol, 78.6 uL, 3 eq) and HATU (85.8 mg, 0.22 mmol, 1.5 eq) in DCM (3 mL) was stirred at 25 °C for 1 hr. Then (lR)-l-(2-pyridyl)ethanamine (22 mg, 0.18 mmol, 1.2 eq) was added at the mixture and the mixture was stirred at 25 °C for another 2 hr. The reaction mixture was diluted with H2O (10 mL) and the mixture was extracted with EA (10 mL * 3). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Xtimate C18 150*25mm*5um;mobile phase: [water(0.05%HCl)-ACN];B%: 65%-95%,7min) to give the title compound (30 mg, 68 umol, 45.2% yield). LCMS (ESI): RT = 0.891 min, mass calcd forC25H19F3N2O2 436.43 m / z found 437.0 [M+H]+; *H NMR (400 MHz, CD3OD) 5 8.54 (d, J= 1.5 Hz, 2H), 8.10 (d, J= 8.8 Hz, 1H), 7.98 - 7.88 (m, 2H), 7.83 (dt, J= 1.8, 7.7 Hz, 1H), 7.66 (d, J= 8.6 Hz, 2H), 7.59 (t, J= 7.9 Hz, 1H), 7.52 (d, J= 8.0 Hz, 1H), 7.32 (ddd, J= 0.9, 5.0, 7.5 Hz, 1H), 7.23 (d, J= 7.0 Hz, 1H), 7.13 (d, J= 8.6 Hz, 2H), 5.34 (q, J= 7.0 Hz, 1H), 1.64 (d, J= 7.1 Hz, 3H).Example 5: (S)-N-(l-methoxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide(Compound 5)

[0306] The mixture of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (50 mg, 0.15 mmol, 1 eq), DIPEA (58.3 mg, 0.45 mmol, 78.6 uL, 3 eq) and HATU (85.8 mg, 0.22 mmol, 1.5 eq) in DCM (3 mL) was stirred at 25 °C for 1 hr. Then (2S)-l-methoxypropan-2-amine (16.1 mg, 0.18 mmol, 1.2 eq) was added at the mixture and the mixture was stirred at 25 °C for another 1 hr. The reaction mixture was diluted with H2O (10 mL) and the mixture was extracted with EA (10 mL * 3). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Xtimate C18 150*25mm*5um;mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN];B%: 60%- 90%,7min) to give the title compound (40 mg, 99.1 umol, 65.9% yield). LCMS (ESI): RT = 0.995 min, mass calcd for C22H20F3NO3 403.39 m / z found 404.0 [M+H]+; 'H NMR (400 MHz, CD3OD) 5 8.46 (d, J= 1.5 Hz, 1H), 8.09 (d, J= 8.8 Hz, 1H), 7.96 - 7.87 (m, 2H), 7.66 (d, J= 8.8 Hz, 2H), 7.58 (t, J= 7.9 Hz, 1H), 7.22 (d, J= 7.6 Hz, 1H), 7.13 (d, J= 8.6 Hz, 2H), 4.40 (sxt, J= 6.5 Hz, 1H), 3.59 - 3.53 (m, 1H), 3.50 - 3.45 (m, 1H), 3.44 - 3.39 (m, 3H), 1.30 (d, J= 6.8 Hz, 3H).Example 6: (S)-N-(l-(pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 6)

[0307] The mixture of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (50 mg, 0.15 mmol, 1 eq), DIPEA (58.3 mg, 0.45 mmol, 78.6 uL, 3 eq) and HATU (85.8 mg, 0.22 mmol, 1.5 eq) in DCM (3 mL) was stirred at 25 °C for Ihr. Then (lS)-l-(2-pyridyl)ethanamine (22 mg, 0.18 mmol, 1.2 eq) was added at the mixture and the mixture was stirred at 25 °C for another 1 hr. Thereaction mixture was diluted with H2O (10 mL) and the mixture was extracted with EA (10 mL * 3). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous ISfeSCU, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Xtimate C18 150*25mm*5um;mobile phase: [water(10mM NH4HCO3)-ACN];B%: 66%-76%,8min) to give the title compound (32 mg, 72.5 umol, 48.2% yield). LCMS (ESI): RT = 0.886 min, mass calcd for C25H19F3N2O2 436.34 m / z found 437.0 [M+H]+; *H NMR (400 MHz, CD3OD 5 8.58 - 8.51 (m, 2H), 8.12 (d, J= 8.8 Hz, 1H), 7.99 - 7.90 (m, 2H), 7.84 (dt, J= 1.6, 7.8 Hz, 1H), 7.68 (d, J = 8.6 Hz, 2H), 7.61 (t, J= 7.9 Hz, 1H), 7.53 (d, J= 7.9 Hz, 1H), 7.33 (dd, J= 5.1, 6.9 Hz, 1H), 7.25(d, J= 7.5 Hz, 1H), 7.15 (d, J= 8.6 Hz, 2H), 5.34 (q, J= 7.1 Hz, 1H), 1.65 (d, J= 7.0 Hz, 3H).Example 7: N-(2-(methylamino)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 7)

[0308] To a solution of tert-butyl N-methyl-N-[2-[[5-[4-(trifluoromethyl)phenoxy]naphthalene-2- carbonyl]amino]ethyl]carbamate (20 mg, 40.9 umol, 1 eq) in HCl / dioxane (4 M, 51.1 uL, 5 eq) was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC to give the title compound (5.0 mg, 11.8 umol, 28.8% yield, HCI). LCMS (ESI): RT = 0.742 min, mass calcd for C21H19F3N2O2 388.38 m / z found 389.0 [M+H]+; 'HNMR (400 MHz, CD3OD) 5 8.56 (s, 1H), 8.14 (d, J= 8.8 Hz, 1H), 7.98 (d, J= 8.8 Hz, 1H), 7.93 (d, J= 8.3 Hz, 1H), 7.68 (d, J= 8.5 Hz, 2H), 7.62 (t, J= 7.9 Hz, 1H), 7.26 (d, J= 7.5 Hz, 1H), 7.15 (d, J= 8.5 Hz, 2H), 3.79 (br t, J= 5.4 Hz, 2H), 3.30 (br s, 2H), 2.80 (s, 3H).Example 8: N-(3-(methylamino)propyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide(Compound 8)

[0309] The mixture of tert-butyl N-methyl-N-[3-[[5-[4-(trifluoromethyl)phenoxy]naphthalene-2- carbonyl]amino]propyl]carbamate (0.02 g, 39.8 umol, 1 eq) in HClZEtOAc (4 M, 0.49 mL, 50 eq) was stirred at 25 °C for 1 hr. The mixture was concentrated in vacuum to afford the crude product.The residue was purified by prep-HPLC to give the title compound (8.5 mg, 19.3 umol, 48.6% yield, HC1). LCMS (ESI): RT = 0.745 min, mass calcd for C22H21F3N2O2 402.41 m / z found 403.0 [M+H]+; 'HNMR (400 MHz, CD3OD) 5 8.52 (s, 1H), 8.13 (d, J= 8.8 Hz, 1H), 7.92 (d, J= 8.4 Hz, 2H), 7.68 (d, J= 8.6 Hz, 2H), 7.62 (t, J= 7.9 Hz, 1H), 7.26 (d, J= 7.5 Hz, 1H), 7.15 (d, J = 8.5 Hz, 2H), 3.58 (t, J= 6.6 Hz, 2H), 3.11 (br t, J= 7.2 Hz, 2H), 2.05 (quin, J= 7.0 Hz, 2H).Example 9: (R)-N-(l-(pyrazin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 9) and (S)-N-(l-(pyrazin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-N-(l-(pyrazin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide

[0310] The mixture of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (100 mg, 0.30 mmol, 1 eq), HATU (171.6 mg, 0.45 mmol, 1.5 eq) and DIPEA (116.6 mg, 0.90 mmol, 0.15 mL, 3 eq) in DCM (2 mL) was stirred at 25 °C for 1 hr. Then l-pyrazin-2-ylethanamine (40.7 mg, 0.33 mmol, 1.1 eq) was added into the mixture and the mixture was stirred at 25 °C for another 1 hr. The reaction mixture was diluted with H2O (10 mL) and the mixture was extracted with EA (10 mL * 3). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous ISfeSCU, filtered and concentrated in vacuum. The residue was purified by prep-HPLC. Compound N-(l- pyrazin-2-ylethyl)-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (22 mg, 49.7 umol, 16.5% yield) was obtained.(R)-N-(l-(pyrazin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 9) and (S)-N-(l-(pyrazin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 10)

[0311] The racemic compound N-(l-pyrazin-2-ylethyl)-5-[4- (trifluoromethyl)phenoxy]naphthalene-2-carboxamide (22 mg, 50.30 umol, 1 eq) was separated by SFC (column: REGIS (s,s) WHELK-01 (250mm*30mm,5um);mobile phase: [0.1%NH3H2O ETOH];B%: 50%-50%,min) to give Compound 9 (6 mg, 13.6 umol, 27.2% yield) LCMS (ESI): RT = 0.970 min, mass calcd for C24HI8F3N3O2 437.41m / z found 438.0 [M+H]+; ‘H NMR (400MHz, CD3OD) 5 8.75 (s, 1H), 8.65 - 8.62 (m, 1H), 8.56 - 8.51 (m, 2H), 8.13 (d, J= 8.8 Hz, 1H), 7.97 - 7.91 (m, 2H), 7.68 (d, J= 8.5 Hz, 2H), 7.61 (t, J= 7.9 Hz, 1H), 7.25 (dd, J= 0.8, 7.8 Hz, 1H), 7.16 (d, J= 8.5 Hz, 2H), 5.42 (q, J= 7.2 Hz, 1H), 1.70 (d, J= 13 Hz, 3H); and Compound 10 (5 mg, 11.4 umol, 22.6% yield) LCMS (ESI): RT = 0.974 min, mass calcd for C24H18F3N3O2 437.41m / z found 438.0 [M+H]+; *H NMR (400 MHz, CD3OD) 5 8.75 (br s, 1H), 8.64 (s, 1H), 8.54 (d, J= 1.5 Hz, 2H), 8.12 (d, J= 8.8 Hz, 1H), 7.98 - 7.90 (m, 2H), 7.68 (d, J= 8.5 Hz, 2H), 7.61 (t, J = 7.9 Hz, 1H), 7.27 - 7.23 (m, 1H), 7.15 (d, J= 8.5 Hz, 2H), 5.42 (q, J= 7.0 Hz, 1H), 1.70 (d, J= 7.0 Hz, 3H).Example 10: (S)-N-(l-(6-aminopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide (Compound 11) and (R)-N-(l-(6-aminopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 12)l-(4-bromopyridin-2-yl)-N-(2,4-dimethoxybenzyl)ethanamine

[0312] To a solution of l-(6-bromo-2-pyridyl)ethanone (3.2 g, 16.00 mmol, 1 eq) and (2,4- dimethoxyphenyl)methanamine (2.67 g, 16.00 mmol, 2.41 mL, 1 eq) in DCE (30 mL) was added HOAc (4.80 g, 79.99 mmol, 4.57 mL, 5 eq) and stirred at 25 °C for 1 hr, and then NaBH(OAc)3 (5.09 g, 24.00 mmol, 1.5 eq) was added. The resulting mixture was stirred at 25 °C for 15 hr. Then iced water (30 mL) was added and the mixture was neutralized to pH = 9~10 with aq. NaOH (2 M). The aqueous phase was extracted with EA (30 mL*3).The combined organic phase was washed with brine (60 mL), dried with anhydrous Na2SC>4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography. Compound l-(6-bromo-2-pyridyl)-N-[(2,4- dimethoxyphenyl)methyl]ethanamine (1.6 g, 4.42 mmol, 27.6% yield) was obtained.N-(l-(6-bromopyridin-2-yl)ethyl)-N-(2,4-dimethoxybenzyl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide

[0313] A mixture of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (473.0 mg, 1.42 mmol, 1 eq), HATU (1.08 g, 2.85 mmol, 2 eq) in DCM (10 mL) was added DIPEA (551.9 mg, 4.27 mmol, 0.74 mL, 3 eq) at 25 °C. After addition, the mixture was stirred at 25°C for 1 hr, and then 1- (6-bromo-2-pyridyl)-N-[(2,4-dimethoxyphenyl)methyl]ethanamine (500 mg, 1.42 mmol, 1 eq) (in DCM (3 mL)) was added. The resulting mixture was stirred at 25 °C for 15 hr. The residue was poured into H2O (50 mL) and stirred for 5 min. The aqueous phase was extracted with EA (30 mL * 3). The combined organic phase was washed with brine (50 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography. Compound N-[l-(6-bromo-2-pyridyl)ethyl]-N-[(2,4-dimethoxyphenyl)methyl]-5-[4- (trifluoromethyl)phenoxy]naphthalene-2-carboxamide (650 mg, 0.97 mmol, 68.6% yield) was obtained.N-(l-(6-bromopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide

[0314] To a solution of N-[l-(6-bromo-2-pyridyl)ethyl]-N-[(2,4-dimethoxyphenyl)methyl]-5-[4- (trifluoromethyl)phenoxy]naphthalene-2-carboxamide (590 mg, 0.88 mmol, 1 eq) in DCM (0.5 mL) was added TFA (9.09 g, 79.69 mmol, 5.90 mL, 89.88 eq). The mixture was stirred at 25 °C for 3 hr. Then iced water (30 mL) was added and the mixture was neutralized to pH = 9~10 with aq. NaOH (2 M). The aqueous phase was extracted with EA (30 mL * 3). The combined organic phase was washed with brine (60 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo to give crude product. The residue was purified by flash silica gel chromatography. Compound N- [l-(6-bromo-2-pyridyl)ethyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (425 mg, 0.82 mmol, 93.0% yield) was obtained.N-(l-(6-aminopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide

[0315] A mixture of N-[l-(6-bromo-2-pyridyl)ethyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene- 2-carboxamide (150 mg, 0.29 mmol, 1 eq), Q12O (41.6 mg, 0.29 mmol, 29.7 uL, 1 eq), NH3.H2O (134.2 mg, 1.46 mmol, 0.14 mL, 38%, 5 eq) in dioxane (1 mL) were loaded in a sealed reaction tube. The reaction temperature was increased to 80 °C and the reaction mixture was stirred at 80 °C for 16 hr. The mixture was poured into H2O (30 mL) and stirred for 5 min. The aqueous phase was extracted with EA(15 mL * 3). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography. Compound N-[l-(6-amino-2-pyridyl)ethyl]-5-[4- (trifluoromethyl)phenoxy]naphthalene-2-carboxamide (98 mg, 0.21 mmol, 74.5% yield) was obtained.(S)-N-(l-(6-aminopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 11) and (R)-N-(l-(6-aminopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide (Compound 12)

[0316] The racemic compound N-[l-(6-amino-2-pyridyl)ethyl]-5-[4- (trifluoromethyl)phenoxy]naphthalene-2-carboxamide (85 mg, 0.18 mmol, 1 eq) was purified by SFC to give Compound 11 (20.2 mg, 42.0 umol, 22.3% yield) LCMS (ESI): RT = 0.776 min, mass calcd for C25H20F3N3O2 451.44 m / z found 452.1 [M+H]+; *H NMR (400 MHz, CD3OD) 5 8.51 (s, 1H), 8.10 (d, J= 8.9 Hz, 1H), 7.98 - 7.87 (m, 2H), 7.66 (d, J= 8.5 Hz, 2H), 7.58 (t, J= 8.0 Hz, 1H), 7.43 (t, J= 7.7 Hz, 1H), 7.23 (d, J= 7.6 Hz, 1H), 7.13 (d, J= 8.6 Hz, 2H), 6.66 (d, J= 13 Hz, 1H), 6.46 (d, J= 8.1 Hz, 1H), 5.18 - 5.07 (m, 1H), 1.56 (d, J= 7.0 Hz, 3H); and Compound 12 (17.6 mg, 37.4 umol, 19.8% yield) LCMS (ESI): RT = 0.773 min, mass calcd for C25H20F3N3O2 451.44 m / z found 452.1 [M+H]+; 'HNMR (400 MHz, CD3OD) 5 8.51 (s, 1H), 8.10 (d, J= 8.8 Hz, 1H), 7.98 - 7.88 (m, 2H), 7.66 (d, J= 8.5 Hz, 2H), 7.59 (t, J= 7.9 Hz, 1H), 7.42 (t, J= 7.8 Hz, 1H), 7.23 (d, J= 7.5 Hz, 1H), 7.13 (d, J= 8.4 Hz, 2H), 6.66 (d, J= 7.5 Hz, 1H), 6.46 (d, J= 8.3 Hz, 1H), 5.12 (q, J= 6.9 Hz, 1H), 1.56 (d, J = 6.9 Hz, 3H).Example 11 : (S)-N-(l-(4-aminopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide (Compound 13) and (R)-N-(l-(4-aminopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 14)N-(l-(4-aminopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide

[0317] To a solution of N-[l-(4-bromo-2-pyridyl)ethyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (200 mg, 0.38 mmol, 1 eq) in dioxane (1 mL) was added NH3.H2O (2.73 g, 23.37 mmol, 3 mL, 30%, 60.21 eq) and Cu2O (55.53 mg, 0.38 mmol, 39.6 uL, 1 eq). The mixture was stirred at 100 °C for 16 hr in a sealed tube. The mixture was added H2O (20mL) and extracted with EA (15 mL * 3). The combined organic layers were washed with brine (20 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to afford N-[l-(4-amino-2-pyridyl)ethyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (88 mg, 0.19 mmol, 49.7% yield).(S)-N-(l-(4-aminopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 13) and (R)-N-(l-(4-aminopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide (Compound 14)

[0318] The racemic compound N-[l-(4-amino-2-pyridyl)ethyl]-5-[4- (trifluoromethyl)phenoxy]naphthalene-2-carboxamide (88 mg, 0.19 mmol, 1 eq) was purified by SFC to give Compound 13 (22.6 mg, 50.0 umol, 25.6% yield) LCMS (ESI): RT = 0.879 min, mass calcd for C25H20F3N3O2 451.44 m / z, found 452.1 [M+H]+; *H NMR (400 MHz, DMSO-d6) 8 8.88 (br d, J= 7.8 Hz, 1H), 8.64 (s, 1H), 8.04 - 7.91 (m, 4H), 7.74 (d, J= 8.5 Hz, 2H), 7.64 (t, J= 7.9 Hz, 1H), 7.33 (d, J= 7.5 Hz, 1H), 7.16 (d, J= 8.4 Hz, 2H), 6.52 (s, 1H), 6.34 (br d, J= 5.5 Hz, 1H), 5.96 (s, 2H), 5.08 - 4.98 (m, 1H), 1.48 (d, J= 7.0 Hz, 3H); and Compound 14 (24.5 mg, 53.1 umol, 27.28% yield) LCMS (ESI): RT = 0.823 min, mass calcd for C25H20F3N3O2 451.44 m / z, found 452.1 [M+H]+; 'HNMR (400 MHz, DMSO-d6) 6 8.92 (br d, J= 7.8 Hz, 1H), 8.65 (s, 1H), 8.06 - 7.90 (m, 4H), 7.75 (d, J= 8.5 Hz, 2H), 7.64 (t, J= 7.9 Hz, 1H), 7.34 (d, J= 7.5 Hz, 1H), 7.16 (d, J= 8.4 Hz, 2H), 6.54 (s, 1H), 6.37 (br d, J= 5.6 Hz, 1H), 6.15 (br s, 2H), 5.04 (quin, J= 7.0 Hz, 1H), 1.49 (d, J = 7.0 Hz, 3H).Example 12: (S)-N-(l-(4-(dimethylamino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)- 2-naphthamide (Compound 15) and (R)-N-(l-(4-(dimethylamino)pyridin-2-yl)ethyl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide (Compound 16)N-(l-(4-(dimethylamino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide

[0319] To a solution of N-[l-(4-bromo-2-pyridyl)ethyl]-5-[4- (trifluoromethyl)phenoxy]naphthalene-2-carboxamide (200 mg, 0.38 mmol, 1 eq) in dioxane (1 mL) was added N-methylmethanamine (2.67 g, 23.69 mmol, 3 mL, 40%, 60 eq) and CU2O (55.5 mg, 0.38 mmol, 39.6 uL, 1 eq). The mixture was stirred at 100 °C for 16 hr in a sealed tube. The reaction mixture was added H2O (20 mL) and extracted with EA (20 mL * 3). The combinedorganic layers were washed with brine (30 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to afford N-[l-[4-(dimethylamino)-2-pyridyl]ethyl]-5-[4- (trifluoromethyl)phenoxy]naphthalene-2-carboxamide (134 mg, 0.27 mmol, 69.8% yield).(S)-N-(l-(4-(dimethylamino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide (Compound 15) and (R)-N-(l-(4-(dimethylamino)pyridin-2-yl)ethyl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide (Compound 16)

[0320] The racemic compound N-[l-[4-(dimethylamino)-2-pyridyl]ethyl]-5-[4- (trifluoromethyl)phenoxy]naphthalene-2-carboxamide (95 mg, 0.19 mmol, 1 eq) was purified by SFC to give Compound 15 (24.3 mg, 50.0 umol, 25.2% yield) LCMS (ESI): RT = 0.885 min, mass calcd for C27H24F3N3O2 479.49 m / z, found 480.1 [M+H]+; *H NMR (400 MHz, DMSO-d6) 8 8.88 (d, J= 8.0 Hz, 1H), 8.61 (s, 1H), 8.08 (d, J= 5.9 Hz, 1H), 8.03 - 7.95 (m, 3H), 7.74 (d, J= 8.5 Hz, 2H), 7.63 (t, J= 7.9 Hz, 1H), 7.33 (d, J= 7.6 Hz, 1H), 7.17 (d, J= 8.6 Hz, 2H), 6.68 (s, 1H), 6.54 - 6.47 (m, 1H), 5.13 (quin, J= 7.2 Hz, 1H), 2.98 - 2.90 (m, 6H), 1.49 (d, J= 7.0 Hz, 3H) Compound 16 (39.6 mg, 81.1 umol, 40.9% yield) LCMS (ESI): RT = 0.882 min, mass calcd for C27H24F3N3O2 479.49 m / z, found 480.1 [M+H]+; 'HNMR (400 MHz, DMSO-d6) 6 8.88 (br d, J= 7.9 Hz, 1H), 8.61 (s, 1H), 8.08 (d, J= 5.9 Hz, 1H), 8.02 - 7.95 (m, 3H), 7.74 (d, J= 8.5 Hz, 2H), 7.63 (t, J= 7.9 Hz, 1H), 7.33 (d, J= 7.6 Hz, 1H), 7.17 (d, J= 8.4 Hz, 2H), 6.68 (s, 1H), 6.50 (br d, J= 5.8 Hz, 1H), 5.13 (quin, J= 7.0 Hz, 1H), 2.94 (s, 6H), 1.50 (d, J = 6.9 Hz, 3H).Example 13: N-(l-(4-bromopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide (Compound 17)l-(4-bromopyridin-2-yl)-N-(2,4-dimethoxybenzyl)ethanamine

[0321] To a solution of l-(4-bromo-2-pyridyl)ethanone (10 g, 49.99 mmol, 1 eq) and (2,4- dimethoxyphenyl)methanamine (8.36 g, 49.99 mmol, 7.53 mL, 1 eq) in DCE (120 mL) was added HOAc (15.01 g, 249.96 mmol, 14.30 mL, 5 eq) and stirred at 25 °C for 1 hr. Then NaBH(OAc)3 (15.89 g, 74.99 mmol, 1.5 eq) was added. The resulting mixture was stirred at 25 °C for 15 hr. Theniced water (50 mL) was added and the mixture was neutralized to pH = 9~10 with aq. NaOH (4 M). The aqueous phase was extracted with EA (100 mL * 3). The combined organic phase was washed with brine (150 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography. Compound l-(4-bromo-2-pyridyl)-N-[(2,4- dimethoxyphenyl)methyl]ethanamine (7.16 g, 15.29 mmol, 30.5% yield) was obtained.N-(l-(4-bromopyridin-2-yl)ethyl)-N-(2,4-dimethoxybenzyl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide

[0322] To a solution of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (2 g, 6.02 mmol, 1 eq) and HATU (2.75 g, 7.22 mmol, 1.2 eq) in DCM (35 mL) was added DIPEA (3.11 g, 24.08 mmol, 4.19 mL, 4 eq). After addition, the mixture was stirred at 25 °C for 0.5 hr, thenl-(4- bromo-2-pyridyl)-N-[(2,4-dimethoxyphenyl)methyl]ethanamine (2.82 g, 6.02 mmol, 1 eq) was added. The resulting mixture was stirred at 25 °C for 1.5 hr. The reaction mixture was added H2O (50 mL) and extracted with EA (50 mL * 3). The combined organic layers were washed with brine (60 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to afford N-[l-(4-bromo-2- pyridyl)ethyl]-N-[(2,4-dimethoxyphenyl)methyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2- carboxamide (3.5 g, 5.15 mmol, 85.6% yield).N-(l-(4-bromopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide

[0323] To a solution of N-[l-(4-bromo-2-pyridyl)ethyl]-N-[(2,4-dimethoxyphenyl)methyl]-5-[4- (trifluoromethyl)phenoxy]naphthalene-2-carboxamide (3.5 g, 5.26 mmol, 1 eq) in DCM (10 mL) was added TFA (61.60 g, 540.24 mmol, 40 mL, 102.7 eg). The mixture was stirred at 25 °C for 16 hr. Iced water (30 mL) was added and the mixture was neutralized to pH = 9~10 with aq. NaOH (4 M). The aqueous phase was extracted with EA (40 mL * 3). The combined organic phase was washed with brine (60 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography to afford N-[l-(4- bromo-2-pyridyl)ethyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (2.68 g, 4.99 mmol, 94.9% yield). The crude product was purified by prep-HPLC. The title compound (72 mg, 0.13 mmol, 75.0% yield) was obtained. LCMS (ESI): RT = 0.951 min, mass calcd for C25Hi8BrF3N2O2 515.32 m / z, found 517.0 [M+H]+; 'HNMR (400 MHz, DMSO-d6) 8 9.08 (d, J = 7.5 Hz, 1H), 8.64 (s, 1H), 8.44 (d, J= 5.3 Hz, 1H), 8.06 - 7.96 (m, 3H), 7.78 - 7.62 (m, 4H), 7.57 (dd, J= 1.8, 5.3 Hz, 1H), 7.34 (d, J= 7.3 Hz, 1H), 7.17 (d, J= 8.5 Hz, 2H), 5.24 (quin, J= 7.2 Hz, 1H), 1.55 (d, .7= 7.0 Hz, 3H).Example 14: (S)-N-(l-(6-(dimethylamino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 18) and (R)-N-(l-(6-(dimethylamino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 19)N-(l-(6-(dimethylamino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide

[0324] A mixture of N-[l-(6-bromo-2-pyridyl)ethyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene- 2-carboxamide (120 mg, 0.23 mmol, 1 eq), CU2O (33.3 mg, 0.23 mmol, 23.8 uL, 1 eq), N- methylmethanamine (1.78 g, 15.79 mmol, 2 mL, 68eg) in dioxane (0.5 mL) were loaded in a sealed reaction tube. The reaction temperature was increased to 80 °C and the reaction mixture was stirred at 80 °C for 16 hr. The filter was poured into H2O (30 mL) and stirred for 5 min. The aqueous phase was extracted with EA (15 mL * 3). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography. Compound N-[l -[6-(dimethylamino)-2-pyridyl]ethyl]-5-[4- (trifluoromethyl)phenoxy]naphthalene-2-carboxamide (88 mg, 0.18 mmol, 78.8% yield) was obtained.(S)-N-(l-(6-(dimethylamino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide (Compound 18) and (R)-N-(l-(6-(dimethylamino)pyridin-2-yl)ethyl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide (Compound 19)

[0325] The racemic compound N-[l-[6-(dimethylamino)-2-pyridyl]ethyl]-5-[4- (trifluoromethyl)phenoxy]naphthalene-2-carboxamide (88 mg, 0.18 mmol, 1 eq) was purified by SFC to give Compound 18 (20.7 mg, 41.0 umol, 22.3% yield) LCMS (ESI): RT = 0.808 min, mass calcd for C27H24F3N3O2 479.49 m / z found 480.2 [M+H]+; ‘H NMR (400 MHz, CD3OD) 5 8.49 (s, 1H), 8.10 (d, J= 8.8 Hz, 1H), 7.96 - 7.84 (m, 2H), 7.65 (d, J= 8.5 Hz, 2H), 7.57 (t, J= 7.9 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.21 (d, J= 7.5 Hz, 1H), 7.12 (d, J = 8.5 Hz, 2H), 6.61 (d, J= 7.3 Hz, 1H), 6.50 (d, J= 8.5 Hz, 1H), 5.18 (q, J= 6.8 Hz, 1H), 3.09 (s, 6H), 1.59 (d, J= 6.9 Hz, 3H); and Compound 19 (22.3 mg, 46.5 umol, 25.3% yield) LCMS (ESI): RT = 0.790 min, mass calcd for C27H24F3N3O2 479.49 m / z found 480.1 [M+H]+; ‘H NMR (400 MHz, CD3OD) 5 8.49 (s, 1H), 8.10(d, J= 8.9 Hz, 1H), 7.96 - 7.84 (m, 2H), 7.65 (d, J= 8.5 Hz, 2H), 7.57 (t, J= 7.9 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.21 (d, J= 7.5 Hz, 1H), 7.12 (d, J = 8.5 Hz, 2H), 6.62 (d, J= 7.4 Hz, 1H), 6.50 (d, J = 8.5 Hz, 1H), 5.18 (q, .7= 6.8 Hz, 1H), 3.09 (s, 6H), 1.59 (d, J = 6.9 Hz, 3H).Example 15: (S)-N-(l-(2-aminopyridin-3-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide (Compound 20) and (R)-N-(l-(2-aminopyridin-3-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 21)(E)-l-(2-aminopyridin-3-yl)ethanone oxime

[0326] To a solution of l-(2-aminopyridin-3-yl)ethan-l-one (300 mg, 2.2 mmol, 1 eq) in Py (6 mL) at 30°C was added hydroxylamine (229.7 mg, 3.31 mmol, 1.5 eq). The mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the residue which purified by flash silica gel chromatography to give (E)-l-(2-aminopyri din-3 -yl)ethanone oxime (375 mg, 2.2 mmol, 99.1% yield). LCMS (ESI): RT = 0.333 min, mass calc, for C7H9N3O 151.07, m / z found 152.1 [M+H]+.3-(l-aminoethyl)pyridin-2-amine

[0327] To a mixture of (E)-l-(2-aminopyri din-3 -yl)ethan one oxime (200 mg, 1.3 mmol, 1 eq) and Zn (345.3 mg, 5.3 mmol, 4 eq) at 20°C was slowly added con. HC1 (3 mL) with vigorous stirring. The mixture was heated at 90°C for 16 hours The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with water (20 mL), then basified with 2N NaOH at 20°C to pH = 9-10, and then extracted with EA (20 mL *3). The combined organic layers were washed with brine (20 mL), dried over anhydrous ISfeSCU, filtered and concentrated under reduced pressure to give 3-(l-aminoethyl)pyridin-2-amine (70 mg, 0.46 mmol, 34.8% yield). 'H NMR (400 MHz, CDC13) 8 7.93 (brd, J= 4.8 Hz, 1H), 7.32 (brd, J= 13 Hz, 1H), 6.60 (brt, J= 6.1 Hz, 1H), 6.01 (brs, 2H), 4.16 (brs, 1H), 1.46 (br d, J= 6.3 Hz, 3H).A-(l-(2-aminopyridin-3-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide

[0328] To a solution of 3-(l-aminoethyl)pyridin-2-amine (50 mg, 0.36 mmol, 1.6 eq) and HATU (129.9 mg, 0.34 mmol, 1.5 eq) in DMF (1 mL) at 20°C were added 5-(4-(trifluoromethyl)phenoxy)- 2-naphthoic acid (75.7 mg, 0.23 mmol, 1 eq) and TEA (69.2 mg, 0.68 mmol, 95 uL, 3 eq). The mixture was stirred at 20°C for 16 h. The reaction mixture was concentrated under reduced pressure to give the residue which was purified by prep-HPLC to give A-(l-(2-aminopyridin-3-yl)ethyl)-5- (4-(trifluoromethyl)phenoxy)-2-naphthamide (50 mg, 0.11 mmol, 48.1% yield). LCMS (ESI): RT = 0.796 min, mass calc, for C25H20F3N3O2 451.15, m / z found 452.0 [M+H+], (S)-N-(l-(2-aminopyridin-3-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 20) and (R)-N-(l-(2-aminopyridin-3-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide (Compound 21)

[0329] A-(l-(2-aminopyridin-3-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (42 mg, 93 umol, 1 eq) was purified by SFC (column: DAICEL CHIRALCEL OD-H (250mm*30mm,5um);mobile phase: [0.1%NH3H2O ETOH];B%: 25%-25%,min) to give Compound 20 (7 mg, 15 umol, 16.3% yield) LCMS (ESI): RT = 0.876 min, mass calc, for C25H20F3N3O2 451.15, m / z found 452.1 [M+H+];J1HNMR (400 MHz, CDC13) 5 8.37 (d, J= 1.3 Hz, 1H), 8.14 (d, J= 8.8 Hz, 1H), 7.88 (brd, J= 5.0 Hz, 1H), 7.84 - 7.76 (m, 2H), 7.64 - 7.57 (m, 3H), 7.54 - 7.48 (m, 1H), 7.15 (d, J= 7.0 Hz, 1H), 7.07 (d, J= 8.5 Hz, 2H), 6.64 (dd, J= 5.4, 7.2 Hz, 1H), 6.54 (brd, J= 9.3 Hz, 1H), 6.03 (brs, 1H), 5.52 - 5.43 (m, 1H), 1.73 (d, J= 7.0 Hz, 3H); and Compound 21 (6 mg, 13 umol, 14% yield)LCMS (ESI): RT = 0.876 min, mass calc, for C25H20F3N3O2 451.15, m / z found 452.0 [M+H+];‘HNMR (400 MHz, CDCI3) 8 8.37 (d, J= 1.5 Hz, 1H), 8.14 (d, J= 8.8 Hz, 1H), 7.91 (brd, J= 4.3 Hz, 1H), 7.82 - 7.77 (m, 2H), 7.62 - 7.58 (m, 3H), 7.52 (t, J= 7.9 Hz, 1H), 7.15 (d, J= 7.0 Hz, 1H), 7.07 (d, J= 8.5 Hz, 2H), 6.64 (dd, J= 5.3, 7.5 Hz, 1H), 6.48 (brd, J= 9.5 Hz, 1H), 5.91 (br s, 1H), 5.55 - 5.42 (m, 1H), 1.73 (d, J= 6.8 Hz, 3H).Example 16: A-[l-(hydroxymethyl)-2-(2-pyridyl)ethyl]-5-[4- (trifluoromethyl)phenoxy]naphthalene-2-carboxamide (Compound 22)2-(tert-butoxycarbonylamino)-3-(2-pyridyl)propanoic acid

[0330] To a solution of compound 2-amino-3-(pyridin-2-yl)propanoic acid (0.2 g, 0.83 mmol, 1 eq, 2HC1) in dioxane (10 mL) and H2O (5 mL) was added Na2COs (354.6 mg, 3.35 mmol, 4 eq) at 0°C. And then BOC2O (237.3 mg, 1.0 mmol, 0.24 mL, 1.3 eq) was added drop-wise to the solution. The reaction was stirred at 25°C for 16 hr. The reaction was diluted with H2O (10 mL) and extracted with EA (20 mL). The aqueous layer was adjusted pH to 3-4 with 0.5M aq. citric and extracted with EA (5*10 mL). The organic layer was dried over Na2SO4 and concentrated. Compound 2- (tert-butoxycarbonylamino)-3-(2-pyridyl)propanoic acid (75 mg, 0.25 mmol, 29.9% yield) was used for next step directly. tert-butyl 7V-[l-(hydroxymethyl)-2-(2-pyridyl)ethyl]carbamate

[0331] To a solution of compound 2-(tert-butoxycarbonylamino)-3-(2-pyridyl)propanoic acid (75 mg, 0.28 mmol, 1 eq) in THF (1 mL) was added LiAlH4 (26.7 mg, 0.7 mmol, 2.5 eq). The reaction was stirred at 25 °C for 16 hr. The reaction was heated at 45 °C for 16 hr. The reaction was quenched by H2O (1 mL), 2M aq. NaOH (1 mL), H2O (10 mL) and extracted with EA (2*10 mL). The organic layer was dried over Na2SO4 and concentrated. Compound tert-butyl A-[l- (hydroxymethyl)-2-(2-pyridyl)ethyl]carbamate (60 mg, 0.12 mmol, 44.7% yield) was used for next step directly.2-amino-3-(2-pyridyl)propan-l-ol

[0332] To a solution of compound tert-butyl A-[l-(hydroxymethyl)-2-(2-pyridyl)ethyl]carbamate (60 mg, 0.12 mmol, 1 eq) in DCM (1 mL) was added TFA (57.4 mg, 0.5 mmol, 37 uL, 4 eq). The reaction was stirred at 25°C for 1 hr. The reaction mixture was concentrated to give 2-amino-3-(2- pyridyl)propan-l-ol (50 mg, crude, 2TFA), which was used for next step directly.A-[l-(hydroxymethyl)-2-(2-pyridyl)ethyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2- carboxamide

[0333] To a solution of compound 5-(4-(trifluoromethyl)phenoxy)-2-naphthoic acid (21.8 mg, 65.7 umol, 1 eq) and HATU (30 mg, 78.9 umol, 1.2 eq) in DCM (1 mL) was added compound 2-amino-3-(2-pyridyl)propan-l-ol (25 mg, 65.7 umol, 1 eq, 2TFA) followed by DIEA (25.4 mg, 0.19 mmol, 34 uL, 3 eq). The reaction was stirred at 25°C for 1 hr. The reaction was diluted with DCM (15 mL) and washed with H2O (2*10 mL). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to give the title compound (2.1 mg, 4.5 umol, 6.8% yield). LCMS (ESI): RT = 0.825 min, mass calcd. for C26H21F3N2O3 466.15, m / z found 467.1 [M+H]+, 'H NMR (400 MHz, CDCI3) 8 8.60 - 8.55 (m, 1H), 8.36 (d, J= 1.5 Hz, 1H), 8.12 (d, J= 8.8 Hz, 1H), 7.83 (dd, J= 1.8, 8.8 Hz, 2H), 7.79 (d, J= 8.3 Hz, 1H), 7.68 (dt, J= 1.8, 7.7 Hz, 1H), 7.60 (d, J= 8.5 Hz, 2H), 7.54 - 7.49 (m, 1H), 7.30 (d, J= 7.6 Hz, 1H), 7.25 - 7.19 (m, 1H), 7.15 (dd, J= 0.8,7.5 Hz, 1H), 7.08 (d, J= 8.4 Hz, 2H), 4.59 - 4.48 (m, 1H), 3.89 - 3.73 (m, 2H), 3.41 - 3.32 (m, 1H), 3.28 - 3.18 (m, 1H).Example 17: 5-(2-chloro-4-(trifluoromethyl)phenoxy)-N-isopropyl-2-naphthamide (Compound 23)

[0334] A mixture of 5-hydroxy-N-isopropyl-naphthalene-2-carboxamide (120 mg, 0.52 mmol, 1 eq), 2-chloro-l-fluoro-4-(trifluoromethyl)benzene (114.3 mg, 0.57 mmol, 1.1 eq), t-BuOK (117.4 mg, 1.05 mmol, 2 eq) in DMF (3 mL) and the mixture was stirred at 100 °C for 3 hr. The mixture was poured into H2O (30 mL) at 0 °C and stirred for 5 min. The aqueous phase was extracted with EA (20 mL * 3). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was purified by prep- HPLC. The title compound (45.6 mg, 0.11 mmol, 21.1% yield) was obtained. LCMS (ESI): RT = 0.951 min, mass calcd for C21H17CIF3NO2 407.81, m / z found 408.0 [M+H]+; 'HNMR (400 MHz, DMSO-d6) 8 8.54 (s, 1H), 8.46 (br d, J= 7.5 Hz, 1H), 8.12 (s, 1H), 8.05 - 7.92 (m, 3H), 7.70 - 7.57 (m, 2H), 7.23 (d, J= 7.5 Hz, 1H), 7.04 (d, J= 8.6 Hz, 1H), 4.16 (qd, J= 6.6, 13.2 Hz, 1H), 1.22 (d, .7= 6.4 Hz, 6H).Example 18: 7V-(3-hydroxy-l-(pyridin-2-yl)propyl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide (Compound 24)(£)-2-methyl-7V-(pyridin-2-ylmethylene)propane-2-sulfinamide

[0335] To a solution of picolinaldehyde (3 g, 28.01 mmol, 1 eq) and 2-methylpropane-2- sulfinamide (4.07 g, 33.61 mmol, 1.2 eq) in DCM (56 mL) at 20°C was added CuSCh (8.94 g, 56.02 mmol, 8.60 mL, 2 eq). The reaction was stirred at 20°C for 16 h. The reaction mixture was filtered to remove the solid and the filtrate was concentrated under reduced pressure to give the residue. The residue was diluted with water (100 mL), and then extracted with EA (100 mL *3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give (£)-2-methyl-A- (pyridin-2-ylmethylene)propane-2-sulfinamide (4.32 g, 20.54 mmol, 73.3% yield), which was used for next step directly. LCMS (ESI): RT = 0.640 min, mass calc, for C10H14N2OS 210.08, m / z found 210.9 [M+H]+. ethyl 3-(l,l-dimethylethylsulfinamido)-3-(pyridin-2-yl)propanoate

[0336] To a solution of ethyl acetate (837.9 mg, 9.51 mmol, 0.93 mL, 2 eq) in THF (5 mL) was added LDA (2 M, 4.76 mL, 2 eq) and the mixture was stirred at -78°C for 10 min, and then a solution of (£)-2-methyl-A-(pyridin-2-ylmethylene)propane-2-sulfinamide (1.0 g, 4.76 mmol, 1 eq) in THF (5 mL) was added slowly at -78°C into the above mixture. The reaction mixture was stirred at -78°C for 20 min. The reaction mixture was diluted with NH4CI (3 mL) and water (40 mL) and extracted with EA (40 mL *3). The combined organic layers were washed with water (20 mL *2) and brine (20 mL *2), dried over Na2SO4, filtered and concentrated under reduced pressure to give ethyl 3-(l,l-dimethylethylsulfinamido)-3-(pyridin-2-yl)propanoate (1.1 g, 3.32 mmol, 69.8% yield), which was used directly for next step. LCMS (ESI): RT = 0.803 min, mass calc, for C14H22N2O3S 298.14, m / z found 298.9 [M+H]+; ‘H NMR (400 MHz, CDCI3) 8 8.55 (brd, J= 4.5 Hz, 1H), 7.67 (dt, J= 1.5, 7.8 Hz, 1H), 7.42 (dd, J= 5.3, 7.8 Hz, 1H), 7.21 - 7.17 (m, 1H), 4.85 (s, 1H), 4.16 - 4.07 (m, 2H), 3.28 - 3.06 (m, 1H), 2.95 - 2.81 (m, 1H), 1.24 (d, J= 4.8 Hz, 9H), 1.23 - 1.17 (m, 3H). ethyl 3-amino-3-(pyridin-2-yl)propanoate

[0337] To a solution of ethyl 3-(l,l-dimethylethylsulfmamido)-3-(pyridin-2-yl)propanoate (100 mg, 0.34 mmol, 1 eq) in MeOH (3 mL) at 20°C was added HCl / MeOH (4 M, 0.42 mL, 5 eq) dropwise, and the mixture was stirred at 20°C for 1 h. The reaction mixture was concentrated to give ethyl 3-amino-3-(pyridin-2-yl)propanoate (65 mg, 0.33 mmol, 99.9% yield), which was used directly for next step.3-amino-3-(pyridin-2-yl)propan-l-ol

[0338] To a solution of ethyl 3-amino-3-(pyridin-2-yl)propanoate (65 mg, 0.33 mmol, 1 eq) in THF (2 mL) at 0°C was added LAH (19.1 mg, 0.50 mmol, 1.5 eq), and the mixture was stirred at 20°C for 1 h. The reaction mixture was quenched at 0°C with water (two drops) and then 2 N NaOH (twodrops), diluted with EA (20 mL), dried over Na2SO4 and then filtered to remove the solid. The filtrate was concentrated to give 3-amino-3-(pyridin-2-yl)propan-l-ol (45 mg, 0.30 mmol, 88.4% yield), which was used directly for next step.7V-(3-hydroxy-l-(pyridin-2-yl)propyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide

[0339] To a solution of 5-(4-(trifluoromethyl)phenoxy)-2-naphthoic acid (40 mg, 0.12 mmol, 1 eq), 3-amino-3-(pyridin-2-yl)propan-l-ol (36.6 mg, 0.24 mmol, 2 eq) and HATU (59.5 mg, 0.16 mmol, 1.3 eq) in DMF (1 mL) at 20°C was added TEA (36.5 mg, 0.36 mmol, 50 uL, 3 eq), and the mixture was stirred at 20°C for 1 h. The mixture was concentrated to give a residue. The residue was purified by prep-HPLC to give the title compound (15.0 mg, 29.8 umol, 24.8% yield, HC1). LCMS (ESI): RT = 0.843 min, mass calc, for C26H21F3N2O3 466.15, m / z found 467.1 [M+H]+; 'H NMR (400 MHz, CD3OD) 5 8.79 (d, J= 5.3 Hz, 1H), 8.63 (t, J= 13 Hz, 1H), 8.58 (d, J= 1.3 Hz, 1H), 8.19 (d, J= 8.3 Hz, 1H), 8.13 (d, J= 8.8 Hz, 1H), 8.01 (t, J= 6.8 Hz, 1H), 7.98 - 7.87 (m, 2H), 7.66 (d, J= 8.8 Hz, 2H), 7.61 (t, J= 8.0 Hz, 1H), 7.25 (d, J= 7.0 Hz, 1H), 7.14 (d, J= 8.5 Hz, 2H), 5.52 (dd, J = 6.3, 8.3 Hz, 1H), 3.83 (ddd, J = 4.0, 7.7, 11.4 Hz, 1H), 3.72 (td, J= 5.4, 11.1 Hz, 1H), 2.46 - 2.36 (m, 1H), 2.34 - 2.24 (m, 1H).Example 19: (R)-N-(l-aminopropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 25) and (S)-N-(l-aminopropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide (Compound 26)tert-butyl(2-(5-(4-(trifluoromethyl)phenoxy)-2-naphthamido)propyl)carbamate

[0340] To a solution of 5-(4-(trifluoromethyl)phenoxy)-2-naphthoic acid (100 mg, 0.3 mmol, 1 eq) and HATU (171.7 mg, 0.45 mmol, 1.5 eq) in DMF (1 mL) at 20 °C was added tert-butyl (2- aminopropyl)carbamate (62.9 mg, 0.36 mmol, 1.2 eq) and TEA (91.4 mg, 0.9 mmol, 0.13 mL, 3 eq). The mixture was stirred at 20 °C for 16 h. The residue was diluted with water (20 mL), and then extracted with EA (20 mL *3). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over anhydrous ISfeSCU, filtered and concentrated under reduced pressureto give tert-butyl(2-(5-(4-(trifluoromethyl)phenoxy)-2-naphthamido)propyl)carbamate (130 mg, 0.27 mmol, 88.4% yield) as a yellow solid. 'HNMR (400 MHz, CDC13) 8 8.43 (s, 1H), 8.10 (d, J = 8.9 Hz, 1H), 7.91 (brd, J= 8.6 Hz, 1H), 7.79 (d, J= 8.4 Hz, 1H), 7.59 (d, J= 8.6 Hz, 2H), 7.50 (t, J = 7.9 Hz, 1H), 7.41 (brd, J= 7.0 Hz, 1H), 7.14 (d, J= 7.5 Hz, 1H), 7.07 (d, J= 8.6 Hz, 2H), 5.00 (brs, 1H), 4.26 (brd, J= 5.9 Hz, 1H), 3.45 - 3.37 (m, 1H), 3.31 - 3.24 (m, 1H), 1.41 (s, 9H), 1.31 (d, .7= 6.6 Hz, 3H). / V-(l-aminopropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide

[0341] To a solution of tert-butyl(2-(5-(4-(trifluoromethyl)phenoxy)-2- naphthamido)propyl)carbamate (130 mg, 0.27 mmol, 1 eq) in DCM (2 mL) at 20 °C was added TFA (364.1 mg, 3.2 mmol, 0.24 mL, 12 eq). The mixture was stirred at 20 °C for 4 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (20 mL), Na2COs (20 mL) and extracted with EA (20 mL *3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue to give compound A-(l-aminopropan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide (100 mg, 0.24 umol, 91.9% yield). LCMS (ESI): RT = 0.825 min, mass calc, for C21H19F3N2O2 388.14, m / z found 389.0 [M+H]+.(R)-N-(l-aminopropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 25) and (S)-N-(l-aminopropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide(Compound 26)

[0342] A-(l-aminopropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (100 mg, 0.26 mmol, 1 eq) was purified by SFC. No monitoring and used for next step directly. The racemic compound was separated by SFC (column: Phenomenex-Cellulose-2 (250mm*30mm, 5um); mobile phase: [0.1%NH3H2O ETOH]; B%: 35%-35%, min) to give Compound 25 (10 mg, 25 umol, 9.90% yield) and Compound 26 (13.5 mg, 35 umol, 13.5% yield) as a white solid. Compound 25 LCMS (ESI): RT = 0.827 min, mass calc, for C21H19F3N2O2 388.14, m / z found 389.0 [M+H+]; 'HNMR (400 MHz, CDCI3) 6 8.38 (s, 1H), 8.05 (d, J= 8.9 Hz, 1H), 7.83 (brd, J =8.8 Hz, 1H), 7.73 (brd, J= 8.4 Hz, 1H), 7.57 (brd, J= 8.6 Hz, 2H), 7.45 (t, J= 7.9 Hz, 1H), 7.10 (d, J= 7.5 Hz, 1H), 7.07 - 7.02 (m, 3H), 4.33 (brs, 1H), 3.02 - 2.91 (m, 2H), 1.27 - 1.24 (m, 1H), 1.25 (brd, J= 6.5 Hz, 2H). Compound 26 LCMS (ESI): RT = 0.833 min, mass calc, for C21H19F3N2O2 388.14, m / z found 389.0 [M+H+]; 'H NMR (400 MHz, CDCI3) 8 8.40 (s, 1H), 8.08 (d, J= 8.8 Hz, 1H), 7.85 (brd, J= 8.8 Hz, 1H), 7.77 (brd, J= 8.3 Hz, 1H), 7.58 (brd, J= 8.5 Hz, 2H), 7.47 (t, J=7.9 Hz, 1H), 7.12 (d, J= 7.5 Hz, 1H), 7.05 (brd, J= 8.5 Hz, 2H), 6.92 (brd, J= 7.0 Hz, 1H), 4.31 (brs, 1H), 2.94 (brs, 2H), 1.28 (brd, J= 6.6 Hz, 3H).Example 20: (R)-N-(3-hydroxy-l-(pyridin-2-yl)propyl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide (Compound 27) and (S)-N-(3-hydroxy-l-(pyridin-2-yl)propyl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide (Compound 28)(£)-2-methyl-AL(pyridin-2-ylmethylene)propane-2-sulfinamide

[0343] To a solution of picolinaldehyde (3 g, 28.01 mmol, 1 eq) and 2-methylpropane-2- sulfinamide (4.07 g, 33.61 mmol, 1.2 eq) in DCM (56 mL) at 20°C was added CuSCh (8.94 g, 56.02 mmol, 8.60 mL, 2 eq). The reaction was stirred at 20°C for 16 h. The reaction mixture was filtered to remove the solid and the filtrate was concentrated under reduced pressure to give the residue. The residue was diluted with water (100 mL), and then extracted with EA (100 mL *3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous ISfeSCU, filtered and concentrated under reduced pressure to give (£)-2-methyl-A- (pyridin-2-ylmethylene)propane-2-sulfinamide (4.32 g, 20.54 mmol, 73.3% yield) as yellow oil, which was used for next step directly. LCMS (ESI): RT = 0.640 min, mass calc, for C10H14N2OS 210.08, m / z found 210.9 [M+H]+. ethyl 3-(l,l-dimethylethylsulfinamido)-3-(pyridin-2-yl)propanoate

[0344] To a solution of ethyl acetate (838.8 mg, 9.52 mmol, 0.93 mL, 2 eq) in THF (5 mL) at - 78°C was added LDA (2 M, 4.76 mL, 2 eq) drop-wise, and the resulting mixture was stirred at - 78°C for 0.5 h. And then the solution of (£)-2-methyl-A-(pyridin-2-ylmethylene)propane-2- sulfinamide (1 g, 4.76 mmol, 1 eq) in THF (5 mL) was added into the above mixture at -78°C. The reaction mixture was stirred at -78°C for another 0.5 h. The reaction mixture was quenched with saturated NH4CI solution (20 mL) and then extracted with EA (20 mL *3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gelchromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient @ 30 mL / min) to give ethyl 3-(l,l-dimethylethylsulfinamido)-3- (pyridin-2-yl)propanoate (1.2 g, 3.98 mmol, 83.6% yield) as a yellow solid. LCMS (ESI): RT = 0.708 min, mass calc, for C14H22N2O3S 298.14, m / z found 298.9 [M+H]+. ethyl 3-amino-3-(pyridin-2-yl)propanoate

[0345] To a solution of ethyl 3-(l,l-dimethylethylsulfmamido)-3-(pyridin-2-yl)propanoate (250 mg, 0.84 mmol, 1 eq) in MeOH (2 mL) at 20°C was added HCl / MeOH (4 M, 1.05 mL, 5 eq). The reaction mixture was stirred at 20°C for Ih. The reaction mixture was concentrated under reduced pressure to give ethyl 3-amino-3-(pyridin-2-yl)propanoate (162 mg, 0.83 mmol, 99.6% yield) as a yellow solid, which was used directly for next step.3-amino-3-(pyridin-2-yl)propan-l-ol

[0346] To a solution of ethyl 3-amino-3-(pyridin-2-yl)propanoate (162 mg, 0.83 mmol, 1 eq) in THF (3 mL) at 0°C was added LAH (63.3 mg, 1.67 mmol, 2 eq). The reaction mixture was stirred at 20°C for 2 h. The reaction mixture was quenched with water (0.06 mL) at 0°C, then 4N NaOH (0.06 mL) and then water (0.18 mL), and then stirred at 20°C for 0.5 h. The mixture was dried over anhydrous Na2SO4, and then filtered to remove the precipitate. The filtrate was concentrated under reduced pressure to give 3-amino-3-(pyridin-2-yl)propan-l-ol (110 mg, 0.72 mmol, 86.7% yield) as yellow oil, which was used directly for next step. 'H NMR (400 MHz, CDCI3) 5 8.57 (brs, IH), 7.71 - 7.61 (m, IH), 7.24 (s, IH), 7.21 - 7.14 (m, IH), 4.47 - 4.19 (m, IH), 3.96 - 3.81 (m, IH), 2.91 - 2.68 (m, IH), 2.15 - 1.83 (m, 2H).7V-(3-hydroxy-l-(pyridin-2-yl)propyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide

[0347] To a solution of 5-(4-(trifluoromethyl)phenoxy)-2-naphthoic acid (120 mg, 0.36 mmol, 1 eq), 3-amino-3-(pyridin-2-yl)propan-l-ol (109.9 mg, 0.72 mmol, 2 eq) in DMF (2 mL) at 20°C was added HATU (178.5 mg, 0.47 mmol, 1.3 eq) and TEA (109.6 mg, 1.08 mmol, 0.15 mL, 3 eq). The reaction mixture was stirred at 20°C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by p / cp-HPLC (column: Welch Xtimate C18 150*25mm*5um;mobile phase: [water(0.05%HCl)- ACN];B%: 30%-60%,8.5min) to give N-(3- hydroxy-l-(pyridin-2-yl)propyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (60 mg, 0.13 mmol, 35.3% yield) as yellow oil. LCMS (ESI): RT = 0.843 min, mass calc, for C26H21F3N2O3 466.15, m / z found 467.0 [M+H]+.(R)-N-(3-hydroxy-l-(pyridin-2-yl)propyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 27) and (S)-N-(3-hydroxy-l-(pyridin-2-yl)propyl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide (Compound 28)

[0348] The sample A-(3-hydroxy-l-(pyridin-2-yl)propyl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide (60 mg, 0.13 mmol, 1 eq) was purified by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, lOum); mobile phase: [0.1%NH3H2O ETOH]; B%: 45%-45%, min) to give Compound 27 (13.1 mg, 27.6 umol, 21.5% yield) as a white solid. LCMS (ESI): RT = 0.848 min, mass calc, for C26H21F3N2O3 466.15, m / z found 467.0 [M+H]+; ‘H NMR (400 MHz, CD3OD) 5 8.55 (d, J= 4.5 Hz, 1H), 8.52 (s, 1H), 8.11 (d, J= 8.8 Hz, 1H), 7.96 - 7.89 (m, 2H), 7.83 (dt, J= 1.6, 7.8 Hz, 1H), 7.66 (d, J= 8.8 Hz, 2H), 7.59 (t, J= 7.9 Hz, 1H), 7.53 (d, J= 7.9 Hz, 1H), 7.32 (dd, J= 5.4, 7.1 Hz, 1H), 7.24 (d, J= 7.6 Hz, 1H), 7.14 (d, J= 8.6 Hz, 2H), 5.42 (dd, J= 5.9, 8.3 Hz, 1H), 3.76 - 3.62 (m, 2H), 2.27 - 2.12 (m, 2H) and Compound 28 (14.0 mg, 30.2 umol, 23.5% yield) as a white solid. LCMS (ESI): RT = 0.857 min, mass calc, for C26H21F3N2O3 466.15, m / z found 467 [M+H]+; 'HNMR (400 MHz, CD3OD) 5 8.56 (d, J= 4.3 Hz, 1H), 8.52 (d, J= 1.5 Hz, 1H), 8.11 (d, J = 8.9 Hz, 1H), 7.96 - 7.89 (m, 2H), 7.87 (dt, J= 1.7, 7.7 Hz, 1H), 7.66 (d, J= 8.6 Hz, 2H), 7.62 - 7.54 (m, 2H), 7.38 - 7.33 (m, 1H), 7.24 (d, J= 7.5 Hz, 1H), 7.14 (d, J= 8.6 Hz, 2H), 5.42 (dd, J= 6.1, 8.3 Hz, 1H), 3.77 - 3.64 (m, 2H), 2.29 - 2.15 (m, 2H).Example 21 : (S)-N-(4-aminobutan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 29) and (R)-N-(4-aminobutan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide (Compound 30)Compound 29 Compound 307V-(4-(l,3-Dioxoisoindolin-2-yl)butan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide

[0349] To a solution of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (100 mg, 0.30 mmol, 1 eq), 2-(3-aminobutyl)isoindoline-l, 3-dione (76.6 mg, 0.30 mmol, 1 eq, HC1) and DIPEA (116 mg, 0.90 mmol, 3 eq) in DCM (3 mL) was added HATU (137 mg, 0.36 mmol, 1.2 eq). The reaction mixture was stirred at 25 °C for 2 hrs. LC-MS showed starting material was consumed completely and one main peak with desired MS was detected. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (30 mL) and the resultant mixture was extracted with EA (50 mL * 3). The combined organic layers were dried over ISfeSCU,filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography over silica gel (petroleum ether: ethyl acetate = 1 :0 to 2: 1) to afford 7V-(4-(l,3- Dioxoisoindolin-2-yl)butan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (150 mg, 92% yield) as a white solid. LCMS (ESI): RT = 1.025 min, mass calcd for C30H23F3N2O4 532.16 m / z, found 533.1 [M+H]+.7V-(4-Aminobutan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide

[0350] NH2NH2.H2O (143 mg, 2.44 mmol, 0.14 mL, 85%, 10 eq) was added to a solution of / V-[3- (l,3-dioxoisoindolin-2-yl)-l-methyl-propyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2- carboxamide (130 mg, 0.24 mmol, 1 eq) in EtOH (8 mL). The reaction mixture was stirred at 25 °C for 5 hrs. LC-MS showed starting material was consumed completely and one main peak with desired MS was detected. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (10 mL) and the resultant mixture was extracted with EA (20 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by p / cp-HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water (0.05%HCl) - ACN]; B%: 20%-50%, 8.5min) to give N-(4- Aminobutan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (85 mg, 78% yield, HC1) as a white solid. LCMS (ESI): RT = 0.837 min, mass calcd for C22H21F3N2O2 402.16 m / z, found 403.1 [M+H]+.(S)-N-(4-aminobutan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 29) and (R)-N-(4-aminobutan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 30)

[0351] 7V-(3-Amino-l-methyl-propyl)-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (85 mg, 0.19 Mmol, 1 eq, HC1) was separate by SFC (column: DAICEL CHIRALCEL OD- H(250mm*30mm,5um);mobile phase: [0.1% NH3H2O MEOH]; B%: 25%-25%, min). The pure fractions were collected and the volatiles were removed under vacuum. The residue was resuspended in water (lOmL) and ACN (1 mL), and then the resulting mixture was lyophilized to dryness to remove the solvent residue completely. Compound 30 (32.08 mg, 79 umol, 41.1% yield) was obtain as a white solid and Compound 29 (35 mg) was obtained as a white solid. The crude product was purified by SFC (column: DAICEL CHIRALCEL OD-H (250mm*30mm, 5um); mobile phase: [0.1%NH3H2O MEOH]; B%: 25%-25%, min), and then the pure fractions were collected and the volatiles were removed under vacuum. The residue was re-suspended in water (lOmL) and ACN (1 mL), and then the resulting mixture was lyophilized to dryness to remove the solvent residue completely to give Compound 29 (29.44 mg, 72 umol, 37.40% yield) as a white solid. Compound 30 LCMS (ESI): RT = 0.847 min, mass calcd for C22H21F3N2O2 402.16 m / z,found 403.0 [M+H]+; 'HNMR (400 MHz, DMSO-t / 6) 8 8.63 - 8.51 (m, 2H), 8.03 - 7.91 (m, 3H), 7.75 (d, J= 8.6 Hz, 2H), 7.64 (t, J= 7.9 Hz, 1H), 7.33 (d, J= 7.0 Hz, 1H), 7.16 (d, J= 8.5 Hz, 2H), 4.25 - 4.09 (m, 1H), 2.70 (t, J= 7.2 Hz, 2H), 1.81 - 1.61 (m, 2H), 1.22 (d, J= 6.6 Hz, 3H).Compound 29 LCMS (ESI): RT = 0.847 min, mass calcd for C22H21F3N2O2 402.16 m / z, found 403.1 [M+H]+.‘HNMR (400 MHz, DMSO-t / 6) 6 8.59 - 8.48 (m, 2H), 8.03 - 7.90 (m, 3H), 7.75 (d, J= 8.6 Hz, 2H), 7.63 (t, J= 7.9 Hz, 1H), 7.32 (d, J= 13 Hz, 1H), 7.16 (d, J= 8.5 Hz, 2H), 4.25 - 4.13 (m, 1H), 2.61 (t, J= 6.8 Hz, 2H), 1.70 - 1.52 (m, 2H), 1.20 (d, J= 6.6 Hz, 3H).Example 22: (R)-N-(4-hydroxybutan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 31) and (S)-N-(4-hydroxybutan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide (Compound 32)N-(3-hydroxy-l-methyl-propyl)-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide

[0352] The mixture of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (90 mg, 0.27 mmol, 1 eq), 3-aminobutan-l-ol (28.9 mg, 0.32 mmol, 1.2 eq), DIPEA (105 mg, 0.81 mmol, 0.14 mL, 3 eq) and HATU (154.4 mg, 0.40 mmol, 1.5 eq) in DCM (10 mL) was stirred at 25 °C for 2 hr. The reaction mixture was diluted with H2O (10 mL) and the mixture was extracted with EA (20 mL * 3). The combined organic phase was washed with brine (10 mL * 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 1 / 0 to 0 / 1). Compound N-(3 -hydroxy- 1-m ethyl-propyl)-5- [4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (100 mg, 0.24 mmol, 91.5% yield) was obtained as white solid.(R)-N-(4-hydroxybutan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 31) and (S)-N-(4-hydroxybutan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 32)

[0353] The racemic compound N-(3-hydroxy-l-methyl-propyl)-5-[4- (trifluoromethyl)phenoxy]naphthalene-2-carboxamide (90 mg, 0.22 mmol, 1 eq) was separated by SFC (column: Phenomenex-Cellulose-2 (250mm*30mm,5um);mobile phase: [0.1%NH3H2O MEOH];B%: 30%-30%,min ). Compound 31 (14.6 mg, 35.5 umol, 15.9% yield) was obtained as white solid. LCMS (ESI): RT = 0.927 min, mass calcd for C22H20F3NO3 403.39 m / z found 404.1[M+H]+. 'HNMR (400 MHz, DMSO-t / 6) 6 ppm 1.19 (d, J= 6.63 Hz, 3 H) 1.61 - 1.80 (m, 2 H) 3.48 (q, J= 5.75 Hz, 2 H) 4.14 - 4.21 (m, 1 H) 4.47 (t, J= 5.07 Hz, 1 H) 7.15 (d, J= 8.63 Hz, 2H) 7.31 (d, J= 7.38 Hz, 1 H) 7.62 (t, J= 7.88 Hz, 1 H) 7.73 (d, J = 8.75 Hz, 2 H) 7.91 - 8.01 (m, 3 H) 8.42 (d, J= 8.13 Hz, 1 H) 8.52 (s, 1 H). Compound 32 (19.23 mg, 47.19 umol, 21.15% yield) was obtained as white solid. LCMS (ESI): RT = 0.926 min, mass calcd for C22H20F3NO3 403.39 m / z found 404.1[M+H]+. 'HNMR (400 MHz, DMSO-t / 6) 8 ppm 1.19 (d, J= 6.63 Hz, 3 H) 1.61 - 1.80 (m, 2 H) 3.41 - 3.52 (m, 2 H) 4.12 - 4.23 (m, 1 H) 4.47 (t, J= 5.13 Hz, 1 H) 7.15 (d, J= 8.63 Hz, 2 H) 7.31 (d, J= 7.50 Hz, 1 H) 7.62 (t, J= 7.94 Hz, 1 H) 7.73 (d, J= 8.63 Hz, 2 H) 7.91 - 8.01 (m, 3 H) 8.42 (br d, J= 8.13 Hz, 1 H) 8.52 (s, 1 H).Example 23: (S)-N-(2-hydroxy-l-(pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide (Compound 33) and (R)-N-(2-hydroxy-l-(pyridin-2-yl)ethyl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide (Compound 34)methyl (2E)-2-hydroxyimino-2-(2-pyridyl)acetate

[0354] To a solution of methyl 2-(2-pyridyl)acetate (1 g, 6.62 mmol, 0.89 mL, 1 eq) in AcOH (1.6 mL) at 0 °C with stirring, an aqueous solution of NaNCL (456.4 mg, 6.62 mmol, 1 eq) in H2O (1.40 g, 77.71 mmol, 1.4 mL, 11.75 eq) was added portion wise. After addition was completed stirring was continued for 1 hr at 25 °C. H2O (3.00 g, 166.53 mmol, 3 mL, 25.17 eq) was added and the mixture was stirred for another 1 hr. The reaction mixture was diluted with H2O (5 mL) and the mixture was extracted with EA (10 mL * 3). The combined organic phase was washed with brine (10 mL * 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 1 / 0 to 1 / 1). Compound methyl (2E)-2-hydroxyimino-2-(2-pyridyl)acetate (670 mg, 3.61 mmol, 54.5% yield) was obtained as white solid.2-amino-2-(2-pyridyl)ethanol

[0355] To a solution of methyl (2E)-2-hydroxyimino-2-(2-pyridyl)acetate (200 mg, 1.11 mmol, 1 eq) in THF (6 mL) was added LAH (210.6 mg, 5.55 mmol, 5 eq) at 0 °C. Then the mixture was stirred at 25 °C for 16 hr. LC-MS showed the desired compound was detected. The reaction mixture was diluted with H2O (2 mL), NaOH (2M, 2.5ml). Then the mixture was concentrated invacuo. No purification. Compound 2-amino-2-(2-pyridyl)ethanol (180 mg, crude) was obtained as yellow solid, which was used into the next step without further purification.N-[2-hydroxy-l-(2-pyridyl)ethyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide

[0356] The mixture of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (150 mg, 0.45 mmol, 1 eq), 2-amino-2-(2-pyridyl)ethanol (68.6 mg, 0.49 mmol, 1.1 eq), DIPEA (175.0 mg, 1.35 mmol, 0.23 mL, 3 eq) and HATU (257.4 mg, 0.67 mmol, 1.5 eq) in DCM (1 mL) was stirred at 25 °C for 2 hr. The reaction mixture was diluted with H2O (10 mL) and the mixture was extracted with EA (20 mL * 3). The combined organic phase was washed with brine (10 mL * 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by p / cp-HPLC (column: Xtimate C18 100*30mm*3um;mobilephase: [water(0.05%HCl)-ACN];B%: 28%- 58%,8.5min). Compound N-[2-hydroxy-l-(2-pyridyl)ethyl]-5-[4- (trifluoromethyl)phenoxy]naphthalene-2-carboxamide (15 mg, 30.5 umol, 6.7% yield) was obtained as yellow solid.(S)-N-(2-hydroxy-l-(pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 33) and (R)-N-(2-hydroxy-l-(pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)- 2-naphthamide (Compound 34)

[0357] The racemic compound N-[2-hydroxy-l-(2-pyridyl)ethyl]-5-[4- (trifluoromethyl)phenoxy]naphthalene-2-carboxamide (20 mg, 44.2 umol, 1 eq) was purified by prep-SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [0.1%NH3H2O ETOH];B%: 40%-40%,min). Compound 33 (2.4 mg, 5.4 umol, 12.3% yield) was obtained as white solid. LCMS (ESI): RT = 0.801 min, mass calcd for C25H19F3N2O3452.43 m / z found 453.0[M+H]+. 'HNMR (400 MHz, CDCI3) 8 4.07 (br dd, J= 11.07, 3.56 Hz, 1 H) 4.20 (dd, J= 11.26, 4.13 Hz, 1 H) 4.36 (br s, 1 H) 5.39 - 5.45 (m, 1 H) 7.08 (d, J= 8.63 Hz, 2 H) 7.16 (d, J= 7.50 Hz, 1 H) 7.30 (dd, J= 6.94, 5.44 Hz, 1 H) 7.48 - 7.56 (m, 2 H) 7.60 (d, J= 8.75 Hz, 2 H) 7.76 (td, .7= 7.66, 1.69 Hz, 1 H) 7.82 (d, J= 8.25 Hz, 1 H) 7.92 (dd, J= 8.76, 1.50 Hz, 1 H) 8.04 (br d, J = 7.13 Hz, 1 H) 8.14 (d, .7= 8.75 Hz, 1 H) 8.46 (s, 1 H) 8.58 (br d, J= 4.63 Hz, 1 H). Compound 34 (2.5 mg, 5.6 umol, 12.7% yield) was obtained as white solid. LCMS (ESI): RT = 0.794 min, mass calcd for C25H19F3N2O3452.43 m / z found 453.0[M+H]+. ‘H NMR (400 MHz, CDCI3) 6 4.07 (dd, J= 11.32, 3.69 Hz, 1 H) 4.20 (dd, J= 11.26, 4.25 Hz, 1 H) 4.36 (br s, 1 H) 5.39 - 5.43 (m, 1 H) 7.08 (d, J= 8.50 Hz, 2 H) 7.16 (d, J= 6.88 Hz, 1 H) 7.28 - 7.33 (m, 1 H) 7.49 - 7.56 (m, 2 H) 7.60 (d, J= 8.50 Hz, 2 H) 7.76 (td, J= 7.69, 1.75 Hz, 1 H) 7.82 (d, J= 8.25 Hz, 1 H) 7.92 (dd, J= 8.82, 1.69 Hz, 1 H) 8.04 (br d, J= 6.75 Hz, 1 H) 8.14 (d, J= 8.75 Hz, 1 H) 8.45 (d, J= 1.38 Hz, 1 H) 8.58 (d, .7= 4.25 Hz, 1 H).Example 24: N-(l,5-dihydroxypentan-3-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 35)3-aminopentane-l,5-diol

[0358] To a solution of dimethyl 3 -aminopentanedioate (120.0 mg, 0.57 mmol, 1 eq, HC1) in THF (1.5 mL) at 0 °C was added LiAlH4 (32.3 mg, 0.85 mmol, 1.5 eq) portion-wise. The resulting mixture was stirred at 0 °C for 1 h and stirred at 20 °C for 16 h. The reaction mixture was quenched with water (50 pL) at 0 °C and then 2 M NaOH solution (50 pL), then diluted with water (150 pL). Then Na2SO4 was added into the reaction and stirred at 20 °C for 0.5 h, and the reaction was filtered and concentrated under reduced pressure to give compound 3-aminopentane-l,5-diol (20.0 mg, 0.17 mmol, 29.6% yield) as colorless oil. 'HNMR (400 MHz, CDC13) 8 3.87 - 3.76 (m, 4H), 3.23 - 3.11 (m, 1H), 1.76 - 1.68 (m, 2H), 1.62 - 1.56 (m, 2H).7V-(l,5-dihydroxypentan-3-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide

[0359] To a solution of 5-(4-(trifluoromethyl)phenoxy)-2-naphthoic acid (38.6 mg, 0.12 mmol, 1.0 eq) and HATU (66.3 mg, 0.17 mmol, 1.5 eq) in DMF (1 mL) at 20 °C was added 3-aminopentane- 1,5-diol (18.0 mg, 0.15 mmol, 1.3 eq) and TEA (35.3 mg, 0.35 mmol, 49 uL, 3 eq). The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated to give a residue, which was purified by p / cp-HPLC (column: Xtimate C18 100*30mm*3um; mobile phase: [water (0.05%HCl)-ACN]; B%: 35%-65%, 8.5min) to give the title compound (3.2 mg, 7 umol, 6.2% yield) as colorless oil. LCMS (ESI): RT = 0.891 min, mass calc, for C23H22F3NO4 433.15, m / z found 434.0 [M+H]+; 'HNMR (400 MHz, CD3OD) 6 8.45 (s, 1H), 8.10 (d, J= 8.8 Hz, 1H), 7.90 (brd, J= 8.5 Hz, 2H), 7.66 (brd, J= 8.6 Hz, 2H), 7.59 (t, J= 7.9 Hz, 1H), 7.23 (d, J= 7.5 Hz, 1H), 7.13 (brd, J= 8.5 Hz, 2H), 4.44 - 4.35 (m, 1H), 3.69 (brt, J= 6.4 Hz, 4H), 1.97 - 1.77 (m, 4H).Example 25: (R)-N-(4-(dimethylamino)butan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide (Compound 36)(R)-N-(4-(l,3-dioxoisoindolin-2-yl)butan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide

[0360] To a solution of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (500 mg, 1.50 mmol, 1 eq) and HATU (855.5 mg, 2.25 mmol, 1.5 eq) in DCM (10 mL)was added DIPEA (581.5 mg, 4.50 mmol, 0.78 mL, 3 eq). After addition, the mixture was stirred at the same temperature (25 °C) for 0.5 hr, and then 2-[(3R)-3-aminobutyl]isoindoline-l, 3-dione (327.3 mg, 1.50 mmol, 1 eq, HC1) was added. The mixture was stirred at 25 °C for 1.5 hr. The reaction mixture was added H2O (20 mL) and extracted with EA (20 mL * 3). The combined organic layers were washed with brine (30 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate / Petroleum ether gradient @ 30 mL / min). Compound N-[(lR)-3-(l,3-dioxoisoindolin-2-yl)-l-methyl-propyl]-5-[4- (trifluoromethyl)phenoxy]naphthalene-2-carboxamide (620 mg, 1.09 mmol, 72.9% yield) was obtained as a white solid.(R)-N-(4-aminobutan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide

[0361] To a solution of N-[(lR)-3-(l,3-dioxoisoindolin-2-yl)-l-methyl-propyl]-5-[4- (trifluoromethyl)phenoxy]naphthalene-2-carboxamide (620 mg, 1.16 mmol, 1 eq) in EtOH (8 mL) was added NH2NH2.H2O (685.7 mg, 11.64 mmol, 0.66 mL, 85%, 10 eq). The mixture was stirred at 25 °C for 6 hr. The reaction mixture was filtered. The cake was washed with EtOH (10 mL), the organic layers concentrated under reduced pressure to give a residue. The residue was added H2O (10 mL) and extracted with DCM (10 mL * 3). The combined organic layers were washed with brine (20 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. It was used into next step without further purification. Compound N- [(lR)-3-amino-l-methyl-propyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (489 mg, 1.08 mmol, 92.8% yield) was obtained as yellow oil.(R)-N-(4-(dimethylamino)butan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide

[0362] To a solution of N-[(lR)-3-amino-l-methyl-propyl]-5-[4- (trifluoromethyl)phenoxy]naphthalene-2-carboxamide (50 mg, 0.12 mmol, 1 eq) and formaldehyde (100.8 mg, 1.24 mmol, 92.5 uL, 10 eq) in MeOH (1 mL) was added Pd / C (30 mg, 0.12 mmol, 10%, 1.00 eq) under H2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 25 °C for 16 hours. The reaction mixture was filtered and the organic layers were concentrated under reduced pressure to give a residue. The residue was purified by / i / c / i-HPLC (column: 3_Phenomenex Luna C18 75*30mm*3um;mobile phase: [water(0.05%HCl)-ACN];B%: 20%-50%,6.5min). The title compound (22.9 mg, 49.0 umol, 39.4% yield, HC1) was obtained as a white solid. LCMS (ESI): RT = 0.867 min, mass calcd for C24H25F3N2O2430.46 m / z found 431.3[M+H]+, ‘H NMR (400 MHz, CDCI3) 8 12.08 (br s, 1H), 8.70 (br s, 1H), 8.17 - 8.03 (m, 2H), 7.88 (br d, J= 8.3 Hz, 1H), 7.70 (br s, 1H), 7.58 (d, J= 8.5 Hz, 2H), 7.49 (t, J= 7.8 Hz, 1H), 7.15 (d, J= 7.5 Hz, 1H), 7.05 (d, J= 8.5 Hz, 2H), 4.32 (br s, 1H), 3.29 - 3.05 (m, 2H), 2.81 (br d, J= 18.1 Hz, 6H), 2.53 - 2.08 (m, 2H), 1.44 (br d, J= 5.3 Hz, 3H).Example 26: (R)-N-(4-(methylamino)butan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide (Compound 37)(R)-N-(4-((2,4-dimethoxybenzyl)amino)butan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide

[0363] To a solution of N-[(lR)-3-amino-l-methyl-propyl]-5-[4- (trifluoromethyl)phenoxy]naphthalene-2-carboxamide (100 mg, 0.24 mmol, 1 eq) and 2,4- dimethoxybenzaldehyde (41.2 mg, 0.24 mmol, 1 eq) in DCM (5 mL) was added AcOH (14.9 mg, 0.24 mmol, 14 uL, 1 eq) and NaBH(OAc)3 (105.3 mg, 0.49 mmol, 2 cv / )The mixture was stirred at 25 °C for 16 hr. The reaction mixture was diluted with H2O (5 mL) and neutralized to pH = 7~8 with 2M NaOH, Then extracted with DCM (15 mL * 3). The combined organic layers were washed with brine (10 mL), dried with anhydrous ISfeSCU, filtered and concentrated under reduced pressure to give a residue. It was used into next step without further purification. Compound N-[(lR)-3- [(2,4-dimethoxyphenyl)methylamino]-l-methyl-propyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (122 mg, 0.16 mmol, 67.5% yield) was obtained as yellow oil.(R)-N-(4-((2,4-dimethoxybenzyl)(methyl)amino)butan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide

[0364] To a solution of N-[(lR)-3-[(2,4-dimethoxyphenyl)methylamino]-l-methyl-propyl]-5-[4- (trifluoromethyl)phenoxy]naphthalene-2-carboxamide (122 mg, 0.16 mmol, 1 eq) and formaldehyde (136.1 mg, 1.68 mmol, 0.12 mL, 10 eq) in MeOH (3 mL) was added Pd / C (100 mg, 0.16 mmol, 16 uL, 10%, 1 eq) under H2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 25°C for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-10% DCM / MeOH @ 20 mL / min). Compound N-[(lR)-3-[(2,4-dimethoxyphenyl)methyl- methyl-amino]-l-methyl-propyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (41 mg, 58.6 umol, 34.9% yield) was obtained as a colorless oil.(R)-N-(4-(methylamino)butan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide

[0365] To a solution of N-[(lR)-3-[(2,4-dimethoxyphenyl)methyl-methyl-amino]-l-methyl- propyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (41 mg, 72.3 umol, 1 eq) in DCE (1 mL) were added DIPEA (18.7 mg, 0.14 mmol, 25 uL, 2 eq) and 1-chloroethyl chloroformate (ACE-CI) (10.3 mg, 72.3 umol, 1 eq) at 0 °C . Then the mixture was stirred at 0 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to remove DCE to give a residue. The residue was quenched with MeOH (5 mL ) and the mixture was concentrated in vacuum. The residue was purified by p / cp-HPLC (column: 3_Phenomenex Luna Cl 8 75*30mm*3um;mobile phase: [water(0.05%HCl)-ACN];B%: 25%-55%,6.5min). The title compound (6.9 mg, 14.9 umol, 20.6% yield, HC1) was obtained as a white solid. LCMS (ESI): RT = 0.873 min, mass calcd for C23H23F3N2O2416.44 m / z found 417.3[M+H]+. ‘H NMR (400 MHz, CDCI3) 8 9.84 (br s, 1H), 9.14 (br s, 1H), 8.47 (br s, 1H), 8.03 (br s, 1H), 7.95 - 7.64 (m, 2H), 7.50 (br d, J= 8.3 Hz, 2H), 7.40 (br s, 1H), 7.05 (br d, J= 7.3 Hz, 1H), 6.97 (br d, J= 8.3 Hz, 2H), 4.25 (br s, 1H), 3.28 - 2.78 (m, 2H), 2.61 (br s, 3H), 2.44 - 1.83 (m, 2H), 1.33 (br s, 3H).Example 27: (R)-N-(4-(ethylamino)butan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide (Compound 38)(R)-N-(4-((2,4-dimethoxybenzyl)amino)butan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide

[0366] To a solution of N-[(lR)-3-amino-l-methyl-propyl]-5-[4- (trifluoromethyl)phenoxy]naphthalene-2-carboxamide (100 mg, 0.24 mmol, 1 eq) and 2,4- dimethoxybenzaldehyde (41.2 mg, 0.24 mmol, 1 eq) in DCM (5 mL) was added AcOH (14.9 mg, 0.24 mmol, 14 uL, 1 eq) and NaBH(OAc)3 (105.3 mg, 0.49 mmol, 2 eq). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was diluted with H2O (5 mL) and neutralized to pH = 7~8 with 2M NaOH, Then extracted with DCM (15 mL * 3). The combined organic layers were washed with brine (10 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient @ 25 mL / min). Compound (R)-N-(4-((2,4-dimethoxybenzyl)amino)butan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide (112 mg, 0.16 mmol, 66.8% yield) was obtained as a colorless oil.(R)-N-(4-((2,4-dimethoxybenzyl)(ethyl)amino)butan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide

[0367] To a solution of N-[(lR)-3-[(2,4-dimethoxyphenyl)methylamino]-l-methyl-propyl]-5-[4- (trifluoromethyl)phenoxy]naphthalene-2-carboxamide (112 mg, 0.16 mmol, 1 eq) and acetaldehyde (73.2 mg, 1.66 mmol, 93 uL, 10 eq) in EtOH (3 mL) was added Pd / C (100 mg, 0.16 mmol, 10%, 1.0 eq) under H2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 25°C for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. It was used into next step without further purification. Compound (R)-N-(4-((2,4-dimethoxybenzyl)(ethyl)amino)butan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide (102 mg, 0.14 mmol, 84.5% yield) was obtained as yellow oil.(R)-N-(4-(ethylamino)butan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide

[0368] To a solution of N-[(lR)-...

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A method for treating mesothelioma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount a TEAD inhibitor, wherein the TEAD inhibitor associates with one or more components of the Hippo pathway network comprising TEAD, transcriptional coactivator with PDZ binding motif (TAZ), or Yes-associated protein transcriptional coactivator (YAP); and wherein the TEAD inhibitor is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:Formula (I) wherein, each X1, X4, X5, and X6is independently N or CRX; each X2and X3is independently N or CRY; each Rxis independently hydrogen, halogen, nitro, -OR3, -SR3, -CN, -C(=O)R3, - C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, - NR3C(=O)R3, -NR3C(=O)OR3, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C2-C4alkenyl, substituted or unsubstituted C2-C4alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each RYis independently hydrogen, halogen, nitro, -CN, -C(=O)R3, -C(=O)N(R3)2, - C(=O)OR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, - NR3C(=O)OR3, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted C2-C4alkenyl, substituted or unsubstituted C2-C4alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted orunsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R is halogen, nitro, -CN, -OR3, -SR3, -C(=O)R3, -C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, - S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, -NR3C(=O)OR3, or substituted or unsubstituted Ci-Cefluoroalkyl;R1is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C2-Cealkenyl, substituted or unsubstituted C2-Cealkynyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2- Cioheterocycloalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, or -S(=O)2R4; each R2is independently halogen, nitro, -N3, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, - C(=O)OR3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2- Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl;R4is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or -NH2; and n is 0, 1, 2, 3, or 4. The method of claim 1, wherein the TEAD inhibitor is a compound of Formula (I-A), or a pharmaceutically acceptable salt or solvate thereof:wherein, each Rxis independently hydrogen, halogen, -OR3, -SR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, - NR3S(=O)2R3, -NR3C(=O)R3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci-Cefluoroalkyl, or substituted or unsubstituted C2-C4alkynyl; each RYis independently hydrogen, halogen, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci- Cefluoroalkyl, or substituted or unsubstituted C2-C4alkynyl;R is halogen, nitro, -CN, -OR3, -C(=O)R3, -C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, - S(=O)2R3, -NR3S(=O)2R3, -NR3C(=O)R3, -NR3C(=O)OR3, or substituted or unsubstituted Ci-Cefluoroalkyl;R1is C1-C6alkyl optionally substituted with(a) -OR3; and R3is hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci-Cefluoroalkyl, or substituted or unsubstituted C3-C10cycloalkyl;(b) 6-membered heteroaryl ring selected from substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, and substituted or unsubstituted triazinyl; or(c) 1, 2, or 3 substituents each independently selected from -OH, -OCH3, -NH2, - NHCH3, -N(CH3)2, and pyridinyl; each R2is independently halogen, nitro, -N3, -CN, -OR3, -SR3, -S(=O)2R3, -N(R3)2, - C(=O)OR3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2- Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl; and n is 0, 1, or 2.

3. The method of claim 1 or 2, wherein the TEAD inhibitor is selected from:The method of any one of claims 1-3, wherein the TEAD inhibitor is, or a pharmaceutically acceptable salt or solvate thereof. The method of any one of claims 1-4, wherein the mesothelioma is a relapsed or refractory mesothelioma. The method of any one of claims 1-4, wherein the mesothelioma comprises a mutation in a neurofibromatosis type 2 (NF2) gene.

7. The method of any one of claims 1-4, wherein the mesothelioma comprises pleural mesothelioma, peritoneal mesothelioma, or pericardial mesothelioma, or any combination thereof.

8. The method of any one of claims 1-4, wherein the mesothelioma comprises epithelioid mesothelioma, sarcomatoid mesothelioma, or dermoplastic mesothelioma, or any combination thereof.9 The method of any one of claims 1-8, wherein administering the TEAD inhibitor inhibits transcriptional coactivator with PDZ binding motif / Yes-associated protein transcriptional coactivator (T AZ / YAP).10 The method of any one of claims 1-9, wherein administering the TEAD inhibitor inhibits one or more of proteins encompassed by, or related to, the Hippo pathway in the subject.11 The method of any one of claims 1-10, wherein:X1is CRX; and each X2and X3is CRY.12 The method of any one of claims 1-11, wherein: each X4, X5, and X6is CRX.13 The method of any one of claims 1-12, wherein: each Rxis independently hydrogen, halogen, -OR3, -SR3, -S(=O)R3, -S(=O)2R3, -N(R3)2, - NR3S(=O)2R3, -NR3C(=O)R3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C2-C4alkynyl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C3-C10cycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl.14 The method of claim 13, wherein: each Rxis independently hydrogen, F, Cl, Br, -CH3, -OH, -OCH3, or -OCF3.15 The method of claim 14, wherein: each Rxis hydrogen.16 The method of any one of claims 1-15, wherein: each RYis independently hydrogen, halogen, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted Ci- Cefluoroalkyl, or substituted or unsubstituted C2-C4alkynyl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C3-C10cycloalkyl; or iftwo R3are on the same nitrogen atom, then two R3are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl.

17. The method of claim 16, wherein: each RYis independently hydrogen, F, Cl, or -CH3.

18. The method of claim 17, wherein: each RYis hydrogen.

19. The method of any one of claims 1-18, wherein:R1is substituted or unsubstituted C1-C6alkyl.

20. The method of claim 19, wherein:R1is C1-C6alkyl substituted with -OR3; and R3is hydrogen, substituted or unsubstituted Ci- Cealkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C3- Ciocycloalkyl.

21. The method of claim 20, wherein:R1is C1-C6alkyl substituted with -OH.

22. The method of claim 19, wherein:R1is C1-C6alkyl substituted with 6-membered heteroaryl ring selected from substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, and substituted or unsubstituted triazinyl.

23. The method of claim 22, wherein:R1is C1-C6alkyl substituted with pyridinyl.

24. The method of claim 19, wherein:R1is C1-C6alkyl substituted with 1, 2, or 3 substituents each independently selected from - OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, and pyridinyl.

25. The method of any one of claims 1-24, wherein:R is halogen, nitro, -CN, -OR3, -C(=O)R3, -C(=O)N(R3)2, -C(=O)OR3, -S(=O)R3, -S(=O)2R3, -NR3S(=O)2R3, -NR3C(=O)R3, -NR3C(=O)OR3, or substituted or unsubstituted Ci- Cefluoroalkyl; and each R3is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted C2-Cioheterocycloalkyl; or if two R3are on the same nitrogen atom, then two R3are taken together with thenitrogen atom to which they are attached to form a substituted or unsubstituted C3-C7 heterocycloalkyl.

26. The method of claim 25, wherein:R is F, Cl, -CN, -OCF3, -CHF2, or -CF3.

27. The method of claim 26, wherein:R is F, Cl, or -CF3.

28. The method of claim 27, wherein:R is -CF3.

29. The method of any one of claims 1-28, wherein: each R2is independently F, Cl, -OCF3, or -CF3.

30. The method of claim 29, wherein: each R2is independently F or Cl.

31. The method of any one of claims 1-30, wherein: n is 0.

32. The method of any one of claims 1-30, wherein: n is 1 or 2.

33. The method of any one of claims 1-32, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered as an oral formulation.

34. The method of any one of claims 1-33, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered in a capsule.

35. The method of any one of claims 1-34, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered in a 15 mg, 25 mg, 50 mg, 70 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg amount.

36. The method of any one of claims 1-35, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered in a 15 mg amount.

37. The method of any one of claims 1-35, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered in a 25 mg amount.

38. The method of any one of claims 1-35, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered in a 50 mg amount.

39. The method of any one of claims 1-35, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered in a 70 mg amount.

40. The method of any one of claims 1-35, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered in a 100 mg amount.

41. The method of any one of claims 1-40, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for at least a week.

42. The method of any one of claims 1-40, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for at least two weeks.

43. The method of any one of claims 1-40, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for at least three weeks.

44. The method of any one of claims 1-43, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of three weeks, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for one week, and not administered for the following two weeks.

45. The method of any one of claims 1-43, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of four weeks, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for one week, and then not administered for the following three weeks.

46. The method of any one of claims 1-43, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of three weeks, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for two weeks, and then not administered for the following week.

47. The method of any one of claims 1-43, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of four weeks, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for two weeks, and then not administered for the following two weeks.

48. The method of any one of claims 1-43, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for 15 days, and then administered on days 1, 8, and 15 thereof.

49. The method of any one of claims 1-43, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of four weeks, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for two weeks, and then not administered for thefollowing two weeks, wherein the compound of Formula (I) or (I- A), or the pharmaceutically acceptable salt or solvate thereof, is administered at 50 mg.

50. The method of any one of claims 1-43, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered in a cycle length of four weeks, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered daily for two weeks, and then not administered for the following two weeks, wherein the compound of Formula (I) or (I-A), or the pharmaceutically acceptable salt or solvate thereof, is administered at 100 mg.

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