Pharmaceutical formulations and dosing schedules of a YAP / TAZ-TEAD inhibitor

Abstract

Provided herein are pharmaceutical formulations of a therapeutically effective amount of YAP / TAZ-TEAD inhibitors in a solid dosage form. Also, provided herein are methods of treating cancer comprising the pharmaceutical formulations of a therapeutically effective amount of YAP / TAZ-TEAD inhibitors in a solid dosage form.

Description

WSGR Docket No.47612-749.601 PHARMACEUTICAL FORMULATIONS AND DOSING SCHEDULES OF A YAP / TAZ- TEAD INHIBITOR CROSS-REFERENCE

[0001] This application claims benefit of U.S. Provisional Patent Application No.63 / 580,552 filed on September 5, 2023, which is incorporated herein by reference in its entirety. BACKGROUND

[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 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

[0003] In one aspect, provided herein are pharmaceutical formulations, comprising a therapeutically effective amount of any one of Compounds 1-16, in a solid dosage form. In some embodiments, the pharmaceutical formulations are useful for the treatment of cancer.

[0004] In another aspect, provided herein are methods for treating cancer in a subject in need thereof by administering to the subject the pharmaceutical formulations described herein. In some embodiments, the methods of treating cancer include, for example, administering the pharmaceutical formulation in a solid dosage form, comprising a therapeutically effective amount of any one of Compounds 1-16 and excipients disclosed herein. In some embodiments, the methods of treating cancer include, for example, administering the pharmaceutical formulation in a solid dosage form, comprising a therapeutically effective amount of the any one of Compounds 1-16 and excipients disclosed herein, wherein the pharmaceutical formulation is administered by a dosing schedule described herein.

[0005] In one aspect, disclosed herein are pharmaceutical formulations in a solid dosage form comprising: (a) about 20% w / w to about 50% w / w of any one of Compounds 1-16; (b) about 15% w / w to about 40% w / w of a first filler; (c) about 15% w / w to about 40% w / w of a second filler; (d) about 1% w / w to about 10% w / w of a first lubricant; (e) about 0.1% w / w to about 1% w / w of a second lubricant; (f) about 1% w / w to about 5% w / w of a disintegrant; and (g) about 0.1% w / w to about 2% w / w of a glidant. In some embodiments, the pharmaceutical formulations comprise aboutWSGR Docket No.47612-749.601 25% w / w to about 45% w / w of the any one of Compounds 1-16. In some embodiments, the pharmaceutical formulations comprise about 30% w / w to about 40% w / w of the any one of Compounds 1-16. In some embodiments, the pharmaceutical formulations comprise about 37% w / w of the any one of Compounds 1-16. In some embodiments, the any one of Compounds 1-16 is in a 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 300 mg, or 400 mg amount. In some embodiments, the any one of Compounds 1-16 is in a 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg or 200 mg amount. In some embodiments, the any one of Compounds 1-16 is in a 25 mg, 50 mg, 100 mg, 125 mg, or 150 mg amount. In some embodiments, the any one of Compounds 1-16 is in a 25 mg, 50 mg, or 100 mg amount. In some embodiments, the any one of Compounds 1-16 is in a 25 mg amount. In some embodiments, the any one of Compounds 1-16 is in a 50 mg amount. In some embodiments, the any one of Compounds 1-16 is in a 100 mg amount. In some embodiments, the pharmaceutical formulations comprise about 20% w / w to about 35% w / w of the first filler. In some embodiments, the pharmaceutical formulations comprise about 25% w / w to about 30% w / w of the first filler. In some embodiments, the pharmaceutical formulations comprise about 27% w / w of the first filler. In some embodiments, the pharmaceutical formulations comprise about 20% w / w to about 35% w / w of the second filler. In some embodiments, the pharmaceutical formulations comprise about 25% w / w to about 30% w / w of the second filler. In some embodiments, the pharmaceutical formulations comprise about 27% w / w of the second filler. In some embodiments, the first filler and second filler are independently selected from lactose, erythritol, sorbitol, mannitol, dicalcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, starch, and pregelatinized starch (Starch 1500). In some embodiments, the first filler is lactose. In some embodiments, the lactose is lactose monohydrate. In some embodiments, the second filler is mannitol. In some embodiments, the mannitol is mannitol 200 SD. In some embodiments, the pharmaceutical formulations comprise about 3% w / w to about 7% w / w of the first lubricant. In some embodiments, the pharmaceutical formulations comprise about 5% w / w of the first lubricant. In some embodiments, the pharmaceutical formulations comprise about 0.3% w / w to about 0.7% w / w of the second lubricant. In some embodiments, the pharmaceutical formulations comprise about 0.5% w / w of the second lubricant. In some embodiments, about 0.3% w / w of the second lubricant is intragranular and about 0.2% w / w of the second lubricant is extragranular. In some embodiments, the first lubricant and second lubricant are independently selected from sodium laureth sulfate, sodium lauryl sulfate, magnesium stearate, stearic acid, sodium stearate, calcium stearate, ammonium lauryl sulfate, and sodium stearyl fumarate. In some embodiments, the first lubricant is sodium lauryl sulfate. In some embodiments, the second lubricant is magnesium stearate. In some embodiments, the pharmaceutical formulationsWSGR Docket No.47612-749.601 comprise about 2% w / w to about 4% w / w of the disintegrant. In some embodiments, the pharmaceutical formulations comprise about 3% w / w of the disintegrant. In some embodiments, the disintegrant is selected from povidone, crospovidone, hypromellose, croscarmellose sodium, carboxymethylcellulose, hydroxypropyl cellulose, and poly(vinyl alcohol). In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the pharmaceutical formulations comprise about 0.5% w / w to about 1.5% w / w of the glidant. In some embodiments, the pharmaceutical formulations comprise about 1% w / w of the glidant. In some embodiments, the glidant is selected from silicate, silicon dioxide, and talc. In some embodiments, the glidant is silicon dioxide. In some embodiments, the silicon dioxide is colloidal silicon dioxide.

[0006] In another aspect, disclosed herein are pharmaceutical formulations in a solid dosage form comprising: (a) about 37% w / w of any one of Compounds 1-16; (b) about 26.7% w / w of lactose monohydrate; (c) about 26.7% w / w of mannitol; (d) about 5% w / w of sodium lauryl sulfate; (e) about 0.5% w / w of magnesium stearate; (f) about 3% w / w of croscarmellose sodium; and (g) about 1% w / w of colloidal silicon dioxide.

[0007] In some embodiments, the pharmaceutical formulation disclosed herein has a half-life of at least 3 days. In some embodiments, the pharmaceutical formulation has a half-life of at least 7 days. In some embodiments, the pharmaceutical formulation has a half-life of 12 to 15 days. In some embodiments, the pharmaceutical formulation has a half-life of 12 days. In some embodiments, the solid dosage form is selected from a powder, a tablet, a bite-disintegration tablet, a chewable tablet, a caplet, a capsule, a gelcap, an effervescent powder, a rapid-disintegration tablet, an abuse- deterrent tablet, a modified release tablet, a modified release caplet, a modified release capsule, and an aqueous suspension produced from a powder. In some embodiments, the solid dosage form is a capsule. In some embodiments, the capsule is a hard gelatin capsule. In some embodiments, the hard gelatin capsule comprises gelatin and titanium dioxide. In some embodiments, the hard gelatin capsule further comprises FD&C Red 40 and FD&C Blue 1. In some embodiments, the solid dosage form is a tablet. In some embodiments, the solid dosage form is a caplet. In some embodiments, the solid dosage form is a dry-granulation blend.

[0008] In another aspect, disclosed herein are methods for treating cancer in a subject in need thereof, comprising administering to the subject a pharmaceutical formulation disclosed herein. In some embodiments, the cancer is mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma, lung cancer, bladder carcinoma, cutaneous neurofibromas, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, or breast cancer.WSGR Docket No.47612-749.601

[0009] In another aspect, disclosed herein are methods for treating cancer in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of any one of Compounds 1-16, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered daily for at least three days. In some embodiments, the therapeutically effective amount of the any one of Compounds 1-16 is administered as an oral formulation. In some embodiments, the therapeutically effective amount of the any one of Compounds 1-16 is administered in a capsule. In some embodiments, the therapeutically effective amount of the any one of Compounds 1-16 is at least 25 mg daily. In some embodiments, the therapeutically effective amount of the any one of Compounds 1-16 is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 300 mg, or 400 mg daily. In some embodiments, the therapeutically effective amount of the any one of Compounds 1-16 is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg daily. In some embodiments, the therapeutically effective amount of the any one of Compounds 1-16 is 25 mg, 50 mg, 100 mg, 125 mg, 150 mg, or 200 mg daily. In some embodiments, the therapeutically effective amount of the any one of Compounds 1- 16 is 25 mg, 50 mg, or 100 mg daily. In some embodiments, the therapeutically effective amount of the any one of Compounds 1-16 is 25 mg daily. In some embodiments, the therapeutically effective amount of the any one of Compounds 1-16 is 50 mg daily. In some embodiments, the therapeutically effective amount of the any one of Compounds 1-16 is 100 mg daily. In some embodiments, the therapeutically effective amount of the any one of Compounds 1-16 is administered daily for at least a week. In some embodiments, the therapeutically effective amount of the any one of Compounds 1-16 is administered daily for at least two weeks. In some embodiments, the therapeutically effective amount of the any one of Compounds 1-16 is administered daily for at least three weeks. In some embodiments, the therapeutically effective amount of the any one of Compounds 1-16 is administered in a cycle length of three weeks, wherein the therapeutically effective amount is administered daily for one week, and then not administered for two weeks. In some embodiments, the therapeutically effective amount of the any one of Compounds 1-16 is administered in a cycle length of three weeks, wherein the therapeutically effective amount is administered daily for one week, and then not administered for two weeks, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered at 200 mg. In some embodiments, the therapeutically effective amount of the any one of Compounds 1-16 is administered in a cycle length of four weeks, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered daily for one week, and then not administered for the following three weeks. In some embodiments, the therapeutically effective amount of the any one of Compounds 1-16 is administered in a cycle length of four weeks, whereinWSGR Docket No.47612-749.601 the therapeutically effective amount of the any one of Compounds 1-16 is administered daily for one week, and then not administered for the following three weeks, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered at 150 mg. In some embodiments, the therapeutically effective amount of the any one of Compounds 1-16 is administered in a cycle length of three weeks, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered daily for two weeks, and then not administered for the following one week. In some embodiments, the therapeutically effective amount of the any one of Compounds 1-16 is administered in a cycle length of three weeks, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered daily for two weeks, and then not administered for the following one week, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered at 200 mg. In some embodiments, the therapeutically effective amount of the any one of Compounds 1-16 is administered in a cycle length of four weeks, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered daily for two weeks, and then not administered for the following two weeks. In some embodiments, the therapeutically effective amount of the any one of Compounds 1-16 is administered in a cycle length of four weeks, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered daily for two weeks, and then not administered for the following two weeks, wherein the therapeutically effective amount of the any one of Compounds 1- 16 is administered at 100 mg. In some embodiments, the therapeutically effective amount of the any one of Compounds 1-16 is administered in a cycle length of four weeks, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered daily for two weeks, and then not administered for the following two weeks, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered at 200 mg. In some embodiments, the therapeutically effective amount of the any one of Compounds 1-16 is administered daily for 15 days, and then administered once weekly for three weeks. In some embodiments, the therapeutically effective amount of the any one of Compounds 1-16 is 50 mg administered once daily for 15 days, and then 50 mg administered once weekly for three weeks. In some embodiments, the therapeutically effective amount of the any one of Compounds 1-16 is 100 mg administered once daily for 15 days, and then 100 mg administered once weekly for three weeks. In some embodiments, the therapeutically effective amount of the any one of Compounds 1-16 is 50 mg administered once daily for 15 days, and then 100 mg administered once weekly for three weeks. In some embodiments, the therapeutically effective amount of the any one of Compounds 1- 16 is administered in at least two cycles. In some embodiments, the cancer is mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma,WSGR Docket No.47612-749.601 lung cancer, bladder carcinoma, cutaneous neurofibromas, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, or breast cancer. INCORPORATION BY REFERENCE

[0010] 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

[0011] 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:

[0012] 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: α-CAT (α-Catenin), AJUB (Ajuba), AMOT (Angiomotin), β-TRCP (β-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 (Pals1-associated tight junction protein), PP2A (Protein phosphatase 2A), PTPN14 (Protein tyrosine phosphatase non-receptor type 14), RASSF (Ras associated factor), SAV (Salvador), SCRIB (Scribble), SIK (Salt inducible kinase), TAO (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).

[0013] Fig.2 illustrates a schematic representation of the Hippo signaling pathway regulated by G alpha proteins. DETAILED DESCRIPTION The Hippo Signaling Network

[0014] 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 mainWSGR Docket No.47612-749.601 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, unregulated upregulation 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.

[0015] Additional core members of the Hippo signaling pathway comprise the serine / threonine kinases MST1 / 2 (homologues of Hippo / Hpo in Drosophila), Lats1 / 2 (homologues of Warts / Wts), and their adaptor proteins Sav1 (homologue of Salvador / Sav) and Mob (MOBKL1A and MOBKL1B; homologues of Mats), respectively (Fig.1). In general, MST1 / 2 kinase complexes with the scaffold protein Sav1, which in turn phosphorylates and activates Lats1 / 2 kinase. Lats1 / 2 is also activated by the scaffold protein Mob. The activated Lats1 / 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.

[0016] In some instances, Lats1 / 2 phosphorylates YAP at the [HXRXXS] consensus motifs. YAP comprises five [HXRXXS] consensus motifs, wherein X denotes any amino acid residue. In some instances, Lats1 / 2 phosphorylates YAP at one or more of the consensus motifs. In some instances, Lats1 / 2 phosphorylates YAP at all five of the consensus motifs. In some instances, Lats1 / 2 phosphorylate at the S127 amino acid position. The phosphorylation of YAP S127 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.

[0017] 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 CK1δ / ε in the degradation motif, which then signals for interaction with the β-TRCP E3 ubiquitin ligase, leading to polyubiquitination and degradation of YAP.

[0018] In some instances, Lats1 / 2 phosphorylates TAZ at the [HXRXXS] consensus motifs. TAZ comprises four [HXRXXS] consensus motifs, wherein X denotes any amino acid residues. In some instances, Lats1 / 2 phosphorylates TAZ at one or more of the consensus motifs. In some instances,WSGR Docket No.47612-749.601 Lats1 / 2 phosphorylates TAZ at all four of the consensus motifs. In some instances, Lats1 / 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.

[0019] In some embodiments, phosphorylated YAP / TAZ accumulates in the cytoplasm, and undergoes SCFβ-TRCP-mediated ubiquitination and subsequent proteasomal degradation. In some instances, the Skp, Cullin, F-box containing complex (SCF complex) is a multi-protein E3 ubiquitin ligase complex that comprises a F-box family member protein (e.g., Cdc4), Skp1, 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, βTrCP1, Fbxw1, hsSlimb, plkappaBalpha-E3 receptor subunit) and S-phase kinase-associated proteins 2 (SKP2). In some embodiments, the SCF complex (e.g., SCFβTrCP1) interacts with an E1 ubiquitin-activating enzyme and an E2 ubiquitin-conjugating enzyme to catalyze the transfer of ubiquitin to the YAP / TAZ substrate. Exemplary E1 ubiquitin-activating enzymes include those encoded by the following genes: UBA1, UBA2, UBA3, UBA5, UBA5, UBA7, ATG7, NAE1, and SAE1. 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.

[0020] 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

[0021] In some embodiments, un-phosphorylated 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.WSGR Docket No.47612-749.601

[0022] 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

[0023] 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 of alpha (Gα), beta (Gβ), and gamma (Gγ) subunits. In some cases, there are several classes of Gαsubunits: Gq / 11α, G12 / 13α, Gi / oα (G inhibitory, G other), and Gsα (G stimulatory).

[0024] In some instances, Giα (G inhibitory), Goα (G other), Gq / 11α, and G12 / 13α coupled GPCRs activate YAP / TAZ and promote nuclear translocation. In other instances, Gsα (G stimulatory) coupled GPCRs suppress YAP / TAZ activity, leading to YAP / TAZ degradation.

[0025] In some cases, Giα (G inhibitory), Goα (G other), Gq / 11α, and G12 / 13α coupled GPCRs activate YAP / TAZ through repression of Lats1 / 2 activities. In contrast, Gsα, in some embodiments, induces Lats1 / 2 activity, thereby promoting YAP / TAZ degradation. GqFamily

[0026] Gqα (also known as Gq / 11protein), 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, IP3then 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.

[0027] In some embodiments, the GPCRs that interact with Gqα include, but are not limited to, 5- hydroxytryptamine receptor (5-HT receptor) types 5-HT2and 5-HT3; alpha-1 adrenergic receptor; vasopressin type 1 receptors 1A and 1B; angiotensin II receptor type 1; calcitonin receptor; histamine H1 receptor; metabotropic glutamate receptor, group I; muscarinic receptors M1, M3, and M5; and trace amine-associated receptor 1.

[0028] In some instances, there are several types of Gqα: Gq, Gq / 11, Gq / 14, and Gq / 15. The Gqprotein is encoded by GNAQ. Gq / 11is encoded by GNA11. Gq / 14is encoded by GNA14. Gq / 15is encoded by GNA15.WSGR Docket No.47612-749.601

[0029] In some instances, mutations or modifications of the Gqα genes have been associated with cancer. Indeed, studies have shown that mutations in Gqα promote uveal melanoma (UM) tumorigenesis. In some instances, about 80% of UM cases have been detected to contain a mutation in GNAQ or GNA11.

[0030] In some instances, mutations or modifications of the Gqα genes have been associated with congenital diseases. In some instances, mutations of Gqα have been observed in congenital diseases such as Port-Wine Stain 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. G12 / 13Family

[0031] G12 / 13α 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.

[0032] In some embodiments, the GPCRs that interact with G12 / 13α include, but are not limited to, purinergic receptors (e.g. P2Y1, P2Y2, P2Y4, P2Y6); muscarinic acetylcholine receptors M1 and M3; receptors for thrombin [protease-activated receptor (PAR)-1, PAR-2]; thromboxane (TXA2); sphingosine 1-phosphate (e.g. S1P2, S1P3, S1P4and S1P5); lysophosphatidic acid (e.g. LPA1, LPA2, LPA3); angiotensin II (AT1); serotonin (5-HT2cand 5-HT4); somatostatin (sst5); endothelin (ETAand ETB); cholecystokinin (CCK1); V1avasopressin receptors; D5dopamine receptors; fMLP formyl peptide receptors; GAL2galanin receptors; EP3prostanoid receptors; A1adenosine receptors; α1adrenergic receptors; BB2bombesin receptors; B2bradykinin receptors; calcium- sensing receptors; KSHV-ORF74 chemokine receptors; NK1tachykinin receptors; and thyroid- stimulating hormone (TSH) receptors.

[0033] In some instances, G12 / 13α is further subdivided into G12and G13types which are encoded by GNA12 and GNA13, respectively. Gi / oFamily

[0034] Gi / oα (G inhibitory, G other) (also known as Gi / G0or Giprotein) 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.

[0035] In some embodiments, the GPCRs that interact with Giα include, but are not limited to, 5- hydroxytryptamine receptor (5-HT receptor) types 5-HT1and 5-HT5; muscarinic acetylcholineWSGR Docket No.47612-749.601 receptors such as M2and M4; adenosine receptors such as A1and A3; adrenergic receptors such as α2A, α2B, and α2C; apelin receptors; calcium-sensing receptor; cannabinoid receptors CB1 and CB2; chemokine CXCR4 receptor; dopamines D2, D3, and D4; GABABreceptor; 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 H3and H4receptors; 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 δ, κ, μ, and nociceptin receptors; prostaglandin receptors such as prostaglandin E receptor 1 (EP1), prostaglandin E receptor 3 (EP3), prostaglandin F receptor (FP), and thromboxane receptor (TP); somatostatin receptors sst1, sst2, sst3, sst4, and sst5; and trace amine-associated receptor 8.

[0036] In some instances, there are several types of Giα: Giα1, Giα2, Giα3, Giα4, Goα, Gt, Ggust, and Gz. Giα1 is encoded by GNAI1. Giα2 is encoded by GNAI2. Giα3 is encoded by GNAI3. Goα, the aosubunit, is encoded by GNAO1. Gtis encoded by GNAT1 and GNAT2. Ggustis encoded by GNAT3. Gzis encoded by GNAZ. GsFamily

[0037] Gsα (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 Gsα include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HT4, 5-HT6, and 5-HT7; adrenocorticotropic hormone receptor (ACTH receptor) (also known as melanocortin receptor 2 or MC2R); adenosine receptor types A2aand A2b; arginine vasopressin receptor 2 (AVPR2); β-adrenergic receptors β1, β2,and β3; calcitonin receptor; calcitonin gene-related peptide receptor; corticotropin-releasing hormone receptor; dopamine receptor D1-like family receptors such as D1and D5; follicle-stimulating hormone receptor (FSH- receptor); gastric inhibitory polypeptide receptor; glucagon receptor; histamine H2receptor; luteinizing hormone / choriogonadotropin receptor; melanocortin receptors such as MC1R, MC2R, MC3R, MC4R, and MC5R; parathyroid hormone receptor 1; prostaglandin receptor types D2and I2; secretin receptor; thyrotropin receptor; trace amine-associated receptor 1; and box jellyfish opsin.

[0038] In some instances, there are two types of Gsα: Gsand Golf. Gsis encoded by GNAS. Golfis encoded by GNAL. Additional Regulators of the Hippo signaling networkWSGR Docket No.47612-749.601

[0039] 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.

[0040] 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.

[0041] 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 α-catenin regulates YAP through sequestering YAP / 14-3-3 complexes in the cytoplasm. In other instances, Ajuba protein family members interact with Lats1 / 2 kinase activity, thereby preventing inactivation of YAP / TAZ.

[0042] 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 (Dlg), KIBRA, PTPN14, NPHP3, LKB1, Ajuba, and ZO1 / 2.

[0043] 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).

[0044] 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 or its coupled GPCR. In some embodiments, anWSGR Docket No.47612-749.601 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 Gqα family proteins such as Gq, Gq / 11, Gq / 14, and Gq / 15; the G12 / 13α family of proteins such as G12and G13; or the Giα family of proteins such as Giα1, Giα2, Giα3, Giα4, Goα, 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 / 11. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gq / 14. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gq / 15. In some embodiments, an inhibitor 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 Giα1. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Giα2. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Giα3. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Giα4. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Goα. 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.

[0045] 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 Sav1. 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.

[0046] 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., 26S proteasome).

[0047] 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.

[0048] 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 guanineWSGR Docket No.47612-749.601 nucleotide exchange factors (GEFs). In some cases, an inhibitor of Cdc42 is a compound disclosed herein.

[0049] 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 ubiquitin- specific protease (USP / UBP) superfamily of cysteine proteases. In some embodiments, the compounds disclosed herein are inhibitors of USP47. Compounds YAP / TAZ-TEAD inhibitors

[0050] In some aspects, the compounds disclosed herein are YAP / TAZ-TEAD inhibitors.

[0051] In some aspects, the present disclosure provides a compound of Formula (A):Formula (A), or a pharmaceutically acceptable salt thereof, wherein: R1is selected from the group consisting of -C(O)-N(Ra)(Rb), C6-20aryl, 5-20 membered heteroaryl, 5-20 membered heterocyclyl, and C1-6alkyl, wherein the C6-20aryl, 5-20 membered heteroaryl, and 5-20 membered heterocyclyl of R1are independently optionally substituted with one or more substituents selected from the group consisting of halo, -OH, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-8cycloalkyl, and C6-10aryl, and wherein the C1-6alkyl of R1is optionally substituted with one or more substituents selected from the group consisting of halo, -OH, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-8cycloalkyl, and C6-10aryl; Raand Rbare each independently H or C1-6alkyl, wherein the C1-6alkyl of Raor Rbis optionally substituted with one or more substituents selected from the group consisting of halo, -OH, - CN, C1-6haloalkyl, and C1-6alkoxy, or Raand Rbare taken, together with the atoms to which they attached, to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halo, -OH, -CN, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy; L1is absent or is *-O-CH2-**, *-CH2-O-**, or -O-, wherein ** denotes the point of attachment to the R2moiety and * denotes the point of attachment to the remainder of the molecule;WSGR Docket No.47612-749.601 R2is C2-12a1ky1, C2-12alkenyl, or C6-10aryl, wherein the C2-12alkyl, C2-12alkenyl, and C6-10aryl of R2are independently optionally substituted with one or more substituents selected from the group consisting of halo, -OH, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C6-10aryl, and C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, and C3-10cycloalkyl are independently optionally substituted with one or more halo, C1-6haloalkyl, C6-10aryl, or C3-10cycloalkyl; and R3and R4are each independently H or C1-6alkyl, wherein the C1-6alkyl of R3or R4is optionally substituted with one or more substituents selected from the group consisting of halo, -OH, - CN, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy, or R3and R4, together with the atoms to which they are attached, form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halo, -OH, -CN. and C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more substituents selected from the group consisting of halo, -OH, -CN, C1-6haloalkyl, and C1-6aikoxy.

[0052] In some embodiments of Formula (A), the compound is of Formula (A-I):Formula (A-I), or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments of Formula (A), the compound is of Formula (A-II):Formula (A-II), or a pharmaceutically acceptable salt thereof, wherein R5is selected from the group consisting of H, halo, OH, cyano, and C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more substituents selected from the group consisting of halo, OH, cyano, C1-6alkyl, C1-5haloalkyl, and C1-6alkoxy.

[0054] In some embodiments of Formula (A-II), the compound is of Formula (A-II-1):Formula (A-II-1),WSGR Docket No.47612-749.601 or a pharmaceutically acceptable salt thereof.

[0055] In some embodiments of Formula (A), such as a compound of Formula (A-II) or Formula (A-II-1), L1is absent. In some embodiments of Formula (A), such as a compound of Formula (A-I), Formula (A-II), or Formula (A-II-1), R2is C6-10aryl, wherein the C6-10aryl of R2is optionally substituted with one or more C3-10cycloalkyl, wherein the C3-10cycloalkyl is optionally substituted with one or more halo, C1-6haloalkyl, C6-10aryl, or C3-10cycloalkyl. In some embodiments, R2is.

[0056] In some embodiments of Formula (A), such as a compound of Formula (A-I), Formula (A- II), or Formula (A-II-1), R1is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Rlis optionally substituted with one or more C1-6alkyl. In some embodiments, R1is 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl of R1is optionally substituted with one or more C1-6alkyl. In some embodiments. R.1is pyrazinyl, wherein the pyrazinyl of R1is optionally substituted with one or more C1-6alkyl. In some embodiments, R1is.

[0057] In some embodiments of Formula (A), the compoundpharmaceutically acceptable salt thereof.

[0058] In sonic embodiments of Formula (A). the compound is of Formula (A-III):Formula (A-III), or a pharmaceutically acceptable salt thereof, wherein R1, R3, and R4are as defined in Formula (A).

[0059] In some embodiments, in conjunction with embodiments above or below, the YAP / TAZ- TEAD inhibitors disclosed herein comprise a compound of Formula (A), (A-I), (A-II), or (A-III), or a pharmaceutically acceptable salt thereof. Description of Formulae (A), (A-I), (A-II), and (A-III) can be found in WO2021 / 108483A1, the entirety of which is incorporated herein by reference. Formulae (A), (A-I), (A-II), and (A-III) are described as Formulae (I), (I-A), (I-B), and (I-C), respectively, in WO2021 / 108483A1 (see, e.g., paragraphs

[0046] -

[0124] ), which paragraphs and description of Formula (I), (I-A), (I-B), or (I-C), and methods of making compounds of FormulaWSGR Docket No.47612-749.601 (I), (I-A), (1-B), or (I-C), are hereby incorporated herein by reference. Moieties of Formula (A), (A- I), (A-II), or (A-III), such as R1, R2, R3, R4, R5, and L1are as defined in WO2021 / 108483A1, including any variations or embodiments thereof, R1, R2, R3, R4, R5, and L1of Formulae (A), (A-I), (A-II), and (A-III) correspond to the moieties R1, R2, R3, R4, R5, and L, respectively, in WO2021 / 108483A1.

[0060] In some embodiments, in conjunction with embodiments above or below, a compound of Formula (A), (A-I), (A-II), or (A-III) is Compound 1, or a pharmaceutically acceptable salt thereof. Compound 1 is chemically described as 5-(4-cyclohexylpheny1)-3-(3-(fluoromethyl)azetidine-1- carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one, having the structure below:Compound 1.

[0061] Description of Compound 1 and methods of making Compound 1can be found in, e.g., Compound 27 on page 31 and Example 27 on pages 140-142 of WO2021 / 108483A1.

[0062] In some embodiments, in conjunction with embodiments above or below, a compound of Formula (A), (A-I), (A-II), or (A-III) is Compound 9, or a pharmaceutically acceptable salt thereof. Compound 9 is chemically described as 5-(4-cyclohexylpheny1)-2-(3-methylpyrazin-2-y1)-3-[rac- (2S,3S)-3-(fluoromethyl)-2-methyl-azetidine-l-carbonyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one, having the structure below:Compound 9.

[0063] Description of Compound 9 and methods of making Compound 9 can be found in, e.g., Compound 44 on page 35 and Example 41 on pages 156-158 of WO2021 / 108483A1.

[0064] In some aspects, the present disclosure provides a compound of Formula (B):Formula (B) or a pharmaceutically acceptable salt thereof, wherein:WSGR Docket No.47612-749.601 X1is N or C-R9, wherein each R9is independently selected from the group consisting of H, - CN, halo, -C(O)-NH2, -N(Rg)(Rh), C3-10cycloalkyl, C1-6alkoxy, C6-20aryl, and C1-6alkyl, wherein the C1-6alkyl of R9is optionally substituted with one or more -OH or -N(Rg)(Rh), or R9of X1is taken together with R7, and the atoms to which they are attached, to form a 5- membered heterocyclyl or a 5-membered heteroaryl, wherein the 5-membered heterocyclyl or 5-membered heteroaryl is optionally substituted with one or more C1-6alkyl, provided that X3is CH; X2is N or C-R9, wherein each R9is independently selected from the group consisting of H, - CN, halo, -C(O)-NH2, -N(Rg)(Rh), C3-10cycloalkyl, C1-6alkoxy, C6-20aryl, and C1-6alkyl, wherein the C1-6alkyl of R9is optionally substituted with one or more -OH or -N(Rg)(Rh); X3is N or C-H, provided that when t1hen at least one of X and X2is N; R5is: (i) oxiranyl or oxetanyl, wherein the oxiranyl or oxetanyl of R5is optionally substituted with one or more C1-6alkyl, wherein the C1-6alkyl is independently optionally substituted with one or more -C(O)-NH2, and L2is absent or is selected from the group consisting of -O-, *-CH2-O-**, *-O-CH2-**, - CH=CH-, and -C≡C-, wherein ** indicates the attachment point to the R6moiety and * indicates the attachment point to the remainder of the molecule, or (ii) -N(Rg)(CN), and L2is absent or is selected from the group consisting of -O-, *-CH2-O-**, *-O-CH2-**, - CH=CH-, and -C≡C-, wherein ** indicates the attachment point to the R6moiety and * indicates the attachment point to the remainder of the molecule, or (iii), wherein Rc, Rd, and Reare each independently selected from the groupconsisting of H, halo, -CN, -OH, C1-6alkyl, C6-20aryl, 3-10 membered heterocyclyl, and 5-20 membered heteroaryl, wherein the C1-6alkyl of Rc, Rd, or Reis optionally substituted with one or more -OH, provided that at least two of Rc, Rd, and Reare H, andWSGR Docket No.47612-749.601 L2is absent or is selected from the group consisting of *-CH2-O-**, *-O-CH2-**, - CH=CH-, and -C≡C-, wherein ** indicates the attachment point to the R6moiety and * indicates the attachment point to the remainder of the molecule, or(iv), wherein Rfis selected from the group consisting of H, halo, -CN, -OH, C1-6a1ky1, C6-20aryl, 3-10 membered heterocyclyl, and 5-20 membered heteroaryl, wherein the C1-6alkyl of Rfis optionally substituted with -OH, and L2is selected from the group consisting of -O-, *-CH2-O-**, *-O-CH2-**, -CH=CH-, and -C≡C-, wherein ** indicates the attachment point to the R6moiety and * indicates the attachment point to the remainder of the molecule; R6is C1-12alkyl, C3-10cycloalkyl, 3-10 membered saturated heterocyclyl, C6-20aryl, C5-13spirocyclyl, or 5-20 membered heteroaryl, wherein: the C1-12alkyl, C3-10cycloalkyl, 3-10 membered saturated heterocyclyl, C6-20aryl, C5-13spirocyclyl, or 5-20 membered heteroaryl of R6is independently optionally substituted with one or two substituents independently selected from the group consisting of -CN, halo, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, -NO2, - N(Rg)(Rh), -O(Rg), and -SF5, provided that, when R6is C1-12alkyl, wherein the C1-12alkyl is independently optionally substituted with one or two substituents selected from the group consisting of -CN, halo, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, -NO2, - N(Rg)(Rh), and -O(Rg), then L2is -CH=CH- or -C≡C-; R7is -CN, C1-6alkyl, C1-4alkoxy, or C2-4alkenyl, wherein the C2-4alkenyl of R7is optionally substituted with -N(Rg)(Rh), or R7is taken together with R9of X1, and the atoms to which they are attached, to form a 5-membered heterocyclyl or a 5-membered heteroaryl, wherein the 5- membered heterocyclyl or 5-membered heteroaryl is optionally substituted with one or more C1-6alkyl, provided that X3is CH, or R7is taken together with the carbon atom of *-CH2-O-** of L2, and the atoms to which they are attached, to form a C6aryl or a 6-membered heteroaryl, provided that: (i) when R7is -CN, C1-6alkyl, C1-4alkoxy, or C2-4alkenyl, wherein the C2-4alkenyl is optionally substituted with -N(Rg)(Rh), andWSGR Docket No.47612-749.601R6is 3-10 membered saturated heterocyclyl or 5-20 membered heteroaryl, wherein the 3-10 membered saturated heterocyclyl or 5-20 membered heteroaryl of R6is independently optionally substituted with one or two substituents independently selected from the group consisting of -CN, halo, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, -NO2, -N(Rg)(Rh), and -O(Rg), then L2is *-CH2-O-**, -CH=CH-, or -C≡C-, wherein ** indicates the attachment point to the R6moiety and * indicates the attachment point to the remainder of the molecule, and (ii) when R7is taken together with R9of X1, and the atoms to which they are attached, to form a 5-membered heterocyclyl or a 5-membered heteroaryl, provided that X3isR6is 3-10 membered saturated heterocyclyl or 5-20 membered heteroaryl, wherein the 3-10 membered saturated heterocyclyl or 5-20 membered heteroaryl of R6is independently optionally substituted with one or two substituents independently selected from the group consisting of -CN, halo, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, -NO2, -N(Rg)(Rh), and -O(Rg), then L2is absent or is *-CH2-O-**, -CH=CH-, or -C≡C-, wherein ** indicates the attachment point to the R6moiety and * indicates the attachment point to the remainder of the molecule, and (iii) when R7is taken together with the carbon atom of *-CH2-O-** of L2, and the atoms to which they are attached, to form a C6aryl or a 6-membered heteroaryl, andthen R6is 3-10 membered saturated heterocyclyl or 5-20 membered heteroaryl, wherein the 3-10 membered saturated heterocyclyl or 5-20 membered heteroaryl is independently optionally substituted with one orWSGR Docket No.47612-749.601 two substituents independently selected from the group consisting of -CN, halo, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, -NO2, -N(Rg)(Rh), and - O(Rg); R8is H or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more -OH; and Rgand Rhare, independently of each other and independently at each occurrence, selected from the group consisting of H, -CN, -OH, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C1-6alkyl-C3-10cycloalkyl, 3-10 membered heterocyclyl, C6-20aryl, and 3-20 membered heteroaryl, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkylnyl, C3-10cycloalkyl, C1-6alkyl-C3-10cycloalkyl, 3-10 membered heterocyclyl, C6-20aryl, and 3-20 membered heteroaryl of Rgand Rhare each independently optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, oxo, - CN, halo, -NO2, and -OH.

[0065] In some embodiments of Formula (B), the R9of X1is taken together with R7, and the atoms to which they are attached, to form a 5-membered heterocyclyl or a 5-membered heteroaryl, wherein the 5-membered heterocyclyl or 5-membered heteroaryl is optionally substituted with one or more C1-6alkyl, provided that X3is CH.

[0066] In some embodiments of Formula (B), the compound is of Formula (B-I):Formula (B-I), or a pharmaceutically acceptable salt thereof.

[0067] In sonic embodiments of Formula (B), the compound is of Formula (B-I-1);Formula (B-I-1), or a pharmaceutically acceptable salt thereof.

[0068] In some embodiments of Formula (B), such as Formula (B-I) and Formula (B-I-1), R5is.WSGR Docket No.47612-749.601

[0069] In some embodiments, each of Rc, Rd, and Reis H.

[0070] In some embodiments of Formula (B), the compoundpharmaceutically acceptable salt thereof.

[0071] In some embodiments of Formula (B), the compound is of Formula (B-II):Formula (B-II), or a stereoisom.er or tautomer thereof, or a pharmaceutically acceptable salt thereof. RcRd5 Re

[0072] In some embodiments of Formula (B-II), R is. In some embodiments, each ofRc, Rd, and Reis H.

[0073] In some embodiments of Formula (B), the compoundpharmaceutically acceptable salt thereof.

[0074] In some embodiments, in conjunction with embodiments above or below, the YAP / TAZ- TEAD inhibitors comprise a compound of Formula (B), (B-I), or (B-II), or a pharmaceutically acceptable salt thereof. Description of Formulae (B), (B-I), and (B-II) can be found in WO2021 / 097110A1, the entirety of which is incorporated herein by reference. Formulae (B), (B-I), and (B-II) are described as Formulae (B-1), (IA), and (IF), respectively, in WO2021 / 097110A I (see, e.g., paragraphs

[0054] ,

[0067] , and

[0087] ), which paragraphs and description of Formula (B- 1), (IA), or (IF), and methods of making compounds of Formula (B-1), (IA), or (IF), are hereby incorporated herein by reference. Moieties of Formula (B), (B-I), or (B-II), such as R5, R6, R7, R8, X1, X2, X3, and L2are as defined in WO2021 / 097110A1 including any variations or embodiments thereof. X1, X2, X3, R5, R6, R7, R8, R9, L2, Rc, Rd, Re, Rf, Rg, and Rhof Formulae (B), (B-I), and (B- II) correspond to the moieties X1, X2, X3, R5, R6, R7, R8, R5, L, Ra, Rb, Rc, Rd, Re, and Rf, respectively, in WO2021 / 097110A1.WSGR Docket No.47612-749.601

[0075] In some embodiments, in conjunction with embodiments above or below, a compound of Formula (B), (B-I), or (B-II) is Compound 2, or a pharmaceutically acceptable salt thereof. Compound 2 is chemically described N-(7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5- yl)acrylamide, having the structure below:Compound 2.

[0076] Description of Compound 2 and methods of making Compound 2 can be found in, e.g., Compound 33 on page 73 and Example 33 on pages 245-246 of WO2021 / 097110A1.

[0077] In some embodiments, in conjunction with embodiments above or below, a compound of Formula (B), (B-I), or (B-II) is Compound 3, or a pharmaceutically acceptable salt thereof. Compound 3 is chemically described N-(6-methoxy-5-((E)-2-((1r,4r)-4- (trifluommethyl)cyclohexyl)vinyl)pyridin-3-yl)acrylamide, having the structure below:Compound 3.

[0078] Description of Compound 3 and methods of making Compound 3 can be found in, e.g., Compound 2 on page 68 and Example 2 on page 192 of WO2021 / 097110A1.

[0079] In some aspects, the present disclosure provides a compound of Formula (C):Formula (C),or a pharmaceutically acceptable salt thereof, wherein: X4is N or C-R14, wherein each R".is independently selected from the group consisting of H, - CN, halo, -C(O)-NH2, -N(Rm)(Rn), C3-10cycloalkyl, C1-6alkoxy, C6-20aryl, and C1-6alkyl, wherein the C1-6alkyl of R14is optionally substituted with one or more -OH or -N(Rm)(Rn), or the R14of X4is taken together with R12, and the atoms to which they are attached, to form a 5- membered heterocyclyl or a 5-membered heteroaryl, wherein the 5-membered heterocyclyl or 5-membered heteroaryl is optionally substituted with one or more C1-6alkyl;WSGR Docket No.47612-749.601 X5is N or C-R14, wherein each R14is independently selected from the group consisting of H, - CN, halo, -C(O)-NH2, -N(Rm)(Rn), C3-10cydoalkyl, C1-6alkoxy, C6-20alyl, and C1-6alkyl, wherein the C1-6alkyl of R14is optionally substituted with one or more -OH or - N(Rm)(Rn); X6is N or C-H; R10is: (i) a 3-5 membered saturated heterocyclyl comprising at least one annular oxygen atom, wherein the 3-5 membered saturated heterocyclyl is optionally substituted with one or more C1-6alkyl, or (ii) -N(Rm)(Rn), or (iii), wherein Ri, Rj, and Rkare each independently selected from the groupconsisting of H, halo, -CN, -OH, -B(OH)2, -C(O)-OH, -C(O)-N(Rm)(Rn), -C(O)-C1-6alkoxy, -C(O)-C1-6alkyl, C1-6alkyl, C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, C5-13spirocyclyl, and 5-20 membered heteroaryl, wherein the C1-6alkyl of Ri, Rj, or Rkis optionally substituted with one or more -OH, or (iv), wherein Rtis selected from the group consisting of H, halo, -CN, -OH, -B(OH)2, -C(O)-OH, -C(O)-N(Rm)(Rn), -C(O)-C1-6alkoxy, -C(O)-C1-6alkyl, C1-6alkyl, C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, C5-13spirocyclyl, and 5-20 membered heteroaryl, wherein. the C1-6alkyl is optionally substituted with one or more -OH; L3is absent or is selected from the group consisting of -O-, *-CH2-O-**, -CH=CH-, and - C≡C-, wherein ** indicates the attachment point to the R11moiety and * indicates the attachment point to the remainder of the molecule; R11is C1-12alkyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, C5-13spirocyclyl, C6-20aryl, or 5-20 membered heteroaryl, wherein the C1-12alkyl, C3-10cycloalkyl, 3-10 membered saturated heterocyclyl, C5- 13spirocyclyl, C6-20aryl, or 5-20 membered heteroaryl of R11is independently optionally substituted with one or more substituents selected from the group consisting of -CN, halo, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, -NO2, -N(Rm)(Rn), and -O(Rm),WSGR Docket No.47612-749.601 provided that, when R11is C1-12alkyl, wherein the C1-12alkyl of R11is independently optionally substituted with one or more substituents selected from the group consisting of -CN, halo, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, -NO2, -N(Rm)(Rn), and -O(Rm), then L3is -CH=CH- or -C≡C-; R12is -CN, C1-6alkyl, C1-4alkoxy, or C2-4alkenyl, wherein the C2-4alkenyl is optionally substituted with -N(Rm)(Rn), or R12is taken together with R14of X4, and the atoms to which they are attached, to form a 5- membered heterocyclyl or a 5-membered heteroaryl, wherein the 5-membered heterocyclyl or 5-membered heteroaryl is optionally substituted with one or more C1-6alkyl, or R12is taken together with the carbon atom of *-CH2-O-** of L3, and the atoms to which they are attached, to form a C6aryl or a 6-membered heteroaryl; R13is H or C1-6alkyl, wherein the C1-6alkyl of R13is optionally substituted with one or more OH; and Rmand Rnare, independently of each other and independently at each occurrence, selected from the group consisting of H, -CN, -OH, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -C1-6alkyl-C3-10cycloalkyl, 3-10 membered heterocyclyl, C5-13spirocyclyl, C6-20aryl, and 5-20 membered heteroaryl, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C1-6alkyl-C3-10cycloalkyl, 3-10 membered heterocyclyl, C5-13spirocyclyl, C6-20aryl, and 5-20 membered heteroaryl of Rmand Rnare each independently optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, oxo, -CN, halo, -NO2, and -OH.

[0080] In some embodiments of Formula (C), the R14of X4is taken together with R12, and the atoms to which they are attached, to form a 5-membered heterocyclyl or a 5-membered heteroaryl, wherein the 5-membered heterocyclyl or 5-membered heteroaryl is optionally substituted with one or more C1-6alkyl.

[0081] In some embodiments of Formula (C), the compound is of Formula (C-I):Formula (C-I),or a pharmaceutically acceptable salt thereof.

[0082] In some embodiments, L3is absent. In some embodiments of Formula (III-A), the compound is of Formula (C-I-l):WSGR Docket No.47612-749.601Formula (C-I-l),or a pharmaceutically acceptable salt thereof.

[0083] In some embodiments of Formula (C), such as a compound of Formula (C-I-l) or Formula ijsome embodiments, R and R areboth H, and Rkis -C(O)OH.

[0084] In some embodiments of Formula (C), such as a compound of Formula (C-I-1) or Formula (C-I-2), R11is C6-20aryl, wherein the C6-20aryl of R11is independently optionally substituted with one or more substituents selected from the group consisting of -CN, halo, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, -NO2, -N(Rm)(Rn), and -O(Rm). In some embodiments, R11is C6-20aryl, wherein the C6-20aryl of R11is independently optionally substituted with one or more C1-6alkyl. In some embodiments. R11is .

[0085] In some embodiments of Formula (C), the compoundor a pharmaceutically acceptable salt thereof.

[0086] In some embodiments, in conjunction with embodiments above or below, a compound of Formula (C), (C-I), or (C-I-1) is Compound 4, or a pharmaceutically acceptable salt thereof, Compound 4 is chemically described as 2-(((4-cyano-7-(4-isopropylpheny1)-2,3- dihydrobenzofuran-5-yl)amino)methyl)acrylic acid, having the structure below:Compound 4.WSGR Docket No.47612-749.601

[0087] Description of Compound 4 and methods of making Compound 4 can be found in, e.g., Compound 3 on page 48 and Example 3 on pages 164-165 of WO2022 / 020716.

[0088] In some aspects, the present disclosure provides a compound of Formula (D):Formula (D) wherein, [A] is a ligase ligand; [B] is a linker moiety; X1, X2, and X3are each independently N or C-R5, wherein each R5is independently selected from the group consisting of H, halo, cyano, C1-12alkyl,O-C1-12alkyl, and C1-12haloalkyl; L1is a bond or is -C≡C-, -CH=CH-, or -(CH2)m-, wherein m is 1-6; R1is H, C1-12alkyl, C3-10cycloalkyl, C1-12alkyl-C3-10cycloalkyl, C1-12haloalkyl, O-C1-12alkyl, O-C3-10cycloalkyl, O-C1-12alkyl-C3-10cycloalkyl, or O-C1-12haloalkyl; and R2is H, C3-10cycloalkyl, C1-12alkyl-C3-10cycloalkyl, 3-10 membered heterocyclyl, C6-20aryl, 5-20 membered heteroaryl, or C5-13spirocyclyl, wherein: C3-10cycloalkyl, C1-12alkyl-C3-10cycloalkyl, 3-10 membered heterocyclyl, C6-20aryl, 5-20 membered heteroaryl, or C5-13spirocycly1 of R2is independently optionally substituted with one or more oxo, cyano, halo, C1-12alkyl, C1-12haloalkyl, C3-10cycloalkyl, C6-20aryl, NO2, N(Rx)(RY), and O(Rx), wherein: each Rxand RYis independently selected from. the group consisting of H, C1-12alkyl, C2-12alkenyl, C2-12alkylnyl, C3-10cycloalkyl, C1-12alkyl-C3-10cycloalkyl, 3-10 membered heterocyclyl, C6-20aryl and 5-20 membered heteroaryl, wherein: each C1-12alkyl, C2-12alkenyl, C2-12alkylnyl, C3-10cycloalkyl, C1-12alkyl-C3-10cycloalkyl, 3-10 membered heterocyclyl, C6-20aryl and 5-20 membered heteroaryl of Rxand Ryis independently optionally substituted with one or more oxo, cyano, halo, NO2, NH2, hydroxy, C1-12alkyl, C1-12haloalkyl, or O-C1-12alkyl; or a pharmaceutically acceptable salt thereof.

[0089] Description of Formula (D) can be found in WO2021 / 178339A1, the entirety of which is incorporated herein by reference. Formula (D) is described as Formula (I) in WO2021 / 178339A (see, e.g., paragraphs

[0057] and

[0058] ), which paragraphs and description of Formula (I), and methods of making compounds of Formula (I) are hereby incorporated herein by reference.WSGR Docket No.47612-749.601 Moieties of Formula (D), such as A, B, R1, R2, X1, X2, X3, and L1are as defined in WO2021 / 178339A1, including any variations or embodiments thereof.

[0090] In some embodiments, in conjunction with embodiments above or below, the YAP / TAZ- TEAD inhibitors comprise a compound of Formula (D-I), (D-II), (D-III), (D-IV), (D-V), or (D-VI):wherein: * of the linker moiety denotes the point of attachment to the ligase ligand and ** of the linker moiety denotes the point of attachment to the remainder of the molecule; L2is -(CH2)n- or -(CH2CH2O)n-, wherein n is 1-12; L3is a bond wher3ein # of L denotes the point of attachment to L2and * of L3denotes the point of attachment to the ligase ligand; andWSGR Docket No.47612-749.601 each of R3aand R3bis independently H, C1-12alkyl, C2-12alkenyl, C2-12alkynyl, C3-10cycloalkyl, C1-12alkyl-C3-10cycloalkyl, C1-12alkyl-C6-20alyl, 3-10 membered heterocyclyl, C6-20aryl, or 5-20 membered heteroaryl, wherein: each C1-12alkyl, C2-12alkenyl, C2-12alkynyl, C3-10cycloalkyl, C1-12alkyl-C3-10cycloalicyl, C1-12alkyl-C6-20aryl, 3-10 membered heterocyclyl, C6-20aryl, or 5-20 membered heteroaryl is independently optionally substituted with at least one of oxo, CN, C1-12alkyl, C1-12haloalkyl, halo, NO2, N(Re)(Rf), C1-12alkyl-C(O)-N(Re)(Rf), and ORe, wherein: each Reand Rfis independently selected from the group consisting of H, C1-12alkyl, C2-12alkenyl, C2-12alkynyl, C3-10cycloalkyl, C1-12alkyl-C3-10cycloalkyl, 3-10 membered heterocyclyl, C6-20aryl, and 5-20 membered heteroaryl, wherein each C1-12alkyl, C2-12alkenyl, C2-12alkynyl, C3-10cycloalkyl, C1-12alkyl-C3-10cycloalkyl, 3-10 membered heterocyclyl, C6-20aryl, or 5-20 membered heteroaryl is independently optionally substituted with one or more oxo, CN, C1-12alkyl, C1-12haloalkyl, halo, NO2, O-O1-12alkyl, or OH; one of Q1and Q2is C=O, and the other of Q1and Q2is C=O or CH2; one of Ra, Rb, Rc, and Rdis thebond to L3of the linker moiety, and the others of Ra, Rb, Rc, and Rdare each independently H, halo, C1-12alkyl, C1-12haloalkyl, or O-C1-12alkyl; and Reis H, halo, C1-12alkyl, C1-12haloalkyl, O-C1-12alkyl, or phenyl, or a pharmaceutically acceptable salt thereof, wherein [A], [B], X1, X2, X3, L1, R1, and R2are as defined in Formula (D). It is understood that [A], [B], X1, X2, X3, L1, R1, and R2of such embodiments of compound of Formulae (D-I), (D-II), (D-III), (D-IV), (D-V), and (D- VI) may include [A], [B], X1, X2, X3, L1, R1, and R2as descried for Formula (D).

[0091] Formulae (D-I), (D-II), (D-III), (D-IV), (D-V), and (D-VI) are described as Formulae (XII), (XIII), (II), (III), (IV), and (V), respectively, in WO2021 / 178339A1 (see, e.g., paragraphs

[0059] -

[0064] , and

[0119] -

[0121] ), which paragraphs and description of Formula (XII), (XIII), (II), (III), (IV), or (V), and methods of making compounds of Formula (XII), (XIII), (II), (III), (IV), or (V) are hereby incorporated herein by reference. Moieties of Formula (D-I), (D-II), (D-III), (D-IV), (D- V), or (D-VI), such as A, B, Ra, Rb, Rc, Rd, Re, R3a, R3b, R1, R2, X1, X2, X3, Q1, Q2, L1, L2, and L3are as defined in WO2021 / 178339A1, including any variations or embodiments thereof.

[0092] In some embodiments, in conjunction with embodiments above or below, a compound of Formula (D), (D-I), (D-II), (D-III), (D-IV), (D-V), or (D-VI) is Compound 5, or a pharmaceutically acceptable salt thereof. Compound 5 is chemically described as N-[[3-[2-[2-[2-[2-[2-[2-[2-(2,6-WSGR Docket No.47612-749.601 dioxo-3-piperidy1)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethyl-methyl- amino]-2-oxo-ethyl]phenyl]methyll-5-methoxy-4-[rac-(E)-2-[4- (trifluoromethyl)cyclohexyl]vinyl]pyridine-2-carboxamide, having the structure below:Compound 5.

[0093] Description of Compound 5 and methods of making Compound 5 can be found in, e.g., Table 1 on page 51 and Example 4 on pages 123-126 of WO2021 / 178339A1.

[0094] In some aspects, the present disclosure provides a compound of Formula (E):Formula (E) wherein, each X1, X4, X5, and X6, is 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 C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C2-C4alkenyl, substituted or unsubstituted C2-C4alkylnyl, substituted or unsubstituted C1- C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, 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 C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C2-C4alkenyl, substituted or unsubstituted C2-C4alkynyl, substituted or unsubstituted C1-WSGR Docket No.47612-749.601 C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R is halogen, nitro, -CN, -OR3, -SR3, -C(=O)R3, -C(=0)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-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, 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 C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-Clocycloalkyl, substituted or unsubstituted C2- C10heterocycloalkyl, 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-C10heterocycloalkyl, 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- C7heterocycloalkyl; 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; or a pharmaceutically acceptable salt thereof.

[0095] Description of Formula (E) can be found in US2020 / 0347009A1, the entirety of which is incorporated herein by reference. Formula (E) is described as Formula (I) in US2020 / 0347009A1. (see, e.g., paragraphs

[0099] -

[0110] ), which paragraphs and description of Formula (I), and methods of making compounds of Formula (I) are hereby incorporated herein by reference. Moieties of Formula (E), such as R1, R2, X1, X2, X3, X4, X5, X6, and n are as defined in US2020 / 0347009A1, including any variations or embodiments thereof.WSGR Docket No.47612-749.601

[0096] In some embodiments, in conjunction with embodiments above or below, a compound of Formula (E) is Compound 6, or a pharmaceutically acceptable salt thereof. Compound 6 is chemically described as N-[(1R)-1-(6-amino-2-pyridyl)ethyl]-5-[4- (trifluoromethyl)phenoxy]naphthalene-2-carboxamide, having the structure below:Compound 6.

[0097] Description of Compound 6 and methods of making Compound 6 can be found in, e.g., Compound 66 on page 46 and Example 55 on pages 112-115 of US2020 / 0347009A1.

[0098] In some aspects, the present disclosure provides a compound of Formula (F):wherein, each X1and X2is independently N, NRX, C(=O), or CRX; each X3and X4is independently N, NRX, C(=O), or CRX; or if both X3and X4are each independently NRXor CRX, then the two RXare taken together with the intervening atoms to which they are attached to form a 5-membered heterocyclic ring; each RXis independently hydrogen, halogen, nitro, oxo, thioxo, imino, oximo, -OR3, - SR3, -CN, -C(=O)R2, -S(=O)R3, -S(=O)2R3, -N(R3)2, -NR3S(=O)2R3, -NR3C(=O)R3, - NR3C(=O)OR3, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C2-C4alkertyl, substituted or unsubstituted C2-C4alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;WSGR Docket No.47612-749.601 R1is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C2-C4alkenyl, substituted or unsubstituted C2-C4alkynyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2- C10heterocycloalkyl, substituted or unsubstituted C1-C6heteroalkyl, or -S(=O)2R4; each R2is independently -N3, -CN, -OR3, -S(=O)2R3, -N(R3)2, -C(=O)OR3, substituted or unsubstituted C1-C6alkyl;substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, 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-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2- C10heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R4is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C10cycloalkyl, or -NH2; each --- is independently a single or double bond; and n is 0.1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof.

[0099] Description of Formula (F) can be found in WO2020 / 097389A1, the entirety of which is incorporated herein by reference. Formula (F) is described as Formula (I) in WO2020 / 097389A1 (see, e.g., paragraphs

[0070] -

[0082] ), which paragraphs and description of Formula (I), and methods of making compounds of Formula (I) are hereby incorporated herein by reference. Moieties of Formula (F), such as R1, R2, X1, X2, X3, X4, and n are as defined in WO2020 / 097389A1, including any variations or embodiments thereof.

[0100] In some embodiments, in conjunction with embodiments above or below, the present disclosure provides a compound of Formula (F-I):Formula (F-I) wherein,WSGR Docket No.47612-749.601 each Rxis independently hydrogen, halogen, -OH, -NH2, -CH3, -CH2CH3, cyclopropyl, -CF3, -OCH3, -OCH2CH3, cyclopropyloxy, or -OCF3; R1is substituted or unsubstituted C1-C6alkyl, wherein if C1-C6alkyl is substituted, then it is substituted with 1 or 2 substituents each independently selected from -OH, - NH2, azetidinyl, pyridyl, and aminopyridyl; R2is F; R5is -CF3; and n is 0 or 1; or a pharmaceutically acceptable salt thereof.

[0101] Formula (F-I) is described as Formula (Ia) in (see, e.g., paragraphs

[0082] -

[0089] of WO2020 / 097389A1, which paragraphs and description of Formula (Ia), and methods of making compounds of Formula (Ia) are hereby incorporated herein by reference. Moieties of Formula (F-I), such as R1R2, R5, RX, and n are as defined in WO2020 / 097389A.1, including any variations or embodiments thereof.

[0102] In some embodiments, in conjunction with embodiments above or below, a compound of Formula (F) or (F-I) is Compound 7, or a pharmaceutically acceptable salt thereof. Compound 7 is chemically described as N-[(1S)-1-(2-pyridyl)ethy1]-5-[4-(trifluoromethyl)phenyl]naphthalene-2- carboxamide, having the structure below:Compound 7

[0103] Description of Compound 7 and methods of making Compound 7 can be found in, e.g., Compound 90 on page 65 and Example 84 on pages 195-196 of WO2020 / 097389A1.

[0104] In some aspects, the present disclosure provides a compound of Formula (G):nFormula (G) wherein,WSGR Docket No.47612-749.601is a substituted or unsubstituted monocyclic 5-memberedheterocyclic containing at least one N atom or a substituted or unsubstituted monocyclic 6-membered heteroaryl ring containing at least one N atom; each RZis independently H, halogen, -CN, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1- C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -L1-Y1or -L2-L3-Y2; m is 0, 1, 2, 3, 4, or 5; L1is substituted or unsubstituted C1-C6alkylene, substituted or unsubstituted C2- C10cyclolkylene, or substituted or unsubstituted C2-C10heterocycloalkylene; Y1is substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; L2is absent, substituted or unsubstituted C1-C6alkylene, substituted or unsubstituted C2- C10cyclolkylene, or substituted or unsubstituted C2-C10heterocycloalkylene; L3is -O-, -S-. -(S=0)-, -(SO2)-, -NR3-, -(C=O)-, -(C=O)O-, -O(C=O)-, -(C=O)NR3-, - (C=O)NR3-O-, -O-NR3(C=O)-, -NR3(C=O)-, -NR3(C=O)NR3-O(C=O)NR3-, - NR3(C=O)O-, -NR3(SO2)NR3-, -NR3(SO2)-, -(SO2)NR3-, -(SO2)NR3-(C=O)-, - (C=O)-NR3(SO2)-, -(SO2)NR3-(C=O)O-, -O(C=O)-NR3(SO2)-, -NR3(SO2)NR3- (C=O)-, -(C=O)-NR3(SO2)NR3-, -O(C=O)-NR3(SO2)-NR3-, or -NR3(SO2)NR3- (C=O)O-; each R3is independently H or substituted or unsubstituted C1-C6alkyl; Y2is H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1- C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2- C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R3and Y2on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle; R is NHR1or R1;WSGR Docket No.47612-749.601 R1is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1- C6haJoalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2- C10heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;is substituted or unsubstituted phenyl or substituted or unsubstitutedcyclohexyl; each R2is independently H, halogen, -N3, -CN, -OR4, -SR4, -(SO2)R4, -N(R4)2, -CO2R4, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1- C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2- C10heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or N N unsubstituted aryl, substituted or unsubstituted heteroaryl, or;n is 0, 1, 2, 3, 4, or 5; and each R4is independently H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2- C10heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or a pharmaceutically acceptable salt thereof.

[0105] Description of Formula (G) can be found in US2020 / 0354325A1, the entirety of which is incorporated herein by reference. Formula (G) is described as Formula (I) in US2020 / 03543525A1 (see, e.g., paragraphs

[0129] -

[0149] ), which paragraphs and description of Formula (I), and methods of making compounds of Formula (I) are hereby incorporated herein by reference. Moieties of Formula (G), such as A, Z, R, RZ, R2, m, and n are as defined in US2020 / 03543525A1, including any variations or embodiments thereof.

[0106] In some embodiments, in conjunction with embodiments above or below, the present disclosure provides a compound of Formula (G-I) or (G-II):WSGR Docket No.47612-749.601,or a pharmaceutically acceptable salt thereof, wherein Z, R, RZ, R2, n, and m are as defined in Formula (G). It is understood that Z, R, RZ, R2, n, and m of such embodiments of compounds of Formulae (G-I) and (G-II) may include Z, R, Rz, R2, n, and m as described for Formula (G).

[0107] Formulae (G-I) and (G-II) are described as Formulae (Id) and (Ie), respectively, in, e.g., paragraphs

[0194] and

[0195] of US2020 / 0354325A1, which paragraphs and description of Formula (Id) or (Ie), and methods of making compounds of Formula (Id) or (Ie) are hereby incorporated herein by reference. Moieties of Formula (G-I) or (G-II), such as Z, R, RZ, R2, m, and n are as defined in US2020 / 0354325A1, including any variations or embodiments thereof.

[0108] In some embodiments, in conjunction with embodiments above or below, a compound of Formula (G), (G-I), or (G-II) is Compound 8, or a pharmaceutically acceptable salt thereof. Compound 8 is chemically described as N-methyl-3-(1-methylimidazol-4-yl)-4-[4- (trifluoromethyl)anilino]benzenesulfonamide, having the structure below:Compound 8

[0109] Description of Compound 8 and methods of making Compound 8 can be found in, e.g., Compound 121 on page 55 and Example 113 on pages 157-158 of US2020 / 0354325A1.WSGR Docket No.47612-749.601

[0110] In some aspects, the present disclosure provides a compound of Formula (H):Formula (H) wherein, ring A represents a five-membered heteroaromatic ring selected from the group consisting of the following ring moieties:A-32, andA-32, wherein RA1represents H, D, C1-6aliphatic, -CH2-ArA1or -CH2-CH2-ArA1; RA2represents H, D. halogen, C1-6aliphatic, -CH2-ArA2or -CH2-CH2-ArA2; RA3represents H, D, C1-6aliphatic, -CH2-ArA3or -CH2-CH2-ArA3; Z1is CRZ1or N; Z2is CRZ2or N;WSGR Docket No.47612-749.601 Z3is CRZ3or N; wherein at least two of Z1, Z2, and Z3are not N; R1represents Ar1, Hetarl, Cyc1, Hetcyc1, L1-Hetar1, L2-Cyc1, L2-Hetcycl, unsubstituted or substituted, straight-chain or branched C1-8aliphatic; R2represents -C(=O)-OR2a, -C(=O)-NR2bR2c, -(CH2)w-C(=O)-NR2bR2c, -(CH2)X-NR2d-C(=O)- R2e, -S-R2f, -S(=O)-R2f, -S(=O)2-R2g, -S(=O)2-NR2hR2i, -S(=O)2-OH, -S(=O)(=NR2i)-OH, - S(=O)(=NR2j)-R2g, S(=O)(=NR2k)-NR21R2m, F, Cl, Br, I, -CN, -(CH2)v-CN, - P(=O)(OR2O)(OR2P), -(CH2)y-NR2qR2r, -(CH2)z-NR2d-S(=O)2-R2g, -C(=O)-N=S(=O)- R2SR2t, -C(=O)-N=S(=N-R2u)-R2SR2t, -B(OH)2, or Hetcycx; ArA1, ArA2, and ArA3represent independently from each other phenyl which may be unsubstituted or mono- or di-substituted with independently from each other RA11or RA12: RZ1represents H or halogen; RZ2represents H or halogen; or forms together with R2a divalent radical -S(=O)2-N(H)- C(=O)-; RZ3represents H or halogen; R2arepresents H, un-substituted or substituted C1-8aliphatic, aryl, heteroaryl, saturated or partially unsaturated heterocyclyl, or carbohydrate derived radical, or Cat; Cat represents a monovalent cation; R2b, R2c, R2q, and R2rrepresent independently from each other H, unsubstituted or substituted C1-8aliphatic including C3-7cycloaliphatic; or form together with the nitrogen atom to which they are attached to an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle with 3, 4, 5, 6, or 7 ring atoms, wherein 1 of said ring atoms is said nitrogen atom and no or one further ring atom is a hetero atom selected from N, O, or S and the remaining are carbon atoms; wherein said heterocycle may optionally be fused with HetarZ; or one of R2band R2crepresents -CN, -NH2, -OH, -O-C1-6alkyl, -S(=O)2-R2g, Ar2, Hetar2, Cyc2, or Hetcyc2, while the other represents H or unsubstituted or substituted C1-8aliphatic; R2d, R2j, R2k, R2O, and R2prepresent independently from each other H, unsubstituted or substituted C1-8aliphatic; R2erepresents H, halogen, unsubstituted or substituted C1-8aliphatic or heteroaryl; R2fand R2grepresent independently from each other unsubstituted of substituted C1-8aliphatic; R2hand R2irepresent independently from each other H, un-substituted or substituted C1-8aliphatic, aryl, heterocyclyl, heteroaryl; or form together with the nitrogen atom to which they are attached to an unsubstituted or substituted saturated, partially unsaturated orWSGR Docket No.47612-749.601 aromatic heterocycle with 3, 4, 5, 6, or 7 ring atoms, wherein 1 of said ring atoms is said nitrogen atom and no or one further ring atom is a hetero atom selected from N, O, or S and the remaining are carbon atoms; R2land R2mrepresent independently from each other H, unsubstituted or substituted C1-8aliphatic; or form together with the nitrogen atom to which they are attached to an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle with 3, 4, 5, 6, or 7 ring atoms, wherein 1 of said ring atoms is said nitrogen atom and no or one further ring atom is a hetero atom selected from N, O, or S and the remaining are carbon atoms; R2Sand R2trepresent independently from each other unsubstituted or substituted C1-8aliphatic; or form together an unsubstituted or substituted divalent C3-6alkylene radical; R2urepresents hydrogen or unsubstituted or substituted C1-6aliphatic; Ar1is a mono-, bi-, or tricyclic aryl with 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring carbon atoms, wherein that aryl may be unsubstituted or substituted with substituents RB1, RB2, RB3, RB4,different; Hetar1is a mono-, bi-, or tricyclic heteroaryl with 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, wherein 1, 2, 3, 4, or 5 of said ring atoms is / are a hetero atom(s) selected from N, O, or S and the remaining are carbon atoms, wherein that heteroaryl may be unsubstituted or substituted with substituents RB1, RB2, RB3, RB4, RB5, RB6, or RB7which may be the same or different; Cyc1is a saturated or partially unsaturated, mono-, bi-, or tricyclic carbocycle with 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ring carbon atoms, wherein that carbocycle may be unsubstituted or substituted with RB8, RB9, RB10, RB11, RB12, or RB13which may be the same or different; and wherein that carbocycle may optionally be fused to ArXvia 2 adjacent ring atoms of said ArXand wherein that fused carbocycle may further be unsubstituted or substituted with RC1, RC2, RC3, RC4, RC5, or RC6which may be the same or different; Hetcyc1is a saturated or partially unsaturated, mono-, bi-, or tricyclic heterocycle with 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ring atoms, wherein 1, 2, 3, 4, or 5 of said ring atoms is / are a hetero atom(s) selected from N, O, or S and the remaining are carbon atoms, wherein that heterocycle may be unsubstituted or substituted with RB8, RB9, RB10, RB11, RB12, or RB13which may be the same or different; L1is a divalent radical selected from the group consisting of -S(=O)2-, -C(=O)-, un- substituted or substituted, straight-chain or branched C1-6alkylene or C2-6alkenylene, inWSGR Docket No.47612-749.601 both of which one of the carbon units of the alkylene or alkenylene chain may be replaced by -O-; L2is a divalent radical selected from the group consisting of unsubstituted or substituted, straight-chain or branched C1-6alkylene or C2-6alkenylene, in both of which one of the carbon units of the alkylene or alkenylene chain may be replaced by -O-; RA11and RA12represent independently from each other halogen or unsubstituted or substituted, straight-chain or branched C1-6aliphatic; RB1, RB2, RB3, RB4, RB5, RB6, and RB7represent independently from each other un-substituted or substituted, straight-chain or branched C1-6aliphatic, C1-6aliphatoxy, -S-C1-6aliphatic; halogen, -CN, -S(=O)-Rb1, S(=O)2-Rbl, -NRb2NRb3, Ar2, -CH2-Ar2, Hetar2, Cyc2, Hetcyc2; or two adjacent RB1, RB2, RB3, RB4, RB5, RB6, or RB7form together a divalent -C2-4alkylene radical in which one of the alkylene carbon units may be replaced by a carbonyl unit (- C(=O)-), or a divalent -O-C1-3alkylene radical or a divalent -O-C1-3alkylene-O-radical; Rb1represents unsubstituted or substituted C1-8aliphatic; Rb2and Rb3represent independently from each other H, unsubstituted or substituted C1-8aliphatic; or form together with the nitrogen atom to which they are attached to an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle with 3, 4, 5, 6, or 7 ring atoms, wherein 1 of said ring atoms is said nitrogen atom and no or one further ring atom is a hetero atom selected from N, O, or S and the remaining are carbon atoms; RB8, RB9, RB10, RB11, RB12, and RB13represent independently from each other halogen, un- substituted or substituted C1-6aliphatic, C1-6aliphatoxy, ArY; or two of RB8, RB9, RB10, RB11, RB12, and RB13which are attached to the same carbon atom of said carbocycle or said heterocycle form a divalent oxo (=O) group; or two of RB8, RB9, RB10, RB11, RB12, and RB13or four of RB8, RB9, RB10, RB11, RB12, and RB13which are attached to the same sulfur atom of said heterocycle form a divalent oxo (=O) group thereby forming either an -S(=O)- or an -S(=O)2- moiety; Ar2is a mono- or bicyclic aryl with 5, 6, 7, 8, 9, or 10 ring carbon atoms, wherein that aryl may be unsubstituted or substituted with substituents RD1, RD2, RD3, RD4, or RD5which may be the same or different; Hetar2is a mono- or bicyclic heteroaryl with 5, 6, 7, 8, 9, or 10 ring atoms, wherein 1, 2, 3, 4, or 5 of said ring atoms is / are a hetero atom(s) selected from N, O, or S and the remaining are carbon atoms, wherein that heteroaryl may be unsubstituted or substituted with substituents RD1, RD2, RD3, RD4, or RD5which may be the same or different;WSGR Docket No.47612-749.601 Cyc2is a saturated or partially unsaturated monocyclic carbocycle with 3, 4, 5, 6, or 7 ring carbon atoms, wherein that carbocycle may be unsubstituted or substituted with RD6, RD7, RD8, RD9, or RD10which may be the same or different; wherein that carbocycle may optionally be fused to Arzor Hetarzvia 2 adjacent ring atoms of said Arzor Hetarzand wherein that fused carbocycle may further be unsubstituted or substituted with RC1, RC2,different; Hetcyc2is a saturated or partially unsaturated, monocyclic heterocycle with 3, 4, 5, 6, or 7 ring atoms, wherein 1 or 2 of said ring atoms is / are a hetero atom(s) selected from N, O, or S and the remaining are carbon atoms, wherein that heterocycle may be unsubstituted or substituted with RD6, RD7, RD8, RD9, or RD10which may be the same or different; wherein that heterocycle may optionally be fused to ArZor HetarZvia 2 adjacent ring atoms of said ArZor HetarZand wherein that fused heterocycle may further be unsubstituted or substituted with RC1, RC2, RC3, RC4, RC5, or RC6which may be the same or different; ArXand ArZare independently from each other an unsubstituted or substituted benzo ring; ArYis an unsubstituted or mono- or di-substituted phenyl; HetarY1is a 5 or 6 membered monocyclic heteroaryl wherein 1, 2, 3, or 4 ring atoms are hetero atoms selected from N, O, or S and the remaining are carbon atoms, wherein that heteroaryl may be unsubstituted or substituted with halogen, C1-4alicyl which may optionally be substituted with OH; HetarZis an unsubstituted or substituted 5 or 6 membered heteroaryl ring selected from the group consisting of pyrrole;furan, thiophene, pyrazole;imidazole, oxazole, isoxazole, thiazole, oxadiazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, and pyran; CycY1is a saturated monocyclic carbocycle with 3, 4, 5, 6, or 7 ring carbon atoms, wherein that carbocycle may be unsubstituted or substituted with halogen, OH, or C1-4alkyl; HetcycXis a saturated, partially unsaturated or aromatic, monocyclic heterocycle with 3, 4, 5, 6, or 7 ring atoms, wherein 1, 2, 3, or 4 of said ring atoms is / are a hetero atom(s) selected from N, O, or S and the remaining are carbon atoms, wherein said heterocycle may be unsubstituted or substituted RX1, RX2, RX3, RX4, RX5, RX6, RX7, or RX8which may be the same or different, and wherein that heterocycle is optionally a carboxylic acid bioisostere; HetcycYis a saturated, partially unsaturated or aromatic, monocyclic heterocycle with 3, 4, 5, 6, or 7 ring atoms, wherein 1, 2, 3, or 4 of said ring atoms is / are a hetero atom(s) selected from N, O, or S and the remaining are carbon atoms;WSGR Docket No.47612-749.601 HetcycY1is a saturated or partially unsaturated monocyclic heterocycle with 5 or 6 ring atoms, wherein 1 or 2 of said ring atoms are heteroatoms selected from N, O, or S and the remaining are carbon atoms; RC1, RC2, RC3, RC4, RC5, and RC6represent independently from each other unsubstituted or substituted C1-6aliphatic; RD1, RD2, RD3, RD4, and RD5represent independently from each other unsubstituted or substituted C1-6aliphatic; RD6, RD7, RD8, RD9, and RD10represent independently from each other unsubstituted or substituted C1-6aliphatic, unsubstituted or substituted C1-6aliphatoxy, halogen, hydroxy; HetarY1, CH2-HetarY1, CycY1, HetcycY1-CH2-HetcycY1; or two of RD6, RD7, RD8, RD9, and RD10which are attached to the same ring atom of said carbocycle or heterocycle may form a divalent C2-6alkylene radical, wherein one or two non-adjacent carbon units of said alkylene radical may optionally be replaced by independently from each other O, N-H, or N-C1-4alkyl, and wherein that alkylene radical may optionally be substituted with OH, C1-4alkyl or -O-C1-4alkyl; or two of RD6, RD7, RD8, RD9, and RD10which are attached to different ring atoms of said carbocycle or heterocycle may form a divalent C1-6alkylene radical, wherein one or two non-adjacent carbon units of said alkylene radical may optionally be replaced by independently from each other O, N-H, or N-C1-4alkyl;RX7, and RX8represent independently from each other unsubstituted or substituted C1-6aliphatic, C1-6aliphatoxy, halogen, -OH, -NR2d-S(=O)2- R2g, HetcycY, O-HetcycY; or two of RX1, RX2, RX3, RX4, RX5, RX6, RX7, and RX8which are attached to the same carbon atom of said heterocycle form a divalent oxo (=O) group; or two of RX1, RX2, RX3, RX4, RX5, RX6, RX7, and RX8or four of RX1, RX2, RX3, RX4, RX5, RX6, RX7, and RX8which are attached to the same sulfur atom of said heterocycle form a divalent oxo (=O) group thereby forming either an -S(=O)- or an -S(=O)2- moiety; halogen is F, Cl, Br, or I; v is 1 or 2; w is 1 or 2; x is 0, 1, or 2; y is 0, 1, or 2; z is 0, 1, or 2; or a pharmaceutically acceptable salt thereof.

[0111] Description of Formula (H) can he found in WO2021 / 224291Al, the entirety of which is incorporated herein by reference. Formula (H) is described as Formula (I-A) in WO2021 / 224291A1WSGR Docket No.47612-749.601 (see, e.g., pages 3-12), which paragraphs and description of Formula (I-A), and methods of making compounds of Formula (I-A) are hereby incorporated herein by reference. Moieties of Formula (H), such as A, Z1, Z2, Z3, R1, and R2are as defined in WO2021 / 224291A1, including any variations or embodiments thereof

[0112] In sonic embodiments, in conjunction with embodiments above or below, the present disclosure provides a compound of Formula (H-I):Formula (H-I) wherein, ring A represents a five-membered heteroaromatic ring selected from the group consisting of the following ring moieties:A-32, andA-32, wherein,WSGR Docket No.47612-749.601 RA1represents H, C1-6aliphatic, -CH2-ArA1, or -CH2-CH2-ArA1; RA2represents H, halogen, C1-6aliphatie, -CH2-ArA2, or -CH2-CH2-ArA2; RA3represents H, C1-6aliphatic, -CH2-ArA3, or -CH2-CH2-ArA3; Z1is CRZ1or N; Z2is CRZ2or N; wherein at least one of Z1and Z2is not N; R1represents Ar1, Hetar1, Cyc1, Hetcycl, L1-Arl, L1-Hetar1, L2-Cyc1, L2-Hetcycl, unsubstituted or substituted, straight-chain or branched C1-8aliphatic; R2represents -C(=O)-OR2a, -C(=O)-NR2bR2c, -(CH2)w-C(=O)-NR2bR2c, -(CH2)X-NR2d- C(=O)-R2e, -S-R2f, -S(=O)-R2f, -S(=O)2-R2g, -S(=O)2-NR2hR2i, -S(=O)2-OH, - S(=O)(=NR2j)-OH, -S(=O)(=NR2j)-R2g, S(=O)(=NR2k)-NR2lR2m, F, Cl, Br, I, -CN, - (CH2)v-CN, -P(=O)(OR2o)(OR2p), -(CH2)y-NR2qR2r, -(CH2)z-NR2d-S(=O)2-R2g, -C(=O)- N=S(=O)-R2sR2t, -C(=O)-N=S(=N-R2u)-R2sR2', -B(OH)2, or Hetcycx; ArAl, ArA2, and ArA3represent independently from each other phenyl which may be unsubstituted or mono- or di-substituted with independently from each other RA11or RA12; RZ1represents H or halogen; RZ2represents H or halogen; or forms together with R2a divalent radical -S(=O)2-N(H)- C(=O)-; R2arepresents H, unsubstituted or substituted C1-8aliphatic, aryl, heteroaryl, saturated or partially unsaturated heterocyclyl, or carbohydrate derived radical, or Cat; Cat represents a monovalent cation; R2b, R2c, R2q, and R2rrepresent independently from each other H, unsubstituted or substituted C1-8aliphatic including C3-7cycloaliphatic; or form together with the nitrogen atom to which they are attached to an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle with 3, 4, 5, 6, or 7 ring atoms, wherein 1 of said ring atoms is said nitrogen atom and no or one further ring atom is a hetero atom selected from N, O, or S and the remaining are carbon atoms; wherein said heterocycle may optionally be fused with HetarZ; or one of R2band R2crepresents -CN, -NH2, -OH, - O-C1-6alkyl, -S(=O)2-R2g, Ar2, Hetar2, Cyc2, or Hetcyc2, while the other of R2band R2crepresents H or unsubstituted or substituted C1-8aliphatic; R2d, R2j, R2k, R2o, and R2prepresent independently from each other H, unsubstituted or substituted C1-8aliphatic; R2erepresents H, halogen, unsubstituted or substituted C1-8aliphatic or heteroaryl;WSGR Docket No.47612-749.601 R2fand R2grepresent independently from each other unsubstituted of substituted C1-8aliphatic; R2hand R2irepresent independently from each other H, un-substituted or substituted C1-8aliphatic, aryl, heterocyclyl, heteroaryl; or form together with the nitrogen atom to which they are attached to an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle with 3, 4, 5, 6, or 7 ring atoms, wherein 1 of said ring atoms is said nitrogen atom and no or one further ring atom is a hetero atom selected from N, O, or S and the remaining are carbon atoms; R2land R2mrepresent independently from each other H, unsubstituted or substituted C1-8aliphatic; or form together with the nitrogen atom to which they are attached to an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle with 3, 4, 5, 6, or 7 ring atoms, wherein 1 of said ring atoms is said nitrogen atom and no or one further ring atom is a hetero atom selected from N, O, or S and the remaining are carbon atoms; R2sand R2trepresent independently from each other unsubstituted or substituted C1-8aliphatic; or form together an unsubstituted or substituted divalent C3-6alkylene radical; R2urepresents hydrogen or unsubstituted or substituted C1-6aliphatic; Ar1is a mono-, bi-, or tricyclic aryl with 5, 6; 7, 8, 9, 10, 11, 12, 13, or 14 ring carbon atoms, wherein that aryl may be unsubstituted or substituted with substituents RB1, RB2, RB3, RB4, RB5, RB6, or RB7which may be the same or different; Hetar1is a mono-, bi- or tricyclic heteroaryl with 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, wherein 1, 2, 3, 4, or 5 of said ring atoms is / are a hetero atom(s) selected from N, O, or S and the remaining are carbon atoms, wherein that heteroaryl may be unsubstituted or substituted with substituents RB1, RB2, RB3, RB4, RB5, RB6, or RB7which may be the same or different; Cyc1is a saturated or partially unsaturated, mono-, bi-, or tricyclic carbocycle with 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ring carbon atoms, wherein that carbocycle may be unsubstituted or substituted with RB8, RB9, RB10, RB11, RB12, or RB13which may be the same or different; and wherein that carbocycle may optionally be fused to ArXvia 2 adjacent ring atoms of said ArXand wherein that fused carbocycle may further be unsubstituted or substituted with RC1, RC2, RC3, RC4, RC5, RC6, which may be the same or different; Hetcyc1is a saturated or partially unsaturated, mono-, bi-, or tricyclic heterocycle with 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ring atoms, wherein 1, 2, 3, 4, or 5 of said ringWSGR Docket No.47612-749.601 atoms is / are a hetero atom(s) selected from N, O, or S and the remaining are carbon atoms, wherein that heterocycle may be unsubstituted or substituted with RB8, RB9, RB10, RB11, RB12, or RB13which may be the same or different; L1is a divalent radical selected from the group consisting of -S(=O)2-, C(=O)-, un- substituted or substituted, straight-chain or branched C1-6alkylene or C2-6alkenylene;in both of which one of the carbon units of the alkylene or alkenylene chain may be replaced by -O-; L2is a divalent radical selected from the group consisting of unsubstituted or substituted, straight-chain or branched C1-6alkylene or C2-6alkenylene, in both of which one of the carbon units of the alkylene or alkenylene chain may be replaced by -O-; RA11and RA12represent independently from each other halogen or unsubstituted or substituted, straight-chain or branched C1-6aliphatic; RB1, RB2, RB3, RB4, RB5, RB6, and RB7represent independently from each other un- substituted or substituted, straight-chain or branched C1-6aliphatic, C1-6aliphatoxy, halogen, -CN, -S(=O)-Rb1, S(=O)2-Rb1, -NRb2NRb3, Ar2, -CH2-Ar2, Hetar2, Cyc2, Hetcyc2; or two adjacent RB1, RB2, RB3, RB4, RB5, RB6, or RB7form together a divalent - C2-4alkylene radical in which one of the alkylene carbon units may be replaced by a carbonyl unit (-C(=O)-), or a divalent -O-C1-3alkylene radical or a divalent -O-C1-3alkylene-O-radical; Rb1represents unsubstituted or substituted C1-8aliphatic; Rb2and Rb3represent independently from each other H, unsubstituted or substituted C1-8aliphatic; or form together with the nitrogen atom to which they are attached to an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle with 3, 4, 5, 6, or 7 ring atoms, wherein 1 of said ring atoms is said nitrogen atom and no or one further ring atom is a hetero atom selected from N, O, or S and the remaining are carbon atoms; RB8, RB9, RB10, RB11, RB12, and RB13represent independently from each other halogen, un- substituted or substituted C1-6aliphatic, C1-6aliphatoxy, ArY; or two of RB8, RB9, RB10, RB11, RB12, and RB13which are attached to the same carbon atom of said carbocycle or said heterocycle form a divalent oxo (=O) group; or two of RB8, RB9, RB10, RB11, RB12, and RB13or four of RB8, RB9, RB10, RB11, RB12, and RB13which are attached to the same sulfur atom of said heterocycle form a divalent oxo (=O) group thereby forming either an -S(=O)- or an. -S(=O)2- moiety;WSGR Docket No.47612-749.601 Ar2is a mono- or bicyclic aryl with 5, 6, 7, 8, 9, or 10 ring carbon atoms, wherein that aryl may be unsubstituted or substituted with substituents RD1, RD2, RD3, RD4or RD5which may be the same or different; Hetar2is a mono- or bicyclic heteroaryl with 5, 6, 7, 8, 9, or 10 ring atoms, wherein 1, 2, 3, 4, or 5 of said ring atoms is / are a hetero atom(s) selected from N, O, or S and the remaining are carbon atoms, wherein that heteroaryl may be unsubstituted or substituted with substituents RD1, RD2, RD3, RD4, or RD5which may be the same or different; Cyc2is a saturated or partially unsaturated monocyclic carbocycle with 3, 4, 5, 6 or 7 ring carbon atoms, wherein that carbocycle may be unsubstituted or substituted with RD6, RD7, RD8, RD9, or RD10which may be the same or different; wherein that carbocycle may optionally be fused to ArZor HetarZvia 2 adjacent ring atoms of said ArZor HetarZand wherein that fused carbocycle may further be unsubstituted or substituted with RC1, RC2, RC3, RC4, RC5, or RC6which may be the same or different; Hetcyc2is a saturated or partially unsaturated, monocyclic heterocycle with 3, 4, 5, 6, or 7 ring atoms, wherein 1 or 2 of said ring atoms is / are a hetero atom(s) selected from N, O, or S and the remaining are carbon atoms, wherein that heterocycle may be unsubstituted or substituted with RD6, RD7, RD8, RD9, or RD10which may be the same or different; wherein that heterocycle may optionally be fused to ArZor HetarZvia 2 adjacent ring atoms of said ArZor HetarZand wherein that fused heterocycle may further be unsubstituted or substituted with RC1, RC2, RC3, RC4, RC5, or RC6which may be the same or different; ArXand ArZare independently from each other an unsubstituted or substituted benzo ring; ArYis an unsubstituted or mono- or di-substituted phenyl; HetarY1is a 5 or 6 membered monocyclic heteroaryl wherein 1, 2, 3, or 4 ring atoms are hetero atoms selected from N, O, or S and the remaining are carbon atoms, wherein that heteroaryl may be unsubstituted or substituted with halogen, C1-4alkyl which may optionally be substituted with OH; HetarZis an unsubstituted or substituted 5 or 6 membered heteroaryl ring selected from the group consisting of pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, thiazole, oxadiazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, and pyran; CycY1is a saturated monocyclic carbocycle with 3, 4, 5, 6 or 7 ring carbon atoms, wherein that carbocycle may be unsubstituted or substituted with halogen, OH, C1-4alkyl; HetcycXis a saturated, partially unsaturated or aromatic, monocyclic heterocycle with 3, 4, 5, 6, or 7 ring atoms, wherein 1, 2, 3, or 4 of said ring atoms is / are a hetero atom(s)WSGR Docket No.47612-749.601 selected from N, O, or S and the remaining are carbon atoms, wherein said heterocycle may be unsubstituted or substituted with RX1, RX2, RX3, RX4, RX5, RX6, RX7, or RX8which may be the same or different, and wherein that heterocycle is optionally a carboxylic acid bioisostere; HetcycYis a saturated, partially unsaturated or aromatic, monocyclic heterocycle with 3, 4, 5, 6, or 7 ring atoms, wherein 1, 2, 3, or 4 of said ring atoms is / are a hetero atom(s) selected from N, O, or S and the remaining are carbon atoms; HetcycY1is a saturated or partially unsaturated monocyclic heterocycle with 5 or 6 ring atoms, wherein 1 or 2 of said ring atoms are heteroatoms selected from N, O, or S and the remaining are carbon atoms; RC1, RC2, RC3, RC4, RC5, and RC6represent independently from each other unsubstituted or substituted C1-6aliphatic; RD1, RD2, RD3, RD4, and RD5represent independently from each other unsubstituted or substituted C1-6aliphatic; RD6, RD7, RD8, RD9, and RD10represent independently from each other unsubstituted or substituted C1-6aliphatic, unsubstituted or substituted C1-6aliphatoxy, halogen, hydroxy; HetarY1, CH2-HetarY1, CycY1, HetcycY1, -CH2-HetcycY1; or two of RD6, RD7, RD8, RD9, and RD10which are attached to the same ring atom of said carbocycle or heterocycle may form a divalent C2-6alkylene radical, wherein one or two non-adjacent carbon units of said alkylene radical may optionally be replaced by independently from each other O, N-H, or N-C1-4alkyl, and wherein that alkylene radical may optionally be substituted with OH, C1-4alkyl or -O-C1-4alkyl; or two of RD6, RD7, RD8, RD9, and RD10which are attached to different ring atoms of said carbocycle or heterocycle may form a divalent C1-6alkylene radical, wherein one or two non-adjacent carbon units of said alkylene radical may optionally be replaced by independently from each other O, N-H, or N-C1-4alkyl; RX1, RX2, RX3, RX4, RX5, RX6, RX7, and RX8represent independently from each other unsubstituted or substituted C1-6aliphatic, C1-6aliphatoxy, halogen, -OH, -NR2d-S(=O)2- R2g, HetcycY, O-HetcycY; or two of RX1, RX2, RX3, RX4, RX5, RX6, RX7, and RX8which are attached to the same carbon atom of said heterocycle form a divalent oxo (=O) group; or two of RX1, RX2, RX3, RX4, RX5, RX6, RX7, and RX8or four of RX1, RX2, RX3, RX4, RX5, RX6, RX7, and RX8which are attached to the same sulfur atom of said heterocycle form a divalent oxo (=O) group thereby forming either an -S(=O)- or an - S(=O)2- moiety;WSGR Docket No.47612-749.601 halogen is F, CI, Br, or I; v is 1 or 2; w is 1 or 2; x is 0, 1, or 2; y is 0, 1, or 2; z is 0, 1, or 2; or a pharmaceutically acceptable salt thereof.

[0113] Formula (H-I) is described as Formula (I) in, e.g., pages 12-94, of WO2021 / 224291A1, which paragraphs and description of Formula (1), and methods of making compounds of Formula (I) are hereby incorporated herein by reference. Moieties of Formula (H-I), such as A, Z1, Z2, R1, and R2are as defined in WO2021 / 224291A1, including any variations or embodiments thereof.

[0114] In some embodiments, in conjunction with embodiments above or below, a compound of Formula (H) or (H-I) is Compound 10, or a pharmaceutically acceptable salt thereof. Compound 10 is chemically described as 2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]lindole- 5-carboxylic acid, having the structure below:Compound 10.

[0115] Description of Compound 10 and methods of making Compound 10 can be found in, e.g., Compound 2 on page 198 and Example 2-4 on page 152 of WO2021 / 224291A1.

[0116] In some embodiments, in conjunction with embodiments above or below, the YAP / TAZ-WSGR Docket No.47612-749.601 ,thereof.

[0117] In some embodiments, in conjunction with embodiments above or below, the YAP / TAZ- TEAD inhibitors disclosed herein comprise a TEAD palmitate pocket binding inhibitor (e.g., any one of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, and Compound 10). TEAD palmitate pocket binding inhibitors are described in, for example, Chan et al. (Nat. Chem. Biol.2016, 12(4): 282-289), Noland et al. (Structure, 2016, 24(1): 179-186), and Kim et al. (Biological Sciences, 2019, 116(20): 9877-9882), each of which. is incorporated herein by reference in its entirety and specifically with respect to TEAD palmitate pocket binding inhibitors described therein.

[0118] In some embodiments, in conjunction with embodiments above or below, the YAP / TAZ- TEAD inhibitors disclosed herein comprise a covalent YAP / TAZ-TEAD inhibitor (e.g., any one of Compound 2, Compound 3, and Compound 4). Covalent YAP / TAZ-TEAD inhibitors are described m., for example, Karats et al. Med. Chem.2020, 63, 11972-11989), Lu et al. (Acta Pharmaceutica Sinica. B, 2021, 11(10): 3206-3219), Fan et al. (Biorxiv, 2022, DOI:10.1101 / 2022.05.10.491316), and Kaneda et al. (Am. J. Cancer Res., 2020, 10(12): 4399-4415), each of which is incorporated herein by reference in its entirety and specifically with respect to covalent YAP / TAZ TEAD inhibitors described herein.WSGR Docket No.47612-749.601

[0119] In some aspects, the present disclosure provides a compound of Formula (I):Formula (I) wherein, W is selected from O and CH-RW; X is selected from CH and N; Y is selected from CH and N; Z is selected from CH2, O, and NH; wherein when Y is N, W is CH-RW, and Z is O; A is selected from (i) phenyl, which phenyl is optionally substituted with halo or haloC1-C3alkoxy; (ii) a 5- or 6-membered aromatic heterocyclic ring comprising at least one heteroatom selected from N, O, and S, which aromatic heterocyclic ring is optionally substituted with hydroxy, C1-C3alkoxy, or oxo; and halohalo (iii) a halobenzodioxole moiety of Formula (I-I) Formula (I-I) Rw is selected from (i) hydrogen; (ii) hydroxy; (iii) C1-C3alkoxy; (iv) hydroxy-C1-C3alkyl; (v) C1-C3alkyl; and (vi) C1-C3alkoxy-C1-C3alkyl; Q is selected from (i) -C(R7)2-N(R8)-R1; (ii) 9- or 10-membered partially saturated heteroaryl comprising at least one N heteroatom; and (iii) 4-, 5-, or 6-membered saturated heterocyclic ring comprising at least one heteroatom or heteroatom group selected from N, O, S, -S(=O), and -S(=O)2, with the proviso that at least one N heteroatom is present, wherein the heterocyclic ring is unsubstituted or substituted with one or more substituents independently selected from hydroxy, C1-C3alkyl, C1-C3alkoxy, halo and C1-C3alkylene forming a bridge between two ring atoms of the saturated heterocyclic ring, thus forming a bridged bicyclic structure; R1 is selected from (i) hydrogen; (ii) C1-C6alkyl which is optionally deuterated; and (iii) (CH2)0- 2R1a; R1ais selected from (i) hydroxyC1-C4alkyl; (ii) C1-C3alkoxy; (iii) a 5- or 6-membered saturated heterocyclic ring comprising at least one heteroatom selected from N and O,WSGR Docket No.47612-749.601 which saturated heterocyclic ring is optionally substituted once or more than once independently with C1-C3alkyl; (CH2)0-1C(O)di(C1-C3alkyl)amino; SO2C1-C3alkyl; C(O)C1-C3alkyl; or oxo; (iv) C3-C6cycloalkyl optionally substituted once or more than once independently with hydroxy; hydroxyC1-C4alkyl; C1-C6alkoxy; C(O)OC1-C3alkyl; CO2H; SO2C1-C3alkyl; haloC1-C3alkyl; NHR1b; (CH2)0-1C(O)NR1cR1d; C1-C6alkyl; haloC1-C3alkoxy-C1-C3alkyl; halo; a 5- or 6-membered aromatic heterocyclic ring comprising at least one heteroatom selected from N, O, and S; or with two R1egroups, wherein the two R1eattached at the same carbon atom form together with the carbon atom to which they are attached a 5-membered saturated heterocyclic ring comprising at least one heteroatom selected from N and O, or a C3-C6cycloalkyl, which saturated heterocyclic ring or cycloalkyl are optionally substituted with hydroxy or oxo; R1bis selected from (i) C(O)C1-C3alkyl; and (ii) SO2C1-C3alkyl; R1cand R1dare each independently selected from (i) hydrogen; (ii) C1-C3alkyl; and (iii) hydroxyC1-C4alkyl; R2is selected from (i) hydrogen and (ii) halo; R3is selected from (i) halo; (ii) haloC1-C3alkyl; and (iii) cyano; R4is selected from (i) hydrogen; (ii) halo; and (iii) C1-C3alkyl; R5is selected from (i) hydrogen; (ii) C1-C6alkoxy optionally substituted with C3-C6cycloalkyl; CO2H; SO2C1-C3alkyl; a 5- or 6-membered aromatic heterocyclic ring comprising at least one heteroatom selected from N, O, and S; or a 5- or 6-membered saturated heterocyclic ring comprising at least one heteroatom selected from N and O, which ring is optionally substituted with C(O)C1-C3alkyl; (iii) halo; (iv) hydroxyC1-Csalkoxy, wherein the alkoxy is optionally deuterated; (v) haloC1-C6alkoxy optionally substituted with hydroxy; (vi) S- haloC1-C3alkyl optionally substituted with hydroxy; (vii) C1-C3alkoxyC1-C3alkoxy; (viii) NR5aR5b; (ix) C1-C3alkyl; (x) a 5- or 6- membered aromatic heterocyclic ring comprising at least one heteroatom selected from N, O, and S; and (xi) hydroxy; R5aand R5bare each independently selected from (i) hydrogen; and (ii) C1-C3alkyl; or R5aand R5btogether with the nitrogen atom to which they are attached form a 5- or 6- membered saturated heterocyclic ring, which saturated heterocyclic ring optionally in addition carries a hydroxy group; R6is selected from (i) hydrogen; (ii) cyano; (iii) C(O)NHRSa; (iv) NHR6b; and (v) C1-C3alkoxy substituted with NH2or hydroxy; R6ais selected from (i) hydrogen; (ii) C1-C3alkyl; (iii) C3-C6cycloalkyl; (iv) a 5- or 6- membered aromatic heterocyclic ring comprising at least one heteroatom selected from N, O, and S which aromatic heterocyclic ring is optionally substituted with C1-C3alkyl;WSGR Docket No.47612-749.601 R6bis C1-C3alkyl substituted with NH2or hydroxy; R7is each independently selected from hydrogen and C1-C3alkyl; and R8is hydrogen or C1-C3alkyl.

[0120] Description of Formula (I) can be found in WO2023031781A1 the entirety of which is incorporated herein by reference. Formula (I) is described as Formula (I) in WO2023031781A1 (see, e.g., pages 31 and 41), which paragraphs and description of Formula (I), and methods of making compounds of Formula (I) are hereby incorporated herein by reference.

[0121] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is of Formula (I-II-1), (I-II-2), or (I-II-3),

[0122] In some embodiments, X is selected from CH and N; A is selected from (i) phenyl, which phenyl is optionally substituted with halo; or haloC1-C3alkoxy; (ii) a 5- or 6-membered aromatic heterocyclic ring comprising at least one heteroatom selected from N, O, and S, preferably from N and S, which aromatic heterocyclic ring is optionally substituted with hydroxy; C1-C3alkoxy; or oxo; and halohalo (iii) a halobenzodioxole moiety of FormulaFormula (I-I) Rwis selected from (i) hydrogen; (ii) hydroxy; (iii) C1-C3alkoxy; (iv) hydroxy-C1-C3alkyl; (v) C1-C3alkyl; and (vi) C1-C3alkoxy-C1-C3alkyl;WSGR Docket No.47612-749.601 Q is selected from (i) -C(R7)2-N(R8)-R1; (ii) 9- or 10-membered partially saturated heteroaryl comprising at least one N heteroatom; and (iii) 4-, 5-, or 6-membered saturated heterocyclic ring comprising at least one heteroatom selected from N, O and S, with the proviso that at least one N heteroatom is present, and wherein the N is optionally present in the α-position to the atom binding Q to the rest of the molecule, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituents independently selected from hydroxy, C1-C3alkyl, C1-C3alkoxy, halo and methylene forming a bridge between two ring atoms of the saturated heterocyclic ring, thus forming a bridged bicyclic structure; R1is selected from hydrogen; C1-C6alkyl; and (CH2)0-2R1awherein R1ais selected from (i) C1-C3alkoxy; (ii) C3-C6cycloalkyl optionally substituted once or more than once independently with hydroxy; hydroxyC1-C4alkyl; C1-C4alkoxy; C(O)OC1-C3alkyl; CO2H; C(O)NR1cR1d; C1-C6alkyl; halo; haloC1-C3alkoxy-C1- C3alkyl; SO2C1-C3alkyl; haloC1-C3alkyl; NHR1b; C(O)NR1cR1d; a 5- or 6-membered aromatic heterocyclic ring comprising at least one heteroatom selected from N, O, and S; or with two R1egroups, wherein the two R1egroups are attached at the same carbon atom and form together with the carbon atom to which they are attached a 5- membered saturated heterocyclic ring comprising at least one heteroatom selected from N and O, or a C3-C6cycloalkyl, which saturated heterocyclic ring or cycloalkyl are optionally substituted with hydroxy or oxo; (iii) a 5- or 6-membered saturated heterocyclic ring comprising at least one heteroatom selected from N and O, which saturated heterocyclic ring is optionally substituted once or more than once independently with C1-C3alkyl; (CH2)0-1C(O)di(C1-C3alkyl)amino; SO2C1-C3alkyl; C(O)C1-C3alkyl; or oxo; R1bis selected from C(O)C1-C3alkyl; and SO2C1-C3alkyl; R1cand R1dare each independently selected from (i) hydrogen; (ii) C1-C3alkyl; and (iii) hydroxyC1-C4alkyl, R2is hydrogen or halo, R3is halo; haloC1-C3alkyl; or cyano, R4is selected from hydrogen; halo; and C1-C3alkyl, R5is selected from (i) hydrogen; (ii) halo-C1-C6alkoxy optionally substituted with hydroxy; (iii) S-haloC1-C3alkyl optionally substituted with hydroxy; (iv) C1-C3alkoxyC1- C3alkoxy; (v) C1-C6alkoxy optionally substituted with SO2C1-C3alkyl, C3-C6cycloalkyl, CO2H or a 5- or 6-membered saturated heterocyclic ring comprising at least oneWSGR Docket No.47612-749.601 heteroatom selected from N and O, which ring is optionally substituted with C(O)C1- C3alkyl; (vi) C1-C3alkyl; (vii) hydroxyC1-C6alkoxy; (viii) a 5- or 6-membered aromatic heterocyclic ring comprising at least one heteroatom selected from N, O, and S, preferably at least one N heteroatom; and (ix) hydroxy, R6is cyano; C(O)NHRSa; NHR6b; or C1-C3alkoxy substituted with NH2or hydroxy, R6ais selected from (i) hydrogen; (ii) C1-C3alkyl; (iii) C3-C6cycloalkyl; and (iv) a 5- or 6-membered aromatic heterocyclic ring comprising at least one heteroatom selected from N, O, and S, preferably at least one N heteroatom, which aromatic heterocyclic ring is optionally substituted with C1-C3alkyl; R6bis C1-C3alkyl substituted with NH2or hydroxy; R7is each independently selected from hydrogen and C1-C3alkyl, and R8is hydrogen or C1-C3alkyl.

[0123] In some embodiments, X is selected from CH and N; A is phenyl, which phenyl is optionally substituted with halo; or haloC1-C3alkoxy; Rwis selected from (i) hydrogen; (ii) C1-C3alkoxy; (iii) hydroxy-C1-C3alkyl; (iv) C1- C3alkyl; and (v) C1-C3alkoxy-C1-C3alkyl; Q is selected from (i) -C(R7)2-NH-R1; and (ii) 4-, 5-, or 6-membered saturated heterocyclic ring comprising one or two heteroatoms independently selected from N, O and S, with the proviso that at least one N heteroatom is present, wherein the N is present in the α- position to the atom binding Q to the rest of the molecule, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituents independently selected from hydroxy, C1-C3alkyl and halo; R1is selected from (i) C1-C6alkyl; and (ii) R1a; wherein R1ais selected from C3-C6cycloalkyl optionally substituted once or more than once independently with hydroxy; C1-C6alkyl; or halo; R2is hydrogen or halo; R3is halo; R4is selected from (i) hydrogen; and (ii) halo; R5is selected from halo-C1-C6alkoxy, hydroxy, C1-C6alkoxy; and hydroxyC1-C6alkoxy; R6is C(O)NHR6a; R6ais selected from (i) hydrogen; and (ii) C1-C3alkyl; and R7is each independently selected from hydrogen and C1-C3alkyl.

[0124] In some embodiments, X is selected from CH and N;WSGR Docket No.47612-749.601 A is phenyl, which phenyl is optionally substituted with halo; or haloC1-C3alkoxy, especially unsubstituted phenyl; Rwis selected from (i) hydrogen and (ii) C1-C3alkyl, Q is selected from (i) -C(R7)2-NH-R1; and (ii) 4-, 5-, or 6-membered saturated heterocyclic ring comprising one or two heteroatoms independently selected from N and O, with the proviso that at least one N heteroatom is present and is in the α-position to the carbon atom binding Q to the rest of the molecule, wherein the heterocyclic ring is unsubstituted or substituted with one or more substituents independently selected from hydroxy, C1-C3alkyl, and halo; R1is selected from (i) C1-C6alkyl and (ii) R1a;wherein R1ais C3-C6cycloalkyl optionally substituted once or more than once independently with hydroxy; C1-C6alkyl; or halo; R2is halo, especially, fluoro; R3is halo, especially, chloro; R4is halo, especially, fluoro; R5is selected from C1-C6alkoxy and hydroxyC1-C6alkoxy; R6is C(O)NHR6a; R6ais selected from (i) hydrogen; and (ii) C1-C3alkyl; and each R7is hydrogen.

[0125] In some aspects, the YAP / TAZ-TEAD inhibitors disclosed herein include a YAP / TAZ- TEAD inhibitor of Formula (I), or a pharmaceutically acceptable salt thereof, for example, Compound 11 (4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3- dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide), Compound 12 (2- ((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3- dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide), Compound 13 (2-((2S,4S)-5-chloro-2- ((((1r,4S)-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4- methoxybenzamide), Compound 14 (2-((2S,4S)-5-chloro-6-fluoro-2-((((1s,4R)-4- hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3- fluorobenzamide), Compound 15 (2-((2S,3S)-5-chloro-6-fluoro-2-((((1r,4S)-4-hydroxy-4- methylcyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)- 2-hydroxypropoxy)benzamide), or Compound 16 (2-((2S,4S)-5-chloro-6-fluoro-2-((((1r,4S)-4- hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3- fluorobenzamide), or a pharmaceutically acceptable salt thereof.WSGR Docket No.47612-749.601

[0126] In some embodiments, the compound of Formula (I) is selected from the group consisting of: (S)-(5-chloro-2,4-diphenyl-2,3-dihydrobenzofuran-2-yl)methanamine; N1-(2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro- phenyl)ethane-1,2-diamine; 2-(2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro- phenoxy)ethanamine; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3- fluorobenzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4- meth-oxybenzamide; 2-((2S,4R)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3- methylbenzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-chloro benzamide trifluoroacetate salt; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-chloro-3- fluoro-benzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3,4-difluoro- benzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2- hydroxyethoxy)benzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoro- methoxy)-3-fluoro benzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2- methoxyethoxy)benzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4- ((S)-2-hydroxypropoxy)benzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4- ((R)-2-hydroxypropoxy)benzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4- ((R)-2-fluoropropoxy)benzamide; 2-(3-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4- carbamoyl-2-fluorophenoxy)acetic acid trifluoroacetate salt;WSGR Docket No.47612-749.601 4-(((R)-4-acetylmorpholin-2-yl)methoxy)-2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl- 2,3-dihydrobenzofuran-4-yl)-3-fluorobenzamide; 4-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6- methoxynicotinamide; 4-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-6- (difluorometh-oxy)-5-fluoronicotinamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4- (methylamino)benzamide; 2-((2S,4S)-5-chloro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3- fluoro-4-methoxybenzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4- methoxy-N-methylbenzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-N- cyclopropyl-3-fluoro-4-methoxybenzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3,4-difluoro- N-(1-methyl-1H-pyrazol-5-yl)benzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4- methoxy-N-(pyridin-3-yl)benzamide; 2-((2S,4S)-5-chloro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3- fluoro-4-methoxy-N-methylbenzamide; 2-((2S,4S)-5-chloro-2-(((trans-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3- dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide; 2-((2S,4S)-5-chloro-2-(((cis-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3- dihydrobenzo-furan-4-yl)-3-fluoro-4-methoxybenzamide; (trans)-4-((((2S,4S)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-2-phenyl-2,3- dihy-drobenzofuran-2-yl)methyl)amino)cyclohexanecarboxylic acid; (cis)-4-((((2S,4S)-4-(6-carbamoyl-2-fluoro-3-methoxyphenyl)-5-chloro-2-phenyl-2,3- dihydro-benzofuran-2-yl)methyl)amino)cyclohexanecarboxylic acid; 2-((2R,4S)-2-(aminomethyl)-5-chloro-2-(thiazol-4-yl)-2,3-dihydrobenzofuran-4-yl)-3- fluoro-4-methoxybenzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-(2,2-difluorobenzo[d][1 ,3]dioxol-4-yl)-2,3- dihydrobenzofuran-4-yl)-3-fluorobenzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-(2-fluorophenyl)-2,3-dihydrobenzofuran-4-yl)-3- fluoro-4-methoxybenzamide;WSGR Docket No.47612-749.601 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3- fluoro benzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3- fluoro-4-methoxybenzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4- (cyclopropylmethoxy)-3-fluorobenzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4- (difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4- (1,1-difluoro-2-hydroxyethoxy)-3-fluoro benzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3- fluoro-4-(2-methoxyethoxy)benzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3- fluoro-4-(2-hydroxyethoxy)benzamide; 2-((2S,4R)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4- ((1,1-difluoro-2-hydroxyethyl)thio)benzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3- fluoro-4-((methylsulfonyl)methoxy)benzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4- (3,3-difluoropropoxy)-3-fluorobenzamide; 4-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5- fluoro-6-methoxynicotinamide; 4-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5- fluoro-6-(2-hydroxyethoxy)nicotinamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3- fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide; 4-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5- fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide; 2-((2S,4S)-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4- yl)-3-fluoro-4-methoxybenzamide; 4-((2S,4S)-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4- yl)-5-fluoro-6-(2-methoxyethoxy)nicotinamide; 2-((2S,4S)-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4- yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide;WSGR Docket No.47612-749.601 4-((2S,4S)-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4- yl)-5-fluoro-6-(2-hydroxyethoxy)nicotinamide; 2-((2S,4S)-5-chloro-2-(((cyclopropylmethyl)amino)methyl)-6-fluoro-2-phenyl-2,3- dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4- yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4- yl)-3-fluoro-4-((S)-2-hydroxypropoxy)-N-methylbenzamide; 4-((2S,4S)-5-chloro-6-fluoro-2-((methylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4- yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide; 2-((2S,4S)-5-chloro-6-fluoro-2-((((cis)-4-(methylsulfonyl)cyclohexyl)amino)methyl)-2- phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-((((trans)-4-(methylsulfonyl)cyclohexyl)amino)methyl)-2- phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluoro benzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-(((4-(fluoromethyl)-4-hydroxycyclohexyl)amino)methyl)-2- phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluoro benzamide; 2-((2S,4S)-2-(((4-acetamidocyclohexyl)amino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3- dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-(((4-(methylsulfonamido)cyclohexyl)amino)methyl)-2- phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-2-(((4-(dimethylcarbamoyl)cyclohexyl)amino)methyl)-6-fluoro-2- phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-(((2-oxo-1-azaspiro[4.5]decan-8-yl)amino)methyl)-2- phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-2-(((1-(2-(dimethylamino)-2-oxoethyl)piperidin-4-yl)amino)methyl)-6- fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluoro benzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-(((4-(hydroxymethyl)cyclohexyl)amino)methyl)-2-phenyl- 2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-(((3-(2-hydroxypropan-2-yl)cyclobutyl)amino)methyl)-2- phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-(((1-(methylsulfonyl)piperidin-4-yl)amino)methyl)-2- phenyl-2.3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-((((trans)-3-(hydroxymethyl)cyclobutyl)amino)methyl)-2- phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide;WSGR Docket No.47612-749.601 2-((2S,4S)-5-chloro-6-fluoro-2-((((cis)-3-(hydroxymethyl)cyclobutyl)amino)methyl)-2- phenyl-2.3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide; 2-((2S,4S)-5-chloro-2-((((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)amino)methyl)- 6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2- hydroxyethoxy)benzamide; 2-((2S,4S)-5-chloro-2-((((2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)amino)methyl)- 6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2- hydroxyethoxy)benzamide; 4-((2S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-2- phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-methoxynicotinamide; 4-((2S,4S)-5-chloro-6-fluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-2- phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-methoxynicotinamide; 2-((2S,4S)-5-chloro-6-fluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-2- phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(((R)-tetrahydrofuran-2- yl)methoxy)benzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-2- phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(((R)-tetrahydrofuran-2- yl)methoxy)benzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-2- phenyl-2,3-dihydrobenzofuran-4-yl)-4-ethyl-3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-2- phenyl-2,3-dihydrobenzofuran-4-yl)-4-ethyl-3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-2- phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(1 H-imidazol-1-yl)benzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-2- phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(1 H-imidazol-1-yl)benzamide; 2-((2S,4S)-2-(((1-acetylpiperidin-4-yl)amino)methyl)-5-chloro-6-fluQro-2-phenyl-2,3- dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-2- phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(pyrimidin-2-ylmethoxy)benzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-2- phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(pyrimidin-2-ylmethoxy)benzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxycyclohexyl)amino)methyl)-2-phenyl- 2,3-dihydro benzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide;WSGR Docket No.47612-749.601 2-((2S,4S)-2-((tert-butylamino)methyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran- 4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-((((R)-2-hydroxypropyl)amino)methyl)-2-phenyl-2,3- dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-((((S)-1-hydroxypropan-2-yl)amino)methyl)-2-phenyl-2,3- dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-(((1-methylcyclopropyl)amino)methyl)-2-phenyl-2,3-di- hydro benzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-(((2-methoxyethyl)amino)methyl)-2-phenyl-2,3-dihydro- benzofuran-4-yl)-4-(difluoromethoxy)-3-fluoro benzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-(((2-(2-oxopyrrolidin-1-yl)ethyl)amino)methyl)-2-phenyl- 2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-2-((((trans)-4-(1 H-tetrazol-1-yl)cyclohexyl)amino)methyl)-5-chloro-6-fluoro-2- phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-2-(((trans-3-((difluoromethoxy)methyl)cyclobutyl)amino)methyl)-6- fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-((((1S,3R,4R)-3-fluoro-4- hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4- (difluoromethoxy)-3-fluoro benzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-((((1 R,3S,4S)-3-fluoro-4- hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4- (difluoromethoxy)-3-fluoro benzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-(((trans-3-fluorocyclobutyl)amino)methyl)-2-phenyl-2,3-di- hydro benzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-((((1 R,3S)-3-hydroxycyclohexyl)amino)methyl)-2-phenyl- 2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-1-methylcyclohexyl)amino)methyl)-2- phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluoro benzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-(((6-hydroxyspiro[3.3]heptan-2-yl)amino)methyl)-2-phenyl- 2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-4-yl)- 3-fluoro-4-methoxybenzamide; 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-4-yl)- 4-(difluoromethoxy)-3-fluoro benzamide;WSGR Docket No.47612-749.601 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-3-hydroxy-2-phenyl-2,3-dihydrobenzofuran-4-yl)- 3-fluoro-4-(2-methoxyethoxy)benzamide; 2-((2R,3S,4S)-2-(aminomethyl)-5-chloro-3-hydroxy-2-(pyridin-2-yl)-2,3- dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide; 2-((2R,3S,4S)-2-(aminomethyl)-5-chloro-3-hydroxy-2-(6-methoxypyridin-2-yl)-2,3- dihydro-benzofuran-4-yl)-4-(difluoromethoxy)-3-fluoro benzamide; 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-3-hydroxy-2-(2-methoxypyridin-3-yl)-2,3- dihydro-benzofuran-4-yl)-3-fluoro-4-methoxybenzamide; 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-3-hydroxy-2-(2-oxo-1 ,2-dihydropyridin-3-yl)-2,3- dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide; 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-3-hydroxy-2-(2-(trifluoromethoxy)phenyl)-2,3- dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide; 2-((2S,3S,4S)-5-chloro-3-hydroxy-2-((((trans)-4-hydroxycyclohexyl)amino)methyl)-2- phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,3S,4S)-5-chloro-3-hydroxy-2-((((cis)-4-hydroxycyclohexyl)amino)methyl)-2- phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2R,3S,4S)-5-chloro-3-hydroxy-2-((((trans)-4-hydroxycyclohexyl)amino)methyl)-2- (pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide; 2-((2R,3S,4S)-5-chloro-3-hydroxy-2-((((cis)-4-hydroxycyclohexyl)amino)methyl)-2- (pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide; 2-((2S,3S,4S)-5-chloro-2-((cyclobutylamino)methyl)-3-hydroxy-2-phenyl-2,3- dihydrobenzo-furan-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydro benzo- furan-4-yl)-3-fluoro-4-methoxybenzamide; 2-((2S,3S,4S)-2-(Aminomethyl)-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2,3-dihydrobenzo- furan-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide; 2-((2S,3S,4S)-5-Chloro-2-((cyclobutylamino)methyl)-6-fluoro-3-hydroxy-2-phenyl-2,3-di- hydro benzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide; 2-((2S,3S,4S)-5-Chloro-6-fluoro-3-hydroxy-2-((((trans)-4- hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4- (difluoromethoxy)-3-fluorobenzamide; 2-((2S,3S,4S)-5-chloro-6-fluoro-3-hydroxy-2-((((cis)-4-hydroxycyclohexyl)amino)methyl)- 2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluoro benzamide;WSGR Docket No.47612-749.601 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-3-methoxy-2-phenyl-2,3-dihydro benzo- furan-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide; 2-((2S,3S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxycyclohexyl)amino)methyl)-3- methoxy- 2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,3S,4S)-5-chloro-6-fluoro-2-((((cis)-4-hydroxycyclohexyl)amino)methyl)-3-methoxy- 2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluoro benzamide; 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)- 4-(difluoromethoxy)-3-fluoro benzamide; 2-((2S,3S,4S)-5-chloro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3-methyl- 2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluoro benzamide; 2-((2S,3S,4S)-5-chloro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3- methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluoro benzamide; 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydro benzofuran-4-yl)-4-(difluoromethoxy)-3-fluoro benzamide; 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydro benzofuran-4-yl)-3-fluoro-4-(2-methoxyethoxy)benzamide; 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydro benzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide; 4-((2S,3S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydro benzofuran-4-yl)-5-fluoro-6-(2-methoxyethoxy)nicotinamide; 2-((2R,3S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-3-methyl-2-(pyridin-2-yl)-2,3-dihydro- benzofuran-4-yl)-3-fluoro-4-methoxybenzamide; 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydro- benzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide; 2-((2R,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-(pyridin-2-yl)-2,3- di-hydro benzofuran-4-yl)-3-fluoro-4-(2-methoxyethoxy)benzamide; 2-((2R,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-(pyridin-2-yl)-2,3- di-hydro benzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide; 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydro- benzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide; 2-((2S,3S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4- methylcyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3- fluoro-4-((S)-2-hydroxypropoxy)benzamide;WSGR Docket No.47612-749.601 2-((2S,3S,4S)-5-chloro-6-fluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)amino)methyl)- 3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2- hydroxypropoxy)benzamide; 2-((2S,3S,4S)-5-chloro-6-fluoro-2-(((trans-4-hydroxycyclohexyl)amino)methyl)-3-methyl- 2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluoro benzamide; 2-((2S,3S,4S)-5-chloro-6-fluoro-2-((((cis)-4-hydroxycyclohexyl)amino)methyl)-3-methyl- 2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluoro benzamide; 2-((2S,3S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4- methylcyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3- fluoro-4-(2-methoxyethoxy)benzamide; 2-((2S,3S,4S)-5-chloro-6-fluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)amino)methyl)- 3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2- methoxyethoxy)benzamide; 2-((2S,3S,4S)-5-chloro-6-fluoro-2-(((trans-4-hydroxy-4-methylcyclohexyl)amino)methyl)- 3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2- hydroxyethoxy)benzamide; 2-((2S,3S,4S)-5-chloro-6-fluoro-2-(((cis-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3- methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide; 2-((2S,3S,4S)-5-chloro-2-((cyclobutylamino)methyl)-6-fluoro-3-methyl-2-phenyl-2,3- dihydro benzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide; 4-((2S,3S,4S)-5-chloro-6-fluoro-2-((((trans-4-hydroxy-4-methylcyclohexyl)amino)methyl)- 3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-5-fluoro-6-(2- hydroxyethoxy)nicotinamide; 2-((2S,3S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4- methylcyclohexyl)amino)methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3- fluoro-4-((S)-2-hydroxypropoxy)benzonitrile; 2-((2S,3S,4S)-5-chloro-6-fluoro-2-(((trans-4-hydroxy-4-methylcyclohexyl)amino)methyl)- 3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)-N- methylbenz-amide; 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydro- benzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)-N-methylbenzamide; 2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-6-fluQrQ-3-methyl-2-phenyl-2,3- dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide;WSGR Docket No.47612-749.601 2-(2-((2S,3S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzo- furan-4-yl)-3,4-difluorophenoxy)ethan-1-ol; 2-((2R,3S,4S)-5-chloro-6-fluoro-2-(6-hydroxypyridin-2-yl)-3-methyl-2- ((methylamino)methyl)-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide; 2-((2R,3S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4- methylcyclohexyl)amino)methyl)-3-methyl-2-(pyridin-2-yl)-2,3-dihydrobenzofuran-4- yl)-3-fluoro-4-(2-methQxyethoxy)benzamide; 2-((2S,3S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4- methylcyclohexyl)amino)methyl)-3-methyl-2-(pyridin-3-yl)-2,3-dihydrobenzofuran-4- yl)-3-fluoro-4-methoxybenzamide; 2-((2S,4R)-2-(aminomethyl)-2-phenyl-5-(trifluoromethyl)-2,3-dihydrobenzofuran-4-yl)-4- methoxybenzamide; 2-((2S,4R)-5-cyano-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-2-phenyl- 2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxy-N-methylbenzamide; (S)-2-((((trans)-4-Hydroxycyclohexyl)amino)methyl)-2,4-diphenyl-2,3-dihydrobenzofuran- 5-carbo nitrile; 2-((2S,4S)-2-(aminomethyl)-5-chloro-2-phenyl-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-3- fluoro-benzamide; 2-(2-(aminomethyl)-6-chloro-2-phenyl-2,3-dihydrobenzofuran-7-yl)-3-fluoro-4-methoxy- benzamide; 2-(2-(aminomethyl)-5-chloro-2-phenylbenzo[d][1 ,3]dioxol-4-yl)-3-fluorobenzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenylindolin-4-yl)-3-fluoro benzamide; 2-((2S,4S)-5-chloro-2-((cyclohexylamino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4- (difluoromethoxy)-3-fluoro benzamide; 2-((2S,3S,4S)-5-chloro-6-fluoro-3-hydroxy-2-((((cis)-4-methoxycyclohexyl)amino)methyl)- 2-phenyl-2,3-dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluoro benzamide; 2-((2S,3S,4S)-5-chloro-6-fluoro-3-hydroxy-2-((((trans)-4- methoxycyclohexyl)amino)methyl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-4- (difluoromethoxy)-3-fluorobenzamide; methyl (cis)-4-((((2S,4S)-4-(6-carbamoyl-2,3-difluorophenyl)-5-chloro-2-phenyl-2,3-di- hydro benzofuran-2-yl)methyl)amino)cyclohexane-1-carboxylate; methyl (trans)-4-((((2S,4S)-4-(6-carbamoyl-2,3-difluorophenyl)-5-chloro-2-phenyl-2,3-di- hydrobenzofuran-2-yl)methyl)amino)cyclohexane-1-carboxylate;WSGR Docket No.47612-749.601 2-((2S,4S)-2-((((trans)-4-carbamoylcyclohexyl)amino)methyl)-5-chloro-2-phenyl-2,3-di- hydro benzofuran-4-yl)-3-fluorobenzamide; 2-((2S,4S)-2-((((cis)-4-carbamoylcyclohexyl)amino)methyl)-5-chloro-2-phenyl-2,3- dihydro-benzofuran-4-yl)-3-fluoro benzamide; 2-((2S,4S)-5-chloro-2-((((trans)-4-(methylcarbamoyl)cyclohexyl)amino)methyl)-2-phenyl- 2,3-dihydro benzofuran-4-yl)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-2-((((cis)-4-(methylcarbamoyl)cyclohexyl)amino)methyl)-2-phenyl- 2,3-dihydrobenzofuran-4-yl)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-2-((((cis)-3-(difluoromethyl)cyclobutyl)amino)methyl)-6-fluoro-2- phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide; 2-((2S,4S)-5-chloro-2-((((trans)-3-(difluoromethyl)cyclobutyl)amino)methyl)-6-fluoro-2- phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide; 2-((2S,4S)-2-(aminomethyl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3- fluoro-4-(2-hydroxyethoxy-1 ,1 ,2,2-d4)-N-methylbenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-(((methyl-d3)amino)methyl)-2-phenyl-2,3- dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluoro benzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-(((methyl-d3)amino)methyl)-2-phenyl-2,3- dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy-1,1,2,2-d4)benzamide; 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3-dihydro benzofuran-4-yl)-3-fluoro-4-methoxybenzamide; 4-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3- dihydrobenzofuran-4-yl)-5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide; 2-((2S,3R,4S)-5-chloro-6-fluoro-3-(methoxyrmethyl)-2-((methylamino)methyl)-2-phenyl- 2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide; 2-((2S,3R,4S)-5-chloro-6-fluoro-3-(hydroxymethyl)-2-((methylamino)methyl)-2-phenyl- 2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide; 2-((2S,3S,4S)-5-chloro-6-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)amino) methyl)-3-methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxy-2- methylpropoxy)benzamide; 2-((2S,4S)-2-(azetidin-2-yl)-5-chloro-6-fluoro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3- fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide; 2-((2S,3S,4S)-2-(azetidin-2-yl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3- dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)-N-methylbenzamide;WSGR Docket No.47612-749.601 2-((2S,3S,4S)-2-(azetidin-2-yl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3- dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)-N-methylbenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)- 3-fluoro-4-(2-hydroxyethoxy)benzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)- 3-fluoro-4-((S)-2-hydroxypropoxy)benzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)- 3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)- 3-fluoro-4-((S)-2-hydroxypropoxy)-N-methylbenzamide; 4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)- 5-fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide, 2-((4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4- yl)-3-fluoro-5-(methylcarbamoyl)pyridin-2-yl)oxy)acetic acid; 4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)- 5-fluoro-6-hydroxy-N-methylnicotinamide; 2-((2S,4S)-5-chlorQ-6-fluoro-2-(4-hydroxypyrrolidin-2-yl)-2-phenyl-2,3- dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-(4-hydroxy-4-methylpyrrolidin-2-yl)-2-phenyl-2,3- dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide; (2S,4R)-2-((S)-5-chloro-6-fluoro-2,4-diphenyl-2,3-dihydrobenzofuran-2-yl)-4- fluoropyrrolidine; 2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-piperidin-2-yl)-2,3-dihydrobenzofuran-4-yl)- 3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide; 3-((S)-5-chloro-6-fluoro-2,4-diphenyl-2,3-dihydrobenzofuran-2-yl)morpholine, 2-((2S,4S)-5-chloro-6-fluoro-2-(morpholin-3-yl)-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3- fluoro-4-methoxybenzamide; 2-((2S,3S,4S)-5-chloro-6-fluoro-3-hydroxy-2-phenyl-2-(pyrrolidin-2-yl)-2,3- dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide; 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methoxy-2-phenyl-2-(pyrrolidin-2-yl)-2,3- dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide; 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methoxy-2-phenyl-2-(pyrrolidin-2-yl)-2,3- dihydrobenzofuran-4-yl)-3-fluoro-4-(2-hydroxyethoxy)benzamide;WSGR Docket No.47612-749.601 2-((2S,3S,4S)-5-chloro-6-fluoro-3-methyl-2-phenyl-2-(pyrrolidin-2-yl)-2,3- dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2-hydroxypropoxy)benzamide; 2-((2S,4S)-2-(1-aminoethyl)-5-chloro-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4- methoxybenzamide; 2-((2S,3S,4S)-2-(1-aminoethyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3- dihydrobenzofuran-4-yl)-3-fluoro-4-(2-methoxyethoxy)benzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)indolin-4-yl)-3-fluoro-4-(2- hydroxyethoxy)benzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)indolin-4-yl)-3-fluoro-4- methoxybenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)indolin-4-yl)-3-fluoro-4-((S)- 2-hydroxypropoxy)-N-methylbenzamide; 4-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)indolin-4-yl)-5-fluoro-6-(2- hydroxyethoxy)-N-methylnicotinamide; 2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)- 3-fluoro-4-methoxybenzamide; 2-((2S,4S)-5-chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)- 3-fluoro-4-methoxy-N-methylbenzamide; and 2-((2S,3S,4S)-2-(Aminomethyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydro benzofuran-4-yl)-3-fluoro-4-methoxybenzamide, or a pharmaceutically acceptable salt thereof.WSGR Docket No.47612-749.601

[0129] In some embodiments, the compound of Formula

[0130] In some embodiments, the compound of Formula

[0131] In some embodiments, the compound of Formula

[0132] In some embodiments, the compound of Formula

[0133] In some embodiments, the compound of FormulaWSGR Docket No.47612-749.601

[0134] In some embodiments, the compound of Formula

[0135] In some embodiments, the compound of Formula

[0138] In some embodiments, the compound of FormulaWSGR Docket No.47612-749.601

[0139] In some embodiments, the compound of Formula (I) is (2P)-2-{(2S)-5-chloro-6-fluoro-2- [(methylamino)methyl]-2-phenyl-2,3-dihydro-1-benzofuran-4-yl}-3-fluoro-4-(2-hydroxyethoxy)- N-methylbenzamide and has the following structure:.

[0140] In some embodiments, the compound of Formula (I) is (2P)-2-[(2S)-5-chloro-6-fluoro-2- ({[(1r,4S)-4-hydroxycyclohexyl]amino}methyl)-2-phenyl-2,3-dihydro-1-benzofuran-4-yl]-4- (difluoromethoxy)-3-fluorobenzamide and has the following structure:.

[0141] In some embodiments, the compound of Formula (I) is (2P)-2-[(2S,3S)-5-chloro-6-fluoro-3- hydroxy-2-({[(1r,4S)-4-hydroxycyclohexyl]amino}methyl)-2-phenyl-2,3-dihydro-1-benzofuran-4- yl]-4-(difluoromethoxy)-3-fluorobenzamide and has the following structure:.

[0142] In some embodiments, the compound of Formula (I) is (2P)-2-[(2S,3S)-5-chloro-6-fluoro-2- ({[(1r,4S)-4-hydroxy-4-methylcyclohexyl]amino}methyl)-3-methyl-2-phenyl-2,3-dihydro-1-WSGR Docket No.47612-749.601 benzofuran-4-yl]-3-fluoro-4-[(2S)-2-hydroxypropoxy]benzamide and has the following structure:.

[0143] In some embodiments, the compound of Formula (I) is (2P)-2-[(2S,3S)-5-chloro-6-fluoro-2- ({[(1r,4S)-4-hydroxy-4-methylcyclohexyl]amino}methyl)-3-methyl-2-phenyl-2,3-dihydro-1- benzofuran-4-yl]-3-fluoro-4-(2-hydroxyethoxy)benzamide and has the following structure:.

[0144] In some embodiments, the compound of Formula (I) is (2P)-2-[(2S,3S)-5-chloro-6-fluoro-2- ({[(1r,4S)-4-hydroxy-4-methylcyclohexyl]amino}methyl)-3-methyl-2-phenyl-2,3-dihydro-1- benzofuran-4-yl]-3-fluoro-4-[(2S)-2-hydroxypropoxy]benzonitrile and has the following structure:.

[0145] In some embodiments, the compound of Formula (I) is (2P)-2-[(2S,3S)-5-chloro-6-fluoro-2- ({[(1r,4S)-4-hydroxy-4-methylcyclohexyl]amino}methyl)-3-methyl-2-phenyl-2,3-dihydro-1-WSGR Docket No.47612-749.601 benzofuran-4-yl]-3-fluoro-4-(2-hydroxyethoxy)-N-methylbenzamide and has the following structure:.

[0146] In some embodiments, the compound of Formula (I) is (2P)-2-{(2S,3S)-5-chloro-6-fluoro- 3-methyl-2-[(methylamino)methyl]-2-phenyl-2,3-dihydro-1-benzofuran-4-yl}-3-fluoro-4-[(2S)-2- hydroxypropoxy]-N-methylbenzamide and has the following structure:.

[0147] In some embodiments, the compound of Formula (I) is (2P)-2-{(2S,3S)-5-chloro-6-fluoro- 3-methyl-2-[(methylamino)methyl]-2-phenyl-2,3-dihydro-1-benzofuran-4-yl}-3-fluoro-4- methoxybenzamide and has the following structure:.

[0148] In some embodiments, the compound of Formula (I) is (4P)-4-{(2S,3S)-5-chloro-6-fluoro- 3-methyl-2-[(methylamino)methyl]-2-phenyl-2,3-dihydro-1-benzofuran-4-yl}-5-fluoro-6-(2- hydroxyethoxy)-A-methylpyridine-3-carboxamide and has the following structure:.WSGR Docket No.47612-749.601

[0149] In some embodiments, the compound of Formula (I) is (4P)-4-{(2S)-5-chloro-6-fluoro-2- phenyl-2-[(2S)-pyrrolidin-2-yl]-2,3-dihydro-1-benzofuran-4-yl}-5-fluoro-6-(2-hydroxyethoxy)-N- methylpyridine-3-carboxamide and has the following structure:.

[0150] In some embodiments, the compound of Formula (I) is (2P)-2-{(2S)-5-chloro-6-fluoro-2- phenyl-2-[(2S)-pyrrolidin-2-yl]-2,3-dihydro-1H-indol-4-yl}-3-fluoro-4-(2- hydroxyethoxy)benzamide and has the following structure:.

[0151] In some embodiments, the term Compound 11 refers

[0152] In some embodiments, the term Compound 12 refers

[0153] In some embodiments, the term Compound 13 refersWSGR Docket No.47612-749.601

[0154] In some embodiments, the term Compound 14 refers

[0155] In some embodiments, the term Compound 15 refers

[0156] In some embodiments, the term Compound 16 refers

[0157] In some embodiments, a YAP / TAZ-TEAD inhibitor is selected from the group consisting of Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, Compound 16, 3- methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2- one, (R)-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)pyridin-3-yl)-1,3,4-oxadiazol-2- yl)pyrrolidin-2-one, (S)-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)pyridin-3-yl)-1,3,4- oxadiazol-2-yl)pyrrolidin-2-one, N-(2-hydroxy-1-(pyridin-2-yl)ethyl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide, (S)-N-(1-(pyridin-2-yl)ethyl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide, N-(3-hydroxy-1-(pyridin-2-yl)propyl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide, (S)-N-(3-hydroxy-1-(pyridin-2-yl)propyl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide, (R)-N-(4-hydroxybutan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide, (S)-N-(4-hydroxybutan-2-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide, (S)-N-(2-hydroxy-1-(pyridin-2-yl)ethyl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide, N-(1,5-dihydroxypentan-3-yl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide, and pharmaceutically acceptable salts thereof.WSGR Docket No.47612-749.601

[0158] In some embodiments, the YAP / TAZ-TEAD inhibitor is selected from the group consisting of Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, Compound 16, and YAP / TAZ-TEAD inhibitors selected from those disclosed in WO201753706, WO2017064277, WO2017058716, WO2018185266, WO2018204532, W02019040380, WO2019113236, WO2019171268, WO2019222431, WO2019232216, W02020097389, WO202014734, W02020051099, WO2020243415, WO2020243423, W02021097110, WO2021102204, WO2021133896 and W02022087008, and pharmaceutically acceptable salts thereof. Each of WO201753706, WO2017064277, WO2017058716, WO2018185266, WO2018204532, W02019040380, WO2019113236, WO2019171268, WO2019222431, WO2019232216, W02020097389, WO202014734, W02020051099, WO2020243415, WO2020243423, W02021097110, WO2021102204, WO2021133896 and W02022087008, and the YAP / TAZ- TEAD inhibitors disclosed therein are incorporated by reference.

[0159] In some embodiments, the YAP / TAZ-TEAD inhibitors are selected from the group consisting of compounds 1-16, as listed in Table 1, or a pharmaceutically acceptable salt thereof. Table 1 Compound Structure Chemical name O 5-(4-Cyclohexylpheny1)-3-(3- N N N (fluoromethyl)azetidine-1- N N 1 H O N carbonyl)-2-(3-methylpyrazin-2- yl)pyrazolo[1,5-a]pyrimidin- F 7(4H)-one O O N-(7-(4-Isopropylphenyl)-2,3- 2Ndihydrobenzofuran-5- H yl)acrylamide N O N-(6-Methoxy-5-((E)-2-((1r,4r)- O N 4- 3HF (trifluommethyl)cyclohexyl)vin F F yl)pyridin-3-yl)acrylamide NC O 2-(((4-Cyano-7-(4- O isopropylphenyl)-2,3- 4 HO N H dihydrobenzofuran-5- yl)amino)methyl)acrylic acidWSGR Docket No.47612-749.601 N-(3-(17-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)oxy)-3- methyl-2-oxo-6,9,12,15- 5 tetraoxa-3- azaheptadecyl)benzyl)-5- methoxy-4-((E)-2-((trans)-4- (trifluoromethyl)cyclohexyl)vin yl)picolinamide F F F N-[(1R)-1-(6-Amino-2- O pyridyl)ethyl)-5-[4- 6 H (trifluoromethyl)phenoxy]naphth N H2N N alene-2-carboxamide O N-[(1S)-1-(2-Pyridyl)ethyl]-5- [4- 7 H N NFF (trifluoromethyl)phenyl]naphthal O F ene-2-carboxamide H NON S N O N-Methyl-3-(1-methylimidazol- NH 4-y1)-4-[4- 8 (trifluoromethyl)anilino]benzene sulfonamide F F F O 5-(4-Cyclohexylpheny1)-2-(3- N N N methylpyrazin-2-y1)-3-[rac- N N (2S,3S)-3-(fluoromethyl)-2- 9 H O N methyl-azetidine-l-carbonyl]- 4H-pyrazolo[1,5-a]pyrimidin-7- F oneWSGR Docket No.47612-749.601 O N HO 2-Methyl-8-[4- N N (trifluoromethyl)phenyl]-2H,8H- 10 pyrazolo[3,4-b]lindole-5- CF3carboxylic acid 4-((2S,4S)-5-Chloro-6-fluoro-2- O N HO H N phenyl-2-((S)-pyrrolidin-2-yl)- F 11 O 2,3-dihydrobenzofuran-4-yl)-5- Cl fluoro-6-(2-hydroxyethoxy)-N- F O HNmethylnicotinamide 2-((2S,3S,4S)-5-chloro-6-fluoro- O H 3-methyl-2- 2N F ((methylamino)methyl)-2- 12OCl phenyl-2,3-dihydrobenzofuran- F O HN 4-yl)-3-fluoro-4- methoxybenzamide O 2-((2S,4S)-5-Chloro-2- NH F2((((1r,4S)-4- O Cl hydroxycyclohexyl)amino)meth 13 O yl)-2-phenyl-2,3- HN dihydrobenzofuran-4-yl)-3- OH fluoro-4-methoxybenzamide 2-((2S,4S)-5-Chloro-6-fluoro-2- F O F NH ((((1s,4R)-4- F2O hydroxycyclohexyl)amino)meth Cl 14 yl)-2-phenyl-2,3- F O HN dihydrobenzofuran-4-yl)-4- OH (difluoromethoxy)-3- fluorobenzamideWSGR Docket No.47612-749.601 OH 2-((2S,3S)-5-Chloro-6-fluoro-2- O ((((1r,4S)-4-hydroxy-4- NH F2methylcyclohexyl)amino)methyl O 15 Cl )-3-methyl-2-phenyl-2,3- F O HN dihydrobenzofuran-4-yl)-3- fluoro-4-((S)-2- OH hydroxypropoxy)benzamide 2-((S)-5-chloro-6-fluoro-2- F O F NH ((((1r,4S)-4- F2O hydroxycyclohexyl)amino)meth Cl 16 yl)-2-phenyl-2,3- F O HN dihydrobenzofuran-4-yl)-4- OH (difluoromethoxy)-3- fluorobenzamide

[0160] In some embodiments, the YAP / TAZ-TEAD inhibitors are selected from the group consisting of: 5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-l-carbonyl)-2-(3-methylpyrazin-2- yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; N-(6-methoxy-5-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)pyridin-3-yl)acrylamide; 2-(((4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)amino)methyl)acrylic acid; N-(3-(17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3-methyl-2-oxo- 6,9,12,15-tetraoxa-3-azaheptadecyl)benzyl)-5-methoxy-4-(2-(4- (trifluoromethyl)cyclohexyl)vinyl)picolinamide; N-(1-(6-aminopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide; N-(1-(pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide; N-methyl-3-(1-methylimidazol-4-yl)-4-[4-(trifluoromethyl)anilino]benzenesulfonamide; 5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(3- methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; and 2-methyl-8-[4-(trifluoromethyl)phenyl1-2H,8H-pyrazolo[3,4-blindole-5-carboxylic acid, or a pharmaceutically acceptable salt thereof.

[0161] Also provided herein are, where applicable, any and all stereoisomers of the YAP / TAZ- TEAD inhibitors depicted herein, including geometric isomers (e.g., cis / trans isomers or E / Z isomers), enantiomers, diastereomers, or mixtures thereof in any ratio, including racemic mixtures.WSGR Docket No.47612-749.601

[0162] In some embodiments, the YAP / TAZ-TEAD inhibitors provided herein, such as compounds of Formula (A), (B), (C), (D), (E), (F), (G), (H), or (I) or any variation or embodiment thereof, are isotopically-labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number. Such isotopically-labeled (e.g., radiolabeled) compounds are considered to be within the scope of this disclosure. Examples of isotopes that can be incorporated into the YAP / TAZ-TEAD inhibitors provided herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, such as, but not limited to,2H,3H, a125nd I, respectively. Certain isotopically-labeled YAP / TAZ-TEAD inhibitor compounds, for example, those incorporating a radioactive isotope, are useful in drug or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.,3H, and carbon-14, i.e.,14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. For example, a YAP / TAZ-TEAD inhibitor provided herein can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.

[0163] For each of the YAP / TAZ-TEAD inhibitors described herein, such as a compound of Formula (A), (B), (C), (D), (E), (F), (G), (H), or (I) or any variation or embodiment thereof, substitution with heavier isotopes such as deuterium, i.e.,2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. It is to be understood that any hydrogen (1H) atom present in any of the compounds disclosed herein may be replaced by a deuterium (2H) atom. In any given compound provided herein, any number of hydrogen atoms may be replaced by the same number of deuterium atoms.

[0164] For each of the YAP / TAZ-TEAD inhibitors described herein, such as a compound of Formula (A), (B), (C), (D), (E), (F), (G), (H), or (I) or any variation or embodiment thereof, substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically- labeled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

[0165] In addition to salt forms, the present disclosure provides YAP / TAZ-TEAD inhibitors, such as a compound of Formula (A), (B), (C), (D), (E), (F), (G), (H), or (I) or any variation or embodiment thereof, which are in a prodrug form. As used herein the term “prodrug” refers to those compounds that readily undergo chemical changes under physiological conditions to provide the YAP / TAZ-TEAD inhibitors of the present disclosure. Additionally, prodrugs can be convertedWSGR Docket No.47612-749.601 to the YAP / TAZ-TEAD inhibitors of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the YAP / TAZ-TEAD inhibitors of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0166] Prodrugs of the YAP / TAZ-TEAD inhibitors provided herein may include phosphates, phosphate esters, alkyl phosphates, alkyl phosphate esters, acyl ethers, or other prodrug moieties as discussed below. In some embodiments, the prodrug moiety is:

[0167] Additional types of prodrugs of the YAP / TAZ-TEAD inhibitors provided herein are also encompassed. For example, where 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 a compound of the present disclosure. The amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, gamma- carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statine, 1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, methylalanine, para- benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone, and tert- butylglycine.

[0168] Additional types of prodrugs of the YAP / TAZ-TEAD inhibitors provided herein are also encompassed. For instance, a free carboxyl group of a compound of the disclosure can be derivatized as an amide or alkyl ester. As another example, YAP / TAZ-TEAD inhibitors of this disclosure comprising free hydroxy groups can be derivatized as prodrugs by converting the hydroxy group into a group such as, but not limited to, a phosphate ester, hemisuccinate, dimethylaminoacetate, or phosphoryloxymethyloxycarbonyl group, as outlined in Fleisher, D. et al., (1996) Improved oral drug delivery: solubility limitations overcome by the use of prodrugs Advanced Drug Delivery Reviews, 19:115. Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxyl groups. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acylWSGR Docket No.47612-749.601 group can be an alkyl ester optionally substituted with groups including, but not limited to, ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed. Prodrugs of this type are described in J. Med. Chem., (1996), 39:10. More specific examples include replacement of the hydrogen atom of the alcohol group with a group such as (C1-6)alkanoyloxymethyl, 1-((C1-6)alkanoyloxy)ethyl, 1-methyl-1-((C1-6)alkanoyloxy)ethyl, (C1-6)alkoxycarbonyloxymethyl, N-(C1-6)alkoxycarbonylaminomethyl, succinoyl, (C1-6)alkanoyl, alpha-amino(C1-4)alkanoyl, arylacyl and alpha-aminoacyl, or alpha- aminoacyl-alpha-aminoacyl, where each alpha-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(C1-6)alkyl)2or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).

[0169] For additional examples of prodrug derivatives that may be suitable for the YAP / TAZ- TEAD inhibitors provided herein, see, for example, a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol.42, p.309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard- Larsen and H. Bundgaard, Chapter 5 “Design and Application of Prodrugs,” by H. Bundgaard p.113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988); and e) N. Kakeya, et al., Chem. Pharm. Bull., 32:692 (1984), each of which is specifically incorporated herein by reference.

[0170] Additionally, the present disclosure provides for metabolites of the YAP / TAZ-TEAD inhibitors of the disclosure, such as a compound of Formula (A), (B), (C), (D), (E), (F), (G), (H), or (I) or any variation or embodiment thereof. As used herein, a “metabolite” refers to a product produced through metabolism in the body of a specified compound or salt thereof. Such products can result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound. Metabolite products typically are identified by preparing a radiolabeled (e.g.,14C or3H) isotope of a YAP / TAZ-TEAD inhibitor of the disclosure, administering it parenterally in a detectable dose (e.g., greater than about 0.5 mg / kg) to an animal such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples. These products are easily isolated since they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g., by MS, LC / MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well known to those skilled in theWSGR Docket No.47612-749.601 art. The metabolite products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the YAP / TAZ-TEAD inhibitors of the disclosure.

[0171] Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present disclosure. Certain compounds of the present disclosure can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure. Pharmaceutical Formulations

[0172] In some aspects, disclosed here are pharmaceutical formulations comprising Formula (A), (B), (C), (D), (E), (F), (G), (H), or (I) and at least one pharmaceutically acceptable excipient in a solid dosage form.

[0173] In some aspects, disclosed here are pharmaceutical formulations comprising any one of Compounds 1-16 and at least one pharmaceutically acceptable excipient in a solid dosage form.

[0174] In one aspect, the present application discloses pharmaceutical formulations in a solid dosage form comprising: (a) about 20% w / w to about 50% w / w of any one of Compounds 1-16; (b) about 15% w / w to about 40% w / w of a first filler; (c) about 15% w / w to about 40% w / w of a second filler; (d) about 1% w / w to about 10% w / w of a first lubricant; (e) about 0.1% w / w to about 1% w / w of a second lubricant; (f) about 1% w / w to about 5% w / w of a disintegrant; and (g) about 0.1% w / w to about 2% w / w of a glidant.

[0175] In some embodiments, the pharmaceutical formulation comprises about 20% w / w to about 50% w / w of any one of Compounds 1-16. In some embodiments, the pharmaceutical formulation comprises about 25% w / w to about 50% w / w of any one of Compounds 1-16. In some embodiments, the pharmaceutical formulation comprises about 30% w / w to about 50% w / w of any one of Compounds 1-16. In some embodiments, the pharmaceutical formulation comprises about 35% w / w to about 50% w / w of any one of Compounds 1-16. In some embodiments, the pharmaceutical formulation comprises about 25% w / w to about 45% w / w of any one of Compounds 1-16. In some embodiments, the pharmaceutical formulation comprises about 30% w / w to about 45% w / w of any one of Compounds 1-16. In some embodiments, the pharmaceutical formulation comprises about 35% w / w to about 45% w / w of any one of Compounds 1-16. In someWSGR Docket No.47612-749.601 embodiments, the pharmaceutical formulation comprises about 30% w / w to about 40% w / w of any one of Compounds 1-16. In some embodiments, the pharmaceutical formulation comprises about 35% w / w to about 40% w / w of any one of Compounds 1-16.

[0176] In some embodiments, the pharmaceutical formulation comprises about 20% w / w of any one of Compounds 1-16. In some embodiments, the pharmaceutical formulation comprises about 25% w / w of any one of Compounds 1-16. In some embodiments, the pharmaceutical formulation comprises about 30% w / w of any one of Compounds 1-16. In some embodiments, the pharmaceutical formulation comprises about 35% w / w of any one of Compounds 1-16. In some embodiments, the pharmaceutical formulation comprises about 37% w / w of any one of Compounds 1-16. In some embodiments, the pharmaceutical formulation comprises about 40% w / w of any one of Compounds 1-16. In some embodiments, the pharmaceutical formulation comprises about 45% w / w of any one of Compounds 1-16. In some embodiments, the pharmaceutical formulation comprises about 50% w / w of any one of Compounds 1-16.

[0177] In some embodiments, the pharmaceutical formulation comprises about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 300 mg, or about 400 mg of any one of Compounds 1-16. In some embodiments, the pharmaceutical formulation comprises about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg or about 200 mg of any one of Compounds 1-16. In some embodiments, the pharmaceutical formulation comprises about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg, or about 200 mg of any one of Compounds 1-16. In some embodiments, the pharmaceutical formulation comprises about 25 mg, about 50 mg, about 100 mg, about 150 mg, or about 200 mg of any one of Compounds 1-16. In some embodiments, the pharmaceutical formulation comprises about 25 mg, about 50 mg, or about 100 mg of any one of Compounds 1-16.

[0178] In some embodiments, the pharmaceutical formulation comprises about 25 mg of any one of Compounds 1-16. In some embodiments, the pharmaceutical formulation comprises about 50 mg of any one of Compounds 1-16. In some embodiments, the pharmaceutical formulation comprises about 75 mg of any one of Compounds 1-16. In some embodiments, the pharmaceutical formulation comprises about 100 mg of any one of Compounds 1-16. In some embodiments, the pharmaceutical formulation comprises about 125 mg of any one of Compounds 1-16. In some embodiments, the pharmaceutical formulation comprises about 150 mg of any one of Compounds 1-16. In some embodiments, the pharmaceutical formulation comprises about 175 mg of any one of Compounds 1-16. In some embodiments, the pharmaceutical formulation comprises about 200 mg of any one of Compounds 1-16. In some embodiments, the pharmaceutical formulation comprisesWSGR Docket No.47612-749.601 about 300 mg of any one of Compounds 1-16. In some embodiments, the pharmaceutical formulation comprises about 400 mg of any one of Compounds 1-16.

[0179] In some aspects, the fillers disclosed herein increase bulk in the pharmaceutical formulation. In some embodiments, the pharmaceutical formulation further comprises about 15% w / w to about 40% w / w of a first filler. In some embodiments, the pharmaceutical formulation comprises about 15% w / w to about 35% w / w of the first filler. In some embodiments, the pharmaceutical formulation comprises about 15% w / w to about 30% w / w of the first filler. In some embodiments, the pharmaceutical formulation comprises about 20% w / w to about 35% w / w of the first filler. In some embodiments, the pharmaceutical formulation comprises about 20% w / w to about 30% w / w of the first filler. In some embodiments, the pharmaceutical formulation comprises about 25% w / w to about 30% w / w of the first filler. In some embodiments, the pharmaceutical formulation comprises about 15% w / w of the first filler. In some embodiments, the pharmaceutical formulation comprises about 20% w / w of the first filler. In some embodiments, the pharmaceutical formulation comprises about 25% w / w of the first filler. In some embodiments, the pharmaceutical formulation comprises about 26% w / w of the first filler. In some embodiments, the pharmaceutical formulation comprises about 27% w / w of the first filler. In some embodiments, the pharmaceutical formulation comprises about 28% w / w of the first filler. In some embodiments, the pharmaceutical formulation comprises about 29% w / w of the first filler. In some embodiments, the pharmaceutical formulation comprises about 30% w / w of the first filler. In some embodiments, the pharmaceutical formulation comprises about 35% w / w of the first filler. In some embodiments, the pharmaceutical formulation comprises about 40% w / w of the first filler.

[0180] In some embodiments, the pharmaceutical formulation further comprises about 15% w / w to about 40% w / w of a second filler. In some embodiments, the pharmaceutical formulation comprises about 15% w / w to about 35% w / w of the second filler. In some embodiments, the pharmaceutical formulation comprises about 15% w / w to about 30% w / w of the second filler. In some embodiments, the pharmaceutical formulation comprises about 20% w / w to about 35% w / w of the second filler. In some embodiments, the pharmaceutical formulation comprises about 20% w / w to about 30% w / w of the second filler. In some embodiments, the pharmaceutical formulation comprises about 25% w / w to about 30% w / w of the second filler. In some embodiments, the pharmaceutical formulation comprises about 15% w / w of the second filler. In some embodiments, the pharmaceutical formulation comprises about 20% w / w of the second filler. In some embodiments, the pharmaceutical formulation comprises about 25% w / w of the second filler. In some embodiments, the pharmaceutical formulation comprises about 26% w / w of the second filler. In some embodiments, the pharmaceutical formulation comprises about 27% w / w of the secondWSGR Docket No.47612-749.601 filler. In some embodiments, the pharmaceutical formulation comprises about 28% w / w of the second filler. In some embodiments, the pharmaceutical formulation comprises about 29% w / w of the second filler. In some embodiments, the pharmaceutical formulation comprises about 30% w / w of the second filler. In some embodiments, the pharmaceutical formulation comprises about 35% w / w of the second filler. In some embodiments, the pharmaceutical formulation comprises about 40% w / w of the second filler.

[0181] In some embodiments, the first filler and second filler are independently selected from lactose, erythritol, sorbitol, mannitol, dicalcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, starch, and pregelatinized starch (Starch 1500).

[0182] In some embodiments, the first filler is selected from lactose, erythritol, sorbitol, mannitol, dicalcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, starch, and pregelatinized starch (Starch 1500). In some embodiments, the first filler is lactose. In some embodiments, the lactose is lactose monohydrate. In some embodiments, the first filler is lactose monohydrate. In some embodiments, the first filler is erythritol. In some embodiments, the first filler is sorbitol. In some embodiments, the first filler is mannitol. In some embodiments, the mannitol is mannitol 200 SD. In some embodiments, the first filler is mannitol 200 SD. In some embodiments, the first filler is dicalcium phosphate. In some embodiments, the first filler is microcrystalline cellulose. In some embodiments, the first filler is silicified microcrystalline cellulose. In some embodiments, the first filler is starch. In some embodiments, the first filler is pregelatinized starch (Starch 1500).

[0183] In some embodiments, the second filler is selected from lactose, erythritol, sorbitol, mannitol, dicalcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, starch, and pregelatinized starch (Starch 1500). In some embodiments, the second filler is lactose. In some embodiments, the lactose is lactose monohydrate. In some embodiments, the second filler is lactose monohydrate. In some embodiments, the second filler is erythritol. In some embodiments, the second filler is sorbitol. In some embodiments, the second filler is mannitol. In some embodiments, the mannitol is mannitol 200 SD. In some embodiments, the second filler is mannitol 200 SD. In some embodiments, the second filler is dicalcium phosphate. In some embodiments, the second filler is microcrystalline cellulose. In some embodiments, the second filler is silicified microcrystalline cellulose. In some embodiments, the second filler is starch. In some embodiments, the second filler is pregelatinized starch (Starch 1500).

[0184] In some aspects, the lubricants disclosed herein are compounds which prevent, reduce, or inhibit adhesion or friction of materials. In some embodiments, the pharmaceutical formulation further comprises about 1% w / w to about 10% w / w of a first lubricant. In some embodiments, theWSGR Docket No.47612-749.601 pharmaceutical formulation comprises about 2% w / w to about 10% w / w of the first lubricant. In some embodiments, the pharmaceutical formulation comprises about 3% w / w to about 10% w / w of the first lubricant. In some embodiments, the pharmaceutical formulation comprises about 4% w / w to about 10% w / w of the first lubricant. In some embodiments, the pharmaceutical formulation comprises about 5% w / w to about 10% w / w of the first lubricant. In some embodiments, the pharmaceutical formulation comprises about 1% w / w to about 9% w / w of the first lubricant. In some embodiments, the pharmaceutical formulation comprises about 1% w / w to about 8% w / w of the first lubricant. In some embodiments, the pharmaceutical formulation comprises about 1% w / w to about 7% w / w of the first lubricant. In some embodiments, the pharmaceutical formulation comprises about 1% w / w to about 6% w / w of the first lubricant. In some embodiments, the pharmaceutical formulation comprises about 1% w / w to about 5% w / w of the first lubricant. In some embodiments, the pharmaceutical formulation comprises about 2% w / w to about 8% w / w of the first lubricant. In some embodiments, the pharmaceutical formulation comprises about 3% w / w to about 7% w / w of the first lubricant. In some embodiments, the pharmaceutical formulation comprises about 3% w / w to about 6% w / w of the first lubricant. In some embodiments, the pharmaceutical formulation comprises about 4% w / w to about 6% w / w of the first lubricant. In some embodiments, the pharmaceutical formulation comprises about 1% w / w of the first lubricant. In some embodiments, the pharmaceutical formulation comprises about 2% w / w of the first lubricant. In some embodiments, the pharmaceutical formulation comprises about 3% w / w of the first lubricant. In some embodiments, the pharmaceutical formulation comprises about 3.5% w / w of the first lubricant. In some embodiments, the pharmaceutical formulation comprises about 4% w / w of the first lubricant. In some embodiments, the pharmaceutical formulation comprises about 4.5% w / w of the first lubricant. In some embodiments, the pharmaceutical formulation comprises about 5% w / w of the first lubricant. In some embodiments, the pharmaceutical formulation comprises about 5.5% w / w of the first lubricant. In some embodiments, the pharmaceutical formulation comprises about 6% w / w of the first lubricant. In some embodiments, the pharmaceutical formulation comprises about 6.5% w / w of the first lubricant. In some embodiments, the pharmaceutical formulation comprises about 7% w / w of the first lubricant. In some embodiments, the pharmaceutical formulation comprises about 8% w / w of the first lubricant. In some embodiments, the pharmaceutical formulation comprises about 9% w / w of the first lubricant. In some embodiments, the pharmaceutical formulation comprises about 10% w / w of the first lubricant.

[0185] In some embodiments, the pharmaceutical formulation further comprises about 0.1% w / w to about 1% w / w of a second lubricant. In some embodiments, the pharmaceutical formulationWSGR Docket No.47612-749.601 comprises about 0.2% w / w to about 1% w / w of the second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.3% w / w to about 1% w / w of the second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.4% w / w to about 1% w / w of the second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.5% w / w to about 1% w / w of the second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.1% w / w to about 0.9% w / w of the second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.1% w / w to about 0.8% w / w of the second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.1% w / w to about 0.7% w / w of the second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.1% w / w to about 0.6% w / w of the second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.1% w / w to about 0.5% w / w of the second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.3% w / w to about 0.7% w / w of the second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.4% w / w to about 0.7% w / w of the second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.5% w / w to about 0.7% w / w of the second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.3% w / w to about 0.6% w / w of the second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.4% w / w to about 0.6% w / w of the second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.5% w / w to about 0.6% w / w of the second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.1% w / w of the second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.2% w / w of the second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.3% w / w of the second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.4% w / w of the second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.5% w / w of the second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.6% w / w of the second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.7% w / w of the second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.8% w / w of the second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.9% w / w of the second lubricant. In some embodiments, the pharmaceutical formulation comprises about 1% w / w of the second lubricant.

[0186] In some embodiments, for the pharmaceutical formulation comprising about 0.5% w / w of the second lubricant, about 0% w / w of the second lubricant is intragranular and about 0.5% w / w of the second lubricant is extragranular. In some embodiments, for the pharmaceutical formulationWSGR Docket No.47612-749.601 comprising about 0.5% w / w of the second lubricant, about 0.1% w / w of the second lubricant is intragranular and about 0.4% w / w of the second lubricant is extragranular. In some embodiments, for the pharmaceutical formulation comprising about 0.5% w / w of the second lubricant, about 0.2% w / w of the second lubricant is intragranular and about 0.3% w / w of the second lubricant is extragranular. In some embodiments, for the pharmaceutical formulation comprising about 0.5% w / w of the second lubricant, about 0.3% w / w of the second lubricant is intragranular and about 0.2% w / w of the second lubricant is extragranular. In some embodiments, for the pharmaceutical formulation comprising about 0.5% w / w of the second lubricant, about 0.4% w / w of the second lubricant is intragranular and about 0.1% w / w of the second lubricant is extragranular. In some embodiments, for the pharmaceutical formulation comprising about 0.5% w / w of the second lubricant, about 0.5% w / w of the second lubricant is intragranular and about 0% w / w of the second lubricant is extragranular.

[0187] In some embodiments, the first lubricant and second lubricant are independently selected from sodium laureth sulfate, sodium lauryl sulfate, magnesium stearate, stearic acid, sodium stearate, calcium stearate, ammonium lauryl sulfate, and sodium stearyl fumarate.

[0188] In some embodiments, the first lubricant is selected from sodium laureth sulfate, sodium lauryl sulfate, magnesium stearate, stearic acid, sodium stearate, calcium stearate, ammonium lauryl sulfate, and sodium stearyl fumarate. In some embodiments, the first lubricant is sodium laureth sulfate. In some embodiments, the first lubricant is sodium lauryl sulfate. In some embodiments, the first lubricant is magnesium stearate. In some embodiments, the first lubricant is stearic acid. In some embodiments, the first lubricant is sodium stearate. In some embodiments, the first lubricant is calcium stearate. In some embodiments, the first lubricant is ammonium lauryl sulfate. In some embodiments, the first lubricant is sodium stearyl fumarate.

[0189] In some embodiments, the second lubricant is selected from sodium laureth sulfate, sodium lauryl sulfate, magnesium stearate, stearic acid, sodium stearate, calcium stearate, ammonium lauryl sulfate, and sodium stearyl fumarate. In some embodiments, the second lubricant is sodium laureth sulfate. In some embodiments, the second lubricant is sodium lauryl sulfate. In some embodiments, the second lubricant is magnesium stearate. In some embodiments, the second lubricant is stearic acid. In some embodiments, the second lubricant is sodium stearate. In some embodiments, the second lubricant is calcium stearate. In some embodiments, the second lubricant is ammonium lauryl sulfate. In some embodiments, the second lubricant is sodium stearyl fumarate.

[0190] In some aspects, the disintegrants disclosed herein facilitate breakup or disintegration of the pharmaceutical formulation after administration. In some embodiments, the pharmaceutical formulation further comprises about 1% w / w to about 5% w / w of a disintegrant. In someWSGR Docket No.47612-749.601 embodiments, the pharmaceutical formulation comprises about 1% w / w to about 4% w / w of the disintegrant. In some embodiments, the pharmaceutical formulation comprises about 1% w / w to about 3% w / w of the disintegrant. In some embodiments, the pharmaceutical formulation comprises about 1% w / w to about 2% w / w of the disintegrant. In some embodiments, the pharmaceutical formulation comprises about 2% w / w to about 5% w / w of the disintegrant. In some embodiments, the pharmaceutical formulation comprises about 2% w / w to about 4% w / w of the disintegrant. In some embodiments, the pharmaceutical formulation comprises about 2.5% w / w to about 3.5% w / w of the disintegrant. In some embodiments, the pharmaceutical formulation comprises about 2% w / w to about 3% w / w of the disintegrant. In some embodiments, the pharmaceutical formulation comprises about 3% w / w to about 4% w / w of the disintegrant. In some embodiments, the pharmaceutical formulation comprises about 1% w / w of the disintegrant. In some embodiments, the pharmaceutical formulation further comprises about 2% w / w of the disintegrant. In some embodiments, the pharmaceutical formulation further comprises about 2.5% w / w of the disintegrant. In some embodiments, the pharmaceutical formulation further comprises about 3% w / w of the disintegrant. In some embodiments, the pharmaceutical formulation further comprises about 3.5% w / w of the disintegrant. In some embodiments, the pharmaceutical formulation further comprises about 4% w / w of the disintegrant. In some embodiments, the pharmaceutical formulation further comprises about 5% w / w of the disintegrant.

[0191] In some embodiments, the disintegrant is selected from povidone, crospovidone, hypromellose, croscarmellose sodium, carboxymethylcellulose, hydroxypropyl cellulose, and poly(vinyl alcohol). In some embodiments, the disintegrant is povidone. In some embodiments, the disintegrant is crospovidone. In some embodiments, the disintegrant is hypromellose. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the disintegrant is carboxymethylcellulose. In some embodiments, the disintegrant is hydroxypropyl cellulose. In some embodiments, the disintegrant is poly(vinyl alcohol).

[0192] In some aspects, the glidants disclosed herein improve the flow characteristics of a powder mixtures. In some embodiments, the pharmaceutical formulation further comprises about 0.1% w / w to about 2% w / w of a glidant. In some embodiments, the pharmaceutical formulation comprises about 0.2% w / w to about 2% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 0.3% w / w to about 2% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 0.4% w / w to about 2% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 0.5% w / w to about 2% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 0.6% w / w to about 2% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises aboutWSGR Docket No.47612-749.601 0.7% w / w to about 2% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 0.8% w / w to about 2% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 0.9% w / w to about 2% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 1% w / w to about 2% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 0.1% w / w to about 1.9% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 0.1% w / w to about 1.8% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 0.1% w / w to about 1.7% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 0.1% w / w to about 1.6% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 0.1% w / w to about 1.5% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 0.1% w / w to about 1.4% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 0.1% w / w to about 1.3% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 0.1% w / w to about 1.2% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 0.1% w / w to about 1.1% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 0.3% w / w to about 1.7% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 0.5% w / w to about 1.5% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 0.7% w / w to about 1.3% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 0.9% w / w to about 1.1% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 1% w / w to about 1.5% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 0.5% w / w to about 1% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 0.1% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 0.2% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 0.3% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 0.4% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 0.5% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 0.6% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 0.7% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 0.8% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 0.9% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 1% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 1.1% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 1.2% w / w of theWSGR Docket No.47612-749.601 glidant. In some embodiments, the pharmaceutical formulation comprises about 1.3% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 1.4% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 1.5% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 1.6% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 1.7% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 1.8% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 1.9% w / w of the glidant. In some embodiments, the pharmaceutical formulation comprises about 2% w / w of the glidant.

[0193] In some embodiments, the glidant is selected from silicate, silicon dioxide, and talc. In some embodiments, the glidant is silicate. In some embodiments, the glidant is silicon dioxide. In some embodiments, the silicon dioxide is colloidal silicon dioxide. In some embodiments, the glidant is colloidal silicon dioxide. In some embodiments, the glidant is talc.

[0194] In some embodiments, disclosed herein are pharmaceutical formulations in a solid dosage form comprising: (a) about 37% w / w of any one of Compounds 1-16; (b) about 26.7% w / w of lactose monohydrate; (c) about 26.7% w / w of mannitol; (d) about 5% w / w of sodium lauryl sulfate; (e) about 0.5% w / w of magnesium stearate; (f) about 3% w / w of croscarmellose sodium; and (g) about 1% w / w of colloidal silicon dioxide.

[0195] In some embodiments, the pharmaceutical formulation has a half-life of at least 1 day. In some embodiments, the pharmaceutical formulation has a half-life of at least 2 days. In some embodiments, the pharmaceutical formulation has a half-life of at least 3 days. In some embodiments, the pharmaceutical formulation has a half-life of at least 4 days. In some embodiments, the pharmaceutical formulation has a half-life of at least 5 days. In some embodiments, the pharmaceutical formulation has a half-life of at least 6 days. In some embodiments, the pharmaceutical formulation has a half-life of at least 7 days. In some embodiments, the pharmaceutical formulation has a half-life of at least 8 days. In some embodiments, the pharmaceutical formulation has a half-life of at least 9 days. In some embodiments, the pharmaceutical formulation has a half-life of at least 10 days. In some embodiments, the pharmaceutical formulation has a half-life of at least 11 days. In some embodiments, the pharmaceutical formulation has a half-life of at least 12 days. In someWSGR Docket No.47612-749.601 embodiments, the pharmaceutical formulation has a half-life of at least 13 days. In some embodiments, the pharmaceutical formulation has a half-life of at least 14 days. In some embodiments, the pharmaceutical formulation has a half-life of at least 15 days.

[0196] In some embodiments, the pharmaceutical formulation has a half-life of 1 to 20 days. In some embodiments, the pharmaceutical formulation has a half-life of 2 to 19 days. In some embodiments, the pharmaceutical formulation has a half-life of 3 to 18 days. In some embodiments, the pharmaceutical formulation has a half-life of 4 to 17 days. In some embodiments, the pharmaceutical formulation has a half-life of 5 to 16 days. In some embodiments, the pharmaceutical formulation has a half-life of 6 to 15 days. In some embodiments, the pharmaceutical formulation has a half-life of 7 to 15 days. In some embodiments, the pharmaceutical formulation has a half-life of 8 to 15 days. In some embodiments, the pharmaceutical formulation has a half-life of 9 to 15 days. In some embodiments, the pharmaceutical formulation has a half-life of 10 to 15 days. In some embodiments, the pharmaceutical formulation has a half-life of 11 to 15 days. In some embodiments, the pharmaceutical formulation has a half-life of 12 to 15 days.

[0197] In some embodiments, the pharmaceutical formulation has a half-life of 1 day. In some embodiments, the pharmaceutical formulation has a half-life of 2 days. In some embodiments, the pharmaceutical formulation has a half-life of 3 days. In some embodiments, the pharmaceutical formulation has a half-life of 4 days. In some embodiments, the pharmaceutical formulation has a half-life of 5 days. In some embodiments, the pharmaceutical formulation has a half-life of 6 days. In some embodiments, the pharmaceutical formulation has a half-life of 7 days. In some embodiments, the pharmaceutical formulation has a half-life of 8 days. In some embodiments, the pharmaceutical formulation has a half-life of 9 days. In some embodiments, the pharmaceutical formulation has a half-life of 10 days. In some embodiments, the pharmaceutical formulation has a half-life of 11 days. In some embodiments, the pharmaceutical formulation has a half-life of 12 days. In some embodiments, the pharmaceutical formulation has a half-life of 13 days. In some embodiments, the pharmaceutical formulation has a half-life of 14 days. In some embodiments, the pharmaceutical formulation has a half-life of 15 days. In some embodiments, the pharmaceutical formulation has a half-life of 16 days. In some embodiments, the pharmaceutical formulation has a half-life of 17 days. In some embodiments, the pharmaceutical formulation has a half-life of 18 days. In some embodiments, the pharmaceutical formulation has a half-life of 19 days. In some embodiments, the pharmaceutical formulation has a half-life of 20 days.WSGR Docket No.47612-749.601 Dosage Forms

[0198] In some aspects, the pharmaceutical formulations, comprising Formula (A), (B), (C), (D), (E), (F), (G), (H), or (I) described herein, are incorporated into a solid unit dosage form.

[0199] In some aspects, the pharmaceutical formulations, comprising any one of Compounds 1-16, described herein, are incorporated into a solid unit dosage form.

[0200] The term "solid unit dosage form" means a dosage form intended to be swallowed as a single unit that is selected from the group consisting of a powder, a tablet, a bite-disintegration tablet, a chewable tablet, a caplet, a capsule, a gelcap, an effervescent powder, a rapid- disintegration tablet, an abuse-deterrent tablet, a modified release tablet, a modified release caplet, a modified release capsule, and an aqueous suspension produced from a powder.

[0201] In some embodiments, the solid dosage form is a powder. In some embodiments, the solid dosage form is a tablet. In some embodiments, the solid dosage form is a bite-disintegration tablet. In some embodiments, the solid dosage form is a chewable tablet. In some embodiments, the solid dosage form is a caplet. In some embodiments, the solid dosage form is a capsule. In some embodiments, the solid dosage form is a gelcap. In some embodiments, the solid dosage form is an effervescent powder. In some embodiments, the solid dosage form is a rapid-disintegration tablet. In some embodiments, the solid dosage form is an abuse-deterrent tablet. In some embodiments, the solid dosage form is a modified release tablet. In some embodiments, the solid dosage form is a modified release caplet. In some embodiments, the solid dosage form is a modified release capsule. In some embodiments, the solid dosage form is an aqueous suspension produced from a powder.

[0202] In some embodiments, the capsule disclosed herein is a hard gelatin capsule. In some embodiments, the hard gelatin capsule comprises gelatin and titanium dioxide. In some embodiments, the hard gelatin capsule is gelatin. In some embodiments, the hard gelatin capsule is titanium dioxide. In some embodiments, the capsule is gelatin. In some embodiments, the capsule is titanium dioxide.

[0203] In some embodiments, the hard gelatin capsule disclosed herein further comprises FD&C Red 40 and FD&C Blue 1. In some embodiments, the hard gelatin capsule disclosed herein further comprises FD&C Red 40. In some embodiments, the hard gelatin capsule disclosed herein further comprises FD&C Blue 1.

[0204] In some embodiments, the solid dosage form is a dry-granulation blend.WSGR Docket No.47612-749.601 Methods

[0205] In some embodiments, the present disclosure provides methods for treating cancer in a subject in need thereof, comprising administering to the subject a pharmaceutical formulation disclosed herein.

[0206] In some embodiments, the present disclosure provides a method for treating cancer in a subject in need thereof, comprising administering to the subject a pharmaceutical formulation disclosed herein, comprising a therapeutically effective amount of any one of Compounds 1-16. In some embodiments, the present disclosure provides a method for treating cancer in a subject in need thereof, comprising administering to the subject a pharmaceutical formulation disclosed herein, comprising a therapeutically effective amount of any one of Compounds 1-16 and at least one pharmaceutically acceptable excipient.

[0207] In some embodiments, the cancer is mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma, lung cancer, bladder carcinoma, cutaneous neurofibromas, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, or breast cancer. In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is hepatocellular carcinoma. In some embodiments, the cancer is meningioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumor. In some embodiments, the cancer is Schwannoma. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is bladder carcinoma. In some embodiments, the cancer is cutaneous neurofibromas. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is glioblastoma. In some embodiments, the cancer is endometrial adenosquamous carcinoma. In some embodiments, the cancer is anaplastic thyroid carcinoma. In some embodiments, the cancer is gastric adenocarcinoma. In some embodiments, the cancer is esophageal adenocarcinoma. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is ovarian serous adenocarcinoma. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is breast cancer.

[0208] In some embodiments, the present application provides methods for treating cancer in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of any one of Compounds 1-16, wherein the therapeutically effective amount of any one of Compounds 1-16 is administered daily for at least three days. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered daily for at least four days. In some embodiments, the therapeutically effective amount of any one of Compounds 1-WSGR Docket No.47612-749.601 16 is administered daily for at least five days. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered daily for at least six days. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered daily for at least seven days. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered daily for at least eight days. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered daily for at least nine days. In some embodiments, the therapeutically effective amount of any one of Compounds 1- 16 is administered daily for at least 10 days. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered daily for at least 11 days. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered daily for at least 12 days. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered daily for at least 13 days. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered daily for at least 14 days. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered daily for at least 15 days. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered daily for at least one week. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered daily for at least two weeks. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered daily for at least three weeks.

[0209] In some embodiments, the therapeutically effective amount of any one of Compounds 1- 16 is administered as an oral formulation.

[0210] In some embodiments, the therapeutically effective amount of any one of Compounds 1- 16 is administered in a capsule.

[0211] In some embodiments, the therapeutically effective amount of any one of Compounds 1- 16 is at least 10 mg daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is at least 15 mg daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is at least 20 mg daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is at least 25 mg daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is at least 50 mg daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is at least 75 mg daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is at least 100 mg daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is at least 125 mg daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is at least 150 mg daily. In someWSGR Docket No.47612-749.601 embodiments, the therapeutically effective amount of any one of Compounds 1-16 is at least 175 mg daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1- 16 is at least 200 mg daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is at least 225 mg daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is at least 250 mg daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is at least 275 mg daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is at least 300 mg daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1- 16 is at least 325 mg daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is at least 350 mg daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is at least 375 mg daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is at least 400 mg daily.

[0212] In some embodiments, the therapeutically effective amount of any one of Compounds 1- 16 is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 300 mg, or 400 mg daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is 25 mg, 50 mg, 100 mg, 125 mg, 150 mg, or 200 mg daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is 25 mg, 50 mg, 100 mg, 150 mg, or 200 mg daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is 25 mg, 50 mg, or 100 mg daily.

[0213] In some embodiments, the therapeutically effective amount of any one of Compounds 1- 16 is 25 mg daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is 50 mg daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is 75 mg daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is 100 mg daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is 125 mg daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is 150 mg daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is 175 mg daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is 200 mg daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is 250 mg daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1- 16 is 300 mg daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is 350 mg daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is 400 mg daily.WSGR Docket No.47612-749.601

[0214] In some embodiments, the therapeutically effective amount of any one of Compounds 1- 16 is administered daily. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered daily for at least a week. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered daily for a week. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered daily for at least two weeks. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered daily for two weeks. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered daily for at least three weeks. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered daily for three weeks. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered daily for four weeks.

[0215] In some embodiments, the therapeutically effective amount of any one of Compounds 1- 16 is administered in a cycle length of three weeks, wherein the therapeutically effective amount of any one of Compounds 1-16 is administered daily for one week, and then not administered for the following two weeks. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in a cycle length of three weeks, wherein the therapeutically effective amount of any one of Compounds 1-16 is 200 mg administered daily for one week, and then not administered for the following two weeks. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in a cycle length of three weeks, wherein the therapeutically effective amount of any one of Compounds 1-16 is 150 mg administered daily for one week, and then not administered for the following two weeks. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in a cycle length of three weeks, wherein the therapeutically effective amount of any one of Compounds 1-16 is 100 mg administered daily for one week, and then not administered for the following two weeks. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in a cycle length of three weeks, wherein the therapeutically effective amount of any one of Compounds 1-16 is 50 mg administered daily for one week, and then not administered for the following two weeks.

[0216] In some embodiments, the therapeutically effective amount of any one of Compounds 1- 16 is administered in a cycle length of three weeks, wherein the therapeutically effective amount of any one of Compounds 1-16 is administered daily for two weeks, and then not administered for the following one week. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in a cycle length of three weeks, wherein the therapeutically effective amount of any one of Compounds 1-16 is 200 mg administered daily for two weeks, andWSGR Docket No.47612-749.601 then not administered for the following one week. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in a cycle length of three weeks, wherein the therapeutically effective amount of any one of Compounds 1-16 is 150 mg administered daily for two weeks, and then not administered for the following one week. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in a cycle length of three weeks, wherein the therapeutically effective amount of any one of Compounds 1-16 is 100 mg administered daily for two weeks, and then not administered for the following one week. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in a cycle length of three weeks, wherein the therapeutically effective amount of any one of Compounds 1-16 is 50 mg administered daily for two weeks, and then not administered for the following one week.

[0217] In some embodiments, the therapeutically effective amount of any one of Compounds 1- 16 is administered in a cycle length of four weeks, wherein the therapeutically effective amount of any one of Compounds 1-16 is administered daily for one week, and then not administered for the following three weeks. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in a cycle length of four weeks, wherein the therapeutically effective amount of any one of Compounds 1-16 is 200 mg administered daily for one week, and then not administered for the following three weeks. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in a cycle length of four weeks, wherein the therapeutically effective amount of any one of Compounds 1-16 is 150 mg administered daily for one week, and then not administered for the following three weeks. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in a cycle length of four weeks, wherein the therapeutically effective amount of any one of Compounds 1-16 is 100 mg administered daily for one week, and then not administered for the following three weeks. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in a cycle length of four weeks, wherein the therapeutically effective amount of any one of Compounds 1-16 is 50 mg administered daily for one week, and then not administered for the following three weeks.

[0218] In some embodiments, the therapeutically effective amount of any one of Compounds 1- 16 is administered in a cycle length of four weeks, wherein the therapeutically effective amount of any one of Compounds 1-16 is administered daily for two weeks, and then not administered for the following two weeks. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in a cycle length of four weeks, wherein the therapeutically effective amount of any one of Compounds 1-16 is 200 mg administered daily for two weeks, andWSGR Docket No.47612-749.601 then not administered for the following two weeks. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in a cycle length of four weeks, wherein the therapeutically effective amount of any one of Compounds 1-16 is 150 mg administered daily for two weeks, and then not administered for the following two weeks. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in a cycle length of four weeks, wherein the therapeutically effective amount of any one of Compounds 1-16 is 100 mg administered daily for two weeks, and then not administered for the following two weeks. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in a cycle length of four weeks, wherein the therapeutically effective amount of any one of Compounds 1-16 is 50 mg administered daily for two weeks, and then not administered for the following two weeks.

[0219] In some embodiments, the therapeutically effective amount of any one of Compounds 1- 16 is administered in a cycle length of four weeks, wherein the therapeutically effective amount of any one of Compounds 1-16 is administered daily for three weeks, and then not administered for the following one week. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in a cycle length of four weeks, wherein the therapeutically effective amount of any one of Compounds 1-16 is 200 mg administered daily for three weeks, and then not administered for the following one week. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in a cycle length of four weeks, wherein the therapeutically effective amount of any one of Compounds 1-16 is 150 mg administered daily for three weeks, and then not administered for the following one week. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in a cycle length of four weeks, wherein the therapeutically effective amount of any one of Compounds 1-16 is 100 mg administered daily for three weeks, and then not administered for the following one week. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in a cycle length of four weeks, wherein the therapeutically effective amount of any one of Compounds 1-16 is 50 mg administered daily for three weeks, and then not administered for the following one week.

[0220] In some embodiments, the therapeutically effective amount of any one of Compounds 1- 16 is 25 mg administered once daily for two weeks, and then 100 mg administered once weekly. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is 50 mg administered once daily for two weeks, and then 100 mg administered once weekly. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is 75 mg administered once daily for two weeks, and then 100 mg administered once weekly. In someWSGR Docket No.47612-749.601 embodiments, the therapeutically effective amount of any one of Compounds 1-16 is 100 mg administered once daily for two weeks, and then 100 mg administered once weekly.

[0221] In some embodiments, the therapeutically effective amount of any one of Compounds 1- 16 is administered daily for 15 days, and then administered once weekly for three weeks. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is 50 mg administered once daily for 15 days, and then 50 mg administered once weekly for three weeks. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is 100 mg administered once daily for 15 days, and then 100 mg administered once weekly for three weeks. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is 50 mg administered once daily for 15 days, and then 100 mg administered once weekly for three weeks.

[0222] In some embodiments, the therapeutically effective amount of any one of Compounds 1- 16 is administered in at least one cycle. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in at least two cycles. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in at least three cycles. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in at least four cycles. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in at least five cycles. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in at least six cycles. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in at least seven cycles. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in at least eight cycles. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in at least nine cycles. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in at least 10 cycles. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in at least 11 cycles. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in at least 12 cycles.

[0223] In some embodiments, the therapeutically effective amount of any one of Compounds 1- 16 is administered in one cycle. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in two cycles. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in three cycles. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in four cycles. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in five cycles. In some embodiments, the therapeutically effectiveWSGR Docket No.47612-749.601 amount of any one of Compounds 1-16 is administered in six cycles. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in seven cycles. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in eight cycles. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in nine cycles. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in 10 cycles. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in 11 cycles. In some embodiments, the therapeutically effective amount of any one of Compounds 1-16 is administered in 12 cycles.

[0224] Further embodiments provided herein include combinations of one or more of the particular embodiments set forth above. Diseases Cancer

[0225] In some embodiments, a pharmaceutical formulation and a method disclosed herein are useful for treating cancer. In some embodiments, provided herein is a pharmaceutical formulation and a method for treating a cancer in a subject in need thereof comprising administering to the subject in need thereof a pharmaceutical formulation, comprising a pharmaceutically effective amount of any one of Compounds 1-16, disclosed herein. In some embodiments, provided herein is a pharmaceutical formulation, comprising a pharmaceutically effective amount of any one of Compounds 1-16, for the use in treating a cancer in a subject in need thereof comprising administering to the subject in need thereof. In some embodiments, provided herein is the use of a pharmaceutical formulation, comprising a pharmaceutically effective amount of any one of Compounds 1-16, disclosed herein in the manufacture of a medicament for treating cancer.

[0226] 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 Gα-protein. In some embodiments, the mutant Gα-protein is selected from G12, G13, Gq, G11, Gi, Go, and Gs. In some embodiments, the mutant Gα-protein is G12. In some embodiments, the mutant Gα-protein is G13. In some embodiments, the mutant Gα-protein is Gq. In some embodiments, the mutant Gα-protein is G11. In some embodiments, the mutant Gα-protein is Gi. In some embodiments, the mutant Gα-protein is Go. In some embodiments, the mutant Gα-protein is Gs.WSGR Docket No.47612-749.601

[0227] 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.

[0228] 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 of bone, 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.

[0229] 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.

[0230] 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,WSGR Docket No.47612-749.601 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.

[0231] 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 cell lymphoma, 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.

[0232] 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.

[0233] 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,WSGR Docket No.47612-749.601 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.

[0234] 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, 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 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.

[0235] 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, 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,WSGR Docket No.47612-749.601 plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.

[0236] 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.

[0237] 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.

[0238] 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 lymphocyticWSGR Docket No.47612-749.601 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.

[0239] In some instances, the cancer is mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma, lung cancer, bladder carcinoma, cutaneous neurofibromas, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, or breast cancer. Non-Cancer Indications

[0240] In some embodiments, the pharmaceutical formulations and methods disclosed herein are useful for treating polycystic kidney disease. In some embodiments, the pharmaceutical formulations and methods 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 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 thereof. In some embodiments, provided herein is use of a compound disclosed herein or a pharmaceutically acceptable salt 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 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 thereof. In some embodiments, provided herein is use of a compound or a pharmaceutically acceptable salt thereof disclosed herein in the manufacture of a medicament for treating liver fibrosis.WSGR Docket No.47612-749.601 Congenital Diseases

[0241] In some embodiments, the pharmaceutical formulations and methods 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 a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt 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 thereof. In some embodiments, provided herein is use of a compound disclosed herein or a pharmaceutically acceptable salt 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 Gα-protein. In some embodiments, the mutant Gα-protein is selected from G12, G13, Gq, G11, Gi, Go, and Gs. In some embodiments, the mutant Gα-protein is G12. In some embodiments, the mutant Gα-protein is G13. In some embodiments, the mutant Gα-protein is Gq. In some embodiments, the mutant Gα-protein is G11. In some embodiments, the mutant Gα- protein is Gi. In some embodiments, the mutant Gα-protein is Go. In some embodiments, the mutant Gα-protein is Gs.

[0242] 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.WSGR Docket No.47612-749.601 Definitions

[0243] 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.

[0244] 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. For example, the term “a sample” includes a plurality of samples, including mixtures thereof. 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.

[0245] As used herein, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0246] 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 µL” means “about 5 µL” and also “5 µL.” Generally, the term “about” includes an amount that is expected to be within experimental error.

[0247] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0248] 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 non- human. 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).WSGR Docket No.47612-749.601

[0249] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0250] "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.

[0251] The terms “formulation” and “composition,” as used herein, are used interchangeably and refer to a mixture of two or more compounds, elements, or molecules. In some aspects, the terms “formulation” and “composition” may be used to refer to a mixture of one or more active agents with a carrier or other excipients.

[0252] The terms “moiety” and “substituent” refer to an atom or group of chemically bonded atoms that is attached to another atom or molecule by one or more chemical bonds thereby forming part of a molecule.

[0253] The term “substituted” refers to the replacement of at least one of hydrogen atom of a compound or moiety with another substituent or moiety. Examples of such substituents include, without limitation, halogen, -OH, -CN, oxo, alkoxy, alkyl, aryl, heteroaryl, haloalkyl, haloalkoxy, cycloalkyl and heterocycle. For example, the term “alkyl substituted by halogen” refers to the fact that one or more hydrogen atoms of an alkyl (as defined below) is replaced by one or more halogen atoms (e.g., trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, etc.).

[0254] The term “alkyl” refers to an aliphatic straight-chain or branched-chain saturated hydrocarbon moiety having 1 to 20 carbon atoms unless provided otherwise. For example, in particular embodiments, the alkyl has 1 to 10 carbon atoms. In particular embodiments the alkyl has 1 to 6 carbon atoms. Alkyl groups may be optionally substituted independently with one or more substituents described herein.

[0255] The term “alkoxy” denotes a group of the formula -O-R’, wherein R’ is an alkyl group. Alkoxy groups may be optionally substituted independently with one or more substituents described herein. Examples of alkoxy moieties include methoxy, ethoxy, isopropoxy, and tert- butoxy.

[0256] “Aryl” means a cyclic aromatic hydrocarbon moiety having a mono-, bi-, or tricyclic aromatic ring of 6 to 20 carbon ring atoms unless provided otherwise. For example, in particular embodiments, the aryl has 6 to 10 carbon atoms. Bicyclic aryl ring systems include fused bicyclics having two fused five-membered aryl rings (denoted as 5-5), having a five-membered aryl ring and a fused six-membered aryl ring (denoted as 5-6 and as 6-5), and having two fused six-memberedWSGR Docket No.47612-749.601 aryl rings (denoted as 6-6). The aryl group can be optionally substituted as defined herein. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, and the like. The term “aryl” also includes partially hydrogenated derivatives of the cyclic aromatic hydrocarbon moiety provided that at least one ring of the cyclic aromatic hydrocarbon moiety is aromatic, each being optionally substituted.

[0257] The term “heteroaryl” denotes an aromatic heterocyclic mono-, bi-, or tri-cyclic ring system of 5 to 20 ring atoms unless provided otherwise, comprising 1, 2, 3, or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. For example, in some aspects, monocyclic heteroaryl rings may be 5-6 membered. In some aspects, heteroaryl rings may contain 5 to 10 carbon atoms. Bicyclic heteroaryl ring systems include fused bicyclics having two fused five- membered heteroaryl rings (denoted as 5-5), having a five-membered heteroaryl ring and a fused six-membered heteroaryl ring (denoted as 5-6 and 6-5), and having two fused six-membered heteroaryl rings (denoted as 6-6). The heteroaryl group can be optionally substituted as defined herein. Examples of heteroaryl moieties include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl.

[0258] The terms “halo”, “halogen” and “halide”, which may be used interchangeably, refer to a substituent fluoro, chloro, bromo, or iodo.

[0259] The term “haloalkyl” denotes an alkyl group wherein one or more of the hydrogen atoms of the alkyl group has been replaced by the same or different halogen atoms, particularly fluoro atoms. Examples of haloalkyl include monofluoro-, difluoro-, or trifluoro-methyl, -ethyl or -propyl, for example 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0260] “Cycloalkyl” means a saturated or partially unsaturated carbocyclic moiety having mono-, bi- (including bridged bicyclic) or tricyclic rings and 3 to 10 carbon atoms in the ring unless provided otherwise. For example, in particular embodiments cycloalkyl contains from 3 to 8 carbon atoms (i.e., (C3-C8)cycloalkyl). In other particular embodiments cycloalkyl contains from 3 to 6 carbon atoms (i.e., (C3-C6)cycloalkyl). Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and partially unsaturated (cycloalkenyl) derivatives thereof (e.g., cyclopentenyl, cyclohexenyl, and cycloheptenyl), bicyclo[3.1.0]hexanyl, bicyclo[3.1.0]hexenyl, bicyclo[3.1.1]heptanyl, and bicyclo[3.1.1]heptenyl.WSGR Docket No.47612-749.601 The cycloalkyl moiety can be attached in a “spirocycloakyl” fashion such as “spirocyclopropyl”:. The cycloalkyl moiety can optionally be substituted with one or more substituents.

[0261] “Heterocycle” or “heterocyclyl” refers to a 3, 4, 5, 6, and 7-membered monocyclic, 7-, 8-, 9-, and 10-membered bicyclic (including bridged bicyclic) or 10-, 11-, 12-, 13-, 14-, and 15- membered bicyclic heterocyclic moiety, unless provided otherwise, that is saturated or partially unsaturated and has one or more (e.g., 1, 2, 3 or 4 heteroatoms selected from oxygen, nitrogen and sulfur in the ring with the remaining ring atoms being carbon. For example, in particular embodiments heterocycle or heterocyclyl refers to a 4-, 5-, 6-, or 7-membered heterocycle. In some aspects, the heterocycle is a heterocycloalkyl. When used in reference to a ring atom of a heterocycle, a nitrogen or sulfur may also be in an oxidized form, and a nitrogen may be substituted with one or more groups such as C1-C6alkyl. The heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Any of the heterocycle ring atoms can be optionally substituted with one or more substituents described herein. Examples of such saturated or partially unsaturated heterocycles include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The term the term heterocycle also includes groups in which a heterocycle is fused to one or more aryl, heteroaryl, or cycloalkyl rings, such as indolinyl, 3H-indolyl, chromanyl, azabicyclo[2.2.1]heptanyl, azabicyclo[3.1.0]hexanyl, azabicyclo[3.1.1]heptanyl, octahydroindolyl, or tetrahydroquinolinyl.

[0262] The term “fused bicyclic” denotes a ring system including two fused rings, including bridged cycloalkyl and bridged heterocycloalkyl as defined elsewhere herein. The rings are each independently, aryl, heteroaryl, cycloalkyl, and heterocycle. In some aspects, the rings are each independently, C5-6aryl, 5-6 membered heteroaryl, C3-6cycloalkyl, and 4-6 membered heterocycle. Non-limiting examples of fused bicyclic ring systems include C5-6aryl-C5-6aryl, C5-6aryl-4-6 membered heteroaryl, and C5-6aryl-C5-6cycloalkyl.

[0263] Unless otherwise indicated, the term “hydrogen” or “hydro” refers to the moiety of a hydrogen atom (-H) and not H2.

[0264] In the description herein, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold wedged, or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. In some cases, however,WSGR Docket No.47612-749.601 where more than one chiral center exists, the structures and names may be represented as single enantiomers to help describe the relative stereochemistry.

[0265] Unless otherwise indicated, the term “a compound of the formula” or “a compound of formula” or “compounds of the formula” or “compounds of formula” refers to any compound selected from the genus of compounds as defined by the formula (including any pharmaceutically acceptable salt or ester of any such compound if not otherwise noted).

[0266] The term “pharmaceutically acceptable salts” refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. As used herein, “pharmaceutically acceptable” refers to a carrier, diluent or excipient that is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Salts may be formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, salicylic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, N- acetylcystein and the like. In addition, salts may be prepared by the addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, and magnesium 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, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins and the like.

[0267] The compounds of the present disclosure can be present in the form of pharmaceutically acceptable salts. Another embodiment provides non-pharmaceutically acceptable salts of the compounds provided herein, which can be useful as an intermediate for isolating or purifying such compounds. The compounds of the present disclosure can also be present in the form of pharmaceutically acceptable esters (e.g., methyl and ethyl esters to be used as prodrugs). The compounds of the present disclosure can also be solvated, e.g., hydrated. The solvation can be affected in the course of the manufacturing process or can take place, e.g., as a consequence of hygroscopic properties of an initially anhydrous compound provided herein.

[0268] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Diastereomers areWSGR Docket No.47612-749.601 stereoisomers with opposite configuration at one or more chiral centers which are not enantiomers. Stereoisomers bearing one or more asymmetric centers that are non-superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, if a carbon atom is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center or centers and is described by the R- and S-sequencing rules of Cahn, Ingold and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-) isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”. In certain embodiments the compound is enriched by at least about 90% by weight with a single diastereomer or enantiomer. In other embodiments the compound is enriched by at least about 95%, 98%, or 99% by weight with a single diastereomer or enantiomer.

[0269] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, regioisomers, and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present disclosure.

[0270] The compounds of the disclosure may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the disclosure, including but not limited to, diastereomers, enantiomers, and atropisomers as well as mixtures thereof such as racemic mixtures, form part of the present disclosure. In some instances, the stereochemistry has not been determined or has been provisionally assigned. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity. Enantiomers may be separated from a racemic mixture by a chiral separation method, such as supercritical fluid chromatography (SFC).WSGR Docket No.47612-749.601 Assignment of configuration at chiral centers in separated enantiomers may be tentative, while stereochemistry is definitively established, such as from X-ray crystallographic data.

[0271] 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 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.

[0272] The terms “effective amount” or “therapeutically effective amount” as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in a disease. An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study.

[0273] The terms “active agent,” “active pharmaceutical agent,” “drug,” “active ingredient,” and variants thereof are used interchangeably to refer to an agent or substance that has measurable specified or selected physiologic activity when administered to a subject in a significant or effective amount.

[0274] While not intending to be bound by any particular theory, certain solid forms are characterized by physical properties (e.g., stability, solubility and dissolution rate) appropriate for pharmaceutical and therapeutic dosage forms. Moreover, while not wishing to be bound by any particular theory, certain solid forms are characterized by physical properties (e.g., density, compressibility, hardness, morphology, cleavage, stickiness, solubility, water uptake, electrical properties, thermal behavior, solid-state reactivity, physical stability, and chemical stability) affecting particular processes (e.g., yield, filtration, washing, drying, milling, mixing, tableting, flowability, dissolution, formulation, and lyophilization) which make certain solid forms suitable for the manufacture of a solid dosage form. Such properties can be determined using particularWSGR Docket No.47612-749.601 analytical chemical techniques, including solid-state analytical techniques (e.g., X-ray diffraction, microscopy, spectroscopy and thermal analysis), as described herein and known in the art. EXAMPLES

[0275] The following illustrative examples are representative of embodiments of the stimulation, systems, and methods described herein and are not meant to be limiting in any way.

[0276] The present disclosure relates to Compounds 1-10, as described in International Application No. PCT / US2022 / 072452, filed May 19, 2022, and published as WO2022 / 246459A1, and of which is hereby incorporated by reference in its entirety.

[0277] The present disclosure relates to Compounds 11-16, as described in International Application No. PCT / IB2022 / 058104, filed August 30, 2022, and published as WO2023 / 031781A1, and of which is hereby incorporated by reference in its entirety.

[0278] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

WSGR Docket No.47612-749.601 CLAIMS What is claimed is:

1. A pharmaceutical formulation in a solid dosage form comprising: (a) about 20% w / w to about 50% w / w of any one of Compounds 1-16; (b) about 15% w / w to about 40% w / w of a first filler; (c) about 15% w / w to about 40% w / w of a second filler; (d) about 1% w / w to about 10% w / w of a first lubricant; (e) about 0.1% w / w to about 1% w / w of a second lubricant; (f) about 1% w / w to about 5% w / w of a disintegrant; and (g) about 0.1% w / w to about 2% w / w of a glidant. 2 The pharmaceutical formulation of claim 1, comprising about 25% w / w to about 45% w / w of the any one of Compounds 1-16. 3 The pharmaceutical formulation of claim 1 or 2, comprising about 30% w / w to about 40% w / w of the any one of Compounds 1-16. 4 The pharmaceutical formulation of any one of claims 1 to 3, comprising about 37% w / w of the any one of Compounds 1-16. 5 The pharmaceutical formulation of any one of claims 1 to 4, wherein the any one of Compounds 1-16 is in a 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 300 mg, or 400 mg amount. 6 The pharmaceutical formulation of any one of claims 1 to 5, wherein the any one of Compounds 1-16 is in a 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg or 200 mg amount. 7 The pharmaceutical formulation of any one of claims 1 to 6, wherein the any one of Compounds 1-16 is in a 25 mg, 50 mg, 100 mg, 125 mg, or 150 mg amount. 8 The pharmaceutical formulation of any one of claims 1 to 7, wherein the any one of Compounds 1-16 is in a 25 mg, 50 mg, or 100 mg amount. 9 The pharmaceutical formulation of any one of claims 1 to 8, wherein the any one of Compounds 1-16 is in a 25 mg amount. 10 The pharmaceutical formulation of any one of claims 1 to 9, wherein the any one of Compounds 1-16 is in a 50 mg amount. 11 The pharmaceutical formulation of any one of claims 1 to 10, wherein the any one of Compounds 1-16 is in a 100 mg amount. 12 The pharmaceutical formulation of any one of claims 1 to 11, comprising about 20% w / w to about 35% w / w of the first filler.WSGR Docket No.47612-749.601 13. The pharmaceutical formulation of any one of claims 1 to 12, comprising about 25% w / w to about 30% w / w of the first filler.

14. The pharmaceutical formulation of any one of claims 1 to 13, comprising about 27% w / w of the first filler.

15. The pharmaceutical formulation of any one of claims 1 to 14, comprising about 20% w / w to about 35% w / w of the second filler.

16. The pharmaceutical formulation of any one of claims 1 to 15, comprising about 25% w / w to about 30% w / w of the second filler.

17. The pharmaceutical formulation of any one of claims 1 to 16, comprising about 27% w / w of the second filler.

18. The pharmaceutical formulation of any one of claims 1 to 17, wherein the first filler and second filler are independently selected from lactose, erythritol, sorbitol, mannitol, dicalcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, starch, and pregelatinized starch (Starch 1500).

19. The pharmaceutical formulation of any one of claims 1 to 18, wherein the first filler is lactose.

20. The pharmaceutical formulation of claim 19, wherein the lactose is lactose monohydrate.

21. The pharmaceutical formulation of any one of claims 1 to 20, wherein the second filler is mannitol.

22. The pharmaceutical formulation of claim 21, wherein the mannitol is mannitol 200 SD.

23. The pharmaceutical formulation of any one of claims 1 to 22, comprising about 3% w / w to about 7% w / w of the first lubricant.

24. The pharmaceutical formulation of any one of claims 1 to 23, comprising about 5% w / w of the first lubricant.

25. The pharmaceutical formulation of any one of claims 1 to 24, comprising about 0.3% w / w to about 0.7% w / w of the second lubricant.

26. The pharmaceutical formulation of any one of claims 1 to 25, comprising about 0.5% w / w of the second lubricant.

27. The pharmaceutical formulation of claim 26, wherein about 0.3% w / w of the second lubricant is intragranular and about 0.2% w / w of the second lubricant is extragranular.

28. The pharmaceutical formulation of any one of claims 1 to 27, wherein the first lubricant and second lubricant are independently selected from sodium laureth sulfate, sodium lauryl sulfate, magnesium stearate, stearic acid, sodium stearate, calcium stearate, ammonium lauryl sulfate, and sodium stearyl fumarate.WSGR Docket No.47612-749.601 29. The pharmaceutical formulation of any one of claims 1 to 28, wherein the first lubricant is sodium lauryl sulfate.

30. The pharmaceutical formulation of any one of claims 1 to 29, wherein the second lubricant is magnesium stearate.

31. The pharmaceutical formulation of any one of claims 1 to 30, comprising about 2% w / w to about 4% w / w of the disintegrant.

32. The pharmaceutical formulation of any one of claims 1 to 31, comprising about 3% w / w of the disintegrant.

33. The pharmaceutical formulation of any one of claims 1 to 32, wherein the disintegrant is selected from povidone, crospovidone, hypromellose, croscarmellose sodium, carboxymethylcellulose, hydroxypropyl cellulose, and poly(vinyl alcohol).

34. The pharmaceutical formulation of any one of claims 1 to 33, wherein the disintegrant is croscarmellose sodium.

35. The pharmaceutical formulation of any one of claims 1 to 34, comprising about 0.5% w / w to about 1.5% w / w of the glidant.

36. The pharmaceutical formulation of any one of claims 1 to 35, comprising about 1% w / w of the glidant.

37. The pharmaceutical formulation of any one of claim 1 to 36, wherein the glidant is selected from silicate, silicon dioxide, and talc.

38. The pharmaceutical formulation of any one of claims 1 to 37, wherein the glidant is silicon dioxide.

39. The pharmaceutical formulation of claim 38, wherein the silicon dioxide is colloidal silicon dioxide.

40. A pharmaceutical formulation in a solid dosage form comprising: (a) about 37% w / w of any one of Compounds 1-16; (b) about 26.7% w / w of lactose monohydrate; (c) about 26.7% w / w of mannitol; (d) about 5% w / w of sodium lauryl sulfate; (e) about 0.5% w / w of magnesium stearate; (f) about 3% w / w of croscarmellose sodium; and (g) about 1% w / w of colloidal silicon dioxide.

41. The pharmaceutical formulation of any one of claims 1 to 40, wherein the pharmaceutical formulation has a half-life of at least 3 days.WSGR Docket No.47612-749.601 42. The pharmaceutical formulation of any one of claims 1 to 41, wherein the pharmaceutical formulation has a half-life of at least 7 days.

43. The pharmaceutical formulation of any one of claims 1 to 42, wherein the pharmaceutical formulation has a half-life of 12 to 15 days.

44. The pharmaceutical formulation of any one of claims 1 to 43, wherein the pharmaceutical formulation has a half-life of 12 days.

45. The pharmaceutical formulation of any one of claims 1 to 44, wherein the solid dosage form is selected from a powder, a tablet, a bite-disintegration tablet, a chewable tablet, a caplet, a capsule, a gelcap, an effervescent powder, a rapid-disintegration tablet, an abuse-deterrent tablet, a modified release tablet, a modified release caplet, a modified release capsule, and an aqueous suspension produced from a powder.

46. The pharmaceutical formulation of any one of claims 1 to 45, wherein the solid dosage form is a capsule.

47. The pharmaceutical formulation of claim 46, wherein the capsule is a hard gelatin capsule.

48. The pharmaceutical formulation of claim 47, wherein the hard gelatin capsule comprises gelatin and titanium dioxide.

49. The pharmaceutical formulation of claim 47 or claim 48, wherein the hard gelatin capsule further comprises FD&C Red 40 and FD&C Blue 1.

50. The pharmaceutical formulation of any one of claims 1 to 45, wherein the solid dosage form is a tablet.

51. The pharmaceutical formulation of any one of claims 1 to 45, wherein the solid dosage form is a caplet.

52. The pharmaceutical formulation of any one of claims 1 to 51, wherein the solid dosage form is a dry-granulation blend.

53. The pharmaceutical formulation of any one of claims 1 to 52, wherein Compounds 1-16 are selected from: 5-(4-Cyclohexylpheny1)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(3-methylpyrazin-2- yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (Compound 1); N-(7-(4-Isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)acrylamide (Compound 2); N-(6-Methoxy-5-((E)-2-((1r,4r)-4-(trifluommethyl)cyclohexyl)vinyl)pyridin-3-yl)acrylamide (Compound 3); 2-(((4-Cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)amino)methyl)acrylic acid (Compound 4);WSGR Docket No.47612-749.601 N-(3-(17-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3-methyl-2-oxo- 6,9,12,15-tetraoxa-3-azaheptadecyl)benzyl)-5-methoxy-4-((E)-2-((trans)-4- (trifluoromethyl)cyclohexyl)vinyl)picolinamide (Compound 5); N-[(1R)-1-(6-Amino-2-pyridyl)ethyl)-5-[4-(trifluoromethyl)phenoxy]naphthalene-2- carboxamide (Compound 6); N-[(1S)-1-(2-Pyridyl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamie (Compound 7); N-Methyl-3-(1-methylimidazol-4-y1)-4-[4-(trifluoromethyl)anilino]benzenesulfonamide (Compound 8); 5-(4-Cyclohexylpheny1)-2-(3-methylpyrazin-2-y1)-3-[rac-(2S,3S)-3-(fluoromethyl)-2-methyl- azetidine-l-carbonyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one (Compound 9); 2-Methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]lindole-5-carboxylic acid (Compound 10); 4-((2S,4S)-5-Chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-5- fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide (Compound 11); 2-((2S,3S,4S)-5-Chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3- dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Compound 12); 2-((2S,4S)-5-Chloro-2-((((1r,4S)-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3- dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Compound 13); 2-((2S,4S)-5-Chloro-6-fluoro-2-((((1s,4R)-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3- dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide (Compound 14); 2-((2S,3S)-5-Chloro-6-fluoro-2-((((1r,4S)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3- methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2- hydroxypropoxy)benzamide (Compound 15); and 2-((S)-5-Chloro-6-fluoro-2-((((1r,4S)-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3- dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide (Compound 16).

54. A method for treating cancer in a subject in need thereof, comprising administering to the subject a pharmaceutical formulation of any one of claims 1 to 53.

55. The method of claim 54, wherein the cancer is mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma, lung cancer, bladder carcinoma, cutaneous neurofibromas, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, or breast cancer.WSGR Docket No.47612-749.601 56. A method for treating cancer in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of any one of Compounds 1-16, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered daily for at least three days.

57. The method of claim 56, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered as an oral formulation.

58. The method of claim 56 or claim 57, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered in a capsule.

59. The method of any one of claims 56 to 58, wherein the therapeutically effective amount of the any one of Compounds 1-16 is at least 25 mg daily.

60. The method of any one of claims 56 to 59, wherein the therapeutically effective amount of the any one of Compounds 1-16 is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 300 mg, or 400 mg daily.

61. The method of any one of claims 56 to 60, wherein the therapeutically effective amount of the any one of Compounds 1-16 is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg daily.

62. The method of any one of claims 56 to 61, wherein the therapeutically effective amount of the any one of Compounds 1-16 is 25 mg, 50 mg, 100 mg, 125 mg, 150 mg, or 200 mg daily.

63. The method of any one of claims 56 to 62, wherein the therapeutically effective amount of the any one of Compounds 1-16 is 25 mg, 50 mg, or 100 mg daily.

64. The method of any one of claims 56 to 63, wherein the therapeutically effective amount of the any one of Compounds 1-16 is 25 mg daily.

65. The method of any one of claims 56 to 63, wherein the therapeutically effective amount of the any one of Compounds 1-16 is 50 mg daily.

66. The method of any one of claims 56 to 63, wherein the therapeutically effective amount of the any one of Compounds 1-16 is 100 mg daily.

67. The method of any one of claims 56 to 62, wherein the therapeutically effective amount of the any one of Compounds 1-16 is 150 mg daily.

68. The method of any one of claims 56 to 62, wherein the therapeutically effective amount of the any one of Compounds 1-16 is 200 mg daily.

69. The method of any one of claim 56 to 68, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered daily for at least a week.

70. The method of any one of claims 56 to 69, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered daily for at least two weeks.WSGR Docket No.47612-749.601 71. The method of any one of claims 56 to 70, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered daily for at least three weeks.

72. The method of any one of claims 56 to 68, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered in a cycle length of three weeks, wherein the therapeutically effective amount is administered daily for one week, and then not administered for two weeks.

73. The method of any one of claims 56 to 62, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered in a cycle length of three weeks, wherein the therapeutically effective amount is administered daily for one week, and then not administered for two weeks, wherein the therapeutically effective amount of the any one of Compounds 1- 16 is administered at 200 mg.

74. The method of any one of claims 56 to 68, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered in a cycle length of four weeks, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered daily for one week, and then not administered for the following three weeks.

75. The method of any one of claims 56 to 62, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered in a cycle length of four weeks, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered daily for one week, and then not administered for the following three weeks, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered at 150 mg.

76. The method of any one of claims 56 to 68, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered in a cycle length of three weeks, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered daily for two weeks, and then not administered for the following one week.

77. The method of any one of claims 56 to 62, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered in a cycle length of three weeks, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered daily for two weeks, and then not administered for the following one week, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered at 200 mg.

78. The method of any one of claims 56 to 68, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered in a cycle length of four weeks, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered daily for two weeks, and then not administered for the following two weeks.WSGR Docket No.47612-749.601 79. The method of any one of claims 56 to 62, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered in a cycle length of four weeks, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered daily for two weeks, and then not administered for the following two weeks, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered at 100 mg.

80. The method of any one of claims 56 to 62, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered in a cycle length of four weeks, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered daily for two weeks, and then not administered for the following two weeks, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered at 200 mg.

81. The method of any one of claims 72 to 80, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered in at least two cycles.

82. The method of any one of claims 56 to 68, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered daily for 15 days, and then administered once weekly for three weeks.

83. The method of any one of claims 56 to 62, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered 50 mg daily for 15 days, and then 50 mg administered once weekly for three weeks.

84. The method of any one of claims 56 to 62, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered 50 mg daily for 15 days, and then 100 mg administered once weekly for three weeks.

85. The method of any one of claims 56 to 62, wherein the therapeutically effective amount of the any one of Compounds 1-16 is administered 100 mg daily for 15 days, and then 100 mg administered once weekly for three weeks.

86. The method of any one of claims 56 to 85, wherein the cancer is mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma, lung cancer, bladder carcinoma, cutaneous neurofibromas, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, or breast cancer.

87. The pharmaceutical formulation of any one of claims 56 to 86, wherein Compounds 1-16 are selected from: 5-(4-Cyclohexylpheny1)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(3-methylpyrazin-2- yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (Compound 1);WSGR Docket No.47612-749.601 N-(7-(4-Isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)acrylamide (Compound 2); N-(6-Methoxy-5-((E)-2-((1r,4r)-4-(trifluommethyl)cyclohexyl)vinyl)pyridin-3-yl)acrylamide (Compound 3); 2-(((4-Cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)amino)methyl)acrylic acid (Compound 4); N-(3-(17-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3-methyl-2-oxo- 6,9,12,15-tetraoxa-3-azaheptadecyl)benzyl)-5-methoxy-4-((E)-2-((trans)-4- (trifluoromethyl)cyclohexyl)vinyl)picolinamide (Compound 5); N-[(1R)-1-(6-Amino-2-pyridyl)ethyl)-5-[4-(trifluoromethyl)phenoxy]naphthalene-2- carboxamide (Compound 6); N-[(1S)-1-(2-Pyridyl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamie (Compound 7); N-Methyl-3-(1-methylimidazol-4-y1)-4-[4-(trifluoromethyl)anilino]benzenesulfonamide (Compound 8); 5-(4-Cyclohexylpheny1)-2-(3-methylpyrazin-2-y1)-3-[rac-(2S,3S)-3-(fluoromethyl)-2-methyl- azetidine-l-carbonyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one (Compound 9); 2-Methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]lindole-5-carboxylic acid (Compound 10); 4-((2S,4S)-5-Chloro-6-fluoro-2-phenyl-2-((S)-pyrrolidin-2-yl)-2,3-dihydrobenzofuran-4-yl)-5- fluoro-6-(2-hydroxyethoxy)-N-methylnicotinamide (Compound 11); 2-((2S,3S,4S)-5-Chloro-6-fluoro-3-methyl-2-((methylamino)methyl)-2-phenyl-2,3- dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Compound 12); 2-((2S,4S)-5-Chloro-2-((((1r,4S)-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3- dihydrobenzofuran-4-yl)-3-fluoro-4-methoxybenzamide (Compound 13); 2-((2S,4S)-5-Chloro-6-fluoro-2-((((1s,4R)-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3- dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide (Compound 14); 2-((2S,3S)-5-Chloro-6-fluoro-2-((((1r,4S)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-3- methyl-2-phenyl-2,3-dihydrobenzofuran-4-yl)-3-fluoro-4-((S)-2- hydroxypropoxy)benzamide (Compound 15); and 2-((S)-5-Chloro-6-fluoro-2-((((1r,4S)-4-hydroxycyclohexyl)amino)methyl)-2-phenyl-2,3- dihydrobenzofuran-4-yl)-4-(difluoromethoxy)-3-fluorobenzamide (Compound 16).

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