Heterocyclic inhibitors of TEADs for treating cancer

Abstract

The present invention relates to compounds and methods of using said compounds for treating TEAD-mediated diseases and conditions, such as cancer, as well as pharmaceutical compositions containing such compounds.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 056,498, filed July 24, 2020, the disclosure of which is incorporated herein by reference in its entirety.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy, created on July 20, 2021, is named P35669-WO_SL.txt and is 33,605 bytes in size.

[0003] Field of Disclosure The present disclosure relates to compounds useful as inhibitors of TEAD, useful for treatment and / or prophylaxis in mammals, particularly useful for treating cancer. [Background technology]

[0004] Short description The Hippo signaling pathway regulates cell proliferation and cell death and determines organ size. This pathway is thought to act as a tumor suppressor in mammals, and disruptions of this pathway are frequently detected in human cancers. This pathway may be involved in and / or regulate the self-renewal and differentiation of stem and progenitor cells. In addition, the Hippo signaling pathway may be involved in wound healing and tissue regeneration. Furthermore, the Hippo signaling pathway crosstalks with other signaling pathways, such as Wnt, Notch, Hedgehog, and MAPK / ERK, which may affect a wide variety of biological events and whose dysfunction may contribute to many human diseases in addition to cancer. For reviews, see, e.g., Halder et al., 2011, Development 138:9-22; Zhao et al., 2011, Nature Cell Biology 13:877-883; Bao et al., 2011, J. Biochem. 149:361-379; Zhao et al., 2010, J. Cell Sci. 123:4001-4006.

[0005] The Hippo signaling pathway is conserved from Drosophila to mammals (Vassilev et al., Genes and Development, 2001, 15, 1229-1241; Zeng and Hong, Cancer Cell, 2008, 13, 188-192). The core of the pathway consists of a cascade of kinases (Hippo-MST1-2 is upstream of Lat1-2 and NDRI-2) that lead to the phosphorylation of two transcriptional coactivators, YAP (Yes-Associated Protein) and TAZ (a transcriptional coactivator with a PDZ-binding motif or tafazzin; Zhao et al., Cancer Res., 2009, 69, 1089-1098; Lei et al., Mol. Cell. Biol., 2008, 28, 2426-2436).

[0006] The Hippo signaling pathway is involved in cancer development because it is a regulator of animal development, organ size control, and stem cell regulation (reviewed in Harvey et al., Nat. Rev. Cancer, 2013, 13, 246-257; Zhao et al., Genes Dev., 2010, 24, 862-874). In vitro, overexpression of YAP or TAZ in breast epithelial cells induces cell transformation through the interaction of both proteins with the TEAD family of transcription factors. Elevated YAP / TAZ transcriptional activity induces oncogenic characteristics such as epithelial-mesenchymal transition (EMT) and has been shown to confer stem cell properties to breast cancer cells. In vivo, overexpression of YAP or its upstream regulator MST1-2 in mouse liver leads to the development of hepatocellular carcinoma (HCC). Furthermore, when the tumor suppressor NF2 is inactivated in mouse liver, HCC development can be completely blocked by co-inactivation of YAP.

[0007] Deregulation of the Hippo tumor suppressor pathway is associated with lung cancer (NSCLC; Zhou et al., Oncogene, 2011, 30, 2181-2186; Wang et al., Cancer Sci., 2010, 101, 1279-1285), breast cancer (Chan et al., Cancer Res., 2008, 68, 2592-2598; Lamar et al., Proc. Natl. Acad. Sci, USA, 2012; 109, E2441-E2250; Wang et al., Eur. J. Cancer, 2012, 48, 1227-1234), head and neck cancer (Gasparotto et al., Oncotarget., 2011, 2, 1165-1175; Steinmann et al., Oncol. Rep., 2009, 22, 1519-1526), ​​colon cancer (Angela et al., Hum. Pathol., 2008, 39, 1582-1589; Yuen et al., PLoS One, 2013, 8, e54211; Avruch et al., Cell Cycle, 2012, 11, 1090-1096), ovarian cancer (Angela et al., Hum. Pathol., 2008, 39, 1582-1589; Chad et al., Cancer Res., 2010, 70, 8517-8525; Hall et al., Cancer Res., 2010, 70, 8517-8525), liver cancer (Jie et al., Gastroenterol. Res. Pract., 2013, 2013, 1870-1870; Ahn et al., Mol. Cancer. Res., 2013, 11, 748-758; Liu et al., Expert. Opin. Ther. Targets, 2012, 16, 243-247), brain tumor (Orr et al., J Neuropathol. Exp. Neurol. 2011, 70, 568-577; Baia et al., Mol. Cancer Res., 2012, 10, 904-913; Striedinger et al., Neoplasia, 2008, 10, 1204-1212) and prostate cancer (Zhao et al., Genes Dev., 2012, 26, 54-68; Zhao et al., Genes Dev., 2007, 21, 2747-2761), mesothelioma (Fujii et al., J. Exp. Med., 2012, 209, 479-494; Mizuno et al., Oncogene, 2012, 31, 5117-5122; Sekido Y., Pathol. Int.It is believed to be a key event in the development of a wide range of malignancies, including but not limited to: sarcoma (Seidel et al., Mol. Carcinog., 2007, 46, 865-871), sarcoma (Seidel et al., Mol. Carcinog., 2011, 61, 331-344), and leukemia (Jimenez-Velasco et al., Leukemia, 2005, 19, 2347-2350).

[0008] Two of the core components of the mammalian Hippo pathway are the nuclear Dbf2-related (NDR) family protein kinases Lats1 and Lats2, which are homologous to the Drosophila Warts (Wts) kinase. Lats1 / 2 proteins are activated by association with the scaffolding protein Mob1A / B (Mps one binder kinase activator-like 1A and 1B), which is homologous to the Drosophila Mats protein. Lats1 / 2 proteins are also activated by phosphorylation by the STE20 family protein kinases Mst1 and Mst2, which are homologous to the Drosophila Hippo kinase. Lats1 / 2 kinases phosphorylate the downstream effectors YAP (Yes-associated protein) and TAZ (WWTR1, a transcriptional coactivator with a PDZ-binding motif), which are homologous to the Drosophila Yorkie protein. Phosphorylation of YAP and TAZ by Lats1 / 2 is a key event in the Hippo signaling pathway. Lats1 / 2 phosphorylates YAP at multiple sites, with Ser127 phosphorylation being critical for YAP inhibition. YAP phosphorylation generates a protein-binding motif for the 14-3-3 protein family, which results in YAP retention and / or sequestration in the cytoplasm of cells upon 14-3-3 protein binding. Similarly, Lats1 / 2 phosphorylates TAZ at multiple sites, with Ser89 phosphorylation being critical for TAZ inhibition. TAZ phosphorylation results in TAZ retention and / or sequestration in the cytoplasm of cells. Furthermore, phosphorylation of YAP and TAZ is thought to destabilize these proteins by activating phosphorylation-dependent degradation catalyzed by YAP or TAZ ubiquitination. Therefore, when the Hippo pathway is "on," YAP and / or TAZ are phosphorylated, inactive, and generally sequestrated in the cytoplasm. In contrast, when the Hippo pathway is "off," YAP and / or TAZ are unphosphorylated, active, and generally found in the nucleus.

[0009] Unphosphorylated, active YAP translocates into the cell nucleus, where its primary target transcription factors are the four proteins in the TEAD domain-containing family (TEAD1–TEAD4, collectively referred to as “TEAD”). YAP, together with other transcription factors such as Smad1, RUNX, ErbB4, and p73, has been shown to induce the expression of various genes, including connective tissue growth factor (CTGF), Gli2, Birc5, Birc2, fibroblast growth factor 1 (FGF1), and amphiregulin (AREG). Similar to YAP, unphosphorylated TAZ translocates into the cell nucleus, where it interacts with multiple DNA-binding transcription factors, including peroxisome proliferator-activated receptor γ (PPARγ), thyroid transcription factor-1 (TTF-1), Pax3, TBX5, RUNX, TEAD1, and Smad2 / 3 / 4. Many of the genes activated by the YAP / TAZ-transcription factor complex mediate cell survival and proliferation. Thus, under some conditions, YAP and / or TAZ act as oncogenes and the Hippo signaling pathway acts as a tumor suppressor.

[0010] Therefore, pharmacological targeting of the Hippo cascade via inhibition of TEADs may be an important approach for the treatment of cancers with functional alterations of this pathway. Summary of the Invention

[0011] Disclosure Overview In some embodiments, the compound of formula (X): JPEG0007796721000001.jpg27170 (in the formula, X1 is C-R5, and R5 of X1 together with R3 and the atom to which they are attached form a 5-membered heterocyclyl or 5-membered heteroaryl, which 5-membered heterocyclyl or 5-membered heteroaryl may be substituted with one or more D; X2 is N or C-R5, and each R5 is independently H, cyano, halo, C(O)NH2, N(R e )(R f ), C 3-10 Cycloalkyl, C 1-6Alkoxy, C 6-20 Aryl, S(O)2-C 1-6 Alkyl and C 1-6 alkyl, and R5 C 1-6 Alkyl is hydroxyl or N(R e )(R f ) may be substituted; X3 is N or CH; R1 is (i) A 3- to 5-membered saturated heterocyclyl containing at least one cyclic oxygen atom, wherein the 3- to 5-membered saturated heterocyclyl is one or more C 1-6 a 3- to 5-membered saturated heterocyclyl optionally substituted with alkyl, or (ii) N(R e )(R f ),or JPEG0007796721000002.jpg20170 (in the formula, R a , R b and R c are each independently H, halo, cyano, hydroxyl, B(OH), C(O)-OH, C(O)-N(R e )(R f ), C(O)-C 1-6 Alkoxy, C(O)-C 1-6 Alkyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-20 Aryl, 3-10 membered heterocyclyl, C 5-13 selected from the group consisting of spirocyclyl and 5- to 20-membered heteroaryl; 1-6 the alkyl may be further substituted with hydroxyl, or JPEG0007796721000003.jpg19170 (in the formula, R d is H, halo, cyano, hydroxyl, B(OH)2, C(O)-OH, C(O)-N(R e )(R f ), C(O)-C 1-6 Alkoxy, C(O)-C 1-6 Alkyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-20Aryl, 3-10 membered heterocyclyl, C 5-13 selected from the group consisting of spirocyclyl and 5- to 20-membered heteroaryl; 1-6 The alkyl may be further substituted with hydroxyl. and; L is absent or -O-, * -CH2-O- ** , * -O-CH2- ** , —CH═CH—, and —C≡C—; ** indicates the point of attachment to the R2 moiety, * indicates the point of attachment to the rest of the molecule, R2 is C 1-12 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 aryl or 5- to 20-membered heteroaryl; Here, C of R2 1-12 Alkyl, C 3-10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 5-13 Spirocyclyl, C 6-20 The aryl or 5- to 20-membered heteroaryl is independently selected from cyano, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, NO2, N(R e )(R f ), O(R e ) and S(R g ) 5, optionally substituted with one or more substituents selected from the group consisting of However, R2 is C 1-12 When R2 is alkyl, 1-12 Alkyl is independently selected from cyano, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, NO2, N(R e )(R f ), O(R e ) and S(R g) optionally substituted with one or more substituents selected from the group consisting of 5), L is -CH=CH- or -C≡C-; R4 is H or C 1-6 alkyl, C 1-6 The alkyl may be substituted with hydroxyl; R e and R f are, independently of each other and independently at each occurrence, H, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 1-6 Alkyl-C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 aryl, and 3- to 20-membered heteroaryl; R e and R f C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-6 Alkyl-C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 The aryl and the 3- to 20-membered heteroaryl are each independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 optionally substituted with one or more substituents selected from the group consisting of alkoxy, oxo, cyano, halo, NO2, and hydroxyl; R g is a halo) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0012] In some embodiments, the compound of formula (I): JPEG0007796721000004.jpg27170 (in the formula, X1 is N or C-R5, and each R5 is independently H, cyano, halo, C(O)NH2, N(R e )(R f ), C 3-10 Cycloalkyl, C 1-6 Alkoxy, C 6-20 Aryl and C 1-6 alkyl, and R5 C 1-6 Alkyl is hydroxyl or N(R e )(R f ), R5 of X1 together with R3 and the atom to which they are attached form a 5-membered heterocyclyl or a 5-membered heteroaryl, and the 5-membered heterocyclyl or 5-membered heteroaryl may be selected from the group consisting of one or more C 1-6 may be substituted with alkyl, X2 is N or C-R5, and each R5 is independently H, cyano, halo, C(O)NH2, N(R e )(R f ), C 3-10 Cycloalkyl, C 1-6 Alkoxy, C 6-20 Aryl and C 1-6 alkyl, and R5 C 1-6 Alkyl is hydroxyl or N(R e )(R f ), X3 is N or CH; R1 is (i) A 3- to 5-membered saturated heterocyclyl containing at least one cyclic oxygen atom, wherein the 3- to 5-membered saturated heterocyclyl is one or more C 1-6 a 3- to 5-membered saturated heterocyclyl optionally substituted with alkyl, or (ii) N(R e )(R f ),or JPEG0007796721000005.jpg19170 (in the formula, R a , R b and R c are each independently H, halo, cyano, hydroxyl, B(OH), C(O)-OH, C(O)-N(Re )(R f ), C(O)-C 1-6 Alkoxy, C(O)-C 1-6 Alkyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-20 Aryl, 3-10 membered heterocyclyl, C 5-13 selected from the group consisting of spirocyclyl and 5- to 20-membered heteroaryl; 1-6 the alkyl may be further substituted with hydroxyl, or JPEG0007796721000006.jpg19170 (in the formula, R d is H, halo, cyano, hydroxyl, B(OH)2, C(O)-OH, C(O)-N(R e )(R f ), C(O)-C 1-6 Alkoxy, C(O)-C 1-6 Alkyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-20 Aryl, 3-10 membered heterocyclyl, C 5-13 spirocyclyl, and 5- to 20-membered heteroaryl; 1-6 The alkyl may be further substituted with hydroxyl. and; L is absent or -O-, * -CH2-O- ** , * -O-CH2- ** , —CH═CH—, and —C≡C—; ** indicates the point of attachment to the R2 moiety, * indicates the point of attachment to the rest of the molecule, R2 is C 1-12 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 aryl or 5- to 20-membered heteroaryl; Here, C of R2 1-12 Alkyl, C 3-10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C5-13 Spirocyclyl, C 6-20 Aryl or 5- to 20-membered heteroaryl is independently selected from cyano, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, NO2, N(R e )(R f ) and O(R e and optionally substituted with one or more substituents selected from the group consisting of: However, R2 is C 1-12 When R2 is alkyl, 1-12 Alkyl is independently selected from cyano, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, NO2, N(R e )(R f ) and O(R e ), L is CH═CH— or —C≡C—; R3 is cyano, C 1-6 Alkyl, C 1-4 Alkoxy or C 2-4 alkenyl, C 2-4 Alkenyl is N(R e )(R f ), or R3, together with R5 of X1 and the atom to which they are attached, form a 5-membered heterocyclyl or a 5-membered heteroaryl, and the 5-membered heterocyclyl or 5-membered heteroaryl may be one or more C 1-6 may be substituted with alkyl, or R3 is the * -CH2-O- ** together with the carbon atoms and the atom to which they are attached form a C6 aryl or 6-membered heteroaryl; R4 is H or C 1-6 alkyl, C 1-6 The alkyl may be substituted by hydroxyl; R e and R fare, independently of each other and independently at each occurrence, H, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-6 Alkyl-C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 aryl, and 3~20 R is selected from the group consisting of: e and R f C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-6 Alkyl-C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 The aryl and the 3- to 20-membered heteroaryl are each independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 optionally substituted with one or more substituents selected from the group consisting of alkoxy, oxo, cyano, halo, NO2 and hydroxyl or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof is provided.

[0013] In some embodiments, there is provided a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, or excipient.

[0014] In some embodiments, there is provided a compound of Formula (X) or Formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof for use in medical therapy.

[0015] In some embodiments, there is provided a compound of Formula (X) or Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for the treatment or prevention of cancer, mesothelioma, sarcoma, or leukemia.

[0016] In some embodiments, there is provided a compound of Formula (X) or Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing cancer, mesothelioma, sarcoma, or leukemia.

[0017] In some embodiments, a method of treating cancer, mesothelioma, sarcoma, or leukemia in a mammal is provided, comprising administering to the mammal a compound of Formula (X) or Formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0018] In some embodiments, a method of treating cancer, mesothelioma, sarcoma, or leukemia in a mammal is provided, comprising administering to the mammal a compound of Formula (X) or Formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof in combination with a second therapeutic agent.

[0019] In some embodiments, a compound of Formula (X) or Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, is provided for modulating TEAD activity.

[0020] In some embodiments, there is provided a compound of Formula (X) or Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for treating or preventing a disease or condition mediated by TEAD activity.

[0021] In some embodiments, provided is a compound of (X) or formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in preparing a medicament for treating or preventing a disease or condition mediated by TEAD activity.

[0022] In some embodiments, a method of modulating TEAD activity is provided, comprising contacting a TEAD with a compound of Formula (X) or Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0023] In some embodiments, a method of treating a disease or condition mediated by TEAD activity in a mammal is provided, comprising administering to the mammal a compound of Formula (X) or Formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION

[0024] Detailed Description definition Unless otherwise indicated, the following specific terms used in the specification and claims are defined as follows:

[0025] The term "moiety" refers 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 the molecule.

[0026] The term "substituted" refers to at least one of the hydrogen atoms of a moiety being replaced with another substituent or moiety.

[0027] The term "alkyl" refers to an aliphatic straight- or branched-chain saturated hydrocarbon moiety having 1 to 20 carbon atoms, e.g., 1 to 12 carbon atoms or 1 to 6 carbon atoms. Alkyl groups may be substituted.

[0028] The term "cycloalkyl" refers to monocyclic or bicyclic (including bridged bicyclic) rings and saturated or partially unsaturated carbocyclic moieties having 3 to 10 carbon atoms in the ring. In certain embodiments, cycloalkyl can contain 3 to 8 carbon atoms (i.e., (C3-C8)cycloalkyl). In other certain embodiments, cycloalkyl can contain 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 their partially unsaturated (cycloalkenyl) derivatives (e.g., cyclopentenyl, cyclohexenyl, and cycloheptenyl). A cycloalkyl moiety can be spirocyclopropyl. They can be linked in a spirocyclic fashion such as JPEG0007796721000007.jpg15170.

[0029] The term "haloalkyl" refers to an alkyl group in which one or more of the alkyl group's hydrogen atoms have been replaced by the same or different halogen atoms, such as fluoro atoms. Examples of haloalkyl include monofluoro-, difluoro-, or trifluoro-methyl, -ethyl, or -propyl, such as 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl, or trifluoromethyl. Haloalkyl groups can be substituted.

[0030] The term "alkenyl" refers to a straight or branched chain alkyl or substituted alkyl group, as defined elsewhere herein, having at least one carbon-carbon double bond. Alkenyl groups may be optionally substituted.

[0031] The term "alkynyl" refers to a straight or branched chain alkyl or substituted alkyl group, as defined elsewhere herein, having at least one carbon-carbon triple bond. Alkynyl groups may be optionally substituted.

[0032] The term "heterocyclyl" or "heterocycle" refers to a 4-, 5-, 6-, or 7-membered monocyclic heterocycle or a 7-, 8-, 9-, or 10-membered bicyclic (including bridged bicycle) heterocyclic moiety that is saturated or partially saturated and has one or more (e.g., 1, 2, 3, or 4) heterocyclic ring members selected from oxygen, nitrogen, and sulfur in the ring, with the remaining ring atoms being carbon. When used in reference to a ring atom of a heterocycle, the nitrogen or sulfur may also be in an oxidized form, and the nitrogen may be substituted. A heterocycle may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and ring atoms may be substituted. Examples of such saturated or partially unsaturated heterocycles include, but are not limited to, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazolyl, thiazepinyl, morpholinyl, and quinuclidinyl. The term heterocycle also includes groups in which a heterocycle is fused to one or more aryl, heteroaryl, or cycloalkyl rings, such as benzothiazolyl, benzofuranyl, furopyridinyl, indolinyl, 3H-indolyl, chromanyl, 2-azabicyclo[2.2.1]heptanyl, octahydroindolyl, or tetrahydroquinolinyl. Heterocyclyl groups may be substituted.

[0033] The term "aryl" refers to a cyclic aromatic hydrocarbon moiety having a monocyclic, bicyclic, or tricyclic aromatic ring of 5 to 20 carbon ring atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and benzyl. The term "aryl" also includes partially hydrogenated derivatives of cyclic aromatic hydrocarbon moieties, provided that at least one ring of the cyclic aromatic hydrocarbon moiety is aromatic and each ring is optionally substituted. In some embodiments, a monocyclic aryl ring may have 5 or 6 carbon ring atoms. The aryl group may be substituted.

[0034] The term "heteroaryl" refers to an aromatic heterocyclic monocyclic or bicyclic ring system of 1 to 20 ring atoms containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. 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, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl. Heteroaryl groups may be optionally substituted.

[0035] The terms "halo" and "halogen" refer to fluoro, chloro, bromo, and iodo. In some embodiments, halogen is fluoro or chloro.

[0036] The term "oxo" refers to a =O moiety.

[0037] The term "cyano" refers to a -C≡N moiety.

[0038] The terms "spirocycle" and "spirocyclyl" refer to a carbocyclic bicyclic ring system containing 5 to 13 carbon atoms, with both rings bonded through a single atom. The rings may be different in size and nature, or identical in size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirodecane. One or more carbon atoms in the spirocycle may be replaced with a heteroatom (e.g., O, N, S, or P). The spirocycle group may be substituted.

[0039] The term "cyclic" refers to a moiety that is a member of a ring, including, but not limited to, a cycloalkyl ring, a cycloalkenyl ring, an aryl ring, a heteroaryl ring, a heterocyclyl ring, or a spirocyclyl ring. For example, if a heteroaryl ring is described as "comprising two or more ring heteroatoms," then two or more ring members of the heteroaryl ring are heteroatoms.

[0040] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the free base or free acid, without being biologically or otherwise undesirable. Salts can be formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, 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, and N-acetylcysteine. In addition, salts can be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, and magnesium salts. Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine resin, trimethylamine resin, diethylamine resin, triethylamine resin, tripropylamine resin, ethanolamine resin, lysine resin, arginine resin, N-ethylpiperidine resin, piperidine resin, and polyamine resin.

[0041] The term "prodrug" refers to a compound that readily undergoes chemical changes under physiological conditions to provide a compound of the present disclosure. Additionally, prodrugs can be converted to a compound of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, a prodrug can be slowly converted to a compound of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0042] In some prodrug embodiments, the prodrug comprises a compound in which an amino acid residue, or a polypeptide chain of two or more (e.g., 2, 3, or 4) amino acid residues, is covalently bonded via an amide or ester bond to a free amino, hydroxy, or carboxylic acid group of a compound of the disclosure. Amino acid residues include, but are not limited to, the 20 naturally occurring amino acids, commonly represented by their three-letter symbols, and also phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosin, isodemosin, gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statin, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, methyl-alanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone, and tert-butylglycine.

[0043] In some other prodrug embodiments, free carboxyl groups of the compounds of the present disclosure may be derivatized as amides or alkyl esters. In still other prodrug embodiments, prodrugs containing free hydroxy groups may be derivatized as prodrugs by converting the hydroxy group to groups such as, but not limited to, phosphate esters, hemisuccinates, dimethylaminoacetates, or phosphoryloxymethyloxycarbonyl groups, 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 hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers is also encompassed, where the acyl group may 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. This type of prodrug is described in J. Med. Chem., (1996), 39:10. More specific examples include prodrugs in which the hydrogen atom of the alcohol group is replaced with (C 1-6 ) alkanoyloxymethyl, 1-((C 1-6 )alkanoyloxy)ethyl, 1-methyl-1-((C 1-6 )alkanoyloxy)ethyl, (C 1-6 )alkoxycarbonyloxymethyl, N-(C 1-6 ) alkoxycarbonylaminomethyl, succinoyl, (C 1-6 ) alkanoyl, alpha-amino (C 1-4 )alkanoyl, arylacyl, and alpha-aminoacyl or alpha-aminoacyl-alpha-aminoacyl groups, each alpha-aminoacyl group independently being a naturally occurring L-amino acid, P(O)(OH), -P(O)(O(C1-6 ) alkyl) 2 or glycosyl (a group resulting from removal of a hydroxyl group from the hemiacetal form of a carbohydrate).

[0044] For additional examples of prodrug derivatives, see, for example, a) Design of Prodrugs, edited by H. Bundgaard (Elsevier, 1985) and Methods in Enzymology, Vol. 42, pp. 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", H. Bundgaard pp. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceuticals, each of which is expressly incorporated herein by reference. See Sciences, 77:285 (1988) and e) N. Kakeya, et al., Chem. Pharm. Bull., 32:692 (1984).

[0045] In addition, the present disclosure provides metabolic products of the compounds of the present disclosure. As used herein, "metabolite" refers to a product produced through metabolism in the body of a particular compound or its salt. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc., of the administered compound.

[0046] The metabolites are typically radiolabeled (e.g., 14 C or 3Identification is accomplished by preparing a H isotope, parenterally administering it to an animal, such as a rat, mouse, guinea pig, monkey, or human, at a detectable dose (e.g., greater than about 0.5 mg / kg), allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours), and isolating the conversion products from urine, blood, or other biological samples. Because such products are labeled, they are easily isolated (otherwise isolated by using antibodies capable of binding to epitopes surviving in the metabolite). The structures of the metabolites are determined by conventional methods, such as MS, LC / MS, or NMR analysis. Metabolite analysis is generally performed in the same manner as conventional drug metabolism testing well known to those skilled in the art. Metabolites, unless otherwise found in vivo, are useful in diagnostic assays for therapeutic administration of the disclosed compounds.

[0047] Some compounds of the present disclosure can exist in unsolvated form and solvated form, including hydrated form.In general, solvated form is equivalent to unsolvated form and is intended to be included within the scope of the present disclosure.Some compounds of the present disclosure can exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the uses discussed in the present disclosure and are intended to be within the scope of the present disclosure.

[0048] 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 called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Diastereomers are stereoisomers with opposite configurations of one or more chiral centers that are not enantiomers. Stereoisomers that possess one or more asymmetric centers that are non-superimposable mirror images of each other are called "enantiomers." For example, when a compound possesses an asymmetric center, a pair of enantiomers is possible if the carbon atom is bonded to four different groups. Enantiomers can be characterized by the absolute configuration of their asymmetric center(s) and are described by the R- and S-sequencing rules of Cahn, Ingold, and Prelog or by the way the molecule rotates the plane of polarized light and are designated as dextrorotatory or levorotatory (i.e., (+) or (-) isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture." In certain embodiments, the compound is at least about 90% by weight enriched in a single diastereomer or enantiomer. In other embodiments, the compound is at least about 95%, 98%, or 99% by weight enriched in a single diastereomer or enantiomer.

[0049] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, positional isomers, and individual isomers (e.g., resolved optical isomers) are all intended to be encompassed within the scope of the present disclosure.

[0050] The compounds of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0051] 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. In some embodiments or aspects, the term also includes pharmaceutically acceptable salts or esters of any such compound, stereoisomers or tautomers of such compounds.

[0052] The term "therapeutically effective amount" of a compound refers to an amount of compound effective to prevent, alleviate, or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determining a therapeutically effective amount is within the skill of the art. The therapeutically effective amount or therapeutically effective dose of a compound according to the present disclosure may vary within wide limits and may be determined in a manner known in the art. Such dosages will be tailored to the individual requirements of each particular case, including the specific compound being administered, the route of administration, the condition being treated, and the patient being treated. Generally, for oral or parenteral administration to an adult weighing approximately 70 kg, a daily dose of about 0.1 mg to about 5,000 mg, 1 mg to about 1,000 mg, or 1 mg to 100 mg may be appropriate, although the lower and upper limits may be exceeded when indicated. The daily dose may be administered as a single dose, in divided doses, or, for parenteral administration, as a continuous infusion.

[0053] The term "pharmaceutically acceptable carrier" is intended to include any and all substances compatible with pharmaceutical administration, including solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and other materials and compounds compatible with pharmaceutical administration. Except insofar as any conventional media or agent is incompatible with the compounds of the present disclosure, its use in the compositions of the present disclosure is contemplated. Supplementary active compounds may be incorporated into the compositions.

[0054] compound In some embodiments, the compound of formula (X): JPEG0007796721000008.jpg27170 (in the formula, X1 is C-R5, and R5 of X1 together with R3 and the atom to which they are attached form a 5-membered heterocyclyl or 5-membered heteroaryl, which 5-membered heterocyclyl or 5-membered heteroaryl may be substituted with one or more D; X2 is N or C-R5, and each R5 is independently H, cyano, halo, C(O)NH2, N(R e )(R f ), C 3-10 Cycloalkyl, C 1-6 Alkoxy, C 6-20 Aryl, S(O)2-C 1-6 Alkyl and C 1-6 alkyl, and R5 C 1-6 Alkyl is hydroxyl or N(R e )(R f ) may be substituted; X3 is N or CH; R1 is (i) A 3- to 5-membered saturated heterocyclyl containing at least one cyclic oxygen atom, wherein the 3- to 5-membered saturated heterocyclyl is one or more C 1-6 a 3- to 5-membered saturated heterocyclyl optionally substituted with alkyl, or (ii) N(R e )(R f ),or JPEG0007796721000009.jpg21170 (in the formula, R a , R b and R c are each independently H, halo, cyano, hydroxyl, B(OH), C(O)-OH, C(O)-N(R e )(R f ), C(O)-C 1-6 Alkoxy, C(O)-C 1-6 Alkyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-20 Aryl, 3-10 membered heterocyclyl, C 5-13 selected from the group consisting of spirocyclyl and 5- to 20-membered heteroaryl; 1-6 the alkyl may be further substituted with hydroxyl, or JPEG0007796721000010.jpg20170 (in the formula, R d is H, halo, cyano, hydroxyl, B(OH)2, C(O)-OH, C(O)-N(R e )(R f ), C(O)-C 1-6 Alkoxy, C(O)-C 1-6 Alkyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-20 Aryl, 3-10 membered heterocyclyl, C 5-13 spirocyclyl, and 5- to 20-membered heteroaryl; 1-6 The alkyl may be further substituted with hydroxyl. and; L is absent or -O-, * -CH2-O- ** , * -O-CH2- ** , —CH═CH—, and —C≡C—; ** indicates the point of attachment to the R2 moiety, * indicates the point of attachment to the rest of the molecule, R2 is C 1-12 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13Spirocyclyl, C 6-20 aryl or 5- to 20-membered heteroaryl; Here, C of R2 1-12 Alkyl, C 3-10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 5-13 Spirocyclyl, C 6-20 The aryl or 5- to 20-membered heteroaryl is independently selected from cyano, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, NO2, N(R e )(R f ), O(R e ) and S(R g ) 5, optionally substituted with one or more substituents selected from the group consisting of However, R2 is C 1-12 When R2 is alkyl, 1-12 Alkyl is independently selected from cyano, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, NO2, N(R e )(R f ), O(R e ) and S(R g ) optionally substituted with one or more substituents selected from the group consisting of 5), L is -CH=CH- or -C≡C-; R4 is H or C 1-6 alkyl, C 1-6 The alkyl may be substituted with hydroxyl; R e and R f are, independently of each other and independently at each occurrence, H, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 1-6 Alkyl-C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20aryl, and 3- to 20-membered heteroaryl; R e and R f C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-6 Alkyl-C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 The aryl and the 3- to 20-membered heteroaryl are each independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 optionally substituted with one or more substituents selected from the group consisting of alkoxy, oxo, cyano, halo, NO2, and hydroxyl; R g is a halo) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0055] In some embodiments, the compound of formula (I): JPEG0007796721000011.jpg27170 (in the formula, X1 is N or C-R5, and each R5 is independently H, cyano, halo, C(O)NH2, N(R e )(R f ), C 3-10 Cycloalkyl, C 1-6 Alkoxy, C 6-20 Aryl and C 1-6 alkyl, and R5 C 1-6 Alkyl is hydroxyl or N(R e )(R f ), R5 of X1 together with R3 and the atom to which they are attached form a 5-membered heterocyclyl or 5-membered heteroaryl, and the 5-membered heterocyclyl or 5-membered heteroaryl may be one or more C 1-6 may be substituted with alkyl, X2 is N or C-R5, and each R5 is independently H, cyano, halo, C(O)NH2, N(R e )(R f ), C 3-10 Cycloalkyl, C 1-6 Alkoxy, C 6-20 Aryl and C 1-6 alkyl, and R5 C 1-6 Alkyl is hydroxyl or N(R e )(R f ), X3 is N or CH; R1 is (i) A 3- to 5-membered saturated heterocyclyl containing at least one cyclic oxygen atom, wherein the 3- to 5-membered saturated heterocyclyl is one or more C 1-6 a 3- to 5-membered saturated heterocyclyl optionally substituted with alkyl, or (ii) N(R e )(R f ),or JPEG0007796721000012.jpg20170v (In the formula, R a , R b and R c are each independently H, halo, cyano, hydroxyl, B(OH), C(O)-OH, C(O)-N(R e )(R f ), C(O)-C 1-6 Alkoxy, C(O)-C 1-6 Alkyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-20 Aryl, 3-10 membered heterocyclyl, C 5-13 selected from the group consisting of spirocyclyl and 5- to 20-membered heteroaryl; 1-6 the alkyl may be further substituted with hydroxyl, or JPEG0007796721000013.jpg18170 (in the formula, R d is H, halo, cyano, hydroxyl, B(OH)2, C(O)-OH, C(O)-N(R e )(R f), C(O)-C 1-6 Alkoxy, C(O)-C 1-6 Alkyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-20 Aryl, 3-10 membered heterocyclyl, C 5-13 spirocyclyl, and 5- to 20-membered heteroaryl; 1-6 The alkyl may be further substituted with hydroxyl. and; L is absent or -O-, * -CH2-O- ** , * -O-CH2- ** , —CH═CH—, and —C≡C—; ** indicates the point of attachment to the R2 moiety, * indicates the point of attachment to the rest of the molecule, R2 is C 1-12 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 aryl or 5- to 20-membered heteroaryl; Here, C of R2 1-12 Alkyl, C 3-10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 5-13 Spirocyclyl, C 6-20 Aryl or 5- to 20-membered heteroaryl is independently selected from cyano, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, NO2, N(R e )(R f ) and O(R e and optionally substituted with one or more substituents selected from the group consisting of: However, R2 is C 1-12 (where C of R2 1-12 Alkyl is independently selected from cyano, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, NO2, N(R e)(R f ) and O(R e ), L is CH═CH— or —C≡C—; R3 is cyano, C 1-6 Alkyl, C 1-4 Alkoxy or C 2-4 alkenyl, C 2-4 Alkenyl is N(R e )(R f ), or R3, together with R5 of X1 and the atom to which they are attached, form a 5-membered heterocyclyl or 5-membered heteroaryl, which 5-membered heterocyclyl or 5-membered heteroaryl may contain one or more C 1-6 may be substituted with alkyl, or R3 is the * -CH2-O- ** together with the carbon atoms and the atom to which they are attached form a C6 aryl or 6-membered heteroaryl; R4 is H or C 1-6 alkyl, where C 1-6 The alkyl may be substituted by hydroxyl; R e and R f are, independently of each other and independently at each occurrence, H, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-6 Alkyl-C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 aryl, and 3~20 R is selected from the group consisting of: e and R f C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-6 Alkyl-C3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 The aryl and the 3- to 20-membered heteroaryl are each independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 optionally substituted with one or more substituents selected from the group consisting of alkoxy, oxo, cyano, halo, NO2 and hydroxyl or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0056] In some embodiments, provided herein are compounds of Formula (I) or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein X1 is C-R5, X2 is C-R5, and X3 is CH. In other embodiments, X1 is C-R5, X2 is C-R5, and X3 is N. In still other embodiments, X1 is C-R5, X2 is N, and X3 is CH. In some embodiments, X1 is C-R5, X2 is N, and X3 is N. In some embodiments, X1 is N, X2 is C-R5, and X3 is CH.

[0057] In certain embodiments, provided herein is a compound of Formula (X) or Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is C-R, and R, together with R of X and the atom to which they are attached, form a 5-membered heterocyclyl or a 5-membered heteroaryl, wherein the 5-membered heterocyclyl or 5-membered heteroaryl contains 1, 2, or 3 ring heteroatoms. In certain embodiments, the 1, 2, or 3 heteroatoms are selected from the group consisting of O, N, and S. In several embodiments, the 5-membered heterocyclyl or 5-membered heteroaryl contains one or more C 1-6 In some embodiments, the 5-membered heterocyclyl or 5-membered heteroaryl is unsubstituted. In some embodiments, the 5-membered heterocyclyl or 5-membered heteroaryl is substituted with one or more D.

[0058] In some embodiments of Formula (X) or Formula (I), X1 is C-R5, and R3, together with R5 of X1 and the atom to which they are attached, form a 5-membered heteroaryl, which contains at least two ring heteroatoms. In some embodiments, X1 is C-R5, and R3, together with R5 of X1 and the atom to which they are attached, form a 5-membered heteroaryl, which contains one ring sulfur atom and one ring nitrogen atom. In multiple embodiments, the 5-membered heteroaryl contains one or more C 1-6 In some embodiments, the 5-membered heteroaryl is unsubstituted. In some embodiments, the 5-membered heteroaryl is substituted with one or more D.

[0059] In certain embodiments of Formula (X) or Formula (I), X1 is C-R5, and R3, together with R5 of X1 and the atom to which they are attached, form a 5-membered heterocyclyl, the 5-membered heteroaryl containing at least one ring heteroatom. In some embodiments, X1 is C-R5, and R3, together with R5 of X1 and the atom to which they are attached, form a 5-membered heterocyclyl containing one ring oxygen atom. In some embodiments, the 5-membered heterocyclyl contains one or more C 1-6 In some embodiments, the 5-membered cyclocyclyl is unsubstituted. In some embodiments, the 5-membered heterocyclyl is substituted with one or more D.

[0060] In one embodiment of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: X1 is C-R5; R3 together with R5 of X1 and the atom to which they are attached form an unsubstituted 5-membered heterocyclyl or an unsubstituted 5-membered heteroaryl; X 2 is N;X 3is N. In one embodiment of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: X is C-R; R, together with R of X and the atom to which they are attached, form a 5-membered heterocyclyl or 5-membered heteroaryl, wherein the 5-membered heterocyclyl or 5-membered heteroaryl is substituted with one or more D; X 2 is N;X 3 is N.

[0061] In one embodiment of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: X1 is C-R5; R3 together with R5 of X1 and the atom to which they are attached form an unsubstituted 5-membered heterocyclyl; X 2 is N;X 3 is N. In one embodiment of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: X is C-R; R, together with R of X and the atom to which they are attached, form a 5-membered heterocyclyl, wherein the 5-membered heterocyclyl is substituted with one or more D; X 2 is N;X 3 is N.

[0062] In one embodiment of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: X1 is C-R5; R3, together with R5 of X1 and the atom to which they are attached, form an unsubstituted 5-membered heterocyclyl or an unsubstituted 5-membered heteroaryl; and L is O. In one embodiment of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: X1 is C-R5; R3, together with R5 of X1 and the atom to which they are attached, form a 5-membered heterocyclyl or a 5-membered heteroaryl, wherein the 5-membered heterocyclyl or 5-membered heteroaryl is substituted with one or more D; and L is O.

[0063] In one embodiment of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: X1 is C-R5; R3, together with R5 of X1 and the atom to which they are attached, form an unsubstituted 5-membered heterocyclyl; and L is O. In one embodiment of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: X1 is C-R5; R3, together with R5 of X1 and the atom to which they are attached, form a 5-membered heterocyclyl, which is substituted with one or more D; and L is O.

[0064] In some embodiments, the compound of Formula (X) or Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound of Formula (X) or Formula (I) is of Formula (IA): Provided herein are compounds of Formula (X) or Formula (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound is: JPEG0007796721000014.jpg33170, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0065] In some embodiments, X2 is C-R5, and R5 of X2 is H, cyano, halo, S(O)2-C 1-6 Alkyl or C 1-6 alkyl, C 1-6 Provided herein are compounds of Formula (X), Formula (I), or Formula (IA), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein alkyl is optionally substituted with one or more hydroxyl. In some embodiments, X2 is C-R5, and R5 of X2 is H, cyano, halo, or C 1-6 alkyl, C 1-6 Provided herein are compounds of Formula (X), Formula (I), or Formula (IA), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein alkyl is optionally substituted with one or more hydroxyl groups. In certain embodiments, R5 of X2 is cyano. In other embodiments, R5 of X2 is H. In still other embodiments, R5 of X2 is F. In some embodiments, R5 of X2 is C1-6 This C is an alkyl 1-6 The alkyl may be substituted with one or more hydroxyl groups. In other embodiments, R5 of X2 is -CH2OH. In some embodiments, R5 of X2 is S(O)2-C 1-6 In some embodiments, R5 of X2 is S(O)2-CH3.

[0066] In some embodiments, L is absent or is -O-, * -CH2-O- ** , * -O-CH2- ** , —CH═CH—, and —C≡C—; ** indicates the point of attachment to the R2 moiety, * Provided herein are compounds of Formula (X), Formula (I), or Formula (IA), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L indicates the point of attachment to the remainder of the molecule. In some embodiments, L is absent.

[0067] In some embodiments, R2 is C 1-12 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 aryl or 5- to 20-membered heteroaryl, and C of R 1-12 Alkyl, C 3-10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 5-13 Spirocyclyl, C 6-20 The aryl or 5- to 20-membered heteroaryl is selected from the group consisting of cyano, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, NO2, N(R e )(R f ), O(R e ) and S(R g ) 5, with the proviso that R2 is C 1-12 When R2 is alkyl, 1-12Alkyl is independently selected from cyano, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, NO2, N(R e )(R f ), O(R e ), and S(R g Provided herein are compounds of Formula (X), Formula (I), or Formula (IA), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L is -CH=CH- or -C≡C-, optionally substituted with one or more substituents selected from the group consisting of: 3-10 Cycloalkyl or C 6-20 aryl, and C in R 3-10 Cycloalkyl or C 6-20 Aryl independently contains one or more O(R e ) or C 1-6 may be substituted with alkyl, C 1-6 The alkyl may be further substituted with one or more halo. In another embodiment, R2 is C 6-20 aryl, and C in R 6-20 Aryl independently contains one or more O(R e ), S(R g )5 or C 1-6 may be substituted with alkyl, 1-6 The alkyl may be further substituted with one or more halo. In some embodiments, R2 is C 6-20 aryl, and C in R 6-20 Aryl independently comprises one or more C 1-6 In certain embodiments, R2 is phenyl substituted with isopropyl. In some embodiments, R2 is C 6-20 aryl, and C in R 6-20 Aryl independently contains one or more S(R g )5. In certain embodiments, R2 is phenyl substituted with SF5. In some embodiments, R2 is O(R eIn some embodiments, R2 is phenyl substituted with OCF3.

[0068] In some embodiments, R2 is C 1-12 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 aryl or 5- to 20-membered heteroaryl, and C of R 1-12 Alkyl, C 3-10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 5-13 Spirocyclyl, C 6-20 The aryl or 5- to 20-membered heteroaryl is independently selected from cyano, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, NO2, N(R e )(R f ), and O(R e ) optionally substituted with one or more substituents selected from the group consisting of: 1-12 When R2 is alkyl, 1-12 Alkyl is independently selected from cyano, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, NO2, N(R e )(R f ), O(R e Provided herein are compounds of Formula (X), Formula (I), or Formula (IA), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L is -CH=CH- or -C≡C-, and R is optionally substituted with one or more substituents selected from the group consisting of: 3-10 Cycloalkyl or C 6-20 aryl, and C in R 3-10 Cycloalkyl or C 6-20 Aryl independently contains one or more O(R e ) or C 1-6 may be substituted with alkyl, C 1-6The alkyl may be further substituted with one or more halo. In other embodiments, R2 is C 6-20 aryl, and C in R 6-20 Aryl independently contains one or more O(R e ) or C 1-6 may be substituted with alkyl, C 1-6 The alkyl may be further substituted with one or more halo. In some embodiments, R2 is C 6-20 aryl, and C in R 6-20 Aryl independently comprises one or more C 1-6 It may be substituted with alkyl. In certain embodiments, R2 is phenyl substituted with isopropyl.

[0069] In some embodiments, R2 is C 1-12 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 aryl or 5- to 20-membered heteroaryl, and C of R 1-12 Alkyl, C 3-10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 5-13 Spirocyclyl, C 6-20 aryl or 5- to 20-membered heteroaryl, independently selected from cyano, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, NO2, N(R e )(R f ), O(R e ) and S(R g ) 5, with the proviso that R2 is C 1-12 When R2 is alkyl, 1-12 Alkyl is independently selected from cyano, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, NO2, N(R e )(R f ), O(R e ), and S(R gProvided herein are compounds of Formula (X), Formula (I), or Formula (IA), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L is -CH=CH- or -C≡C-, and R is optionally substituted with one or more substituents selected from the group consisting of: 3-10 Cycloalkyl or C 6-20 aryl, and C in R 3-10 Cycloalkyl or C 6-20 Aryl independently contains one or more O(R e ) or C 1-6 may be substituted with alkyl, C 1-6 The alkyl may be further substituted with one or more halo. In other embodiments, R2 is C 6-20 aryl, and C in R 6-20 Aryl independently contains one or more O(R e ) or C 1-6 may be substituted with alkyl, C 1-6 The alkyl may be further substituted with one or more halo. In some embodiments, L is absent and R is C 6-20 aryl, and C in R 6-20 Aryl independently contains one or more C 1-6 In certain embodiments, L is absent and R2 is phenyl substituted with isopropyl. In some embodiments, L is absent and R2 is C 6-20 aryl, and C in R 6-20 Aryl independently contains one or more S(R g )5. In certain embodiments, L is absent and R2 is phenyl substituted with SF5. In some embodiments, L is absent and R2 is O(R e In some embodiments, L is absent and R2 is phenyl substituted with OCF3.

[0070] In some embodiments, L is absent and R2 is C 1-12 Alkyl, C 3-10Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 aryl or 5- to 20-membered heteroaryl, and C of R 1-12 Alkyl, C 3-10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 5-13 Spirocyclyl, C 6-20 aryl or 5- to 20-membered heteroaryl, independently selected from cyano, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, NO2, N(R e )(R f ), and O(R e ) optionally substituted with one or more substituents selected from the group consisting of: 1-12 When R2 is alkyl, 1-12 Alkyl is independently selected from cyano, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, NO2, N(R e )(R f ), O(R e Provided herein are compounds of Formula (X), Formula (I), or Formula (IA), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L is -CH=CH- or -C≡C-. In some embodiments, L is absent and R2 is C 3-10 Cycloalkyl or C 6-20 aryl, and C in R 3-10 Cycloalkyl or C 6-20 Aryl independently contains one or more O(R e ) or C 1-6 may be substituted with alkyl, C 1-6 The alkyl may be further substituted with one or more halo. In other embodiments, R2 is C 6-20 aryl, and C in R 6-20 Aryl independently contains one or more O(R e ) or C 1-6may be substituted with alkyl, C 1-6 The alkyl may be further substituted with one or more halo. In some embodiments, L is absent and R is C 6-20 aryl, and C in R 6-20 Aryl independently contains one or more C 1-6 In certain embodiments, L is absent and R2 is phenyl substituted with isopropyl.

[0071] In some embodiments, the compound of formula (I) has formula (IA-1): Provided herein are compounds, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L is absent, such that the compound is JPEG0007796721000015.jpg35170.

[0072] In some embodiments, X2 is C-R5, and R5 of X2 is H, cyano, halo, or S(O)2-C 1-6 Alkyl or C 1-6 alkyl, C 1-6 Provided herein are compounds of Formula (X), Formula (I), or Formula (IA), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein alkyl is optionally substituted with one or more hydroxyl. In some embodiments, X2 is C-R5, and R5 of X2 is H, cyano, halo, or C 1-6 alkyl, C 1-6 Provided herein are compounds of Formula (X), Formula (I), or Formula (IA), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein alkyl is optionally substituted with one or more hydroxyl groups. In certain embodiments, R5 of X2 is cyano. In other embodiments, R5 of X2 is H. In still other embodiments, R5 of X2 is F. In some embodiments, R5 of X2 is C 1-6 This C is an alkyl 1-6 The alkyl may be substituted with one or more hydroxyl groups. In other embodiments, R5 of X2 is -CH2OH. In some embodiments, R5 of X2 is S(O)2-C 1-6In some embodiments, R5 of X2 is S(O)2-CH3.

[0073] In some embodiments, R2 is phenyl, and the phenyl is independently selected from cyano, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, NO2, N(R e )(R f ), O(R e ) and S(R g Provided herein are compounds of Formula (X), Formula (I), or Formula (IA-1), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein the phenyl is optionally substituted with one or more substituents selected from the group consisting of O(R e ), S(R g )5, or C 1-6 may be substituted with alkyl, C 1-6 The alkyl may be further substituted with one or more halo. In certain embodiments, the phenyl is substituted with isopropyl. In some embodiments, the phenyl is S(R g )5. In some embodiments, the phenyl is substituted with SF5. In some embodiments, the phenyl is substituted with O(R e ) In some embodiments, the phenyl is substituted with OCF3.

[0074] In some embodiments, R2 is phenyl, and the phenyl is independently selected from cyano, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, NO2, N(R e )(R f ) and O(R eProvided herein are compounds of Formula (X), Formula (I), or Formula (IA-1), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein the phenyl is optionally substituted with one or more substituents selected from the group consisting of: O(R e ) or C 1-6 may be substituted with alkyl, 1-6 The alkyl may be further substituted with one or more halo, hi certain embodiments, the phenyl is substituted with isopropyl.

[0075] In some embodiments, R1 is JPEG0007796721000016.jpg20170 (in the formula, R a , R b and R c are each independently H, B(OH), C(O)-OH, C(O)-N(R e )(R f ), C(O)-C 1-6 Alkoxy and C(O)-C 1-6 alkyl, and R4 is H or C 1-6 alkyl, and R e and R f are, independently of each other and independently at each occurrence, H, hydroxyl and C 1-6 alkyl) Provided herein are compounds of Formula (X), Formula (I), or Formula (IA-1), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein C 1-6 Alkyl is methyl or isopropyl. In embodiments, C(O)-C 1-6 Alkoxy C 1-6 Alkoxy is methoxy.

[0076] In some embodiments, R1 is JPEG0007796721000017.jpg21170 (in the formula, R a , R b and R care each independently H, B(OH), C(O)-OH, C(O)-N(R e )(R f ), C(O)-C 1-6 Alkoxy and C(O)-C 1-6 alkyl, and R4 is H or C 1-6 alkyl, and R e and R f are, independently of each other and independently at each occurrence, H, hydroxyl, C 1-6 Alkoxy and C 1-6 alkyl) Provided herein are compounds of Formula (X), Formula (I), or Formula (IA-1), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein C 1-6 Alkyl is methyl or isopropyl. In some embodiments, C 1-6 Alkoxy is methoxy.

[0077] In embodiments, X2 is C-R5, and R5 is independently H, cyano, halo, S(O)2-C 1-6 Alkyl and C 1-6 alkyl, and R5 C 1-6 Provided herein are compounds of Formula (X), Formula (I), or Formula (IA-1), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein alkyl is optionally substituted with hydroxyl. In some embodiments, X2 is C-R5, and R5 is independently selected from H, cyano, halo, and C 1-6 alkyl, and R5 C 1-6 Provided herein are compounds of Formula (X), Formula (I), or Formula (IA-1), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein the alkyl is optionally substituted with hydroxyl. In one embodiment, R5 is H. In one embodiment, R5 is cyano. In several embodiments, R5 is C substituted with hydroxyl. 1-6 In some embodiments, R is S(O)-C.1-6 In some embodiments, R5 is S(O)2-CH3.

[0078] In embodiments, provided herein are compounds of Formula (X), Formula (I), or Formula (IA-1), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X3 is CH.

[0079] In some embodiments, R1 is JPEG0007796721000018.jpg20170, R a , R b and R c are each independently H, B(OH)2, C(O)-OH, C(O)-N(R e )(R f ), C(O)-C 1-6 Alkoxy, C(O)-C 1-6 alkyl; R e and R f independently of each other, H, hydroxyl, C 1-6 C optionally substituted with alkoxy and one or more halo substituents 1-6 Provided herein are compounds of Formula (X), Formula (I), or Formula (IA-1), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of alkyl. In some embodiments, R is JPEG0007796721000019.jpg21170, R a , R b and R c are each independently H, B(OH)2, C(O)-OH, C(O)-N(R e )(R f ), C(O)-C 1-6 Alkoxy, C(O)-C 1-6 alkyl; R e and R f are, independently of one another, H, hydroxyl and C, which in each occurrence are optionally substituted with one or more halo substituents; 1-6Provided herein are compounds of Formula (X), Formula (I), or Formula (IA-1), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of alkyl, a and R b are each H. In some embodiments, R a and R b are H and R c is H, B(OH)2, C(O)-OH, C(O)-N(R e )(R f ), C(O)-C 1-6 Alkoxy and C(O)-C 1-6 In some embodiments, C 1-6 Alkyl is methyl. In some embodiments, C 1-6 Alkoxy is methoxy. In embodiments, R c is C(O)—OH. In some embodiments, R c is C(O)-N(R e )(R f In some embodiments, R e and R f are each H. In some embodiments, R e and R f One of the two is H and the other is R e and R f The other is C 1-6 In some embodiments, R e and R f One of the two is H and the other is R e and R f and the other is methyl. In some embodiments, R e and R f One of the two is H and the other is R e and R f The other is OH.

[0080] In some embodiments, R2 is C 1-6 Alkyl, C 1-6 Haloalkyl, O(R e ) and S(R gC optionally substituted with one or more substituents selected from the group consisting of 6-20 Provided herein are compounds of Formula (X), Formula (I), or Formula (IA-1), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R is aryl. In some embodiments, R is C 1-6 Alkyl, C 1-6 Haloalkyl, and O(R e C, optionally substituted with one or more substituents selected from the group consisting of 6-20 Provided herein are compounds of Formula (X), Formula (I), or Formula (IA-1), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R is aryl. In some embodiments, R is phenyl. In some embodiments, R is C 1-6 In some embodiments, R2 is phenyl substituted with alkyl. In some embodiments, R2 is phenyl substituted with isopropyl. In some embodiments, R2 is C 1-6 In some embodiments, R2 is phenyl substituted with -CF3. In some embodiments, R2 is phenyl substituted with -CH2(CH3)CF3. In some embodiments, R2 is O(R e phenyl substituted with R e is a C substituted with one or more halo substituents 1-6 In some embodiments, R e is —CF. In some embodiments, R is S(R g )5. In embodiments, R2 is phenyl substituted with SF5.

[0081] In some embodiments, R4 is H or C 1-6 Provided herein are compounds of Formula (X), Formula (I), or Formula (IA-1), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R is alkyl. In embodiments, R is H. In embodiments, R is methyl.

[0082] In some embodiments, X2 is C-R5, where R5 is H; X3 is CH; and R1 is JPEG0007796721000020.jpg20170, R a and R b are H and R c is H, B(OH)2, C(O)-OH, C(O)-N(R e )(R f ), C(O)-C 1-6 Alkoxy, C(O)-C 1-6 alkyl, and R e and R f are, independently of each other and independently at each occurrence, H, hydroxyl and C 1-6 alkyl; R2 is selected from the group consisting of C 1-6 Alkyl, C 1-6 Haloalkyl, and O(R e phenyl substituted with R e C substituted with one or more halo substituents 1-6 Provided herein are compounds of Formula (I) or Formula (IA-1), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R is alkyl; and R4 is H.

[0083] In some embodiments, X2 is C-R5, where R5 is cyano; X3 is CH; and R1 is JPEG0007796721000021.jpg21170, where R a and R b are H and R c is H, B(OH)2, C(O)-OH, C(O)-N(R e )(R f ), C(O)-C 1-6 Alkoxy, C(O)-C 1-6 alkyl, where R e and R f are, independently of each other and independently at each occurrence, H, hydroxyl and C 1-6 alkyl; R2 is selected from the group consisting of C 1-6 Alkyl, C 1-6 Haloalkyl, and O(Re phenyl substituted with R e is a C substituted with one or more halo substituents 1-6 is alkyl; R4 is H.

[0084] In some embodiments, the compound is Provided herein is a compound of Formula (X) or Formula (I), such as a compound of Formula (IA) or Formula (IA-1), selected from the group consisting of: JPEG0007796721000022.jpg252170JPEG0007796721000023.jpg227170JPEG0007796721000024.jpg238170JPEG0007796721000025.jpg147170, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0085] In some embodiments, the compound is Provided herein is a compound of Formula (X) or Formula (I), such as a compound of Formula (IA) or Formula (IA-1), selected from the group consisting of: JPEG0007796721000026.jpg253170JPEG0007796721000027.jpg175170, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0086] In some embodiments, X1 is C-R5, and R3 together with R5 of X1 and the atom to which they are attached form a 5-membered heterocyclyl or 5-membered heteroaryl, L is absent, and R2 is C 6-20 aryl, and C in R 6-20 aryl independently comprises one or more C 1-6 Provided herein are compounds of formula (X), formula (I) or formula (IA), or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, optionally substituted with alkyl. In certain embodiments, the compound of formula (X), formula (I) or formula (IA) is of formula (IB): Provided herein is a compound of Formula (X), Formula (I) or Formula (IA), which is a compound of JPEG0007796721000028.jpg41170, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0087] In some embodiments, R1 is a 3- to 5-membered saturated heterocyclyl containing at least one ring oxygen atom, and the 3- to 5-membered saturated heterocyclyl is selected from the group consisting of one or more C 1-6 Provided herein are compounds of Formula (X), Formula (I), Formula (IA), or Formula (IB), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, optionally substituted with alkyl. In certain embodiments, R is a 3-membered saturated heterocyclyl containing at least one ring oxygen atom, wherein the 3-membered saturated heterocyclyl is selected from the group consisting of one or more C 1-6 In some embodiments, R is oxiranyl, which may be substituted with one or more C alkyl groups. 1-6 In some embodiments, R1 is optionally substituted with alkyl. JPEG0007796721000029.jpg16170. In another embodiment, R1 is JPEG0007796721000030.jpg16170.

[0088] In some embodiments, R is N(R e )(R f ) and R e and R f are independently of each other and independently at each occurrence H, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 1-6 Alkyl-C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 aryl, and 3- to 20-membered heteroaryl; R e and Rf C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-6 Alkyl-C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 aryl, and 3- to 20-membered heteroaryl are each independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Provided herein are compounds of Formula (X), Formula (I), Formula (IA), or Formula (IB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, optionally substituted with one or more substituents selected from the group consisting of alkoxy, oxo, cyano, halo, NO, and hydroxyl. In some embodiments, R is N(R e )(R f ) and R e and R f are independently of each other and independently at each occurrence H, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-6 Alkyl-C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 aryl, and 3- to 20-membered heteroaryl; R e and R f C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-6 Alkyl-C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 aryl, and 3- to 20-membered heteroaryl are each independently C 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Provided herein are compounds of Formula (X), Formula (I), Formula (IA), or Formula (IB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, optionally substituted with one or more substituents selected from the group consisting of alkoxy, oxo, cyano, halo, NO, and hydroxyl. In certain embodiments, R e and R f are, independently of each other and independently at each occurrence, H, cyano, and C 1-6 alkyl.

[0089] In some embodiments, R1 is JPEG0007796721000031.jpg20170, R a , R b , and R c are each independently H, halo, cyano, hydroxyl, B(OH), C(O)-OH, C(O)-N(R e )(R f ), C(O)-C 1-6 Alkoxy, C(O)-C 1-6 Alkyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-20 Aryl, 3-10 membered heterocyclyl, C 5-13 spirocyclyl, and 5- to 20-membered heteroaryl; 1-6 Provided herein are compounds of Formula (X), Formula (I), Formula (IA), or Formula (IB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the alkyl is optionally further substituted with hydroxyl. In certain embodiments, R a , R b and R c At least two of R a , R b and R c Exactly two of the are H and R a , R b and R c Exactly one of B(OH)2, C(O)-OH, C(O)-N(R e)(R f ), C(O)-C 1-6 Alkoxy or C(O)-C 1-6 In some embodiments, R a and R b are both H, and R c is B(OH)2, C(O)-OH, C(O)-N(R e )(R f ), C(O)-C 1-6 Alkoxy or C(O)-C 1-6 In some embodiments, R a , R b and R c Exactly two of the are H and R a , R b and R c Exactly one of R is C(O)—OH. In certain embodiments, R a and R b are both H, and R c is C(O)-OH. R a , R b or R c is C(O)-N(R e )(R f In some embodiments, C(O)—N(R e )(R f )R e and R f are independently H, C 1-6 R is alkyl or hydroxyl. a , R b or R c is C(O)-N(R e )(R f In some embodiments, C(O)—N(R e )(R f )R e and R f are independently H, C 1-6 Alkyl, C 1-6 It is alkoxy or hydroxyl.

[0090] In some embodiments, the compound is Provided herein is a compound of Formula (X), Formula (I), Formula (IA), or Formula (IB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, selected from the group consisting of: JPEG0007796721000032.jpg253170JPEG0007796721000033.jpg201170.

[0091] In some embodiments, the compound is Provided herein is a compound of Formula (X), Formula (I), Formula (IA), or Formula (IB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, selected from the group consisting of: JPEG0007796721000034.jpg254170JPEG0007796721000035.jpg73170

[0092] In some embodiments, the compound of Formula (X), Formula (I), Formula (IA), or Formula (IB) has Formula (IC): Provided herein is a compound of Formula (X), Formula (I), Formula (IA), or Formula (IB), which is a compound of JPEG0007796721000036.jpg42170, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0093] In some embodiments, provided herein are compounds of formula (IC), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X2 is C-R5 and X3 is CH. In some embodiments, X2 is C-R5 and R5 is H, cyano, halo, or C 1-6 alkyl, C 1-6 The alkyl may be substituted with hydroxyl, and X3 is CH. In other embodiments, X2 is C-R5, R5 is cyano, and X3 is CH. In other embodiments, X2 is C-R5, R5 is cyano, and X3 is N. In still other embodiments, X2 is N and X3 is CH. In certain embodiments, X2 is N and X3 is N.

[0094] In some embodiments, provided herein are compounds of formula (IC), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R is H. In other embodiments, R is C 1-6 alkyl, C 1-6 The alkyl may be substituted with hydroxyl. In certain embodiments, R4 is methyl. In some embodiments, X2 is C-R5, where R5 is H, cyano, halo, or C 1-6 alkyl, C 1-6 Provided herein are compounds of formula (IC), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein alkyl may be substituted with hydroxyl, X3 is CH, and R4 is H. In other embodiments, provided herein are compounds of formula (IC), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X2 is C-R5, R5 is cyano, X3 is CH, and R4 is H.

[0095] In some embodiments, R a , R b and R c Provided herein are compounds of formula (IC), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein at least two of R a , R b and R c Exactly two of the are H and R a , R b and R c Exactly one of B(OH)2, C(O)-OH, C(O)-N(R e )(R f ), C(O)-C 1-6 Alkoxy or C(O)-C 1-6 alkyl, C(O)—N(R e )(R f )R e and R f are independently H, C 1-6 Alkyl, C 1-6 In some embodiments, R is alkoxy or hydroxyl. a , Rb and R c Exactly two of the are H and R a , R b and R c Exactly one of B(OH)2, C(O)-OH, C(O)-N(R e )(R f ), C(O)-C 1-6 Alkoxy or C(O)-C 1-6 alkyl, C(O)—N(R e )(R f )R e and R f are independently H, C 1-6 alkyl or hydroxyl. In some embodiments, R a , R b and R c Exactly two of the are H and R a , R b and R c In some embodiments, exactly one of R a is H and R b is H and R c is C(O)—OH. In some embodiments, R a is H and R b is H and R c is C(O)-NH(OH).

[0096] In certain embodiments, X2 is C-R5, where R5 is H, cyano, halo, S(O)2-C 1-6 Alkyl or C 1-6 alkyl, C 1-6 The alkyl may be substituted with hydroxyl, X3 is CH, R4 is H, and R a , R b and R c Provided herein are compounds of formula (IC), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein at least two of are H. In certain embodiments, X2 is C-R5, and R5 is H, cyano, halo, or C 1-6 alkyl, C 1-6The alkyl may be substituted with hydroxyl, X3 is CH, R4 is H, and R a , R b , and R c Provided herein are compounds of formula (IC), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein at least two of are H. In certain embodiments, X2 is C-R5, and R5 is H, cyano, halo, S(O)2-C 1-6 Alkyl, or C 1-6 alkyl, C 1-6 The alkyl may be substituted with hydroxyl, X3 is CH, R4 is H, and R a , R b and R c Exactly two of the are H and R a , R b and R c Exactly one of B(OH)2, C(O)-OH, C(O)-N(R e )(R f ), C(O)-C 1-6 Alkoxy, or C(O)- 1-6 alkyl, or C(O)—N(R e )(R f )R e and R f are independently H, C 1-6 Provided herein are compounds of formula (IC), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is C-R, and R is H, cyano, halo, or C. 1-6 alkyl, C 1-6 The alkyl may be substituted with hydroxyl, X3 is CH, R4 is H, and R a , R b , and R c Exactly two of the are H and R a , R b , and R c Exactly one of B(OH)2, C(O)-OH, C(O)-N(R e )(R f ), C(O)-C 1-6Alkoxy, or C(O)-C 1-6 alkyl, C(O)—N(R e )(R f )R e and R f However, H and C are independent of each other. 1-6 Provided herein are compounds of formula (IC), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is C-R, and R is H, cyano, halo, S(O)-C, or a hydroxyl. 1-6 Alkyl or C 1-6 alkyl, C 1-6 The alkyl may be substituted with hydroxyl, X3 is CH, R4 is H, and R a , R b and R c Exactly two of the are H and R a , R b and R c Provided herein are compounds of formula (IC), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein exactly one of X is C(O)-OH. In some embodiments, X is C-R, and R is H, cyano, halo, or C. 1-6 alkyl, C 1-6 The alkyl may be substituted with hydroxyl, X3 is CH, R4 is H, and R a , R b , and R c Exactly two of the are H and R a , R b , and R c Provided herein are compounds of formula (IC), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein exactly one of X is C(O)-OH. In some embodiments, X is C-R, and R is H, cyano, halo, S(O)-C 1-6 Alkyl or C 1-6 alkyl, C 1-6 The alkyl may be substituted with hydroxyl, X3 is CH, R4 is H, and R a , R b and Rc Exactly two of the are H and R a , R b and R c Provided herein are compounds of formula (IC), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein exactly one of is C(O)-NH(OH). In some embodiments, X2 is C-R5, and R5 is H, cyano, halo, or C 1-6 alkyl, C 1-6 The alkyl may be substituted with hydroxyl, X3 is CH, R4 is H, and R a , R b , and R c Exactly two of the are H and R a , R b , and R c Provided herein are compounds of formula (IC), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein exactly one of is C(O)—NH(OH).

[0097] In some embodiments, the compound of formula (IC) is Provided herein are compounds of formula (IC), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, selected from the group consisting of: JPEG0007796721000037.jpg253170JPEG0007796721000038.jpg200170.

[0098] In some embodiments, the compound of formula (IC) is Provided herein are compounds of formula (IC), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, selected from the group consisting of: JPEG0007796721000039.jpg253170JPEG0007796721000040.jpg73170.

[0099] In some embodiments, R1 is JPEG0007796721000041.jpg18170, R dH, halo, cyano, hydroxyl, B(OH)2, C(O)-OH, C(O)-N(R e )(R f ), C(O)-C 1-6 Alkoxy, C(O)-C 1-6 Alkyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-20 Aryl, 3-10 membered heterocyclyl, C 5-13 spirocyclyl, and 5- to 20-membered heteroaryl; 1-6 Provided herein are compounds of Formula (X), Formula (I), Formula (IA), or (IB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the alkyl is optionally further substituted with hydroxyl.

[0100] In some embodiments, R3 is cyano, C 1-6 Alkyl, C 1-4 Alkoxy or C 2-4 alkenyl, C 2-4 Alkenyl is N(R e )(R f Provided herein are compounds of Formula (I), Formula (IA), or (IB), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, optionally substituted with (R). In some embodiments, R is cyano. In other embodiments, R is C 1-4 It is an alkoxy.

[0101] In some embodiments, R3 is L * -CH2-O- ** Provided herein are compounds of formula (I), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein R3 is selected from the group consisting of the carbon atoms of L, R4, L5, L6, L7, L8, L9, L10, L11, L12, L13, L14, L15, L16, L17, L18, L19, L20, L21, L22, L23, L24, L25, L36, L37, L48, L49, L50, L51, L52, L53, L64, L65, L76, L77, L78, L89, L99, L91, L92, L93, L94, L95, L96, L97, L98, L99, L99, L109, L110, L120, L130, L140, L150, L161, L172, L183, L194, L195, L196, L197, L198, L199, L210, L221, L231, L242, L253, L261, L272, L283, L294, L295, L296, L297, L298, L299, L300, L310, L311, L312, L313, L41, L42, L43, L44, L45, L46, L47, L54, L55, L56, L57, L58, L69, L69, L70, L71, L72, L83, L84, L95, L105, L116, L117, L125, L130, L141, L15 * -CH2-O- ** and the atom to which they are attached form a C6 aryl. * -CH2-O- **together with the carbon atoms and the atom to which they are attached form a 6-membered heteroaryl.

[0102] In some embodiments, R4 is H or C 1-6 alkyl, C 1-6 Provided herein are compounds of Formula (X), Formula (I), Formula (IA), Formula (IB), or Formula (IC), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein alkyl is optionally substituted with hydroxyl. In other embodiments, R4 is H.

[0103] In one embodiment, X1 is C-R5, where R5 of X1 together with R3 and the atom to which they are attached form a 5-membered heterocyclyl or 5-membered heteroaryl optionally substituted with one or more D; X2 is N or C-R5, where each R5 is H, cyano, halo, C(O)NH2, S(O)2-C 1-6 Alkyl and C 1-6 alkyl, and R5 C 1-6 The alkyl may be substituted with hydroxyl; X3 is N or CH; R1 is JPEG0007796721000042.jpg21170, where R a and R b are H and R c is H, B(OH)2, C(O)-OH, C(O)-N(R e )(R f ), C(O)-C 1-6 Alkoxy, and C(O)-C 1-6 alkyl; L is absent; R2 is selected from the group consisting of C 6-20 aryl or 5- to 20-membered heteroaryl, wherein C 6-20 aryl or 5- to 20-membered heteroaryl, independently selected from halo, C 1-6 Alkyl, C 1-6 Haloalkyl, O(R e ), and S(R g ) 5, wherein R eand R f independently of each other and independently at each occurrence H, hydroxyl, and C 1-6 alkyl; R e or R f C 1-6 The alkyl may be optionally substituted with one or more halo, and R g Provided herein are compounds of Formula (X), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein is halo.

[0104] In some of the above-mentioned embodiments, provided herein are compounds of formula (X), or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein X1 is C-R5, and R5 of X1 together with R3 and the atom to which they are attached form a 5-membered heterocyclyl optionally substituted with one or more D; X2 is C-R5, and R5 is independently selected from the group consisting of H or cyano; and X3 is CH.

[0105] In some of the foregoing embodiments, provided herein are compounds of Formula (X), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R5 of X1, together with R3 and the atom to which they are attached, form a tetrahydrofuranyl, optionally substituted with one or more D. In some embodiments, the tetrahydrofuranyl is unsubstituted.

[0106] In some of the foregoing embodiments, provided herein are compounds of Formula (X), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R5 of X1, together with R3 and the atom to which they are attached, form a thiazolyl, which is optionally substituted with one or more D. In some embodiments, the thiazolyl is unsubstituted.

[0107] In some of the foregoing embodiments, R1 is JPEG0007796721000043.jpg19170, R a and R b are H and R cis B(OH)2, C(O)-OH, C(O)-N(R e )(R f ), C(O)-C 1-6 Alkoxy, C(O)-C 1-6 alkyl; R e and R f are, independently of each other and independently at each occurrence, H, hydroxyl, and C 1-6 Provided herein are compounds of Formula (X), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of alkyl.

[0108] In some of the foregoing embodiments, L is absent and R2 is C 1-6 Alkyl, C 1-6 Haloalkyl, O(R e ), and S(R g phenyl optionally substituted with one or more substituents selected from the group consisting of phenyl, ... e But H and C 1-6 alkyl; R e C 1-6 The alkyl may be optionally substituted with one or more halo, and R g Provided herein are compounds of Formula (X), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein is halo.

[0109] In some of the foregoing embodiments, provided herein are compounds of Formula (X), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein L is absent and R is selected from the group consisting of phenyl, thiazolyl, thienyl, pyridyl, pyrazolyl, and furanyl, and each R phenyl, thiazolyl, thienyl, pyridyl, pyrazolyl, or furanyl is independently optionally substituted. In some embodiments, L is absent and R is selected from the group consisting of phenyl, thiazolyl, thienyl, pyridyl, pyrazolyl, and furanyl, and each R phenyl, thiazolyl, thienyl, pyridyl, pyrazolyl, or furanyl is independently optionally substituted. 1-6 Alkyl, C 1-6 Haloalkyl, O(Re ) and S(R g ) 5, and R e is H and C 1-6 alkyl; R e C 1-6 The alkyl may be substituted with one or more halo, R g is a halo.

[0110] In some aspects, the compound of Formula (X) or Formula (I), or any variation or embodiment thereof, is selected from the compounds listed in Table 1 below, including racemic mixtures and resolved isomers, as appropriate. [Table 1] JPEG0007796721000045.jpg229170JPEG0007796721000046.jpg237170JPEG0007796721000047.jpg232170JPEG0007796721000048.jpg23217 0JPEG0007796721000049.jpg228170JPEG0007796721000050.jpg249170JPEG0007796721000051.jpg208170JPEG0007796721000052.jpg76170

[0111] 2-[[[7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enamide; 2-[[[4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enamide; 2-[[[4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]-N-methyl-prop-2-enamide; 2-[[[4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]-N,N-dimethyl-prop-2-enamide; 2-[[[4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl]-methyl-amino]methyl]prop-2-enoic acid; Methyl 2-[[[4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoate; 2-[[[4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enehydroxamic acid; 1-[[[4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]vinylboronic acid; 7-(4-isopropylphenyl)-5-[(2-methylene-3-oxo-butyl)amino]-2,3-dihydrobenzofuran-4-carbonitrile; 2-[[[4-(hydroxymethyl)-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[4-(hydroxymethyl)-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enamide; 2-[[4-(hydroxymethyl)-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enehydroxamic acid; 2-[[[4-cyano-7-[4-(trifluoromethyl)phenyl]-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[4-cyano-7-[4-[2,2,2-trifluoro-1-methyl-ethyl]phenyl]-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[4-cyano-7-[4-[2,2,2-trifluoro-1-methyl-ethyl]phenyl]-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[4-cyano-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[4-cyano-7-[4-(1,1-difluoroethyl)phenyl]-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[4-(4-isopropylphenyl)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl]amino]methyl]prop-2-enoic acid; 2-[[[4-fluoro-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[4-cyano-7-(4-isopropylphenyl)-2,3-dihydrofuro[2,3-c]pyridin-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[7-(4-isopropylphenyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[7-cyano-4-[4-(1,1-difluoroethyl)phenyl]-1,3-benzothiazol-6-yl]amino]methyl]prop-2-enoic acid; 2-[[[6-Methoxy-5-[2-[4-(trifluoromethyl)cyclohexyl]vinyl]-3-pyridyl]amino]methyl]prop-2-enoic acid; 2-[[[6-cyano-5-[2-[4-(trifluoromethyl)cyclohexyl]vinyl]-3-pyridyl]amino]methyl]prop-2-enoic acid; 2-[[[4-cyano-7-(5-isopropylthiazol-2-yl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enehydroxamic acid; 2-[[[4-cyano-7-(2,6-difluoro-4-isopropyl-phenyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[4-cyano-3,3-dideuterio-7-(4-isopropylphenyl)-2H-benzofuran-5-yl]amino]methyl]prop-2-enehydroxamic acid; 2-[[[4-cyano-7-(2-fluoro-4-isopropyl-phenyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[4-cyano-7-(4-isopropylthiazol-2-yl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enehydroxamic acid; 2-[[[4-cyano-7-(4-isopropyl-2-thienyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[4-cyano-3,3-dideuterio-7-(4-isopropylphenyl)-2H-benzofuran-5-yl]amino]methyl]prop-2-enamide; 2-[[[4-Carbamoyl-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[4-(hydroxymethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enamide; 2-[[[4-cyano-7-(3-isopropylpyrazol-1-yl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enehydroxamic acid; 2-[[[4-cyano-2,2-dideuterio-7-[4-(trifluoromethoxy)phenyl]-3H-benzofuran-5-yl]amino]methyl]prop-2-enehydroxamic acid; 2-[[[4-cyano-7-[4-(pentafluoro-lambda-6-sulfanyl)phenyl]-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enehydroxamic acid; 2-[[[4-cyano-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enehydroxamic acid; 2-[[[4-cyano-3,3-dideuterio-7-(4-isopropylphenyl)-2H-benzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[7-cyano-4-[4-(trifluoromethoxy)phenyl]-1,3-benzothiazol-6-yl]amino]methyl]prop-2-enehydroxamic acid; 2-[[[7-cyano-4-[4-(trifluoromethoxy)phenyl]-1,3-benzothiazol-6-yl]amino]methyl]prop-2-enamide; 2-[[[4-cyano-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydrobenzofuran-5-yl]amino]methyl]-N-hydroxy-N-methyl-prop-2-enamide; 2-[[[4-cyano-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enamide; 2-[[[4-cyano-7-[4-(pentafluoro-lambda-6-sulfanyl)phenyl]-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[4-(hydroxymethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enehydroxamic acid; 2-[[[4-cyano-7-(5-isopropyl-2-pyridyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[4-cyano-7-[4-(pentafluoro-lambda-6-sulfanyl)phenyl]-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enamide; 2-[[[4-cyano-7-(5-isopropylthiazol-2-yl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[7-(4-isopropylphenyl)-4-methylsulfonyl-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; and 2-[[[7-cyano-4-[4-(pentafluoro-lambda 6-sulfanyl)phenyl]-1,3-benzothiazol-6-yl]amino]methyl]prop-2-enehydroxamic acid, or a pharmaceutically acceptable salt thereof. Also provided herein are any and all stereoisomers of the compounds set forth herein, including, where applicable, any ratio of geometric isomers (e.g., cis / trans or E / Z isomers), enantiomers, diastereomers, tautomers, or mixtures thereof, including racemic mixtures.

[0112] 2-[[[7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enamide; 2-[[[4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enamide; 2-[[[4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]-N-methyl-prop-2-enamide; 2-[[[4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]-N,N-dimethyl-prop-2-enamide; 2-[[[4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl]-methyl-amino]methyl]prop-2-enoic acid; Methyl 2-[[[4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoate; 2-[[[4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enehydroxamic acid; 1-[[[4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]vinylboronic acid; 7-(4-isopropylphenyl)-5-[(2-methylene-3-oxo-butyl)amino]-2,3-dihydrobenzofuran-4-carbonitrile; 2-[[[4-(hydroxymethyl)-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[4-(hydroxymethyl)-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enamide; 2-[[4-(hydroxymethyl)-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enehydroxamic acid; 2-[[[4-cyano-7-[4-(trifluoromethyl)phenyl]-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[4-cyano-7-[4-[2,2,2-trifluoro-1-methyl-ethyl]phenyl]-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[4-cyano-7-[4-[2,2,2-trifluoro-1-methyl-ethyl]phenyl]-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[4-cyano-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[4-cyano-7-[4-(1,1-difluoroethyl)phenyl]-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[4-(4-isopropylphenyl)-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl]amino]methyl]prop-2-enoic acid; 2-[[[4-fluoro-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[4-cyano-7-(4-isopropylphenyl)-2,3-dihydrofuro[2,3-c]pyridin-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[7-(4-isopropylphenyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[7-cyano-4-[4-(1,1-difluoroethyl)phenyl]-1,3-benzothiazol-6-yl]amino]methyl]prop-2-enoic acid; 2-[[[4-cyano-7-(5-isopropylthiazol-2-yl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enehydroxamic acid; 2-[[[4-cyano-7-(2,6-difluoro-4-isopropyl-phenyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[4-cyano-3,3-dideuterio-7-(4-isopropylphenyl)-2H-benzofuran-5-yl]amino]methyl]prop-2-enehydroxamic acid; 2-[[[4-cyano-7-(2-fluoro-4-isopropyl-phenyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[4-cyano-7-(4-isopropylthiazol-2-yl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enehydroxamic acid; 2-[[[4-cyano-7-(4-isopropyl-2-thienyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[4-cyano-3,3-dideuterio-7-(4-isopropylphenyl)-2H-benzofuran-5-yl]amino]methyl]prop-2-enamide; 2-[[[4-Carbamoyl-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[4-(hydroxymethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enamide; 2-[[[4-cyano-7-(3-isopropylpyrazol-1-yl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enehydroxamic acid; 2-[[[4-cyano-2,2-dideuterio-7-[4-(trifluoromethoxy)phenyl]-3H-benzofuran-5-yl]amino]methyl]prop-2-enehydroxamic acid; 2-[[[4-cyano-7-[4-(pentafluoro-lambda-6-sulfanyl)phenyl]-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enehydroxamic acid; 2-[[[4-cyano-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enehydroxamic acid; 2-[[[4-cyano-3,3-dideuterio-7-(4-isopropylphenyl)-2H-benzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[7-cyano-4-[4-(trifluoromethoxy)phenyl]-1,3-benzothiazol-6-yl]amino]methyl]prop-2-enehydroxamic acid; 2-[[[7-cyano-4-[4-(trifluoromethoxy)phenyl]-1,3-benzothiazol-6-yl]amino]methyl]prop-2-enamide; 2-[[[4-cyano-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydrobenzofuran-5-yl]amino]methyl]-N-hydroxy-N-methyl-prop-2-enamide; 2-[[[4-cyano-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enamide; 2-[[[4-cyano-7-[4-(pentafluoro-lambda-6-sulfanyl)phenyl]-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[4-(hydroxymethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enehydroxamic acid; 2-[[[4-cyano-7-(5-isopropyl-2-pyridyl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[4-cyano-7-[4-(pentafluoro-lambda-6-sulfanyl)phenyl]-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enamide; 2-[[[4-cyano-7-(5-isopropylthiazol-2-yl)-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; 2-[[[7-(4-isopropylphenyl)-4-methylsulfonyl-2,3-dihydrobenzofuran-5-yl]amino]methyl]prop-2-enoic acid; and 2-[[[7-cyano-4-[4-(pentafluoro-lambda 6-sulfanyl)phenyl]-1,3-benzothiazol-6-yl]amino]methyl]prop-2-enehydroxamic acid, or a pharmaceutically acceptable salt thereof. Also provided herein are any and all stereoisomers of the compounds presented herein, including geometric isomers (e.g., cis / trans or E / Z isomers), enantiomers, diastereomers, tautomers, or mixtures thereof, in any ratio, including racemic mixtures, if applicable.

[0113] In one aspect, JPEG0007796721000053.jpg218170JPEG0007796721000054.jpg255170JPEG0007796721000055.jpg245170JPEG0007796721000056.jpg252170 or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0114] In one aspect, JPEG0007796721000057.jpg217170JPEG0007796721000058.jpg253170JPEG0007796721000059.jpg248170JPEG0007796721000060.jpg211170, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0115] In one aspect, the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof is JPEG0007796721000061.jpg253170JPEG0007796721000062.jpg223170 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0116] In one aspect, the compound of Formula (X) or Formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof is JPEG0007796721000063.jpg253170JPEG0007796721000064.jpg179170 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0117] In one aspect, compounds of formula (I) include 2-[[[6-methoxy-5-[(E)-2-[trans-4-(trifluoromethyl)cyclohexyl]vinyl]-3-pyridyl]amino]methyl]prop-2-enoic acid, and 2-[[[6-cyano-5-[(E)-2-[trans-4-(trifluoromethyl)cyclohexyl]vinyl]-3-pyridyl]amino]methyl]prop-2-enoic acid, and stereoisomers, tautomers, and pharmaceutically acceptable salts thereof. In other embodiments, compounds of Formula (I) exclude 2-[[[6-methoxy-5-[(E)-2-[trans-4-(trifluoromethyl)cyclohexyl]vinyl]-3-pyridyl]amino]methyl]prop-2-enoic acid, and 2-[[[6-cyano-5-[(E)-2-[trans-4-(trifluoromethyl)cyclohexyl]vinyl]-3-pyridyl]amino]methyl]prop-2-enoic acid, and stereoisomers, tautomers, and pharmaceutically acceptable salts thereof.

[0118] In one aspect, the compound of formula (I) comprises JPEG0007796721000065.jpg42170 and stereoisomers, tautomers, and pharmaceutically acceptable salts thereof. In another embodiment, the compound of formula (I) is JPEG0007796721000066.jpg43170 and its stereoisomers, tautomers, and pharmaceutically acceptable salts are excluded.

[0119] In some embodiments, the compounds of the present disclosure are isotopically labeled by having one or more atoms therein replaced by atoms having different atomic masses or mass numbers.Such isotopically labeled (i.e., radiolabeled) compounds of formula (X) or formula (I) are considered to be within the scope of the present disclosure.Examples of isotopes that can be incorporated into compounds of formula (X) or formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, for example, 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I. These isotopically labeled compounds may be useful, for example, to help determine or measure the effectiveness of a compound by characterizing the site or mode of action, or binding affinity to TEAD. Certain isotopically labeled compounds of formula (X) or formula (I), for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e., 3 H and carbon-14, i.e., 14 C are particularly useful for this purpose given their ease of incorporation and ready means of detection. For example, compounds of formula (X) or formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99% of a given isotope.

[0120] Heavier isotopes, such as deuterium, i.e. 2 Substitutions such as H may result in greater metabolic stability and may confer certain therapeutic advantages, for example, by increasing in vivo half-life or requiring lower dosages.

[0121] 11 C. 18 F, 15 O and 13 Substitution with positron-emitting isotopes, such as N, can be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds of formula (X) or formula (I) may generally be prepared by conventional techniques known to those skilled in the art, or by methods similar to those described in the Examples set forth below, substituting an appropriate isotopically labeled reagent for the previously used non-labeled reagent.

[0122] Also provided herein are pharmaceutically acceptable salts or esters of any of the compounds provided herein, as well as stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes, or prodrugs of such compounds, or pharmaceutically acceptable salts of such compounds. Pharmaceutical Compositions and Administration

[0123] In addition to one or more of the compounds provided above (including stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes, pharmaceutically acceptable salts or prodrugs thereof), the present disclosure also provides compositions and medicaments comprising a compound of the present disclosure or an embodiment or aspect thereof and at least one pharmaceutically acceptable carrier. The compositions of the present disclosure can be used to selectively inhibit TEAD in patients (e.g., humans).

[0124] In one aspect, the disclosure provides pharmaceutical compositions or medicaments comprising a compound of the disclosure (or embodiments and aspects thereof, including stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes, pharmaceutically acceptable salts, and prodrugs) and a pharmaceutically acceptable carrier, diluent, or excipient. In another aspect, the disclosure provides the preparation of a composition (or medicament) comprising a compound of the disclosure. In other embodiments, the disclosure provides the administration of a compound of the disclosure or a composition comprising a compound of the disclosure to a patient (e.g., a human patient) in need thereof.

[0125] Carriers may be selected from various oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, particularly for injectable solutions (when isotonic with blood). For example, formulations for intravenous administration include sterile aqueous solutions of the compounds of the present disclosure, prepared by dissolving the solid compound in water to produce an aqueous solution and sterilizing the solution. Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, talc, gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, nonfat dry milk, glycerol, propylene glycol, water, ethanol, and the like. The compositions may contain conventional pharmaceutical excipients such as preservatives, stabilizers, wetting or emulsifying agents, salts for adjusting osmotic pressure, buffers, and the like. Suitable pharmaceutical carriers and their formulations are described in Remington's Pharmaceutical Sciences by E.W. Martin. Such compositions will, in any event, contain an effective amount of a compound of the present disclosure, together with a suitable carrier so as to prepare the proper dosage form for proper administration to the recipient.

[0126] The composition is formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this regard include the specific disorder to be treated, the specific mammal to be treated, the clinical condition of the individual patient, the cause of the disorder, the drug delivery site, the administration method, the administration schedule, and other factors known to medical professionals. The effective amount of the compound to be administered is governed by such considerations and is the minimum amount required to inhibit TEAD activity, which is required to prevent or treat undesirable diseases or disorders, such as pain. For example, this amount may be below the amount that is toxic to normal cells or to the mammal as a whole.

[0127] In one example, the therapeutically effective amount of a compound of the present disclosure administered parenterally per dose ranges from about 0.01 to 100 mg / kg, alternatively, for example, from about 0.1 to 20 mg / kg of patient body weight per day; a typical initial range for the compound used is 0.3 to 15 mg / kg / day. In certain embodiments, the daily dose is administered once daily or in divided doses two to six times daily, or in sustained-release form. For a 70 kg adult, the total daily dose will generally be from about 7 mg to about 1,400 mg. This dosing regimen can be adjusted to provide the optimal therapeutic response. The compound may be administered on a regimen of one to four times daily, preferably one to two times daily.

[0128] The compounds of the present disclosure may be administered in any convenient dosage form, such as tablets, powders, capsules, liquids, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional components of pharmaceuticals, such as diluents, carriers, pH adjusters, sweeteners, fillers, and additional active agents.

[0129] Compositions comprising the disclosed compounds (or embodiments or aspects thereof, including stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes, pharmaceutically acceptable salts, and prodrugs) are typically formulated in accordance with standard pharmaceutical practice as pharmaceutical compositions. A typical formulation is prepared by mixing a compound of the disclosure with a diluent, carrier, or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C., Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, fragrances, flavorings, diluents, and other known additives to provide proper presentation of the drug (i.e., a compound of the present disclosure or a pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical product (i.e., a medicament).Suitable carriers, diluents, carriers, and excipients are well known to those skilled in the art and include buffers and other organic acids such as phosphate, citrate, and methionine; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl, or benzyl alcohol; alkylparabens such as methyl or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; serum albumin; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes), and / or non-ionic surfactants such as TWEEN™, PLURONICS™, or polyethylene glycol (PEG). The active pharmaceutical ingredients of the present disclosure (e.g., compounds of Formula (I), or embodiments or aspects thereof) can also be encapsulated in microcapsules, such as hydroxymethylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules, prepared by coacervation techniques or by interfacial polymerization, colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or macroemulsions. Such techniques are disclosed in Remington: The Science and Practice of Pharmacy: Remington the Science and Practice of Pharmacy (2005) 21st Edition, Lippincott Williams & Wilkins, Philadelphia, PA.The specific carrier, diluent, or additive used depends on the means and purpose for which the compound of the present disclosure is applied. Solvents are generally selected based on solvents recognized by those skilled in the art as safe (GRAS) for administration to mammals. Generally, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), etc., and mixtures thereof.

[0130] Sustained-release preparations of the compounds of the present disclosure (e.g., compounds of Formula (X) or Formula (I), or embodiments or aspects thereof) can be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a compound of Formula (X) or Formula (I), or an embodiment or aspect thereof, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman et al., Biopolymers 22:547, 1983), non-degradable ethylene-vinyl acetate (Langer et al., J. Biomed. Mater. Res. 15:167, 1981), degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid (EP 133,988A). Sustained-release compositions also include liposome-encapsulated compounds that can be prepared by methods known per se (Epstein et al., Proc. Natl. Acad. Sci. USA 82:3688, 1985; Hwang et al., Proc. Natl. Acad. Sci. USA 77:4030, 1980; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324A). Typically, the liposomes are small (about 200-800 angstroms), unilamellar, with a lipid content of more than about 30 mol% cholesterol, the ratio selected being adjusted for optimal therapy.

[0131] In one example, a compound of the present disclosure, or an embodiment or aspect thereof, can be formulated by mixing at ambient temperature with a physiologically acceptable carrier, i.e., a carrier that is not toxic to recipients at the dosages and concentrations used in herbal dosage forms, at an appropriate pH and desired purity. The pH of the formulation will depend primarily on the particular application and compound concentration, but preferably ranges from about 3 to about 8. In one example, a compound of the present disclosure (or an embodiment or aspect thereof) is formulated in acetate buffer at pH 5. In other aspects, a compound of the present disclosure, or an embodiment thereof, is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0132] Formulations of the compounds described herein suitable for oral administration may be prepared as discrete units such as pills, capsules, cachets, or tablets, each containing a predetermined amount of a compound of the disclosure.

[0133] Compressed tablets can be prepared by compressing in a suitable machine a compound of the present disclosure in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active agent, or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of a moistened powdered compound of the present disclosure with an inert liquid diluent. The tablets can optionally be coated or slotted, and can optionally be formulated to provide delayed or sustained release of the compound of the present disclosure therefrom.

[0134] Tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, such as gelatin capsules, syrups, or elixirs can be prepared for oral use.The formulation of the compound of the present disclosure intended for oral use can be prepared according to any method known in the art of manufacturing pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable preparation.Tablets containing the compound of the present disclosure mixed with non-toxic pharmaceutically acceptable excipients suitable for tablet manufacture are acceptable.These excipients can be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating agents and disintegrating agents such as corn starch or alginic acid, binders such as starch, gelatin, or acacia, and lubricants such as magnesium stearate, stearic acid, or talc. The tablets may be uncoated or they may be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period, for example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

[0135] Examples of suitable oral dosage forms include about 0.1 mg, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 30 mg, about 50 mg, about 80 mg, about 100 mg, about 150 mg, about 250 mg, about 300 mg, and about 500 mg of a compound of the present disclosure compounded with a filler (e.g., lactose, e.g., about 90-30 mg anhydrous lactose), a disintegrant (e.g., croscarmellose, e.g., about 5-40 mg croscarmellose sodium), a polymer (e.g., polyvinylpyrrolidone (PVP), a cellulose (e.g., hydroxypropyl methylcellulose (HPMC) and / or copovidone, e.g., about 5-30 mg PVP, HPMC, or copovidone), and a lubricant (e.g., magnesium stearate, e.g., about 1-10 mg). (or an embodiment or aspect thereof). Wet granulation, dry granulation, or dry blending may be used. In one wet granulation embodiment, powdered ingredients are first mixed together and then mixed with a solution or suspension of a polymer (e.g., PVP). The resulting composition may be dried, granulated, mixed with a lubricant, and compressed into tablet form using conventional equipment. An example aerosol formulation may be prepared by dissolving, for example, 5-400 mg of a compound of the present disclosure in a suitable buffer solution, such as phosphate buffer, and, if desired, adding a tonicifier, e.g., a salt such as sodium chloride. The solution may be filtered, for example, using a 0.2 micron filter, to remove impurities and contaminants.

[0136] For treatment of the eye or other external tissues, such as the mouth and skin, the formulation is preferably applied as a topical ointment or cream containing a compound of the present disclosure in an amount of 0.075-20 wt%. When formulated in an ointment, the compound of the present disclosure may be used with either a paraffinic or water-miscible ointment base. Alternatively, the compound of the present disclosure may be formulated into a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may contain a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol (including PEG 400), and mixtures thereof. Topical formulations may optionally contain a compound that enhances absorption or penetration of the compound of the present disclosure through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogs.

[0137] For topical use, it is desirable to administer an effective amount of a pharmaceutical composition according to the present disclosure to a target area adjacent to the peripheral neuron being treated, such as the skin surface and mucous membranes. This amount generally ranges from about 0.0001 mg to about 1 g of a compound of the present disclosure per application, depending on the area to be treated, the severity of the condition, and the nature of the topical vehicle used, whether the use is diagnostic, prophylactic, or therapeutic. A preferred topical preparation is an ointment, in which about 0.001 to about 50 mg of a compound of the present disclosure is used per cc of ointment base. Pharmaceutical compositions may be formulated as transdermal compositions or transdermal delivery devices ("patches"). Such compositions include, for example, a backing, a reservoir of the compound of the present disclosure, a control membrane, a liner, and a contact adhesive. Such transdermal patches can be used to provide continuous pulsatile or on-demand delivery of the compounds of the present disclosure, as desired.

[0138] The formulations can be packaged in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) state, requiring only the addition of a sterile liquid carrier, for example, water, for injection immediately before use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the type described above. Preferred unit dosage forms are those containing the daily dose or daily unit sub-dose of the compound of the present disclosure as described herein above, or an appropriate fraction thereof.

[0139] When the binding target is located in the brain, certain aspects of the present disclosure provide the compounds of the present disclosure (or embodiments or aspects thereof) for crossing the blood-brain barrier. Because certain neurodegenerative diseases are associated with increased permeability of the blood-brain barrier, the compounds of the present disclosure (or embodiments or aspects thereof) can be easily introduced into the brain. When the blood-brain barrier remains intact, there are several technically known approaches for transporting molecules across the blood-brain barrier, including but not limited to physical methods, lipid-based methods, and receptor and channel-based methods.

[0140] Physical methods of transporting a compound of the present disclosure (or an embodiment or aspect thereof) across the blood-brain barrier include, but are not limited to, bypassing the blood-brain barrier entirely or creating an opening in the blood-brain barrier.

[0141] Workarounds include, but are not limited to, direct injection into the brain (see, e.g., Papanastassiou et al., Gene Therapy 9:398-406, 2002), interstitial injection / convection-enhanced delivery (see, e.g., Bobo et al., Proc. Natl. Acad. Sci. USA 91:2076-2080, 1994), and implantation of a delivery device into the brain (see, e.g., Gill et al., Nature Med. 9:589-595, 2003; and Gliadel Wafers™, Guildford Pharmaceutical).

[0142] Methods for creating openings in the barrier include, but are not limited to, ultrasound (see, e.g., U.S. Patent Application Publication No. 2002 / 0038086), osmotic pressure (e.g., by administration of hypertonic mannitol (Neuwelt, E.A., "Implications of the Blood-Brain Barrier and Its Manipulation," Vols. 1 and 2, Plenum Press, New York (1989)) and permeabilization with, for example, bradykinin or permeabilizing agent A-7 (see, e.g., U.S. Patent Nos. 5,112,596, 5,268,164, 5,506,206, and 5,686,416).

[0143] Lipid-based methods of transporting a compound of the present disclosure (or an embodiment or aspect thereof) across the blood-brain barrier include, but are not limited to, encapsulating a compound of the present disclosure (or an embodiment or aspect thereof) in a liposome that is coupled to an antibody binding fragment that binds to a receptor on the vascular endothelium of the blood-brain barrier (see, e.g., U.S. Patent Publication No. 2002 / 0025313), and coating a compound of the present disclosure (or an embodiment or aspect thereof) in low-density lipoprotein particles (see, e.g., U.S. Patent Publication No. 2004 / 0204354) or apolipoprotein E (see, e.g., U.S. Patent Publication No. 2004 / 0131692).

[0144] Receptor- and channel-based methods of transporting a compound of the present disclosure (or an embodiment or aspect thereof) across the blood-brain barrier include, but are not limited to, increasing the permeability of the blood-brain barrier using glucocorticoid blockers (see, e.g., U.S. Patent Publication Nos. 2002 / 0065259, 2003 / 0162695, and 2005 / 0124533); activating potassium channels (see, e.g., U.S. Patent Publication No. 2005 / 0089473), inhibiting ABC drug transporters (see, e.g., U.S. Patent Publication No. 2003 / 0073713), coating a compound of the present disclosure (or an embodiment or aspect thereof) with transferrin and modulating the activity of one or more transferrin receptors (see, e.g., U.S. Patent Publication No. 2003 / 0129186), and cationizing antibodies (see, e.g., U.S. Patent No. 5,004,697).

[0145] For intracerebral use, in certain embodiments, the compound can be administered continuously by infusion into a fluid reservoir in the CNS, although bolus injection is also acceptable. The inhibitor can be administered intracerebroventricularly or otherwise introduced into the CNS or spinal fluid. Administration can be achieved by continuous administration means, such as the use of an indwelling catheter and a pump. Alternatively, it can be administered by implantation, for example, intracerebral implantation of a sustained-release vehicle. More specifically, the inhibitor can be injected through a chronically implanted cannula or chronically infused with the aid of an osmotic minipump. Subcutaneous pumps are available to deliver proteins into the ventricles through small tubes. Highly sophisticated pumps can be refilled through the skin, and their delivery rate can be set without surgical intervention. Examples of suitable administration protocols and delivery systems involving continuous intraventricular infusion through a subcutaneous pump device or a completely implanted drug delivery system, used to administer dopamine, dopaminergic agents, and cholinergic agents to patients with Alzheimer's disease and animal models of Parkinson's disease, are described in Harbaugh, J. Neural Transm. Suppl. 24:271, 1987; and DeYebenes et al., Mov. Disord. 2:143, 1987.

[0146] Indications and Treatments Representative compounds of the present disclosure have been shown to modulate TEAD activity.

[0147] In some embodiments, the compound that modulates TEAD activity has formula (B): JPEG0007796721000067.jpg27170 (in the formula, X1 is C-R5, and R5 of X1 together with R3 and the atom to which they are attached form a 5-membered heterocyclyl or 5-membered heteroaryl, which 5-membered heterocyclyl or 5-membered heteroaryl may be substituted with one or more D; X2 is N or C-R5, and each R5 is independently H, cyano, halo, C(O)NH2, N(R e )(R f ), C 3-10 Cycloalkyl, C 1-6 Alkoxy, C 6-20 Aryl, S(O)2-C 1-6 Alkyl and C 1-6 alkyl, and R5 C 1-6 Alkyl is hydroxyl or N(R e )(R f ) may be substituted; X3 is N or CH; R1 is (i) A 3- to 5-membered saturated heterocyclyl containing at least one cyclic oxygen atom, wherein the 3- to 5-membered saturated heterocyclyl is one or more C 1-6 a 3- to 5-membered saturated heterocyclyl optionally substituted with alkyl, or (ii) N(R e )(R f ),or JPEG0007796721000068.jpg21170 (in the formula, R a , R b and R c are each independently H, halo, cyano, hydroxyl, B(OH), C(O)-OH, C(O)-N(R e )(R f ), C(O)-C1-6 Alkoxy, C(O)-C 1-6 Alkyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-20 Aryl, 3-10 membered heterocyclyl, C 5-13 selected from the group consisting of spirocyclyl and 5- to 20-membered heteroaryl; 1-6 the alkyl may be further substituted with hydroxyl, or JPEG0007796721000069.jpg20170 (in the formula, R d is H, halo, cyano, hydroxyl, B(OH)2, C(O)-OH, C(O)-N(R e )(R f ), C(O)-C 1-6 Alkoxy, C(O)-C 1-6 Alkyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-20 Aryl, 3-10 membered heterocyclyl, C 5-13 spirocyclyl, and 5- to 20-membered heteroaryl; 1-6 The alkyl may be further substituted with hydroxyl. and; L is absent or -O-, * -CH2-O- ** , * -O-CH2- ** , —CH═CH—, and —C≡C—; ** indicates the point of attachment to the R2 moiety, * indicates the point of attachment to the rest of the molecule, R2 is C 1-12 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 aryl or 5- to 20-membered heteroaryl; Here, C of R2 1-12 Alkyl, C 3-10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 5-13 Spirocyclyl, C 6-20The aryl or 5- to 20-membered heteroaryl is independently selected from cyano, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, NO2, N(R e )(R f ), O(R e ) and S(R g ) 5, optionally substituted with one or more substituents selected from the group consisting of R4 is H or C 1-6 alkyl, C 1-6 The alkyl may be substituted with hydroxyl; R e and R f are, independently of each other and independently at each occurrence, H, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 1-6 Alkyl-C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 aryl, and 3- to 20-membered heteroaryl; R e and R f C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-6 Alkyl-C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 The aryl and the 3- to 20-membered heteroaryl are each independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 optionally substituted with one or more substituents selected from the group consisting of alkoxy, oxo, cyano, halo, NO2, and hydroxyl; R g is a halo) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0148] In some embodiments, the compound that modulates TEAD activity has formula (A): JPEG0007796721000070.jpg28170 (in the formula, X1 is N or C-R5, and each R5 is independently H, cyano, halo, C(O)NH2, N(R e )(R f ), C 3-10 Cycloalkyl, C 1-6 Alkoxy, C 6-20 Aryl and C 1-6 alkyl, and R5 C 1-6 Alkyl is hydroxyl or N(R e )(R f ), R5 of X1 together with R3 and the atom to which they are attached form a 5-membered heterocyclyl or 5-membered heteroaryl, and the 5-membered heterocyclyl or 5-membered heteroaryl may be one or more C 1-6 may be substituted with alkyl, X2 is N or C-R5, and each R5 is independently H, cyano, halo, C(O)NH2, N(R e )(R f ), C 3-10 Cycloalkyl, C 1-6 Alkoxy, C 6-20 Aryl and C 1-6 alkyl, and R5 C 1-6 Alkyl is hydroxyl or N(R e )(R f ), X3 is N or CH; R1 is (i) A 3- to 5-membered saturated heterocyclyl containing at least one cyclic oxygen atom, wherein the 3- to 5-membered saturated heterocyclyl is one or more C 1-6 a 3- to 5-membered saturated heterocyclyl optionally substituted with alkyl, or (ii) N(R e)(R f ),or JPEG0007796721000071.jpg21170 (in the formula, R a , R b and R c are each independently H, halo, cyano, hydroxyl, B(OH), C(O)-OH, C(O)-N(R e )(R f ), C(O)-C 1-6 Alkoxy, C(O)-C 1-6 Alkyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-20 Aryl, 3-10 membered heterocyclyl, C 5-13 selected from the group consisting of spirocyclyl and 5- to 20-membered heteroaryl; 1-6 the alkyl may be further substituted with hydroxyl, or JPEG0007796721000072.jpg18170 (in the formula, R d is H, halo, cyano, hydroxyl, B(OH)2, C(O)-OH, C(O)-N(R e )(R f ), C(O)-C 1-6 Alkoxy, C(O)-C 1-6 Alkyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-20 Aryl, 3-10 membered heterocyclyl, C 5-13 spirocyclyl, and 5- to 20-membered heteroaryl; 1-6 The alkyl may be further substituted with hydroxyl. and; L is absent or -O-, * -CH2-O- ** , * -O-CH2- ** , —CH═CH—, and —C≡C—; ** indicates the point of attachment to the R2 moiety, * indicates the point of attachment to the rest of the molecule, R2 is C 1-12 Alkyl, C 3-10Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 aryl or 5- to 20-membered heteroaryl; Here, C of R2 1-12 Alkyl, C 3-10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 5-13 Spirocyclyl, C 6-20 Aryl or 5- to 20-membered heteroaryl is independently selected from cyano, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, NO2, N(R e )(R f ) and O(R e and optionally substituted with one or more substituents selected from the group consisting of: R3 is cyano, C 1-6 Alkyl, C 1-4 Alkoxy or C 2-4 alkenyl, C 2-4 Alkenyl is N(R e )(R f ), or R3, together with R5 of X1 and the atom to which they are attached, form a 5-membered heterocyclyl or 5-membered heteroaryl, which 5-membered heterocyclyl or 5-membered heteroaryl may contain one or more C 1-6 may be substituted with alkyl, or R3 is the * -CH2-O- ** together with the carbon atoms and the atom to which they are attached form a C6 aryl or 6-membered heteroaryl; R4 is H or C 1-6 alkyl, where C 1-6 The alkyl may be substituted by hydroxyl, and R e and R f are, independently of each other and independently at each occurrence, H, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-10 Cycloalkyl, C 1-6 Alkyl-C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 aryl, and 3~20 R is selected from the group consisting of: e and R f C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-6 Alkyl-C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 The aryl and the 3- to 20-membered heteroaryl are each independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 optionally substituted with one or more substituents selected from the group consisting of alkoxy, oxo, cyano, halo, NO2 and hydroxyl or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0149] In some embodiments, the compound that modulates TEAD activity has formula (X): JPEG0007796721000073.jpg28170 (in the formula, X1 is C-R5, and R5 of X1 together with R3 and the atom to which they are attached form a 5-membered heterocyclyl or 5-membered heteroaryl, which 5-membered heterocyclyl or 5-membered heteroaryl may be substituted with one or more D; X2 is N or C-R5, and each R5 is independently H, cyano, halo, C(O)NH2, N(R e )(R f ), C 3-10 Cycloalkyl, C 1-6 Alkoxy, C 6-20 Aryl, S(O)2-C 1-6 Alkyl and C 1-6alkyl, and R5 C 1-6 Alkyl is hydroxyl or N(R e )(R f ) may be substituted; X3 is N or CH; R1 is (i) A 3- to 5-membered saturated heterocyclyl containing at least one cyclic oxygen atom, wherein the 3- to 5-membered saturated heterocyclyl is one or more C 1-6 a 3- to 5-membered saturated heterocyclyl optionally substituted with alkyl, or (ii) N(R e )(R f ),or JPEG0007796721000074.jpg21170 (in the formula, R a , R b and R c are each independently H, halo, cyano, hydroxyl, B(OH), C(O)-OH, C(O)-N(R e )(R f ), C(O)-C 1-6 Alkoxy, C(O)-C 1-6 Alkyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-20 Aryl, 3-10 membered heterocyclyl, C 5-13 selected from the group consisting of spirocyclyl and 5- to 20-membered heteroaryl; 1-6 the alkyl may be further substituted with hydroxyl, or JPEG0007796721000075.jpg20170 (in the formula, R d is H, halo, cyano, hydroxyl, B(OH)2, C(O)-OH, C(O)-N(R e )(R f ), C(O)-C 1-6 Alkoxy, C(O)-C 1-6 Alkyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-20 Aryl, 3-10 membered heterocyclyl, C 5-13 spirocyclyl, and 5- to 20-membered heteroaryl;1-6 The alkyl may be further substituted with hydroxyl. and; L is absent or -O-, * -CH2-O- ** , * -O-CH2- ** , —CH═CH—, and —C≡C—; ** indicates the point of attachment to the R2 moiety, * indicates the point of attachment to the rest of the molecule, R2 is C 1-12 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 aryl or 5- to 20-membered heteroaryl; Here, C of R2 1-12 Alkyl, C 3-10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 5-13 Spirocyclyl, C 6-20 The aryl or 5- to 20-membered heteroaryl is independently selected from cyano, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, NO2, N(R e )(R f ), O(R e ) and S(R g ) 5, optionally substituted with one or more substituents selected from the group consisting of However, R2 is C 1-12 When R2 is alkyl, 1-12 Alkyl is independently selected from cyano, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, NO2, N(R e )(R f ), O(R e ) and S(R g ) optionally substituted with one or more substituents selected from the group consisting of 5), L is -CH=CH- or -C≡C-; R4 is H or C 1-6 alkyl, C1-6 The alkyl may be substituted with hydroxyl; R e and R f are, independently of each other and independently at each occurrence, H, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 1-6 Alkyl-C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 aryl, and 3- to 20-membered heteroaryl; R e and R f C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-6 Alkyl-C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 The aryl and the 3- to 20-membered heteroaryl are each independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 optionally substituted with one or more substituents selected from the group consisting of alkoxy, oxo, cyano, halo, NO2, and hydroxyl; R g is a halo) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0150] In some embodiments, the compound that modulates TEAD activity has formula (I); JPEG0007796721000076.jpg28170 (in the formula, X1 is N or C-R5, and each R5 is independently H, cyano, halo, C(O)NH2, N(R e )(R f ), C 3-10Cycloalkyl, C 1-6 Alkoxy, C 6-20 Aryl and C 1-6 alkyl, and R5 C 1-6 Alkyl is hydroxyl or N(R e )(R f ), R5 of X1 together with R3 and the atom to which they are attached form a 5-membered heterocyclyl or 5-membered heteroaryl, and the 5-membered heterocyclyl or 5-membered heteroaryl may be one or more C 1-6 may be substituted with alkyl, X2 is N or C-R5, and each R5 is independently H, cyano, halo, C(O)NH2, N(R e )(R f ), C 3-10 Cycloalkyl, C 1-6 Alkoxy, C 6-20 Aryl and C 1-6 alkyl, and R5 C 1-6 Alkyl is hydroxyl or N(R e )(R f ), X3 is N or CH; R1 is (i) A 3- to 5-membered saturated heterocyclyl containing at least one cyclic oxygen atom, wherein the 3- to 5-membered saturated heterocyclyl is one or more C 1-6 a 3- to 5-membered saturated heterocyclyl optionally substituted with alkyl, or (ii) N(R e )(R f ),or JPEG0007796721000077.jpg21170 (in the formula, R a , R b and R c are each independently H, halo, cyano, hydroxyl, B(OH), C(O)-OH, C(O)-N(R e )(R f ), C(O)-C 1-6 Alkoxy, C(O)-C 1-6 Alkyl, C 1-6Alkyl, C 3-10 Cycloalkyl, C 6-20 Aryl, 3-10 membered heterocyclyl, C 5-13 selected from the group consisting of spirocyclyl and 5- to 20-membered heteroaryl; 1-6 the alkyl may be further substituted with hydroxyl, or JPEG0007796721000078.jpg18170 (in the formula, R d is H, halo, cyano, hydroxyl, B(OH)2, C(O)-OH, C(O)-N(R e )(R f ), C(O)-C 1-6 Alkoxy, C(O)-C 1-6 Alkyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-20 Aryl, 3-10 membered heterocyclyl, C 5-13 spirocyclyl, and 5- to 20-membered heteroaryl; 1-6 alkyl may be further substituted with hydroxyl; L is absent or -O-, * -CH2-O- ** , * -O-CH2- ** , —CH═CH—, and —C≡C—; ** indicates the point of attachment to the R2 moiety, * indicates the point of attachment to the rest of the molecule, R2 is C 1-12 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 aryl or 5- to 20-membered heteroaryl; Here, C of R2 1-12 Alkyl, C 3-10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 5-13 Spirocyclyl, C 6-20 Aryl or 5- to 20-membered heteroaryl is independently selected from cyano, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C3-10 Cycloalkyl, NO2, N(R e )(R f ) and O(R e and optionally substituted with one or more substituents selected from the group consisting of: However, R2 is C 1-12 When R2 is alkyl, 1-12 Alkyl is independently selected from cyano, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, NO2, N(R e )(R f ) and O(R e ), L is CH═CH— or —C≡C—; R3 is cyano, C 1-6 Alkyl, C 1-4 Alkoxy or C 2-4 alkenyl, C 2-4 Alkenyl is N(R e )(R f ), or R3, together with R5 of X1 and the atom to which they are attached, form a 5-membered heterocyclyl or 5-membered heteroaryl, which 5-membered heterocyclyl or 5-membered heteroaryl may contain one or more C 1-6 may be substituted with alkyl, or R3 is the * -CH2-O- ** together with the carbon atoms and the atom to which they are attached form a C6 aryl or 6-membered heteroaryl; R4 is H or C 1-6 alkyl, where C 1-6 The alkyl may be substituted by hydroxyl, and R e and R f are, independently of each other and independently at each occurrence, H, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, C 1-6 Alkyl-C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 aryl, and 3~20 R is selected from the group consisting of: e and R f C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-6 Alkyl-C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 The aryl and the 3- to 20-membered heteroaryl are each independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 optionally substituted with one or more substituents selected from the group consisting of alkoxy, oxo, cyano, halo, NO2 and hydroxyl or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0151] The compounds of the present disclosure (or any embodiment or aspect thereof) are useful as medical therapies for treating diseases and conditions mediated by TEAD activity, such as acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, Craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, abnormal proliferation (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's sarcoma, fibrosarcoma, follicular lymphoma, testicular germ cell cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, Lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma , ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, erythrocyte vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovium, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor.

[0152] In certain embodiments, the disclosed compounds (or embodiments or aspects thereof) are useful in treating acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, and leukemia-associated leukemia. Disease, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, abnormal proliferation (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing's sarcoma, fibrosarcoma, follicular lymphoma, testicular germ cell cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatocellular carcinoma, hormone insensitive prostate cancer, leiomyosarcoma, Leukemia, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, It may be administered as a medical therapy for proliferative disorders including osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, erythrocyte vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovium, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor.

[0153] In one aspect, a compound of the disclosure (or an embodiment or aspect thereof) is used to treat acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, , colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, abnormal proliferation (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing's sarcoma, fibrosarcoma, follicular lymphoma, testicular germ cell cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatocellular carcinoma, hormone insensitive prostate cancer, leiomyosarcoma, Leukemia, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, It is administered as medical therapy to treat osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, erythrocyte vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovium, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor.

[0154] In other aspects, the present disclosure provides methods for treating a variety of cancers, including acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, and leukemia. Follicular lymphoma, abnormal proliferation (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing's sarcoma, fibrosarcoma, follicular lymphoma, testicular germ cell cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hepatocellular carcinoma, hepatocellular carcinoma, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and and non-Hodgkin's), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, erythremia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, thoracic leukemia, thyroid cancer ... Provided are methods for treating rhabdomyosarcoma, sarcoma, sebaceous carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovium, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to Formula (A), or (I) (or an embodiment or aspect thereof), as described elsewhere herein.

[0155] In another aspect, the disclosure provides a compound of Formula (B), Formula (A), Formula (X), or Formula (I) (or any embodiment or aspect thereof) as described elsewhere herein for modulating TEAD activity. In some embodiments, the disclosure provides a pharmaceutically acceptable salt of a compound of Formula (B), Formula (A), Formula (X), or Formula (I) for modulating TEAD activity.

[0156] In another aspect, the present disclosure provides a compound of Formula (B), Formula (A), Formula (X) or Formula (I), or an embodiment or aspect thereof, such as a pharmaceutically acceptable salt thereof, as described elsewhere herein, for use in medical therapy.

[0157] In other aspects, the present disclosure provides methods for treating leukemia, including but not limited to, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, and leukemia. Lymphoma, abnormal proliferation (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing's sarcoma, fibrosarcoma, follicular lymphoma, testicular germ cell cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hepatocellular carcinoma, hepatocellular carcinoma, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's) Hodgkin's disease), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, erythremia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, striated muscle Provided are methods for treating or preventing sarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovium, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (A) or Formula (I) (or an embodiment or aspect thereof) as described elsewhere herein.

[0158] In other aspects, the present disclosure provides methods for treating a variety of cancers, including: acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, and leukemia. Follicular lymphoma, abnormal proliferation (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing's sarcoma, fibrosarcoma, follicular lymphoma, testicular germ cell cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatocellular carcinoma, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and and non-Hodgkin's), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, erythremia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma Provided are compounds of Formula (B), Formula (A), Formula (X), or Formula (I), or an embodiment or aspect thereof, such as a pharmaceutically acceptable salt thereof, as described elsewhere herein, for use in the treatment or prevention of rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovium, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor.

[0159] In other aspects, the present disclosure provides methods for treating leukemia, including but not limited to, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, and leukemia. Lymphoma, abnormal proliferation (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing's sarcoma, fibrosarcoma, follicular lymphoma, testicular germ cell cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hepatocellular carcinoma, hepatocellular carcinoma, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's) Hodgkin's disease), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, erythremia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, striated muscle Provided is the use of a compound of Formula (B), Formula (A), Formula (X), or Formula (I), or an embodiment or aspect thereof, such as a pharmaceutically acceptable salt thereof, as described elsewhere herein, for the preparation of a medicament for the treatment or prevention of sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovium, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor.

[0160] In other aspects, the present disclosure provides a method for the treatment of a variety of cancers, including acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, thyroid cancer ... Diffuse large B-cell lymphoma, abnormal proliferation (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's sarcoma, fibrosarcoma, follicular lymphoma, testicular germ cell cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hepatocellular carcinoma, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma ( Hodgkin's and non-Hodgkin's), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, erythremia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma The present invention provides a method for treating tumors, including rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovium, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor, comprising administering to a mammal a compound of Formula (A), or Formula (I), or an embodiment or aspect thereof, e.g., a pharmaceutically acceptable salt thereof, as described elsewhere herein.

[0161] In another aspect, the disclosure provides a method of modulating TEAD activity comprising contacting a TEAD with a compound of Formula (B), Formula (A), Formula (X), or Formula (I), as described elsewhere herein, or an embodiment or aspect thereof, e.g., a pharmaceutically acceptable salt thereof.

[0162] In another aspect, the present disclosure provides a compound of Formula (B), Formula (A), Formula (X), or Formula (I), as described elsewhere herein, or an embodiment or aspect thereof, such as a pharmaceutically acceptable salt thereof, for treating or preventing a disease or condition mediated by TEAD activity. Within aspects of this embodiment, the disease or condition may be acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, colon cancer, Cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, abnormal proliferation (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing's sarcoma, fibrosarcoma, follicular lymphoma, testicular germ cell cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatocellular carcinoma, hormone insensitive prostate cancer, smooth muscle Myosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, midline thyroid carcinoma (NMT), non-small cell lung cancer, Oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, vera erythremia, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovium, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor.

[0163] In another aspect, the disclosure provides the use of a compound of Formula (B), Formula (A), Formula (X), or Formula (I), as described elsewhere herein, or an embodiment or aspect thereof, such as a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing a disease or condition mediated by TEAD activity. Within aspects of this embodiment, the disease or condition may be acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, colon cancer, Cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, abnormal proliferation (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing's sarcoma, fibrosarcoma, follicular lymphoma, testicular germ cell cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatocellular carcinoma, hormone insensitive prostate cancer, smooth muscle Myosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, midline thyroid carcinoma (NMT), non-small cell lung cancer, Oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, vera erythremia, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovium, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor.

[0164] In one aspect, the compounds of the present disclosure exhibit increased potency compared to other analogs. Combination Therapy

[0165] The compounds of Formula (B), (A), (X), (I), (IA), (IB), or (IC), or their stereoisomers, tautomers, or pharmaceutically acceptable salts, may be used alone or in combination with other therapeutic agents. For example, the second agent in a pharmaceutical combination formulation or dosing regimen may have complementary activity to the compounds of Formula (B), (A), (X), (I), (IA), (IB), or (IC), so as not to adversely affect each other. The compounds may be administered together in a single pharmaceutical composition or separately. In one embodiment, the compounds or pharmaceutically acceptable salts may be co-administered with a cytotoxic agent to treat proliferative diseases and conditions.

[0166] The term "co-administration" refers to simultaneous administration or any manner of separate, sequential administration of a compound of Formula (B), (A), (X), (I), (IA), (IB), or (IC), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and additional active pharmaceutical ingredients, including cytotoxic agents and radiation therapy. If administration is not simultaneous, the compounds are administered close in time to each other. Furthermore, it is not important whether the compounds are administered in the same dosage form; for example, one compound may be administered topically and the other compound may be administered orally.

[0167] These additional agents can be administered separately from the compound-containing composition of the present invention as part of a multiple dose regimen. Alternatively, these agents can be part of a single dosage form that is mixed with the compound of the present invention in a single composition. When administered as part of a multiple dose regimen, the two active agents can be presented simultaneously, sequentially, or within a certain period of each other, usually within 5 hours of each other.

[0168] As used herein, the terms "combination," "combined," and related terms refer to simultaneous or sequential administration of therapeutic agents according to the present invention. For example, the compounds of the present invention may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or together in a single unit dosage form. Thus, the present invention provides a single unit dosage form comprising a compound of Formula I or Formula II, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0169] The amount of both the compounds of the invention and additional therapeutic agents (in compositions containing such additional therapeutic agents) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. In certain embodiments, the compositions of the invention are formulated so that a dosage of 0.01 to 100 mg / kg body weight / day of the invention can be administered.

[0170] Typically, any agent that is active against the disease or condition being treated may be co-administered. Examples of such agents can be found in V.T.Devita and S. Hellman (eds.), 6th Edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. Those skilled in the art will be able to identify which combinations of agents are useful based on the specific characteristics of the drugs and the disease involved.

[0171] In one embodiment, the method of treatment comprises co-administration of a compound of Formula (B), (A), (X), (I), (IA), (IB) or (IC) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof with at least one cytotoxic agent. As used herein, the term "cytotoxic agent" refers to a substance that inhibits or prevents the function of cells and / or causes cell death or destruction. Cytotoxic agents include radioisotopes (e.g., At 211 , I 131 , I 125 , Y 90 ,Re 186 ,Re 188 , Sm 153 , Bi 212 , P 32, Pb 212 , and radioactive isotopes of Lu); chemotherapeutic agents; growth inhibitory agents; enzymes and fragments thereof, such as nucleases; and toxins (including fragments and / or variants thereof), such as small molecule or enzymatically active toxins of bacterial, fungal, plant, or animal origin.

[0172] Exemplary cytotoxic agents may be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, pro-apoptotic agents, LDH-A inhibitors, fatty acid biosynthesis inhibitors, cell cycle signaling inhibitors, HDAC inhibitors, proteasome inhibitors, and metabolic inhibitors.

[0173] "Chemotherapeutic agents" include chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents and their derivatives include: erlotinib (TARCEVA®, Genentech / OSI Pharm.), bortezomib (VELCADE®, Millennium), and cerebrospinal fluid (CFU). Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), Radicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca), sunitib (SUTENT®, Pfizer / Sugen), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), finasteride (VATALANIB®, Novartis), oxaliplatin (®, Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®, GSK572016, GlaxoSmithKline), Kline), lonafamib (SCH66336), sorafenib (NEXAVAR®, Bayer Alkylating agents such as cyclophosphamide (CYTOXAN®), alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylmelamine; acetogenins (especially bullatacin and bullatacinone); camptothecins (including topotecan and irinotecan); bryostatin; kallistatin; CC-1065 (including synthetic analogs of adozelesin, carzelesin, and bizelesin); cryptophycins (especially cryptophycin 1 and cryptophycin 8); adrenocorticosteroids (including prednisone and prednisolone); cyproterone acetate;5α-reductase inhibitors, including finasteride and dutasteride; vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat; dolastatins; aldesleukin, talc; duocarmycins (including synthetic analogs, KW-2189 and CB1-TM1); eletarobin; pancratistatin; sarcodictine; spongistatins; chlorambucil, chromafadine, chlorophosphamide, estramustine, ifosfamide, mechlorestamine, mechlorestamine oxide hydrochloride, melphalan, nobembine, phenesterine, prednimustine, trofosfamide, nitrogen mustards such as uracil mustard, nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as enidine antibiotics (e.g., calicheamicin, particularly calicheamicin γ1I and calicheamicin ω1I (Angew Chem. Intl. Ed. Engl. 199433:183-186); dynemicins, including dynemicin A; bisphosphonates such as clodronate; neocarzinostatin chromophores and related enediyne antibiotic chromophores, as well as esperamicin (enediyne antibiotic chromophores), aclacinomycin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino Anti-metabolic agents such as doxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolinodoxorubicin, deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, chelamycin, rodorubicin, streptozocin, tuberculin, ubenimex, zinostatin, zorubicin, methotrexate, and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimetrexate;Purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiosteine, and testolactone; antiadrenergics such as aminoglutethimide, mitotane, and trilosteine; folic acid supplements such as furoic acid; acegraton; aldophosphamide glycosides; aminolevulinic acid; Eniluracil; Amsacrine; Bestravsil; Bisantrene; Edatraxate; Defofamine; Demecolcine; Diaziquion; Elfomitin; Elliptine acetate; Amepothilone; Etoglucide; Gallium nitrate; Hydroxyurea; Lentinan; Lonidynin; Maytansinoids such as maytansin and ansamitocin; Mitoguazone; Mitoxantrone; Mopidamol; Nitraerin; Pentostatin; Fenamet; Pirarubicin; Rosoxantrone; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; PSK (registered trademark) polysaccharide complex (JHS) Natural Products, Eugene, Oreg.); razoxane; rhizoxin; schizofuran; spirogermanium; tenuazonic acid; triaziquione; 2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2 toxin, veraculin A, roridin A, and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, such as TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE® (Cremophofree), an albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumburg, Illinois), and TAXOTERE® (docetaxel;Sanofi-Aventis), chlorambucil, GEMZAR® (gemcitabine), 6-thioguanine, mercaptopurine, methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ibosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); nobandrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids, and derivatives of any of the above.

[0174] Chemotherapeutic agents also include: (i) antihormonal agents that act to regulate or inhibit hormone action on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), e.g., tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, ketoxifene, LY117018, onapristone, and FARESTON® (trimethylenediamine diphosphate citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal gland, such as 4(5)-imidazole, aminoglutethimide, MEGASE® (megstrol acetate), AROMASIN® (exemestane; Pfizer), formestany, fadrozole, RIVISOR® (borzole), FEMARA® (letrozole; Novartis), ARIMIDEX® (anastrozole; AstraZeneca), etc. Antiandrogens, (iii) antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; buserelin, triplerin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all-trans retinoic acid, fenretinide, as well as troxacitabine (1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, especially those used to inhibit abnormal cell proliferation. those that inhibit the expression of genes in signal transduction pathways involved in proliferation, e.g., PKC-α, Ralf, and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) gene therapy vaccines, e.g., ALLOVECTIN®, LEUVECTIN®, and VAXID®; topoisomerase 1 inhibitors such as PROLEUKIN®, rIL-2; LURTOTECAN®; ABARELIX rmRH; and (ix) pharmaceutically acceptable salts, acids, and derivatives of any of the above.

[0175] Chemotherapeutic agents also include antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech), cetuximab (ERBITUX®, Imclone), panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech / Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody-drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the present invention include apolizumab, acelizumab, atlizumab, bapineuzumab, bivatuzumab mertansine (bivatuzumab mertansine), cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidutuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motavizumab, natalizumab, nimotuzumab, norobizumab, numavizumab, ocrelizumab, omalizumab Mab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resivizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab-tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab-celmoleukin, tuxituzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and interleukin-12 and anti-interleukin-12 (ABT-874 / J695, Wyeth Research and Abbott Laboratories), a recombinant, exclusively human sequence, full-length IgG1λ antibody genetically engineered to recognize the p40 protein.

[0176] Chemotherapeutic agents also include "EGFR inhibitors," alternatively referred to as "EGFR antagonists," which refer to compounds that bind to or otherwise directly interact with EGFR and block or reduce its signaling activity. Examples of such agents include antibodies and small molecules that bind to EGFR. Examples of antibodies that bind to EGFR include MAb579 (ATCC CRL HB8506), MAb455 (ATCC CRL HB8507), MAb225 (ATCC CRL8508), MAb528 (ATCC CRL8509) (see U.S. Pat. No. 4,943,533, Mendelsohn et al.), and variants thereof, such as chimerized 225 (C225 or cetuximab; ERBUTIX®) and reshaped human 225 (H225) (see WO 96 / 40210, Imclone Systems, Inc.). Inc.); the fully human EGFR-targeting antibody IMC-11F8 (Imclone); antibodies that bind type II mutant EGFR (U.S. Pat. No. 5,212,290); humanized and chimeric antibodies that bind EGFR, such as those described in U.S. Pat. No. 5,891,996; and human antibodies that bind EGFR, such as ABX-EGF or Panitumumab (WO 98 / 50433, Abgenix / Amgen); EMD 55900 (Stragliotto et al., Eur. J. Cancer 32A:636-640 (1996)); EMD7200 (matuzumab) (EMD / Merck), a humanized EGFR antibody against EGFR that competes with both EGF and TGF-α for EGFR binding; the human EGFR antibody, HuMax-EGFR (GenMab); the fully human antibodies known as E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, and E7.6.3, and described in U.S. Pat. No. 6,235,883, MDX-447 (Medarex Inc), and mAb806 or humanized mAb806 (Johns et al., J. Biol. Chem. 279(29):30375-30384 (2004)).Anti-EGFR antibodies can be conjugated to cytotoxic agents to form immunoconjugates (see, e.g., European Patent No. 659,439A2, Merck Patent GmbH). EGFR antagonists include those described in U.S. Patent Nos. 5,616,582, 5,457,105, 5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,39 and 5,747,498, and the following PCT publications: WO 98 / 14451, WO 98 / 50038, WO 99 / 09016, and WO 99 / 24037.Specific small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA®, Genentech / OSI Pharmaceuticals), PD183805 (CI1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.), ZD1839, gefitinib (IRESSA®) 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca), ZM105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca), BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim), Ingelheim), PKI-166 ((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol), (R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine), CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide), EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7 -ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butynamide) (Wyeth), AG1478 (Pfizer), AG1571 (SU5271, Pfizer), and dual EGFR / HER2 tyrosine kinase inhibitors such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6[5[[[2methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine).

[0177] Chemotherapeutic agents also include the EGFR-targeted drugs mentioned in the paragraph above; small molecule HER2 tyrosine kinase inhibitors such as TAK165 available from Takeda; CP-724, 714, an oral selective inhibitor of ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual HER inhibitors such as EKB-569 (available from Wyeth), which preferentially binds to EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016; available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors such as canertinib (CI-1033; Pharmacia); Raf-1 inhibitors, e.g., ISIS-5132, an antisense drug available from ISIS Pharmaceuticals that inhibits Raf-1 signaling; non-HER-targeted TK inhibitors, e.g., imatinib mesylate (Glaxo GLEEVEC® available from SmithKline; multi-targeted tyrosine kinase inhibitors, such as sunitinib (SUTENT® available from Pfizer); VEGF receptor tyrosine kinase inhibitors, such as vatalanib (PTK787 / ZK222584 available from Novartis / Schering AG); CI-1040, a MAPK extracellular regulated kinase I inhibitor (available from Pharmacia); quinazolines, such as PD153035, 4-(3-chloroanilino)quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines such as CGP59326, CGP60261, and CGP62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrazole; chloro[2,3-d]pyrimidines; curcumin (diferuloylmethane, 4,5-bis(4-fluoroanilino)phthalimide); tryphostins containing a nitrothiophene moiety; PD-0183805 (Warner-Lambert); antisense molecules (e.g., those that bind to HER-encoding nucleic acids); quinoxalines (U.S. Patent No. 5,804,396); tryphostins (U.S. Patent No. 5,804,396); ZD6474 (Astra Zeneca);pan-HER inhibitors such as PTK-787 (Novartis / Schering AG); CI-1033 (Pfizer); Affinitac (ISIS3521; Isis / Lilly); imatinib mesylate (GLEEVEC®); PKI 166 (Novartis); GW2016 (GlaxoSmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis / Schering AG); INC-1C11 (Imclone), rapamycin (sirolimus, RAPAMUNE®); or those described in any of the following patent documents: U.S. Pat. No. 5,804,396; WO 1999 / 09016 (American Cyanamid); WO 1998 / 43960 (American Also included are "tyrosine kinase inhibitors," including Cyanamid; WO 1997 / 38983 (Warner Lambert); WO 1999 / 06378 (Warner Lambert); WO 1999 / 06396 (Warner Lambert); WO 1996 / 30347 (Pfizer, Inc); WO 1996 / 33978 (Zeneca); WO 1996 / 3397 (Zeneca), and WO 1996 / 33980 (Zeneca);

[0178] Chemotherapeutic agents also include dexamethasone, interferon, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, live BCG, bevacuzimab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, erotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, and interferon alfa -2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, as well as pharmaceutically acceptable salts thereof.

[0179] Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-butyrate, hydrocortisone-17-butyrate, thizone-17-valerate, aclomethasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate, and fluprednidene acetate; immunoselective anti-inflammatory peptides (ImSAIDs), such as phenylalanine-glutamine-glycine (FEG) and its D-isomer form (feG) (IMULAN) BioTherapeutics, LLC; antirheumatic drugs, such as azathioprine, cyclosporine (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomide, minocycline, sulfasalazine, tumor necrosis factor alpha (TNFα) blockers, such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi ), interleukin 1 (IL-1) blockers such as anakinra (Kineret), T cell costimulation blockers such as abatacept (Orencia), interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMERA®); interleukin 13 (IL-13) blockers such as lebrikizumab; interferon alpha (IFN) blockers such as rontalizumab; beta 7 integrin blockers such as rhuMAb Beta7; IgE pathway blockers such as anti-M1 prime; secreted homotrimeric LTa3 and membrane-bound heterotrimeric LTa1 / β2 blockers such as anti-lymphotoxin alpha (LTa); radioisotopes (e.g., At 211 , I 131 , I125 、Y 90 、Re 186 、Re 188 、Sm 153 、Bi 212 、P 32 、Pb 212, and radioactive isotopes of Lu); various therapeutic agents, such as thioplatin, PS-341, phenylbutyrate, ET-18-OCH3, or farnesyltransferase inhibitors (L-739749, L-744832); polyphenols, such as quercetin, resveratrol, piceatannol, epigallocatechin gallate, theaflavin, flavanols, procyanidins, betulinic acid and its derivatives; autophagy inhibitors, such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol, MARINOL®; beta-lapachone; lapachol; colchicine; betulinic acid; acetylcamptothecin, scopolectin, and 9-aminocamptothecin; podophyllotoxin; tegafur (UFTORAL®); bexarotene (TARGRETIN®); bisphosphonates, such as clodronate (e.g., BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid / zoledronate methadone (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®); and epidermal growth factor inhibitors (EGF-R); vaccines, such as the THERATOPE® vaccine; perifosine, COX-2 inhibitors (e.g., celecoxib or etoricoxib), proteosome inhibitors (e.g., PS341); CCI-779; tipifarnib (R1 1577); orafenib, ABT510; Bcl-2 inhibitors, e.g., oblimersen sodium (GENASENSE®); pixantrone; farnesyltransferase inhibitors, e.g., lonafarnib (SCH6636, SARASAR™); and pharmaceutically acceptable salts, acids, or derivatives of any of the above; and combinations of two or more of the above, e.g., CHOP, an abbreviation for cyclophosphamide, doxorubicin, vincristine, and prednisolone combination therapy;and FOLFOX, an abbreviation for a treatment regimen using oxaliplatin (ELOXATIN™) in combination with 5-FU and leucovorin.

[0180] Chemotherapeutic agents can also include nonsteroidal anti-inflammatory drugs that have analgesic, antipyretic and anti-inflammatory effects.NSAIDs include the nonselective inhibitors of enzyme cyclooxygenase.Specific examples of NSAIDs include aspirin, propionic acid derivatives such as ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen, acetic acid derivatives such as indomethacin, sulindac, etodolac, diclofenac, enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam and isoxicam, fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, and COX-2 inhibitors such as celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, rofecoxib and valdecoxib. NSAIDs may be indicated for the symptomatic relief of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathy, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhea, metastatic bone pain, headache and migraine, post-operative pain, mild to moderate pain due to inflammation and tissue injury, fever, intestinal obstruction, and renal colic.

[0181] In certain embodiments, chemotherapeutic agents include, but are not limited to, doxorubicin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, interferon, platinum derivatives, taxanes (e.g., paclitaxel, docetaxel), vinca alkaloids (e.g., vinblastine), anthracyclines (e.g., doxorubicin), epipodophyllotoxins (e.g., etoposide), cisplatin, mTOR inhibitors (e.g., rapamycin), methotrexate, actinomycin D, dolastatin 10, colchicine, trimetrexate, metoprine, cyclosporine, daunorubicin, teniposide, amphotericin, alkylating agents (e.g., chlorambucil), 5-fluorouracil, camptothecin, cisplatin, metronidazole, and imatinib mesylate, among others. In another embodiment, a compound of the invention is administered in combination with a biologic agent, such as bevacizumab or panitumumab.

[0182] In certain embodiments, the compound of the present invention or a pharmaceutically acceptable composition thereof is selected from the group consisting of abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, anastrozole, arsenic trioxide, asparaginase, azacitidine, live BCG, bevaximab, fluorouracil, bexarotene, bleomycin, bortezomib, busulfan, calsterone, capecitabine, camptothecin, carboplatin, carmustine, cetuximab, chlorambucil, cladribine, clofarabine, cyclophosphamide, cyclosporine ... Amido, cytarabine, dactinomycin, darbepoetin, daunetin, denilequin, dexrazoxane, docetaxel, doxorubicin (neutral), doxorubicin hydrochloride, dromostanolone propionate, epirubicin, epoetin alfa, erotinib, estramustine, etoposide phosphate, etoposide, exemestane, filgrastim, floxuridine, fludarabine, fulvestrant, gefitinib, gemcitabine, gemtuzumab, goserelin acetate, histrelin acetate, hydroxyurea, ibritumomab, idarubicin, ifosfa Imatinib mesylate, interferon alfa-2a mesylate, interferon alfa-2b, irinotecan, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, megestrol acetate, melphalan, mercaptopurine, 6-MP, mesna, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone, nelarabine, nofetumomab, oprelvekin, oxaliplatin, paclitaxel, palifermin, pamidronate, pegademase, pegasparga pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, porfimer sodium, procarbazine, quinacrine, rasburicase, rituximab, sargramostim, sorafenib, streptozocin, sunitinib maleate, talc, tamoxifen, temozolomide, teniposide, VM-26, testolactone, thioguanine, 6-TG, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, ATRA, uracil mustard, valrubicin, vinblastine,Administered in combination with an antiproliferative or chemotherapeutic agent selected from any one or more of vincristine, vinorelbine, zoledronate, or zoledronic acid.

[0183] Chemotherapeutic agents also include treatments for Alzheimer's disease such as donepezil hydrochloride and rivastigmine, treatments for Parkinson's disease such as L-DOPA / carbidopa, entacapone, lopyrrole, pramipexole, bromocriptine, pergolide, trihexefendil, and amantadine, agents for treating multiple sclerosis (MS) such as beta interferons (e.g., Avonex® and Rebif®), glatiramer acetate, and mitoxantrone, treatments for asthma such as albuterol and montelukast sodium, agents for treating schizophrenia such as Zyprexa, risperdal, seroquel, and haloperidol, anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1RA, azathioprine, cyclophosphamide, and sulfasalazine, cyclosporine immunomodulators and immunosuppressants such as tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, and antiparkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and antivirals; agents for treating blood disorders such as corticosteroids; anti-leukemia agents and growth factors; and agents for treating immune deficiency disorders, e.g., gamma globulin.

[0184] Additionally, the chemotherapeutic agents include pharmaceutically acceptable salts, acids, or derivatives of any of the chemotherapeutic agents described herein, as well as combinations of two or more thereof.

[0185] In another embodiment, there is provided a method of using a compound of Formula (B), (A), (X), (I), (IA), (IB) or (IC), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or an embodiment or aspect thereof, as described elsewhere herein, to treat cancer in combination with a PD-1 axis-binding antagonist.

[0186] The term "PD-1 axis binding antagonist" refers to a molecule that inhibits the interaction of a PD-1 axis binding partner with one or more of its binding partners to eliminate T cell dysfunction resulting from signaling on the PD-1 signaling axis, thereby restoring or enhancing T cell function (e.g., proliferation, cytokine production, target cell killing). As used herein, PD-1 axis binding antagonists include PD-1 binding antagonists, PD-L1 binding antagonists, and PD-L2 binding antagonists.

[0187] The term "PD-1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, abrogates, or prevents signaling resulting from the interaction of PD-1 with one or more of its binding partners, e.g., PD-L1, PD-L2. In some embodiments, a PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to one or more of its binding partners. In a specific aspect, a PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and / or PD-L2. For example, PD-1 binding antagonists include anti-PD-1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, abrogate, or prevent signaling resulting from the interaction of PD-1 with PD-L1 and / or PD-L2. In one embodiment, the PD-1 binding antagonist reduces the negative costimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes that mediated signaling through PD-1, rendering dysfunctional T cells less dysfunctional (e.g., enhancing the effector response to antigen recognition). In some embodiments, the PD-1 binding antagonist is an anti-PD-1 antibody. Specific examples of PD-1 binding antagonists are provided below.

[0188] The term "PD-L1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, abrogates, or prevents signaling resulting from the interaction of PD-L1 with any one or more of its binding partners, e.g., PD-1, B7-1. In some embodiments, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partners. In particular aspects, PD-L1 binding antagonists inhibit the binding of PD-L1 to PD-1 and / or B7-1. In some embodiments, PD-L1 binding antagonists include anti-PD-L1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, eliminate, or prevent signaling resulting from the interaction of PD-L1 with one or more of its binding partners, e.g., PD-1, B7-1. In one embodiment, the PD-L1 binding antagonist reduces the negative costimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes that mediate PD-L1-mediated signaling, thereby alleviating the dysfunctional state of dysfunctional T cells (e.g., enhancing the effector response to antigen recognition). In some embodiments, the PD-L1 binding antagonist is an anti-PD-L1 antibody. Specific examples of PD-L1 binding antagonists are provided below.

[0189] The term "PD-L2 binding antagonist" refers to a molecule that reduces, blocks, inhibits, abrogates, or prevents signaling that occurs as a result of the interaction of PD-L2 with one or more of its binding partners, such as PD-1. In some embodiments, a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to one or more of its binding partners. In a specific aspect, a PD-L2 binding antagonist inhibits the binding of PD-L2 to PD-1. In some embodiments, PD-L2 antagonists include anti-PD-L2 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, abrogate, or prevent signaling that results from the interaction of PD-L2 with one or more of its binding partners, such as PD-1. In one embodiment, the PD-L2 binding antagonist reduces the negative costimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes that mediated signaling through PD-L2, rendering dysfunctional T cells less dysfunctional (e.g., enhancing the effector response to antigen recognition). In some embodiments, the PD-L2 binding antagonist is an immunoadhesin.

[0190] PD-1 axis binding antagonists

[0191] Provided herein are methods for treating cancer in an individual, the methods comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and a compound of Formula (B), (A), (I), (X), (IA), (IB), or (IC), as described elsewhere herein, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. Also provided herein are methods for enhancing immune function or response in an individual (e.g., an individual with cancer), the methods comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and a compound of Formula (B), (A), (I), (X), (IA), (IB), or (IC), as described elsewhere herein, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0192] In such methods, the PD-1 axis-binding antagonist includes a PD-1 binding antagonist, a PDL1 binding antagonist, and / or a PDL2 binding antagonist. Alternative names for "PD-1" include CD279 and SLEB2. Alternative names for "PDL1" include B7-H1, B7-4, CD274, and B7-H. Alternative names for "PDL2" include B7-DC, Btdc, and CD273. In some embodiments, the PD-1, PDL1, and PDL2 are human PD-1, PDL1, and PDL2.

[0193] In some embodiments, the PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to its ligand-binding partner. In certain aspects, the PD-1 ligand-binding partner is PDL1 and / or PDL2. In other embodiments, the PDL1 binding antagonist is a molecule that inhibits the binding of PDL1 to its binding partner. In a specific aspect, the PDL1 binding partner is PD-1 and / or B7-1. In other embodiments, the PDL2 binding antagonist is a molecule that inhibits the binding of PDL2 to its binding partner. In a specific aspect, the PDL2 binding partner is PD-1. The antagonist may be an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, or a small molecule. When the antagonist is an antibody, in some embodiments, the antibody comprises a human constant region selected from the group consisting of IgG1, IgG2, IgG3, and IgG4.

[0194] Anti-PD-1 antibody

[0195] In some embodiments, the PD-1 binding antagonist is an anti-PD-1 antibody. A variety of anti-PDL1 antibodies may be utilized in the methods disclosed herein. In any of the embodiments herein, the PD-1 antibody may bind to human PD-1 or a variant thereof. In some embodiments, the anti-PD-1 antibody is a monoclonal antibody. In some embodiments, the anti-PD-1 antibody is an antibody fragment selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab')2 fragments. In some embodiments, the anti-PD-1 antibody is a chimeric or humanized antibody. In some embodiments, the anti-PD-1 antibody is a human antibody.

[0196] In some embodiments, the anti-PD-1 antibody is nivolumab (CAS Registry Number: 946414-94-4). Nivolumab (Bristol-Myers Squibb / Ono), also known as MDX-1106-04, MDX-1106, ONO-4538, BMS-936558, and OPDIVO®, is an anti-PD-1 antibody described in WO 2006 / 121168. Nivolumab comprises heavy and light chain sequences, wherein: (a) The heavy chain has the amino acid sequence: QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWY DGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 1), and (b) the light chain has the amino acid sequence: Contains EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRAT GIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 2).

[0197] In some embodiments, the anti-PD-1 antibody comprises six HVR sequences derived from SEQ ID NO:1 and SEQ ID NO:2 (e.g., three heavy chain HVRs from SEQ ID NO:1 and three light chain HVRs from SEQ ID NO:2). In some embodiments, the anti-PD-1 antibody comprises a heavy chain variable domain derived from SEQ ID NO:1 and a light chain variable domain derived from SEQ ID NO:2.

[0198] In some embodiments, the anti-PD-1 antibody is pembrolizumab (CAS Registry Number: 1374853-91-4). Pembrolizumab (Merck), also known as MK-3475, Merck3475, lambrolizumab, SCH-900475, and KEYTRUDA®, is an anti-PD-1 antibody described in WO 2009 / 114335. Pembrolizumab comprises heavy and light chain sequences, wherein: (a) The heavy chain has the amino acid sequence: QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGG INPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYW GQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCP APEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTK PREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN YKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 3), and (b) the light chain has the amino acid sequence: Contains EIVLTQSPAT LSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLES GVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIKRTVAAPSVF IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 4).

[0199] In some embodiments, the anti-PD-1 antibody comprises six HVR sequences derived from SEQ ID NO:3 and SEQ ID NO:4 (e.g., three heavy chain HVRs derived from SEQ ID NO:3 and three light chain HVRs derived from SEQ ID NO:4). In some embodiments, the anti-PD-1 antibody comprises a heavy chain variable domain derived from SEQ ID NO:3 and a light chain variable domain derived from SEQ ID NO:4.

[0200] In some embodiments, the anti-PD-1 antibody is MEDI-0680 (AMP-514; AstraZeneca). MEDI-0680 is a humanized IgG4 anti-PD-1 antibody.

[0201] In some embodiments, the anti-PD-1 antibody is PDR001 (CAS Registry Number 1859072-53-9, Novartis). PDR001 is a humanized IgG4 anti-PD-1 antibody that blocks the binding of PDL1 and PDL2 to PD-1.

[0202] In some embodiments, the anti-PD-1 antibody is REGN2810 (Regeneron). REGN 2810 is a human anti-PD1 antibody.

[0203] In some embodiments, the anti-PD-1 antibody is BGB-108 (BeiGene). In some embodiments, the anti-PD-1 antibody is BGB-A317 (BeiGene).

[0204] In some embodiments, the anti-PD-1 antibody is JS-001 (Shanghai Junshi). JS-001 is a humanized anti-PD1 antibody.

[0205] In some embodiments, the anti-PD-1 antibody is STI-A1110 (Sorrento). STI-A1110 is a human anti-PD1 antibody.

[0206] In some embodiments, the anti-PD-1 antibody is INCSHR-1210 (Incyte). INCSHR-1210 is a human IgG4 anti-PD1 antibody.

[0207] In some embodiments, the anti-PD-1 antibody is PF-06801591 (Pfizer).

[0208] In some embodiments, the anti-PD-1 antibody is TSR-042 (also known as ANB011, Tesaro / AnaptysBio).

[0209] In some embodiments, the anti-PD-1 antibody is AM0001 (ARMO Biosciences).

[0210] In some embodiments, the anti-PD-1 antibody is ENUM 244C8 (Enumeral Biomedical Holdings), an anti-PD-1 antibody that inhibits PD-1 function without blocking the binding of PDL1 to PD-1.

[0211] In some embodiments, the anti-PD-1 antibody is ENUM388D4 (Enumeric Biomedical Holdings). ENUM388D4 is an anti-PD-1 antibody that competitively inhibits the binding of PDL1 to PD-1.

[0212] In some embodiments, the PD-1 antibody is a PD-1 antibody described in International Publication No. WO2015 / 112800 (applicant: Regeneron), International Publication No. WO2015 / 112805 (applicant: Regeneron), International Publication No. WO2015 / 112900 (applicant: Novartis), U.S. Patent No. 20150210769 (assigned to Novartis), International Publication No. WO2016 / 089873 (applicant: Celgene), International Publication No. WO2015 / 035606 (applicant: Beigene), International Publication No. WO2015 / 085847 (applicant: Shanghai Hengrui Pharmaceutical / Jiangsu Hengrui Medicine), International Publication No. WO2014 / 206107 (applicant: Shanghai Junshi Biosciences / Junmeng Biosciences), International Publication No. WO2012 / 145493 (applicant: Amplimmune), U.S. Patent No. 9,205,148 (assigned to MediImmune), International Publication No. WO2015 / 119930 (applicant: Pfizer / Merck), International Publication No. WO2015 / 119923 (applicant: Pfizer / Merck), International Publication No. WO2016 / 032927 (applicant: Pfizer / Merck) , six HVR sequences (e.g., three heavy chain HVRs and three light chain HVRs) from the PD-1 antibodies described in International Publication Nos. WO2014 / 179664 (applicant: AnaptysBio), WO2016 / 106160 (applicant: Enumeral), and WO2014 / 194302 (applicant: Sorrento), and / or three heavy chain variable domains and light chain variable domains.

[0213] Anti-PDL1 antibody

[0214] In some embodiments, the PD-1 axis binding antagonist is an anti-PDL1 antibody. Various anti-PDL1 antibodies are contemplated and described herein. In any embodiment herein, the isolated anti-PDL1 antibody can bind to human PDL1, e.g., human PDL1 set forth in UniProtKB / Swiss-Prot accession number Q9NZQ7.1, or a variant thereof. In some embodiments, the anti-PDL1 antibody can inhibit the binding between PDL1 and PD-1 and / or between PDL1 and B7-1. In some embodiments, the anti-PDL1 antibody is a monoclonal antibody. In some embodiments, the anti-PDL1 antibody is an antibody fragment selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab')2 fragments. In some embodiments, the anti-PDL1 antibody is a chimeric antibody or a humanized antibody. In some embodiments, the anti-PDL1 antibody is a human antibody. Examples of anti-PDL1 antibodies useful in the methods of the present invention, and methods for making them, are described in PCT Patent Application No. 2010 / 077634 and U.S. Patent No. 8,217,149, both of which are incorporated herein.

[0215] In some embodiments, the anti-PDL1 antibody is atezolizumab (CAS Registry Number: 1422185-06-5). Atezolizumab (Genentech), also known as MPDL3280A, is an anti-PDL1 antibody.

[0216] Atezolizumab is (a) HVR-H1, HVR-H2, and HVR-H3 sequences of GFTFSDSWIH (SEQ ID NO: 5), AWISPYGGSTYYADSVKG (SEQ ID NO: 6), and RHWPGGFDY (SEQ ID NO: 7), respectively; (b) comprising the HVR-L1, HVR-L2, and HVR-L3 sequences of RASQDVSTAVA (SEQ ID NO: 8), SASFLYS (SEQ ID NO: 9), and QQYLYHPAT (SEQ ID NO: 10), respectively.

[0217] Atezolizumab comprises heavy and light chain sequences, wherein: (a) The heavy chain variable region sequence has the amino acid sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS (SEQ ID NO: 11), and (b) the light chain variable region sequence has the amino acid sequence: Contains DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIY SASF LYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO: 12).

[0218] Atezolizumab comprises heavy and light chain sequences, wherein: (a) The heavy chain has the amino acid sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 13), and (b) the light chain has the amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 14).

[0219] In some embodiments, the anti-PDL1 antibody is avelumab (CAS Registry Number: 1537032-82-8). Avelumab, also known as MSB0010718C, is a human monoclonal IgG1 anti-PDL1 antibody (Merck KGaA, Pfizer). Atezolizumab comprises heavy and light chain sequences, wherein: (a) The heavy chain has the amino acid sequence: EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVSSIYPSGGITFYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVDYWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 15), and (b) the light chain has the amino acid sequence: QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSSKSGNTASLTISGLQAEDEADYYCSSYTSSSTRVFGTGTKVTVLGQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 16).

[0220] In some embodiments, the anti-PDL1 antibody comprises six HVR sequences from SEQ ID NO: 15 and SEQ ID NO: 16 (e.g., three heavy chain HVRs of SEQ ID NO: 15 and three light chain HVRs of SEQ ID NO: 16). In some embodiments, the anti-PDL1 antibody comprises a heavy chain variable domain from SEQ ID NO: 15 and a light chain variable domain from SEQ ID NO: 16.

[0221] In some embodiments, the anti-PDL1 antibody is durvalumab (CAS Registry Number: 1428935-60-7). Durvalumab, also known as MEDI4736, is an Fc-optimized human monoclonal IgG1 kappa anti-PDL1 antibody (MedImmune, AstraZeneca) described in WO 2011 / 066389 and U.S. Patent Application Publication No. 2013 / 034559. Durvalumab comprises heavy and light chain sequences, wherein: (a) The heavy chain has the amino acid sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPP CPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 17), and (b) the light chain has the amino acid sequence: EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 18).

[0222] In some embodiments, the anti-PDL1 antibody comprises six HVR sequences from SEQ ID NO: 17 and SEQ ID NO: 18 (e.g., three heavy chain HVRs of SEQ ID NO: 17 and three light chain HVRs of SEQ ID NO: 18). In some embodiments, the anti-PDL1 antibody comprises a heavy chain variable domain from SEQ ID NO: 17 and a light chain variable domain from SEQ ID NO: 18.

[0223] In some embodiments, the anti-PDL1 antibody is MDX-1105 (Bristol Myers Squibb). MDX-1105, also known as BMS-936559, is an anti-PDL1 antibody described in WO 2007 / 005874.

[0224] In some embodiments, the anti-PDL1 antibody is LY3300054 (Eli Lilly).

[0225] In some embodiments, the anti-PDL1 antibody is STI-A1014 (Sorrento). STI-A1014 is a human anti-PDL1 antibody.

[0226] In some embodiments, the anti-PDL1 antibody is KN035 (Suzhou Alphamab), a single domain antibody (dAB) generated from a camel phage display library.

[0227] In some embodiments, the anti-PDL1 antibody is comprised of a cleavable site or linker that, upon cleavage (e.g., by proteases in the tumor microenvironment), activates the antibody antigen-binding domain, rendering it capable of binding its antigen, e.g., by removing a non-binding steric site. In some embodiments, the anti-PDL1 antibody is CX-072 (CytomX Therapeutics).

[0228] In some embodiments, the PDL1 antibody comprises six HVR sequences (e.g., three heavy chain HVRs and three light chain HVRs) and / or heavy and light chain variable domains from the PDL1 antibodies described in U.S. Patent Application Publication No. 20160108123 (assigned to Novartis), WO 2016 / 000619 (applicant: Beigene), WO 2012 / 145493 (applicant: Amplimmune), U.S. Patent No. 9205148 (assigned to Medimmune), WO 2013 / 181634 (applicant: Sorrento), and WO 2016 / 061142 (applicant: Novartis).

[0229] In yet a further specific aspect, the PD-1 or PDL1 antibody has reduced or minimal effector function. In a further specific aspect, the minimal effector function results from an "effectorless Fc mutation" or glycosylation mutation. In yet a further embodiment, the effectorless Fc mutation is an N297A or D265A / N297A substitution in the constant region. In some embodiments, the isolated anti-PDL1 antibody is aglycosylated. Antibody glycosylation is typically either N-linked or O-linked. N-linked refers to the attachment of a carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine (where X is any amino acid except proline) are recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Thus, the presence of either of these tripeptide sequences within a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the attachment of the sugars N-acetylgalactosamine, galactose, or xylose to one hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine can also be used. Removal of a glycosylation site from an antibody is conveniently accomplished by modifying the amino acid sequence to remove one of the tripeptide sequences described above (for N-linked glycosylation sites). This modification can be made by substituting an asparagine, serine, or threonine residue within the glycosylation site with another amino acid residue (e.g., glycine, alanine, or a conservative substitution).

[0230] Other PD-1 antagonists

[0231] In some embodiments, the PD-1 binding antagonist is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence). In some embodiments, the PD-1 binding antagonist is AMP-224. AMP-224 (CAS Registry Number 1422184-00-6; GlaxoSmithKline / MedImmune), also known as B7-DCIg, is a PDL2-Fc fusion soluble receptor described in WO 2010 / 027827 and WO 2011 / 066342.

[0232] In some embodiments, the PD-1 binding antagonist is a peptide or a small molecule compound. In some embodiments, the PD-1 binding antagonist is AUNP-12 (PierreFabre / Aurigene). See, e.g., WO 2012 / 168944, WO 2015 / 036927, WO 2015 / 044900, WO 2015 / 033303, WO 2013 / 144704, WO 2013 / 132317, and WO 2011 / 161699.

[0233] In some embodiments, the PDL1 binding antagonist is a small molecule that inhibits PD-1. In some embodiments, the PDL1 binding antagonist is a small molecule that inhibits PD-1. In some embodiments, the PDL1 binding antagonist is a small molecule that inhibits PDL1 and VISTA. In some embodiments, the PDL1 binding antagonist is CA-170 (also known as AUPM-170). In some embodiments, the PDL1 binding antagonist is a small molecule that inhibits PDL1 and TIM3. In some embodiments, the small molecule is a compound described in WO 2015 / 033301 and WO 2015 / 033299.

[0234] In some embodiments, a method of treatment comprises the simultaneous administration of a compound of Formula (B), (A), (I), (X), (IA), (IA-1), (IB), or (IC), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and at least one mitogen-activated protein kinase (MAPK) inhibitor. In some embodiments, a method of treatment comprises the simultaneous administration of a compound of Formula (B), (A), (I), (X), (IA), (IA-1), (IB), or (IC), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and at least one inhibitor of the RAS / MAPK pathway. In some embodiments, a method of treatment comprises the simultaneous administration of a compound of Formula (B), (A), (I), (X), (IA), (IA-1), (IB), or (IC), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and at least one epidermal growth factor receptor (EGFR) inhibitor. In some embodiments, the inhibitor of the RAS / MAPK pathway is a KRAS inhibitor, a RAF inhibitor, such as a BRAF monomer or RAF dimer inhibitor, a MEK inhibitor, an ERK inhibitor, an EGFR inhibitor, or a MAPK inhibitor, or any combination thereof. In some embodiments, the inhibitor of the RAS / MAPK pathway is an EGFR inhibitor or a MAPK inhibitor, or a combination thereof. Examples of EGFR inhibitors, MAPK inhibitors, and / or RAS / MAPK pathway inhibitors are described in Moore, AR, Rosenberg, SC, McCormick, F. et al., incorporated herein by reference.RAS-targeted therapies: is the undruggable drugged? are described in Nat Rev Drug Discov (2020) and include, but are not limited to: sotorasib (AMG510, Amgen), MRTX849 (Mirati Therapeutics), JNJ-74699157 / ARS-3248 (J&J Wellspring Biosciences), LY3499446 (Eli Lilly), GDCBI 1701963 (Boehringer Ingelheim), mRNA-5671 (Moderna Therapeutics), G12D inhibitors (Mirati Therapeutics), RAS(ON) inhibitors (Revolution Medicines), BBP-454 (BridgeBio Pharma), SP600125, PLX4032, GW5074, AZD6244, PD98059, simvastatin, alisertib, teriflunomide, NSC95397, PD325901, PD98059, lovastatin, sorafenib (NEXAVAR®, Bayer Labs), vemurafenib (ZELBORAF®, Hoffman-La Roche Inc.), dabrafenib (TAFLINAR®, Novartis Pharmaceuticals Corporation), selumetinib (KOSELUGO™, AstraZeneca Pharmaceuticals LP), trametinib (MEKINIST®, Novartis Pharmaceuticals Corporation), ulixertinib, silymarin, sirolimus (RAPAMUNE®, PV Prism CV), lapatinib (TYKERB® / TYVERB®, GlaxoSmithKline), crizotinib (XALKORI®, PF Prism CV), taselisib (Roche), PF-0491502, PF502, enterolactone, PLX4720, PD0325901, PD184352, SC-514, alistelib (MLN8237), SB415286, PLX4720, obtaoclax (GX15-070), pimasterib, venetoclax (ABT-199 / VENCLEXTA® / VENCLYXTO®), eprenetapopt (APR-246), gemcitabine (GEMZAR®), virinapant (TL32711), pexmetinib (ARRY-614), afuresertib, ralimetinib (LY2228820, Eli Lilly), cobimetinib (COTELLIC®, Exelixis / Genentech), prexasertib (LY2606368), erlotinib (TARCEVA®, OSI Pharmaceuticals), bevacizumab (AVASTIN®, Genentech), belvalafenib (Hanmi Pharm. / Genentech, Inc.), and binimetinib (MEKTOVI®, Array Biopharma Inc.).

[0235] As used herein, "combination" refers to any mixing or substitution of one or more compounds of the present disclosure with one or more other compounds of the present disclosure or one or more additional therapeutic agents. Unless the context clearly indicates otherwise, "combination" can include simultaneous or sequential delivery of a compound of the present disclosure and one or more therapeutic agents. Unless the context clearly indicates otherwise, "combination" can include dosage forms of a compound of the present disclosure and other therapeutic agents. Unless the context clearly indicates otherwise, "combination" can include routes of administration of a compound of the present disclosure and other therapeutic agents. Unless the context clearly indicates otherwise, "combination" can include formulations of a compound of the present disclosure and other therapeutic agents. Dosage forms, routes of administration, and pharmaceutical compositions include, but are not limited to, those described herein.

[0236] Enumerated Embodiments The embodiments listed below are representative of some aspects of the present invention. 1. Formula (I): JPEG0007796721000079.jpg28170 (in the formula, X1 is N or C-R5, and each R5 is independently H, cyano, halo, C(O)NH2, N(R e )(R f ), C 3-10 Cycloalkyl, C 1-6 Alkoxy, C 6-20 Aryl and C 1-6 alkyl, and R5 C 1-6 Alkyl is hydroxyl or N(R e )(R f ), R5 of X1 together with R3 and the atom to which they are attached form a 5-membered heterocyclyl or 5-membered heteroaryl, and the 5-membered heterocyclyl or 5-membered heteroaryl may be one or more C 1-6 may be substituted with alkyl, X2 is N or C-R5, and each R5 is independently H, cyano, halo, C(O)NH2, N(R e )(R f ), C 3-10Cycloalkyl, C 1-6 Alkoxy, C 6-20 Aryl and C 1-6 alkyl, and R5 C 1-6 Alkyl is hydroxyl or N(R e )(R f ), X3 is N or CH; R1 is (i) A 3- to 5-membered saturated heterocyclyl containing at least one cyclic oxygen atom, wherein the 3- to 5-membered saturated heterocyclyl is one or more C 1-6 a 3- to 5-membered saturated heterocyclyl optionally substituted with alkyl, or (ii) N(R e )(R f ),or JPEG0007796721000080.jpg21170 (in the formula, R a , R b and R c are each independently H, halo, cyano, hydroxyl, B(OH), C(O)-OH, C(O)-N(R e )(R f ), C(O)-C 1-6 Alkoxy, C(O)-C 1-6 Alkyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-20 Aryl, 3-10 membered heterocyclyl, C 5-13 selected from the group consisting of spirocyclyl and 5- to 20-membered heteroaryl; 1-6 the alkyl may be further substituted with hydroxyl, or JPEG0007796721000081.jpg20170 (in the formula, R d is H, halo, cyano, hydroxyl, B(OH)2, C(O)-OH, C(O)-N(R e )(R f ), C(O)-C 1-6 Alkoxy, C(O)-C 1-6 Alkyl, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-20Aryl, 3-10 membered heterocyclyl, C 5-13 spirocyclyl, and 5- to 20-membered heteroaryl; 1-6 The alkyl may be further substituted with hydroxyl. and; L is absent or -O-, * -CH2-O- ** , * -O-CH2- ** , —CH═CH—, and —C≡C—; ** indicates the point of attachment to the R2 moiety, * indicates the point of attachment to the rest of the molecule, R2 is C 1-12 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 aryl or 5- to 20-membered heteroaryl; Here, C of R2 1-12 Alkyl, C 3-10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 5-13 Spirocyclyl, C 6-20 Aryl or 5- to 20-membered heteroaryl is independently selected from cyano, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, NO2, N(R e )(R f ) and O(R e and optionally substituted with one or more substituents selected from the group consisting of: However, R2 is C 1-12 When R2 is alkyl, 1-12 Alkyl is independently selected from cyano, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, NO2, N(R e )(R f ) and O(R e ), L is CH═CH— or —C≡C—; R3 is cyano, C 1-6 Alkyl, C 1-4 Alkoxy or C 2-4 alkenyl, C 2-4 Alkenyl is N(R e )(R f ), or R3, together with R5 of X1 and the atom to which they are attached, form a 5-membered heterocyclyl or 5-membered heteroaryl, which 5-membered heterocyclyl or 5-membered heteroaryl may contain one or more C 1-6 may be substituted with alkyl, or R3 is the * -CH2-O- ** together with the carbon atoms and the atom to which they are attached form a C6 aryl or 6-membered heteroaryl; R4 is H or C 1-6 alkyl, where C 1-6 The alkyl may be substituted by hydroxyl, and R e and R f are, independently of each other and independently at each occurrence, H, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-6 Alkyl-C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 aryl, and 3~20 R is selected from the group consisting of: e and R f C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-6 Alkyl-C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-13 Spirocyclyl, C 6-20 The aryl and the 3- to 20-membered heteroaryl are each independently C1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 optionally substituted with one or more substituents selected from the group consisting of alkoxy, oxo, cyano, halo, NO2 and hydroxyl or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. 2. The compound of embodiment 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X1 is C-R5, X2 is C-R5, and X3 is CH. 3. The compound of embodiment 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X1 is C-R5, X2 is C-R5, and X3 is N. 4. The compound of embodiment 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X1 is C-R5, X2 is N, and X3 is CH. 5. The compound of embodiment 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X1 is C-R5, X2 is N, and X3 is N. 6. X1 is C-R5, and R3 together with R5 of X1 and the atom to which they are attached form a 5-membered heterocyclyl or 5-membered heteroaryl, and the 5-membered heterocyclyl or 5-membered heteroaryl is selected from the group consisting of one or more C 1-6 6. The compound of any one of embodiments 1 to 5, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, optionally substituted with alkyl. 7. A compound according to any one of embodiments 1 to 5, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X1 is C-R5 and R3 together with R5 of X1 and the atom to which they are attached form a 5-membered heterocyclyl. 8. X1 is C-R5 and R3, together with R5 of X1 and the atom to which they are attached, form a 5-membered heterocyclyl, and the compound of formula (I) has formula (IA): JPEG0007796721000082.jpg34170, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. 9. The compound of embodiment 8, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L is absent. 10. The compound of formula (IA) is represented by formula (IA-1): 9. The compound of embodiment 8, which is the compound of formula JPEG0007796721000083.jpg33170, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. 11.X2 is C-R5, and R5 of X2 is H, cyano, halo, or C 1-6 alkyl, C 1-6 The compound of any one of embodiments 8-10, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein alkyl is optionally substituted with one or more hydroxyl. 12. The compound according to any one of embodiments 1-3 or 6-8, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R5 of X2 is cyano. 13. A compound is 12. The compound of any one of embodiments 8 to 11, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, selected from the group consisting of: JPEG0007796721000084.jpg253170JPEG0007796721000085.jpg179170, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. 14.R2 is C 3-10 Cycloalkyl or C 6-20 aryl, and C in R 3-10 Cycloalkyl or C 6-20 The aryl may independently be one or more O(R e ) or C 1-6 may be substituted with alkyl, C 1-6The compound of any one of embodiments 8-12, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein alkyl is optionally further substituted with one or more halo. 15.R2 is C 6-20 aryl, and C in R 6-20 Aryl independently contains one or more C 1-6 13. The compound of any one of embodiments 1 to 12, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, optionally substituted with alkyl. 16. The compound of formula (IB) JPEG0007796721000086.jpg41170, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. 17. A compound of formula (IB): 17. The compound of embodiment 16, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, selected from the group consisting of: JPEG0007796721000087.jpg180170JPEG0007796721000088.jpg148170, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. 18.R1 JPEG0007796721000089.jpg21170, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. 19. A compound having the formula (IC): 19. The compound of embodiment 18, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, having the structure: JPEG0007796721000090.jpg41170, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. 20.R a , R b and R cand n is 0 or 1. The compound of embodiment 18 or embodiment 19, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein at least two of are H. 21.R a , R b and R c Exactly two of the are H and R a , R b and R c Exactly one of B(OH)2, C(O)-OH, C(O)-N(R e )(R f ), C(O)-C 1-6 Alkoxy or C(O)-C 1-6 The compound of any one of embodiments 18-20, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R is alkyl. 22.C(O)-N(R e )(R f )R e and R f However, independently, H, C 1-6 The compound of embodiment 21, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein is alkyl or hydroxyl. 23.R a , R b and R c Exactly two of the are H and R a , R b and R c or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. 24.R a and R b are H and R c The compound of any one of embodiments 18-20, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein is C(O)—OH. 25. A compound of formula (IC) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, 23. The compound of embodiment 22, selected from the group consisting of: JPEG0007796721000091.jpg253170JPEG0007796721000092.jpg74170, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. 26. The compound according to any one of embodiments 1-12, 14-16 and 18-24, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R4 is H. 27. JPEG0007796721000093.jpg143170JPEG0007796721000094.jpg252170JPEG0007796721000095.jpg80170, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. 28. JPEG0007796721000096.jpg143170JPEG0007796721000097.jpg253170JPEG0007796721000098.jpg36170, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. 29. The compound according to embodiment 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X1 is N, X2 is C-R5, and X3 is CH. 30. A pharmaceutical composition comprising (i) a compound according to any one of embodiments 1-29, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable carrier, diluent, or excipient. 31. A compound according to any one of embodiments 1-29, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in medical therapy. 32. Acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large cell type B Cell lymphoma, proliferation abnormalities (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, testicular germ cell cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatocellular carcinoma, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma tumors (Hodgkin's and non-Hodgkin's), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, 30. The compound of any one of embodiments 1-29, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovium, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor. 33. A method for treating cancer in a mammal, comprising administering to the mammal a compound according to any one of embodiments 1-29, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. 34. A compound according to any one of embodiments 1-29, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in modulating TEAD activity. 35. A compound according to any one of embodiments 1-29, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of a disease or condition mediated by TEAD activity. 36. The disease or condition is: acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, head cancer Opiopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, proliferation abnormalities (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, testicular germ cell cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung Cancer, lymphangiosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic The compound for use according to embodiment 35, wherein the compound is sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovium, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor. 37. Use of a compound according to any one of embodiments 1 to 29, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of the prevention of a disease or condition mediated by TEAD activity. 38. The disease or condition is: acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, head cancer Opiopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, proliferation abnormalities (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, testicular germ cell cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung Cancer, lymphangiosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic The compound for use according to embodiment 33, wherein the compound is sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovium, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor. 39. A method for modulating TEAD activity, comprising contacting a TEAD with a compound according to any one of embodiments 1 to 29, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. 40. A method for treating a disease or condition mediated by TEAD activity in a mammal, comprising administering to the mammal a compound according to any one of embodiments 1-29, or a pharmaceutically acceptable salt thereof. 41. The disease or condition is acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer , craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, proliferation abnormalities (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, testicular germ cell cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, fatty liver tumors, lung cancer, lymphangiosarcoma, lymphangioblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer 41. The method of embodiment 40, wherein the cancer is selected from the group consisting of osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovium, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor. 42. Use of a compound according to any one of embodiments 1-29, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, for modulating TEAD activity. 43. Use of a compound according to any one of embodiments 1 to 29, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, for the treatment and / or prevention of a disease or condition mediated by TEAD activity. 44. The disease or condition is acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer , craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, proliferation abnormalities (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, testicular germ cell cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, fatty liver tumors, lung cancer, lymphangiosarcoma, lymphangioblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer , osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovium, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer and Wilms' tumor. 45. Formula (I): JPEG0007796721000099.jpg27170, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, comprising: JPEG0007796721000100.jpg20170 (wherein Boc is a tert-butyloxycarbonyl group and halo is a halogen) A method comprising: 46. ​​A compound, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, prepared by the method of embodiment 45. 47. The invention as hereinbefore described.

[0237] Preparation of compounds The following synthetic reaction schemes, detailed in the general schemes and examples, are merely illustrative of some of the ways in which the compounds of this disclosure (or one embodiment or aspect thereof) may be synthesized. Various modifications to these synthetic reaction schemes can be made and will be suggested to those skilled in the art in view of the disclosure contained herein.

[0238] The starting materials and reagents used in the preparation of these compounds are generally available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art according to procedures described in references such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, 1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals; and Organic Reactions, Wiley & Sons: New York, 1991, Volumes 1-40.

[0239] The starting materials and the intermediates of the synthetic reaction schemes may be isolated and purified if necessary using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, etc. Such materials may be characterized using conventional means, including physical constants and spectral data.

[0240] Unless otherwise specified, the reactions described herein are preferably carried out under an inert atmosphere at atmospheric pressure, at reaction temperatures ranging from about -78°C to about 150°C, more preferably from about 0°C to about 125°C.

[0241] While certain exemplary embodiments are illustrated and described herein, compounds of the disclosure (or embodiments or aspects thereof) may be prepared using appropriate starting materials according to methods generally described herein and / or by methods available to those skilled in the art.

[0242] Intermediates and final compounds were purified either by flash chromatography, and / or by reverse phase preparative HPLC (high performance liquid chromatography), and / or by supercritical fluid chromatography and / or preparative thin layer chromatography (preparative TLC).

[0243] Mass spectrometry (MS) was performed using either (1) a Sciex 15 mass spectrometer in ES+ mode or (2) a Shimadzu liquid chromatography-mass spectrometry (LCMS) 2020 mass spectrometer in ESI+ mode. Unless otherwise specified, mass spectrometry spectral data typically show only the parent ion. MS or HRMS data, when shown, are provided for specific intermediates or compounds.

[0244] Nuclear magnetic resonance spectroscopy (NMR) was performed using a (1) Bruker AV III 300 NMR spectrometer, (2) Bruker AV III 400 NMR spectrometer, or (3) Bruker AV III 500 NMR spectrometer and was referenced to tetramethylsilane. NMR data is provided for specific intermediates or compounds where indicated.

[0245] All reactions involving air-sensitive reagents were performed under an inert atmosphere. Reagents were used as received from commercial suppliers unless otherwise noted.

[0246] The following generalized schemes are used to prepare the disclosed compounds, intermediates, and pharmaceutically acceptable salts thereof. The disclosed compounds and intermediates can be prepared from commercially available starting materials and reagents using standard organic synthesis techniques. It is understood that the synthetic procedures used to prepare the disclosed compounds and intermediates will depend on the specific substituents present in the compound or intermediate, and that various protection, deprotection, and transformation steps that are standard in organic synthesis may be required, but which may not be shown according to the general schemes. It is also understood that any of the steps shown in any of the following general schemes can be used in any combination and in any order that is chemically feasible to obtain the desired intermediate or disclosed compound. Scheme 1 JPEG0007796721000101.jpg24170

[0247] Scheme 1 describes a general synthetic route for converting a -CH2-halo group to a -CH=CHR2 moiety using a phosphate compound and an aldehyde compound. R2, R3, X1, X2, and X3 are as defined above for Formula (B), (A), (X), or (I). Halo refers to any halogen. In some embodiments, halogen is chlorine, bromine, or iodine. In some embodiments, the phosphate compound is P(OR y )3, where R y For example, C 1-8 It may be any suitable atom or group, including alkyl. In a particular variation, the phosphate compound is P(OEt)3. The JPEG0007796721000102.jpg11170 moiety may be, for example, a halogen, such as chlorine, bromine, or iodine, or -NR s R t (In the formula, R s and R t may each independently be any suitable atom or group, including, for example, any suitable atom or group, including a protecting group. s and R t In other variations, Rs and R t is the same. In one embodiment, -NR s R t is -NO2. Scheme 2 JPEG0007796721000103.jpg19170

[0248] Scheme 2 describes a general synthetic route for converting a -CH2-OH group to a -CH=CHR2 moiety using a phosphate compound and an aldehyde compound. R2, R3, X1, X2, and X3 are as defined above for Formula (B), (A), (X), or (I). Halo refers to any halogen. In some embodiments, halogen is chlorine, bromine, or iodine. In some embodiments, the phosphate compound is P(OR y )3, where R y For example, C 1-8 It may be any suitable atom or group, including alkyl. In a particular variation, the phosphate compound is P(OEt)3. The JPEG0007796721000104.jpg10170 moiety may be, for example, a halogen, such as chlorine, bromine, or iodine, or -NR s R t (In the formula, R s and R t may each independently be any suitable atom or group, including, for example, any suitable atom or group, including a protecting group. s and R t In other variations, R s and R t is the same. In one embodiment, -NR s R t is -NO2. Scheme 3 JPEG0007796721000105.jpg19170

[0249] Scheme 3 describes a general synthetic route for converting a halogen (halo) group to a -CH=CHR2 moiety using a boronic acid or boronic ester compound. Halo refers to any halogen. In some embodiments, the halogen group is chlorine, bromine, or iodine. R2, R3, X1, X2, and X3 are as defined above for formula (B), (A), (X), or (I). R" can be any suitable atom or group, including, for example, hydrogen. In certain embodiments, the R" substituents, together with the atoms to which they are attached, can form a ring structure. In some embodiments, the formula The compound in JPEG0007796721000106.jpg11170 is The file is JPEG0007796721000107.jpg20170. The JPEG0007796721000108.jpg12170 moiety may be, for example, a halogen, such as chlorine, bromine, or iodine, or -NR s R t (In the formula, R s and R t may each independently be any suitable atom or group, including, for example, any suitable atom or group, including a protecting group. s and R t In other variations, R s and R t is the same. In one embodiment, -NR s R t is -NO2. Scheme 4 JPEG0007796721000109.jpg21170

[0250] Scheme 4 describes a general synthetic route for converting a halogen (halo) group to the -L-R2 moiety defined above for Formula (B), (A), (X), or (I) using a halo compound. Halo refers to any halogen. In some embodiments, the halogen is chlorine, bromine, or iodine. R2, R3, X1, X2, and X3 are as defined above for Formula (B), (A), (X), or (I). The JPEG0007796721000110.jpg11170 moiety may be, for example, a halogen, such as chlorine, bromine, or iodine, or -NR s R t (In the formula, R s and R t may each independently be any suitable atom or group, including, for example, any suitable atom or group, including a protecting group. s and R t In other variations, R s and R t is the same. In one embodiment, -NR s R t is -NO2.

[0251] Scheme 5 JPEG0007796721000111.jpg19170

[0252] Scheme 5 describes a general synthetic route for converting a halogen (halo) group to the R2 moiety defined above for Formula (B), (A), (X), or (I) using a boronic acid or boronic ester compound. Halo refers to any halogen. In some embodiments, the halogen group is chlorine, bromine, or iodine. R2, R3, X1, X2, and X3 are as defined above for Formula (A) or Formula (I). R'' can be any suitable atom or group, including, for example, hydrogen. The JPEG0007796721000112.jpg11170 moiety may be, for example, a halogen, such as chlorine, bromine, or iodine, or -NR s R t (In the formula, R s and R t may each independently be any suitable atom or group, including, for example, any suitable atom or group, including a protecting group. s and R t In other variations, R s and R t is the same. In one embodiment, -NR s R tis -NO2. Scheme 6 JPEG0007796721000113.jpg19170

[0253] Scheme 6 describes a general synthetic route for converting a -CH-halo group to a -CH-O-R moiety using a halo compound. Halo refers to any halogen. In some embodiments, the halogen is chlorine, bromine, or iodine. R, R, X, X, and X are as defined above for Formula (B), (A), (X), or (I). The JPEG0007796721000114.jpg11170 moiety may be, for example, a halogen, such as chlorine, bromine, or iodine, or -NR s R t (In the formula, R s and R t may each independently be any suitable atom or group, including, for example, any suitable atom or group, including a protecting group. s and R t In other variations, R s and R t is the same. In one embodiment, -NR s R t is -NO2. Scheme 7 JPEG0007796721000115.jpg20170

[0254] Scheme 7 describes a general synthetic route for converting a halogen (halo) group to an amino (NH) moiety. Halo refers to any halogen. In some embodiments, the halogen is chlorine, bromine, or iodine. R, X, X, and X are as defined above for Formula (B), (A), (X), or (I). The JPEG0007796721000116.jpg9170 moiety can be any suitable atom or group, including, for example, a halogen, such as chlorine, bromine, or iodine, or includes the -L-R2 moiety defined above for formula (B), (A), (X), or (I). In one embodiment, the halogen (halo) group is reacted with a suitable catalyst, such as CuI, a suitable base, such as KPO, and NH3·H2O, and N 1 ,N 2 - is converted to an amino (NH2) moiety in the presence of bis(5-methyl-[1,1'-biphenyl]-2-yl)oxalamide. Scheme 8 JPEG0007796721000117.jpg29170

[0255] Scheme 8 describes a general synthetic route for converting a halogen (halo) group to an amino (NH) moiety using an imine compound. R, X, X, and X are as defined above for Formula (A) or Formula (I). R' can be, for example, C 6-20 Aryl is any suitable atom or group. The JPEG0007796721000118.jpg10170 moiety can be any suitable atom or group, including, for example, a halogen, such as chlorine, bromine, or iodine, or includes the -L-R moiety defined above for formula (B), (A), (X), or (I). Scheme 9 JPEG0007796721000119.jpg20170

[0256] Scheme 9 illustrates the conversion of an amino (NH) group to a hydroxy group as defined above for formula (B), (A), (X), or (I). JPEG0007796721000120.jpg17170. A general synthetic route for converting to the moiety is described below. R3, X1, X2, and X3 are as defined above for formula (B), (A), (X), or (I). The JPEG0007796721000121.jpg11170 moiety can be any suitable atom or group, including, for example, a halogen, such as chlorine, bromine, or iodine, or includes the -L-R moiety defined above for formula (B), (A), (X), or (I). In one embodiment, the amino (NH) moiety is JPEG0007796721000122.jpg21170 and in the presence of N-methylmorpholine It is converted to the JPEG0007796721000123.jpg18170 part. Scheme 10 JPEG0007796721000124.jpg31170

[0257] Scheme 10 describes a general synthetic route for preparing compounds of Formula (A) or Formula (I) in which R3, together with R5 of X1 and the atom to which they are attached, form a 5-membered heterocyclyl. X2 and X3 are as defined above for Formula (B), (A), (X) or (I). The JPEG0007796721000125.jpg10170 moiety can be any suitable atom or group, including, for example, a halogen, such as chlorine, bromine, or iodine, or includes the -L-R moiety defined above for formula (B), (A), (X), or (I). The JPEG0007796721000126.jpg11170 moiety can be, for example: H, a halogen, such as chlorine, bromine or iodine, or -NR s R t where R s and R t are each independently any suitable atom or group, including, for example, a protecting group. s and R t In other variations, R s and R t is the same. In one embodiment, -NR s R tis —NO 2 . In one embodiment, the three steps outlined in Scheme 10 comprise: (i) reacting a suitable electrophile, e.g. JPEG0007796721000127.jpg13170(ii) in the presence of an available acid, such as diethylaluminum chloride, and (iii) in the presence of a suitable acid, such as aluminum trifluoromethanesulfonate (aluminum triflate). Scheme 11 JPEG0007796721000128.jpg25170

[0258] Scheme 11 describes a general synthetic route for preparing compounds of formula (B), (A), (X), or (I), where R3, together with R5 of X1 and the atom to which they are attached, form a 5-membered heterocyclyl. X2 and X3 are as defined above for formula (B), (A), (X), or (I). The JPEG0007796721000129.jpg10170 moiety can be any suitable atom or group, including, for example, a halogen, such as chlorine, bromine, or iodine, or includes the -L-R moiety defined above for formula (B), (A), (X), or (I). The JPEG0007796721000130.jpg10170 moiety can be, for example: H, a halogen, such as chlorine, bromine, or iodine, or -NR s R t where R s and R t are each independently any suitable atom or group, including, for example, a protecting group. s and R t In other variations, R s and R t is the same. In one embodiment, -NR s R tis —NO. In one embodiment, the three steps outlined in Scheme 11 are carried out sequentially in the presence of (i) a suitable electrolyte such as 2-bromo-1,1-diethoxyethane, (ii) a suitable acid such as phenylpropanolamine (PPA), and (iii) a suitable catalyst such as Rh / C. Scheme 12 JPEG0007796721000131.jpg24170

[0259] Scheme 12 describes a general synthetic route for preparing compounds of Formula (B), (A), (X), or (I) where R3, together with R5 of X1 and the atom to which they are attached, form a 5-membered heteroaryl. X2 and X3 are as defined above for Formula (B), (A), (X), or (I). For example, the JPEG0007796721000132.jpg11170 part is:C 1-6 It may be any suitable atom or group, including alkyl, such as methyl; halogen, such as chlorine, bromine, or iodine; or the -L-R2 moiety defined above for formula (B), (A), (X), or (I). The JPEG0007796721000133.jpg11170 moiety can be, for example: H, a halogen, such as chlorine, bromine, or iodine, or -NR s R t where R s and R t are each independently any suitable atom or group, including, for example, a protecting group. s and R t In other variations, R s and R t is the same. In one embodiment, -NR s R t is -NO. In one embodiment, the three steps outlined in Scheme 12 are carried out sequentially in the presence of (i) a suitable acid such as HNO, (ii) a suitable catalyst such as Fe, and (iii) a suitable nucleophile such as NHCl. Scheme 13 JPEG0007796721000134.jpg31170

[0260] Scheme 13 shows that R1 is

[0049] A general synthetic route for preparing a compound of formula (B), (A), (X), or (I), JPEG0007796721000135.jpg19170, is described. Boc is a tert-butyloxycarbonyl group. Halo refers to any halogen atom, such as chlorine, bromine, or iodine. In step (i) of scheme 13, any suitable base can be used, including, for example, trimethylamine (TEA). In step (ii) of scheme 13, any suitable base can be used, including, for example, NaH. Scheme 14 JPEG0007796721000136.jpg90170

[0261] Scheme 14 shows that R1 is

[0049] A general synthetic route for preparing compounds of formula (B), (A), (X), or (I), where -L-R2 is an aromatic moiety, is described below. Boc is a tert-butyloxycarbonyl group. Halo refers to any halogen atom, such as chlorine, bromine, or iodine. Ar is any aromatic group, including, for example, substituted or unsubstituted phenyl. For Scheme 14, any suitable base can be used, such as trimethylamine (TEA) or NaH.

[0262] Formula (II): Certain intermediates are provided herein, including compounds having the structure: y For example, C 1-8 In certain embodiments, R is any suitable atom or group, including alkyl. y is ethyl. The JPEG0007796721000139.jpg11170 moiety can be any suitable atom or group, such as, for example, a halogen, e.g., chlorine, bromine, or iodine; a —N(R)CHR moiety according to formula (B), (A), (X), or (I); or a —NR s R t (In the formula, R s and R t may each independently be any suitable atom or group, including, for example, a protecting group. In some variations, R s and R t In other variations, R s and R t is the same. In one embodiment, -NR s R t is -NO2.

[0263] In other embodiments, disclosed herein are intermediates A through E, as set forth in the Examples below. [Example]

[0264] Intermediate A Preparation of 7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-amine

[0265] The general reaction scheme was as follows: JPEG0007796721000140.jpg75170

[0266] Step 1: Preparation of 1,3-dibromo-2-(2-bromoethoxy)benzene JPEG0007796721000141.jpg28170

[0267] A mixture of 2,6-dibromophenol (525 g, 2.08 mol), NaOH (91.7 g, 2.29 mol), and 1,2-dibromoethane (180.43 mL, 2.08 mol) in water (1.5 L) was stirred at 100 °C for 16 h. After cooling to room temperature, the oily product was separated through a separatory funnel and washed with NaOH (1 M) (200 mL × 2) to remove the starting material. The product was dissolved in petroleum ether (800 mL), dried over NaSO, filtered, and concentrated to give the title compound (520 g, 69%) as a yellow liquid. 1 H NMR(400 MHz,DMSO-d6):δ 7.68(dd,J=8.0,2.4 Hz,2H),7.07(t,J=8.0 Hz,1H),4.28(t,J=5.6 Hz,2H),3.85(t,J=5.6 Hz,2H).

[0268] Step 2: Preparation of 7-bromo-2,3-dihydrobenzofuran JPEG0007796721000142.jpg21170

[0269] To a mixture of 1,3-dibromo-2-(2-bromoethoxy)benzene (200 g, 557.34 mmol) in THF (1.5 L) was added n-BuLi (227.39 mL in hexane, 568.48 mmol, 2.5 mol / L) dropwise at −78° C. The mixture was stirred at −78° C. for 1 hour. The reaction was quenched with water (500 mL). The mixture was diluted with water (1 L) and extracted with ethyl acetate (1 L×2), and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (100 g, 90%) as a colorless oil. 1 H NMR (400MHz, CDCl3): δ 7.30-7.23(m,1H),7.10(dd,J=7.2,1.2Hz,1H),6.71(t,J=7.6Hz,1H),4.65(t,J=8.8Hz,2H),3.30(t,J=8.8Hz,2H).

[0270] Step 3: Preparation of 7-bromo-5-nitro-2,3-dihydrobenzofuran JPEG0007796721000143.jpg21170

[0271] To a mixture of 7-bromo-2,3-dihydrobenzofuran (100 g, 502.41 mmol) in DCM (1 L) was added a mixed solution of concentrated aqueous HSO (70 mL) and concentrated aqueous HNO (68.6 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min. The mixture was quenched with water (500 mL), the pH was carefully adjusted to 9 with 25% NaOH solution, and extracted with EtOAc (1 L × 3). The organic layer was washed with water (1 L × 3), dried over NaSO, filtered, and concentrated to give the title compound (98 g, 80%) as a yellow solid. 1 H NMR(400 MHz, CDCl3): δ 8.30(d,J=2.4 Hz,1H),8.04(d,J=2.4 Hz,1H),4.85(t,J=8.8 Hz,2H),3.43(t,J=8.8 Hz,1H).

[0272] Step 4: Preparation of 7-bromo-2,3-dihydrobenzofuran-5-amine JPEG0007796721000144.jpg21170

[0273] A solution of 7-bromo-5-nitro-2,3-dihydrobenzofuran (100 g, 409.77 mmol), NHCl (110 g, 2.05 mol), and iron powder (115 g, 2.05 mol) in water:ethanol (1:1) (2.5 L) was stirred at 80 °C for 3 h. After cooling to room temperature, the reaction mixture was filtered and concentrated. The mixture was then extracted with EtOAc (500 mL × 3), and the organic layer was washed with water (500 mL × 5). The combined organic layers were dried over NaSO, filtered, and concentrated. The crude product was dissolved in DCM (200 mL), and petroleum ether (400 mL) was added. The solid was collected to give the title compound (70.2 g, 80%) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 6.64(s,1H),6.53(s,1H),4.59(t,J=8.8 Hz,2H),3.42(br s,2H),3.23(t,J=8.8 Hz,2H).

[0274] Step 5: Preparation of 7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-amine JPEG0007796721000145.jpg33170

[0275] A mixture of 7-bromo-2,3-dihydrobenzofuran-5-amine (100 g, 467.16 mmol), (4-isopropylphenyl)boronic acid (78.15 g, 476.5 mmol), Pd(dppf)Cl2 (17.09 g, 23.36 mmol), Na2CO3 (149 g, 1.41 mol) in 1,4-dioxane (1 L) and water (100 mL) was stirred at 100 °C for 2 h under a N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0–30% EtOAc in petroleum ether) to give the title compound (116 g, 98%) as a yellow solid. 1 H NMR(400 MHz,CDCl3):δ 7.61(d,J=8.0 Hz,2H),7.29(d,J=8.0 Hz,2H),6.66(d,J=2.4 Hz,1H),6.59(d,J=2.4 Hz,1H),4.56(t,J=8.8 Hz,2H),3.18(t,J=8.8 Hz,2H),3.00-2.92(m,1H),1.30(d,J=6.8 Hz,6H);LCMS(ESI):m / z 254.1(M+H) + .

[0276] Intermediate B Preparation of 4-bromo-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-amine

[0277] The general reaction scheme was as follows: JPEG0007796721000146.jpg82170

[0278] Step 1: Preparation of N-(7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)acetamide JPEG0007796721000147.jpg33170

[0279] To a solution of 7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-amine (150 g, 592.09 mmol) and TEA (99.03 mL, 710.51 mmol) in DCM (1.5 L) was added acetyl chloride (46.31 mL, 651.3 mmol) dropwise at −78° C. The reaction was stirred at −78° C. for 2 hours. The reaction was quenched with water (200 mL) and extracted with dichloromethane (1 L×2). The combined organic layers were dried over NaSO and concentrated. The residue was triturated with DCM and hexane (1:10) and filtered to give the title compound (222 g, 83%) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 7.58(d,J=8.0 Hz,2H),7.48(s,1H),7.25(d,J=8.0 Hz,2H),7.21(s,1H),7.19(s,1H),4.60(t,J=8.8 Hz,2H),3.24(t,J=8.8 Hz,2H),2.96-2.90(m,1H),2.16(s,3H),1.27(d,J=6.8 Hz,6H);LCMS(ESI):m / z 296.1(M+H) + .

[0280] Step 2: Preparation of N-(4-bromo-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)acetamide JPEG0007796721000148.jpg34170

[0281] A mixture of N-(7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)acetamide (100 g, 338.55 mmol) and bromine (19.08 mL, 372.4 mmol) in acetic acid (500 mL) was stirred at 50° C. for 10 minutes. The reaction mixture was diluted with water (1 L), and the pH was adjusted to 7 with 2 M aqueous NaOH. The mixture was extracted with EtOAc (1 L × 3), and the combined organic layers were dried over NaSO and concentrated. The residue was dissolved in DCM (200 mL), and MTBE was added until a precipitate appeared. The heterogeneous mixture was cooled to 0° C. for 20 minutes. The precipitate was then filtered to give the title compound (38 g, 30%) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 8.09(s,1H),7.62(d,J=8.0 Hz,2H),7.27(d,J=8.0 Hz,2H),4.65(t,J=8.8 Hz,2H),3.28(t,J=8.8 Hz,2H),2.93-2.88(m,1H),2.22(s,3H),1.28(d,J=6.8 Hz,6H);LCMS(ESI):m / z 374.1(M+H) + .

[0282] Step 3: Preparation of 4-bromo-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-amine JPEG0007796721000149.jpg34170

[0283] A mixture of 12 M aqueous hydrochloric acid (334 mL, 4.01 mol) and N-(4-bromo-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)acetamide (150 g, 400.78 mmol) in ethanol (1.5 L) was stirred at 80° C. for 5 h. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was diluted with water, and the pH was adjusted to 9 with 2 M aqueous NaOH. The mixture was extracted with EtOAc (1 L×3), and then the combined organic layers were dried over NaSO and evaporated to give the title compound (124 g, 93%) as a brown solid. 1H NMR(400 MHz,CDCl3):δ 7.54(d,J=8.0 Hz,2H),7.25(d,J=8.0 Hz,2H),6.72(s,1H),4.58(t,J=8.8 Hz,2H),3.78(s,2H),3.23(t,J=8.8 Hz,2H),2.93-2.89(m,1H),1.25(d,J=6.8 Hz,6H);LCMS(ESI):m / z 332.1(M+H) + .

[0284] Intermediate C Preparation of 5-amino-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-4-carbonitrile

[0285] The general reaction scheme was as follows: JPEG0007796721000150.jpg40170

[0286] A mixture of t-BuXPhos Pd G3 (19.0 g, 23.92 mmol), Zn(CN)2 (176.7 g, 1.51 mol), and 4-bromo-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-amine (100 g, 301 mmol) in N,N-dimethylacetamide (1 L) was stirred at 140 °C for 16 h. After cooling to room temperature, the reaction solution was added to water (2 L). The mixture was filtered, and the filter cake was washed with water (2 L). The filter cake was dissolved in EtOAc (2 L), dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (0–50% EtOAc in petroleum ether) to give 80 g of crude product. The crude product was triturated with DCM:hexane (1:10) and filtered to give the title compound (59 g, 70%) as a yellow solid. 1H NMR(400 MHz,CDCl3):δ 7.59(dd,J=8.0,1.6 Hz,2H),7.30(d,J=8.0 Hz,2H),6.68(s,1H),4.64(t,J=8.8 Hz,2H),4.08(br s,2H),3.36(t,J=8.8 Hz,2H),2.97-2.95(m,1H),1.28(d,J=6.8 Hz,6H);LCMS(ESI):m / z 279.1(M+H) + .

[0287] Intermediate D Preparation of (5-amino-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-4-yl)methanol

[0288] The general reaction scheme was as follows: JPEG0007796721000151.jpg36170

[0289] Step 1: Preparation of methyl 5-amino-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-4-carboxylate JPEG0007796721000152.jpg34170

[0290] A mixture of 4-bromo-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-amine (5.0 g, 15.1 mmol), Pd(dppf)Cl (2.2 g, 3.0 mmol), TEA (10.5 mL, 75.3 mmol) in methanol (25 mL) and DMF (25 mL) was stirred under CO (15 psi) at 100° C. for 16 h. The solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography (0–10% EtOAc in petroleum ether) to give the title compound (2.3 g, 49%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.61(d,J=8.0 Hz,2H),7.29(d,J=8.0 Hz,2H),6.65(s,1H),5.38(s,2H),4.54(t,J=8.8 Hz,2H),3.89(s,3H),3.51(t,J=8.8 Hz,2H),2.99-2.88(m,1H),1.28(d,J=6.8 Hz,6H).

[0291] Step 2: Preparation of (5-amino-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-4-yl)methanol JPEG0007796721000153.jpg33170

[0292] To a mixture of methyl 5-amino-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-4-carboxylate (1.4 g, 4.5 mmol) in THF (20 mL) was added LiAlH (170 mg, 4.5 mmol) slowly at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with saturated aqueous KHSO (1.0 mL). The reaction mixture was dried over MgSO, filtered, and concentrated under reduced pressure to give the title compound (1.0 g, 79%) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6):δ 7.52(d,J=8.0 Hz,2H),7.25(d,J=8.0 Hz,2H),6.62(s,1H),4.92(t,J=5.2 Hz,1H),4.57(s,2H),4.49-4.37(m,4H),3.15(t,J=8.8 Hz,2H),2.93-2.84(m,1H),1.21(d,J=6.8 Hz,6H).LCMS(ESI):m / z 284.2(M+H) + .

[0293] Intermediate E Preparation of 5-amino-7-chloro-2,3-dihydrobenzofuran-4-carbonitrile

[0294] The general reaction scheme was as follows: JPEG0007796721000154.jpg53170

[0295] Step 1: Preparation of 4-bromo-1-chloro-2-(2,2-diethoxyethoxy)benzene

[0296] A mixture of 5-bromo-2-chlorophenol (90 g, 433.8 mmol), K2CO3 (90 g, 650.8 mmol), and 2-bromo-1,1-diethoxyethane (94 g, 477.2 mmol) in DMF (900 mL) was heated at 135 °C for 16 h. The reaction mixture was concentrated, diluted with EtOAc (600 mL), and washed with brine (500 mL × 5). The organic layer was dried over Na2SO4, filtered, and concentrated to give the title compound (140 g, 99%) as a brown oil. The crude was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3): δ 7.22(d,J=8.4 Hz,1H),7.10(d,J=2.0 Hz,1H),7.04(dd,J=8.4,2.0 Hz,1H),4.87(t,J=5.2 Hz,1H),4.05(d,J=5.2 Hz,2H),3.87-3.76(m,2H),3.73-3.62(m,2H),1.26(t,J=7.2 Hz,6H).

[0297] Step 2: Preparation of 4-bromo-7-chlorobenzofuran JPEG0007796721000155.jpg21170

[0298] A reaction mixture of 4-bromo-1-chloro-2-(2,2-diethoxyethoxy)benzene (140 g, 432.6 mmol) and PPA (140 g) in toluene (1.4 L) was heated at 110° C. for 5 hours. The reaction mixture was quenched with saturated aqueous NaHCO and extracted with EtOAc (1.0 L×3). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether 100%) to give the title compound (44.0 g, 44%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.74(d,J=2.0 Hz,1H),7.35(d,J=8.4 Hz,1H),7.20(d,J=8.4 Hz,1H),6.87(d,J=2.0 Hz,1H).

[0299] Step 3: Preparation of 4-bromo-7-chloro-2,3-dihydrobenzofuran JPEG0007796721000156.jpg21170

[0300] A mixture of Rh / C (10.0 g, 95.0 mmol) and 4-bromo-7-chlorobenzofuran (44.0 g, 190 mmol) in EtOH (440 mL) was stirred under an atmosphere of H (15 psi) at room temperature for 2 hours. The reaction was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether 100%) to give the title compound (33.0 g, 74%) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 7.01(d,J=8.8 Hz,1H),6.93(d,J=8.8 Hz,1H),4.72(t,J=8.8 Hz,2H),3.30(t,J=8.8 Hz,2H).

[0301] Step 4: Preparation of 4-bromo-7-chloro-5-nitro-2,3-dihydrobenzofuran JPEG0007796721000157.jpg21170

[0302] To a mixture of 4-bromo-7-chloro-2,3-dihydrobenzofuran (30.0 g, 128.5 mmol) in TFA (300 mL) was added HNO (11.4 mL, 257.0 mmol) slowly dropwise at 0 °C. The reaction mixture was stirred for 2 h. At this time, the reaction mixture was quenched with 1 M aqueous NaOH, and the mixture was extracted with EtOAc (1.0 L × 3). The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (0–10% EtOAc in petroleum ether) to afford the title compound (27.0 g, 76%) as a white solid.1 H NMR (400 MHz, CDCl3): δ 7.97(s,1H),4.88(t,J=8.8 Hz,2H),3.42(t,J=8.8 Hz,2H).

[0303] Step 5: Preparation of 7-chloro-5-nitro-2,3-dihydrobenzofuran-4-carbonitrile JPEG0007796721000158.jpg21170

[0304] To a solution of 4-bromo-7-chloro-5-nitro-2,3-dihydrobenzofuran (12.0 g, 43.1 mmol) in DMF (100 mL) was added CuCN (8.0 g, 86.2 mmol). The mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched with water (200 mL) and extracted with EtOAc (500 mL × 2). The combined organic layers were washed with brine (300 mL × 2), dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (0-10% EtOAc in petroleum ether) to give the title compound (5.3 g, 55%) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 8.26(s,1H),4.98(t,J=8.8 Hz,2H),3.64(t,J=8.8 Hz,2H).

[0305] Step 6: 5-amino-7-chloro-2,3-dihydrobenzofuran-4-carbonitrile JPEG0007796721000159.jpg22170

[0306] To a mixture of 7-chloro-5-nitro-2,3-dihydrobenzofuran-4-carbonitrile (5.3 g, 23.6 mmol) in HOAc (50 mL) was added Fe (6.6 g, 118.0 mmol). The mixture was stirred at 80 °C for 2 h. The reaction was adjusted to pH = 8 with saturated aqueous NaHCO3 and extracted with EtOAc (300 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (0-10% EtOAc in petroleum ether) to give the title compound (4.0 g, 87%) as a yellow solid. 1 H NMR(400 MHz,CDCl3):δ 6.58(s,1H),4.68(t,J=8.8 Hz,2H),4.10(s,2H),3.38(t,J=8.8 Hz,2H).LCMS(ESI):m / z 195.0(M+H) + .

[0307] Example 1 Preparation of 2-(((7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)amino)methyl)acrylic acid

[0308] The general reaction scheme was as follows: JPEG0007796721000160.jpg53170

[0309] Step 1: Preparation of tert-butyl-(7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)carbamate JPEG0007796721000161.jpg33170

[0310] To a solution of 7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-amine (500 mg, 1.97 mmol) in THF (6 mL) was added TEA (0.55 mL, 3.95 mmol) and BocO (474 ​​mg, 2.17 mmol). The mixture was stirred at room temperature for 16 hours, and then the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-30% EtOAc in petroleum ether) to afford the title compound (632.5 mg, 91%) as a yellow solid. 1 H NMR(400 MHz,CD3OD):δ 7.60(d,J=8.0 Hz,2H),7.25-7.23(m,4H),4.58(t,J=8.8 Hz,2H),3.22(t,J=8.8 Hz,2H),2.95-2.88(m,1H),1.52(s,9H),1.27(d,J=6.8 Hz,6H).LCMS(ESI):m / z 376.0(M+Na) + .

[0311] Step 2: Preparation of 2-(((tert-butoxycarbonyl)(7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)amino)methyl)acrylic acid JPEG0007796721000162.jpg33170

[0312] To a solution of tert-butyl (7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)carbamate (430.0 mg, 1.22 mmol) in DMF (8 mL) was slowly added NaH (60% in mineral oil, 58.4 mg, 1.46 mmol) and methyl 2-(bromomethyl)acrylate (262 mg, 1.46 mmol) under a N atmosphere at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then quenched with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic layers were combined, washed with brine (45 mL × 2), dried over Na SO , and concentrated. The residue was purified by column chromatography on silica gel (0-10% EtOAc in petroleum ether) to give the title compound (342 mg, 64%) as a yellow oil. LCMS (ESI): m / z 460.1 (M+Na).+ .

[0313] Step 3: Preparation of 2-(((7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)amino)methyl)acrylic acid JPEG0007796721000163.jpg33170

[0314] To a mixture of 2-(((tert-butoxycarbonyl)(7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)amino)methyl)acrylic acid (340 mg, 0.78 mmol) in DCM (3 mL) was added TFA (1.0 mL, 7.45 mmol) at room temperature. The reaction solution was stirred at room temperature for 2 hours, at which point the reaction mixture was concentrated. The residue was purified by preparative HPLC (Boston Green ODS 150 × 30 mm × 5 μm; water (0.2% FA)-ACN; 45 / 75) and preparative TLC (10% methanol in dichloromethane) to give the title compound (8.4 mg, 3%) as a white solid. 1 H NMR (400 MHz, DMSO-d): δ 7.52(d,J=8.0 Hz,2H),7.25(d,J=8.0 Hz,2H),6.47(s,1H),6.44(s,1H),5.88(s,1H),5.43(s,1H),4.41(t,J=8.4 Hz,2H),3.80(s,2H),3.10(t,J=8.4 Hz,2H),2.92-2.86(m,1H),1.22(d,J=6.4 Hz,6H);LCMS(ESI):m / z 337.9(M+H) + .

[0315] Example 2 Preparation of 2-(((7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)amino)methyl)acrylamide

[0316] The general reaction scheme was as follows: JPEG0007796721000164.jpg26170

[0317] Step 1: Preparation of tert-butyl (2-carbamoylallyl)(7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)carbamate JPEG0007796721000165.jpg34170

[0318] To a mixture of 2-(((tert-butoxycarbonyl)(7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)amino)methyl)acrylic acid (342.0 mg, 0.78 mmol), ammonium chloride (47 mg, 0.86 mmol), DIPEA (0.41 mL, 2.35 mmol) in DMF (8 mL) was added HATU (447 mg, 1.18 mmol). The reaction solution was stirred at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate (50 mL), washed with brine (30 mL), dried over Na2SO4, and concentrated to give the title compound (549 mg) as a crude yellow oil, which was used directly in the next step. LCMS (ESI): m / z 337.1 (M-Boc). + .

[0319] Step 2: Preparation of 2-(((7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)amino)methyl)acrylamide JPEG0007796721000166.jpg33170

[0320] A mixture of tert-butyl (2-carbamoylallyl)(7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)carbamate (340 mg, 0.78 mmol) and TFA (1.0 mL, 7.45 mmol) in dichloromethane (3 mL) was stirred at room temperature for 1 hour, at which point the reaction mixture was concentrated. The residue was purified by preparative HPLC (Welch Xtimate C18 150 × 25 mm × 5 μm; water (0.2% FA)-CAN; 40 / 70) and preparative TLC (5% methanol in dichloromethane) to give the title compound (61.9 mg, 23%) as a yellow solid. 1H NMR(400 MHz,DMSO-d6):δ 7.55(s,1H),7.52(d,J=8.0 Hz,2H),7.25(d,J=8.0 Hz,2H),7.09(s,1H),6.49(d,J=2.4 Hz,1H),6.45(d,J=2.4 Hz,1H),5.79(s,1H),5.48(s,1H),5.46(s,1H),4.41(t,J=8.4 Hz,2H),3.84(d,J=3.2 Hz,2H),3.10(t,J=8.4 Hz,2H),2.93-2.84(m,1H),1.21(d,J=6.8 Hz,6H);LCMS(ESI):m / z 336.9(M+H) + .

[0321] Example 3 Preparation of 2-(((4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)amino)methyl)acrylic acid

[0322] The general reaction scheme was as follows: JPEG0007796721000167.jpg41170

[0323] To a mixture of 5-amino-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-4-carbonitrile (15.0 g, 53.89 mmol) in N,N-dimethylformamide (150 mL) was added 2-(bromomethyl)acrylic acid (8.89 g, 53.89 mmol). The mixture was stirred at 80° C. for 2 hours, at which time the reaction mixture was purified by preparative HPLC (SANPONT C18, 250×80 mm×10 μm, 100A, water (0.225% FA)-ACN, 40%-80%) to give the title compound (8.2 g, 42%) as a yellow solid. 1H NMR(400 MHz,DMSO-d6):δ 12.75(s,1H),7.55(d,J=8.0 Hz,2H),7.31(d,J=8.0 Hz,2H),6.46(s,1H),6.11(s,1H),6.01(t,J=6.0 Hz,1H),5.67(s,1H),4.55(t,J=8.8 Hz,2H),4.05(d,J=5.2 Hz,2H),3.30(t,J=8.8 Hz,2H),2.93-2.90(m,1H),1.22(d,J=6.8 Hz,6H);LCMS(ESI):m / z 363.2(M+H) + .

[0324] Example 4 Preparation of 2-(((4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)amino)methyl)acrylamide

[0325] The general reaction scheme was as follows: JPEG0007796721000168.jpg32170

[0326] To a mixture of 2-(((4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)amino)methyl)acrylic acid (200 mg, 0.49 mmol), NHCl (78 mg, 1.46 mmol), DIPEA (0.34 mL, 1.95 mmol) in N,N-dimethylformamide (3 mL) was added HATU (370 mg, 0.97 mmol). The resulting mixture was stirred at room temperature for 16 hours, at which time the reaction mixture was purified by preparative HPLC (Welch Xtimate C18 150 × 25 mm × 5 um, water (0.2% FA)-ACN, 52%-82%) to afford the title compound (133.93 mg, 76%) as a pale yellow solid. 1H NMR(400 MHz,DMSO-d6):δ 7.61(s,1H),7.56(d,J=8.4 Hz,2H),7.30(d,J=8.4 Hz,2H),7.15(s,1H),6.48(s,1H),5.98(t,J=5.6 Hz,1H),5.81(s,1H),5.45(s,1H),4.54(t,J=8.8 Hz,2H),4.01(d,J=5.6 Hz,2H),3.29(d,J=8.8 Hz,2H),2.93-2.85(m,1H),1.21(d,J=6.8 Hz,6H);LCMS(ESI):m / z 362.2(M+H) + .

[0327] Example 5 Preparation of 2-(((4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)amino)methyl)-N-methylacrylamide

[0328] The general reaction scheme was as follows: JPEG0007796721000169.jpg34170

[0329] To a mixture of 2-(((4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)amino)methyl)acrylic acid (200 mg, 0.49 mmol), DIPEA (0.34 mL, 1.95 mmol), methanamine hydrochloride (99 mg, 1.46 mmol) in DMF (3 mL) was added HATU (370 mg, 0.97 mmol). The resulting mixture was stirred at room temperature for 16 hours, at which time the reaction mixture was purified by preparative HPLC (Welch Xtimate C18 150 x 25 mm x 5 um, water (0.2% FA)-ACN, 56%-86%) to afford the title compound (118.56 mg, 67%) as a pale yellow solid. 1H NMR(400 MHz,DMSO-d6):δ 8.08(d,J=4.8 Hz,1H),7.56(d,J=8.4 Hz,2H),7.30(d,J=8.4 Hz,2H),6.48(s,1H),6.00(t,J=5.2 Hz,1H),5.71(s,1H),5.41(s,1H),4.54(t,J=8.8 Hz,2H),4.03(d,J=5.2 Hz,2H),3.29(t,J=8.8 Hz,2H),2.93-2.83(m,1H),2.65(d,J=4.8 Hz,3H),1.21(d,J=6.8 Hz,6H);LCMS(ESI):m / z 376.2(M+H) + .

[0330] Example 6 Preparation of 2-(((4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)amino)methyl)-N,N-dimethylacrylamide

[0331] The general reaction scheme was as follows: JPEG0007796721000170.jpg34170

[0332] To a mixture of 2-(((4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)amino)methyl)acrylic acid (200 mg, 0.49 mmol), N,N-diisopropylethylamine (0.34 mL, 1.95 mmol), dimethylamine hydrochloride (119 mg, 1.46 mmol) in DMF (3 mL) was added HATU (370 mg, 0.97 mmol). The resulting mixture was stirred at room temperature for 16 hours, at which time the reaction mixture was purified by preparative HPLC (Welch Xtimate C18 150 × 25 mm × 5 um, water (0.2% FA)-ACN, 60%-90%) to afford the title compound (110 mg, 63%) as a pale yellow solid. 1H NMR(400 MHz,DMSO-d6):δ 7.60(d,J=8.4 Hz,2H),7.31(d,J=8.4 Hz,2H),6.64(s,1H),6.15(t,J=3.6 Hz,1H),5.32(s,1H),5.14(s,1H),4.55(t,J=8.8 Hz,2H),3.99(d,J=3.6 Hz,2H),3.29(t,J=8.8 Hz,2H),2.94(s,3H),2.93-2.89(m,1H),2.85(s,3H),1.22(d,J=6.8 Hz,6H);LCMS(ESI):m / z 390.3(M+H) + .

[0333] Example 7 Preparation of 2-(((4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)(methyl)amino)methyl)acrylic acid

[0334] The general reaction scheme was as follows: JPEG0007796721000171.jpg32170

[0335] To a mixture of 2-(((4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)amino)methyl)acrylic acid (200 mg, 0.55 mmol) and 1 drop of HOAc in 1,2-dichloroethane (3 mL) was added paraformaldehyde (448 mg, 5.52 mmol) and NaBH(OAc)3 (585 mg, 2.76 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (Welch Xtimate C18 150 × 25 mm × 5 μm, water (0.2% FA)-ACN, 65% to 95%) to give the title compound (90.46 mg, 44%) as a pale yellow solid. 1H NMR(400 MHz,DMSO-d6):δ 12.62(s,1H),7.62(d,J=8.4 Hz,2H),7.32(d,J=8.4 Hz,2H),6.98(s,1H),6.20(s,1H),5.77(s,1H),4.62(t,J=8.8 Hz,2H),4.01(s,2H),3.33(t,J=8.8 Hz,2H),2.96-2.86(m,1H),2.83(s,3H),1.22(d,J=6.8 Hz,6H);LCMS(ESI):m / z 377.2(M+H) + .

[0336] Example 8 Preparation of methyl 2-(((4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)amino)methyl)acrylate

[0337] The general reaction scheme was as follows: JPEG0007796721000172.jpg30170

[0338] To a mixture of 2-(((4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)amino)methyl)acrylic acid (100 mg, 0.28 mmol), methanol (27 mg, 0.83 mmol) in DMF (2 mL) was added HATU (315 mg, 0.83 mmol). The mixture was stirred at room temperature for 2 hours, at which time the reaction mixture was purified by preparative HPLC (Welch Xtimate C18 150 × 25 mm × 5 μm, water (0.2% FA)-ACN, 65%-95%) to give the title compound (26 mg, 25%) as a yellow solid. 1H NMR(400 MHz,DMSO-d6):δ 7.55(d,J=8.4 Hz,2H),7.31(d,J=8.4 Hz,2H),6.46(s,1H),6.15(d,J=1.2 Hz,1H),6.05(t,J=6.0 Hz,1H),5.71(s,1H),4.55(t,J=8.8 Hz,2H),4.08(d,J=6.0 Hz,2H),3.73(s,3H),3.30(t,J=8.8 Hz,2H),2.94-2.88(m,1H),1.22(d,J=6.8 Hz,6H);LCMS(ESI):m / z 377.1(M+H) + .

[0339] Example 9 Preparation of 2-(((4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)amino)methyl)-N-hydroxyacrylamide

[0340] The general reaction scheme was as follows: JPEG0007796721000173.jpg26170

[0341] Step 1: Preparation of 2-(((4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)amino)methyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acrylamide JPEG0007796721000174.jpg33170

[0342] To a mixture of 2-(((4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)amino)methyl)acrylic acid (200 mg, 0.49 mmol), triethylamine (0.27 mL, 1.95 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (171 mg, 1.46 mmol) in DMF (3 mL) was added BOP (431 mg, 0.97 mmol). The resulting mixture was stirred at room temperature for 16 hours. At this time, the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL), and the organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by preparative TLC (40% EtOAc in petroleum ether) to afford the title compound (40 mg, 18%) as a pale yellow solid. 1 H NMR(400 MHz,DMSO-d6):δ 11.34(s,1H),7.58(d,J=8.0 Hz,2H),7.31(d,J=8.0 Hz,2H),6.50(s,1H),6.04(t,J=6.0 Hz,1H),5.67(s,1H),5.47(s,1H),4.88(s,1H),4.55(t,J=8.8 Hz,2H),4.03(d,J=5.6 Hz,2H),3.99(s,1H),3.49-3.45(m,1H),3.31(d,J=8.8 Hz,2H),2.94-2.90(m,1H),1.69-1.65(m,3H),1.54-1.50(m,3H),1.22(d,J=6.8 Hz,6H);LCMS(ESI):m / z 484.1(M+Na) + .

[0343] Step 2: Preparation of 2-(((4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)amino)methyl)-N-hydroxyacrylamide JPEG0007796721000175.jpg34170

[0344] To a mixture of 2-(((4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)amino)methyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acrylamide (40 mg, 0.090 mmol) in methyl alcohol (2 mL) was added 2 M HCl (0.5 mL, 1.0 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was then purified by preparative HPLC (Welch Xtimate C18 150 × 25 mm × 5 μm, water (0.2% FA)-ACN, 60%-90%) to give the title compound (15.3 mg, 47%) as a pale yellow solid. 1 H NMR(400 MHz,DMSO-d6):δ 10.86(s,1H),8.96(s,1H),7.58(d,J=8.4 Hz,2H),7.31(d,J=8.4 Hz,2H),6.51(s,1H),6.04(t,J=6.0 Hz,1H),5.63(s,1H),5.40(s,1H),4.55(t,J=8.8 Hz,2H),4.03(d,J=6.0 Hz,2H),3.30(d,J=8.8 Hz,2H),2.98-2.83(m,1H),1.22(d,J=6.8 Hz,6H);LCMS(ESI):m / z 378.2(M+H) + .

[0345] Example 10 Preparation of (3-((4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)amino)prop-1-en-2-yl)boronic acid

[0346] The general reaction scheme was as follows: JPEG0007796721000176.jpg66170

[0347] Step 1: Preparation of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl methanesulfonate JPEG0007796721000177.jpg22170

[0348] To a mixture of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-ol (2.0 g, 10.87 mmol) and TEA (2.26 mL, 16.3 mmol) in DCM (20 mL) at 0 °C was added methanesulfonic anhydride (2.84 g, 16.3 mmol). The reaction was stirred at room temperature for 16 h, at which point the reaction was concentrated. The residue was purified by flash chromatography on silica gel (0 to 25% ethyl acetate in petroleum ether) to afford the title compound (1.2 g, 42%) as a colorless liquid. 1 H NMR (400 MHz, CDCl3): δ 6.07(s,1H),6.02(s,1H),4.82(s,2H),3.03(s,3H),1.29(s,12H).

[0349] Step 2: Preparation of (3-((4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)amino)prop-1-en-2-yl)boronic acid JPEG0007796721000178.jpg33170

[0350] A mixture of 5-amino-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-4-carbonitrile (500 mg, 1.8 mmol) and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl methanesulfonate (704 mg, 2.69 mmol) in DMF (10 mL) was stirred at 80° C. for 2 h. The reaction mixture was purified by preparative HPLC (Boston Uni C18 40 × 150 × 5 μm, water (0.225% FA)-ACN, 50–80%) and preparative HPLC (Boston Prime C18 150 × 30 mm × 5 μm, water (0.05% NH 3H 2 O)-ACN, 51–81%) to give the title compound (8.16 mg, 1%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.59(d,J=8.4 Hz,2H),7.31(d,J=8.4 Hz,2H),6.76(s,1H),5.97(s,1H),5.91(s,1H),5.17(s,1H),4.65(t,J=8.8 Hz,2H),4.01(s,2H),3.38(t,J=8.8 Hz,2H),2.99-2.92(m,1H),1.28(d,J=6.8 Hz,6H);LCMS(ESI):m / z 363.1(M+H) + .

[0351] Example 11 Preparation of 7-(4-isopropylphenyl)-5-((2-methylene-3-oxobutyl)amino)-2,3-dihydrobenzofuran-4-carbonitrile

[0352] The general reaction scheme was as follows: JPEG0007796721000179.jpg62170

[0353] Step 1: Preparation of 3,4-dibromo-3-methylbutan-2-one

[0354] To a mixture of 3-methylbut-3-en-2-one (5.0 g, 59.44 mmol) in DCM (50 mL) was added Br (3.04 mL, 59.44 mmol). The reaction mixture was then stirred at 0 °C for 2 h. The reaction was then diluted with water (40 mL × 3). The organics were dried over MgSO, filtered, and concentrated to give the title compound (14.3 g, 98%) as a yellow solid. 1 H NMR (400MHz, CDCl3): δ 4.55-4.34(m,2H),2.42(s,3H),1.96(s,3H).

[0355] Step 2: Preparation of 3-(bromomethyl)but-3-en-2-one JPEG0007796721000180.jpg18170

[0356] To a mixture of 3,4-dibromo-3-methylbutan-2-one (5.0 g, 59.44 mmol) in DMF (50 mL) was added KBr (11.32 g, 95.10 mmol). The reaction mixture was then stirred at 80 °C for 12 h. At this time, the reaction was diluted with water (40 mL x 3), and the organics were dried over MgSO, filtered, and concentrated to give the title compound (2.2 g, 23%) as a brown liquid. 1 H NMR (400 MHz, CDCl3): δ 6.03(s,1H),5.92(s,1H),4.17(s,2H),1.92(s,3H).

[0357] Step 3: Preparation of 7-(4-isopropylphenyl)-5-((2-methylene-3-oxobutyl)amino)-2,3-dihydrobenzofuran-4-carbonitrile JPEG0007796721000181.jpg32170

[0358] To a mixture of 5-amino-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-4-carbonitrile (500 mg, 1.8 mmol) in DMF (5 mL) was added 3-(bromomethyl)but-3-en-2-one (585 mg, 3.59 mmol). The reaction mixture was stirred at room temperature for 16 hours. At this time, the reaction was diluted with water (20 mL) and extracted with ethyl acetate (40 mL × 2). The organics were washed with brine (20 mL × 2), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (20% ethyl acetate in petroleum ether) and preparative HPLC (Welch Xtimate C18 150 × 25 mm × 5 μm, water (0.2% FA)-ACN, 70–100%) to give the title compound (4.27 mg, 0.66%) as a white solid. 1H NMR(400 MHz,CDCl3):δ 7.60(d,J=8.4 Hz,2H),7.32(d,J=8.4 Hz,2H),6.46(s,1H),6.08(s,1H),5.90(s,1H),5.31-5.23(m,1H),4.63(t,J=8.8 Hz,2H),4.40(d,J=4.0 Hz,2H),3.38(t,J=8.8 Hz,2H),2.99-2.92(m,1H),1.98(s,3H),1.29(d,J=6.8 Hz,6H);LCMS(ESI):m / z 361.0(M+H) + .

[0359] Example 12 Preparation of 2-(((4-(hydroxymethyl)-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)amino)methyl)acrylic acid

[0360] The general reaction scheme was as follows: JPEG0007796721000182.jpg36170

[0361] A solution of (5-amino-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-4-yl)methanol (200 mg, 0.71 mmol, Intermediate D) and 2-(bromomethyl)acrylic acid (105 mg, 0.64 mmol) in DMF (4 mL) was stirred at room temperature for 2 hours. At this time, the reaction solution was diluted with water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (10% MeOH in DCM) and preparative HPLC (Phenomenex Gemini NX-C18 (75 × 30 mm × 3 um) water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN, 20% to 50%) to give the title compound (14.5 mg, 6%) as a white solid. 1H NMR(400 MHz,DMSO-d6):δ 7.50(d,J=8.0 Hz,2H),7.25(d,J=8.0 Hz,2H),6.35(s,1H),6.04(s,1H),5.64(s,1H),4.46-4.35(m,4H),3.93(s,2H),3.18(t,J=8.8 Hz,2H),2.89-2.85(m,1H),1.21(d,J=6.8 Hz,6H);LCMS(ESI):m / z 368.0(M+H) + .

[0362] Example 13 Preparation of 2-(((4-(hydroxymethyl)-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)amino)methyl)acrylamide

[0363] The general reaction scheme was as follows: JPEG0007796721000183.jpg26170

[0364] Step 1: Preparation of 2-(((4-(hydroxymethyl)-7-(4-isop...

Claims

1. Formula (X): (In the formula, X １ is C-R ５ and X １ R ５ is R ３ and together with the atom to which they are attached form a 5-membered heterocyclyl or a 5-membered heteroaryl, wherein the 5-membered heterocyclyl contains one ring oxygen atom and the 5-membered heteroaryl contains one ring sulfur atom and one ring nitrogen atom, and the 5-membered heterocyclyl or 5-membered heteroaryl is optionally substituted with one or more D; X ２ is N or C-R ５ and R ５ is H, cyano, halo, C(O)NH ２ , N(R ｅ ) (R ｆ ), C ３－１０ Cycloalkyl, C １－６ Alkoxy, C ６－２０ Aryl, S(O) ２ -C １－６ Alkyl and C １－６ alkyl; R ５ C １－６ Alkyl is hydroxyl or N(R ｅ ) (R ｆ ) optionally substituted with; X ３ is N or C—H, R １ teeth, (i) A 3- to 5-membered saturated heterocyclyl containing at least one cyclic oxygen atom, wherein the 3- to 5-membered saturated heterocyclyl is one or more C １－６ a 3- to 5-membered saturated heterocyclyl optionally substituted with alkyl, or (ii) N(R ｅ ) (R ｆ ),or (In the formula, R ａ , R ｂ and R ｃ are each independently H, halo, cyano, hydroxyl, B(OH) ２ , C(O)-OH, C(O)-N(R ｅ ) (R ｆ ), C(O)-C １－６ Alkoxy, C(O)-C １－６ Alkyl, and C １－６ alkyl, C １－６ the alkyl may be further substituted with hydroxyl, or (In the formula, R ｄ is H, halo, cyano, hydroxyl, B(OH) ２ , C(O)-OH, C(O)-N(R ｅ ) (R ｆ ), C(O)-C １－６ Alkoxy, C(O)-C １－６ Alkyl, and C １－６ alkyl, C １－６ The alkyl may be further substituted with hydroxyl. and L is absent or -O-; ＊ -CH ２ -O- ＊＊ , ＊ -O-CH ２ - ＊＊ , —CH═CH—, and —C≡C—; ＊＊ is R ２ indicates the point of attachment to the moiety, ＊ indicates the point of attachment to the rest of the molecule, R ２ is C １－１２ Alkyl, C ３－１０ cycloalkyl, 3- to 10-membered heterocyclyl, C ５－１３ Spirocyclyl, C ６－２０ aryl or 5- to 20-membered heteroaryl; Here, R ２ C １－１２ Alkyl, C ３－１０ cycloalkyl, 3- to 10-membered heterocyclyl, C ５－１３ Spirocyclyl, C ６－２０ Aryl or 5- to 20-membered heteroaryl is independently cyano, halo, C １－６ Alkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, NO ２ , N(R ｅ ) (R ｆ ), O(R ｅ ) and S(R ｇ ) ５ and optionally substituted with one or more substituents selected from the group consisting of: However, R ２ is C １－１２ When R ２ C １－１２ Alkyl is independently selected from cyano, halo, C １－６ Alkyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, NO ２ , N(R ｅ ) (R ｆ ), O(R ｅ ) and S(R ｇ ) ５ L is —CH═CH— or —C≡C—; R ４ is H or C １－６ alkyl, C １－６ The alkyl may be substituted with hydroxyl; R ｅ and R ｆ are, independently of each other and independently at each occurrence, H, cyano, hydroxyl, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, C ３－１０ Cycloalkyl, C １－６ Alkyl-C ３－１０ cycloalkyl, 3- to 10-membered heterocyclyl, C ５－１３ Spirocyclyl, C ６－２０ aryl and 3- to 20-membered heteroaryl; R ｅ and R ｆ C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C １－６ Alkyl-C ３－１０ cycloalkyl, 3- to 10-membered heterocyclyl, C ５－１３ Spirocyclyl, C ６－２０ The aryl and the 3- to 20-membered heteroaryl are each independently C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, oxo, cyano, halo, NO ２ and hydroxyl; R ｇ is a halo) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

2. X ２ is C-R ５ and X ３ 2. The compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein is C—H.

3. X ２ is C-R ５ and X ３ 2. The compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein

4. X ２ is N and X ３ 2. The compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein is C—H.

5. X ２ is N and X ３ 2. The compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein

6. X １ is C-R ５ and R ３ is X １ R ５ and together with the atom to which they are attached form a 5-membered heterocyclyl, which 5-membered heterocyclyl contains one ring oxygen atom, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

7. The compound has the formula (IA):

2. The compound of claim 1, which is a compound of the formula:

8. 8. The compound of claim 7, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L is absent.

9. The compound of formula (IA) may be represented by formula (IA-1):

9. The compound of claim 8, which is a compound of the formula: or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

10. X ２ is C-R ５ and X ２ R ５ H, cyano, halo, C(O)NH ２ , S(O) ２ -C １－６ Alkyl or C １－６ alkyl, C １－６ 10. The compound of any one of claims 7 to 9, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein alkyl is optionally substituted with one or more hydroxyl.

11. X ２ R ５ 11. The compound of claim 10, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein is cyano.

12. The compound 11. The compound of any one of claims 7 to 10, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, selected from the group consisting of:

13. R ２ is C ３－１０ Cycloalkyl or C ６－２０ aryl, and R ２ C ３－１０ Cycloalkyl or C ６－２０ The aryl independently has one or more O(R ｅ ), S(R ｇ ) ５ or C １－６ may be substituted with alkyl, １－６ 12. The compound of any one of claims 7 to 11, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein alkyl is optionally further substituted with one or more halo.

14. R ２ is C ６－２０ aryl, and R ２ C ６－２０ Aryl independently comprises one or more C １－６ 14. The compound according to any one of claims 7 to 11 and 13, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is optionally substituted with alkyl.

15. The compound has formula (IB):

15. The compound according to any one of claims 7 to 11, 13 and 14, which is a compound of the formula: or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

16. The compound of formula (IB) 16. The compound of claim 15, selected from the group consisting of: or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

17. R １ but 16. The compound of any one of claims 1 to 11 and 13 to 15, wherein:

18. 3. The compound of formula (IC):

18. The compound of claim 17, which is a compound of the formula: or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

19. R ａ , R ｂ and R ｃ 19. The compound of claim 17 or 18, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein at least two of are H.

20. R ａ , R ｂ and R ｃ Exactly two of the ａ , R ｂ and R ｃ Exactly one of the ２ , C(O)-OH, C(O)-N(R ｅ ) (R ｆ ), C(O)-C １－６ Alkoxy or C(O)-C １－６ 20. The compound of any one of claims 17 to 19, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R is alkyl.

21. C(O)-N(R ｅ ) (R ｆ ) R ｅ and R ｆ are each independently H, C １－６ 21. The compound of claim 20, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is alkyl or hydroxyl.

22. R ａ , R ｂ and R ｃ Exactly two of the ａ , R ｂ and R ｃ 20. The compound of any one of claims 17 to 19, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein exactly one of: is C(O)-OH.

23. R ａ and R ｂ are H and R ｃ The compound of any one of claims 17 to 19, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein is C(O)-OH.

24. R ａ , R ｂ and R ｃ Exactly two of the ａ , R ｂ and R ｃ or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

25. R ａ and R ｂ are H and R ｃ 20. The compound of any one of claims 17 to 19, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein is C(O)-NH(OH).

26. The compound of formula (IC) 21. The compound of claim 20, selected from the group consisting of: or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

27. R ４ 26. The compound of any one of claims 1 to 11, 13 to 15 and 17 to 25, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein 28. A compound selected from the group consisting of: or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

29. A compound selected from the group consisting of: or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

30. 30. A pharmaceutical composition comprising: (i) a compound according to any one of claims 1 to 29, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier, diluent, or excipient.

31. A pharmaceutical for treating cancer in a mammal, comprising a compound according to any one of claims 1 to 29, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

32. A pharmaceutical for regulating TEAD activity, comprising a compound according to any one of claims 1 to 29, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

33. A pharmaceutical for the treatment or prevention of a disease or condition mediated by TEAD activity, comprising a compound according to any one of claims 1 to 29, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

34. If the disease or condition is acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, head and neck cancer, or Opiopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, proliferation abnormalities (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, testicular germ cell cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma , lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer , osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovium, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor.

35. 30. Use of a compound according to any one of claims 1 to 29, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of a disease or condition mediated by TEAD activity.

36. If the disease or condition is acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, head and neck cancer, or Opiopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, proliferation abnormalities (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, testicular germ cell cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma , lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer , osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovium, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer and Wilms' tumor.

37. A process for preparing the compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, comprising: wherein Boc is a tert-butyloxycarbonyl group and halo is a halogen.

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