Therapeutic Compounds and Methods of Use

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

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Application No. 62 / 935,015, filed November 13, 2019, and U.S. Provisional Application No. 63 / 056,502, filed July 24, 2020, each of which is incorporated by reference in its entirety. [0001.1] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format, the entire contents of which are incorporated herein by reference. The ASCII copy, created on November 11, 2020, is named P35805-WO_SL.txt and is 34,037 bytes in size. [Technical Field]

[0002] 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]

[0003] Short description The Hippo pathway is a signaling pathway that regulates cell proliferation and cell death and determines organ size. It is believed to play a role as a tumor suppressor in mammals, and pathway disorders are often detected in human cancers. It may be involved in and / or regulate the self-renewal and differentiation of stem and progenitor cells. Additionally, the Hippo pathway may be involved in wound healing and tissue regeneration. Furthermore, the Hippo pathway interacts with other signaling pathways, such as Wnt, Notch, Hedgehog, and MAPK / ERK, which may affect a wide variety of biological events. It is believed that dysfunction of the Hippo pathway could be involved in 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.

[0004] 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-MST 1-2 is upstream of Lat 1-2 and NDRI-2) that phosphorylates two transcriptional coactivators, YAP (Yes-Associated Protein) and TAZ (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).

[0005] The Hippo signaling pathway is involved in cancer development because it regulates 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 mammalian epithelial cells induces cellular transformation through the interaction of both proteins with the TEAD family of transcription factors. Increased YAP / TAZ transcriptional activity has also been shown to confer stem cell properties to breast cancer cells by inducing oncogenic properties such as epithelial-mesenchymal transition. In vivo, overexpression of YAP or genetic knockout of its upstream regulators MST1-2 in mouse liver induces hepatocellular carcinoma development. Furthermore, when the tumor suppressor NF2 is inactive in mouse liver, hepatocellular carcinoma development can be completely blocked by co-inactivation of YAP.

[0006] Deregulation of the Hippo tumor suppressor pathway has been shown to be a key factor in 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), and head and neck cancer (Gasparotto et al., Oncotarget., 2011, 2, 1165-1175; Steinmann et al. 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. al.,Gastroenterol.Res.Pract.,2013,2013,187070;Ahn et al.,Mol.Cancer.Res.,2013,11,748-758;Liu et al.,Expert.Opin.Ther.Targets,2012,16,243-247), brain cancer (Orr et al. al.,JNeuropathol.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.,2011,61,331-344), sarcoma (Seidel et al.,Mol.Carcinog.,2007,46,865-871), and leukemia (Jimenez-Velasco et al.,Leukemia,2005,19,2347-2350).

[0007] 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. Lates1 / 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 kinase. 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. Lts1 / 2 kinases phosphorylate the downstream effectors YAP (Yes-associated protein) and TAZ (transcriptional coactivator with a PDZ-binding motif, WWTR1), which are homologous to the Drosophila Yorkie kinase. 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.

[0008] Unphosphorylated, active YAP translocates to 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, along 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 to 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. Therefore, under some conditions, YAP and / or TAZ act as oncogenes and the Hippo pathway acts as a tumor suppressor.

[0009] 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

[0010] Disclosure Overview In some embodiments, the compound represented by the following formula (B-1): TIFF0007629916000001.tif31170 or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, [In the formula, X1 is N or C-R5, where 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, wherein R5 is C1~6 Alkyl is hydroxyl or N(R e )(R f ), or R5 of X1 together with R3 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 selected from one or more C 1~6 may be substituted with alkyl, X2 is N or C-R5, where 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, wherein R5 is C 1~6 Alkyl is hydroxyl or N(R e )(R f ), X3 is N or CH; However, X3 is N and R1 is TIFF0007629916000002.tif21170, then at least one of X1 and X2 is N, R1 is (i) oxiranyl or oxetanyl, wherein the oxiranyl or oxetanyl is one or more C 1~6 and optionally substituted with alkyl, wherein C 1~6 The alkyl may be substituted with one or more -C(O)NH2; L is absent or -O-, *-CH2-O-**, *-O-CH2-**, is selected from the group consisting of -CH=CH- and -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule; or (ii) N(R e )(CN), L is absent or -O-, *-CH2-O-**, *-O-CH2-**, is selected from the group consisting of -CH=CH- and -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule; or (iii) TIFF0007629916000003.tif20170, where R a , R b and R c are each independently H, halo, cyano, hydroxyl, or C 1~6 Alkyl, C 6~20 aryl, 3- to 10-membered heterocyclyl, and 5- to 20-membered heteroaryl, wherein C 1~6 The alkyl may be further substituted with hydroxyl, provided that R a , R b and R c at least two of are H; L is absent or selected from the group consisting of *-CH2-O-**, *-O-CH2-**, -CH=CH- and -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule; or (iv) TIFF0007629916000004.tif16170, where R d is H, halo, cyano, hydroxyl, C 1~6 Alkyl, C 6~20 aryl, 3- to 10-membered heterocyclyl, and 5- to 20-membered heteroaryl, wherein C 1~6 The alkyl may be further substituted with hydroxyl; L is selected from the group consisting of -O-, *-CH2-O-**, *-O-CH2-**, -CH=CH-, and -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule; R2 is C 1~12 Alkyl, C 3~10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 6~20 Aryl, C 5~13 spirocyclyl, or 5- to 20-membered heteroaryl, wherein R2 C 1~12 Alkyl, C 3~10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 6~20 Aryl, C 5~13 The spirocyclyl 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 SF5, However, R2 is C 1~12 alkyl, C 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-, when optionally substituted with one or two 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, wherein the 5-membered heterocyclyl or 5-membered heteroaryl is selected from one or more C 1~6 and optionally substituted with alkyl, provided that X3 is CH, or R3 together with the carbon atoms of *-CH2-O-** of L and the atoms to which they are attached form a C6 aryl or 6-membered heteroaryl; however, (i) R3 is cyano, C 1~6 Alkyl, C1~4 Alkoxy or C 2~4 alkenyl, C 2~4 Alkenyl is N(R e )(R f ), R1, TIFF0007629916000005.tif21170, R2 is a 3- to 10-membered saturated heterocyclyl or a 5- to 20-membered heteroaryl, wherein the 3- to 10-membered saturated heterocyclyl or the 5- to 20-membered heteroaryl is independently cyano, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, NO2, N(R e )(R f ) and O(R e ), wherein the alkyl group is optionally substituted with one or two substituents selected from the group consisting of L is *-CH2-O-**, -CH=CH- or -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the rest of the molecule; (ii) R3 together with R5 of X1 and the atom to which they are attached form a 5-membered heterocyclyl or 5-membered heteroaryl, and X3 is CH; R1, TIFF0007629916000006.tif21170, R2 is a 3- to 10-membered saturated heterocyclyl or a 5- to 20-membered heteroaryl, wherein the 3- to 10-membered saturated heterocyclyl or the 5- to 20-membered heteroaryl is independently cyano, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, NO2, N(R e )(R f ) and O(R e ), wherein the alkyl group is optionally substituted with one or two substituents selected from the group consisting of L is absent, *-CH2-O-**, -CH=CH-, or -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the rest of the molecule; (iii) R3 together with the carbon atom of *-CH2-O-** of L and the atom to which they are attached form a C6 aryl or 6-membered heteroaryl; R1, If the file is TIFF0007629916000007.tif21170, R2 is a 3- to 10-membered saturated heterocyclyl or a 5- to 20-membered heteroaryl, wherein the 3- to 10-membered saturated heterocyclyl or the 5- to 20-membered heteroaryl is independently 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 two substituents selected from the group consisting of: 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 of 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 6~20 aryl, and 3- to 20-membered heteroaryl, wherein 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 3~10Cycloalkyl, 3-10 membered heterocyclyl, 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 and 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.

[0011] In some embodiments, the compound of formula (B) TIFF0007629916000008.tif31170 or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, [In the formula, X1 is N or C-R5, where 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, wherein R5 is C 1~6 Alkyl is hydroxyl or N(R e )(R f ), or R5 of X1 together with R3 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 selected from one or more C 1~6 and optionally substituted with alkyl, provided that X3 is CH; X2 is N or C-R5, where 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 1~6alkyl, wherein R5 is C 1~6 Alkyl is hydroxyl or N(R e )(R f ), X3 is N or CH; However, X3 is N and R1 is TIFF0007629916000009.tif21170, then at least one of X1 and X2 is N, R1 is (i) oxiranyl or oxetanyl, wherein the oxiranyl or oxetanyl is one or more C 1~6 may be substituted with alkyl, L is absent or -O-, *-CH2-O-**, *-O-CH2-**, is selected from the group consisting of -CH=CH- and -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule; or (ii) N(R e )(CN), L is absent or -O-, *-CH2-O-**, *-O-CH2-**, is selected from the group consisting of -CH=CH- and -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule; or (iii) TIFF0007629916000010.tif20170, where R a , R b and R c are each independently H, halo, cyano, hydroxyl, or C 1~6 Alkyl, C 6~20 aryl, 3- to 10-membered heterocyclyl, and 5- to 20-membered heteroaryl, wherein C 1~6 The alkyl may be further substituted with hydroxyl, provided that R a , R b and R c at least two of are H; L is absent or selected from the group consisting of *-CH2-O-**, *-O-CH2-**, -CH=CH- and -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule; or (iv) TIFF0007629916000011.tif16170, where R d is H, halo, cyano, hydroxyl, C 1~6 Alkyl, C 6~20 aryl, 3- to 10-membered heterocyclyl, and 5- to 20-membered heteroaryl, wherein C 1~6 The alkyl may be further substituted with hydroxyl; L is selected from the group consisting of -O-, *-CH2-O-**, *-O-CH2-**, -CH=CH-, and -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule; R2 is C 1~12 Alkyl, C 3~10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 6~20 Aryl, C 5~13 spirocyclyl, or 5- to 20-membered heteroaryl, wherein R2 C 1~12 Alkyl, C 3~10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 6~20 Aryl, C 5~13 The spirocyclyl 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 two substituents selected from the group consisting of: However, R2 is C 1~12 alkyl, C 1~12 Alkyl is independently selected from cyano, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10Cycloalkyl, NO2, N(R e )(R f ) and O(R e L is -CH=CH- or -C≡C-, when optionally substituted with one or two 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, wherein the 5-membered heterocyclyl or 5-membered heteroaryl is selected from one or more C 1~6 and optionally substituted with alkyl, provided that X3 is CH, or R3 together with the carbon atoms of *-CH2-O-** of L and the atoms to which they are attached form a C6 aryl or 6-membered heteroaryl; however, (i) 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 ), R1, TIFF0007629916000012.tif21170, R2 is a 3- to 10-membered saturated heterocyclyl or a 5- to 20-membered heteroaryl, wherein the 3- to 10-membered saturated heterocyclyl or the 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 ), wherein the alkyl group is optionally substituted with one or two substituents selected from the group consisting of L is *-CH2-O-**, -CH=CH- or -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule; or (ii) R3, together with R5 of X1 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 selected from one or more C 1~6 and optionally substituted with alkyl, provided that X3 is CH, and R1, TIFF0007629916000013.tif21170, R2 is a 3- to 10-membered saturated heterocyclyl or a 5- to 20-membered heteroaryl, wherein the 3- to 10-membered saturated heterocyclyl or the 5- to 20-membered heteroaryl is independently cyano, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, NO2, N(R e )(R f ) and O(R e ), wherein the alkyl group is optionally substituted with one or two substituents selected from the group consisting of L is absent, *-CH2-O-**, -CH=CH- or -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule; or (iii) R3, together with the carbon atom of *-CH2-O-** of L and the atom to which they are attached, form a C6 aryl or 6-membered heteroaryl; R1, If the file is TIFF0007629916000014.tif21170, R2 is a 3- to 10-membered saturated heterocyclyl or a 5- to 20-membered heteroaryl, wherein the 3- to 10-membered saturated heterocyclyl or the 5- to 20-membered heteroaryl is independently 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 two substituents selected from the group consisting of: 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 of 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 6~20 aryl, and 3- to 20-membered heteroaryl, wherein 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 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 and 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.

[0012] In some embodiments of the disclosure, the compound, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, has the following formula (I): TIFF0007629916000015.tif32170[In the formula, X1 and X2 are each independently N or C-R5, where R5 is hydrogen, cyano, halo, C(O)NH2, NH(R e ), C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Alkoxy and C 6~20 aryl, wherein C 1~6 The alkyl may be substituted with hydroxyl; X3 is N or CH with the proviso that when X3 is N, at least one of X1 and X2 is N; R1 is TIFF0007629916000016.tif18170, where R a , R b and R c are each independently H, halo, cyano, hydroxyl, or C 1~6 Alkyl, C 6~20 aryl, 3- to 10-membered heterocyclyl, and 5- to 20-membered heteroaryl, wherein C 1~6 The alkyl may be further substituted with hydroxyl, provided that R a , R b and R c at least two of are H, and L is absent or selected from the group consisting of *-CH2-O-**, *-O-CH2-**, -CH=CH-, and -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the rest of the molecule; or R1 is TIFF0007629916000017.tif16170, where R d is H, halo, cyano, hydroxyl, C 1~6 Alkyl, C 6~20 aryl, 3- to 10-membered heterocyclyl, and 5- to 20-membered heteroaryl, wherein C 1~6the alkyl may be further substituted with hydroxyl; L is selected from the group consisting of -O-, *-CH2-O-**, *-O-CH2-**, -CH=CH-, and -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule; R2 is C 1~12 Alkyl, C 3~10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 6~20 Aryl or C 5~13 spirocyclyl, where C 1~12 Alkyl, C 3~10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 6~20 Aryl or C 5~13 Spirocyclyl can be independently 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 1, 2, 3, or 4 substituents selected from the group consisting of: where R e and R f are independently H, 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 6~20 aryl, and 3- to 20-membered heteroaryl, wherein 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 6~20 The aryl and the 3- to 20-membered heteroaryl are each independently C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6optionally substituted with one or more substituents selected from the group consisting of alkoxy, oxo, cyano, halo, NO2, and hydroxyl; However, R2 is C 1~12 alkyl, C 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 wherein L is -CH=CH- or -C≡C-, R3 is cyano, C 1~6 Alkyl, C 1~4 Alkoxy or C 2~4 alkenyl, where C 2~4 Alkenyl is NH(R e or R3 together with R5 of X1 and the atoms to which they are attached form a 5-membered heterocyclyl or a 5-membered heteroaryl, with the proviso that X3 is CH or R3 together with the carbon atom of *-CH2-O-** of L and the atoms to which they are attached form a C6 aryl or a 6-membered heteroaryl; however, (i) 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 ), wherein R2 is a 3- to 10-membered saturated heterocyclyl or a 5- to 20-membered heteroaryl, and the 3- to 10-membered saturated heterocyclyl or the 5- to 20-membered heteroaryl is independently substituted with 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 *-CH2-O-**, -CH=CH- or -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the rest of the molecule; or (ii) R3 together with R5 of X1 and the atom to which they are attached form a 5-membered heterocyclyl or a 5-membered heteroaryl, provided that X3 is CH and R2 is a 3- to 10-membered saturated heterocyclyl or a 5- to 20-membered heteroaryl, wherein the 3- to 10-membered saturated heterocyclyl or the 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 ), L is absent or is *-CH2-O-**, -CH=CH- or -C≡C, where ** indicates the point of attachment to R2 and * indicates the point of attachment to the rest of the molecule; or (iii) R3, together with the carbon atom of *-CH2-O-** of L and the atom to which they are attached, form a C6 aryl or 6-membered heteroaryl, and R2 is a 3- to 10-membered saturated heterocyclyl or a 5- to 20-membered heteroaryl, wherein the 3- to 10-membered saturated heterocyclyl or the 5- to 20-membered heteroaryl is independently 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 ) and O(R e ), L is *-CH2-O-**, -CH=CH- or -C≡C-, where ** indicates the point of attachment of the part to R2 and * indicates the point of attachment to the rest of the molecule; and R4 is H or C 1~6 alkyl, where C 1~6The alkyl may be substituted by a hydroxyl. It is of the type.

[0013] In some embodiments, a pharmaceutical composition is provided comprising a compound described herein, e.g., a compound of Formula (B-1), Formula (B), or Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0014] In some embodiments, compounds described herein, such as compounds of Formula (B-1), Formula (B) or Formula (I), or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, are provided for use in medical therapy.

[0015] In some embodiments, compounds described herein, e.g., compounds of Formula (B-1), Formula (B), or Formula (I), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, are provided for the treatment or prevention of cancer, mesothelioma, sarcoma, or leukemia.

[0016] In some embodiments, a compound described herein, e.g., a compound of Formula (B-1), Formula (B), or Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, is provided for the manufacture of a medicament for the treatment or prevention of cancer, mesothelioma, sarcoma, or leukemia.

[0017] In some embodiments, provided are methods for treating cancer, mesothelioma, sarcoma, or leukemia in a mammal, comprising administering to the mammal a compound described herein, e.g., a compound of Formula (B-1), Formula (B), or Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0018] In some embodiments, provided are methods for treating cancer, mesothelioma, sarcoma, or leukemia in a mammal, comprising administering to the mammal a compound described herein, e.g., a compound of Formula (B-1), Formula (B), or Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent.

[0019] In some embodiments, compounds described herein, such as compounds of Formula (B-1), Formula (B), or Formula (I), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, are provided for modulating TEAD activity.

[0020] In some embodiments, compounds described herein, such as compounds of Formula (B-1), Formula (B), or Formula (I), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, are provided for treating or preventing diseases or conditions mediated by TEAD activity.

[0021] In some embodiments, a compound described herein, e.g., a compound of Formula (B-1), Formula (B), or Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, is provided for use in manufacturing a medicament for treating or preventing a disease or condition mediated by TEAD activity.

[0022] In some embodiments, a method for modulating TEAD activity is provided, comprising contacting a compound described herein, e.g., a compound of Formula (B-1), Formula (B), or Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, with a TEAD.

[0023] In some embodiments, provided are methods for treating a disease or condition mediated by TEAD activity in a mammal, comprising administering to the mammal a compound described herein, e.g., a compound of Formula (B-1), Formula (B), or Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION

[0024] Detailed Description 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 the 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). Cycloalkyl moieties can also be formed in a spirocyclic fashion, such as spirocyclopropyl. It can be combined into TIFF0007629916000018.tif14170.

[0029] The term "haloalkyl" refers to an alkyl group in which one or more of the alkyl group's hydrogen atoms are 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 the ring atoms may be substituted. Examples of such saturated or partially unsaturated heterocyclic rings include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Other examples of such saturated or partially unsaturated heterocyclic rings include, but are not limited to, oxiranyl and oxetanyl. The term heterocyclic ring also includes groups in which a heterocyclic ring is fused to one or more aryl, heteroaryl, or cycloalkyl rings, such as 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 may be optionally substituted. In some embodiments, a monocyclic aryl ring may have 5 or 6 carbon ring atoms. The aryl group may be optionally 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 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 15 carbon atoms, with both rings bonded through a single atom. The rings may be different in size and nature, or may be identical in size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirodecane. One or more of the carbon atoms in the spirocycle may be replaced with a heteroatom (e.g., O, N, S, or P); in such embodiments, the spirocycle may contain from 3 to 14 carbon atoms. 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, potassium, lithium, ammonium, calcium, and magnesium salts, and the like. 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 easily undergoes chemical changes under physiological conditions to provide a compound of the present disclosure. In addition, prodrugs can be converted to a compound of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs 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 can be derivatized as amides or alkyl esters. In still other prodrug embodiments, prodrugs containing free hydroxy groups can 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 can be an alkyl ester optionally substituted with groups including, but not limited to, ether, amine, and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above. 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, where the alpha-aminoacyl groups are independently selected from the naturally occurring L-amino acids, P(O)(OH), -P(O)(O(C 1~6 ) 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 Pharmaceutical Sciences, 77:285 (1988); and e) N. Kakeya, et al., each of which is expressly incorporated herein by reference. See, al., Chem. Pharm. Bull., 32:692 (1984).

[0045] In addition, the present disclosure provides metabolic products of the disclosed compounds. 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, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound.

[0046] The metabolites are typically radiolabeled (e.g., 14 C or 3 Identification 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 (others are isolated by the use of 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 studies well known to those skilled in the art. Metabolites are useful in diagnostic assays for therapeutic dosing of the disclosed compounds, unless otherwise observed in vivo.

[0047] Certain compounds of the present disclosure can exist in non-solvated form and solvated form, including hydrated form.In general, solvated form is equivalent to non-solvated form and is intended to be included in the scope of the present disclosure.Certain compounds of the present disclosure can exist in multiple crystalline forms or amorphous forms.In general, all physical forms are equivalent for the use contemplated by 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 in 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 at one or more chiral centers that are not enantiomers. Stereoisomers with one or more asymmetric centers that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, when a carbon atom is bonded to four different groups, a pair of enantiomers is possible. 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% enriched by weight in a single diastereomer or enantiomer. In other embodiments, the compound is at least about 95%, 98%, or 99% enriched by weight 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 to prolong the survival of a subject being treated. Determining a therapeutically effective amount is within the skill of those in the art. The therapeutically effective amount or therapeutically effective dose of a compound according to the present disclosure can vary within wide limits and can be determined in a manner known in the art. Such doses will be tailored to the individual requirements in 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 can be administered as a single dose, in divided doses, or for parenteral administration, it may also be administered 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 can also be incorporated into the compositions. compound

[0054] In some embodiments of the present disclosure, the compound, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, has the following formula (B-1): TIFF0007629916000019.tif31170 or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, [In the formula, X1 is N or C-R5, where each R5 is independently H, cyano, halo, C(O)NH2, N(R e )(R f ), C3~10 Cycloalkyl, C 1~6 Alkoxy, C 6~20 Aryl and C 1~6 alkyl, wherein R5 is C 1~6 Alkyl is hydroxyl or N(R e )(R f ), or R5 of X1 together with R3 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 selected from one or more C 1~6 and optionally substituted with alkyl, provided that X3 is CH; X2 is N or C-R5, where 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, wherein R5 is C 1~6 Alkyl is hydroxyl or N(R e )(R f ), X3 is N or CH; However, X3 is N and R1 is TIFF0007629916000020.tif21170, then at least one of X1 and X2 is N, R1 is (i) oxiranyl or oxetanyl, wherein the oxiranyl or oxetanyl is one or more C 1~6 and optionally substituted with alkyl, wherein C 1~6 The alkyl may be substituted with one or more -C(O)NH2; L is absent or -O-, *-CH2-O-**, *-O-CH2-**, is selected from the group consisting of -CH=CH- and -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule; or (ii) N(R e )(CN), and L is absent or -O-, *-CH2-O-**, *-O-CH2-**, is selected from the group consisting of -CH=CH- and -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule; or (iii) TIFF0007629916000021.tif20170, where R a , R b and R c are each independently H, halo, cyano, hydroxyl, or C 1~6 Alkyl, C 6~20 aryl, 3- to 10-membered heterocyclyl, and 5- to 20-membered heteroaryl, wherein C 1~6 The alkyl may be further substituted with hydroxyl, provided that R a , R b and R c at least two of are H; L is absent or selected from the group consisting of *-CH2-O-**, *-O-CH2-**, -CH=CH- and -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule; or (iv) TIFF0007629916000022.tif16170, where R d is H, halo, cyano, hydroxyl, C 1~6 Alkyl, C 6~20 aryl, 3- to 10-membered heterocyclyl, and 5- to 20-membered heteroaryl, wherein C 1~6 The alkyl may be further substituted with hydroxyl, and L is selected from the group consisting of -O-, *-CH2-O-**, *-O-CH2-**, -CH=CH-, and -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule; R2 is C 1~12 Alkyl, C 3~10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 6~20 Aryl, C 5~13 spirocyclyl, or 5- to 20-membered heteroaryl, wherein R2 C 1~12 Alkyl, C 3~10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 6~20 Aryl, C 5~13 The spirocyclyl 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 SF5, However, R2 is C 1~12 alkyl, C 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-, when optionally substituted with one or two 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, wherein the 5-membered heterocyclyl or 5-membered heteroaryl is selected from one or more C 1~6 and optionally substituted with alkyl, provided that X3 is CH, or R3 together with the carbon atoms of *-CH2-O-** of L and the atoms to which they are attached form a C6 aryl or 6-membered heteroaryl; however, (i) 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 ), R1, TIFF0007629916000023.tif21170, R2 is a 3- to 10-membered saturated heterocyclyl or a 5- to 20-membered heteroaryl, wherein the 3- to 10-membered saturated heterocyclyl or the 5- to 20-membered heteroaryl is independently cyano, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, NO2, N(R e )(R f ) and O(R e ), wherein the alkyl group is optionally substituted with one or two substituents selected from the group consisting of L is *-CH2-O-**, -CH=CH- or -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule; or (ii) R3 together with R5 of X1 and the atom to which they are attached form a 5-membered heterocyclyl or 5-membered heteroaryl, provided that X3 is CH; R1, TIFF0007629916000024.tif21170, R2 is a 3- to 10-membered saturated heterocyclyl or a 5- to 20-membered heteroaryl, wherein the 3- to 10-membered saturated heterocyclyl or the 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 ), wherein the alkyl group is optionally substituted with one or two substituents selected from the group consisting of L is absent, *-CH2-O-**, -CH=CH- or -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule; or (iii) R3, together with the carbon atom of *-CH2-O-** of L and the atom to which they are attached, form a C6 aryl or 6-membered heteroaryl; R1, If the file is TIFF0007629916000025.tif21170, R2 is a 3- to 10-membered saturated heterocyclyl or a 5- to 20-membered heteroaryl, wherein the 3- to 10-membered saturated heterocyclyl or the 5- to 20-membered heteroaryl is independently 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 two substituents selected from the group consisting of: 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 of each occurrence, H, cyano, hydroxyl, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C1~6 Alkyl-C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 6~20 aryl, and 3- to 20-membered heteroaryl, wherein 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 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 and 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.

[0055] In some embodiments of the present disclosure, the compound, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, has the following formula (B): TIFF0007629916000026.tif31170 or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, [In the formula, X1 is N or C-R5, where 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, wherein R5 is C 1~6 Alkyl is hydroxyl or N(R e )(R f ), or R5 of X1 together with R3 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 selected from one or more C 1~6 and optionally substituted with alkyl, provided that X3 is CH; X2 is N or C-R5, where 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, wherein R5 is C 1~6 Alkyl is hydroxyl or N(R e )(R f ), X3 is N or CH; However, X3 is N and R1 is TIFF0007629916000027.tif21170, then at least one of X1 and X2 is N, R1 is (i) oxiranyl or oxetanyl, wherein the oxiranyl or oxetanyl is one or more C 1~6 may be substituted with alkyl, L is absent or -O-, *-CH2-O-**, *-O-CH2-**, is selected from the group consisting of -CH=CH- and -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule; or (ii) N(R e )(CN), and L is absent or -O-, *-CH2-O-**, *-O-CH2-**, is selected from the group consisting of -CH=CH- and -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule; or (iii) TIFF0007629916000028.tif20170, where R a , R b and R c are each independently H, halo, cyano, hydroxyl, or C 1~6 Alkyl, C 6~20 aryl, 3- to 10-membered heterocyclyl, and 5- to 20-membered heteroaryl, wherein C 1~6 The alkyl may be further substituted with hydroxyl, provided that R a , R b and R c at least two of are H; L is absent or selected from the group consisting of *-CH2-O-**, *-O-CH2-**, -CH=CH- and -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule; or (iv) TIFF0007629916000029.tif16170, where R d is H, halo, cyano, hydroxyl, C 1~6 Alkyl, C 6~20 aryl, 3- to 10-membered heterocyclyl, and 5- to 20-membered heteroaryl, wherein C 1~6 The alkyl may be further substituted with hydroxyl, and L is selected from the group consisting of -O-, *-CH2-O-**, *-O-CH2-**, -CH=CH-, and -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule; R2 is C 1~12 Alkyl, C 3~10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 6~20 Aryl, C 5~13 spirocyclyl, or 5- to 20-membered heteroaryl, wherein R2 C 1~12 Alkyl, C 3~10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 6~20 Aryl, C 5~13The spirocyclyl 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 two substituents selected from the group consisting of: However, R2 is C 1~12 alkyl, C 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-, when optionally substituted with one or two 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, wherein the 5-membered heterocyclyl or 5-membered heteroaryl is selected from one or more C 1~6 and optionally substituted with alkyl, provided that X3 is CH, or R3 together with the carbon atoms of *-CH2-O-** of L and the atoms to which they are attached form a C6 aryl or 6-membered heteroaryl; however, (i) 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 ), and R1, TIFF0007629916000030.tif21170, R2 is a 3- to 10-membered saturated heterocyclyl or a 5- to 20-membered heteroaryl, wherein the 3- to 10-membered saturated heterocyclyl or the 5- to 20-membered heteroaryl is independently cyano, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, NO2, N(R e )(R f ) and O(R e ), wherein the alkyl group is optionally substituted with one or two substituents selected from the group consisting of L is *-CH2-O-**, -CH=CH- or -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule; or (ii) R3, together with R5 of X1 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 selected from one or more C 1~6 and optionally substituted with alkyl, provided that X3 is CH, and R1, TIFF0007629916000031.tif21170, and R2 is a 3- to 10-membered saturated heterocyclyl or a 5- to 20-membered heteroaryl, wherein the 3- to 10-membered saturated heterocyclyl or the 5- to 20-membered heteroaryl is independently cyano, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, NO2, N(R e )(R f ) and O(R e ), wherein the alkyl group is optionally substituted with one or two substituents selected from the group consisting of L is absent, *-CH2-O-**, -CH=CH- or -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule; or (iii) R3, together with the carbon atoms of *-CH2-O-** of L and the atoms to which they are attached, form a C6 aryl or 6-membered heteroaryl; and R1, If the file is TIFF0007629916000032.tif21170, R2 is a 3- to 10-membered saturated heterocyclyl or a 5- to 20-membered heteroaryl, wherein the 3- to 10-membered saturated heterocyclyl or the 5- to 20-membered heteroaryl is independently 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 two substituents selected from the group consisting of: 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 of 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 6~20 aryl, and 3- to 20-membered heteroaryl, wherein 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 6~20 The aryl and the 3- to 20-membered heteroaryl are each independently C 1~6 Alkyl, C 1~6 Haloalkyl, C1~6 and 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 an embodiment, X1 is N or C-R5, where R5 is H, C 3~10 Cycloalkyl and C 1~6 alkyl, or R5 of X1 together with R3 and the atom to which they are attached form a 5-membered heterocyclyl or a 5-membered heteroaryl, wherein the 5-membered heterocyclyl or the 5-membered heteroaryl is selected from the group consisting of one or more C 1~6 It may be substituted with alkyl, provided that X3 is CH.

[0057] In embodiments, X2 is N or C-R5, where each R5 is independently H, cyano, halo, C(O)NH2, C 1~6 Alkoxy, C 6~20 Aryl and C 1~6 alkyl, wherein R5 is C 1~6 The alkyl may be substituted with a hydroxyl.

[0058] In embodiments, X3 is N or CH, provided that X3 is N and R1 is TIFF0007629916000033.tif21170, then at least one of X1 and X2 is N.

[0059] In an embodiment, R1 is (i) one or more C 1~6 and L is an optionally substituted oxiranyl group with alkyl, and L is absent or (ii) N(R e )(CN) and L is absent, or (iii) TIFF0007629916000034.tif20170, where R a , R b and R c are independently H, cyano, or C 6~20 C optionally substituted with aryl and hydroxyl 1~6 alkyl, and L is absent or selected from the group consisting of -CH=CH- and *-CH2-O-**, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the rest of the molecule; or (iv) TIFF0007629916000035.tif16170, where R d is H and L is -CH=CH-.

[0060] In an embodiment, R2 is C 1~12 Alkyl, C 3~10 Cycloalkyl, C 6~20 Aryl and C 5~13 spirocyclyl, wherein C 1~12 Alkyl, C 3~10 Cycloalkyl, C 6~20 Aryl and C 5~13 Spirocyclyl may independently be halo, C 1~6 Alkyl and C 1~6 haloalkyl, provided that R2 is C 1~12 When L is alkyl, it is -CH=CH- or -C≡C-.

[0061] In an embodiment, R3 is cyano, or C 1~4 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, wherein the 5-membered heterocyclyl or the 5-membered heteroaryl is selected from one or more C 1~6It may be substituted by alkyl, provided that X3 is CH or R3 together with the carbon atom of *-CH2-O-** of L and the atom to which they are attached form a C6 aryl or 6-membered heteroaryl.

[0062] In an embodiment, R4 is H.

[0063] In embodiments, R e and R f are, independently of each other and for each occurrence, H and C 1~6 alkyl.

[0064] In some embodiments of the disclosure, the compound, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, has the following formula (I): TIFF0007629916000036.tif23170[In the formula, X1 and X2 are each independently N or C-R5, where R5 is hydrogen, cyano, halo, C(O)NH2, NH(R e ), C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Alkoxy and C 6~20 aryl, wherein C 1~6 The alkyl may be substituted with hydroxyl; X3 is N or CH with the proviso that when X3 is N, at least one of X1 and X2 is N; R1 is TIFF0007629916000037.tif20170, where R a , R b and R c are each independently H, halo, cyano, hydroxyl, or C 1~6 Alkyl, C 6~20 aryl, 3- to 10-membered heterocyclyl, and 5- to 20-membered heteroaryl, wherein C 1~6 The alkyl may be further substituted with hydroxyl, provided that Ra , R b and R c at least two of are H, and L is absent or selected from the group consisting of *-CH2-O-**, *-O-CH2-**, -CH=CH-, and -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the rest of the molecule; or R1 is TIFF0007629916000038.tif16170, where R d is H, halo, cyano, hydroxyl, C 1~6 Alkyl, C 6~20 aryl, 3- to 10-membered heterocyclyl, and 5- to 20-membered heteroaryl, wherein C 1~6 the alkyl may be further substituted with hydroxyl; L is selected from the group consisting of -O-, *-CH2-O-**, *-O-CH2-**, -CH=CH-, and -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule; R2 is C 1~12 Alkyl, C 3~10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 6~20 Aryl or C 5~13 spirocyclyl, where C 1~12 Alkyl, C 3~10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 6~20 Aryl or C 5~13 Spirocyclyl can be independently 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 1, 2, 3, or 4 substituents selected from the group consisting of: where R e and R f are independently H, 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 6~20 aryl, and 3- to 20-membered heteroaryl, wherein 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 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; However, R2 is C 1~12 alkyl, C 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 wherein L is -CH=CH- or -C≡C-, R3 is cyano, C 1~6 Alkyl, C 1~4 Alkoxy or C 2~4 alkenyl, where C 2~4 Alkenyl is NH(R e or R3 together with R5 of X1 and the atoms to which they are attached form a 5-membered heterocyclyl or a 5-membered heteroaryl, with the proviso that X3 is CH or R3 together with the carbon atom of *-CH2-O-** of L and the atoms to which they are attached form a C6 aryl or a 6-membered heteroaryl; however, (i) 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 ), wherein R2 is a 3- to 10-membered saturated heterocyclyl or a 5- to 20-membered heteroaryl, and the 3- to 10-membered saturated heterocyclyl or the 5- to 20-membered heteroaryl is independently 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 *-CH2-O-**, -CH=CH- or -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the rest of the molecule; or (ii) R3 together with R5 of X1 and the atom to which they are attached form a 5-membered heterocyclyl or a 5-membered heteroaryl, provided that X3 is CH and R2 is a 3- to 10-membered saturated heterocyclyl or a 5- to 20-membered heteroaryl, wherein the 3- to 10-membered saturated heterocyclyl or the 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 ), L is absent or is *-CH2-O-**, -CH=CH- or -C≡C, where ** indicates the point of attachment to R2 and * indicates the point of attachment to the rest of the molecule; or (iii) R3, together with the carbon atom of *-CH2-O-** of L and the atom to which they are attached, form a C6 aryl or 6-membered heteroaryl, and R2 is a 3- to 10-membered saturated heterocyclyl or a 5- to 20-membered heteroaryl, wherein the 3- to 10-membered saturated heterocyclyl or the 5- to 20-membered heteroaryl is independently 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 ) and O(R e ), L is *-CH2-O-**, -CH=CH- or -C≡C-, where ** indicates the point of attachment of the part to R2 and * indicates the point of attachment to the rest of the molecule; and R4 is H or C 1~6 alkyl, where C 1~6 The alkyl may be substituted by a hydroxyl. It is of the type.

[0065] In certain embodiments, provided herein are compounds of Formula (B-1), Formula (B), or Formula (I), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, in which R3, together with R5 of X1 and the atom to which they are attached, forms a 5-membered heterocyclyl or 5-membered heteroaryl. It should be understood that the "5-member" size designation of the heterocyclyl or heteroaryl formed by combining R3 and R5 of X1 refers to the size of the monocyclic moiety formed by combining R3 and R5 of X1. Furthermore, the 5-membered heterocyclyl or 5-membered heteroaryl formed by combining R3 and R5 of X1 can be referred to by the chemical name of the resulting 5-membered monocyclic ring moiety. For example, if the structure of a compound of Formula (B-1), (B), or (I) is When R3 together with R5 of X1 and the atom to which they are attached form a 5-membered heterocyclyl, as in TIFF0007629916000039.tif26170, the ring formation can be described as follows: "R3 together with R5 of X1 and the atom to which they are attached form tetrahydrofuranyl."

[0066] In certain embodiments, provided herein are compounds of Formula (B-1), Formula (B) or Formula (I), or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein R3, together with R5 of X1 and the atom to which they are attached, form a 5-membered heterocyclyl, with the proviso that X3 is CH. In some embodiments, the 5-membered cyclocyclyl is unsubstituted. In certain embodiments, the 5-membered heterocyclyl is selected from one or more C 1~6 In some embodiments, the 5-membered heterocyclyl is substituted with alkyl. In some embodiments, the 5-membered heterocyclyl is substituted with one or more methyl. In some embodiments, the 5-membered heterocyclyl contains 1, 2, 3, or 4 ring heteroatoms, wherein each heteroatom is independently selected from the group consisting of sulfur, oxygen, and nitrogen. In some embodiments, the 5-membered heterocyclyl contains 1 or 2 ring heteroatoms. In some embodiments, the 5-membered heterocyclyl contains 1 ring atom.

[0067] In some embodiments, R3 together with R5 of X1 and the atom to which they are attached form a 5-membered heterocyclyl, whereby the compound of Formula (B-1), Formula (B) or Formula (I) has Formula (IA): Provided herein is a compound of Formula (B-1), Formula (B) or Formula (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound of Formula (B-1), Formula (B) or Formula (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof: TIFF0007629916000040.tif27170

[0068] In some embodiments, the compound of formula (IA) is TIFF0007629916000041.tif119170, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0069] In other embodiments, the compound of formula (IA) is TIFF0007629916000042.tif129170, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0070] In some embodiments, the compound of formula (IA) is TIFF0007629916000043.tif79170, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0071] In some embodiments, provided herein are compounds of formula (IA), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, where X2 is C-R5. In certain embodiments, R5 of X2 is cyano. In some embodiments, X2 is C-R5, where R5 of X2 is cyano, L is absent, and R2 is C 6~20 aryl, where C 6~20 Aryl includes cyano, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, NO2, N(R e )(R f ) and O(R e In some embodiments, R2 may be substituted with one or two substituents selected from the group consisting of: 6~20 Aryl is one or two C 1~6 In some embodiments, C may be substituted with alkyl. 1~6 In certain embodiments, the compound of formula (IA) has the formula (IJ): TIFF0007629916000044.tif32170, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0072] In some embodiments, the compound of formula (IJ) is TIFF0007629916000045.tif107170, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (IJ) is TIFF0007629916000046.tif41170, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0073] In some embodiments, R1 is oxiranyl or oxetanyl, wherein the oxiranyl or oxetanyl is one or more C 1~6 Provided herein are compounds of formula (IJ), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, optionally substituted with alkyl. In some embodiments, R is oxiranyl or oxetanyl, wherein the oxiranyl or oxetanyl is selected from one or more C 1~6 and optionally substituted with alkyl, wherein C 1~6 The alkyl may be substituted with one or more -C(O)NH. In some embodiments, R is oxetanyl, wherein the oxetanyl is one or more C 1~6 In some embodiments, R is oxetanyl, wherein the oxetanyl is substituted with one or more C alkyl. 1~6 and optionally substituted with alkyl, wherein C 1~6 The alkyl may be substituted with one or more -C(O)NH2. In some embodiments, R1 is oxiranyl, and the oxiranyl is unsubstituted. In some embodiments, R1 is oxiranyl, and the oxiranyl is one or more C(O)NH2. 1~6In some embodiments, R1 is oxiranyl, where the oxiranyl is substituted with one or more methyl. In some embodiments, R1 is oxetanyl, where the oxetanyl is substituted with one or more C 1~6 and optionally substituted with alkyl, wherein C 1~6 The alkyl may be substituted with one or more -C(O)NH. In some embodiments, R is oxetanyl, wherein the oxetanyl is optionally substituted with -CH-CH-C(O)NH.

[0074] In some embodiments, R is oxiranyl, and the oxiranyl is one or more C 1~6 may be substituted with alkyl, C 1-6 Provided herein are compounds of formula (IJ), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein alkyl is optionally substituted with one or more —C(O)NH. In certain embodiments, one or more C 1~6 In certain embodiments, the compound of Formula (B), (IA) or (IJ) has the formula (IK): TIFF0007629916000047.tif32170, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R g is H or C 1~6 alkyl, C 1~6 The alkyl may be substituted with one or more -C(O)NH. In some embodiments, R g is H. In other embodiments, R g is methyl. In other embodiments, R g is —CH2—CH2—C(O)NH2.

[0075] In some embodiments, the compound of formula (IK) is TIFF0007629916000048.tif114170, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0076] In some embodiments, R is N(R e )(CN) and R e 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 6~20 aryl, and 3- to 20-membered heteroaryl; R e 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 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 (IJ), 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.

[0077] In certain embodiments, the compound of formula (IJ) has formula (IL): Provided herein is a compound of Formula (IJ), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound of Formula (IJ) of TIFF0007629916000049.tif32170, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In certain embodiments, R e is H. In other embodiments, R e is C1~6 In certain embodiments, R 1 is methyl.

[0078] In certain embodiments, R3, together with R5 of X1 and the atom to which they are attached, form a 5-membered heterocyclyl, and the compound of Formula (B-1), Formula (B) or Formula (I) has Formula (IB) TIFF0007629916000050.tif31170, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0079] In some embodiments, provided herein are compounds of Formula (B-1), Formula (B), or Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R3, together with R5 of X1 and the atom to which they are attached, form a 5-membered heteroaryl, with the proviso that X3 is CH. In some embodiments, the 5-membered heteroaryl is unsubstituted. In certain embodiments, the 5-membered heteroaryl is selected from the group consisting of one or more C 1~6 In some embodiments, the 5-membered heteroaryl is substituted with one or more methyl groups. In some embodiments, R3, together with R5 of X1 and the atom to which they are attached, form a 5-membered heteroaryl, provided that X3 is CH, and the 5-membered heteroaryl contains 1, 2, 3, or 4 ring heteroatoms, each heteroatom independently selected from the group consisting of oxygen and nitrogen. In some embodiments, the 5-membered heteroaryl has 1 or 2 ring heteroatoms.

[0080] In some embodiments, R3, together with R5 of X1 and the atom to which they are attached, form a 5-membered heteroaryl, and the compound of Formula (B-1), Formula (B) or Formula (I) is of Formula (IC): TIFF0007629916000051.tif28170, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0081] In some embodiments, R3, together with R5 of X1 and the atom to which they are attached, form a 5-membered heteroaryl, and the compound of Formula (B-1), Formula (B) or Formula (I) has the formula (IC-1): TIFF0007629916000052.tif28170, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0082] In some embodiments, compounds of Formula (B-1), Formula (B) or Formula (I), or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, are provided wherein R3, together with the carbon atom of *-CH2-O-** of L and the atom to which they are attached, form a C6 aryl or 6-membered heteroaryl.

[0083] In some embodiments, R3, together with the carbon atom of *-CH2-O-** of L and the atom to which they are attached, form a C6 aryl. In some embodiments, R3, together with the carbon atom of *-CH2-O-** of L and the atom to which they are attached, form a C6 aryl, and the compound of Formula (B-1), Formula (B) or Formula (I) has the formula (ID) TIFF0007629916000053.tif26170, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0084] In some embodiments, R3, together with the carbon atom of *-CH2-O-** of L and the atom to which they are attached, form a 6-membered heteroaryl. In some embodiments, the 6-membered heteroaryl contains 1, 2, 3, or 4 ring heteroatoms, where each heteroatom is independently selected from the group consisting of oxygen and nitrogen. In some embodiments, the 6-membered heteroaryl contains 1 ring heteroatom.

[0085] In some embodiments, R3, together with the carbon atom of *-CH2-O-** of L and the atom to which they are attached, form a 6-membered heteroaryl, such that the compound of Formula (B-1), Formula (B) or Formula (I) has the formula (IE) TIFF0007629916000054.tif25170, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0086] In some embodiments, provided herein are compounds of Formula (B-1), Formula (B), or Formula (I), or a 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 a hydroxyl.

[0087] In some embodiments, X3 is CH, L is -CH=CH-, and R2 is C 3~10 cycloalkyl, where C 3~10 Cycloalkyl 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 R3 is optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of C 1~4 Provided herein is a compound of Formula (B-1), Formula (B) or Formula (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R is alkoxy and R is H. In certain embodiments, the compound of Formula (B-1), Formula (B) or Formula (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, is a compound of Formula (IF) TIFF0007629916000055.tif37170, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0088] In certain embodiments, the compound of formula (IF) is TIFF0007629916000056.tif168170, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0089] In some embodiments of the present disclosure, R Provided herein is a compound of Formula (B-1), Formula (B) or Formula (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound is TIFF0007629916000057.tif18170. In some embodiments, the compound of Formula (B-1), Formula (B) or Formula (I) is Formula (IG): TIFF0007629916000058.tif23170, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0090] In embodiments, R a , R b , and R c

[0023] In another embodiment, compounds of formula (IG) are provided, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein each R a and R b One of the two is H and the other is R a and R b The other is cyano, and R c is H. In some embodiments, compounds of formula (IG), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, are provided wherein R a is H and R b is cyano and R c is H. In other embodiments, R a is H and R b is H and R c C 6~20 In some embodiments, compounds of formula (IG) are provided wherein R is aryl, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.a is H and R b is H and R c In another embodiment, R is C6 aryl, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. a is H and R b is H and R c C 1~6 alkyl, C 1~6 Provided are compounds of formula (IG), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the alkyl is further substituted with hydroxyl.

[0091] In some embodiments of the present disclosure, R1 is TIFF0007629916000059.tif19170, and R2 is C 3~10 cycloalkyl, where C 3~10 Cycloalkyl 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 each R e and R f are independently H, 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 6~20 aryl, and 3- to 20-membered heteroaryl, wherein 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 6~20The aryl and the 3- to 20-membered heteroaryl are each independently C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Provided are compounds of Formula (B-1), Formula (B) or Formula (I), or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, optionally substituted with one or more substituents selected from the group consisting of alkoxy, oxo, cyano, halo, NO2 and hydroxyl.

[0092] In some embodiments, the compound of Formula (B-1), Formula (B), or Formula (I) is of Formula (IH): TIFF0007629916000060.tif26170, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0093] In some embodiments, n is 0, 1, 2, 3, or 4, and each R x , if present, independently represent 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 each R e and R f However, independently, H, 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 6~20 aryl, and 3- to 20-membered heteroaryl; 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 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 Provided are compounds of formula (IH), 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.

[0094] In some embodiments, n is 0, 1, or 2, and each R x When present, independently, 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 each R e and R f However, independently, H, 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 6~20 aryl, and 3- to 20-membered heteroaryl; 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 6~20 The aryl and the 3- to 20-membered heteroaryl are each independently C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6Provided are compounds of formula (IH), 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.

[0095] In an embodiment, R a , R b , and R c are H, n is 1, and R x C 1~6 In some embodiments, compounds of formula (IH), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, are provided, wherein R is haloalkyl. x C 1~6 Haloalkyl is CF. In some embodiments, R a , R b and R c are H, n is 2, and both R x is halo. In certain embodiments, both R x is F.

[0096] In some embodiments, compounds of Formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK) or (IL), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, are provided wherein X is N, X is N, and X is CH. In other embodiments, compounds of Formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK) or (IL), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, are provided wherein X is C-R, R is H, X is N, and X is CH. In other embodiments, X1 is C-R5, and R5 is C 1~6In yet another embodiment, a compound of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, is provided, wherein X is alkyl, X is N, and X is CH. 3~10

[0013] Provided are compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK) or (IL), or, as applicable, a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein X is N and X is CH. In other embodiments, provided are compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK) or (IL), or, as applicable, a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein X is N and X is C-R, where R is H and X is CH. In other embodiments, compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK) or (IL) are provided where X1 is N, X2 is C-R5, where R5 is cyano and X3 is CH, or, as applicable, a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. In other embodiments, X1 is N and X2 is C-R5, where R5 is C 6~20

[0023] In another embodiment, X is N and X is C-R, where R is C substituted with hydroxyl. 1~6

[0023] Provided are compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK) or (IL), or, as applicable, a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein X is alkyl and X is CH. In other embodiments, X is N and X is C-R, where R is C. 1~6

[0013] Provided are compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK) or (IL), or, as applicable, a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein X is alkoxy and X is CH. In other embodiments, provided are compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK) or (IL), or, as applicable, a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein X is N and X is C-R, where R is C(O)NH and X is CH. In other embodiments, compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK) or (IL), or, as applicable, stereoisomers, tautomers or pharmaceutically acceptable salts thereof, are provided wherein X1 and X2 are C-R5, where R5 are each H and X3 is CH. In other embodiments, compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK) or (IL), or, if applicable, a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, are provided wherein X1 is C-R5, R5 is H, and X2 is C-R5, where R5 is halo and X3 is CH. In still other embodiments, there is provided a compound of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK) or (IL), or, as applicable, a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein X1 is C-R5, where R5 is H, X2 is N and X3 is N.

[0097] In some embodiments, R1 is TIFF0007629916000061.tif20170, where Ra , R b and R c are each independently H, halo, cyano, hydroxyl, or C 1~6 Alkyl, C 6~20 aryl, 3- to 10-membered heterocyclyl, and 5- to 20-membered heteroaryl, wherein C 1~6 The alkyl may be further substituted with hydroxyl, provided that R a , R b and R c is H, and L is absent or selected from the group consisting of *-CH2-O-**, *-O-CH2-**, -CH=CH- and -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule, or, where permitted, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In certain embodiments, R1 is In some embodiments, a compound of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL) is TIFF0007629916000062.tif20170, or, where acceptable, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. a , R b and R c are each H. In another embodiment, R1 is TIFF0007629916000063.tif20170, where R a , R b and R c In some embodiments, one of R is cyano. TIFF0007629916000064.tif20170, where R a is H and R b is cyano and R cis H. In other embodiments, R1 is TIFF0007629916000065.tif20170, where R a , R b and R c One of them is C 6-20 In some embodiments, R is aryl. TIFF0007629916000066.tif20170, where R a is H and R b is H and R c is C 6~20 In another embodiment, R is aryl. TIFF0007629916000067.tif20170, where R a , R b and R c One of them is C 1~6 alkyl, C 1~6 The alkyl is further substituted with hydroxyl. In some embodiments, R1 is TIFF0007629916000068.tif20170, where R a is H and R b is H and R c is C 1~6 alkyl, C 1~6 The alkyl is further substituted with a hydroxyl.

[0098] In some embodiments, R1 is TIFF0007629916000069.tif16170, where R d H, halo, cyano, hydroxyl, C 1~6 Alkyl, C 6~20 aryl, 3- to 10-membered heterocyclyl, and 5- to 20-membered heteroaryl, wherein C 1~6Compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK) or (IL), or, where permitted, stereoisomers, tautomers or pharmaceutically acceptable salts thereof, are provided, wherein alkyl may be further substituted with hydroxyl, and L is selected from the group consisting of -O-, *-CH2-O-**, *-O-CH2-**, -CH=CH- and -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule. In certain embodiments, R1 is TIFF0007629916000070.tif16170, where R d is C 1~6 It is substituted with alkyl.

[0099] In some embodiments, R1 is and L is absent or selected from the group consisting of *-CH2-O-**, *-O-CH2-**, -CH=CH-, and -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule, or, where permitted, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, R1 is TIFF0007629916000073.tif16170 and L is absent. In some embodiments, R1 is TIFF0007629916000074.tif16170, and L is -CH=CH-. In other embodiments, R1 is TIFF0007629916000075.tif16170, and L is -CH-O-. In some embodiments, R is TIFF0007629916000076.tif16170, where L is -CH=CH-.

[0100] In some embodiments, R1 is and L is selected from the group consisting of -O-, *-CH2-O-**, *-O-CH2-**, -CH=CH-, and -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule, or, where permissible, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0101] In some embodiments, R is oxiranyl or oxetanyl, wherein the oxiranyl or oxetanyl is selected from one or more C 1~6 and optionally substituted with alkyl, wherein C 1~6

[0013] Compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, where permitted, are provided, wherein alkyl is optionally substituted with one or more -C(O)NH; and L is absent or selected from the group consisting of -O-, *-CH-O-**, *-O-CH-**, -CH=CH-**, and -C≡C-, where ** indicates the point of attachment to the R moiety and * indicates the point of attachment to the remainder of the molecule. In certain embodiments, L is absent. In some embodiments, R is oxiranyl, where oxiranyl is selected from one or more C 1~6 and optionally substituted with alkyl, wherein C 1~6The alkyl may be substituted with one or more -C(O)NH2. In some embodiments, R1 is oxiranyl, where the oxiranyl is unsubstituted. In some embodiments, R1 is oxiranyl, where the oxiranyl is one or more C 1~6 and optionally substituted with alkyl, wherein C 1~6 The alkyl may be substituted with one or more -C(O)NH2. In some embodiments, R1 is oxiranyl, where the oxiranyl is substituted with one or more methyl. In some embodiments, R1 is TIFF0007629916000078.tif12170. In other embodiments, R1 is TIFF0007629916000079.tif12170. In other embodiments, R1 is The file is TIFF0007629916000080.tif26170.

[0102] In certain embodiments, R is N(R e )(CN), where R e 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 6~20 aryl, and 3- to 20-membered heteroaryl; R e 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 6~20 aryl, and 3- to 20-membered heteroaryl are each independently C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6Compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, where permitted, are provided, wherein L is absent or selected from the group consisting of -O-, *-CH-O-**, *-O-CH-**, -CH=CH-, and -C≡C-, where ** indicates the point of attachment to the R moiety and * indicates the point of attachment to the remainder of the molecule, and optionally substituted with one or more substituents selected from the group consisting of alkoxy, oxo, cyano, halo, NO, and hydroxyl. In certain embodiments, L is absent. In some embodiments, R e is H or C 1~6 In certain embodiments, R e is H. In other embodiments, R e is C 1~6 In some embodiments, R 1 is methyl. In some embodiments, L is absent and R e is H. In other embodiments, L is absent and R e is C 1~6 In some embodiments, L is absent and R e is methyl.

[0103] In certain embodiments, compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL) are provided where L is -CH=CH-, or, where permitted, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In certain embodiments, the carbon-carbon double bond is such that the L moiety is -CH=CH-. In other embodiments, the carbon-carbon double bond is trans, such that the L moiety is In certain embodiments, the carbon-carbon double bond is cis, such that the L moiety is TIFF0007629916000083.tif10170. In other embodiments, the carbon-carbon double bond is E such that the L moiety It is Z, as is TIFF0007629916000084.tif13170.

[0104] In some embodiments, R2 is C 3~10 cycloalkyl, where C 3~10 Cycloalkyl is independently selected from cyano, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, NO2, SF5, N(R e )(R f ) and O(R e and each R e and R f However, independently, H, 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 6~20 aryl, and 3- to 20-membered heteroaryl, wherein 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 6~20 The aryl and the 3- to 20-membered heteroaryl are each independently C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6Provided are compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), or, where permitted, 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 C 3~10 cycloalkyl, where C 3~10 Cycloalkyl is a group consisting of 1, 2, 3 or 4 C 1~6 In some embodiments, R2 is cyclohexyl, wherein the cyclohexyl is optionally substituted with 1, 2, 3, or 4 CF3. In some embodiments, R2 is C 3~10 cycloalkyl, where C 3~10 Provided are compounds of Formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein cycloalkyl is optionally substituted with 1, 2, 3, or 4 halo. In some embodiments, R2 is cyclohexyl, wherein the cyclohexyl is optionally substituted with 1, 2, 3, or 4 F. In other embodiments, R2 is cyclobutyl, wherein the cyclobutyl is optionally substituted with 1, 2, 3, or 4 F.

[0105] In certain embodiments, R2 is C 5~13 In some embodiments, compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL) are provided, or, where permitted, stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein C 5~13 Spirocyclyl is The file is TIFF0007629916000085.tif18170.

[0106] In certain embodiments, R2 is C 1~12 alkyl, C 1~12 Alkyl is independently selected from cyano, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, NO2, SF5, N(R e )(R f ) and O(R e and each R e and R f However, independently, H, 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 6~20 aryl, and 3- to 20-membered heteroaryl, wherein 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 6~20 The aryl and the 3- to 20-membered heteroaryl are each independently C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6Provided are compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), or, where permitted, stereoisomers, tautomers, or pharmaceutically acceptable salts 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 methyl, and the methyl is substituted with cyclopentyl. In some embodiments, R is TIFF0007629916000086.tif20170. In another embodiment, R2 is The file is TIFF0007629916000087.tif16170.

[0107] In certain embodiments, R2 is C 6~20 aryl, where C 6~20 Aryl is independently cyano, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, NO2, SF5, N(R e )(R f ) and O(R e and each R e and R f However, independently, H, 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 6~20 aryl, and 3- to 20-membered heteroaryl, wherein 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, C6~20 The aryl and the 3- to 20-membered heteroaryl are each independently C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Provided are compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), or, where permitted, stereoisomers, tautomers, or pharmaceutically acceptable salts 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 is C 6~20 aryl, where C 6~20 The aryl may be substituted with 1, 2, 3, or 4 halo. In certain embodiments, R2 is C 6~20 aryl, where C 6~20 The aryl is substituted with 1, 2, 3, or 4 Cl. In other embodiments, R2 is C 6~20 aryl, where C 6~20 Aryl is a group consisting of 1, 2, 3 or 4 C 1~6 In some embodiments, R2 is phenyl, wherein the phenyl is substituted with 1, 2, 3, or 4 isopropyl. In some embodiments, R2 is phenyl, wherein the phenyl is substituted with 1, 2, 3, or 4 SF5.

[0108] In certain embodiments, R2 is a 3- to 10-membered saturated heterocyclyl, and the 3- to 10-membered saturated heterocyclyl is independently selected from cyano, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, NO2, SF5, N(R e )(R f ) and O(R e and each R e and R f However, independently, H, C 1~6 Alkyl, C2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 6~20 aryl, and 3- to 20-membered heteroaryl, wherein 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 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 Provided are compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), or, where permitted, 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 tetrahydropyran, wherein the tetrahydropyran has 1, 2, 3, or 4 C 1~6 In certain embodiments, C is substituted with haloalkyl. 1~6 Haloalkyl is CF3.

[0109] In some embodiments, R2 is tetrahydropyran substituted with CF3, and the stereochemistry of the -L-R2 moiety is

[0013] Provided is a compound of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R2 is (3S,6S) such that the -L-R2 moiety is As in TIFF0007629916000089.tif21170, it is (3R,6R).

[0110] In some embodiments, L is -CH=CH- and R is C 3~10 cycloalkyl, and R2 is C 3~10 Cycloalkyl is independently selected from cyano, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, NO2, SF5, N(R e )(R f ) and O(R e and each R e and R f However, independently, H, 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 6~20 aryl, and 3- to 20-membered heteroaryl, wherein 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 6~20 The aryl and the 3- to 20-membered heteroaryl are each independently C 1~6Alkyl, C 1~6 Haloalkyl, C 1~6 Provided are compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), or, where permitted, 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, L is -CH=CH- and R is C 3~10 cycloalkyl, where C 3~10 Cycloalkyl is a group consisting of 1, 2, 3 or 4 C 1~6 In some embodiments, L is -CH=CH- and R2 is cyclohexyl, where the cyclohexyl is optionally substituted with 1, 2, 3, or 4 CF3. In some embodiments, L is -CH=CH- and R2 is C 3~10 cycloalkyl, where C 3~10

[0013] Provided are compounds of Formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), or, where permitted, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein cycloalkyl is optionally substituted with 1, 2, 3, or 4 halo. In certain embodiments, L is -CH=CH- and R2 is cyclohexyl, wherein the cyclohexyl is optionally substituted with 1, 2, 3, or 4 F. In other embodiments, L is -CH=CH- and R2 is cyclobutyl, wherein the cyclobutyl is optionally substituted with 1, 2, 3, or 4 F.

[0111] In some embodiments, L is —CH—O— and R is C 5~13

[0013] Provided are compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), or, where permitted, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L is *-CH2-O-** and R2 is The file is TIFF0007629916000090.tif19170.

[0112] In some embodiments, L is —CH—O— and R is C 3~10 cycloalkyl, and R2 is C 3~10 Cycloalkyl is independently selected from cyano, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, NO2, SF5, N(R e )(R f ) and O(R e and each R e and R f However, independently, H, 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 6~20 aryl, and 3- to 20-membered heteroaryl, wherein 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 6~20 The aryl and the 3- to 20-membered heteroaryl are each independently C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6Provided are compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), or, where permitted, 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, L is —CH—O— and R is C 3~10 cycloalkyl, where C 3~10 Cycloalkyl is a group consisting of 1, 2, 3 or 4 C 1~6 In some embodiments, L is *-CH2-O-** and R2 is cyclohexyl, where the cyclohexyl is optionally substituted with 1, 2, 3, or 4 CF3. In some embodiments, L is *-CH2-O-** and R2 is C 3~10 cycloalkyl, where C 3~10

[0013] Provided are compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), or, where permitted, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein cycloalkyl is optionally substituted with 1, 2, 3, or 4 halo. In certain embodiments, L is *-CH2-O-** and R2 is cyclohexyl, wherein cyclohexyl is optionally substituted with 1, 2, 3, or 4 F.

[0113] In certain embodiments, L is absent and R2 is C 6~20 aryl, where C 6~20 Aryl is independently cyano, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, NO2, SF5, N(R e )(R f ) and O(R eand each R e and R f However, independently, H, 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 6~20 aryl, and 3- to 20-membered heteroaryl, wherein 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 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 Provided are compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), or, where permitted, 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 other embodiments, L is absent and R is C 6~20 aryl, where C 6~20 Aryl is a group consisting of 1, 2, 3 or 4 C 1~6 In some embodiments, L is absent, R2 is phenyl, and the phenyl is substituted with 1, 2, 3, or 4 isopropyl. In some embodiments, L is absent, R2 is phenyl, and the phenyl is substituted with 1, 2, 3, or 4 SF5.

[0114] In certain embodiments, L is -CH=CH- and R2 is a 3-10 membered saturated heterocyclyl, wherein the 3-10 membered saturated heterocyclyl is independently selected from cyano, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, NO2, SF5, N(R e )(R f ) and O(R e and each R e and R f However, independently, H, 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 6~20 aryl, and 3- to 20-membered heteroaryl, wherein 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 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

[0010] Provided are compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), or, where permitted, 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, L is -CH=CH- and R is tetrahydropyran, wherein the tetrahydropyran has 1, 2, 3, or 4 C 1~6 In certain embodiments, C is substituted with haloalkyl.1~6 Haloalkyl is CF3.

[0115] In certain embodiments, L is -CH=CH- and R is C 6~20 aryl, where C 6~20 Aryl is independently cyano, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, NO2, SF5, N(R e )(R f ) and O(R e each R is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of e and R f However, independently, H, 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 6~20 aryl, and 3- to 20-membered heteroaryl, wherein 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 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 Provided are compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), or, where permitted, 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, L is -CH=CH- and R is C6~20 aryl, where C 6~20 The aryl may be substituted with 1, 2, 3, or 4 halo. In some embodiments, L is -CH=CH- and R is C 6~20 aryl, where C 6~20 The aryl is substituted with 1, 2, 3 or 4 Cl.

[0116] In certain embodiments, L is -CH=CH- or -C≡C- and R is C 1~12 alkyl, C 1~12 Alkyl is independently selected from cyano, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, NO2, SF5, N(R e )(R f ) and O(R e and each R e and R f However, independently, H, 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 6~20 aryl, and 3- to 20-membered heteroaryl, wherein 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 6~20 The aryl and the 3- to 20-membered heteroaryl are each independently C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6Provided are compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK) or (IL), or, where permitted, stereoisomers, tautomers or pharmaceutically acceptable salts thereof, optionally substituted with one or more substituents selected from the group consisting of alkoxy, oxo, cyano, halo, NO and hydroxyl.

[0117] In certain embodiments, L is -CH=CH- and R is C 1~12 alkyl, C 1~12 Alkyl is independently selected from cyano, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, NO2, SF5, N(R e )(R f ) and O(R e and each R e and R f However, independently, H, 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 6~20 aryl, and 3- to 20-membered heteroaryl, wherein 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 6~20 The aryl and the 3- to 20-membered heteroaryl are each independently C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6Provided are compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK) or (IL), or, where permitted, stereoisomers, tautomers or pharmaceutically acceptable salts thereof, optionally substituted with one or more substituents selected from the group consisting of alkoxy, oxo, cyano, halo, NO and hydroxyl.

[0118] In other embodiments, L is -C≡C- and R is C 1~12 alkyl, C 1~12 Alkyl is independently selected from cyano, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, NO2, SF5, N(R e )(R f ) and O(R e and each R e and R f However, independently, H, 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 6~20 aryl, and 3- to 20-membered heteroaryl, wherein 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 6~20 The aryl and the 3- to 20-membered heteroaryl are each independently C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6Provided are compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK) or (IL), or, where permitted, stereoisomers, tautomers or pharmaceutically acceptable salts thereof, optionally substituted with one or more substituents selected from the group consisting of alkoxy, oxo, cyano, halo, NO and hydroxyl.

[0119] In certain embodiments, L is -CH=CH- and R is C 1~12 alkyl, C 1~12 Alkyl is independently selected from cyano, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, NO2, SF5, N(R e )(R f ) and O(R e and each R e and R f However, independently, H, 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 6~20 aryl, and 3- to 20-membered heteroaryl, wherein 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 6~20 The aryl and the 3- to 20-membered heteroaryl are each independently C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6Provided are compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), or, where permitted, stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, optionally substituted with one or more substituents selected from the group consisting of alkoxy, oxo, cyano, halo, NO, and hydroxyl. In some embodiments, L is -CH=CH- and R is methyl, wherein the methyl is substituted with cyclopentyl. In some embodiments, L is -CH=CH- and R is - TIFF0007629916000091.tif20170. In other embodiments, L is -CH=CH- and R2 is The file is TIFF0007629916000092.tif16170.

[0120] 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 In certain embodiments, R3 is optionally substituted with C 1~4 In certain embodiments, R3 is alkoxy. In certain embodiments, R3 is methoxy. In other embodiments, R3 is cyano.

[0121] In some embodiments, provided herein are compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK) or (IL), or, where permitted, stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein R3, together with R5 of X1 and the atom to which they are attached, form a 5-membered heterocyclyl or a 5-membered heteroaryl, with the proviso that X3 is CH.

[0122] In certain embodiments, R3, together with R5 of X1 and the atom to which they are attached, form a 5-membered heterocyclyl, provided that X3 is CH. In some embodiments, R3, together with R5 of X1 and the atom to which they are attached, form a 5-membered heterocyclyl, provided that X3 is CH, and the 5-membered heteroaryl contains 1, 2, 3, or 4 ring heteroatoms, each of which is independently selected from the group consisting of oxygen and nitrogen. In certain embodiments, R3, together with R5 of X1 and the atom to which they are attached, form a 5-membered heterocyclyl, provided that X3 is CH, and the 5-membered heterocyclyl contains 1, 2, 3, or 4 ring heteroatoms, the heteroatom being oxygen or nitrogen. In certain embodiments, R3, together with R5 of X1 and the atom to which they are attached, form a 5-membered heterocyclyl, provided that X3 is CH, and the 5-membered heterocyclyl contains 1, 2, 3, or 4 ring heteroatoms, the heteroatom being oxygen or nitrogen.

[0123] In some embodiments, R3 is cyano, C 1~6 Alkyl, C 1~4 Alkoxy or C 2~4 alkenyl, where C 2~4 Alkenyl is N(R e )(R f ), and R1 is TIFF0007629916000093.tif21170, and R2 is a 3- to 10-membered saturated heterocyclyl or a 5- to 20-membered heteroaryl, wherein the 3- to 10-membered saturated heterocyclyl or the 5- to 20-membered heteroaryl is independently 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 ) and O(R e), wherein L is *-CH2-O-**, -CH=CH- or -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the rest of the molecule. In one embodiment of the above, R1 is TIFF0007629916000094.tif20170. In one embodiment of the above, R1 is The file is TIFF0007629916000095.tif16170.

[0124] In some embodiments, R3, together with R5 of X1 and the atom to which they are attached, form a 5-membered heterocyclyl or 5-membered heteroaryl, wherein X3 is CH and R2 is TIFF0007629916000096.tif21170, and R2 is a 3- to 10-membered saturated heterocyclyl or a 5- to 20-membered heteroaryl, wherein the 3- to 10-membered saturated heterocyclyl or the 5- to 20-membered heteroaryl is independently 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 ) and O(R e ), wherein L is absent or is *-CH2-O-**, -CH=CH- or -C≡C, where ** indicates the point of attachment to R2 and * indicates the point of attachment to the rest of the molecule. In one embodiment of the above, R1 is TIFF0007629916000097.tif20170. In one embodiment of the above, R1 is The file is TIFF0007629916000098.tif16170.

[0125] In some embodiments, R3 together with the carbon atom of *-CH2-O-** of L and the atom to which they are attached form a C6 aryl or 6-membered heteroaryl, and R1 is TIFF0007629916000099.tif21170, and R2 is a 3- to 10-membered saturated heterocyclyl or a 5- to 20-membered heteroaryl, wherein the 3- to 10-membered saturated heterocyclyl or the 5- to 20-membered heteroaryl is independently 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 ) and O(R e In one embodiment of the above, R1 is optionally substituted with one or two substituents selected from the group consisting of TIFF0007629916000100.tif20170. In one embodiment of the above, R1 is The file is TIFF0007629916000101.tif16170.

[0126] In certain embodiments, compounds of Formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof are provided wherein R4 is H. In other embodiments, R4 is C 1~6 alkyl, C 1~6 The alkyl may be substituted with a hydroxyl.

[0127] In an embodiment, X1 is C-R5, where R5 is H, X2 is C-R5, where R5 is H, and X3 is CH.

[0128] In an embodiment, X1 is N and X2 is C-R5, where R5 is H and X3 is CH.

[0129] In an embodiment, X1 is C-R5, where R5 is H, X2 is N, and X3 is CH.

[0130] In an embodiment, X1 is N, X2 is N, and X3 is CH.

[0131] In an embodiment, R1 is TIFF0007629916000102.tif20170, where R a , R b and R c are H respectively.

[0132] In embodiments, L is -CH=CH- and R2 is halo, C 1~6 Alkyl, C 1~6 Haloalkyl, O(R e C optionally substituted with one or two substituents selected from the group consisting of SF5 3~10 It is cycloalkyl.

[0133] In an embodiment, L is -CH=CH- and R2 is C substituted with one or two halo. 3~10 It is cycloalkyl.

[0134] In an embodiment, L is -CH=CH- and R2 is C 1~6 Haloalkyl-substituted C 3~10 It is cycloalkyl.

[0135] In an embodiment, L is -CH=CH- and R2 is cyclohexyl substituted with CF3.

[0136] In an embodiment, L is -CH=CH- and R2 is cyclohexyl substituted with one or two fluoro.

[0137] In an embodiment, R3 is C 1~4 It is an alkoxy.

[0138] In an embodiment, R3 is methoxy.

[0139] In an embodiment, R4 is H.

[0140] In an embodiment, X1 is C-R5, where R5 is H, X2 is C-R5, where R5 is H, X3 is CH, and R1 is TIFF0007629916000103.tif20170, where R a , R b and R c are each H, L is -CH=CH-, and R2 is C 1~6 Haloalkyl-substituted C 3~10 cycloalkyl and R3 is C 1~4 alkoxy and R4 is H.

[0141] In an embodiment, X1 is C-R5, where R5 is H, X2 is C-R5, where R5 is H, X3 is CH, and R1 is TIFF0007629916000104.tif20170, where R a , R b and R c are each H, L is -CH=CH-, R2 is cyclohexyl substituted with CF3, R3 is methoxy, and R4 is H.

[0142] In an embodiment, X1 is C-R5, where R5 is H, X2 is C-R5, where R5 is H, X3 is CH, and R1 is TIFF0007629916000105.tif20170, where R a , R b and R c are each H, L is -CH=CH-, and R2 is C substituted with one or two halo groups. 3~10 cycloalkyl and R3 is C 1~4 alkoxy and R4 is H.

[0143] In an embodiment, X1 is C-R5, where R5 is H, X2 is C-R5, where R5 is H, X3 is CH, and R1 is TIFF0007629916000106.tif20170, where R a , R b and R c are each H, L is -CH=CH-, and R2 is C substituted with one or two fluoro groups. 3~10 is cycloalkyl, R3 is methoxy, and R4 is H.

[0144] In an embodiment, X1 is N and X2 is C-R5, where R5 is H, X3 is CH, and R1 is TIFF0007629916000107.tif20170, where R a , R b and R c are each H, L is -CH=CH-, and R2 is C 1~6 Haloalkyl-substituted C 3~10 cycloalkyl and R3 is C 1~4 alkoxy and R4 is H.

[0145] In an embodiment, X1 is N and X2 is C-R5, where R5 is H, X3 is CH, and R1 is TIFF0007629916000108.tif20170, where R a , R b and R c are each H, L is -CH=CH-, R2 is cyclohexyl substituted with CF3, R3 is methoxy, and R4 is H.

[0146] In an embodiment, X1 is N and X2 is C-R5, where R5 is H, X3 is CH, and R1 is TIFF0007629916000109.tif20170, where R a , R b and R c are each H, L is -CH=CH-, and R2 is C substituted with one or two halo groups. 3~10 cycloalkyl and R3 is C 1~4alkoxy and R4 is H.

[0147] In an embodiment, X1 is N and X2 is C-R5, where R5 is H, X3 is CH, and R1 is TIFF0007629916000110.tif20170, where R a , R b and R c are each H, L is -CH=CH-, and R2 is C substituted with one or two fluoro groups. 3~10 is cycloalkyl, R3 is methoxy, and R4 is H.

[0148] In an embodiment, X1 is C-R5, where R5 is H, X2 is N, X3 is CH, and R1 is TIFF0007629916000111.tif20170, where R a , R b and R c are each H, L is -CH=CH-, and R2 is C 1~6 Haloalkyl-substituted C 3~10 cycloalkyl and R3 is C 1~4 alkoxy and R4 is H.

[0149] In an embodiment, X1 is C-R5, where R5 is H, X2 is N, X3 is CH, and R1 is TIFF0007629916000112.tif20170, where R a , R b and R c are each H, L is -CH=CH-, R2 is cyclohexyl substituted with CF3, R3 is methoxy, and R4 is H.

[0150] In an embodiment, X1 is C-R5, where R5 is H, X2 is N, X3 is CH, and R1 is TIFF0007629916000113.tif20170, where R a, R b and R c are each H, L is -CH=CH-, and R2 is C substituted with one or two halo groups. 3~10 cycloalkyl and R3 is C 1~4 alkoxy and R4 is H.

[0151] In an embodiment, X1 is C-R5, where R5 is H, X2 is N, X3 is CH, and R1 is TIFF0007629916000114.tif20170, where R a , R b and R c are each H, L is -CH=CH-, and R2 is C substituted with one or two fluoro groups. 3~10 is cycloalkyl, R3 is methoxy, and R4 is H.

[0152] In an embodiment, X1 is N, X2 is N, X3 is CH, and R1 is TIFF0007629916000115.tif20170, where R a , R b and R c are each H, L is -CH=CH-, and R2 is C 1~6 Haloalkyl-substituted C 3~10 cycloalkyl and R3 is C 1~4 alkoxy and R4 is H.

[0153] In an embodiment, X1 is N, X2 is N, X3 is CH, and R1 is TIFF0007629916000116.tif20170, where R a , R b and R c are each H, L is -CH=CH-, and R2 is C substituted with CF3. 3~10 is cycloalkyl, R3 is methoxy, and R4 is H.

[0154] In an embodiment, X1 is N, X2 is N, X3 is CH, and R1 is TIFF0007629916000117.tif20170, where R a , R b and R c are each H, L is -CH=CH-, and R2 is C substituted with one or two halo groups. 3~10 cycloalkyl and R3 is C 1~4 alkoxy and R4 is H.

[0155] In an embodiment, X1 is N, X2 is N, X3 is CH, and R1 is TIFF0007629916000118.tif20170, where R a , R b and R c are each H, L is -CH=CH-, and R2 is C substituted with one or two fluoro groups. 3~10 is cycloalkyl, R3 is methoxy, and R4 is H.

[0156] In an embodiment, L is absent and R2 is C 1~6 Alkyl, C 1~6 Haloalkyl, SF5 and O(R e C optionally substituted with one or two substituents selected from the group consisting of 6~20 aryl, where R e C may be substituted with one or more halo 1~6 It is alkyl.

[0157] In an embodiment, L is absent and R2 is C 1~6 Alkyl-substituted C 6~20 It is aryl.

[0158] In an embodiment, L is absent and R2 is C 1~6 It is phenyl substituted with alkyl.

[0159] In an embodiment, L is absent and R2 is phenyl substituted with isopropyl.

[0160] In an embodiment, X1 is N, X2 is C-R5, where R5 is H or fluoro, X3 is CH, and R1 is TIFF0007629916000119.tif20170, where R a , R b and R c are each H, L is absent, and R2 is C 1~6 Alkyl, C 1~6 Haloalkyl, SF5 and O(R e C optionally substituted with one or two substituents selected from the group consisting of 6~20 aryl, where R e C may be substituted with one or more halo 1~6 alkyl and R3 is C 1~4 alkoxy and R4 is H.

[0161] In an embodiment, X1 is N, X2 is C-R5, where R5 is H or fluoro, X3 is CH, and R1 is TIFF0007629916000120.tif20170, where R a , R b and R c are each H, L is absent, and R2 is C 1~6 Alkyl-substituted C 6~20 aryl and R3 is C 1~4 alkoxy and R4 is H.

[0162] In an embodiment, X1 is N, X2 is C-R5, where R5 is H or fluoro, X3 is CH, and R1 is TIFF0007629916000121.tif20170, where R a , R b and R care each H, L is absent, R2 is phenyl substituted with isopropyl, R3 is methoxy, and R4 is H.

[0163] In embodiments, 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 a 5-membered heteroaryl, and the 5-membered heterocyclyl or 5-membered heteroaryl may be selected from one or more C 1~6 It may be substituted with alkyl.

[0164] In embodiments, X1 is C-R5, where R5 of X1 together with R3 and the atoms to which they are attached form one or more C 1~6 Forms a 5-membered heterocyclyl optionally substituted with alkyl.

[0165] In embodiments, X1 is C-R5, where R5 of X1 together with R3 and the atoms to which they are attached form one or more C 1~6 This forms a tetrahydrofuranyl which may be substituted with alkyl.

[0166] In an embodiment, X1 is C-R5, where R5 of X1 together with R3 and the atom to which they are attached form tetrahydrofuranyl optionally substituted with one methyl.

[0167] In embodiments, 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 a 5-membered heteroaryl, and the 5-membered heterocyclyl or 5-membered heteroaryl may be selected from one or more C 1~6 It may be substituted with alkyl, X2 is C-R5, where R5 is H or cyano, and X3 is CH.

[0168] In embodiments, X1 is C-R5, where R5 of X1 together with R3 and the atoms to which they are attached form one or more C1~6 Forms a 5-membered heterocyclyl optionally substituted with alkyl, wherein X2 is C-R5, where R5 is H or cyano, and X3 is CH.

[0169] In embodiments, X1 is C-R5, where R5 of X1 together with R3 and the atoms to which they are attached form one or more C 1~6 Forming an optionally alkyl-substituted tetrahydrofuranyl, X2 is C-R5, where R5 is H or cyano, and X3 is CH.

[0170] In an embodiment, X1 is C-R5, where R5 of X1 together with R3 and the atom to which they are attached form tetrahydrofuranyl optionally substituted with one methyl, X2 is C-R5, where R5 is H or cyano, and X3 is CH.

[0171] In embodiments, 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 a 5-membered heteroaryl, and the 5-membered heterocyclyl or 5-membered heteroaryl may be selected from one or more C 1~6 X2 is C-R5, where R5 is H, cyano, halo, or C optionally substituted with hydroxyl. 1~6 alkyl and X3 is CH.

[0172] In embodiments, X1 is C-R5, where R5 of X1 together with R3 and the atoms to which they are attached form one or more C 1~6 and X2 is C-R5, where R5 is H, cyano, halo, or C optionally substituted with hydroxyl. 1~6 alkyl and X3 is CH.

[0173] In embodiments, X1 is C-R5, where R5 of X1 together with R3 and the atoms to which they are attached form one or more C 1~6 and X2 is C-R5, where R5 is H, cyano, halo, or C optionally substituted with hydroxyl. 1~6 alkyl and X3 is CH.

[0174] In an embodiment, X1 is C-R5, where R5 of X1 together with R3 and the atoms to which they are attached form tetrahydrofuranyl optionally substituted with one methyl, and X2 is C-R5, where R5 is H, cyano, halo, or C optionally substituted with hydroxyl. 1~6 alkyl and X3 is CH.

[0175] In embodiments, 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 a 5-membered heteroaryl, and the 5-membered heterocyclyl or 5-membered heteroaryl may be selected from one or more C 1~6 X2 is C-R5, where R5 is H, cyano, halo, or C optionally substituted with hydroxyl. 1~6 is alkyl, X3C-H, and R1 is TIFF0007629916000122.tif20170, where R a , R b and R c are H respectively.

[0176] In embodiments, X1 is C-R5, where R5 of X1 together with R3 and the atoms to which they are attached form one or more C 1~6 and X2 is C-R5, where R5 is H, cyano, halo, or C optionally substituted with hydroxyl. 1~6 alkyl, X3 is CH, and R1 is TIFF0007629916000123.tif20170, where R a , R b and R c are H respectively.

[0177] In embodiments, X1 is C-R5, where R5 of X1 together with R3 and the atoms to which they are attached form one or more C 1~6 and X2 is C-R5, where R5 is H, cyano, halo, or C optionally substituted with hydroxyl. 1~6 alkyl, X3 is CH, and R1 is TIFF0007629916000124.tif20170, where R a , R b and R c are H respectively.

[0178] In an embodiment, X1 is C-R5, where R5 of X1 together with R3 and the atom to which they are attached form tetrahydrofuranyl optionally substituted with one methyl, and R1 is TIFF0007629916000125.tif20170, where R a , R b and R c are H respectively.

[0179] In embodiments, 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 a 5-membered heteroaryl, and the 5-membered heterocyclyl or 5-membered heteroaryl may be selected from one or more C 1~6 X2 is C-R5, where R5 is H, cyano, halo, or C optionally substituted with hydroxyl. 1~6 alkyl, X3 is CH, and R1 is TIFF0007629916000126.tif20170, where R a , Rb and R c are H, and R4 is H or C 1~6 alkyl, where C 1~6 The alkyl may be substituted with a hydroxyl.

[0180] In embodiments, X1 is C-R5, where R5 of X1 together with R3 and the atoms to which they are attached form one or more C 1~6 and X2 is C-R5, where R5 is H, cyano, halo, or C optionally substituted with hydroxyl. 1~6 alkyl, X3 is CH, and R1 is TIFF0007629916000127.tif20170, where R a , R b and R c are H, and R4 is H or C 1~6 alkyl, where C 1~6 The alkyl may be substituted with a hydroxyl.

[0181] In embodiments, X1 is C-R5, where R5 of X1 together with R3 and the atoms to which they are attached form one or more C 1~6 and X2 is C-R5, where R5 is H, cyano, halo, or C optionally substituted with hydroxyl. 1~6 alkyl, X3 is CH, and R1 is TIFF0007629916000128.tif20170, where R a , R b and R c are H, and R4 is H or C 1~6 alkyl, where C 1~6 The alkyl may be substituted with a hydroxyl.

[0182] In an embodiment, X1 is C-R5, where R5 of X1 together with R3 and the atoms to which they are attached form tetrahydrofuranyl optionally substituted with one methyl, and X2 is C-R5, where R5 is H, cyano, halo, or C optionally substituted with hydroxyl. 1~6 alkyl, X3 is CH, and R1 is TIFF0007629916000129.tif20170, where R a , R b and R c are H, and R4 is H or C 1~6 alkyl, where C 1~6 The alkyl may be substituted with a hydroxyl.

[0183] In an embodiment, R is a C(O)NH group optionally further substituted with -C(O)NH 1~6 It is oxiranyl which may be substituted with alkyl.

[0184] In embodiments, R is N(R e )(CN).

[0185] In some embodiments, R1 is TIFF0007629916000130.tif20170, where R a , R b and R c are each independently H, cyano, or C 1~6 Alkyl, C 6~20 aryl, wherein C 1~6 The alkyl may be further substituted with hydroxyl, provided that R a , R b and R c At least two of these are H.

[0186] In an embodiment, R1 is TIFF0007629916000131.tif16170, where R d is H.

[0187] In an embodiment, R is a C(O)NH group optionally further substituted with -C(O)NH 1~6 R4 is H or C 1~6 alkyl, where C 1~6 The alkyl may be substituted with a hydroxyl.

[0188] In embodiments, R is N(R e )(CN), and R4 is H or C 1~6 alkyl, where C 1~6 The alkyl may be substituted with a hydroxyl.

[0189] In an embodiment, R1 is TIFF0007629916000132.tif20170, where R a , R b and R c are each independently H, cyano, or C 1~6 Alkyl, C 6~20 aryl, wherein C 1~6 The alkyl may be further substituted with hydroxyl, provided that R a , R b and R c At least two of are H, and R4 is H or C 1~6 alkyl, where C 1~6 The alkyl may be substituted with a hydroxyl.

[0190] In an embodiment, R1 is TIFF0007629916000133.tif16170, R d is H and R4 is H or C 1~6 alkyl, where C 1~6 The alkyl may be substituted with a hydroxyl.

[0191] In embodiments, 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 a 5-membered heteroaryl, and the 5-membered heterocyclyl or 5-membered heteroaryl may be selected from one or more C 1~6 X2 is C-R5, where R5 is H or cyano, X3 is CH, and R1 is C(O)NH2, which may be further substituted with -C(O)NH2. 1~6 It is oxiranyl which may be substituted with alkyl.

[0192] In embodiments, X1 is C-R5, where R5 of X1 together with R3 and the atoms to which they are attached form one or more C 1~6 and X2 is C-R5, where R5 is H or cyano, X3 is CH, and R1 is C-(O)NH2, optionally further substituted with -C(O)NH2. 1~6 It is oxiranyl which may be substituted with alkyl.

[0193] In embodiments, X1 is C-R5, where R5 of X1 together with R3 and the atoms to which they are attached form one or more C 1~6 and forming a tetrahydrofuranyl optionally substituted with alkyl, wherein X2 is C-R5, where R5 is H or cyano, X3 is CH, and R1 is C-substituted or substituted with -C(O)NH2. 1~6 It is oxiranyl which may be substituted with alkyl.

[0194] In an embodiment, X1 is C-R5, where R5 of X1 together with R3 and the atom to which they are attached form tetrahydrofuranyl optionally substituted with one methyl, X2 is C-R5, where R5 is H or cyano, X3 is CH, and R1 is C-R5 optionally further substituted with -C(O)NH2. 1~6 It is oxiranyl which may be substituted with alkyl.

[0195] In embodiments, 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 a 5-membered heteroaryl, and the 5-membered heterocyclyl or 5-membered heteroaryl may be selected from one or more C 1~6 X2 is C-R5, where R5 is cyano, X3 is CH, and R1 is C(O)NH2, which may be further substituted with alkyl. 1~6 oxiranyl optionally substituted with alkyl, L is absent, and R2 is C 1~6 Alkyl-substituted C 6~20 It is aryl.

[0196] In embodiments, X1 is C-R5, where R5 of X1 together with R3 and the atoms to which they are attached form one or more C 1~6 and X2 is C-R5, where R5 is H or cyano, X3 is CH, and R1 is C-(O)NH2, optionally further substituted with -C(O)NH2. 1~6 oxiranyl optionally substituted with alkyl, L is absent, and R2 is C 1~6 Alkyl-substituted C 6~20 It is aryl.

[0197] In embodiments, X1 is C-R5, where R5 of X1 together with R3 and the atoms to which they are attached form one or more C 1~6 and forming a tetrahydrofuranyl optionally substituted with alkyl, wherein X2 is C-R5, where R5 is H or cyano, X3 is CH, and R1 is C-substituted or substituted with -C(O)NH2. 1~6 oxiranyl optionally substituted with alkyl, L is absent, and R2 is C 1~6 Alkyl-substituted C 6~20 It is aryl.

[0198] In an embodiment, X1 is C-R5, where R5 of X1 together with R3 and the atom to which they are attached form tetrahydrofuranyl optionally substituted with one methyl, X2 is C-R5, where R5 is H or cyano, X3 is CH, and R1 is C-R5 optionally further substituted with -C(O)NH2. 1~6 oxiranyl optionally substituted with alkyl, L is absent, and R2 is C 1~6 Alkyl-substituted C 6~20 It is aryl.

[0199] In embodiments, 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 a 5-membered heteroaryl, and the 5-membered heterocyclyl or 5-membered heteroaryl may be selected from one or more C 1~6 X2 is C-R5, where R5 is cyano, X3 is CH, and R1 is C(O)NH2, which may be further substituted with alkyl. 1~6 oxiranyl optionally substituted with alkyl, L is absent, and R2 is C 1~6 It is phenyl substituted with alkyl.

[0200] In embodiments, X1 is C-R5, where R5 of X1 together with R3 and the atoms to which they are attached form one or more C 1~6 and X2 is C-R5, where R5 is H or cyano, X3 is CH, and R1 is C-(O)NH2, optionally further substituted with -C(O)NH2. 1~6 oxiranyl optionally substituted with alkyl, L is absent, and R2 is C substituted with C alkyl. 6~20 It is aryl.

[0201] In embodiments, X1 is C-R5, where R5 of X1 together with R3 and the atoms to which they are attached form one or more C 1~6and forming a tetrahydrofuranyl optionally substituted with alkyl, wherein X2 is C-R5, where R5 is H or cyano, X3 is CH, and R1 is C-substituted or substituted with -C(O)NH2. 1~6 oxiranyl optionally substituted with alkyl, L is absent, and R2 is C 1~6 It is phenyl substituted with alkyl.

[0202] In an embodiment, X1 is C-R5, where R5 of X1 together with R3 and the atom to which they are attached form tetrahydrofuranyl optionally substituted with one methyl, X2 is C-R5, where R5 is H or cyano, X3 is CH, and R1 is C-R5 optionally further substituted with -C(O)NH2. 1~6 oxiranyl optionally substituted with alkyl, L is absent, and R2 is C 1~6 It is phenyl substituted with alkyl.

[0203] In embodiments, 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 a 5-membered heteroaryl, and the 5-membered heterocyclyl or 5-membered heteroaryl may be selected from one or more C 1~6 X2 is C-R5, where R5 is cyano, X3 is CH, and R1 is C(O)NH2, which may be further substituted with alkyl. 1~6 It is oxiranyl optionally substituted with alkyl, L is absent, and R2 is phenyl substituted with isopropyl.

[0204] In embodiments, X1 is C-R5, where R5 of X1 together with R3 and the atoms to which they are attached form one or more C 1~6 and X2 is C-R5, where R5 is H or cyano, X3 is CH, and R1 is C-(O)NH2, optionally further substituted with -C(O)NH2. 1~6It is oxiranyl optionally substituted with alkyl, L is absent, and R2 is phenyl substituted with isopropyl.

[0205] In embodiments, X1 is C-R5, where R5 of X1 together with R3 and the atoms to which they are attached form one or more C 1~6 and forming a tetrahydrofuranyl optionally substituted with alkyl, wherein X2 is C-R5, where R5 is H or cyano, X3 is CH, and R1 is C-substituted or substituted with -C(O)NH2. 1~6 It is oxiranyl optionally substituted with alkyl, L is absent, and R2 is phenyl substituted with isopropyl.

[0206] In an embodiment, X1 is C-R5, where R5 of X1 together with R3 and the atom to which they are attached form tetrahydrofuranyl optionally substituted with one methyl, X2 is C-R5, where R5 is H or cyano, X3 is CH, and R1 is C-R5 optionally further substituted with -C(O)NH2. 1~6 It is oxiranyl optionally substituted with alkyl, L is absent, and R2 is phenyl substituted with isopropyl.

[0207] In embodiments, 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 a 5-membered heteroaryl, and the 5-membered heterocyclyl or 5-membered heteroaryl may be selected from one or more C 1~6 X2 is C-R5, where R5 is cyano, X3 is CH, and R1 is C(O)NH2, which may be further substituted with alkyl. 1~6 oxiranyl optionally substituted with alkyl, L is -CH=CH-, R2 is halo, C 1~6 Alkyl, C 1~6 Haloalkyl, O(R eC optionally substituted with one or two substituents selected from the group consisting of SF5 3~10 It is cycloalkyl.

[0208] In embodiments, X1 is C-R5, where R5 of X1 together with R3 and the atoms to which they are attached form one or more C 1~6 and X2 is C-R5, where R5 is H or cyano, X3 is CH, and R1 is C-(O)NH2, optionally further substituted with -C(O)NH2. 1~6 oxiranyl optionally substituted with alkyl, L is -CH=CH-, R2 is halo, C 1~6 Alkyl, C 1~6 Haloalkyl, O(R e C optionally substituted with one or two substituents selected from the group consisting of SF5 3~10 It is cycloalkyl.

[0209] In embodiments, X1 is C-R5, where R5 of X1 together with R3 and the atoms to which they are attached form one or more C 1~6 and forming a tetrahydrofuranyl optionally substituted with alkyl, wherein X2 is C-R5, where R5 is H or cyano, X3 is CH, and R1 is C-substituted or substituted with -C(O)NH2. 1~6 oxiranyl optionally substituted with alkyl, L is -CH=CH-, R2 is halo, C 1~6 Alkyl, C 1~6 Haloalkyl, O(R e C optionally substituted with one or two substituents selected from the group consisting of SF5 3~10 It is cycloalkyl.

[0210] In embodiments, X1 is C-R5, where R5 of X1 together with R3 and the atoms to which they are attached form one or more C 1~6and forming a tetrahydrofuranyl optionally substituted with alkyl, wherein X2 is C-R5, where R5 is H or cyano, X3 is CH, and R1 is C-substituted or substituted with -C(O)NH2. 1~6 oxiranyl optionally substituted with alkyl, L is -CH=CH-, R2 is halo, C 1~6 Alkyl, C 1~6 Haloalkyl, O(R e C optionally substituted with one or two substituents selected from the group consisting of SF5 3~10 It is cycloalkyl.

[0211] In embodiments, 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 a 5-membered heteroaryl, and the 5-membered heterocyclyl or 5-membered heteroaryl may be selected from one or more C 1~6 X2 is C-R5, where R5 is cyano, X3 is CH, and R1 is C(O)NH2, which may be further substituted with alkyl. 1~6 and R2 is a C substituted with one or two substituents selected from the group consisting of halo. 3~10 It is cycloalkyl.

[0212] In embodiments, X1 is C-R5, where R5 of X1 together with R3 and the atoms to which they are attached form one or more C 1~6 and X2 is C-R5, where R5 is H or cyano, X3 is CH, and R1 is C-(O)NH2, optionally further substituted with -C(O)NH2. 1~6 and R2 is a C substituted with one or two substituents selected from the group consisting of halo. 3~10 It is cycloalkyl.

[0213] In embodiments, X1 is C-R5, where R5 of X1 together with R3 and the atoms to which they are attached form one or more C 1~6 and R1 is C--R5, where R5 is H or cyano, X3 is CH, and R1 is C--R5, which may be further substituted with -C(O)NH2. 1~6 and R2 is a C substituted with one or two substituents selected from the group consisting of halo. 3~10 It is cycloalkyl.

[0214] In an embodiment, X1 is C-R5, where R5 of X1 together with R3 and the atom to which they are attached form tetrahydrofuranyl optionally substituted with one methyl, X2 is C-R5, where R5 is H or cyano, X3 is CH, and R1 is C-R5 optionally further substituted with —C(O)NH2. 1~6 and R2 is a C substituted with one or two substituents selected from the group consisting of halo. 3~10 It is cycloalkyl.

[0215] In embodiments, 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 a 5-membered heteroaryl, and the 5-membered heterocyclyl or 5-membered heteroaryl may be selected from one or more C 1~6 X2 is C-R5, where R5 is cyano, X3 is CH, and R1 is C(O)NH2, which may be further substituted with alkyl. 1~6 It is oxiranyl optionally substituted with alkyl, L is -CH=CH-, and R2 is cyclohexyl substituted with one or two fluoro groups.

[0216] In embodiments, X1 is C-R5, where R5 of X1 together with R3 and the atoms to which they are attached form one or more C 1~6 and X2 is C-R5, where R5 is H or cyano, X3 is CH, and R1 is C-(O)NH2, optionally further substituted with -C(O)NH2. 1~6 It is oxiranyl optionally substituted with alkyl, L is -CH=CH-, and R2 is cyclohexyl substituted with one or two fluoro groups.

[0217] In embodiments, X1 is C-R5, where R5 of X1 together with R3 and the atoms to which they are attached form one or more C 1~6 and forming a tetrahydrofuranyl optionally substituted with alkyl, wherein X2 is C-R5, where R5 is H or cyano, X3 is CH, and R1 is C-substituted or substituted with -C(O)NH2. 1~6 It is oxiranyl optionally substituted with alkyl, L is -CH=CH-, and R2 is cyclohexyl substituted with one or two fluoro groups.

[0218] In an embodiment, X1 is C-R5, where R5 of X1 together with R3 and the atom to which they are attached form tetrahydrofuranyl optionally substituted with one methyl, X2 is C-R5, where R5 is H or cyano, X3 is CH, and R1 is C-R5 optionally further substituted with -C(O)NH2. 1~6 It is oxiranyl optionally substituted with alkyl, L is -CH=CH-, and R2 is cyclohexyl substituted with one or two fluoro groups.

[0219] In embodiments, L is *-CH2-O-**, where ** indicates the point of attachment to the R2 moiety, * indicates the point of attachment to the remainder of the molecule, and R2 is C 1~6 Haloalkyl-substituted C 3~10 It is cyclohexyl.

[0220] In an embodiment, L is *-CH2-O-**, where ** indicates the point of attachment to the R2 moiety, * indicates the point of attachment to the remainder of the molecule, and R2 is cyclohexyl substituted with CF3.

[0221] In embodiments, L is *-CH2-O-**, where ** indicates the point of attachment to the R2 moiety, * indicates the point of attachment to the remainder of the molecule, and R2 is a C substituted with one or two halo. 3~10 It is cyclohexyl.

[0222] In an embodiment, L is *-CH2-O-**, where ** indicates the point of attachment to the R2 moiety, * indicates the point of attachment to the remainder of the molecule, and R2 is cyclohexyl substituted with one or two fluoros.

[0223] In embodiments, L is *-CH2-O-**, where ** indicates the point of attachment to the R2 moiety, * indicates the point of attachment to the remainder of the molecule, and R2 is C 5~13 It is a spirocyclyl.

[0224] In an embodiment, L is *-CH2-O-**, where ** indicates the point of attachment to the R2 moiety, * indicates the point of attachment to the remainder of the molecule, and R2 is spirohexane.

[0225] In an embodiment, L is -CH=CH- and R is C 1~12 It is alkyl.

[0226] In an embodiment, L is -CH=CH- and R2 is C 3~10 Cycloalkyl-substituted C 1~12 It is alkyl.

[0227] In some embodiments, L is CH=CH- and R2 is methylene substituted with cyclopentyl.

[0228] In an embodiment, L is -CH=CH- and R2 is C 1~6 It is a 3- to 10-membered saturated heterocyclyl substituted with haloalkyl.

[0229] In an embodiment, L is CH=CH- and R2 is tetrahydropyran substituted with CF3.

[0230] In some embodiments, the compounds described herein, such as compounds of Formula (B-1), Formula (B) or Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, are selected from the compounds listed in Table 1 below, including racemic mixtures, resolved isomers, tautomers, and pharmaceutically acceptable salts thereof: [Table 1] TIFF0007629916000135.tif252170TIFF0007629916000136.tif222170TIFF000 7629916000137.tif239170TIFF0007629916000138.tif228170TIFF0007629916 000139.tif240170TIFF0007629916000140.tif222170TIFF0007629916000141. tif249170TIFF0007629916000142.tif240170TIFF0007629916000143.tif97170

[0231] 3-cyano-N-(5-methoxy-4-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)pyridin-2-yl)acrylamide; N-(6-methoxy-5-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)pyridin-3-yl)acrylamide; N-(6-methoxy-5-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)pyridin-3-yl)but-2-ynamide; N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-6-methoxypyridin-3-yl)acrylamide; N-(6-methoxy-5-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)pyridazin-3-yl)acrylamide; N-(5-methoxy-4-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)pyridin-2-yl)acrylamide; N-(4-(2-(4,4-difluorocyclohexyl)vinyl)-5-methoxypyridin-2-yl)acrylamide; N-(5-methoxy-6-methyl-4-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)pyridin-2-yl)acrylamide; N-(6-methoxy-5-(((4-(trifluoromethyl)cyclohexyl)oxy)methyl)pyridin-3-yl)acrylamide; N-(5-(((4,4-difluorocyclohexyl)oxy)methyl)-6-methoxypyridin-3-yl)acrylamide; N-(6-methoxy-5-((spiro[2.3]hexan-5-yloxy)methyl)pyridin-3-yl)acrylamide; N-(6-cyclopropyl-5-methoxy-4-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)pyridin-2-yl)acrylamide; N-(2-cyano-6-methoxy-5-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)pyridin-3-yl)acrylamide; N-(3-(3-cyclopentylprop-1-en-1-yl)-4-methoxyphenyl)acrylamide; N-(2-hydroxyethyl)-N-(5-methoxy-4-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)pyridin-2-yl)acrylamide; N-(4-fluoro-4'-isopropyl-6-methoxy-[1,1'-biphenyl]-3-yl)acrylamide; N-(7-(4-chlorostyryl)-2,3-dihydrobenzofuran-5-yl)acrylamide; N-(6-methoxy-5-(4-methylpent-1-en-1-yl)pyridin-3-yl)acrylamide; N-(5-(2-(3,3-difluorocyclobutyl)vinyl)-6-methoxypyridin-3-yl)acrylamide; N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-6-methoxypyridin-3-yl)-2-phenylacrylamide; 3-cyano-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-6-methoxypyridin-3-yl)acrylamide; N-(4-methoxy-3-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)phenyl)acrylamide; N-(3-(2-(4,4-difluorocyclohexyl)vinyl)-4-methoxyphenyl)acrylamide; N-(6-methoxy-2-phenyl-5-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)pyridin-3-yl)acrylamide; N-(2-(hydroxymethyl)-6-methoxy-5-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)pyridin-3-yl)acrylamide; N-(2,6-dimethoxy-5-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)pyridin-3-yl)acrylamide; N-(4-(2-(4,4-difluorocyclohexyl)vinyl)-5-methoxypyrimidin-2-yl)acrylamide; 3-acrylamido-6-methoxy-5-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)picolinamide; N-(5-cyano-4-(2-(4,4-difluorocyclohexyl)vinyl)pyridin-2-yl)acrylamide; 2-(hydroxymethyl)-N-(6-methoxy-5-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)pyridin-3-yl)acrylamide; N-(6-cyano-5-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)pyridin-3-yl)-2-(hydroxymethyl)acrylamide; N-(7-(2-(4,4-difluorocyclohexyl)vinyl)-2,3-dihydrobenzofuran-5-yl)acrylamide; N-(7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)acrylamide; N-(7-(((4-(trifluoromethyl)cyclohexyl)oxy)methyl)-2,3-dihydrobenzofuran-5-yl)acrylamide; N-(7-(2-(4,4-difluorocyclohexyl)vinyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)acrylamide; N-(7-(2-(4,4-difluorocyclohexyl)vinyl)-2,3-dihydrobenzofuran-5-yl)-N-(2-hydroxyethyl)acrylamide; N-(7-(2-(4,4-difluorocyclohexyl)vinyl)-4-fluoro-2,3-dihydrobenzofuran-5-yl)acrylamide; N-(5-((4-(trifluoromethyl)cyclohexyl)oxy)quinolin-3-yl)acrylamide; N-(5-((4-(trifluoromethyl)cyclohexyl)oxy)-1,6-naphthyridin-3-yl)acrylamide; N-(7-(2-(4,4-difluorocyclohexyl)vinyl)benzo[d]oxazol-5-yl)acrylamide; N-(5-(4-isopropylphenyl)-6-methoxypyridin-3-yl)acrylamide; N-(6-methoxy-5-(2-(6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)vinyl)pyridin-3-yl)acrylamide; N-(4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)-2-methyloxirane-2-carboxamide; N-(4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)-2-methyloxirane-2-carboxamide; N-(4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)oxirane-2-carboxamide; N-(4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)oxirane-2-carboxamide; 3-(4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)-1-cyano-1-methylurea; 1-(4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)-3-cyano-1-methylurea; N-(4-cyano-7-(4-(1,1-difluoroethyl)phenyl)-2,3-dihydrobenzofuran-5-yl)oxirane-2-carboxamide; N-(4-cyano-7-(4-(1,1-difluoroethyl)phenyl)-2,3-dihydrobenzofuran-5-yl)oxirane-2-carboxamide; N-(4-cyano-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzofuran-5-yl)oxirane-2-carboxamide; N-(4-cyano-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzofuran-5-yl)oxirane-2-carboxamide; N-(4-(hydroxymethyl)-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzofuran-5-yl)acrylamide; 2-(3-amino-3-oxopropyl)-N-(4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)oxirane-2-carboxamide; N-[4-(hydroxymethyl)-7-[4-(pentafluoro-6-sulfanyl)phenyl]-2,3-dihydrobenzofuran-5-yl]prop-2-enamide; and N-(7-cyano-4-(4-(trifluoromethoxy)phenyl)benzo[d]thiazol-6-yl)acrylamide, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. Also provided herein are any and all stereoisomers of the compounds presented herein, including, where applicable, their geometric isomers (e.g., cis / trans or E / Z isomers), enantiomers, diastereomers, or mixtures in any ratio, including racemic mixtures.

[0232] 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 (B-1), formula (B) 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 (B-1), formula (B) or formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, respectively, such as 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 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 (B-1), formula (B) or formula (I), for example, compounds 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., 14C are particularly useful for this purpose given their ease of incorporation and ready means of detection. For example, compounds of Formula (B-1), Formula (B) or Formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95 or 99% of a given isotope.

[0233] 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.

[0234] 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 (B-1), Formula (B), or Formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the Examples set forth below, substituting appropriate isotopically labeled reagents for the previously employed non-isotopically labeled reagents.

[0235] 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

[0236] 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).

[0237] 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.

[0238] Carriers can 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 (when isotonic with blood) for liquid injectables. 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, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. The compositions may contain conventional pharmaceutical additives, 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.

[0239] 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 delivery site of the agent, 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.

[0240] 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, with a typical initial range of the compound used being 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 1400 mg. This dosing regimen can be adjusted to provide the optimal therapeutic response. The compound can be administered one to four times daily, preferably one to two times daily.

[0241] The compounds of the present disclosure may be administered in any convenient dosage form, such as, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions contain elements common in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and additional active agents.

[0242] 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 diluents, 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; alkyl parabens such as methyl or propyl paraben; 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 (B-1), Formula (B), or Formula (I), or embodiments or aspects thereof) can also be encapsulated in microcapsules, such as hydroxymethylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules, respectively, prepared, for example, 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 described in "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.

[0243] Sustained-release preparations of the compounds of the present disclosure (e.g., compounds of Formula (B-1), Formula (B) 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 (B-1), Formula (B) 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)), polylactide (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. 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 Pat. No. 133,988). Sustained-release compositions also include liposome-encapsulated compounds, which 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. Patent Nos. 4,485,045 and 4,544,545; European Patent No. 102,324A). Typically, liposomes are small (approximately 200-800 angstroms), unilamellar, with a lipid content of more than about 30 mol% cholesterol, the ratio selected being adjusted for optimal treatment.

[0244] 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 concentration of the compound, 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 an 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.

[0245] 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.

[0246] 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.

[0247] 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 can be accepted.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. Tablets may be uncoated or 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.

[0248] 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 disclosure (or thereof) 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). The present invention relates to a tablet containing a compound of formula (I) or (II). Wet granulation, dry granulation, or dry blending can 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 can be dried, granulated, mixed with a lubricant, and compressed into tablet form using conventional equipment. An example aerosol formulation can 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 adding a tonicifier, e.g., a salt such as sodium chloride, if desired. The solution may be filtered, for example, using a 0.2 micron filter, to remove impurities and contaminants.

[0249] 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 w / w%. When formulated in an ointment, the compound of the present disclosure can be used with either a paraffinic or water-miscible ointment base. Alternatively, the compound of the present disclosure can be formulated into a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base can 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 can 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.

[0250] 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.

[0251] 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.

[0252] 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.

[0253] 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.

[0254] Methods of circumvention 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).

[0255] 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).

[0256] 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).

[0257] 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).

[0258] 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 by continuous administration means, such as the use of an indwelling catheter and a pump, or 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, including continuous intraventricular infusion via subcutaneous pump devices or fully implanted drug delivery systems, are those used for the administration of dopamine, dopamine agonists, and cholinergic agonists to Alzheimer's disease patients and animal models of Parkinson's disease, as described in Harbaugh, J. Neural Transm. Suppl. 24:271, 1987; and DeYebenes et al., Mov. Disord. 2:143, 1987. Indications and Treatment Methods

[0259] Representative compounds of the present disclosure have been shown to modulate TEAD activity. In some embodiments, the compound that modulates TEAD activity has formula (C-1): TIFF0007629916000144.tif32170[In the formula, X1 is N or C-R5, where 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, wherein R5 is C 1~6Alkyl is hydroxyl or N(R e )(R f ), or R5 of X1 together with R3 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 selected from the group consisting of one or more C 1~6 may be substituted with alkyl, X2 and X3 are each independently N or C-R5, where 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, wherein R5 is C 1~6 Alkyl is hydroxyl or N(R e )(R f ), X3 is N or CH; R1 is (i) oxiranyl or oxetanyl, wherein the oxiranyl or oxetanyl is one or more C 1~6 and optionally substituted with alkyl, wherein C 1~6 The alkyl may be substituted with one or more -C(O)NH2, or (ii) N(R e )(CN), or (iii) TIFF0007629916000145.tif20170, where R a , R b and R c are each independently H, halo, cyano, hydroxyl, or C 1~6 Alkyl, C 6~20 aryl, 3- to 10-membered heterocyclyl, and 5- to 20-membered heteroaryl, wherein C 1~6 The alkyl may be further substituted with a hydroxyl, or (iv) TIFF0007629916000146.tif16170, where R d is H, halo, cyano, hydroxyl, C 1~6 Alkyl, C 6~20 aryl, 3- to 10-membered heterocyclyl, and 5- to 20-membered heteroaryl, wherein C 1~6 The alkyl may be further substituted with hydroxyl; L is absent or selected from the group consisting of -O-, *-CH2-O-**, *-O-CH2-**, -CH=CH-, and -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule; R2 is C 1~12 Alkyl, C 3~10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 6~20 Aryl, C 5~13 spirocyclyl, or 5- to 20-membered heteroaryl, wherein R2 C 1~12 Alkyl, C 3~10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 6~20 Aryl, C 5~13 The spirocyclyl 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 SF5, 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, wherein the 5-membered heterocyclyl or 5-membered heteroaryl is selected from one or more C 1~6 and optionally substituted with alkyl, provided that X3 is CH, or R3 together with the carbon atoms of *-CH2-O-** of L and the atoms 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 of 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 6~20 aryl, and 3- to 20-membered heteroaryl, wherein 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 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 and 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.

[0260] In some embodiments, the compound that modulates TEAD activity has formula (C): TIFF0007629916000147.tif32170[In the formula, X1 is N or C-R5, where 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, wherein R5 is C 1~6 Alkyl is hydroxyl or N(R e )(R f ), or R5 of X1 together with R3 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 selected from the group consisting of one or more C 1~6 may be substituted with alkyl, X2 and X3 are each independently N or C-R5, where 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, wherein R5 is C 1~6 Alkyl is hydroxyl or N(R e )(R f ), X3 is N or CH; R1 is (i) oxiranyl or oxetanyl, wherein the oxiranyl or oxetanyl is one or more C 1~6 may be substituted with alkyl, or (ii) N(R e )(CN), or (iii) TIFF0007629916000148.tif20170, where R a , R b and R c are each independently H, halo, cyano, hydroxyl, or C 1~6 Alkyl, C 6~20 aryl, 3- to 10-membered heterocyclyl, and 5- to 20-membered heteroaryl, wherein C 1~6 The alkyl may be further substituted with a hydroxyl, or (iv) TIFF0007629916000149.tif16170, where R d is H, halo, cyano, hydroxyl, C 1~6 Alkyl, C 6~20 aryl, 3- to 10-membered heterocyclyl, and 5- to 20-membered heteroaryl, wherein C 1~6 The alkyl may be further substituted with hydroxyl; L is absent or selected from the group consisting of -O-, *-CH2-O-**, *-O-CH2-**, -CH=CH-, and -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule; R2 is C 1~12 Alkyl, C 3~10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 6~20 Aryl, C 5~13 spirocyclyl, or 5- to 20-membered heteroaryl, wherein R2 C 1~12 Alkyl, C 3~10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 6~20 Aryl, C 5~13 The spirocyclyl 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 eand optionally substituted with one or two 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, wherein the 5-membered heterocyclyl or 5-membered heteroaryl is selected from one or more C 1~6 and optionally substituted with alkyl, provided that X3 is CH, or R3 together with the carbon atoms of *-CH2-O-** of L and the atoms 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 of 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 6~20 aryl, and 3- to 20-membered heteroaryl, wherein 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 6~20 The aryl and the 3- to 20-membered heteroaryl are each independently C1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 and 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.

[0261] In some embodiments, the compound that modulates TEAD activity has formula (A): TIFF0007629916000150.tif31170[In the formula, X1, X2, and X3 are each independently N or C-R5, where 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, wherein C 3~10 Cycloalkyl, C 1~6 Alkoxy, C 6~20 Aryl or C 1~6 The alkyl may be substituted; R1 is TIFF0007629916000151.tif21170, where R a , R b , R c and R d are each independently H, halo, cyano, hydroxyl, or C 1~6 Alkyl, C 6~20 aryl, 3- to 10-membered heterocyclyl, and 5- to 20-membered heteroaryl, wherein C 1~6 Alkyl, C 6~20 The aryl, 3- to 10-membered heterocyclyl, or 5- to 20-membered heteroaryl are independently optionally substituted; L is absent or -O-, *-CH2-O-**, * is selected from the group consisting of -O-CH2-**, -CH=CH-, and -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule; R2 is C 1~12 Alkyl, C 3~10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 6~20 Aryl, C 5~13 spirocyclyl, or 5- to 20-membered heteroaryl, where C 1~12 Alkyl, C 3~10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 6~20 Aryl, C 5~13 The spirocyclyl or 5- to 20-membered heteroaryl is independently optionally substituted; R3 is cyano, C 1~6 Alkyl, C 1~4 Alkoxy or C 2~4 alkenyl, where C 1~6 Alkyl, C 1~4 Alkoxy, or C 2~4 the alkenyl may be substituted, 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, or R3 together with the carbon atom of *-CH2-O-** of L and the atom to which they are attached form a C6 aryl or a 6-membered heteroaryl; R4 is H or C 1~6 alkyl, where C 1~6 The alkyl may be substituted. or a pharmaceutically acceptable salt thereof.

[0262] In some embodiments, the compound that modulates TEAD activity is a compound of formula (B-1), formula (B), or formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In other embodiments, the compound that modulates TEAD activity is a compound of formula (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0263] The disclosed compounds (or embodiments or aspects thereof) are useful as medical therapies for treating diseases and conditions mediated by TEAD activity, 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, and 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.

[0264] 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, 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, smooth muscle tumors, 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 In some embodiments, the compounds 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.

[0265] In one aspect, a compound of the disclosure (or an embodiment or aspect thereof) is used to treat or prevent the development of leukemia, 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 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.

[0266] In other aspects, the present disclosure provides a method for treating or preventing the development of leukemia, 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. tumors, 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), bladder , malignant tumors and hyperproliferative disorders of the 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, rhabdomyosarcoma, sarcoma, sebaceous carcinoma, seminiferous carcinoma

[0013] Provided is a method for treating ovarian cancer, 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 cancer, uterine cancer, and Wilms' tumor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to Formula (A), (B), (B-1), (C), (C-1), or (I) (or an embodiment or aspect thereof), as described elsewhere herein.

[0267] In other aspects, the disclosure provides compounds of Formula (A), (B), (B-1), (C), (C-1), or (I) or (embodiments or aspects thereof) as described elsewhere herein for modulating TEAD activity. In some embodiments, the disclosure provides pharmaceutically acceptable salts of compounds of Formula (A), (B), (B-1), (C), (C-1), or (I) for modulating TEAD activity.

[0268] In another aspect, there is provided a compound of Formula (A), (B), (B-1), (C), (C-1) or (I) or an embodiment or aspect thereof, such as a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, as described elsewhere herein, for use in medical therapy.

[0269] In other aspects, the present disclosure provides a method for the treatment of various types of cancer 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 , 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), bladder, breast Malignant tumors and hyperproliferative disorders of the abdomen, 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, 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), (B), (B-1), (C), (C-1), or (I) (or an embodiment or aspect thereof) as described elsewhere herein.

[0270] In other aspects, the present disclosure provides a method for treating or preventing the development of leukemia, 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. tumors, 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), bladder , malignant tumors and hyperproliferative disorders of the 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, rhabdomyosarcoma, sarcoma, sebaceous carcinoma, seminiferous carcinoma In one embodiment, a compound of Formula (A), (B), (B-1), (C), (C-1) or (I), or an embodiment or aspect thereof, such as a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, as described elsewhere herein, is provided for use in the treatment or prevention of ovarian cancer, 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 cancer, uterine cancer and Wilms' tumor.

[0271] In other aspects, the present disclosure provides a method for the treatment of various types of cancer 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 , 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), bladder, breast , malignant tumors and hyperproliferative disorders of the 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, rhabdomyosarcoma, sarcoma, sebaceous carcinoma, seminoma, skin Provided is the use of a compound of Formula (A), (B), (B-1), (C), (C-1) or (I), or an embodiment or aspect thereof, such as a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, as described elsewhere herein, for the preparation of a medicament for the treatment or prevention of 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.

[0272] In other aspects, the present disclosure provides a method for the treatment of various types of cancer 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. 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), bladder cancer 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, rhabdomyosarcoma, sarcoma, sebaceous carcinoma, Provided is the use of a compound of Formula (A), (B), (B-1), (C), (C-1) or (I), or an embodiment or aspect thereof, such as a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, as described elsewhere herein, for the treatment or prevention of 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.

[0273] 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, diffuse large cell car ... Alveolar 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), bladder , malignant tumors and hyperproliferative disorders of the 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, rhabdomyosarcoma, sarcoma, sebaceous carcinoma, seminoma, skin

[0013] Provided are methods for treating 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), (B), (B-1), (C), (C-1) or (I), or an embodiment or aspect thereof, such as a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, as described elsewhere herein.

[0274] In another aspect, the disclosure provides a method for modulating TEAD activity, comprising contacting a TEAD with a compound of Formula (A), (B), (B-1), (C), (C-1) or (I), as described elsewhere herein, or an embodiment or aspect thereof, such as a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0275] In another aspect, there is provided a compound of Formula (A), (B), (B-1), (C), (C-1) or (I) as described elsewhere herein, or an embodiment or aspect thereof, such as a stereoisomer, tautomer or 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, thyroid cancer ... Intestinal 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.

[0276] In another aspect, there is provided the use of a compound of Formula (A), (B), (B-1), (C), (C-1) or (I), as described elsewhere herein, or an embodiment or aspect thereof, such as a stereoisomer, tautomer or 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, thyroid cancer ... Intestinal 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.

[0277] In one aspect, the compounds of the present disclosure exhibit greater potency compared to other analogs. Combination Therapy

[0278] The compound of formula (A), (B), (B-1), (C), (C-1), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK) or (IL) or its salt may be used alone or in combination with other therapeutic agents. For example, the second agent in a combined pharmaceutical formulation or administration regimen may have complementary activity to the compound of formula (A), (B), (B-1), (C), (C-1), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK) or (IL) so as not to adversely affect each other. The compounds may be administered together in one pharmaceutical composition or separately. In one embodiment, the compound or pharmaceutically acceptable salt may be co-administered with a cytotoxic agent to treat a proliferative disease.

[0279] The term "co-administering" refers to either simultaneous administration or separate, sequential administration in any manner of a compound of Formula (A), (B), (B-1), (C), (C-1), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL) or a salt thereof, and additional pharmaceutically active 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.

[0280] 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.

[0281] 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.

[0282] The amount of both the compounds of the invention and additional therapeutic agent (in compositions containing such additional therapeutic agents) that can 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.

[0283] Typically, any agent that is active against the disease or condition being treated can be co-administered.Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T.Devita and S.Heilman (eds.), 6th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers.Those skilled in the art will be able to identify which combination of agents is useful based on the specific characteristics of drug and involved disease.

[0284] In one embodiment, a method of treatment comprises co-administration of a compound of Formula (A), (B), (B-1), (C), (C-1), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK) or (IL), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and at least one cytotoxic agent. As used herein, the term "cytotoxic agent" refers to a substance that inhibits or prevents cellular function 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 such as nucleases and fragments thereof, and toxins (including fragments and / or variants thereof) such as small molecule or enzymatically active toxins of bacterial, fungal, plant or animal origin.

[0285] 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.

[0286] "Chemotherapeutic agent" includes 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 erythropoietinib (VELCADE®, Millennium). 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), morpholinodoxorubicin, 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; anti-metabolic agents such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, 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 calusterone, 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; bestravcil; bisantrene; edatraxate; defofamine; demecolcine; diaziquione; elfomitine; elliptine acetate; ampothilone; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidynin; maytansinoids such as maytansine and ansamitocin Mitoguazone; mitoxantrone; mopidamol; nitraelin; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK® 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, e.g., TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE® (Cremophofree), an albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumburg, IL), 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; the topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids, and derivatives of any of the above.

[0287] 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), for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droxifene, iodoxifene, 4-hydroxytamoxifen, trioxifene, ketoxifene, LY117018, onapristone, and FARESTON® (toremifene 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), and ARIMIDEX® (anastrozole; AstraZeneca). (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 that inhibit signaling involved in abnormal cell proliferation. those that inhibit the expression of genes in the IL-1 signaling pathway, such as PKC-α, Ralf, and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) gene therapy vaccines, such as 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;

[0288] 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.

[0289] 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 MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB 8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (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 to type II mutant EGFR (U.S. Pat. No. 5,212,290), humanized and chimeric antibodies that bind to EGFR such as those described in U.S. Pat. No. 5,891,996 and human antibodies that bind to 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), a humanized EGFR antibody against EGFR that competes with both EGF and TGF-α for EGFR binding, human EGFR antibodies, which may be known as HuMax-EGFR (GenMab), E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, and E7.6.3, and the fully human antibody described in U.S. Pat. No. 6,235,883, MDX-447 (Medarex Inc.), and mAb 806 or arsenated mAb 806 (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, 6,399,602, 6,344,459, 6,602,863, 6,391,874, 6,344,455, 5,760,041, 6,002,008, 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).

[0290] Chemotherapeutic agents include "tyrosine kinase inhibitors," such as the EGFR-targeted drugs described in the previous paragraph; small molecule HER2 tyrosine kinase inhibitors, such as TAK165 available from Takeda; CP-724,714 (Pfizer and OSI), an oral selective inhibitor of ErbB2 receptor tyrosine kinase; 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); oral HER2 and EGFR tyrosine kinase inhibitors; PKI-166 (available from Novartis); pan-HER inhibitors, such as canertinib (CI-1033, Pharmacia); Raf-1 inhibitors, such as ISIS, which inhibits Raf-1 signaling. antisense agent ISIS-5132 available from GlaxoSmithKline Pharmaceuticals; non-HER-targeted TK inhibitors such as imatinib mesylate (GLEEVEC®, available from GlaxoSmithKline); 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); MAPK extracellular regulated kinase I inhibitor CI-1040 (available from Pharmacia); quinazolines such as PD 153035, 4-(3-chloroanilino)quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines such as CGP 59326, CGP 60261, and CGP 62706; pyrazolopyrimidine, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidine; curcumin (diferuloylmethane, 4,5-bis(4-fluoroanilino)phthalimide); tyrphostins containing a nitrothiophene moiety; PD-0183805 (Warner-Lamber); antisense molecules (e.g., those that bind to HER-encoding nucleic acids), quinoxalines (U.S. Patent No. 5,804,396); tryphostin (U.S. Patent No. 5,804,396); ZD6474 (Astra Zeneca);PTK-787 (Novartis / Schering AG); pan-HER inhibitors, e.g., CI-1033 (Pfizer); Affinitac (ISIS 3521, 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 the following patent publications: U.S. Pat. No. 5,804,396, WO 1999 / 09016 (American Cyanamid), WO 1998 / 43960 (American 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).

[0291] 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.

[0292] Also, examples of chemotherapeutic agents 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, fluocortone, hydrocortisone-17-butyrate, hydrocortisone-17-butyrate, and hydrocortisone-17-butyrate. Immunoselective anti-inflammatory peptides (ImSAIDs) such as lutisone-17-valerate, aclomethasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortone caproate, fluocortone pivalate and fluprednidene acetate, phenylalanine-glutamine-glycine (FEG) and its D-isomer form (IMULAN) BioTherapeutics, LLC; antirheumatic drugs such as azathioprine, cyclosporine (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomide minocycline, and sulfasalazine; interleukin-1 (IL-1) blockers such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Tymzia), golimumab (Simponi), and anakinra (Kinere), T-cell costimulation blockers such as abatacept (Orencia), interleukin-6 (IL-6) blockers such as tocilizumab (ACTEMERA®), and interleukin-13 (IL-13) blockers such as lebrikizumab; interferon alpha (IFN) blockers such as rontalizumab; rhuMAb Beta7 integrin blockers such as Beta7; IgE pathway blockers such as anti-M1 prime; membrane-bound heterotrimeric LTa1 / β2 blockers such as secreted homotrimeric LTa3 and anti-lymphotoxin alpha (LTa); radioisotopes (e.g., At 211 , I 131 , I 125 , Y 90 ,Re 186 ,Re 188 , Sm 153、Bi 212 、P 32 、Pb 212and radioactive isotopes of Lu); other investigational drugs such as thioplatin, PS-341, phenylbutyrate, ET-18-OCH3, or farnesyltransferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechin gallate, theaflavins, flavanols, procyanidins, betulinic acid and their derivatives; autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol, MARINOL®); beta-lapachone; lapachol; colchicine; betulinic acid and its derivatives; acetylcamptothecin, scopolectin, and 9-aminocamptothecin; podophyllotoxin; tegafur (UFTORAL®); bexarotene (TARGRETIN®); clodronate (e.g., BONEFOS®) Bisphosphonates such as benzodiazepine (Trademark) or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid / zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®); as well as epidermal growth factor receptor (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 (R11577); orafenib, ABT510; Bcl-2 inhibitors such as oblimersen sodium (GENASENSE®); pixantrone; lonafarnib (SCH 6636, SARASAR™); and pharmaceutically acceptable salts, acids, or derivatives of any of the above; and combinations of two or more of the above, such as CHOP, which stands for cyclophosphamide, doxorubicin, vincristine, and prednisolone, and FOLFOX, which stands for the treatment regimen of oxaliplatin combined with 5-FU and leucovorin (ELOXATIN™).

[0293] 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.

[0294] 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.

[0295] In certain embodiments, the compound of the present invention or a pharmaceutically acceptable composition thereof is administered with or without the use of any of the following drugs: 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, cytarabine, dactinoma, thiazolinone ... Isin, darbepoetin, daunetin, denilequine, 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, ifosfamide, imatinib mesylate, interferon alfa-2 mesylatea, 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, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, and administered in combination with an antiproliferative or chemotherapeutic agent selected from any one or more of rufimer 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, vincristine, vinorelbine, zoledronate, or zoledronic acid.

[0296] Chemotherapeutic agents also include those for treating Alzheimer's disease, such as donepezil hydrochloride and rivastigmine; those for treating Parkinson's disease, such as L-DOPA / carbidopa, entacapone, lopyrole, pramipexole, bromocriptine, pergolide, trihexefendil, and amantadine; those for treating multiple sclerosis (MS), such as beta interferons (e.g., Avonex® and Rebif®), glatiramer acetate, and mitoxantrone; those for treating asthma, such as albuterol and montelukast sodium; those for treating schizophrenia, such as Zyprexa, risperdal, seroquel, and haloperidol; corticosteroids, TNF blockers, IL-1 immunomodulators and immunosuppressants such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferon, 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, interferon, 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.

[0297] 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.

[0298] In other embodiments, methods are provided using a compound of Formula (A), (B), (B-1), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK) or (IL), 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.

[0299] 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.

[0300] 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 certain aspects, 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.

[0301] 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 a specific aspect, a PD-L1 binding antagonist inhibits 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 mediated PD-L1-mediated signaling, 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.

[0302] The term "PD-L2 binding antagonist" refers to a molecule that reduces, blocks, inhibits, 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 any one or more of its binding partners, e.g., 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.

[0303] PD-1 axis binding antagonists

[0304] In other embodiments, provided herein are methods for treating cancer, comprising administering to an individual an effective amount of a PD-1 axis binding antagonist and a compound of Formula (A), (B), (B-1), (C), (C-1), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), as described elsewhere herein, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. Also provided herein are methods of enhancing immune function or response in an individual (e.g., an individual with cancer), comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and a compound of Formula (A), (B), (B-1), (C), (C-1), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK) or (IL), as described elsewhere herein, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0305] 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.

[0306] In some embodiments, the PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to its ligand-binding partner. In a specific aspect, the ligand-binding partner of PD-1 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 binding partner of PDL1 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 binding partner of PDL2 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.

[0307] Anti-PD-1 antibody

[0308] In some embodiments, the PD-1 binding antagonist is an anti-PD-1 antibody. A variety of anti-PDL1 antibodies can be utilized in the methods disclosed herein. In any of the embodiments herein, the PD-1 antibody can 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 antibody or a humanized antibody. In some embodiments, the anti-PD-1 antibody is a human antibody.

[0309] 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).

[0310] In some embodiments, the anti-PD-1 antibody comprises six HVR sequences from SEQ ID NO:1 and SEQ ID NO:2 (e.g., three heavy chain HVRs of SEQ ID NO:1 and three light chain HVRs of SEQ ID NO:2). In some embodiments, the anti-PD-1 antibody comprises a heavy chain variable domain from SEQ ID NO:1 and a light chain variable domain from SEQ ID NO:2.

[0311] In some embodiments, the anti-PD-1 antibody is pembrolizumab (CAS Registry Number: 1374853-91-4). Pembrolizumab (Merck), also known as MK-3475, Merck 3475, lambrolizumab, KEYTRUDA®, and SCH-900475, 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).

[0312] In some embodiments, the anti-PD-1 antibody comprises six HVR sequences from SEQ ID NO:3 and SEQ ID NO:4 (e.g., three heavy chain HVRs of SEQ ID NO:3 and three light chain HVRs of SEQ ID NO:4). In some embodiments, the anti-PD-1 antibody comprises a heavy chain variable domain from SEQ ID NO:3 and a light chain variable domain from SEQ ID NO:4.

[0313] In some embodiments, the anti-PD-1 antibody is MEDI-0680 (AMP-514; AstraZeneca). MEDI-0680 is a humanized IgG4 anti-PD-1 antibody.

[0314] 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.

[0315] In some embodiments, the anti-PD-1 antibody is REGN2810 (Regeneron). REGN2810 is a human anti-PD1 antibody.

[0316] In some embodiments, the anti-PD-1 antibody is BGB-108 (BeiGene). In some embodiments, the anti-PD-1 antibody is BGB-A317 (BeiGene).

[0317] In some embodiments, the anti-PD-1 antibody is JS-001 (Shanghai Junshi). JS-001 is a humanized anti-PD-1 antibody.

[0318] In some embodiments, the anti-PD-1 antibody is STI-A1110 (Sorrento). STI-A1110 is a human anti-PD-1 antibody.

[0319] In some embodiments, the anti-PD-1 antibody is INCSHR-1210 (Incyte). INCSHR-1210 is a human IgG4 anti-PD1 antibody.

[0320] In some embodiments, the anti-PD-1 antibody is PF-06801591 (Pfizer).

[0321] In some embodiments, the anti-PD-1 antibody is TSR-042 (also known as ANB011, Tesaro / AnaptysBio).

[0322] In some embodiments, the anti-PD-1 antibody is AM0001 (ARMO Biosciences).

[0323] In some embodiments, the anti-PD-1 antibody is ENUM 244C8 (Enumeral Biomedical Holdings). ENUM 244C8 is an anti-PD-1 antibody that inhibits the function of PD-1 without blocking the binding of PDL1 to PD-1.

[0324] In some embodiments, the anti-PD-1 antibody is ENUM 388D4 (Enumeral Biomedical Holdings). ENUM 388D4 is an anti-PD-1 antibody that competitively inhibits the binding of PDL1 to PD-1.

[0325] In some embodiments, the PD-1 antibody is one selected from the group consisting of antibodies disclosed in WO 2015 / 112800 (applicant: Regeneron), WO 2015 / 112805 (applicant: Regeneron), WO 2015 / 112900 (applicant: Novartis), U.S. Patent Application Publication No. 20150210769 (assigned to Novartis), WO 2016 / 089873 (applicant: Celgene), WO 2015 / 035606 (applicant: Beigene), WO 2015 / 085847 (applicant: Shanghai Hengrui Pharmaceutical / Jiangsu Hengrui Medicine), WO 2014 / 206107 (applicant: Shanghai Junshi Biosciences / Junmeng Biosciences), WO 2012 / 145493 (applicant: Amplimmune), U.S. Patent No. 9,205,148 (assigned to MediImmune), WO 2015 / 119930 (applicant: Pfizer / Merck), WO 2015 / 119923 (applicant: Pfizer / Merck), WO 2016 / 032927 (applicant: Pfizer / Merck) k), six HVR sequences (e.g., three heavy chain HVRs and three light chain HVRs) and / or heavy chain and light chain variable domains from the PD-1 antibodies described in WO 2014 / 179664 (applicant: AnaptysBio), WO 2016 / 106160 (applicant: Enumeral), and WO 2014 / 194302 (applicant: Sorrento).

[0326] Anti-PDL1 antibody

[0327] 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.

[0328] 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.

[0329] 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.

[0330] 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).

[0331] 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).

[0332] 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).

[0333] 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.

[0334] 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).

[0335] 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.

[0336] 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.

[0337] In some embodiments, the anti-PDL1 antibody is LY3300054 (Eli Lilly).

[0338] In some embodiments, the anti-PDL1 antibody is STI-A1014 (Sorrento). STI-A1014 is a human anti-PDL1 antibody.

[0339] In some embodiments, the anti-PDL1 antibody is KN035 (Suzhou Alphamab), a single domain antibody (dAB) generated from a camel phage display library.

[0340] In some embodiments, the anti-PDL1 antibody is comprised of a cleavable moiety or linker that, when cleaved (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 moiety. In some embodiments, the anti-PDL1 antibody is CX-072 (CytomX Therapeutics).

[0341] 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).

[0342] 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. Glycosylation of antibodies 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 a 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 one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may 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).

[0343] Other PD-1 antagonists

[0344] In some embodiments, the PD-1 binding antagonist is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PDL1 or PDL2 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.

[0345] 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.

[0346] 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. 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.

[0347] In some embodiments, the method of treatment comprises co-administration of a compound of Formula (A), (B), (B-1), (C), (C-1), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK) or (IL), or a stereoisomer, tautomer, or pharmaceutically acceptable salt of any of the foregoing, and at least one mitogen-activated protein kinase (MAPK) inhibitor. In some embodiments, the method of treatment comprises co-administration of a compound of Formula (A), (B), (B-1), (C), (C-1), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK) or (IL), or a stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing, and at least one inhibitor of the RAS / MAPK pathway. In some embodiments, the therapeutic method comprises co-administration of a compound of Formula (A), (B), (B-1), (C), (C-1), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, 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 certain 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 (Amgen's AMG 510), MRTX 849 (Mirati Therapeutics), JNJ-74699157 / ALS-3248 (J&J Wellspring Biosciences), LY 3499446 (Eli Lilly), GDCBI 1701963 (Boehringer Ingelheim), mRNA-5671 (Moderna Therapeutics), G12D inhibitors (Mirati Therapeutics), RAS(ON) inhibitors (Revolution Medicines), BBP-454 (BridgeBio Pharma), SP600125, PLX 4032, GW5074, AZD6244, PD98059, simvastatin, alisertib, teriflunomide, NSC95397, PD325901, PD98059, lovastatin, sorafenib (NEXAVAR®, Bayer Labs), velmurafenib (ZELBORAF®, Hoffman La Roche Inc.), dabrafenib (TAFLINAR®, Novatris 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, PF 502, enterolactone, PLX4720, PD0325901, PD184352, SC-514, alistarib (MLN8237), SB415286, PLX4720, oftaoclax (GX15-070), pimasterib, venetoclax (ABT-199 / VENCLEXTA® / VENCLYXTO®), eprenetapt (APR-246), gemcitabine (GEMZAR®), virinapant (TL32711), pexemetinib (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.).

[0348] 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. Enumerated Embodiments

[0349] The embodiments listed below are representative of some aspects of the present invention. 1. Formula (I): TIFF0007629916000152.tif25170[In the formula, X1 and X2 are each independently N or C-R5, where 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, wherein C 1~6 Alkyl is hydroxyl or N(R e )(R f ) may be further substituted with X3 is N or CH; provided that when X3 is N, at least one of X1 and X2 is N; R1 is TIFF0007629916000153.tif20170, where R a , R b and R care each independently H, halo, cyano, hydroxyl, or C 1~6 Alkyl, C 6~20 aryl, 3- to 10-membered heterocyclyl, and 5- to 20-membered heteroaryl, wherein C 1~6 The alkyl may be further substituted with hydroxyl, provided that R a , R b and R c at least two of are H, and L is absent or selected from the group consisting of *-CH2-O-**, *-O-CH2-**, -CH=CH-, and -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the rest of the molecule; or R1 is TIFF0007629916000154.tif16170, R d is H, halo, cyano, hydroxyl, C 1~6 Alkyl, C 6~20 aryl, 3- to 10-membered heterocyclyl, and 5- to 20-membered heteroaryl, wherein C 1~6 the alkyl may be further substituted with hydroxyl; L is selected from the group consisting of -O-, *-CH2-O-**, *-O-CH2-**, -CH=CH-, and -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule; R2 is C 1~12 Alkyl, C 3~10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 6~20 Aryl, C 5~13 spirocyclyl, or 5- to 20-membered heteroaryl, wherein C 1~12 Alkyl, C 3~10 Cycloalkyl, 3-10 membered saturated heterocyclyl, C 6~20 Aryl, C 5~13 The spirocyclyl or 5- to 20-membered heteroaryl is independently selected from cyano, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, N, N(R e )(R f), and O(R e and optionally substituted with one or two substituents selected from the group consisting of: Each R e and R f H, Independently, 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 6~20 is selected from the group consisting of aryl and 3- to 20-membered heteroaryl, 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 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; however, R2 is C 1~12 alkyl, C 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 ), wherein the alkyl group is optionally substituted with one or two substituents selected from the group consisting of L is -CH=CH- or -C≡C-; R3 is cyano, C 1~6 Alkyl, C 1~4 Alkoxy or C 2~4 alkenyl, C 2~4Alkenyl 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, with the proviso that X3 is CH; or R3 together with the carbon atoms of *-CH2-O-** of L and the atoms to which they are attached form a C6 aryl or 6-membered heteroaryl; however, (i) R3 is cyano, C 1~6 Alkyl, C 1~4 Alkoxy or C 2~4 alkenyl, C 2~4 alkenyl optionally is N(R e )(R f ), wherein R2 is a 3- to 10-membered saturated heterocyclyl or a 5- to 20-membered heteroaryl, and the 3- to 10-membered saturated heterocyclyl or the 5- to 20-membered heteroaryl is independently cyano, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, NO2, N(R e )(R f ) and O(R e ), wherein the alkyl group is optionally substituted with one or two substituents selected from the group consisting of L is *-CH2-O-**, -CH=CH- or -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule; or (ii) R3 together with R5 of X1 and the atom to which they are attached form a 5-membered heterocyclyl or a 5-membered heteroaryl, provided that X3 is CH and R2 is a 3- to 10-membered saturated heterocyclyl or a 5- to 20-membered heteroaryl, wherein the 3- to 10-membered saturated heterocyclyl or the 5- to 20-membered heteroaryl is independently cyano, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, NO2, N(R e )(R f ) and O(Re and optionally substituted with one or two substituents selected from the group consisting of: L is absent, *-CH2-O-**, -CH=CH- or -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule; or (iii) R3, together with the carbon atom of *-CH2-O-** of L and the atom to which they are attached, form a C6 aryl or 6-membered heteroaryl, and R2 is a 3- to 10-membered saturated heterocyclyl or a 5- to 20-membered heteroaryl, wherein the 3- to 10-membered saturated heterocyclyl or the 5- to 20-membered heteroaryl is independently 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 ) and O(R e ), wherein the alkyl group is optionally substituted with one or two substituents selected from the group consisting of L is *-CH2-O-**, -CH=CH- or -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule; or R4 is H or C 1~6 alkyl, where C 1~6 The alkyl may be substituted by a hydroxyl. or a pharmaceutically acceptable salt thereof. 2. X1 is C-R5, where R5 is C 1~6 Alkyl, C 1~6 Alkoxy, or NH(R e ) and A compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein R3, together with R5 of X1 and the atom to which they are attached, form a 5-membered heterocyclyl, with the proviso that X3 is CH. 3. The compound of formula (I) has the formula (IA): TIFF0007629916000155.tif28170, or a pharmaceutically acceptable salt thereof. 4. The compound of formula (I) is: TIFF0007629916000156.tif122170, or a pharmaceutically acceptable salt thereof. 5. The compound of formula (I) has the formula (IB): TIFF0007629916000157.tif32170, or a pharmaceutically acceptable salt thereof. 6. X1 is C-R5, where R5 is C 1~6 Alkyl, C 1~6 Alkoxy, or NH(R e ) and A compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein R3, together with R5 of X1 and the atom to which they are attached, form a 5-membered heteroaryl, with the proviso that X3 is CH. 7. The compound of formula (I) has the formula (IC): 7. The compound of embodiment 6, which is a compound of TIFF0007629916000158.tif29170, or a pharmaceutically acceptable salt thereof. 8.L is *-CH2-O-**, A compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein R3, together with the carbon atom of *-CH2-O-** of L and the atom to which they are attached, forms a C6 aryl. 9. The compound of formula (I) has the formula (ID): 9. The compound of embodiment 8, which is a compound of TIFF0007629916000159.tif26170, or a pharmaceutically acceptable salt thereof. 10.L is *-CH2-O-**, The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein R3, together with the carbon atoms of *-CH2-O-** of L and the atom to which they are attached, form a 6-membered heteroaryl. 11. The compound of formula (I) has the formula (IE): 11. The compound of embodiment 10, which is a compound of TIFF0007629916000160.tif26170, or a pharmaceutically acceptable salt thereof. 12.X3 is CH, L is -CH-CH-; R2 is C 3~10 cycloalkyl, where C 3~10 Cycloalkyl 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 two substituents selected from the group consisting of: R3 is C 1~4 is an alkoxy; The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein R4 is H. 13. The compound of formula (I) has the formula (IF): 13. The compound of embodiment 12, which is a compound of TIFF0007629916000161.tif37170, or a pharmaceutically acceptable salt thereof. 14. The compound of formula (IF) is: TIFF0007629916000162.tif166170, or a pharmaceutically acceptable salt thereof. 15.R1 TIFF0007629916000163.tif20170, where R a , R b and R c are each independently H, halo, cyano, hydroxyl, or C1~6 Alkyl, C 6~20 aryl, 3- to 10-membered heterocyclyl, and 5- to 20-membered heteroaryl, wherein C 1~6 The alkyl may be further substituted with hydroxyl, provided that R a , R b and R c are H, and L is absent or selected from the group consisting of *-CH2-O-**, *-O-CH2-**, -CH=CH-, and -C≡C-, where ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule, or a pharmaceutically acceptable salt thereof. 16. The compound of formula (I) has the formula (IG): 16. The compound of embodiment 15, which is a compound of TIFF0007629916000164.tif25170, or a pharmaceutically acceptable salt thereof. 17.L is -CH=CH- and R2 is C 3~10 cycloalkyl, where C 3~10 Cycloalkyl 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 17. The compound of embodiment 15 or 16, or a pharmaceutically acceptable salt thereof, optionally substituted with one or two substituents selected from the group consisting of: 18. The compound of formula (I) has the formula (IH): TIFF0007629916000165.tif25170[In the formula, n is 0, 1, or 2; Each R x , if present, independently represent cyano, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, NO2, N(R e )(R f ) and O(R e) selected from the group consisting of or a pharmaceutically acceptable salt thereof. 19.R2 is C 1~12 alkyl, where C 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 and L is —CH═CH— or —C≡C—, or a pharmaceutically acceptable salt thereof. 20. The compound of embodiment 19, or a pharmaceutically acceptable salt thereof, wherein L is -CH=CH-. 21. The compound of embodiment 19, or a pharmaceutically acceptable salt thereof, wherein L is —C≡C—. twenty two. [table] TIFF0007629916000166.tif39170TIFF0007629916000167.tif240170TIFF0007629916000168.tif234170TIFF0007629916000169.tif233170TIFF0007629916000170.tif112170. 23. A pharmaceutical composition comprising a compound according to any one of embodiments 1-22, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. 24. A compound according to any one of embodiments 1-22, or a pharmaceutically acceptable salt thereof, for use in medical therapy. 25. 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 carcinoma 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 Hematologic malignancies, lymphomas (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, true erythrocyte 23. The compound of any one of embodiments 1-22, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of cytopenia, 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. 26. A method for treating cancer in a mammal, comprising administering to the mammal a compound according to any one of embodiments 1-22, or a pharmaceutically acceptable salt thereof. 27. A compound according to any one of embodiments 1-22 or a pharmaceutically acceptable salt thereof for use in modulating TEAD activity. 28. A compound according to any one of embodiments 1-22, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of a disease or condition mediated by TEAD activity. 29. 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, craniopharynx cancer, Cephaloma, 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 , 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 sarcoma, ovarian cancer 29. The compound for use according to embodiment 28, wherein the cancer is follicular carcinoma, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, vera erythrocyte migraine, 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. 30. Use of a compound according to any one of embodiments 1-22, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prophylactic treatment of a disease or condition mediated by TEAD activity. 31. 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, Opiopharyngioma, 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, bone The use according to embodiment 30, wherein the cancer is myeloma, 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. 32. A method for modulating TEAD activity, comprising contacting a compound according to any one of embodiments 1 to 22, or a salt thereof, with a TEAD. 33. 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 1-22, or a pharmaceutically acceptable salt thereof. 34. 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, Opiopharyngioma, 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, bone 34. The method of embodiment 33, wherein th...

Claims

1. Formula (B-1) [In the formula, X １ is N or C-R ５ where each R ５ are independently H, cyano, halo, C(O)NH ２ , N(R ｅ ) (R ｆ ), C ３～１０ Cycloalkyl, C １～６ Alkoxy, C ６～２０ Aryl and C １～６ alkyl, where R ５ C １～６ Alkyl is hydroxyl or N(R ｅ ) (R ｆ ), or X １ R ５ is R ３ and together with 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 selected from one or more C １～６ may be substituted with alkyl, provided that X ３ is CH, X ２ is N or C-R ５ where each R ５ are independently H, cyano, halo, C(O)NH ２ , N(R ｅ ) (R ｆ ), C ３～１０ Cycloalkyl, C １～６ Alkoxy, C ６～２０ Aryl and C １～６ alkyl, where R ５ C １～６ Alkyl is hydroxyl or N(R ｅ ) (R ｆ ) may be substituted with X ３ is N or C—H, However, X ３ is N and R １ but, If X １ and X ２ At least one of is N, R １ teeth, (i) oxiranyl or oxetanyl, where oxiranyl or oxetanyl is one or more C １～６ Optionally substituted with alkyl, where C １～６ Alkyl is one or more -C(O)NH ２ may be substituted with L is absent, -O-, *-CH ２ -O-**, *-O-CH ２ -**, -CH=CH-, and -C≡C-, where ** is R ２ indicates the point of attachment to the moiety, * indicates the point of attachment to the remainder of the molecule, or (ii) N(R ｅ ) (CN), L is absent, -O-, *-CH ２ -O-**, *-O-CH ２ -**, -CH=CH-, and -C≡C-, where ** is R ２ indicates the point of attachment to the moiety, * indicates the point of attachment to the remainder of the molecule, or (iii) where R ａ , R ｂ and R ｃ are each independently H, halo, cyano, hydroxyl, C １～６ Alkyl, C ６～２０ aryl, 3- to 10-membered heterocyclyl, and 5- to 20-membered heteroaryl, wherein C １～６ The alkyl may be further substituted with hydroxyl, provided that R ａ , R ｂ and R ｃ at least two of are H; L is absent or *-CH ２ -O-**, *-O-CH ２ -**, -CH=CH-, and -C≡C-, where ** is R ２ indicates the point of attachment to the moiety, * indicates the point of attachment to the remainder of the molecule, or (iv) where R ｄ is H, halo, cyano, hydroxyl, C １～６ Alkyl, C ６～２０ aryl, 3- to 10-membered heterocyclyl, and 5- to 20-membered heteroaryl, wherein said C １～６ The alkyl may be further substituted with hydroxyl. L is -O-, *-CH ２ -O-**, *-O-CH ２ -**, -CH=CH-, and -C≡C-, where ** is R ２ indicates the point of attachment to the moiety, * indicates the point of attachment to the remainder of the molecule, R ２ is C １～１２ Alkyl, C ３～１０ Cycloalkyl, 3-10 membered saturated heterocyclyl, C ６～２０ Aryl, C ５～１３ spirocyclyl, or 5- to 20-membered heteroaryl, R ２ C １～１２ Alkyl, C ３～１０ Cycloalkyl, 3-10 membered saturated heterocyclyl, C ６～２０ Aryl, C ５～１３ The spirocyclyl or 5- to 20-membered heteroaryl 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.F. ５ and optionally substituted with one or two substituents selected from the group consisting of: However, R ２ C １～１２ alkyl, 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 ) and O(R ｅ L is -CH=CH- or -C≡C-, when optionally substituted with one or two substituents selected from the group consisting of R ３ Cyano, C １～６ Alkyl, C １～４ Alkoxy or C ２～４ alkenyl, ２～４ Alkenyl is N(R ｅ ) (R ｆ ), or R ３ , X １ R ５ and together with 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 selected from one or more C １～６ may be substituted with alkyl, provided that X ３ is CH, or R ３ is L's *-CH ２ Together with the carbon atoms of —O-** and the atoms to which they are attached, C ６ forming an aryl or a 6-membered heteroaryl; however, (i) R ３ But Cyano, C １～６ Alkyl, C １～４ Alkoxy or C ２～４ alkenyl, ２～４ Alkenyl is N(R ｅ ) (R ｆ ) may be substituted with R １ but, and R ２ is a 3- to 10-membered saturated heterocyclyl or a 5- to 20-membered heteroaryl, wherein the 3- to 10-membered saturated heterocyclyl or the 5- to 20-membered heteroaryl 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 ) and O(R ｅ wherein the aryl group is optionally substituted with one or two substituents selected from the group consisting of L is *-CH ２ -O-**, -CH=CH- or -C≡C-, where ** is R ２ indicates the point of attachment to the moiety, * indicates the point of attachment to the remainder of the molecule, (ii) R ３ But, X １ R ５ and together with the atom to which they are attached form a 5-membered heterocyclyl or 5-membered heteroaryl, with the proviso that X ３ is CH, R １ but, and R ２ is a 3- to 10-membered saturated heterocyclyl or a 5- to 20-membered heteroaryl, wherein the 3- to 10-membered saturated heterocyclyl or the 5- to 20-membered heteroaryl 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 ) and O(R ｅ wherein the aryl group is optionally substituted with one or two substituents selected from the group consisting of L is absent or *-CH ２ -O-**, -CH=CH- or -C≡C-, where ** is R ２ indicates the point of attachment to the moiety, * indicates the point of attachment to the remainder of the molecule, (iii) R ３ But L's *-CH ２ Together with the carbon atoms of —O-** and the atoms to which they are attached, C ６ forming an aryl or a 6-membered heteroaryl; R １ but, If R ２ is a 3- to 10-membered saturated heterocyclyl or a 5- to 20-membered heteroaryl, wherein the 3- to 10-membered saturated heterocyclyl or the 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 ) and O(R ｅ and optionally substituted with one or two substituents selected from the group consisting of: R ４ is H or C １～６ alkyl, where 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 ３～１０ Cycloalkyl, C １～６ Alkyl-C ３～１０ Cycloalkyl, 3- to 10-membered heterocyclyl, C ６～２０ aryl, and 3- to 20-membered heteroaryl, where 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 ６～２０ Aryl and 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. or a stereoisomer, tautomer or pharma- ceutically acceptable salt thereof.

2. X １ is C-R ５ where R ５ is C １～６ Alkyl, C １～６ Alkoxy, or NH(R ｅ ) and R ３ But, X １ R ５ and together with the atom to which they are attached form a 5-membered heterocyclyl, where the 5-membered heterocyclyl is one or more C １～６ may be substituted with alkyl, provided that X ３ 2. The compound of claim 1, or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof, wherein is CH.

3. The compound of formula (B-1) is represented by formula (IA):

3. The compound of claim 1 or 2, which is a compound of the formula: or a stereoisomer, tautomer or pharma- ceutically acceptable salt thereof.

4. The compound of formula (IA) or a stereoisomer, tautomer or pharma- ceutically acceptable salt thereof.

4. The compound of claim 3, which is a compound selected from the group consisting of:

5. L does not exist and R ２ C ６～２０ aryl, where C ６～２０ Aryl is one or more C １～６ 4. The compound of claim 3, or a stereoisomer, tautomer or pharma- ceutically acceptable salt thereof, which is optionally substituted with alkyl.

6. X ２ is C-R ５ where R ５ is cyano, or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof.

7. The compound of formula (IA) may be represented by formula (IJ):

7. The compound of claim 6, which is a compound of the formula: or a stereoisomer, tautomer or pharma- ceutically acceptable salt thereof.

8. The compound of formula (IJ) 8. The compound of claim 7, selected from the group consisting of: or a stereoisomer, tautomer, or a pharma- ceutically acceptable salt thereof.

9. R １ is oxiranyl or oxetanyl, wherein the oxiranyl or oxetanyl is one or more C １～６ Optionally substituted with alkyl, where C １～６ Alkyl is one or more -C(O)NH ２ 8. The compound of claim 7, or a stereoisomer, tautomer or pharma- ceutically acceptable salt thereof, optionally substituted with:

10. The compound of formula (IJ) may be represented by the formula (IK): [In the formula, R ｇ is H or C １～６ alkyl, where C １～６ Alkyl is one or more -C(O)NH ２ 10. The compound of claim 9, wherein the compound is:

11. R １ N (R ｅ 8. The compound of claim 7, wherein:

12. The compound of formula (IJ) may be represented by the formula (IL):

12. The compound of claim 11, which is a compound of the formula: or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof.

13. R ｅ is hydrogen or C １～６ 13. The compound of claim 12, or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

14. The compound of formula (B-1) is represented by formula (IB):

3. The compound of claim 2, which is a compound of the formula: or a stereoisomer, tautomer or pharma- ceutically acceptable salt thereof.

15. X １ is C-R ５ where R ５ is C １～６ Alkyl, C １～６ Alkoxy, or NH(R ｅ ) and R ３ But, X １ R ５ and together with the atom to which they are attached form a 5-membered heteroaryl, wherein said 5-membered heteroaryl is one or more C １～６ may be substituted with alkyl, provided that X ３ 2. The compound of claim 1, or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof, wherein is CH.

16. The compound of formula (B-1) is represented by formula (IC):

16. The compound of claim 15, which is a compound of the formula: or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof.

17. The compound of formula (B-1) is represented by the formula (IC-1):

16. The compound of claim 15, which is a compound of the formula: or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof.

18. L is *-CH ２ -O-**, R ３ But L's *-CH ２ Together with the carbon atoms of —O-** and the atoms to which they are attached, C ６ 2. The compound of claim 1, or a stereoisomer, tautomer or pharma- ceutically acceptable salt thereof, which forms an aryl.

19. The compound of formula (B-1) is represented by the formula (ID):

20. The compound of claim 18, which is a compound of the formula: or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof.

20. L is *-CH ２ -O-**, R ３ But L's *-CH ２ 2. The compound of claim 1, or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof, wherein the carbon atoms of -O-** together with the atom to which they are attached form a 6-membered heteroaryl.

21. The compound of formula (B-1) is represented by formula (IE):

21. The compound of claim 20, which is a compound of the formula: or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof.

22. X ３ is CH, L is -CH=CH-, R ２ C ３～１０ cycloalkyl, where C ３～１０ Cycloalkyl is independently cyano, halo, C １～６ Alkyl, C １～６ Haloalkyl, C ３～１０ Cycloalkyl, NO ２ , N(R ｅ ) (R ｆ ) and O(R ｅ and optionally substituted with one or two substituents selected from the group consisting of: R ３ C １～４ is an alkoxy; R ４ is H, or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof.

23. The compound of formula (B-1) is represented by formula (IF):

23. The compound of claim 22, which is a compound of the formula: or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof.

24. The compound of formula (IF) 24. The compound of claim 23, selected from the group consisting of: or a stereoisomer, tautomer, or a pharma- ceutically acceptable salt thereof.

25. R １ but where R ａ , R ｂ and R ｃ are each independently H, halo, cyano, hydroxyl, C １～６ Alkyl, C ６～２０ aryl, 3- to 10-membered heterocyclyl, and 5- to 20-membered heteroaryl, wherein C １～６ The alkyl may be further substituted with hydroxyl, provided that R ａ , R ｂ and R ｃ At least two of are H and L is absent or *-CH ２ -O-**, *-O-CH ２ -**, -CH=CH-, and -C≡C-, where ** is R ２ 24. The compound of any one of claims 1-3, 5-7 and 14-23, or a stereoisomer, tautomer or pharma- ceutically acceptable salt thereof, wherein * indicates the point of attachment to the remainder of the molecule, and * indicates the point of attachment to the remainder of the molecule.

26. The compound of formula (B-1) is represented by formula (IG):

26. The compound of claim 25, which is a compound of the formula: or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof.

27. L is -CH=CH-, and R ２ C ３～１０ cycloalkyl, where C ３～１０ Cycloalkyl is independently cyano, halo, C １～６ Alkyl, C １～６ Haloalkyl, C ３～１０ Cycloalkyl, NO ２ , N(R ｅ ) (R ｆ ) and O(R ｅ 27. The compound of claim 26, or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof, optionally substituted with one or two substituents selected from the group consisting of:

28. The compound of formula (B-1) is represented by formula (IH): [In the formula, n is 0, 1, or 2; Each R ｘ When present, each independently represents cyano, halo, C １～６ Alkyl, C １～６ Haloalkyl, C ３～１０ Cycloalkyl, NO ２ , N(R ｅ ) (R ｆ ) and O(R ｅ ) selected from the group consisting of 28. The compound of claim 27, which is a compound of the formula: or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof.

29. The compound of formula (IH) 30. The compound of claim 28, selected from the group consisting of: or a stereoisomer, tautomer, or a pharma- ceutically acceptable salt thereof.

30. R ２ C １～１２ alkyl, where 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 ) and O(R ｅ 2. The compound of claim 1, or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof, wherein L is -CH=CH- or -C≡C-, and wherein L is optionally substituted with one or two substituents selected from the group consisting of:

31. 31. The compound of claim 30, or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof, wherein L is -CH=CH-.

32. 32. The compound of claim 31, or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof, wherein L is -C≡C-.

33. A compound selected from the group consisting of: or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof.

34. The compound of claim 33, or a stereoisomer, tautomer, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

35. The compound of claim 33, or a stereoisomer, tautomer, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

36. 36. A pharmaceutical composition comprising: (i) a compound according to any one of claims 1 to 35, or a stereoisomer, tautomer or pharma- ceutically acceptable salt thereof; and (ii) a pharma- ceutically acceptable carrier, diluent or excipient.

37. 36. Use of a compound according to any one of claims 1 to 35, or a stereoisomer, tautomer or pharma- ceutically acceptable salt thereof, for the preparation of a medicament for the treatment and / or prevention of a disease or condition mediated by TEAD activity.

38. 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 myelogenous (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharynx cancer, Cephaloma, 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, Lymphangiosarcoma, Lymphoblastic leukemia, Lymphoma (Hodgkin and non-Hodgkin), 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, Bone 38. The use according to claim 37, which is for the cancer of the tumors selected from the group consisting of myeloma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, vera erythrocytosis, 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. 36. A method for modulating a TEAD activity, comprising contacting a TEAD with a compound according to any one of claims 1 to 35, or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof.

40. 36. Use of a compound according to any one of claims 1 to 35, or a stereoisomer, tautomer or pharma- ceutically acceptable salt thereof, for modulating TEAD activity.

41. A pharmaceutical for the treatment and / or prevention of a disease or condition mediated by TEAD activity, comprising a compound according to any one of claims 1 to 35, or a stereoisomer, tautomer or pharma- ceutically acceptable salt thereof.

42. 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 myelogenous (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharynx cancer, Cephaloma, 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, Lymphangiosarcoma, Lymphoblastic leukemia, Lymphoma (Hodgkin and non-Hodgkin), 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, Bone The pharmaceutical agent according to claim 41, which is selected from the group consisting of myeloma, 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.

43. Formula (C-1): [In the formula, X １ is N or C-R ５ where each R ５ are independently H, cyano, halo, C(O)NH ２ , N(R ｅ ) (R ｆ ), C ３～１０ Cycloalkyl, C １～６ Alkoxy, C ６～２０ Aryl and C １～６ alkyl, where R ５ C １～６ Alkyl is hydroxyl or N(R ｅ ) (R ｆ ), or X １ R ５ is R ３ and together with 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 selected from one or more C １～６ may be substituted with alkyl, X ２ and X ３ are each independently N or C-R ５ where each R ５ are independently H, cyano, halo, C(O)NH ２ , N(R ｅ ) (R ｆ ), C ３～１０ Cycloalkyl, C １～６ Alkoxy, C ６～２０ Aryl and C １～６ alkyl, where R ５ C １～６ Alkyl is hydroxyl or N(R ｅ ) (R ｆ ) may be substituted with X ３ is N or C—H, R １ teeth, (i) oxiranyl or oxetanyl, where oxiranyl or oxetanyl is one or more C １～６ Optionally substituted with alkyl, where C １～６ Alkyl is one or more -C(O)NH ２ or (ii) N(R ｅ ) (CN), or (iii) where R ａ , R ｂ and R ｃ are each independently H, halo, cyano, hydroxyl, C １～６ Alkyl, C ６～２０ aryl, 3- to 10-membered heterocyclyl, and 5- to 20-membered heteroaryl, wherein C １～６ The alkyl may be further substituted with a hydroxyl, or (iv) where R ｄ is H, halo, cyano, hydroxyl, C １～６ Alkyl, C ６～２０ aryl, 3- to 10-membered heterocyclyl, and 5- to 20-membered heteroaryl, wherein C １～６ The alkyl may be further substituted with hydroxyl. L is absent, -O-, *-CH ２ -O-**, *-O-CH ２ -**, -CH=CH-, and -C≡C-, where ** is R ２ indicates the point of attachment to the moiety, * indicates the point of attachment to the remainder of the molecule, R ２ is C １～１２ Alkyl, C ３～１０ Cycloalkyl, 3-10 membered saturated heterocyclyl, C ６～２０ Aryl, C ５～１３ spirocyclyl or 5- to 20-membered heteroaryl, R ２ C １～１２ Alkyl, C ３～１０ Cycloalkyl, 3-10 membered saturated heterocyclyl, C ６～２０ Aryl, C ５～１３ The spirocyclyl or 5- to 20-membered heteroaryl 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.F. ５ and optionally substituted with one or two substituents selected from the group consisting of: R ３ Cyano, C １～６ Alkyl, C １～４ Alkoxy or C ２～４ alkenyl, where C ２～４ Alkenyl is N(R ｅ ) (R ｆ ), or R ３ , X １ R ５ and together with 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 selected from one or more C １～６ may be substituted with alkyl, provided that X ３ is CH, or R ３ is L's *-CH ２ Together with the carbon atoms of —O-** and the atoms to which they are attached, C ６ forming an aryl or a 6-membered heteroaryl; R ４ is H or C １～６ alkyl, where 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 ３～１０ Cycloalkyl, C １～６ Alkyl-C ３～１０ Cycloalkyl, 3- to 10-membered heterocyclyl, C ６～２０ aryl, and 3- to 20-membered heteroaryl, where 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 ６～２０ Aryl and 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. or a stereoisomer, tautomer or pharma- ceutically acceptable salt thereof, comprising reacting an amino (NH ２ ) group to an amide (NHC(O)R １ ) group using an acyl chloride compound. Including, The method according to the present invention, provided that the compound of formula (C-1) is not any one of N-{3-[2-amino-6-(ethylamino)pyrimidin-4-yl]-4-methylphenyl}prop-2-enamide, 3,4-dimethoxyacrylanilide, and N-[3-[2-methoxy-5-(trifluoromethyl)phenoxy]-4-methyl-phenyl]prop-2-enamide.

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