Therapeutic Compounds and Methods of Use

Abstract

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

Description

[0001] Cross - reference to related patent applications

[0002] This patent application claims priority to U.S. Provisional Patent Application No. 62 / 935,015, filed on November 13, 2019, and U.S. Provisional Patent Application No. 62 / 056,502, filed on July 24, 2020. The entire disclosures of these two provisional patent applications are incorporated herein by reference in their entirety.

[0003] Sequence Listing

[0004] This application for patent contains a sequence listing, which has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy was created on November 11, 2020, named P35805 - WO_SL.TXT, and is 34,037 bytes in size. Technical Field

[0005] The present disclosure relates to compounds that can be used for treating and / or preventing in mammals, particularly as inhibitors of TEAD that can be used for treating cancer.

[0006] Brief Description

[0007] The Hippo pathway is a signaling pathway that regulates cell proliferation and cell death and determines organ size. It is believed that this pathway acts as a tumor suppressor in mammals, and disorders of this pathway are often detected in human cancers. This pathway is involved in and / or may regulate the self - renewal and differentiation of stem cells and progenitor cells. In addition, the Hippo pathway may be involved in wound healing and tissue regeneration. Furthermore, it is believed that as the Hippo pathway cross - talks with other signaling pathways such as Wnt, Notch, Hedgehog, and MAPK / ERK, it may affect a variety of biological events, and its dysfunction may be involved in many human diseases in addition to being involved in 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.

[0008] 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 this pathway consists of a kinase cascade (Hippo-MST1-2 is upstream of Lats 1-2 and NDR1-2) that leads to the phosphorylation of two transcriptional coactivators, YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif or tafazzin; Zhao et al., Cancer Res., 2009, 69, 1089-1098; Lei et al., Mol. Cell. Biol., 2008, 28, 2426-2436).

[0009] Because the Hippo signaling pathway is a regulator of animal development, organ size control, and stem cell regulation, it has been implicated in cancer development (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 cell transformation through the interaction of these two proteins with TEAD family transcription factors. Increased YAP / TAZ transcriptional activity induces cancerous properties such as epithelial-mesenchymal transition, and it has also been found to endow breast cancer cells with stem cell properties. In vivo, in the mouse liver, overexpression of YAP or gene knockout of its upstream regulators MST1-2 triggers the development of hepatocellular carcinoma. Additionally, when the tumor suppressor NF2 is inactivated in the mouse liver, the development of hepatocellular carcinoma can be completely blocked by co-inactivation of YAP.

[0010] Deregulation of the Hippo tumor suppressor pathway is believed to be a major event in the development of a variety of malignancies, including but not limited to lung cancer (NSCLC; Zhou et al., Oncogene, 2011, 30, 2181-2186; Wang et al., Cancer Sci., 2010, 101, 1279-1285), breast cancer (Chan et al., Cancer Res., 2008, 68, 2592-2598; Lamar et al., Proc. Natl. Acad. Sci, USA, 2012; 109, E2441-E2250; Wang et al., Eur. J. Cancer, 2012, 48, 1227-1234), head and neck cancer (Gasparotto et al., Oncotarget., 2011, 2, 1165-1175; Steinmann et al., Oncol. Rep., 2009, 22, 1519-1526), colon cancer (Angela et al., Hum. Pathol., 2008, 39, 1582-1589; Yuen et al., PLoS One, 2013, 8, e54211; Avruch et al., Cell Cycle, 2012, 11, 1090-1096), ovarian cancer (Angela et al., Hum. Pathol., 2008, 39, 1582-1589; Chad et al., Cancer Res., 2010, 70, 8517-8525; Hall et al., Cancer Res., 2010, 70, 8517-8525), liver cancer (Jie et al., Gastroenterol. Res. Pract., 2013, 2013, 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., 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).

[0011] Two core components of the mammalian Hippo pathway are Lats1 and Lats2, which are nuclear Dbf2 - related (NDR) family protein kinases homologous to Drosophila Warts (Wts). Lats1 / 2 proteins are activated by binding to the scaffold proteins Mob1A / B (Mps, a binding kinase activator - like 1A and 1B) homologous to Drosophila Mats. Lats1 / 2 proteins can also be activated by phosphorylation by the STE20 family protein kinases Mst1 and Mst2 homologous to Drosophila Hippo. Lats1 / 2 kinases phosphorylate the downstream effectors YAP (Yes - associated protein) and TAZ (transcriptional co - activator with PDZ - binding motif; WWTR1) homologous to Drosophila Yorkie. Phosphorylation of YAP and TAZ by Lats1 / 2 is a key event within the Hippo signaling pathway. Lats1 / 2 phosphorylates YAP at multiple sites, but phosphorylation of Ser127 is crucial for YAP inhibition. Phosphorylation of YAP generates a protein - binding motif for the 14 - 3 - 3 family of proteins, which upon binding to 14 - 3 - 3 proteins, leads to the retention and / or sequestration of YAP in the cytoplasm. Similarly, Lats1 / 2 phosphorylates TAZ at multiple sites, but phosphorylation of Ser89 is crucial for TAZ inhibition. Phosphorylation of TAZ results in the retention and / or sequestration of TAZ in the cytoplasm. Additionally, phosphorylation of YAP and TAZ is believed to destabilize these proteins by activating phosphorylation - dependent degradation catalyzed by YAP or TAZ ubiquitination. Thus, when the Hippo pathway is "on", YAP and / or TAZ are phosphorylated, inactivated, and generally sequestered in the cytoplasm; conversely, when the Hippo pathway is "off", YAP and / or TAZ are unphosphorylated, active, and generally present in the nucleus.

[0012] Non-phosphorylated, activated YAP is transported into the nucleus, where its major target transcription factors are four proteins of the TEAD domain-containing family (TEAD1 to TEAD4, collectively "TEAD"). It has been found that YAP and TEAD (or other transcription factors such as Smad1, RUNX, ErbB4, and p73) together induce the expression of a variety of genes, including connective tissue growth factor (CTGF), Gli2, Birc5, Birc2, fibroblast growth factor 1 (FGF1), and amphiregulin (AREG). Similar to YAP, non-phosphorylated TAZ is transported into the nucleus, where it interacts with a variety of DNA-binding transcription factors such as peroxisome proliferator-activated receptor γ (PPARγ), thyroid transcription factor-1 (TTF-1), Pax3, TBX5, RUNX, TEAD1, and Smad2 / 3 / 4. Many genes activated by the YAP / TAZ-transcription factor complex mediate cell survival and proliferation. Thus, under some conditions, YAP and / or TAZ play an oncogenic role, while the Hippo pathway plays a tumor suppressor role.

[0013] Therefore, pharmacological targeting of the Hippo cascade by inhibiting TEAD would be a valuable approach for treating cancers with alterations in the function of this pathway. SUMMARY OF THE INVENTION

[0014] In some aspects, there is provided a compound of formula (B-1) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

[0015]

[0016] or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:

[0017] X1 is N or C-R5, wherein each R5 is independently selected from the group consisting of: 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 the C 1-6 alkyl of R5 is optionally substituted with hydroxy or N(R e )(R f ), or

[0018] R5 of X1, together with R3 and the atoms to which they are attached, form a 5-membered heterocyclic group or 5-membered heteroaryl, wherein the 5-membered heterocyclic group or 5-membered heteroaryl is optionally substituted with one or more C 1-6 alkyl;

[0019] X2 is N or C-R5, where each R5 is independently selected from the group consisting of: 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, where the C 1-6 alkyl of R5 is optionally substituted with hydroxy or N(R e )(R f );

[0020] X3 is N or C-H,

[0021] provided that when X3 is N and R1 is , then at least one of X1 and X2 is N;

[0022] R1 is:

[0023] (i) oxiranyl or oxetanyl, where the oxiranyl or oxetanyl is optionally substituted with one or more C 1-6 alkyl, where the C 1-6 alkyl is optionally substituted with one or more -C(O)NH2, and

[0024] 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 rest of the molecule, or

[0025] (ii) N(R e )(CN), and

[0026] 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 rest of the molecule, or

[0027] (iii) where R a , R b and R c are each independently selected from the group consisting of: H, halo, cyano, hydroxy, C 1-6 alkyl, C 6-20 aryl, 3- to 10-membered heterocyclic group and 5- to 20-membered heteroaryl, where the C 1-6 alkyl is further optionally substituted with hydroxy, provided that R a , Rb and R c at least two of which are H, and

[0028] L is absent or is 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

[0029] (iv) wherein R d is selected from the group consisting of: H, halo, cyano, hydroxy, C 1-6 alkyl, C 6-20 aryl, 3- to 10-membered heterocycloalkyl and 5- to 20-membered heteroaryl, wherein the C 1-6 alkyl is further optionally substituted by hydroxy, and

[0030] 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;

[0031] R2 is C 1-12 alkyl, C 3-10 cycloalkyl, 3- to 10-membered saturated heterocycloalkyl, C 6-20 aryl, C 5-13 spirocyclic or 5- to 20-membered heteroaryl, wherein

[0032] the C of R2 1-12 alkyl, C 3-10 cycloalkyl, 3- to 10-membered saturated heterocycloalkyl, C 6-20 aryl, C 5-13 spirocyclic or 5- to 20-membered heteroaryl is independently optionally substituted by one or two substituents selected from the group consisting of: cyano, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, NO2, N(R e )(R f )、O(R e ), and SF5,

[0033] provided that when R2 is C 1-12 alkyl, wherein the C 1-12 alkyl is independently optionally substituted by one or two substituents 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 ), then L is -CH=CH- or -C≡C-;

[0034] R3 is cyano, C 1-6 alkyl, C 1-4 alkoxy or C 2-4 alkenyl, wherein the C 2-4 alkenyl is optionally substituted by N(R e )(R f ), or

[0035] R3, together with R5 of X1 and the atoms to which they are attached, forms a 5-membered heterocyclic group or a 5-membered heteroaryl group, wherein the 5-membered heterocyclic group or 5-membered heteroaryl group is optionally substituted by one or more C 1-6 alkyl, provided that X3 is CH, or

[0036] R3, together with the carbon atom of *-CH2-O-* of L and the atoms to which they are attached, forms a C6 aryl or 6-membered heteroaryl group,

[0037] provided that:

[0038] (i) when R3 is cyano, C 1-6 alkyl, C 1-4 alkoxy or C 2-4 alkenyl, wherein the C 2-4 alkenyl is optionally substituted by N(R e )(R f ), and

[0039] R1 is and

[0040] R2 is a 3- to 10-membered saturated heterocyclic group or a 5- to 20-membered heteroaryl group, wherein the 3- to 10-membered saturated heterocyclic group or 5- to 20-membered heteroaryl group is independently optionally substituted by one or two substituents 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 ), then

[0041] L is *-CH2-O-*, -CH=CH- or -C≡C-, where * indicates the point of attachment to the rest of the molecule and ** indicates the point of attachment to the R2 moiety, and

[0042] (ii) when R3, together with R5 of X1 and the atoms to which they are attached, forms a 5-membered heterocyclic group or a 5-membered heteroaryl group, and X3 is CH, and

[0043] R1 is and

[0044] R2 is a 3- to 10-membered saturated heterocyclic group or a 5- to 20-membered heteroaryl group, where the 3- to 10-membered saturated heterocyclic group or the 5- to 20-membered heteroaryl group is independently optionally substituted with one or two substituents 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 ); when

[0045] then L is absent or is *-CH2-O-*, -CH═CH-, or -C≡C-, where * indicates the point of attachment to the rest of the molecule and ** indicates the point of attachment to the R2 moiety, and

[0046] (iii) when R3 together with the carbon atom of the *-CH2-O-* of L and the atoms to which they are attached forms a C6 aryl or 6-membered heteroaryl, and

[0047] R1 is ; when

[0048] then R2 is a 3- to 10-membered saturated heterocyclic group or a 5- to 20-membered heteroaryl group, where the 3- to 10-membered saturated heterocyclic group or the 5- to 20-membered heteroaryl group is independently optionally substituted with one or two substituents 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 );

[0049] R4 is H or C 1-6 alkyl, where the C 1-6 alkyl is optionally substituted with a hydroxyl group; and

[0050] R e and R f are each independently and at each occurrence independently selected from the group consisting of: 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 heterocyclic group, C 6-20 aryl, and 3- to 20-membered heteroaryl, where Re and R f said C of 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 heterocyclic group, C 6-20 aryl and 3- to 20-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, oxo, cyano, halo, NO2, and hydroxy.

[0051] In some aspects, there is provided a compound of formula (B) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

[0052]

[0053] or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:

[0054] X1 is N or C-R5, where each R5 is independently selected from the group consisting of: 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, where the C 1-6 alkyl of R5 is optionally substituted with hydroxy or N(R e )(R f ), or

[0055] R5 of X1 and R3, together with the atoms to which they are attached, form a 5-membered heterocyclic group or 5-membered heteroaryl, where the 5-membered heterocyclic group or 5-membered heteroaryl is optionally substituted with one or more C 1-6 alkyl, provided that X3 is CH;

[0056] X2 is N or C-R5, where each R5 is independently selected from the group consisting of: 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, where the C 1-6 alkyl of R5 is optionally substituted with hydroxy or N(R e )(Rf ) substituted;

[0057] X3 is N or C-H,

[0058] provided that when X3 is N and R1 is then at least one of X1 and X2 is N;

[0059] R1 is:

[0060] (i) oxiranyl or oxetanyl, wherein the oxiranyl or oxetanyl is optionally substituted by one or more C 1-6 alkyl groups, and

[0061] 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 rest of the molecule, or

[0062] (ii) N(R e )(CN), and

[0063] 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 rest of the molecule, or

[0064] (iii) wherein R a 、R b and R c are each independently selected from the group consisting of: H, halo, cyano, hydroxy, C 1-6 alkyl, C 6-20 aryl, 3- to 10-membered heterocyclic group, and 5- to 20-membered heteroaryl, wherein the C 1-6 alkyl is further optionally substituted by hydroxy, provided that at least two of R a 、R b and R c are H, and

[0065] 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

[0066] (iv) wherein R d is selected from the group consisting of: H, halo, cyano, hydroxy, C 1-6 alkyl, C6-20 an aryl group, a 3- to 10-membered heterocyclic group, and a 5- to 20-membered heteroaryl group, wherein the C 1-6 alkyl group is further optionally substituted with a hydroxyl group, and

[0067] 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;

[0068] R2 is C 1-12 alkyl, C 3-10 cycloalkyl, a 3- to 10-membered saturated heterocyclic group, C 6-20 aryl, C 5-13 spirocyclic group, or a 5- to 20-membered heteroaryl group, wherein

[0069] the C 1-12 alkyl, C 3-10 cycloalkyl, a 3- to 10-membered saturated heterocyclic group, C 6-20 aryl, C 5-13 spirocyclic group, or a 5- to 20-membered heteroaryl group is independently optionally substituted with one or two substituents 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 );

[0070] provided that when R2 is C 1-12 alkyl, wherein the C 1-12 alkyl is independently optionally substituted with one or two substituents 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 ), then L is -CH═CH- or -C≡C-;

[0071] R3 is cyano, C 1-6 alkyl, C 1-4 alkoxy, or C 2-4 alkenyl, wherein the C 2-4 alkenyl is optionally substituted with N(R e )(R f ), or

[0072] R3, together with the R5 of X1 and the atoms to which they are attached, forms a 5-membered heterocyclic group or 5-membered heteroaryl group, wherein the 5-membered heterocyclic group or 5-membered heteroaryl group is optionally substituted by one or more C 1-6 alkyl groups, provided that X3 is CH, or

[0073] R3, together with the carbon atom of *-CH2-O-* of L and the atoms to which they are attached, forms a C6 aryl group or 6-membered heteroaryl group,

[0074] provided that:

[0075] (i) When R3 is cyano, C 1-6 alkyl, C 1-4 alkoxy or C 2-4 alkenyl, wherein the C 2-4 alkenyl is optionally substituted by N(R e )(R f ), and

[0076] R1 is and

[0077] R2 is a 3- to 10-membered saturated heterocyclic group or 5- to 20-membered heteroaryl group, wherein the 3- to 10-membered saturated heterocyclic group or 5- to 20-membered heteroaryl group is independently optionally substituted by one or two substituents 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 ), then

[0078] L is *-CH2-O-*, -CH=CH- or -C≡C-, where * indicates the point of attachment to the rest of the molecule and ** indicates the point of attachment to the R2 moiety, or

[0079] (ii) When R3, together with the R5 of X1 and the atoms to which they are attached, forms a 5-membered heterocyclic group or 5-membered heteroaryl group, wherein the 5-membered heterocyclic group or 5-membered heteroaryl group is optionally substituted by one or more C 1-6 alkyl groups, provided that X3 is CH, and

[0080] R1 is and

[0081] R2 is a 3- to 10-membered saturated heterocyclic group or 5- to 20-membered heteroaryl group, wherein the 3- to 10-membered saturated heterocyclic group or 5- to 20-membered heteroaryl group is independently optionally substituted by one or two substituents selected from the group consisting of: cyano, halo, C 1-6 alkyl, C 1-6 haloalkyl, C3-10 Cycloalkyl, NO2, N(R e )(R f ) and O(R e )hour,

[0082] then L is absent or 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

[0083] (iii) when R3 together with the carbon atom of *-CH2-O-** of L and the atoms to which they are attached form a C6 aryl or 6-membered heteroaryl group, and

[0084] R1 is hour,

[0085] Then R2 is a 3- to 10-membered saturated heterocyclic group or a 5- to 20-membered heteroaryl group, wherein the 3- to 10-membered saturated heterocyclic group or the 5- to 20-membered heteroaryl group is independently optionally substituted by one or two substituents selected from the group consisting of cyano, halo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, NO2, N(R e )(R f ) and O(R e );

[0086] R4 is H or C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted with hydroxy; and

[0087] R e and R f independently from one another and at each occurrence are selected from the group consisting of: 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 heterocyclic group, C 6-20 Aryl and 3- to 20-membered heteroaryl, wherein R e and R f The 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 heterocyclic group, C 6-20An aryl and a 3- to 20-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, oxo, cyano, halo, NO2, and hydroxy.

[0088] In some aspects of the present disclosure, a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof has the following formula (I):

[0089]

[0090] Wherein:

[0091] X1 and X2 are each independently N or C-R5, where R5 is selected from the group consisting of: 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 alkyl is optionally substituted with hydroxy;

[0092] X3 is N or CH, provided that when X3 is N, at least one of X1 and X2 is N;

[0093] R1 is Where R a , R b and R c are each independently selected from the group consisting of: H, halo, cyano, hydroxy, C 1-6 alkyl, C 6-20 aryl, 3- to 10-membered heterocyclic, and 5- to 20-membered heteroaryl, wherein C 1-6 alkyl is further optionally substituted with hydroxy, provided that at least two of 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 rest of the molecule, or

[0094] R1 is Where R d is selected from the group consisting of: H, halo, cyano, hydroxy, C 1-6 alkyl, C 6-20 aryl, 3- to 10-membered heterocyclic, and 5- to 20-membered heteroaryl, wherein C 1-6The alkyl group is further optionally substituted with a hydroxyl group, 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 rest of the molecule;

[0095] R2 is C 1-12 alkyl, C 3-10 cycloalkyl, a 3- to 10-membered saturated heterocyclic group, C 6-20 aryl, or C 5-13 spirocyclic group, where C 1-12 alkyl, C 3-10 cycloalkyl, a 3- to 10-membered saturated heterocyclic group, C 6-20 aryl, or C 5-13 the spirocyclic group is independently optionally substituted with one, two, three, or four substituents 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 ),

[0096] where each R e and R f is independently selected from the group consisting of 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, a 3- to 10-membered heterocyclic group, C 6-20 aryl, and a 3- to 20-membered heteroaryl, where C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 1-6 alkyl-C 3-10 cycloalkyl, a 3- to 10-membered heterocyclic group, C 6-20 aryl, and a 3- to 20-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, oxo, cyano, halo, NO2, and hydroxyl,

[0097] provided that when R2 is C 1-12 alkyl, where C 1-12The alkyl groups are independently optionally substituted with one, two, three or four substituents 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 -CH=CH- or -C≡C-;

[0098] R3 is cyano, C 1-6 alkyl, C 1-4 alkoxy or C 2-4 alkenyl, wherein the C 2-4 alkenyl is optionally substituted with NH(R e ); or R3 together with R5 of X1 and the atoms to which they are attached forms a 5-membered heterocyclic group or a 5-membered heteroaryl group, provided that X3 is CH; or R3 together with the carbon atom of the *-CH2-O-* of L and the atoms to which they are attached forms a C6 aryl group or a 6-membered heteroaryl group,

[0099] provided that:

[0100] (i) When R3 is cyano, C 1-6 alkyl, C 1-4 alkoxy or C 2-4 alkenyl, wherein the C 2-4 alkenyl is optionally substituted with N(R e )(R f ) and R2 is a 3- to 10-membered saturated heterocyclic group or a 5- to 20-membered heteroaryl group, wherein the 3- to 10-membered saturated heterocyclic group or the 5- to 20-membered heteroaryl group is independently optionally substituted with one or two substituents 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 ), then 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

[0101] (ii) When R3 together with R5 of X1 and the atoms to which they are attached forms a 5-membered heterocyclic group or a 5-membered heteroaryl group, provided that X3 is CH and R2 is a 3- to 10-membered saturated heterocyclic group or a 5- to 20-membered heteroaryl group, wherein the 3- to 10-membered saturated heterocyclic group or the 5- to 20-membered heteroaryl group is independently optionally substituted with one or two substituents selected from the group consisting of: cyano, halo, C 1-6 alkyl, C1-6 haloalkyl, C 3-10 cycloalkyl, NO2, N(R e )(R f ) and O(R e ), then L is absent or is *-CH2-O-*, -CH=CH- or -C≡C-, where * indicates the point of attachment to the remainder of the molecule and ** indicates the point of attachment to the R2 moiety, or

[0102] (iii) When R3 together with the carbon atom of *-CH2-O-* of L and the atoms to which they are attached forms a C6 aryl or 6-membered heteroaryl, and R2 is a 3- to 10-membered saturated heterocyclic group or a 5- to 20-membered heteroaryl, where the 3- to 10-membered saturated heterocyclic group or the 5- to 20-membered heteroaryl is independently optionally substituted with one or two substituents 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 ), then L is *-CH2-O-*, -CH=CH- or -C≡C-, where * indicates the point of attachment to the remainder of the molecule and ** indicates the point of attachment to the R2 moiety; and

[0103] R4 is H or C 1-6 alkyl, where the C 1-6 alkyl is optionally substituted with a hydroxy group.

[0104] In some aspects, there is provided a pharmaceutical composition comprising a compound as described herein, such as 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, diluent or excipient.

[0105] In some aspects, there is provided a compound as described herein, such as a compound of formula (B-1), formula (B) or formula (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, for use in a pharmaceutical therapy.

[0106] In some aspects, there is provided a compound as described herein, such as a compound of formula (B-1), formula (B) or formula (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, for the treatment or prevention of cancer, mesothelioma, sarcoma or leukemia.

[0107] In some aspects, there is provided a compound as described herein, such as a compound of formula (B-1), formula (B) or formula (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of cancer, mesothelioma, sarcoma or leukemia.

[0108] In some aspects, there is provided a method of treating cancer, mesothelioma, sarcoma or leukemia in a mammal, the method comprising administering to the mammal a compound as described herein, such as a compound of formula (B-1), formula (B) or formula (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0109] In some aspects, there is provided a method of treating cancer, mesothelioma, sarcoma or leukemia in a mammal, the method comprising administering to the mammal a compound as described herein, such as 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.

[0110] In some aspects, there is provided a compound as described herein, such as a compound of formula (B-1), formula (B) or formula (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, for modulating TEAD activity.

[0111] In some aspects, there is provided a compound as described herein, such as a compound of formula (B-1), formula (B) or formula (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, for treating or preventing a disease or disorder mediated by TEAD activity.

[0112] In some aspects, there is provided a compound as described herein, such as a compound of formula (B-1), formula (B) or formula (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for treating or preventing a disease or disorder mediated by TEAD activity.

[0113] In some aspects, there is provided a method of modulating TEAD activity, the method comprising contacting TEAD with a compound as described herein, such as a compound of formula (B-1), formula (B) or formula (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0114] In some aspects, there is provided a method of treating a disease or disorder mediated by TEAD activity in a mammal, the method comprising administering to the mammal a compound as described herein, such as a compound of formula (B-1), formula (B) or formula (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. Detailed Description

[0115] Definitions

[0116] Unless otherwise indicated, the following specific terms and phrases used in the specification and claims are defined as follows.

[0117] The term "moiety" refers to an atom or a group of atoms bonded by chemical bonds, which is attached to another atom or molecule by one or more chemical bonds to form part of a molecule.

[0118] The term "substituted" refers to the fact that at least one hydrogen atom of the moiety is replaced by another substituent or moiety.

[0119] The term "alkyl" refers to an aliphatic straight-chain or branched-chain saturated hydrocarbon moiety having from 1 to 20 carbon atoms, such as from 1 to 12 carbon atoms or from 1 to 6 carbon atoms. The alkyl group may be optionally substituted.

[0120] The term "cycloalkyl" means a saturated or partially unsaturated carbocyclic moiety having a monocyclic or bicyclic (including bridged bicyclic) ring and from 3 to 10 carbon atoms within the ring. In certain aspects, the cycloalkyl may contain from 3 to 8 carbon atoms (i.e., (C3-C8) cycloalkyl). In other certain aspects, the cycloalkyl may contain from 3 to 6 carbon atoms (i.e., (C3-C6) cycloalkyl). Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and their partially unsaturated derivatives (cycloalkenyl) (e.g., cyclopentenyl, cyclohexenyl and cycloheptenyl). The cycloalkyl moiety may be attached in a spiro manner, such as spiropropyl:

[0121] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms of the alkyl have been replaced by the same or different halogen atoms, such as fluorine atoms. Examples of haloalkyls include monofluoro-, difluoro- or trifluoro-methyl, -ethyl or -propyl, e.g., 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl or trifluoromethyl. The haloalkyl group may be optionally substituted.

[0122] The term "alkenyl" refers to a straight-chain or branched-chain alkyl or substituted alkyl group as defined elsewhere herein having at least one carbon-carbon double bond. The alkenyl group may be optionally substituted.

[0123] The term "alkynyl" refers to a straight-chain or branched-chain alkyl or substituted alkyl group as defined elsewhere herein having at least one carbon-carbon triple bond. The alkynyl group may be optionally substituted.

[0124] The terms "heterocyclic group" and "heterocycle" refer to 4-, 5-, 6- and 7-membered monocyclic or 7-, 8-, 9- and 10-membered bicyclic (including bridged bicyclic) heterocyclic moieties, which are saturated or partially unsaturated and have one or more (e.g., 1, 2, 3 or 4) heteroatoms selected from oxygen, nitrogen and sulfur located in the ring, and the remaining ring atoms are carbon. When used to refer to the ring atoms of a heterocycle, nitrogen or sulfur may also be in oxidized form, and nitrogen may be substituted. The heterocycle can be attached to its side groups at any heteroatom or carbon atom, resulting in a stable structure, and any ring atom can be optionally substituted. Examples of such saturated or partially unsaturated heterocycles include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxepinyl, thiepinyl, morpholinyl and quinuclidinyl. Other examples of such saturated or partially unsaturated heterocycles include, but are not limited to, oxiranyl and oxetanyl. The term heterocycle also includes groups in which the heterocycle 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. The heterocyclic group can be optionally substituted.

[0125] The term "aryl" refers to a cyclic aromatic hydrocarbon moiety of a monocyclic, bicyclic or tricyclic aromatic ring having 5 to 20 carbon ring atoms. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, benzyl, etc. The term "aryl" also includes partially hydrogenated derivatives of the cyclic aromatic hydrocarbon moiety, provided that at least one ring of the cyclic aromatic hydrocarbon moiety is aromatic, each being optionally substituted. In some aspects, the monocyclic aromatic ring can have 5 or 6 carbon ring atoms. The aryl group can be optionally substituted.

[0126] The term "heteroaryl" refers to a monocyclic or bicyclic system of an aromatic heterocycle having 1 to 20 ring atoms, which contains 1, 2, 3 or 4 heteroatoms selected from N, O and S, and the remaining ring atoms are carbon. Examples of heteroaryl moieties include pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, isoxazolyl, benzofuryl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuryl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl. The heteroaryl group can be optionally substituted.

[0127] The terms "halo" and "halogen" refer to fluoro, chloro, bromo, and iodo. In some aspects, halo is fluoro or chloro.

[0128] The term "oxo" refers to the =O moiety.

[0129] The term "cyano" refers to the -C≡N moiety.

[0130] The terms "spiro" and "spiro group" refer to a carbocyclic bicyclic ring system containing 5 to 15 carbon atoms and having both rings joined by a single atom. The size and nature of the rings can be different or can be the same in size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spiroketone, or spirodecane. One or more carbon atoms in the spiro ring can be replaced by a heteroatom (e.g., O, N, S, or P), where in these aspects, the spiro ring can contain 3 to 14 carbon atoms. The spiro group can be optionally substituted.

[0131] The term "cyclic" refers to a moiety that is a member of a ring, which includes but is not limited to a cycloalkyl ring, a cycloalkenyl ring, an aryl ring, a heteroaryl ring, a heterocyclic ring, or a spiro group ring. For example, if a heteroaryl ring is described as "containing two or more cyclic heteroatoms", then two or more of the ring members of the heteroaryl ring will be heteroatoms.

[0132] The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the free base or free acid and are not biologically or otherwise undesirable. Salts can be formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., preferably hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, salicylic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, N-acetylcysteine, etc. In addition, salts can be prepared by the addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include but are not limited to sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, and magnesium salts, etc. Salts derived from organic bases include but are not limited to salts including the following: primary amines, secondary amines, and tertiary amines, naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins, etc.

[0133] The term "prodrug" refers to those compounds that readily undergo chemical change under physiological conditions to provide the compounds of the present disclosure. In addition, prodrugs can be converted to the compounds of the present disclosure in an indirect in vivo environment by chemical or biochemical means. For example, when a prodrug is placed in a transdermal patch reservoir having a suitable enzyme or chemical reagent, the prodrug can be slowly converted to the compounds of the present disclosure.

[0134] In some aspects of prodrugs, the prodrug includes a compound in which an amino acid residue or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues is covalently linked to a free amino group, a hydroxyl group, or a carboxylic acid group of a compound of the present disclosure through an amide or ester bond. Amino acid residues include, but are not limited to, the 20 natural amino acids typically represented by three-letter symbols, and also include phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, dehydroglucose, isododecane, γ-carboxyglutamic acid, hippuric acid, octahydroindole-2-carboxylic acid, statine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, β-alanine, γ-aminobutyric acid, citrulline, homocysteine, homoserine, methylalanine, p-benzoyl-phenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone, and tert-butylglycine.

[0135] In some other aspects of prodrugs, the free carboxyl group of a compound of the present disclosure can be derivatized to an amide or an alkyl ester. In other aspects of prodrugs, a prodrug containing a free hydroxyl group can be derivatized to a prodrug by converting the hydroxyl group to a group such as, but not limited to, a phosphate ester, a hemisuccinate ester, a dimethylaminoacetate ester, or a phosphonyloxymethoxycarbonyl, 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. Also included are carbamate prodrugs of hydroxyl and amino groups, such as carbonate prodrugs of hydroxyl groups, sulfonate esters, and sulfate esters. Also covered are derivatizations of hydroxyl groups to (acyloxy)methyl and (acyloxy)ethyl ethers, where the acyl group can be an alkyl ester optionally substituted with groups including, but not limited to, ether, amine, and carboxylic acid functional groups, or where the acyl group is an amino acid ester as described above. Such prodrugs are as described in J. Med. Chem., (1996), 39:10. More specific examples include replacing the hydrogen atom of an alcohol group with a group such as: (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, succinyl, (C 1-6 ) alkanoyl, α-amino(C 1-4)alkanoyl, aryl and α-aminoacyl, or α-aminoacyl-α-aminoacyl, wherein the α-aminoacyl groups are each independently selected from naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(C 1-6 )alkyl)2 or glycosyl (radical produced by removal of the hydroxy group of the hemiacetal form of the carbohydrate).

[0136] For other examples of prodrug derivatives, see, for example, a) Design of Prodrugs, edited by H. Bundgaard (Elsevier, 1985) and Methods in Enzymology, Volume 42, pages 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, H. Bundgaard, Chapter 5 "Design and Application of Prodrugs" pages 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H. Bundgaard et al., Journal of Pharmaceutical Sciences, 77:285 (1988); and e) N. Kakeya et al., Chem. Pharm. Bull., 32:692 (1984), each of which is specifically incorporated herein by reference.

[0137] In addition, the present disclosure provides metabolites of the compounds of the present disclosure. As used herein, "metabolite" refers to a product produced by the metabolism of a particular compound or its salt in vivo. Such products can be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound.

[0138] Metabolites are generally prepared by radiolabeling the compounds of the present disclosure (e.g., 14 C or 3The isotopes of [[ID=]]H) are identified and administered parenterally 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) to allow sufficient time for metabolism (usually about 30 seconds to 30 hours), and the conversion products are isolated from urine, blood, or other biological samples. Since these products are labeled, they are easily isolated (other products are isolated by using antibodies capable of binding to epitopes surviving in the metabolite). In a conventional manner, for example, by MS, LC / MS, or NMR analysis, the structure of the metabolite is determined. Generally, the analysis of metabolites is carried out in the same manner as conventional drug metabolism studies well known to those skilled in the art. As long as no metabolites are found in vivo, it can be used for diagnostic assays of the therapeutic dose of the disclosed compound.

[0139] Certain compounds of the present disclosure may exist in unsolvated forms as well as solvated forms, including hydrated forms. Generally, the solvated forms are equivalent to the unsolvated forms and are intended to be encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. Generally, for the uses contemplated by the present disclosure, all physical forms are equivalent and are intended to be encompassed within the scope of the present disclosure.

[0140] Compounds having the same molecular formula but differing in the bonding properties or order of their atoms or in the spatial arrangement of their atoms are called "isomers". Isomers that differ in the spatial arrangement of their atoms are called "stereoisomers". Diastereoisomers are stereoisomers that have opposite configurations at one or more chiral centers but are not enantiomers. Stereoisomers bearing 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, if a carbon atom is bonded to four different groups, there may be a pair of enantiomers. An enantiomer can be characterized by the absolute configuration of one or more of its asymmetric centers and described by the R- and S-rules of Cahn, Ingold, and Prelog, or by the mode by which the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., the (+)-isomer or (-)-isomer, respectively). Chiral compounds can exist as individual enantiomers or as mixtures of individual enantiomers. A mixture containing equal proportions of enantiomers is called a "racemic mixture". In some aspects, the compound is enriched to at least about 90% by weight of a single diastereoisomer or enantiomer. In other aspects, the compound is enriched to at least about 95%, 98%, or 99% by weight of a single diastereoisomer or enantiomer.

[0141] Certain compounds of the present disclosure possess asymmetric carbon atoms (chiral centers) or double bonds; racemates, diastereoisomers, geometric isomers, positional isomers, and individual isomers (e.g., isolated enantiomers) are all intended to be encompassed within the scope of the present disclosure.

[0142] 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 of different energies that interconvert via a low energy barrier. For example, prototropic tautomers (also known as prototropic tautomeric forms) include interconversions via proton migration, such as keto - enol and imine - enamine isomerizations. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0143] Unless otherwise specified, the term "the compound(s) of formula... " or "compound(s) of formula... " or "the multiple compounds of formula... " or "multiple compounds of formula... " refers to any compound selected from the group of compounds defined by the formula. In some embodiments or aspects, the term also includes pharmaceutically acceptable salts or esters of any such compound, as well as stereoisomers and tautomers of such compounds.

[0144] The term "therapeutically effective amount" of a compound means an amount of the compound that is effective to prevent, alleviate, or reduce the symptoms of a disease or to extend the survival period of a treated subject. Determination of a therapeutically effective amount is within the skill in the art. The therapeutically effective amount or dose of the compounds according to the present disclosure can vary within a wide range and can be determined in a manner known in the art. This dose will be adjusted according to the individual needs in each particular case, which include the specific compound being administered, the route of administration, the disorder being treated, and the patient being treated. Generally, in the case of oral or parenteral administration to an adult of approximately 70 kg body weight, a daily dose of about 0.1 mg to 5,000 mg, 1 mg to about 1,000 mg, or 1 mg to 100 mg may be appropriate, but can exceed the lower and upper limits when indicated. The daily dose can be administered as a single dose or divided doses, or for parenteral administration, it can be given as a continuous infusion.

[0145] The term "pharmaceutically acceptable carrier" is intended to include any and all materials compatible with drug administration, including solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and other materials and compounds compatible with drug administration. It is contemplated for use in the compositions of the present disclosure except in cases where any conventional medium or agent is incompatible with the compounds of the present disclosure. Supplementary active compounds can also be incorporated into the compositions.

[0146] Compound

[0147] In some aspects of the present disclosure, a compound or its stereoisomer, tautomer or pharmaceutically acceptable salt has the following formula (B-1):

[0148]

[0149] or its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein:

[0150] X1 is N or C-R5, wherein each R5 is independently selected from the group consisting of: 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 the C 1-6 alkyl of R5 is optionally substituted with hydroxy or N(R e )(R f ), or

[0151] the R5 of X1 and R3 and the atoms to which they are attached together form a 5-membered heterocyclic group or 5-membered heteroaryl, wherein the 5-membered heterocyclic group or 5-membered heteroaryl is optionally substituted with one or more C 1-6 alkyl, provided that X3 is CH;

[0152] X2 is N or C-R5, wherein each R5 is independently selected from the group consisting of: 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 the C 1-6 alkyl of R5 is optionally substituted with hydroxy or N(R e )(R f );

[0153] X3 is N or C-H,

[0154] provided that when X3 is N and R1 is , then at least one of X1 and X2 is N;

[0155] R1 is:

[0156] [[ID=6"]](i) oxiranyl or oxetanyl, wherein the oxiranyl or oxetanyl is optionally substituted with one or more C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more -C(O)NH2, and

[0157] L is absent or 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

[0158] (ii) N(R e )(CN), and

[0159] L is absent or 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

[0160] (iii) wherein R a 、R b and R c each independently is selected from the group consisting of: H, halo, cyano, hydroxy, C 1-6 alkyl, C 6-20 aryl, 3- to 10-membered heterocyclic group, and 5- to 20-membered heteroaryl, wherein said C 1-6 alkyl is further optionally substituted with hydroxy, provided that at least two of R a 、R b and R c are H, and

[0161] L is absent or is 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

[0162] (iv) wherein R d is selected from the group consisting of: H, halo, cyano, hydroxy, C 1-6 alkyl, C 6-20 aryl, 3- to 10-membered heterocyclic group, and 5- to 20-membered heteroaryl, wherein said C 1-6 alkyl is further optionally substituted with hydroxy, and

[0163] 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;

[0164] R2 is C 1-12 alkyl, C 3-10Cycloalkyl, 3- to 10-membered saturated heterocyclic group, C 6-20 Aryl, C 5-13 Spiro group or 5- to 20-membered heteroaryl, wherein

[0165] The C of R2 1-12 Alkyl, C 3-10 Cycloalkyl, 3- to 10-membered saturated heterocyclic group, C 6-20 Aryl, C 5-13 Spiro group or 5- to 20-membered heteroaryl is independently optionally substituted by one or two substituents selected from the group consisting of: cyano, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, NO2, N(R e )(R f ), O(R e ) and SF5,

[0166] Provided that when R2 is C 1-12 Alkyl, wherein the C 1-12 Alkyl is independently optionally substituted by one or two substituents 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 ), then L is -CH=CH- or -C≡C-;

[0167] R3 is cyano, C 1-6 Alkyl, C 1-4 Alkoxy or C 2-4 Alkenyl, wherein the C 2-4 Alkenyl is optionally substituted by N(R e )(R f ), or

[0168] R3, together with R5 of X1 and the atoms to which they are attached, forms a 5-membered heterocyclic group or 5-membered heteroaryl, wherein the 5-membered heterocyclic group or 5-membered heteroaryl is optionally substituted by one or more C 1-6 Alkyl, provided that X3 is CH, or

[0169] R3, together with the carbon atom of *-CH2-O-* of L and the atoms to which they are attached, forms a C6 aryl or 6-membered heteroaryl,

[0170] Provided that:

[0171] (i) When R3 is cyano, C 1-6 Alkyl, C 1-4 Alkoxy or C2-4 Alkenyl, wherein said C 2-4 The alkenyl is optionally substituted by N(R e )(R f ), and

[0172] R1 is and

[0173] R2 is a 3- to 10-membered saturated heterocyclic group or a 5- to 20-membered heteroaryl group, wherein the 3- to 10-membered saturated heterocyclic group or the 5- to 20-membered heteroaryl group is independently optionally substituted by one or two substituents 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 ), when

[0174] then L is *-CH2-O-*, -CH=CH-, or -C≡C-, where * indicates the point of attachment to the rest of the molecule and ** indicates the point of attachment to the R2 moiety, or

[0175] (ii) When R3 and the R5 of X1 and the atoms to which they are attached together form a 5-membered heterocyclic group or a 5-membered heteroaryl group, provided that X3 is CH, and

[0176] R1 is and

[0177] R2 is a 3- to 10-membered saturated heterocyclic group or a 5- to 20-membered heteroaryl group, wherein the 3- to 10-membered saturated heterocyclic group or the 5- to 20-membered heteroaryl group is independently optionally substituted by one or two substituents 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 ), when

[0178] then L is absent or is *-CH2-O-*, -CH=CH-, or -C≡C-, where * indicates the point of attachment to the rest of the molecule and ** indicates the point of attachment to the R2 moiety, or

[0179] (iii) When R3 and the carbon atom of *-CH2-O-* of L and the atoms to which they are attached together form

[0180] a C6 aryl or 6-membered heteroaryl group, and

[0181] R1 is When

[0182] R2 is a 3- to 10-membered saturated heterocyclic group or a 5- to 20-membered heteroaryl group, wherein the 3- to 10-membered saturated heterocyclic group or the 5- to 20-membered heteroaryl group is independently optionally substituted with one or two substituents 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 );

[0183] R4 is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with a hydroxyl group; and

[0184] R e and R f are each independently and each occurrence independently selected from the group consisting of: 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 heterocyclic group, C 6-20 aryl and 3- to 20-membered heteroaryl, wherein the C e and R f of the 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 heterocyclic group, C 6-20 aryl and 3- to 20-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, oxo, cyano, halo, NO2 and hydroxyl.

[0185] In some aspects of the present disclosure, the compound or its stereoisomer, tautomer or pharmaceutically acceptable salt has the following formula (B):

[0186]

[0187] or its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein:

[0188] X1 is N or C-R5, where each R5 is independently selected from the group consisting of: 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, where the C 1-6 alkyl of R5 is optionally substituted by hydroxy or N(R e )(R f ), or

[0189] the R5 of X1 together with R3 and the atoms to which they are attached form a 5-membered heterocyclic group or a 5-membered heteroaryl group, where the 5-membered heterocyclic group or 5-membered heteroaryl group is optionally substituted by one or more C 1-6 alkyl, provided that X3 is CH;

[0190] X2 is N or C-R5, where each R5 is independently selected from the group consisting of: 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, where the C 1-6 alkyl of R5 is optionally substituted by hydroxy or N(R e )(R f );

[0191] X3 is N or C-H,

[0192] provided that, when X3 is N and R1 is , then at least one of X1 and X2 is N;

[0193] R1 is:

[0194] (i) oxiranyl or oxetanyl, where the oxiranyl or oxetanyl is optionally substituted by one or more C 1-6 alkyl, and

[0195] L is absent or 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 rest of the molecule, or

[0196] (ii) N(R e )(CN), and

[0197] L is absent or 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 rest of the molecule, or

[0198] (iii) wherein R a 、R b and R c are each independently selected from the group consisting of: H, halo, cyano, hydroxy, C 1-6 alkyl, C 6-20 aryl, 3- to 10-membered heterocyclic group, and 5- to 20-membered heteroaryl, wherein said C 1-6 alkyl is further optionally substituted with hydroxy, provided that at least two of R a 、R b and R c are H, and

[0199] L is absent or is 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

[0200] (iv) wherein R d is selected from the group consisting of: H, halo, cyano, hydroxy, C 1-6 alkyl, C 6-20 aryl, 3- to 10-membered heterocyclic group, and 5- to 20-membered heteroaryl, wherein said C 1-6 alkyl is further optionally substituted with hydroxy, and

[0201] 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 rest of the molecule;

[0202] R2 is C 1-12 alkyl, C 3-10 cycloalkyl, 3- to 10-membered saturated heterocyclic group, C 6-20 aryl, C 5-13 spiro group, or 5- to 20-membered heteroaryl, wherein

[0203] the C 1-12 alkyl, C 3-10 cycloalkyl, 3- to 10-membered saturated heterocyclic group, C 6-20 aryl, C 5-13The spiro group or 5- to 20-membered heteroaryl is independently optionally substituted by one or two substituents 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 ),

[0204] provided that when R2 is C 1-12 alkyl, wherein the C 1-12 alkyl is independently optionally substituted by one or two substituents 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 ), then L is -CH=CH- or -C≡C-;

[0205] R3 is cyano, C 1-6 alkyl, C 1-4 alkoxy or C 2-4 alkenyl, wherein the C 2-4 alkenyl is optionally substituted by N(R e )(R f ), or

[0206] R3, together with the R5 of X1 and the atoms to which they are attached, forms a 5-membered heterocyclic group or 5-membered heteroaryl, wherein the 5-membered heterocyclic group or 5-membered heteroaryl is optionally substituted by one or more C 1-6 alkyl, provided that X3 is CH, or

[0207] R3, together with the carbon atom of the *-CH2-O-* of L and the atoms to which they are attached, forms a C6 aryl or 6-membered heteroaryl,

[0208] provided that when:

[0209] (i) R3 is cyano, C 1-6 alkyl, C 1-4 alkoxy or C 2-4 alkenyl, wherein the C 2-4 alkenyl is optionally substituted by N(R e )(R f ), and

[0210] R1 is and

[0211] R2 is a 3- to 10-membered saturated heterocyclic group or a 5- to 20-membered heteroaryl group, wherein the 3- to 10-membered saturated heterocyclic group or the 5- to 20-membered heteroaryl group is independently optionally substituted with one or two substituents 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 ), and when

[0212] then L is *-CH2-O-*, -CH=CH-, or -C≡C-, where * indicates the point of attachment to the rest of the molecule and ** indicates the point of attachment to the R2 moiety, or

[0213] (ii) R3, together with the R5 of X1 and the atoms to which they are attached, forms a 5-membered heterocyclic group or a 5-membered heteroaryl group, wherein the 5-membered heterocyclic group or the 5-membered heteroaryl group is optionally substituted with one or more C 1-6 alkyl, provided that X3 is CH, and

[0214] R1 is and

[0215] R2 is a 3- to 10-membered saturated heterocyclic group or a 5- to 20-membered heteroaryl group, wherein the 3- to 10-membered saturated heterocyclic group or the 5- to 20-membered heteroaryl group is independently optionally substituted with one or two substituents 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 ), and when

[0216] then L is absent or is *-CH2-O-*, -CH=CH-, or -C≡C-, where * indicates the point of attachment to the rest of the molecule and ** indicates the point of attachment to the R2 moiety, or

[0217] (iii) R3, together with the carbon atom of the *-CH2-O-* of L and the atoms to which they are attached, forms a C6 aryl group or a 6-membered heteroaryl group, and

[0218] R1 is and when

[0219] then R2 is a 3- to 10-membered saturated heterocyclic group or a 5- to 20-membered heteroaryl group, wherein the 3- to 10-membered saturated heterocyclic group or the 5- to 20-membered heteroaryl group is independently optionally substituted with one or two substituents selected from the group consisting of: cyano, halo, C 1-6alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, NO2, N(R e )(R f ) and O(R e );

[0220] R4 is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with a hydroxyl group; and

[0221] R e and R f are each independently and at each occurrence independently selected from the group consisting of: 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 heterocyclic group, C 6-20 aryl and 3- to 20-membered heteroaryl, wherein the C e and R f of the 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 heterocyclic group, C 6-20 aryl and 3- to 20-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, oxo, cyano, halo, NO2 and hydroxyl.

[0222] In an embodiment, X1 is N or C-R5, where R5 is selected from the group consisting of H, C 3-10 cycloalkyl and C 1-6 alkyl, or the R5 of X1 together with R3 and the atoms to which they are attached form a 5-membered heterocyclic group or a 5-membered heteroaryl, where the 5-membered heterocyclic group or 5-membered heteroaryl is optionally substituted with one or more C 1-6 alkyl, provided that X3 is CH.

[0223] In an embodiment, X2 is N or C-R5, where each R5 is independently selected from the group consisting of: H, cyano, halo, C(O)NH2, C 1-6 alkoxy, C 6-20 aryl and C 1-6 alkyl, wherein the C of R51-6 The alkyl group is optionally substituted by a hydroxyl group.

[0224] In an embodiment, X3 is N or C-H, provided that when X3 is N and R1 is then at least one of X1 and X2 is N.

[0225] In an embodiment, R1 is

[0226] (i) oxiranyl, which is optionally substituted by one or more C 1-6 alkyl groups and L is absent; or

[0227] (ii) N(R e )(CN), and L is absent; or

[0228] (iii) wherein R a , R b and R c are each independently selected from the group consisting of: H, cyano, C 6-20 aryl and C 1-6 alkyl optionally substituted by a hydroxyl group, and L is absent or is 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

[0229] (iv) wherein R d is H and L is -CH=CH-.

[0230] In an embodiment, R2 is selected from the group consisting of C 1-12 alkyl, C 3-10 cycloalkyl, C 6-20 aryl and C 5-13 spirocyclic group, wherein C 1-12 alkyl, C 3-10 cycloalkyl, C 6-20 aryl and C 5-13 spirocyclic group are independently optionally substituted by one or two substituents selected from the group consisting of halo, C 1-6 alkyl and C 1-6 haloalkyl, provided that when R2 is C 1-12 alkyl, then L is -CH=CH- or -C≡C-.

[0231] In an embodiment, R3 is cyano or C 1-4 alkoxy; or R3, together with R5 of X1 and the atoms to which they are attached, forms a 5-membered heterocyclic group or a 5-membered heteroaryl group, wherein the 5-membered heterocyclic group or 5-membered heteroaryl group is optionally substituted by one or more C 1-6Alkyl substitution, provided that X3 is CH; or R3, together with the carbon atom of *-CH2-O-* of L and the atoms to which they are attached, forms a C6 aryl or 6-membered heteroaryl.

[0232] In an embodiment, R4 is H.

[0233] In an embodiment, R e and R f are each independently and, each time they appear, independently selected from the group consisting of H and C 1-6 alkyl.

[0234] In some aspects of the present disclosure, the compound or its stereoisomers, tautomers or pharmaceutically acceptable salts have the following formula (I):

[0235]

[0236] Wherein:

[0237] X1 and X2 are each independently N or C-R5, where R5 is selected from the group consisting of: 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 alkyl is optionally substituted with a hydroxyl group;

[0238] X3 is N or CH, provided that when X3 is N, at least one of X1 and X2 is N;

[0239] R1 is wherein R a , R b and R c are each independently selected from the group consisting of: H, halo, cyano, hydroxyl, C 1-6 alkyl, C 6-20 aryl, 3- to 10-membered heterocyclic group and 5- to 20-membered heteroaryl, wherein C 1-6 alkyl is further optionally substituted with a hydroxyl group, provided that at least two of 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 rest of the molecule, or

[0240] R1 is wherein R dSelected from the group consisting of: H, halo, cyano, hydroxy, C 1-6 Alkyl, C 6-20 aryl, 3- to 10-membered heterocyclic group and 5- to 20-membered heteroaryl, wherein C 1-6 The alkyl group is further optionally substituted with hydroxyl, and L is selected from the group consisting of: -O-, *-CH2-O-**, *-O-CH2-**, -CH=CH-, and -C≡C-, wherein ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the rest of the molecule;

[0241] R2 is C 1-12 Alkyl, C 3-10 Cycloalkyl, 3- to 10-membered saturated heterocyclic group, C 6-20 Aryl or C 5-13 Spirocyclyl, wherein C 1-12 Alkyl, C 3-10 Cycloalkyl, 3- to 10-membered saturated heterocyclic group, C 6-20 Aryl or C 5-13 The spiro group is optionally substituted independently with one, two, three or four substituents selected from the group consisting of cyano, halo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, NO2, N(R e )(R f ) and O(R e ),

[0242] Each R e and R f Independently selected from the group consisting of: 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- to 10-membered heterocyclic group, 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- to 10-membered heterocyclic group, C 6-20 The aryl group and the 3- to 20-membered heteroaryl group are each independently optionally substituted with one or more substituents selected from the group consisting of: C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, oxo, cyano, halo, NO2 and hydroxyl,

[0243] The condition is that when R2 is C 1-12 alkyl, where C 1-12 alkyl is independently optionally substituted by one, two, three or four substituents 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 ), and L is -CH=CH- or -C≡C-;

[0244] R3 is cyano, C 1-6 alkyl, C 1-4 alkoxy or C 2-4 alkenyl, where C 2-4 alkenyl is optionally substituted by NH(R e ); or R3, together with R5 of X1 and the atoms to which they are attached, forms a 5-membered heterocyclic group or a 5-membered heteroaryl group, provided that X3 is CH; or R3, together with the carbon atom of *-CH2-O-* of L and the atoms to which they are attached, forms a C6 aryl group or a 6-membered heteroaryl group,

[0245] The condition is:

[0246] (i) When R3 is cyano, C 1-6 alkyl, C 1-4 alkoxy or C 2-4 alkenyl, where C 2-4 alkenyl is optionally substituted by N(R e )(R f ) and R2 is a 3- to 10-membered saturated heterocyclic group or a 5- to 20-membered heteroaryl group, where the 3- to 10-membered saturated heterocyclic group or the 5- to 20-membered heteroaryl group is independently optionally substituted by one or two substituents 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 ), and 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

[0247] (ii) When R3, together with R5 of X1 and the atoms to which they are attached, forms a 5-membered heterocyclic group or 5-membered heteroaryl group, provided that X3 is CH and R2 is a 3- to 10-membered saturated heterocyclic group or a 5- to 20-membered heteroaryl group, wherein the 3- to 10-membered saturated heterocyclic group or 5- to 20-membered heteroaryl group is independently optionally substituted with one or two substituents 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 absent or 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

[0248] (iii) When R3, together with the carbon atom of *-CH2-O-** of L and the atoms to which they are attached, forms a C6 aryl group or 6-membered heteroaryl group, and R2 is a 3- to 10-membered saturated heterocyclic group or a 5- to 20-membered heteroaryl group, wherein the 3- to 10-membered saturated heterocyclic group or 5- to 20-membered heteroaryl group is independently optionally substituted with one or two substituents 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 to the R2 moiety and * indicates the point of attachment to the rest of the molecule; and

[0249] R4 is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with a hydroxyl group.

[0250] 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 atoms to which they are attached form a 5-membered heterocyclic group or a 5-membered heteroaryl group. It should be understood that the "5-membered" size descriptor of the heterocyclic group or heteroaryl group formed by connecting R3 and R5 of X1 refers to the size of the monocyclic moiety formed by connecting R3 and R5 of X1. In addition, the 5-membered heterocyclic group or 5-membered heteroaryl group formed by connecting R3 and R5 of X1 can be referred to by the chemical name of the resulting 5-membered monocyclic moiety. For example, if R3 together with R5 of X1 and the atoms to which they are attached form a 5-membered heterocyclic group such that the structure of the compound of formula (B-1), (B) or (I) is then the ring formation can be described as follows: "R3 together with R5 of X1 and the atoms to which they are attached form tetrahydrofuranyl".

[0251] 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 atoms to which they are attached form a 5-membered heterocyclic group, provided that X3 is CH. In some embodiments, the 5-membered heterocyclic group is unsubstituted. In certain embodiments, the 5-membered heterocyclic group is substituted with one or more C 1-6 alkyl groups. In some embodiments, the 5-membered heterocyclic group is substituted with one or more methyl groups. In some embodiments, the 5-membered heterocyclic group contains 1, 2, 3 or 4 ring heteroatoms, wherein the heteroatoms are each independently selected from the group consisting of sulfur, oxygen and nitrogen. In some embodiments, the 5-membered heterocyclic group contains 1 or 2 ring heteroatoms. In other embodiments, the 5-membered heterocyclic group contains 1 ring heteroatom.

[0252] In some 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 atoms to which they are attached form a 5-membered heterocyclic group such that the compound of formula (B-1), formula (B) or formula (I) is a compound of formula (IA) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

[0253]

[0254] In some embodiments, the compound of formula (IA) is a compound selected from the group consisting of:

[0255] or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0256] In other embodiments, the compound of formula (IA) is a compound selected from the group consisting of:

[0257] or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0258] In some embodiments, the compound of formula (IA) is a compound selected from the group consisting of:

[0259] or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0260] In some embodiments, provided herein is a compound of formula (IA) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein X2 is C-R5. In certain embodiments, R5 of X2 is cyano. In some embodiments, X2 is C-R5, wherein R5 of X2 is cyano, L is absent, and R2 is C 6-20 aryl, wherein C 6-20 aryl is optionally substituted with one or two substituents 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 some embodiments, C 6-20 aryl of R2 is optionally substituted with one or two C 1-6 alkyl. In some embodiments, C 1-6 alkyl is isopropyl. In certain embodiments, the compound of formula (IA) is a compound of formula (IJ):

[0261]

[0262] or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0263] In some embodiments, the compound of formula (IJ) is selected from the group consisting of:

[0264]

[0265]

[0266] or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (IJ) is selected from the group consisting of, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0267] In some embodiments, provided herein are compounds of formula (IJ) or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein R1 is an oxiranyl or oxetanyl group, wherein the oxiranyl or oxetanyl group is optionally substituted with one or more C 1-6 alkyl groups. In some embodiments, R1 is an oxiranyl or oxetanyl group, wherein the oxiranyl or oxetanyl group is optionally substituted with one or more C 1-6 alkyl groups, wherein the C 1-6 alkyl group is optionally substituted with one or more -C(O)NH2 groups. In some embodiments, R1 is an oxetanyl group, wherein the oxetanyl group is optionally substituted with one or more C 1-6 alkyl groups. In some embodiments, R1 is an oxetanyl group, wherein the oxetanyl group is optionally substituted with one or more C 1-6 alkyl groups, wherein the C 1-6 alkyl group is optionally substituted with one or more -C(O)NH2 groups. In some embodiments, R1 is an oxiranyl group, wherein the oxiranyl group is unsubstituted. In some embodiments, R1 is an oxiranyl group, wherein the oxiranyl group is substituted with one or more C 1-6 alkyl groups. In certain embodiments, R1 is an oxiranyl group, wherein the oxiranyl group is substituted with one or more methyl groups. In some embodiments, R1 is an oxetanyl group, wherein the oxetanyl group is optionally substituted with one or more C 1-6 alkyl groups, wherein the C 1-6 alkyl group is optionally substituted with one or more -C(O)NH2 groups. In some embodiments, R1 is an oxetanyl group, wherein the oxetanyl group is optionally substituted with -CH2-CH2-C(O)NH2.

[0268] In some embodiments, provided herein are compounds of formula (IJ) or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein R1 is an oxiranyl group, wherein the oxiranyl group is optionally substituted with one or more C 1-6 alkyl groups, wherein the C 1-6 alkyl group is optionally substituted with one or more -C(O)NH2 groups. In certain embodiments, the one or more C 1-6 alkyl groups are isopropyl groups. In some embodiments, the compound of formula (B), (IA) or (IJ) is a compound of formula (IK):

[0269]

[0270] or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein R g is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more -C(O)NH2 groups. In some embodiments, Rg is H. In other embodiments, R g is methyl. In other embodiments, R g is -CH2-CH2-C(O)NH2.

[0271] In some embodiments, the compound of formula (IK) is selected from the group consisting of:

[0272] or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0273] In some embodiments, provided herein is a compound of formula (IJ) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R1 is N(R e )(CN), wherein R e is selected from the group consisting of: H, cyano, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 1-6 alkyl-C 3-10 cycloalkyl, a 3- to 10-membered heterocyclic group, C 6-20 aryl and a 3- to 20-membered heteroaryl, wherein the C e of R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 1-6 alkyl-C 3-10 cycloalkyl, a 3- to 10-membered heterocyclic group, C 6-20 aryl and a 3- to 20-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, oxo, cyano, halo, NO2 and hydroxy.

[0274] In certain embodiments, provided herein is a compound of formula (IJ) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound of formula (IJ) is a compound of formula (IL):

[0275]

[0276] or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. In certain embodiments, R e is H. In other embodiments, R e is C 1-6 alkyl. In some embodiments, R e is methyl.

[0277] In certain embodiments, R3, together with R5 of X1 and the atoms to which they are attached, forms a 5-membered heteroaryl group such that the compound of formula (B-1), formula (B) or formula (I) is a compound of formula (IB) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

[0278]

[0279] In some 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 atoms to which they are attached, forms a 5-membered heteroaryl group, provided that X3 is CH. In some embodiments, the 5-membered heteroaryl group is unsubstituted. In certain embodiments, the 5-membered heteroaryl group is substituted with one or more C 1-6 alkyl groups. In some embodiments, the 5-membered heteroaryl group is substituted with one or more methyl groups. In some embodiments, R3, together with R5 of X1 and the atoms to which they are attached, forms a 5-membered heteroaryl group, provided that X3 is CH, wherein the 5-membered heteroaryl group contains 1, 2, 3 or 4 ring heteroatoms, wherein the heteroatoms are each independently selected from the group consisting of oxygen and nitrogen. In certain embodiments, the 5-membered heteroaryl group contains 1 or 2 ring heteroatoms.

[0280] In some embodiments, R3, together with R5 of X1 and the atoms to which they are attached, forms a 5-membered heteroaryl group such that the compound of formula (B-1), formula (B) or formula (I) is a compound of formula (IC) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

[0281]

[0282] In some embodiments, R3, together with R5 of X1 and the atoms to which they are attached, forms a 5-membered heteroaryl group such that the compound of formula (B-1), formula (B) or formula (I) is a compound of formula (IC-1) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

[0283]

[0284] In some embodiments, provided are compounds of formula (B-1), formula (B) or formula (I) or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein R3, together with the carbon atom of *-CH2-O-* of L and the atoms to which they are attached, forms a C6 aryl group or a 6-membered heteroaryl group.

[0285] In some embodiments, R3, together with the carbon atoms of *-CH2-O-* of L and the atoms to which they are attached, forms a C6 aryl group. In some embodiments, R3, together with the carbon atoms of *-CH2-O-* of L and the atoms to which they are attached, forms a C6 aryl group such that the compound of formula (B-1), formula (B) or formula (I) is a compound of formula (ID) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

[0286]

[0287] In some embodiments, R3, together with the carbon atoms of *-CH2-O-* of L and the atoms to which they are attached, forms a 6-membered heteroaryl group. In some embodiments, the 6-membered heteroaryl group contains 1, 2, 3 or 4 ring heteroatoms, wherein the heteroatoms are each independently selected from the group consisting of oxygen and nitrogen. In some embodiments, the 6-membered heteroaryl group contains 1 ring heteroatom.

[0288] In some embodiments, R3, together with the carbon atoms of *-CH2-O-* of L and the atoms to which they are attached, forms a 6-membered heteroaryl group such that the compound of formula (B-1), formula (B) or formula (I) is a compound of formula (IE) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

[0289]

[0290] In some embodiments, provided herein are compounds of formula (B-1), formula (B) or formula (I) or pharmaceutically acceptable salts thereof, wherein R4 is H. In other embodiments, R4 is C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with a hydroxy group.

[0291] In some embodiments, provided herein are compounds of formula (B-1), formula (B) or formula (I) or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein X3 is CH; L is -CH=CH-; R2 is C 3-10 cycloalkyl, wherein C 3-10 cycloalkyl is independently optionally substituted with one, two, three or four substituents 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 ); R3 is C 1-4 alkoxy; and R4 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) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

[0292]

[0293] In certain embodiments, the compound of formula (IF) is a compound selected from the group consisting of:

[0294] or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0295] In some aspects of the present disclosure, there is provided a compound of formula (B-1), formula (B) or formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R1 is In some embodiments, there is provided a compound of formula (B-1), formula (B) or formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound of formula (B-1), formula (B) or formula (I) is a compound of formula (IG):

[0296]

[0297] or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0298] In embodiments, there is provided a compound of formula (IG) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R a , R b and R c are each H. In other embodiments, there is provided a compound of formula (IG) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein one of R a and R b is H, the other of R a and R b is cyano and R c is H. In some embodiments, R a is H, R b is cyano, and R c is H. In other embodiments, there is provided a compound of formula (IG) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R a is H, R b is H, and R c is C 6-20 aryl. In some embodiments, there is provided a compound of formula (IG) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R a is H, R b is H, and R c is C6 aryl. In other embodiments, there is provided a compound of formula (IG) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R a is H, Rb is H, and R c is C 1-6 alkyl, wherein C 1-6 alkyl is further substituted with a hydroxyl group.

[0299] In some aspects of the present disclosure, there are provided compounds of formula (B-1), formula (B) or formula (I) or their stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R1 is and R2 is C 3-10 cycloalkyl, wherein C 3-10 cycloalkyl is independently optionally substituted with one, two, three or four substituents 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 each R e and R f is independently selected from the group consisting of: 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- to 10-membered heterocyclic group, 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- to 10-membered heterocyclic group, C 6-20 aryl and 3- to 20-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, oxo, cyano, halo, NO2 and hydroxyl.

[0300] In some embodiments, there are provided compounds of formula (B-1), formula (B) or formula (I) or their stereoisomers, tautomers or pharmaceutically acceptable salts, wherein the compound of formula (B-1), formula (B) or formula (I) is a compound of formula (IH):

[0301]

[0302] or its stereoisomers, tautomers or pharmaceutically acceptable salts.

[0303] In some embodiments, there is provided a compound of formula (IH) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, 3 or 4, and each R x when present 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 each R e and R f is independently selected from the group consisting of: 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- to 10-membered heterocyclic group, 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- to 10-membered heterocyclic group, C 6-20 aryl and 3- to 20-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, oxo, cyano, halo, NO2 and hydroxy.

[0304] In some embodiments, there is provided a compound of formula (IH) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2, and each R x when present 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 each R e and R f is independently selected from the group consisting of: H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C1-6 alkyl-C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, 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- to 10-membered heterocyclic group, C 6-20 aryl and 3- to 20-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, oxo, cyano, halo, NO2 and hydroxy.

[0305] In some embodiments, there is provided a compound of formula (IH) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R1's R a , R b and R c are each H, n is 1, and R x is C 1-6 haloalkyl. In some embodiments, the C x of R 1-6 haloalkyl is CF3. In some embodiments, R1's R a , R b and R c are each H, n is 2, and the two R x are both halo. In certain embodiments, the two R x are both F.

[0306] In some 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) (if applicable), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X1 is N, X2 is N, and X3 is CH. In 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) (if applicable), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X1 is C-R5, where R5 is H, X2 is N, and X3 is CH. In 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) (if applicable), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X1 is C-R5, where R5 is C 1-6 alkyl, X2 is N, and X3 is CH. In some 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) (if applicable), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X1 is C-R5, where R5 is C 3-10The cycloalkyl group, X2 is N, and X3 is CH. In other embodiments, there are provided compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK) or (IL) (if applicable) or their stereoisomers, tautomers or pharmaceutically acceptable salts, wherein X1 is N, X2 is C-R5, where R5 is H, and X3 is CH. In other embodiments, there are provided compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK) or (IL) (if applicable) or their stereoisomers, tautomers or pharmaceutically acceptable salts, wherein X1 is N, X2 is C-R5, where R5 is cyano, and X3 is CH. In other embodiments, there are provided compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK) or (IL) (if applicable) or their stereoisomers, tautomers or pharmaceutically acceptable salts, wherein X1 is N, X2 is C-R5, where R5 is C 6-20 aryl, and X3 is CH. In other embodiments, there are provided compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK) or (IL) (if applicable) or their stereoisomers, tautomers or pharmaceutically acceptable salts, wherein X1 is N, X2 is C-R5, where R5 is C 1-6 alkyl substituted by hydroxy, and X3 is CH. In other embodiments, there are provided compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK) or (IL) (if applicable) or their stereoisomers, tautomers or pharmaceutically acceptable salts, wherein X1 is N, X2 is C-R5, where R5 is C 1-6an alkoxy group, and X3 is CH. In 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) (if applicable) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X1 is N, X2 is C-R5, wherein R5 is C(O)NH2, and X3 is CH. In 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) (if applicable) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein both X1 and X2 are C-R5, wherein each R5 is H, and X3 is CH. In 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) (if applicable) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X1 is C-R5, wherein R5 is H, X2 is C-R5, wherein R5 is halo, and X3 is CH. In 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) (if applicable) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X1 is C-R5, wherein R5 is H, X2 is N, and X3 is N.

[0307] In some 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) (if applicable) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R1 is wherein R a , R b and R c are each independently selected from the group consisting of: H, halo, cyano, hydroxy, C 1-6 alkyl, C 6-20 aryl, 3- to 10-membered heterocyclic group, and 5- to 20-membered heteroaryl, wherein C 1-6 alkyl is further optionally substituted with hydroxy, provided that R a , R b and R cAt least two of them 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. In certain 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) (if applicable) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R1 is In some embodiments, R a , R b and R c are each H. In other embodiments, R1 is wherein one of R a , R b and R c is cyano. In some embodiments, R1 is wherein R a is H, R b is cyano, and R c is H. In other embodiments, R1 is wherein one of R a , R b and R c is C 6-20 aryl. In some embodiments, R1 is wherein R a is H, R b is H, and R c is C 6-20 aryl. In other embodiments, R1 is wherein one of R a , R b and R c is C 1-6 alkyl, wherein the C 1-6 alkyl is further substituted with a hydroxyl group. In some embodiments, R1 is wherein R a is H, R b is H, and R c is C 1-6 alkyl, wherein the C 1-6 alkyl is further substituted with a hydroxyl group.

[0308] In some 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) (if applicable), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R1 is wherein R d is selected from the group consisting of: H, halo, cyano, hydroxy, C 1-6 alkyl, C 6-20 aryl, 3- to 10-membered heterocycloalkyl, and 5- to 20-membered heteroaryl, wherein the C 1-6 alkyl is further optionally substituted with hydroxy and L is selected from the group consisting of: -O-, *-CH2-O-**, *-O-CH2-**, -CH═CH-, and -C≡C-, wherein ** 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 wherein R d is substituted with C 1-6 alkyl.

[0309] In some 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) (if applicable), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R1 is and L is absent or is selected from the group consisting of: *-CH2-O-**, *-O-CH2-**, -CH═CH-, and -C≡C-, wherein ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the remainder of the molecule. In some embodiments, R1 is and L is absent. In some embodiments, R1 is and L is -CH═CH-. In other embodiments, R1 is and L is -*CH2-O-**. In certain embodiments, R1 is and L is -CH═CH-.

[0310] In some 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) (if applicable), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein 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 rest of the molecule.

[0311] In some 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) (if applicable) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R1 is oxiranyl or oxetanyl, wherein the oxiranyl or oxetanyl is optionally substituted with one or more C 1-6 alkyl groups, wherein the C 1-6 alkyl group is optionally substituted with one or more -C(O)NH2 groups, and L is absent or 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 rest of the molecule. In certain embodiments, L is absent. In some embodiments, R1 is oxiranyl, wherein the oxiranyl is optionally substituted with one or more C 1-6 alkyl groups, wherein the C 1-6 alkyl group is optionally substituted with one or more -C(O)NH2 groups. In some embodiments, R1 is oxiranyl, wherein the oxiranyl is unsubstituted. In some embodiments, R1 is oxiranyl, wherein the oxiranyl is substituted with one or more C 1-6 alkyl groups, wherein the C 1-6 alkyl group is optionally substituted with one or more -C(O)NH2 groups. In certain embodiments, R1 is oxiranyl, wherein the oxiranyl is substituted with one or more methyl groups. In some embodiments, R1 is In other embodiments, R1 is In other embodiments, R1 is

[0312] In certain 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) (if applicable) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R1 is N(R e )(CN), wherein R e is selected from the group consisting of: H, cyano, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6Alkynyl, C 3-10 Cycloalkyl, C 1-6 Alkyl-C 3-10 Cycloalkyl, 3- to 10-membered heterocyclic group, C 6-20 Aryl and 3- to 20-membered heteroaryl, wherein R e of 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 heterocyclic group, C 6-20 Aryl and 3- to 20-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, oxo, cyano, halo, NO2, and hydroxy, and L is absent or 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 rest of the molecule. In certain embodiments, L is absent. In some embodiments, R e is H or C 1-6 Alkyl. In certain embodiments, R e is H. In other embodiments, R ? e is C 1-6 Alkyl. In some embodiments, R e 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 Alkyl. In some embodiments, L is absent and R e is methyl.

[0313] In some embodiments, provided are compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL) (if applicable) or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein L is -CH═CH-. In certain embodiments, the carbon-carbon double bond is trans, such that the L moiety is In other embodiments, the carbon-carbon double bond is cis, such that the L moiety is In certain embodiments, the carbon-carbon double bond is E, such that the L moiety is In other embodiments, the carbon-carbon double bond is Z, such that the L moiety is Note: There seems to be a formatting or content issue around "R e is C " where the text might be incomplete or incorrect in the original. The translation is done as accurately as possible based on the provided text.

[0314] In some embodiments, provided are compounds of Formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), as applicable, or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein R2 is C 3-10 Cycloalkyl, wherein C 3-10 The cycloalkyl groups are independently optionally substituted with one, two, three or four substituents selected from the group consisting of cyano, halo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, NO2, SF5, N(R e )(R f ) and O(R e ), where each R e and R f Independently selected from the group consisting of: 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- to 10-membered heterocyclic group, 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- to 10-membered heterocyclic group, C 6-20 The aryl group and the 3- to 20-membered heteroaryl group are each independently optionally substituted with one or more substituents selected from the group consisting of: C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 In some embodiments, R2 is C 3-10 Cycloalkyl, wherein C 3-10 The cycloalkyl group is optionally substituted by one, two, three or four C 1-6Halogenoalkyl substitution. In some embodiments, R2 is cyclohexyl, where the cyclohexyl is optionally substituted with one, two, three, or four CF3 groups. In some embodiments, there are provided compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL) (if applicable), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, where R2 is C 3-10 cycloalkyl, where C 3-10 cycloalkyl is optionally substituted with one, two, three, or four halogens. In certain embodiments, R2 is cyclohexyl, where the cyclohexyl is optionally substituted with one, two, three, or four F atoms. In other embodiments, R2 is cyclobutyl, where the cyclobutyl is optionally substituted with one, two, three, or four F atoms.

[0315] In some embodiments, there are provided compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL) (if applicable), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, where R2 is C 5-13 spirocyclic group. In some embodiments, C 5-13 the spirocyclic group is

[0316] In certain embodiments, there are provided compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL) (if applicable), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, where R2 is C 1-12 alkyl, where C 1-12 alkyl is independently optionally substituted with one, two, three, or four substituents selected from the group consisting of: cyano, halogeno, C 1-6 alkyl, C 1-6 halogenoalkyl, C 3-10 cycloalkyl, NO2, SF5, N(R e )(R f ), and O(R e ), where each R e and R f is independently selected from the group consisting of: H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 1-6 alkyl-C 3-10Cycloalkyl, 3- to 10-membered heterocyclic group, 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- to 10-membered heterocyclic group, C 6-20 aryl, and 3- to 20-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, oxo, cyano, halo, NO2, and hydroxy. In some embodiments, R2 is methyl, wherein the methyl is substituted with cyclopentyl. In some embodiments, R2 is In other embodiments, R2 is

[0317] In certain 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) (if applicable) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R2 is C 6-20 aryl, wherein C 6-20 aryl is independently optionally substituted with one, two, three, or four substituents selected from the group consisting of: 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 ), wherein each R e and R f is independently selected from the group consisting of: 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- to 10-membered heterocyclic group, 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- to 10-membered heterocyclic group, C6-20 An aryl and a 3- to 20-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, oxo, cyano, halo, NO2, and hydroxy. In certain embodiments, R2 is C 6-20 aryl, wherein C 6-20 aryl is optionally substituted with one, two, three, or four halos. In some embodiments, R2 is C 6-20 aryl, wherein C 6-20 aryl is substituted with one, two, three, or four Cl. In other embodiments, R2 is C 6-20 aryl, wherein C 6-20 aryl is optionally substituted with one, two, three, or four C 1-6 alkyl. In some embodiments, R2 is phenyl, wherein the phenyl is substituted with one, two, three, or four isopropyl groups. In some embodiments, R2 is phenyl, wherein the phenyl is substituted with one, two, three, or four SF5.

[0318] In certain 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) (if applicable) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R2 is a 3- to 10-membered saturated heterocyclic group, wherein the 3- to 10-membered saturated heterocyclic group is independently optionally substituted with one, two, three, or four substituents selected from the group consisting of 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 ), wherein each R e and R f is independently selected from the group consisting of 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, a 3- to 10-membered heterocyclic group, C 6-20 aryl, and a 3- to 20-membered heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C1-6 Alkyl-C 3-10 Cycloalkyl, 3- to 10-membered heterocyclic group, C 6-20 The aryl group and the 3- to 20-membered heteroaryl group are each independently optionally substituted with one or more substituents selected from the group consisting of: C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 In some embodiments, R2 is tetrahydropyran, wherein the tetrahydropyran is replaced by one, two, three or four C 1-6 In certain embodiments, C 1-6 The haloalkyl group is CF3.

[0319] In some embodiments, provided are compounds of Formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), as applicable, or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein R2 is tetrahydropyran substituted with CF3, and wherein the stereochemistry of the -L-R2 moiety is (3S, 6S), such that the -L-R2 moiety is In other embodiments, R2 is tetrahydropyran substituted with CF3, wherein the stereochemistry of the -L-R2 moiety is (3R, 6R), such that the -L-R2 moiety is

[0320] In some embodiments, provided are compounds of Formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), as applicable, or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein L is -CH=CH- and R2 is C 3-10 Cycloalkyl, wherein R2 is C 3-10 Cycloalkyl, which is independently optionally substituted with one, two, three or four substituents selected from the group consisting of cyano, halo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, NO2, SF5, N(R e )(R f ) and O(R e ), where each R e and R f Independently selected from the group consisting of: H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Naphthenyl, C 1-6 Alkyl-C 3-10 Naphthenyl, 3- to 10-membered heterocyclic group, C 6-20 Aryl and 3- to 20-membered heteroaryl, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Naphthenyl, C 1-6 Alkyl-C 3-10 Naphthenyl, 3- to 10-membered heterocyclic group, C 6-20 Aryl and 3- to 20-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of: C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, oxo, cyano, halogenated, NO2, and hydroxy. In some embodiments, L is -CH=CH- and R2 is C 3-10 Naphthenyl, where C 3-10 Naphthenyl is optionally substituted with one, two, three, or four C 1-6 Halogenated alkyl. In some embodiments, L is -CH=CH- and R2 is cyclohexyl, where cyclohexyl is optionally substituted with one, two, three, or four CF3. In some embodiments, there are provided compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL) (if applicable) or their stereoisomers, tautomers, or pharmaceutically acceptable salts, where L is -CH=CH- and R2 is C 3-10 Naphthenyl, where C 3-10 Naphthenyl is optionally substituted with one, two, three, or four halogenated. In certain embodiments, L is -CH=CH- and R2 is cyclohexyl, where cyclohexyl is optionally substituted with one, two, three, or four F. In other embodiments, L is -CH=CH- and R2 is cyclobutyl, where cyclobutyl is optionally substituted with one, two, three, or four F.

[0321] In some embodiments, there are provided compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL) (if applicable) or their stereoisomers, tautomers, or pharmaceutically acceptable salts, where L is *-CH2-O-* and R2 is C 5-13 Spiro group. In some embodiments, L is *-CH2-O-* and R2 is

[0322] In some embodiments, provided are compounds of Formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), as applicable, or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein L is *-CH2-O-** and R2 is C 3-10 Cycloalkyl, wherein R2 is C 3-10 The cycloalkyl groups are independently optionally substituted with one, two, three or four substituents selected from the group consisting of cyano, halo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, NO2, SF5, N(R e )(R f ) and O(R e ), where each R e and R f Independently selected from the group consisting of: 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- to 10-membered heterocyclic group, 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- to 10-membered heterocyclic group, C 6-20 The aryl group and the 3- to 20-membered heteroaryl group are each independently optionally substituted with one or more substituents selected from the group consisting of: C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 In some embodiments, L is *-CH2-O-** and R2 is C 3-10 Cycloalkyl, wherein C 3-10 The cycloalkyl group is optionally substituted by one, two, three or four C 1-6Halogenoalkyl substitution. In some embodiments, L is *-CH2-O-* and R2 is cyclohexyl, where the cyclohexyl is optionally substituted with one, two, three, or four CF3 groups. In some embodiments, there are provided compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL) (where applicable) or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, where L is *-CH2-O-* and R2 is C 3-10 cycloalkyl, where C 3-10 cycloalkyl is optionally substituted with one, two, three, or four halogens. In certain embodiments, L is *-CH2-O-* and R2 is cyclohexyl, where the cyclohexyl is optionally substituted with one, two, three, or four F atoms.

[0323] In certain embodiments, there are provided compounds of formula (B-1), (B), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL) (where applicable) or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, where L is absent and R2 is C 6-20 aryl, where C 6-20 aryl is independently optionally substituted with one, two, three, or four substituents selected from the group consisting of: cyano, halogen, C 1-6 alkyl, C 1-6 halogenoalkyl, C 3-10 cycloalkyl, NO2, SF5, N(R e )(R f ) and O(R e ), where each R e and R f is independently selected from the group consisting of: 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- to 10-membered heterocyclic group, C 6-20 aryl, and 3- to 20-membered heteroaryl, where 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 heterocyclic group, C 6-20An aryl and a 3- to 20-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, oxo, cyano, halo, NO2, and hydroxy. In other embodiments, L is absent and R2 is C 6-20 aryl, wherein C 6-20 aryl is optionally substituted with one, two, three, or four C 1-6 alkyl groups. In some embodiments, L is absent and R2 is phenyl, wherein the phenyl is substituted with one, two, three, or four isopropyl groups. In some embodiments, L is absent and R2 is phenyl, wherein the phenyl is substituted with one, two, three, or four SF5 groups.

[0324] In certain 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) (if applicable) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L is -CH=CH- and R2 is a 3- to 10-membered saturated heterocyclic group, wherein the 3- to 10-membered saturated heterocyclic group is independently optionally substituted with one, two, three, or four substituents selected from the group consisting of: 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 ), wherein each R e and R f is independently selected from the group consisting of: 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, a 3- to 10-membered heterocyclic group, C 6-20 aryl, and a 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, a 3- to 10-membered heterocyclic group, C 6-20 aryl, and a 3- to 20-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of: C 1-6 alkyl, C1-6 haloalkyl, C 1-6 alkoxy, oxo, cyano, halo, NO2, and hydroxy. In some embodiments, L is -CH=CH- and R2 is tetrahydropyran, where tetrahydropyran is substituted with one, two, three, or four C 1-6 haloalkyl substituents. In certain embodiments, C 1-6 haloalkyl is CF3.

[0325] In certain 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) (if applicable) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L is -CH=CH- and R2 is C 6-20 aryl, wherein C 6-20 aryl is independently optionally substituted with one, two, three, or four substituents selected from the group consisting of: 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 ), wherein each R e and R f is independently selected from the group consisting of: 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- to 10-membered heterocyclic group, 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- to 10-membered heterocyclic group, C 6-20 aryl, and 3- to 20-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, oxo, cyano, halo, NO2, and hydroxy. In certain embodiments, L is -CH=CH- and R2 is C 6-20 aryl, wherein C 6-20The aryl is optionally substituted by one, two, three or four halogens. In some embodiments, L is -CH=CH- and R2 is C 6-20 aryl, wherein C 6-20 aryl is substituted by one, two, three or four Cl.

[0326] In certain 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) (if applicable) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein L is -CH=CH- or -C≡C- and R2 is C 1-12 alkyl, wherein C 1-12 alkyl is independently optionally substituted by one, two, three or four substituents selected from the group consisting of: 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 ), wherein each R e and R f is independently selected from the group consisting of: 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- to 10-membered heterocyclic group, 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- to 10-membered heterocyclic group, C 6-20 aryl and 3- to 20-membered heteroaryl are each independently optionally substituted by one or more substituents selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, oxo, cyano, halo, NO2 and hydroxy.

[0327] In certain 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) (if applicable), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L is -CH=CH- and R2 is C 1-12 alkyl, wherein C 1-12 alkyl is independently optionally substituted with one, two, three, or four substituents selected from the group consisting of 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 ), wherein each R e and R f is independently selected from the group consisting of 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- to 10-membered heterocycloalkyl, 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- to 10-membered heterocycloalkyl, C 6-20 aryl, and 3- to 20-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, oxo, cyano, halo, NO2, and hydroxy.

[0328] In 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) (if applicable), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L is -C≡C- and R2 is C 1-12 alkyl, wherein C 1-12 alkyl is independently optionally substituted with one, two, three, or four substituents selected from the group consisting of cyano, halo, C 1-6 alkyl, C1-6 haloalkyl, C 3-10 cycloalkyl, NO2, SF5, N(R e )(R f ) and O(R e ), wherein each R e and R f is independently selected from the group consisting of: 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- to 10-membered heterocyclic group, 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- to 10-membered heterocyclic group, C 6-20 aryl and 3- to 20-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, oxo, cyano, halo, NO2 and hydroxy.

[0329] In certain 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) (if applicable) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein L is -CH=CH- and R2 is C 1-12 alkyl, wherein C 1-12 alkyl is independently optionally substituted with one, two, three or four substituents selected from the group consisting of: 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 ), wherein each R e and R f is independently selected from the group consisting of: H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C1-6 alkyl-C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, 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- to 10-membered heterocyclic group, C 6-20 aryl and 3- to 20-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, oxo, cyano, halo, NO2, and hydroxy. In some embodiments, L is -CH=CH- and R2 is methyl, wherein the methyl is substituted with cyclopentyl. In some embodiments, L is -CH=CH- and R2 is In other embodiments, L is -CH=CH- and R2 is

[0330] In some embodiments, R3 is cyano, C 1-6 alkyl, C 1-4 alkoxy, or C 2-4 alkenyl, wherein C 2-4 alkenyl is optionally substituted with NH(R e )). In certain embodiments, R3 is C 1-4 alkoxy. In certain embodiments, R3 is methoxy. In other embodiments, R3 is cyano.

[0331] In some 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) (if applicable) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R3 together with the R5 of X1 and the atoms to which they are attached forms a 5-membered heterocyclic group or a 5-membered heteroaryl, provided that X3 is CH.

[0332] In certain embodiments, R3 together with R5 of X1 and the atoms to which they are attached form a 5-membered heterocyclyl, provided that X3 is CH. In certain embodiments, R3 together with R5 of X1 and the atoms to which they are attached form a 5-membered heterocyclyl, provided that X3 is CH, wherein the 5-membered heterocyclyl contains 1, 2, 3, or 4 cyclic heteroatoms, wherein each heteroatom is independently selected from the group consisting of oxygen and nitrogen. In certain embodiments, R3 together with R5 of X1 and the atoms to which they are attached form a 5-membered heterocyclyl, provided that X3 is CH, wherein the 5-membered heterocyclyl contains a single cyclic heteroatom, wherein the heteroatom is oxygen or nitrogen. In certain embodiments, R3 together with R5 of X1 and the atoms to which they are attached form a 5-membered heterocyclyl, provided that X3 is CH, wherein the 5-membered heterocyclyl contains a single cyclic heteroatom, wherein the heteroatom is oxygen.

[0333] In some embodiments, R3 is cyano, C 1-6 Alkyl, C 1-4 Alkoxy or C 2-4 Alkenyl, where C 2-4 The alkenyl group is optionally substituted with N(R e )(R f ) substituted; R1 is R2 is a 3- to 10-membered saturated heterocyclic group or a 5- to 20-membered heteroaryl group, wherein the 3- to 10-membered saturated heterocyclic group or the 5- to 20-membered heteroaryl group is independently optionally substituted by one or two substituents selected from the group consisting of cyano, halo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, NO2, N(R e )(R f ) and O(R e ); and 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 foregoing, R1 is In another embodiment of the foregoing embodiment, R1 is

[0334] In some embodiments, R3 and R5 of X1 and the atoms to which they are attached together form a 5-membered heterocyclic group or a 5-membered heteroaryl group; X3 is CH; R1 is R2 is a 3- to 10-membered saturated heterocyclic group or a 5- to 20-membered heteroaryl group, wherein the 3- to 10-membered saturated heterocyclic group or the 5- to 20-membered heteroaryl group is independently optionally substituted by one or two substituents selected from the group consisting of cyano, halo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, NO2, N(Re )(R f ) and O(R e ); and L is absent or 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. In one embodiment of the foregoing embodiments, R1 is In another embodiment of the foregoing embodiments, R1 is

[0335] In some embodiments, R3 together with the carbon atom of *-CH2-O-** of L and the atoms to which they are attached forms a C6 aryl or 6-membered heteroaryl; R1 is and R2 is a 3- to 10-membered saturated heterocyclic group or a 5- to 20-membered heteroaryl, wherein the 3- to 10-membered saturated heterocyclic group or the 5- to 20-membered heteroaryl is independently optionally substituted with one or two substituents 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 foregoing embodiments, R1 is In another embodiment of the foregoing embodiments, R1 is

[0336] 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 stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein R4 is H. In other embodiments, R4 is C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with a hydroxyl group.

[0337] In an embodiment, X1 is C-R5, where R5 is H; X2 is C-R5, where R5 is H; and X3 is C-H.

[0338] In an embodiment, X1 is N; X2 is C-R5, where R5 is H; and X3 is C-H.

[0339] In an embodiment, X1 is C-R5, where R5 is H; X2 is N; and X3 is C-H.

[0340] In an embodiment, X1 is N; X2 is N; and X3 is C-H.

[0341] In an embodiment, R1 is: where R a 、R b and R c Each is H.

[0342] In the embodiment, L is -CH=CH-; R2 is C 3-10 Cycloalkyl, which is optionally substituted by one or two substituents selected from the group consisting of halo, C 1-6 Alkyl, C 1-6 Haloalkyl, O(R e ) and SF5.

[0343] In the embodiment, L is -CH=CH-; R2 is C substituted by one or two halogen groups. 3-10 Cycloalkyl.

[0344] In the embodiment, L is -CH=CH-; R2 is C 1-6 Haloalkyl substituted C 3-10 Cycloalkyl.

[0345] In an embodiment, L is -CH=CH-; and R2 is cyclohexyl substituted with CF3.

[0346] In an embodiment, L is -CH=CH-; and R2 is cyclohexyl substituted with one or two fluorine groups.

[0347] In an embodiment, R3 is C 1-4 Alkoxy.

[0348] In an embodiment, R3 is methoxy.

[0349] In an embodiment, R4 is H.

[0350] In an embodiment, X1 is C-R5, wherein R5 is H; X2 is C-R5, wherein R5 is H; X3 is CH; R1 is: where R a 、R b and R c Each is H; L is -CH=CH-; R2 is C 1-6 Haloalkyl substituted C 3-10 Cycloalkyl; R3 is C 1-4 alkoxy; and R4 is H.

[0351] In an embodiment, X1 is C-R5, wherein R5 is H; X2 is C-R5, wherein R5 is H; X3 is CH; R1 is: where R a 、R b and R cEach is H; L is -CH=CH-; R2 is a cyclohexyl group substituted by CF3; R3 is a methoxy group; and R4 is H.

[0352] In the examples, X1 is C-R5, where R5 is H; X2 is C-R5, where R5 is H; X3 is C-H; R1 is: where R a 、R b and R c Each is H; L is -CH=CH-; R2 is a C 3-10 cycloalkyl group substituted by one or two halogen atoms; R3 is a C 1-4 alkoxy group; and R4 is H.

[0353] In the examples, X1 is C-R5, where R5 is H; X2 is C-R5, where R5 is H; X3 is C-H; R1 is: where R a 、R b and R c Each is H; L is -CH=CH-; R2 is a C 3-10 cycloalkyl group substituted by one or two fluorine atoms; R3 is a methoxy group; and R4 is H.

[0354] In the examples, X1 is N; X2 is C-R5, where R5 is H; X3 is C-H; R1 is: where R a 、R b and R c Each is H; L is -CH=CH-; R2 is a C 1-6 cycloalkyl group substituted by a C 3-10 haloalkyl group; R3 is a C 1-4 alkoxy group; and R4 is H.

[0355] In the examples, X1 is N; X2 is C-R5, where R5 is H; X3 is C-H; R1 is: where R a 、R b and R c Each is H; L is -CH=CH-; R2 is a cyclohexyl group substituted by CF3; R3 is a methoxy group; and R4 is H.

[0356] In the examples, X1 is N; X2 is C-R5, where R5 is H; X3 is C-H; R1 is: where R a 、R b and R c Each is H; L is -CH=CH-; R2 is a C 3-10 cycloalkyl group substituted by one or two halogen atoms; R3 is a C 1-4an alkoxy group; and R4 is H.

[0357] In an embodiment, X1 is N; X2 is C-R5, where R5 is H; X3 is C-H; R1 is: where R a , R b and R c are each H; L is -CH=CH-; R2 is a C 3-10 cycloalkyl group substituted with one or two fluorines; R3 is a methoxy group; and R4 is H.

[0358] In an embodiment, X1 is C-R5, where R5 is H; X2 is N; X3 is C-H; R1 is: where R a , R b and R c are each H; L is -CH=CH-; R2 is a C 1-6 cycloalkyl group substituted with a C 3-10 haloalkyl group; R3 is a C 1-4 alkoxy group; and R4 is H.

[0359] In an embodiment, X1 is C-R5, where R5 is H; X2 is N; X3 is C-H; R1 is: where R a , R b and R c are each H; L is -CH=CH-; R2 is a cyclohexyl group substituted with CF3; R3 is a methoxy group; and R4 is H.

[0360] In an embodiment, X1 is C-R5, where R5 is H; X2 is N; X3 is C-H; R1 is: where R a , R b and R c are each H; L is -CH=CH-; R2 is a C 3-10 cycloalkyl group substituted with one or two halogens; R3 is a C 1-4 alkoxy group; and R4 is H.

[0361] In an embodiment, X1 is C-R5, where R5 is H; X2 is N; X3 is C-H; R1 is: where R a , R b and R c are each H; L is -CH=CH-; R2 is a C 3-10 cycloalkyl group substituted with one or two fluorines; R3 is a methoxy group; and R4 is H.

[0362] In an embodiment, X1 is N; X2 is N; X3 is C-H; R1 is: wherein R a , R b and R c are each H; L is -CH=CH-; R2 is a C 1-6 cycloalkyl substituted by a C 3-10 haloalkyl; R3 is a C 1-4 alkoxy; and R4 is H.

[0363] In an embodiment, X1 is N; X2 is N; X3 is C-H; R1 is: wherein R a , R b and R c are each H; L is -CH=CH-; R2 is a C 3-10 cycloalkyl substituted by CF3; R3 is methoxy; and R4 is H.

[0364] In an embodiment, X1 is N; X2 is N; X3 is C-H; R1 is: wherein R a , R b and R c are each H; L is -CH=CH-; R2 is a C 3-10 cycloalkyl substituted by one or two halogens; R3 is a C 1-4 alkoxy; and R4 is H.

[0365] In an embodiment, X1 is N; X2 is N; X3 is C-H; R1 is: wherein R a , R b and R c are each H; L is -CH=CH-; R2 is a C 3-10 cycloalkyl substituted by one or two fluorines; R3 is methoxy; and R4 is H.

[0366] In an embodiment, L is absent; and R2 is a C 6-20 aryl optionally substituted by one or two substituents selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, SF5 and O(R e ), wherein R e is a C 1-6 alkyl, which is optionally substituted by one or more halogens.

[0367] In an embodiment, L is absent; and R2 is a C 1-6 aryl substituted by a C 6-20 alkyl.

[0368] In an embodiment, L is absent; and R2 is a C 1-6Alkyl-substituted phenyl.

[0369] In an embodiment, L is absent; and R2 is phenyl substituted with isopropyl.

[0370] In an embodiment, X1 is N; X2 is C-R5, where R5 is H or fluorine; X3 is C-H; R1 is: where R a , R b and R c are each H; L is absent; and R2 is C 6-20 aryl, which is optionally substituted with one or two substituents selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, SF5, and O(R e ), where R e is C 1-6 alkyl, which is optionally substituted with one or more halogens; R3 is C 1-4 alkoxy; and R4 is H.

[0371] In an embodiment, X1 is N; X2 is C-R5, where R5 is H or fluorine; X3 is C-H; R1 is: where R a , R b and R c are each H; L is absent; and R2 is C 1-6 aryl substituted with C 6-20 alkyl; R3 is C 1-4 alkoxy; and R4 is H.

[0372] In an embodiment, X1 is N; X2 is C-R5, where R5 is H or fluorine; X3 is C-H; R1 is: where R a , R b and R c are each H; L is absent; and R2 is phenyl substituted with isopropyl; R3 is methoxy; and R4 is H.

[0373] In an embodiment, X1 is C-R5, where R5 of X1 together with R3 and the atoms to which they are attached forms a 5-membered heterocyclic group or a 5-membered heteroaryl group, where the 5-membered heterocyclic group or 5-membered heteroaryl group is optionally substituted with one or more C 1-6 alkyl.

[0374] In an embodiment, X1 is C-R5, where R5 of X1 together with R3 and the atoms to which they are attached forms a 5-membered heterocyclic group, which is optionally substituted with one or more C 1-6 alkyl.

[0375] In an embodiment, X1 is C-R5, wherein R5 of X1, together with R3 and the atoms to which they are attached, forms a tetrahydrofuranyl group, and the tetrahydrofuranyl group is optionally substituted with one or more C 1-6 alkyl groups.

[0376] In an embodiment, X1 is C-R5, wherein R5 of X1, together with R3 and the atoms to which they are attached, forms a tetrahydrofuranyl group, and the tetrahydrofuranyl group is optionally substituted with a methyl group.

[0377] In an embodiment, X1 is C-R5, wherein R5 of X1, together with R3 and the atoms to which they are attached, forms a 5-membered heterocyclic group or a 5-membered heteroaryl group, and the 5-membered heterocyclic group or 5-membered heteroaryl group is optionally substituted with one or more C 1-6 alkyl groups; X2 is C-R5, wherein R5 is H or cyano; and X3 is C-H.

[0378] In an embodiment, X1 is C-R5, wherein R5 of X1, together with R3 and the atoms to which they are attached, forms a 5-membered heterocyclic group, and the 5-membered heterocyclic group is optionally substituted with one or more C 1-6 alkyl groups; X2 is C-R5, wherein R5 is H or cyano; and X3 is C-H.

[0379] In an embodiment, X1 is C-R5, wherein R5 of X1, together with R3 and the atoms to which they are attached, forms a tetrahydrofuranyl group, and the tetrahydrofuranyl group is optionally substituted with one or more C 1-6 alkyl groups; X2 is C-R5, wherein R5 is H or cyano; and X3 is C-H.

[0380] In an embodiment, X1 is C-R5, wherein R5 of X1, together with R3 and the atoms to which they are attached, forms a tetrahydrofuranyl group, and the tetrahydrofuranyl group is optionally substituted with a methyl group; X2 is C-R5, wherein R5 is H or cyano; and X3 is C-H.

[0381] In an embodiment, X1 is C-R5, wherein R5 of X1, together with R3 and the atoms to which they are attached, forms a 5-membered heterocyclic group or a 5-membered heteroaryl group, and the 5-membered heterocyclic group or 5-membered heteroaryl group is optionally substituted with one or more C 1-6 alkyl groups; X2 is C-R5, wherein R5 is H, cyano, halo, or C 1-6 alkyl optionally substituted with a hydroxyl group; and X3 is C-H.

[0382] In an embodiment, X1 is C-R5, wherein R5 of X1, together with R3 and the atoms to which they are attached, forms a 5-membered heterocyclic group optionally substituted with one or more C 1-6 alkyl groups; X2 is C-R5, wherein R5 is H, cyano, halo, or C 1-6an alkyl group; and X3 is C-H.

[0383] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a tetrahydrofuranyl group, which tetrahydrofuranyl group is optionally substituted with one or more C 1-6 alkyl groups; X2 is C-R5, wherein R5 is H, cyano, halo, or C optionally substituted with hydroxy 1-6 alkyl groups; and X3 is C-H.

[0384] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a tetrahydrofuranyl group optionally substituted with a methyl group; X2 is C-R5, wherein R5 is H, cyano, halo, or C optionally substituted with hydroxy 1-6 alkyl groups; and X3 is C-H.

[0385] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a 5-membered heterocyclic group or a 5-membered heteroaryl group, wherein the 5-membered heterocyclic group or 5-membered heteroaryl group is optionally substituted with one or more C 1-6 alkyl groups; X2 is C-R5, wherein R5 is H, cyano, halo, or C optionally substituted with hydroxy 1-6 alkyl groups; X3 is C-H; and R1 is: wherein R a 、R b and R c are each H.

[0386] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a 5-membered heterocyclic group, which 5-membered heterocyclic group is optionally substituted with one or more C 1-6 alkyl groups; X2 is C-R5, wherein R5 is H, cyano, halo, or C optionally substituted with hydroxy 1-6 alkyl groups; X3 is C-H; and R1 is: wherein R a 、R b and R c are each H.

[0387] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a tetrahydrofuranyl group, which tetrahydrofuranyl group is optionally substituted with one or more C 1-6 alkyl groups; X2 is C-R5, wherein R5 is H, cyano, halo, or C optionally substituted with hydroxy 1-6 alkyl groups; X3 is C-H; and R1 is: wherein R a 、R b and Rc Each is H.

[0388] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a tetrahydrofuranyl group, which tetrahydrofuranyl group is optionally substituted by a methyl group; and R1 is: wherein R a 、R b and R c Each is H.

[0389] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a 5-membered heterocyclic group or a 5-membered heteroaryl group, wherein the 5-membered heterocyclic group or 5-membered heteroaryl group is optionally substituted by one or more C 1-6 alkyl groups; X2 is C-R5, wherein R5 is H, cyano, halo, or C 1-6 alkyl optionally substituted by a hydroxyl group; X3 is C-H; R1 is: wherein R a 、R b and R c Each is H; and R4 is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted by a hydroxyl group.

[0390] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a 5-membered heterocyclic group, which 5-membered heterocyclic group is optionally substituted by one or more C 1-6 alkyl groups; X2 is C-R5, wherein R5 is H, cyano, halo, or C 1-6 alkyl optionally substituted by a hydroxyl group; X3 is C-H; R1 is: wherein R a 、R b and R c Each is H; and R4 is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted by a hydroxyl group.

[0391] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a tetrahydrofuranyl group, which tetrahydrofuranyl group is optionally substituted by one or more C 1-6 alkyl groups; X2 is C-R5, wherein R5 is H, cyano, halo, or C 1-6 alkyl optionally substituted by a hydroxyl group; X3 is C-H; and R1 is: wherein R a 、R b and R c Each is H; and R4 is H or C 1-6 alkyl, wherein the C1-6 The alkyl group is optionally substituted by a hydroxyl group.

[0392] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a tetrahydrofuranyl group, which tetrahydrofuranyl group is optionally substituted by a methyl group; X2 is C-R5, wherein R5 is H, cyano, halo or C 1-6 alkyl group optionally substituted by a hydroxyl group; X3 is C-H; R1 is: wherein R a , R b and R c are each H; and R4 is H or C 1-6 alkyl group, wherein the C 1-6 alkyl group is optionally substituted by a hydroxyl group.

[0393] In an embodiment, R1 is an oxiranyl group, which is optionally substituted by C 1-6 alkyl group, and the C 1-6 alkyl group is further optionally substituted by -C(O)NH2.

[0394] In an embodiment, R1 is N(R e )(CN).

[0395] In an embodiment, R1 is wherein R a , R b and R c are each independently selected from the group consisting of: H, cyano, C 1-6 alkyl group, C 6-20 aryl group, wherein the C 1-6 alkyl group is further optionally substituted by a hydroxyl group, provided that at least two of R a , R b and R c are H.

[0396] In an embodiment, R1 is wherein R d is H.

[0397] In an embodiment, R1 is an oxiranyl group, which is optionally substituted by C 1-6 alkyl group, and the C 1-6 alkyl group is further optionally substituted by -C(O)NH2; and R4 is H or C 1-6 alkyl group, wherein the C 1-6 alkyl group is optionally substituted by a hydroxyl group.

[0398] In an embodiment, R1 is N(R e )(CN); and R4 is H or C 1-6 alkyl group, wherein the C 1-6The alkyl group is optionally substituted by a hydroxyl group.

[0399] In an embodiment, R1 is wherein R a , R b and R c are each independently selected from the group consisting of: H, cyano, C 1-6 alkyl, C 6-20 aryl, wherein the C 1-6 alkyl is further optionally substituted by a hydroxyl group, provided that at least two of R a , R b and R c are H; and R4 is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted by a hydroxyl group.

[0400] In an embodiment, R1 is wherein R d is H; and R4 is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted by a hydroxyl group.

[0401] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a 5-membered heterocyclic group or a 5-membered heteroaryl group, wherein the 5-membered heterocyclic group or 5-membered heteroaryl group is optionally substituted by one or more C 1-6 alkyl; X2 is C-R5, wherein R5 is H or cyano; X3 is C-H; R1 is oxiranyl, which is optionally substituted by C 1-6 alkyl, and the C 1-6 alkyl is further optionally substituted by -C(O)NH2.

[0402] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a 5-membered heterocyclic group, which is optionally substituted by one or more C 1-6 alkyl; X2 is C-R5, wherein R5 is H or cyano; X3 is C-H; R1 is oxiranyl, which is optionally substituted by C 1-6 alkyl, and the C 1-6 alkyl is further optionally substituted by -C(O)NH2.

[0403] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a tetrahydrofuranyl group, which is optionally substituted by one or more C 1-6 alkyl; X2 is C-R5, wherein R5 is H or cyano; X3 is C-H; and R1 is oxiranyl, which is optionally substituted by C 1-6 alkyl, and the C1-6 The alkyl group is further optionally substituted by -C(O)NH2.

[0404] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a tetrahydrofuranyl group, which is optionally substituted by a methyl group; X2 is C-R5, wherein R5 is H or cyano; X3 is C-H; and R1 is an oxiranyl group, which is optionally substituted by C 1-6 alkyl group, and the C 1-6 alkyl group is further optionally substituted by -C(O)NH2.

[0405] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a 5-membered heterocyclic group or a 5-membered heteroaryl group, wherein the 5-membered heterocyclic group or 5-membered heteroaryl group is optionally substituted by one or more C 1-6 alkyl groups; X2 is C-R5, wherein R5 is cyano; X3 is C-H; R1 is an oxiranyl group, which is optionally substituted by C 1-6 alkyl group, and the C 1-6 alkyl group is further optionally substituted by -C(O)NH2; L is absent; and R2 is a C 1-6 alkyl group-substituted C 6-20 aryl group.

[0406] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a 5-membered heterocyclic group, which is optionally substituted by one or more C 1-6 alkyl groups; X2 is C-R5, wherein R5 is H or cyano; X3 is C-H; R1 is an oxiranyl group, which is optionally substituted by C 1-6 alkyl group, and the C 1-6 alkyl group is further optionally substituted by -C(O)NH2; L is absent; and R2 is a C 1-6 alkyl group-substituted C 6-20 aryl group.

[0407] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a tetrahydrofuranyl group, which is optionally substituted by one or more C 1-6 alkyl groups; X2 is C-R5, wherein R5 is H or cyano; X3 is C-H; and R1 is an oxiranyl group, which is optionally substituted by C 1-6 alkyl group, and the C 1-6 alkyl group is further optionally substituted by -C(O)NH2; L is absent; and R2 is a C 1-6 alkyl group-substituted C 6-20 aryl group.

[0408] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a tetrahydrofuranyl group, which tetrahydrofuranyl group is optionally substituted by a methyl group; X2 is C-R5, wherein R5 is H or cyano; X3 is C-H; and R1 is an oxiranyl group, which is optionally substituted by a C 1-6 alkyl group, which C 1-6 alkyl group is further optionally substituted by -C(O)NH2; L is absent; and R2 is a phenyl group substituted by a C 1-6 alkyl group. 6-20 aryl group.

[0409] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a 5-membered heterocyclic group or a 5-membered heteroaryl group, wherein the 5-membered heterocyclic group or 5-membered heteroaryl group is optionally substituted by one or more C 1-6 alkyl groups; X2 is C-R5, wherein R5 is cyano; X3 is C-H; R1 is an oxiranyl group, which is optionally substituted by a C 1-6 alkyl group, which C 1-6 alkyl group is further optionally substituted by -C(O)NH2; L is absent; and R2 is a phenyl group substituted by a C 1-6 alkyl group.

[0410] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a 5-membered heterocyclic group, which 5-membered heterocyclic group is optionally substituted by one or more C 1-6 alkyl groups; X2 is C-R5, wherein R5 is H or cyano; X3 is C-H; R1 is an oxiranyl group, which is optionally substituted by a C 1-6 alkyl group, which C 1-6 alkyl group is further optionally substituted by -C(O)NH2; L is absent; and R2 is a phenyl group substituted by a C 1-6 alkyl group.

[0411] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a tetrahydrofuranyl group, which tetrahydrofuranyl group is optionally substituted by one or more C 1-6 alkyl groups; X2 is C-R5, wherein R5 is H or cyano; X3 is C-H; and R1 is an oxiranyl group, which is optionally substituted by a C 1-6 alkyl group, which C 1-6 alkyl group is further optionally substituted by -C(O)NH2; L is absent; and R2 is a phenyl group substituted by a C 1-6 alkyl group.

[0412] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a tetrahydrofuranyl group, which tetrahydrofuranyl group is optionally substituted by a methyl group; X2 is C-R5, wherein R5 is H or cyano; X3 is C-H; and R1 is an oxiranyl group, which is optionally substituted by a C 1-6 alkyl group, which C 1-6 alkyl group is further optionally substituted by -C(O)NH2; L is absent; and R2 is a phenyl group substituted by a C 1-6 alkyl group.

[0413] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a 5-membered heterocyclic group or a 5-membered heteroaryl group, wherein the 5-membered heterocyclic group or 5-membered heteroaryl group is optionally substituted by one or more C 1-6 alkyl groups; X2 is C-R5, wherein R5 is cyano; X3 is C-H; R1 is an oxiranyl group, which is optionally substituted by a C 1-6 alkyl group, which C 1-6 alkyl group is further optionally substituted by -C(O)NH2; L is absent; and R2 is a phenyl group substituted by an isopropyl group.

[0414] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a 5-membered heterocyclic group, which 5-membered heterocyclic group is optionally substituted by one or more C 1-6 alkyl groups; X2 is C-R5, wherein R5 is H or cyano; X3 is C-H; R1 is an oxiranyl group, which is optionally substituted by a C 1-6 alkyl group, which C 1-6 alkyl group is further optionally substituted by -C(O)NH2; L is absent; and R2 is a phenyl group substituted by an isopropyl group.

[0415] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a tetrahydrofuranyl group, which tetrahydrofuranyl group is optionally substituted by one or more C 1-6 alkyl groups; X2 is C-R5, wherein R5 is H or cyano; X3 is C-H; and R1 is an oxiranyl group, which is optionally substituted by a C 1-6 alkyl group, which C 1-6 alkyl group is further optionally substituted by -C(O)NH2; L is absent; and R2 is a phenyl group substituted by an isopropyl group.

[0416] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a tetrahydrofuranyl group, which tetrahydrofuranyl group is optionally substituted by a methyl group; X2 is C-R5, wherein R5 is H or cyano; X3 is C-H; and R1 is an oxiranyl group, which is optionally substituted by a C 1-6Alkyl substitution, and the C 1-6 alkyl is further optionally substituted with -C(O)NH2; L is absent; and R2 is phenyl substituted with isopropyl.

[0417] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a 5-membered heterocyclic group or a 5-membered heteroaryl group, and the 5-membered heterocyclic group or 5-membered heteroaryl group is optionally substituted with one or more C 1-6 alkyl groups; X2 is C-R5, wherein R5 is cyano; X3 is C-H; R1 is oxiranyl, which is optionally substituted with C 1-6 alkyl groups, and the C 1-6 alkyl is further optionally substituted with -C(O)NH2; L is -CH=CH-; R2 is C 3-10 cycloalkyl, which is optionally substituted with one or two substituents selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 haloalkyl, O(R e ), and SF5.

[0418] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a 5-membered heterocyclic group, and the 5-membered heterocyclic group is optionally substituted with one or more C 1-6 alkyl groups; X2 is C-R5, wherein R5 is H or cyano; X3 is C-H; R1 is oxiranyl, which is optionally substituted with C 1-6 alkyl groups, and the C 1-6 alkyl is further optionally substituted with -C(O)NH2; L is -CH=CH-; R2 is C 3-10 cycloalkyl, which is optionally substituted with one or two substituents selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 haloalkyl, O(R e ), and SF5.

[0419] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form tetrahydrofuranyl, and the tetrahydrofuranyl is optionally substituted with one or more C 1-6 alkyl groups; X2 is C-R5, wherein R5 is H or cyano; X3 is C-H; and R1 is oxiranyl, which is optionally substituted with C 1-6 alkyl groups, and the C 1-6 alkyl is further optionally substituted with -C(O)NH2; L is -CH=CH-; R2 is C 3-10 cycloalkyl, which is optionally substituted with one or two substituents selected from the group consisting of: halo, C 1-6 alkyl, C 1-6Halogenated alkyl, O(R e ) and SF5.

[0420] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a tetrahydrofuranyl group, which is optionally substituted with a methyl group; X2 is C-R5, wherein R5 is H or cyano; X3 is C-H; and R1 is an oxiranyl group, which is optionally substituted with a C 1-6 alkyl group, and the C 1-6 alkyl group is further optionally substituted with -C(O)NH2; L is -CH=CH-; R2 is a C 3-10 cycloalkyl group, which is optionally substituted with one or two substituents selected from the group consisting of: halogenated, C 1-6 alkyl, C 1-6 halogenated alkyl, O(R e ) and SF5.

[0421] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a 5-membered heterocyclic group or a 5-membered heteroaryl group, wherein the 5-membered heterocyclic group or 5-membered heteroaryl group is optionally substituted with one or more C 1-6 alkyl groups; X2 is C-R5, wherein R5 is cyano; X3 is C-H; R1 is an oxiranyl group, which is optionally substituted with a C 1-6 alkyl group, and the C 1-6 alkyl group is further optionally substituted with -C(O)NH2; L is -CH=CH-; R2 is a C 3-10 cycloalkyl group, which is substituted with one or two substituents selected from the group consisting of halogenated.

[0422] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a 5-membered heterocyclic group, which is optionally substituted with one or more C 1-6 alkyl groups; X2 is C-R5, wherein R5 is H or cyano; X3 is C-H; R1 is an oxiranyl group, which is optionally substituted with a C 1-6 alkyl group, and the C 1-6 alkyl group is further optionally substituted with -C(O)NH2; L is -CH=CH-; R2 is a C 3-10 cycloalkyl group, which is substituted with one or two substituents selected from the group consisting of halogenated.

[0423] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a tetrahydrofuranyl group, which is optionally substituted with one or more C 1-6 alkyl groups; X2 is C-R5, wherein R5 is H or cyano; X3 is C-H; and R1 is an oxiranyl group, which is optionally substituted with a C1-6 alkyl substitution, and the C 1-6 alkyl is further optionally substituted with -C(O)NH2; L is -CH=CH-; R2 is C 3-10 cycloalkyl, which is substituted with one or two substituents selected from the group consisting of halo.

[0424] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a tetrahydrofuranyl group, which is optionally substituted with a methyl group; X2 is C-R5, wherein R5 is H or cyano; X3 is C-H; and R1 is an oxiranyl group, which is optionally substituted with C 1-6 alkyl substitution, and the C 1-6 alkyl is further optionally substituted with -C(O)NH2; L is -CH=CH-; R2 is C 3-10 cycloalkyl, which is substituted with one or two substituents selected from the group consisting of halo.

[0425] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a 5-membered heterocyclic group or a 5-membered heteroaryl group, wherein the 5-membered heterocyclic group or 5-membered heteroaryl group is optionally substituted with one or more C 1-6 alkyl substitution; X2 is C-R5, wherein R5 is cyano; X3 is C-H; R1 is an oxiranyl group, which is optionally substituted with C 1-6 alkyl substitution, and the C 1-6 alkyl is further optionally substituted with -C(O)NH2; L is -CH=CH-; R2 is a cyclohexyl group substituted with one or two fluorines.

[0426] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a 5-membered heterocyclic group, which is optionally substituted with one or more C 1-6 alkyl substitution; X2 is C-R5, wherein R5 is H or cyano; X3 is C-H; R1 is an oxiranyl group, which is optionally substituted with C 1-6 alkyl substitution, and the C 1-6 alkyl is further optionally substituted with -C(O)NH2; L is -CH=CH-; R2 is a cyclohexyl group substituted with one or two fluorines.

[0427] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a tetrahydrofuranyl group, which is optionally substituted with one or more C 1-6 alkyl substitution; X2 is C-R5, wherein R5 is H or cyano; X3 is C-H; and R1 is an oxiranyl group, which is optionally substituted with C 1-6 alkyl substitution, and the C 1-6The alkyl group is further optionally substituted by -C(O)NH2; L is -CH=CH-; R2 is a cyclohexyl group substituted by one or two fluorines.

[0428] In an embodiment, X1 is C-R5, wherein R5 of X1 together with R3 and the atoms to which they are attached form a tetrahydrofuranyl group, which is optionally substituted by a methyl group; X2 is C-R5, wherein R5 is H or cyano; X3 is C-H; and R1 is an oxiranyl group, which is optionally substituted by C 1-6 alkyl group, the C 1-6 The alkyl group is further optionally substituted by -C(O)NH2; L is -CH=CH-; R2 is a cyclohexyl group substituted by one or two fluorines.

[0429] In an embodiment, L is *-CH2-O-*, where * indicates the point of attachment to the rest of the molecule and * indicates the point of attachment to the R2 moiety; and R2 is C 1-6 haloalkyl-substituted C 3-10 cycloalkyl.

[0430] In an embodiment, L is *-CH2-O-*, where * indicates the point of attachment to the rest of the molecule and * indicates the point of attachment to the R2 moiety; and R2 is a cyclohexyl group substituted by CF3.

[0431] In an embodiment, L is *-CH2-O-*, where * indicates the point of attachment to the rest of the molecule and * indicates the point of attachment to the R2 moiety; and R2 is a C 3-10 cycloalkyl substituted by one or two halogens.

[0432] In an embodiment, L is *-CH2-O-*, where * indicates the point of attachment to the rest of the molecule and * indicates the point of attachment to the R2 moiety; and R2 is a cyclohexyl group substituted by one or two fluorines.

[0433] In an embodiment, L is *-CH2-O-*, where * indicates the point of attachment to the rest of the molecule and * indicates the point of attachment to the R2 moiety; and R2 is C 5-13 spiro group.

[0434] In an embodiment, L is *-CH2-O-*, where * indicates the point of attachment to the rest of the molecule and * indicates the point of attachment to the R2 moiety; and R2 is spirohexane.

[0435] In an embodiment, L is -CH=CH-, and R2 is C 1-12 alkyl.

[0436] In an embodiment, L is -CH=CH-, and R2 is C 3-10Cycloalkyl-substituted C 1-12 alkyl group.

[0437] In an embodiment, L is -CH=CH-, and R2 is a methylene group substituted with a cyclopentyl group.

[0438] In an embodiment, L is -CH=CH-, and R2 is a 3- to 10-membered saturated heterocyclic group substituted with a 1-6 haloalkyl group.

[0439] In an embodiment, L is -CH=CH-, and R2 is a tetrahydropyran substituted with CF3.

[0440] In some aspects, compounds as described herein, such as compounds of formula (B-1), formula (B) or formula (I), or their stereoisomers, tautomers or pharmaceutically acceptable salts, are selected from the compounds listed in Table 1 below, including their racemic mixtures, resolved isomers, tautomers and pharmaceutically acceptable salts:

[0441] Table 1

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451] Compounds are provided herein that are selected from the group consisting of:

[0452] 3-Cyano-N-(5-methoxy-4-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)pyridin-2-yl)acrylamide;

[0453] N-(6-Methoxy-5-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)pyridin-3-yl)acrylamide;

[0454] N-(6-Methoxy-5-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)pyridin-3-yl)but-2-ynamide;

[0455] N-(5-(2-(4,4-Difluorocyclohexyl)vinyl)-6-methoxypyridin-3-yl)acrylamide;

[0456] N-(6-Methoxy-5-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)pyridazin-3-yl)acrylamide;

[0457] N-(5-Methoxy-4-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)pyridin-2-yl)acrylamide;

[0458] N-(4-(2-(4,4-Difluorocyclohexyl)vinyl)-5-methoxypyridin-2-yl)acrylamide;

[0459] N-(5-Methoxy-6-methyl-4-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)pyridin-2-yl)acrylamide;

[0460] N-(6-Methoxy-5-(((4-(trifluoromethyl)cyclohexyl)oxy)methyl)pyridin-3-yl)acrylamide;

[0461] N-(5-(((4,4-Difluorocyclohexyl)oxy)methyl)-6-methoxypyridin-3-yl)acrylamide;

[0462] N-(6-Methoxy-5-((spiro[2.3]hexan-5-yloxy)methyl)pyridin-3-yl)acrylamide;

[0463] N-(6-Cyclopropyl-5-methoxy-4-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)pyridin-2-yl)acrylamide;

[0464] N-(2-Cyano-6-methoxy-5-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)pyridin-3-yl)acrylamide;

[0465] N-(3-(3-Cyclopentylprop-1-en-1-yl)-4-methoxyphenyl)acrylamide;

[0466] N-(2-Hydroxyethyl)-N-(5-methoxy-4-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)pyridin-2-yl)acrylamide;

[0467] N-(4-Fluoro-4'-isopropyl-6-methoxy-[1,1'-biphenyl]-3-yl)acrylamide;

[0468] N-(7-(4-Chlorostyryl)-2,3-dihydrobenzofuran-5-yl)acrylamide;

[0469] N-(6-methoxy-5-(4-methylpent-1-en-1-yl)pyridin-3-yl)acrylamide;

[0470] N-(5-(2-(3,3-difluorocyclobutyl)vinyl)-6-methoxypyridin-3-yl)acrylamide;

[0471] N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-6-methoxypyridin-3-yl)-2-phenylacrylamide;

[0472] 3-cyano-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-6-methoxypyridin-3-yl)acrylamide;

[0473] N-(4-methoxy-3-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)phenyl)acrylamide;

[0474] N-(3-(2-(4,4-difluorocyclohexyl)vinyl)-4-methoxyphenyl)acrylamide;

[0475] N-(6-methoxy-2-phenyl-5-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)pyridin-3-yl)acrylamide;

[0476] N-(2-(Hydroxymethyl)-6-methoxy-5-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)pyridin-3-yl)acrylamide;

[0477] N-(2,6-dimethoxy-5-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)pyridin-3-yl)acrylamide;

[0478] N-(4-(2-(4,4-difluorocyclohexyl)vinyl)-5-methoxypyrimidin-2-yl)acrylamide;

[0479] 3-Acrylamido-6-methoxy-5-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)picolinamide;

[0480] N-(5-cyano-4-(2-(4,4-difluorocyclohexyl)vinyl)pyridin-2-yl)acrylamide;

[0481] 2-(Hydroxymethyl)-N-(6-methoxy-5-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)pyridin-3-yl)acrylamide;

[0482] N-(6-cyano-5-(2-(4-(trifluoromethyl)cyclohexyl)vinyl)pyridin-3-yl)-2-(hydroxymethyl)acrylamide;

[0483] N-(7-(2-(4,4-difluorocyclohexyl)vinyl)-2,3-dihydrobenzofuran-5-yl)acrylamide;

[0484] N-(7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)acrylamide;

[0485] N-(7-(((4-(trifluoromethyl)cyclohexyl)oxy)methyl)-2,3-dihydrobenzofuran-5-yl)acrylamide;

[0486] N-(7-(2-(4,4-difluorocyclohexyl)vinyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)acrylamide;

[0487] N-(7-(2-(4,4-difluorocyclohexyl)vinyl)-2,3-dihydrobenzofuran-5-yl)-N-(2-hydroxyethyl)acrylamide;

[0488] N-(7-(2-(4,4-difluorocyclohexyl)vinyl)-4-fluoro-2,3-dihydrobenzofuran-5-yl)acrylamide;

[0489] N-(5-((4-(trifluoromethyl)cyclohexyl)oxy)quinolin-3-yl)acrylamide;

[0490] N-(5-((4-(trifluoromethyl)cyclohexyl)oxy)-1,6-naphthyridin-3-yl)acrylamide;

[0491] N-(7-(2-(4,4-difluorocyclohexyl)vinyl)benzo[d]oxazol-5-yl)acrylamide;

[0492] N-(5-(4-isopropylphenyl)-6-methoxypyridin-3-yl)acrylamide;

[0493] N-(6-methoxy-5-(2-(6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)vinyl)pyridin-3-yl)acrylamide;

[0494] N-(4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)-2-methyloxirane-2-carboxamide;

[0495] N-(4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)-2-methyloxirane-2-carboxamide;

[0496] N-(4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)oxirane-2-carboxamide;

[0497] N-(4-Cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)oxirane-2-carboxamide;

[0498] 3-(4-Cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)-1-cyano-1-methylurea;

[0499] 1-(4-Cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)-3-cyano-1-methylurea;

[0500] N-(4-Cyano-7-(4-(1,1-difluoroethyl)phenyl)-2,3-dihydrobenzofuran-5-yl)oxirane-2-carboxamide;

[0501] N-(4-Cyano-7-(4-(1,1-difluoroethyl)phenyl)-2,3-dihydrobenzofuran-5-yl)oxirane-2-carboxamide;

[0502] N-(4-Cyano-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzofuran-5-yl)oxirane-2-carboxamide;

[0503] N-(4-Cyano-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzofuran-5-yl)oxirane-2-carboxamide;

[0504] N-(4-(Hydroxymethyl)-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzofuran-5-yl)acrylamide;

[0505] 2-(3-Amino-3-oxopropyl)-N-(4-cyano-7-(4-isopropylphenyl)-2,3-dihydrobenzofuran-5-yl)oxirane-2-carboxamide;

[0506] N-[4-(Hydroxymethyl)-7-[4-(pentafluoro-6-thioxo) phenyl]-2,3-dihydrobenzofuran-5-yl]prop-2-enamide; and

[0507] N-(7-Cyano-4-(4-(trifluoromethoxy)phenyl)benzothiazol-6-yl)acrylamide,

[0508] or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. Where applicable, any and all stereoisomers of the compounds described herein are also provided herein, including geometric isomers (e.g., cis / trans isomers or E / Z isomers), enantiomers, diastereomers or mixtures thereof in any ratio (including racemic mixtures).

[0509] In some aspects, the compounds of the present disclosure are isotopically labeled by substituting one or more atoms therein with 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 the compounds of Formula (B-1), Formula (B) or Formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as but not limited to, respectively 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I and 125 I. These isotopically labeled compounds will be useful in determining or measuring the effectiveness of the compounds by, for example, characterizing the site or mode of action, or the binding affinity of TEAD. Certain isotopically labeled compounds of Formula (B-1), Formula (B) or Formula (I) (e.g., those containing radioactive isotopes) can be used in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) are particularly useful in this regard because they are readily incorporated and detection means are readily available. For example, the 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.

[0510] Substitution with heavier isotopes such as deuterium (i.e., 2 H) can provide certain therapeutic advantages due to greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.

[0511] Substitution with positron emitting isotopes such as 11 C, 18 F, 15 O and 13 N) can be used in positron emission tomography (PET) studies to examine 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 similar to those described in the examples set forth below using appropriate isotopically labeled reagents in place of the previously used unlabeled reagents.

[0512] The present disclosure also provides a pharmaceutically acceptable salt or ester of any compound provided herein, as well as stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes or prodrugs of such compounds or pharmaceutically acceptable salts of such compounds.

[0513] Pharmaceutical Compositions and Administration

[0514] In addition to one or more of the compounds provided above (including their 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 example or aspect thereof and at least one pharmaceutically acceptable carrier. The compositions of the present disclosure can be used to selectively inhibit TEAD in a patient (e.g., a human).

[0515] In one aspect, the present disclosure provides a pharmaceutical composition or medicament comprising a compound of the present disclosure (or an example and aspect 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 present disclosure provides a method for preparing a composition (or medicament) comprising a compound of the present disclosure. In another aspect, the present disclosure provides a method for administering a compound of the present disclosure or a composition comprising a compound of the present disclosure to a patient (e.g., a human patient) in need thereof.

[0516] The carrier can be selected from various oils, including oils of petroleum, animal, vegetable or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil, etc. Water, saline, aqueous dextran and glycols are preferred liquid carriers, especially (when isotonic with blood) for injectable solutions. For example, a formulation for intravenous administration comprises a sterile aqueous solution of a compound of the present disclosure, which is prepared by dissolving a solid compound of the present disclosure in water to produce an aqueous solution and rendering the solution sterile. Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, talc, gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, skim milk, glycerol, propylene glycol, water, ethanol, etc. The compositions can be subjected to conventional pharmaceutical additives such as preservatives, stabilizers, wetting agents or emulsifiers, salts for adjusting osmotic pressure, buffers, etc. Suitable pharmaceutical carriers and their formulations are described in Remington's Pharmaceutical Sciences by E.W. Martin. In any case, such compositions will contain an effective amount of a compound of the present disclosure together with a suitable carrier to prepare a suitable dosage form for proper administration to a subject.

[0517] The composition is formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the timing of administration, and other factors known to the practicing physician. The effective amount of the compound to be administered will be determined by these considerations and is the minimum amount required to inhibit TEAD activity to prevent or treat an undesirable disease or disorder, such as pain. For example, the amount may be less than an amount toxic to normal cells or to the mammal as a whole.

[0518] In one example, a therapeutically effective amount of a compound of the present disclosure administered parenterally per dose will be in the range of from about 0.01 - 100 mg / kg of patient body weight per day, alternatively in the range of from about 0.1 to 20 mg / kg of patient body weight, with the initial range for the compounds commonly used being 0.3 to 15 mg / kg / day. In certain aspects, the daily dose is administered as a single daily dose or in two to six divided doses per day, or in a sustained release form. For a 70 kg adult, the total daily dose will generally be from about 7 mg to about 1,400 mg. The dosage regimen may be adjusted to provide the optimal therapeutic response. The compound may be administered according to a regimen of 1 to 4 times per day, preferably once or twice per day.

[0519] The compounds of the present disclosure may be administered in any convenient form of administration, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional components in pharmaceutical formulations, for example, diluents, carriers, pH adjusters, sweeteners, fillers, and other active agents.

[0520] Compositions containing the compounds of the present disclosure (or embodiments or aspects thereof including their stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes, pharmaceutical salts, and prodrugs) are typically formulated into pharmaceutical compositions according to standard pharmaceutical practice. Conventional formulations are prepared by mixing the compounds of the present disclosure with diluents, carriers, or excipients. 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 and 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 formulations may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, coloring agents, sweetening agents, flavoring agents, diluents, and other known additives to provide an aesthetically pleasing presentation of the medicament (i.e., the compound of the present disclosure or its pharmaceutical composition) or to facilitate the preparation of the pharmaceutical product (i.e., the drug). Suitable carriers, diluents, and excipients are well known to those skilled in the art and include buffers such as phosphates, citrates, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as cetyltrimethylammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butanol, or benzyl alcohol; alkyl esters of p-hydroxybenzoic acid such as methyl p-hydroxybenzoate or propyl p-hydroxybenzoate; catechol; resorcinol; cyclohexanol; 3-pentanol; m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; 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 dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., zinc protein complexes); and / or nonionic surfactants such as TWEEN TM , PLURONICSTM 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 embedded in microcapsules (e.g., hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively) prepared by, for example, coacervation techniques or by interfacial polymerization, encapsulated in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or in coarse-drop emulsions. Such techniques are disclosed in Remington: The Science and Practice of Pharmacy: Remington the Science and Practice of Pharmacy (2005), 21st Edition, Lippincott Williams & Wilkins, Philadelphia, PA. The particular carrier, diluent, or excipient used will depend on the manner and purpose for which the compounds of the present disclosure are administered. Solvents are generally selected based on solvents generally recognized as safe (GRAS) for administration to mammals by those skilled in the art. Generally, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents soluble in or miscible with water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG 400, PEG 300), etc. and mixtures thereof.

[0521] 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 containing solid hydrophobic polymers of compounds of formula (B-1), formula (B), or formula (I) or embodiments or aspects thereof, the matrix being in the form of shaped articles such as membranes or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate), or poly(vinyl alcohol)), polylactic acid (U.S. Patent No. 3,773,919), copolymers of L-glutamic acid and γ-ethyl-L-glutamate (Sidman et al., Biopolymers 22:547, 1983), non-degradable ethylene-vinyl acetate (Langer et al., J. Biomed. Mater. Res. 15:167, 1981), degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT TM(Injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprorelin acetate) and poly-D-(-)-3-hydroxybutyric acid (EP 133,988A). The sustained-release composition also includes a liposome-encapsulated compound, which can be prepared by methods known per se (Epstein et al., Proc. Natl. Acad. Sci. U.S.A. 82:3688, 1985; Hwang et al., Proc. Natl. Acad. Sci. U.S.A. 77:4030, 1980; U.S. Patent Nos. 4,485,045 and 4,544,545; and EP 102,324A). Generally, the liposomes are small (about 200 - 800 angstroms) unilamellar liposomes, where the lipid content is greater than about 30 mol% cholesterol, and the selected ratio is adjusted for optimal therapy.

[0522] In one example, a compound or an embodiment or aspect of the present disclosure can be formulated into a galenical administration form by mixing at ambient temperature at an appropriate pH with a physiologically acceptable carrier (i.e., a carrier that is non-toxic to the subject at the doses and concentrations used). The pH of the formulation depends mainly on the specific use and concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, the compound (or an embodiment or aspect thereof) of the present disclosure is formulated in an acetate buffer at pH 5. In another aspect, the compound or an embodiment thereof of the present disclosure is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized preparation, or as an aqueous solution.

[0523] Formulations of the compounds of the present disclosure suitable for oral administration can be prepared as discrete units, such as pills, capsules, cachets, or tablets, each containing a predetermined amount of the compound of the present disclosure.

[0524] Compressed tablets can be prepared by compressing the compound of the present disclosure in a free-flowing form (such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant) in a suitable machine. Molded tablets can be prepared by molding a mixture of the powdered compound of the present disclosure moistened with an inert liquid diluent in a suitable machine. The tablets can optionally be coated or scored and can optionally be formulated to provide slow or controlled release of the compound of the present disclosure therefrom.

[0525] Tablets, buccal tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, such as gelatin capsules, syrups or elixirs for oral administration can be prepared. The formulations of the compounds of the present disclosure for oral administration can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions can contain one or more agents including sweetening agents, flavoring agents, coloring agents and preservatives to provide palatable formulations. Tablets containing the compounds of the present disclosure admixed with non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets are acceptable. These excipients can be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binding agents such as starch, gelatin or gum arabic; lubricating agents such as magnesium stearate, stearic acid or talc. The tablets can be uncoated or can be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thus provide a sustained action over a longer period of time. For example, delayed release materials such as glyceryl monostearate or glyceryl distearate used alone or in combination with waxes can be used.

[0526] Examples of suitable oral dosage forms are tablets containing 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 the compounds of the present disclosure (or embodiments or aspects thereof) admixed with fillers (e.g., lactose such as about 90 - 30 mg anhydrous lactose), disintegrants (e.g., cross-linked carboxymethyl cellulose such as about 5 - 40 mg sodium cross-linked carboxymethyl cellulose), polymers (e.g., polyvinylpyrrolidone (PVP), cellulose (e.g., hydroxypropyl methylcellulose (HPMC)) and / or copovidone such as about 5 - 30 mg PVP, HPMC or copovidone) and lubricants (e.g., magnesium stearate such as about 1 - 10 mg). Wet granulation, dry granulation or dry blending can be used. In one aspect of wet granulation, the powdered ingredients are first mixed together and then admixed with a solution or suspension of a polymer (e.g., PVP). The resulting composition can be dried, granulated, admixed with the lubricant and compressed into tablet form using conventional equipment. Examples of aerosol formulations can be prepared by dissolving the compounds of the present disclosure (e.g., 5 - 400 mg) in a suitable buffer solution (e.g., phosphate buffer) and, if desired, adding an osmotic agent (e.g., a salt such as sodium chloride). The solution can be filtered, for example, using a 0.2 micron filter to remove impurities and contaminants.

[0527] For the treatment of the eye or other external tissues (such as the oral cavity and skin), the preparation is preferably administered in the form of a topical ointment or cream, which contains, for example, the compound of the present disclosure in an amount of 0.075% w / w to 20% w / w. When formulated as an ointment, the compound of the present disclosure can be used with paraffin or a water-miscible ointment base. Alternatively, the compound of the present disclosure can be formulated as a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base can include polyols, i.e., alcohols having two or more hydroxyl groups, such as propylene glycol, 1,3-butanediol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG 400) and mixtures thereof. The topical preparation can desirably include a compound that enhances the absorption or penetration of the compound of the present disclosure through the skin or other affected area. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues.

[0528] For topical preparations, it is desirable to administer an effective amount of the pharmaceutical composition according to the present disclosure to a target area adjacent to the peripheral neurons to be treated, such as the skin surface, mucous membrane, etc. Depending on the area to be treated, whether the use is diagnostic, prophylactic, or therapeutic, the severity of the symptoms, and the nature of the topical vehicle used, the amount is typically about 0.0001 mg to about 1 g of the compound of the present disclosure (or an example or aspect thereof) per application. A preferred topical preparation is an ointment, in which about 0.001 mg to about 50 mg of the compound of the present disclosure is used per cubic centimeter of the ointment base. The pharmaceutical composition can be formulated as a transdermal composition or a transdermal delivery device ("patch"). Such a composition includes, 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 a continuous pulse or on-demand delivery of the desired compound of the present disclosure.

[0529] The preparation can be packaged in unit-dose or multi-dose containers, such as sealed ampoules and vials, and can be stored under lyophilized (freeze-dried) conditions, requiring only the addition of a sterile liquid carrier for injection, such as water, before use. Temporary injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the foregoing types. Preferred unit-dose preparations are those that contain the daily dose or unit daily sub-dose of the compound of the present disclosure as described above herein, or an appropriate fraction thereof.

[0530] When the target is located in the brain, certain aspects of the present disclosure provide for the compound of the present disclosure (or an example or aspect thereof) to cross the blood-brain barrier. Certain neurodegenerative diseases are associated with an increased permeability of the blood-brain barrier, such that the compound of the present disclosure (or an example or aspect thereof) can be easily introduced into the brain. When the blood-brain barrier remains intact, there are several methods known in the art for crossing this blood-brain barrier with transport molecules, including but not limited to physical methods, lipid-based methods, and receptor- and channel-based methods.

[0531] Physical methods for transporting a compound (or an embodiment or aspect thereof) of the present disclosure across the blood-brain barrier include, but are not limited to, completely circumventing the blood-brain barrier or forming an opening in the blood-brain barrier.

[0532] 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 infusion / convection enhanced delivery (see, e.g., Bobo et al., Proc. Natl. Acad. Sci. U.S.A. 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 TM , Guildford Pharmaceutical).

[0533] Methods of forming an opening in the barrier include, but are not limited to, ultrasound (see, e.g., U.S. Patent Publication No. 2002 / 0038086), osmotic pressure (e.g., by administration of hypertonic mannitol (Neuwelt, E.A., Implication of the Blood-Brain Barrier and its Manipulation, Volumes 1 and 2, Plenum Press, N.Y., 1989)), and permeabilization by, for example, bradykinin or permeabilizer A-7 (see, e.g., U.S. Patent Nos. 5,112,596, 5,268,164, 5,506,206, and 5,686,416).

[0534] Lipid-based methods for transporting a compound (or an embodiment or aspect thereof) of the formula of the present disclosure across the blood-brain barrier include, but are not limited to, encapsulating the compound (or an embodiment or aspect thereof) of the present disclosure in liposomes that are conjugated to antibody binding fragments that bind to receptors on the vascular endothelium of the blood-brain barrier (see, e.g., U.S. Patent Application Publication No. 2002 / 0025313), and coating the compound (or an embodiment or aspect thereof) of the present disclosure in low density lipoprotein particles (see, e.g., U.S. Patent Application Publication No. 2004 / 0204354) or apolipoprotein E (see, e.g., U.S. Patent Application Publication No. 2004 / 0131692).

[0535] Receptor- and channel-based methods for delivering the compounds (or embodiments or aspects thereof) of the present disclosure across the blood-brain barrier include, but are not limited to, using glucocorticoid blockers to increase the permeability of the blood-brain barrier (see, e.g., U.S. Patent Application Publication Nos. 2002 / 0065259, 2003 / 0162695, and 2005 / 0124533); activating potassium channels (see, e.g., U.S. Patent Application Publication No. 2005 / 0089473), inhibiting ABC drug transporters (see, e.g., U.S. Patent Application Publication No. 2003 / 0073713); coating the compounds (or embodiments or aspects thereof) of the present disclosure with transferrin and modulating the activity of one or more transferrin receptors (see, e.g., U.S. Patent Application Publication No. 2003 / 0129186), and cationized antibodies (see, e.g., U.S. Patent No. 5,004,697).

[0536] For intracerebral use, in certain aspects, the compounds can be administered continuously by infusion into a reservoir of the CNS, although bolus injections are acceptable. The inhibitor can be administered into the cerebral ventricle or otherwise introduced into the CNS or spinal fluid. Administration can be carried out by using an indwelling catheter and a continuous administration means such as a pump, or can be administered by intracerebral implantation of, for example, a sustained-release vehicle. More specifically, the inhibitor can be injected through a long-term implanted cannula, or infused long-term with the aid of an osmotic micropump. Subcutaneous pumps for delivering proteins into the cerebral ventricle through a small tube are available. The highly sophisticated pump can be refilled through the skin, and its delivery rate can be set without surgical intervention. Examples of suitable administration regimens and administration systems involving subcutaneous pump devices or continuous intraventricular infusion through a fully implanted drug delivery system are the administration regimens and administration systems for administering dopamine, dopamine agonists, and cholinergic agonists to patients with Alzheimer's disease and animal models of Parkinson's disease, as described by Harbaugh, J. Neural Transm. Suppl. 24:271, 1987; and DeYebenes et al., Mov. Disord. 2:143, 1987.

[0537] Indications and methods of treatment

[0538] Representative compounds of the present disclosure have been shown to modulate TEAD activity. In some embodiments, the compounds that modulate TEAD activity are compounds of formula (C-1) or their stereoisomers, tautomers, or pharmaceutically acceptable salts:

[0539]

[0540] X1 is N or C-R5, where each R5 is independently selected from the group consisting of: 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 said C of R5 1-6 alkyl is optionally substituted by hydroxy or N(R e )(R f ), or

[0541] R5 of X1 and R3, together with the atoms to which they are attached, form a 5 - membered heterocyclic group or a 5 - membered heteroaryl group, wherein the 5 - membered heterocyclic group or 5 - membered heteroaryl group is optionally substituted by one or more C 1-6 alkyl;

[0542] X2 and X3 are each independently N or C - R5, wherein each R5 is independently selected from the group consisting of: 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 said C of R5 1-6 alkyl is optionally substituted by hydroxy or N(R e )(R f );

[0543] X3 is N or C - H,

[0544] R1 is:

[0545] (i) oxiranyl or oxetanyl, wherein the oxiranyl or oxetanyl is optionally substituted by one or more C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted by one or more - C(O)NH2, or

[0546] (ii) N(R e )(CN), or

[0547] (iii) wherein R a , R b and R c are each independently selected from the group consisting of: H, halo, cyano, hydroxy, C 1-6 alkyl, C 6-20 aryl, 3 - to 10 - membered heterocyclic group and 5 - to 20 - membered heteroaryl group, wherein the C 1-6 alkyl is further optionally substituted by hydroxy, or

[0548] (iv) wherein R dSelected from the group consisting of: H, halo, cyano, hydroxy, C 1-6 alkyl, C 6-20 aryl, 3- to 10-membered heterocyclic group, and 5- to 20-membered heteroaryl, wherein C 1-6 alkyl is further optionally substituted with hydroxy;

[0549] 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 rest of the molecule;

[0550] R2 is C 1-12 alkyl, C 3-10 cycloalkyl, 3- to 10-membered saturated heterocyclic group, C 6-20 aryl, C 5-13 spiro group, or 5- to 20-membered heteroaryl, wherein

[0551] the C 1-12 alkyl, C 3-10 cycloalkyl, 3- to 10-membered saturated heterocyclic group, C 6-20 aryl, C 5-13 spiro group, or 5- to 20-membered heteroaryl is independently optionally substituted with one or two substituents selected from the group consisting of: cyano, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, NO2, N(R e )(R f ), O(R e ), and SF5;

[0552] R3 is cyano, C 1-6 alkyl, C 1-4 alkoxy, or C 2-4 alkenyl, wherein the C 2-4 alkenyl is optionally substituted with N(R e )(R f ), or

[0553] R3, together with the R5 of X1 and the atoms to which they are attached, forms a 5-membered heterocyclic group or 5-membered heteroaryl, wherein the 5-membered heterocyclic group or 5-membered heteroaryl is optionally substituted with one or more C 1-6 alkyl, provided that X3 is CH, or

[0554] R3, together with the carbon atom of the *-CH2-O-** of L and the atoms to which they are attached, forms a C6 aryl or 6-membered heteroaryl;

[0555] R4 is H or C 1-6 alkyl, wherein C1-6 The alkyl group is optionally substituted by a hydroxyl group; and

[0556] R e and R f are each independently and, in each occurrence, independently selected from the group consisting of: 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 heterocyclic group, C 6-20 aryl, and 3- to 20-membered heteroaryl, wherein the C e of R f and R 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 heterocyclic group, C 6-20 aryl, and 3- to 20-membered heteroaryl are each independently optionally substituted by one or more substituents selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, oxo, cyano, halo, NO2, and hydroxyl.

[0557] In some embodiments, the compound that modulates TEAD activity is a compound of formula (C) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

[0558]

[0559] X1 is N or C-R5, where each R5 is independently selected from the group consisting of: 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 the C 1-6 alkyl of R5 is optionally substituted by a hydroxyl group or N(R e )(R f ), or

[0560] R5 of X1 and R3, together with the atoms to which they are attached, form a 5-membered heterocyclic group or a 5-membered heteroaryl group, wherein the 5-membered heterocyclic group or 5-membered heteroaryl group is optionally substituted by one or more C 1-6 alkyl;

[0561] X2 and X3 are each independently N or C-R5, where each R5 is independently selected from the group consisting of: 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, where the C 1-6 alkyl of R5 is optionally substituted with hydroxy or N(R e )(R f );

[0562] X3 is N or C-H,

[0563] R1 is:

[0564] (i) oxiranyl or oxetanyl, where the oxiranyl or oxetanyl is optionally substituted with one or more C 1-6 alkyl, or

[0565] (ii) N(R e )(CN), or

[0566] (iii) where R a , R b , and R c are each independently selected from the group consisting of: H, halo, cyano, hydroxy, C 1-6 alkyl, C 6-20 aryl, 3- to 10-membered heterocyclic group, and 5- to 20-membered heteroaryl, where the C 1-6 alkyl is further optionally substituted with hydroxy, or

[0567] (iv) where R d is selected from the group consisting of: H, halo, cyano, hydroxy, C 1-6 alkyl, C 6-20 aryl, 3- to 10-membered heterocyclic group, and 5- to 20-membered heteroaryl, where the C 1-6 alkyl is further optionally substituted with hydroxy;

[0568] L is absent or 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;

[0569] R2 is C 1-12 alkyl, C 3-10Cycloalkyl, 3- to 10-membered saturated heterocyclic group, C 6-20 Aryl, C 5-13 spiro or 5- to 20-membered heteroaryl, wherein

[0570] R2 C 1-12 Alkyl, C 3-10 Cycloalkyl, 3- to 10-membered saturated heterocyclic group, C 6-20 Aryl, C 5-13 The spirocyclic group or the 5- to 20-membered heteroaryl group is optionally substituted by one or two substituents selected from the group consisting of cyano, halo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, NO2, N(R e )(R f ) and O(R e );

[0571] R3 is cyano, C 1-6 Alkyl, C 1-4 Alkoxy or C 2-4 alkenyl, wherein the C 2-4 The alkenyl group is optionally substituted with N(R e )(R f ) or

[0572] R3 and R5 of X1 and the atoms to which they are attached together form a 5-membered heterocyclic group or a 5-membered heteroaryl group, wherein the 5-membered heterocyclic group or the 5-membered heteroaryl group is optionally substituted by one or more C 1-6 Alkyl substituted, provided that X3 is CH, or

[0573] R3 together with the carbon atom of *-CH2-O-** of L and the atoms to which they are attached form a C6 aryl or 6-membered heteroaryl group;

[0574] R4 is H or C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted with hydroxy; and

[0575] R e and R f independently from one another and at each occurrence are selected from the group consisting of: 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 heterocyclic group, C 6-20 Aryl and 3- to 20-membered heteroaryl, wherein R e and R f The C1-6 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 heterocyclic group, C 6-20 aryl and 3- to 20-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, oxo, cyano, halo, NO2, and hydroxy.

[0576] In some embodiments, the compound that modulates TEAD activity is a compound of formula (A) or a pharmaceutically acceptable salt thereof:

[0577]

[0578] X1, X2, and X3 are each independently N or C-R5, where each R5 is independently selected from the group consisting of: 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, where C 3-10 cycloalkyl, C 1-6 alkoxy, C 6-20 aryl, or C 1-6 alkyl is optionally substituted;

[0579] R1 is where R a , R b , R c , and R d are each independently selected from the group consisting of: H, halo, cyano, hydroxy, C 1-6 alkyl, C 6-20 aryl, 3- to 10-membered heterocyclic group, and 5- to 20-membered heteroaryl, where C 1-6 alkyl, C 6-20 aryl, 3- to 10-membered heterocyclic group, or 5- to 20-membered heteroaryl is independently optionally substituted;

[0580] 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 rest of the molecule;

[0581] R2 is C1-12 alkyl, C 3-10 cycloalkyl, 3- to 10-membered saturated heterocyclic group, C 6-20 aryl, C 5-13 spirocyclic group or 5- to 20-membered heteroaryl, wherein C 1-12 alkyl, C 3-10 cycloalkyl, 3- to 10-membered saturated heterocyclic group, C 6-20 aryl, C 5-13 spirocyclic group or 5- to 20-membered heteroaryl is independently optionally substituted;

[0582] R3 is cyano, C 1-6 alkyl, C 1-4 alkoxy or C 2-4 alkenyl, wherein C 1-6 alkyl, C 1-4 alkoxy or C 2-4 alkenyl is independently optionally substituted; or R3 together with the R5 of X1 and the atoms to which they are attached forms a 5-membered heterocyclic group or 5-membered heteroaryl; or R3 together with the carbon atom of the *-CH2-O-* of L and the atoms to which they are attached forms a C6 aryl or 6-membered heteroaryl; and

[0583] R4 is H or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted.

[0584] In some embodiments, the compound that modulates TEAD activity is a compound of formula (B-1), formula (B) or formula (I) as defined above 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) as defined above or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0585] The compounds (or embodiments or aspects thereof) of the present disclosure can be used as a pharmaceutical therapy for treating diseases and disorders mediated by TEAD activity. Such diseases and disorders include, but are not limited to, cancer, which includes acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, granulocytic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchial carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic granulocytic leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysplastic and metaplastic changes, embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's lymphoma and non-Hodgkin's lymphoma), malignant and hyperproliferative disorders of the bladder, 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, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor.

[0586] In a specific embodiment, a compound of the present disclosure (or an embodiment or aspect thereof) can be administered as a pharmaceutical therapy to treat proliferative disorders, including acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, granulocytic, adenocarcinomatous, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchial carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic granulocytic leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysplastic and metaplastic proliferative changes, embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's lymphoma and non-Hodgkin's lymphoma), malignant and hyperproliferative disorders of the bladder, 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, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor.

[0587] In one specific aspect, the compounds (or embodiments or aspects thereof) of the present disclosure can be administered as a pharmaceutical therapy to treat acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, granulocytic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic), acute T cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic granulocytic leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B cell lymphoma, dysplastic and metaplastic changes (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's lymphoma and non-Hodgkin's lymphoma), 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, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor. <00041 / 12> It should be noted that in the original text,

[0588] seems to be an incorrect tag. I have translated it as <00041 / 12> according to the format you provided. If this is not what you expected, please clarify the correct form of this tag.In another aspect, the present disclosure provides a method for treating acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, granulocytic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchial carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic granulocytic leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysplastic and metaplastic changes, embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's lymphoma and non-Hodgkin's lymphoma), malignant tumors and hyperproliferative disorders of the bladder, 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, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula (A), (B), (B-1), (C), (C-1), or (I) (or an example or aspect thereof) as described elsewhere herein.

[0589] In another aspect, the present disclosure provides a compound of formula (A), (B), (B-1), (C), (C-1), or (I) (or an example or aspect thereof) as described elsewhere herein for modulating TEAD activity. In some embodiments, the present disclosure provides a pharmaceutically acceptable salt of a compound of formula (A), (B), (B-1), (C), (C-1), or (I) for modulating TEAD activity.

[0590] In another aspect, the present disclosure provides a compound of formula (A), (B), (B-1), (C), (C-1) or (I) as described elsewhere herein for use in a pharmaceutical therapy, or an embodiment or aspect thereof (such as a stereoisomer, tautomer or pharmaceutically acceptable salt thereof).

[0591] In another aspect, the present disclosure provides a method of treating or preventing acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, granulocytic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic granulocytic leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B cell lymphoma, dysplastic and metaplastic changes, embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's lymphoma and non-Hodgkin's lymphoma), malignant and hyperproliferative disorders of the bladder, 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, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula (A), (B), (B-1), (C), (C-1) or (I) as described elsewhere herein (or an embodiment or aspect thereof).

[0592] In another aspect, the present disclosure provides 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 acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, granulocytic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic granulocytic leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B cell lymphoma, dysplastic and metaplastic changes, embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's lymphoma and non-Hodgkin's lymphoma), 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, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor.

[0593] On the other hand, the present disclosure provides 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 its stereoisomers, tautomers or pharmaceutically acceptable salts), in the preparation of a medicament for the treatment or prevention of acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, granulocytic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchial carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic granulocytic leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B cell lymphoma, dysplastic and metaplastic changes, embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's lymphoma and non-Hodgkin's lymphoma), 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, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor.

[0594] In another aspect, the present disclosure provides 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), in the treatment or prevention of acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, granulocytic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelogenous (granulocytic) leukemia, chronic granulocytic leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B cell lymphoma, dysplastic and metaplastic proliferative changes, embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's lymphoma and non-Hodgkin's lymphoma), 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, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor.

[0595] In another aspect, the present disclosure provides a method for treating acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, granulocytic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic), acute T cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchial carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic granulocytic leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B cell lymphoma, dysplastic and metaplastic changes, embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's lymphoma and non-Hodgkin's lymphoma), malignant tumors and hyperproliferative disorders of the bladder, 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, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor in a mammal (e.g., a human), which comprises administering to the mammal a compound of formula (A), (B), (B-1), (C), (C-1), or (I) or an example or aspect thereof (such as its stereoisomers, tautomers, or pharmaceutically acceptable salts) as described elsewhere herein.

[0596] In another aspect, the present disclosure provides a method for modulating TEAD activity, which comprises contacting TEAD with a compound of formula (A), (B), (B-1), (C), (C-1), or (I) or an example or aspect thereof (such as its stereoisomers, tautomers, or pharmaceutically acceptable salts) as described elsewhere herein.

[0597] In another aspect, the present disclosure provides 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 disorder mediated by TEAD activity. In various aspects of this embodiment, the disease or disorder is acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, granulocytic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelogenous (granulocytic) leukemia, chronic granulocytic leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B cell lymphoma, dysplastic and metaplastic changes, embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's lymphoma and non-Hodgkin's lymphoma), malignant tumors and hyperproliferative disorders of the bladder, 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, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor.

[0598] In another aspect, the present disclosure provides 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 its stereoisomers, tautomers or pharmaceutically acceptable salts), in the preparation of a medicament for treating or preventing a disease or disorder mediated by TEAD activity. In various aspects of this embodiment, the disease or disorder is acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, granulocytic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchial carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic granulocytic leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B cell lymphoma, dysplastic and metaplastic changes, embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's lymphoma and non-Hodgkin's lymphoma), malignant tumors and hyperproliferative disorders of the bladder, 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, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor.

[0599] In one aspect, the compounds of the present disclosure exhibit higher potency compared to other analogues.

[0600] Combination therapy

[0601] Compounds 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 salts thereof can be used alone or in combination with other medicaments for treatment. For example, the second medicament of a pharmaceutical combination preparation or dosing regimen can have an activity complementary to that of the compounds of formula (A), (B), (B-1), (C), (C-1), (I), (IA), (IB), (IC), (IC-1), (ID), (IE), (IF), (IG), (IH), (IJ), (IK) or (IL) such that they have no adverse effects on each other. The compounds can be administered together or separately in a single pharmaceutical composition. In one embodiment, the compound or pharmaceutical salt can be co-administered with a cytotoxic agent to treat proliferative diseases and cancers.

[0602] The term "co-administer" means the simultaneous administration of the compounds 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 salts thereof with one or more other active pharmaceutical ingredients (including cytotoxic agents and radiotherapy) or sequential administration in any manner. If the administrations are not simultaneous, the compounds should be administered within a close time proximity to each other. Additionally, it is immaterial whether the compounds are administered in the same dosage form, for example, one compound can be administered topically while another can be administered orally.

[0603] Those other reagents can be administered separately from the composition containing the compounds of the present invention as part of a multi-dose regimen. Alternatively, those medicaments can be part of a single dosage form, mixed together with the compounds of the present invention in a single composition. If administered as part of a multi-dose regimen, the two active agents can be administered simultaneously, sequentially or at intervals from each other (usually within five hours of each other).

[0604] As used herein, the terms "combination", "combined" and related terms refer to the simultaneous or sequential administration of the therapeutic agents according to the present invention. For example, the compounds of the present invention can be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of formula I or formula II, another therapeutic agent and a pharmaceutical carrier, adjuvant or vehicle.

[0605] The amounts of the compounds of the invention and other therapeutic agents (in those compositions that include other therapeutic agents as described above) that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. In certain embodiments, the compositions of the invention are formulated such that a dose of from 0.01 to 100 mg / kg body weight / day of the invention can be administered.

[0606] Generally, any agent that is active against the disease or condition being treated can be co-administered. Examples of such drugs can be found in Cancer Principles and Practice of Oncology (V.T. Devita and S. Hellman (eds.), 6th Edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. Based on the specific characteristics of the drugs and diseases involved, one of ordinary skill in the art will be able to discern which combinations of agents will be useful.

[0607] In one embodiment, the method of treatment comprises co-administering 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 arrests cell function and / or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioisotopes (e.g., radioisotopes of At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 and Lu); chemotherapeutic agents; growth inhibitors; enzymes and fragments thereof, such as nucleolytic enzymes; and toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and / or variants thereof.

[0608] Exemplary cytotoxic agents can 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 cancer metabolism inhibitors.

[0609] "Chemotherapeutic agent" includes chemical compounds that can be used to treat cancer. Examples of chemotherapeutic agents include erlotinib ( Genentech / OSI Pharm.), bortezomib ( Millennium Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant ( AstraZeneca), sunitinib ( Pfizer / Sugen), letrozole ( Novartis), imatinib mesylate ( Novartis), phenoxodiol ( Novartis), oxaliplatin ( Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (sirolimus, Wyeth), lapatinib ( GSK572016, Glaxo Smith Kline), lonafamib (SCH 66336), sorafenib ( Bayer Labs), gefitinib ( AstraZeneca), AG1478; alkylating agents such as thiotepa and Cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolmelamine; acetogenins (especially bullatacin and bullatacinone); camptothecin (including topotecan and irinotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycin (especially cryptophycin 1 and cryptophycin 8); corticosteroids (including prednisone and prednisolone); cyproterone acetate; 5α-reductase inhibitors (including finasteride and dutasteride); vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat, dolastatin; aldesleukin, talc, duocarmycin (including synthetic analogs KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlorotepa, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine hydrochloride, melphalan, novembichin, phenyl mustard chloromethyl cholesteryl, prednimustine, trofosfamide, uracilmustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine and ranimustine; antibiotics such as enediyne antibiotics (e.g., calicheamicin, especially calicheamicin γ1I and calicheamicin ω1I (Angew Chem.Intl.Ed.Engl.1994 33:183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; esmycin; and neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores; aclacinomysin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunomycin, detorubicin, 6-azido-5-oxo-L-norleucine, . Doxorubicin, morpholino-doxorubicin, cyano-morpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxy-doxorubicin, epirubicin, isorubicin, idarubicin, marcellomycin; mitomycin, such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, methylmitomycin, puromycin, quelamycin, rodorubicin, streptothricin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-Fu); folic acid analogs, such as denopterin, methotrexate, pteropterin, trimethoprim; purine analogs, such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, didoxuridine, doxifluridine, enocitabine, floxuridine; androgens, such as calusterone, drostanolone propionate, cytrterone acetate, mepitiostane, testolactone; antiadrenal drugs, such as aminoglutethimide, mitotane, trilostane; folic acid supplements, such as folinic acid; glucuronolactone; aldophosphamide glycoside; aminolevulinic acid; enuracil; aclarubicin; bestrabucil; bisantrene; edatraxate; defofamine; colchicine amide; iminostilbene; elfomithine; elisidepsin; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansine alkaloids, such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidamnol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazine; procarbazine; Polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; germanium spiroamine; tenuazonic acid; triaziquone; 2,2',2”-trichloroethylamine; trichothecenes (especially T-2 toxin, verracurin A, myrothecin A, and anguidine); urethane; vindesine; dacarbazine; mannomustine; dibromomannitol; dibromodulcitol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes, such as TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), (without Cremophor) albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.) and (docetaxel; Sanofi-Aventis); chlorambucil; (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs, such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid; and pharmaceutically acceptable salts, acids, and derivatives of any of the foregoing.

[0610] The chemotherapeutic agents also include (i) antihormonal agents that act to regulate or inhibit the action of hormones on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trvoxifene, keoxifene, LY117018, onapristone, and (Toremifene citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which can regulate estrogen production in the adrenal gland, such as 4(5)-imidazoles, aminoglutethimide, (Megestrol acetate), (Exemestane; Pfizer), formestanie, fadrozole, (Vorozole), (Letrozole; Novartis) and (Anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprorelin and goserelin; buserelin, triptorelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all-trans retinoic acid, fenretinide and troxacitabine (1,3-dioxolane nucleoside cytosine analogue); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those that inhibit gene expression in signal transduction pathways implicated in abnormal cell proliferation, such as, for example, PKC-α, Ralf and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, e.g., and rIL-2; topoisomerase 1 inhibitors such as rmRH; and (ix) pharmaceutically acceptable salts, acids and derivatives of any of the above.

[0611] Chemotherapeutic agents also include antibodies, such as alemtuzumab (Campath), bevacizumab ( Genentech); cetuximab ( Imclone); panitumumab ( Amgen), rituximab ( Genentech / Biogen Idec), pertuzumab ( 2C4, Genentech), trastuzumab ( Genentech), tositumomab (Bexxar, Corixia) and antibody-drug conjugates, gemtuzumab ozogamicin ( (Wyeth). Other humanized monoclonal antibodies with therapeutic potential in combination with the compounds of the present invention include: apolizumab, aselizumab, alizumab, barbuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, moxetumomab pasudotox, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, siltuximab, selicizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, ublituximab, ustekinumab, visilizumab, and anti-interleukin-12 (ABT-874 / J695,Wyeth Research and Abbott Laboratories) (Anti-Interleukin-12 is a recombinant human full-length IgG1λ antibody with a specific sequence that has been genetically modified to recognize the Interleukin-12p40 protein).

[0612] The chemotherapeutic agent also includes an "EGFR inhibitor", which refers to a compound that binds to or directly interacts with EGFR and blocks or reduces its signaling activity, and is alternatively referred to as an "EGFR antagonist". 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 HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see, U.S. Patent No. 4,943,533, Mendelsohn et al.) and variants thereof, such as chimeric 225 (C225 or cetuximab; ) and reshaped human 225 (H225) (see, WO96 / 40210, Imclone Systems Inc.); IMC-11F8, a fully human antibody targeting EGFR (Imclone); an antibody that binds to mutant type II EGFR (U.S. Patent No. 5,212,290); humanized and chimeric antibodies that bind to EGFR as described in U.S. Patent No. 5,891,996; and human antibodies that bind to EGFR, such as ABX-EGF or panitumumab (see WO98 / 50433, Abgenix / Amgen); EMD55900 (Stragliotto et al. Eur. J. Cancer 32A:636-640 (1996)); EMD7200 (matuzumab), a humanized EGFR antibody against EGFR, which competes with EGF and TGF-α for binding to EGFR (EMD / Merck); human EGFR antibody, HuMax-EGFR (GenMab); fully human antibodies, designated E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 and E7.6.3, and described in US 6,235,883; MDX-447 (Medarex Inc.); and mAb806 or humanized mAb 806 (Johns et al., J. Biol. Chem. 279(29):30375-30384 (2004)). Anti-EGFR antibodies can be conjugated to cytotoxic agents to produce immunoconjugates (see, for example, EP659,439A2, Merck Patent GmbH). EGFR antagonists include small molecules, such as 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 compounds described in the following PCT publications: WO98 / 14451, WO98 / 50038, WO99 / 09016 and WO99 / 24037. Specific small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, Genentech / OSI Pharmaceuticals); PD 183805 (CI 1033, 2 - acrylamide, N - [4 - [(3 - chloro - 4 - fluorophenyl)amino]-7 - [3 - (4 - morpholinyl)propoxy]-6 - quinazolinyl]-, dihydrochloride, Pfizer); ZD1839, gefitinib( 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6 - amino - 4-(3 - methylphenyl - amino)-quinazoline, Zeneca); BIBX - 1382 (N8-(3 - chloro - 4 - fluorophenyl)-N2-(1 - methyl - piperidin - 4 - yl)-pyrimidinyl[5,4 - d]pyrimidine - 2,8 - diamine, Boehringer Ingelheim); PKI - 166 ((R)-4-[4-[(1 - phenylethyl)amino]-1H - pyrrolidino[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 - butenamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU5271; Pfizer); dual EGFR / HER2 tyrosine kinase inhibitors, such as lapatinib( GSK572016 or N - [3 - chloro - 4-[(3 - fluorophenyl)methoxy]phenyl]-6[5[[[2(methylsulfonyl)ethyl]amino]methyl]-2 - furanyl]-4 - quinazolinamine).

[0613] The chemotherapeutic agents also include "tyrosine kinase inhibitors", including the EGFR-targeted drugs described above; small molecule HER2 tyrosine kinase inhibitors such as TAK165 available from Takeda; CP-724,714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual HER inhibitors such as EKB-569 (available from Wyeth), which preferentially binds to EGFR but also inhibits cells overexpressing HER2 and EGFR; lapatinib (GSK572016; available from GlaxoSmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors such as canertinib (CI-1033; Pharmacia); Raf-1 inhibitors such as the antisense agent ISIS-5132 that inhibits Raf-1 signaling available from ISIS Pharmaceuticals; non-HER-targeted TK inhibitors such as imatinib mesylate ( available from GlaxoSmithKline); multi-targeted tyrosine kinase inhibitors such as sunitinib ( 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 PD153035, 4-(3-chloroanilino)quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines such as CGP59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidine; curcumin (difluoromethyl ketone, 4,5-bis(4-fluoroanilino)phthalimide); tyrosine tyrphostins containing a nitrothiophene moiety; PD-0183805 (Warner-Lambert); antisense molecules (e.g., molecules that bind to HER-encoding nucleic acids); quinoxalines (U.S. Patent No. 5,804,396); tyrosine phosphorylation inhibitors (U.S. Patent No. 5,804,396); ZD6474 (AstraZeneca); PTK-787 (Novartis / Schering AG); pan-HER inhibitors such as CI-1033 (Pfizer); Affinitac (ISIS3521; Isis / Eli Lilly); imatinib mesylate PKI 166 (Novartis); GW2016 (GlaxoSmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); semaxanib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis / Schering); INC-1C11 (Imclone), rapamycin (sirolimus, ); or as described in any of the following patent publications: U.S. Patent No. 5,804,396, WO1999 / 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 WO1996 / 33980 (Zeneca).

[0614] The chemotherapeutic agents also include dexamethasone, interferon, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, live BCG, bevacizumab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, erlotinib, filgrastim, histrelin acetate, ibritumomab, interferon α-2a, interferon α-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 and their pharmaceutically acceptable salts.

[0615] Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, thiocortisol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, flucortolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, flucortolone hexanoate, flucortolone valerate, and fluprednidene acetate; immunoselective anti-inflammatory peptides (ImSAIDs), such as phenylalanine-glutamine-glycine (FEG) and its D-isomer form (feG) (IMULAN BioTherapeutics, LLC); antirheumatic drugs, such as azathioprine, cyclosporine (cyclosporin A), D-penicillamine, gold salts, hydroxychloroquine, leflunomide, minocycline, sulfasalazine; tumor necrosis factor α (TNFα) blockers, such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab (Cimzia), golimumab (Simponi); interleukin 1 (IL-1) blockers, such as anakinra (Kineret); T cell costimulation blockers, such as abatacept (Orencia); interleukin 6 (IL-6) blockers, such as tocilizumab Interleukin 13 (IL-13) blockers, such as lebrikizumab; interferon α (IFN) blockers, such as rilonacept; β7 integrin blockers, such as rhuMAbβ7; IgE pathway blockers, such as anti-M1 primer; secreted homotrimeric LTa3 and membrane-bound heterotrimeric LTa1 / β2 blockers, such as anti-lymphotoxin α (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; various test agents such as sulfur-platinum, PS-341, phenyl butyrate, ET-18-OCH3 or farnesyl transferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, picric acid, epigallocatechin gallate, theaflavin, flavanol, proanthocyanidin, betulinic acid and its derivatives; autophagy inhibitors such as chloroquine; δ-9-tetrahydrocannabinol (dronabinol, ); β-lapachone; lapachol; colchicine; betulinic acid; acetylcamptothecin, scopolectin and 9-aminocamptothecin); podophyllotoxin; tegafur Bexarotene Bisphosphonates such as clodronate (e.g., or ), etidronate NE-58095, zoledronic acid / zoledronate Alendronate Pamidronate Tiludronate or risedronate and epidermal growth factor receptor (EGF-R); vaccines such as vaccines; perifosine; COX-2 inhibitors (e.g., celecoxib or etoricoxib); proteasome inhibitors (e.g., PS341); CCI-779; tipifarnib (R11577); sorafenib, ABT510; Bcl-2 inhibitors such as oblimersen sodium Pixantrone; farnesyl transferase inhibitors such as lonafarnib (SCH 6636, SARASAR TM ); and pharmaceutically acceptable salts, acids or derivatives of any of the above; and combinations of two or more of the above, such as CHOP (abbreviation for combination therapy of cyclophosphamide, doxorubicin, vincristine and prednisolone); and FOLFOX (abbreviation for treatment regimen of oxaliplatin (ELOXATIN TM ) combined with 5-FU and calcium folinate).

[0616] The chemotherapeutic agents also include non-steroidal anti-inflammatory drugs having analgesic, antipyretic and anti-inflammatory effects. The NSAIDs include non-selective inhibitors of cyclooxygenase. Specific examples of NSAIDs include aspirin, propionic acid derivatives (e.g., ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, and naproxen), acetic acid derivatives (e.g., indomethacin, sulindac, etodolac, diclofenac), enolic acid derivatives (e.g., piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, and isoxicam), fenamic acid derivatives (e.g., mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid), and COX-2 inhibitors (e.g., celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, valdecoxib). The NSAIDs can be applicable to relieve the symptoms of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthritis, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhea, metastatic bone pain, headache and migraine, postoperative pain, mild to moderate pain due to inflammation and tissue damage, fever, intestinal obstruction, and renal colic.

[0617] In certain embodiments, the 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), podophyllotoxins (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, campthothecin, cisplatin, metronidazole, and imatinib mesylate, etc. In other embodiments, the compounds of the present invention are administered in combination with a biological agent (such as bevacizumab or panitumumab).

[0618] In certain embodiments, the compounds of the invention or their pharmaceutical compositions are administered in combination with an anti - proliferative agent or a chemotherapeutic agent, and the chemotherapeutic agent is selected from any one or more of the following: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, anastrozole, arsenic trioxide, asparaginase, azacitidine, live BCG, bevacizumab, fluorouracil, bexarotene, bleomycin, bortezomib, busulfan, calusterone, capecitabine, camptothecin, carboplatin, carmustine, cetuximab, chlorambucil, cladribine, clofarabine, cyclophosphamide, cytarabine, dactinomycin, darbepoetin alfa, daunorubicin, denileukin, dexrazoxane, docetaxel, doxorubicin (neutral), doxorubicin hydrochloride, dimethisterone, epirubicin, epoetin alfa, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, filgrastine, floxuridine, fludarabine, fulvestrant, gefitinib, gemcitabine, gemtuzumab, goserelin acetate, histidine acetate, hydroxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alpha - 2a, interferon alpha - 2b, irinotecan, lenalidone, letrozole, leucovorin, megestrol acetate, levamisole, lomustine, progesterone acetate, melphalan, mercaptopurine, 6 - MP, methanesulfonic acid, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone, nelarabine, nomograms, oprelvekin, oxaliplatin, paclitaxel, palifermin, pamidronate, pegademase, pegaspargase, filgrastine, pemetrexed disodium, pentostatin, pipobroman, plicamycin, porfimer sodium, procarbazine, quinacrine, rasburicase, rituximab, sargramostim, sorafenito, streptozocin, sunitinib malate, talc, tamoxifen, temozolomide, teniposide, VM - 26, testosterone lactone, thioguanine, 6 - TG, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, ATRA, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, zoledronate or zoledronic acid.

[0619] The chemotherapeutic agents also include those for the treatment of Alzheimer's disease, such as donepezil hydrochloride and rivastigmine; those for the treatment of Parkinson's disease, such as L - DOPA / carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexyphenidyl and amantadine; agents for the treatment of multiple sclerosis (MS), such as beta interferon (e.g., and ) glatiramer acetate and mitoxantrone; for the treatment of asthma, such as albuterol and montelukast sodium; agents for the treatment of schizophrenia, such as Zyprexa, Risperdal, Seroquel and haloperidol; anti-inflammatory agents, such as corticosteroids, TNF blockers, IL-1RA, azathioprine, cyclophosphamide and sulfasalazine; immunomodulators and immunosuppressants, such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine and sulfasalazine; neurotrophic factors, such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole and anti-Parkinson's disease agents; agents for the treatment of cardiovascular diseases, such as β-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers and statins; agents for the treatment of liver diseases, such as corticosteroids, cholestyramine, interferons and antiviral agents; agents for the treatment of blood disorders, such as corticosteroids, anti-leukemia agents and growth factors; and agents for the treatment of immunodeficiency disorders, such as gamma globulin.

[0620] Additionally, chemotherapeutic agents include pharmaceutically acceptable salts, acids or derivatives of any of the chemotherapeutic agents described herein, and combinations of two or more of them.

[0621] In another embodiment, there is provided a method of treating cancer by using a compound of formula (A), (B), (B-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, or an example or aspect thereof in combination with a PD-1 axis binding antagonist.

[0622] The term "PD-1 axis binding antagonist" refers to a molecule that inhibits the interaction of a PD-1 axis binding ligand with one or more of its binding partners to eliminate T cell dysfunction caused by signal transduction 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.

[0623] The term "PD-1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, eliminates, or interferes with the signal transduction generated by the interaction of PD-1 with one or more of its binding partners (such as PD-L1, PD-L2). In some embodiments, the PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to one or more of its binding partners. In a specific aspect, the 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 and their antigen-binding fragments, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, eliminate, or interfere with the signal transduction generated by the interaction of PD-1 with PD-L1 and / or PD-L2. In one embodiment, the PD-1 binding antagonist can reduce the negative co-stimulatory signal mediated by or through the signal transduction through PD-1 mediated by cell surface proteins expressed on T lymphocytes, thereby making dysfunctional T cells less dysfunctional (e.g., enhancing the effector's 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.

[0624] The term "PD-L1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, eliminates, or interferes with the signal transduction generated by the interaction of PD-L1 with one or more of its binding partners (such as PD-1, B7-1). In some embodiments, the PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partner. In a specific aspect, the 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, their antigen-binding fragments, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, eliminate, or interfere with the signal transduction generated by the interaction of PD-L1 with one or more of its binding partners (such as PD-1, B7-1). In one embodiment, the PD-L1 binding antagonist can reduce the negative co-stimulatory signal mediated by or through the signal transduction through PD-L1 mediated by cell surface proteins expressed on T lymphocytes, thereby making dysfunctional T cells less dysfunctional (e.g., enhancing the effector's 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.

[0625] The term "PD-L2 binding antagonist" refers to a molecule that reduces, blocks, inhibits, eliminates, or interferes with the signal transduction generated by 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, the 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, eliminate, or interfere with the signal transduction generated by the interaction of PD-L2 with one or more of its binding partners (such as PD-1). In one embodiment, the PD-L2 binding antagonist can reduce the negative co-stimulatory signal mediated by signal transduction through PD-L2 mediated by cell surface proteins expressed on T lymphocytes, thereby making dysfunctional T cells less dysfunctional (e.g., enhancing the effector's response to antigen recognition). In some embodiments, the PD-L2 binding antagonist is an immunoadhesin.

[0626] PD-1 axis binding antagonist

[0627] Provided herein are methods of treating cancer in an individual, which comprise 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. Also provided herein are methods of enhancing the immune function or response of an individual (e.g., an individual suffering from cancer), which comprise 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.

[0628] 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. Aliases of "PD-1" include CD279 and SLEB2. Aliases of "PDL1" include B7-H1, B7-4, CD274, and B7-H. Aliases of "PDL2" include B7-DC, Btdc, and CD273. In some embodiments, PD-1, PDL1, and PDL2 are human PD-1, PDL1, and PDL2.

[0629] In some embodiments, a PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to its ligand binding partner. In a specific aspect, the PD-1 ligand binding partner is PDL1 and / or PDL2. In another embodiment, a PDL1 binding antagonist is a molecule that inhibits the binding of PDL1 to its binding partner. In a specific aspect, the PDL1 binding partner is PD-1 and / or B7-1. In another embodiment, a PDL2 binding antagonist is a molecule that inhibits the binding of PDL2 to its binding partner. In a particular aspect, the PDL2 binding partner is PD-1. The antagonist can be an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, or a small molecule. If the antagonist is an antibody, then in some embodiments, the antibody comprises a human constant region selected from the group consisting of IgG1, IgG2, IgG3, and IgG4.

[0630] Anti-PD-1 antibody

[0631] 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', Fab'-SH, Fv, scFv, and (Fab')2 fragments. In some embodiments, the anti-PD-1 antibody is a chimeric or humanized antibody. In other embodiments, the anti-PD-1 antibody is a human antibody.

[0632] 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 [[ID=1|1]] is the anti-PD-1 antibody described in WO2006 / 121168. Nivolumab comprises heavy and light chain sequences, wherein:

[0633] (a) the heavy chain comprises the following amino acid sequence.

[0634] QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWY DGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQ ID NO:1) and

[0635] (b) The light chain comprises the following amino acid sequence:

[0636] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRAT GIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:2).

[0637] 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 from SEQ ID NO:1 and three light chain HVRs from SEQ ID NO:2). In some embodiments, the anti-PD-1 antibody comprises the heavy chain variable domain from SEQ ID NO:1 and the light chain variable domain from SEQ ID NO:2.

[0638] In some embodiments, the anti-PD-1 antibody is pembrolizumab (CAS Registry Number: 1374853-91-4). Pembrolizumab (Merck), also known as MK-3475, Merck3475, Keytruda, SCH-900475, and is the anti-PD-1 antibody described in WO2009 / 114335. Pembrolizumab comprises heavy and light chain sequences, wherein:

[0639] (a) The heavy chain comprises the following amino acid sequence:

[0640] QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGG INPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYW GQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCP APEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTK PREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN YKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:3) and

[0641] (b) The light chain comprises the following amino acid sequence:

[0642] EIVLTQSPAT LSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLES GVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKV QWKVDNALQSGNSQESVTEQ DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:4).

[0643] 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 from SEQ ID NO:3 and three light chain HVRs from SEQ ID NO:4). In some embodiments, the anti-PD-1 antibody comprises the heavy chain variable domain from SEQ ID NO:3 and the light chain variable domain from SEQ ID NO:4.

[0644] In some embodiments, the anti-PD-1 antibody is MEDI-0680 (AMP-514; AstraZeneca). MEDI-0680 is a humanized IgG4 anti-PD-1 antibody.

[0645] In some embodiments, the anti-PD-1 antibody is PDR001 (CAS Registry Number 1859072-53-9; Novartis). PDR001 is a humanized IgG4 anti-PD1 antibody that blocks the binding of PDL1 and PDL2 to PD-1.

[0646] In some embodiments, the anti-PD-1 antibody is REGN2810 (Regeneron). REGN2810 is a human anti-PD1 antibody.

[0647] In some embodiments, the anti-PD-1 antibody is BGB-108 (BeiGene). In some embodiments, the anti-PD-1 antibody is BGB-A317 (BeiGene).

[0648] In some embodiments, the anti-PD-1 antibody is JS-001 (Shanghai Junshi). JS-001 is a humanized anti-PD1 antibody.

[0649] In some embodiments, the anti-PD-1 antibody is STI-A1110 (Sorrento). STI-A1110 is a human anti-PD1 antibody.

[0650] In some embodiments, the anti-PD-1 antibody is INCSHR-1210 (Incyte). INCSHR-1210 is a human IgG4 anti-PD1 antibody.

[0651] In some embodiments, the anti-PD-1 antibody is PF-06801591 (Pfizer).

[0652] In some embodiments, the anti-PD-1 antibody is TSR-042 (also known as ANB011; Tesaro / AnaptysBio).

[0653] In some embodiments, the anti-PD-1 antibody is AM0001 (ARMO Biosciences).

[0654] In some embodiments, the anti-PD-1 antibody is ENUM 244C8 (Enumeral Biomedical Holdings). ENUM 244C8 is an anti-PD1 antibody that inhibits the function of PD-1 without preventing the binding of PDL1 to PD-1.

[0655] In some embodiments, the anti-PD-1 antibody is ENUM 388D4 (Enumeral Biomedical Holdings). ENUM 388D4 is an anti-PD1 antibody that competitively inhibits the binding of PDL1 to PD-1.

[0656] In some embodiments, the PD-1 antibody comprises six HVR sequences (e.g., three heavy chain HVRs and three light chain HVRs) and / or the heavy chain variable domain and the light chain variable domain from the PD-1 antibodies described in the following documents: WO2015 / 112800 (Applicant: Regeneron), WO2015 / 112805 (Applicant: Regeneron), WO2015 / 112900 (Applicant: Novartis), US20150210769 (assigned to Novartis), WO2016 / 089873 (Applicant: Celgene), WO2015 / 035606 (Applicant: Beigene), WO2015 / 085847 (Applicant: Shanghai Hengrui Pharmaceutical / Jiangsu Hengrui Medicine), WO2014 / 206107 (Applicant: Shanghai Junshi Biosciences / Junmeng Biosciences), WO2012 / 145493 (Applicant: Amplimmune), US9205148 (assigned to MedImmune), WO2015 / 119930 (Applicant: Pfizer / Merck), WO2015 / 119923 (Applicant: Pfizer / Merck), WO2016 / 032927 (Applicant: Pfizer / Merck), WO2014 / 179664 (Applicant: AnaptysBio), WO2016 / 106160 (Applicant: Enumeral), and WO2014 / 194302 (Applicant: Sorrento).

[0657] Anti-PDL1 antibody

[0658] In some embodiments, the PD-1 axis binding antagonist is an anti-PDL1 antibody. A variety of anti-PDL1 antibodies are contemplated and described herein. In any embodiment herein, an isolated anti-PDL1 antibody can bind to human PDL1, such as the human PDL1 shown in UniProtKB / Swiss-Prot accession number Q9NZQ7.1, or a variant thereof. In some embodiments, the anti-PDL1 antibody is capable of inhibiting 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 or humanized antibody. In some embodiments, the anti-PDL1 antibody is a human antibody. Examples of anti-PDL1 antibodies useful in the methods of the invention and methods for their preparation are described in PCT patent application WO2010 / 077634 and U.S. Patent No. 8,217,149, both of which are incorporated herein by reference.

[0659] 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.

[0660] Atezolizumab comprises:

[0661] (a) HVR-H1, HVR-H2, and HVR-H3 sequences that are GFTFSDSWIH (SEQ ID NO:5), AWISPYGGSTYYADSVKG (SEQ ID NO:6), and RHWPGGFDY (SEQ ID NO:7), respectively, and

[0662] (b) HVR-L1, HVR-L2, and HVR-L3 sequences that are RASQDVSTAVA (SEQ ID NO:8), SASFLYS (SEQ ID NO:9), and QQYLYHPAT (SEQ ID NO:10), respectively.

[0663] Atezolizumab comprises heavy and light chain sequences, wherein:

[0664] (a) The heavy chain variable region sequence comprises the following amino acid sequence:

[0665] EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS (SEQ ID NO:11) and

[0666] (b) The light chain variable region sequence contains the following amino acid sequence:

[0667] DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIY SASF LYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO:12).

[0668] Atezolizumab contains heavy and light chain sequences, wherein:

[0669] (a) The heavy chain contains the following amino acid sequence:

[0670] EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:13) and

[0671] (b) The light chain contains the following amino acid sequence:

[0672] DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:14).

[0673] 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). Avelumab comprises heavy and light chain sequences, wherein:

[0674] (a) The heavy chain comprises the following amino acid sequence:

[0675] EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVSSIYPSGGITFYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ ID NO:15) and

[0676] (b) The light chain comprises the following amino acid sequence:

[0677] QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTRVFGTGTKVTVLGQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS(SEQ ID NO:16).

[0678] 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 from SEQ ID NO:15 and three light chain HVRs from SEQ ID NO:16). In some embodiments, the anti-PDL1 antibody comprises the heavy chain variable domain from SEQ ID NO:15 and the light chain variable domain from SEQ ID NO:16.

[0679] 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 IgG1κ anti-PDL1 antibody (MedImmune, AstraZeneca) described in WO2011 / 066389 and US2013 / 034559. Durvalumab comprises heavy and light chain sequences, wherein:

[0680] (a) the heavy chain comprises the following amino acid sequence:

[0681] EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:17) and

[0682] (b) The light chain comprises the following amino acid sequence:

[0683] EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:18).

[0684] 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 from SEQ ID NO:17 and three light chain HVRs from SEQ ID NO:18). In some embodiments, the anti-PDL1 antibody comprises the heavy chain variable domain from SEQ ID NO:17 and the light chain variable domain from SEQ ID NO:18.

[0685] In some embodiments, the anti-PDL1 antibody is MDX-1105 (Bristol Myers Squibb). MDX-1105, also known as BMS-936559, is the anti-PDL1 antibody described in WO2007 / 005874.

[0686] In some embodiments, the anti-PDL1 antibody is LY3300054 (Eli Lilly).

[0687] In some embodiments, the anti-PDL1 antibody is STI-A1014 (Sorrento). STI-A1014 is a human anti-PDL1 antibody.

[0688] In some embodiments, the anti-PDL1 antibody is KN035 (Suzhou Alphamab). KN035 is a single domain antibody (dAB) generated from a camelid phage display library.

[0689] In some embodiments, the anti-PDL1 antibody comprises a cleavable moiety or linker that, when cleaved (e.g., by a protease in the tumor microenvironment), activates the antibody antigen-binding domain (e.g., by removing a non-binding steric moiety) to enable binding to its antigen. In some embodiments, the anti-PDL1 antibody is CX-072 (CytomX Therapeutics).

[0690] In some embodiments, the PDL1 antibody comprises six HVR sequences (e.g., three heavy chain HVRs and three light chain HVRs) and / or heavy chain variable domain and light chain variable domain from the PDL1 antibodies described in US20160108123 (assigned to Novartis), WO2016 / 000619 (applicant: Beigene), WO2012 / 145493 (applicant: Amplimmune), US9205148 (assigned to MedImmune), WO2013 / 181634 (applicant: Sorrento), and WO2016 / 061142 (applicant: Novartis).

[0691] In yet another specific aspect, the PD-1 or PDL1 antibody has reduced or minimal effector function. In yet another specific aspect, the minimal effector function results from a "null effector Fc mutation" or a deglycosylation mutation. In another embodiment, the null effector Fc mutation is an N297A or D265A / N297A substitution in the constant region. In some embodiments, the isolated anti-PDL1 antibody is deglycosylated. Glycosylation of antibodies is generally 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 other than proline, are the recognition sequences for the enzymatic attachment of a carbohydrate moiety to the asparagine side chain. Thus, the presence of any one of these tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the attachment of one of galactosamine, galactose, or xylose to a hydroxy amino acid, which is most commonly serine or threonine, but can also be 5-hydroxyproline or 5-hydroxylysine. By altering the amino acid sequence to remove one of the above tripeptide sequences (for N-linked glycosylation sites), glycosylation sites can be conveniently removed from the antibody. Mutations can be made by substituting the asparagine, serine, or threonine residue within the glycosylation site with another amino acid residue (e.g., glycine, alanine, or a conservative substitution).

[0692] Other PD-1 antagonists

[0693] In some embodiments, the PD-1 binding antagonist is an immunoadhesin (e.g., an immunoadhesin comprising the extracellular or PD-1 binding portion of PDL1 or PDL2 fused to a constant region (e.g., the 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 WO2010 / 027827 and WO2011 / 066342.

[0694] 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 (Pierre Fabre / Aurigene). See, for example, WO2012 / 168944, WO2015 / 036927, WO2015 / 044900, WO2015 / 033303, WO2013 / 144704, WO2013 / 132317, and WO2011 / 161699.

[0695] 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 WO2015 / 033301 and WO2015 / 033299.

[0696] In some embodiments, the treatment method comprises co-administering 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 compounds, and at least one mitogen-activated protein kinase (MAPK) inhibitor. In some embodiments, the treatment method comprises co-administering 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 compounds, and at least one inhibitor of the RAS / MAPK pathway. In some embodiments, the treatment method comprises co-administering 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 compounds, 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 any combination thereof.Examples of EGFR inhibitors, MAPK inhibitors, and / or RAS / MAPK pathway inhibitors are disclosed in Moore, A.R., Rosenberg, S.C., McCormick, F. et al. RAS-targeted therapies: is the undruggable drugged?. Nat Rev Drug Discov (2020), which is incorporated herein by reference, including but not limited to: sotorasib (AMG 510, from Amgen), MRTX849 (from Mirati Therapeutics), JNJ-74699157 / ARS-3248 (from J&J Wellspring Biosciences), LY3499446 (from Eli Lilly), GDCBI 1701963 (from Boehringer Ingelheim), mRNA-5671 (from Moderna Therapeutics), G12D inhibitor (from Mirati Therapeutics), RAS(ON) inhibitor (from Revolution Medicines), BBP-454 (from BridgeBio Pharma), SP600125, PLX4032, GW5074, AZD6244, PD98059, simvastatin, alisertib, teriflunomide, NSC95397, PD325901, PD98059, lovastatin, sorafenib, Bayer Labs), vemurafenib, Hoffman La Roche Inc.), dabrafenib, Novartis Pharmaceuticals Corportation), selumetinib, KOSELUGO TM , AstraZeneca Pharmaceuticals LP), trametinib, Novartis Pharmaceuticals), ulixertinib, silimarin, sirolimus, PV Prism CV), lapatinib, GlaxoSmithKline), crizotinib, PF Prism CV), taselisib (Roche), PF-0491502, PF502, enterolactone, PLX4720, PD0325901, PD184352, SC-514, alisterib (MLN8237), SB415286, PLX4720, obtaoclax (GX15-070), pimasterib, venetoclax (ABT-199 / ), eprenetapopt (APR-246), gemcitabine, ), birinapant (TL32711), pemigatinib (ARRY-614), afuresertib, ralimetinib (LY2228820, Eli Lilly), cobimetinib, Exelixis / Genentech), prexasertib (LY2606368), erlotinib, OSI Pharmaceuticals), bevacizumab Genentech), belvarafenib (Hanmi Pharmaceutical / Genentech), and binimetinib, Array BiopharmaInc.).

[0697] As used herein, "combination" refers to any mixture or arrangement of one or more compounds of the present disclosure (or embodiments or aspects thereof) with one or more other compounds of the present disclosure or one or more other therapeutic agents. Unless the context clearly indicates otherwise, a "combination" can include simultaneous or sequential delivery of a compound of the invention with one or more therapeutic agents. Unless the context clearly indicates otherwise, a "combination" can include a dosage form of a compound of the present disclosure with another therapeutic agent. Unless the context clearly indicates otherwise, a "combination" can include a route of administration of a compound of the present disclosure with another therapeutic agent. Unless the context clearly indicates otherwise, a "combination" can include a formulation of a compound of the present disclosure with another therapeutic agent. Dosage forms, routes of administration, and pharmaceutical compositions include, but are not limited to, those described herein.

[0698] Enumerated embodiments

[0699] The following enumerated embodiments represent some aspects of the present invention.

[0700] 1. A compound of formula (I):

[0701]

[0702] or a pharmaceutically acceptable salt thereof, wherein:

[0703] X1 and X2 are each independently N or C-R5, where each R5 is independently selected from the group consisting of: 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, where C 1-6 alkyl is further optionally substituted with hydroxy or N(R e )(R f );

[0704] X3 is N or CH,

[0705] provided that when X3 is N, at least one of X1 and X2 is N;

[0706] R1 is where R a , R b and R c are each independently selected from the group consisting of: H, halo, cyano, hydroxy, C 1-6 alkyl, C 6-20 aryl, 3- to 10-membered heterocycloalkyl, and 5- to 20-membered heteroaryl, where C 1-6 alkyl is further optionally substituted with hydroxy, provided that at least two of 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 rest of the molecule; or

[0707] R1 is where R d is selected from the group consisting of: H, halo, cyano, hydroxy, C 1-6 alkyl, C 6-20 aryl, 3- to 10-membered heterocycloalkyl, and 5- to 20-membered heteroaryl, where C1-6 The alkyl group is further optionally substituted with hydroxyl, and L is selected from the group consisting of: -O-, *-CH2-O-**, *-O-CH2-**, -CH=CH-, and -C≡C-, wherein ** indicates the point of attachment to the R2 moiety and * indicates the point of attachment to the rest of the molecule;

[0708] R2 is C 1-12 Alkyl, C 3-10 Cycloalkyl, 3- to 10-membered saturated heterocyclic group, C 6-20 Aryl, C 5-13 spiro or 5- to 20-membered heteroaryl, wherein

[0709] C 1-12 Alkyl, C 3-10 Cycloalkyl, 3- to 10-membered saturated heterocyclic group, C 6-20 Aryl, C 5-13 The spirocyclic group or the 5- to 20-membered heteroaryl group is optionally substituted by one or two substituents selected from the group consisting of cyano, halo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, NO2, N(R e )(R f ) and O(R e ),in

[0710] Each R e and R f Independently selected from the group consisting of: 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- to 10-membered heterocyclic group, C 6-20 Aryl and 3- to 20-membered heteroaryl, wherein

[0711] 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 heterocyclic group, C 6-20 The aryl group and the 3- to 20-membered heteroaryl group are each independently optionally substituted with one or more substituents selected from the group consisting of: C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, oxo, cyano, halo, NO2 and hydroxyl;

[0712] Provided that

[0713] when R2 is C 1-12 alkyl, where C 1-12 alkyl is independently optionally substituted by one or two substituents 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 ), and L is -CH=CH- or -C≡C-;

[0714] R3 is cyano, C 1-6 alkyl, C 1-4 alkoxy or C 2-4 alkenyl, where the C 2-4 alkenyl is optionally substituted by N(R e )(R f ), or

[0715] R3, together with the R5 of X1 and the atoms to which they are attached, forms a 5-membered heterocyclic group or a 5-membered heteroaryl group, provided that X3 is CH, or

[0716] R3, together with the carbon atom of the *-CH2-O-* of L and the atoms to which they are attached, forms a C6 aryl group or a 6-membered heteroaryl group;

[0717] Provided that:

[0718] (i) when R3 is cyano, C 1-6 alkyl, C 1-4 alkoxy or C 2-4 alkenyl, where the C 2-4 alkenyl is optionally substituted by N(R e )(R f ), and R2 is a 3- to 10-membered saturated heterocyclic group or a 5- to 20-membered heteroaryl group, where the 3- to 10-membered saturated heterocyclic group or the 5- to 20-membered heteroaryl group is independently optionally substituted by one or two substituents 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 ),

[0719] 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

[0720] (ii) When R3, together with the R5 of X1 and the atoms to which they are attached, forms a 5-membered heterocyclic group or 5-membered heteroaryl group, provided that X3 is CH and R2 is a 3- to 10-membered saturated heterocyclic group or a 5- to 20-membered heteroaryl group, wherein the 3- to 10-membered saturated heterocyclic group or 5- to 20-membered heteroaryl group is independently optionally substituted with one or two substituents 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 ),

[0721] L is absent or is *-CH2-O-*, -CH=CH- or -C≡C-, where * indicates the point of attachment to the rest of the molecule and ** indicates the point of attachment to the R2 moiety, or

[0722] (iii) When R3, together with the carbon atom of *-CH2-O-* of L and the atoms to which they are attached, forms a C6 aryl group or 6-membered heteroaryl group, and R2 is a 3- to 10-membered saturated heterocyclic group or a 5- to 20-membered heteroaryl group, wherein the 3- to 10-membered saturated heterocyclic group or 5- to 20-membered heteroaryl group is independently optionally substituted with one or two substituents 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 ),

[0723] L is *-CH2-O-*, -CH=CH- or -C≡C-, where * indicates the point of attachment to the rest of the molecule and ** indicates the point of attachment to the R2 moiety; and

[0724] R4 is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with a hydroxyl group.

[0725] 2. The compound or its pharmaceutically acceptable salt according to Example 1, wherein:

[0726] X1 is C-R5, where R5 is C 1-6 alkyl, C 1-6 alkoxy or NH(R e ), and

[0727] R3, together with the R5 of X1 and the atoms to which they are attached, forms a 5-membered heterocyclic group, provided that X3 is CH.

[0728] 3. The compound or its pharmaceutically acceptable salt as described in Example 2, wherein the compound of formula (I) is a compound of formula (IA):

[0729]

[0730] or its pharmaceutically acceptable salt.

[0731] 4. The compound or its pharmaceutically acceptable salt as described in Example 3, wherein the compound of formula (IA) is a compound selected from the group consisting of:

[0732] or its pharmaceutically acceptable salt.

[0733] 5. The compound or its pharmaceutically acceptable salt as described in Example 2, wherein the compound of formula (I) is a compound of formula (IB):

[0734]

[0735] or its pharmaceutically acceptable salt.

[0736] 6. The compound or its pharmaceutically acceptable salt as described in Example 1, wherein:

[0737] X1 is C-R5, where R5 is C 1-6 alkyl, C 1-6 alkoxy or NH(R e ), and

[0738] R3, together with the R5 of X1 and the atoms to which they are attached, forms a 5-membered heteroaryl, provided that X3 is CH.

[0739] 7. The compound or its pharmaceutically acceptable salt as described in Example 6, wherein the compound of formula (I) is a compound of formula (IC):

[0740]

[0741] or its pharmaceutically acceptable salt.

[0742] 8. The compound or its pharmaceutically acceptable salt as described in Example 1, wherein:

[0743] L is *-CH2-O-*, and

[0744] R3, together with the carbon atom of *-CH2-O-* of L and the atoms to which they are attached, forms a C6 aryl.

[0745] 9. The compound or its pharmaceutically acceptable salt as described in Example 8, wherein the compound of formula (I) i...

Claims

1. A compound of formula (B-1): or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: X1 is N or C-R 5a , wherein each R 5a is independently selected from the group consisting of: H, halo, C 3-10 cycloalkyl, C 1-6 alkoxy and C 1-6 alkyl; X2 is N or C-R 5b , wherein each R 5b is independently selected from the group consisting of: H, cyano, halo, C(O)NH2, C 1-6 alkoxy, phenyl, naphthyl, and C 1-6 alkyl. wherein R 5b said C 1-6 alkyl group is optionally substituted with a hydroxyl group; X3 is N or C-H, Provided that when X3 is N and R1 is then at least one of X1 and X2 is N; R1 is: (i) wherein R a , R b and R c are each independently selected from the group consisting of: H, halo, cyano, C 1-6 alkyl, phenyl and naphthyl, wherein said C 1-6 alkyl is further optionally substituted with a hydroxyl group, provided that at least two of 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 rest of the molecule and ** indicates the point of attachment to the R2 moiety, or (ii) wherein R d is selected from the group consisting of: H, halo, C 1-6 alkyl, and L is selected from the group consisting of: *-CH2-O-*, *-O-CH2-*, -CH=CH- and -C≡C-, where * indicates the point of attachment to the rest of the molecule and ** indicates the point of attachment to the R2 moiety; R2 is C 1-12 alkyl, C 3-10 cycloalkyl, a 3- to 10-membered saturated heterocyclic group, phenyl, naphthyl or C 5-13 spiro group, wherein Said C of R2 1-12 alkyl, C 3-10 cycloalkyl, 3- to 10-membered saturated heterocyclic group, phenyl, naphthyl or C 5-13 spiro group is independently optionally substituted by one or two substituents selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 haloalkyl and C 3-10 cycloalkyl, Provided that when R2 is C 1-12 alkyl, wherein said C 1-12 alkyl is independently optionally substituted with one or two substituents selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl, then L is - CH=CH- or -C≡C-; R3 is cyano or methoxy, provided that: (i) when R3 is cyano or methoxy, and R1 is and R2 is a 3- to 10-membered saturated heterocyclic group, wherein the 3- to 10-membered saturated heterocyclic group is independently optionally substituted with one or two substituents selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl, then L is *-CH2-O-*, -CH=CH- or -C≡C-, where * indicates the point of attachment to the rest of the molecule and ** indicates the point of attachment to the R2 moiety; R4 is H or C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with a hydroxyl group.

2. The compound according to claim 1, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein L is absent; R2 is phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted by one or more C 1-6 alkyl groups; and X2 is C-R 5b , wherein R 5b is cyano.

3. The compound according to claim 1 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: X3 is CH, L is -CH=CH-, R2 is C 3-10 cycloalkyl, wherein said C 3-10 cycloalkyl is independently optionally substituted with one or two substituents selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, R3 is methoxy, and R4 is H.

4. The compound according to claim 1, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R2 is C 1-12 alkyl, wherein said C 1-12 alkyl is independently optionally substituted with one or two substituents selected from the group consisting of: halogenated, C 1-6 alkyl, C 1-6 haloalkyl and C 3-10 cycloalkyl, and L is -CH=CH- or -C≡C-.

5. The compound according to claim 1, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, selected from the group consisting of: or its stereoisomers, tautomers or pharmaceutically acceptable salts.

6. A pharmaceutical composition comprising (i) a compound according to any one of claims 1 to 5 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and (ii) a pharmaceutical carrier, diluent or excipient.

7. Use of a compound according to any one of claims 1 to 5 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of cancer in a mammal.

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